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Pseudomonas aeruginosa (P.a.) are resistant to most antibiotics and cause life-threatening infections of wounds or the lungs. The P.a. bacteria species has an entire arsenal of strategies for evading the immune system and infecting tissue. Researchers working with Prof. Dr. Winfried Römer and Dr. Carsten Schwan of the University of Freiburg and the Excellence Cluster CIBSS — Centre for Integrative Biological Signalling Studies — have identified a previously unknown, natural, defense mechanism that protects cells from Pseudomonas infection. The study has been published in Cell Reports.
Pseudomonas aeruginosa also enter cells in a targeted way
Surrounded by nutrients and undetected by the immune system, the interior of a cell is the ideal place for pathogenic bacteria to reproduce. Nevertheless, it was long thought that they existed outside of cells for the most part. “In the meantime, it’s clear that the picture is more complex and the bacteria target the cells they penetrate,” explains Römer. With the aid of live cell imaging microscopy, this can be observed in the laboratory. The bacteria take up close contact to the cell and make indentations in its membrane until they are completely engulfed by it.
Pseudomonas triggers the denting of the cell’s membrane by binding the virulence factor LecA to sugar molecules on the membrane’s surface. Proteins that bind with sugars are common in the natural world and are also observed on other bacteria and viruses. The strong binding of the bacteria and host cells leads to the cell membrane closing itself like a zipper around the bacteria — a process that Römer’s working group has been examining for quite some time.
“Now we’ve intentionally focused on the role septins play in Pseudomonas infection,” says Schwan, describing the objective of the current study. “It’s known of other bacteria that they manipulate host cell septins and can exploit them to ease penetration. Yet at the same time, septins can also encapsulate bacteria that have already penetrated and induce their liquidation, so they have an ambivalent function in infections,” Schwan continues. Septins are part of the cytoskeleton and serve as a key structural element similar to a modular scaffold that can be flexibly put together and taken apart. They also frequently play a role precisely when curved membranes are involved.
The binding of LecA is sufficient to induce septin accumulation
In their latest study, the researchers used human lung cells that they infected with Pseudomonas aeruginosa in the lab. They found the attachment of the bacteria led to septins gathering at the site within a few seconds or minutes. If the bacteria failed to penetrate, the accumulation then dissolved again quickly. The researchers could also observe this effect when instead of bacteria small polymer beads coated with LecA were given to the cells. This showed that binding via LecA was enough to induce septin accumulation.

The discovery of a genetic variant that is relatively common among people of Polynesian ancestry, but incredibly rare in most other populations, is giving clues to the genetic underpinnings of high cholesterol in all people, according to new research led by University of Pittsburgh School of Public Health geneticists in partnership with several other groups, including the University of Otago and the Samoan health research community.
The surprising finding, published this week in the journal Human Genetics and Genomics Advances, demonstrates the importance of ensuring diversity in genetic databases.
“If we had only been looking in populations with European ancestry, we might have missed this finding entirely,” said lead author Dr. Jenna Carlson, assistant professor of human genetics and biostatistics at Pitt Public Health. “It was through the generosity of thousands of Polynesian people that we were able to find this variant, which is a smoking gun that will spark new research into the biology underlying cholesterol.”
High cholesterol is a major cause of disease burden in countries of all income levels, is a risk factor for heart disease and stroke, and is estimated to cause 2.6 million deaths annually worldwide, according to the World Health Organization.
Carlson and her team built their study to explore a signal that popped up in a large genome-wide survey looking for genes associated with lipids, or fats, in the body. It suggested that a gene variant on chromosome 5 could be associated with cholesterol. The team set out to “fine map” the region using genetic data from 2,851 Samoan adults from the Obesity, Lifestyle, And Genetic Adaptations (OLAGA, which means “life” in Samoan) Study Group who had also provided health information, including lipid panels. To double-check the finding, the team looked for the association in 3,276 other Polynesian people from Samoa, American Samoa and Aotearoa New Zealand, and the same connection between the variant and cholesterol was seen in them.
Using data from the western Polynesian Samoan participants, the team was able to fill in the missing information around the region they were interested in on chromosome 5. This led them to BTNL9 — a gene that directs the production of the BTNL9 protein. Proteins typically signal to cells to perform actions, though scientists still haven’t characterized the precise role of the BTNL9 protein.
It turned out that Polynesian people with low levels of HDL “good” cholesterol and high levels of triglycerides had a “stop-gain” variant in BTNL9, which means the gene was being directed to stop doing its protein-production job, a strong hint that the BTNL9 protein is involved in helping cells maintain healthy cholesterol levels.
“We don’t know a lot about this variant because it’s not seen in published genome references, which overrepresent European ancestry individuals — it’s virtually nonexistent in European ancestry populations, has very low frequency in South Asians and isn’t even particularly common in eastern Polynesian people, such as Māori living in Aotearoa New Zealand,” Carlson said. “But the way it’s linked to lipid panels in Samoan people tells us that this gene is important to cholesterol, something we didn’t know before. By further exploring BTNL9, we might someday discover new ways to help everyone maintain healthy cholesterol levels.”
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Materials provided by University of Pittsburgh. Original written by Allison Hydzik. Note: Content may be edited for style and length.

Biomedical engineers at Duke University have demonstrated the most effective treatment for pancreatic cancer ever recorded in mouse models. While most mouse trials consider simply halting growth a success, the new treatment completely eliminated tumors in 80% of mice across several model types, including those considered the most difficult to treat.
The approach combines traditional chemotherapy drugs with a new method for irradiating the tumor. Rather than delivering radiation from an external beam that travels through healthy tissue, the treatment implants radioactive iodine-131 directly into the tumor within a gel-like depot that protects healthy tissue and is absorbed by the body after the radiation fades away.
The results appear online October 19 in the journal Nature Biomedical Engineering.
“We did a deep dive through over 1100 treatments across preclinical models and never found results where the tumors shrank away and disappeared like ours did,” said Jeff Schaal, who conducted the research during his PhD in the laboratory of Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke. “When the rest of the literature is saying that what we’re seeing doesn’t happen, that’s when we knew we had something extremely interesting.”
Despite accounting for only 3.2% of all cancer cases, pancreatic cancer is the third leading cause of cancer-related death. It is a very difficult to treat because its tumors tend to develop aggressive genetic mutations that make it resistant to many drugs, and it is typically diagnosed very late, when it has already spread to other sites in the body.
The current leading treatment combines chemotherapy, which keeps cells in a stage of reproduction vulnerable to radiation for longer periods of time, with a beam of radiation targeted at the tumor. This approach, however, is ineffective unless a certain threshold of radiation reaches the tumor. And despite recent advances in shaping and targeting radiation beams, that threshold is very difficult to reach without risking severe side effects.

Women at risk of pregnancy loss who need a specialist surgical procedure could benefit from a single-stranded suture thread to reduce risk of infection, results from the C-STICH clinical trial found.
The trial was the largest of its type and is published in The Lancet. It involved more than 2000 expectant mothers who needed a procedure called a cerclage, where a purse string suture is placed around the neck of the womb (the cervix) during their pregnancy. Women were randomly allocated to have the surgical procedure performed using either a single stranded thread or a braided thread.
Researchers tested whether there would be any difference in miscarriage or stillbirth, due to an increased risk of infection, from using a braided suture thread. The research, which is funded by the National Institute For Health and Care Research, the research partner of the NHS, public health and social care, demonstrates that single stranded sutures could potentially improve outcomes for mothers at risk of preterm birth.
The team led by researchers from the University of Birmingham and Birmingham Women’s and Children’s Hospital found that the mothers treated with single stranded threads had no differences in pregnancy loss or preterm birth but reported fewer instances of infection and sepsis. This could have important implications for the health outcomes of mothers and babies who are treated with a cervical cerclage in their pregnancy.
Dr Vicky Hodgetts-Morton, NIHR Clinical Lecturer in Obstetrics at the University of Birmingham and Birmingham Women’s Hospital explained the implications of the trial results. Dr Hodgetts-Morton said:
“Preterm birth is a significant problem, complicating approximately one in ten pregnancies around the world. The consequences of preterm birth may be significant with some babies being born too early to survive, and those that survive are at increased risk of health complications. One cause for preterm birth is cervical insufficiency, occurring in 0.5% to 1% of pregnant women for which the placement of a vaginal cervical cerclage can be an effective treatment.”
“Suture thread choice has the potential to improve how well a cerclage works in preventing miscarriage, stillbirth and preterm birth. Both single stranded and braided threads are commonly used to perform cerclages and our findings show no differences in pregnancy loss and preterm birth. The C-STICH trial results did show an increased risk of infections in labour and around the time of delivery with braided threads and this supported our hypothesis that a single stranded thread could reduce the risk of infection developing during the pregnancy.”
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Materials provided by University of Birmingham. Note: Content may be edited for style and length.

A team led by scientists at Scripps Research and the University of Amsterdam has achieved an important goal in virology: mapping, at high resolution, critical proteins that stud the surface of the Hepatitis C virus (HCV) and enable it to enter host cells.
The discovery, reported in Science on October 21, 2022, details key sites of vulnerability on the virus — sites that can now be targeted effectively with vaccines.
“This long sought-after structural information on HCV puts a wealth of previous observations into a structural context and paves the way for rational vaccine design against this incredibly difficult target,” says study co-senior author Andrew Ward, PhD, professor in the Department of Integrative Structural and Computational Biology at Scripps Research.
The study was the product of a multi-year collaboration that included the Ward laboratory, the lab of Gabriel Lander, PhD (also a professor in the Department of Integrative Structural and Computational Biology at Scripps Research); the lab of Rogier Sanders, PhD, of the University of Amsterdam; and the lab of Max Crispin, DPhil, at the University of Southampton.
It is projected that roughly 60 million people globally — including about two million Americans — have chronic HCV infections. The virus infects liver cells, typically establishing a “silent” infection for decades until liver damage becomes severe enough to cause symptoms. It is a leading cause of chronic liver disease, liver transplants and primary liver cancers.
The origins of the virus are uncertain, but it is thought to have emerged at least several hundred years ago, and then eventually spread globally — especially via blood transfusions — in the latter half of the 20th century. While the virus was mostly eliminated from blood banks after its initial discovery in 1989, it continues to spread chiefly via needle-sharing among intravenous drug users in developed countries, and by the use of unsterilized medical instruments in developing countries. The leading HCV antiviral drugs are effective but far too expensive for large-scale treatment.

Passive smartphone monitoring of people’s walking activity can be used to construct population-level models of health and mortality risk, according to a new study publishing October 20thin the open access journal PLOS Digital Health by Bruce Schatz of University of Illinois at Urbana-Champaign, USA, and colleagues.
Previous studies have used measures of physical fitness, including walk tests and self-reported walk pace, to predict individual mortality risk. These metrics focus on quality rather than quantity of movement; measuring an individual’s gait speed has become a standard practice for certain clinical settings, for example. The rise of passive smartphone activity monitoring opens the possibility for population-level analyses using similar metrics.
In the new study, researchers studied 100,000 participants in the UK Biobank national cohort who wore activity monitors with motion sensors for 1 week. While the wrist sensor is worn differently than how smartphone sensors are carried, their motion sensors can both be used to extract information on walking intensity from short bursts of walking — a daily living version of a walk test.
The team was able to successfully validate predictive models of mortality risk using only 6 minutes per day of steady walking collected by the sensor, combined with traditional demographic characteristics. The equivalent of gait speed calculated from this passively collected data was a predictor of 5-year mortality independent of age and sex (pooled C-index 0.72). The predictive models used only walking intensity to simulate smartphone monitors.
“Our results show passive measures with motion sensors can achieve similar accuracy to active measures of gait speed and walk pace,” the authors say. “Our scalable methods offer a feasible pathway towards national screening for health risk.”
Schatz adds, “I have spent a decade using cheap phones for clinical models of health status. These have now been tested on the largest national cohort to predict life expectancy at population scale.”
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Materials provided by PLOS. Note: Content may be edited for style and length.

Scientists at UC San Francisco (UCSF) have developed a new way of looking at sex-biased diseases that is rooted in evolutionary biology.
They theorize that males and females took opposing paths in a tradeoff between immunity and metabolism that occurs in the liver. This helped males fight bacterial infections from wounds received in dominance fights, while helping females store subcutaneous fat to survive when food is scarce.
Working in mice, the scientists delineate the activity of a signaling pathway that regulates lipids, storing fat in the liver in males and releasing it into the bloodstream in females. This pathway also responds to growth hormone.
This phenomenon may have shaped male biology in ways that hold risks in today’s high calorie environment. The findings have particular relevance for fatty liver, which affects a quarter of the U.S. population. It is seen predominantly in men until women reach menopause.
“Scientists have only recently started to understand there are these profound differences between males and females,” said Holly Ingraham, PhD, Herzstein Professor of Molecular Physiology at UCSF and co-senior author of the study, which appears Oct. 21, 2022, in Science. “Understanding these differences is going to be the key to unlocking therapeutics for sex-biased diseases. Fatty liver is one example.”
The experiments found that male mice were three times more likely than females to survive infection with the bacteria E. coli. The females developed hyperlipidemia, a condition that is also seen in humans with severe sepsis. Lowering their lipid levels helped them to survive.

University of Massachusetts Amherst research into genetic mutations that affect circadian rhythms offers new insight into the rest-wake cycle and provides a new model for investigating human disease and ultimately developing medical treatments.
Disruptions to the body’s internal clock — which coordinates the timing of biochemical, physiological and behavioral processes — are associated with a range of diseases, including cancer, cardiovascular conditions and susceptibility to infections, as well as a higher risk for accidents. Common disruptions of circadian rhythms are jet lag and shift work, which is performed by some 30 million people in the U.S.
“We are studying two mutations, both of which affect our ability to respond to shifts of the light cycle,” says neurobiologist Eric Bittman, Professor Emeritus of Biology. “Both of them speed up the clock. They reveal how vulnerable we are to disruptions in the light:dark schedule.”
In mammals, circadian rhythms are generated internally by a master pacemaker in the suprachiasmatic nucleus of the hypothalamus in the brain. In addition, every cell in the body has its own circadian clock, which the master pacemaker coordinates. In the normal, light:dark and fluctuating environment, circadian clocks create 24-hour cycles. However, in constant conditions, such as when hamsters are studied in darkness, the rhythms generate cycles whose period is longer or shorter than 24 hours.
“What this reveals to us is that there’s some internal mechanism that is generating rhythmicity, and that the animals are using cues from the environment, the most powerful of which is the light:dark cycle, to sync it up to exactly 24 hours,” Bittman says.
In previous research, Bittman and team identified a recessive mutation, which they call duper, as a defect in the circadian regulator gene Cryptochrome 1 (CRY1) of Syrian hamsters. By improving the draft of the hamster genome using fast homozygosity mapping, they created a modern genetic research model for investigating human diseases.

Scientists at Oregon Health & Science University have identified a long-sought gene-encoded protein that enables the brain to communicate a broad range of signals across gaps between neurons, known as synapses.
The discovery published today in the journal Nature.
Known as synaptotagmin-3, or SYT3, the protein helps to replenish the supply of chemical neurotransmitters that carry signals between neurons.
“When brain cells are active, they release neurotransmitters to communicate with their neighbors,” said senior author Skyler Jackman, Ph.D., assistant scientist in the OHSU Vollum Institute. “If a cell is very active it can exhaust its supply of neurotransmitters, which can cause a breakdown of communication and brain disfunction.
“It turns out that cells have a boost mode that replenishes their supply of neurotransmitters, but until now, we didn’t know the molecule that was responsible. We found that SYT3 is directly responsible for that neurotransmitter boost,” he said. “This gives us new insight about how brains can break down and fail to process information properly.”
Researchers generated “knock-out” mice that did not have the SYT3 gene. They found that those mice lacked the more robust level of synaptic transmission, compared with control mice that had the gene.
Notably, mutations of the SYT3 gene have been implicated in human cases of epilepsy and autism spectrum disorder. The research published today suggests the possibility of developing gene therapies or pharmaceutical approaches targeting SYT3, Jackman said.
“Imbalances in neurotransmitter release are the underlying causes for many neurological disorders,” said lead author Dennis Weingarten, Ph.D., a postdoctoral researcher in the Jackman lab. In the future, he said, “understanding these molecular switches — such as SYT3 — is a crucial step for us to combat these diseases.”
Jackman’s lab specializes in the study of synaptic transmission. The human brain contains hundreds of trillions of synapses. Discovering the molecules that endow these specialized structures with their unique properties is essential for understanding brain function and neurological disorders.
“Synaptic transmission is fundamental for sensing our surroundings, making decisions and nearly every other feature of our inner world,” Jackman said.
This work was supported by the Whitehall Foundation, the Medical Research Foundation, and the National Institutes of Health Imaging Core Facility, award P30NS061800.
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Materials provided by Oregon Health & Science University. Original written by Erik Robinson. Note: Content may be edited for style and length.

Eating a handful of almonds a day significantly increases the production of butyrate, a short-chain fatty acid that promotes gut health.
A team of researchers from King’s College London investigated the impact of whole and ground almonds on the composition of gut microbes. The study, published today in the American Journal of Clinical Nutrition, is funded by the Almond Board of California.
The gut microbiome consists of thousands of micro-organisms living in the gut. These play a vital role in digesting nutrients and can have a positive or negative influence on our health, including our digestive and immune systems. The mechanisms of how the gut microbiomes have an impact on human health is still being investigated, but evidence suggests eating specific types of food can positively influence the types of bacteria in our gut or what they do in our gut.
Researchers at King’s College London recruited 87 healthy adults who were already eating less than the recommended amount of dietary fibre and who snacked on typical unhealthy snacks (e.g. chocolate, crisps). Participants were split into three groups: one group changed their snacks for 56 g of whole almonds a day, another for 56 g of ground almonds a day, and the control group ate energy-matched muffins as a control. The trial lasted four weeks.
Researchers found that butyrate was significantly higher among almond eaters compared to those who consumed the muffin. Butyrate is a short-chain fatty acid that is the main source of fuel for the cells lining the colon. When these cells function effectively, it provides an ideal condition for gut microbes to flourish, for the gut wall to be strong and not leaky or inflamed and for nutrients to be absorbed.
No significant difference was observed in gut transit time — the time it takes for food to move all the way through the gut — however whole-almond eaters had an additional 1.5 bowel movements per week compared to the other groups. These findings suggest eating almonds could also benefit those with constipation.
Testing showed that eating whole and ground almond improved peoples’ diets, having higher intakes of monosaturated fatty acids, fibre, potassium and other important nutrients compared to the control group.
Lead author Professor Kevin Whelan, Head of Department of Nutritional Sciences at King’s College London, said: “Part of the way in which the gut microbiota impact human health is through the production of short-chain fatty acids, such as butyrate. These molecules act as a fuel source for cells in the colon, they regulate absorption of other nutrients in the gut, and help balance the immune system. We think these findings suggest almond consumption may benefit bacterial metabolism in a way that has the potential to influence human health.”
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Materials provided by King’s College London. Note: Content may be edited for style and length.