Researchers have identified two proteins that play an essential role in the formation of new blood vessels. The proteins are part of the Hippo signaling pathway, which regulates organ growth and size. “Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue’s metabolic milieu and often occurs at nutrient-deficient sites,” explained the researchers in the paper. “However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown.”

Blood vessels are essential for providing nutrients to all body tissues, and if those blood vessels stop working properly it can lead to the development of diseases. Age-related cardiovascular conditions can cause blood vessels to atrophy, while cancerous tumors often involve excessive growth of misrouted blood vessels. In order to develop targeted therapies for patients, it is important to understand how the growth of new blood vessels is regulated in the body.

The researchers found that these processes were instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD), which is a transcriptional module whose function is highly responsive to changes in the tissue environment. In a mouse model, they determined that ECs that lack YAP/TAZ, or their transcriptional partners TEAD1, 2 and 4, failed to divide, which resulted in stunted vascular growth in mice. When there was activation of TAZ, there was a proliferation of new blood vessel formation, leading to vascular hyperplasia.

“By sensing and responding to mechanical, metabolic, and soluble signals, these proteins coordinate tissue growth responses,” explained the researchers. When YAP and TAZ are active in the cells of the endothelium, they read genes which leads to the increased growth of certain surface transporters, which allows the cells to absorb more nutrients that are necessary for growth and cell division. The increased absorption triggers the activation of another protein, mTOR, which is a control point in cells that trigger growth and cell division, which allows new blood vessel networks to expand.

The researchers have not established what signals regulate YAP and TAZ activity in endothelial cells, must have identified a mechanism that allows blood vessels to align growth with their surroundings, which prevents endothelial cells from dividing if the metabolic resources to support that process are not there. The researchers are now studying the extent to which this mechanism is involved in regeneration and repair processes, which rely heavily on blood vessels, and whether malfunctions in the hippo signaling pathway can cause vascular disease in humans.

You can read more about the study in the paper – A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth – which was recently published in Nature Metabolism. DOI: 10.1038/s42255-022-00584-y

A machine learning algorithm has been developed by researchers at Imperial College London that is capable of diagnosing Alzheimer’s disease from a single magnetic resonance imaging (MRI) scan. The tool can diagnose the disease in the early stages when it would otherwise be very difficult to detect and can diagnose the disease without the need for a subject matter expert.

Alzheimer’s disease is the most common form of dementia and affects more than 500,000 people in the United Kingdom. The disease is most common in individuals over the age of 65, although Alzheimer’s disease can affect younger individuals. The disease affects thinking, can cause problems with language and problem solving, affects behavior, and causes memory loss.

There is currently no cure for Alzheimer’s disease, but getting an early diagnosis is important as treatments are available for helping patients manage the symptoms, and early diagnosis ensures Alzheimer’s disease patients can get the support and care they need and can plan for the future. A diagnosis is usually made after tests of cognitive function, memory, and brain scans, but diagnosing Alzheimer’s disease in the early stages using these methods is difficult.

The researchers developed their algorithm from one that was used for classifying cancerous tumors and trained it to look for changes in the brain. They divided the brain into 115 different regions and trained the algorithm to look at 660 different features in those brain regions and assess changes, which allowed the algorithm to accurately predict whether the patient had Alzheimer’s disease, long before there was any obvious shrinkage of the brain. According to the researchers, “For each patient, a biomarker called “Alzheimer’s Predictive Vector” (ApV) was derived using a two-stage least absolute shrinkage and selection operator (LASSO).”

The algorithm was tested using brain scans from more than 400 patients with early- or late-stage Alzheimer’s disease obtained from the Alzheimer’s Disease Neuroimaging Initiative. They also tested it on brain scans from more than 80 patients who were undergoing diagnostic tests for Alzheimer’s disease at Imperial College Healthcare NHS Trust.

The algorithm was able to correctly diagnose Alzheimer’s disease in 98% of patients and could distinguish between early- and late-stage Alzheimer’s disease in 79% of patients.  When patients visit clinics with complaints of memory problems, they often have other neurological conditions. The researchers demonstrated their tool was able to differentiate between patients with Alzheimer’s disease and other neurological conditions. The tool also identified changes in the brain in areas previously not associated with Alzheimer’s disease, such as the cerebellum and ventral diencephalon, which could open new avenues to explore in Alzheimer’s disease research.

“This method provides a biomarker able to detect an early stage of AD with a significant potential improvement of the clinical decision support system,” explained the researchers in the paper. “Our ApV is robust and repeatable across MRI scans, demonstrating its potential for applicability in clinical practice in the future.”

You can read more about the study in the paper – A predictive model using the mesoscopic architecture of the living brain to detect Alzheimer’s disease – which was recently published in Nature Communications Medicine. DOI: 10.1038/s43856-022-00133-4

A new technique has been developed for generating dopamine-producing neurons from induced pluripotent stem cells (IPSCs). The technique could be used to generate patient-specific neurons that could help to accelerate research into new therapies for Parkinson’s disease.

Dopaminergic neurons in the midbrain are the main source of the neurotransmitter dopamine. Dopamine has many functions in cells and is involved in sleep and arousal, behavior and cognition, pleasure reward and motivation, memory, and helps to regulate body movements. There are three main types of dopaminergic nerve cells in the midbrain – A8, A9, and A10 – and each plays a different role in the function of the brain. It is the degeneration of A9 dopaminergic DA neurons in the substantia nigra region of the brain that is the main cause of motor symptoms in Parkinson’s disease patients.

“These neurons are pacemakers that continuously fire action potentials regardless of excitatory inputs from other neurons,” said Jian Feng, PhD, professor of physiology and biophysics at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo and lead author of the study. “Their pacemaking property is very important to their function and underlies their vulnerability in Parkinson’s disease.”

Researchers have been working on techniques for generating dopaminergic nerve cells from IPSCs for research and to develop more effective therapies; however, differentiating IPSCs into the right types of neurons has proven to be a challenge. Feng and his team have now developed a new technique that allows them to make A9 dopamine neurons from IPSCs, which means patient-specific neurons can be generated for any Parkinson’s disease patient to study their disease and potentially provide personalized therapy.

A9 dopaminergic neurons are possibly the largest cells in the body and have around four times the volume of a human egg. “Over 99 percent of the volume is contributed by their extremely extensive axon branches. The total length of axon branches of a single A9 DA neuron is about 4.5 meters,” said Feng. “The cell is like the water supply system in a city, with a relatively small plant and hundreds of miles of water pipes going to each building”

In order to maintain their pacemaking functions, these cells depend on Ca2+ channels and need to deal with considerable stress from handling both Ca2+ ions and dopamine. The cells are particularly vulnerable, and the key to developing new treatments for diseases such as Parkinson’s disease involves learning about those vulnerabilities and finding ways to protect the neurons and prevent their loss.

Now that a reliable method has been developed for generating these neurons in the lab, it will be possible to conduct studies to identify compounds that can protect them and prevent their loss due to Parkinson’s disease. These cells could also potentially be candidates for transplantation therapies for Parkinson’s disease patients.

Feng said the differentiation process from human IPSCs occurs in three stages, with each stage of the differentiation process controlled by different chemicals that mimic natural differentiation processes. One of the main challenges has been determining the right combination and concentration of those chemicals, and the duration that each needs to be applied. That has been a painstaking process, which has been based on previous studies at the Jacobs School of Medicine and the work of other researchers. “There was previously no way to make human dopamine neurons from a PD patient so we could study these neurons to find out what goes wrong,” said Feng.

You can read more about the study in the paper – Generation of human A9 dopaminergic pacemakers from induced pluripotent stem cells – which was recently published in Molecular Psychiatry. DOI: 10.1038/s41380-022-01628-1

New research has shed light on the reasons why some people develop severe COVID-19 symptoms while others experience no symptoms at all. From quite early in the pandemic, risk factors were identified that were linked to severe COVID-19 infections including pre-existing illnesses such as diabetes, a high body mass index, and age, but those risk factors alone did not account for many severe cases and deaths, such as individuals with no known health conditions who were young and not overweight.

An international team of researchers from the University of Sheffield in the UK and Stanford University in the United States conducted a multiomic analysis that revealed cell-type-specific molecular determinants of COVID-19 severity and identified more than 1,000 genes that were linked to the development of severe COVID-19.

Identifying patterns in vast amounts of data is a considerable challenge, so the researchers developed a machine learning tool to identify the genetic basis for diseases such as COVID-19 that are poorly understood. If the genetic factors that lead to the development of severe disease are not known, it limits the opportunity for early intervention and the provision of treatments that could reduce disease severity and prevent death.

The researchers used multiple large data sets for their study, including genetic information from healthy human lung tissue which allowed them to identify gene expression for 19 different lung cell types. Data was also used from the COVID-19 Host Genetics Initiative, which was one of the largest genetic studies of critically ill coronavirus patients. That dataset was used to identify genetic clues as to why some individuals were at a higher risk of developing severe disease than others. Mutations that were present or absent in individuals with severe COVID-19 suggested the mutations may be involved in the severity of the disease. The researchers also used data that described the different regions of the genome that were important for different cell types within lung tissue and overlapped the mutations onto the cell-specific genomes, which allowed them to identify which genes were dysfunctional within each cell type.

The researchers’ machine learning tool – RefMap – identified more than 1,000 risk genes across 19 cell types that accounted for 77% of the SNP-based heritability for severe disease. While a broad range of genes increased risk, the greatest number were related to the immune system.  “Genetic risk is particularly focused within natural killer (NK) cells and T cells, placing the dysfunction of these cells upstream of severe disease, “explained the researchers. “Mendelian randomization and single-cell profiling of human NK cells support the role of NK cells and further localize genetic risk to CD56bright NK cells, which are key cytokine producers during the innate immune response. Rare variant analysis confirms the enrichment of severe-disease-associated genetic variation within NK-cell risk genes.”

The study has significantly improved understanding of why some people have more serious COVID-19 symptoms than others and has identified potential therapeutic targets. “Our findings lay the foundation for a genetic test that can predict who is born with an increased risk for severe COVID-19,” said study lead, Michael P. Snyder, Ph.D., of the Department of Genetics at Stanford University. “Imagine there are 1,000 changes in DNA linked to severe COVID-19. If you have 585 of these changes, that might make you pretty susceptible, and you’d want to take all the necessary precautions.”

You can read more about the study in the paper – Multiomic analysis reveals cell-type-specific molecular determinants of COVID-19 severity – which was recently published in Cell Systems. DOI: 10.1016/j.cels.2022.05.007

Researchers have developed a new method for treating sepsis that has had promising results in studies on mice. Sepsis is caused when the body’s immune system goes into overdrive in response to an infection and starts attacking the body’s own organs and tissues. Sepsis is a life-threatening condition that requires emergency medical treatment, which can progress to septic shock, resulting in severe damage to organs or death.

According to data from the Centers for Disease Control and Prevention (CDC), at least 1.7 million people develop sepsis each year, resulting in 270,000 deaths. The treatment for sepsis is antibiotics, which can be effective if provided quickly, but some patients do not respond to treatment. Patients that survive sepsis can suffer long-term effects that can be extremely debilitating, and they face an increased risk of death.

A team of researchers led by Shaoqin Sarah Gong, professor at the Wisconsin Institute for Discovery at the University of Wisconsin–Madison, has been working on a new treatment for sepsis that involves nanoparticles, which deliver antibiotics and anti-inflammatory molecules. The new treatment was used in a study on mice with induced sepsis and improved the survival rate compared to the control group.

Sepsis involves major inflammation which can impair blood flow and leads to the formation of blood clots, which can cause organ death. In response, the body suppresses the immune system, which can lead to infections. Nicotinamide adenine dinucleotide (NAD+) is a molecule naturally produced in the body that has anti-inflammatory properties. There is potential for NAD+ to be used for the treatment of sepsis to reduce inflammation, however, NAD+ cannot be taken into cells directly, which has limited clinical applications.

The researchers loaded nanoparticles with a reduced form of NAD+ – NAD(H) – then engineered the NAD(H)-loaded nanoparticles to enable direct cellular transport to allow the delivery of NAD(H) to the targeted organs or cells along with antibiotics. The NAD(H)-loaded nanoparticles were engineered to prevent premature release of NAD(H) and degradation in the bloodstream.

The researchers tested their new treatment on several mouse models of sepsis, including endotoxemia, multidrug-resistant pathogen-induced polymicrobial bacteremia, and puncture-induced sepsis with secondary infection by P. aeruginosa. In the endotoxemia model, mice that received no treatment or were treated with NAD(H) alone died within two days, but all mice treated with the nanoparticles survived. The treatment was also effective in mice with multidrug-resistant pathogen-induced bacteremia, and improved outcomes for mice with secondary P. aeruginosa infections following caecal ligation and puncture.

“The NAD(H) nanoparticles have the potential to treat many other diseases because NAD(H) is involved with so many biological pathways. There is strong evidence for the use of NAD(H) as an intervention or aid in critical illnesses,” said Gong.

You can read more about the study in the paper – NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis – which was recently published in Nature Nanotechnology. DOI: 10.1038/s41565-022-01137-w

Alzheimer’s disease is characterized by the formation of beta-amyloid plaques, which are clumps of protein pieces in the tissue between nerve cells and neurofibrillary tangles, which are twisted tau protein filaments. The beta-amyloid plaques are thought to have toxic effects on the surrounding brain cells, although the exact role the plaques play in the progression of the disease is not well understood, such as whether they cause or are simply a byproduct of Alzheimer’s disease. It is also unclear what causes the process of plaque formation to begin, but it is thought that the process begins years before the symptoms of Alzheimer’s disease develop.

The amyloid cascade hypothesis postulates that the build-up of beta-amyloid plaques is a key first step in Alzheimer’s disease pathology, and that has been a major focus of research for more than 20 years. Several drugs have been developed that aimed to reduce amyloid-β production or aggregation; however, the drugs have failed in Phase III clinical trials. Now a new study conducted at NYU Grossman School of Medicine and the Nathan Kline Institute using mouse models of Alzheimer’s disease suggests the plaques form as a result of the failure of a process in the brain for getting rid of waste, and it is the breakdown of that waste removal process that ultimately results in neurodegeneration. That process begins well before the plaques start to form outside cells.

Metabolic waste products are recycled or removed by lysosomes, which are sacs of enzymes found in all cells. They are involved in the breakdown, recycling, and removal of waste from cells to maintain cellular homeostasis. That includes breaking down, removing, and recycling metabolic waste from normal cell processes and from disease, and breaking down cell components when they die. The latter is termed autophagy. Autophagy can be induced by cell stress or disease to remove abnormal proteins, damaged cell structures, and aggregates. The researchers explained that autophagy is markedly impaired in Alzheimer’s disease patients.

The new study saw the researchers track decreasing acid activity inside intact mouse cell lysosomes as cells became injured from Alzheimer’s disease. They developed imaging tests to track the removal of cellular waste and found that certain brain cell lysosomes became enlarged when they fused with autophagic vacuoles (AVs) filled with waste that had not been broken down, and that the AVs contained earlier forms of amyloid beta.

The researchers report that in neurons that are the most heavily damaged and will die, the vacuoles formed flower-like patterns and bulged out from the cells’ outer membranes, massing around the cell nucleus. “In more compromised yet still intact neurons, profuse Aß-positive AVs pack into large membrane blebs forming flower-like perikaryal rosettes. This unique pattern, termed PANTHOS (poisonous anthos (flower)), is also present in AD brains.”

In different mouse models, the researchers found accumulations of amyloid beta formed filaments inside the cell, which is characteristic of Alzheimer’s disease, and almost fully formed plaques formed inside some of the damaged neurons. This is the first time that it has been demonstrated that rather than the damage associated with Alzheimer’s disease being caused by beta-amyloid build-up outside of brain cells, it is problems inside the lysosomes of brain cells where beta-amyloid first appears.

“β-amyloid plaque formation in AD has commonly been considered to originate from extracellular deposition of β-amyloid derived from secreted Aβ, which then triggers secondary neuritic dystrophy and neuronal cell death,” explained the researchers. “By contrast, our evidence in diverse AD models supports the opposite sequence—namely, extracellular plaques mainly evolve from intraneuronal build-up of β-amyloid within membrane tubules, forming a centralized amyloid ‘core’ within single intact PANTHOS neurons that subsequently degenerate to give rise to the classical senile plaque.” The researchers suggest that PANTHOS neurons are the origin of the vast majority of senile plaques in AD mouse models.”

The researchers say their findings could answer the question of why drugs that aim to reduce amyloid-β production or aggregation fail, and suggest it could be because brain cells are already crippled before the plaques fully form outside cells. The research could open up a new avenue for Alzheimer’s disease therapeutics that aim to reverse lysosomal dysfunction and rebalance acid levels inside the brain’s neurons.

You can read more about the study in the paper – Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques – which was recently published in Nature Neuroscience. DOI: s41593-022-01084-8.

The researchers are now working on developing experimental therapies that tackle the lysosomal problems they identified in their research and have shown that the gene PSEN1, which has long been known to cause Alzheimer’s disease, plays a role in lysosomal dysfunction. They have also shown that the neuronal damage in PSEN1 mouse models of Alzheimer’s disease can be reversed if proper acid levels in lysosomes are restored.

Vitamin D deficiency is common around the world, with one study suggesting approximately 1 billion people worldwide have vitamin D deficiency, while around 50% of the world population has vitamin D insufficiency. Vitamin D has high physiological importance. A lack of vitamin D can cause bone deformities in children and osteomalacia in adults. A lack of vitamin D has been associated with an increased risk of cardiovascular disease, cognitive impairment in adults, cancer, and several autoimmune diseases.

One of the best-known sources of vitamin D comes from exposure of the skin to sunlight. UVB radiation synthesizes vitamin D from 7-dehydrocholesterol (7-DHC), or provitamin D3 as it is also known; however, individuals who shun the sun or who otherwise have very little exposure to sunlight need to get vitamin D from their diet but most foods contain little or no vitamin D. Good sources of vitamin D are oily fish, red meat, liver, and egg yolks, which poses a problem for vegans. Plants typically have little or no vitamin D, so the vitamin needs to come from fortified foods or supplements.

There could, however, be an alternative. Researchers have used the CRISPR gene editing tool to create biofortified tomatoes, which they claim could provide a new route to vitamin D sufficiency. Tomatoes do produce low levels of provitamin D3, but only in their leaves, which are usually discarded. Provitamin D3 does not accumulate in the fruit, as it is converted as part of cholesterol and steroidal glycoalkaloid (SGA) synthesis. The researchers engineered the plants to accumulate provitamin D3 by turning off an enzyme called Sl7-DR2 enzyme using CRISPR-Cas9. The Sl7-DR2 enzyme normally converts 7-DHC for cholesterol and SGA synthesis.

“Recently it has been shown that a duplicate pathway operates in Solanaceous species, including tomato, where specific isoforms of some enzymes, that are generally responsible for phytosterol and brassinosteroid biosynthesis, produce cholesterol for the formation of SGAs,” explained the researchers. “The existence of a ‘duplicate’ pathway for SGA biosynthesis in tomato makes the engineering of 7-DHC accumulation relatively straightforward.”

The researchers demonstrated their technique resulted in a significant accumulation of provitamin D3 in both the leaves and the fruit, which can be converted to vitamin D3 during exposure to UVB light. After tomatoes were treated with UVB light they were found to contain the same amount of vitamin D as two medium eggs or 28g of tuna, while the leaves of the pant contained up to 600 ug of provitamin D3 per gram of dry weight, which could be converted to vitamin D by shining UVB light on the leaves for 1 hour. Knocking out the enzyme had no effect on plant growth, development, or yield.

In addition to biofortifying tomatoes, the leaves of the fruit could be used for manufacturing vitamin D3 supplements or for fortifying food. It would also be possible to use the same technique in other plants in the nightshade family that share the same biochemical pathway, such as potato, eggplant, and pepper.

You can read more about the study in the paper – Biofortified tomatoes provide a new route to vitamin D sufficiency – which was recently published in Nature Plants. DOI: 10.1038/s41477-022-01154-6

The gut and the microbiome play a huge role in overall health and the influence microbes have on health is becoming better understood; however, there are challenges to overcome when studying the gut and microbiota. It is possible to conduct investigations of fecal matter and the blood, but these provide indirect measurements of what is happening in the gut. Endoscopy can be used to examine the health of the gut, but since fasting and purging are required, this method has severe limitations.

A team of scientists has developed a novel way of investigating gut health that involves the use of genetically engineered E. coli sentinel cells. These cells can pass through the gut safely and have been engineered to record changes in gene expression on their journey. Bacteria in the gut respond to each other and the host’s diet and immune system, so when the E. coli cells are excreted, they can be analyzed to reveal information about the intestinal tract and the microbes that colonize it.

“Deep sequencing of these DNA recordings revealed characteristic signatures based on dietary, host, and microbiota contents at different levels of the intestine. This work provides additional perspectives on how diet, inflammation, and microbial interactions in the body shape the health of mammalian hosts,” explained the researchers in the paper.

To record transcriptional changes, the researchers developed a recording method called Record-seq. The CRISPR-Cas system is used by bacteria to incorporate genetic material from viruses into their own genomes – in CRISPR arrays -which gives the bacteria a memory of the viruses they have encountered in the past and allows them to attack them again when they are encountered. This system was harnessed to create a recording mechanism. The researchers incorporated DNA into spacer sequences in CRISPR arrays within the genomes of the cells, which reveal which genes are activated as the bacteria pass through the gut. That information can be obtained by analyzing the excreted E. coli cells.

In this study, the researchers added the CRISPR array of Fusicatenibacter saccharivorans into an E. coli strain, and included a reverse transcriptase that transcribes RNA into DNA, as well as the CRISPR-associated proteins necessary for incorporating the DNA fragment into the CRISPR array. The researchers analyzed the bacterial DNA to discover how often a specific mRNA molecule is manufactured during the journey through the gut, and which genes were activated. The researchers were also able to show how the sentinel bacteria adapted their metabolism to the nutrient supply in the gut.

“Transcriptional recording sentinel cells open avenues in basic research and medicine. We now have a tool that can reveal host and microbial physiology within the intact and unperturbed intestine,” said Randall Platt, PhD, a professor of biological engineering at ETH Zurich, and senior author of the study.

The study was conducted on mice and would need to be adapted for use in humans, as the system only works with E. Coli, which is far from ideal. Platt and the team are now conducting experiments to identify other bacteria that could be used that do not survive in open environments and would be safe to use in humans.

You can read more about the study in the paper – Noninvasive assessment of gut function using transcriptional recording sentinel cells – which was recently published in Science. DOI: 10.1126/science.abm6038

A mouse model of chronic stress, depression, and anxiety has been used to investigate their impact on the effectiveness of drugs that lower cholesterol.

Research has shown that individuals suffering from severe stress, depression, and anxiety have a higher chance of developing cardiovascular disease. “The risk of developing cardiovascular disease increases in proportion to depression severity,” said Özlem Tufanli Kireccibasi, PhD, a postdoctoral fellow at the Cardiovascular Research Center at NYU Grossman School of Medicine in New York, and lead researcher of the study. “When both a major depressive disorder and cardiovascular disease are present, the prognosis is worse for both conditions.”

To investigate the effect of stress, depression, and anxiety on the effectiveness of cholesterol-lowering drugs, the researchers used a new mouse model. The mice lacked a low-density lipoprotein receptor (LDLr), which is required to clear LDL cholesterol from the body. LDL cholesterol is often referred to as bad cholesterol, as high levels of LDL cholesterol in the blood increase the risk of developing coronary artery disease.

As is the case with humans that lack the LDLr, the mice are prone to develop plaque build-ups in their arteries and aggressive cardiovascular disease. The plaque build-ups can be unstable, causing parts to break away which can lead to blood clots, which can cause strokes and heart attacks. The researchers mimicked human plaque build-ups in the arteries by feeding the mice an LDL-rich diet for 24 weeks.

The mice were divided into two groups, one of which was exposed to social stress, and the other served as the control group. Social stress occurred by placing mice in living spaces with larger, aggressive mice for short periods each day over a 10-day period. The researchers then evaluated the mice after each stressful event for social avoidance and behaviors associated with depression and anxiety. Those mice were then further divided into two groups – those that were susceptible to depression-like and anxiety-like behaviors and those that were resistant and were able to cope with the stress.

Previous research has shown that the arterial plaques in LDLr-deficient mice became less inflammatory and more stable after treatment with LDL-reducing medications. The mice in the susceptible group and the control group were then treated with LDL-reducing medications for a period of three weeks.

The researchers assessed the mice to identify changes in the number of inflammatory cells in the plaque, the levels of inflammatory monocytes circulating in the blood, and the number of bone marrow cells – the precursors to the immune cells that are abundant in plaque.

Compared to the control group, the susceptible mice had 50% more immune cells within the arterial plaque, twice the number of circulating monocytes, an 80% increase in immune-cell precursors in bone marrow, and less collagen in the plaque – collagen makes the plaque more stable. The mice exposed to social stress had similar reductions in lipid levels as the control group after treatment.

“The major finding is that repeated stress and the physiological and behavioral effects of hostile interactions (social defeat) appear to prevent the full beneficial changes to plaques that should be induced by lipid-lowering medications,” said Kireccibasi.

The findings of the research were presented at the American Heart Association event, Vascular Discovery: From Genes to Medicine Scientific Sessions.

Researchers have identified a drug that inhibits the growth of meningiomas, the most common type of primary intercranial tumor. Meningiomas are tumors that form in the meninges, for which treatment is surgery to remove the tumor and radiation therapy. Most meningiomas are benign and grow slowly, and the 5-year survival rate is 64% but around 20% of meningiomas are highly aggressive and can lead to disabilities and death.

While surgery and radiation therapy can be successful, if those treatments are not successful there are no further medical interventions for patients as there are no drugs that have been approved for treating the tumors. One of the problems with developing drugs to treat meningiomas has been the limited understanding of the biology of meningiomas.

Researchers at Northwestern Medicine, the University of California, San Francisco, and the University of Hong Kong used DNA methylation profiling on 656 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic, and single-cell approaches, and demonstrated that meningiomas consist of three molecular subgroups, each of which has distinct clinical outcomes, biological drivers, and therapeutic vulnerabilities.

By identifying these three DNA methylation groups, the researchers have been able to predict recurrence rates far more accurately than is possible using the current classification methods. They have also identified a drug that has been shown to inhibit the growth of most meningiomas.

Merlin-intact meningiomas, which account for 34% of all meningiomas, have the best outcomes and are susceptible to cytotoxic therapy. Immune-enriched meningiomas, which account for 38% of meningiomas, have intermediate outcomes, and hypermitotic meningiomas –28% of meningiomas – have the worst outcomes. This latter group is distinguished by convergent genetic and epigenetic mechanisms, which drive the cell cycle and are resistant to cytotoxic therapy.

The researchers found that aggressive meningiomas have several molecular changes in a cell division pathway, which allows them to divide more and return after surgery. The researchers identified a drug – abemaciclib – that blocks the cell division cycle, thus inhibiting tumor growth. The researchers demonstrated the effectiveness of the drug at inhibiting the growth of meningiomas in cell cultures, organoids, mouse models, and also used it for treating some patients in compassionate use cases, and their tumors decreased in size and symptoms eased, suggesting the drug could be used in clinical trials.

The researchers are now planning on making their molecular profiling generalizable to allow it to be offered to all patients with meningiomas to determine the likelihood of the tumor returning and to identify the patients who would benefit from treatment with the drug.

You can read more about the study in the paper – Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities – which was recently published in Nature Genetics. DOI: 10.1038/s41588-022-01061-8