But now it appears that selfish genetic elements might not be so selfish after all. According to new research conducted by scientists at the University of California, San Diego, a certain kind of selfish genetic element—an intron containing a homing endonuclease—can give its host, a phage, a survival advantage over the phage’s peers.

Detailed findings recently appeared in Science, in an article titled, “An intron endonuclease facilitates interference competition between coinfecting viruses.”

“[We] studied intron-encoded homing endonuclease gp210 in bacteriophage ΦPA3 and found that it contributes to viral competition by interfering with the replication of a coinfecting phage, ΦKZ,” the article’s authors wrote. “We show that gp210 targets a specific sequence in ΦKZ, which prevents the assembly of progeny viruses.

“This is the first time a selfish genetic element has been demonstrated to confer a competitive advantage to the host organism it has invaded,” said study co-first author Erica Birkholz, a postdoctoral scholar in the Department of Molecular Biology. “Understanding that selfish genetic elements are not always purely ‘selfish’ has wide implications for better understanding the evolution of genomes in all kingdoms of life.”

In the new study, which focused on investigating “jumbo” phages, the researchers analyzed the dynamics as two phages co-infect a single bacterial cell and compete against each other. The researchers looked closely at the endonuclease, an enzyme that serves as a DNA cutting tool. The endonuclease from one phage’s mobile intron, the studies showed, interferes with the genome of the competing phage. The endonuclease therefore is now regarded as a combat tool since it has been documented cutting an essential gene in the competing phage’s genome. This sabotages the competitor’s ability to appropriately assemble its own progeny and reproduce.

“We were able to clearly delineate the mechanism that gives an advantage and how that happens at the molecular level,” said Biological Sciences graduate student Chase Morgan, the paper’s co-first author. “This incompatibility between selfish genetic elements becomes molecular warfare.”

The results of the study are important as phage viruses emerge as therapeutic tools in the fight against antibiotic resistant bacteria. Since doctors have been deploying cocktails of phage to combat infections in this growing crisis, the new information is likely to come into play when multiple phage are implemented. Knowing that certain phage are using selfish genetic elements as weapons against other phage could help researchers understand why certain combinations of phage may not reach their full therapeutic potential.

“The phages in this study can be used to treat patients with bacterial infections associated with cystic fibrosis,” said Biological Sciences Professor Joe Pogliano. “Understanding how they compete with one another will allow us to make better cocktails for phage therapy.”

The post Phages Can Weaponize Selfish Genetic Elements to Outcompete Peers appeared first on GEN - Genetic Engineering and Biotechnology News.

The preclinical study, in fruit flies and mice, also identified ways to block this process, which could have implications for treating or preventing the muscle wasting sometimes associated with inflammatory diseases—including bacterial infections—Alzheimer’s disease and long COVID.

“We are interested in understanding the very deep muscle fatigue that is associated with some common illnesses,” said senior author Aaron Johnson, PhD, an associate professor of developmental biology. “Our study suggests that when we get sick, messenger proteins from the brain travel through the bloodstream and reduce energy levels in skeletal muscle. This is more than a lack of motivation to move because we don’t feel well. These processes reduce energy levels in skeletal muscle, decreasing the capacity to move and function normally.”

Johnson and colleagues reported on their findings in Science Immunology, in a paper titled “Infection and chronic disease activate a systemic brain-muscle signaling axis.” In their report the team concluded, “Our study argues that infections and chronic diseases activate a conserved IL-6–mediated systemic brain-muscle signaling axis, which could be a therapeutic target to improve muscle outcomes in affected patients.”

“Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show non-neural symptoms including muscle pain and muscle fatigue,” the authors wrote. “The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood.”

To investigate the effects of brain inflammation on muscle function, the researchers modeled three different types of diseases—an E. coli bacterial infection, a SARS-CoV-2 viral infection and Alzheimer’s. When the brain is exposed to inflammatory proteins characteristic of these diseases, damaging chemicals called reactive oxygen species (ROS) build up. The reactive oxygen species cause brain cells to produce an immune-related molecule called interleukin-6 (IL-6), which travels throughout the body via the bloodstream.

Johnson added, “Flies and mice that had COVID-associated proteins in the brain showed reduced motor function—the flies didn’t climb as well as they should have, and the mice didn’t run as well or as much as control mice.” We saw similar effects on muscle function when the brain was exposed to bacterial-associated proteins and the Alzheimer’s protein amyloid beta. We also see evidence that this effect can become chronic. Even if an infection is cleared quickly, the reduced muscle performance remains many days longer in our experiments.” Reporting on their experiments, the team further stated, “Using genetic rescue experiments and pharmacological treatments, we conclude cytokine signaling from the CNS is sufficient to impair motor function and that IL-6 could be a therapeutic target to treat muscle dysfunction in response to infections and chronic disease. Brain muscle-communication is thus a central regulator of muscle performance.”

Johnson, along with collaborators at the University of Florida and first author Shuo Yang, PhD—who did this work as a postdoctoral researcher in Johnson’s lab—make the case that the same processes are likely relevant in people. The bacterial brain infection meningitis is known to increase IL-6 levels and can be associated with muscle issues in some patients, for instance. Among COVID-19 patients, inflammatory SARS-CoV-2 proteins have been found in the brain during autopsy, and many long COVID patients report extreme fatigue and muscle weakness even long after the initial infection has cleared. Patients with Alzheimer’s disease also show increased levels of IL-6 in the blood as well as muscle weakness.

The study pinpoints potential targets for preventing or treating muscle weakness related to brain inflammation. Several therapeutics already approved by the Food and Drug Administration for other diseases can block this JAK-STAT pathway, the team pointed out. JAK inhibitors as well as several monoclonal antibodies against IL-6 are approved to treat various types of arthritis and manage other inflammatory conditions. “IL-6 inhibitors have been used to treat autoimmune diseases such as rheumatoid arthritis, and clinical trials are ongoing to expand the inflammatory disorders that can be targeted with IL-6 inhibitors,” the researchers stated.

“We’re not sure why the brain produces a protein signal that is so damaging to muscle function across so many different disease categories,” Johnson said. “If we want to speculate about possible reasons this process has stayed with us over the course of human evolution, despite the damage it does, it could be a way for the brain to reallocate resources to itself as it fights off disease. We need more research to better understand this process and its consequences throughout the body.

“In the meantime, we hope our study encourages more clinical research into this pathway and whether existing treatments that block various parts of it can help the many patients who experience this type of debilitating muscle fatigue,” he said. Acknowledging limitations of their study, and noting results from previous clinical studies using IL-6 inhibitors or JAK inhibitors, the team further concluded, “These clinical results argue that systemic treatment with IL-6 and JAK inhibitors could inhibit changes to muscle performance induced by the brain-muscle signaling axis and prevent muscle dysfunction associated with chronic and infectious diseases.”

The post Brain Inflammation and Muscle Weakness Linked by Signaling Axis appeared first on GEN - Genetic Engineering and Biotechnology News.

The findings are published in Nature in an article titled, “CryoET of β-amyloid and tau within post-mortem Alzheimer’s disease brain,” and led by scientists at the University of Leeds in collaboration with scientists at Amsterdam UMC, Zeiss Microscopy, and the University of Cambridge.

“A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures,” the scientists wrote. “In Alzheimer’s disease, this is characterized by the deposition of β-amyloid and tau with disease-specific conformations. The in situ structure of amyloid in the human brain is unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out and cryo-electron tomography, we determined in-tissue architectures of β-amyloid and tau pathology in a postmortem Alzheimer’s disease donor brain.”

The study zoomed in on two proteins that cause dementia—”β-amyloid,” a protein that forms microscopic sticky plaques, and “tau”—another protein that in Alzheimer’s disease forms abnormal filaments that grow inside cells and spread throughout the brain.

Rene Frank, PhD, lead author and associate professor in the University of Leeds’s School of Biology, said: “This first glimpse of the structure of molecules inside the human brain offers further clues to what happens to proteins in Alzheimer’s disease but also sets out an experimental approach that can be applied to better understand a broad range of other devastating neurological diseases.”

This study carried out at the University of Leeds in collaboration with scientists at Amsterdam UMC, Zeiss Microscopy, and the University of Cambridge, is part of new efforts by structural biologists to study proteins directly within cells and tissues, their native environment—and how proteins work together and affect one another, particularly in human cells and tissues ravaged by disease. In the longer term, it is hoped that observing this interplay of proteins within tissues will accelerate the identification of new targets for next-generation mechanism-based therapeutics and diagnostics.

The post Deep Dive into Brain’s Molecular Structures Affected by Alzheimer’s Disease appeared first on GEN - Genetic Engineering and Biotechnology News.

Following their success against COVID-19 infections, interest in RNA-based therapeutics is growing rapidly. And as demand for RNA drugs continues to grow and “additional products come to market, we will exceed the current global supply of acetonitrile, the organic solvent used in chemical RNA synthesis methods,” said co-first author Jonathan Rittichier, PhD, a former postdoctoral fellow at the Wyss and HMS. 

Besides reducing the creation of toxic synthesis byproducts, the technology that Rittichier and his collaborators, which includes George Church, PhD, Wyss core faculty member and HMS professor of genetics, have developed incorporates common molecular modifications found in RNA drugs today and can be used with novel RNA chemistries to develop new therapies. “Delivering RNA drugs to the world at these scales requires a paradigm shift to a renewable, aqueous synthesis, and we believe our proprietary enzymatic technology will enable that shift,” Rittichier said.

The starting point for the technology is an enzyme from Schizosaccharomyces pombe, a strain of yeast, that is used to form RNA strands. The scientists engineered a more efficient version of the enzyme that can also incorporate nonstandard nucleotides into RNA—a necessary improvement since every FDA-approved RNA drug includes modified nucleotides that increase their stability in the body or equip them with new functions. Their approach also uses milder methods to remove protecting groups which are added to nucleotides to protect them during the synthesis process. 

Furthermore, the researchers modified the nucleotides by attaching a chemical group called a “blocker” that ensures that nucleotides are added to the RNA chain one at a time. Once the desired nucleotide has been added to the link, the blocker is removed to allow the next nucleotide in the sequence to bind. This two-step process is simpler and uses fewer reagents than the typical four-step chemical synthesis. According to the scientists, their process is also 95% efficient and can build RNA molecules as long as 23 nucleotides. However, they noted that “overall yields in bulk phase were lower than those in standard RNA oligonucleotide synthesis” likely due to “multiple rounds of purification after both extension and deblocking.”

“Enzymatic nucleotide synthesis technologies offer many advantages as an alternative to chemical-based methods,” Church said in a statement. “This platform can help unlock the immense potential of RNA therapeutics in a sustainable way, especially manufacturing high-quality guide RNA molecules for CRISPR/Cas gene editing.” 

Rittichier, Church, and others launched EnPlusOne Biosciences in 2022 to commercialize the technology with funding from Northpond Ventures, Breakout Ventures, and Coatue. The company is currently using the technology to manufacture small interfering RNAs that could be used to treat various diseases. 

The post Harvard Scientists Publish Details of Enzymatic RNA Synthesis Tech Commercialized by EnPlusOne appeared first on GEN - Genetic Engineering and Biotechnology News.

The multi-product facility, which doubles Rentschler Biopharma’s global cGMP capacity, is focusing mainly on commercial production of highly complex molecules. The original Milford site went from a single-product commercial facility to producing multiple products in an up to 500L bioreactor setup.

The new production line has added 22,000 square feet of manufacturing cleanroom space and houses four new 2,000L single-use bioreactors, bringing the total of production lines at the site up to three.

“The completion of our new production line is an important milestone for our company and emphasizes Rentschler Biopharma’s strong capabilities in the U.S.,” said Benedikt von Braunmühl, CEO of Rentschler Biopharma. “Indeed, in 2023, Rentschler Biopharma was proud to contribute to nearly 25% of the biopharmaceuticals approved by the FDA.”

The post Rentschler Biopharma’s New Production Line in Massachusetts Now Fully Operational appeared first on GEN - Genetic Engineering and Biotechnology News.

Kappler said the bacterium had a unique ability to “talk” to and deactivate the immune system, convincing it there was no threat. “These bacteria are especially damaging to vulnerable groups, such as those with cystic fibrosis, asthma, the elderly, and Indigenous communities,” Kappler said. “In some conditions, such as asthma and chronic obstructive pulmonary disease, they can drastically worsen symptoms. Our research shows the bacterium persists by essentially turning off the body’s immune responses, inducing a state of tolerance in human respiratory tissues.”

The researchers reported on their studies, and results, in PLOS Pathogens, in a paper titled “Tolerance to Haemophilus influenzae infection in human epithelial cells: Insights from a primary cell-based model.”

Respiratory tract infections are highly debilitating, and Haemophilus influenzae is a bacterial pathogen that is associated with persistent acute and chronic respiratory tract infections, particularly among vulnerable individuals, the authors explained. “Haemophilus influenzae is a human-adapted pathobiont that inhabits the nasopharynx as a commensal but causes disease in other parts of the respiratory tract.” What are classed as nontypeable strains of H. influenzae (NTHi) are the most common type of clinical isolate, the team continued. In addition to causing acute diseases such as pneumonia, these strains are a major cause of exacerbations of chronic lung diseases, including in patients recovering from COVID-19. Interactions between the bacteria and the respiratory epithelia represent a key factor in NTHi virulence,” the team continued. “Despite this, insights into the molecular interactions that allow NTHi to persist in contact with human epithelia are lacking, but likely hold the key to uncovering both bacterial and host processes that are crucial for infection.”

For their newly reported studies the team generated primary normal human nasal epithelia (NHNE), derived from cells from five healthy donors, and monitored the effects on tissue gene expression of NTHi infection. They first prepared the human nasal tissue in the lab, growing it to resemble the surfaces of the human respiratory tract. They then monitored post infection (p.i.) gene expression changes over a 14-day period of “infection” with the NTHi. “Persistent infections rely on close molecular interactions between the human respiratory cells and the bacterial pathogen,” the team noted, “… and here we have investigated changes in host and bacterial cells during persistent, long-term infections with H. influenzae.”

Their found very limited production of inflammation molecules over time, which normally would be produced within hours of bacteria infecting human cells. “We then applied both live and dead Haemophilus influenzae, showing the dead bacteria caused a fast production of the inflammation makers, while live bacteria prevented this,” professor Kappler said.  “This proved that the bacteria can actively reduce the human immune response.”

In their paper the authors wrote, “… Physiological assays combined with dualRNAseq revealed that NHNE from five healthy donors all responded to H. influenzae infection with an initial, ‘unproductive’ inflammatory response that included a strong hypoxia signature but did not produce pro-inflammatory cytokines. Subsequently, an apparent tolerance to large extracellular and intraepithelial burdens of H. influenzae developed, with NHNE transcriptional profiles resembling the pre-infection state.”

This is the first time that large-scale, persistence-promoting immunomodulatory effects of H. influenzae during infection have been observed, they stated. “In addition to providing first molecular insights into mechanisms enabling persistence of H. influenzae in the host, our data further indicate the presence of infection stage-specific gene expression modules, highlighting fundamental similarities between immune responses in NHNE and canonical immune cells, which merit further investigation.”

Co-author and pediatric respiratory physician emeritus professor Peter Sly, MD, at UQ’s Faculty of Medicine, said the results show how Haemophilus influenzae can cause chronic infections, essentially living in the cells that form the surface of the respiratory tract.

“This is a rare behavior that many other bacteria don’t possess,” professor Sly said.
“If local immunity drops, for example during a viral infection, the bacteria may be able to ‘take over’ and cause a more severe infection.” The findings will lead to future work towards new treatments to prevent these infections by helping the immune system to recognize and kill these bacteria. “We’ll look at ways of developing treatments that enhance the immune system’s ability to detect and eliminate the pathogen before it can cause further damage,” Kappler added.

In their paper the authors concluded, “… our data provide first evidence that NTHi infections can delay strong inflammatory responses in human epithelia and induce an apparent tolerance of NTHi infection that had not been previously observed, but could be a driver of NTHi persistence in the human respiratory tract. This state of ‘peaceful’ coexistence of NHNE and NTHi required infection with live NTHi, which indicates an active immunomodulatory role for NTHi.”

They pointed out that further research is needed to investigate whether bacterial effector proteins or metabolites are involved in triggering NHNE tolerance of NTHi infection, and what mechanisms within human epithelia cause differences in tolerance of NTHi infections.

The post Respiratory Bacteria “Talk” Immune System into Tolerating Infection appeared first on GEN - Genetic Engineering and Biotechnology News.

The existing analytical workflow for biomanufacturing is full of blind spots and bottlenecks that contribute to increased time to market and manufacturing costs for critical drugs, according to a number of experts. Therapeutic development is an iterative and complicated process requiring analysis at each step of the process and suffers from either no data or slow data collection. If samples are taken, they are typically sent to a core analytical lab for HPLC analysis, and drug development timelines are often delayed for 4–6 weeks waiting on its retrospective data.

Atlas, powered by tunable laser spectroscopy (HPTLS) technology, reportedly enables simultaneous analysis of buffer excipients, such as surfactants and amino acids, and high concentration proteins, such as monoclonal antibodies, peptides, and vaccines in one minute throughout the bioprocess.

Critical data

“This simple to use system delivers critical data with the accuracy and sensitivity of HPLC, bringing the power of the core lab right to the point of sampling,” said Greg Crescenzi, CEO of Nirrin. “Atlas quickly reveals blind spots and overlooked issues that can become bigger problems throughout the bioprocess, giving scientists more predictive and proactive control over their process like never before. Armed with the needed insights to make confident decisions in-hand, they can eliminate unnecessary wait time and be more selective on which samples are sent to the core lab for further analysis.”

Early adopter studies conducted by ten top global pharmaceutical companies demonstrated the potential of Atlas’ HPTLS as a reliable method that overcomes the limitations of traditional analysis techniques and opens new possibilities for studying and optimizing protein formulations, continued Crescenzi.

Nirrin’s HPTLS technology unlocks the power of near-infrared (NIR) spectroscopy with a tunable laser source to provide unique, quantitative signatures for excipients, proteins, surfactants and more, noted. Bryan Hassell, PhD, Nirrin founder and CTO.

“Bioprocess groups shouldn’t have to wait for retrospective data from the core lab, they need data they can trust, now,” said Hassell. “Atlas debottlenecks current analytical workflows with a system anyone can use and get accurate, reliable data in a minute or less. There are no other at-line technologies that can provide the data-driven insights biopharma needs to react quickly and effectively.”

“With Atlas, bioprocess groups now have a single tool that can be used to benchmark their unique processes in both development and manufacturing, and deliver cost-effective, actionable answers on-demand,” added Crescenzi. “Atlas is Nirrin’s first step towards what the biopharmaceutical industry has been waiting on for a long time—real-time monitoring and integrated control of their bioprocess. Our current development focus is on continuous manufacturing, and early collaborators are already having great success with Atlas for analysis of their critical process parameters.”

The post Nirrin Launches Atlas for At-Line Analysis at the Point of Sampling appeared first on GEN - Genetic Engineering and Biotechnology News.

These so-called microproteins or noncoding ORF-derived (ncORF) peptides are small proteins expressed only by cancer cells that can be used to activate the immune system against cancer. Furthermore, these molecules are generated by genes that were once considered incapable of encoding proteins. The scientists discovered the proteins in this study by integrating and analyzing information from tumor and healthy tissue collected from over a hundred patients with hepatocellular carcinoma including RNA sequencing, immunopeptidomics, and ribosome profiling data. 

There is significant interest in cancer vaccines which rely on the immune system’s ability to recognize foreign proteins generated as a result of mutations in cancerous cells. The challenge lies with cancers with low mutation rates like liver cancers. Microproteins could be a solution in these cases. The results reported in the paper highlight the potential of using microproteins exclusively expressed in tumor cells as targets for new treatments. Specifically, the researchers identified “a subset of 33 tumor-specific long noncoding RNAs expressing novel cancer antigens shared by more than 10% of the HCC samples analyzed, which, when combined, cover a large proportion of the patients,” according to the paper.

In fact, “we have seen that some of these microproteins can stimulate the immune system, potentially generating a response against cancer cells,” said Puri Fortes, PhD, one of the paper’s authors and a researcher at CIMA as well as the Network Biomedical Research Center for Liver and Digestive Diseases (CIBERehd). According to the paper, when the team tested four ncORF-derived peptides in transgenic mice, they found that two of them could generate a significant immune response involving CD8+ T cells.  “This response can be enhanced with vaccines, similar to the coronavirus vaccines, but producing these microproteins. These vaccines could stop or reduce tumor growth,” said Fortes. 

Also, unlike other types of vaccines based on patient-specific mutations, a potential anticancer vaccine that targets ncORF peptides could be used to treat multiple people, as the same microprotein is expressed in various patients, the researchers noted. 

The post Liver Tumor Microproteins Could Be Key to Developing New Cancer Vaccines appeared first on GEN - Genetic Engineering and Biotechnology News.

“One of the remarkable things about these findings is that if we hadn’t been studying female mice, which unfortunately is the norm in biomedical research, then we could have completely missed out on this finding,” said Holly Ingraham, PhD, professor of cellular molecular pharmacology at UCSF. “It underscores just how important it is to look at both male and female animals across the lifespan to get a full understanding of biology.”

Ingraham is senior author of the team’s published paper in Nature, titled “A maternal brain hormone that builds bone,” in which they concluded, “Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.”

More than 200 million people worldwide suffer from osteoporosis, a severe weakening of the bones that can cause frequent fractures. Women are at particularly high risk of osteoporosis after menopause because of declining levels of the sex hormone estrogen (estradiol; E2), which normally promotes bone formation. “For women, estrogen depletion following menopause or anti-hormone therapies degrades bone mass, an effect that underscores the anabolic features of estrogen on bone,” the authors wrote.

Estrogen levels are also low during breastfeeding, yet osteoporosis and bone fractures are much rarer during this time, suggesting that something other than estrogen promotes bone growth. “… the intimate association between estrogen and bone is uncoupled during lactation when the E2 surge in late-stage pregnancy drops precipitously,” the team continued, “Moreover, bone remodeling increases sharply in rodents and in primates to meet the high calcium demand by progeny.” The possibility exists, therefore, the team reasoned, that “…dedicated mechanisms drive the anabolic pathway of bone remodeling during lactation.”

Ingraham’s lab previously discovered that in female mice, but not male mice, blocking a particular estrogen receptor found in select neurons in a small area of the brain led to huge increases in bone mass. They suspected that a hormone in the blood was responsible for the super-strong bones but, at the time, could not find it—a quest that was further protracted during the worldwide pandemic.

For their newly reported research, Ingraham and collaborators carried out an exhaustive search for this bone-building hormone and finally pinpointed CCN3 as the factor responsible in mutant females. Initially, the team was surprised by this result, as CCN3 did not fit the typical profile of a secreted hormone from neurons. But in confirmation of the result, they also found CCN3 in the same brain region in lactating female mice. Without the production of CCN3 in these select KISS1 neurons, lactating female mice rapidly lost bone, and their babies began to lose weight, confirming the importance of the hormone in maintaining bone health during lactation.

“… to verify that CCN3 is an anabolic brain hormone during lactation, viral vector delivery of short hairpin RNA (shRNA) targeting Ccn3 (shCcn3) was used to knockdown CCN3 in the ARC of adult virgin females before pregnancy,” the authors stated. Despite their ability to suckle, pups nursed by a shCcn3 mother failed to thrive, eventually leading to increased mortality. “Pup viability depended on the status of brain CCN3 in mothers, as transfer of pups to a shCcn3 mother resulted in 10% weight loss compared with 30% weight gain when nursed by dams injected with control shRNA (shCtrl).”

Through further experiments, the scientists showed that when strategies to increase circulating CCN3 were implemented in young adult and older female or male mice, bone mass and strength in these animals increased dramatically over the course of weeks. In some female mice who lacked all estrogen or were very old, CCN3 was able to more than double bone mass.

When Ingraham’s UC Davis scientific collaborator, Thomas Ambrosi, PhD, tested these bones, he was surprised by their strength. “There are some situations where highly mineralized bones are not better; they can be weaker and actually break more easily,” he explained. “But when we tested these bones, they turned out to be much stronger than usual.”

“Our data across several models established that CCN3-mediated formation of new bone is coupled with higher bone quality and healthy bone remodeling,” the authors stated. “Although our study is seemingly at odds with suggestions that CCN3 inhibits osteogenesis and bone regeneration, these differences could reflect a dose effect of CCN3, with higher levels resulting in compensatory cellular responses or nonspecific receptor activation in bone niches that are anti-osteogenesis.”

Ambrosi looked closely at the stem cells within the bones that are responsible for generating new bone and found that when these cells were exposed to CCN3, they were much more prone to generate new bone cells.

To test the ability of the hormone to assist in bone healing, the researchers created a hydrogel patch that could be applied directly to the site of a bone fracture, where it would slowly release CCN3 for two weeks. In elderly mice, bone fractures don’t usually heal well. However, the CCN3 patch spurred the formation of new bone at the site of the fracture, contributing to youthful healing of the fracture. “We’ve never been able to achieve this kind of mineralization and healing outcome with any other strategy,” Ambrosi said. “We’re really excited to follow it up and potentially apply CCN3 in the context of other problems, such as regrowing cartilage.”

The researchers plan to carry out future studies on the molecular mechanisms of CCN3, its levels in breastfeeding women, as well as the potential of the hormone to treat a variety of bone conditions. “Whether MBH is eventually exported to milk is unclear, the team noted. “We suggest that hormones, such as MBH, are in place to coordinate adaptive physiological responses in peripheral tissues, including the skeleton and gut,  to meet the high demands of motherhood. Future directions of research include the potential translation of MBH in genetic and chronic bone diseases.”

Muriel Babey, MD, a co-first author and mentored physician-scientist in the Division of Endocrinology at UCSF, is keen to begin asking how CCN3 impacts bone metabolism in clinically relevant disease settings. Partnering with the UCSF Catalyst program, William Krause, PhD, a senior scientist and co-lead on this project will begin translating these new results. Bone loss happens not only in post-menopausal women but often occurs in breast cancer survivors that take certain hormone blockers; in younger, highly trained elite female athletes; and in older men whose relative survival rate is poorer than women after a hip fracture,” Ingraham said. “It would be incredibly exciting if CCN3 could increase bone mass in all these scenarios.”

The post Osteoporosis Treatment Suggested by Bone-Protecting Hormone in Lactating Women appeared first on GEN - Genetic Engineering and Biotechnology News.

Because the process of aging increases the risk for memory problems and dementia, researchers must understand why as a first step toward delaying cognitive issues until later in life. The Hevolution Foundation invests in science that aims to uncover the root causes of aging.

“As we have longer life spans, it’s really important to identify ways to simultaneously promote increased health spans. It’s challenging when you have loved ones who have severe illness or cognitive impairment, yet they are not dying; they are physically able to keep living. We want to help people stay healthier longer,” said Hevolution grant recipient Shannon Conley, PhD, an assistant professor of cell biology in the OU College of Medicine, who is leading the work with Anna Csiszar, PhD, a professor of neurosurgery in the OU College of Medicine.

Blood vessel function

In their project, they are trying to better understand how two types of cells in blood vessels work together for brain health but become dysfunctional as a person ages. Endothelial cells, which line the blood vessels, and smooth muscle cells, which are on the outside of the vessels, collaborate to help the brain respond to everyday stimuli, like sound or taste.

During aging, they can undergo cellular senescence, a kind of limbo when the cells aren’t dead, but neither are they functioning normally and proliferating. As a result, the cells can no longer perform their usual tasks, which then causes the blood vessels to have trouble contracting and relaxing normally. That vascular dysfunction sets the stage for cognitive impairment and eventually dementia. The researchers want to understand how cellular senescence leads to blood vessel dysfunction.

“We believe the link is something called de-differentiation: The endothelial cells and smooth muscle cells essentially lose their identity during senescence and become generic cells that don’t function well,” Conley said. “Understanding these mechanisms that lead to age-related defects in blood vessel function is really important for making progress toward a treatment or cure for dementia. You wouldn’t necessarily think that the blood vessels are the place to look, but there is so much evidence that blood vessel dysfunction is one of the earliest changes in the brains of people who develop dementia.

“When we think about dementia, we think about damage to the neurons in your brain. But if the blood vessels in the brain are not functioning well, then the neurons don’t have enough energy or oxygen and eventually will degenerate. In addition, the blood vessels are important for clearing waste materials, so if the blood vessels aren’t working properly, then you have an accumulation of abnormal material that will contribute to neuronal dysfunction.”

Metabolic factors and aging

The second grant recipient, Sreemathi Logan, PhD, an assistant professor of biochemistry and physiology at the OU College of Medicine, wants to understand the metabolic factors, including obesity, that influence cognition during aging. A central question of her research is why some people’s brains seem to be resilient, while others are susceptible to cognitive problems and diseases like Alzheimer’s.

For her studies, she separates aging mice into two groups: those with “intact” cognition and those with impaired cognition.

“Because we separate mice into different subgroups of varying cognitive function, we can better try to understand what specific cells are doing in the brain that contribute to healthy brain aging vs. impaired cognition,” she said. “My previous research has shown that mice mirror the differential cognitive abilities that humans exhibit and thus are a good model to investigate the incidence and progression of dementia with age.”

The group of cognitively impaired, older mice experience dysfunction of their mitochondria, which are responsible for providing energy to the brain. Loss of mitochondrial function can lead to persistent inflammation that is driven by cellular senescence, a hallmark of aging. Even though senescent cells have stopped dividing, they remain active, spewing out harmful substances that cause inflammation, further impairing cognition.

With this grant, Logan is studying the brain-adipose axis: how excess fat in the body, especially around the belly, affects cognition during aging. In particular, she is testing whether a ketogenic diet (high fat and reduced carbohydrates) can target cellular senescence. Existing research suggests that reducing carbohydrates, even in a high-fat diet, helps the body use fat more efficiently. Theoretically, that would lower the inflammatory factors of senescence and reduce the negative effects of fat on the brain.

Logan’s grant also allows her to investigate whether senolytics (drugs that target senescent cells) can positively affect cognition by regulating fat metabolism, the process of breaking down fat in the diet so it can be used for energy.

“Cognitive health is an important part of health span,” Logan said. “By understanding the biological underpinnings of why some mice perform better than others, we hope to eventually translate our findings to humans with varying cognitive abilities and design individualized treatments to improve cognitive function in older adults.”

The post Improving Health Span by Slowing Age-Related Cognitive Decline appeared first on GEN - Genetic Engineering and Biotechnology News.