A closer look at rebel T cells

Video Credit: La Jolla Institute

Scientists at La Jolla Institute for Immunology (LJI) are investigating a talented type of T cell.

Most T cells only work in the person who made them. Your T cells fight threats by responding to molecular fragments that belong to a pathogen—but only when these molecules are bound with markers that come from your own tissues. Your influenza-fighting T cells can’t help your neighbor, and vice versa.

“However, we all have T cells that do not obey these rules,” says LJI Professor and President Emeritus Mitchell Kronenberg, Ph.D. “One of these cell types is mucosal-associated invariant T (MAIT) cells.”

Now Kronenberg and his LJI colleagues have uncovered another MAIT cell superpower: MAIT cells can recognize the same markers whether they come from humans or mice. Kronenberg calls this finding “astounding.” “Humans diverged from mice in evolution 60 million years ago,” he says.

This new research, published in Science Immunology, sheds light on the genes and nutrients that give MAIT cells their fighting power. The findings are an important step toward one day harnessing these cells to treat infectious diseases and improve cancer immunotherapies.

Researchers identify previously unknown step in cholesterol absorption in the gut

Illustration Credit: Scientific Frontline

UCLA researchers have described a previously unknown step in the complex process by which dietary cholesterol is processed in the intestines before being released into the bloodstream – potentially revealing a new pathway to target in cholesterol treatment.

Although an existing drug and statins impact part of the process, an experimental drug being studied in UCLA research labs appears to specifically target the newfound pathway, possibly adding a new approach to the cholesterol management toolbox.

“Our results show that certain proteins in the Aster family play a critical role in moving cholesterol through the absorption and uptake process,” said Dr. Peter Tontonoz, a UCLA professor and researcher in Pathology and Laboratory Medicine and Biological Chemistry, senior author of an article in Science. “The Aster pathway appears to be a potentially attractive target for limiting intestinal cholesterol absorption and reducing levels of plasma cholesterol.”

Cholesterol from food is absorbed by cells that line the inner surface of the intestines – enterocytes – where it is processed into droplets that eventually reach the bloodstream. But this journey involves a multistep process.

Scientists are taking major steps towards completing the world’s first synthetic yeast.

Photo Credit: Karyna Panchenko

A UK-based team of Scientists, led by experts from the University of Nottingham and Imperial College London, have completed construction of a synthetic chromosome as part of a major international project to build the world’s first synthetic yeast genome.

The work, which is published today in Cell Genomics, represents completion of one of the 16 chromosomes of the yeast genome by the UK team, which is part of the biggest project ever in synthetic biology; the international synthetic yeast genome collaboration.

The collaboration, known as 'Sc2.0' has been a 15-year project involving teams from around the world (UK, US, China, Singapore, UK, France and Australia), working together to make synthetic versions of all of yeast's chromosomes. Alongside this paper, another 9 publications are also released today from other teams describing their synthetic chromosomes. The final completion of the genome project - the largest synthetic genome ever - is expected next year.

New antifungal molecule kills fungi without toxicity in human cells, mice

The mechanism for a critical but highly toxic antifungal is revealed in high resolution. Self-assembled Amphotericin B sponges (depicted in light blue) rapidly extract sterols (depicted in orange and white) from cells. This atomic level understanding yielded a novel kidney-sparing antifungal agent. 
Illustration Credit: Jose Vazquez

A new antifungal molecule, devised by tweaking the structure of prominent antifungal drug Amphotericin B, has the potential to harness the drug’s power against fungal infections while doing away with its toxicity, researchers at the University of Illinois Urbana-Champaign and collaborators at the University of Wisconsin-Madison report in the journal Nature.

Amphotericin B, a naturally occurring small molecule produced by bacteria, is a drug used as a last resort to treat fungal infections. While AmB excels at killing fungi, it is reserved as a last line of defense because it also is toxic to the human patient – particularly the kidneys. 

Temperature increase triggers viral infection

Illustration of phage virus injecting its DNA into a cell
Illustration Credit: Alex Evilevitch and Ting Liu

Researchers at Lund University, together with colleagues at the NIST Synchrotron Facility in the USA, have mapped on an atomic level what happens in a virus particle when the temperature is raised.

"When the temperature rises, the virus's genetic material changes its form and density, becoming more fluid-like, which leads to its rapid injection into the cell," says Alex Evilevitch who led the study.

Viruses lack their own metabolism and the ability to replicate independently; they are entirely dependent on a host cell to multiply. Instead, the virus hijacks the internal machinery of the infected cell to produce new virus particles, which are then released and spread to infect other cells.

In most cases, the virus's genetic material, DNA, is enclosed within a protective protein shell called a capsid. A research group at Lund University is working to understand the process by which the virus ejects its genetic material from the capsid and into cells and what causes the virus's DNA to be released.

It all began with a study published in 2014, where the Lund University researchers observed that there seems to be a sudden change in the virus's genetic material when exposed to the infection temperature, around 37 degrees.

‘Alien’ wasps thriving in tropical forests, study finds

Dolichomitus
Photo Credit: Pjt56
(CC BY-SA 4.0 DEED)

Researchers say they have discovered high diversity of Darwin wasps in a tropical rainforest in Brazil, wasps which were previously thought to thrive more in cooler habitats.

The wasps, which survive by living off host insects and spiders until adult-sized, were discovered on a mountain in the Brazilian Atlantic Rainforest. The number of types found were similar to that previously found in the whole of the UK.

The latest findings adds to a growing body of evidence that debunks the widely held belief that the Darwin wasp does not thrive in tropical environments and points to the possibility of many wasp species unknown to researchers in the past.

Researchers say it also provides further evidence of the biodiversity of the Brazilian Atlantic Rainforest and the significance of protecting and restoring the land from the effects of climate change and damage caused by human activities.

Scientists engineer potent immune cells for ‘off-the-shelf’ cancer immunotherapy

Illustration Credit: Scientific Frontline

UCLA scientists have developed a new method to engineer more powerful immune cells that can potentially be used for “off-the-shelf” cell therapy to treat challenging cancers.

“Off-the-shelf” cell therapy, also known as allogenic therapy, uses immune cells derived from healthy donors instead of patients. The approach can bring cell therapies, like chimeric antigen receptor (CAR) T cell therapy, to more patients in a timelier manner, which is one of the major barriers in getting these life-saving treatments to patients.

“Time is often of the essence when it comes to treating people with advanced cancers,” said Lili Yang, associate professor of microbiology, immunology and molecular genetics and member of the UCLA Health Jonsson Comprehensive Cancer Center. “Currently, these types of therapies need to be tailored to the individual patient. We have to extract white blood cells from a patient, genetically engineer the cells and then re-infuse them back into the patient. This process can take weeks to months and can cost hundreds of thousands of dollars to treat each patient.”

Poison dart frogs: Personality determines reproductive strategies

The Allobates femoralis species of poison dart frogs follows different strategies during reproduction according to their behavioral type.
Photo Credit: Eva Ringler

Poison frogs of the species Allobates femoralis are common in the rainforests in South America. Their highly poisonous relatives, such as frogs of the genus Phyllobates, were frequently used by indigenous people of Colombia to extract toxins by rubbing the skin onto arrowheads for the purposes of hunting and fighting. Allobates femoralis frogs are not poisonous. Like many other animal species, however, they have distinct personality traits. Both the males and females, for example, may be particularly bold, aggressive, or eager to explore. Poison frogs mate with several partners over the course of a reproductive period and their character traits have a considerable influence on the reproductive strategies employed by individual animals. 

Most of the previous studies in other animal taxa have examined the effect of personality traits on a single measure of reproductive success. In two recently published studies, researchers in the Institute of Ecology and Evolution at the University of Bern have presented new results on the effects of different combinations of personality traits in both males and females on different components of reproductive success. They examined the influence of personality on mating success, the number of clutches produced, as well as the numbers of offspring that survive into adulthood. The researchers were able to show that certain personality traits are already present in poison dart frogs at tadpole stage and that they also persist after the subsequent metamorphosis. 

Under Pressure: Seeing the Squeeze in Living Organisms

Double emulsion droplet (pink and cyan) located in between cells (yellow) of a living zebrafish embryo. Monitoring the changes in droplet size allows scientists to measure the osmotic pressure in the tissue.
Image Credit: © PoL / Antoine Vian

In order to survive, organisms must control the pressure inside them, from the single-cell level to tissues and organs. Measuring these pressures in living cells and tissues in physiological conditions has been very challenging. Now, researchers from the Cluster of Excellence Physics of Life (PoL) at the Technical University in Dresden (TU Dresden), Germany, report in the journal Nature Communications a new technique to ‘visualize’ these pressures as organisms develop. These measurements can help understand how cells and tissues survive under pressure, and reveal how problems in regulating pressures lead to disease. 

When molecules dissolved in water are separated into different compartments, water has the tendency to flow from one compartment to another to equilibrate their concentrations, a process known as osmosis. If some molecules cannot cross compartments, a pressure imbalance, known as osmotic pressure, builds up across them. This principle is the basis for many technical applications, such as the desalination of seawater or the development of moisturizing creams. It turns out that maintaining a healthy functioning organism makes the list too. 

Scientists use quantum biology, AI to sharpen genome editing tool

ORNL scientists developed a method that improves the accuracy of the CRISPR Cas9 gene editing tool used to modify microbes for renewable fuels and chemicals production. This research draws on the lab’s expertise in quantum biology, artificial intelligence and synthetic biology.
Illustration Credit: Philip Gray/ORNL, U.S. Dept. of Energy

Scientists at Oak Ridge National Laboratory used their expertise in quantum biology, artificial intelligence and bioengineering to improve how CRISPR Cas9 genome editing tools work on organisms like microbes that can be modified to produce renewable fuels and chemicals.

CRISPR is a powerful tool for bioengineering, used to modify genetic code to improve an organism’s performance or to correct mutations. The CRISPR Cas9 tool relies on a single, unique guide RNA that directs the Cas9 enzyme to bind with and cleave the corresponding targeted site in the genome. Existing models to computationally predict effective guide RNAs for CRISPR tools were built on data from only a few model species, with weak, inconsistent efficiency when applied to microbes.

“A lot of the CRISPR tools have been developed for mammalian cells, fruit flies or other model species. Few have been geared towards microbes where the chromosomal structures and sizes are very different,” said Carrie Eckert, leader of the Synthetic Biology group at ORNL. “We had observed that models for designing the CRISPR Cas9 machinery behave differently when working with microbes, and this research validates what we’d known anecdotally.”

Warmer, wetter winters bring risks to river insects

Professor Steve Ormerod, School of Biosciences
Photo Credit: Courtesy of Cardiff University

Research by Cardiff University has shown that the warmer, wetter winters in the UK caused by climate change are likely to impact the stability of insect populations in streams.

The research, spanning four decades, has demonstrated that stream insects are affected by warmer, wetter winters caused by fluctuating climate over the Atlantic Ocean. The consequences are felt by insect populations even in the smallest Welsh river sources.

“UK winters are becoming warmer and wetter on average, and we wanted to understand how this might impact our rivers. Streams and rivers are profoundly affected by climate through changes in global air temperatures and precipitation which affect flow patterns and water temperature.

“Over the years, we’ve noticed increasingly that changes in our rivers also track global climatic patterns over the Atlantic and these provide important clues about climate change” said Professor Steve Ormerod, the Water Research Institute at Cardiff University.

World’s first smart breathing tube for mechanically ventilated patients set for human trials

Professor Steve Morgan
Photo Credit: Courtesy of University of Nottingham

The University of Nottingham has secured £1.1 million in funding from the Medical Research Council to undertake human trials for the world’s first optical fiber sensor-equipped endotracheal tube (iTraXS).

Seriously ill or anaesthetized patients are unable to breathe naturally, so clinicians often use endotracheal tubes (ETTs), which are placed in the trachea (windpipe) to maintain an open airway and allow the patient to breathe through a mechanical ventilator. To do this, the tube is placed into the airway and a cuff (balloon) is inflated at the trachea to create a gas seal that allows air to be delivered to the lungs effectively. However, incorrect cuff inflation pressure can cause two main problems.

If pressure is too low, it can risk fluid getting past the cuff and causing ventilator-associate pneumonia (VAP). VAP increases the likelihood of death, affecting up to 20% of people in intensive care, and costs the NHS between £10,000 and £20,000 per patient. Conversely, if pressure is too high it can cause a pressure injury in the trachea, ranging from moderate to severe sore throats through to permanent scarring and narrowing of the windpipe.

European wildcats avoided introduced domestic cats for 2000 years

A wildcat which is part of the Saving Wildcats conservation breeding for release program which conducted the first release of wildcats to the Cairngorms National Park, Scotland in 2023
Photo Credit: Saving Wildcats

Domestic cats introduced from the Near East and wildcats native to Europe did not mix until the 1960s, despite being exposed to each other for two thousand years.

Two studies published today in Current Biology involving new archaeological and genetic evidence rewrites the history of cats in Europe.

The international team of researchers sequenced and analyzed both wildcats and domestic cats including 48 modern individuals and 258 ancient samples excavated from 85 archaeological sites over the last 8,500 years. They then assessed the patterns of hybridization (or interbreeding) after domestic cats were introduced to Europe over 2,000 years ago, and came into contact with native European wildcats.

The results of the studies demonstrate that, since their introduction, domestic cats and European wildcats generally avoided mating with each other. About 50 years ago in Scotland, however, that all changed and rates of interbreeding between wildcats and domestic cats rose rapidly. This may have happened as a result of dwindling wildcat populations and a lack of opportunity to mate with other wildcats.

Success of Wolbachia-infected mosquitoes in fighting dengue may be underestimated

Alex Perkins, associate professor of biological science
Photo Credit: Courtesy of University of Notre Dame

The fight against dengue fever has a new weapon: a mosquito infected with the bacteria Wolbachia, which prevents the spread of the virus. These mosquitoes have now been deployed in several trials demonstrating their potential in preventing disease transmission.

Now, researchers at the University of Notre Dame have conducted an analysis of the World Mosquito Program’s randomized control trial of Wolbachia-infected mosquitoes in Indonesia, looking at how excluding transmission dynamics impacted the original interpretation of the trial’s results.

“Randomized controlled trials are the gold standard for evaluating the efficacy of any medical or public health intervention. That is very difficult for vector interventions against dengue because incidence of the disease can be somewhat unpredictable and sporadic, requiring very large-scale trials,” said Alex Perkins, associate professor of biological sciences at Notre Dame and senior author on the study.

Improving the efficacy of cancer immunotherapy with modified CAR-T cells

Water color art illustrates the publication by Velasco et al. The authors systematically engineered novel Chimeric Antigen Receptors (CARs), each containing one of the signaling chains of the natural T cell receptor: epsilon, gamma, delta and zeta (from left to right, from top to bottom) to create innovative CAR T cells. The work demonstrated that each signaling chain imprints the functioning of the CAR T cells (represented by the different colors) impacting thus their anti-tumor activity.
Illustration Credit: Sara Wossning Minguet

CAR-T cell therapy is a last hope for many patients with blood, bone marrow or lymph gland cancer when other treatments such as chemotherapy are unsuccessful. A limiting factor of this otherwise very effective and safe therapy is that the cells used in the process quickly reach a state of exhaustion. Researchers at the University of Freiburg have now been able to prevent this exhaustion and thus significantly improve the effect of the therapy in a preclinical animal model. The new results have been published in the journal Nature Immunology.

Using the body’s own defenses against cancer

CAR-T cells are one of the personalized cancer therapies and have been used in specialized centers in Europe since 2018. In this complex treatment, immune cells, or more precisely T cells, are taken from the blood of cancer patients, genetically engineered in the laboratory with a chimeric antigen receptor (CAR) and then re-administered. The receptor helps the T cells to identify and kill cancer cells. As a result, the therapy utilizes the body’s own cells to permanently eradicate the cancer.

Potential inheritable effects and ethical considerations of epigenome editing

Illustration Credit: Courtesy of Institute for the Advanced Study of Human Biology

Epigenome editing is an emerging technology used to regulate gene function by controlling epigenetic states at specific locations on the genome. This method is distinct from traditional genetic editing, which involves permanently altering the DNA sequence. Notably, the intervention effects of epigenome editing are thought to be reversible, making this technology particularly attractive for its potential therapeutic applications in the treatment of genetic disorders and chronic diseases. Although some researchers argue that it presents fewer ethical issues compared with permanent genome editing, especially in terms of its impact on offspring, the potential for transgenerational epigenetic inheritance has also been reported, suggesting that epigenetic changes could be inherited across generations in mammals. This study sought to examine the ethical and practical questions of epigenome editing and its use for therapeutic purposes, especially in the context of transgenerational epigenetic inheritance and the potential consequences for future generations.

One Punch Isn’t Enough to Overcome a Common Cancer Mutation

Acute myeloid leukemia as seen under a microscope.
Image Credit: Animalculist
(CC BY-SA 4.0)

Cancer cells are often a mess of mutations. About 20 to 25 percent of cancers involve mutations in a complex of molecules called SWI/SNF. Yet drugs designed to block SWI/SNF activity haven’t always worked as expected.

Researchers at Harvard Medical School have now figured out why.

As reported Nov. 2 in Cell, the team found that when drugs block SWI/SNF, a second molecule steps up to compensate.

Blocking this second molecule alongside SWI/SNF suppressed cancer cell growth in lab dishes, suggesting that a two-drug approach could make treatments more effective in people.

“I am excited about this work because it shows an alternative path forward for treating cancers in which the SWI/SNF complex is mutated,” said senior author Karen Adelman, the Edward S. Harkness Professor of Biological Chemistry and Molecular Pharmacology in the Blavatnik Institute at HMS, whose lab conducted the work.

“What’s interesting and meaningful about this study is it shows that a one-two punch, a double-agent therapy, could be really useful for keeping these cancer cells at bay,” she said.

FSU researchers capture high-resolution images of magnesium ions interacting with CRISPR gene-editing enzyme

Hong Li, professor in the Department of Chemistry and Biochemistry and director of the Institute of Molecular Biophysics.
Photo Credit: Devin Bittner/FSU College of Arts and Sciences

The gene-editing technology known as CRISPR has led to revolutionary changes in agriculture, health research and more.

In research published in Nature Catalysis, scientists at Florida State University produced the first high-resolution, time-lapsed images showing magnesium ions interacting with the CRISPR-Cas9 enzyme while it cut strands of DNA, providing clear evidence that magnesium plays a role in both chemical bond breakage and near-simultaneous DNA cutting.

“If you are cutting genes, you don’t want to have only one strand of DNA broken, because the cell can repair it easily without editing. You want both strands to be broken,” said Hong Li, professor in the Department of Chemistry and Biochemistry and director of the Institute of Molecular Biophysics. “You need two cuts firing close together. Magnesium plays a role in that, and we saw exactly how that works.”

Atherosclerosis: RNA fragment creates prospect for new therapies

Image Credit: © Weber Lab, IPEK

Atherosclerosis is considered a frequent cause of cardiovascular diseases and strokes. Despite medical progress, case numbers are constantly rising. Targeted new therapeutic approaches are therefore more important than ever. An international team led by Professor Christian Weber, Director of the Institute for Cardiovascular Prevention (IPEK) at the University Hospital of Munich, and Professor Donato Santovito, leader of the Translational Vascular Therapy research group at IPEK, has now identified a specific microRNA molecule as a promising starting point for the investigation of new therapies.

Some time ago, the researchers had already demonstrated that the transmembrane protein CXCR4 plays a significant role in the development of atherosclerosis. The protein transmits signals to the cell interior. If CXCR4 is specifically silenced in arterial endothelial cells or in smooth muscle cells, it results in more severe atherosclerotic lesions. At the same time, there is increased leukocyte ingress into the cell, which leads to inflammatory processes. With regard to leukocytes, however, the presence of CXCR4 can also promote the development of inflammatory processes. “It made sense, therefore, to only boost the expression of CXCR4 on the cells of the vascular wall in order to counteract the atherosclerosis,” says Santovito. “The challenge, however, is not to influence any biological processes, as the protein occurs in all cells and exercises various important functions.”

Preventing the Exhaustion of T Cells

Healthy (red) and exhausted (green) T cells in the spleen of chronically infected mouse.
Image Credit: Ana Maria Mansilla / Institut für Systemimmunologie, Universität Würzburg

In the immune system's fight against cancer and infections, the T cells often lose their power. The team of Würzburg immunologist Martin Vaeth has found a possible explanation for this phenomenon.

In the immune system, chronic infections and the defense against tumors often lead to the phenomenon of T cell exhaustion: In this process, the T lymphocytes gradually lose their function, which impairs their responses against cancer and infections. The molecular mechanisms that control this loss of function have not been fully unraveled.

It is now certain that the exhaustion process is significantly influenced by the “powerhouses of the cells”, the mitochondria.

When mitochondrial respiration fails, a cascade of reactions is triggered, culminating in the genetic and metabolic reprogramming of T cells – a process that drives their functional exhaustion. But this "burnout" of the T cells can be counteracted: pharmacological or genetic optimization of cellular metabolism increases the longevity and functionality of T cells. This can be achieved, for example, by overexpressing a mitochondrial phosphate transporter that drives the production of the energy-providing molecule adenosine-triphosphate.