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Cryo-microscopy reveals nano-sized copy machine implicated in origin of life

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Cryo-microscopy reveals nano-sized copy machine implicated in origin of life


RNA is thought to have sparked the origin of life by self-copying. Researchers from Aarhus University, Denmark, and MRC LMB Cambridge, England, have revealed the atomic structure of an “RNA copy machine” through cryo-EM. This breakthrough sheds light on a primordial RNA world and fuels advancements in RNA nanotechnology and medicine.

How the intricate molecular machinery of life arose from simple beginnings has been a long-standing question. Several lines of evidence point towards a primordial”RNA world,” where an “RNA copy machine” (a so-called replicase) started making copies of itself and other RNA molecules to kick-start evolution and life itself. However, the ancient replicase appears to have been lost in time and its role in modern biology has been taken over by more efficient protein machines. To support the RNA world hypothesis, researchers have been seeking to re-create an equivalent of the RNA replicase in the laboratory. While such molecular “Doppelgangers” of the ancient replicase have been discovered, both their detailed molecular structure and mode of action has remained elusive due to the difficulty of determining the structure of dynamic RNA molecules.

Structure of an ice-loving RNA replicase

In a research paper published in PNAS, a team of researchers now report the first atomic structure of an RNA replicase using cryogenic electron microscopy (cryo-EM). The RNA replicase being studied was developed by the Holliger lab (MRC LMB Cambridge, UK) to be efficient at copying long templates using nucleotide triplets in the eutectic ice phase (similar to slush-ice). Returning from postdoctoral studies in the Holliger lab, Emil L. Kristoffersen, currently assistant professor at Aarhus University, facilitated a collaboration with the Andersen lab (Aarhus University, Denmark) to determine the structure of the RNA replicase by cryo-EM. Interestingly, the structure shows striking similarities to protein-based polymerases with domains for template binding, polymerization, and substrate discrimination arranged in a molecular shape resembling an open hand.

“It was surprising to find that a ribozyme that we evolved artificially in the test tube would display features of naturally occurring protein polymerases. This indicates that evolution can discover convergent molecular solutions no matter if the material is RNA or protein,” explains Philipp Holliger, program leader at MRC LMB Cambridge, UK.

Model for RNA synthesis in an RNA world

To better understand how the RNA replicase works, the researchers did a comprehensive mutational study to highlight the crucial elements of the RNA structure. This analysis confirmed features of the catalytic site but also revealed the importance of two so-called kissing-loop interactions, which bind the scaffolding and the catalytic subunits together, as well as the importance of a specific RNA domain for fidelity, that is the accuracy with which the replicase copies RNA strands. While the researchers could not determine the structure of the replicase “in-action” while actively copying RNA, it was possible to build a model for RNA-based RNA copying that is consistent with all experimental data.

“Cryo-EM is a powerful method for studying the structure and dynamical features of RNA molecules. By combing cryo-EM data with experiments, we were able to build a model of the inner workings of this complex RNA machine,” tells Ewan McRae, who did the cryo-EM work as a postdoc in the Andersen lab at Aarhus University but has now started his own research group at Houston Methodist Research Institute, Texas, USA.

Inspiration for RNA nanotechnology and medicine

The study provides an exciting first glimpse of an RNA replicase thought to reside at the very root of the tree of life. The currently developed RNA-based replicases are however very inefficient (as compared to protein-based polymerases) and cannot yet sustain their own replication and evolution. The structural insight provided by the reported study may help in designing more efficient replication mechanisms and thus get us closer to developing RNA world scenarios in the test tube.

“The properties of RNA replicases may be further improved by using chemical modifications that could exist in an RNA world. In addition, research into the origin of life leads to the discovery of several novel RNA building blocks that may be used in the emerging field of RNA nanotechnology and medicine,” explains Ebbe Sloth Andersen, associate professor at Aarhus University, Denmark.



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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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