Toxoplasma gondii parasite uses unconventional method to make proteins for evasion of drug treatment

 A study by Indiana University School of Medicine researchers sheds new light on how Toxoplasma gondii parasites make the proteins they need to enter a dormant stage that allows them to escape drug treatment. It was recently published with special distinction in the Journal of Biological Chemistry.

Toxoplasma gondii is a single-celled parasite that people catch from cat feces, unwashed produce or undercooked meat. The parasite has infected up to one-third of the world's population, and after causing mild illness, it persists by entering a dormant phase housed in cysts throughout the body, including the brain.Toxoplasma cysts have been linked to behavior changes and neurological disorders like schizophrenia. They can also reactivate when the immune system is weakened, causing life-threatening organ damage. While drugs are available to put toxoplasmosis into remission, there is no way to clear the infection. A better understanding of how the parasite develops into cysts would help scientists find a cure.

Through years of collaborative work, IU School of Medicine Showalter Professors Bill Sullivan, PhD, and Ronald C. Wek, PhD, have shown that Toxoplasma forms cysts by altering which proteins are made. Proteins govern the fate of cells and are encoded by mRNAs.

"But mRNAs can be present in cells without being made into protein," Sullivan said. "We've shown that Toxoplasma switches which mRNAs are made into protein when converting into cysts."

Lead Author Vishakha Dey, PhD, a postdoctoral fellow at the IU School of Medicine and a member of the Sullivan lab, examined the so-called leader sequences of genes named BFD1 and BFD2, both of which are necessary for Toxoplasma to form cysts.

"mRNAs not only encode for protein, but they begin with a leader sequence that contains information on when that mRNA should be made into protein," Dey said.

All mRNAs have a structure called a cap at the beginning of their leader sequence. Ribosomes, which convert mRNA into protein, bind to the cap and scan the leader until it finds the right code to begin making the protein.

"What we found was that, during cyst formation, BFD2 is made into protein after ribosomes bind the cap and scan the leader, as expected," Dey said. "But BFD1 does not follow that convention. Its production does not rely on the mRNA cap like most other mRNAs."

The team further showed that BFD1 is made into protein only after BFD2 binds specific sites in the BFD1 mRNA leader sequence.

Sullivan said this is a phenomenon called cap-independent translation, which is more commonly seen in viruses.

"Finding it in a microbe that has cellular anatomy like our own was surprising," Sullivan said. "It speaks to how old this system of protein production is in cellular evolution. We're also excited because the players involved do not exist in human cells, which makes them good potential drug targets."

"This paper describes a mechanism by which a parasite that causes toxoplasmosis in humans can respond to stress and allow the parasite to thrive," said George N. DeMartino, PhD, associate editor of the Journal of Biological Chemistry and a professor at the University of Texas Southwestern Medical Center. "The discovery of this mechanism provides a basis for treating these infections. Moreover, a similar mechanism is important in cancer, suggesting that it may be a therapeutic target for multiple human diseases."

Source: ScienceDaily

Study offers insight into chloroplast evolution

 One of the most momentous events in the history of life involved endosymbiosis -- a process by which one organism engulfed another and, instead of ingesting it, incorporated its DNA and functions into itself. Scientific consensus is that this happened twice over the course of evolution, resulting in the energy-generating organelles known as mitochondria and, much later, their photosynthetic counterparts, the plastids.

A new study published in the journal Nature Communications explores the origin of chloroplasts, the plastids that allow plants to extract carbon from the atmosphere to build their own structures and tissues. By focusing on an energy-transport molecule common to plastids, the researchers found evidence suggesting that the primary role of primitive chloroplasts may have been to produce chemical energy for the cell and only later shifted so that most or all of the energy they generated was used for carbon assimilation.

Chloroplasts are believed to have evolved from photosynthetic cyanobacteria, but it isn't clear what functions the cyanobacteria originally performed for the cells that engulfed them, said University of Illinois Urbana-Champaign chemistry professor Angad Mehta, who led the new research.

"We asked the question: What chemical role did the primitive symbiont that led to chloroplasts perform for the host cell?" he said. "Was it carbon assimilation or ATP synthesis or both?"

Various lines of evidence suggest that the plastids in red algae and another group of photosynthesizing organisms known as glaucophytes resemble more ancient stages of evolution than the chloroplasts of land plants. But current bioinformatics methods can take the field only so far, Mehta said.

A key to the functional evolution of mitochondria and plastids lies in their energy-generating capacities, he said. Both produce ATP, an energy-packed molecule that drives most of the chemical interactions in living cells. And both mitochondria and plastids make use of ADP/ATP carrier translocases, which reside in the membranes of the organelles and swap ATP with its energy-depleted precursor, ADP.

Mehta and his colleagues focused on differences in the activity of the translocases in the plastids of land plants, red algae and glaucophytes to determine whether these differences could offer insight into chloroplast evolution.

In a series of experiments, the researchers engineered cyanobacteria to express one of the three types of translocases. Then they induced artificial endosymbiosis between the engineered cyanobacteria and budding yeast cells. By controlling the laboratory conditions in which these cells lived, the researchers forced the yeast to rely entirely on the cyanobacterial endosymbionts for their energy needs. Mehta's lab first developed the technique for artificially forcing yeast to internalize cyanobacterial endosymbionts in a study published in 2022.

The experiments revealed striking differences between the activity of the translocases.

"Most notably, we saw that the endosymbionts expressing translocases from the plastids of red algae and glaucophytes were able to export ATP to support endosymbiosis, whereas those from chloroplasts actually imported ATP and were unable to support the energy needs of the endosymbiotic cells," Mehta said. The land plant chloroplast translocases were importing ATP and expelling ADP.

Because the plastids of red algae and glaucophytes appear to resemble a more ancient form of the photosynthetic organelles, the new findings suggest that chloroplasts once shared their primary function of providing energy to the larger cell. At some point in their evolutionary history, however, the chloroplasts of land plants appear to have shifted to use the ATP they produced via photosynthesis to drive their own carbon-assimilation tasks. It appears that chloroplasts even siphon off some of the ATP generated by mitochondria, Mehta said.

While the new findings do not definitively prove that this is how chloroplasts evolved, it does offer evidence to support this view, Mehta said.

"The proposal is that the initial interaction between the endosymbiont and cell was based on ATP production and ATP supply," he said. "Now, you can imagine a scenario in which, as these organisms go on to become land plants, they grow in oxygen-rich conditions. This allows the mitochondria to become specialized in ATP synthesis and chloroplasts to focus and become an engine that drives carbon assimilation."

Source: ScienceDaily

Study breaks the silence on how fish and lizards regenerate hearing

 A new USC Stem Cell study published in the Proceedings of the National Academy of Sciences (PNAS) has identified key gene regulators that enable some deafened animals -- including fish and lizards -- to naturally regenerate their hearing. The findings could guide future efforts to stimulate the regeneration of sensory hearing cells in patients with hearing loss and balance disorders.

Led by first author Tuo Shi and co-corresponding authors Ksenia Gnedeva and Gage Crump at the Keck School of Medicine of USC, the study focuses on two cell types in the inner ear: the sensory cells that detect sound, and the supporting cells that create an environment where sensory cells can thrive. In highly regenerative species such as fish and lizards, supporting cells can also transform into replacement sensory cells after injury -- a capacity absent in humans, mice and all other mammals.

To better understand this remarkable regenerative process, the scientists determined how genes normally only found in the sensory cells can be re-activated in the supporting cells of regenerative species. To achieve that, the scientists determined how the genome is folded in the sensory cells and supporting cells of the inner ears of regenerative zebrafish and green anole lizards. They then compared DNA control elements for sensory genes in zebrafish and green anole lizards to those in mice, which cannot replace sensory hearing cells after injury.

"By comparing two different regenerative vertebrates -- zebrafish and lizards -- to non-regenerative vertebrates such as mice, we found something that was fundamental to the way sensory cells can be replaced to restore hearing in some vertebrates," said Crump, professor of the Department of Stem Cell Biology and Regenerative Medicine at USC.

Their experiments revealed a class of DNA control elements known as "enhancers" that, after injury, amplify the production of a protein called ATOH1, which in turn induces a suite of genes required to make sensory cells of the inner ear.

Using CRISPR, a gene editing tool, the scientists deleted five of these enhancers in zebrafish, impairing both the formation of sensory hearing cells during development and their regeneration following injury.

"In the past, deletion of individual enhancers most often does not have much of an effect," said Crump. "But by targeting all five enhancers in zebrafish, we discovered their critical role in both development and regeneration."

Interestingly, although zebrafish also possess the same type of sensory cell in a specialized aquatic organ called the lateral line, which senses water flow and pressure, the genetic deletions only impacted cells in their inner ears.

The researchers found that mice possess equivalent enhancers that are active during embryonic development in the progenitor cells that give rise to the sensory and supporting cells of the inner ear. However, only regenerative species such as fish and lizards maintain these enhancers in an open configuration in their supporting cells into adulthood, preserving their capacity to replace damaged sensory cells.

"What we have found is that sister cell types in regenerative vertebrates maintain open enhancers from development into adult stages, thus allowing these related cells to replace each other following damage," said Crump. "In the future, targeted strategies to open up these enhancers in the human inner ear could be used to boost our natural regenerative abilities and reverse deafness."

Source:ScienceDaily

A new twist: The molecular machines that loop our chromosomes also twist DNA

 Scientists from the Kavli Institute of Delft University of Technology and the IMP Vienna Biocenter discovered a new property of the molecular motors that shape our chromosomes. While six years ago they found that these so-called SMC motor proteins make long loops in our DNA, they now discovered that these motors also put significant twists into the loops that they form. These findings help us better understand the structure and function of our chromosomes.They also provide insight into how disruption of twisted DNA looping can affect health -- for instance, in developmental diseases like 'cohesinopathies'. The scientists published their findings in Science Advances.

The struggle of our cells

Imagine trying to fit two meters of rope into a space much smaller than the tip of a needle -- that's the challenge every cell in your body faces when packing its DNA into its tiny nucleus. To achieve this, nature employs ingenious strategies, like twisting the DNA into coils of coils, so-called 'supercoils' (see pictures for a visualisation) and wrapping it around special proteins for compact storage.

Small DNA loops regulate chromosome functions

However, compaction isn't enough. Cells also need to regulate the chromosome structure to enable its function. For example, when genetic information needs to be accessed, the DNA is locally read off. In particular when it's time for a cell to divide, the DNA must first unpack, duplicate, and then properly separate into two new cells. Specialised protein machines called SMC complexes (Structural Maintenance of Chromosomes) play a critical role in these processes. Just a few years ago, scientists at Delft and other places discovered that these SMC proteins are molecular motors that make long loops in our DNA, and that these loops are the key regulators of chromosome function.

A new twist

In the lab of Cees Dekker at TU Delft, postdocs Richard Janissen and Roman Bath now provide clues that help to crack this puzzle. They deloped a new way to use 'magnetic tweezers' by which they could watch individual SMC proteins make looping steps in DNA. Importantly, they were also able to resolve if the SMC protein would change the twist in the DNA. And strikingly, the team found that it did: the human SMC protein cohesin does indeed not only pull DNA into a loop, but also twists the DNA in a left-handed way by 0.6 turns in each step of creating the loop.

A glimpse into the evolution of SMC proteins

What's more, the team found that this twisting action isn't unique to humans. Similar SMC proteins in yeast behave the same way. Strikingly, all the various types of SMC proteins from human and yeast add the same amount of twist -- they turn DNA 0.6 times at every at every DNA loop extrusion step. This shows that the DNA extrusion and twisting mechanisms stayed the same for very long times during evolution. No matter whether DNA is looped in humans, yeast, or any other cell -- nature employs the same strategy.

Source:ScienceDaily

Intermittent fasting inhibits hair regeneration in mice

 Intermittent fasting has proven benefits for metabolic health, but a new study shows that it could slow hair growth -- at least in mice. Researchers report December 13 in the Cell Press journal Cell that mice subjected to intermittent fasting regimes showed improved metabolic health but slower hair regeneration compared to mice with 24/7 access to food. A similar process might occur in humans, based on a small clinical trial that the team also conducted, but it's likely to be less severe since humans have a much slower metabolic rate and different hair growth patterns compared to mice.

"We don't want to scare people away from practicing intermittent fasting because it is associated with a lot of beneficial effects -- it's just important to be aware that it might have some unintended effects," says senior author and stem cell biologist Bing Zhang of Westlake University in Zhejiang, China.

In addition to its metabolic benefits, previous studies have shown that fasting can improve the stress resistance of stem cells associated with blood, intestinal, and muscle tissue, but little is known about how it impacts peripheral tissues such as skin and hair. Zhang's team hypothesized that fasting might also be beneficial for skin tissue regeneration, the process by which old and damaged cells are replaced.

To test this, they examined hair regrowth in mice that were shaved and then subjected to different intermittent fasting regimes. Some mice were fed on a time-restricted feeding (TRF) schedule that involved 8 hours of food access and 16 hours of fasting each day, while other mice were subjected to alternate-day feeding (ADF).

They were surprised to find that fasting inhibited hair regeneration. While control mice that had unlimited access to food had regrown most of their hair after 30 days, mice on both intermittent fasting regimes showed only partial hair regrowth after 96 days.

The team showed that this inhibited hair growth occurs because hair follicle stem cells (HFSCs) are unable to cope with the oxidative stress associated with switching from using glucose to fat. HFSCs go through phases of activity and dormancy, and hair regrowth depends on these cells becoming active. While the control mice's HFSCs began to become activated around day 20 post-shaving and remained active until their hair had regrown, the intermittent fasting mice's activated HFSCs underwent apoptosis (programmed cell death) during extended fasting periods.

Using genetic engineering methods, the team showed that this fasting-induced apoptosis was driven by an increased concentration of free fatty acids near the hair follicles, which caused a build-up of harmful radical oxygen species within the HFSCs. Free fatty acids also caused human HFSCs to undergo apoptosis in vitro.

Source: ScienceDaily

Study sheds light on the origin of the genetic code

Despite awe-inspiring diversity, nearly every lifeform -- from bacteria to blue whales -- shares the same genetic code. How and when this code came about has been the subject of much scientific controversy.

Taking a fresh approach at an old problem, Sawsan Wehbi, a doctoral student in the Genetics Graduate Interdisciplinary Program at the University of Arizona, discovered strong evidence that the textbook version of how the universal genetic code evolved needs revision. Wehbi is the first author of a study published in the journal PNAS suggesting the order with which amino acids -- the code's building blocks -

were recruited is at odds with what is widely considered the "consensus" of genetic code evolution.

"The genetic code is this amazing thing in which a string of DNA or RNA containing sequences of four nucleotides is translated into protein sequences using 20 different amino acids," said Joanna Masel, the paper's senior author and aprofessor of ecology and evolutionary biology at the U of A. "It's a mind-bogglingly complicated process, and our code is surprisingly good. It's nearly optimal for a whole bunch of things, and it must have evolved in stages."

The study revealed that early life preferred smaller amino acid molecules over larger and more complex ones, which were added later, while amino acids that bind to metals joined in much earlier than previously thought. Finally, the team discovered that today's genetic code likely came after other codes that have since gone extinct.

The authors argue that the current understanding of how the code evolved is flawed because it relies on misleading laboratory experiments rather than evolutionary evidence. For example, one of the cornerstones of conventional views of genetic code evolution rests on the famous Urey-Miller experiment of 1952, which attempted to simulate the conditions on early Earth that likely witnessed the origin of life.

While valuable in demonstrating that nonliving matter could give rise to life's building blocks, including amino acids, through simple chemical reactions, the experiment's implications have been called into question. For example, it did not yield any amino acids containing sulfur, despite the element being abundant on early Earth. As a result, sulfuric amino acids are believed to have joined the code much later. However, the result is hardly surprising, considering that sulfur was omitted from the experiment's ingredients. 

According to co-author Dante Lauretta, Regents Professor of Planetary Science and Cosmochemistry at the U of A Lunar and Planetary Laboratory, early life's sulfur-rich nature offers insights for astrobiology, particularly in understanding the potential habitability and biosignatures of extraterrestrial environments.

"On worlds like Mars, Enceladus and Europa, where sulfur compounds are prevalent, this could inform our search for life by highlighting analogous biogeochemical cycles or microbial metabolisms," he said. "Such insights might refine what we look for in biosignatures, aiding the detection of lifeforms that thrive in sulfur-rich or analogous chemistries beyond Earth."

The team used a new method to analyze sequences of amino across the tree of life, all the way back to the last universal common ancestor, or LUCA, a hypothesized population of organisms that lived around 4 billion years ago and represents the shared ancestor of all life on Earth today. Unlike previous studies, which used full-length protein sequences, Wehbi and her group focused on protein domains, shorter stretches of amino acids.

"If you think about the protein being a car, a domain is like a wheel," Wehbi said. "It's a part that can be used in many different cars, and wheels have been around much longer than cars."

To get a handle on when a specific amino acid likely was recruited into the genetic code, the researchers used statistical data analysis tools to compare the enrichment of each individual amino acid in protein sequences dating back to LUCA, and even farther back in time. An amino acid that shows up preferentially in ancient sequences was likely incorporated early on. Conversely, LUCA's sequences are depleted for amino acids that were recruited later but became available by the time less ancient protein sequences emerged.

Source: ScienceDaily

Activating the hidden pharmaceutical potential of bacteria

 Microorganisms produce a wide variety of natural products that can be used as active ingredients to treat diseases such as infections or cancer. The blueprints for these molecules can be found in the microbes' genes, but often remain inactive under laboratory conditions. A team of researchers at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) has now developed a groundbreaking genetic method that leverages a natural bacterial mechanism for the transfer of genetic material and uses it for the production of new active ingredients. The team published its results in the journal Science.

In contrast to humans, bacteria have the remarkable ability to exchange genetic material with each other. A well-known example with far-reaching consequences is the transfer of antibiotic resistance genes between bacterial pathogens. This gene transfer allows them to adapt quickly to different environmental conditions and is a major driver of the spread of antibiotic resistance. Researchers at the HIPS and the German Center for Infection Research (DZIF) have now harnessed this natural principle to amplify and isolate genetic blueprints for new bioactive natural products from bacteria, known as biosynthetic gene clusters. Their innovative approach, called "ACTIMOT," makes it possible to either produce the natural products encoded in the gene clusters directly in the native bacterium or to transfer them into more suitable microbial production strains to produce the new molecules there. The HIPS is a site of the Helmholtz Centre for Infection Research (HZI) in collaboration with Saarland University.

ACTIMOT -- short for "Advanced Cas9-mediaTed In vivo MObilization and mulTiplication of BGCs" -- leverages the CRISPR-Cas9 technology, which has become known as "gene scissors," and accordingly allows precise interventions in the genetic material of bacteria. Since biosynthetic gene clusters are often less active under laboratory conditions, they are extracted from the genome using ACTIMOT and inserted into a mobile genetic unit that is then multiplied by the bacterium itself. All these steps are performed exploiting the molecular mechanism that also allows bacteria to transfer resistance genes amongst each other. In many instances, the amplification of the gene clusters on these so-called plasmids is already sufficient to enable the production of the encoded natural products. If this does not succeed, the formed plasmids can be easily transferred into an alternative production strain to produce the encoded natural products. The authors provide successful examples of both approaches in the present study.

"Many biosynthetic gene clusters remain suppressed under laboratory conditions for various reasons, and current efforts to reveal the natural products they encode only address a limited number of them," says Chengzhang Fu, junior research group leader at HIPS and last author of the study. "Our approach mimics the natural bacterial gene transfer process to directly liberate and amplify entire biosynthetic gene clusters within the native bacterial cell, granting access to previously hidden natural products. Using this technology, we can access the biosynthetic potential of bacteria much faster and easier, as compared to existing methods."

Source: ScienceDaily

Tiny poops in the ocean may help solve the carbon problem

 A Dartmouth-led study proposes a new method for recruiting trillions of microscopic sea creatures called zooplankton in the fight against climate change by converting carbon into food the animals would eat, digest, and send deep into the ocean as carbon-filled feces.

The technique harnesses the animals' ravenous appetites to essentially accelerate the ocean's natural cycle for removing carbon from the atmosphere, which is known as the biological pump, according to the paper in Nature Scientific Reports.

It begins with spraying clay dust on the surface of the ocean at the end of algae blooms. These blooms can grow to cover hundreds of square miles and remove about 150 billion tons of carbon dioxide from the atmosphere each year, converting it into organic carbon particulates. But once the bloom dies, marine bacteria devour the particulates, releasing most of the captured carbon back into the atmosphere.

The researchers found that the clay dust attaches to carbon particulates before they re-enter the atmosphere, redirecting them into the marine food chain as tiny sticky pellets the ravenous zooplankton consume and later excrete at lower depths.

"Normally, only a small fraction of the carbon captured at the surface makes it into the deep ocean for long-term storage," says Mukul Sharma, the study's corresponding author and a professor of earth sciences. Sharma also presented the findings Dec. 10 at the American Geophysical Union annual conference in Washington, D.C.

"The novelty of our method is using clay to make the biological pump more efficient -- the zooplankton generate clay-laden poops that sink faster," says Sharma, who received a Guggenheim Award in 2020 to pursue the project.

"This particulate material is what these little guys are designed to eat. Our experiments showed they cannot tell if it's clay and phytoplankton or only phytoplankton -- they just eat it," he says. "And when they poop it out, they are hundreds of meters below the surface and the carbon is, too."

The team conducted laboratory experiments on water collected from the Gulf of Maine during a 2023 algae bloom. They found that when clay attaches to the organic carbon released when a bloom dies, it prompts marine bacteria to produce a kind of glue that causes the clay and organic carbon to form little balls called flocs.The flocs become part of the daily smorgasbord of particulates that zooplankton gorge on, the researchers report. Once digested, the flocs embedded in the animals' feces sinks, potentially burying the carbon at depths where it can be stored for millennia. The uneaten clay-carbon balls also sink, increasing in size as more organic carbon, as well as dead and dying phytoplankton, stick to them on the way down, the study found.

In the team's experiments, clay dust captured as much as 50% of the carbon released by dead phytoplankton before it could become airborne. They also found that adding clay increased the concentration of sticky organic particles -- which would collect more carbon as they sink -- by 10 times. At the same time, the populations of bacteria that instigate the release of carbon back into the atmosphere fell sharply in seawater treated with clay, the researchers report.

In the ocean, the flocs become an essential part of the biological pump called marine snow, Sharma says. Marine snow is the constant shower of corpses, minerals, and other organic matter that fall from the surface, bringing food and nutrients to the deeper ocean.

"We're creating marine snow that can bury carbon at a much greater speed by specifically attaching to a mixture of clay minerals," Sharma says.

Zooplankton accelerate that process with their voracious appetites and incredible daily sojourn known as the diel vertical migration. Under cover of darkness, the animals -- each measuring about three-hundredths of an inch -- rise hundreds, and even thousands, of feet from the deep in one immense motion to feed in the nutrient-rich water near the surface. The scale is akin to an entire town walking hundreds of miles every night to their favorite restaurant.

When day breaks, the animals return to deeper water with the flocs inside them where they are deposited as feces. This expedited process, known as active transport, is another key aspect of the ocean's biological pump that shaves days off the time it takes carbon to reach lower depths by sinking.

sources-science daily

New gene therapy reverses heart failure in large animal model

 A new gene therapy can reverse the effects of heart failure and restore heart function in a large animal model. The therapy increases the amount of blood the heart can pump and dramatically improves survival, in what a paper describing the results calls "an unprecedented recovery of cardiac function."

Currently, heart failure is irreversible. In the absence of a heart transplant, most medical treatments aim to reduce the stress on the heart and slow the progression of the often-deadly disease. But if the gene therapy shows similar results in future clinical trials, it could help heal the hearts of the 1 in 4 people alive today who will eventually develop heart failure.

A "night and day" change

The researchers were focused on restoring a critical heart protein called cardiac bridging integrator 1 (cBIN1). They knew that the level of cBIN1 was lower in heart failure patients -- and that, the lower it was, the greater the risk of severe disease. "When cBIN1 is down, we know patients are not going to do well," says Robin Shaw, MD, PhD, director of the Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI) at the University of Utah and a co-senior author on the study. "It doesn't take a rocket scientist to say, 'What happens when we give it back?'"

To try and increase cBIN1 levels in cases of heart failure, the scientists turned to a harmless virus commonly used in gene therapy to deliver an extra copy of the cBIN1 gene to heart cells. They injected the virus into the bloodstream of pigs with heart failure. The virus moved through the bloodstream into the heart, where it delivered the cBIN1 gene into heart cells.

For this heart failure model, heart failure generally leads to death within a few months. But all four pigs that received the gene therapy in their heart cells survived for six months, the endpoint of the study.

Importantly, the treatment didn't just prevent heart failure from worsening. Some key measures of heart function actually improved, suggesting the damaged heart was repairing itself.

Shaw emphasizes that this kind of reversal of existing damage is highly unusual. "In the history of heart failure research, we have not seen efficacy like this," Shaw says. Previous attempted therapies for heart failure have shown improvements to heart function on the order of 5-10%. cBIN1 gene therapy improved function by 30%. "It's night and day," Shaw adds.

The treated hearts' efficiency at pumping blood, which is the main measure of the severity of heart failure, increased over time -- not to fully healthy levels, but to close that of healthy hearts. The hearts also stayed less dilated and less thinned out, closer in appearance to that of non-failing hearts. Despite the fact that, throughout the trial, the gene-transferred animals experienced the same level of cardiovascular stress that had led to their heart failure, the treatment restored the amount of blood pumped per heartbeat back to entirely normal levels.

"Even though the animals are still facing stress on the heart to induce heart failure, in animals that got the treatment, we saw recovery of heart function and that the heart also stabilizes or shrinks," says TingTing Hong, MD, PhD, associate professor of pharmacology and toxicology and CVRTI investigator at the U and co-senior author on the study. "We call this reverse remodeling. It's going back to what the normal heart should look like."

A keystone of the heart

The researchers think that cBIN1's ability to rescue heart function hinges on its position as a scaffold that interacts with many of the other proteins important to the function of heart muscle. "cBIN1 serves as a centralized signaling hub, which actually regulates multiple downstream proteins," says Jing Li, PhD, associate instructor at CVRTI. By organizing the rest of the heart cell, cBIN1 helps restore critical functions of heart cells. "cBIN1 is bringing benefits to multiple signaling pathways," Li adds.

Indeed, the gene therapy seemed to improve heart function on the microscopic level, with better-organized heart cells and proteins. The researchers hope that cBIN1's role as a master regulator of heart cell architecture could help cBIN1 gene therapy succeed and introduce a new paradigm of heart failure treatment that targets heart muscle itself.

Along with industry partner TikkunLev Therapeutics, the team is currently adapting the gene therapy for use in humans and intend to apply for FDA approval for human clinical trial in fall of 2025. While the researchers are excited about the results so far, the therapy still has to pass toxicology testing and other safeguards. And, like many gene therapies, it remains to be seen if it will work for people who have picked up a natural immunity to the virus that carries the therapy.

sources-science daily

Pregnancy enhances natural immunity to block severe flu

 McGill University scientists have discovered that pregnancy may trigger a natural immunity to boost protection against severe flu infection.

Contrary to the common belief that pregnancy increases vulnerability to infections, researchers found that it strengthened an immune defense in mice, blocking the Influenza A virus from spreading to the lungs, where it can cause severe infection."Our results are surprising because of the current dogma, but it makes sense from an evolutionary perspective," said co-lead author Dr. Maziar Divangahi, Professor in McGill's Faculty of Medicine and Health Sciences and Senior Scientist at the Research Institute of the McGill University Health Centre (The Institute).

"A mother needs to stay healthy to protect her developing baby, so the immune system adapts to provide stronger defenses. This fascinating response in the nasal cavity is the body's way of adding an extra layer of protection, which turns on during pregnancy."

Exploring benefits for pregnancy and beyond

The researchers used a mouse model to observe how a certain type of immune cell activates in the nasal cavity of mice during pregnancy, producing a powerful molecule that boosts the body's antiviral defenses, especially in the nose and upper airways.

"Influenza A virus remains among the deadliest threats to humanity," said first author Julia Chronopoulos, who carried out the research while completing her PhD at McGill. "This natural immunity in pregnancy could change the way we think about flu protection for expectant mothers."

The Public Health Agency of Canada recommends pregnant women and pregnant individuals get the flu vaccine, as they are at high risk of severe illness and complications like preterm birth. The new insights offer promise for more targeted vaccines for influenza, which is among the top 10 leading causes of death in Canada.

"The broader population could also benefit, as our findings suggest the immune response we observed could be replicated beyond pregnancy," said co-lead author Dr. James Martin, Professor in McGill's Faculty of Medicine and Health Sciences and Senior Scientist at the RI-MUHC. This could mean new nasal vaccines or treatments that increase protective molecules, known as Interleukin-17.

The team's next focus is on finding ways to reduce lung damage during viral infections like the flu or COVID-19. Rather than targeting the virus, as previous research has done, they aim to prevent dysregulated immune systems from overreacting, an approach that could lower the risk of serious complications associated with flu infection.

The research was funded by the Canadian Institutes of Health Research.

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A new discovery about the source of the vast energy in cosmic rays

 Ultra-high energy cosmic rays, which emerge in extreme astrophysical environments -- like the roiling environments near black holes and neutron stars -- have far more energy than the energetic particles that emerge from our sun. In fact, the particles that make up these streams of energy have around 10 million times the energy of particles accelerated in the most extreme particle environment on earth, the human-made Large Hadron Collider.

Where does all that energy come from? For many years, scientists believed it came from shocks that occur in extreme astrophysical environments -- when, for example, a star explodes before forming a black hole, causing a huge explosion that kicks up particles.

That theory was plausible, but, according to new research published this week in The Astrophysical Journal Letters, the observations are better explained by a different mechanism. The source of the cosmic rays' energy, the researchers found, is more likely magnetic turbulence. The paper's authors found that magnetic fields in these environments tangle and turn, rapidly accelerating particles and sharply increasing their energy up to an abrupt cutoff.

"These findings help solve enduring questions that are of great interest to both astrophysicists and particle physicists about how these cosmic rays get their energy," said Luca Comisso, associate research scientist in the Columbia Astrophysics Lab, and one of the paper's authors.

The paper complements research published last year by Comisso and collaborators on the sun's energetic particles, which they also found emerge from magnetic fields in the sun's corona. In that paper, Comisso and his colleagues discovered ways to better predict where those energetic particles would emerge.

Ultra-high energy cosmic rays are orders of magnitude more powerful than the sun's energetic particles: They can reach up to 1020 electron volts, whereas particles from the Sun can reach up to 1010 electron volts, a 10-order-of-magnitude difference. (To give an idea of this vast difference in scale, consider the difference in weight between a grain of rice with a mass of about 0.05 grams and a 500-ton Airbus A380, the world's largest passenger aircraft.) "It's interesting that these two extremely different environments share something in common: their magnetic fields are highly tangled and this tangled nature is crucial for energizing particles," Comisso said.

"Remarkably, the data on ultra-high energy cosmic rays clearly prefers the predictions of magnetic turbulence over those of shock acceleration. This is a real breakthrough for the field," said Glennys R. Farrar, an author on the paper and professor of physics at New York University.

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Innovative immunotherapy shows promise in early clinical trial for breast cancer

 A groundbreaking phase one clinical trial exploring a novel cell-based immunotherapy for breast cancer has been accepted for publication in JAMA Oncology. The technology tested in the trial was co-developed by Gary Koski, Ph.D., professor in Kent State University's Department of Biological Sciences, and Brian J. Czerniecki, M.D., Ph.D., chair and senior member in the Moffitt Cancer Center's Department of Breast Oncology. The study focuses on a new treatment approach that aims to harness the body's immune system to enhance patient responses and reduce the need for conventional chemotherapy and its associated toxicities.

The trial involved 12 patients with locally advanced stage I-III HER2 breast cancer.

This research builds upon insights gained from previous studies funded by a Department of Defense Breakthrough Award research grant."We are hopeful that we will be able to use this new immunotherapy instead of chemotherapy, or at least dramatically reduce the need for chemotherapy, for all types of breast cancer," Czerniecki said.

The immunotherapy leverages dendritic cells, critical components of the immune system that normally identify infection and mobilize other elements of immunity to repel a microbial attack.

By removing some of these dendritic cells from the body, biochemically reprogramming them for anti-cancer activity and injecting them directly into breast tumors, the researchers could trigger a powerful, organized immune system attack on the cancer.

This led to the significant shrinkage of tumors before standard chemotherapy was administered.

Eight out of the 12 patients demonstrated at least a 50% reduction in tumor volume after just six weeks of immunotherapy.

This treatment produced only minimal side effects, primarily mild flu-like symptoms, compared with the severe side effects often associated with traditional chemotherapy.

"These exciting results are the culmination of nearly 30 years of collaborative research between my laboratory and Dr. Czerniecki's," Koski said.

The researchers have already begun a larger phase two trial to test higher doses of the immunotherapy, further exploring the potential effectiveness of this new technology.

The published clinical trial was supported by the Moffitt Breast Cancer Research Fund, the Don Shula Foundation and donations from the Pennies in Action organization, which has raised approximately $7 million over the last decade to support this innovative cancer research. This unique funding model allows patients to directly contribute to advancements in treatments that may benefit them and others in the future.

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Single mutation in H5N1 influenza surface protein could enable easier human infection

 A single modification in the protein found on the surface of the highly pathogenic avian influenza (HPAI) H5N1 influenza virus currently circulating in U.S. dairy cows could allow for easier transmission among humans, according to new research funded by the National Institutes of Health (NIH) and published today in the journal Science. The study results reinforce the need for continued, vigilant surveillance and monitoring of HPAI H5N1 for potential genetic changes that could make the virus more transmissible in humans.

Current strains of the bovine (cow) H5N1 virus are not known to be transmissible among people; however, infections have occurred in people exposed to infected wild birds, poultry, dairy cows and other mammals. As part of pandemic preparedness efforts, researchers have monitored the H5N1 virus for years to understand viral genetic mutations that occur in nature and what impact they may have on transmissibility.Influenza viruses attach to cells with a surface viral protein called hemagglutinin (HA). The HA latches on to sugar (glycan) molecule receptors on cells to cause infection. Avian (bird) influenza viruses -- like H5N1 -- have not infected people often because the human upper respiratory tract lacks the avian-type cell receptors found in birds. Scientists are concerned that viruses could evolve to recognize human-type cell receptors in the upper airways and acquire the ability to infect people and spread between them.

Scientists at Scripps Research used the H5N1 strain isolated from the first U.S. human infection with the bovine strain 2.3.4.4b (A/Texas/37/2024) to test how mutations in the HA gene sequence affected the binding of that protein with avian versus human-type cell receptors. The researchers introduced several mutations into the viral HA protein that had been observed to occur naturally in the past and found that one mutation, called Q226L, improved the ability of the protein to attach to receptors typically found on human cells, especially when an additional mutation was present. Importantly, the researchers introduced the genetic mutations only into the HA surface protein and did not create or conduct experiments with a whole, infectious virus.

The experimental finding with the Q226L mutation alone does not mean HPAI H5N1 is on the verge of causing a widespread pandemic, the authors note. Other genetic mutations would likely be required for the virus to transmit among people. In the setting of a growing number of H5N1 human cases resulting from direct contact with infected animals, the findings stress the importance of continued efforts at outbreak control and continued genomic surveillance to monitor for the emergence of HPAI H5N1 genetic changes and maintain public health preparedness.

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Scientists identify mutation that could facilitate H5N1 'bird flu' virus infection and potential transmission in humans

 Avian influenzaviruses typically require several mutations to adapt and spread among humans, but what happens when just one change can increase the risk of becoming a pandemic virus? A recent study led by scientists at Scripps Research reveals that a single mutation in the H5N1 "bird flu" virus that has recently infected dairy cows in the U.S. could enhance the virus' ability to attach to human cells, potentially increasing the risk of passing from person to person. The findings -- published in Science on December 5, 2024 -- highlight the need to monitor H5N1's evolution.

Currently, there are no documented cases of H5N1 transmitting between people: bird flu cases in humans have been linked to close contact with contaminated environments as well as infected birds (including poultry), dairy cows and other animals. However, public health officials are concerned about the potential for the virus to evolve to transmit efficiently between humans, which could lead to a new, potentially deadly pandemic.

The flu virus attaches to its host via a protein called hemagglutinin that binds to glycan receptors on the surfaces of host cells. Glycans are chains of sugar molecules on cell surface proteins that can act as binding sites for some viruses. Avian (bird) influenza viruses like H5N1 primarily infect hosts with sialic acid-containing glycan receptors found in birds (avian-type receptors). While the viruses rarely adapt to humans, if they evolve to recognize sialylated glycan receptors found in people (human-type receptors), they could gain the ability to infect and possibly transmit between humans.

"Monitoring changes in receptor specificity (the way a virus recognizes host cells) is crucial because receptor binding is a key step toward transmissibility," says Ian Wilson, DPhil, co-senior author and the Hansen Professor of Structural Biology at Scripps Research. "That being said, receptor mutations alone don't guarantee that the virus will transmit between humans."

Past cases in which avian viruses adapted to infect and transmit between people required multiple mutations, usually at least three. But for the H5N1 2.3.4.4b strain (A/Texas/37/2024) isolated from the first human infection with a bovine H5N1 virus in the United States, researchers found that just a single amino acid mutation in the hemagglutinin could switch specificity to binding human-type receptors. Here, bovine refers to the species for dairy cows that were the immediate source of the virus for the human infection. Importantly, the mutation wasn't introduced into the whole virus -- only the hemagglutinin protein to study its receptor-binding properties.

For their study, the research team introduced several mutations into the H5N1 2.3.4.4b hemagglutinin protein that had been involved in receptor specificity changes in previous avian viruses. These mutations were selected to mimic genetic changes that could occur naturally. When the team assessed the impact of one of these mutations, Q226L, on the virus' ability to bind to human-type receptors, they found that that mutation significantly improved how the virus attached to glycan receptors, which represent those found in human cells.

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Diet rich in whole plant foods and fish may keep colon cancer at bay

 

• With bowel cancer diagnoses rising among people under 50, researchers are urging the public to increase fibre intake and adopt healthier eating habits to reduce the risk of gastrointestinal cancers.
• Studies from Flinders University reveal that diets rich in fruits, vegetables, whole grains and healthy fats, while limiting sugar and alcohol, may significantly lower cancer risk and improve outcomes.
• However, researchers point out that further clinical trials are needed to better understand how dietary patterns influence cancer development and to expand education on nutrition as a preventive measure.

Research from Flinders University and Medical Research Institute in Australia, published in the European Journal of Nutrition, builds upon existing evidence uncovered by the same team, which shows that a diet high in fruits, vegetables, whole grains, fish, legumes and dairy may help protect against gastrointestinal cancers.

Researchers have found strong connections between poor diet and a higher risk of digestive cancers.

They suggest that eating more healthy fats and vegetables, while cutting down on sugar and alcohol, can greatly lower the risk of colorectal and other types of cancer.

Conversely, unhealthy eating patterns — characterised by high consumption of red and processed meats, fast foods, refined grains, alcohol and sugary drinks — are strongly associated with a higher risk of gastrointestinal cancers.

First author Zegeye Abebe Abitew, a research assistant in the College of Medicine and Public Health at Flinders University, told Medical News Today that “a diet rich in healthy fats, oils, dark green vegetables, and other vegetables, combined with low intake of sugar, beer, and liquor, was linked to a lower risk of colorectal cancer.”

“Vegetables are packed with fiber, vitamins, minerals, and antioxidants, which help reduce inflammation and support overall health,” he explained.

“On the other hand, a diet high in carbohydrates and fiber, including citrus fruits, other fruits, non-wholegrains, wholegrains, sugar, and dark green vegetables, showed no clear connection to [colorectal cancer] risk,” said Abitew.

“While fiber is known to protect against [colorectal cancer], the high intake of non-wholegrains and sugar in this pattern may balance out its protective effects,” he detailed.

Diet impacts gut health and aids cancer prevention

Senior author Yohannes Melaku, MSc, MPH, PhD, explained that “these findings reinforce the importance of a balanced diet rich in fibre and healthy fats as a potential preventative measure against [colorectal cancer].”

“Public health initiatives could focus on increasing access to and awareness of such foods to help reduce cancer risks. While the study does not suggest dietary patterns influence survival outcomes once [colorectal cancer] occurs, promoting healthy eating could contribute broadly to cancer prevention strategies.”

– Yohannes Melaku, MSc, MPH, PhD

The researchers highlight the role of high-fibre foods, such as fruits and vegetables, in supporting healthy gut bacteria.

These bacteria can help reduce inflammation, making fibre and healthy fats essential components of a balanced diet.

The researchers note that while there is more evidence showing that diet changes can help prevent or delay some diseases, more research is needed to fully understand how diet affects cancer.

However, they note that diet is just one part of what affects our overall health.

Nutrition plays role in preventing gastrointestinal cancers

Gastrointestinal cancers, which include cancers of the esophagus, stomach, pancreas, intestines, colon, and rectum, make up more than one in four cancer cases and cause more than one in three cancer deaths worldwide.

With more awareness of colorectal cancer, researchers are stressing how important good nutrition is for preventing disease.

They recommend healthy eating habits as a way to protect long-term health, especially since digestive cancers, like bowel cancer, are becoming more common in people under 50.

The findings align with the dietary guidelines from the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR), which recommend diets high in whole grains, vegetables, fruits and legumes, while limiting red and processed meats, sugary drinks and processed foods.

The researchers say their findings support current dietary guidelines and show the protective benefits of choices like eating more fiber to help prevent digestive cancers.

They emphasize that following a healthy diet is one of the easiest and most effective ways to improve overall health and lower the risk of diseases, including cancer.

Lena Bakovic, MS, RDN, CNSC, a registered dietitian nutritionist specializing in gut health, chronic disease, weight management, intuitive eating, oncology, and general health and wellness at Top Nutrition Coaching, not involved in this research, agreed that this is an effective way to keep cancer at bay..

“Colorectal cancer is an illness which we know is particularly vulnerable to dietary behaviors,” Bakovic told MNT.

“These results are well-aligned with the scientific/medical community and current recommendations for mostly plant-based diets aiming to benefit risk reduction for colorectal cancer incidence. Specific examples of this alignment include current recommendations for the inclusion of more unsaturated fatty acids found in plant-based foods and oils, and lower intakes of saturated fatty acids contained within animal products such as red and processed meats. Likewise, dietary fiber is also found in plants, and primarily derived from fruits and vegetables.”

– Lena Bakovic, MS, RDN, CNSC

The studies highlight the importance of teaching people about good nutrition and promoting healthy eating habits to lower the risk of digestive cancers and help patients do better.

“This has been well-established in previous clinical trials predominantly correlating a high dietary intake of processed meat, red meat, and alcohol combined with low intakes of fruits and vegetables, and the resultant association with a higher prevalence of colorectal cancers,” Bakovic noted.

“These recommendations include following mostly plant-based diets, which are rich in a variety of fruits and vegetables, include sufficient amounts of dietary fiber (20-30 grams per day), moderate amounts of lean protein sources, incorporation of plant-based proteins, and higher intakes of healthy plant-based fats sourced from foods such as olive oil and avocados,” she advised.

Bakovic added that these findings “will be tremendously helpful in lessening confusion for the public pertaining to nutrition recommendations.”

This is because there is “already such an abundance of information profusely present on the internet which further complicates the discernment between evidence-based and opinion-based nutrition sources.”

Source - Medical News Today