**Peroxisomes are compartments where cells turn fatty molecules into energy and useful materials, like the myelin sheaths that protect nerve cells. In humans, peroxisome dysfunction has been linked to severe metabolic disorders, and peroxisomes may have wider significance for neurodegeneration, obesity, cancer and age-related disorders.**

Peroxisomes are also highly conserved, from plants to yeast to humans, and Bartel said there are hints that these structures may be general features of peroxisomes.

“Peroxisomes are a basic organelle that has been with eukaryotes for a very long time, and there have been observations across eukaryotes, often in particular mutants, where the peroxisomes are either bigger or less packed with proteins, and thus easier to visualize,” she said. But people didn’t necessarily pay attention to those observations because the enlarged peroxisomes resulted from known mutations.

The researchers aren’t sure what purpose is served by the subcompartments, but Wright has a hypothesis.

“When you’re talking about things like beta-oxidation, or metabolism of fats, you get to the point that the molecules don’t want to be in water anymore,” Wright said. “When you think of a traditional kind of biochemical reaction, we just have a substrate floating around in the water environment of a cell—the lumen—and interacting with enzymes; that doesn’t work so well if you’ve got something that doesn’t want to hang around in the water.”

“So, if you’re using these membranes to solubilize the water-insoluble metabolites, and allow better access to lumenal enzymes, it may represent a general strategy to more efficiently deal with that kind of metabolism,” he said.

Bartel said the discovery also provides a new context for understanding peroxisomal disorders.

“This work could give us a way to understand some of the symptoms, and potentially to investigate the biochemistry that’s causing them,” she said.

In his first year of graduate school, Rice University biochemist Zachary Wright discovered something hidden inside a common piece of cellular machinery that’s essential for all higher order life from yeast to humans.

What Wright saw in 2015—subcompartments inside organelles called peroxisomes—is described in a study published today in Nature Communications.

“This is, without a doubt, the most unexpected thing our lab has ever discovered,” said study co-author Bonnie Bartel, Wright’s Ph.D. advisor and a member of the National Academy of Sciences. “This requires us to rethink everything we thought we knew about peroxisomes.”

In a review published in the journal *Science*, Jain and Steele Laboratories colleagues Hadi T. Nia, PhD, and Lance L. Munn, PhD, describe four distinct physical hallmarks of cancer that affect both cancer cells and the tumor microenvironment, contributing to both tumor growth and the development of resistance to powerful cancer drugs.

One widely accepted model of cancer holds that a normal cell goes rogue because of genetic mutations or an environmental insult. In this model, the altered cell starts replicating out of control and takes over normal tissues, displaying eight hallmarks that include the ability to promote and sustain the growth of tumors, evade immune system attempts to suppress growth, stimulate blood flow to tumors and both invade local tissues and metastasize (spread) elsewhere in the body.

But this model fails to take into account how physical processes affect tumor progression and treatment, say the authors. In addition to the aforementioned eight biological hallmarks of cancer proposed by Robert Weinberg, PhD, from MIT, and Douglas Hanahan, PhD, from the Swiss Federal Institute of Technology in Lausanne, Jain and colleagues propose adding four distinct physical hallmarks that capture the biomechanical abnormalities in tumors: elevated solid stress; elevated interstitial fluid pressure; increased stiffness and altered material properties; and altered tissue micro-architecture.

Three decades of research in the Steele Laboratories led to the discovery and clinical translation of the first two hallmarks. “Solid stresses are created as proliferating and migrating cells push and stretch solid components of the surrounding tissue. They are large enough to compress blood and lymphatic vessels in and around tumors, impairing blood flow and the delivery of oxygen, drugs and immune cells,” Jain says.

Elevated interstitial fluid pressure is caused by abnormally permeable blood vessels in tumors leaking blood plasma into tissues surrounding the tumor, and by insufficient drainage of lymphatic fluid. The interstitial fluid carries various growth factors with it, causing edema (swelling), elution (release) of drugs and growth factors, and facilitating cancer invasion of local and distant tissues.

Increased stiffness is caused by the deposition of cellular matrix (scaffolding) and remodeling of tissues. This stiffness has traditionally been used as a diagnostic marker for tumor growth, and more recently it has come to be recognized as a marker for prognosis. Increased stiffness activates signaling pathways that promote proliferation, invasiveness and metastasis of cancer cells, Jain explains.

“Finally, when normal tissue architecture is disrupted by cancer growth and invasion, micro-architecture is altered,” he says. “Stromal (supporting) cells, cancer cells and extracellular matrix adopt new organization. This changes the interactions between an individual cell and its surrounding matrix and cells, which affects signaling pathways associated with invasion and metastasis.”

Jain says that with the review article in Science, he and his colleagues hope to bridge the gap between the physical and biological sciences “by exploring the biological origins and repercussions of the physical hallmarks of cancer from the perspectives of cancer biologists and oncologists — who work to understand and overcome the physical abnormalities at the bench and in the clinic — and from the perspectives of physicists and engineers who develop new models and strategies for research, diagnosis and treatment.”

An evolving understanding of cancer that incorporates the physical properties of tumors and their surrounding tissues into existing biologic and genetic models can direct cancer researchers down previously uncharted avenues, potentially leading to new drugs and new treatment strategies, say investigators from Massachusetts General Hospital (MGH), Harvard Medical School (HMS) and the Ludwig Center at HMS.

“We believe that progress in cancer research relies on close collaboration between cancer biologists, oncologists, physical scientists and engineers. A comprehensive understanding of the physical hallmarks of cancer requires a rigorous and broad perspective spanning the physical and biological sciences,” says Rakesh K. Jain, PhD, an investigator in the Edwin L. Steele Laboratories in the Department of Radiation Oncology at MGH and HMS.

In a review published in the journal Science, Jain and Steele Laboratories colleagues Hadi T. Nia, PhD, and Lance L. Munn, PhD, describe four distinct physical hallmarks of cancer that affect both cancer cells and the tumor microenvironment, contributing to both tumor growth and the development of resistance to powerful cancer drugs.

Virtual reality software which allows researchers to ‘walk’ inside and analyse individual cells could be used to understand fundamental problems in biology and develop new treatments for disease.

The software, called vLUME, was created by scientists at the University of Cambridge and 3D image analysis software company Lume VR Ltd. It allows super-resolution microscopy data to be visualised and analysed in virtual reality, and can be used to study everything from individual proteins to entire cells. Details are published in the journal Nature Methods.

Super-resolution microscopy, which was awarded the Nobel Prize for Chemistry in 2014, makes it possible to obtain images at the nanoscale by using clever tricks of physics to get around the limits imposed by light diffraction. This has allowed researchers to observe molecular processes as they happen. However, a problem has been the lack of ways to visualise and analyse this data in three dimensions.

In first-of-their-kind observations in the human brain, an international team of researchers has revealed two well-known neurochemicals–dopamine and serotonin–are at work at sub-second speeds to shape how people perceive the world and take action based on their perception.

Furthermore, the neurochemicals appear to integrate people’s perceptions of the world with their actions, indicating dopamine and serotonin have far more expansive roles in the human nervous system than previously known.

Known as neuromodulators, dopamine and serotonin have traditionally been linked to reward processing–how good or how bad people perceive an outcome to be after taking an action.

The study online today in the journal *Neuron* opens the door to a deeper understanding of an expanded role for these systems and their roles in human health.

“An enormous number of people throughout the world are taking pharmaceutical compounds to perturb the dopamine and serotonin transmitter systems to change their behavior and mental health,” said P. Read Montague, senior author of the study and a professor and director of the Center for Human Neuroscience Research and the Human Neuroimaging Laboratory at the Fralin Biomedical Research Institute at Virginia Tech Carilion. “For the first time, moment-to-moment activity in these systems has been measured and determined to be involved in perception and cognitive capacities. These neurotransmitters are simultaneously acting and integrating activity across vastly different time and space scales than anyone expected.”

…

“These neuromodulators play a much broader role in supporting human behavior and thought, and in particular they are involved in how we process the outside world,” Bang said. “For example, if you move through a room and the lights are off, you move differently because you’re uncertain about where objects are. Our work suggests these neuromodulators–serotonin in particular– are playing a role in signaling how uncertain we are about the outside environment.”

WOODS HOLE, Mass. — The dialogue between neurons is of critical importance for all nervous system activities, from breathing to sensing, thinking to running. Yet neuronal communication is so fast, and at such a small scale, that it is exceedingly difficult to explain precisely how it occurs. A preliminary observation in the Neurobiology course at the Marine Biological Laboratory (MBL), enabled by a custom imaging system, has led to a clear understanding of how neurons communicate with each other by modulating the “tone” of their signal, which previously had eluded the field. The report, led by Grant F. Kusick and Shigeki Watanabe of Johns Hopkins University School of Medicine, is published this week in Nature Neuroscience.

In 2016 Watanabe, then on the Neurobiology course faculty, introduced students to the debate over how many synaptic vesicles can fuse in response to one action potential (see this 2-minute video for a quick brush-up on neurotransmission). To probe this controversy, they used a “zap-and-freeze” imaging technology conceived by co-authors M. Wayne Davis, Watanabe and Erik Jorgensen, and built by Leica for testing in the Neurobiology course. They zapped a neuron with electricity to induce an action potential, then quickly froze the neuron and took an image. They saw multiple vesicles fusing at once at many synapses, the first novel finding of this Nature Neuroscience report.

But there was more. Back at Johns Hopkins, Kusick and Watanabe decided to walk through the neurotransmission process with zap-and-freeze, taking images every 3 milliseconds after the action potential. That’s when they found an answer to an even larger question — how do neurons change the tone of their neurotransmission signal?

Emotional dysregulation and anxiety are common in people at clinical high risk for psychosis (CHR) and are associated with altered neural responses to emotional stimuli in the striatum and medial temporal lobe. Using a randomised, double-blind, parallel-group design, 33 CHR patients were randomised to a single oral dose of CBD (600 mg) or placebo. Healthy controls (n = 19) were studied under identical conditions but did not receive any drug. Participants were scanned with functional magnetic resonance imaging (fMRI) during a fearful face-processing paradigm. Activation related to the CHR state and to the effects of CBD was examined using a region-of-interest approach. During fear processing, CHR participants receiving placebo (n = 15) showed greater activation than controls (n = 19) in the parahippocampal gyrus but less activation in the striatum. Within these regions, activation in the CHR group that received CBD (n = 15) was intermediate between that of the CHR placebo and control groups. These findings suggest that in CHR patients, CBD modulates brain function in regions implicated in psychosis risk and emotion processing. These findings are similar to those previously evident using a memory paradigm, suggesting that the effects of CBD on medial temporal and striatal function may be task independent.

From the data, the GTEx team could identify the relationship between specific genes and a type of regulatory DNA called expression quantitative trait loci, or eQTL. At least one eQTL regulates almost every human gene, and each eQTL can regulate more than one gene, influencing expression, GTEx member and human geneticist Kristin Ardlie of the Broad Institute tells Science.

Another major takeaway from the analyses was that sex affected gene expression in almost all of the tissue types, from heart to lung to brain cells. “The vast majority of biology is shared by males and females,” yet the gene expression differences are vast and might explain differences in disease progression, GTEx study coauthor Barbara Stranger of Northwestern University’s Feinberg School of Medicine tells Science. “In the future, this knowledge may contribute to personalized medicine, where we consider biological sex as one of the relevant components of an individual’s characteristics,” she says in a statement issued by the Centre for Genome Regulation in Barcelona, where some of the researchers who participated in the GTEx project work.

Another of the studies bolsters the association between telomere length, ancestry, and aging. Telomere length is typically measured in blood cells; GTEx researchers examined it in 23 different tissue types and found blood is indeed a good proxy for overall length in other tissues. The team also showed that, as previously reported, shorter telomeres were associated with aging and longer ones were found in people of African ancestry. But not all earlier results held; the authors didn’t see a pattern of longer telomeres in females or constantly shorter telomeres across the tissues of smokers as previous studies had.

Not everyone is singing the project’s praises. Dan Graur, an evolutionary biologist at the University of Houston who often criticizes big projects like GTEx, tells Science the results are hard to parse and there was little diversity, with 85 percent of the tissue donors being white. He also was critical of the use of deceased donor tissue, questioning if it truly reflects gene activity in living humans. “It’s like studying the mating behaviour of roadkill.”

Other scientists say there’s much work to be done. The gene regulation map leaves many unanswered questions about the exact sequences that cause disease and how gene regulation systems work in tandem. Genomicist Ewan Birney, the deputy director general of EMBL, tells Science, “We shouldn’t pack up our bags and say gene expression is solved.”

A decade-long effort to probe gene regulation reveals differences between males and females, points to essential regulatory elements, and offers insight into past work on telomeres.

People who were children when their parents were divorced showed lower levels of oxytocin — the so-called “love hormone” — when they were adults than those whose parents remained married, according to a study led by Baylor University. That lower level may play a role in having trouble forming attachments when they are grown.

Oxytocin — secreted in the brain and released during bonding experiences such as delivery of a baby or sexual interaction or nursing, even being hugged by a romantic partner — has been shown in previous research to be important for social behavior and emotional attachments in early life. The oxytocin system also has been linked to parenting, attachment and anxiety.

The new study, published in the Journal of Comparative Psychology, delves into an area that has not been well researched — a link between oxytocin, early experience and adult outcomes.

“Since the rates of divorce in our society began to increase, there has been concern about the effects of divorce on the children,” said lead author Maria Boccia, Ph.D., professor of child and family studies at Baylor University in the Robbins College of Health and Human Sciences. “Most research has focused on short-term effects, like academic performance, or longer-term outcomes like the impact on relationships. How divorce causes these effects, however, is unknown.

“Oxytocin is a neurohormone that is important in regulating these behaviors and is also sensitive to the impact of stressful life events in early life,” she said. “This is a first step towards understanding what mechanisms might be involved.”

Previous studies of children whose parents were divorced have found that the experience was associated with mood disorders and substance abuse — behaviors found to be related to oxytocin, Boccia said. Additionally, such childhood experiences as divorce or death of a parent are associated with depression and anxiety in adolescents and adults, as well as with poorer parenting in adulthood, less parental sensitivity and warmth, overreaction and increased use of punishment.

Researchers in the Baylor study examined the effect of the experience of parental divorce in childhood on later adult oxytocin levels. They also asked participants to complete a set of questionnaires on attachment style and other measures.

“What we found was that oxytocin was substantially lower in people who experienced parental divorce compared to those who did not and correlated with responses on several measures of attachment,” Boccia said. “These results suggest that oxytocin levels are adversely affected by parental divorce and may be related to other effects that have been documented in people who experience parental divorce.”

Animal studies also suggest that one mechanism contributing to the negative effects of early parental separation may be suppression of oxytocin activity.

For the latest study, researchers recruited 128 individuals ages 18 to 62 at two institutions of higher learning in the Southeast United States. Of those, 27.3% indicated their parents were divorced. The average age for participants when their parents divorced was 9 years.

Upon arriving at the study site, participants were asked to empty their bladders, then given a 16-ounce bottle of water to drink before filling out questionnaires about their parents and peers during childhood, as well as their current social functioning. The questions addressed their parents’ style, including affection, protection, indifference, over-control and abuse; and their own levels of confidence, discomfort with closeness, need for approval and their styles of relationships and caregiving.

After participants completed the questionnaires, urine samples were collected, and researchers analyzed oxytocin concentrations. The levels were substantially lower in individuals whose childhood experience included their parents’ divorce.

Further analysis showed that those individuals rated their parents as less caring and more indifferent. They also rated their fathers as more abusive. Those who experienced parental divorce during childhood were less confident, more uncomfortable with closeness and less secure in relationships. They rated their own caregiving style as less sensitive and close than did the participants whose parents had not divorced.

“One of the first questions I am asked when presenting this research to other scientists is ‘does how old the child is when the divorce occurs matter?’ That is the most pressing question that we need to explore,” Boccia said.

Scientists at Cold Spring Harbor Laboratory (CSHL) and Stanford University have pinpointed the circuit in the brain that is responsible for sleepless nights in times of stress—and it turns out that circuit does more than make you toss and turn. Their study, done in mice, ties the same neuronal connections that trigger insomnia to stress-induced changes in the immune system, which weaken the body’s defenses against a host of threats.

The study, reported September 9, 2020, in the journal Science Advances, connects and explains two familiar problems, says CSHL Assistant Professor Jeremy Borniger. “This sort of stress-induced insomnia is well known among anybody that’s tried to get to sleep with a looming deadline or something the next day,” he says. “And in the clinical world, it’s been known for a long time that chronically stressed patients typically do worse on a variety of different treatments and across a variety of different diseases.”

Like many aspects of the body’s stress response, these effects are thought to be driven by the stress hormone cortisol. Working in the Stanford lab of Luis de Lecea, where Borniger completed a postdoctoral fellowship prior to joining CSHL, the research team found a direct connection between stress-sensitive neurons in the brain that trigger cortisol’s release and nearby neurons that promote insomnia.

… The same connection, they found, also has a potent effect on the immune system. Stress significantly disrupts the abundance of certain immune cells in the blood, as well signaling pathways inside them, and the team was able to recreate these changes simply by stimulating the same neurons that link stress to insomnia.

Understanding this circuitry opens the door to a deeper understanding of the consequences of stress, not just in healthy individuals but also in disease, Borniger says:

“I’m really interested in how we can manipulate distinct circuits in the brain to control not just the immune system at baseline, but in disease states like inflammatory bowel disease or in cancer or in psoriasis—things that are associated with systemic inflammation. Because if we can understand and manipulate the immune system using the natural circuitry in the body rather than using a drug that hits certain targets within the system, I think that would be much more effective in the long run, because it just co-opts the natural circuits in the body.”

A recent study in Science Advances by researchers at Karolinska Institutet and Max Planck Institute, shows that neurons can counteract degeneration and promote survival by adapting their metabolism. It challenges the long-standing view that neurons cannot adjust their metabolism and therefore irreversibly degenerate. These findings may contribute to developing therapeutic approaches for patients with mitochondrial diseases and other types of neurodegeneration, such as Parkinson’s Disease.

Mitochondria are the power plants of our cells and play an important role in providing energy for normal function of the tissues in our body. Nerve cells are particularly dependent on mitochondria for their activity. A growing body of evidence has linked mitochondrial dysfunction to some of the most devastating forms of neurodegeneration, such as Parkinson’s disease, different ataxias and several peripheral neuropathies.

However, despite the urge to find strategies to prevent or arrest neurodegeneration, our understanding of the precise events underlying neuronal death caused by mitochondrial dysfunction is very limited.