New approach successfully traces genomic variants back to genetic disorders

Doctors researching DNA and genetics.
Illustration Credit: Julia Fekecs, NHGRI

National Institutes of Health researchers have published an assessment of 13 studies that took a genotype-first approach to patient care. This approach contrasts with the typical phenotype-first approach to clinical research, which starts with clinical findings. A genotype-first approach to patient care involves selecting patients with specific genomic variants and then studying their traits and symptoms; this finding uncovered new relationships between genes and clinical conditions, broadened the traits and symptoms associated with known disorders, and offered insights into newly described disorders. The study was published in the American Journal of Human Genetics.

“We demonstrated that genotype-first research can work, especially for identifying people with rare disorders who otherwise might not have been brought to clinical attention,” says Caralynn Wilczewski, Ph.D., a genetic counselor at the National Human Genome Research Institute’s (NHGRI) Reverse Phenotyping Core and first author of the paper.

Typically, to treat genetic conditions, researchers first identify patients who are experiencing symptoms, then they look for variants in the patients’ genomes that might explain those findings. However, this can lead to bias because the researchers are studying clinical findings based on their understanding of the disorder. The phenotype-first approach limits researchers from understanding the full spectrum of symptoms of the disorders and the associated genomic variants.

New kind of scissors discovered

Professor Chase Beisel and Dr. Oleg Dmytrenko in the Würzburg HIRI laboratory.
Photo Credit: HIRI

Like a Swiss Army knife: a newly discovered component of bacterial immune defense paralyzes infected cells. He could advance molecular biological diagnostics.

Bacteria can also be infected by viruses, and they have developed their own immune defense strategies in this case. Bacterial defense systems such as CRISPR-Cas have various proteins and functions that help the bacteria protect themselves against intruders.

The defense is based on a common basic mechanism: a CRISPR ribonucleic acid (crRNA), which serves as a "lead RNA", helps to identify regions of a foreign genome, such as the DNA of a virus, in order to make them specifically harmless. The nuclease led by a crRNA can cut its target like scissors. It is a strategy of nature that humans have made use of technologically in a variety of ways.

"When you consider how well different nucleases have been implemented in new and improved technologies, any discovery in this area could bring new benefits to society," Professor Chase Beisel describes a research motivation of his laboratory at the Helmholtz Institute for RNA-based in Würzburg Infection research (HIRI). The facility is a location of the Helmholtz Center for Infection Research in Braunschweig in cooperation with the Julius Maximilians University, to which Chase Beisel is the head of the chair for synthetic RNA biology.

How to turn a tentacle into a foot

Hydra with reduced Zic4 content. The red arrowheads indicate the tentacles that have been transformed into feet, the asterisk indicates the animal's mouth.
Illustration Credit:  Galliot, Brigitte CC-BY-NC

By identifying a key cell identity regulator, a team from UNIGE and the IMF has managed to modify the structure and function of tentacle cells in the hydra.

Humans, animals, plants: all multicellular organisms consist of so-called differentiated specialized cells. Thus, the cells that make up the epidermis do not have the same identity - nor the same function - as those that line the digestive system, for example. However, the mechanisms allowing these cells to maintain their identity are still poorly understood. Working on hydra, a team from the University of Geneva (UNIGE), in collaboration with the Friedrich Miescher Institute for Biomedical Research (IMF) in Basel, discovered one of the key regulators: the factor of transcription Zic4. After reducing its expression, researchers have found that the tentacle cells of the hydra change their identity and turn into foot cells, forming functional feet in the animal's head. These results are to be discovered in the journal Science Advances.

Researchers detect fluoride in water with new simple color change test

Photo Credit: Henryk Niestrój

Test is first to use artificial cell sensors to detect environmental contaminant

A team of synthetic biologists at Northwestern is developing a sensor platform that will be able to detect a range of environmental and biological targets in real-world samples.

Environmental contaminants like fluoride, lead and pesticides exist all around and even within us. While researchers have simple ways to measure concentrations of such contaminants inside lab environments, levels are much more difficult to test in the field. That’s because they require costly specialized equipment.

Recent efforts in synthetic biology have leveraged cellular biosensors to both detect and report environmental contaminants in a cost-effective and field-deployable manner. Even as progress is being made, scientists have struggled to answer the question of how to protect sensor components from substances that naturally exist in extracted samples.

How a CRISPR Protein Might Yield New Tests for Many Viruses

In this illustration based on cryo-electron microscope images, a Cas12a2 protein unzips a DNA double helix, allowing it to cut the single strands of DNA (blue and green).
Illustration Credit: Jack Bravo/University of Texas at Austin

In a first for the genetic toolset known as CRISPR, a recently discovered protein has been found to act as a kind of multipurpose self-destruct system for bacteria, capable of degrading single-stranded RNA, single-stranded DNA and double-stranded DNA. With its abilities to target so many types of genetic material, the discovery holds potential for the development of new inexpensive and highly sensitive at-home diagnostic tests for a wide range of infectious diseases, including COVID-19, influenza, Ebola and Zika, according to the authors of a new study in the journal Nature.

Using a high-resolution imaging technique called cryo-EM, the team discovered that when this protein, named Cas12a2, binds to a specific sequence of genetic material from a potentially dangerous virus, called a target RNA, a side portion of Cas12a2 swings out to reveal an active site, similar to a sprung-open switchblade knife. Then, the active site starts to indiscriminately cut any genetic material it comes into contact with. The researchers discovered that, with a single mutation to the Cas12a2 protein, the active site degrades only single-stranded DNA—a feature especially useful in developing new diagnostics tailored for any of a wide range of viruses.

Zebrafish testing identifies a gene potentially at the root of domestication

Zebrafish
Photo Credit: Petr Kuznetsov

The research, published in iScience, looked at genetically modified zebrafish that fail to make the baz1b protein. The results suggest the gene is not only at the cornerstone of physical and behavioral changes in the fish and other domesticated species, but potentially also human beings’ social relationships.

Domesticated species - such as dogs and cats - show genetic differences compared to their wild type counterparts, including variation in the baz1b gene. These genetic changes correlate with physical and behavioral traits including smaller facial features such as skulls and teeth, as well as being more sociopositive, less aggressive, and having less fear.

However, studies have also suggested that modern humans domesticated themselves after they split from their extinct relatives, Neanderthals and Denisovans. In doing so, we experienced similar physical and behavioral changes.

Those changes have all been linked to the fact that domesticated animals have fewer of a certain type of stem cell, called neural crest stem cells.

The research led by the Queen Mary team builds on this by studying the impact of removing baz1b gene function, and the impact of doing so on neural crest development and social behavior.

Movement throttles insulin production

The figure shows the relationships between movement and regulation of the insulin-producing cells in the fruit fly.
Illustration Credit: Sander Liessem / University of Würzburg

If a fruit fly starts to run or fly, its insulin-producing cells are immediately inhibited. This could explain why exercise promotes health.

Insulin is an essential hormone for humans and many other living things. Its most well-known task is to regulate sugar metabolism. How it does this job is well researched. Much less is known about how the activity of the insulin-producing cells and consequently the release of insulin is controlled.

A team from the Biozentrum of the Julius Maximilians University (JMU) Würzburg is now providing news on this question in the journal Current biology in front. The group of Dr. used as the object of investigation. Jan Ache the fruit fly Drosophila melanogaster. Interestingly, this fly also releases insulin after a meal - but the hormone does not come from the pancreas like in humans, but from nerve cells in the brain.

Good hydration linked to healthy aging

NIH findings may provide early clues about increased risks for advanced biological aging and premature death.
Photo Credit: engin akyurt

Adults who stay well-hydrated appear to be healthier, develop fewer chronic conditions, such as heart and lung disease, and live longer than those who may not get sufficient fluids, according to a National Institutes of Health study published in eBioMedicine.

Using health data gathered from 11,255 adults over a 30-year period, researchers analyzed links between serum sodium levels – which go up when fluid intake goes down – and various indicators of health. They found that adults with serum sodium levels at the higher end of a normal range were more likely to develop chronic conditions and show signs of advanced biological aging than those with serum sodium levels in the medium ranges. Adults with higher levels were also more likely to die at a younger age.

“The results suggest that proper hydration may slow down aging and prolong a disease-free life,” said Natalia Dmitrieva, Ph.D., a study author and researcher in the Laboratory of Cardiovascular Regenerative Medicine at the National Heart, Lung, and Blood Institute (NHLBI), part of NIH.

Self-assembling proteins can store cellular “memories”

MIT engineers have devised a way to induce cells to inscribe the history of cellular events in a long protein structure that can be imaged using a light microscope.
Credit: Courtesy of the researchers

As cells perform their everyday functions, they turn on a variety of genes and cellular pathways. MIT engineers have now coaxed cells to inscribe the history of these events in a long protein chain that can be imaged using a light microscope.

Cells programmed to produce these chains continuously add building blocks that encode particular cellular events. Later, the ordered protein chains can be labeled with fluorescent molecules and read under a microscope, allowing researchers to reconstruct the timing of the events.

This technique could help shed light on the steps that underlie processes such as memory formation, response to drug treatment, and gene expression.

“There are a lot of changes that happen at organ or body scale, over hours to weeks, which cannot be tracked over time,” says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology, a professor of biological engineering and brain and cognitive sciences at MIT, a Howard Hughes Medical Institute investigator, and a member of MIT’s McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research.

A glimpse of a cell’s sense of touch

Confocal image of the presomitic mesoderm of a zebrafish embryo. N-cadherin adhesion molecules are shown (they appear black because the image is inverted). This shows the cell borders.
Image Credit: Campàs Lab

A research team at the Cluster of Excellence Physics of Life of TU Dresden and the University of California, Santa Barbara, reveals how cells sense their mechanical environment as they build tissues during embryogenesis.

Building tissues and organs is one of the most complex and essential tasks that cells must accomplish during embryogenesis. In this collective task, cells communicate through a variety of communication methods, including biochemical signals - similar to a cell's sense of smell - and mechanical cues - the cell's sense of touch. Researchers in a variety of disciplines have been fascinated by cell communication for decades. Professor Otger Campàs together with his colleagues from the Physics of Life (PoL) Cluster of Excellence at Technische Universität Dresden and from the University of California Santa Barbara (UCSB) have now been able to unravel another mystery surrounding the question of how cells use their sense of touch to make vital decisions during embryogenesis. Their paper has now been published in the journal Nature Materials.

Diving birds are more prone to extinction, says new study

Diving birds like puffins are highly adapted for their environment, but that means they can't adapt so well to changing conditions.
Photo Credit: Michael Blum

Diving birds like penguins, puffins and cormorants may be more prone to extinction than non-diving birds, according to a new study by the Milner Centre for Evolution at the University of Bath. The authors suggest this is because they are highly specialized and therefore less able to adapt to changing environments than other birds.

The ability to dive is quite rare in birds, with less than a third of the 727 species of water bird using this way of hunting for food.

Evolutionary scientists Joshua Tyler and Dr Jane Younger studied of the evolution of diving in modern waterbirds to investigate how diving impacted: the physical characteristics of the birds (morphology); how the species evolved to increase diversity (rate of speciation); and how prone the species were to extinction.

The study, published in Proceedings of the Royal Society B, found that diving evolved independently 14 times, and that once a group had evolved the ability to dive, subsequent evolution didn’t reverse this trait.

The researchers found that body size amongst the diving birds had evolved differently depending on the type of diving they did.

Polarity proteins shape efficient “breathing” pores in grasses

One of the two “compass proteins” (POLAR, in pink) orients the future cell division. In grey there are cell outlines on the developing leaf.
Image Credit: ZVG / Courtesy of Michael T. Raissig

A research group at the University of Bern is studying how plants "breathe". They have gained new insights into how grasses develop efficient "breathing pores" on their leaves. If important landmark components in this development process are missing, the gas exchange between plant and atmosphere is impaired. The findings are also important regarding climate change.

Grasses have "respiratory pores" (called stomata) that open and close to regulate the uptake of carbon dioxide for photosynthesis on the one hand and water loss through transpiration on the other. Unlike many other plants, stomata in grasses form lateral "helper cells". Thanks to these cells, the stomata of grasses can open and close more quickly, which optimizes plant-atmosphere gas exchange and thus saves water.

Why Don’t T Cells Destroy Solid Tumors during Immunotherapy?

3-D image of a T cell experiencing cell stress: endoplasmic reticulum (green), mitochondria (purple).
 Illustration Credit: Elizabeth Hunt, Thaxton lab

Led by Jessica Thaxton, PhD, MsCR, UNC School of Medicine scientists and colleagues found that targeting key proteins that control the T cell response to stress could help researchers develop more potent cancer immunotherapies.

The great hope of cancer immunotherapy is to bolster our own immune cells in specific ways to keep cancer cells from evading our immune system. Although much progress has been made, immunotherapy does not always work well. Jessica Thaxton, PhD, MsCR, in the immunotherapy group at the UNC Lineberger Comprehensive Cancer Center, wants to know why. She thinks one reason is the stress response experienced by T cells once they infiltrate solid cancers.

The Thaxton lab’s latest work, published in the journal Cancer Research, shows in detail how the stress response in T cells can lead to their inability to curtail tumor growth. Thaxton’s group found that T cells exposed to the environment of solid cancers undergo a natural response to stress that shuts off their function, limiting T cell ability to kill tumors. By manipulating multiple proteins in the stress response pathway inside T cells, Thaxton’s team showed that it was possible to overcome the intrinsic T cell stress response to allow the immune system to thwart cancer growth.

The clever glue keeping the cell’s moving parts connected

This liquid droplet is actually made from protein molecules. It acts as a glue that keeps the microtubule attached, via moving motor proteins, to an actin cable – a process essential for cell division to proceed.
 Illustration Credit: Ella Maru Studios, Courtesy of Paul Scherrer Institute

Researchers from Paul Scherrer Institute PSI and ETH Zurich have discovered how proteins in the cell can form tiny liquid droplets that act as a smart molecular glue. Clinging to the ends of filaments called microtubules, the glue they discovered ensures the nucleus is correctly positioned for cell division. The findings, published in Nature Cell Biology, explain the long-standing mystery of how moving protein structures of the cell’s machinery are coupled together.

Couplings are critical to machines with moving parts. Rigid or flexible, whether the connection between the shafts in a motor or the joints in our body, the material properties ensure that mechanical forces are transduced as desired. Nowhere is this better optimized than in the cell, where the interactions between moving subcellular structures underpin many biological processes. Yet how nature makes this coupling has long baffled scientists.

Now researchers, investigating a coupling crucial for yeast cell division, have revealed that to do this, proteins collaborate such that they condense into a liquid droplet. The study was a collaboration between the teams of Michel Steinmetz at Paul Scherrer Institute PSI and Yves Barral at ETH Zurich, with the help of the groups of Eric Dufresne and Jörg Stelling, both at ETH Zurich.

Scientists from NUS and NUHS identify predictive blood biomarker for cognitive impairment and dementia

Prof Barry Halliwell (left) and Dr Irwin Cheah (right), together with their collaborators from the National University Health System, have discovered that low levels of ergothioneine in blood plasma may predict an increased risk of cognitive impairment and dementia.
Photo Credit: National University of Singapore

Identification of elderly persons at risk of developing cognitive impairment and dementia could be made possible by examining ergothioneine levels in the blood

A recent study by a team comprising researchers from the National University of Singapore (NUS) and the National University Health System (NUHS) revealed that low levels of ergothioneine (ET) in blood plasma may predict an increased risk of cognitive impairment and dementia, suggesting possible therapeutic or early screening measures for cognitive impairment and dementia in the elderly.

The research teams were led by Professor Barry Halliwell from the Department of Biochemistry under the NUS Yong Loo Lin School of Medicine and Associate Professor Christopher Chen and Dr Mitchell Lai from the Memory, Ageing and Cognition Centre under NUHS. The results of their most recent study were published in the scientific journal Antioxidants.

Why aren’t all black bears black?

Cinnamon Black Bear
Resized Image using AI by SFLORG
Photo Credit: Appalachian Encounters / CC BY 2.0

Sometimes a name is just a name. Take bears, for example. In Yellowstone National Park, black bears outnumber their brownish-colored grizzly bear cousins, and in coastal areas of the Pacific Northwest, if someone says “brown bear,” they mean grizzly bear. But not all brown bears are grizzly bears.

American black bears (Ursus americanus), which one would logically assume are, well, black, actually come in a range of colors, including brown (also known as cinnamon), blond, or bluish-grey. Others have coats that are a mixture of several colors. So, how do you tell a cinnamon-colored Ursus americanus from its brown (grizzly) Ursus arctos cousin? Differences in body shape and size can be subtle. One hypothesis for the cinnamon color of Ursus americanus is that it mimics the appearance of a grizzly bear, helping with camouflage or defense.

Now, researchers at the HudsonAlpha Institute for Biotechnology, the University of Memphis, and the University of Pennsylvania, have discovered what causes the cinnamon color, which sheds some light on this color confusion.

Researchers have identified the origins of a serious illness in children

Egle Kvedaraite, doctor and researcher.
Photo Credit: Sebastien Teissier.

The origins of the serious cancer-like disease LCH have been identified by researchers from Karolinska Institutet in collaboration with Karolinska University Hospital. The findings presented in Science Immunology may lead to new, targeted treatments.

Langerhans’ Cell Histiocytosis (LCH) is a serious type of cancer-like disease that mainly affects children and can be fatal in severe cases. About five to ten children get the disease in Sweden every year, usually before the age of ten.  

The immune cells are affected by cancer mutations

LCH is a disease in which the cancer mutation occurs in the immune cells, which otherwise have the task of detecting and eliminating cancer cells. 

Scientists use materials to make stem cells behave like human embryos

Stem cells confined in a circular shape on a soft gel display characteristic of embryonic development.
Photo Credit: University of New South Wales

A serendipitous discovery in the lab has the potential to revolutionize embryo models and targeted drug therapies.

Materials scientists at UNSW Sydney have shown that human pluripotent stem cells in a lab can initiate a process resembling the gastrulation phase – where cells begin differentiating into new cell types – much earlier than occurs in mother nature.

For an embryo developing in the womb, gastrulation occurs at day 14. But in a lab at UNSW’s Kensington campus, Scientia Associate Professor Kris Kilian oversaw an experiment where a gastrulation-like event was triggered within two days of culturing human stem cells in a unique biomaterial that, as it turned out, set the conditions to mimic this stage of embryo development.

“Gastrulation is the key step that leads to the human body plan,” says A/Prof. Kilian.

“It is the start of the process where a simple sheet of cells transforms to make up all the tissues of the body – nerves, cardiovascular and blood tissue and structural tissue like muscle and bone. But we haven’t really been able to study the process in humans because you can’t study this in the lab without taking developing embryonic tissue.

Untangling the Evolution of Complex Life

Dartmouth researchers report octopuses have high numbers of molecules linked to advanced cognition.
Photo Credit: Diane Picchiottino

Octopuses have captured the attention of scientists and the public with their remarkable intelligence, including the use of tools, engaging in creative play and problem-solving, and even escaping from aquariums. Now, their acuity may provide a critical link in understanding the evolution of complex life and cognition, including the human brain.

An international team led by researchers at Dartmouth and the Max Delbrück Center in Germany report in the journal Science Advances that octopuses are the first known invertebrates—creatures that lack a backbone and constitute roughly 95% of animal species—to contain a high number of gene-regulating molecules known as microRNAs.

The genes of two octopus species show an increase in microRNAs—which are linked to the development of advanced cells with specific functions—over evolutionary time that has so far only been found in humans, mammals, and other vertebrates.

Scandinavian wolves carry many harmful mutations

Researchers from Uppsala University have discovered that each wolf in the Scandinavian wolf population has an average of approximately 100,000 harmful mutations across the entire genome.
Photo Credit: Hans Veth

In a new scientific study, researchers at Uppsala University have shown that Scandinavian wolves carry around 100,000 harmful mutations in their genome. As long as the harmful mutations can be compensated by a healthy genetic variant, this does not need to pose a problem. However, as there has been a high level of inbreeding in the wolf population, the occurrence of double harmful variants has increased with each generation.

Mutations occur constantly in all organisms, and many of the changes can have a harmful effect on survival and reproduction. However, as there are two copies of each chromosome, individuals are often protected by one of the copies remaining intact. But in the case of inbreeding, it can happen that individuals carry two copies of a harmful mutation, which leads to a problem known as inbreeding depression.