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Researchers led by Azusa Inoue at the RIKEN Center for Integrative Medical Sciences (IMS) in Japan have discovered a gene responsible for prenatal death when critical transgenerational instructions are missing from egg cells. Published April 28 in Genes & Development, the study shows that in mice, failed epigenetic suppression of an X-chromosome gene called Xist leads to miscarriage and developmental abnormalities.
“This study identified genes critical for fetal development whose expression is controlled by histone modifications transmitted from eggs to the next generation,” says Inoue. “The findings have implications for understanding infertility and developing treatments.”
For embryos to develop normally, egg and sperm cells need to receive important biological instructions before they meet up. Once an egg is fertilized, some of these instructions tell genes to be turned on or off depending on whether they came from the mother or father. This process is called genomic imprinting and is the focus of the new study.
When modifications in gene expression are passed on to the next generation, they are called transgenerational epigenetic changes because they’re inheritable changes even though the DNA code remains unchanged. Inoue and his team have been studying a specific set of transgenerational epigenetic instructions given to egg cells called histone H3 lysine 27 (H3K27) trimethylation. In previous studies, they found that preventing these instructions led to prenatal death, particularly for male embryos, and also to enlarged placentas in the mothers. The new study asked whether those outcomes were directly related to failed imprinting.
The study began by knocking out a gene required for H3K27 trimethylation in eggs so that the transgenerational instructions could not be given. Next, the team added a knockout of the Xist gene to these eggs. Because the male offspring tended to die, the researchers suspected that the culprit was a gene on the sex chromosome. As it turns out, there are nine maternal genes known to be suppressed in embryos in favor of the ones with paternal origins. And only one, Xist, is on the X-chromosome.
The results were almost as expected. Prenatal death was greatly reduced, and the male-skewed lethality was gone after knocking out Xist. This showed that failed Xist imprinting was the reason for the prenatal death. However, the placenta was still enlarged. Reasoning that this was likely related excess expression of the other eight genes that failed to imprint, the team created eight different deletion mutants in the double knockout embryos. They found that for three of the genes, this resulted in normal-sized placentas.
“We succeeded in curing developmental defects in a mouse model that otherwise suffers from prenatal lethality and placental malformation due to the lack of transgenerational epigenetic instructions from mothers,” says Inoue. The researchers plan to conduct more experiments to determine how these specific biological instructions are established when egg cells are created, and whether environmental factors can influence the process.
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Inside embryonic cells, specific proteins control the rate at which genetic information is transcribed from DNA to messenger RNA — a crucial regulatory step before proteins are created. Then, organs develop and hopefully function properly. Those specific “regulatory” proteins are called transcription factors, and they do their thing by binding to specific DNA sequences at just the right time.
Scientists have known that mutations to three cardiac transcription factors — GATA4, NKX2-5 and TBX5 — lead to a range of congenital heart disease states. Researchers have thought that an inability of these mutated genes to “turn on” cardiac genes is what led to heart disease.
Now, the lab of Frank Conlon, PhD, professor of biology and genetics at the University of North Carolina at Chapel Hill, discovered there’s more to the story. It involves non-cardiac genes, as well as answering a question researchers have struggled with for years.
Aside from the aforementioned transcription factors, past research showed that a protein complex subunit called CHD4 seems to play a major role in congenital heart disease. Deleting it causes embryonic death in animal models. Mutations to it cause major problems with proteins involved in skeletal and muscle development.
Turns out, CHD4 is essential for numerous developmental events, such as ensuring proper timing of the switch from stem cell lineages to differentiated cell types — that is, the moment when stem cells turn into, say, heart cells or leg muscle cells. CDH4 also is essential for maintaining cell differentiation — keeping heart cells healthy heart cells. And CDH4 is a player in activating cellular processes to deal with DNA damage.
Yet, CHD4 cannot bind DNA. It needs to be brought to a specific location, or genetic loci, of a cardiac gene to do its things. So, scientists could not answer the key question of how CHD4 played its role in cardiac disease.
Conlon’s lab, in collaboration with colleagues at UNC-Chapel Hill, Princeton, and Boston Children’s Hospital, shows that GATA4, NKX2-5 and TBX5 interact with CHD4 inside the embryonic heart, recruiting it for action, and that’s how CHD4 plays its role in heart health and disease.
These findings, published in the journal Genes & Development, imply that heart disease states are not only due to loss of cardiac gene expression, but that these genes’ recruitment of CHD4 can lead to a misexpression of non-cardiac genes, leading in the end to faulty heart development.
To put this implication to the test, Conlon and his collaborators removed the binding site for Nkx2-5 in the skeletal muscle gene Acta1 in mice and, independently, the GATA4 binding site in the smooth muscle gene Myh11.
“In both instances, the mutation led to the inappropriate expression of the non-cardiac genes in the heart in a dominant manner,” said Conlon, a member of the UNC McAllister Heart Institute. “This provides a mechanism for the prevalence of congenital heart disease in humans with just one mutated copy of Nkx2-5, Gata4 or Tbx5.”
Other authors include, co-first authors Zachary L. Robbe and Wei Shi in the Conlon lab; Lauren K. Wasson, Angel P. Scialdone, Caralynn M. Wilczewski1, Austin J. Hepperla, and Ian J. Davis at UNC-Chapel Hill; Brynn N. Akerberg and William T. Pu at Boston Children’s Hospital; and Ileana M. Cristea and Xinlei Sheng at Princeton University.
This work was supported by grants from the NIH/NHLBI (R01HL156424) to Frank Conlon, and (R01HD089275) to Frank Conlon and and Ileana Cristae, and (NIH-2UM1HL098166) to William Pu.

Casey D. Morrow, Ph.D., and colleagues at the University of Alabama at Birmingham previously developed a microbiome “fingerprint” method called WSS that identifies single strains of particular gut bacteria, through analysis of metagenomics data from fecal samples. They have shown that particular strains in adults tend to remain stable over time, unless perturbed by events like antibiotics or obesity surgery. They also saw that a donor fecal transplant strain given to treat drug-resistant Clostridium difficile infections persisted in the recipient for as long as two years after the transplant.
Morrow and Hyunmin Koo, Ph.D., refined the fingerprint method to include looking for single-nucleotide variants in KEGG metabolic pathways of a particular strain. These variants can identify sub-strains of a single strain identified by WSS. To look at sub-strains of a Bacteroides vulgatus strain, for example, Morrow and Koo examined 23 different KEGG metabolic pathways present in that bacteria.
They have now applied this magnified analysis to monitor changes in sub-strains over shorter periods of time, days or weeks, in two key gut bacteria — B. vulgatus and Bacteroides uniformis. Comparing a small number of healthy individuals and hospitalized COVID-19 patients, they see a difference in sub-strain dynamics that they say foreshadows a slowing down of the intrinsic rates of strain variation in the sick patients. This slowing could eventually lead to a dysbiosis in the microbial strain community that may portend a shift in the dominant strains of the gut microbiome.
Both of the Bacteroides species are found in high abundance in the gut flora, and they may be keystone species, organisms that help define an entire ecosystem.
Koo and Morrow’s study, “Early indicators of microbial strain dysbiosis in the human gastrointestinal microbial community of certain healthy humans and hospitalized COVID?19 patients,” is published in the journal Scientific Reports.
Koo and Morrow first analyzed previously published metagenomics data from 41 individuals sampled one year apart and 11 individuals sampled 90 days apart. They looked at a single dominant strain of B. vulgatus in each individual at the two time points to see if they had showed different KEGG metabolic sub-strain patterns, as detected from analysis of single-nucleotide variants in KEGG metabolic pathways, or PKS. In general, most showed a different sub-strain PKS pattern between the two time points of each individual.

Hokkaido University researchers have shown how chronic pain leads to maladaptive anxiety in mice, with implications for treatment of chronic pain-related psychiatric disorders in humans.
Chronic pain is persistent and inescapable, and can lead to maladaptive emotional states. It is often comorbid with psychiatric disorders, such as depression and anxiety disorders. It is thought that chronic pain causes changes in neural circuits, and gives rise to depression and anxiety.
Researchers at Hokkaido University have identified the neuronal circuit involved in chronic pain-induced anxiety in mice. Their research, which was recently published in Science Advances, could lead to the development of new treatments for chronic pain and psychiatric disorders such as anxiety disorders and major depressive disorder.
“Clinicians have known for a long time that chronic pain often leads to anxiety and depression, however the brain mechanism for this was unclear,” said Professor Masabumi Minami of the Faculty of Pharmaceutical Sciences at Hokkaido University, the corresponding author of the paper.
The researchers looked at how neuronal circuits were affected by chronic pain in mice. They used an electrophysiological technique to measure the activities of neurons after four weeks of chronic pain. They found that chronic pain caused the neuroplastic change which suppressed the neuronal pathway projecting from the brain region called bed nucleus of the stria terminalis (BNST) to the region called lateral hypothalamus (LH).
Using chemogenetics, an advanced technique to manipulate neuronal activity, they showed that restoration of the suppressed activity of this neuronal pathway attenuated the chronic pain-induced anxiety. These findings indicate that chronic pain-induced functional changes in the neuronal circuits within the BNST leads to maladaptive anxiety.
“These findings could not only lead to improved treatment of chronic pain, but also to new therapeutics for anxiety disorders,” says Minami.
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Currently available therapies to treat multiple sclerosis (MS) lack precision and can lead to serious side effects. Researchers at Karolinska Institutet in Sweden have now developed a method for identifying the immune cells involved in autoimmune diseases, and have identified four new target molecules of potential significance for future personalised treatment of MS. The results, which are published in Science Advances, have been obtained in collaboration with KTH Royal Institute of Technology and Region Stockholm.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that usually develops between the ages of 20 and 40. The disease is driven by immune cells that mistakenly attack the tissue surrounding neurons in the brain and spinal cord. MS causes neurological symptoms such as sensory disorders, difficulties with walking and balance and impaired vision. There is currently no cure, only treatments that reduce relapse rates and alleviate symptoms.
“Existing MS treatments are quite indiscriminate in their effect on the immune system, which risks eventually causing complications, such as infections,” says Mattias Bronge, PhD student in Hans Grönlund’s research group at the Department of Clinical Neuroscience, Karolinska Institutet. “Guiding future treatments more accurately towards the immune cells driving the disease can therefore lead to greater efficacy and fewer side effects.”
Working alongside Professor Tomas Olsson’s research group at Karolinska Institutet, Grönlund and his team have developed a method that makes it possible to identify the T cells that react to certain target molecules — so called autoantigens. The present study describes four new autoantigens that can be added to the handful of ones previously identified in MS and will make a significant contribution to future developments in diagnosis and treatment.
“Our method makes it possible to present these autoantigens in a way that enables us to identify and subsequently disable the T cells that react to them,” says Hans Grönlund, Docent of immunology.
Given that people with MS can react to different autoantigens, it is important to identify each patient’s disease-driving immune cells. This way of creating personalised treatment is called precision medicine.
“Once a patient’s individual autoantigen profile is identified, a treatment can be adapted accordingly,” explains Dr Grönlund. “Most autoimmune diseases are driven by T cells and, if we can find a way to target them in diseases like MS, we can pave the way for more precise treatments with fewer side effects for other autoimmune diseases. Thanks to our long-standing collaboration with Professor Roland Martin at the University of Zürich, our method will be included in a phase 2 clinical study that aims to ‘switch off’ the aggressive T cells which drive MS development and progression.”
The present study involved 63 proteins analysed in blood samples from MS patients and healthy controls, four of which demonstrated autoimmune reactivity in MS; FABP7, PROK2, RTN3 and SNAP91. The tested proteins were selected in collaboration with the Human Protein Atlas and Professor Torbjörn Gräslund at KTH Royal Institute of Technology, and the study was conducted by KI, KTH and Region Stockholm.
The study was financed by Vinnova, the Swedish Research Council, the Swedish Brain Fund, Neuro, the Margareta af Uggla Foundation, Stratneuro and Region Stockholm. Hans Grönlund is founder of NEOGAP Therapeutics AB which has patented the method used and jointly holds the patent for the autoantigens featured in the study with Mattias Bronge. Co-authors Claudia Carvalho-Queiroz, Ola B. Nilsson, Andreas Kaiser and Guro Gafvelin are employed by NEOGAP Therapeutics AB.
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In the gym, you are not just pumping iron, you are oxygenating muscle cells which keeps those muscles healthy, strong and growing — a process called hypertrophy, or an increase in muscle mass due to an increase in muscle cell size. Conversely, under the covers, lounging, your muscles may begin to atrophy, or shrink.
Scientists understand that a few signaling proteins are activated in various conditions of muscle atrophy and hypertrophy, but they have been stumped about the role and mechanisms by which TAK1, a protein that regulates innate immunity and the proinflammatory signaling pathways, regulates skeletal muscle mass, until University of Houston researchers began exploring.
“We demonstrate that supraphysiological activation of TAK1 in skeletal muscle stimulates translational machinery, protein synthesis and myofiber growth,” reports Ashok Kumar, UH College of Pharmacy Else and Philip Hargrove Endowed Professor and chair, Department of Pharmacological and Pharmaceutical Sciences, in Nature Communications.
Using genetic approaches, Kumar and research assistant professor Anirban Roy demonstrated that TAK1 is indispensable for maintaining healthy neuromuscular junctions, which are involved in transmitting nerve impulses to skeletal muscle and allow muscle contractions.
“Our findings demonstrate that targeted inactivation of TAK1 causes derangement of neuromuscular junctions and severe muscle wasting, very similar to muscle wasting observed during nerve damage, aging and cancer cachexia. We have also identified a novel interplay between TAK1 and BMP (Bone Morphogenetic Protein) signaling pathway that promotes muscle growth,” said Roy.
Nutrients, growth hormones and weight training all result in an increase in skeletal muscle mass in healthy individuals. Conversely, many disease conditions often lead to a loss in lean muscle mass. Understanding the mechanisms regulating protein and organelle content is highly important to identify drug targets for various muscle wasting conditions and neuromuscular disorders.
The team also reports that activation of TAK1 in skeletal muscle beyond normal levels can prevent excessive muscle loss due to nerve damage. Loss of muscle mass has a devastating impact on standard-of-care treatment during aging and terminal illnesses, such as cancer, COPD, kidney failure and in many genetic neuromuscular diseases.
“Recognizing the impact of TAK1 signaling in supporting muscle growth, our research opens up new avenues to develop therapies for these and many other pathological conditions and improve quality of life,” said Roy.
Future studies will investigate whether the activation of TAK1 using small molecules is sufficient to promote muscle growth and prevent atrophy in the elderly and various disease states.
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Materials provided by University of Houston. Original written by Laurie Fickman. Note: Content may be edited for style and length.

The immune system remembers. Often this memory, primed by past encounters with threats like bacteria or viruses, is an asset. But when that memory is sparked by internal drivers, like chronic inflammation, it can prove detrimental, perpetuating a misguided immune response.
In a new paper in Cell, researchers from the School of Dental Medicine, together with an international team including colleagues at the Technical University of Dresden, lay out the mechanism by which innate immune memory can cause one type of inflammatory condition — in this example, gum disease — to increase susceptibility to another — here, arthritis — through alterations to immune cell precursors in the bone marrow. In a mouse model, the team demonstrated that recipients of a bone marrow transplant were predisposed to more severe arthritis if their donor had inflammatory gum disease.
“Although we use periodontitis and arthritis as our model, our findings go above and beyond these examples,” says George Hajishengallis, a professor in Penn Dental Medicine and a corresponding author on the work. “This is in fact a central mechanism, a unifying principle underlying the association between a variety of comorbidities.”
The researchers note that this mechanism may also prompt a reconsideration of how bone marrow donors are selected, as donors with certain types of immune memory caused by underlying inflammatory conditions might put bone marrow transplant recipients at a higher risk of inflammatory disorders.
Basis in the bone marrow
In previous work, Hajishengallis had partnered with co-corresponding author Triantafyllos Chavakis of Technical University of Dresden and collaborators to explore the role of innate immune memory. Their findings showed that, just like the adaptive immune system’s T cells and B cells, the innate immune system’s myeloid cells, such as neutrophils and macrophages, could “remember” past encounters, becoming more responsive when exposed to a new threat. The work also pinpointed how this memory was encoded, tracing it to the bone marrow, and showed that this “trained immunity” could be transferred from one organism to another through a bone marrow transplant, protecting recipients from cancer through an innate immune response.

A new detailed microsimulation, using a database of 40 million people, has examined the future of Japan’s aging population up to 2043. It projects that more people will live longer, and that overall years spent living with dementia will decrease. However, the model highlighted the diversity of impacts on different segments of the population, as Japanese women with a less than high school education aged 75 and over may be disproportionately affected by both dementia and frailty. Better understanding where health gaps like this exist can help inform public health planning, to minimize future economic costs and support those most in need.
Taking care of the older members of society is a common concern around the world. Japan is famous for its long-lived residents, the number of which continues to rise. In 2020, almost 30% of the Japanese population was aged 65 years or older, and this age group is not projected to peak until 2034. Caring for people with age-related ailments, such as dementia and frailty, poses a challenge both to individuals and public health care systems.
Microsimulation models, which are computer models that can provide detailed analysis on an individual basis, are currently used to project future population health in some countries, such as the U.K. and the U.S. Professor Hideki Hashimoto and researchers at the University of Tokyo, along with researchers from Stanford University in the U.S., wanted to create a new microsimulation model for Japan, which would take into account more diverse conditions than had been considered before.
“We developed a new Japanese microsimulation model that accounts for 13 chronic conditions (including heart disease, stroke, diabetes, depression and dependency), as well as frailty and dementia,” explained Hashimoto. “Using an ultralarge data system, we were able to ‘follow’ a virtual cohort of more than 40 million people aged 60 and over from 2016 to 2043.”
According to Hashimoto, projections of aging in Japan usually rely on the “average” status of older people and so don’t consider the diversity of the population. “I believe that problems of aging are a matter of health gaps over the course of people’s lives,” he said. “Our projection brings attention to a widening health gap among older people. It highlighted that women with a less than high school education aged 75 or over are more likely to be affected.”
Identifying where health gaps like this exist could be used to better inform public policy, not only about health care but other influential aspects of life. “Japan’s case may suggest that improvement in educational attainment, as well as population health, could be a key to making a healthier and more manageable aging society,” said Hashimoto.
Positively, this study shows hope for a future where many people live longer and more healthy lives. “People might believe that an increase in cases of dementia is inescapable, given population aging. However, in this study we found that in Japan, despite an aging population, the number of people with dementia is expected to decrease over the next two decades,” said Hashimoto. “Population aging does not necessarily mean an increase of social burden for care, but it does bring a diversity of problems that requires careful study and science-based policy attention, to close the health gap.”
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Scientists at the Babraham Institute have shown that two RNA binding proteins hold the key to a stronger immune response to influenza in mice. Their findings, published today in Nature Communications, reveal that the absence of these proteins changes the potency of T cells that arise at the start on an infection. Further research could lead to implications for therapies that harness the immune system, and for vaccine design.
Researchers from the Turner lab focussed on the activity of the RNA binding proteins ZFP36 and ZFP36L1. By studying mice lacking these RNA binding proteins, the researchers were able to show that their absence in T cells during the initial phase of a viral infection leads to a superior cytotoxic immune response.
When the researchers infected mice with influenza, those lacking the RNA binding proteins in T cells showed signs of fighting the infection more successfully than those with the proteins present. They also transferred cells that lacked ZFP36 and ZFP36L1 into normal mice and found that even small numbers of transferred T cells provided the same advantage when fighting an influenza infection.
Their results were surprising, explains Dr Georg Petkau, a postdoctoral researcher who led the work “One striking observation of our study is that although the absence of RNA binding proteins in T cells results in stable accelerated differentiation and enhanced cytotoxicity, this does not lead to signs of disease or tissue damage, which is often a logical consequence of overt cytotoxicity during an immune response.”
The researchers speculate that the lack of negative knock on effects could be due to accelerated viral clearance and could be explained by a faster resolution of infection in young mice. It would be interesting to see whether upon recurrent infections a large accumulation of memory cells which show enhanced cytotoxicity in absence of RNA binding proteins would become potentially dangerous with age. Understanding how these RNA binding proteins limit T cell activation may thus also have implications for autoimmune disease formation in aged individuals.
The priming of the immune response once a pathogen is detected is a critical step which significantly changes the course of an immune response; it is the point at which immune cells decide to adjust the quality and duration of the immune response to a threat. In a sense the T cells in this study have to choose their weapons before they start to battle the infection and this choice is made by RNA binding proteins. By understanding more about how the immune system processes information within hours of infection and how RNA binding proteins integrate signals to activate T cells, the researchers hope to inform how we approach vaccine design and cell therapies.
“Going forward we want to investigate how the absence of RNA binding proteins affects the formation of immune memory and whether the enhanced cytotoxicity acquired early in the response is imprinted and maintained in the memory phase.” explained Dr Martin Turner, head of the Immunology research programme. Therefore, the researchers will seek to explain their findings by investigating how the stable cytotoxic program is established early after T cell activation.
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Human skin has evolved to allow maximum durability and flexibility, according to new research from Binghamton University, State University of New York.
Associate Professor of Biomedical Engineering Guy German, along with former students Christopher Maiorana and Rajeshwari Jotawar have published new research regarding the structure of human skin and the amount of damage it can sustain.
The team created membranes from polydimethylsiloxane (PDMS), an inert and nontoxic material used in biomedical research. They mimicked the structure of mammalian skin by covering a soft, compliant layer with a thinner, stiffer outer later.
The “artificial skin” then underwent a series of tests to see how much stress it could take to break. Under the pressure of a sharp or blunt rod, the samples indented to form huge divots before breaking. The researchers also made an interesting discovery.
“There’s a certain structural formation that is optimal,” said German.
“We found that when the artificial skin has the same outer (stratum corneum) and inner layer thickness (dermis) as mammalian skin, the rubber membranes maximized both their puncture toughness and deformability. We believe that mammalian skin has evolved or adapted itself to offer the toughest option to mechanical threats while also remaining as deformable as possible.”
Most organisms have a tougher outer layer that can protect a more compliant layer beneath from threats in their environments. In addition to animals, think about nuts, fruits, insects and even microorganisms.
“Mammalian skin offers maximum locomotion and maximum mechanical toughness,” German said. “If it went one way, it would be less flexible, or the other way you would get more flexibility but less toughness. So it’s optimized.”
German and the team also discovered a new type of failure, one that they call coring. If you puncture a material, typically the fracture will begin below the indenter tip, just like piercing a piece of paper with a pencil. But with hyperelastic two-layered materials such as human skin and these artificial skin membranes, fracture occurs far from the indenter tip at large indentation depths. Here, rupture occurs where the membrane is stretched the greatest, on the sides of the divot, leaving a cylindrical core in the membrane. They don’t believe this phenomenon has been observed previously.
German points out that a better understanding about the structure of skin — and artificial skin — will help with an array of different technologies, from flexible electronics and medical devices to product packaging, bulletproof vests and treatments for burn victims. All of these potential uses (and more) mean that researching human skin and how it evolved into its current form is increasingly popular in recent years.
“Scientists and engineers are attracted to studying skin because it’s difficult to understand,” he said. “Skin is heterogeneous and structurally very complex.”
He believes the increase in the power of computers has helped better understand skin biomechanics: “Traditional materials like steel and cement are uniform in composition and easy to characterize. Nowadays, engineers are using their computational know-how to study really complex materials such as skin.”
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Materials provided by Binghamton University. Original written by Chris Kocher. Note: Content may be edited for style and length.