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Clever dosage control mechanism of biallelic genes

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Clever dosage control mechanism of biallelic genes


Researchers have uncovered a mechanism that safeguards the biallelic expression of haploinsufficient genes, shedding light on the importance of having two copies of each chromosome. A study by the lab of Asifa Akhtar identified the epigenetic regulator MSL2 an “anti-monoallelic” factor that maintains biallelic gene dosage. This discovery not only reveals a communication system between parental alleles but also points to potential therapeutic strategies for diseases associated with haploinsufficient genes.

Have you ever wondered why we carry two copies of each chromosome in all of our cells? During reproduction, we receive one from each of our parents. This means that we also receive two copies, or alleles, of each gene — one allele per chromosome or parent.

Both alleles are able to produce messenger RNA, which is the recipe needed to make proteins and keep cells running. Scientists hypothesize that having two alleles for each gene is the cell’s in-built redundancy system. If there is ever a mutation or drop in messenger RNA production from the allele carried on one of the chromosomes, the allele on the second chromosome will serve as a backup and will be able to step up to produce sufficient messenger RNA output to compensate for loss of the first allele. This redundancy enables us as humans to be largely resistant to the effects of recessive mutations.

However, a class of genes known as haploinsufficient genes, rely on the continuous expression of two intact alleles. If just one allele of a haploinsufficient gene is compromised, it will lead to human disease. It was therefore hypothesized that the cell may have a special “safety” mechanism to safeguard the messenger RNA expression from this special class of genes. A study featured in the scientific journal Nature led by Asifa Akhtar discovered exactly such a mechanism.

MSL2 is an epigenetic dosage-sensor

The researchers found that the epigenetic regulator MSL2 guarantees the expression of both alleles of specific haploinsufficient genes, ensuring the right messenger RNA dosage. This is crucial because genes require different dosage depending on the tissues they are expressed in. With MSL2, the team has identified, for the first time, a protein that can sense these dosage-sensitive genes and ensure their biallelic expression in the relevant tissue or developmental stage.

“We were always wondering whether the copy of the gene on the chromosome coming from the mother could communicate with the second copy on the chromosome coming from the father. Our findings imply an underlying communication between the two alleles and we speculate that MSL2 ensures that mom and dad can talk to each other — at least molecularly,” says Asifa Akhtar, Director at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg.

Tracking down the allelic regulator with a genetic trick

Fascinated by their discovery of a mechanism which safeguards the biallelic expression of haploinsufficient genes, the researchers investigated how this MSL2 mechanism works at the molecular level. To tackle this, the team used a trick. “We crossed genetically distant mouse strains with each other — a bit like crossing a Chihuahua with a Great Dane. This allowed us to see which alleles were inherited from the mother and which from the father,” says Yidan Sun, the first author of the paper, explaining the method of allele-specific gene expression analysis. With this hybrid mouse system, the team could analyze the activity of individual alleles. She adds: “In contrast to the standard method of expression data analysis, in which the gene products are summed over the two alleles, this gave us the resolution necessary to track the expression status of each allele individually.”

A future for novel therapeutic strategies to address diseases

Their experiments demonstrated that when MSL2 was lost in hybrid mouse cells, certain haploinsufficient genes could only achieve monoallelic expression. This implies that in mammalian cells, MSL2 is necessary for the biallelic expression of genes, ensuring their functionality and, consequently, the overall health of the organism. Interestingly, many of the haploinsufficient genes regulated by MSL2 are associated with neurological disorders.

“But what adds a fascinating layer to this discovery is the tissue- and cell-type specificity of these genes. Looking at the organism as a whole, it makes you wonder whether a backup system orchestrated by epigenetic factors such as MSL2 might explain why people, even with similar lifelong habits like smoking or diet, have different health outcomes or disease risks,” says Meike Wiese, one of the first authors of the study.

An evolutionarily conserved mechanism that regulates gene dosage

“My lab started out studying dosage compensation in fruit flies, which is the process by which males with one X chromosome can achieve the same level of gene products as females with two X chromosomes. Over the years we have been fascinated by how male fruit flies with just one X chromosome do double duty to produce the same messenger RNA compared to the females with two X chromosomes. Without this double dose males simply die! It looks like this strategy has been cleverly adapted by mammals. Our results clearly illustrate how the same tools, like MSL2, are again used in evolution to regulate dosage of genes. Gene dosage matters, and our study provides a new level of understanding of how the cells in our body ensure that we get the right dose of messenger RNAs,” says Asifa Akhtar.

What truly excites the scientists is that this discovery opens new directions to delve deeper into understanding the modulation of gene dosage within our cells. MSL2, as revealed, may just be one example of such an allelic regulator, suggesting the existence of other factors performing similar roles. This newfound knowledge carries profound implications for understanding diseases and holds promise for developing potential treatments.



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Bedtime battles: 1 in 4 parents say their child can’t go to sleep because they’re worried or anxious

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Bedtime battles: 1 in 4 parents say their child can’t go to sleep because they’re worried or anxious


Many bedtime battles stem from children’s after dark worries, suggests a new national poll.

And while most families have bedtime rituals to help their little ones ease into nighttime, many rely on strategies that may increase sleep challenges long term, according to the University of Michigan Health C.S. Mott Children’s Hospital National Poll on Children’s Health.

Overall, one in four parents describe getting their young child to bed as difficult — and these parents are less likely to have a bedtime routine, more likely to leave on a video or TV show, and more likely to stay with their child until they’re asleep.

“Our report reinforces the common struggle of getting young children to sleep. When this transition to bedtime becomes a nightly conflict, some parents may fall into habits that work in the moment but could set them up for more sleep issues down the road,” said Mott Poll co-director Sarah Clark, M.P.H.

“Establishing a consistent bedtime routine is crucial. When children don’t get enough rest, it can impact their physical development, emotional regulation and behavior.”

Nearly one in five parents say they have given their kids melatonin to help with sleep while a third stay in the room until their child completely dozes off, according to the nationally representative poll that includes responses from 781 parents of children ages one to six surveyed in February.

Nighttime worries interfere with sleep

Parents share common reasons behind bedtime struggles, with nearly a quarter saying their child’s sleep is often or occasionally delayed due to being worried or anxious.

A particular challenge, parents say, is when children don’t stay asleep. More than a third of parents say their child wakes up upset or crying, with more than 40% saying their child moves to their parents’ bed and about 30% saying children insist that the parent sleep in their room.

“Many young children go through stages when they become scared of the dark or worry that something bad might happen, causing them to delay bedtime or become distressed by parents leaving the room. Bad dreams or being awakened in the middle of the night can also disrupt sleep,” Clark said.

“Although this is a normal part of a child’s development, it can be frustrating when parents already feel tired themselves at the end of the day. Parents should find a balance between offering reassurance and comfort while maintaining some boundaries that help ensure everyone — both kids and adults — get adequate sleep.”

More findings from the report, plus Clark’s recommendations for helping young children fall and stay asleep:

Stick to a regular bedtime routine

Most parents polled report having a bedtime routine for their child, often including brushing teeth, reading bedtime stories and/or bathing. Less than half also say their child has a drink of water or snack, turns off devices, prays and talks about their day.

Other bedtime habits include holding a blanket or stuff animal or sucking a pacifier or fingers.

Not only does having a consistent bedtime routine help make the nighttime transition smoother, Clark says, it also provides one-on-one time, allowing the child to get their parent’s full attention.

“A predictable bedtime routine provides a sense of security and comfort and signals to the child that it’s time to slow down,” she said.

“Knowing what to expect next can reduce anxiety and help children feel safe and relaxed. Having this dedicated time with parents also promotes bonding and emotional connection, creating positive associations with bedtime.”

Nearly two-thirds of parents also said children staying up to play was a major factor in delaying sleep. Clark says, highlighting the need to wind down at least an hour before bed.

Promote an environment conducive to sleep

A little less than half of parents polled say their child sleeps in their own bedroom while less than a quarter share a bedroom with siblings or in the parents’ bedroom. One in 10 kids spend part the night in their own bedroom and part of the night with parents.

More than two-fifths of parents polled said noise from other rooms interfered with their child’s sleep.

“The sleep environment can have a major effect on a child’s sleep quality, including getting to sleep and staying asleep through the night,” Clark said.

“When possible, children should have their own bed in a room that is quiet, without a lot of noise from other family members.”

Many parents polled also use a nightlight or crack the bedroom door so the child isn’t in complete darkness, Clark says, but parents should make sure the light does not shine directly at the child’s face.

Some parents also play calming music or stories to help their child go to sleep, while others use a white noise machine or app. However, Clark cautions to keep white noise machines at no more than 50 decibels and placed at least seven feet from the child’s bed to prevent unintended damage to the child’s hearing.

Talk to a doctor before using aids like melatonin

Many types of melatonin products are advertised as being appropriate for children but these products have not undergone rigorous testing for safety and effectiveness, and their side effects and long term impact on a child’s growth and development are unknown, Clark says.

“Although melatonin is a natural hormone that regulates sleep-wake cycles and may be fine to use occasionally, parents shouldn’t rely on it as a primary sleep aid,” Clark said.

“Parents who are considering giving melatonin to their young child should consult with their pediatrician to discuss options and rule out other causes of sleep problems first.”

If using melatonin, parents should also start with the lowest dose possible.

In addition, it’s important to keep electronics such as tablets or televisions out of children’s bedroom, as the blue light emitted by many of these screens interferes with the natural production of melatonin.

Offer comfort but enforce boundaries

Parents can help ease little ones’ anxiety by allowing extra time to let them talk about their day, which might draw out specific worries and give parents a chance to provide compassion and reassurance, Clark said.

Rather than remaining in the room, parents can also offer to check on the child every few minutes, which acknowledges the child’s fears and offers a reassuring presence, but still maintains a calm sleep environment and promotes sleep independence.

“Families can incorporate comforting rituals to help transform nighttime fears into a calming experience,” Clark said.

Have a consistent approach when children wake up in the night

Some children are prone to vivid dreams or nightmares and may have difficulty getting back to sleep. Parents should decide on their approach to this situation and stick with it, Clark says, whether it’s taking the child back to bed or allowing them to stay in the parents’ room.

“Being consistent in carrying out that approach will help the child adjust and be more likely to return to sleep,” Clark said.

Ease into changes in sleep patterns, such as dropping naps

For young children, a major sleep-related transition is discontinuing daytime naps. In general, children ages one to two should get 11-14 hours of sleep with naps while the amount of recommended sleep decreases slightly from ages three to six.

If children are taking longer to fall asleep at nap time, resisting naps or suddenly having difficulty falling asleep at night or waking up earlier than usual in the morning, it may be time to drop the nap, Clark says.

“Parents may need to adjust sleep routines gradually to transition to changes to a child’s sleep patterns,” Clark said.

Other changes that can affect a child’s sleep include transitioning from a crib to a toddler bed, starting school, having a change in their daytime routine, or being outdoors for longer than usual.



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Direct evidence found for dairy consumption in the Pyrenees in the earliest stages of the Neolithic

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Direct evidence found for dairy consumption in the Pyrenees in the earliest stages of the Neolithic


A joint study conducted by the Universitat Autònoma de Barcelona, the University of Zaragoza and the University of Strasbourg on the remains of the Chaves and Puyascada caves, both located in the province of Huesca, Spain, yields the first direct proof of the consumption and processing of dairy products in the Pyrenees already at the start of the Neolithic period, approximately 7,500 years ago, as well as the consumption of pig. The results lead to doubts about the belief that these products were first used much later in the Pyrenean mountain range.

The analysis of the content and use of prehistoric vessels has become a valuable source of information on the food patterns and subsistence practices of past societies. A research conducted on the materials found at the Huescan sites of Cueva de Chaves (Bastaràs), at 640 metres above sea level, and at Espluga de la Puyascada (La Fueva), at 1,300 metres above sea level, in a strictly Pyrenean mountain region, now has yielded the first direct evidence of dairy product consumption and processing in the Pyrenees during the earliest stages of the Neolithic.

The study was conducted by prehistorians from the Universitat Autònoma de Barcelona (UAB) and the University of Zaragoza, and chemists from the University of Strasbourg, France, on materials on display at the Huesca Museum. The findings have now been published in the journal Archaeological and Anthropological Sciences.

The research was conducted through a combination of techniques used to identify organic residues and the isotopic characterisation of fatty acids to determine animal origin, as well as data obtained of the morphology and functionality of ceramics and the archaeozoological studies of both sites.

The analysis of organic residues preserved in the argillaceous matrix of the interior of 36 ceramic vessels indicates that 7,500 years ago dairy products were already processed and consumed in the Central Pyrenees. The correlation between the residues of dairy fats and the different forms of the pottery suggests, moreover, that all the processes (preparation, consumption and storage) were carried out in both settlements.

This “questions previous considerations in which dairy consumption in the Pyrenees was thought to have begun much later,” points out Nàdia Tarifa, researcher from the University of Strasbourg when this study was conducted, and lead autor of the paper. “It was always thought that prehistoric social dynamics in mountainous regions were slower or ‘less evolved’ than in coastal regions. Our study adds solid proof to previous faunistic studies conducted in both sites, which had pointed to dairy farming in these mountainous regions at the very early stages of the Neolithic period,” Tarifa states.

The study also shows how pig-derived products may have been processed or stored in ceramic vessels at both sites, which would indicate the importance of this species for the early mountain farming economies. In contrast to the results for milk, researchers also observed variations between the two sites in terms of the exploitation of meat from ruminants and pigs, with a predominance of the former in Espluga de la Puyascada and the latter in Cueva de Chaves. These differences could be related to the characteristics of the settlements and their surroundings, and to the methods of meat processing.

The researchers also identified residues from processed vegetables, as well as from pine resin. The latter substance would have been used to waterproof the inside of the vessels.

The results support the idea that in the early Neolithic period in the Pyrenean area there was a mixed economy based on integrated agriculture and livestock farming (in which one supported the other), with sheep herds as the main source of meat and milk.

“Our findings provide a better understanding of consumption habits and the technological use of resources in the early Neolithic period in the Pyrenees and open up new avenues of research to deepen our understanding of the social and economic dynamics of ancient societies, especially in mountainous areas,” says Alejandro Sierra, researcher at the UAB and co-author of the study.



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A high-fat diet may fuel anxiety

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A high-fat diet may fuel anxiety


When stressed out, many of us turn to junk food for solace. But new University of Colorado Boulder research suggests this strategy may backfire.

The study found that in animals, a high-fat diet disrupts resident gut bacteria, alters behavior and, through a complex pathway connecting the gut to the brain, influences brain chemicals in ways that fuel anxiety.

“Everyone knows that these are not healthy foods, but we tend to think about them strictly in terms of a little weight gain,” said lead author Christopher Lowry, a professor of integrative physiology at CU Boulder. “If you understand that they also impact your brain in a way that can promote anxiety, that makes the stakes even higher.”

Lowry’s team divided adolescent rats into two groups: Half got a standard diet of about 11% fat for nine weeks; the others got a high-fat diet of 45% fat, consisting mostly of saturated fat from animal products.

The typical American diet is about 36% fat, according to the Centers for Disease Control and Prevention.

Throughout the study, the researchers collected fecal samples and assessed the animals’ microbiome, or gut bacteria. After nine weeks, the animals underwent behavioral tests.

When compared to the control group, the group eating a high-fat diet, not surprisingly, gained weight. But the animals also showed significantly less diversity of gut bacteria. Generally speaking, more bacterial diversity is associated with better health, Lowry explained. They also hosted far more of a category of bacteria called Firmicutes and less of a category called Bacteroidetes. A higher Firmicutes to Bacteroidetes ratio has been associated with the typical industrialized diet and with obesity.

The high-fat diet group also showed higher expression of three genes (tph2, htr1a, and slc6a4) involved in production and signaling of the neurotransmitter serotonin — particularly in a region of the brainstem known as the dorsal raphe nucleus cDRD, which is associated with stress and anxiety.

While serotonin is often billed as a “feel-good brain chemical,” Lowry notes that certain subsets of serotonin neurons can, when activated, prompt anxiety-like responses in animals. Notably, heightened expression of tph2, or tryptophan hydroxylase, in the cDRD has been associated with mood disorders and suicide risk in humans.

“To think that just a high-fat diet could alter expression of these genes in the brain is extraordinary,” said Lowry. “The high-fat group essentially had the molecular signature of a high anxiety state in their brain.”

Lowry suspects that an unhealthy microbiome compromises the gut lining, enabling bacteria to slip into the body’s circulation and communicate with the brain via the vagus nerve, a pathway from the gastrointestinal tract to the brain.

“If you think about human evolution, it makes sense,” Lowry said. “We are hard-wired to really notice things that make us sick so we can avoid those things in the future.”

Lowry stresses that not all fats are bad, and that healthy fats like those found in fish, olive oil, nuts and seeds can be anti-inflammatory and good for the brain.

His advice: Eat as many different kinds of fruits and vegetables as possible, add fermented foods to your diet to support a healthy microbiome and lay off the pizza and fries. Also, if you do have a hamburger, add a slice of avocado. Some research shows that good fat can counteract some of the bad.



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