Archive for December, 2019

When Brooke Brumfield wasnt battling morning sickness, she craved nachos. Like many first-time expectant mothers, she was nervous and excited about her pregnancy. She had just bought a house with her husband, a wildland firefighter who had enrolled in paramedic school to transition to firefighting closer to home. Everything was going according to plan until 20 weeks into Brumfields pregnancy, when she lost her job at a financial technology startup and, with it, her salary and three months paid maternity leave. After building a new business to support her family, she had clients, but childcare was limited, and her husbands schedule was always shifting. By the time her baby arrived, everything was beyond overwhelming, Brumfield says. I pretty much felt like a truck hit me.

Brumfield had heard stories from friends and family about a way to minimize the stress and emotional fallout of the postpartum period: consuming her placenta, the vascular organ that nourishes and protects the fetus during pregnancy and is expelled from the body after birth. The women swore by the results. They said their milk supply improved and their energy spiked. The lows caused by plummeting hormone levels didnt feel as crushing, they explained.

Brumfield enlisted her doula who, for a fee, would steam, dehydrate, and pulverize her placenta, pouring the fine powder into small capsules. She swallowed her placenta pills for about six weeks after delivering her daughter. She said they helped her feel more even, less angry and emotional. When her milk supply dipped, she says, I re-upped my intake and [the problem] was solved.

Social scientists and medical researchers call the practice of consuming ones own placenta placentophagy. Once confined to obscure corners of alternative medicine and the countercultures crunchier communities, it has been picked up by celebrities (Kourtney and Kim Kardashian, January Jones, Mayim Bialik, Alicia Silverstone, Chrissy Teigen) and adopted by the wider public.

Although there are no official estimates of how many women ingest their placenta after delivery, the internet is increasingly crowded with placenta service providers preparers of pills, smoothies, and salves to support new mothers in the slog to recovery. But the purported benefits are disputed. Depending on whom you ask, placenta-eating is either medicine or a potentially dangerous practice based on myth. How did this practice go mainstream, despite a lack of reported scientific or clinical benefits? The answer may say much more about the world new mothers live in than it does about the placenta.

In any doctors office or primary care setting, a provider treating a patient will often mention new research that supports a recommended treatment. A pregnant woman diagnosed with preeclampsia, for example, might learn from her health care provider that low-dose aspirin has been shown in recent studies to reduce serious maternal or fetal complications. But the basis for placentophagy, a practice that lies beyond the boundaries of biomedicine, is a 16th-century text.

Li Shizhens Compendium of Materia Medica, or Bencao gangmu, first published in 1596, is a Chinese pharmacopoeia and the most celebrated book in the Chinese tradition of pharmacognosy, or the study of medicinal plants. It appears on the websites of placenta service providers and in the pages of the standard references for practitioners of traditional Chinese medicine (TCM), a millennia-old medical system with a growing global reach.

The basis for placentophagy, a practice that lies beyond the boundaries of biomedicine, is a 16th-century text.

A physician and herbalist, Li drew on his empirical experiences treating patients but also on anecdotes, poetry, and oral histories. His encyclopedia of the natural world is a textual cabinet of natural curiosities, according to historian Carla Nappis The Monkey and the Inkpot, a study of Lis life and work. Containing nearly 1,900 substances, from ginseng and peppercorn to dragons bone and turtle sperm, Lis book describes dried human placenta as a drug that invigorated people, and was used to treat impotence and infertility, among other conditions. For advocates of placentophagy, this book serves as ethnomedical proof of the long-standing history of the practice and by extension, its efficacy and safety.

But like many claims to age-old provenance, the origins of placentophagy as a postpartum treatment are disputed. Sabine Wilms, an author and translator of more than a dozen books on Chinese medicine, scrutinized classical Chinese texts on gynecology and childbirth and told me theres no written evidence at all of a woman consuming her own placenta after birth as a mainstream traditional practice in China, even if formulas containing dried human placenta were prescribed for other conditions, as described in Lis book.

Beyond Lis 400-year-old encyclopedia, evidence of postpartum placenta-eating is nearly impossible to find in the historical record. Womens voices are notoriously difficult to unearth from the archives, and even in the 19th century, the details of childbirth and what happened to the placenta went largely unreported. But when two University of Nevada, Las Vegas anthropologists pored over ethnographic data from 179 societies, they discovered a conspicuous absence of cultural traditions associated with maternal placentophagy.

The earliest modern recorded evidence of placentophagy appears in a June 1972 issue of Rolling Stone. I pushed the placenta into a pot, wrote an anonymous author, responding to the magazines call asking readers to share stories from their personal lives. It was magnificent purple and red and turquoise. Describing her steamed placenta as wonderfully replenishing and delicious, she recounted eating and sharing it with friends after delivering her son.

Evidence of postpartum placenta-eating is nearly impossible to find in the historical record.

Raven Lang, who is credited with reviving the oldest known and most commonly used recipe for postpartum placenta preparation, witnessed placentophagy while helping women as a homebirth midwife and TCM practitioner in California in the early 1970s. These women lived off the land, she explained, and might have drawn inspiration from livestock and other animals in their midst.

It wasnt long before placentophagy made its way beyond Californias hippie enclaves. In 1984, Mary Field, a certified midwife and registered nurse in the U.K., recounted eating her placenta, an unmentionable experience, to ward off postpartum depression after the birth of her second child. I remain secretive, Field wrote, for the practice verges on that other taboo cannibalism as it is human flesh and a part of your own body. She recalled choking down her own placenta. I could not bear to chew or taste it.

The rise of encapsulation technology, developed for the food industry and picked up by placenta service providers in the early aughts, put an end to visceral experiences like Fields. No longer must women process their own placenta or subject themselves to its purported offal-like flavor. Tidy, pre-portioned placenta pills resembling vitamins can be prepared by anyone with access to a dehydrator, basic supplies, and online training videos.

The boom in placentophagy highlights a longstanding puzzle for researchers. Almost every non-human mammal consumes its placenta after delivery, for reasons that remain unclear to scientists. Why did humans become the exception to this nearly universal mammalian rule? For Daniel Benyshek, an anthropologist and co-author of the UNLV study that found no evidence of placentophagy being practiced anywhere in the world, the human exception raises a red flag: It suggests the reasons that humans have eschewed placentophagy arent just cultural or symbolic, but adaptive that theres something dangerous about it, or at least there has been in our evolutionary history.

Scientific data on the potential benefits and risks of placentophagy is scarce, but a few small studies suggest that any nutrients contained in cooked or encapsulated placental tissue are unlikely to be absorbed into the bloodstream at concentrations large enough to produce significant health effects. Whether and in what quantity reproductive hormones such as estrogen survive placental processing has been little studied, but ingesting them after birth could have negative effects on milk production and may also increase the risk of blood clots.

Almost every non-human mammal consumes its placenta after delivery, for reasons that remain unclear to scientists.

Yet placental encapsulation services which remain unregulated in the U.S. have found a receptive audience of American consumers. (The food safety agency of the European Union declared the placenta a novel food in 2015, effectively shuttering the encapsulation business on the continent.) Mostly small and women-owned, placenta service businesses position themselves as an alternative to a highly medicalized, bureaucratized birthing process that has often neglected the needs of women. Postpartum checkups focus narrowly on pelvic examinations and contraceptive education. One survey of U.S. mothers found that one in three respondents who received a postpartum checkup felt that their health concerns were not addressed. In contrast, placenta service providers speak the language of empowerment.

That language can resonate with new mothers like Brumfield, who face overwhelming pressures to care for a newborn, nurse on demand, manage a household, and return to work amid anxieties about postpartum depression, dwindling energy, and inadequate milk supply.

In some ways, placenta consumption is motivated by a desire to perform good mothering, wrote scholars from Denmark and the United States in a paper on the emergence of the placenta economy. It reflects the idea of maternity as a neoliberal project, in which new mothers are responsible for their own individual well-being as well as that of their babies, they added.

Meanwhile, rates of postpartum depression keep climbing, maternity leave policies are stingy, and child care costs are often prohibitive. Its easy to see why many women would be eager to seek help, real or perceived, wherever they can find it.

Daniela Blei is a historian, writer, and book editor based in San Francisco.

Continued here:
Medicine or Myth? The Dubious Benefits of Placenta-Eating - Undark Magazine

I lay on my side, cradling my iPhone, looking up bleeding after sex and dabbing a piece of toilet paper between my legs. I thought about whether or not I should wake my new boyfriend up.

The Healthy Woman website stated, Its common for women of all ages to have bleeding after sex at one time or another.In fact, up to 9 percent of all women experience post coital bleeding (outside of first sex) at some point in their lives.Most of the time its nothing major and goes away on its own.But bleeding after sex can also be a sign of something more serious. SIGN OF SOMETHING SERIOUS?

Great. I had already had acute myeloid leukemiamultiple times, and now, when things were looking up, WebMD saidthis new symptom could mean I have pelvic organ prolapse (when pelvic organs, like the bladder or uterus, jut beyond the vaginal walls).

I found a site where someone asked, Could my uterus fall out? No, it couldnt. At least I had that.

The most important thing to pay attention to is the rate and volume of bleeding, the article read. Most bleeding after sex is fairly light. Heavy bleeding where youre soaking through a pad every hour or passing clots larger than the size of a quarter warrants a visit to the emergency room.

I didnt have a quarter, but I did have a clock that showed it had been two hours. The doctor on call for my internists office, around 2 or 3 a.m., sounded annoyed.

You should have called your gynecologist, he said. But he called ahead to the ER. I shook my boyfriend awake, and off we went into the spring night that had held so much promise. Intellectually I knew it wasnt my fault, but I was more embarrassed than if I had been wearing white shorts and gotten my period in gym class.

On the TLC series, Sex Sent Me to the ER, worse things happen, such as objects stuck where they shouldnt be. My issue was more mundane, but I found out also very common: lack of information after my cancer treatment.

Nobody told me that chemotherapy, which Id undergone after my diagnosis in 2003 and again after relapses in 2007 and 2008, could cause a sudden loss of estrogen production in my ovaries, and that this could lead to symptoms of menopause such as a thinning vagina and vaginal dryness. (Actually, the first round put me into early menopause at 48.) Nobody told me that vaginal dryness can cause pain and bleeding during intercourse.

Yet data shows that the incidence of sexual dysfunction among female cancer survivors is somewhat common.Common sexual side effects are difficulty reaching climax, less energy for sexual activity, loss of desire, reduced size of the vagina, and pain during penetration.

For my part, it had been a 10-year dry spell. You shouldnt need a reason for not having sex, but I had good ones: treatment in 2009 for relapsed leukemia, life-threatening infections after a rare fourth stem cell transplant, a coma, a four-month hospitalization and a year just to get back on my feet.

My 13-year marriage, long over, had consisted of 10 good years and three downhill all the way along a road full of land mines. Afterward, a four-year relationship with an English professor ended in fitting dramatic form when he rediscovered his childhood sweetheart while I was mourning the death of my father. Pulling his hands through his long gray hair, he declared, Were like Heathcliff and Cathy. I love her more than I love you! I had to brush up on my Wuthering Heights to get it. Heathcliff and Catherine were soulmates.

My soulmate was nowhere to be found. He was not the guy who walked into a restaurant looking pale and pasty and nothing like the photo of the fit guy on his online profile, making me think of climbing out the bathroom window. He was not the guy I met at a Matzo Ball, where Jewish singles go on Christmas Eve to comport themselves like eighth graders at a school dance; we lasted for about six months until he complained that he was lower on the totem pole than my three children. I thought he might be the tennis player who strung my rackets and said he was falling in love with me, but he disappeared, in a feat I later learned had a name: hanging you out to dry.

I decided to follow the advice of friends who were tired of hearing me talk about heartbreak and disappointment: Live your best single life. I stopped paying for dating websites but left a profile on a free one.

Stop trying to find something, and then if youre lucky, you will find it, or it will find you. A nice guy wrote that he liked my profile (ugh, I hated writing those things). He thought we had a lot in common (running, kids, reading, similar politics) and would love to have a conversation. Is it corny to say that as we walked toward each other in front of the restaurant where we were to meet, we were being pulled together? Maybe it was just relief that he seemed normal and resembled his profile photo.

We sat at a high table in the bar. Our fingertips brushed together when we held up our phones to show each other photos; his, of places he had traveled, and mine, of kids and dogs. The next day, we went for a walk, and he passed a big test: meeting my chocolate Labrador retriever. She got a crush on him. I think its the soft voice. It works on me, too.

I had been using a vaginal estrogen cream, Estrace (generic name estradiol), twice a week, to reduce symptoms of menopause such as vaginal dryness, burning, and itching. Though I was concerned about side effects, my doctor said the small amount was not absorbed outside the vagina, unlike hormone replacement therapy, which goes into the bloodstream. She said it was also OK to use Estrace once a week and Replens, a nonhormonal moisturizer, the rest of the time if I wanted to.

I remembered hearing that I would need to up the dosage if I wanted to have sex again. I made an appointment with my gynecologist to see if I should do anything else to prepare for physical intimacy.

The physicians assistant who saw me said, Go to the toy store. I was confused. My children were grown. Why did I need a toy store? I learned that she meant the sex toy store tucked behind a doorway next to a pizza place.

I got a set of six pink dilators. They started pinky-sized and increased by gradations up to a dauntingly large one. They didnt come with instructions regarding how long to leave them in. The small one went in OK. I kept it in for a few minutes and then put in the next larger one, increasing in size until I had had enough. Theres not much you can do when youre lying around with a fake pink penis in your vagina.

When it finally came time for real sex, I liked it. It hurt after a while, so we stopped, but I thought that was normal. Next I felt something sticky on my legs. It was blood. Blood on the sheets, blood on our legs. We got in the shower, changed the sheets, and got back into bed. It couldnt have been less romantic.

The emergency room was even worse grungy and poorly lit. He sat with me, holding my hand and looking as upset as I was, until a nurse called me in and he went to sleep in the car.

Please tell me youve seen worse than this, I said to the nurse as I lay on the exam table feeling raw, emotionally and physically. She said she had. The doctor did an internal examination and said the blood had likely come from chafing. It was dawn when we finally got out of there. We went out to breakfast. Ordering my traditional blueberry pancake with an egg over hard brought a sense of normalcy to the misadventure.

The next week, I returned to the doctors office and this time saw the gynecologist herself.

Lets start from scratch, she said. I was to leave a dilator in for between 15 and 30 minutes, while doing diaphragmatic breathing. She sent me to pelvic floor therapy to learn relaxation exercises. I used the Estrace for two weeks straight. By the time we had sex again, it didnt hurt, but I nervously checked the sheets for a long time afterward. I figured if we could get through a post-coital visit to the ER, we could get through most anything.

I may not have known much about sex after cancer, but its a topic thats starting to be talked about more. I learned that after years of dismissing womens sexual function as just one of those things that cancer takes away, many see womens sexual health as a survivorship issue. Anexpert who I interviewed for a story onsex after cancereven called the dearth of information for female cancer survivors a health equity issue.

Many cancer centers are beginning to open sexual health programs. My own cancer center was among them. You missed us by about a year, the director told me.

Luckily, Im no worse for the wear and am still with the nice guy. I use Estrace (and sometimes Replens) twice a week and a lubricant when having sex. Doctors say that one of the best ways to treat vaginal dryness is to have more sex, because increased blood flow stimulates lubrication.

Now that memory of the ER visit is almost three years in the past, that seems like a fine idea to me.

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I Didnt Have Sex For 10 Years. When I Finally Did, It Sent Me To The ER. - HuffPost

For the first time, we are starting to see research that targets aging as a health condition in and of itself. Finding ways to regulate those "longevity gene" pathways referenced by Lipman above (specifically the mTOR, AMPK, and sirtuins) is central to scientists' work in identifying lifestyle habits, nutritional compounds, and future drugs that could slow and even treat (yes, treat) aging.*

As Sinclair views it, aging is most definitely a disease, and the FDA classifying it as such will help the field move forward even faster, allowing for more research and development of drugs to target processes thatlead to age-related disease. "The definition of a disease is that over time you lose function, you become decrepit, disabled, and eventually, if it's a bad disease, you die from it," says Sinclair. "That sounds a lot like aging, right? If you go to the medical dictionary, the only difference between aging and a disease is that a disease affects less than half the populationand that 50% cutoff is completely arbitrary."

How likely is that to happen? In 2018, the World Health Organization classified aging as a disease and added it to the International Classifications of Diseases system. And right now, scientists at the Albert Einstein College of Medicine are examining the anti-aging effects of metformin in the Targeting Aging With Metformin (TAME) study. If researchers can show significant benefits of metformin in delaying problems such as cancer, dementia, stroke, and heart attacks, the FDA may consider classifying aging as a treatable condition.

But why study metformin? This widely prescribed diabetes drug, derived from compounds in the French lilac plant, has been noted for its benefits beyond diabetesand Sinclair predicts it will be the first drug prescribed specifically to treat aging. Turns out, "metformin had a protective effect against cancer, heart disease, and frailty in patients taking the drug for long-term diabetes treatment," says Sinclair. "Which sounds a lot like a molecule that can slow aging." Animal studies have also confirmed that metformin can improve life span, and, more importantly, health span in mice. And, in a first-of-its-kind study in humans published in September 2019, researchers were actually able to take 2.5 years off participants' biological clock using a combination of metformin, dehydroepiandrosterone (DHEA), and growth hormone.

Experts believe metformin may activate similar pathways as caloric restriction to stimulate autophagyor cellular cleaning. This cellular upkeep is believed to be a key factor in extending health span. "It's a relatively safe AMPK pathway activator, and that's thought to mimic the effects of fasting and exercising," says Sinclair, who takes metformin daily as part of his healthy aging regimen.

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Why We Aren't Anti-Aging, We Are Pro-Healthy Aging - mindbodygreen.com

For marginalized people, the tech worlds constant barrage of innovations is getting exhausting. It seems like every week, science and tech pioneers are revealing new projects that pose a clear threat to anyone not white, cisgender, or malewhether its porn deepfakes or algorithms that judge womens boobs.

Enter Harvard Medical School, where researchers are creating a new dating app that matches people based on their DNA. The goal is to create a system that screens out matches that would result in a child with an inherited disease, according to a report aired Sunday night on 60 Minutes.

In other words, its a dating app for eugenicsthe disturbing ideological practice of systematically discriminating against people based on genetic qualities judged to be undesirable or inferior.

The app is being developed by a team of geneticists led by George Church, who, in the same interview, defended accepting money for his lab donated by convicted pedophile Jeffrey Epstein. Churchs lab is most famous for its work on the gene-editing technology CRISPR/Cas9, and its researchers are looking at ways to make humans immune to viruses, reverse the effects of aging, and de-extinct animals. Its 7,000 diseases, its about 5 percent of the population, [and] about $1 trillion a year worldwide in medical expenses, Church told 60 Minutes.

But for anyone not white, cis, able-bodied, or male, its obvious where all this is going.

Eugenics has long been a fascination of Nazis and white supremacists, who dream of creating a white and genetically pure master race. Dystopian sci-fi tales like Gattaca have also warned of the horrifying dangers of organizing society based on the perceived desirability (or undesirability) of peoples genetic code.

For people who exist outside mainstream gender norms, these dangers are very real. Last week, Newsweek reported on a team of researchers at the University of Michigan who are attempting to identify regions of the brain associated with gender dysphoriathe discomfort which occurs when a persons gender does not match the sex they were assigned at birth.

Many, but not all transgender people experience gender dysphoria, and it has been used to establish a system of medical gatekeeping that pathologizes trans people and controls access to treatments like hormone replacement therapy and gender-affirming surgeries. But even if scientists identified some hypothetical trait that causes people to be trans, choosing to edit out those traits would be an attempt to effectively erase trans people from existence.

Meanwhile, research into trans medical treatments remains severely underfunded. The federal government is also trying to make it legal for medical providers to refuse to treat trans patientswhether for gender dysphoria or a broken arm.

In other words, these cis researchers, funders, and policymakers seem more interested in curing or erasing trans people than finding better and cheaper ways of treating themor anyone else labeled as falling outside the norm of biologic desirability. Churchs lab, for example, recently received over $100 million for its work on gene-editing.

Church says he is being careful, and claims his lab has appointed a full-time ethicist on its staff to work toward the goal of genetic equitywhere all people have access to genetic technology, regardless of race or economic status.

But for marginalized people suffering under deeply unequal and discriminatory systems of power, that mission seems dangerously naive. If the people who risk being most harmed by these innovations arent intimately involved in their development, maybe its better toyou knownot make them at all?

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A Genetic Dating App Is a Horrifying Thing That Shouldnt Exist - Free

Chun-Jun Guo

Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.Jill Roberts Institute for Research in Inflammatory Bowel Disease, Department of Medicine, Weill Cornell Medicine, NY 10021, USA.

Breanna M. Allen

Graduate Program in Biomedical Sciences, Departments of Otolaryngology and Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Kamir J. Hiam

Graduate Program in Biomedical Sciences, Departments of Otolaryngology and Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Dylan Dodd

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Will Van Treuren

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Steven Higginbottom

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Kazuki Nagashima

Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.

Curt R. Fischer

Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Justin L. Sonnenburg

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Matthew H. Spitzer

Graduate Program in Biomedical Sciences, Departments of Otolaryngology and Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Michael A. Fischbach

Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

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Depletion of microbiome-derived molecules in the host using Clostridium genetics - Science Magazine

Incidence rates for hormone receptor positive (HR+) breast cancers are considerably higher in black men than white men, which is in stark contrast to lower incidence rates of those cancer subtypes in black versus white women to according to a new American Cancer Society appearing in the journalJNCI Cancer Spectrum.

In this study, researchers examined subtype specific breast cancer incidence rates in both black and white men in the U.S. using a contemporary nationwide database.

According to the study results, found that rates for all subtypes were higher among black than white men, with rates for HR+/HER- breast cancers about 41% higher among black men compared to white men; about 65% higher for HR+/HER2+, more than 2.5 times higher for HR-/HER2+, and 2.27 times higher for triple-negative breast cancer. Conversely, among women, rates in blacks were 21% lower for HR+/HER2- and comparable for HR+/HER2+, but 29% and 93% higher for HR-/HER2+ and triple-negative subtypes, respectively.

Reasons for the elevated risk of breast cancer in black men are largely unknown but may involve multitude of risk factors including genetic and non-genetic factors, the authors wrote according to a press release. Racial differences in the prevalence of mammography and menopausal hormone supplements are thought to have contributed to the historically higher incidence rate of HR+ cancers in white women, but these are not factors in breast cancer in men.

Well-known risk factors for male breast cancer include family history of breast and/or ovarian cancers, pathogenic mutations in BRCA2, radiation exposure, and conditions that alter hormonal balance such as Klinefelter syndrome and gynecomastia, and potentially obesity and diabetes. Moreover, previous studies have found higher level of estradiol was found to be associated with increased risk of male breast cancer after controlling for body mass index, suggesting a presence of estrogen-mediated carcinogenesis in male breast cancer. However, whether associations of these risk factors vary by tumor subtypes remains unknown and should be considered in future etiologic studies.

Continued here:
Breast Cancer Incidence Differs Among Black and White Males - DocWire News

Hemp seed production is vital, as growers get ready to ramp up production. The question is, is there enough feminized hempseed to go around.

Western Farms Seed LLC in Scottsbluff will help in filling the demand, by growing seed for producers at its greenhouse.

The newly created business is owned by cousins, P.J. Hoehn, Mike Hoehn, their uncles Ed and Art Hoehn, and business partner Mark Johnson.

The business kicked off when Mike Hoehn received one of the 10 permits the Nebraska Department of Agriculture allotted to individuals in 2019 to grow hemp. Nebraska did a lottery where they allowed only ten businesses or individuals to grow hemp after the 2018 Farm Bill legalized the plant.

Hoehn grew a one-acre test plot outside of Mitchell, with three varieties of hemp seed.

The current varieties are Wife, Franklin, and Montana, we also have T1s, said P.J. Hoehn, president of the company. Well be crossbreeding them and making new varieties.

The three varieties have been proven to perform well for growers out in the field for the last couple of seasons.

Feminized seeds are bred explicitly in a way that eliminates the male chromosomes, drastically decreasing the chances of producing a male marijuana plant. Male marijuana plants are not desirable to any degree, except for pollination.

The genetics, which we have chosen are specific for industrial hemp, said Johnson, public relations for the company. We feel pretty safe that we wont have an impact from industrial hemps cousin (marijuana).

Western Farms Seed is also working in collaboration with the University of Nebraska-Lincoln through the Panhandle Research and Extension Center on hemp production.

Were producers ourselves, so we want to number one make sure the quality is there and everything else, our germination, our testing will all be there, Hoehn said.

He adds they are also making sure they will be able to advise growers on the equipment, such which as plates to use and vacuum. So, when farmers go to plant, they are ready, and if needed, Western Farms Seed would provide support in the knowledge of equipment, planting, and harvesting.

In terms of growing the crop, Johnson said a hemp crop is similar to corn or dry edible bean crops. Hemp should be planted by May or June and harvested after a 90 to 110 day growing period before frost.

We found hemp to be very resilient after our two hail storms this summer, said Johnson. The crop was able to recover from both hail storms in really good fashion. Ending up producing a nice crop in light of Mother Nature.

The business, with winter, has moved growing operations into the greenhouse. The five interconnected greenhouse buildings have 21,000 sq feet of growing spaces and house the female plants.

The plants will need light at different times, and when they enter the vegetative stage will need light for up to 16 hours a day.

Industrial hemp has two different growth stages, vegetative, which requires more light, and reproductive growth, said Johnson. So people might notice the greenhouse lights being on longer when we go to the next stage of production.

Both Hoehn and Johnson say producers should start small with an acre or so and of course, make sure they have a buyer before they even plant.

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Ag business to grow and market hemp seed - KTIC

While wrestling with the Christmas lights under his tree recently, a wave of sadness washed over Neil Turner. He couldnt help but think of his daughter Colby, who died in 2010 at just two years oldfrom a rare genetic disorder.

Suddenly, the thought of another Christmas without her swept in and replaced my frustration with tears, says Turner, an engineer in Oklahoma and father of two. Not a day goes by that I dont miss her and think about her. But if I focus on just the loss and the heartache, suicidal thoughts come quickly.

Grief isnt linear. It can hit by surprise. It is ongoing and it evolves, says Turner. It is acomplicated emotion for many people, and it can be particularly complex for fathers. Even today, dads might feel pressured to be strong for others and put their own feelings aside after a loss, which can have damaging psychological consequences. And although the expectations regarding so-called masculine behaviorare evolving for the better, many men still feel isolated in their grief and less comfortable opening up about it.

There is a deeply ingrained social conditioning that will take some work to undo and reverse, says David Klow, a licensed marriage and family therapist in the Chicago area and author of You Are Not Crazy: Letters From Your Therapist. A number of men are working to define new models of masculinity, but theres still a lot of work to be done.

Men are generally less willing to talk about their grief, more reticent to express emotion, and less likely to seek support, says Jan Everhart Newman, JD, Ph.D., a psychologist in Charlotte, North Carolina.

Sadly, this pattern can be reinforced when boys and men seek comfort after a loss around more vulnerable emotions such as sadness and are rebuffed and given messages like Dont cry or Stay strong, Newman says. Often, my male clients will report that another family member is more outwardly expressive of intense emotions and that they felt that they couldnt put any more stress on that person [by expressing their own grief].

How many toys are you planning on giving each of your kids this holiday season?

Thanks for the feedback!

Grief from a male perspective has received little research interest, but some of the articles that have been written suggest that mens grief is often diminished or even dismissed. The authors of arecent study of combat veterans noted that grief is a long-overlooked toll of war. In her study of fathers and pregnancy loss, published in 2004, author Bernadette Susan McCreight wrote, the loss can be devastating for fathers yet, very often, the world that surrounds them tends to discount their loss, and emotional support and cultural rituals that are normally available to other bereaved individuals are often absent for this group of men.

Newman agrees. At the funeral of a Special Forces veteran recently, she saw a heartbreaking example of how people dont seem to know how to respond to mens grief. The manwas buried with full military honors, which can be a long affair.Kids clustered in a group poking one another and laughing, Newman says, while adults stood around together, somber and chatting. Then she saw the adult son,who was on his knees at the coffin sobbing entirely alone.

The only person who came to comfort him was his young son, Newman says. There is something about grief that can be frightening and is difficult for others to accept.

Human beings will do anything to avoid discomfort. As it makes them think of their own mortality and lack of control, death is at the top of the list of things that make people uncomfortable, she says. Additionally, traditional gendered expectations might influence how couples deal with grief. Klow says he has counseled women who say they want their male partners to be more in touch with their feelings but dont actually like seeing them cry or express emotions.

Some men might feel isolated in their grief not because they dont know how to feel emotions but because they dont feel its okay to express them.

A web content strategist in the UK, Kevin lost his father last year, shortly before he and his partner found out they were having a baby. He now lives in his fathers house with his family and thinks of his dad often, such as when hes dancing around the kitchen to The Beatles to entertain his son and get him to stop crying. Kevin says he often apologizes for talking about his father even though his partner says she doesnt mind.

It feels wrong that hes not here to enjoy the newborn, Kevin says. It will always feel socially unacceptable for me to express my grief no matter how hard people try to make me feel comfortable.

Cultural background and upbringing have a huge impact on how much men might adhere to stereotypical male tendencies, such as stoicism, that might make them feel less comfortable feeling and expressing grief. And it might be doing men a disservice to expect them to grieve more like women tend to, with outward shows of emotion, according to J. Scott Janssen, MSW, LCSW. Janssen says men who grieve more quietly and keep their emotions in check around others might simply have a more masculine style of grieving that isnt necessarily unhealthy and shouldnt be dismissed.

Of course, caveats exist. You have to be careful with the terms masculine and feminine, which are bound by culture and tradition, and in the age of gender neutrality, this distinction may even be meaningless, Newman says. It comes down to whether a man feels free to express his emotions without judgment and is simply choosing not to versus not expressing emotions because thats not what a man should do.

The latter situation a man feeling like a bad person because theyre experiencing normal, painful emotions is harmful.

There are signs that the walls around male grief are coming down. Recently, comedian Michael Cruz Kayne tweeted on the 10th anniversary of his son Fishers death and received an outpouring of support, as did James Van Der Beekwhen hewrote about the grief he and his wife felt about losing a baby to miscarriage in a heartfelt Instagram post. Comedian Patton Oswalt also has talked openlyabout grieving the death of his first wife, author Michelle McNamara, the mother of his daughter, Alice.

Many men (and women) need time to grieve privately, which is not the same thing as isolating.Although he also talked about his loss with others, Turner says he also needed alone time to process Colbys death.

For quite a few years, two hours into any car ride by myself I would be in tears having that much time alone with my thoughts, Turner says. But if I didnt get that time regularly, my emotions were more likely to come out sideways, in non-preferred ways.

Theres no timeline to it, Klow says. Ten years later, a long solo drive or the dog getting sick can trigger grief all over again. Healthy grieving changes from person to person.It can take a lot of different forms. To help process the loss, it can help to have a social gathering with friends and family to say goodbye and celebrate the life of the person who has died, says Elgin, Illinois, funeral home owner and director, US Army Reserve First Sergeant and father of two Dan Symonds.

Symonds was stationed in Afghanistan when his family told him his father was dying. He lost it for about 15 seconds in front of his Commander, he says, but didnt cry again for a while after his fathers death. He returned home and busied himself arranging military honors for his dad, an example of instrumental grieving that includes task like tending to the estate and cleaning out the house of the person who died. Those tasks shouldnt be dismissed as avoidance they can help people process the loss, Klow says.

Being alone with grief for stretches of time, however, isnt necessarily unhealthy. It can help to put thoughts and feelings into words, Klow says. Humans are social creatures; reaching out to social networks and naming the person theyre grieving and talking about memories and what theyre feeling tends to help.

What helps me is talking about my dad with my children, telling them what he was like and how he would have loved them so much, Symonds says. We keep his memory alive every day.

Klow suggests finding several people to listen to about grief; that can maximize someones avenues of support and alleviate the worry that theyre overburdening one person. That network can include a partner, family members, friends, or a therapist. Klow holds group therapy sessions for men and says many seem relieved to have a safe space in which to express themselves.

Its important not to be alone in grief, Klow says.

Someones partner can be a life-saving source of support, but they might have to work on making the relationship as egalitarian as possible, he adds: You dont have to be perfect, but both partners need to hold space for each other so that there isnt just one person whos the designated feeler of feelings, he says.

It can be difficult to do, but the Turners were able to give each other permission to be in different places in their grief.

We were okay if one of us was sad and the other was not. We werent afraid to give each other space, Turner says. We did see other couples that would get upset with one another with out-of-sync feelings of They need to move on or Why arent they still sad? Im not sure why, but we didnt fall into that trap.

A therapeutic retreat for bereaved parents, if it can fit into the budget, also might be helpful. Turner and his wife went to one after friends suggested it.

I had never been in any therapy session at all, and although it was emotionally and physically exhausting, we found it helpful, he says, but adds, The next year they even invited us back to help lead the retreat as we were the only couple in the group still married. The divorce rate among bereaved parents is really high.

The Turners also found a fulfilling way to process their grief through charity work with the American Heart Association. His daughter, Ella, got involved, too, raising more than $60,000 for the ACS after an event she participated in received media attention.

It gave us the opportunity to talk about Colby and use her story in a positive way, Turner says.

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For Men, Dealing With Grief Is Lonely and Isolating. This Needs to Change - Fatherly

A fathers diet can have a significant effect on the future health of his offspring, affecting everything from blood pressure to heart function and putting them at greater risk of cardiovascular disease, according to research.

The lead author of a British study says the findings show that men who want to start a family should have a healthy, balanced diet from at least three months before conception.

A study from researchers at the University of Nottingham published in the Journal of Physiology shows that poor paternal diet, specifically one that is low in protein, may impact the heart health of the offspring by changing sperm, and the seminal fluid, which bathes sperm.

We have known for a very long time that what a mother eats during pregnancy can influence how her child develops, and whether or not it will develop obesity, type two diabetes and heart disease, explains senior author of the study, and lead researcher, Prof Adam Watkins, assistant professor in reproductive biology at the universitys faculty of medicine and health sciences. However, the importance of the fathers diet on the health of the offspring has been largely ignored or overlooked. We were interested in investigating whether a fathers poor-quality diet at the time of conception might affect the long-term health of its offspring.

Researchers carried out their study on male mice on a poor, low-protein diet, monitoring the cardiovascular health of their offspring. The way mice produce sperm, the way the embryo develops, the way the foetus develops and the way a mouses blood and heart function are all very similar to humans. This means we can use mice to identify important biological processes which we can then look at in human patients.

What his research found, he reports, was both that the way the mices blood vessels worked, and the level of certain important factors in their blood, which regulate heart and blood vessel function, were significantly altered in response to the poor diet of the father: The blood vessels in the offspring did not work as well as they should do. This can ultimately affect blood pressure.

The normal proteins in the blood which would regulate blood vessels and heart function were altered, says Prof Watkins, adding that essentially what this meant was that the young mice were at increased risk of developing cardiovascular ill-health or heart disease.

We know that a poor lifestyle in men does have negative influences on sperm quality and that being overweight or smoking, or consuming excessive alcohol is not good for reproductive health. What we dont know yet is what the long-term implications of a fathers poor diet or lifestyle might be, he says.

We know that the sperm provides genetic information from a father to the egg it fertilises, and we know that poor diet in males can change that. We also know that the seminal fluid in which sperm is carried, interacts with the uterus and initiates a range of responses in the maternal immune system. These responses prime the uterus for the embryo.

We know that the sperm provides genetic information and that the seminal fluid primes the uterus for the embryo, so here are two possible ways that a fathers diet could influence how the offspring might develop.

Essentially, Prof Watkins explains, the Nottingham research shows that the health of mice offspring is influenced by sperm and fluid and that both of them have an equal influence on offspring health.

However, he says, while the research has to date only been carried out on mice, it has significant implications for human fertility in fact the researchers hope to run clinical trials on humans within the next two or three years.

We know that it can take about 75 days to make a sperm, and that seminal fluid is reproduced every 24-48 hours, says Prof Watkins.

If a man goes on a crash diet a week before getting his partner pregnant, he explains, the sperm will continue to reflect the old, poor quality diet,while the seminal fluid will reflect the newer, better-quality diet.

Therefore there may be a situation where the sperm and the fluid are not compatible to each other, so we are saying that if the sperm and the fluid are different, we see the biggest effect on offspring health.

The potential message is this, he warns: If men and women are thinking about changing their lifestyle and becoming parents, we would say that ideally they begin the changes three months before trying to start a family. That is an ideal time frame to change over from a poor diet and lifestyle to a healthier one in terms of its implications for the mans reproductive health.

The Nottingham research findings have interesting implications for what we know about the role of seminal fluid and sperm DNA fragmentation (a term used for the presence of abnormal genetic material within the sperm, which may lead to male subfertility, in-vitro fertilisation failure and miscarriage) believes Dr Bart Kuczera, consultant gynaecologist and fertility expert at Beacon Care Fertility:

What we know is that men with a poor lifestyle in terms of diet, smoking and drinking can have a condition called sperm DNA fragmentation.

Men are advised to live a healthy lifestyle in order to keep their sperm in the best condition, because, he explains: Sperm DNA fragmentation can be affected by poor diet, stress and overeating, for example. This study would make the case for a good diet and lifestyle for men; that is, a normal balanced protein diet.

Sperm quality of men in the western world, he warned, has been shown to have deteriorated in the last 40 years: We believe this is very linked to lifestyle and the environment, to the sedentary lifestyle and a poor diet which reaches the recommended carbohydrate level but would not include a diversity of food.

In the greater picture you could potentially have a population of children who would be affected in terms of physical health problems and weight gain as a result of the paternal diet at conception. It is important to spread the responsibility between the man and the woman at the time of conception, he says, adding that this study suggests that the father may have an equally significant impact on his offsprings health problems.

This study has implications for our knowledge about diet and lifestyle in terms of fertility and men should be made aware of it, believes Dr Hans Arce, fertility consultant and medical director of ReproMed, a leading Irish fertility and IVF clinic network. The majority of our knowledge in relation to diet and lifestyle in terms of fertility comes because we studied women. Women were the ones who got pregnant and they were the focus. We saw, for example, that women with obesity had children with a higher risk of obesity and diabetes.

However this study showed the offspring of male mice with poor diets ended up having the expression of inflammation, and more of a tendency to high blood pressure, for example.

Men should be made aware of this. Its something the schools, the public health service and the GP should be telling men about that our diets can affect their future childrens health. Studies like these have implication for human beings, he says, adding that the results point in the direction of the fact that the health of a man may have implications for the health of his offspring.

What this study says, he observes, is that a mans diet will not just affect his own health, but potentially has implications for the health of his offspring: We dont have proper human studies yet this is mice but it is pointing in that direction!

Lifestyle is the single biggest issue when it comes to fertility, believes consultant nutritionist Gaye Godkin.

Godkin believes the University of Nottingham study is a further endorsement of what she says, is the role of epigenetics in health outcomes from pre-conception health across the life course.

There is a growing body of evidence showing just how much the fathers diet impacts on the pre-conception phase, in terms of its impact on sperm and seminal fluid and from there on to the long-term health of his offspring.

Epigenetics, she explains, is the environment in which the sperm lives prior to penetrating the egg. Sperm is produced around every 75 days or so but new seminal fluid is produced every 24 to 48 hours.

If the man has a long-term poor diet, it will affect his sperm, she says, adding however, that a man can have healthy sperm, while at the same time his seminal fluid could be of much lower quality because of a poor diet just before conception.

Normal sperm carries DNA. A poor diet has a negative effect on the DNA and the DNA enzymes which in turn are crucial to the formation of a healthy foetus.

In fertility clinics, they measure the level of a condition called DNA fragmentation in the male sperm. This test shows the quality of the sperm. For years I have worked with men who have high levels of DNA fragmentation in their sperm. I believe that it is strongly linked to diet, as well as to lifestyle factors such as smoking, alcohol consumption, excess weight and the effect of pesticides.

While the Nottingham study was based on a mouse model, she says, its findings were moving in the right direction in terms of our understanding of the volatility of sperm quality and what affects it, as well as its relationship with the internal environment of the male body.

While there is no medical treatment available for DNA fragmentation, says Godkin, she has found that 90 days on a good-quality diet which also features a reversal of poor lifestyle factors can lead to fragmentation levels being significantly reduced to the extent that a couple are in a position to use their own sperm to achieve conception.

Excerpt from:
Diets of fathers can affect future health of offspring, study finds - The Irish Times

This image shows Channelrhodopsin-eYFP neurons (green) expressed in the central amygdala (CeA) neurotensin (NTS) containing neurons. The magenta is antibody staining for the neuropeptide NTS. Credit: McElligott Lab

The UNC School of Medicine lab of Zoe McElligott, PhD, found that alcohol consumption is regulated by the activity of a particular set of neurons in a specific brain region, a discovery that could lead to a better understanding of why some casual drinkers develop an alcohol use disorder.

Scientists have known that a region of the brain called the central nucleus of the amygdala (CeA) plays a role in behaviors related to alcohol use and consumption in general. Its been less known which precise populations of brain cells and their projections to other brain regions mediate these behaviors. Now, UNC School of Medicine scientists discovered that specific neurons in the CeA contribute to reward-like behaviors, alcohol consumption in particular.

Published in the Journal of Neuroscience, this research pinpoints a specific neural circuit that when altered caused animal models to drink less alcohol.

Zoe McElligott, Ph.D. Credit: University of North Carolina Health Care

The fact that these neurons promote reward-like behavior, that extremely low levels of alcohol consumption activate these cells, and that activation of these neurons drive alcohol drinking in animals without extensive prior drinking experience suggests that they may be important for early alcohol use and reward, said senior author Zoe McElligott, Ph.D., assistant professor of psychiatry and pharmacology. Its our hope that by understanding the function of this circuit, we can better predict what happens in the brains of people who transition from casual alcohol use to subsequent abuse of alcohol, and the development of alcohol use disorders.

McElligott, who is also a member of the UNC Bowles Center for Alcohol Studies, set out to investigate if a population of neurons that express a specific neuropeptide (neurotensin or NTS) contributes to reward-like behaviors and alcohol drinking. She was especially interested in these neurons in the context of inexperienced alcohol use, such as when a person first begins to drink alcohol. Also, NTS neurons are a subpopulation of other neurons in this CeA brain region that have been implicated in anxiety and fear known as the somatostatin and corticotropin releasing factor neurons.

Using modern genetic and viral technologies in male mice, McElligott and colleagues found that selectively lesioning or ablating the NTS neurons in the CeA, while maintaining other types of CeA neurons, would cause the animals to drink less alcohol. This manipulation did not alter anxiety-like behavior. It also did not affect the consumption of other palatable liquids such as sucrose, saccharin, and bitter quinine solutions.

We found that these NTS neurons in the CeA send a strong projection to the hindbrain, where they inhibit the parabrachial nucleus, near the brainstem, McElligott said.

Mara Luisa Torruella Suarez. Credit: University of North Carolina Health Care

Using optogenetics a technique where light activates these neurons the researchers stimulated the terminal projections of the CeA-NTS neurons in the parabrachial and found that this stimulation inhibited the neurons in the parabrachial. When the scientists stimulated this projection with a laser in one half of the animals box, animals would spend more time where the stimulation would occur.

Animals also learned to perform a task to get the laser stimulation to turn on, and they would do this repeatedly, suggesting that they found this stimulation to be rewarding.

Furthermore, when we stimulated this projection, animals would drink more alcohol as compared to when they had an opportunity to drink alcohol without laser stimulation, McElligott said. In contrast to our study where we ablated the NTS neurons, laser stimulation of this parabrachial pathway also caused the animals to consume caloric and non-caloric sweetened beverages. When the animals were presented with regular food and a sweet food, however, laser stimulation did not enhance the consumption regardless of the mouses hunger state. This suggests that different circuits may regulate the consumption of rewarding fluids and solids.

McElligott and her graduate student Mara Luisa Torruella Suarez, the first author of this study, hope to explore how alcohol experience may change these neurons over time.

Would these cells respond differently after animals have been drinking high quantities of alcohol over time? McElligott said. We also want to discover which populations of neurons in the parabrachial are receiving inputs from these neurons. Fully understanding this circuit could be the key to developing therapeutics to help people with alcohol use disorders.###

Reference: Manipulations of central amygdala neurotensin neurons alter the consumption of ethanol and sweet fluids in mice by Mara Luisa Torruella-Surez, Jessica R. Vandenberg, Elizabeth S. Cogan, Gregory J. Tipton, Adonay Teklezghi, Kedar Dange, Gunjan K. Patel, Jenna A. McHenry, J. Andrew Hardaway, Pranish A. Kantak, Nicole A. Crowley, Jeffrey F. DiBerto, Sara P. Faccidomo, Clyde W. Hodge, Garret D. Stuber and Zo A. McElligott, 19 November 2019, Journal of Neuroscience.DOI: 10.1523/JNEUROSCI.1466-19.2019

The National Institutes of Health, The North Carolina Translational Clinical Science (NC TraCS) Institute, the Alcohol Beverage Medical Research Foundation, and The UNC Bowles Center for Alcohol Studies funded this research.

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Alcohol Consumption Is Regulated by Particular Set of Neurons in Specific Brain Region - SciTechDaily

There are some new kids on the block at the Old Man on His Back (OMB) Prairie and Heritage Conservation Area that will help to bring vitality and diversity to the bison herd.

The Nature Conservancy of Canada (NCC) is adding five young bison bulls to the herd as part of a revised management plan to grow the herd.

The bulls have already arrived at OMB and will be integrated with the herd during the annual roundup, when the herd is moved to their winter pasture.

It will definitely shake things up a little bit, because the existing bulls in the herd are all quite a bit older than these ones, NCC Program Director for Southwest Saskatchewan Michael Burak said. We don't anticipate that they'll consider them to be too much of a threat necessarily. There definitely will be a couple of squabbles here and there. It will really depend largely on the attitude of the five that we just brought in. If they're really trying to push boundaries and trying to test some of those older animals, they'll be put in their place pretty quickly.

The introduction of the young bulls during the annual roundup is done on purpose to make their arrival less noticeable, because there is a lot of movement and change during the herds shift from the summer to winter pasture.

Everybody is a little bit confused and there was a really big kind of change and a shift that happened, he said. They all go through a handling system. So they're all a little bit stressed out. It's kind of the perfect time to just push everybody out into their winter pasture at the same time and hopefully they will not notice that there's all of a sudden these extra individuals that weren't there previously.

The five bulls arrived about a month ago. They were released into a separate paddock to give them time to adjust to their new surroundings and their health can also be monitored before their introduction to the herd.

The date for the roundup will depend on when the herd decides to come into the corral, which usually only happens when there is already a good snow cover and they can be attracted with bales of hay.

All five bulls were born in 2017 and they are around two-and-a-half years old. They were born and raised in Canada, but their lineage can be traced back to the northern United States, including the bison herd at Theodore Roosevelt National Park in North Dakota.

They came from three different producers. Three are from different areas of Saskatchewan. Two are from a producer in the Prince Albert area and another one was obtained from a producer near Shaunavon. Two came from a producer in central Alberta.

The OMB herd is genetically pure plains bison and the new arrivals were evaluated to confirm they are also the same. Genetic samples were submitted to the University of California, Davis, where tests were done to determine the presence of any cattle genes in those animals. The Alberta producer has done regular genetic tests on his herd, and he picked bulls that he knew are genetically pure.

These bulls will have a lot more space to roam when they join the herd on the vast plains of the OMB conservation area.

I think it's definitely going to be a bit of a change for them, Burak said. They may not be used to having quite as much open space, but I don't think it would be too big a transition for them. Normally with bison, they tend to just want to stick socially close to each other.

The OMB conservation area covers 13,088 acres (5,297 hectares) and is located in the R.M. of Frontier, 15 kilometres west of Claydon and 210 kilometres southwest of Swift Current. NCC manages OMB as a working ranch, and the bison will graze on about 9,000 acres of land. The remaining 4,000 acres are used for annual grazing by about 200 cattle from around 11 neighbouring ranchers from early June to mid October.

We're really pleased with how the whole bison introduction and the bison program have been going, he said. We're definitely achieving the goals that we set for ourselves as far as keeping the property healthy and making sure the grass is nice and productive, and that it is being grazed in a sustainable way. We're really proud of the way that we are able to showcase the differences or the similarities as well between cattle and bison grazing.

The original introduction of a group of 50 two-year-old plains bison to the OMB conservation area took place in the winter of 2003. They came from Elk Island National Park in central Alberta. There were 25 males and 25 females, but over time the NCC staff realized this 50 per cent split between the two sexes did not work. There were too many male animals, and over time the composition of the herd was changed.

There are currently seven adult bulls (excluding the five new arrivals), 68 adult cow, and nine calves (six yearling heifers and three yearling bulls) that were kept back from the previous calving. The introduction of the five young bulls will help to diversify the genetics of the herd and the goal is to increase the size of the herd to about 100 breeding individuals.

We've been in the process of rewriting a management plan for that herd for probably the better part of a year now to shift towards managing them in a more natural kind of way, Burak said. That would involve the herd being larger for one, as well as we'll have more breadth within our age classes. Right now, the majority of our herd is about 10 years old and older, whereas in a natural herd you would probably have your largest age class from about four to eight years old and then you would have a continuum of younger animals and then some older.

The easiest and least expensive way to grow the herd will be to just keep their own calves back every year, but that will have a potentially negative effect on genetic diversity.

If we're keeping calves with only our current herd bulls left in there, then we have a pretty good chance that they'll actually end up bred back to their relatives or even their fathers, he explained. That's why we brought five more in so that we have a bit more variation and we can spread that out a bit more and dilute the effect of any inbreeding that we might see.

NCC staff still need to do more work to evaluate the carrying capacity of the conservation area as part of the implementation of the revised management plan. They will look at the kind of grass production on the property and that information will be compared with data on the forage needs of bison. They also have to take into account the needs of other foragers, and they will calculate the natural grazing rate of other wild ungulates such as deer.

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Five bulls joining bison herd at Old Man on His Back conservation area - Prairie Post

Interferon Insight

Uncontrolled type I IFN activity has been linked to several human pathologies, but evidence implicating this cytokine response directly in disease has been limited. Here, Duncan et al. identified a homozygous missense mutation in STAT2 in siblings with severe early-onset autoinflammatory disease and elevated IFN activity. STAT2 is a transcription factor that functions downstream of IFN, and this STAT2R148W variant was associated with elevated responses to IFN/ and prolonged JAK-STAT signaling. Unlike wild-type STAT2, the STAT2R148W variant could not interact with ubiquitin-specific protease 18, which prevented STAT2-dependent negative regulation of IFN/ signaling. These findings provide insight into the role of STAT2 in regulating IFN/ signaling in humans.

Excessive type I interferon (IFN/) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFN/, which manifest as prolonged Janus kinasesignal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFN/ signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFN/ signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFN/ activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

Type I interferons (including IFN/) are antiviral cytokines with pleiotropic functions in the regulation of cellular proliferation, death, and activation. Reflecting their medical importance, type I IFNs have been shown to be essential to antiviral immunity in humans (1), whereas their potent immunomodulatory effects have been exploited to treat both cancer and multiple sclerosis (2, 3).

IFN/ also demonstrates considerable potential for toxicity, which became apparent in initial studies in rodents (4) and subsequent clinical experience in patients (5, 6). Thus, the production of and response to type I IFNs must be tightly controlled (7). Transcriptional biomarker studies increasingly implicate dysregulated IFN/ activity in a diverse spectrum of pathologies ranging from autoimmune to neurological, infectious and vascular diseases (811).

The immunopathogenic potential of IFN/ is exemplified by a group of monogenic inborn errors of immunity termed type 1 interferonopathies, wherein enhanced IFN/ production is hypothesized to be directly causal (12). Neurological disease is typical of these disorders, which manifest as defects of neurodevelopment in association with intracranial calcification and white matter changes on neuroimaging, suggesting that the brain is particularly vulnerable to the effects of excessive type I IFN activity (9). A spectrum of clinical severity is recognized, from prenatal-onset neuroinflammatory disease that mimics in utero viral infectionAicardi-Goutires syndrome (13)to a clinically silent elevation of IFN activity (14).

However, the central tenet of the type I interferonopathy hypothesis, namely, the critical pathogenic role of type I IFNs (12), has yet to be formally established (15). Evidence for an IFN-independent component to disease includes (i) recognition that other proinflammatory cytokines are also induced by nucleic acid sensing, which might contribute to pathogenesis (16); (ii) imperfect correlations between IFN biomarker status and disease penetrance (14); (iii) the absence of neuropathology in mouse models of Aicardi-Goutires syndrome despite signatures of increased IFN activity (17); and (iv) the observation that crossing to a type I IFN receptor deficient background does not rescue the phenotype in certain genotypes (e.g., STING and ADAR1) (18, 19), although it does in others (e.g., TREX1 or USP18) (20, 21). Here, we provide concrete evidence of the pathogenicity of type I IFNs in humans, shedding new light on the critical importance of signal transducer and activator of transcription 2 (STAT2) in the negative regulation of this pathway.

We evaluated two male siblings, born in the United Kingdom to second cousin Pakistani parents. Briefly, patient II:3, born at 34 weeks + 6 days with transient neonatal thrombocytopenia, was investigated for neurodevelopmental delay at 6 months (which was attributed to compensated hypothyroidism). Aged 8 months, he presented with the first of three episodes of marked neuroinflammatory disease, associated with progressive intracranial calcification, white matter disease, and, by 18 months, intracranial hemorrhage (Fig. 1A). These episodes were associated with systemic inflammation and multiorgan dysfunction, including recurrent fever, hepatosplenomegaly, cytopenia with marked thrombocytopenia, raised ferritin, and elevated liver enzymes. Latterly, acute kidney injury with hypertension and nephrotic range proteinuria developed (see Table 1, Supplementary case summary, and table S1).

(A) Neuroimaging demonstrating calcifications [brainstem/hypothalamus (proband II:3, top), cerebral white matter/basal ganglia/midbrain/optic tract (sibling II:4, top and middle)], hemorrhages [occipital/subdural/subarachnoid (proband II:3, middle)], and cerebral white matter and cerebellar signal abnormality with parenchymal volume loss (both, bottom), accompanied by focal cystic change and cerebellar atrophy (sibling II:4). (B) Whole blood RNA-seq ISG profiles: controls (n = 5); proband II:3 (n = 4); and patients with mutations in: TREX1 (n = 6), RNASEH2A (n = 3), RNASEH2B (n = 7), RNASEH2C (n = 5), SAMHD1 (n = 5), ADAR1 (n = 4), IFIH1 (n = 2), ACP5 (n = 3), TMEM173 (n = 3), and DNASE2 (n = 3). (C) IFN scores (RT-PCR) of patients, parents, and n = 29 healthy controls. ****P < 0.001, ANOVA with Dunnetts posttest. (D) Renal histopathology in proband (400 magnification) showing TMA with extensive double contouring of capillary walls (silver stain, top left); endothelial swelling, mesangiolysis, and red cell fragmentation (top right); arteriolar fibrinoid necrosis (bottom left); and myxoid intimal thickening of an interlobular artery (bottom right, all hematoxylin and eosin). (E) Transcriptional response to JAK inhibitor (JAKi) ruxolitinib in both patients (RT-PCR).

HLH, hemophagocytic lymphohistiocytosis; EEG, electroencephalogram.

This clinical phenotype was reminiscent of a particularly severe form of type I interferonopathy. In keeping with this observation, IFN-stimulated gene (ISG) transcripts in whole blood, measured by RNA sequencing (RNA-seq) and reverse transcription polymerase chain reaction (RT-PCR), were substantially elevated over multiple time points at similar magnitudes to recognized type I interferonopathies (Fig. 1, B and C), notably without evidence of concomitant induction of IFN-independent inflammatory pathways (fig. S1). Disease in the proband, which not only met the diagnostic criteria for hemophagocytosis but also included features of a thrombotic microangiopathy (TMA) (Fig. 1D), was partially responsive to dexamethasone and stabilized with the addition of the Janus kinase (JAK) inhibitor ruxolitinib (Fig. 1E and fig. S2). Sadly, however, this child succumbed to overwhelming Gram-negative bacterial sepsis during hematopoietic stem cell transplantation.

Patient II:4, his infant brother, presented with abnormal neurodevelopment and neuroimaging in the neonatal period, characterized by apneic episodes from 3 weeks of age in conjunction with parenchymal calcifications and hemorrhage, abnormal cerebral white matter, and brainstem and cerebellar atrophy (Fig. 1A). Blood tests revealed an elevated ISG score (Fig. 1, B and C), anemia, elevation of D-dimers, and red cell fragmentation on blood film, together with proteinuria and borderline elevations of ferritin and lactate dehydrogenase; renal function was normal, and blood pressure was on the upper limit of the normal range for gestational age. Introduction of ruxolitinib led to prompt suppression of ISG expression in whole blood (Fig. 1E) and an initial reduction in apneic episodes, but neurological damage was irretrievable, and he succumbed to disease at 3 months of age. Mothers pregnancy with patient II:4 had been complicated by influenza B at 23 weeks gestation.

Whole-exome sequencing analysis of genomic DNA from the kindred, confirmed by Sanger sequencing (Fig. 2, A and B), identified an extremely rare variant in STAT2 (c.442C>T), which substituted tryptophan for arginine at position 148 in the coiled-coil domain (CCD) of STAT2 (p.Arg148Trp, Fig. 2C). The Arg148Trp variant was present in the homozygous state in both affected children and was heterozygous in each parent and one healthy sibling, consistent with segregation of an autosomal recessive trait (table S2). This variant was found in the heterozygous state at extremely low frequency in publicly available databases of genomic variation [frequency < 0.00001 in Genome Aggregation Database (22)], and no homozygotes were reported. A basic amino acid, particularly arginine, at position 148 is highly conserved (fig. S3). In silico tools predicted that this missense substitution was probably deleterious to protein function (table S2). STAT2 protein expression in patient cells was unaffected by the Arg148Trp variant, in contrast to the situation for pathogenic loss-of-expression STAT2 variants, which resulted in a distinct phenotype of heightened viral susceptibility (Fig. 2D) (23, 24). Filtering of exome data identified an additional recessive variant in CFH (c.2336A>G and p.Tyr779Cys; fig. S4) present in the homozygous state in II:3 but absent from II:4. We considered the possibility that this contributed to TMA in the proband, but functional studies of this variant showed negligible impact on factor H function (fig. S5).

(A) Pedigree, (B) capillary sequencing verification, (C) protein map, and (D) immunoblot (fibroblasts) showing normal expression of STAT2 protein. DBD, DNA binding domain; LD, linker domain; SH2, Src homology 2 domain; TAD, trans-activation domain.

The transcription factor STAT2 is essential for transcriptional activation downstream of the receptors for the innate IFN-/ (IFNAR) and IFN- and their associated JAK adaptor proteins. In the current paradigm (25), STAT2 is activated by tyrosine phosphorylation, associated with IFN regulatory factor 9 (IRF9) and phosphorylated STAT1 (pSTAT1) to form the IFN-stimulated gene factor 3 (ISGF3) to effect gene transcription by binding to IFN-stimulated response elements in the promoters of ISGs. Although loss-of-function variants in STAT2 increase susceptibility to viral disease (23, 24), evidence here suggested pathological activation. Germline gain-of-function variants have been reported in STAT1 (26, 27) and STAT3 (28, 29) but not hitherto STAT2. Consistent with the apparent gain of IFN activity associated with mutant STAT2R148W, we observed in patient fibroblasts (Fig. 3, A and B) and peripheral blood mononuclear cells (PBMCs; fig. S6) the enhanced expression of ISG protein products across a range of IFN concentrations. However, basal and induced production of IFNB mRNA by fibroblasts was indistinguishable from controls (Fig. 3C); nor was IFN protein substantially elevated in patient samples of cerebrospinal fluid (II:3) or plasma (II:4) as measured by a highly sensitive digital enzyme-linked immunosorbent assay (ELISA) assay (30), albeit samples were acquired during treatment (table S3). Thus, the response to type I IFNs, but not their synthesis, was exaggerated. This heightened IFN sensitivity was accompanied by enhancement of key effector functions, as revealed by assays of IFN-mediated viral protection (Fig. 3D) and cytotoxicity (Fig. 3E). Collectively, these data indicated that STAT2R148W was not constitutively active but rather resulted in an exaggerated response upon IFN exposure. To confirm that the Arg148Trp variant was responsible for this cellular phenotype, we transduced STAT2-null U6A cells (31) and STAT2-deficient primary fibroblasts (23) with lentiviruses encoding either wild type (WT) or STAT2R148W, recapitulating the heightened sensitivity of cells expressing the latter to IFN (Fig. 3, F and G, and fig. S7).

Unless stated, all data are from patient II:3 and control fibroblasts. (A) ISG expression (immunoblot, IFN for 24 hours) and (B) densitometry analysis (n = 3, t test). MX1, MX dynamin like GTPase 1; IFIT1, IFN-induced protein with tetratricopeptide repeats 1; RSAD2, radical S-adenosyl methionine domain containing 2. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. (C) IFNB mRNA (RT-PCR) external polyinosinic:polycytidylic acid (poly I:C) treatment (25 g/ml for 4 hours; n = 3, t test). US, unstimulated. (D) Antiviral protection assay (mCherry-PIV5). Twofold dilutions from IFN (16 IU/ml), IFN (160 IU/ml) n = 7 replicates, representative of n = 2 experiments (two-way ANOVA with Sidaks posttest). (E) Cytopathicity assay (IFN for 72 hours; n = 3, t test). (F) As in (A), ISG expression in STAT2/ U6A cells reconstituted with STAT2WT or STAT2R148W (immunoblot, IFN for 24 hours). (G) As in (B), n = 3 to 4, t test. Data are presented as means SEM of repeat experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. n.s., nonsignificant.

To explore the underlying mechanism for heightened type I IFN sensitivity, we first probed STAT2 activation in IFN-stimulated fibroblasts. In control lysates, levels of pSTAT2 had almost returned to baseline between 6 and 24 hours of treatment despite the continued presence of IFN (Fig. 4, A and B). In contrast, pSTAT2 persisted for up to 48 hours in patient cells. This abnormally prolonged pSTAT2 response to IFN was also observed in PBMCs of both patients (fig. S8). Consistent with immunoblot data, immunofluorescence analysis showed persistent ( 6 hours) nuclear localization of STAT2 in patient fibroblasts after IFN treatment, at times when STAT2 staining was predominantly cytoplasmic in control cells (Fig. 4, C and D, and fig. S9). This was accompanied by continued expression of ISG transcripts for 36 hours after the washout of IFN in patient cells as measured by RNA-seq and RT-PCR (Fig. 4, E and F). Thus, the type I IFN hypersensitivity of patient cells was linked to prolonged IFNAR signaling.

All data are from patient II:3 and control fibroblasts. (A) pSTAT2 time course [immunoblot, IFN (1000 IU/ml)] and (B) densitometry analysis (n = 5 experiments, two-way ANOVA with Sidaks posttest). (C) Immunofluorescence analysis [IFN (1000 IU/ml); scale bar, 100 m; representative of n = 3 experiments] with (D) image analysis of STAT2 nuclear translocation (n = 100 cells per condition, ANOVA with Sidaks posttest). A.U., arbitrary units. (E) RNA-seq analysis of IFN-regulated genes (n = 3 controls) with (F) validation by RT-PCR (n = 3, two-way ANOVA with Sidaks posttest). CPM, read counts per million. (G) pSTAT2 decay (immunoblot). IFN (1000 IU/ml; 30 min) followed by extensive washing and treatment with 500 nM staurosporine (STAU). Times relative to STAU treatment. (H) No significant differences by densitometry analysis (n = 3, t test). Data are presented as means SEM of repeat experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

The IFNAR signaling pathway is subject to multiple layers of negative regulation that target STAT phosphorylation directlythrough the action of tyrosine phosphatasesor indirectly by disrupting upstream signal transduction (7). Prolonged tyrosine phosphorylation is reported with gain-of-function mutations in STAT1, in association with impaired sensitivity to phosphatase activity (27). By contrast, we observed no impairment of dephosphorylation of STAT2R148W in pulse-chase assays with the kinase inhibitor staurosporine (Fig. 4, G and H), implying instead a failure of negative feedback upon the proximal signaling events that generate pSTAT2.

To localize this defect, we analyzed by phosflow and immunoblot the successive activation steps downstream of IFNAR ligand binding in Epstein-Barr virus (EBV)transformed B cells from the proband (II:3) and a heterozygous parent (I:2). As was the case for STAT2 phosphorylation, we also observed prolonged phosphorylation of both JAK1 and STAT1 after IFN treatment (Fig. 5, A to D). This points to a defect in regulation of the most proximal IFNAR signaling events, upstream of STAT2 (7). We observed no evidence of this phenotype in cells bearing STAT2R148W in the heterozygous state, consistent with autosomal recessive inheritance and the lack of clinical disease or up-regulation of IFN activity in heterozygous carriers. This genetic architecture provides a notable contrast to gain-of-function mutations affecting other STAT proteins, all of which are manifest in the heterozygous state (2629).

Time course of IFN stimulation (1000 IU/ml) in EBV B cells from patient II:3 [homozygous (hom)], parent I:2 [heterozygous (het)], and n = 3 controls. (A) Immunoblot and (B) densitometry analyses. (C) Representative histograms (flow cytometry) and (D) mean fluorescence intensity (MFI). Data are means SEM of three repeat experiments (*P < 0.05, **P < 0.01, t test).

Known negative regulators of IFNAR signaling are suppressor of cytokine signaling (SOCS) 1 and SOCS3 (32) and the ubiquitin-specific protease 18 (USP18) (33). SOCS1 and SOCS3 participate in regulation of additional JAK-STAT signaling pathways, such as those activated by IFN and interleukin 6 (IL-6) (34, 35), whereas USP18 acts specifically upon IFNAR signaling (33). To better localize the molecular defect in patient cells, we examined the signaling responses to IFN (STAT1 phosphorylation) and IL-6 (STAT3 phosphorylation), based on the prediction that defects of SOCS1 or SOCS3 regulation would manifest under these conditions. These experiments revealed that regulation of STAT1 and STAT3 phosphorylation was normal in patient fibroblasts (fig. S10). Together with the absence of evidence of up-regulation of the IFN and IL-6 pathways in the analysis of whole blood RNA-seq data (fig. S1), these observations effectively ruled out the involvement of SOCS1 and SOCS3 in the clinical phenotype, leading us to suspect a defect of USP18 regulation.

To investigate this possibility, we primed patient and control cells with IFN for 12 hours, washed them extensively, and rested and restimulated them with IFN or IFN after 48 hours. In these experiments, IFN-induced pSTAT2 and pSTAT1 were strongly inhibited by priming in control cells, consistent with desensitization, a well-established phenomenon of type I IFN biology (Fig. 6, A and B) (36). In marked contrast, the response to IFN restimulation in patient cells was minimally suppressed, indicating a failure of desensitization. Desensitization has been shown to be exclusively mediated by USP18, an IFN-induced isopeptidase (37), through its displacement of JAK1 from the receptor subunit IFNAR2 (38, 39)a function that is independent of its isopeptidase activity toward the ubiquitin-like protein ISG15 (33). STAT2 plays a critical role as an adaptor protein by supporting binding of USP18 to IFNAR2 (Fig. 6C) (40). Both the clinical and cellular effects of STAT2R148W resemble homozygous USP18 deficiency, which was recently described as the molecular cause of a severe pseudo-TORCH syndrome associated with elevated type I IFN expression (table S4) (41). Although this STAT2:USP18 interaction has been shown to be essential for negative regulation of type I IFN signaling in vitro (40), its significance in vivo has not previously been examined. Furthermore, the precise residue(s) of STAT2 that bind USP18 were unresolved, although this interaction had been localized to a region including the CCD and/or DNA binding domain(s) of STAT2 (40).

(A) Desensitization assay (immunoblot, fibroblasts) with (B) pSTAT densitometry analysis (pSTAT/tubulin, ratio to unprimed; n = 4, ANOVA with Sidaks posttest). (C) Schematic of USP18 mechanism of action and proposed model of STAT2R148W pathomechanism. (D) Modeling of exposed WT (R148)/mutant (W148) residue, demonstrating charge-change (blue, positive; red, negative) and possible steric restriction. (E) Coimmunoprecipitation of USP18 by STAT2 in U6A cells expressing STAT2WT or STAT2R148W with (F) densitometry analysis (USP18/STAT2, ratio to WT; one-sample t test). Data are means SEM (**P < 0.01, ****P < 0.0001). IB, immunoblot.

Because USP18 was induced normally in patient cells (Fig. 6, A and B) and in vivo (Fig. 1B), our data implied that STAT2R148W impedes the proper interaction of STAT2 with USP18, compromising its regulatory function (Fig. 6C). Molecular modeling of STAT2R148W placed the substituted bulky aromatic tryptophan, and resulting charge change, at an exposed site within the CCD (Fig. 6D). Consistent with our suspicion that this might impair the STAT2:USP18 interaction through electrostatic or steric hindrance, coimmunoprecipitation experiments in U6A cells stably expressing WT or STAT2R148W demonstrated a statistical significance reduction of USP18 pull down STAT2R148W compared with WT (Fig. 6, E and F), providing a molecular mechanism for the USP18 insensitivity of patient cells.

Although disruption to the STAT2R148W:USP18 interaction was the most plausible explanation for the clinical and molecular phenotype, we also considered the contribution of alternative regulatory functions of STAT2. Beyond the role of tyrosine phosphorylated STAT2 in innate IFN signal transduction, the unphosphorylated form of STAT2 (uSTAT2) has additional, recently described functions in the regulation of other cytokine signaling pathways. For example, uSTAT2 negatively regulates the activity of IFN (and other inflammatory cytokines that signal via STAT1 homodimers) by binding to uSTAT1 via its CCD (42). This interaction appears to limit the pool of STAT1 available for incorporation into transcriptionally active (tyrosine phosphorylated) STAT1 homodimers. Conversely, uSTAT2, induced by type I IFN signaling, has been reported to promote the transcriptional induction of IL6 through an interaction with the nuclear factor B subunit p65 (43). To investigate the potential relevance of these regulatory functions of STAT2, we first examined the induction of IL6 by RT-PCR analysis of RNA isolated from whole blood of patients, their heterozygous parents, and healthy controls. We found no evidence of increased expression of IL6 or its target gene SOCS3 (fig. S11, A and B), consistent with our previous pathway analysis of RNA-seq data (fig. S1) and implying that STAT2R148W does not influence IL-6 induction. Next, to explore any impact on STAT2s negative regulatory activity toward STAT1, we examined the transcriptional responses to IFN in patient fibroblasts and in U6A cells expressing STAT2R148W. Although we were able to reproduce the previously reported findings of heightened transcription of the IFN-regulated gene CXCL10 in U6A cells lacking STAT2, alongside a nonsignificant trend for IRF1 (fig. S12, A and B) (42), STAT2R148W did not enhance transcript levels of either CXCL10 or IRF1 above WT, in agreement with the data showing the preserved ability of STAT2R148W to bind STAT1 in a coimmunoprecipitation assay (fig. S12, C and D). Together, these studies effectively exclude a contribution of the USP18-independent regulatory functions of STAT2 to the disease phenotype.

To conclusively demonstrate the impairment of STAT2:USP18-mediated negative regulation in patient cells, we tested the impact of overexpression or knockdown of USP18. First, we probed IFNAR responses in fibroblasts stably expressing USP18. As predicted, USP18 was significantly impaired in its ability to suppress IFN signaling in patient cells, relative to controls, both in terms of STAT phosphorylation (Fig. 7, A and B) and STAT2 nuclear translocation (Fig. 7, C and D), recapitulating our prior observations with IFN priming (Fig. 6A). The reciprocal experiment, in which USP18 expression was stably knocked down using short hairpin RNA (shRNA), revealed significantly prolonged STAT2 phosphorylation in control cells at 24 hours, recapitulating the phenotype of patient cells (Fig. 7, E and F). In contrast, there was no effect of USP18 knockdown in patient cells, demonstrating that they are USP18 insensitive. Incidentally, we noted that the early peak (1 hour) of STAT2 phosphorylation in USP18-knockdown control fibroblasts was marginally reduced (Fig. 7E). This subtle reduction was also apparent in STAT2R148W patient fibroblasts (Fig. 4B), although not in EBV B cells (Fig. 5). We speculate that the cell typespecific induction of other negative regulator(s) of IFNAR signaling at early times after IFN treatment, such as SOCS1, might be responsible for this observation. RT-PCR analysis confirmed the increased expression of SOCS1 mRNA in whole blood of patients (fig. S11C), whereas examination of RNA-seq data from IFN-treated fibroblasts revealed an eightfold enhancement of SOCS1 expression at 6 hours in patient cells as compared with controls (Padj = 0.0001; Fig 4E). Together, these data provide preliminary support for the hypothesis that alternative negative regulator(s) of IFNAR signaling may be up-regulated in patient cells. Nevertheless, such attempts at compensation are clearly insufficient to restrain IFNAR responses in the context of STAT2R148W, reflecting the nonredundant role of STAT2/USP18 in this process (39). Collectively, these data support a model in which the homozygous presence of the Arg148Trp STAT2 variant compromises an essential adaptor function of STAT2 toward USP18, rendering cells USP18 insensitive and culminating in unrestrained, immunopathogenic IFNAR signaling.

All data are from patient II:3 and control fibroblasts. (A) STAT phosphorylation in USP18 and vector expressing fibroblasts (immunoblot) with (B) pSTAT densitometry analysis (pSTAT/tubulin, ratio to unprimed; n = 3, ANOVA with Sidaks posttest). (C) Immunofluorescence analysis of STAT2 nuclear translocation [IFN (1000 IU/ml 30 min); representative of n = 3 experiments] with (D) image analysis (n = 100 cells per condition, ANOVA with Sidaks posttest). (E) Time course of STAT phosphorylation upon IFN stimulation (1000 IU/ml for 0, 1, 6, and 24 hours) of cells transduced with USP18 shRNA or nontargeting (NT) shRNA with (F) densitometry analysis of pSTAT2 (n = 3, t test). Data are means SEM (**P < 0.01, ***P < 0.001, ****P < 0.0001).

We report a type I interferonopathy, caused by a homozygous missense mutation in STAT2, and provide detailed studies to delineate the underlying molecular mechanism. Our data indicate the failure of mutant STAT2R148W to support proper negative regulation of IFNAR signaling by USP18revealing an essential regulatory function of human STAT2. This defect in STAT2 regulation results in (i) an inability to properly restrain the response to type I IFNs and (ii) the genesis of a life-threating early-onset inflammatory disease. This situation presents a marked contrast with monogenic STAT2 deficiency, which results in heightened susceptibility to viral infection due to the loss of the transcription factor complex ISGF3 (23, 24). Thus, just as allelic variants of STAT1 and STAT3 are recognized that either impair or enhance activity of the cytokine signaling pathways in which they participate (44), we can now add to this list STAT2. Our findings also highlight an apparently unique property of human STAT2: That it participates directly in both the positive and negative regulation of its own cellular signaling pathway. Whether this is true of STAT2 in other species remains to be determined. Our findings also localize the interaction with USP18 to the CCD of STAT2, indicating a specific residue critical for this interaction. This structural insight may be relevant to efforts to therapeutically interfere with the STAT2:USP18 interaction to promote the antiviral action of IFNs.

This monogenic disease of STAT2 regulation provides incontrovertible evidence of the pathogenic effects of failure to properly restrain IFNAR signaling in humans. The conspicuous phenotypic overlap with existing defects of IFN/ overproduction, particularly with regard to the neurological manifestations, provides compelling support for the type I interferonopathy hypothesis, strengthening the clinical rationale for therapeutic blockade of IFNAR signaling (15). JAK1/2 inhibition with ruxolitinib was highly effective in controlling disease in the proband; however, the damage that already accrued at birth in his younger brother was irreparable, emphasizing the importance of timely IFNAR blockade in prevention of neurological sequelae. A notable aspect of the clinical phenotype in patient II:3 was the occurrence of severe TMA. Our studies did not support a pathogenic contribution of the coinherited complement factor H variant in patient II:3. This evidence, together with clinical hematological and biochemical results suggestive of incipient vasculopathy in patient II:4who did not carry the CFH variantsuggests that type I IFN may have directly contributed to the development of TMA. Although it is not classically associated with type I interferonopathies, TMA is an increasingly recognized complication of both genetic (41, 42) and iatrogenic states of IFN excess (43), consistent with the involvement of vasculopathy in the pathomechanism of IFN-mediated disease. The fact that STAT2R148W is silent in the heterozygous state at first sight offers a confusing contrast with gain-of-function mutations of its sister molecules STAT1 and STAT3, both of which produce autosomal dominant disease with high penetrance (2629). However, the net gain of IFNAR signaling activity results from the isolated loss of STAT2s regulatory function, which evidently behaves as a recessive trait. There are other examples of autosomal recessive loss-of-function disorders of negative regulators, including USP18 itself (41, 45); the unique aspect in the case of STAT2R148W is that the affected molecule is itself a key positive mediator within the regulated pathway.

In light of the intimate relationship between STAT2 and USP18 revealed by these and other recent data (40), it is reasonable to conclude that the clinical manifestations of human USP18 deficiency are dominated by the loss of its negative feedback toward IFNAR rather than the STAT2-independent functions of USP18 including its enzymatic activity (40, 46, 47). In mouse, white matter pathology associated with microglia-specific USP18 deficiency is prevented in the absence of IFNAR (21). There are now three human autosomal recessive disorders that directly compromise the proper negative regulation of IFNAR signaling and thus produce a net gain of signaling function: USP18 deficiency, which leads to embryonic or neonatal lethality with severe multisystem inflammation (41); STAT2R148W, which largely phenocopies USP18 deficiency; and ISG15 deficiency, in which there is a much milder phenotype of neurological disease without systemic inflammation (45). ISG15 stabilizes USP18, and human ISG15 deficiency leads to a partial loss of USP18 protein (41). Thus, a correlation is clearly evident between the extent of USP18 dysfunction and the clinical severity of these disorders, with STAT2R148W closer to USP18 deficiency and ISG15 on the milder end of the spectrum (table S4). Those molecular defects that result in a failure of negative regulation of IFNAR signaling (i.e., STAT2R148W and USP18/) lead to more serious and extensive systemic inflammatory disease than do defects of excessive IFN/ production (41), suggesting that the STAT2:USP18 axis acts to limit an immunopathogenic response toward both physiological (48) and pathological (41) levels of IFN/. Thus, variability in the efficiency of this process of negative regulation might be predicted to influence the clinical expressivity of interferonopathies. Determining the cellular source(s) of physiological type I IFNs and the molecular pathways that regulate their production are important areas for future investigation.

Some limitations of our results should be acknowledged. Although strenuous efforts were made, we were only able to identify a single kindred, which probably reflects the rarity of this variant. As more cases are identified, our understanding of the clinical phenotypic spectrum will inevitably expand. Furthermore, for practical and cultural/ethical reasons, limited amounts of cellular material and tissues were available for analysis. As a result, we were unable to formally evaluate the relevance of STAT2 regulation toward type III IFN signaling; however, existing data suggest that USP18 plays a negligible role in this context (38). Together, our findings confirm an essential regulatory role of STAT2, supporting the hypothesis that type I IFNs play a causal role in a diverse spectrum of human disease, with immediate therapeutic implications.

We investigated a kindred with a severe, early-onset, presumed genetic disease, seeking to determine the underlying pathomechanism by ex vivo and in vitro studies. Written informed consent for these studies was provided, and ethical/institutional approval was granted by the NRES Committee North East-Newcastle and North Tyneside 1 (ref: 16/NE/0002), South Central-Hampshire A (ref: 17/SC/0026), and Leeds (East) (ref: 07/Q1206/7).

Dermal fibroblasts from patient II:3 and healthy controls were obtained by standard methods and cultured in Dulbeccos modified Eagles medium supplemented by 10% fetal calf serum and 1% penicillin/streptomycin (DMEM-10), as were human embryonic kidney 293 T cells and the STAT2-deficient human sarcoma cell line U6A (31). PBMCs and EBV-transformed B cells were cultured in RPMI medium supplemented by 10% fetal calf serum and 1% penicillin/streptomycin (RPMI-10). Unless otherwise stated, cytokines/inhibitors were used at the following concentrations: human recombinant IFN-2b (1000 IU/ml; Intron A, Schering-Plough, USA); IFN- (1000 IU/ml; Immunikin, Boehringer Ingelheim, Germany); IL-6 (25 ng/ml; PeproTech, USA); and 500 nM staurosporine (ALX-380-014-C250, Enzo Life Sciences, NY, USA). Diagnostic histopathology, immunology, and virology studies were conducted in accredited regional diagnostic laboratories to standard protocols.

Whole-exome sequencing analysis was performed on DNA isolated from whole blood from patients I:1, I:2, II:3, and II:4. Capture and library preparation was undertaken using the BGI V4 exome kit (BGI, Beijing, China) according to manufacturers instructions, and sequencing was performed on a BGISEQ (BGI). Bioinformatics analysis and variant confirmation by Sanger sequencing are described in the Supplementary Materials.

RNA was extracted by lysing fibroblasts in TRIzol reagent (Thermo Fisher Scientific) or from whole blood samples collected in PAXgene tubes (PreAnalytix), as described previously (49). Further details, including primer/probe information, are summarized in the Supplementary Materials and table S5.

Whole-blood transcriptome expression analysis was performed using nine whole blood samples, from the proband taken before and during treatment, and five controls. In addition, the four patient II:3 samples taken before treatment and samples from six patients with mutations in TREX1, three with mutations in RNASEH2A, seven with mutations in RNASEH2B, five with mutations in RNASEH2C, five with mutations in SAMHD1, four with mutations in ADAR1, two with mutations in IFIH1, three with mutations in ACP5, three with mutations in TMEM173, and three with mutations in DNASE2 were analyzed, as described in the Supplementary Materials. RNA integrity was analyzed with Agilent 2100 Bioanalyzer (Agilent Technologies). mRNA purification and fragmentation, complementary DNA (cDNA) synthesis, and target amplification were performed using the Illumina TruSeq RNA Sample Preparation Kit (Illumina). Pooled cDNA libraries were sequenced using the HiSeq 4000 Illumina platform (Illumina). Fibroblasts grown in six-well plates were mock-treated or treated with IFN for 6 or 12 hours, followed by extensive washing and 36-hour rest, before RNA extraction. The experiment was performed with patient II:3 and control cells (n = 3) in triplicate per time point. RNA was extracted using the ReliaPrep RNA Miniprep kit (Promega) according to manufacturers instructions and processed as described above, before sequencing on an Illumina NextSeq500 platform. Bioinformatic analysis is described in the Supplementary Materials. PMBC and fibroblast STAT2 patient and control data have been deposited in ArrayExpress (E-MTAB-7275) and Gene Expression Omnibus (GSE119709), respectively.

Details of lentiviral constructs, mutagenesis, and preparation are included in the Supplementary Materials. Cells were spinoculated in six-well plates for 1.5 hours at 2000 rpm, with target or null control viral particles, at various dilutions in a total volume of 0.5 ml of DMEM-10 containing hexadimethrine bromide [polybrene (8 g/ml); Sigma-Aldrich]. Cells were rested in virus-containing medium for 8 hours and then incubated in fresh DMEM-10 until 48 hours, when they were subjected to selection with puromycin (2.0 g/ml) or blastocidin (2.5 g/ml) (Sigma-Aldrich). Antibiotic-containing medium was refreshed every 72 hours.

EBV B cells were seeded at a density of 8 105 cells/ml in serum-free X-VIVO 15 medium (Lonza, Basel, Switzerland) and stimulated with IFN (1000 IU/ml) for the indicated times. After staining with Zombie UV (BioLegend, San Diego, CA, USA), cells were fixed using Cytofix buffer (BD Biosciences, Franklin Lakes, NJ, USA). Permeabilization was achieved by adding ice-cold PermIII buffer (BD Biosciences, Franklin Lakes, NJ, USA), and cells were incubated on ice for 20 min. After repeated washing steps with phosphate-buffered saline (PBS)/2% fetal bovine serum (FBS), cells were stained for 60 min at room temperature with directly conjugated antibodies (table S6). Samples were acquired on a Symphony A5 flow cytometer (BD Biosciences) and analyzed using FlowJo (FlowJo LLC, Ashland, OR, USA). The gating strategy is shown in fig. S13.

Immunoblotting was carried out as previously described (1) and analyzed using either a G:BOX Chemi (Syngene, Hyarana, India) charge-coupled device camera with GeneSnap software (Syngene) or a LI-COR Odyssey Fc (LI-COR, NE, USA). Densitometry analysis was undertaken using ImageStudio software (version 5.2.5, Li-COR). For complement studies, sodium dodecyl sulfate (SDS)polyacrylamide gel electrophoresis (PAGE) under nonreducing conditions was performed on patient/parental serum [diluted 1:125 in nonreducing buffer (PBS)] or affinity-purified factor H (diluted to 200 ng in nonreducing buffer), separated by electrophoresis on a 6% SDS-PAGE gel, and transferred to nitrocellulose membranes for immunoblotting (antibodies in table S6). Blots were developed with Pierce ECL Western blotting substrate (Thermo Fisher Scientific) and imaged on a LI-COR Odyssey Fc (LI-COR).

U6A cells were lysed in immunoprecipitation buffer [25 mM Tris (pH 7.4), 1 mM EDTA, 150 mM NaCl, 1% Nonidet P-40, 1 mM sodium orthovanadate, and 10 mM sodium fluoride, with complete protease inhibitor (Roche, Basel, Switzerland)]. Lysates were centrifuged at 13,000 rpm at 4C for 10 min. Soluble fractions were precleared for 1 hour at 4C with Protein G Sepharose 4 (Fast Flow, GE Healthcare, Chicago, USA) that had been previously blocked with 1% bovine serum albumin (BSA) IP buffer for 1 hour. Precleared cell lysates were immunoprecipitated overnight with blocked beads that were incubated with anti-STAT2 antibody (A-7) for 1 hour and then washed three times in IP buffer before boiling with 4 lithium dodecyl sulfate buffer at 95C for 10 min to elute the absorbed immunocomplexes. Immunoblot was carried out as described above.

Fibroblasts grown on eight-well chamber slides (Ibidi, Martinsried, Germany) were fixed with 4% paraformaldehyde in PBS for 15 min at room temperature before blocking/permeabilization with 3% BSA/0.1% Triton X-100 (Sigma-Aldrich) in PBS. Cells were incubated overnight with anti-STAT2 primary antibody (10 g/ml; C20, Santa Cruz Biotechnology, Dallas, USA) at 4C, and cells were washed three times with PBS. Secondary antibody [goat anti-rabbit Alexa Fluor 488 (1 g/ml), Thermo Fisher Scientific] incubation was performed for 1 hour at room temperature, followed by nuclear staining with 4,6-diamidino-2-phenylindole (DAPI; 0.2 g/ml; Thermo Fisher Scientific). Cells were imaged with an EVOS FL fluorescence microscope with a 10 objective (Thermo Fisher Scientific). The use of STAT2-deficient cells (23) demonstrated the specificity and lack of nonspecific background of the staining approach. Image analysis was performed in ImageJ. The DAPI (nuclear) image was converted to binary, and each nucleus (object) was counted. This mask was overlaid onto the STAT2 image, and the mean fluorescence intensity of STAT2 within each nucleus was calculated (see also fig. S9). About n = 100 cells were analyzed per image.

The structure of human STAT2 has not been experimentally determined. We therefore used comparative modeling to predict the structure. The sequences of both the WT and mutant were aligned to mouse STAT2 (Protein Data Bank code 5OEN, chain B). For each sequence, 20 models were built using MODELLER (50), and the one with the lowest discrete optimized protein energy score was chosen. Protein structures and electrostatic surfaces were visualized with PyMOL (Schrodinger, USA).

Fibroblasts grown on 96-well plates were treated with IFN (1000 or 10,000 IU/ml) or DMEM-10 alone for 72 hours. Cells were fixed in PBS containing 5% formaldehyde for 15 min at room temperature and then incubated with crystal violet stain. Plates were washed extensively then allowed to air dry. The remaining cell membrane-bound stain was solubilized with methanol and absorbance at 595 nm measured on a TECAN Sunrise plate reader (Tecan, Switzerland). Background absorbance was subtracted from all samples, and the results were expressed as a percentage of the absorbance values of untreated cells.

Fibroblasts grown on 96-well plates were pretreated in septuplicate for 18 hours with twofold serial dilutions of IFN and IFN, followed by infection with mCherry-expressing parainfluenza virus 5 (PIV5) in DMEM/2% FBS for 24 hours. Monolayers were fixed with PBS containing 5% formaldehyde, and infection was quantified by measuring mean fluorescence intensity of mCherry (excitation, 580/9; emission, 610/20) using a TECAN Infinite M200 Pro plate reader (Tecan, Switzerland). Background fluorescence was subtracted from all samples, and the results were expressed as a percentage of the fluorescence values of untreated, virus-infected cells.

Unless otherwise stated, all experiments were repeated a minimum of three times. Data were normalized/log10-transformed before parametric tests of significance in view of the limitations of ascertaining distribution in small sample sizes and the high type II error rates of nonparametric tests in this context. Comparison of two groups used t test or one-sample t test if data were normalized to control values. Comparisons of more than one group used one-way analysis of variance (ANOVA) or two-way ANOVA as appropriate, with posttest correction for multiple comparisons. Statistical testing was undertaken in GraphPad Prism (v7.0). All tests were two-tailed with 0.05.

immunology.sciencemag.org/cgi/content/full/4/42/eaav7501/DC1

Materials and Methods

Supplementary case summary

Fig. S1. Ingenuity pathway analysis of whole blood RNA-seq data.

Fig. S2. Longitudinal series of laboratory parameters.

Fig. S3. Multiple sequence alignment of STAT2.

Fig. S4. Factor H genotyping and mutant factor H purification strategy.

Fig. S5. Functional analysis of factor H Tyr779Cys variant.

Fig. S6. Immunoblot analysis of MX1 expression in PBMCs.

Fig. S7. Transduction of STAT2-deficient primary fibroblasts.

Fig. S8. Prolonged STAT2 phosphorylation in PBMCs.

Fig. S9. STAT2 immunofluorescence image analysis.

Fig. S10. STAT phosphorylation is not prolonged in patient cells in response to IFN or IL-6.

Fig. S11. RT-PCR analysis of gene expression in whole blood.

Fig. S12. STAT2R148W does not impair regulation of STAT1 signaling.

Fig. S13. Phosflow gating strategy.

Table S1. Laboratory parameters, patients II:3 and II:4.

Table S2. Rare variants segregating with disease.

Table S3. Digital ELISA detection of IFN protein concentration.

Table S4. Phenotypes of monogenic defects of USP18 expression and/or function.

Table S5. RT-PCR primers and probes.

Table S6. Antibodies.

Data file S1. Raw data (Excel).

References (5159)

Acknowledgments: We are grateful to the patients and our thoughts are with their family. Funding: British Infection Association (to C.J.A.D.), Wellcome Trust [211153/Z/18/Z (to C.J.A.D.), 207556/Z/17/Z (S.H.), and 101788/Z/13/Z (to D.F.Y. and R.E.R.)], Sir Jules Thorn Trust [12/JTA (to S.H.)], UK National Institute of Health Research [TRF-2016-09-002 (to T.A.B.)], NIHR Manchester Biomedical Resource Centre (to T.A.B.), Medical Research Foundation (to T.A.B.), Medical Research Council [MRC, MR/N013840/1 (to B.J.T.)], MRC/Kidney Research UK [MR/R000913/1 (to Vicky Brocklebank)], Deutsche Forschungsgemeinschaft [GO 2955/1-1 (to F.G.)], Agence Nationale de la Recherche [ANR-10-IAHU-01 (to Y.J.C.) and CE17001002 (to Y.J.C. and D.D.)], European Research Council [GA 309449 (Y.J.C.); 786142-E-T1IFNs], Newcastle University (to C.J.A.D.), and ImmunoQure for provision of antibodies (Y.J.C. and D.D.). C.L.H. and R.S. were funded by start-up funding from Newcastle University. D.K. has received funding from the Medical Research Council, Wellcome Trust, Kidney Research UK, Macular Society, NCKRF, AMD Society, and Complement UK; honoraria for consultancy work from Alexion Pharmaceuticals, Apellis Pharmaceuticals, Novartis, and Idorsia; and is a director of and scientific advisor to Gyroscope Therapeutics. Author contributions: Conceptualization: C.J.A.D., S.H., and T.A.B. Data curation: C.F., G.I.R., A.J.S., J.C., A.M., R.H., Ronnie Wright, and L.A.H.Z. Statistical analysis: C.J.A.D., B.J.T., R.C., G.I.R., F.G., D.F.Y., S.C.L., V.G.S., A.J.S., L.A.H.Z., C.L.H., D.K., and T.A.B. Funding acquisition: C.J.A.D., D.D., Y.J.C., R.E.R., D.K., S.H., and T.A.B. Investigation: C.J.A.D., B.J.T., R.C., F.G., G.I.R., D.F.Y., Vicky Brocklebank, V.G.S., B.C., Vincent Bondet, D.D., S.C.L., A.G., M.A., B.A.I., R.S., Ronnie Wright, C.L.H., and T.A.B. Methodology: C.J.A.D., B.J.T., R.C., F.G., D.F.Y., A.J.S., D.D., K.R.E., Y.J.C., R.E.R., C.L.H., and D.K. Project administration: C.J.A.D., K.R.E., S.H., and T.A.B. Resources: S.M.H., Robert Wynn, T.A.B., J.H.L., J.P., E.C., S.B., K.W., and D.K. Software: C.F., A.J.S., M.Z., L.A.H.Z., and Ronnie Wright. Supervision: C.J.A.D., K.R.E., Y.J.C., D.D., C.L.H., R.E.R., D.K., S.H., and T.A.B. Validation: B.J.T., R.C., A.J.S., V.G.S., and C.L.H. Visualization: C.J.A.D., B.J.T., R.C., and S.C.L. Writing (original draft): C.J.A.D., with B.J.T., R.C., S.H., and T.A.B. Writing (review and editing): C.J.A.D., G.I.R., A.J.S., S.C.L., M.Z., S.M.H., K.R.E., R.E.R., D.K., S.H., and T.A.B. Competing interests: The authors declare that they have no competing interests. Data and materials availability: GEO accession: GSE119709. ArrayExpress accession: E MTAB-7275. Materials/reagents are available on request from the corresponding author(s). MBI6 is available from Claire Harris under a material agreement with Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the UK Department of Health.

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Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2 - Science

Cannadabis Medical INC they intend to create a healthier and more consciously aware environment for the cannabis industry, and its participants, to thrive in.

Did you know that Cannadabis are Partners with us? Discover their featured Partner Page about a healthier, environmentally conscious cannabis industry.

The company is a family run company that was founded in Humboldt, Saskatchewan.

Founders, Alexander Calkins, BSc and Markus Li, P.Chem, MBA, are personally and emotionally invested in the science of cannabis. They each have family members that are dealing with incurable ailments, complications of which can often become fatal.

In the search for natural products that will improve the quality and longevity of life, the founders began working with cannabis. While there is no likelihood of a cure, the symptom management has been very positive for their family members. After witnessing the improvements, Cannadabis founders Calkins and Li, have dedicated themselves to furthering the medical cannabis movement.

Calkins and Li both have backgrounds in technical science and business. They are experienced cultivators and have a strong understanding of energy systems (practically essential for a power-hungry industry), process automation, and large-scale development.

Their familiarity with multi-industry supply chains has leveraged them into a cannabis development that is simultaneously high-tech, old school, and simple.

Through observation of established global industries, Cannadabis is building a multi-faceted business model based on sustainable practices, a strong genetics portfolio, disruptive technologies, hyper-specialisation, and holistic production.

Driven by a passion to help others in need, Calkins and Li took it upon themselves to bring their methods and expertise to the cannabis world. They recognise and praise the patient independence that medical cannabis can provide.

While they champion the practice of homegrown medicine, they have obligated themselves to providing the safest and highest quality medical products to those who are unable to grow for themselves.

Once Cannadabis has perfected its organic growing system, they will build and operate all future cultivation sites according to (EU) GMP and ISO:9001 2015 standards. By adopting these standards, Cannadabis will have the ability to share their cultivated passion with the world.

To meet the sanitary requirements of GMP and processing limitations of an organic certification, Cannadabis will be using a combination of reactive oxygen, electrolysed water, and radio frequency pasteurisation technologies.

Being a medically focused company, Cannadabis recognises that medical consumers have turned to cannabis because they are looking for natural remedies and are becoming increasingly weary of synthetic medicines.

For Cannadabis, producing medical cannabis using anything other than organic methods would transgress the fundamental sentiment that drives the global, medical movement. That is why Cannadabis is committed to attaining internationally recognised organic certifications on expanded production.

The companys flagship facility is intended to be an R&D focused proving ground for state-of-the-art organic cultivation methods. Cannadabis currently uses an inhouse blended soil, made only with organic ingredients. Their living soil has the benefit of creating terpene dense medicine, reducing cost, and simplifying processes.

With all the nutrients available in the soil, the plants require only water from transplant to harvest. Additionally, the growing medium and all organic waste can be recycled through vermicomposting, further reducing long term costs and needless waste.

Cannadabis will adopt various technologies to reduce energy demand and environmental impact. In addition to using LEDs and solar panels, Cannadabis will use combined heat and power (CHP) (or cooling combined heat power (CCHP)) at their cultivation facilities. CHP units burn natural gas to generate power and the waste heat is used to heat water and the workspace. CHPs are quickly becoming popular for reducing carbon emissions. In certain applications, CHPs reduce carbon emissions by 30-40%, compared to when power is taken from the grid.

Cannadabis will also divert the combustion CO2 into the growing space. CO2 supplementing supercharges growth naturally, increasing yield by 30-60%, and further reducing the carbon emissions from power generation. In the future, expanded cultivations may integrate pyrolysis of waste biomass, which will supply power and nutrient dense biochar to the living soil.

Cannadabis is aspiring to build a unique indoor growing system that uses a combination of solar power, water recycling, CHP (CCHP), pyrolysis, CO2 supplementation and vermicompost to create a no waste, carbon neutral, minimal input, self-regenerating nutrient, off grid, medical grade, organic, indoor cultivation.

Calkins and Li hope to validate the system and then apply the techniques to food cultivation; this type of system could revolutionise the food production in remote locations, like the northern territories, Alaska and would deliver food supply independence to small communities or reservations. Where biomass is abundant, this system would produce all year, requires only labour as inputs, self-generate power off-grid, and would also be carbon negative over extended time frames.

On their path to improving growing efficiency, Cannadabis has developed proprietary tissue culture methods specifically for cannabis. These methods are based upon the decades old horticultural practice that has been essential for the sterile propagation of ornamental and food cultivars; non seed propagation.

Developing an inhouse tissue culture system has the following benefits:1

Tissue culture revitalises cultivars and produces more vigorous plants Regeneration from meristem rids systemic disease; Propagation is significantly more efficient; Starting with 100 traditional cuttings; able to produce 70,000 annual clones; Start with 200 tissue culture vials; produce 2 million annual clones; Uses 1/10 the space of traditional cloning; Per square foot, tissue culturing is >100x more efficient; and Two million annual clones could be produced in less than 3000 square feet.

1000 mother cultivars could be stored inside a refrigerator with no care or maintenance for months, sometimes over a year; and Pest invasion would not affect mother cultures (many cultivators without tissue culture have lost their entire genetic inventory to viruses and fungi).

Cannadabis will be sharing its tissue culture methods with industry members who want to stay one step ahead of pests and systemic disease. Following more development, they will also be making their organic formulations available.

Having collected and grown a large variety of cultivars, both through seed and clone, the Cannadabis founders have noticed a distinct lack of quality in the genetics market. Over time, most of the popular cultivars of the world have been slowly degraded by deleterious breeding practices like selfing (feminising), backcrossing, and poor mother plant maintenance which promotes genetic drift.

The current genetics market is rife with breeders that take prized clones and spray them with colloidal silver to produce feminised seed, or they are crossed onto their own cultivars and backcrossed until stable seed is produced.

While these name sake creations may capture some of the qualities of the original strain, like trichome density or terpene profile, the progeny will lack the genetic diversity needed to produce healthy plants. Often, these weakened strains have reduced yield, potency, and pest resistance. In response to this, Cannadabis has focused on breeding their own high yield, high potency, flavour dense strains for commercial production.

The Cannadabis team is eager to unveil their propriety strains to the domestic and international medical markets. Over the past few years, the founders have started breeding their own cultivars. Currently, the team has focused on a selection of stabilised true breeds (landrace or F5+) for creating original F1 breeds.

Where the F1 generation is created by breeding male and female plants that are distinctly unique from each other; traditional F1s are created by crossing landrace indicas with landrace sativas.

These crosses need to be done with highly stable and uniquely different parents to produce a true F1 progeny that has abundant hybrid vigour. A plant with true hybrid vigour will typically have higher potency, increased pest resistance, and a higher yield than both parent plants; on average yield can be as high as 20% more than either parent.

Due to the nature of the F1 progeny, very few breeders release true F1 seeds. If highly stable progenitors are not used, the seedstock will be incredibly variable, which is unfavourable for consumers, who typically want consistency in their seed. However, as commercial cultivators, Cannadabis believes that F1 hybrids are essential for producing at large scale. The breeding and phenotyping can be a long and arduous process, the fruits of labour are not without commercial benefit.

Building upon the tissue culture and breeding practices, Cannadabis is quickly developing polyploidisation methods for creating ultra-premium cultivars. Polyploidisation is another common horticultural practice that Cannadabis expects to apply to their cannabis breeding projects.

Polyploidisation is a naturally occurring mechanism where the chromosomes of the plant cells become doubled within the same nucleus. This mechanism has played a significant role in speciation of crops, occurring frequently in nature, usually due to stress response.

In the 100 years since scientists discovered polyploidy, there has been rapid development of polyploid breeds. It is estimated that up to 80% of all flowering plants have polyploid varieties.2 Common polyploid cultivars includes wheat, coffee, banana, strawberry, potato, etc.

Polyploidy has been researched since the early 1900s. Scientists first used heat and electrical stress to induce those mechanisms. Today polyploidy is more commonly, and consistently, induced with radiation and stressing chemicals. Interestingly, induced polyploidy is explicitly exempt by most organic certification bodies. These types of breeds typically do not fall under genetically modified until foreign, non-similar species, DNA is introduced to the plant cell.

These polyploids are called autopolyploid (same species), and plants made with dissimilar species are called allopolyploids. Cannadabis will also be exploring organic permitted cell fusion; this would allow breeding with two male plants, or two female plants.

In the past, the following horticulture benefits have been derived from polyploidy and cell fusion, which Cannadabis hopes to similarly apply to the cannabis plant:3

The same can apply to cannabis. Strains can be developed that would never seed regardless of direct pollination; massive utility available to outdoor or indoor cultivators with seeding problems.

Cannadabis hopes to release their first polyploid strains in late 2020.

Cannadabis has begun manufacturing premade tissue culture mediums and are currently distributing them to Western Canadian horticulture stores and Amazon Marketplace; the mediums are a standard blend that works on 95%+ of the founders cultivars. The founders tissue culture experience is being provided to the public in both consumer and commercial grade products.

The introductory products show unfamiliar users how to do tissue culture at home, using proven methods that do not require expensive laboratory equipment. Besides what comes in the starter kit, the everyday home grower will usually have all the remaining materials at home. Commercial format mediums are intended for growers that want the best value and space savings.

Cultivators of any background can find information or help on tissue culture through the Cannadabis homepage. They are posting helpful videos and literature on cannabis tissue culture and hope to share the benefits with every grower. All horticulturalists, cannabis or not, can benefit from having their cloning area be 100x more efficient, through stackable containers. Furthermore, their mother plants can easily be maintained with minimal care. 100-1000 mother cultures can be stored within a refrigerator for 4-8 months, no adding nutrient or water. For larger cultivators, Cannadabis provides PGR matrices to more easily troubleshoot difficult cultivars. They also will custom blend and sterilise mediums to customer preference.

Cannadabis has begun developing an automated cell culture process for mass propagation of cultivars. The economies of scale of which are expected to change the supply chain of the entire cannabis industry. Automated cell culturing will provide starting materials to the industry at a fraction of the cost of inhouse cloning. Clones produced through cell culturing will also have the benefit of being totally sterile and free from disease.

Cannadabis has been offered an NRC-IRAP grant for initial developments of the process and are in early negotiations with a Canadian cannabis company to commercialise. The founders are expecting to file patents, mid 2020, and begin construction of a commercial scale process by mid-2021. Cannadabis anticipates that a 5000 sq ft facility will produce 5+ million clones annually, with minimal labour.

The project is looking to possibly incorporate the production of artificial seeds, which would simplify transportation and ease of storage for cultivators. They will also be developing cryogenic preservation methods. Cultivators around the world are encouraged to reach out to Cannadabis if they are looking to simplify their process, access cell culture benefits, and maximise growing space.

Working with Cannadabis cultured clones will be the most affordable, safe, and efficient way of acquiring starting material. Their services would include meristem culturing to remove systemic disease, and long-term storage of genetic inventory. Partners who end up with a pest could rest easy knowing their mother cultures will be perfectly preserved in tissue culture, and fifty thousand clones for the next crop are still on the way.

Cannadabis Medical and Delta 9 Cannabis have teamed up to provide an affordable, turnkey, tissue culture laboratory, complete with operating procedures, equipment, and cannabis medium recipes.

The two companies have co developed this system for their own commercial use and have recently made the system available for other cultivators. Both companies have recognised that the cannabis industry is still reliant on black market methods of propagation, and as a result, there have been countless incidents of crop and genetic loss in the legal industry; many of the stories circulating are understandably refuted by the companies experiencing such loss.

Rather than ignore the inevitable pest problems, the two companies are going toe to toe with mother nature, developing half century old technology and making it specifically for cannabis. Hopefully delivering the same modicum of control to the rest of the industry; cultivators slow to develop tissue culture science may soon find their genetics and crop totally destroyed by a single, often microscopic pest. On a commercial scale, these pests become essentially impossible to remove without the use of tissue culture.

With feet rooted in genuine care, Cannadabis and Delta 9 are prepared and excited to deliver a tissue culturing system to the global cannabis industry. They recognise the value and utility available to growers, and they also recognise that learning tissue culturing can feel out of reach for cultivators with no prior knowledge, or excess funding to hire an inhouse specialist.

Instead of missing out or paying specialists, cultivators can rely on Cannadabis and Delta 9 to deliver a ready to use laboratory, the development of which was based on maximising value for the growers.

The laboratory comes with only bare essentials and extensive, yet simple, operating procedures. Training materials will detail cannabis specific mediums, sanitation protocols, along with troubleshooting methods for finicky cultivars; an inexperienced grower will be comfortably blending and using mediums on the same day of commissioning. The whole system, equipment and all, will be much more affordable than hiring a tissue culture specialist.

Over the next three years, Cannadabis will be working to establish an expanded cultivation with the hope of supplying medical, organic, indoor grown cannabis to domestic and international markets.

They will also pioneer an original cell culture process that expects to be the most affordable source for starting materials in the world; Cannadabis is especially excited to deliver their polyploid cultivars as starting materials to industry members.

Cannadabis would like to offer an open invitation to all scientists, entrepreneurs, and industry professionals for collaboration. We are actively seeking partners who share a similar vision for the cannabis industry. Any professionals who are driven by a sense of genuine care and have a passion for cannabis medicine are encouraged to reach out.

References

1 hempindustrydaily.com/hemp-cultivators-tissue-culture-increase-propagation-preserve-genetics/2 Meyers, L. A., and Levin, D. A. (2006). On the abundance of polyploids in flowering plants. Evolution 60, 11981206. doi: 10.1111/j.0014 3820.2006.tb01198.x3 http://www.slideshare.net/ranganihennayaka/plant-polyploids4 http://www.frontiersin.org/articles/10.3389/fpls.2019.00476/full5 plantbreeding.coe.uga.edu/index.php?title=5._Polyploidy

Alexander CalkinsCEOCANNADABIS Medical INC+1 306 552 4242alexander@cannadabismedical.caTweet @cannadabiscannadabismedical.ca

This article will appear in the first issue ofMedical Cannabis Networkwhich will be out in January.Clickhereto subscribe.

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Cannadabis: tissue culture and the future of cannabis cultivation - Health Europa

Female cyclists are at a lower risk of suffering Sudden Cardiac Death than male athletes, but women should still learn about ways to screen for heart problems before engaging in endurance sports.

Dr. Mehreen Quhreshi is a cardiologist with advanced training in stress testing and cardiac imaging from Columbia University Medical Center in New York. She practices in Harrisburg, Pennsylvania and serves as the director of the Preventative Cardiology Program and the Nuclear Stress Lab at UPMC Pinnacle Heart and Vascular Institute. Dr. Bill Apollo, an amateur bike racer, runner, and duathlete is a Harrisburg, Pennsylvania-based cardiologist, who directs the UPMC Pinnacle Sports and Exercise Cardiology Clinic.

At the Paris Olympics in 1900, endurance sports were exclusively dominated by men; a mere 22 women participated, competing in the five gentrified events of croquet, equestrian, golf, tennis, and sailing. It took until the latter half of the twentieth century for the world to witness women competing in major Olympic endurance sports such as cycling (Los Angeles, 1984) and triathlon (Sydney, 2000).

Wider womens participation in the Olympics roughly coincided with the establishment of Title IX of the United States Educational Amendments of 1972, which mandated equal access for women in any program that received Federal funding including sports in public schools and universities. These two major developments fueled an explosion of female participation in a variety of events at all skill levels. The percentage of women finishers in marathons in the U.S. rose from only 10% in 1980 to a robust 45% by 2015. Women set a new record for Olympic participation at the 2016 Rio Olympics, with nearly equal numbers (5,176 athletes, or 45% of total), and with representation in all events included in the games.

Paradoxically, women have generally been under-represented in medical research studies looking at cardiac health, adaptation to endurance training and its potential consequences. Despite this surge of female athletic participation, we still havent achieved gender equality when it comes to understanding and caring for the female athletes heart. And recent small-scale studies suggest that there are in fact important cardiac differences between the sexes.

Some of the key questions are: to what extent do underlying genetic and hormonal factors impact normal changes in a womans heart related to exercise? How do these influences alter her risk for developing chronic heart problems or sudden cardiac death during competition? Are women better equipped to handle endurance training by design? Some recent research suggests that pregnancy subjects the female body to cardiac stresses similar to those that male athletes experience in even the most competitive events, including events like the Tour de France.

Below we examine the current understanding of cardiac development and risks in women endurance athletes, how and why women may differ from men in this regard, and recommended precautions that should be taken in training and competition by elite female endurance athletes.

Sudden cardiac death (SCD) during athletic competition is fortunately a rare occurrence, and it tends to affect men more commonly than women. In fact, a womans risk of SCD during endurance sports is estimated to be some 10 times lower than for her male colleagues. Professional cycling, during the past 3 seasons, has seen a total of 6 elite men tragically die directly from heart problems during races (5 in road racing, 1 on the track), with the most recent being Robbert de Greef in March 2019. During the same time period, there were zero incidents involving women, and indeed there are no known reports of SCD during elite womens cycling events for the past 20 years. Professional female cyclists are far more likely to die from training accidents (usually involving automobile collisions) than from heart problems.

Interestingly, these observations regarding SCD in cycling seem not to be true for other endurance sports. Marathon running has a huge participant base much larger than the womens pro peloton with nearly a half million participants in 2019 alone. This huge statistical sampling clarifies the measure of SCD risk: 1 incident per 150,000 participants overall, but more commonly occurring in men (1/ 100,000), and much less likely to occur in women (1/243,000).

Despite this fairly low risk of SCD in women, the sheer volume of running participants makes it easier to find reports of SCD. For example, Taylor Ceepo, age 22, died in May 2019 less than 1 mile from the finish line at the Rite-Aid Cleveland Marathon. The medical examiners report indicated that Ceepo experienced sudden cardiac death in association with physical exertion, pseudoephedrine use (a fairly benign over-the-counter decongestant) and cardiomyopathy. Her tragedy should remind us that even in very young and apparently healthy women, undiagnosed heart disease is still a common killer (3rd behind unintentional injuries and cancer in her age group), and her autopsy findings highlight the importance of screening women for underlying heart problems.

The most common causes of SCD are generally driven by age rather than sex. Athletes under age 35 both men and women alike are susceptible to genetically inherited structural heart problems including hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), as well as potentially lethal heart rhythm problems called channelopathies. Above age 35, coronary artery disease predominates, with women being preferentially protected by their higher estrogen levels, until they reach menopause. Initially, the ten-fold higher incidence of SCD in men was thought to be simply due to the much larger numbers of men participating in endurance sports. But now that participation rates are becoming nearly equal, womens risk of SCD is still not as high as that experienced in the male population.

Several theories exist that might explain why women appear to be more protected from SCD during intense competition. One explanation may lie in the sympathetic nervous system, which is responsible for the bodys fight or flight response. Male physiology is observed to be wound more tightly, meaning that their arteries and blood vessels tend to constrict more during intense activity than women. The increased blood pressure adds resistance to blood the heart is pumping out. When this increased pressure load is coupled with an outpouring of adrenaline during competition, the strains placed on the heart may trigger lethal rhythm problems in susceptible individuals generally those with underlying inherited cardiac problems or acquired fibrosis (scarring) from long-term training. For unclear reasons, even in the context of equal training volumes, men more commonly develop potentially lethal fibrosis substrate, placing them at higher risk of SCD than women.

Another possible explanation relates to obvious hormonal differences between men and women. In some animal models, testosterone has been shown to affect the way the heart conducts impulses making men, at least in theory more susceptible than women to developing electrical instability resulting in malignant heart arrhythmias. Clinically, testosterone promotes thickening of the heart muscle, which may explain why men are more susceptible than women in developing complications from diseases like HCM and ARVC. Estrogens, on the other hand, are protective in this regard, and delay that same process of heart muscle thickening. Despite equal patterns of genetic transmission of HCM and ARVC between both sexes, hormonal differences may explain why these maladies tend to remain latent for a longer period of time in women, presumably translating to a survival advantage and lower risk of SCD.

Sports medicine screening programs are designed to identify potential cardiac risks in individuals who exhibit no outward symptoms of heart problems. Such programs aim to increase participation but to do so with a reasonable level of caution, to ensure the safety of the athlete. Despite the lower risk of SCD in women, screening is still important.

Pre-participation screening typically involves a comprehensive medical history review, focused physical examination, and in some cases an electrocardiogram (EKG). EKG tests are proven to be more sensitive than history and physical examination alone in detecting pathology, especially regarding heart rhythm issues. EKG interpretation should always be completed by a skilled reader able to distinguish the fine line between normal adaptation to exercise and pathology. Guidelines like the International Recommendations for EKG Interpretation in Athletes will increase reading accuracy and reduce the number of false findings, which often lead to expensive and unnecessary longitudinal testing. Men exhibit changes in their EKG patterns more often than women, and these variations in many instances are considered normal purely as the result of physiologic adaptation to training. On the other hand, women are less likely to stray from normal parameters, so most EKG changes are concerning and more likely represent a real problem.

Consistent endurance training induces physiologic remodeling, or normal adaptations to the heart resulting in improved efficiency of an athletes engine. Cyclists are unique because they typically perform the most prolonged exercise pattern more hours per day and more days per year than nearly any other athletes. Cyclists often sustain markedly elevated heart rates for extended periods of time during two distinct types of high cardiac output workouts. First, high intensity aerobic workouts at near peak efficiency, coupled with sustained elevations in heart rate, create a dynamic stress, or a volume load on the heart. And second, long tempo efforts punctuated by intense anaerobic dashes create static stress, exposing the heart to a pressure load because of sustained increases in blood pressure.

Cyclists therefore typically exhibit prominent changes in heart structure due to a combination of dynamic stress (volume overload) and static stress (pressure overload) resulting in generally increased cardiac mass, with mildly enlarged hearts and mildly increased heart wall thickness at least in men. Statistically, women are generally smaller than men with lower lean body mass. Due to their higher estrogen levels, women tend to adapt to exercise in a qualitatively similar manner, but quantitatively different than men showing only minimal heart enlargement and virtually no heart wall thickening. In fact, only about 7% of healthy women show any significant increase in their heart size due to habitual exercise, whereas 47% of men show cardiac enlargement.

Symptoms of heart problems in women are often different to those reported by men. For example, women are less likely to experience classic chest pain due to a heart problem, but may report more subtle symptoms like indigestion, heartburn, fatigue, or poor exercise performance. Misinterpretation of these sometimes confusing symptoms often leads to a delay in diagnosis and poorer long-term outcomes for women. An unexplained decline in athletic performance is obviously concerning to any elite athlete whether male or female because this may be the only clue to a serious underlying heart problem.

However, in young women, such nonspecific symptoms are often incorrectly blamed on things like menstrual problems, eating disorders, iron deficiency anemia, pregnancy, or thyroid disease. In many cases it is the womans primary care provider who must be savvy enough to exclude these other diagnoses, realizing there is a potential heart problem and then making an appropriate referral to a cardiologist.

Estrogen generally protects women from developing CAD at young ages, but the risk rises as they reach menopause. And paradoxically, some young women may actually be at increased risk for CAD because of a syndrome called Relative Energy Deficiency in Sports (RED-S). Sports which favor lean body mass are often associated with heavy training loads and dieting to achieve optimal body weight. In some women this results in the Female Athlete Triad of menstrual dysfunction, unexplained decline in performance (with or without an eating disorder), and decreased bone density, leading to increased probability of fractures.

Prolonged endurance training in young women can lead to menstrual irregularities resulting in the same kind of reduced estrogen levels typically seen in older postmenopausal women. These athletes should be evaluated for the more traditional cardiac risk factors such as high blood pressure, cholesterol problems, and diabetes, with appropriate intervention to modify their risk. Treatment of the Female Athlete Triad is challenging and may require a multidisciplinary approach to improve an athletes overall energy balance. Strategies include decreasing training volume, modifying dietary habits, medically replacing estrogen levels, promoting bone health with dietary supplements, and seeking appropriate professional help to correct eating disorders if present. Due to the focused and highly competitive nature of many endurance athletes, this is often a tall order to fill since they may resist decreasing their training volume.

Regular exercise is the cornerstone of prevention and treatment of many cardiac and non-cardiac diseases. But some researchers suggest that the benefits of exercise are like a drug the benefits of moderate training reach a plateau and exceeding that plateau, or overdosing, may be detrimental to the athletes health. Several studies have reported unexpected abnormalities in endurance athletes primarily in men suggesting either transient or permanent heart damage which puts them at risk for chronic heart issues. Findings have included a five-fold increased risk of atrial fibrillation (AFIB), increased coronary artery calcium deposits (which indicate clinically silent CAD), and scarring of the heart muscle. However, there are several general guidelines that all athletes should be aware of:

The biological adaptation to handle the stress of pregnancy may be a key reason for the apparently better female adaptation to endurance training. Recent research has highlighted that during pregnancy, the body functions at a basal metabolic rate of 2.2 times the normal burning up to 4000 calories a day. Extended over a period of 40 weeks, pregnancy can essentially be considered the ultimate endurance event a true test on the limits of human performance. Under typical circumstances, a body functioning above 2.5 times the normal metabolic rate over a prolonged period will begin to break down. But most women emerge from pregnancy and go on to live healthy lives, having tolerated a level of metabolic strain considered by some to be similar to that experienced by athletes participating in some of the most competitive endurance events.

There are also massive changes in the amount of fluid in a womans body during pregnancy, creating cardiac stresses similar to endurance training. In order to support the developing fetus, she must increase her blood volume by a massive 50%, and her cardiac output by 40-50% constituting the ultimate dynamic stress on the heart. The female body appears to require less adaptation by the heart muscle and chambers to accommodate these changes.

More overlap in research examining the similarities between the effects of endurance training in women and the cardiac demands placed on them during pregnancy may help to explain these gender-based differences in adaptation to exercise and related cardiac risk. Additional research specifically devoted to women is critical to a better understanding of how gender influences normal cardiac adaptation to exercise, as well as to more accurately identify pathologic conditions which sometimes seem to overlap with normal physiology.

Despite the substantially lower risk of SCD in women, cardiac risk screening of female endurance athletes and at-risk pregnant women is still important, and should be carried out by clinicians familiar with the differences in adaptive physiology between men and women. Women often experience challenging and atypical cardiac symptoms, requiring a high index of suspicion on the part of their doctors often at the primary care level to identify these underlying problems. As the current generation of elite female athletes matures into tomorrows Masters champions, we will undoubtedly learn a great deal more about the long-term cardiac implications of endurance training in women.

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The Outer Line: The impact of endurance training on the cardiac health of women - VeloNews

The results of rodent studies by a Stanford University School of Medicine-led research team have shown that the abuse potential of the illicit street drug, ecstasy()3,4-methylenedioxymethamphetamine (MDMA)involves a different neuronal signaling pathway to that which mediates the potentially therapeutic, prosocial effects of the drug. If the findings can be confirmed in humans, they could lead to the development of novel treatments for psychiatric disorders that are associated with social awkwardness and withdrawal.

Weve figured out how MDMA promotes social interaction and showed thats distinct from how it generates abuse potential among its users, said research lead Robert Malenka, MD, PhD, the Nancy Friend Pritzker professor in psychiatry and behavioral sciences. Malenka and colleagues reported their findings in Science Translational Medicine, in a paper titled, Distinct neural mechanisms for the prosocial and rewarding properties of MDMA.

MDMA is a mind-altering drug that is used by an estimated three million people in the United States every year. It gives users a sense of wellbeing, making them extremely sociable, and can even generate feelings of unguarded empathy for strangers, which makes MDMA a natural fit for raves and dance parties.

These features of MDMA use may also have applications in psychiatry, and the drug is in late-stage, multicenter clinical trials as an adjunct to psychotherapy for post-traumatic stress disorder (PTSD). The goal is to harness MDMAs prosocial effects to strengthen the bond between patient and therapist. Its hoped that people who have experienced trauma may be able to feel comfortable reliving it through guided therapy.

About 25 million people in the United States who suffer from PTSD could benefit from a drug that helps to establish, with a single dose in a therapists office, a trust level that would otherwise typically take months or years to achieve, said Boris Heifets, MD, PhD, assistant professor of anesthesiology, perioperative and pain medicine, who is the newly reported studys lead author.

The flip side is that MDMA can be addictive. Taken in the wrong settings or in repeated or oversized doses, it can have life-threatening consequences. MDMAs abuse potential stems from its capacity to stimulate the brains reward circuitry, Malenka said. The brains reward circuitry tells us something is good for our survival and propagation. It evolved to tell us food is good when were hungry, water is good when were thirsty, and warmth is good when were cold. For most of us, hanging out with friends is fun, because over the course of our evolution its promoted our survival.

This reward circuitry involves neural connections projecting from one midbrain structure, the ventral tegmental area, to another, the nucleus accumbens (NAc), which is a conserved brain region that regulates appetitive behavior, the authors noted. When those neurons release a chemical called dopamine, the nucleus accumbens forwards signals throughout the brain that induce a sense of reward. Malenka further commented, Drugs of abuse trick our brains by causing an unnatural dopamine surge in the nucleus accumbens. This massive increase is much higher and more rapid than the one you get from eating ice cream or having sex.

MDMA also releases serotonin, but the role of this neurotransmitter is less clear. MDMA is a substituted amphetamine with high affinity for the serotonin [5-hydroxytryptamine (5-HT)] and dopamine (DA) transporters (SERT and DAT, respectively), through which it stimulates release of these neurotransmitters, the team explained. MDMAs acute reinforcing effects, which strongly predict addictive liability, have been linked to its DA-releasing properties, whereas the role of SERT in this action is uncertain.

There have been some pointers, however. Serotonin-releasing neurons in the dorsal raphe nucleus of the brain send projections to the same part of the nucleus accumbens that is connected by the dopamine-releasing neurons. And neuroscientists had previously shown that MDMA triggers the release of far more serotonin than dopamine. We, therefore, hypothesized that MDMAs interaction with SERT specifically in the NAc could fully account for MDMAs prosocial effect but not its rewarding effect, the authors commented. To investigate this they carried out a suite of behavioral, and complementary genetic and brain region-specific pharmacological manipulations in mice, together with in vivo calcium imaging, to demonstrate that MDMA acts at SERT-containing 5-HT terminals in the NAc.

The researchers tested whether an explorer mouse given a relatively low dose of MDMA or, control mice given saline, preferred to spend time in a chamber holding another mouse under an upside-down mesh cup (to keep that mouse from moving about) or in an otherwise identical chamber with a cup but no mouse. They found, consistently, that the saline-treated explorer mice get bored after 10 minutes with another mouse. But an explorer mouse given MDMA sustained its social curiosity for at least 30 minutes.

You cant ask mice how theyre feeling about other mice, Malenka said. But you can infer it from their behavior. Its also likely that the same effects would be seen in humans because the midbrain areas have been remarkably conserved among mammalian species over evolutionary time, Malenka said.

The test results also clearly implicated serotonin as the signaling substance responsible for promoting social behavior in both male, and in female mice. Heifets added, Giving MDMA to both mice enhanced the effect even further. It makes you wonder if maybe the therapist should also be taking MDMA.

Like humans, mice will return to places where theyve had a good time. This can also be linked to the brains reward circuitry. To determine MDMAs addictive potential, the researchers gave mice an MDMA dose equal to the one in the first, social experiment, but only when the mice were in a particular room of a two-room structure. The next day, the mice showed no preference for either room. This provided evidence that at the dose used, MDMA hadnt noticeably triggered the reward circuitry.

However, mice given a higher MDMA dose exhibited both its social and abuse-potential effects. Further tests determined that the secretion of dopamine triggered by MDMA is not necessary for promoting sociability. Serotonin release, triggered by the low MDMA dose, was all it took. And in a subsequent set of experiments, the scientists were able to induce sociability in mice by infusing the drug only into the animals nucleus accumbens, providing further evidence that this is where the serotonin, released as a result of MDMA administration, exerts its sociability-inducing effect.

Where, exactly, in the brain thats happening hadnt been proven, Heifets said. If you dont know where somethings happening, youre going to have a hell of a time figuring out how its happening.

The researchers made this discovery when they showed that blocking a specific subtype of serotonin receptor in the nucleus accumbens fully inhibited MDMAs prosocial effect. And giving the mice a different serotonin-releasing drug, fenfluramine, (FEN), which does not cause dopamine release, was enough to mimic the prosocial effects of MDMA, without causing any addictive, or rewarding, effects. Consistent with the enhancement of sociability by FEN in our experiments, early clinical data suggest that higher doses of FEN have subjective effects reminiscent of MDMA, team pointed out. FEN has been reported to improve social deficits in children with autism.

Fenfluramine, is also the fen part of the once-popular diet pill called fen/phen, a two-drug combination developed in the 1960s. Fen/phen was pulled off the market in the 1990s after 30% of patients taking it were found to be showing signs of heart disease, including pulmonary hypertension. And as the authors pointed out, like MDMA, long-term and/or heavy use of FEN is associated with cardiovascular and neurological toxicity Furthermore, tolerance to MDMAs acute effects may develop with frequent use. They suggested that it would seem prudent to use these drugs sparingly and infrequently, consistent with recent clinical trial designs for MDMA.

Although the long-term cardiovascular and neurotoxic effects of MDMA and FEN mean that neither drug would be suitable for any indications requiring daily use, Heifets pointed out that the damaging effects of chronic use would be highly unlikely to occur in the one or two sessions that would be required for patient-therapist bonding in a psychiatric setting. Even so, the authors concluded, Given MDMAs long history of abuse and potential toxicity, it would be prudent to develop drugs or other therapies that mimic its prosocial effects with reduced associated morbidities. We propose that future therapeutic strategies, including drug design and brain stimulation approaches, may be more successfully developed by targeting relevant brain circuits rather than by modifying existing drugs based on putative structure/activity relationships.

Link:
Rave Drug Ecstasy's Therapeutic, Addictive Qualities Teased Apart - Genetic Engineering & Biotechnology News

Gene editing using the CRISPR system has been established as the most powerful tool in the search for new drugs and is now being exploited for therapeutic purposes. Here, Pushpanathan Muthuirulan discusses the promises and wider opportunities of using CRISPR technology to open up the possibility of large-scale screening of drug targets. He also highlights the importance of implementing CRISPR technology into clinical practice for development of next-generation therapeutics and patient-tailored medicine.

THE DRUG discovery process, in which new drug candidates are discovered and evaluated for therapeutic use, has resulted in both promising and life-saving therapies for numerous diseases including inherited genetic disorders and pathogenic infections.1 However, the discovery and testing of a new drug candidate typically takes more than a decade and the total cost associated with drug discovery processes can exceed $1 billion.2 In the United States, the drug discovery process takes an average of 12 years and in excess of $1 billion to develop a new drug.3 Furthermore, only a few drug candidates actually make it to market; the chance of a new drug actually reaching market is only one in 5,000. The high cost and lengthy effort of getting new drugs to market make the drug development process a risky endeavour for pharmaceutical companies, which consequently hinders discovery and development of new therapies. The recent emergence of genome editing technologies and advances in our understanding of human genome sequences have raised hope that direct manipulation of the genome could potentially revolutionise the process of drug discovery and therapeutics.4 In particular, new technologies like CRISPR-Cas9 are key to unlocking potential drug targets and could have a profound impact on modern drug discovery and development.1,5

Originally posted here:
CRISPR: kick-starting the revolution in drug discovery - Drug Target Review

An artist's illustration of a DNA double helix. New technology makes it easy to edit the human genome, even the germline which can affect all of human evolution. (Image:. U.S. National Human Genome Research Institute/Reuters

By making genetic research so much easier, the recent technology known as CRISPR has allowed scientists an enormous advantage in research into so many areas.

Unfortunately theres a downside which raises serious ethical questions.

Franoise Baylis (CM, ONS, PhD, FRSC, FCAHS), is a research professor at Dalhousie University Halifax who has written on the subject.

The concern with gene-editing is with experiments into modification of human DNA, which could lead in theory to changing of the human genome forever. It could in theory enable creating designer babies. Indeed its been just over a year since the first genome edited babies were created by a Chinese scientist. A Russian researcher has since announced plans to carry out similar human gene editing experiments. Other Chinese experiments involve putting human genes into monkeys. All of these, and other potential experiments, have raised the concern of the scientific world that some of its members are going beyond ethical concerns of science.

Research professor Francoise Baylis at Dalhousie University, Halifax

While some experts have expressed concern about state manipulation to create specific charachteristics, Professor Bayliss suggests that designer babies could result in greater class divide. This would be due to the expense making such technology accessible to the upper echelons and entrenching elite advantage, and thus privilege, in their DNA.

However she says these experiments have resulted in governments and the scientific community coming out with regulations and recommendations to slow down or halt such research until such time as serious ethical discussions take place to establish limits on what should be done and how.

F Baylis on the ethical questions involving CRISPR technology and gene editing of the human genome , Harvard University Press

She says the human genome belongs to all of us and any single or small group of scientists shouldnt be altering it on their own.

As a direct consequence of increasingly audacious moves by some scientists to engineer future generations, important decisions must now be made decisions that will set a new course for science, society, and humanity. May these decisions be inclusive and consensual. May they be characterized by wisdom and benevolence. And, may we never lose sight of our responsibilities to us all. F Bayliss: Altered Inheritance: CRISPR and the Ethics of Human Genome Editing F Bayliss: Altered Inheritance: CRISPR and the Ethics of Human Genome Editing

Fortunately some action has been taken. The WHO has convened a multi-disciplinary Expert Advisory Committee on Human Genome Editing to examine the scientific, ethical, social and legal challenges associated with human genome editing (both somatic and germ cell). Professor Bayliss is a member of the group which met for the first time this spring.

She lauds those countries that have established regulations regarding such research but notes there is always the chance of rogue scientists.

She also notes that scientists are usually very concerned about recognition by their peers and being shunned for having crossed established ethical lines is something they would very likely avoid

Additional information

The Conversation: F Bayliss: Dec 10/19: A year after the first CRISPR babies, stricter regulations are now in place

Excerpt from:
CRISPR: Ethics and the gene editing of humans - Radio Canada International (en)

We can already edit genes in human embryos. We can even do it in a way to pass the edits down generations, fundamentally changing a familys genetic makeup.

Doing it well, however, is far more difficult.

Its impossible to talk about human germline genome editing without bringing up the CRISPR baby fiasco. Over a year ago, a rogue Chinese scientist performed an edit on fertilized human embryos that, in theory, makes them resistant to HIV infection. Two twin girls were born, and both had multiple unplanned edits in their genome with unknown health consequencesconsequences that may be passed on to their offspring.

The brash attempt at making scientific history clearly shows that, ethics and morality issues aside, when it comes to germline editingthat is, performing gene edits in egg, sperm, or the embryowere simply technologically not there. Make no mistake: CRISPR may one day wipe out devastating genetic diseases throughout entire family lines, or even the human race. But to harness its power responsibly, there are plenty of technical challenges we need to master first.

This week, Rebecca Lea and Dr. Kathy Niakan at the Human Embryo and Stem Cell Laboratory at the Francis Crick Institute in London, UK, laid out those challenges in a sweeping articlein Nature. CRISPR as a gene editor is getting more specific and efficient by the day, they explained. However, for it to gradually move into germline editing, we also need to understand how the tool tangos with cells during early human development.

The data, they argue, will not only let us zoom into the creation of human life. It will also help inform the debate about potential safe and effective clinical uses of this technology, and truly unlock the doors to the human genome for good.

Correcting dangerous genetic mutations is one reason to pursue germline editing, but CRISPRing human embryos can also unveil insights into the very first stages of human embryo development. Research shows that trying to understand how human embryos form by studying mice might not be the best route, especially when it comes to using those results to tackle infertility and other medical problems. With CRISPR, we have insight into these early stages that were previously completely unattainable. We might only solve infertility issues, but perhaps also allow same-sex couples to have genetic children in the future.

Another argument is that couples already screen for life-threatening mutations during IVF, and using CRISPR on top of that is unnecessary. Not true, the authors argued. When both parents carry a similar mutation that robs them of the ability to have a healthy child, CRISPRnot selection during IVFis the answer. Ultimately, providing more options for patients empowers them to make the choice that is best for their family and circumstances, they said.

This is where it gets complicated.

The big one: were still trying to tease out how CRISPR works in cells that form the embryo, in hopes that we can cut down on potential mistakes.

Let me explain: all cells in the body have a cell cycle, somewhat analogous to a persons life cycle. Many checkpoint life events happen along the way. The cell could decide to divide and have kids, so to speak, or temporarily halt its cycle and stop its own aging. During a cycle, the cells DNA dramatically changes in number and packaging in preparation for its next stage in life.

The problem? The way CRISPR works heavily depends on the cell cycle. Although dubbed an editor, CRISPR actually vandalizes the genome, creating breaks in the DNA strands. What we call gene editing is the cells DNA repair system kicking into high gear, trying to patch up the mess CRISPR left behind. Adult cells that cant be repaired stop their own life cycle at a checkpoint for the greater good. In embryos, however, cells arent nearly as altruistic. Their checkpoints arent fully developed, so they might continue to develop even with severe mutations. Zooming back to the full picture, it means that the resulting early-stage embryo may keep accumulating damage, until it fails in the mothers womb.

To get around this, scientists have tried other ways to push an embryo into accepting a healthy DNA template after a CRISPR snip, which in theory would cut down on unwanted mutations. One idea is injecting the CRISPR machinery at a specific time into fertilized eggs, so it catches the early-stage embryo at just the right time to reduce DNA breaks in both strands. While theoretically possible, the process is kind of like a person trying to jump from a high-speed train into a specific cabin on a rapidly rotating Ferris wheel while blindfolded.

But science is making progress. Although we dont have a detailed movie of cell cycles in human embryos yet, multiple labs are beginning to piece one together, with hopes itll eventually help take off the blindfold when injecting CRISPR. Others are looking into adding CRISPR to sperm before fertilization as an alternative.

At the same time, scientists are also trying to characterize the entire scope of mutations caused by CRISPR. Its not just adding, swapping, or deleting specific letters in genes. Rather, the range of mutations is more complex, including large swaths of genetic rearrangements, unintended cuts relatively far from targeted spots, and other dramatic DNA lesions following CRISPR action. Its perhaps not surprising that the edits in CRISPR babies didnt work as intended.

Base editors, which swap one genetic letter for another, might be a better approach compared to the classic hack-and-paste, the authors said. So far, however, the tools havent yet been validated in embryosnot even those from mice.

Finally, for the edit to make a difference to the child, the embryo has to develop normally inside a womb into a baby. But success rates for assisted reproductive technologies are already fairly low. Add in a dose of genetic editing tool that cuts into an already-sensitive genomic landscape, and it becomes incredibly hard to maintain the health of the edited embryo.

Putting it all together, there is simply not enough data at present to understand the capability of early[embryos] to repair DNA, the authors said.

Far from it. Although theres much we dont yet understand, we do have an impressive range of tools to predict and evaluate mutations in human embryos. Exactly how to determine whether a gene-edited embryo is healthy remains up for debatefor example, is five unexpected mutations considered ok? What about 500 or 5,000?

That said, just having tools to diagnose the genetic health of an embryo from a tiny bit of DNA is already extremely useful, especially if we as a society decide to move into germline editing as a treatment.

With machine learning making an ever-larger splash in computational biology, these predictive tools will only become more accurate. Add to that ever-more-effective CRISPR variations, and were on the right trackas long as any potential applications of embryo editing only come after in-depth public and policy discussions and fit a number of strict ethical and safety criteria, the authors said.

In response to the CRISPR baby scandal, multiple governments and the World Health Organization have all drafted new guidelines or legislation to tap on the brakes. The technology isnt mature enough for clinical use, the authors said, and much more work is needednot just to further improve CRISPR tools, but especially for understanding how it works in human embryos.

Ultimately, were talking about potentially engineering the future of the human race. Tiptoeing, rather than stumbling ahead, is the least we can do. One must ensure that the outcome will be the birth of healthy, disease-free children, without any potential long-term complications, the authors concluded.

Image Credit: Image by marian anbu juwan from Pixabay

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How Far Are We from (Accurately and Safely) Editing Human Embryos? - Singularity Hub

Increase in applications of CRISPR and Cas gene editing technology in bacteria and usage of gene editing technology for prevention of various diseases are the major factors anticipated to drive the market from 2018 to 2026. Rise in need of alternative medicine for chronic diseases and increase in investments by key players in Asia Pacific are projected to propel the market during the forecast period.

The report also provides profiles of leading players operating in the global CRISPR and Cas market such as Synthego, Thermo Fisher Scientific, Inc., GenScript, Addgene, Merck KGaA (Sigma-Aldrich), Integrated DNA Technologies, Inc., Transposagen Biopharmaceuticals, Inc., OriGene Technologies, Inc., New England Biolabs, Dharmacon, Cellecta, Inc., Agilent Technologies, and Applied StemCell, Inc.

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Increase in Usage of DNA-free Cas

DNA-free Cas9 is most commonly used with synthetic crRNA tracrRNA and chosen by researchers who strive to avoid unwanted vector DNA integration into their genomic DNA. CRISPR-Cas9 utilizing mRNA or protein is ideal for applications such as knocking of a fluorescent reporter using HDR or knockout cell line generation. Advantages such as gene editing with DNA-free CRISPR-Cas9 components to reduce potential off-targets and potential usage of CRISPR-Cas9 gene editing to find correlations with human diseases in model systems drive the segment.

Rise in Incidence of Genetic Disorders and Increase in Applications of CRISPR and Cas Genes to Propel Market

Genetic diseases are generally termed as rare diseases. According to NCBI, prevalence of these rare diseases is approximately 5 in 10,000. There are 6,000 to 8,000 rare diseases, with 250 to 280 new diseases diagnosed every year. Hence, 6% to 8% of the global population is projected to be affected by rare diseases i.e., genetic diseases in the near future. Researchers are developing treatments for these diseases with applications of new technologies such as CRISPR. The applications of CRISPR technology are expanding in other industrial sectors. This is expected to drive the market during the forecast period.

Usage of CRISPR/Cas9 technology in plant research has enabled the investigation of plant biology in detail which has helped to create innovative applications in crop breeding. Site-directed mutagenesis and site-specific integration of a gene, which is also called knock-in, are important in precision crop breeding. Cas9/gRNA-mediated site-directed mutagenesis and knock-in is widely used in rice and Arabidopsis protoplasts. CRISPR/Cas9 provides a simple method to generate a DSB at a target site to trigger HDR repair.

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Asia Pacific Market to Witness Exponential Growth

In terms of revenue, the CRISPR and Cas genes market in Asia Pacific is expected to expand at a CAGR of 22.0% during the forecast period. Growth of the market in the region can be attributed to increase in incidence of chronic diseases such as cancer and the need of development of genetic engineered treatment options. According to the report, Call for Action: Expanding Cancer Care for Women in India, 2017, an estimated 0.7 million women in India are suffering from cancer. China dominated the CRISPR and Cas genes market in Asia Pacific. In 2016, scientists based in China launched the first known human trials of CRISPR, the genomic tech that involves slicing and dicing the bodys very source code to fight cancer. Japan was the second largest market for CRISPR and Cas genes in Asia Pacific.

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CRISPR and Cas Genes Market will Likely Rise to US$ 7,234.5 Mn by the End of 2026 - Montana Ledger

In the wake of the Conservative Partys crushing victory in the election in the United Kingdom, Prime Minister Boris Johnson is poised to navigate Britains exit from the European Union. Once out of the EU, the UK could regain full control over its laws and regulations. And that might open the door to a reversal on what scientists consider its backward-looking policies on GMOs and CRISPR gene editing in agriculture.

Though the election debate has centered around immigration, security and healthcare, the question of what direction the UK should take in terms of science policy persists. Will the UK manage to unleash the potential of its biotechnological sector and become a global advocate for innovation and consumer choice, or will it retain the EUs antiquated approach?

In a manifesto released in November, the Conservatives pledged to take the path of science-led, evidence-based policy to improve the quality of food, agriculture and land management. Previously, Johnson hadpromised to liberate the UKs biotech sector from the EUs anti-genetic modification rules.

The laws that concern genetically modified organisms in the UK are primarily based on European Union regulations. For years, the EU has backpedaled on agricultural innovation, preventing European consumers from accessing biologically enhanced food. This can be seen in the very limited number of genetically modified crops authorized for cultivation in the EU, and a very cumbersome and expensive process of importing genetically modified crops from other countries. In July 2018, the European Court of Justice (ECJ) decided that gene-edited plants should be regulated the same way that genetically modified organisms are regulated, rendering them practically illegal and hindering innovation even further.

If the UK chooses to move away from these EU-based regulations as a consequence of Brexit, it could become a forward-looking global biotech powerhouse.

The first step would be to replace fear-based skepticism of genetic modification with an evidence-based, pro-innovation approach. Despite popular rhetoric, there is no substantial scientific evidence behind the alleged health and environmental risks ascribed to GM products. Abandoning these baseless assertions and creating and sustaining the conditions under which UK farmers could innovate, lower their production costs, and use fewer chemicals would be an enterprising move on the part of the UK government.

Approving GM pest-resistant crops, for instance, could save about 60 million ($79 million) a year in pesticide use in the UK. Moreover, 60 million in savings would mean more leeway for competitive food pricing in a country where prices at the grocery store are rising 2 percent annually.

Once restrictive genetic modification laws are relaxed, it would be necessary to enable easy market access for GM foods. Under current EU legislation, products containing GMOs need to be labeled as such, and the requirements also apply to non-prepacked foods. It is legally established that such products (soy, for example) not only require written documentation but also should have an easily readable notice about their origin. No such rule exists with regards to foods that are 100% GMO-free, meaning there is explicit discrimination in place giving GMO-free food an unfair advantage on the market.

The EUs strict regulations on the use of GM technology have been, first and foremost, harmful to consumers, depriving them access to innovative options such as Impossible Foods plant-based burger, which so closely mimics meat thanks to an ingredient produced with the help of genetically engineered yeast. Vastly popular in the US and now expanding to Asia, vegan burgers using plant-based substitutes for meat and dairy products, are absent from the European market due to backwards-looking anti-GM rules.

The United Kingdom should strive for the smartest regulation in the field of approval and market access to GMOs. Relaxed regulations on gene-editing methods like CRISPR-Cas9 could also attract massive investment and lead to wide-reaching biotech innovation in the UK.

Enabling gene-editing is an essential part of unleashing scientific innovation in the United Kingdom after Brexit. Skepticism of gene-editing centers around the potential but largely exaggerated adverse effects of the technology and ignores the astonishing benefits that could accrue to both farmers and consumers.

If the UK manages to replace the EUs overly cautious biotech rules with a pro-innovation and prosperity-fostering regulatory scheme, it could become a true global biotech powerhouse. This is an ambitious, exciting, and above all, achievable future.

Maria Chaplia is a European Affairs Associate at the Consumer Choice Center. Visit her website and follow her on Twitter @mchapliaa

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Viewpoint: With Conservative sweep of the 'Brexit election', Boris Johnson poised to steer the UK out of 'outdated' EU GMO, CRISPR regulations -...

MELVILLE, N.Y., Dec. 12, 2019 (GLOBE NEWSWIRE) -- BioRestorative Therapies, Inc. (BioRestorative or the Company) (BRTX), a life sciences company focused on stem cell-based therapies, today announced that the Israeli Patent Office has issued BioRestorative a Notice of Allowance on its patent application for a method of generating brown fat stem cells. This is the eighth patent issued, in the United States and other countries, for the Companys brown fat technology related to BioRestoratives metabolic program (ThermoStem Program).

Once issued in Israel, the final patent will allow for a method of isolating and differentiating a non-embryonic human brown adipose-derived stem cell into functional human brown adipocytes and a method of identifying compounds that modifies metabolic activity of human brown adipocytes. The technology is applicable for potential therapeutic uses for treating a wide range of degenerative and metabolic disorders, including but not limited to diabetes, obesity, hypertension and cardiac deficiency.

We continue to drive innovative and novel technology focusing on transformative therapies for our brown fat program, said Mark Weinreb, CEO of BioRestorative Therapies. We are pleased to add to our intellectual property library this recently issued patent by the Israeli Patent Office for our metabolic program to help power disruptive ways to treat metabolic disorders.

About BioRestorative Therapies, Inc.

BioRestorative Therapies, Inc. (www.biorestorative.com) develops therapeutic products using cell and tissue protocols, primarily involving adult stem cells. Our two core programs, as described below, relate to the treatment of disc/spine disease and metabolic disorders:

Forward-Looking Statements

This press release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events or results to differ materially from those projected in the forward-looking statements as a result of various factors and other risks, including, without limitation, whether the Company will be able to consummate the private placement and the satisfaction of closing conditions related to the private placement and those set forth in the Company's Form 10-K filed with the Securities and Exchange Commission. You should consider these factors in evaluating the forward-looking statements included herein, and not place undue reliance on such statements. The forward-looking statements in this release are made as of the date hereof and the Company undertakes no obligation to update such statements.

CONTACT:Email: ir@biorestorative.com

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BioRestorative Therapies Receives Patent in Israel For Its Metabolic Program - Yahoo Finance

A synopsis of the global canine stem cell therapy market with reference to the global healthcare pharmaceutical industry

Despite the economic and political uncertainty in the recent past, the global healthcare industry has been receiving positive nudges from reformative and technological disruptions in medical devices, pharmaceuticals and biotech, in-vitro diagnostics, and medical imaging. Key markets across the world are facing a massive rise in demand for critical care services that are pushing global healthcare spending levels to unimaginable limits.

A rapidly multiplying geriatric population; increasing prevalence of chronic ailments such as cancer and cardiac disease; growing awareness among patients; and heavy investments in clinical innovation are just some of the factors that are impacting the performance of the global healthcare industry. Proactive measures such as healthcare cost containment, primary care delivery, innovation in medical procedures (3-D printing, blockchain, and robotic surgery to name a few), safe and effective drug delivery, and well-defined healthcare regulatory compliance models are targeted at placing the sector on a high growth trajectory across key regional markets.

Parent Indicators Healthcare Current expenditure on health, % of gross domestic product Current expenditure on health, per capita, US$ purchasing power parities (current prices, current PPPs) Annual growth rate of current expenditure on health, per capita, in real terms Out-of-pocket expenditure, % of current expenditure on health Out-of-pocket expenditure, per capita, US$ purchasing power parity (current prices, current PPPs) Physicians, Density per 1000 population (head counts) Nurses, Density per 1000 population (head counts) Total hospital beds, per 1000 population Curative (acute) care beds, per 1000 population Medical technology, Magnetic Resonance Imaging units, total, per million population Medical technology, Computed Tomography scanners, total, per million population

Research Methodology

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XploreMR utilizes a triangulation methodology that is primarily based on experimental techniques such as patient-level data, to obtain precise market estimations and insights on Molecule and Drug Classes, API Formulations and preferred modes of administration. Bottom-up approach is always used to obtain insightful data for the specific country/regions. The country specific data is again analysed to derive data at a global level. This methodology ensures high quality and accuracy of information.

Secondary research is used at the initial phase to identify the age specific disease epidemiology, diagnosis rate and treatment pattern, as per disease indications. Each piece of information is eventually analysed during the entire research project which builds a strong base for the primary research information.

Primary research participants include demand-side users such as key opinion leaders, physicians, surgeons, nursing managers, clinical specialists who provide valuable insights on trends and clinical application of the drugs, key treatment patterns, adoption rate, and compliance rate.

Quantitative and qualitative assessment of basic factors driving demand, economic factors/cycles and growth rates and strategies utilized by key players in the market is analysed in detail while forecasting, in order to project Year-on-Year growth rates. These Y-o-Y growth projections are checked and aligned as per industry/product lifecycle and further utilized to develop market numbers at a holistic level.

On the other hand, we also analyse various companies annual reports, investor presentations, SEC filings, 10k reports and press release operating in this market segment to fetch substantial information about the market size, trends, opportunity, drivers, restraints and to analyse key players and their market shares. Key companies are segmented at Tier level based on their revenues, product portfolio and presence.

Please note that these are the partial steps that are being followed while developing the market size. Besides this, forecasting will be done based on our internal proprietary model which also uses different macro-economic factors such as per capita healthcare expenditure, disposable income, industry based demand driving factors impacting the market and its forecast trends apart from disease related factors.

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Standard Report Structure Executive Summary Market Definition Macro-economic analysis Parent Market Analysis Market Overview Forecast Factors Segmental Analysis and Forecast Regional Analysis Competition Analysis

Target Audience Production Companies Suppliers Channel Partners Marketing Authorities Subject Matter Experts Research Institutions Financial Institutions Market Consultants Government Authorities

Market Taxonomy

The global canine stem cell therapy market has been segmented into:

Product Type: Allogeneic Stem Cells Autologous Stem cells

Application: Arthritis Dysplasia Tendonitis Lameness Others

End User: Veterinary Hospitals Veterinary Clinics Veterinary Research Institutes

Region: North America Latin America Europe Asia Pacific Japan Middle East & Africa

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Canine Stem Cell Therapy Market Industry Outlook, Size, Share, Growth Prospects, Key Opportunities, Trends and Forecast - Downey Magazine

KRAS mutations occur in approximately 20% of people with non-small cell lung cancer, and some previous studies have suggested that these mutations are associated with a poorer response to treatment, said Dr. Jonathan Cheng, vice president, oncology clinical research, Merck Research Laboratories. It was therefore encouraging to see in this exploratory analysis that KEYTRUDA monotherapy was associated with a survival benefit in certain patients with metastatic nonsquamous non-small cell lung cancer, regardless of KRAS mutational status.

The objective of the exploratory analysis was to assess the prevalence of KRAS mutations and their association with efficacy in the KEYNOTE-042 trial. Of the 1,274 untreated patients with metastatic nonsquamous NSCLC whose tumors expressed PD-L1 (TPS 1%) enrolled in KEYNOTE-042, 301 patients had KRAS evaluable data (n=232 without any KRAS mutation; n=69 with any KRAS mutation, including n=29 with the KRAS G12C mutation). Tissue tumor mutational burden (tTMB) and KRAS mutational status were determined by whole-exome sequencing (WES) of tumor tissue and matched normal DNA (blood). Patients were randomized 1:1 to receive KEYTRUDA 200 mg intravenously every three weeks (Q3W) (n=637) or investigators choice of chemotherapy (pemetrexed or paclitaxel) (n=637). Treatment continued until progression of disease or unacceptable toxicity. The primary endpoint was OS with a TPS of 50%, 20% and 1%, which were assessed sequentially. The secondary endpoints were PFS and ORR.

Findings from this exploratory analysis showed that KEYTRUDA monotherapy was associated with improved clinical outcomes, regardless of KRAS mutational status, in patients with metastatic nonsquamous NSCLC versus chemotherapy. In this analysis, KEYTRUDA reduced the risk of death by 58% (HR=0.42 [95% CI, 0.22-0.81]) in patients with any KRAS mutation and by 72% (HR=0.28 [95% CI, 0.09-0.86]) in patients with the KRAS G12C mutation compared to chemotherapy. The safety profile of KEYTRUDA was consistent with what has been seen in previously reported studies among patients with metastatic NSCLC.

Additional efficacy results from this exploratory analysis showed:

With Any KRAS Mutation

With KRAS G12CMutation

Without Any KRAS Mutation

KEYTRUDA Mono-therapy

(N = 30)

Chemo-therapy

(N = 39)

KEYTRUDA Mono-therapy(N = 12)

Chemo-therapy(N = 17)

KEYTRUDA Mono-therapy

(N = 127)

Chemo-therapy(N = 105)

OS, median, mo(95% CI)

28 (23-NR)

11 (7-25)

NR (23-NR)

8 (5-NR)

15 (12-24)

12 (11-18)

OS, HR(95% CI)

0.42 (0.22-0.81)

0.28 (0.09-0.86)

0.86 (0.63-1.18)

ORR, %(95% CI)

56.7

18.0

66.7

23.5

29.1

21.0

PFS, median, mo(95% CI)

12 (8-NR)

6 (4-9)

15 (10-NR)

6 (4-8)

6 (4-7)

6 (6-8)

PFS, HR(95% CI)

0.51 (0.29-0.87)

0.27 (0.10-0.71)

1.00 (0.75-1.34)

Data from an exploratory analysis of KEYNOTE-189 (Abstract #LBA5), which evaluated KRAS mutations and their association with efficacy outcomes for KEYTRUDA in combination with pemetrexed and platinum chemotherapy, were also presented in a mini-oral session today at the ESMO Immuno-Oncology Congress 2019. KEYNOTE-189 was conducted in collaboration with Eli Lilly and Company, the makers of pemetrexed (ALIMTA).

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon and breast cancers combined. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of all cases. Small cell lung cancer (SCLC) accounts for about 10 to 15% of all lung cancers. Lung cancer can also be characterized by the presence of different biomarkers, including PD-L1, KRAS, ALK, EGFR and ROS1. KRAS mutations occur in about 20% of NSCLC cases. Between 2008 and 2014, the five-year survival rate for patients diagnosed in the U.S. with advanced NSCLC was only 5%.

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,000 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [CPS 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grade 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

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Data from Exploratory Analysis Show Merck's KEYTRUDA (pembrolizumab) Improved Overall Survival as Monotherapy for the First-Line Treatment of...

Transparency Market Research (TMR)has published a new report on the globalcell separation technology marketfor the forecast period of 20192027. According to the report, the global cell separation technology market was valued at ~US$ 5 Bnin 2018, and is projected to expand at a double-digit CAGR during the forecast period.

Overview

Cell separation, also known as cell sorting or cell isolation, is the process of removing cells from biological samples such as tissue or whole blood. Cell separation is a powerful technology that assists biological research. Rising incidences of chronic illnesses across the globe are likely to boost the development of regenerative medicines or tissue engineering, which further boosts the adoption of cell separation technologies researchers.

Expansion of the global cell separation technology market is attributed to an increase in technological advancements and surge in investments in research & development, such asstem cellresearch and cancer research. The rising geriatric population is another factor boosting the need for cell separation technologies Moreover, the geriatric population, globally, is more prone to long-term neurological and other chronic illnesses, which, in turn, is driving research to develop treatment for chronic illnesses. Furthermore, increase in the awareness about innovative technologies, such as microfluidics, fluorescent-activated cells sorting, and magnetic activated cells sorting is expected to propel the global cell separation technology market.

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North America dominated the global cell separation technology market in 2018, and the trend is anticipated to continue during the forecast period. This is attributed to technological advancements in offering cell separation solutions, presence of key players, and increased initiatives governments for advancing the cell separation process. However, insufficient funding for the development of cell separation technologies is likely to hamper the global cell separation technology market during the forecast period. Asia Pacific is expected to be a highly lucrative market for cell separation technology during the forecast period, owing to improving healthcare infrastructure along with rising investments in research & development in the region.

Rising Incidences of Chronic Diseases, Worldwide, Boosting the Demand for Cell Therapy

Incidences of chronic diseases such as diabetes, obesity, arthritis, cardiac diseases, and cancer are increasing due to sedentary lifestyles, aging population, and increased alcohol consumption and cigarette smoking. According to the World Health Organization (WHO), 2020, the mortality rate from chronic diseases is expected to reach73%, and in developing counties,70%deaths are estimated to be caused chronic diseases. Southeast Asia, Eastern Mediterranean, and Africa are expected to be greatly affected chronic diseases. Thus, the increasing burden of chronic diseases around the world is fuelling the demand for cellular therapies to treat chronic diseases. This, in turn, is driving focus and investments on research to develop effective treatments. Thus, increase in cellular research activities is boosting the global cell separation technology market.

To Obtain All-Inclusive Information On Forecast Analysis Of Global Market, Request A PDF Brochure Here.

Increase in Geriatric Population Boosting the Demand for Surgeries

The geriatric population is likely to suffer from chronic diseases such as cancer and neurological disorders more than the younger population. Moreover, the geriatric population is increasing at a rapid pace as compared to that of the younger population. Increase in the geriatric population aged above 65 years is projected to drive the incidences of Alzheimers, dementia, cancer, and immune diseases, which, in turn, is anticipated to boost the need for corrective treatment of these disorders. This is estimated to further drive the demand for clinical trials and research that require cell separation products. These factors are likely to boost the global cell separation technology market.

According to the United Nations, the geriatric population aged above 60 is expected to double 2050 and triple 2100, an increase from962 millionin 2017 to2.1 billionin 2050 and3.1 billion2100.

Productive Partnerships in Microfluidics Likely to Boost the Cell Separation Technology Market

Technological advancements are prompting companies to innovate in microfluidics cell separation technology. Strategic partnerships and collaborations is an ongoing trend, which is boosting the innovation and development of microfluidics-based products. Governments and stakeholders look upon the potential in single cell separation technology and its analysis, which drives them to invest in the development ofmicrofluidics. Companies are striving to build a platform utilizing their expertise and experience to further offer enhanced solutions to end users.

Stem Cell Research to Account for a Prominent Share

Stem cell is a prominent cell therapy utilized in the development of regenerative medicine, which is employed in the replacement of tissues or organs, rather than treating them. Thus, stem cell accounted for a prominent share of the global market. The geriatric population is likely to increase at a rapid pace as compared to the adult population, 2030, which is likely to attract the use of stem cell therapy for treatment. Stem cells require considerably higher number of clinical trials, which is likely to drive the demand for cell separation technology, globally. Rising stem cell research is likely to attract government and private funding, which, in turn, is estimated to offer significant opportunity for stem cell therapies.

Biotechnology & Pharmaceuticals Companies to Dominate the Market

The number of biotechnology companies operating across the globe is rising, especially in developing countries. Pharmaceutical companies are likely to use cells separation techniques to develop drugs and continue contributing through innovation. Growing research in stem cell has prompted companies to own large separate units to boost the same. Thus, advancements in developing drugs and treatments, such as CAR-T through cell separation technologies, are likely to drive the segment.

As per research, 449 public biotech companies operate in the U.S., which is expected to boost the biotechnology & pharmaceutical companies segment. In developing countries such as China, China Food and Drug Administration(CFDA) reforms pave the way for innovation to further boost biotechnology & pharmaceutical companies in the country.

Global Cell Separation Technology Market: Prominent Regions

North America to Dominate Global Market, While Asia Pacific to Offer Significant Opportunity

In terms of region, the global cell separation technology market has been segmented into five major regions: North America, Europe, Asia Pacific, Latin America, and the Middle East & Africa. North America dominated the global market in 2018, followed Europe. North America accounted for a major share of the global cell separation technology market in 2018, owing to the development of cell separation advanced technologies, well-defined regulatory framework, and initiatives governments in the region to further encourage the research industry. The U.S. is a major investor in stem cell research, which accelerates the development of regenerative medicines for the treatment of various long-term illnesses.

The cell separation technology market in Asia Pacific is projected to expand at a high CAGR from 2019 to 2027. This can be attributed to an increase in healthcare expenditure and large patient population, especially in countries such as India and China. Rising medical tourism in the region and technological advancements are likely to drive the cell separation technology market in the region.

Launching Innovative Products, and Acquisitions & Collaborations Key Players Driving Global Cell Separation Technology Market

The global cell separation technology market is highly competitive in terms of number of players. Key players operating in the global cell separation technology market include Akadeum Life Sciences, STEMCELL Technologies, Inc., BD, Bio-Rad Laboratories, Inc., Miltenyi Biotech, 10X Genomics, Thermo Fisher Scientific, Inc., Zeiss, GE Healthcare Life Sciences, PerkinElmer, Inc., and QIAGEN.

These players have adopted various strategies such as expanding their product portfolios launching new cell separation kits and devices, and participation in acquisitions, establishing strong distribution networks. Companies are expanding their geographic presence in order sustain in the global cell separation technology market. For instance, in May 2019, Akadeum Life Sciences launched seven new microbubble-based products at a conference. In July 2017, BD received the U.S. FDAs clearance for its BD FACS Lyric flow cytometer system, which is used in the diagnosis of immunological disorders.

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Cell Separation Technology Market Overview, Growth Forecast, Demand and Development Research Report to 2027 - VaporBlash

Dmitry Kaminskiy speaks as though he were trying to unload everything he knows about the science and economics of longevityfrom senolytics research that seeks to stop aging cells from spewing inflammatory proteins and other molecules to the trillion-dollar life extension industry that he and his colleagues are trying to fosterin one sitting.

At the heart of the discussion with Singularity Hub is the idea that artificial intelligence will be the engine that drives breakthroughs in how we approach healthcare and healthy aginga concept with little traction even just five years ago.

At that time, it was considered too futuristic that artificial intelligence and data science might be more accurate compared to any hypothesis of human doctors, said Kaminskiy, co-founder and managing partner at Deep Knowledge Ventures, an investment firm that is betting big on AI and longevity.

How times have changed. Artificial intelligence in healthcare is attracting more investments and deals than just about any sector of the economy, according to data research firm CB Insights. In the most recent third quarter, AI healthcare startups raised nearly $1.6 billion, buoyed by a $550 million mega-round from London-based Babylon Health, which uses AI to collect data from patients, analyze the information, find comparable matches, then make recommendations.

Even without the big bump from Babylon Health, AI healthcare startups raised more than $1 billion last quarter, including two companies focused on longevity therapeutics: Juvenescence and Insilico Medicine.

The latter has risen to prominence for its novel use of reinforcement learning and general adversarial networks (GANs) to accelerate the drug discovery process. Insilico Medicine recently published a seminal paper that demonstrated how such an AI system could generate a drug candidate in just 46 days. Co-founder and CEO Alex Zhavoronkov said he believes there is no greater goal in healthcare todayor, really, any venturethan extending the healthy years of the human lifespan.

I dont think that there is anything more important than that, he told Singularity Hub, explaining that an unhealthy society is detrimental to a healthy economy. I think that its very, very important to extend healthy, productive lifespan just to fix the economy.

The surge of interest in longevity is coming at a time when life expectancy in the US is actually dropping, despite the fact that we spend more money on healthcare than any other nation.

A new paper in the Journal of the American Medical Association found that after six decades of gains, life expectancy for Americans has decreased since 2014, particularly among young and middle-aged adults. While some of the causes are societal, such as drug overdoses and suicide, others are health-related.

While average life expectancy in the US is 78, Kaminskiy noted that healthy life expectancy is about ten years less.

To Zhavoronkovs point about the economy (a topic of great interest to Kaminskiy as well), the US spent $1.1 trillion on chronic diseases in 2016, according to a report from the Milken Institute, with diabetes, cardiovascular conditions, and Alzheimers among the most costly expenses to the healthcare system. When the indirect costs of lost economic productivity are included, the total price tag of chronic diseases in the US is $3.7 trillion, nearly 20 percent of GDP.

So this is the major negative feedback on the national economy and creating a lot of negative social [and] financial issues, Kaminskiy said.

That has convinced Kaminskiy that an economy focused on extending healthy human lifespansincluding the financial instruments and institutions required to support a long-lived populationis the best way forward.

He has co-authored a book on the topic with Margaretta Colangelo, another managing partner at Deep Knowledge Ventures, which has launched a specialized investment fund, Longevity.Capital, focused on the longevity industry. Kaminskiy estimates that there are now about 20 such investment funds dedicated to funding life extension companies.

In November at the inaugural AI for Longevity Summit in London, he and his collaborators also introduced the Longevity AI Consortium, an academic-industry initiative at Kings College London. Eventually, the research center will include an AI Longevity Accelerator program to serve as a bridge between startups and UK investors.

Deep Knowledge Ventures has committed about 7 million ($9 million) over the next three years to the accelerator program, as well as establishing similar consortiums in other regions of the world, according to Franco Cortese, a partner at Longevity.Capital and director of the Aging Analytics Agency, which has produced a series of reports on longevity.

One of the most recent is an overview of Biomarkers for Longevity. A biomarker, in the case of longevity, is a measurable component of health that can indicate a disease state or a more general decline in health associated with aging. Examples range from something as simple as BMI as an indicator of obesity, which is associated with a number of chronic diseases, to sophisticated measurements of telomeres, the protective ends of chromosomes that shorten as we age.

While some researchers are working on moonshot therapies to reverse or slow agingwith a few even arguing we could expand human life on the order of centuriesKaminskiy said he believes understanding biomarkers of aging could make more radical interventions unnecessary.

In this vision of healthcare, people would be able to monitor their health 24-7, with sensors attuned to various biomarkers that could indicate the onset of everything from the flu to diabetes. AI would be instrumental in not just ingesting the billions of data points required to develop such a system, but also what therapies, treatments, or micro-doses of a drug or supplement would be required to maintain homeostasis.

Consider it like Tesla with many, many detectors, analyzing the behavior of the car in real time, and a cloud computing system monitoring those signals in real time with high frequency, Kaminskiy explained. So the same shall be applied for humans.

And only sophisticated algorithms, Kaminskiy argued, can make longevity healthcare work on a mass scale but at the individual level. Precision medicine becomes preventive medicine. Healthcare truly becomes a system to support health rather than a way to fight disease.

Image Credit: Photo byh heyerleinonUnsplash

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Why AI Will Be the Best Tool for Extending Our Longevity - Singularity Hub