Archive for the ‘Male Genetics’ Category

Diagnosis

Many infertile couples have more than one cause of infertility, so it's likely you will both need to see a doctor. It might take a number of tests to determine the cause of infertility. In some cases, a cause is never identified.

Infertility tests can be expensive and might not be covered by insurance find out what your medical plan covers ahead of time.

Diagnosing male infertility problems usually involves:

Your semen is then sent to a laboratory to measure the number of sperm present and look for any abnormalities in the shape (morphology) and movement (motility) of the sperm. The lab will also check your semen for signs of problems such as infections.

Often sperm counts fluctuate significantly from one specimen to the next. In most cases, several semen analysis tests are done over a period of time to ensure accurate results. If your sperm analysis is normal, your doctor will likely recommend thorough testing of your female partner before conducting any more male infertility tests.

Your doctor might recommend additional tests to help identify the cause of your infertility. These can include:

Often, an exact cause of infertility can't be found. Even if an exact cause isn't clear, your doctor might be able to recommend treatments or procedures that will lead to conception.

In cases of infertility, it's recommended that the female partner also be checked. There may be specific treatments recommended for your partner. Or, you may learn that proceeding with assisted reproductive techniques is appropriate in your situation.

Treatments for male infertility include:

In rare cases, male fertility problems can't be treated, and it's impossible for a man to father a child. Your doctor might suggest that you and your partner consider using sperm from a donor or adopting a child.

Our caring team of Mayo Clinic experts can help you with your health concerns. Visit Mayo Clinic Men's Health to get started.

There are a few steps you can take at home to increase your chances of achieving pregnancy:

Evidence is limited on whether or how much herbs or supplements might help increase male fertility. None of these supplements treats a specific underlying cause of infertility, such as a sperm duct defect or chromosomal disorder.

Supplements with studies showing possible benefits for improving sperm count or quality include:

Talk with your doctor before taking dietary supplements for male infertility. There is no clear evidence that they work, and some supplements may cause side effects or interact adversely with medications you take.

Coping with infertility can be difficult. It's an issue of the unknown you can't predict how long it will last or what the outcome will be. Infertility isn't necessarily solved with hard work. The emotional burden on a couple is considerable, and plans for coping can help.

If you have never been evaluated by a doctor, you might begin by seeing your family doctor. If, however, you have a known condition resulting in infertility or have any abnormalities on your testing by your primary care doctor, then you may be referred to a specialist.

Here's some information to help you get ready for your appointment, and what to expect from your doctor.

Examples of questions to ask include:

Don't hesitate to ask additional questions at any time during your appointment.

Be ready to answer questions your doctor is likely to ask, including:

Our caring team of Mayo Clinic experts can help you with your health concerns. Visit Mayo Clinic Men's Health to get started.

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Male infertility - Diagnosis and treatment - Mayo Clinic

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Sexual male enhancement, as the euphemism goes, is big business. Last year, Viagra, the pharmaceutical market leader, raked in about $2 billion.

That success has spawned a shadow industry of largely unregulated "natural male enhancement," or sex pill, products. But according to the FDA, some of these products aren't natural, aren't tested and some might even be dangerous.

Here's a list of 10 sex pill products the FDA issued health warnings about this year or told manufacturers to get them off the shelves.

The issue, says the agency, is the product uses "sulfoaildenafil, a chemical similar to sildenafil, the active ingredient in Viagra."

Like Viagra, sulfoaildenafil can have dangerous interactions with other prescription drugs such as nitrates, and can cause dangerously low blood pressure. But because consumers think they are taking a "natural" product they are usually not under a doctor's care.

Also, sulfoaildenafil has not undergone the same clinical trials as sildenafil, so all its effects are not known.

FDA Warning

It's not clear if "Stiff Nights" is a "dietary supplement" as its maker claims, or a bad b-movie title, but in either case the FDA says men looking to "regain the thunder" should stay clear because the pill really contains sulfoaildenafil, an untested chemical similar to the active ingredient in Viagra, which can interact badly with nitrates and cause low blood pressure.

FDA Warning.

The marketing geniuses behind "Stiff Nights" also sell "Rock Hard Weekend." Same unregulated chemical, says the FDA, different laugh out loud brand.

FDA Warning.

It's not clear who Don Wands is or how he became so magical, but the FDA didn't seem to care.

In August 2010, they told the manufacturer of this supplement to drop the magic act and take it off the shelves because the product's two main ingredients, hydroxyhomosildenafil and sulfoaildenafil, aren't listed on the box, aren't "supplements" and aren't really tested.

FDA Warning.

Magic Power Coffee's website says the extra mojo comes from honey goat weed and goji berries.

FDA Warning.

If you wind up with Duro Extend in your stocking this year, you might want to send it back to Santa.

The FDA recalled the product in early December 2010 because the "dietary supplement" is secretly supplemented with sulfoaidenafil, a drug similar to Viagra, but not tested.

FDA Warning.

"This product is dangerous to consumers because it claims to contain only natural ingredients when it actually contains a prescription drug ingredient," says the FDA's warning letter.

Dangerous interactions with nitrates and low blood pressure are possible.

FDA Warning.

FDA Warning.

The FDA doesn't recommend hitting up Luong for pills, however. They say Vitalex's "all natural" and "herbal" concoction is really acetildenafil, another chemical similar to the drug in Viagra, but not tested.

FDA Warning.

Eager men trying to get their hands on a box of Xiadafil VIP, might have to wait in line. In July 2010, U.S. Marshals seized almost $75,000 worth of it after the manufacturer refused an FDA request to recall it.

The problem? The FDA says the product's VIP power comes from hydroxyhomosildenafil, a drug similar to Viagra, but untested.

FDA Warning.

Read more:
Dangerous Male Sex Pills - CBS News

Male honey bee

A drone is a male honey bee. Unlike the female worker bee, drones do not have stingers. They gather neither nectar nor pollen and are unable to feed without assistance from worker bees. A drone's only role is to mate with an unfertilized queen.

Drones carry only one type of allele at each chromosomal position, because they are haploid (containing only one set of chromosomes from the mother). During the development of eggs within a queen, a diploid cell with 32 chromosomes divides to generate haploid cells called gametes with 16 chromosomes. The result is a haploid egg, with chromosomes having a new combination of alleles at the various loci. This process is called arrhenotokous parthenogenesis or simply arrhenotoky.

Because the male bee technically has only a mother, and no father, its genealogical tree is unusual. The first generation has one member (the male). One generation back also has one member (the mother). Two generations back are two members (the mother and father of the mother). Three generations back are three members. Four back are five members. This sequence 1, 1, 2, 3, 5, 8, and so on is known as the Fibonacci sequence.[1]

Much debate and controversy exists in scientific literature about the dynamics and apparent benefit of the combined forms of reproduction in honey bees and other social insects, known as the haplodiploid sex-determination system. The drones have two reproductive functions: each drone grows from the queen's unfertilized haploid egg and produces some 10 million male sperm cells, each genetically identical to the egg. Drones also serve as a vehicle to mate with a new queen to fertilize her eggs. Female worker bees develop from fertilized eggs and are diploid in origin, which means that the sperm from a father provides a second set of 16 chromosomes for a total of 32: one set from each parent. Since all the sperm cells produced by a particular drone are genetically identical, full sisters are more closely related than full sisters of other animals where the sperm is not genetically identical.

A laying worker bee exclusively produces totally unfertilized eggs, which develop into drones. As an exception to this rule, laying worker bees in some subspecies of honey bees may also produce diploid (and therefore female) fertile offspring in a process called thelytoky, in which the second set of chromosomes comes not from sperm, but from one of the three polar bodies during anaphase II of meiosis.

In honey bees, the genetics of offspring can best be controlled by artificially inseminating (referred to in beekeeping as 'instrumental insemination') a queen with drones collected from a single hive, where the drones' mother is known. In the natural mating process, a queen mates with multiple drones,[2] which may not come from the same hive. Therefore, batches of female offspring have fathers of a completely different genetic origin.

A drone is characterized by eyes that are twice the size of those of worker bees and queens, and a body size greater than that of worker bees, though usually smaller than the queen bee. His abdomen is stouter than the abdomen of workers or queen. Although heavy bodied, the drone must be able to fly fast enough to accompany the queen in flight. The average flight time for a drone is about 20 minutes.

An Apis cerana colony has about 200 drones during high summer peak time.Drones depend on worker bees to feed them.

Drones die off or are ejected from the hive by the worker bees in late autumn, dying from exposure and the inability to protect or feed themselves, and do not reappear in the bee hive until late spring. The worker bees evict them as the drones would deplete the hive's resources too quickly if they were allowed to stay.[3]

The drones' main function is to be ready to fertilize a receptive queen. Drones in a hive do not usually mate with a virgin queen of the same hive because the queen flies further to a drone congregation area than the drones do. Mating generally takes place in or near drone congregation areas. How these areas are selected is not understood, but they do exist. When a drone mates with a queen of the same hive, the resultant queen will have a spotty brood pattern (numerous empty cells on a brood frame) due to the removal of diploid drone larvae by nurse bees (i.e., a fertilized egg with two identical sex genes will develop into a drone instead of a worker). The worker bees remove the inbred brood and consume it to recycle the protein.

Mating occurs in flight, which accounts for drones needing better vision, which is provided by their large eyes. Should a drone succeed in mating, the first thing that happens is all of the drone's blood in his body rushes to his endophallus which causes him to lose control over his entire body. His body falls away, leaving a portion of his endophallus attached to the queen which helps guide the next drone in the queen.

Honey bee queen breeders may breed drones to be used for instrumental insemination[4] or open mating. A queen mating yard must have many drones to be successful.

In areas with severe winters, all drones are driven out of the hive in the autumn. A colony begins to rear drones in spring and drone population reaches its peak coinciding with the swarm season in late spring and early summer. The life expectancy of a drone is about 90 days.

Although the drone is highly specialized to perform one function, mating and continuing the propagation of the hive, they may have other purposes. All bees, when they sense the hive's temperature deviating from proper limits, either generate heat by shivering, or exhaust heat by moving air with their wingsbehaviours which drones share with worker bees.

Drones do not exhibit typical worker bee behaviors such as nectar and pollen gathering, nursing, or hive construction. While drones are unable to sting, if picked up, they may swing their tails in an attempt to frighten the disturber.[5] In some species, drones buzz around intruders in an attempt to disorient them if the nest is disturbed.

Drones fly in abundance in the early afternoon and are known to congregate in drone congregation areas a good distance away from the hive.

The everted endophallus, with the cornua in focus, resembling hooks.

The extended bulbus of the endophallus, containing sperm, is in focus.

The drone endophallus is designed to disperse a large quantity of seminal fluid and spermatozoa with great speed and force. The endophallus is held internally in the drone. During mating, the organ is everted (turned inside out), into the queen. The eversion of the endophallus is achieved by contracting abdominal muscles, which increases hemolymph pressure, effectively "inflating" the endophallus. Cornua claspers at the base of the endophallus help to grip the queen.

Mating between a single drone and the queen lasts less than 5 seconds, and it is often completed within 12 seconds. Mating occurs mid-flight, and 1040m (33131ft) above ground. Since the queen mates with 519 drones, and drones die after mating, each drone must make the most of his single shot. The drone makes first contact from above the queen, his thorax above her abdomen, straddling her. He then grasps her with all six legs, and everts the endophallus into her opened sting chamber. If the queen's sting chamber is not fully opened, mating is unsuccessful, so some males that mount the queen do not transfer semen. Once the endophallus has been everted, the drone is paralyzed, flipping backwards as he ejaculates. The process of ejaculation is explosivesemen is blasted through the queen's sting chamber and into the oviduct. The process is sometimes audible to the human ear, akin to a "popping" sound. The ejaculation is so powerful that it ruptures the endophallus, disconnecting the drone from the queen. The bulb of the endophallus is broken off inside of the queen during matingso drones mate only once, and die shortly after. The leftover endophallus remaining in the queen's vagina is referred to as the "mating sign". The plug will not prevent the next drone from mating with the same queen, but may prevent semen from flowing out of the vagina.[6]

Mating between the drones and a virgin queen takes place away from the colony, in mid-air mating sites. These mating sites, called 'congregation areas', are specific locations, where drones wait for the arrival of virgin queens. A congregation area is typically 1040m (33131ft) above ground, and can have a diameter of 30200m (98656ft). The boundaries of a congregation area are distinct; queens flying a few meters outside the boundaries are mostly ignored by the drones. Congregation areas are typically used year after year, with some spots showing little change over 12 years. Since drones are expelled from a colony during the winter, and new drones are raised each spring, inexperienced drones must find these congregation areas anew. This suggests some environmental cues define a congregation area, although the actual cues are unknown.

Congregation areas are typically located above open ground, away from trees or hills, where flight is somewhat protected from the wind (calm winds may be helpful during mating flight). At the same time, many congregation areas do not show such characteristics, such as those located above water or the forest canopy. Some studies have suggested that magnetic orientation could play a role, since drones older than 6 days contain cells in the abdomen that are rich in magnetite.

Congregation areas can be located by attaching a virgin queen (in a cage) to a balloon floating above ground. The person then moves around, taking note of where drones are attracted to the caged queen. Congregation areas are not found closer than 90m (300ft) from an apiary, and congregation areas located farther away from apiaries receive more drones. In a congregation area, drones accumulate from as many as 200 colonies, with estimates of up to 25,000 individual drones. This broad mixing of drones is how a virgin queen can ensure she will receive the genetic diversity needed for her colony. By flying to congregation areas further away from her colony, she further increases the probability of out-breeding.

A single drone visits multiple congregation areas during his lifetime, often taking multiple trips per afternoon. A drone's mating flight averages 2025 minutes, before he must return to the colony to refuel with honey. While at the site, the drones fly around passively, waiting for the arrival of a virgin. When the virgin queen arrives to the congregation area, the drones locate her by visual and olfactory cues. At this point, it is a race to mate with the virgin queen, to be genetically represented in the newly founded colony. The swarming drones, as they actively follow the queen, reportedly resemble a "drone comet", dissolving and reforming as the drones chase the virgin queen. Drones greatly outnumber the quantity of virgin queens produced per season, so even with multiple mating by the queen, very few drones mate successfully (estimated at less than one in 1,000). If needed, a virgin queen can embark on multiple 'nuptial flights', to be sure to receive enough semen from enough drones.

Varroa destructor, a parasitic mite, propagates within the brood cell of bees. The Varroa mite prefers drone brood as it guarantees a longer development period, which is important for its own propagation success. The number of Varroa mites can be kept in check by removing the capped drone brood and either freezing the brood comb or heating it.

Read more here:
Drone (bee) - Wikipedia

Jamie Lo, M.D., M.C.R.,associate professor of obstetrics and gynecology (perinatology and maternal-fetal medicine), OHSU School of Medicine, and Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center at OHSU. (OHSU/Christine Torres Hicks)

A physician-scientist at Oregon Health & Science University is one of just six researchers across the country to receive an Avenir Award in Genetics and Epigenetics of Substance Abuse from the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.

Jamie Lo, M.D., M.C.R., will use the award to develop and execute creative and transformative research to explore how parents behavior and environment affects their offspring before birth in some cases, even before conception.

The award is expected to provide $1.5 million over five years. NIDAs DP1 Avenir Awards support early-career investigators proposing new areas of research for the genetics or epigenetics of addiction.

Lo is an associate professor of obstetrics and gynecology (maternal-fetal medicine) in the OHSU School of Medicine and the Division of Reproductive and Developmental Sciences at the Oregon National Primate Research Center (ONPRC) at OHSU.

Being a scientist at ONPRC has allowed for leading-edge scientific pursuits across scientific and clinical disciplines with researchers at OHSU and at other institutions, and has allowed me to leverage the translational strength of nonhuman primate models that drive scientific discovery, she said. Im grateful and really looking forward to new discoveries we can achieve next.

In her clinical practice, Lo focuses on caring for people with high-risk pregnancies. She frequently encounters patients asking about the safety of cannabis use and other substances while theyre trying to conceive, while pregnant and during breastfeeding..

Most recently, Lo published two widely publicized studies suggesting that chronic use of cannabis may greatly affect male fertilityand reproductive outcomes, and female reproductive health, including increased menstrual cycle length. The male fertility study, in nonhuman primates, used edible cannabis similar to human dosages and found significant decreases in male reproductive hormones, including testosterone, and greater than 50% shrinkage of the testicles.

In earning the elite Avenir Award, Lo credits the support shes received from her clinical and academic departments, along with collaborations forged with other scientists at OHSU, including those in the departments of urology and biomedical engineering, and researchers at other top academic institutions.

Lo plans to use the new funding to delve into how the active ingredient in cannabis, THC, affects the expression of genes in the brains of offspring. The research will set out to determine how a fathers or mothers consumption of cannabis may affect their offspring both in early childhood and later in life or even their childrens offspring.

Were going to look at whether or not those changes that happen to the sperm, egg, fetus or infant are then inherited and how they impact offspring development, she said.

Generally, due to the lack of safety data and the preliminary findings of her work, she advises expectant parents to refrain from cannabis use while pregnant and for those who cannot quit to limit use.

Lo said she feels privileged to be part of ONPRCs team of scientists making discoveries that she can bring back to patients in the clinic.

We do know that cannabis use seems likely to impact reproductive health and fertility in both males and females, and that prenatal cannabis exposure can adversely affect the placenta and fetus, Lo said. But its very hard to study cannabis in humans, especially in pregnancy, because people are often using other substances, affected by their socioeconomic conditions, limited by the inaccuracies of self-reporting, and the quantity and dose of THC used is often difficult to determine.

Using a nonhuman primate model, scientists can control background variables, including diet and exercise, that would not be possible to achieve in people. The award number is 1DP1DA056493-01, through the National Institute on Drug Abuse of the NIH.

OHSU IACUC

All research involving animal subjects at OHSU must be reviewed and approved by the universitysInstitutional Animal Care and Use Committee(IACUC). The IACUCs priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.

Excerpt from:
Prestigious award advances OHSU research on impact of drug use over generations - OHSU News

While looking towards the excitement of candy and costumes this Halloween, October is also a time to pull out the pink for Breast Cancer Awareness Month. While women who are 40 years old have the option to begin an annual breast cancer screening with mammograms, familiarizing oneself with their lemonsregardless of agecan assist with early detection if breast cancer occurs.

Breast cancer is fairly common. About 1 in 8 women are going to be diagnosed with breast cancer at some point in their lives, said Marianne Vivien, a genetic counselor at Overlake Clinics & Medical Center.

According to Vivien about 5-10% of cancer cases are due to genetic mutations or hereditary conditions, while over 90% of cancer cases are random, sporadic, and are usually due to age, and environmental and lifestyle factors.

We all have cancer genes and their job is to protect us from cancer generally, but if someone is born with a mutation or inherits that mutation from a parent, all that really means is theres a change in the DNA, said Vivien.

The change in the DNA causes the gene to no longer function properly, and when this happens to a cancer gene, tumors develop more easily and at earlier ages. BRCA 1 and BRCA 2 are the most common breast cancer genes that are also associated with ovarian cancer, pancreatic cancer, melanoma and prostate cancer, said Vivien.

The general population risk for female breast cancer over a lifetime is 12%, according to Vivien, which increases to greater than 60% with BRCA mutations.

Male breast cancer is pretty rare in the general population. I believe its roughly a half a percent chance over a lifetime for someone who was born male to develop breast cancer, said Vivien, who said that risk increases to about 7% over a lifetime with BRCA mutations.

Vivien expressed that if an individual has any breast tissue, regardless of gender, its important to screen for breast cancer.

We definitely have that conversation with our patients who are Trans[gender], said Vivien. Depending on what surgeries they may or may not have had already, we would discuss essentially what screening or management would be recommended based on the particular gene that were concerned with and what other cancers are associated with that gene.

A breakdown of breast cancer rates on the Eastside

The Washington State Cancer Registry collects incidence data for numerous types of cancer across the state, including female breast cancer. Incidence rates are per 100,000 and the registry data for female breast cancer from 2014-2018 include:

Further data from the National Cancer Institutes state cancer profiles shows that the age-adjusted incidence rate cases per 100,000 for females in King County who are under 50 years old is 50.7; the average annual count is 372 cases and that the recent trends of rates for this demographic are rising.

The lens of a genetic counselor

Part of Viviens work as a genetic counselor includes talking to patients who have received a cancer diagnosis from their primary care physician, or those who received a referral to see if genetic testing would be beneficial.

Im starting to see a lot younger peoplewomen in their twentiescoming in and having that conservation, said Vivien. It doesnt necessarily mean were doing testing right now or were starting screening right now, but were having a conversation so that we can determine when testing or when screening should start and what that might look like for them.

In addition to seeing younger women, Vivien has also been seeing patients who want to know their risks because they were adopted and have no information on their family history.

During the counseling sessions, Viven conducts a thorough family history and medical history to decide if genetic testing is appropriate and to assist with developing a personalized management care plan moving forward. Red flags with genetics include individuals diagnosed at 50 years of age or younger and multiple generations having been affected by breast and other types of cancer, said Vivien.

Ideally, if were getting this information ahead of time, or even if somebody is already diagnosed with breast cancer, were able to make better decisions in terms of treatment, surgical decisions and then management moving forward, said Vivien.

Vivien mentioned how genetic testing and breast cancer screenings are generally covered by health insurance if an individual meets specific criteria. If the criteria is not met and health insurance wont cover, the majority of labs offer genetic testing for approximately $250, said Vivien. For those who are uninsured or underinsured, Vivien feels like breast cancer screenings can be moreso a barrier when compared to genetic testing.

Testing can only get you so far. If youre not going to follow through with the management then testing is a little bit pointless, said Vivien.

You can call them lemons, or you can call them limes

While Vivien believes that Breast Cancer Awareness Month shouldnt be merely one month, she said a good way to celebrate the month is by learning how to conduct a self breast exam.

Know Your Lemons, a nonprofit organization focused on improving early detection of breast cancer through education, provides signs and symptoms of breast cancer, which include:

While theres never a bad time to conduct a self breast exam, Know Your Lemons suggests conducting the exam after ones period, which is when the breast is the least tender and swollen.

A self breast exam can be conducted while standing, sitting or lying down. One should flatten their breast by stretching their arm behind their head. Then, the individual should feel the area (using any pattern such as circles, side to side, and up-down/all around) from their armpit to their collarbone, and then to the bottom of their ribs where lymph nodes live. According to Know Your Lemons, sometimes the areas where lymph nodes are located swell when cancer is present.

Milk lobes and lymph nodes are normal lumps in breasts that feel like soft peas or beans. To be more specific, the soft feeling peas are milk lobes while the soft feeling beans are lymph nodes. Cancerous lumps feel hard like a lemon seed, are usually immovable and can be any shape or size. On the other hand, those hard feeling lemon seeds could potentially be cysts.

See the rest here:
Breast Cancer Awareness Month: The importance of getting to know your lemons - Bothell-Kenmore Reporter

Identification of DEGs after weight loss

After standardizing gene sets (Fig.1), 1011 DEGs (|logFC|>1, p<0.05) were screened out from GSE103766, GSE35411, GSE112307, GSE43471, and GSE35710 based on the above method. The results included 513 downregulated and 498 upregulated genes, as shown in the volcano plot (Fig.2 and Supplementary Table S1). The abscissa in the volcano plot is log2 (fold change) value, and the ordinate is log10 (p-value).

Box-plots of the expression profiles after consolidation and standardization. The x-axis label represents the sample symbol and the y-axis label represents gene expression values. The black line in the box-plot represents the median value of gene expression. (a) Standardization of GSE43471, (b) Standardization of GSE35411, (c) Standardization of GSE103766, (d) Standardization of GSE35710, (e) Standardization of GSE112307.

Volcano plot to identify differentially expressed genes (DEGs). (a) GSE43471, (b) GSE35710, (c) GSE35411, (d) GSE103766, (e) GSE112307. The x-axis label represents fold changes and the y-axis label represents the p-values. Red dots represent the 498 upregulated genes and green dots represent the 513 downregulated genes.

As shown in Supplementary Fig. S1, the PPI network of DEGs, based on the Search Tool for the Retrieval of Interacting Genes (STRING) database, includes 584 nodes and 1417 edges. Using the MCODE plugin in Cytoscape software, the most significant modules (score=6.667) were recognized from the PPI network as comprising 27 hub genes, including ACP5, CETP, COL1A1, COL1A2, CSF1, DNMT3B, EED, HIST1H2AI, HIST1H2BB, HIST1H2BD, HIST1H4B, HIST1H4H, HIST2H3C, HP, LCN2, LIPC, LPA, MMP2, MMP7, MMP9, MSR1, MUC1, PLA2G7, SPP1, THBS1, THBS2, and VLDLR (Table 1 and Fig.3).

Subnetwork of 27 hub genes from the proteinprotein interaction (PPI) network. Node size and temperature color reflect the degree of connectivity (bigger node represents a higher degree and smaller node represents a lower degree; red node represents a higher degree and yellow node represents a lower degree).

An enrichment analysis bubble chart was drawn under GO level 2 classifications using Omicshare tools (Fig.4 and Supplementary Table S2). As shown in the figure, hub genes were significantly enriched in regulating plasma lipoprotein particle levels, lipid transport, extracellular matrix (ECM) organization, response to reactive oxygen species, and the oxygen-containing compound for biological process (BP). The hub genes were significantly enriched for cell composition (CC) in lipoprotein particles, extracellular regions, ECM, extracellular exosomes, and secretory granules. For molecular function (MF), the hub genes were significantly elevated in lipoprotein particle binding, glycosaminoglycan binding, ECM structural constituents, and peptidase activity.

Biological functions based on Gene Ontology (GO) analysis of obesity-related hub genes. Advanced bubble chart shows significance in GO enrichment items of hub genes in three functional groups: biological process (BP), cell composition (CC), and molecular function (MF). The x-axis label represents the gene ratio (Rich Factor) and the y-axis label represents GO terms.

KEGG pathway enrichment analysis showed that the hub genes were primarily enriched in ECMreceptor interaction, cholesterol metabolism, PI3K-Akt, IL-17, and TNF signaling pathways, endocrine resistance, and leukocyte transendothelial migration (Fig.5 and Supplementary Table S3).

Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of hub genes. The x-axis label represents the gene ratio (Rich factor) and the y-axis label represents the pathway.

We converted 27 gene names of the hub genes into protein names that could be recognized through the TCMSP database using the Universal Protein Resource (Uniprot). Moreover, the hub genes can be input in the required format to identify potential herbs with anti-obesity effects from the TCMSP database. After excluding the genes that were not present in the databases or those that had no related ingredients, nine were screened for further research, namely, COL1A1, MMP2, MMP9, SPP1, DNMT3B, MMP7, CETP, COL1A2, and MUC1. These genes corresponded to 16 ingredients [(-)-epigallocatechin-3-gallate (EGCG), arachidonic acid, arctiin, baicalein, beta-carotene, capillarisin, deoxypodophyllotoxin, ellagic acid, fisetin, irisolidone, luteolin, matrine, nobiletin, quercetin, rutaecarpine, tanshinone IIa] showing adequate OB and DL values (OB30%, DL0.18) (Supplementary Table S4).

There were 254 herbs with active ingredients in the databases. The top 10 herbs were Aloe, Portulacae Herba, Mori Follum, Silybum Marianum, Phyllanthi Fructus, Pollen Typhae, Ginkgo Semen, Leonuri Herba, Eriobotryae Folium, and Litseae Fructus. These were associated with more DEGs (related genes=6) and were, therefore, selected as crucial herbs in our study and annotated using Chinese pharmaceutical properties (CMPs), including characters, tastes, and meridian tropisms (Table 2).

We screened the key ingredients in treating obesity using an Ingredients-Targets network containing 25 nodes and 27 edges (Fig.6). The nine orange nodes represent the target genes and 16 green nodes represent the active ingredients. As most genes could be linked (degree=4), quercetin and EGCG were considered the most critical components in the treatment of obesity.

Ingredients-Targets network. Nine orange nodes represent the target genes, whereas the 16 green nodes represent the active compounds. The edges represent the interaction between the compounds and targets.

As shown in Fig.7a, the Herbs-Ingredients-Targets network containing 24 nodes and 43 edges was constructed to demonstrate the relationship between them: the 10 green nodes represent the key herbs and the six yellow nodes represent the active ingredients in them; the eight blue nodes depict the target genes. By analyzing the network, Phyllanthi Fructus and Portulacae Herba were associated with the most ingredients (degree=4). Moreover, quercetin was the most frequent active ingredient (degree=23) found in all herbs. Regarding gene targets, MMP2 was targeted by most ingredients (degree=5) followed by MMP9 (degree=4). Other genes were only acted upon by one component (degree=1).

Herbs-Ingredients-Targets network (a) and Herbs-Taste-Meridian tropism (b) network. (a) Yellow nodes represent the active ingredients and the blue nodes represent the target genes. (b) Yellow nodes represent tastes and purple nodes represent meridian tropisms. In all networks, the light green nodes represent cold-cool herbs, medium green nodes represent calm herbs, and dark green nodes represent warm herbs.

We also established the Herbs-Taste-Meridian tropism network containing 24 nodes and 40 edges to clarify the distribution of CMPs (Fig.7b). Five yellow nodes represent tastes and eight purple nodes represent meridian tropisms. To indicate different characters, we presented 10 nodes of herbs having different greens (light green, medium green, and dark green). Regarding characters, cold-cool herbs like Mori Follum were the most frequent (nodes=7), followed by herbs having calm (nodes=2) and warm (nodes=1) characters. In terms of taste, herbs were mostly bitter (edges=6), followed by sweet (edges=4), acid (edges=2), symplectic (edges=2), and astringent (edges=2). Regarding meridian tropism, most herbs belonged to the liver meridian (edges=6), followed by the stomach and lung (edges=4), large intestine (edges=2), bladder (edges=2), kidney (edges=2), pericardium (edges=2), spleen (edges=1), and gallbladder (edges=1) meridians.

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Identification of hub genes and candidate herbal treatment in obesity through integrated bioinformatic analysis and reverse network pharmacology |...

The Neanderthals have won a Nobel prize. Well, almost. Even if most people havent heard of Svante Pbo, the Swedish geneticist whose work on ancient genomes and human evolution has landed him with 2022s award for physiology or medicine, or the exact science behind palaeogenomics and ancient DNA, they certainly have heard of Neanderthals.

Honouring his contribution to building this incredibly vibrant field of palaeogenomics, the award is much deserved: you need vision, persistence and pioneering methods to recover and sequence immensely old, fragile genetic material. But its also a recognition of the astonishing revelations about our deep history that have come from palaeogenomics, which holds many untapped secrets about who we are today, including settling the long-debated question of whether Neanderthals and Homo sapiens ever encountered each other and, lets say, warmed up those icy tundra nights (the answer is yes, many times).

For research communities, the prize also feels like a recognition of the relevance of work on palaeogenomics, human origin and archaeology more broadly and its continuing importance. Research in the 21st century on our hominin relations, including Neanderthals, is an entirely interdisciplinary, collaborative endeavour. All kinds of material analyses take place, in all sorts of ways. We use photogrammetry or lasers to record entire caves in 3D; trace how stone tools were moved across the land; examine microlayers within ancient hearths; even pick out the starches preserved in grot between ancient teeth. And the advent of the ability to retrieve palaeogenomics from extraordinarily old contexts was nothing short of revolutionary. Today, DNA can be extracted not only from bones, but even from cave sediments: the dust of long vanished lives, waiting for millennia to be found. It has made it possible to assess individual Neanderthals genetic profiles, and has opened windows into previously invisible population histories and interactions.

More than a decade on from the first big findings, today there is a huge community of palaeogenomics researchers, in large part thanks to Pbo, with many having trained with him. Among the younger generations at the front end of the sampling, processing and analytical work who may be the first to make and recognise key new discoveries many are women. They include Mateja Hajdinjak of the Crick Institute whose work has identified complex patterns of interbreeding among Neanderthals and the earliest Homo sapiens in Europe, and Samantha Brown from the University of Tbingen, whose meticulous work on unidentifiable bone scraps found the only known first-generation hybrid, a girl whose mother was Neanderthal and father Denisovan (closely related hominins from eastern Eurasia). Alongside wielding scientific clout, they are overturning outdated ideas that the hard sciences of statistics and white coats (or, in palaeogenomics, full-body protection) are male domains.

As an incredibly fast-moving field, palaeogenomics has achieved an enormous amount in a relatively short space of time. Innovative approaches are constantly being developed, and it must be admitted, even for those of us working in human origins, that keeping up with new methods and jargon can be challenging. The rapidity of advances, especially in competitive academic contexts, has also led to a number of ethical issues. While many are being tackled, the direction of some research may soon force the field to lay out official standards and draw ethical red lines when, for example, reconstructing the brains of Neanderthals using genetic engineering.

Ultimately, while decoding ancient hominin genomes has allowed us to identify which inherited genes we have today hence the physiology or medicine element of the Nobel prize the recognition of Pbos work seems more about much deeper themes, resonating with something of a Neanderthal zeitgeist. Since the discovery of their fossils more than 165 years ago, science has been engaged in dethroning Homo sapiens, demoting us from special creations to something still marvellous but not entirely unique.

Palaeogenomics bolstered this vision of an Earth that hosted many sorts of human, at least five of which were still walking around just 40,000 years ago; translate that figure to a generational scale, and youd see a chain of just 2,000 people linking hands. Ancient DNA has confirmed that we are both embedded within a rich history of hominin diversity, and that we still embody that history ourselves. Alongside the genetic material we acquired sideways through interbreeding with Neanderthals and other species, a recent study found that less than 10% of our genome is distinctive to Homo sapiens, evolved uniquely in us.

Most strikingly, popular understanding has shifted too. While some still drag out Neanderthal as a slur, it now seems somewhat abstracted from general public views. The archaeological evidence for Neanderthals complex, sophisticated minds, with genetic revelations of how close we really are to them, has transformed opinion on who they were, and what that means for us. The knowledge that the very stuff of Neanderthals is still present today in each human heart, thumping with fear or joy has forged a new emotional connection not just to them, but to all our other hominin relations. It also underlines the fact that they, and we, have always been part of a planetary web of life.

The most profound legacy of Pbos establishment of palaeogenomics is, or should be, humility. Because it turns out that many of the earliest Homo sapiens populations entering Eurasia eventually shared the same fate as the Neanderthals they met and mingled with. Their lineages vanished, culturally but also genetically, leaving behind no descendants among living humans. Perhaps the greatest inheritance they left us is understanding that our story is not one of predestined, exceptional success, but a blend of serendipity and coincidence; and that being the last hominin standing is not necessarily something to be proud of.

Excerpt from:
Behind this Nobel prize is a very human story: theres a bit of Neanderthal in all of us - The Guardian

Zainabu was in good health in the days before she gave birth to her fourth baby, despite the fact that her blood pressure was likely somewhere around 280/220.

For a human, such a reading would be catastrophic. Spiking blood pressure in a pregnant or recently postpartum woman is a sign of preeclampsia, a common but potentially fatal condition that can affect the heart, lungs, liver and kidneys.

Zainabu, fortunately, is a Masai giraffe at the Los Angeles Zoo. Giraffes have the highest known blood pressure in the animal kingdom, but this has no apparent effect on fetal or maternal health.

Zainabu, a Masai giraffe, with her fourth baby at the Los Angeles Zoo.

(Los Angeles Zoo)

For Dr. Barbara Natterson-Horowitz, a UCLA cardiologist with a long-standing interest in cross-species health, this raises some compelling questions.

What adaptations have evolved in female giraffes that protect their cardiovascular systems from the damage high blood pressure can cause?

And why dont we know enough about the physiology of human females to prevent a common complication like preeclampsia?

Natterson-Horowitzs side gig treating animals at the L.A. Zoo has led her to explore health connections across species. She and collaborator Kathryn Bowers wrote the 2012 bestseller Zoobiquity about the intersection of human medicine, veterinary medicine and evolutionary biology, followed by 2019s Wildhood, which examined adolescence across the animal kingdom.

Her latest focus is on cross-species similarities in female health, a field that has long been underfunded, understudied and misunderstood. Diseases that primarily affect women get a disproportionately small amount of research money relative to the years of healthy life they steal. (The reverse is true for diseases that primarily affect men.) In addition, women have historically been a minority of clinical trial participants, and for several years those of childbearing age were barred as research subjects in the U.S., a policy the National Institutes of Health reversed in 1986.

We cant go back in time, Natterson-Horowitz says. But we can fill some of the gaps by looking to the animal world.

Many of the species that share our planet are exposed to similar stressors and environmental contaminants. Some endure the same chronic diseases that humans do, while others appear to be naturally resistant. Solutions to some of medicines most vexing questions could be walking on four feet beside us.

Theres a pretty vast landscape of unexamined assumptions about human uniqueness, Natterson-Horowitz said. Failing to recognize our place in the animal kingdom, she added, can prevent us from recognizing connections that, were we to see and understand them, could allow us to better understand the cause of disease and to be better at innovating effective solutions.

Natterson-Horowitz grew up in Los Angeles as the daughter of two psychotherapists. She made occasional trips to the zoo as a child, with no inkling that some of the animals she was looking at would later become her patients.

She studied evolutionary biology at Harvard under famed biologists E.O. Wilson and Stephen Jay Gould. She returned to California for medical school at UC San Francisco and a residency and fellowship at UCLA.

Shed been on the faculty at UCLA for a decade when, in 2005, she got a call from the zoo asking for assistance with a transesophageal echocardiogram, a type of ultrasound exam she specialized in. This one would be for a chimpanzee, her first nonhuman patient.

It was a procedure shed performed countless times before. But probing the internal biology of a fellow primate, albeit one that wasnt human, was like that gleam of light you see when you crack open a door, she recalled: In this case, the door happened to be separating my world of modern human medicine and the natural worlds endless health insights.

Physicians tend to be human-centric in their approach. But veterinarians investigating perplexing problems often look to the medical histories of other species including Homo sapiens.

Natterson-Horowitz feeds a giraffe at the Los Angeles Zoo. Giraffes have the highest known blood pressure in the animal kingdom, but this has no apparent effect on fetal or maternal health.

(Robert Gauthier / Los Angeles Times)

Weve always done that, because we know that theres a lot more research that goes on in many of these diseases in humans, said Jane Sykes, a professor of small animal internal medicine at the UC Davis School of Veterinary Medicine. Were always looking for parallels. ... Is there anything in humans that can help this dog in front of us?

Now Natterson-Horowitz wanted to do the same thing, just in the other direction. The more she consulted with the L.A. Zoo, the more she came to admire that inclusive approach and to question its absence in human medicine.

Anthropocentrism is a blindfold, she said of humans fixation on our own species. If we can move beyond that, we could see connections that are meaningful and powerful.

One of the first patients to spark her interest in female health was a lioness with pericardial effusion, or fluid in the sac around her heart. The condition affects at least 20% of cancer patients, both feline and human, and breast cancer is common in lions. Those two facts made veterinarians worry the lioness had an advanced case of the disease.

Natterson-Horowitz started researching. She knew that breast cancers in some women were connected to BRCA1, a gene on the 17th chromosome. People born with certain versions of the gene are more likely to develop breast cancer when exposed to an environmental or hormonal trigger.

Natterson-Horowitz visits the flamingo enclosure at the zoo. Theres a pretty vast landscape of unexamined assumptions about human uniqueness, she said.

(Robert Gauthier / Los Angeles Times)

What she had not realized was how many non-primate species shared this vulnerability. English springer spaniels with certain BRCA1 variants were four times more likely to develop breast cancer than dogs with the most common version of the gene, Natterson-Horowitz noted in Zoobiquity. Another study found that zoo jaguars taking a particular type of hormonal birth control developed breast cancer in rates similar to human women with high-risk BRCA1 variants, and that the cancer was common in lions and other big cats.

Many factors influence breast cancer rates in females across the animal kingdom: age, genetics, the frequency and duration of lactation, environmental factors and hormonal changes.

Column One

A showcase for compelling storytelling from the Los Angeles Times.

Taken together, the range of mammals vulnerable to breast cancers could offer a trove of valuable comparative data, Natterson-Horowitz realized. But virtually no one was looking for it even for a disease that claims the lives of more than 42,000 women in the U.S. alone each year.

So she started researching these evolutionary links herself. As she dug in, she said she noticed something else: Not only is human medicine anthropocentric, its androcentric that is, focused on cisgender men.

Until the 1993 passage of the NIH Revitalization Act, women and people of color were not required to be part of research studies or clinical trials funded by the NIH, and as a result they usually werent. The same preference for males is even seen in research on mice. In 2016, NIH set a new policy requiring researchers to at least consider biological sex as a variable in the design of human cell and animal studies, though they can study one only sex if they can show strong justification for it.

The good news is that today, over half of the participants in NIH clinical trials are women, said Dr. Janine Austin Clayton, director of the NIH Office of Research on Womens Health. But, she noted, women are still underrepresented in studies of several major diseases, including cardiovascular disease, kidney disease, hepatitis and HIV/AIDS.

Until we have representation across every disease category that affects women and men, she said, we still have work to do.

A male-centered research approach manifests in many ways. It isnt just the dearth of funding for conditions primarily affecting women, like endometriosis and rheumatoid arthritis. Its that data on female bodies are often absent from medical research altogether, resulting in skewed results that can shortchange all genders.

The result is that researchers often havent even realized when their results apply only to men.

Take heart attacks. When the Physicians Health Study, whose sample consisted of 22,071 men and zero women, found in 1989 that a low regular dose of aspirin led to a 44% decrease in heart attacks, many physicians recommended the treatment to men and women alike.

But the 39,876 participants in the Womens Health Study allowed researchers to report in 2005 that for women younger than 65, aspirin didnt help at all. And for those 65 and older, aspirin prevented not only heart attacks but strokes a benefit that was not apparent in the all-male study and would have remained unseen without studying women.

Excluding women from research studies forces doctors to treat them as guinea pigs, generation after generation after generation, said Chloe Bird, a sociologist who heads the Center for Health Equity Research at Tufts Medical Center in Boston.

For the record:

1:22 p.m. Oct. 14, 2022An earlier version of this article reported that the Center for Health Equity Research was at Tufts University. It is based at Tufts Medical Center, which is not part of the university.

Bird has not been involved in Natterson-Horowitzs efforts to take a broader look at the female population of the animal kingdom, which she called fantastic, and so needed.

There is a tremendous opportunity to look across species, and begin to understand ... what happens with what systems and why, and how we could improve healthcare, Bird said.

Natterson-Horowitz is now leading a team of obstetrician/gynecologists, wildlife veterinarians and veterinary pathologists to study giraffe pregnancy to understand why animals like Zainabu who delivered a healthy, 172-pound calf in April are not vulnerable to the cardiovascular crises that strike pregnant humans. Shes also working with dairy veterinarians to better understand mastitis, a common but painful inflammation of breast tissue, to come up with improved treatments and design a better breast pump for women.

But Natterson-Horowitz knows unlocking the secrets of the animal world is not a one-person job. Since 2011 she has organized Zoobiquity conferences that have brought together thousands of physicians, veterinarians and evolutionary biologists to examine health issues from multispecies perspectives. The most recent, titled Female Health Across the Tree of Life, took place in July in Lisbon, Portugal.

She also teaches the relevance of the animal world to undergraduates and medical students at UCLA and Harvard, and is heartened to see the eagerness of a new generation of physicians to look across species for answers.

Climate change and urbanization have blurred the boundaries between the human and nonhuman animal worlds, Natterson-Horowitz pointed out. Zoonotic diseases like COVID-19 and influenza have shown us how closely were tied to fellow members of the animal kingdom.

When she first got into medicine, she pledged to do no harm. Today, she believes, If we can move from an androcentric, anthropocentric view to a sex-, gender-, and species-spanning perspective, then we can do good.

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Column One: Why this UCLA professor is studying female animals to gain insights into women's health - Los Angeles Times

Simone Kaho.

Tulia Thompson talks to Simone Kaho about writing, surviving PTSD and the silencing of survivors

When you study poetry at university you are told you can write a poem about anything as long as it is well-crafted, but then you also learn that poetry in Aotearoa actually means restrained, lyric poems about nature. There's an invisible forcefield around what "counts" as a good poem.

Poets like Hera Lindsay Bird and Chris Tse push past the forcefield. Tongan-Pkeh writer Simone Kaho's stunning collection of poetry, Heal!, about being attacked, fighting back and experiencing PTSD, is a vital challenge to the poetry canon.

Kaho is a documentary-maker who works as a reporter/director for Tagata Pasifika. In Heal! the sexual assault acts as a refracting prism for her interactions with men, who are revealed to be rape-complicit by expressing "common-sense" views that support rape. There's the British guy she swims naked with who says, "Perhaps it's because you are so beautiful." When she is stalked, there is a drunk boss: "You're a sexy beast / he said / you / should / expect / stalkers."

When she posts a poem about the stalker, a male in the poetry community says, "What if he'd committed suicide?" It is the ordinary, banal comments from men that convey to women that they see us as sexually available, able to be objectified, and given less empathy. It's a profoundly uncomfortable read, in part because these views are so familiar.

It reminds me a lot of Claudia Rankine's award-winning Citizen: An American Lyric, about white privilege, in which short prose poems about things white people said to her create a sustained, multilayered impression of racism. In both poetry collections, the repeated incidents reveal their force.

While not being strictly narrative, Heal! maintains narrative tension, and a sense of movement. Assault has given Kaho a different lens on past events. In one poem, set during her childhood, she remembers her Tongan dad taking a machete to the bus stop, trying to find a man who sexually assaulted her.

She writes, "The machete is evidence of love and she enjoys the moment quietly." Kaho asked me when we met if anything surprised me about the collection. I said, "No, nothing really surprised me." But it was a lie. What actually surprised me was that another girl had felt about her dad's machete the way I felt about my dad's machete that it was an ordinary, protective and appropriate weapon.

Tulia Thompson: It's a very brave book. What made you decide to tell this story?

Simone Kaho: Can I just ask you why you think it's brave?

TT: I think it's brave because it's explicitly talking about rape and PTSD. Within New Zealand poetry, it feels like you're discouraged from writing about experiences like this, not necessarily explicitly, but just through the atmosphere.

SK: Yeah, I haven't heard anybody say to me, "You shouldn't write about that." But it feels like there's just a vibe about it. Like it's sharp or the wrong colour or too pungent or visceral or too political. This is not something that fits in.

But I didn't think about that writing this. I'd done the South Seas Film and Television course in 2017, when a lot of my PTSD symptoms were really becoming noticeable. I was really struggling.

I tried to make an action film about a female vigilante. And there was pushback. Pushback can be quite subtle. I was discouraged from making a film about a female protagonist responding violently to male violence. When I was pitching it to industry professionals in front of the whole school, it was questioned whether it was morally right, what the protagonist wanted to do. The horror film pitched straight after me featured a guy eating his mother's face, and got the feedback, "That was a delicious moment!"

So the pushback I got led to an understanding that I was being hushed. And at some point, I just really was like "Nah, f*** this s***." I need to use the most powerful way I have to express myself, which is poetry.

TT: If you're a woman, you are used to men making excuses for male violence. It's just so pervasive.

SK: It's co-opted into politeness. Boys will be boys. That's a blind spot that we all have to agree on. If you respond aggressively or even just assertively to predatory male behaviour, you're being rude. You're the problem. That is definitely something I felt all the time. I was enraged all the time. It was so tiring. And because I'd been in that moment, physically fighting a man during the assault, when I knew there was nothing between us that could protect me, all of those "boys will be boys" behaviours happening afterwards triggered the same sort of horror I'd felt in that moment. Like the only difference between them and the attacker was that he'd made a decision to commit and deal with the consequences.

TT: There's a rigour to your poetry. Is that because of your time at the International Institute of Modern Letters?

SK: I became the poet I am at the IIML, because you're absorbed in it. I had Hinemoana Baker as my supervisor. She said, "Do you care about line breaks? I want you to have no punctuation." And this guttural voice appeared. It's not blaming, even, it's just like brutal truth.

TT: There are men in the book who say sorry that happened, but they don't change their own misogyny. It seems very difficult to create change without men taking more responsibility for talking about sexual violence. What do you think needs to happen?

SK: My concern is with people who've been through sexual violence. My first concern is around our ability to talk about it it's not a crime that we have done. I don't mean with no regard for context or incessantly but in the same way that if somebody robbed your house and beat you up [you'd talk about it]. It's been really hard, working and going back to life, and trying to find a safe place. It's a lot to navigate. I really want to smash the hushing and shaming that makes survivors of sexual violence have to be brave just to talk about it.

Heal! by Simone Kaho (Saufo'i Press, $30) is out now.

Aroha, by Dr Hinemoana Elder, was Aotearoa's biggest-selling non-fiction title of last year. The acclaimed psychiatrist is following up with Wawata: Moon Dreaming (Penguin, $30), a book of wisdom centred around the cycle of the moon which offers 30 lessons based on the 30 faces of Hina, the Maori moon goddess.

Black Ferns star Ruby Tui's new biography, Straight Up (Allen & Unwin, $37), lays it all out there. Her tough childhood, her drive to overcome personal tragedy, her love of rugby and her incredible rise to international fame.

The fifth short story collection from a master of the form, George Saunders, Liberation Day (Bloomsbury, $33) is out on Tuesday. Saunders won the Man Booker Prize for his only novel, Lincoln in the Bardo, in 2017 but is best known for his short stories and essays.

1. You deliver an ecological message in the guise of a coffee table book. Is the artwork a lure?

It was too good an opportunity to miss. Collectively our early painters and photographers produced a rich and unique record of a relatively pristine New Zealand, at the time when settlement from Europe was just beginning. For example, the book includes two paintings, from 1839 and 1840, by Charles Heaphy of the kauri forests on the Wairoa River, Kaipara.

Such images were used as propaganda by the New Zealand Company, to encourage immigration, with the result that vast areas of kauri were felled and destroyed in the process to provide timber for the new settlers' homes. Then there's Alfred Sharpe's 1876 subtly elevated panorama of the Waikato plains, which provides a stark contrast with a photograph of a similar view 140 years later, of the Taupiri interchange on the Waikato Expressway.

2. If a reader takes away one nugget from this book, what do you hope it will be?

My aim in compiling the book was to record the various changes that a thousand or so years of human settlement have inflicted on the New Zealand landscape. With those in mind, I hope it will encourage us to question where we go from here. As we become increasingly aware of the effects of climate change, we must wonder how, and to what extent, we can keep on modifying our natural environment. This is, of course, not just a New Zealand problem. It's worldwide, and at its heart is the ability of the Earth's resources to sustain a growing population in the manner to which it has grown accustomed. As for New Zealanders, this poses such challenges as the degree to which our towns and cities can continue to sprawl, destroying remaining areas of bush and gobbling up good agricultural land.

3. Do you have a favourite image in the book?

There are many "landmark" images, such as the well-known and starkly symbolic Frozen Flames, painted in 1931 by Christopher Perkins, which depicts the aftermath of a bush burn-off. Another of my favourites is Kennett Watkins' 1885 painting, The Haunt of the Moa: A Scene in a Puriri Forest, also in the collection of the Auckland Art Gallery Toi o Tmaki. Deep withIn a dark forest of nkaupalms and gnarled puriri trunks, a hapless moa emerges from behind a tree and is about to reveal itself to a pair of Mori stalkers. The big bird appears to be at the crossroads, for if the hunt is successful it might mark the extinction of the species.

4. You are that rare thing in New Zealand, a full-time writer. How do you make that work?

I had never planned to be a full-time writer. Back in 1997, along with two dozen other staff members, I was made redundant (as Curator of Display) at the Auckland War Memorial Museum. That unexpected change of direction gave me the opportunity to spend more time on what had previously been just an after-hours activity. A quarter of a century and some 40 books later, I'm still at it. I enjoy coming up with ideas for books, and am grateful to publishers who have given me opportunities to realise them. I also enjoy the challenge of dreaming up and researching articles for our leading art quarterly, Art New Zealand.

5. What book have you read this year that you are recommending to others?

I have recently read and enjoyed A Brief History of Everyone Who Ever Lived: The Stories in Our Genes, by English science writer and genetics expert Adam Rutherford (no relation to Sir Ernest). He divulges the startling fact that anyone of European extraction is descended from Charlemagne, the first emperor of the Holy Roman Empire, who lived from 747 to 814AD. The point is that the further we go back up our family trees, the more interconnected and related all of us are. Perhaps if humanity at large was more aware of this fact, the world would be a much happier place.

Footprints on the Land, by Richard Wolfe (Oratia Books, $45), is out now.

View original post here:
Books wrap: Simone Kaho on her new poetry collection and PTSD; a conversation with Richard Wolfe; and more - New Zealand Herald

The fourth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO "blue book"), published in 2016, contains significant revisions. These revisions were performed after consideration by a large international group of pathologists with special expertise in this area. A subgroup of these persons met at the WHO Consensus Conference in Zurich, Switzerland, in 2015 to finalize the revisions. This review summarizes the most significant differences between the newly published classification and the prior version for renal, penile, and testicular tumours. Newly recognized epithelial renal tumours are hereditary leiomyomatosis and renal cell carcinoma (RCC) syndrome-associated RCC, succinate dehydrogenase-deficient RCC, tubulocystic RCC, acquired cystic disease-associated RCC, and clear cell papillary RCC. The WHO/International Society of Urological Pathology renal tumour grading system was recommended, and the definition of renal papillary adenoma was modified. The new WHO classification of penile squamous cell carcinomas is based on the presence of human papillomavirus and defines histologic subtypes accordingly. Germ cell neoplasia in situ (GCNIS) of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours, and testicular germ cell tumours are now separated into two fundamentally different groups: those derived from GCNIS and those unrelated to GCNIS. Spermatocytic seminoma has been designated as a spermatocytic tumour and placed within the group of non-GCNIS-related tumours in the 2016 WHO classification.

Patient summary: The 2016 World Health Organization (WHO) classification contains new renal tumour entities. The classification of penile squamous cell carcinomas is based on the presence of human papillomavirus. Germ cell neoplasia in situ of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours.

Keywords: Male genital organs; Urogenital tract; WHO classification.

See more here:
The 2016 WHO Classification of Tumours of the Urinary System and Male ...

Since the dawn of civilization, people have searched for the secret to long life. Famously, Gianni Pes, Michel Poulain and Dan Buettner proposed that diet drives a persons longevity. Other researchers have favored a genetics based explanation for longevity. Recently, a study published in Science found that a mouses genes determine its lifespan, and that there are human orthologs, or analogous genes. The study also found that female and male mice have different genes controlling their lifespans, which is interesting considering that female mice have longer lifespans. The study firmly lands on the side of those who have argued that genes directly determine lifespan. This means that reducing the risk of disease alone is not enough to increase longevity.

While the idea of aging is universal, in scientific terms, it does not have a precise measure. Much as Socrates asked us to investigate the real meaning of widely discussed concepts, scientists have had to work out ways to measure aging, and, this implies, asking what aging really is. Broadly, as the authors of the study note, it is a progressive decline in physical, mental and reproductive capacities, in which a person accumulates morbidities and the risk of dying increases. However, it is not known what the exact interplay is between genes, sex and environment, in determing lifespan.

Researchers have measured aging through a number of traits, such as lifespan, and age-related disease onset. Researchers believe that if they can figure out what the genetic and nongenetic drivers of longevity are, they can develop treatments to improve not just quality of life, but longevity.

A team of scientists led by Robert Williams, looked at the determinants of longevity in 3276 UM-HET3 mice, a type of, or genetically diverse mice that the National Institute on Agings (NIA) Interventions Testing Program (ITP) had been studying. The NIAs TIP had collected this data in 2003, when they were trying to see if dietary interventions would affect the longevity of mice. The mice were raised in closely controlled, homogeneous conditions, and the program collected tissue from them, so they could isolate the impact of genes on the lifespan of mice. The diversity of mice was a result of the need to mirror the diversity in the human genepool. Typically, mice do tend to inbreed, and this warps studies on longevity.

The NIAs TIP did not study the genetic drivers of longevity, and that is the point at which Robert WIlliams and his team began their study. The team were charged with figuring out whether the genetic drivers of longevity are related to sex and age, and whether the nongenetic drivers, such as litter size, or having a good diet from early in life, was important to longevity. In studying these drivers, they were able to classify the changes in liver gene expression of mice in the same genetic cross, according to whether they were driven by age or genotype. The last step in the study was to bring those results together with the orthogonal or itnesecting datasets, to undertake quantitative trait locus mapping, associating phenotypes with genotypes. This would allow the team to figure out which genes are associated with increased longevity.

The team was able to determine genetic loci important for longevity. Sevel of these loci were found in female mice, but, at first, no genetic loci linked specifically to longevity in male mice, were found. When the scientists removed the data for male mice who died at the beginning of the study, they then found genetic loci associated specifically with longevity in male mice. They also found that the factors such as body weight and litter size also impact longevity. For instance, mice with larger body weights and who grew up in smaller litters, died earlier. Consequently, genes linked to body weight and litter size could arguably be linked to longevity. Longevity could be indirectly impacted by the effect of these genes on those factors. However, it is important to note that not all longevity genes are correlated with those factors, opening up the door to the possibility that there are other genes influencing longevity.

The goal of this study was to say something meaningful about longevity in humans, so the study then went to human genome biobanks, and the researchers found sequences that mirrored those in mice. In addition, there was a similar relationship between early development and longevity. They then looked at genes in worms, to see if a similar relationship existed, and if broader conclusions could be drawn about the association of these genes and longevity. Ultimately, they concluded that genes are the primary determinants of longevity.

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The Genetic Drivers Of Longevity In Mice, Humans And Worms - Science 2.0

Most species of squirrels -- rodents that inhabit various regions across the globe -- can be grouped as tree or ground squirrels. Information about each groups behaviors and physical traits provides insight needed to determine whether the squirrel of that group is male or female. The sex of a squirrel is difficult to determine if attempting to go by obvious physical characteristics, because male and female squirrels are usually of the same size, shape and color.

Both male and female squirrels are communal, interacting with other squirrels within their immediate living area. However, the nesting habits of male and female tree squirrels differ. Males can be observed nesting together during winter months. It is uncommon for some female tree squirrels, such as fox squirrels, to nest together. An adult squirrel observed interacting with a litter is likely to be the mother of the litter. Male squirrels of any kind do not participate in the rearing process.

Female ground squirrels emerge from hibernation later than their male counterparts. For this reason, ground squirrels observed the soonest after a hibernation period are more likely to be male. Juvenile ground squirrel males exhibit much more movement, exploration and boldness compared to juvenile females. In accordance with this increased movement and exploration, all male juvenile ground squirrels leave the area in which they are born by the time they are one year old. Female ground squirrels stay near the burrows they were born in and form communes with other related females.

The squirrel mating ritual involves a single male or multiple males chasing a female. The males also compete with each other by chasing each other. The most dominant male is the one who typically mates with the female first. The female will sometimes mate with additional suitors afterwards. For some species of tree squirrels, the mating window is so short that the female only remains in estrus, the period of time when pregnancy is possible, for a few hours.

Certain telltale traits of male and female squirrels emerge during the mating season. The scrotum of male squirrels becomes visible because it enlarges and descends. During non-mating periods, the testes are withdrawn into the body. The nipples of adult female squirrels become more prominent during the mating season. The location of the genitals differs between male and female squirrels. The male reproductive organs are located closer to the navel, while the females' are located closer to the anus.

To prevent injury to themselves or the rodents, people should avoid attempting to handle wild squirrels. Feeding squirrels with human food or even a squirrel feeder is discouraged for several reasons. These reasons include accidentally providing food for invasive species, diminishing squirrels' protective fear of humans or providing unhealthy food to the squirrels.

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How to Tell If a Squirrel Is Male or Female | Sciencing

When youre trying to conceive or dealing with fertility issues, it may be tempting to reach for one of the many supplements marketed to boost male fertility. However, research on the safety and efficacy of these supplements is limited.

Since supplements arent regulated by the U.S. Food and Drug Administration (FDA) the way medications are, it can be challenging to know if a supplement contains what it says it does, and what effect it will have on the body, explains Philip Cheng, M.D., a male infertility doctor and urologist with Reproductive Medicine Associates of New Jersey. In order to get the nutrients you need to support healthy sperm production, he recommends focusing on a healthy diet.

Research suggests the following supplements may improve sperm quality, especially if you arent getting enough of the nutrients they provide through your dietbut remember, its always a good idea to check with your physician before adding new supplements to your regimen to avoid interactions with any medications you are taking.

Research notes Coenzyme Q10, also known as ubiquinol, is one of the most studied and promising supplements for improving male fertility. Coenzyme Q10 is an antioxidant naturally produced in your body and stored in your mitochondria (the energy factories in your cells). Its antioxidant properties may help protect sperm from damaging free radicals.

One review found that men who supplemented with CoQ10 experienced significant increases in sperm concentration and sperm motility compared to those who took a placebo.

Russell Hayden, M.D., a Harvard-trained urologist with a sub-specialty in male infertility and microsurgery, recommends 300 milligrams to 400 milligrams of a generic coenzyme Q10 supplement daily to his male infertility patients.

When it comes to supplements for male fertility, DHA omega-3 fatty acid supplementation appears to have some of the strongest data supporting its use, says Lauren Manaker, a registered dietitian and author of Fueling Male Fertility.

Fatty acids like docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are important components of sperm cell membranes, and omega-3 fatty acid intake directly correlates to sperm qualityso the more you consume, you may have higher quality of sperm.

A recent review on the effects of the omega-3 fatty acids EPA and DHA on male infertility found that men who took omega-3 treatments had significantly increased sperm motility compared with men who took a placebo.

If your intake of omega-3s from foods like fatty fish, walnuts, chia and flax seeds is low, you might benefit from taking a supplement.

Women who are trying to conceive are routinely advised to take a prenatal vitamin, but mens prenatals are starting to become popular as well, notes licensed dietitian Becca Romero, a functional nutritionist specializing in fertility. She recommends mens prenatal multivitamins WeNatal For Him and Needed to her patients.

WeNatal For Him is a prenatal supplement for men that is formulated to support overall sperm health. It contains a range of vitamins and minerals along with other ingredients and antioxidants that are marketed to boost male fertility, like maca, CoQ10 and acetyl L-carnitine.

Needed Mens Multi is recommended for men before conceiving and in the years that follow. It contains a wide range of vitamins and minerals, as well as an organic antioxidant blend of foods like grape, cranberry, pomegranate, blueberry, apple, mangosteen, bilberry, chokeberry and goji berry.

A male prenatal multivitamin can fill any nutrition gaps in your diet and help you avoid deficiencies that could impact your sperm quality. When choosing a mens prenatal supplement, steer clear of formulations that contain unstudied ingredients or excessive amounts of vitamins and minerals.

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A Guide To The Best Fertility Supplements And Vitamins For Men - Forbes

Like a few other plant species, cannabis plants can be male or female and sometimes hermaphrodite. For growers of these dioecious plants, its crucial to determine their gender on time.

To the untrained eye, these plant genders have no obvious differences. However, expert growers can identify some early tell-tale signs of the plants gender.

Thus, contrary to popular belief, you can tell a plants gender even before its flowering. After a while of growing cannabis plants, it becomes easier to tell which of your plants are male and female.

Even after four weeks of germination, while plants are still in a vegetative phase, some signs could help you identify the gender of your cannabis plants. The difference between both genders is apparent in the appearance of their pre-flowers, just 3 to 6 weeks after germination.

The gender of a cannabis plant would determine its potency. Female cannabis plants grow highly resinous buds that are rich in cannabinoids such as delta-9 THC. On the other hand, male cannabis plants have low levels of THC.Some of the delta-9 THC products include delta-9 gummies, vapes and tablets.

For this reason, many growers focus on growing only female plants. Growers would prefer the entire crop to be female cannabis to prevent seed production due to male and female plant fertilization.

Plants that have been fertilized have a lower cannabinoid content than unfertilized female plants. With fertilized female buds, youll find more seeds in the crop and fewer THC-rich buds.

The seedless female plant, Sinsemilla, is loved by many for its high THC content and for the duration of time it keeps producing buds.

Some growers use feminized seeds to ensure that every one of their plants is female. If you plant regular cannabis seeds, your harvest will likely be equal parts male and female.

An important identifier of the male cannabis plant is that it does not produce buds. Instead of buds, the sex organ of these male marijuana plants produces pollen sacs. These pollen sacs are responsible for fertilizing the female buds to produce seeds.

Growers do all to avoid having seedy female buds, as these buds produce poor-quality cannabis. This cannabis is not potent and has low levels of cannabinoids. Growers are wary of this situation.

Thus, they always remove the male and hermaphrodite cannabis plants from the crop. If you do this early enough, you can protect your female buds and reap a bountiful harvest.

During a cannabis first sign of flowering stage, you can identify a female plant by its buds. The plants teardrop-shaped buds begin to produce white hairy strands called stigma.

These stigmas protrude from the buds of a female plant, forming a part of the female reproductive organ (pistil). The pistils are located at the plants node, which is the point where the branches grow out of the plants stalks.

These wispy white hairs appear four to six weeks after germinating a cannabis plant. Over time, the white hairs begin to get darker.

Depending on several factors, the female plants pistils and stigma can grow at the top or lower regions of the marijuana plant. However, it is more common to see them growing at the top part of the plant, close to the light source.

The sex organs of the male and female cannabis plants differ significantly. You can identify that a cannabis plant is male as early as four weeks after germinating. This is unlike the female plant that often gets to six weeks before revealing its sex.

Unlike female plants, male cannabis plants produce pollen sacs. These sacs are situated at the points between the nodes and the plants stalk. At first, these sacs appear to look like female buds.

However, they do not have the white hairs that female sacs are known to produce. Also, the male pre-flowers often resemble the shape of a spade, unlike young female buds that have a teardrop shape.

Besides these, there are other morphological features that each plant produces that can help you easily identify their gender. One of these identifiers is the length of the plant. More often than not, male plants tend to grow taller than female marijuana plants.

Also, the stalks of the male marijuana plant would be much thicker to provide support for the plants weight. Generally, a female plant would look shorter and bushier than a male plant.

These attributes are, however, not a conclusive way to identify gender. Some conditions could cause your plant not to appear how it should. The surest way to identify your plants gender remains by the appearance of buds or pollen sacs.

Certain conditions can cause a cannabis plant to become hermaphrodite. Such a plant would have both male and female reproductive organs. Deficiencies in nutrients, disease and other stressful conditions can often lead to a plant forming both sex organs.

The first way to identify a hermaphrodite plant is when it grows both male pollen sacs and female buds. Another sign is when anthers begin to grow among the plants buds. An anther has a yellowish color and is shaped like a banana.

These anthers are capable of fertilizing the female plant as soon as they start forming. Thus, its important to look out for any appearance of anthers in your female crop and trim them off to protect your female plants.

Inspecting your female plants to ensure they do not have male sacs is crucial, as this could lead to self-pollination. Its essential to do this, as even just one hermaphrodite plant can pollinate your entire crop of plants and reduce the quality of your yield.

Even to expert growers, it is impossible to tell the gender of a seed by simply looking at it. The only way to tell its gender is to plant it and wait some weeks for it to mature. The growth of buds or sacs will help you easily identify your male and female plants.

However, some seeds called feminized seeds are bred to grow only female plants. You can even grow some of the top rated CBD strains or weed strains to sell them and earn profit. Thus, if you acquire feminized cannabis seeds from a reputable vendor, you are certain to grow female plants.

Note, however, that it is possible for a small percentage of feminized seeds to sprout hermaphrodite plants. This might be a result of less-than-ideal growing conditions and genetics.

All in all, always ensure to check your female crops frequently to ensure that none are becoming hermaphrodites. If you purchase feminized seeds, also ensure to check your crop to ensure that your vendor mistakenly added no male seeds to the feminized seeds.

Chemical leaf testing has become a popular means of identifying the gender of a cannabis plant. Its become a popular alternative to visual inspection, as the plants can take up to six weeks to reveal their gender.

A chemical test can be carried out on the plants leaves to determine its gender just a few days after germinating.

This chemical test involves the use of DNA and can identify other features of the plant, like its cannabinoid content. Chemical tests have become the go-to choice for expert growers who wish to identify their plants gender early.

To reduce the likelihood of producing hermaphrodite plants, avoid any stress and triggers when the plant is flowering.

To ensure optimal growing conditions, you should observe perfect hygiene and use a balanced nutrient solution to water the plants.

Some growers will retain their male plants for genetic pool diversity. Inbreeding plants and self-pollination can increase the future probability of hermaphrodite plants.

Thus, some growers might keep male plants for that purpose. However, it would be best if you did not keep the male plants close to the female or handle the female plant after contacting pollen grains.

These male plants also produce some terpenes that are great for pest control. Unlike female flowers, male flowers could also contain limited amounts of cannabinoids like CBD and THC and can be used to make hashish.

If you are a hobbyist or expert cannabis grower, you already know that female plants are the most desirable. They produce high-quality cannabis rich in cannabinoids like THC. Thus, its necessary to find out the gender of your plants on time.

Wispy white hairs on the nodes of your plant signify a female cannabis plant, while pollen sacs signify a male plant. However, since these signs can take up to six weeks to show, you might want to consider chemical leaf testing.

All in all, ensure to check your crop often to identify male or hermaphrodite plants and cut them off.

Multiplex Content Recommendation - 1

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Early Signs Of Male Plant And Female Plant-How To Identify The Difference? - The Island Now

House of the Dragon fans were left scratching their heads last week when the children of a Targaryen and Velaryon union had dark hair.

Viewers saw how the children of Princess Rhaenyra Targaryen (Emma D'Arcy) and Laenor Velaryon (John Macmillan) were fair skinned, brunette ladsthe complete antithesis of their platinum haired parents.

Laenor also happens to be black, adding further mystery to the children's appearance.

House of the Dragon quickly explains the anomaly, revealing the boys were the result of Rhaenyra's affair with Ser Harwin Strong.

In George R. R. Martin's book upon which House of the Dragon and its predecessor Game of Thrones are based, the Targaryens are described as having silver-gold hair with purple eyes that was so distinct it almost looked white thanks to their Valyrian heritage.

Even knowing the boys' true lineage, their brunette coloring still does not entirely explain why their mother's half-siblingsAegon II (Ty Tennant), Helaena (Evie Allen) and Aemond (Leo Ashton)sport the trademark Targaryen blondeness.

They are also the products of a mixed-race union, that of King Viserys Targaryen (Paddy Considine) and Alicent Hightower (Olivia Cooke), a very brunette queen.

In fact, another famous Targaryen from the original Game of Thrones series, Jon Snow (Kit Harrington), was well known for his luscious locks of dark curly hair.

Born as Aegon Targaryen, Snow was the son of Lyanna Stark and Rhaegar Targaryen, a fact only revealed towards the final episodes of the HBO series.

Plenty of fans have theorized over the years as to why some of the most important Targaryens are not blonde at all.

Using 'real world' genetics they analyzed how it would be possible for some mixed race Targaryens are born fair-haired while others do not.

The fans used genome knowledge of dominant and recessive genes to make their conclusions. A dominant gene "refers to the relationship between two versions of a gene," according to the National Genome Research Institute.

Individuals receive two versions of each gene from each of their parents and if the genes differ, the dominant gene will present in their offspring, whether it be in hair color, susceptibility to disease, or other markers.

Fans concluded the Targaryen genes were recessive, but when it came to children of a Targaryen male and non-Valyrian mother their first would be born with darker features, while subsequent offspring were blonde.

"Targaryen males somehow transfer Targaryen traits to their wives and lovers, so second child of the couple inherits Targaryen traits from both mother and father and has Valyrian look. Targaryen genes are somehow "infectious," wrote one fan on a Game of Thornes forum.

This theory works well to explain Snow's dark hair, but is not conclusive because the law of recessive and dominant genes do not seem to be applied consistently across Westeros.

Game of Thrones blogger, Lady Knits A Lot, pointed out that in the original books, three of the five children of Ned and Catelyn Stark were born with the "'Tully look' of red hair and blue eyes, and both of these traits are recessive traits."

"[But] Ned's parents, grandparents and damn near the entire North are described as dark haired and grey eyed," they added.

"So maybe recessive traits are a furphy that we should ignore in Westeros?"

This point was reinforced by Robert Oliver, co-host of The Longest Night podcast dedicated to talking all things Game of Thrones and House of the Dragon.

Oliver told Newsweek the inconsistencies across the shows come down to the fact that how these characters look is key to a plot point.

Rhaenyra's children prove she had an affair, and Jon's very dark hair helped hide the fact he was a Targaryen until the final season.

"It's just storytelling, it needs to be done to move a plot forward," he told Newsweek.

In the case of the House of the Dragon, Rhaenyra's children portrayed as brunette are critical to the conflict which is about to ensue within the dynasty.

"For the purposes of the show, I think what it's doing is it's helpful for Alicent who is trying to implore and impress upon everybody that surrounds her that Rhynaera is not worthy and her children aren't worthy," she said.

"And that it's her children [Alicent's] who should rule after Viserys."

Oliver's assertion comes after Martin himself admitted things don't always add up in the books or series, because it's a fictional world.

"What the fans have to keep in mind... but we're making this s**t up," he told the History of Westeros YouTube channel.

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Why Not All 'House of the Dragon' Mixed Race Targaryens Are Blonde - Newsweek

Identification of the CYCD and CDK gene families in Populus tomentosa

To identify CYCD and CDK genes in P. tomentosa, hidden Markov models (HMMs) and Blastp were used to query the whole genome. After the elimination of redundant sequences and examination of domains, we finally identified 43 CYCD and 27 CDK family members (Table S1). A phylogenetic tree was constructed with 24 CYCD and 18 CDK in Populus trichocarpa (PtrCYCD and PtrCDK) to classify and name the successfully identified members12 (Fig.1). Results showed that 47 PotomCYCDs were divided into six subclasses, of which 12, 4, 10, 6, 9 and 2 members belonged to D1, D2/4, D3, D5, D6 and D7 subclasses, respectively. A total of 27 PotomCDKs were divided into seven subclasses, which belonged to 2 members of the CDKA subclass, 1 member of the CDKB subclass, 5 members of the CDKC subclass, 4 members of the CDKD subclass, 4 members of the CDKE subclass, 2 members of the CDKF subclass, and 9 members of the CDKG subclass. The identified members of the P. tomentosa gene family were named in accordance with the gene family members of P. trichocarpa. Considering that P. tomentosa is an allodiploid, a was added to the name of the gene searched from subgenome A (PtA), and b was added to the name of the gene searched from subgenome D (PtD). In phylogenetic tree analysis, most of genes had their alleles with close relationships. However, we found PotomCYCD6;3a was closer to the orthologs gene PtrCYCD6;3 rather than its allele PotomCYCD6;3b. This phenomenon was also found between PotomCYCD3;5, PotomCYCD5;1, PotomCYCD7;1, PotomCDKA;1, PotomCDKE;1 and PotomCDKF;1 and there corresponding orthologs, which revealed that these alleles differentiated during the evolutionary process. An interesting finding was that a small number genes PotomCYCD6;2b, PotomCDKG;2a, PotomCDKC;2a, PotomCDKC3;b, PotomCDKC4;b and PotomCDKB1;1a were lack of their alleles. We speculated that it was the chromosomal variation and transposon insertion that resulted in the loss of these alleles. All these evidences indicated that PotomCYCDs and PotomCDKs were both conserved and differentiated.

Phylogenetic tree analysis of D-type cyclin (CYCD) and cyclin-dependent kinases (CDK) gene family in P. tomentosa and P. trichocarpa. A PotomCYCA gene from P. tomentosa genome was selected as an outgroup gene. (a) Phylogenetic tree analysis of 43 PotomCYCDs and 22 PtrCYCDs. All CYCDs were classified into six distinct groups on the basis of the subfamily of P. trichocarpa CYCDs (from D1 to D7) and were distinguished by different colours. (b) Phylogenetic tree analysis of 27 PotomCDKs and 18 PtrCDKs. All CDKs were classified into seven distinct groups on the basis of the subfamily of P. trichocarpa CDKs (from CDKA to CDKG) and were distinguished by different colours.

To analyse the sequence differences of alleles from different subgenome, we analysed the protein sequence identity of all members of the two gene families. Results showed that in the PotomCYCD gene family, PotomCYCD1;3a and PotomCYCD1;3b (99.0%) had the highest sequence similarity, and PotomCYCD1;2a and PotomCYCD1;2b (80.6%) had the lowest sequence similarity (Table S2). In the PotomCDK gene family, the highest sequence similarity was PotomCDKE;2a and PotomCDKE;2b (99.5%), and the lowest sequence similarity was PotomCDKA;1a and PotomCDKA;1b (82.4%, Table S3). At the same time, we also investigated the basic characteristics of the two family members, such as their AA length, isoelectric point (PI), molecular weight (MW), and subcellular localization (Table S4). Results showed that the AA length of PotomCYCD gene family varied from 256 to 408 AA. The largest protein was PotomCYCD2;1b (45.24kDa), and the smallest protein was PotomCYCD6;2b (29.51kDa). The PI of most CYCD proteins varied around 57. Subcellular localisation prediction results indicated that all PotomCYCD proteins were located in the nucleus. The difference was that the basic characteristics of different subclasses of proteins in the PotomCDK gene family varied remarkably, but the characteristics of different members of the same subclass were relatively similar. The CDKG subclass (except PotomCDKG;2a) had the largest protein (78.6589.63kDa), and the CDKA and CDKB subclasses had the smallest protein (33.7936.53kDa). Although PotomCDKG;2a is only 117aa in length, it contains part of the conserved domains required by CDK, and it is speculated that it might not be functional due to its short length or mutated during evolution. The protein PIs of different CDK subclasses different but were very similar in the same subclass. Subcellular localisation prediction results showed that all PotomCDK proteins were located in the nucleus and that PotomCDKA;1b might also be located in the cytoplasm. PotomCDKG;4b might also be located in the cell membrane and cytoplasm. PotomCDKG;5a might also be located in the cell membrane.

Gene structural diversity and conserved motif divergence are possible mechanisms for the evolution of multigene families43. To further study the gene and protein structure of the CYCD and CDK gene family, we analysed the number and distribution of exons. The results of gene structure analysis showed that the structures of PotomCYCD genes were similar and that the number of exons varied from 4 to 7. The number of exons in the D3 subclass was 4, and the number of exons in other subclasses except PotomCYCD2;1b and PotomCYCD2;2a was 5 or 6 (Fig.2a). The results of the gene structure analysis of PotomCDK genes showed that the number of exons in CDK ranged from 1 to 13. The gene structure amongst members of the same subclass was relatively conserved. For example, none of the four members of CDKE were introns. Amongst the nine members of CDKG, eight members consisted of 1 long exon and 5/6 short exons. A high number of exons were found in CDKA and CDKC, whereas only 3 exons were observed in the CDKF subclass (Fig.2c).

Gene structure and conserved motif compositions of PotomCYCDs and PotomCDKs. (a) Exon/intron structures of PotomCYCDs. (b) Architecture of conserved protein motifs of PotomCYCDs. (c) Exon/intron structures of PotomCDKs. Yellow boxes and black lines indicate exons and introns, respectively, at each CYCD and CDK gene. (d) Architectures of conserved protein motifs of PotomCDKs. These coloured boxes indicate distinct motifs and their corresponding positions in each CYCD and CDK protein sequence. The detailed characteristics of each motif are shown in Table S5.

To elucidate the distribution of the motifs in CYCD and CDK proteins and their function, ten types of motifs and their distributions of CYCDs and CDKs were predicted using the MEME program (Fig.2). Our results indicated that CYCDs contained similar motif types. However, some differences existed amongst different subclasses. Motifs 15 were contained in all subclasses. Motif 6 was unique to D1 and D2/4 subclasses. Motifs 7 and 8 were contained in most subclasses except D5 and D7. Motif 9 was only D7 subclass Class missing. Motif 10 was included in most subclasses except D1 and D2/4 (Fig.2b). In the CDK gene family, motif 1, 2 and 68 were included in all subclasses. Motif 3 was included in most subclasses except CDKA and CDKB. Motif 4 was not found in CDKA subclasses. Motif 5 was not found in CDKF. Motif 9 was only found in CDKE and CDKG subclasses. Motif 10 was unique to CDKG (Fig.2d). Some interesting findings appeared in some alleles. The PotomCYCD5;1a has one more exon than its allele PotomCYCD5;1b and motif 3 presented in the former but not the latter. PotomCYCD6;2b without allele was lack of motif 7 when comparing to other PotomCYCD6. PotomCDKB1;1a, the only one member in PotomCDKB, had almost the same motifs but an extra motif 4 than the PotomCDKA;1. PotomCDKC;4b was lack of the motif 3 and motif 5 when comparing to other PotomCDKC. These findings revealed that some special alleles might have different gene structures and conserved motifs leading to different functions.

At the same time, we analysed the domains and conserved motifs of CYCDs. LxCxE is a key motif for CYCD binding to RBR33. The PEST sequence, a region full of P(Pro), E(Glu), S(Ser) and T(Thr), might result in itself degradation and were often found in D-type cyclins32,33,34. Results showed that all PotomCYCD proteins had Cyclin_N and Cyclin_C domains. No LxCxE motif was observed in the CYCD6 subclass, and the LxCxE motif existed in other subclass proteins. Most CYCD proteins had the PEST motif, but the position of the PEST motif was not fixed (Fig. S1). Multiple sequence alignment with P. trichocarpa CDK gene family proteins showed that their conserved domains were highly consistent with their orthologous proteins in P. trichocarpa (File S1). Amongst them, CDKA had PSTAIRE, CDKB had PPTALRE or PPTTLRE, CDKC had PITAIRE, CDKE had SPTAIRE, and CDKG had PLTSLRE9. However, PotomCDKC;3b and PotomCDKC;4b were not observed with this characteristic motif.

Specific cis-element motifs can be recognised by transcription factors and participate in gene expression regulation. To further study the potential regulatory mechanisms of PotomCYCDs and PotomCDKs in a diversified biological process, particularly in plant hormones and specific expression, 2.0kb upstream sequences from the translation start sites of CYCD and CDK genes were submitted to the PlantCARE database to detect cis-elements. Results showed that the types and numbers of various cis-acting elements of genes in PotomCYCDs and PotomCDKs were similar, thereby implying their functional relatedness. Multiple hormone-responsive elements, such as ABA responsive (DRE1, ABRE, ABRE2, ABRE3a, ABRE4, TCA-element), auxin and/or salicylic acid activation (as-1), auxin responsive (TGA-element), ethylene responsive (ERE), gibberellin responsive (GARE-motif, P-box, TATC-box) and MeJA responsive (CGTCA-motif, TGACG-motif) elements, were found in cis-acting elements in two gene families. Cis-acting element prediction results showed that the two gene families had similar responses to hormones and had the most responsive elements responsive to ABA followed by ethylene responsive. The numbers and positions of various hormone responsive elements on the promoters of each gene are shown in the Fig. S2S3. In the CYCD gene family, the numbers of ABA responsive and ethylene responsive elements in the D7 subclass with only 2 members were 13 and 10, respectively, but no gibberellin responsive and auxin responsive elements were found in the D7 subclass, which might suggest that the D7 The subclass predominantly responded to ABA and ethylene. The number of MeJA responsive elements in the D5 subclass with 6 members was 18, which was the largest amongst all subclasses. This result might suggest that the D5 subclass predominantly responded to MeJA. In the D6 subclass with only 9 members, 16 Gibberellin responsive elements were found, accounting for the largest proportion and suggesting that the D6 subclass predominantly responded to gibberellin. The auxin responsive element was found in all D1D5 subclasses but not in D6 and D7 subclasses (Fig. S2). In the CDK gene family, the number of ABA and ethylene responsive elements in CDKD subclasses with only 4 members was as high as 20 and 17, but gibberellin responsive and auxin responsive elements were not found in CDKD subclasses, which might imply that CDKD subclasses responded to ABA and ethylene. The numbers of MeJA responsive, gibberellin responsive and auxin responsive elements accounted for 8, 3 and 2, respectively, in CDKF subclasses with only 2 members and had the largest proportion. Auxin responsive element was not found in CDKA, CDKB and CDKD subclasses (Fig. S3).

A number of specific expression elements was also found in cis-acting elements in the two gene families, and the proportions of specific expression elements in the two gene family members were also similar. Pollen specific activation elements were the most numerous, with 49 and 41 in CYCD and CDK families, respectively. In addition, two families also included some different cis-acting elements, such as the seed specific regulation element (RY-element) that only existed in the CDK gene family and the cell cycle regulation element (MSA- like) that only existed in the CYCD gene family (Fig. S2S3).

On the basis of the information from the P. tomentosa genomic database, we determined the chromosomal distributions of CYCD and CDK genes (Table S4). Results suggested that CYCD genes were distributed on 26 chromosomes, whereas CDK genes were mapped onto 21 chromosomes (Fig.3). Although 35 chromosomes contained CYCD or CDK genes, the overall distribution was mostly nonuniform. Chromosomes 2A, 2D, 14A and 14D all contained three CYCD genes, whereas only one CYCD gene was distributed on chromosome 4A. Chromosomes 12A and 12D both contained 3 members of CDK genes, whereas chromosome 1A contained only one CDK gene. Interestingly, chromosomes 16D, 17A and 17D did not contain any CYCD or CDK gene.

Circos figure for chromosome distribution with synteny links. Grey and colourful lines represent synteny blocks and duplicated CYCD and CDK gene pairs, respectively, in P. tomentosa. The gene ids in red font are members of the PotomCYCD gene family, and the gene ids in blue font are members of the PotomCDK gene family.

We constructed a synteny analysis between CYCD and CDK genes in P. tomentosa (Table S6). The synteny blocks and the duplicated CYCD and CDK gene pairs were showen by the grey and colourful lines (Fig.3). All CYCD genes and 24 of 27 CDK genes were identified as collinear genes involving WGD or segmental duplication, whereas 2 CDK genes (i.e. PotomCDKC;4b and PotomCDKG;2a) were considered as dispersed genes, and 1 CDK gene (i.e. PotomCDKB1;1a) was considered as a singleton gene (Table S6). Remarkably, some CYCD and CDK genes were associated with at least five syntenic gene pairs, which implied that these genes might be involved in some critical roles during the evolutionary process. Interestingly, tandem duplication events were not found between CYCD and CDK genes in P. tomentosa. Evidence suggested that WGD or segmental duplication led the expansion of CYCD and CDK genes in P. tomentosa.

To further explore the evolutionary relationships of the CYCD and CDK gene families, we performed syntenic analyses amongst Arabidopsis, P. trichocarpa and P. tomentosa (Table S7). Between Arabidopsis and P. trichocarpa, 7 CYCD and 11 CDK gene pairs were found. A total of 81 CYCD and 38 CDK gene pairs were identified between P. trichocarpa and P. tomentosa (Fig.4). We found that 4 of 7 CYCD gene pairs and 9 of 11 CDK gene pairs between Arabidopsis and P. trichocarpa, respectively, were distributed on chromosome 1 and 4 in Arabidopsis. In P. trichocarpa, CYCD gene pairs were predominantly distributed on chromosomes 1, 2, 7, 9, 14 and 19, whereas CDK gene pairs were predominantly located on chromosomes 1, 3, 8, 10 and 12. The situations of CYCD and CDK gene pair distributions on chromosomes in P. tomentosa were similar to P. trichocarpa. Between P. trichocarpa and P. tomentosa, although abundant gene pairs were identified, 1 CYCD (i.e. PotomCYCD6;3b) and 2 CDK (i.e. PotomCDKC;4b and PotomCDKG;2a) genes did not find any syntenic gene.

Synteny of CYCD and CDK genes in Arabidopsis, P. trichocarpa and P. tomentosa. Red and blue lines represent duplicated CYCD and CDK gene pairs, respectively.

To investigate the possible roles of the PotomCYCDs and PotomCDKs, the expression levels of 43 CYCD and 27 CDK genes were determined by transcriptome results in three various tissues, i.e. leaf, stem and root41. Our results indicated that CYCD and CDK genes showed similar expression profiles in different tissues. Most genes were expressed in all three tissues, and alleles from different subgenomes had similar or even the same expression pattern (Figs. S4S5). In CYCD and CDK gene families, most genes showed this expression trend, with the highest expression in stems, followed by roots and leaves. In the CYCD gene family, most D3 subclass gene expression levels conformed to this trend. However, CYCD3;1a, CYCD3;2a and CYCD3;2b gene expression levels were highest in roots, and the expression of CYCD3;2b in leaves was highest amongst all genes. In terms of the overall expression levels of genes in different subclasses, D3 subclass genes had the highest expression, followed by the D1 and D2 subclasses, whereas the D7 subclass was not expressed in all tissues. In the CDK gene family, the expression trends of CDKA and CDKB subclass genes were the same as those mentioned before. The genes of other subclasses are also highly expressed in leaves and roots, such as CDKC;1a/b and CDKG;1a/b had the highest expression in leaves and CDKC;2a/b and CDKG;4a/b had the highest expression in roots. In terms of the overall expression levels of genes in different subclasses, the CDKA subclass had the highest gene expression followed by the CDKG subclass. These results suggested that CYCD and CDK genes had similar expression patterns, implying their functional relevance, and the overall expression level of CYCD genes was lower than that of CDK genes. These results might also indicate that alleles with the same function as in an allodiploid species co-regulated the growth and development of the organism.

In order to analyze the interaction between different CYCD and CDK proteins, the STRING website was used to predict the interaction between different CYCD subclasses and CDK proteins. First, all PotomCYCD and PotomCDK genes were compared with the Arabidopsis database of the STRING website. The comparison results and annotation information are shown in Table S8. The interaction between different subclasses of CYCD and CDK was predicted and the line thickness indicates the strength of data support (Fig.5). Results showed that CDKA (CDC2) was at the core of the interaction relationship. The protein interaction prediction results showed that the D1 subclass could interact with CDKA, CDKD1;1 and CDKE;1 and had the strongest interaction with CDKA. The D2/4 subclass only could have a strong interaction with CDKA. In the D3 subclass, the proteins CYCD3;1 and CYCD3;3 were obtained from the alignment and could interact with CDC2 and CDKE;1, and the interaction with CDKA was stronger. The D5 subclass could interact with CDKA, CDKB1;2, CDKD1;1, CDKD1;3, CDKE;1 and CAK1AT (CDKF). The D6 subclass could interact with CDKA, CDKB1;2, CDKD1;1 and CDKD1;3 has an interaction relationship. The D7 subclass only had a weak interaction relationship with CDKA (Fig.5). These results suggested that different subclasses of CYCD proteins might differ in gene sequence and protein properties and in their interaction with CDKs.

Prediction of the interaction between different subfamilies of PotomCYCDs and PotomCDKs gene family proteins by using the STRING website. (a) Interaction between D1 subfamily and CDKs. (b) Interaction between D2/4 subfamily and CDKs. (c) Interaction between D3 subfamily and CDKs. (d) Interaction between D5 subclass and CDKs. (e) Interaction between D6 subfamily and CDKs. (f) Interaction between D7 subfamily and CDKs. Line thickness indicates the strength of data support.

Previous in vitro yeast two-hybrid (Y2H) experiments and molecular docking experiments showed that PtoCYCD3;3 protein interacts with 12 PtoCDK proteins, of which the strongest interaction is PtoCDKE;212. To verify the reliability of the in vitro Y2H results, in vivo validation in plants was performed using the Bimolecular Fluorescent Complimentary (BIFC) assay. The 12 PtoCDKs screened by Y2H and PtoCYCD3;3 were fused to the N- and C-termini of YFP to construct fusion vectors (YFPNPtoCDKs and YFPCPtoCYCD3;3), and transient infection mediated by Agrobacterium in two fusion proteins were co-expressed in the lower epidermal cells of tobacco. If the two proteins interacted, the two fragments of the fluorescent protein will be close to each other in space, complementary to each other and reconstructed into an active and complete fluorescent protein molecule, thereby generating fluorescence. At the same time, GUS was fused to the N-terminus of YFP (YFPNGUS) and co-expressed with YFPCPtoCYCD3;3 as a negative control. The 12 PtoCDKs (PtoCDKA;1, PtoCDKB1;1, PtoCDKB1;2, PtoCDKB2;1, PtoCDKB2;2, PtoCDKC;2, PtoCDKD;1, PtoCDKD;2, PtoCDKE;2, PtoCDKF;1, PtoCDKG;3 and PtoCDKG;4) and PtoCYCD3;3, showed fluorescence in the nuclei of tobacco epidermal cells (Fig.6). The results indicated that PtoCYCD3;3 also interacted with these 12 PtoCDKs proteins in plants.

BiFC validation in tobacco epidermis. PtoCYCD3;3 connects pSPYCE(MR) vector and PtoCDKs connects pSPYNE(R)173 vector. After co-expression in tobacco leaf epidermal cells, the fluorescence signal was observed under a laser confocal microscope. YFPC-PtoCYCD3;3+YFPN-GUS were used as negative control.YFP: yellow fluorescent signal; NLS-mCherry: nuclear signal localisation label; Bright field: brightfield vision; Merge: superposition of fluorescence signals, bar=50m.

Our previous research found that transgenic PtoCYCD2;1 and transgenic PtoCYCD3;3 poplars have completely opposite phenotypes. Transgenic PtoCYCD2;1 plants have reduced plant height, curled leaves and thin stems42, whereas transgenic PtoCYCD3;3 poplar plants have increased height, curled leaves, thickened stem and branched in advance12. Cloned PtoCYCD2;1 and PtoCYCD3;3 genes were combined with the CYCD gene families of P. tomentosa and P. trichocarpa to construct a phylogenetic tree. Results showed that PtoCYCD2;1 and PtoCYCD3;3 belonged to the D2 and D3 subclasses, respectively, and closely related to the PotomCYCD gene (Fig. S6).

In order to find out the interaction between PtoCYCD2;1 and PtoCDKs, in vitro Y2H and in vivo BIFC experiments were used to detect the interaction. Y2H vectors (pGBKT7PtoCYCD2;1 and pGADT7PtoCDKs) were constructed and co-transformed into yeast AH109 competent cells, and the successfully identified positive yeast strains were spread on different AA-deficient media for Y2H experiment. As a competitive inhibitor of HIS3, 3-AT can inhibit the expression of HIS3 to a certain extent by adding this substance to the culture medium. The growth rates on SD-Trp-Leu-His+10/20mM 3-AT and SD-Trp-Leu-His-Ade culture media were observed to detect the interaction strength between PtoCYCD2;1 and different PtoCDKs proteins. During the 6day observation period, PtoCDKD;3, PtoCDKF;1 and PtoCDKG;5 could grow on SD-Trp-Leu, SD-Trp-Leu-His+10/20mM 3-AT and SD-Trp-Leu-His-Ade culture media, suggesting the strongest interaction. PtoCDKA;1, PtoCDKB1;1, PtoCDKB2;1, PtoCDKB2;2, PtoCDKD;2, PtoCDKE;1, PtoCDKE;2 and PtoCDKG;1 could grow on SD-Trp-Leu, SD-Trp-Leu-His+10/20mM 3-AT culture media, suggesting a strong interaction. PtoCDKC;1, PtoCDKD;1, PtoCDKG;3 and PtoCDKG;4 could only grow on SD-Trp-Leu culture medium, but not on SD-Trp-Leu-His+10/20mM 3-AT and SD-Trp-Leu-His-Ade culture media, indicating that no direct interaction between these proteins (Fig.7). The growths on the SD-Trp-Leu-His+10/20mM 3-AT and SD-Trp-Leu-His-Ade culture media for 3 and 6days were photographed and observed, and the interaction strength of the PtoCDKs gene family members with PtoCYCD2;1 was observed to have the following relationships: PtoCDKD;3=PtoCDKF;1=PtoCDKG;5>PtoCDKA;1>PtoCDKG;1>PtoCDKE;2>PtoCDKE;1>PtoCDKB2;1>PtoCDKB2;2>PtoCDKD;2>PtoCDKB1;1.

Proteinprotein interactions of PtoCYCD2;1 with PtoCDKs. Yeast cells were co-transformed with pGBKT7 and pGADT7 constructs carrying the corresponding genes and grown on SD-Trp-Leu, SD-Leu-Trp-His+10mM 3-AT, SD-Leu-Trp-His+20mM 3-AT, SD-Leu-Trp-His-Ade. AD+BD, AD+BD-PtoCYCD2;1 and AD-PtoCDKs+BD, were used as negative control. Day represents the number of days of growth on the corresponding medium. The triangle represents dilution in a 0.1-fold gradient (1,0.1 and 0.01).

To verify the interaction between PtoCYCD2;1 and PtoCDKD;3, PtoCDKF;1, PtoCDKG;5 and the fastest-growing PtoCDKA;1 on SD-Trp-Leu-His+10/20mM 3-AT culture medium in plants, we successfully constructed BIFC vectors (YFPNPtoCDKs and YFPCPtoCYCD2;1), which were transiently expressed in the lower epidermis of tobacco through Agrobacterium-mediated transient infection. Results showed that only PtoCDKA;1 and PtoCYCD2;1 showed fluorescence in the nuclei of tobacco cells and that PtoCDKD;3, PtoCDKF;1, PtoCDKG;5 and PtoCYCD2;1 co-expressed no fluorescence signal (Fig.8). These results indicated that PtoCYCD2;1 only interacted with PtoCDKA;1 in plants.

BiFC validation in tobacco epidermis. PtoCYCD2;1 connect pSPYCE(MR) vector and PtoCDKs connect pSPYNE(R)173 vector. After co-expression in tobacco leaf epidermal cells, the fluorescence signal was observed under laser confocal microscopy. YFP: yellow fluorescent signal; NLS-mCherry: nuclear signal localisation label; Bright field: bright field vision; Merge: superposition of fluorescence signals. Scale bars forYFPC-PtoCYCD2;1+YFPN-PtoCDKD;3, 50m; for others, 25m.

Continued here:
Study on the interaction preference between CYCD subclass and CDK family members at the poplar genome level | Scientific Reports - Nature.com

Researchers performed a nationwide cohort study of the use of calcium-channel blockers and adenosine modulators and risk of hospitalization in bipolar disorder.

CASE VIGNETTE

Mr Amir is a 48-year-old male from the Balkans with a 17-year history of bipolar I disorder with psychotic features. He was last hospitalized for affective symptoms at age 35. He has chronic insomnia, low energy, impaired concentration, and suspiciousness. He also has episodic irritability and anger. He has been on a stable psychotropic regimen of quetiapine 100 mg in the morning and 400 mg at bedtime, and valproic acid 750 mg daily. Mr Amir was diagnosed with comorbid hypertension after multiple elevated readings at his outpatient psychiatry visits. He does not have a primary care physician, so his psychiatrist started him on amlodipine, which was titrated to 10 mg daily. His blood pressure control subsequently improved, without any change in his psychiatric symptoms.

Inadequate response and treatment resistance remain issues in bipolar disorder.1 One approach to identifying novel treatments is drug repurposing, whereby a drug approved for 1 disease is investigated for its potential for a new indication. Previous reviews include the adenosine modulator allopurinol2 and calcium-channel blockers (CCBs)3 for potential repurposing in bipolar disorder, although evidence for the latter has been inconclusive. Allopurinol and dipyridamole are adenosine modulators that may have potential in the treatment of bipolar disorder and other severe mental illnesses.4 Allopurinol is a xanthine oxidase inhibitor used to treat gout and hyperuricemia.4 Dipyridamole is an antithrombotic and vasodilator that inhibits adenosine reuptake.5

The Current Study

Lintunen and colleagues6 investigated the risk of psychiatric hospitalization associated with CCBs (dihydropyridines, verapamil, diltiazem) and adenosine modulators (allopurinol, dipyridamole) in a nationwide Finnish cohort of individuals with bipolar disorder. They identified individuals diagnosed with bipolar disorder between 1987 and 2018 from inpatient, specialized outpatient, sickness absence, and disability pension registers. Follow-up started on January 1, 1996, or at the date of diagnosis, and ended at death, diagnosis of schizophrenia, or on December 31, 2018 (whichever occurred first).

The primary exposures were use of CCBs and adenosine modulators. Thiazide diuretics were used as a negative control. Information on medication use was obtained from the Prescription Register and modeled with PRE2DUP method, which predicts periods of use and non-use.7 The primary outcome was hospitalization due to affective symptoms, based on the Hospital Discharge register. Secondary outcomes were hospitalization due to manic or depressive symptoms or any psychiatric hospitalization. The risk of non-psychiatric hospitalization was also analyzed to consider potential adverse somatic effects of CCBs or adenosine modulators.

Data were analyzed using within-individual models, where individuals act as their own control, based on periods of exposure and non-exposure, using stratified Cox regression. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated for hospitalization-based outcomes comparing periods when the individual was using versus no using the medication. Models were adjusted for use of antipsychotics, mood stabilizers, benzodiazepines and Z-drugs, antidepressants, temporal order of treatments, and time since cohort entry.

The study cohort included 60,045 individuals, with a median follow-up of 8.4 years. Approximately 9056 individuals (15%) used primary dihydropyridines (91%). The most commonly used dihydropyridine was amlodipine (64%). Approximately 2967 individuals (5%) used adenosine modulators (57% allopurinol and 43% dipyridamole). Thiazides were used by 1286 individuals (2%).

Use of CCBs was associated with a decreased risk of hospitalization due to affective symptoms (aHR=0.83, 95% CI 0.78-0.88). The beneficial effect was associated with diltiazem and dihydropyridines, but not verapamil. Results were similar for hospitalization due to depressive symptoms or any reason. However, verapamil and dihydropyridinesbut not diltiazemwere associated with decreased risk of hospitalization due to mania.

Use of adenosine modulators was associated with a decreased risk of hospitalization due to affective symptoms (aHR=0.87, 95% CI 0.79-0.96). Effects were similar for both allopurinol and dipyridamole. Results were similar for any psychiatric hospitalization. Allopurinol, but not dipyridamole, was associated with a decreased risk of hospitalization due to depressive symptoms. There was no association between adenosine modulators and hospitalization due to manic symptoms. Allopurinol was associated with an increased risk of non-psychiatric hospitalization (aHR=1.10, 95% CI 1.03-1.17). The decrease in risk of hospitalization with these medications was greater in individuals under versus over 40 years of age.

Study Conclusions

The authors found that CCBs and adenosine modulators were associated with a decreased risk of hospitalization due to affective symptoms in individuals with bipolar disorder. Study strengths include the large nationwide cohort, long follow-up period, and use of within-individual models, which control for time-invariant factors (eg, genetics). Study limitations include the absence of ratings of symptom severity, the fact that the authors did not adjust for psychosocial treatments, and the potential for selection bias in observational studies.

The Bottom Line

Findings support potential roles for calcium, the purinergic system, and adenosine modulators in the pathophysiology of bipolar disorder. CCBs and adenosine modulators warrant further study in these individuals.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Gitlin M. Treatment-resistant bipolar disorder.Mol Psychiatry. 2006;11(3):227-240.

2. Bartoli F, Cavaleri D, Bachi B, et al. Repurposed drugs as adjunctive treatments for mania and bipolar depression: a meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials.J Psychiatr Res. 2021;143:230-238.

3. Cipriani A, Saunders K, Attenburrow MJ, et al. A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.Mol Psychiatry. 2016;21(10):1324-1332.

4. Hirota T, Kishi T. Adenosine hypothesis in schizophrenia and bipolar disorder: a systematic review and meta-analysis of randomized controlled trial of adjuvant purinergic modulators.Schizophr Res. 2013;149(1-3):88-95.

5. Gamboa A, Abraham R, Diedrich A, et al. Role of adenosine and nitric oxide on the mechanisms of action of dipyridamole.Stroke. 2005;36(10):2170-2175.

6. Lintunen J, Lhteenvuo M, Tanskanen A, et al. Allopurinol, dipyridamole and calcium channel blockers in the treatment of bipolar disorder - a nationwide cohort study.J Affect Disord. 2022;313:43-48.

7. Taipale H, Tanskanen A, Koponen M, et al. Agreement between PRE2DUP register data modeling method and comprehensive drug use interview among older persons.Clin Epidemiol. 2016;8:363-371.

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Calcium-Channel Blocker and Adenosine Modulator Use and Risk of Hospitalization in Bipolar Disorder - Psychiatric Times

'Israel is advanced in research related to aquaculture and has the capacity to create adequate innovation'

Ahead of a groundbreaking international conference organized by Israels Agriculture and Rural Development Ministry on Marine Aquaculture and Food Technology, i24NEWS had the honor of visiting companies leading in innovation.

Specializing in marine and desert agriculture, the companies have developed solutions to alleviate global food insecurity at a time when certain animal species are threatened with extinction.

Given the rate of population growth, global warming, climate change, rising sea levels, and diminishing fertile areas for agricultural crops, a significant part of the futures food must come from the sea and the desert.

With this in mind, the conference to be held in the southern Israeli resort town of Eilat from October 18 to 20 will bring together agriculture ministers scientists, and major entrepreneurs from Israel, Bahrain, Malta, Morocco, and Jordan.

"We are all aware of the problem of food insecurity and that is why we are trying to provide more protein in our diets, Michal Levy, scientist and senior deputy director general of Israels Agriculture Ministry, told i24NEWS.

Climate change and its influence on agriculture and new forms of food are subjects that we must be concerned about today. We know that Israel is very advanced in research related to aquaculture, and has the capacity to create fish and develop adequate innovations, she said.

The current government is emphasizing programs for students focusing on aquaculture in the Eilat region, which has many advantages in terms of seaweed and fish farming. Additionally, it is encouraging the creation of infrastructure in order to improve the ecosystem of Eilat as well as the rest of Israel to then export such knowledge abroad.

At the Faculty of Agriculture, Food and Environment in Rehovot of central Israel, the team of Dr. Lior David an expert in animal sciences is carrying out advanced studies in fish production to increase sustainability.

In fish, David is studying the genetics of resistance to infectious diseases and sex determination. Knowledge from their basic research is then used to select genetically improved strains of fish to solve problems that hinder fish farming.

"We want to control the male-female ratio by producing more females to produce more births, through hormone injection methods, David explained.

Aquaculture has become the main source of protein production from fish, but the appearance of diseases 20 years ago, in Europe and Israel, which now affect the whole world, complicates the process.

At the Faculty, researchers are particularly working to develop a vaccine that could be injected into fish to reduce the spread of disease. They also inject specific genes into fish eggs to control reproduction and increase the quantity of fish, as well as for cultured fish meat which makes it possible to create real meat by growing animal cells directly from fish.

Spirulina to replace meat?

i24NEWS traveled to the village of Tel Mond near Netanya in central Israel where Simpliigood is located, the first company in the world to exploit a large-scale biomass production technology of spirulina, algae with high nutritional quality.

Through a multidisciplinary approach involving biology, engineering, chemistry, and computer science, Simpliigood is creating the most efficient natural food source on earth Spirulina, one of the most nutritional and plant-based sources of protein on the planet.

About 74 percent of Simpliigoods spirulina is made from crude protein, which provides 18 of the 20 amino acids needed for the body to function properly. It contains three times more protein than meat and helps fight anemia.

"Our company started about ten years ago with the aim of taking spirulina from a luxurious dietary supplement to a staple in our diet; then we started to market it, Bach Baruch CTO at Simpliigood, told i24NEWS.

We are trying to produce yogurts, cheese, ice cream, fish, and even meat from spirulina thanks to solar energy, salt, and water essential to cultivate it.

Spirulina can also replace gluten, create textures, or serve as an emulsifier, but its main purpose is to make diets healthier and richer.

"We harvest fresh spirulina with natural methods without antibiotics or hormones. We can also add flavor and customize colors to make it look like the real thing, Bach said.

At Simpliigood, it is grown in two micro-farms with state-of-the-art technology in 50-degree freshwater ponds to maintain an ideal growth environment.

The company offers a sustainable, affordable, and clean, minimally-processed food alternative with immense value.

Vertical greenhouses: Growing out of season

Producing strawberries in winter? This is one of the missions given to the startup Vertical Field, created in 2006 near the central Israeli city of Raanana.

Using state-of-the-art technology, it meets the needs of the growing population by growing produce in any indoor or outdoor urban space.

The company designed integrated vertical platforms and quickly achieved international success with more than 500 projects worldwide. We are the future in agriculture because we can grow produce out of season, said Gilad Marek, chief agronomist at Vertical Field.

They thus circumvent the disadvantages linked to the climate without entering into competition with farmers. On the contrary, Marek assured that "they work together."

"We use 90 percent water, no pesticides or chemicals, to grow herbs such as basil, lettuce, mint, parsley, coriander, and eventually we hope to produce strawberries, mushrooms, or even cherry tomatoes, Ronen Redel, VP of Business Development at Vertical Field, told i24NEWS.

"We wanted to set up a method that is as close as possible to nature. This technology has several advantages, based on air control, irrigation, and lighting that allow plants to be given the conditions and nutrients they need to grow in 21 days.

Farmers can also supply themselves daily from the container.

Vertical Field developed pilot projects in Australia, Vienna, and the United States, as well as in Ukraine and Russia before the war broke out.

"We can also play with day and night lighting to promote growth, and easily monitor the development of each of the plants. By isolating them from the environment, the plants are thus protected from the parasites and dust responsible for their deterioration, Marek emphasized.

Will Israel's sustainability know-how succeed on the world stage?

Original post:
Israel, A Pioneer In Agriculture Of The Future - I24NEWS - i24NEWS

The Irish Limousin Cattle Societys 50th Anniversary Extravaganza took place in Carrick-on-Shannon last weekend, beginning on Friday (September 30) and drawing to a close on Sunday (October 2).

There was plenty of excitement over the weekend, with the commercial show, pedigree show, heifer sale and Mega Moo raffle being some of the highlights.

A number of sponsors form the agricultural sector contributed to the event including Agriland Media Group, which sponsored a class in the commercial show ring.

The event not only drew crowds from the four corners of Ireland, it witnessed a large delegation from both the UK, Europe and in particular France the home of the Limousin breed.

Prior to the show day, the society offered 100 tickets at a price of 100 each for the Mega Moo draw, the winner of which was Donal Moloney, who selected Eoghan Breslins heifer as his first choice.

The owner of the chosen heifer, Breslin, received a prize of 10,000 from the society, while Moloney walked away from the event with a commercial Limousin heifer for 100.Donal Moloney with his chosen Mega Moo heifer and pictured with owner Eoghan Breslin

Topping the Pre-Inspected Elite Heifer Sale was Co. Cavan breeder Eddie Lynch with his Ernevalley Sweetheart ET which sold for 11,000.

Sample prices from the Elite Heifer Sale:

In the pedigree show classes, the judges on the day were Rikke Benoit from France and Chris Penny from the UK.

The Senior Male Champion went to Killcastle Pierson, owned by Alan and Paul Kelly. This March 2019-born Ampertaine Commander son was out of Killcastle Izzy Monique ET.Killcastle Pierson owned by Alan and Paul Kelly

The Intermediate Male, Overall Male and Overall Limousin Reserve Champion title went to Carrickmore Schumacher ET, owned by the Connell Brothers. This impressive bull is out of Baileys Iceprincess and sired by Sympa.

Carrickmore Schumacher ET was sold privately in the yard for 30,000.Carrickmore Schumacher ET owned by the Connell Brothers

It will be another weekend to remember for William Smiths Milbrook Limousin Herd based in Oldcastle, Co. Meath.

It was Milbrook Nikkiespice ET, a daughter of the famous Milbrook Gingerspice, who was tapped out as Overall Limousin Champion of the Show after earlier being crowned Senior Female Champion and Overall Female Champion.

It was a clean sweep for the Milbrook Limousin Herd in the Overall Female Championship as the reserve champion was also awarded to William Smith for his April 2021-born heifer, Milbrook Senorita ET.

This heifer is a Wilodge Tonka-sired heifer out of Milbrook Enya. She was also crowned Intermediate Female Champion on the day.Milbrook Senorita ET owned by William Smith

The Reserve Champion in the Senior Female Championship was again awarded to William Smith and the Milbrook Herd for Milbrook Nenya ET, a Wilodge Vantastic-sired cow out of Milbrook Enya.Milbrook Nenya ET owned by William Smith

In the Junior Female Championship, it was Co. Cavan man Eddie Lynch with his heifer, Ernevalley Sweetheart ET, who took home the champion sash. This December 2021-born heifer was sired by Nenuphar out of Ernevalley Nadine ET.Ernevalley Sweetheart ET owned by Eddie Lynch

Reserve Champion went to Thomas OShea with his heifer Templequain Selena. She was first in the twelfth class and was sired by Whinfellpark Lomu and out of Templequain Mabelle.Templequain Selena owned by Thomas OShea

With the pedigree males, Castlebrock Trafford ET, a March 2022-born bull bred by Gerard Davis, was awarded Reserve Overall Male Champion.

Trafford was sired by Mereside Godolphin and out of Lomond Lexie. He was earlier tapped out as Junior Male Champion.Castlebrock Trafford ET, Gerard Davis

James OGrady, with his June 2020-born bull Meenross Ring Leader ET, was awarded the Reserve Senior Male Champion sash. This bull was sired by Hatcliff Dancer out of the dam Castleview Felicity.Meenross Ring Leader ET owned by James OGrady

The Connell Brothers took the top spot in the Intermediate Championship, but Darragh OMeara secured reserve champion with his bull Hurricane Scat Man ET who was sired by Ampertaine Foreman and out of Hurricane Lady Hawk ET.Hurricane Scat Man ET owned by Darragh OMeara

The Junior Male Champion was awarded to Gerard Davis, but Padraic Golden took the reserve title with his November 2021-born bull, Clew Bay Smokey.

This bull was sired by Plumtree Fantastic and out of the dam Clew Bay Laoise.Clew Bay Smokey owned by Padraic Golden

The Milbrook Herd finished the day in style by winning the Best Pair of Limousins by the same breeder, while it was A and P Kelly who won Best Group of Three by the same breeder.

The society thanked all who made the event a huge success and gave a particular mention to the council, breeders, organising committee and all who helped out over the weekend.

A special word of thanks was also mentioned to the title sponsors FBD Insurance, and the partner sponsors ABP, Univet, Progressive Genetics and Munster Bovine, as well as all class sponsors on the day.

Read more:
Results: Limousin society's 50th anniversary show and sale - Agriland

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Hair supplements seem like the golden ticket to great hair: all you have to do is pop a pill, sit back, and wait for glossy, thicker hair to reveal itself, right? The reality is a little more complex. When supplements do work, they take time to work, and not all supplements are created equal. Supplements arent regulated by the Food and Drug Administration, which means its difficult to tell which brands are using the highest quality ingredients and which rely on a lot of inexpensive fillers that may sound impressive, but arent going to target your hair follicles in any meaningful way. Unfortunately, a supplements price tag doesnt always tell an accurate story, either.

So, how much should you expect from a hair supplement and what are its limitations? Do supplements actually help hair growth? We asked an expert.

First and foremost, no one treatment will work for all people. Its important to consider the reason why you are shedding hair before finding a solution that works for you (and thats something that should ideally be determined with the help of a board-certified dermatologist).

Hairsupplementsshould be customized to the cause ofhairloss, says Dr. Yoram Harth, board certified dermatologist and medical director ofMDhair. Women with postpartum or stress-relatedhairloss should get a different kind ofsupplementthan women after 40 with post-menopausal or genetic-relatedhairloss. Well-chosensupplementscan help provide the first group with the micronutrients essential forhairregrowth. The second group should look forsupplementsthat include,in addition to essentialvitaminsand minerals, DHT blockers that counteract the effect of dehrdotestoren on thehairfollicles, and plant-like ashwagandhaand reishi and maitake mushrooms can helphairregrowth by reducing inflammation and stress.

There are no miracles in a bottle. And many supplement brands try to skate by adding less-than-effective filler ingredients to their formulas. Knowing the limitations of certain supplements can help temper your expectations and save you money.

Unfortunately, some overhypedhairsupplementscan do more damage than good, says Dr. Harth. Examples are sugary gummysupplementsthat maintain high amounts of biotin. Biotin is a good ingredient, but there is evidence that using it as a single ingredient significantly affectshairregrowth. The high amount of sugar in most of these gummies can hurthairregrowth and its other health disadvantages.

In people with pregnancy, stress, or nutrition related, the most effective ingredients to look for arevitaminsand minerals, according to Dr. Harth. Good addition in these cases in collagen peptide, preferably sourced from wild-caught fish. People with genetically relatedhairloss need to look forsupplementsthat contain natural DHT-blockers combined with thesevitaminsin minerals.

Ready for a shock? Despite how often we hear about the benefits of biotin, it is one of the most hyped hair growth ingredients. Biotin is a good ingredient, but there is evidence that using it as a single ingredient significantly affectshairregrowth, Dr. Harth says. In very high amounts, it can also cause acne breakouts.

The common causes forhairloss in women are genetics, postpartum (pregnancy), crash diets, wrong hairstyling, autoimmune diseases, and hormonal imbalances Dr. Harth says.

The bestsupplementsto help regrowhairare the ones that target the root cause of yourhairloss, Dr. Harth says. Here are some ingredients that Dr. Harth says can aid in hair growth for a number of different hair shedding culprits.

The best naturalsupplementsfor genetic, age, and hormonal-relatedhairloss are plants that can reduce the effect of male hormones, mainly dihydrotestosterone (DHT), on thehairfollicles, Dr. Harth says.

Examples of those plants are:

Saw palmetto is a plant extract believed to block the effects of male hormones on thehairfollicle and reduce excessivehairshedding. These ingredients can be found in topical scalp serums and oralhairsupplements.

Ginseng: A few types of ginseng are believed to help withhairgrowth. For optimal results, look forhairsupplementsplants-based serum that contains the Panax Ginseng Root.

Pygeum Bark Extract: Rich in phytosterols that block the effect of DHT onhairfollicles to enhancehairgrowth.

Broccoli Powder contains antioxidants that reduce free radical damage to the scalp. Bvitaminsin broccoli extract help reduce stress, contributing tohairloss.

The best naturalsupplementsfor Postpartumhairloss will need to replenish thevitamins, minerals, and micronutrients that were depleted during pregnancy, Dr. Harth says and these samesupplementsshould also be safe for breastfeeding women.

Examples of ingredients needed:

Iron helps boost circulation and carries oxygen to the roots of thehair, which allows thehairto grow faster and longer. An iron deficiency can lead tohairloss.

VitaminsC, D, E Having the right amount of thesevitaminsis required for a healthy scalp and regrowth of healthier, thicker newhair.

Vitamin B12 and Folic Acid Helphairfollicles regenerate and heal faster to produce new healthierhair.

Iodine, Magnesium, Zinc, Selenium, Manganese, and Chromium Having the right amount of these minerals is required for a healthy scalp and regrowth of healthier, thicker newhair.

Calcium An essential mineral that helps reducehairbreakage, dry scalp, and brittle nails.

Vitamin K2 By stimulating blood flow to the scalp, it enhances healthyhairregrowth.

Combiningvitamins, minerals, and adaptogens can reduce this type ofhairloss, Dr. Harth says. Examples of natural adaptogens are the Maitake and Reishi Mushrooms. Potent adaptogens, immunomodulatory, and inhibitors of 5-reductase, these mushroom extracts support a healthy scalp and regrowth of newhair.

Hair supplements can be extremely helpful but only if they are targeting your hair loss concern and contain effective ingredients for your personal needs. Before you start any new supplement, check with your doctor. Get a thorough exam to determine the cause of your hair loss and be patient it can take time to experience the benefits of a quality supplement.

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Do Supplements Help Hair Growth? We Asked An Expert - SheFinds

Expression of genes depending on parentage

Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed or not, depending on whether they are inherited from the mother or the father.[1][2][3][4][5] Genes can also be partially imprinted. Partial imprinting occurs when alleles from both parents are differently expressed rather than complete expression and complete suppression of one parent's allele.[6] Forms of genomic imprinting have been demonstrated in fungi, plants and animals.[7][8] In 2014, there were about 150 imprinted genes known in mice and about half that in humans.[9] As of 2019, 260 imprinted genes have been reported in mice and 228 in humans.[10]

Genomic imprinting is an inheritance process independent of the classical Mendelian inheritance. It is an epigenetic process that involves DNA methylation and histone methylation without altering the genetic sequence. These epigenetic marks are established ("imprinted") in the germline (sperm or egg cells) of the parents and are maintained through mitotic cell divisions in the somatic cells of an organism.[11]

Appropriate imprinting of certain genes is important for normal development. Human diseases involving genomic imprinting include Angelman syndrome, PraderWilli syndrome and male infertility.[3]

In diploid organisms (like humans), the somatic cells possess two copies of the genome, one inherited from the father and one from the mother. Each autosomal gene is therefore represented by two copies, or alleles, with one copy inherited from each parent at fertilization. The expressed allele is dependent upon its parental origin. For example, the gene encoding insulin-like growth factor 2 (IGF2/Igf2) is only expressed from the allele inherited from the father. Although imprinting accounts for a small proportion of mammalian genes they play an important role in embryogenesis particularly in the formation of visceral structures and the nervous system.[12]

The term "imprinting" was first used to describe events in the insect Pseudococcus nipae.[13] In Pseudococcids (mealybugs) (Hemiptera, Coccoidea) both the male and female develop from a fertilised egg. In females, all chromosomes remain euchromatic and functional. In embryos destined to become males, one haploid set of chromosomes becomes heterochromatinised after the sixth cleavage division and remains so in most tissues; males are thus functionally haploid.[14][15][16]

That imprinting might be a feature of mammalian development was suggested in breeding experiments in mice carrying reciprocal chromosomal translocations.[17] Nucleus transplantation experiments in mouse zygotes in the early 1980s confirmed that normal development requires the contribution of both the maternal and paternal genomes. The vast majority of mouse embryos derived from parthenogenesis (called parthenogenones, with two maternal or egg genomes) and androgenesis (called androgenones, with two paternal or sperm genomes) die at or before the blastocyst/implantation stage. In the rare instances that they develop to postimplantation stages, gynogenetic embryos show better embryonic development relative to placental development, while for androgenones, the reverse is true. Nevertheless, for the latter, only a few have been described (in a 1984 paper).[18][19][20]

No naturally occurring cases of parthenogenesis exist in mammals because of imprinted genes. However, in 2004, experimental manipulation by Japanese researchers of a paternal methylation imprint controlling the Igf2 gene led to the birth of a mouse (named Kaguya) with two maternal sets of chromosomes, though it is not a true parthenogenone since cells from two different female mice were used. The researchers were able to succeed by using one egg from an immature parent, thus reducing maternal imprinting, and modifying it to express the gene Igf2, which is normally only expressed by the paternal copy of the gene.

Parthenogenetic/gynogenetic embryos have twice the normal expression level of maternally derived genes, and lack expression of paternally expressed genes, while the reverse is true for androgenetic embryos. It is now known that there are at least 80 imprinted genes in humans and mice, many of which are involved in embryonic and placental growth and development.[11][21][22][23] Hybrid offspring of two species may exhibit unusual growth due to the novel combination of imprinted genes.[24]

Various methods have been used to identify imprinted genes. In swine, Bischoff et al. compared transcriptional profiles using DNA microarrays to survey differentially expressed genes between parthenotes (2 maternal genomes) and control fetuses (1 maternal, 1 paternal genome).[25] An intriguing study surveying the transcriptome of murine brain tissues revealed over 1300 imprinted gene loci (approximately 10-fold more than previously reported) by RNA-sequencing from F1 hybrids resulting from reciprocal crosses.[26] The result however has been challenged by others who claimed that this is an overestimation by an order of magnitude due to flawed statistical analysis.[27][28]

In domesticated livestock, single-nucleotide polymorphisms in imprinted genes influencing foetal growth and development have been shown to be associated with economically important production traits in cattle, sheep and pigs.[29][30]

At the same time as the generation of the gynogenetic and androgenetic embryos discussed above, mouse embryos were also being generated that contained only small regions that were derived from either a paternal or maternal source.[31][32] The generation of a series of such uniparental disomies, which together span the entire genome, allowed the creation of an imprinting map.[33] Those regions which when inherited from a single parent result in a discernible phenotype contain imprinted gene(s). Further research showed that within these regions there were often numerous imprinted genes.[34] Around 80% of imprinted genes are found in clusters such as these, called imprinted domains, suggesting a level of co-ordinated control.[35] More recently, genome-wide screens to identify imprinted genes have used differential expression of mRNAs from control fetuses and parthenogenetic or androgenetic fetuses hybridized to gene expression profiling microarrays,[36] allele-specific gene expression using SNP genotyping microarrays,[37] transcriptome sequencing,[38] and in silico prediction pipelines.[39]

Imprinting is a dynamic process. It must be possible to erase and re-establish imprints through each generation so that genes that are imprinted in an adult may still be expressed in that adult's offspring. (For example, the maternal genes that control insulin production will be imprinted in a male but will be expressed in any of the male's offspring that inherit these genes.) The nature of imprinting must therefore be epigenetic rather than DNA sequence dependent. In germline cells the imprint is erased and then re-established according to the sex of the individual, i.e. in the developing sperm (during spermatogenesis), a paternal imprint is established, whereas in developing oocytes (oogenesis), a maternal imprint is established. This process of erasure and reprogramming[40] is necessary such that the germ cell imprinting status is relevant to the sex of the individual. In both plants and mammals there are two major mechanisms that are involved in establishing the imprint; these are DNA methylation and histone modifications.

Recently, a new study[41] has suggested a novel inheritable imprinting mechanism in humans that would be specific of placental tissue and that is independent of DNA methylation (the main and classical mechanism for genomic imprinting). This was observed in humans, but not in mice, suggesting development after the evolutionary divergence of humans and mice, ~80 Mya. Among the hypothetical explanations for this novel phenomenon, two possible mechanisms have been proposed: either a histone modification that confers imprinting at novel placental-specific imprinted loci or, alternatively, a recruitment of DNMTs to these loci by a specific and unknown transcription factor that would be expressed during early trophoblast differentiation.

The grouping of imprinted genes within clusters allows them to share common regulatory elements, such as non-coding RNAs and differentially methylated regions (DMRs). When these regulatory elements control the imprinting of one or more genes, they are known as imprinting control regions (ICR). The expression of non-coding RNAs, such as antisense Igf2r RNA (Air) on mouse chromosome 17 and KCNQ1OT1 on human chromosome 11p15.5, have been shown to be essential for the imprinting of genes in their corresponding regions.[42]

Differentially methylated regions are generally segments of DNA rich in cytosine and guanine nucleotides, with the cytosine nucleotides methylated on one copy but not on the other. Contrary to expectation, methylation does not necessarily mean silencing; instead, the effect of methylation depends upon the default state of the region.[43]

The control of expression of specific genes by genomic imprinting is unique to therian mammals (placental mammals and marsupials) and flowering plants. Imprinting of whole chromosomes has been reported in mealybugs (Genus: Pseudococcus)[13][14][15][16] and a fungus gnat (Sciara).[44] It has also been established that X-chromosome inactivation occurs in an imprinted manner in the extra-embryonic tissues of mice and all tissues in marsupials, where it is always the paternal X-chromosome which is silenced.[35][45]

The majority of imprinted genes in mammals have been found to have roles in the control of embryonic growth and development, including development of the placenta.[21][46] Other imprinted genes are involved in post-natal development, with roles affecting suckling and metabolism.[46][47]

A widely accepted hypothesis for the evolution of genomic imprinting is the "parental conflict hypothesis".[48] Also known as the kinship theory of genomic imprinting, this hypothesis states that the inequality between parental genomes due to imprinting is a result of the differing interests of each parent in terms of the evolutionary fitness of their genes.[49][50] The father's genes that encode for imprinting gain greater fitness through the success of the offspring, at the expense of the mother. The mother's evolutionary imperative is often to conserve resources for her own survival while providing sufficient nourishment to current and subsequent litters. Accordingly, paternally expressed genes tend to be growth-promoting whereas maternally expressed genes tend to be growth-limiting.[48] In support of this hypothesis, genomic imprinting has been found in all placental mammals, where post-fertilisation offspring resource consumption at the expense of the mother is high; although it has also been found in oviparous birds[51][52] where there is relatively little post-fertilisation resource transfer and therefore less parental conflict. A small number of imprinted genes are fast evolving under positive Darwinian selection possibly due to antagonistic co-evolution.[53] The majority of imprinted genes display high levels of micro-synteny conservation and have undergone very few duplications in placental mammalian lineages.[53]

However, our understanding of the molecular mechanisms behind genomic imprinting show that it is the maternal genome that controls much of the imprinting of both its own and the paternally-derived genes in the zygote, making it difficult to explain why the maternal genes would willingly relinquish their dominance to that of the paternally-derived genes in light of the conflict hypothesis.[54]

Another hypothesis proposed is that some imprinted genes act coadaptively to improve both fetal development and maternal provisioning for nutrition and care.[9][54][55] In it, a subset of paternally expressed genes are co-expressed in both the placenta and the mother's hypothalamus. This would come about through selective pressure from parent-infant coadaptation to improve infant survival. Paternally expressed 3 (PEG3) is a gene for which this hypothesis may apply.[9]

Others have approached their study of the origins of genomic imprinting from a different side, arguing that natural selection is operating on the role of epigenetic marks as machinery for homologous chromosome recognition during meiosis, rather than on their role in differential expression.[56] This argument centers on the existence of epigenetic effects on chromosomes that do not directly affect gene expression, but do depend on which parent the chromosome originated from.[57] This group of epigenetic changes that depend on the chromosome's parent of origin (including both those that affect gene expression and those that do not) are called parental origin effects, and include phenomena such as paternal X inactivation in the marsupials, nonrandom parental chromatid distribution in the ferns, and even mating type switching in yeast.[57] This diversity in organisms that show parental origin effects has prompted theorists to place the evolutionary origin of genomic imprinting before the last common ancestor of plants and animals, over a billion years ago.[56]

Natural selection for genomic imprinting requires genetic variation in a population. A hypothesis for the origin of this genetic variation states that the host-defense system responsible for silencing foreign DNA elements, such as genes of viral origin, mistakenly silenced genes whose silencing turned out to be beneficial for the organism.[58] There appears to be an over-representation of retrotransposed genes, that is to say genes that are inserted into the genome by viruses, among imprinted genes. It has also been postulated that if the retrotransposed gene is inserted close to another imprinted gene, it may just acquire this imprint.[59]

Unfortunately, the relationship between the phenotype and genotype of imprinted genes is solely conceptual. The idea is frameworked using two alleles on a single locus and hosts three different possible classes of genotypes.[60] The reciprocal heterozygotes genotype class contributes to understanding how imprinting will impact genotype to phenotype relationship. Reciprocal heterozygotes have a genetically equivalent, but they are phenotypically nonequivalent.[61] Their phenotype may not be dependent on the equivalence of the genotype. This can ultimately increase diversity in genetic classes, expanding flexibility of imprinted genes.[62] This increase will also force a higher degree in testing capabilities and assortment of tests to determine the presences of imprinting.

When a locus is identified as imprinted, two different classes express different alleles.[60] Inherited imprinted genes of offspring are believed to be monoallelic expressions. A single locus will entirely produce one's phenotype although two alleles are inherited. This genotype class is called parental imprinting, as well as dominant imprinting.[63] Phenotypic patterns are variant to possible expressions from paternal and maternal genotypes. Different alleles inherited from different parents will host different phenotypic qualities. One allele will have a larger phenotypic value and the other allele will be silenced.[60] Underdominance of the locus is another possibility of phenotypic expression. Both maternal and paternal phenotypes will have a small value rather than one hosting a large value and silencing the other.

Statistical frameworks and mapping models are used to identify imprinting effects on genes and complex traits. Allelic parent-of -origin influences the vary in phenotype that derive from the imprinting of genotype classes.[60] These models of mapping and identifying imprinting effects include using unordered genotypes to build mapping models.[62] These models will show classic quantitative genetics and the effects of dominance of the imprinted genes.

Imprinting may cause problems in cloning, with clones having DNA that is not methylated in the correct positions. It is possible that this is due to a lack of time for reprogramming to be completely achieved. When a nucleus is added to an egg during somatic cell nuclear transfer, the egg starts dividing in minutes, as compared to the days or months it takes for reprogramming during embryonic development. If time is the responsible factor, it may be possible to delay cell division in clones, giving time for proper reprogramming to occur.[citation needed]

An allele of the "callipyge" (from the Greek for "beautiful buttocks"), or CLPG, gene in sheep produces large buttocks consisting of muscle with very little fat. The large-buttocked phenotype only occurs when the allele is present on the copy of chromosome 18 inherited from a sheep's father and is not on the copy of chromosome 18 inherited from that sheep's mother.[64]

In vitro fertilisation, including ICSI, is associated with an increased risk of imprinting disorders, with an odds ratio of 3.7 (95% confidence interval 1.4 to 9.7).[65]

Epigenetic deregulations at H19 imprinted gene in sperm have been observed associated with male infertility.[66] Indeed, methylation loss at H19 imprinted gene has been observed associated with MTHFR gene promoter hypermethylation in semen samples from infertile males. [66]

The first imprinted genetic disorders to be described in humans were the reciprocally inherited Prader-Willi syndrome and Angelman syndrome. Both syndromes are associated with loss of the chromosomal region 15q11-13 (band 11 of the long arm of chromosome 15). This region contains the paternally expressed genes SNRPN and NDN and the maternally expressed gene UBE3A.

DIRAS3 is a paternally expressed and maternally imprinted gene located on chromosome 1 in humans. Reduced DIRAS3 expression is linked to an increased risk of ovarian and breast cancers; in 41% of breast and ovarian cancers the protein encoded by DIRAS3 is not expressed, suggesting that it functions as a tumor suppressor gene.[67] Therefore, if uniparental disomy occurs and a person inherits both chromosomes from the mother, the gene will not be expressed and the individual is put at a greater risk for breast and ovarian cancer.

Other conditions involving imprinting include Beckwith-Wiedemann syndrome, Silver-Russell syndrome, and pseudohypoparathyroidism.[68]

Transient neonatal diabetes mellitus can also involve imprinting.[69]

The "imprinted brain hypothesis" argues that unbalanced imprinting may be a cause of autism and psychosis.

In insects, imprinting affects entire chromosomes. In some insects the entire paternal genome is silenced in male offspring, and thus is involved in sex determination. The imprinting produces effects similar to the mechanisms in other insects that eliminate paternally inherited chromosomes in male offspring, including arrhenotoky.[70]

In placental species, parent-offspring conflict can result in the evolution of strategies, such as genomic imprinting, for embryos to subvert maternal nutrient provisioning. Despite several attempts to find it, genomic imprinting has not been found in the platypus, reptiles, birds, or fish. The absence of genomic imprinting in a placental reptile, the Pseudemoia entrecasteauxii, is interesting as genomic imprinting was thought to be associated with the evolution of viviparity and placental nutrient transport.[71]

Studies in domestic livestock, such as dairy and beef cattle, have implicated imprinted genes (e.g. IGF2) in a range of economic traits,[72][73][29] including dairy performance in Holstein-Friesian cattle.[74]

A study published in March, 2022,[75] documents that foraging behavior in mice studied was influenced by a sexually dimorphic allele expression implicating a cross-gender imprinting influence that varies throughout the body and may dominate expression and shape a behavior.[76]

A similar imprinting phenomenon has also been described in flowering plants (angiosperms).[77] During fertilization of the egg cell, a second, separate fertilization event gives rise to the endosperm, an extraembryonic structure that nourishes the embryo in a manner analogous to the mammalian placenta. Unlike the embryo, the endosperm is often formed from the fusion of two maternal cells with a male gamete. This results in a triploid genome. The 2:1 ratio of maternal to paternal genomes appears to be critical for seed development. Some genes are found to be expressed from both maternal genomes while others are expressed exclusively from the lone paternal copy.[78] It has been suggested that these imprinted genes are responsible for the triploid block effect in flowering plants that prevents hybridization between diploids and autotetraploids.[79] Several computational methods to detect imprinting genes in plants from reciprocal crosses have been proposed. [80][81][82]

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When a doctor recommended to Steven Kalister that he get screened for genes associated with breast cancer a few years ago, the Columbus Northwest Side resident was surprised.

Kalister, 50, did not have breast cancer a disease uncommon (though not unheard of) among men or any form of malignancy, for that matter. But his father had died from metastatic prostate cancer, so Steve was seeking precautions besides common tests like digital rectal exams and prostate-specific antigen screenings.

The oncologist, Dr. Steven Clinton at Ohio State Universitys comprehensive cancer care center, explained to Kalister that mutations in two genes, known as BRCA1 and BRCA2, could have caused his fathers cancer, and might have been passed down to him. BRCA stands for Breast Cancer Gene, because that is what researchers first found it to be associated it with.However, science has since connected the BRCA genes with a range of malignant tumors that affect men and women, from melanoma to pancreatic, ovarian, and prostate cancers.

Kalister decided to take a simple blood test and learned that, indeed, he had a mutation in the BRCA2 gene.Since then, he has undertaken a variety of precautions that could help him ward off any significant tumor, and he shared the news with family members who also got tested.

Kalister said he would encourage anyone who is thinking about genetic testing to go seea counselor.

My wife thought maybe Id get paranoid or have a lot of anxiety from these results. But thats not the case at all.Knowledge is power, he said.

'Pay it forward': One testicular cancer survivor raises funds for research

Researchers and clinicians say that the publics understanding of BRCA genes needs updating.Because of the genes association with breast cancer and therefore cisgender women, until recently BRCA testing was not covered by insurance or encouraged for men diagnosed with prostate cancer but with no family history of the disease.

However, recent research has shown that men with mutations to BRCA2 have a three-times higher risk of prostate cancer than the general population, and people with mutations in BRCA1 and BRCA2 are six and 14 times more susceptible to pancreatic cancer, respectively. Today, genetic counselors recommend that certain male cancer patients and men with family histories of cancer get tested for mutations in BRCA and a suite of other cancer-associated genes.

The BRCA genes code for proteins that help prevent cancer by fixing damaged DNA.

Like everything in our bodies, DNA is susceptible to damage from radiation, chemicals, or other factors, like random chance during the process of creating new cells. Cells containing damaged DNA can become cancerous if fixes are not made by DNA-repairing proteins. Mutations in the BRCA genes can create proteins that are less effective at fixing DNA damage, thus upping cancer risk.

Everyone has two copies of each BRCA gene one from each parent but only some people have harmful mutations in the gene. If a parent has a harmful mutation in either gene, each of their children has a 50% chance of inheriting it, according to Lindsey Byrne, a licensed genetic counselor at Ohio State University's Wexner Medical Center.

More: United we ride: Pelotonia brings cancer survivors, loved ones together to find a cure

Byrne leads a genetics clinic at the OSU Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. As a licensed genetic counselor, she helps patients decide whether to undergo genetic screening, how to interpret results, and next steps.

Byrne encourages genetic testing for anyone with a strong family history of cancer, and for patients who have cancer at an early age or particularly aggressive cancers.

That includes prostate cancer.

I think there hasnt been enough messaging to say: prostate cancer is something you should have genetic testing (for). There is a lot of media and coverage about breast cancer and genetics, but the message was not as strong for prostate cancer until recently, she said.

Certain people may want to consider genetic screening based on their ethnicity.While only one in 400 individuals in the general population has a harmful BRCA mutation, that statistic rises to about one in 50 among Ashkenazi Jews, who trace their ancestry to central and eastern Europe.

Kalister works at The James as a service line administrator, but he said there was a lot he didnt understand about cancer and genes until he sought out genetic counseling.

Knowing he is positive for a BRCA2 mutation has helped him take precautionary measures. He is more careful about sun exposure than he used to be (because BRCA2 is linked with melanoma), and tries to eat more healthful foods.

Byrne also helped him connect with an ongoing National Cancer Institute study, which takes MRIs of his prostate on a regular basis to detect any abnormalities.

So far, so good, he said.

Kalister plans to encourage his twin 9-year-old sons, Ian and Colin, to get genetic screening as well when the time comes.

Ill tell them about how its not scary its about how you use that knowledge to your advantage, he said.

Insurance covers most patients for genetic cancer screenings, but it depends on the policy and ones medical and family cancer history, said Byrne.

Testing is very low out of pocket,and for Medicare and Medicaid patients, its usually zero out-of-pocket, she said. Medicaid and Medicare have covered genetic screening for metastatic prostate cancer patients since 2018.

Even if one were to self-pay, the cost of screening is just a few hundred dollars, compared to several thousand dollars a decade or more ago.

Although BRCA is a common genetic cause of cancer, it is not the only one.Byrne says she typically tests for a suite of 12 other genes, in addition to the two BRCAs.

Some genes that cause cancer including prostate cancer may have yet to be discovered.

For example, Black men, who are 60% to 80% more likely than white men to be diagnosed with prostate cancer, do not have higher-than-normal incidences of BRCA.

There must be something else going on, said Byrne.

It could be a combination of a whole bunch of small risk factors, or it could be a gene we havent discovered, and its because we havent studied genetics as much in individuals who are Black as we have in whites. The problem with some research is its not validated for all populations, and thats a huge equity issue.

Byrne says some patients come to her with privacy concerns over genetic testing, but she is usually able to allay their fears.

Unlike some companies that test DNA to identify relatives, none of OSUs genetic testing partners share information with the police, she told The Dispatch.

Individuals are also protected by the 2008 Genetic Information Nondiscrimination Act (GINA), which prevents employers and health insurers from asking about genetic information when making decisions.However, exceptions are made for life insurance and long-term care insurers, who can ask for such information. It is often best to buy such coverage before undergoing genetic testing, said Byrne.

Kalister said that for at-risk individuals like himself, genetic counseling should be a no-brainer.

The counselors are really really good, he said.This is what they do they talk to people about this kind of testing, these results, theyre there to answer questions.

OSU also provides Family HealthLink, a free online tool that estimates cancer risk by reviewing family patterns.

Peter Gill covers immigration and new American communities for The Dispatch in partnership with Report for America. You can support work like his with a tax-deductible donation to Report for Americahere:bit.ly/3fNsGaZ.

pgill@dispatch.com

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BRCA beyond breast cancer: links to prostate, pancreatic, other tumors - The Columbus Dispatch

A retrospective study that analyzed sex disparities in patients with COVID-19 and rheumatoid arthritis found that men had more baseline comorbidities and increased risk of COVID-19related outcomes, compared with females.

Differences in genetics between sex and sex steroid hormones may play a role in predisposition to COVID-19 infection as well as modulating the disease progression, according to Xiaofeng Zhou, PhD, senior director at Pfizer, New York, and the studys lead author.

Zhou presented her findings at The Lancet Summit: Sex and gender in rheumatology in late September.

Patients with chronic rheumatic diseases treated with immunomodulatory therapies may be at higher risk for more severe COVID-19 outcomes, including hospitalization, complications, and death. Research on sex-based disparities in RA patients with COVID-19 in the United States is limited, said Zhou, who embarked on a retrospective cohort study to examine the demographic and clinical characteristics of RA patients with COVID-19 and estimate the risk of possible COVID-19 outcomes by sex.

Zhou and colleagues used U.S. COVID-19 data collected through electronic health records by Optum during 2020 to June 2021. The study included adult patients with RA and a COVID-19 diagnosis ( 1 diagnosis code or positive SARS-CoV-2 laboratory test) and 183 days of database enrollment who received treatment with immunomodulatory therapies prior to the diagnosis date. They were stratified by sex.

Investigators used logistic regression to estimate the risk of 11 possible COVID-19related outcomes within 30 days of the COVID-19 diagnosis (hospitalization, ICU admission, pneumonia, kidney failure, thrombotic event, heart failure, acute respiratory distress syndrome [ARDS], sepsis/septic shock, mechanical ventilation/extracorporeal membrane oxygenation [ECMO], in-hospital death, and all-cause mortality), adjusting for demographics and baseline clinical covariates.

A total of 4476 COVID-19 patients with RA (78% females) took part in the study. Male patients trended older (64 vs 60 years) and had lower African American representation and Medicaid enrollment than females, but they had more baseline comorbidities such as hypertension (55% vs 45%), hyperlipidemia (45% vs 33%), diabetes (25% vs 20%), coronary artery disease (28% vs 12%), and chronic kidney disease (20% vs 15%).

Eight of the 11 COVID-19 outcomes were significantly more likely to occur in men than women (hospitalization: odds ratio [OR], 1.32 [95% CI, 1.11-1.56]; ICU admission: OR, 1.80 [95% CI, 1.36-2.40]; mechanical ventilation/ECMO: OR, 1.48 [95% CI, 1.04-2.11]; in-hospital death: OR, 1.53 [95% CI, 1.13-2.07]; all-cause mortality: OR, 1.42 [95% CI, 1.09-1.86]; sepsis: OR, 1.55 [95% CI, 1.20-2.02]; kidney failure: OR, 1.46 [95% CI, 1.15-1.85]; ARDS: OR, 1.39 [95% CI, 1.15-1.69]).

The data illustrated that men with RA had more baseline comorbidities and increased risk of COVID-19 outcomes than females.

Sex hormones regulate virus entry into host cells, respiratory function, immune response, the cardiovascular system, and coagulation, explained Zhou.

Estrogen and progesterone in women could help develop stronger and efficient immune responses to viruses and reduce virus entry into the host cells. Also, larger number of copies of ACE2 genes in women, [which] is linked with protection in the lungs against edema, permeability, and pulmonary damage, could be associated with lower incidence of severe COVID-19 outcomes, such as respiratory-related mortality and mortality, Zhou said.

By comparison, androgens in men may increase virus entry into the host cells and promote unfavorable immune response through the induction of cytokine production and reducing the antibody response to the virus. This could lead to severe infection, Zhou said.

Sex-based differences in steroid hormones may also explain the higher incidence of morbidity and fatality thats been observed in other studies of male patients with other infectious diseases, such as severe acute respiratory syndrome and Middle East respiratory syndrome.

The results add real-world evidence to the limited literature on sex disparities in COVID-19 outcomes among patients with RA in the United States, Zhou said. The differential role in sex steroid hormones among women and men may shed light on clinical management of COVID-19 patients and the need to consider sex-specific approaches in clinical trials in preventing and treating COVID-19 patients, she said.

Considering that all patients are recommended to get COVID-19 vaccinations, It is difficult to say how this impacts clinical practice, said Janet Pope, MD, MPH, professor of medicine in the division of rheumatology at the University of Western Ontario, London, Ontario, Canada, who was not involved with the study.

Sharing results with some patients may help to encourage vaccination, thus reducing risk of poor COVID-19 outcomes, Pope said.

In future studies, Zhou suggests using multiple databases and considering other geographies beyond the United States to further understand the etiology of sexual dimorphism in COVID-19 and expand generalizability. In addition, future research will seek to provide insights into health equity gaps in the management of COVID-19. This may inform development of precision medicines and vaccines, especially among patients on immunosuppressive treatments, she said.

The study was sponsored by Pfizer. Zhou and other study authors are Pfizer employees and hold Pfizer stock.

The Lancet Summit: Sex and gender in rheumatology: Abstract P.37. Presented Sept. 22, 2022.

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

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Severe COVID-19Related Outcomes Found Worse in Men With RA - Medscape

There is something about bees that in all ages has taken men captive.Brother Adam, Beekeeping at Buckfast Abbey*

On isolated, swampy Thorah Island in Lake Simcoe, Ontario, researchers bring virgin queen bees to take their mating flights. Each year, the Honey Bee Research Centre at the University of Guelph brings Buckfast queens to this mating station, which restricts the queens options. Thorah Island is situated far enough from the mainland that queens can only breed with the finest male Buckfast drone (male) bees, also brought by the researchers, who express the traits theyve selected for; here, mainland bees wont fly over water at such a distance.

Researchers and beekeepers work intensely to maintain the Buckfast honeybee genes because the strain is valued for its gentle nature, its hardiness in challenging climates, and its ability to produce high amounts of honey. Today, the Honey Bee Research Centre follows the same breeding program to preserve the bee lines developed in the early twentieth century by a monk named Brother Adam Kehrle.

A Benedictine monk of Buckfast Abbey in England, Br. Adam studied and bred the first Buckfast bee lines around 1920, and over the course of his nearly eighty-year beekeeping career wrote three books regarded as classics on the subject: Beekeeping at Buckfast Abbey, In Search of the Best Strains of Bees, and Breeding the Honeybee.

These texts remain important references for beekeepers and those interested in breeding bee species, and while they offer poetic and meticulous practical detailsqueen selection for optimum fecundity, fertilization, and pest controlBrother Adams writing reveals his deep admiration for honeybees, as well as the more esoteric aims and considerations in the practice of beekeeping.

Their extraordinary sense of order and precision, their ability to adapt themselves to anything and everything, their amazing versatility, these and many other characteristics provide an inexhaustible source of interest and delight for the professional bee-keeper with his 2,000 stocks as well as for the amateur with his few hives in the corner of his garden.

One of Br. Adams most enigmatic instructions with regard to what bees may need from those who tend to them was to Let the bees tell you. Still, while seemingly inscrutable, this idea holds important weight among even expert beekeepers. Many elements of beekeeping cannot be learned by text or even detailed instruction, or by applying past experience to current colonies, whose behavior is as changeable as weather patterns.

As Br. Adams advice suggests, its only with keen and patient attention that beekeepers can understand what may be happening inside a hive; and with this observation, beekeepers need to be attuned to how they contribute to, not engineer, the outcome of a colony; as he says, not attempting the impossible of mastering her, but rather doing all we can to serve her needs.

Honeybees must be, in a sense, decoded. In a failing hive, many would expect the bees foraging to be weak or that a queen is placed into a hive with limited capacity, but Brother Adam emphasized that, all too often, it is the beekeeper who is at fault for failing to serve the bees needs. Certain codes exist even within the beekeeping lexicon.

In one of the more obvious instances, in the world of queen bee breeding and rearinga competitive industry involving larvae graftingqueens are marked with a specific color for the year theyre bred. There are five queen bee marking colors that follow the recognized color sequenceas queens do not live more than a maximum of five years, the color code starts over in the sixth year. A common mnemonic to remember the colors is Will you raise good bees (white yellow red green blue).

On beekeeping message boards one sees speculations about brood patterns, whether a colony is thriving, signs of swarming (abandoning a hive), and, if a colony dies, beekeepers perform hive autopsies, assessing mysteries which can largely only be identified through experience; watching and interpreting, in other words, is letting the bees tell you. The beekeeper must, Br. Adam writes, with his signature esteem for the insects, at all times heed the instincts and highly developed organisation of the bees.

Brother Adam wrote this specific advice in Beekeeping at Buckfast Abbey. You may envision Br. Adam as hes depicted in the many photos featured in this text: a seemingly gentle, gray-haired and fastidious man, dressed not in white suit or a veil, but in a monks dark habitperhaps not the first visual that comes to mind with regard to honeybees and their keepers.

While the history of beekeeping is vast and worldwide, in Europe, beekeeping was taken on regularly by abbeys and monasteries during the Middle Ages; different regions established their traditional forms of housing for bee hives, or skeps, which resemble overturned baskets, some woven and others made from pottery, wood, or cork. Traditionally, skeps were used to house bees and their honeycomb, but harvesting the honey required the destruction of the colony, killing the bees.

Up to a hundred years before Brother Adam was writing, honeybee breeding was the exclusive prerogative of nature, and harvests were challenging. Humans, he writes, had little influence before the movable frame hive became common in the 19th century, borrowed, its said, from top-bar (movable honeycomb) hives in Greece, which preserve the bees. Later, the Langstroth hivethe most popular among apiarists, those recognizable, stackable boxes opened from the topprovided perfect amounts of bee space between frames of comb to keep both honeybees and their honey harvesting stewards content.

As many of us become aware of the dangers of human intervention with honeybeesrelying on industrial beekeeping to support the pollination of monoculture crops, and the (likely) connected colony collapse disorderits important to clarify that apiculture, like agriculture, holds much diversity and nuance. Some contemporary beekeepers support Buckfast strains of bees for the same reasons Br. Adam developed them: gentle temperament (a bonus for keepers), low swarm tendencies, and stability in unpredictable climates.

University of Guelph Honeybee Research Centre brings around a hundred Buckfast mating nucleus colonies to Thorah Island each year; colorful nucs piled like blocks get ferried across the water on a beater pickup truck. From this isolated place, after their lofty mating flights with Buckfast drones, mated queens are harvested on a two-week cycle. These young, fertile Buckfast queens, who will each lay thousands of eggs and populate their own Buckfast colonies, are then used to re-queen HBRC colonies or sold to beekeepers.

The careful steps involved in maintaining these lines of bees requires a commitment to Brother Adams breeding system, and only registered Buckfast breeders are allowed to use the term Buckfast when advertising colonies or queens for sale. Similarly, in Br. Adams pedigree bee-breeding, he isolated his colonies to ensure queens could only mate with selected drones. Buckfast Abbey was relatively close to the wilds of Dartmoor, a relatively treeless expanse utterly inhospitable to bees, which ensured that the only honeybees interbreeding would be Br. Adams Buckfast strain.

Honeybees provided materials that became integrated into the material life of the Catholic Church: fermented honey was used medicinally, and to make mead in areas where grapes could not be grown for wine; beeswax was highly prized for making candles for church services, as they give a purer, longer burn than typical animal tallow candles.

Further, the candles themselves were considered sacred: The wick denoted the soul and mortality of Christ, the light the divine person of the Saviour, writes Hilda Ransome in The Sacred Bee in Ancient Times and Folklore. Apparently, beeswax candles were the preferred method for lighting in Catholic Churches, a practice which survived into the 20th century when the requirement was ended by the Pope.

Aside from the practical usage of their wax and honey, beekeeping among monks and religious communities has long been seen as a meditative, even holy practice. Beekeeping was the responsibility of many monks and nuns, and some religious, like Br. Adam, held positions entirely devoted to working with the bees.

Its not a huge leap to transpose the widely held cultural view of honeybee coloniesas intelligent, industrious, sweet, working in harmony for the greater goodonto religious communities like Buckfast Abbey. In Brother Adams writing, we find admiration for his colonys collective work, its rituals and devotion to a higher power, and his desire to emulate it in his work at the abbey.

*

Karle Kehrle arrived at Buckfast Abbey from Germany in 1909, at just 11 years of age, to join the order, taking the name Brother Adam. Lay monks typically learned practical skills, evidently vital to Buckfast as it was still undergoing a revitalization begun in the late 19th century. As he wasnt suited for stonemasonry, Adam started as an assistant in the apiary with Br. Columban.

At the time, the abbey kept two breeds of honeybees: the native English black beeshardy and well suited for the unpredictable British weatherand Italian honeybees. Soon after Br. Adam joined, thirty of the Abbeys forty-six honeybee colonies (or hives) were lost to what experts thought to be a disease caused by tracheal mites known as acarine. All of the bees that died were of the native black bee variety. The bees that survived were of Italian origin, a discrepancy that struck Br. Adam, and led him to study the importance of species and genetics in apiculture.

Upon Br. Columbans retirement in 1919, Br. Adam took on the apiarist role and slowly rebuilt the lost colonies. His pursuit of a successful strain of honeybee came at an opportune time. As he took on the role at Buckfast Abbey, the Isle of Wight Disease, as it was then called, had brought native bees in England practically to extinction. Italian honeybees could not be managed in the same way as the indigenous variety; the beekeeping practices used elsewhere, in more temperate climates with longer flowering seasons, were unsuitable for the British Isles. Br. Adam sought to use cross-breeding between the English native black bee and the Italian honeybee to develop a new species that would be tough like the black bee, pest- and disease-resistant like the Italian bee, gentle, and, of course, an intrepid producer of honey.

Br. Adam found that providing the hybrid bees with a larger brood chamber (ample breeding space, that is), made way for bees to thrive. In undertaking this breeding of an ideal honeybee, Br. Adam looked to heterosis, also known as hybrid vigor, to develop the superior qualities of genetic lineages; inevitable, though, in hybridizing animals is the persistence of undesirable qualities. In honeybees, this can look like aggression (stinging), slow honey production, or weakly fertile queen lines. The resultant Buckfast bee is more industrious, more thrifty, less disposed to swarm, more resistant to disease, particularly acarine As for temper, she is unusually docile and will tolerate handling in unfavourable weather.

As queen bee genetics determine generations of their own colony, breeding them was vital, and soon Br. Adam was consumed by the search for an ideal bee. Bee breeding typically requires isolation; unlike other livestock, its difficult to predict bee crosses, and, even more difficult to control their pairings. Queens mate while flying, and so bee breeders face the time-consuming task of ensuring queens are limited to top-choice drones.

Directed breeding looks to the best qualities in honeybees, which according to Br. Adam are: fecundity (honey-gathering and brood-rearing abilities), industry (boundless capacity to work), resistance to disease, and disinclination to swarm. He also outlines the charmingly named qualities of indirect value, which do not influence honey production, but facilitate the beekeepers tasks. These involve bees exhibiting good temper, calm behavior, and a keen sense of orientation back to their home hive (for bees that wont drift to neighboring colonies).

There is no perfect or ideal bee, Br. Adam wrote, though he traveled extensively throughout the world to be sure. In his research trips he studied and sourced breeding stock for his bee program. He concentrated on countries with distinct indigenous species of bees, going chiefly to isolated rural regions where the purity of the native strains had been maintained. According to the Buckfast Abbey website, over the years, he traveled more than 100,000 miles in search of the best strains of bees, which of course he documented in In Search of the Best Strains of Bees.

In Beekeeping at Buckfast Abbey, Br. Adam discusses the preferred structure of hives, apiary location (a southerly sunny aspect and shelter from the prevailing wind), and the aims of beekeeping itself. These aims outline objectives, as Brother Adam saw them: over years spent with apiaries and bees, the beekeeper will gain a knowledge and insight into the mysterious ways of the honeybee, usually denied to the scientist in the laboratory. This surrender to natures mystery is likely what compels readers and beekeepers alike.

Br. Adams ongoing acknowledgement of our inability to control honeybees is heartening, especially in the context of genetic selection. He concedes that breeding bees is a blind-mans game and the honeybee will, despite genetic expectations and human interference, follow her instincts regardless of our wishes. The tasks of the modern beekeeper might more aptly be described as a service; in fact, we are more truly servants than masters.

While many others had bred bees before him, it is Brother Adams reverential, poetic writing that makes him a particularly captivating figure. Upon his death in 1996, the Washington Post called his creation the legendary Buckfast Superbee. Adams research led to a breed of honeybee which is exclusive yet popular, highly productive, and more resistant to parasites and the pervasive varroa mites that trouble beekeepers and decimate bee colonies.

Brother Adams hybrid queens, foundational for todays Buckfast honeybees, were so highly valued that in 1982 thieves stole two queens from the Buckfast Abbey apiaries. Police circulated a description of the bees: three-quarters of an inch in length, with dark brown and dark gray stripes.

Buckfast bees are treasured by commercial beekeepers and honey fanatics alike; and, of course, they contribute to their surrounding environment by doing what honeybees do: visiting flowers and pollinating plants that enhance our farming and our ecosystems.

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Let the Bees Tell You. On the Holy Bible (For Beekeepers) of Buckfast Abbey - Literary Hub