Publisher Health

Investigators at Cedars-Sinai have uncovered a new pathway that helps explain how consuming too much alcohol causes damage to the liver, specifically mitochondrial dysfunction in alcohol-associated liver disease.
The discovery, published in the peer-reviewed journal Nature Communications, can also help lead to a new treatment approach for people suffering from the disease.
Cases of alcohol-associated liver disease continue to rise and is one of the leading causes of alcohol-related deaths. The spectrum of the disease includes hepatitis, fibrosis to cirrhosis and liver cancer. Cirrhosis alone causes 1.6 million deaths worldwide and over 50% of cases are due to alcohol abuse. Besides abstinence, there currently are no effective therapies for treating people with the disease.
“Alcohol-associated liver disease is a major problem in the world,” said Shelly C. Lu, MD, director of the Karsh Division of Gastroenterology and Hepatology in the Department of Medicine and senior author of the study. “We’ve known for a long time that alcohol somehow damages mitochondria, but until now, it’s not been clear as to what the mechanisms are for this damage to occur.”
The liver is very rich in mitochondria, known as the powerhouse of all cells, and plays a critical role in liver function. Alcohol, however, can alter the structure and function of the mitochondria, leading to liver injury.
To better understand the mechanisms for mitochondrial damage in alcohol-associated liver disease, Lu and her team looked at the role of an enzyme called MAT?1 that’s responsible for providing the liver vital nutrients for survival.

Aneurysms are weak, bulging portions of blood vessel walls. These blood-filled sacs resemble balloons in structure and have necks like balloons. Some aneurysms have larger necks and are called “wide-neck” aneurysms. These aneurysms, identified through imaging, can be significantly more difficult to treat.
Justin Mascitelli, MD, FAANS, a neurosurgeon at The University of Texas Health Science Center at San Antonio (UT Health San Antonio), is a co-author on recently published multicenter studies that compared a pair of treatments for wide-neck aneurysms: endovascular therapy and microsurgery. One study, published Nov. 5, 2021, evaluated the treatments in ruptured wide-neck aneurysms (the EVERRUN Registry). The second study, published Dec. 24, 2021, made the comparison in unruptured wide-neck aneurysms. The studies are published in the Journal of Neurosurgery and were supported by a 2017 grant from The Bee Foundation.
Endovascular therapy is a minimally invasive way to seal off the aneurysm by means of metal coils and/or mesh stents. The coils or stents are delivered to the aneurysm or blood vessel, respectively, through a catheter. These devices promote thrombosis of the aneurysm and prevention of aneurysm rupture (or rerupture) in the future.
During microsurgery, meanwhile, surgeons approach the aneurysm through the skull using a microscope to surgically dissect the small blood vessels. A small metal clip is placed on the aneurysm neck to seal off the blood flow, again to prevent aneurysm rupture (or rerupture) in the future.
The EVERRUN Registry analysis published Nov. 5 reviewed one-year outcomes of 87 ruptured aneurysms: 55 in patients treated with endovascular therapy and 32 treated with microsurgery. The study demonstrated similar clinical outcomes in the two groups. Microsurgery was longer lasting, with 12.7 percent of patients in the endovascular therapy group needing retreatment versus no patients whose aneurysms were clipped during microsurgery.
The analysis of unruptured aneurysms published Dec. 24 reviewed one-year outcomes of 224 unruptured wide-neck aneurysms: 140 in the endovascular therapy group and 84 in the microsurgery group. Superior clinical outcomes and fewer complications were observed in the endovascular therapy group of patients, but better outcomes on angiograms of aneurysms were seen in the microsurgery group.
“I was not surprised by the results in the ruptured aneurysm cohort of EVERRUN,” Dr. Mascitelli, lead author of the publications, said. “The hypothesis was that microsurgical clipping would compare well to advanced endovascular techniques for ruptured wide-neck aneurysms, which is what we found. In the unruptured aneurysm cohort, however, the complication rate in the microsurgical arm was higher than expected. More investigations are warranted.”
Dr. Mascitelli will continue the studies through a $25,000 grant from the Joe Niekro Foundation. Mr. Niekro was a major league baseball pitcher who died at age 61 in October 2006 after suffering a brain aneurysm. A knuckleballer, he won more than 140 games with the Houston Astros.
Co-authors of the Journal of Neurosurgery articles are from UT Health San Antonio; the Barrow Neurological Institute in Phoenix, Ariz.; the Icahn School of Medicine at Mount Sinai Hospital, Mount Sinai Health System, New York; and the Yale School of Medicine.
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Materials provided by University of Texas Health Science Center at San Antonio. Original written by Will Sansom. Note: Content may be edited for style and length.

A Caltech-led team of researchers has discovered that a small-molecule metabolite, produced by bacteria that reside in the mouse gut, can travel to the brain and alter the function of brain cells, leading to increased anxiety in mice. The work helps uncover a molecular explanation for recent observations that gut microbiome changes are associated with complex emotional behaviors.
The research was conducted primarily in the laboratory of Sarkis Mazmanian, Luis B. and Nelly Soux Professor of Microbiology and affiliated faculty member with the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech. A paper describing the study appears on February 14 in the journal Nature.
Decades of research have shown that the communities of bacteria that inhabit the intestines of animals (the microbiome) influence the immune system and metabolism; studies in the last few years have linked the microbiome to brain function and mood. People with certain neurological conditions have distinctly different gut bacteria communities. Further, studies in mice have shown that manipulating these communities can alter neurodevelopmental and neurodegenerative states, either ameliorating or exacerbating symptoms.
“It’s been really difficult to show causation between something that’s happening in the gut and the brain, rather than just associations between the disease states and the presence or absence of certain microbes,” says Brittany Needham, first author of the new study and a postdoctoral scholar in the Mazmanian lab. “We were interested in trying to understand the molecular messages that are going between the gut and the brain, and how these signals may lead to changes in behavior.”
This study focused on a bacterial metabolite (a by-product of microbes) called 4-ethylphenyl sulfate, or 4EPS. Initially produced by microbes in the intestines, 4EPS is then absorbed into the bloodstream and circulates throughout the body in both humans and mice. In 2013, the Mazmanian lab showed that this particular molecule was present in higher levels in mice with altered neurological development, specifically, a mouse model of autism and schizophrenia. Though other aspects of the altered microbiome differed from the healthy microbiome, 4EPS levels were by far the most different. Additionally, in a screen of human blood samples from 231 individuals, 4EPS levels were about seven times higher in children on the autism spectrum than in neurotypical children.
In this work, the team focused on the effects of 4EPS on mouse models of anxiety. While anxiety disorders in humans are complex, animal models provide a way to study the precise changes in the brain and body that lead to anxious behaviors. “Anxiety” in mice is measured by their willingness to explore or hide in a new space as well as the time spent in a risky environment. Bold mice will explore a new space, sniffing around, but anxious mice will hide, as if facing a predator, instead of exploring.

A key technical challenge in creating new sulphur-based medicines has been overcome by scientists at Nanyang Technological University, Singapore (NTU Singapore), leading to the prospect of many new therapeutic ‘weapons’ in the fight against disease and illness.
Every successful drug has a part of it that physically fits into the exact biochemical pathway it is trying to disrupt. This part of the drug is known as a ‘pharmacophore’ and generating new ones is a key goal in drug discovery.
Sulphur-based pharmacophores are highly versatile and seen as very promising to drug developers but are rare due to the challenges of synthesising them.
Now, scientists at NTU Singapore have designed a method to generate sulphur pharmacophores using a catalyst specially developed by the scientists themselves, known as pentanidium.
Their method could be used to synthesise a broad range of new pharmacophores that could be paired with different types of molecules to form new drugs.
They also showed that the new sulphur pharmacophores could be used to modify and repurpose existing drugs, potentially leading to new therapies. Their work is published in the top peer-reviewed scientific journal Nature today.

Following up on a 2018 study that identified an epigenetic modifier known as histone deacetylase 11 (HDAC11) as a potential therapeutic target for treating obesity and diabetes, researchers from the University of Colorado School of Medicine have published new research that finds HDAC11 regulates G protein-coupled receptors (GPCRs) called beta-adrenergic receptors (β-ARs).
The details of the study are published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), the official journal of the National Academy of Sciences.
Lead author of the study, Rushita Bagchi, PhD, is now a faculty member at the University of Arkansas for Medical Sciences and was previously a postdoctoral fellow in the laboratory of Timothy McKinsey, PhD (on Twitter @McKinseyLab), professor of medicine in the Division of Cardiology, who is the corresponding author of the article. Both are part of the Consortium for Fibrosis Research & Translation, a program funded by the CU School of Medicine to improve understanding of fibrotic diseases across various organ systems.
The scientists originally studied the biological function of HDAC11, a lysine demyristoylase enzyme, and determined that deleting it in animal models stimulates the formation of brown adipose tissue (BAT). The absence of HDAC11 also triggered “beiging,” turning white adipose tissue (WAT) into brown-like adipose tissue. BAT and beige WAT are unique forms of fat that are stimulated in response to cold temperature. BAT and beige WAT produce heat, and in so doing, burn calories. From a therapeutic perspective, there is intense interest in developing drugs that activate BAT or convert normal WAT into beige WAT as a means of triggering weight loss in the context of obesity and diabetes. One approach to doing this is to stimulate β2- and β3–ARs. However, drugs targeting these GPCRs have underperformed as anti-obesity therapies in the clinic, perhaps due to the high doses required, which can cause cardiovascular side effects.
“Our new research shows that inhibiting HDAC11 promotes β-AR signaling in fat cells through a previously unrecognized mechanism called lysine myristoylation,” McKinsey says. “The findings lay the foundation for developing therapeutics for obesity and diabetes based on enhancing GPCR signaling in adipose tissue by inhibiting HDAC11. Reversible lysine myristoylation is a very unique mechanism that has never been described for the regulation of a GPCR. Given the critical roles of β-ARs in various physiological and pathophysiological processes, we think this work will be of interest to a broad audience, and has great potential for clinical translation.”
“Before taking anything like this into the clinic, there’s a lot of additional work that needs to be done at the bench,” Bagchi adds. “This paper describes only the second myristoylated substrate of HDAC11. There are likely many more proteins that are substrates for HDAC11, and thus, we are at the tip of the iceberg when it comes to understanding the biological consequences and the therapeutic potential of inhibiting this fascinating demyristoylase.”
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Materials provided by University of Colorado Anschutz Medical Campus. Original written by Greg Glasgow. Note: Content may be edited for style and length.

Disease and health are the result of a complex interaction between humans and their pathogens. Genetic factors that partly determine host defenses sometimes differ significantly between people and populations. This is shown in a publication in the American Journal of Human Genetics by researchers from the Netherlands, Tanzania and India. More genetic and immunological research in non-European populations will provide a better and more complete picture of how the human immune system works.
You never become ill on your own. It always involves a combination of host and guest, the human being infected by a virus, for example. The course of such an infection can vary greatly. One person may become seriously ill from a flu virus, while another may hardly notice it at all. How does that work exactly? What makes someone clear up a viral infection without a problem while someone else gets seriously ill? To a large extent, the explanation lies in our immune system, which can vary enormously from one individual to another. But there can also be clear differences in the immune system between different population groups.
Immune response regulators
To gain more insight into these differences, Collins Boahen from Radboudumc and his colleagues focused their research on the role of genetic factors in regulating cytokine production. Cytokines are an important and early link in the coordination of immune response. Like directors, they determine the immune system’s response to invading pathogens. The group of cytokines includes interferons, interleukins, chemokines and tumor necrosis factors. All these different factors make the cytokine response a complex one, which can also vary greatly from person to person and from population to population. “Variations in the cytokine response determine not only the risk of infectious disease,” says Boahen, “but also, for example, susceptibility to inflammation and autoimmune disease.”
Tanzania
Cytokine responses in the Western European population (Caucasian race) have been studied many times. What is particularly lacking are data on cytokine responses in populations from other geographical areas. Together with Blandina T Mmbaga, director of the Kilimanjaro Clinical Research Institute in Tanzania, and her colleagues Godfrey Temba and Vesla Kullaya, Boahen investigated how these responses occur in healthy Tanzanian adults of East African descent. “In doing so, we also looked at the underlying genetic variations that may influence cytokine responses,” says Mmbaga. “In other words, are there genetic differences between populations that cause some to respond differently to infection than others?”
Genetic and immunological differences
The research fits within the Human Functional Genomics Project (HFGP), which investigates how genetic variation in human DNA affects physiological processes, with a special focus on the immune system in health and human disease. Boahen: “The research shows that both genetically and immunologically, there are clear differences between the European and African populations. Genetically, for example, we see small variations — called SNPs — between the two groups that affect the production of cytokines. Put more simply, we see significant differences in the genetic basis for cytokine production in people from Tanzania in East Africa and Western Europe.”
More focus on non-European populations
The results of this study, published in the American Journal of Human Genetics (AJHG), point to the need for more research in non-European populations. This is the only way to gain a full understanding of the diversity of the human immune system. Vinod Kumar, last author of the article, therefore argues for the inclusion of underrepresented populations in genetic research to enable new discoveries about differences in health and disease both between individuals and populations.
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Materials provided by Radboud University Medical Center. Note: Content may be edited for style and length.

Single-cell RNA sequencing, or “scRNA-seq” for short, is a technique that allows scientists to study the expression of genes in an individual cell within a mixed population — which is virtually how all cells exist in the body’s tissues. Part of a larger family of “single-cell sequencing” techniques, scRNA-seq involves capturing the RNA of a single cell and, after multiple molecular conversion reactions, sequencing it. Since RNA is the intermediate step from gene (DNA) to protein, it provides an overview about which genes in that particular cell are active and which are not.
Because scRNA-seq captures the activity of all genes in the cell’s genome — thousands of genes at once — it has become the gold standard for defining cell states and phenotypes. This kind of data can reveal rare cell types within a cell population, even types never seen before.
Cost and efficiency
But scRNA-seq isn’t just a tool for basic cell biology; it has been widely adopted in medical and pharmacological research as it is capable of identifying which cells are actively dividing in a tissue, or which are reacting to a particular drug or treatment.
“These single-cell approaches have transformed our ability to resolve cellular properties across systems,” says Professor Bart Deplancke at EPFL’s School of Life Sciences. “The problem is that they are currently tailored toward large cell inputs.”
This isn’t a trivial problem, as scRNA-seq methods require over a thousand cells for a useful measurement. Dr Johannes Bues, a researcher in Deplancke’s group, adds: “This renders them inefficient and costly when processing small, individual samples such as small tissues or patient biopsies, which tends to be resolved by loading bulk samples, yielding confounded mosaic cell population read-outs.”
The DisCo solution

Cells push and pull on surrounding tissue to move in groups as they form organs in an embryo, track down invading bacteria, and as they become cancerous and spread.
Published online in Nature Cell Biology on February 14, a new study found in a living embryo that the back ends of moving cell groups push the group forward. This runs contrary to previous findings, where cell groups grown in dishes of nutrients (cultures) pulled themselves forward with their front edges.
Led by researchers from NYU Grossman School of Medicine and the NYU Courant Institute of Mathematical Sciences, the study used a new technique to measure the forces applied by a cell group as it moved along a “road-like” tissue membrane and into place in a developing animal. Specifically, the study found for the first time in an animal tissue that proteins called integrins on the surfaces of the cells at the rear attach in greater numbers to the membrane as they move along, and exert more force in one direction, than the cells in the group’s front. The integrin clusters (focal adhesions) observed in the embryo were smaller than those seen in culture studies, and broke down faster.
Confirmation of such mechanistic details in living tissue have important implications, say the researchers, as many cancers spread in cell groups, and may use the newfound “rear engine propulsion.”
“Our results clarify how cell groups that will become organs move into place, and reaffirm that cells behave differently when removed from their natural environments,” said senior study author Holger Knaut, PhD, associate professor in the Department of Cell Biology at NYU Langone Health.
Study Details
The study results are based on mechanisms of cell movement established by past studies. For instance, a protein called actin is known to form the protein “skeleton” of cells, with actin chains able to grow in a certain direction, and apply force that change a cell’s shape. Integrins, proteins built into outer cell membranes, interact both with actin networks, and proteins outside of cells. These and other proteins form a system that a cell uses to briefly attach to and “roll along” a basement membrane, a pliable mesh of proteins and sugars. What was unknown going into the current study was how tissues in living animals apply force in groups to generate this motion.

Minor everyday rises in blood pressure due to short-term stressors can be linked to a brain area that controls conscious and learned motor skills. This discovery, presented by University of Gothenburg researchers, paves the way for a chance to influence the rises in blood pressure and, in the long run, prevent hypertension.
In roughly half of all people with hypertension — persistently high blood pressure (BP) — there is no known cause. One plausible theory is, however, that hypertension might be the result of a long period of many recurrent BP peaks. Hundreds or thousands of micro-stress events may occur daily — the telephone ringing, a car horn sounding in the street — with BP spiking every time as a result.
For nearly 20 years now, a University of Gothenburg research group has been investigating how this kind of micro-stress affects nerve signals to our muscles and the throughput (perfusion) of blood in their vessels (muscle vasculature). In half of the over 150 men included in the group’s studies to date, the pattern of their reaction system leads to BP peaks, while for the other half the reactions taking place in their bodies do not bring about any change in BP.
Ultramodern brain-imaging techniques
The latest results are published in Scientific Reports. For the study, 20 men aged 19-45 were examined. The experiment involved triggering a response in the nervous system with unexpected electric shocks that emulate the sudden and/or stressful stimuli to which we are exposed daily. The researchers combined two measurement methods. In one, a traditional research technique called microneurography, very thin needle electrodes are used to probe the signaling in nerve fibers (specifically, muscle sympathetic nerve activity, MSNA) directed to the vascular bed (blood vessels) of the muscles. The other was a modern brain-imaging technique known as magnetoencephalography (MEG).
For the first time, the researchers can now link the increased susceptibility to micro-stress to a reflex-like signal in the brain. The brain area (the “rolandic area”) that activates the signal controls several conscious brain functions. This finding opens the question of whether the BP peaks may be learned and could therefore also, with training, be eliminated.

Nanoparticles, or particles whose size varies between 1 and 100 nanometers, have shown tremendous potential in many areas of science and technology, including therapeutics. However, conventional, synthetic nanoparticles are complicated and expensive to produce. Extracellular vesicles (EVs), which have emerged as an alternative option to synthetic nanoparticles, show challenges for mass production.
Another recently emerging option is that of plant-derived nanoparticles (NPs), which can be easily produced in high levels at relatively lower costs. Like EVs, these nanoparticle-based systems also contain bioactive molecules, including polyphenols (which are known antioxidants) and microRNA, and they can deliver drugs to target organs in our bodies.
Leveraging this knowledge, researchers from the Tokyo University of Science (TUS) recently developed bionanoparticles with anticancer activity, using corn (maize) as the raw material. Prof. Makiya Nishikawa of Tokyo University of Science, Japan, who led the research team in this endeavor, elucidates, “By controlling the physicochemical properties of nanoparticles, we can control their pharmacokinetics in the body; so, we wanted to explore the nanoparticulation of edible plants. Maize, or corn, is produced in large quantities worldwide in its native form as well as in its genetically modified forms. That is why we selected it for our study.” The results of this study were published online on 24 November 2021 in Scientific Reports.
The team created a homogeneous mixture of super sweet corn in water, then centrifuged this corn juice at a high speed, subsequently filtering it through a syringe filter with a pore size of 0.45 μm. The filtered samples were then ultracentrifuged to obtain NPs derived from corn. The corn-derived NPs (cNPs) were approximately 80 nm in diameter. Quite interestingly, these cNPs also carried a tiny net negative charge of -17 mV.
The research team then set up experiments to see whether these cNPs were being taken up by various types of cells. In a series of promising results, the cNPs were taken up by multiple types of cells, including the clinically relevant colon26 tumor cells (cancer cells derived from mice), RAW264.7 macrophage-like cells, and normal NIH3T3 cells. RAW264.7 cells are commonly used as in vitro screens for immunomodulators―drugs that primarily target various cancer pathways.
The results were astounding: of the three types of cells, cNPs only significantly inhibited the growth of colon26 cells, indicating their selectivity for carcinogenic cell lines. Moreover, cNPs were able to successfully induce the release of tumor necrosis factor-α (TNF-α) from RAW264.7 cells. It is a well-documented fact that TNFα is primarily secreted by macrophages, natural killer cells, and lymphocytes―three key ingredients of our highly evolved immune system and which help mount an anticancer response. “The strong TNFα response was encouraging and indicated the role of cNPs in treating various types of cancer,” explains Dr. Daisuke Sasaki, first author of the study and an instructor and researcher at TUS.
The research team then conducted a reporter assay with the enzyme “luciferase” (derived from fireflies), which is a sensitive reporter for studying various biological responses. This luciferase-based assay revealed that the potent combination of cNPs and RAW264.7 cells significantly suppressed the proliferation of colon26 cells. Finally, the research team studied the effect of cNPs on laboratory mice bearing subcutaneous tumors. Once again, the results were astonishing: injecting cNPs into colon26 tumors on a daily basis significantly suppressed tumor growth, without causing serious side effects, or weight loss.
“By optimizing nanoparticle properties and by combining them with anticancer drugs, we hope to devise safe and efficacious drugs for various cancers,” observes an optimistic Prof. Nishikawa.
Summarizing these impactful findings, Dr. Kosuke Kusamori, co-author and assistant professor at TUS says, “These cNPs exhibit excellent anti-tumor properties, are easy to develop, and are economically viable. Moreover, they do not exhibit any serious adverse effects, at least in mice so far!”
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Materials provided by Tokyo University of Science. Note: Content may be edited for style and length.