Red and processed meat consumption associated with higher type 2 diabetes risk, study of two million people finds

 Meat consumption, particularly consumption of processed meat and unprocessed red meat, is associated with a higher type 2 diabetes risk, an analysis of data from 1.97 million participants, published today in The Lancet Diabetes and Endocrinology, has found.

Global meat production has increased rapidly in recent decades and meat consumption exceeds dietary guidelines in many countries. Earlier research indicated that higher intakes of processed meat and unprocessed red meat are associated with an elevated risk of type 2 diabetes, but the results have been variable and not conclusive.

Poultry such as chicken, turkey, or duck is often considered to be an alternative to processed meat or unprocessed red meat, but fewer studies have examined the association between poultry consumption and type 2 diabetes.

To determine the association between consumption of processed meat, unprocessed red meat and poultry and type 2 diabetes, the team led by researchers at the University of Cambridge used the global InterConnect project to analyse data from 31 study cohorts in 20 countries. Their extensive analysis took into account factors such as age, gender, health-related behaviours, energy intake and body mass index.

The researchers found that the habitual consumption of 50 grams of processed meat a day -- equivalent to 2 slices of ham -- is associated with a 15% higher risk of developing type 2 diabetes in the next 10 years. The consumption of 100 grams of unprocessed red meat a day -- equivalent to a small steak -- was associated with a 10% higher risk of type 2 diabetes.

Habitual consumption of 100 grams of poultry a day was associated with an 8% higher risk, but when further analyses were conducted to test the findings under different scenarios the association for poultry consumption became weaker, whereas the associations with type 2 diabetes for each of processed meat and unprocessed meat persisted.

Professor Nita Forouhi of the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, and a senior author on the paper, said:

"Our research provides the most comprehensive evidence to date of an association between eating processed meat and unprocessed red meat and a higher future risk of type 2 diabetes. It supports recommendations to limit the consumption of processed meat and unprocessed red meat to reduce type 2 diabetes cases in the population.

While our findings provide more comprehensive evidence on the association between poultry consumption and type 2 diabetes than was previously available, the link remains uncertain and needs to be investigated further."

InterConnect uses an approach that allows researchers to analyse individual participant data from diverse studies, rather than being limited to published results. This enabled the authors to include as many as 31 studies in this analysis, 18 of which had not previously published findings on the link between meat consumption and type 2 diabetes. By including this previously unpublished study data the authors considerably expanded the evidence base and reduced the potential for bias from the exclusion of existing research.

Lead author Dr Chunxiao Li, also of the MRC Epidemiology Unit, said:

"Previous meta-analysis involved pooling together of already published results from studies on the link between meat consumption and type 2 diabetes, but our analysis examined data from individual participants in each study. This meant that we could harmonise the key data collected across studies, such as the meat intake information and the development of type 2 diabetes.

Using harmonised data also meant we could more easily account for different factors, such as lifestyle or health behaviours, that may affect the association between meat consumption and diabetes. "

Professor Nick Wareham, Director of the MRC Epidemiology Unit, and a senior author on the paper said:

"InterConnect enables us to study the risk factors for obesity and type 2 diabetes across populations in many different countries and continents around the world, helping to include populations that are under-represented in traditional meta-analyses.

Most research studies on meat and type 2 diabetes have been conducted in USA and Europe, with some in East Asia. This research included additional studies from the Middle East, Latin America and South Asia, and highlighted the need for investment in research in these regions and in Africa.

Using harmonised data and unified analytic methods across nearly 2 million participants allowed us to provide more concrete evidence of the link between consumption of different types of meat and type 2 diabetes than was previously possible."

InterConnect was initially funded by the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602068.

Story Source:

Materials provided by University of Cambridge. The original text of this story is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Note: Content may be edited for style and length.

Journal Reference:

1. Chunxiao Li et al. Meat consumption and incident type 2 diabetes: an individual-participant federated meta-analysis of 1·97 million adults with 100 000 incident cases from 31 cohorts in 20 countries. The Lancet Diabetes & Endocrinology, 2024 DOI: 10.1016/S2213-8587(24)00179-7

Courtesy:

University of Cambridge. "Red and processed meat consumption associated with higher type 2 diabetes risk, study of two million people finds." ScienceDaily. ScienceDaily, 20 August 2024. <www.sciencedaily.com/releases/2024/08/240820221808.htm>.

A switch for immune memory and anti-tumor immunity

 A Ludwig Cancer Research study has identified a metabolic switch in the immune system's T cells that is essential to the generation of memory T cells -- which confer lasting immunity to previously encountered pathogens -- and a T cell subtype found in tumors that drives anti-tumor responses during immunotherapy.

Led by Ludwig Lausanne's Ping-Chih Ho and Alessio Bevilacqua and published in the current issue of Science Immunology, the study identifies PPARβ/δ, a master regulator of gene expression, as that essential molecular switch. Ho, Bevilacqua and their colleagues also show that the switch's dysfunction compromises T cell "memory" of previously encountered viruses as well as the induction of anticancer immune responses in mice.

"Our findings suggest that we might be able to engage this switch pharmacologically to improve the efficacy of cancer immunotherapies," said Ho.

When killer (or CD8+) T cells, which kill sick and cancerous cells, are activated by their target antigen, they switch on metabolic pathways that most other healthy cells only use when starved of oxygen. This type of metabolism -- involving a metabolic process known as aerobic glycolysis -- supports multiple processes essential to the killer T cell's ability to proliferate and destroy its target cells.

Most killer T cells die off after they've cleared an infection. A few, however, transform into central memory CD8+ T cells (Tcms) that linger in the circulation to establish what we call immunity: the ability to mount a swift and lethal response to the same pathogen if it is ever encountered again. To achieve this transformation, T cells switch off aerobic glycolysis and otherwise adapt their metabolism to persist over the long term in tissues or in the circulation. How precisely they do this was until now unknown.

Aware that PPARβ/δ activates many of the metabolic processes characteristic of Tcms, Ho, Bevilacqua and their colleagues hypothesized it might play a key role in Tcm formation. They examined immunologic gene expression data collected from yellow fever vaccine recipients long after vaccination and, as expected, saw that the PPARβ/δ was produced abundantly in their Tcms.

Their studies in mice revealed that PPARβ/δ is activated in T cells not in the peak phase of the immune response to viral infection but as that response winds down. Further, CD8+ T cells were unable to make the metabolic switch required to become circulating Tcms if they failed to express PPARβ/δ. Disrupting its expression impaired survival of such Tcms and resident memory T cells in the intestines following infection.

The researchers show that T cell exposure to interleukin-15 -- an immune factor important for Tcm formation -- and their expression of a protein named TCF1 engages the PPARβ/δ pathway. TCF1 is already known to be critical to the rapid expansion of Tcms when they encounter their target pathogen. The researchers show in this study that it is also important to the maintenance of TCMs.

As it happens, TCF1 expression is a hallmark of a subset of CD8+ T cells -- progenitor-exhausted T cells -- that are found in tumors. These progenitor-exhausted T cells follow one of two paths: they either become completely lethargic, "terminally exhausted" T cells; or, given the appropriate stimulus, proliferate to produce "effector" CD8+ T cells that kill cancer cells. Checkpoint blockade immunotherapies, like anti-PD-1 antibodies, can provide such stimulus.

The observation that TCF1 modulates the PPARβ/δ pathway in T cells raised the possibility that it might also be essential to the formation and maintenance of progenitor-exhausted T cells. The researchers showed that this is indeed the case. Deleting the PPARβ/δ gene from T cells led to the loss of progenitor-exhausted T cells in a mouse model of melanoma. They also demonstrate that the PPARβ/δ pathway curtails the tendency of progenitor-exhausted T cells to stagger toward terminal exhaustion.

To assess the therapeutic potential of their findings, Ho, Bevilacqua and their colleagues exposed T cells to a molecule that stimulates PPARβ/δ activity and used the treated cells against a mouse model of melanoma. These cells delayed the growth of melanoma tumors in mice more efficiently than their untreated counterparts and bore biochemical hallmarks of progenitor exhausted T cells primed to generate cancer-killing descendants.

"Based on these findings," said Bevilacqua, "we suggest that targeting PPARβ/δ signaling may be a promising approach to improve T cell-mediated anti-tumor immunity.

How exactly this might be achieved in people is a subject for further study that will doubtless be pursued by the Ho laboratory.

This study was supported by Ludwig Cancer Research, the Swiss National Science Foundation, the European Research Council, the Swiss Cancer Foundation, the Cancer Research Institute, Helmut Horten Stiftung, the Melanoma Research Alliance, the Taiwan Ministry of Science and Technology, the NYU Abu Dhabi Research Institute Award and Academia Sinica.

Ping-Chih Ho is a member of the Lausanne Branch of the Ludwig Institute for Cancer Research and a full professor at the University of Lausanne.

Story Source:

Materials provided by Ludwig Institute for Cancer Research. Note: Content may be edited for style and length.

Journal Reference:

1. Alessio Bevilacqua, Fabien Franco, Ya-Ting Lu, Nabil Rahiman, Kung-Chi Kao, Yu-Ming Chuang, Yanan Zhu, Werner Held, Xin Xie, Kristin C. Gunsalus, Zhengtao Xiao, Shih-Yu Chen, Ping-Chih Ho. PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8 + T cells. Science Immunology, 2024; 9 (98) DOI: 10.1126/sciimmunol.adn2717

Courtesy:

Ludwig Institute for Cancer Research. "A switch for immune memory and anti-tumor immunity." ScienceDaily. ScienceDaily, 23 August 2024. <www.sciencedaily.com/releases/2024/08/240823185109.htm>.

Spike mutations help SARS-CoV-2 infect the brain

 Scientists have discovered a mutation in SARS-CoV-2, the virus that causes COVID-19, that plays a key role in its ability to infect the central nervous system. The findings may help scientists understand its neurological symptoms and the mystery of "long COVID," and they could one day even lead to specific treatments to protect and clear the virus from the brain.

The new collaborative study between scientists at Northwestern University and the University of Illinois-Chicago uncovered a series of mutations in the SARS-CoV-2 spike protein (the outer part of the virus that helps it penetrate cells) that enhanced the virus' ability to infect the brains of mice.

"Looking at the genomes of viruses found in the brain compared to the lung, we found that viruses with a specific deletion in spike were much better at infecting the brains of these animals," said co-corresponding author Judd Hultquist, assistant professor of medicine (infectious diseases) and microbiology-immunology at Northwestern University Feinberg School of Medicine. "This was completely unexpected, but very exciting."

The study will be published Aug. 23 in Nature Microbiology.

Changes in spike help the virus infect different cells in the body

In this study, researchers infected mice with SARS-CoV-2 and sequenced the genomes of viruses that replicated in the brain versus the lung. In the lung, the spike protein looked very similar to the virus used to infect the mice. In the brain, however, most viruses had a deletion or mutation in a critical region of spike that dictates how it enters a cell. When viruses with this deletion were used to directly infect the brains of mice, it was largely repaired when it traveled to the lungs.

"In order for the virus to traffic from the lung to the brain, it required changes in the spike protein that are already known to dictate how the virus gets into different types of cells," Hultquist said. "We think this region of spike is a critical regulator of whether or not the virus gets into the brain, and it could have large implications for the treatment and management of neurological symptoms reported by COVID-19 patients."

SARS-CoV-2 has long been associated with various neurological symptoms, such as the loss of smell and taste, "brain fog" and "long COVID."

"It's still not known if long COVID is caused by direct infection of cells in the brain or due to some adverse immune response that persists beyond the infection," Hultquist said. "If it is caused by infection of cells in the central nervous system, our study suggests there may be specific treatments that could work better than others in clearing the virus from this compartment."

Other Northwestern authors on the study include Lacy M. Simons, Tanushree Dangi, Egon A. Ozer, Pablo Penaloza-MacMaster and Ramon Lorenzo-Redondo.

Funding for this study, "Evolution of SARS-CoV-2 in the murine central nervous system drives viral diversification," was provided by the National Institutes of Health (grants R01AI150672; R56DE033249; R21AI163912 and U19AI135964); the Department of Defense (grant MS200290); and through institutional support for the Center for Pathogen Genomics and Microbial Evolution and the Northwestern University Clinical & Translational Sciences Institute (NUCATS).

Story Source:

Materials provided by Northwestern University. Note: Content may be edited for style and length.

Journal Reference:

1. Jacob Class, Lacy M. Simons, Ramon Lorenzo-Redondo, Jazmin Galván Achi, Laura Cooper, Tanushree Dangi, Pablo Penaloza-MacMaster, Egon A. Ozer, Sarah E. Lutz, Lijun Rong, Judd F. Hultquist, Justin M. Richner. Evolution of SARS-CoV-2 in the murine central nervous system drives viral diversification. Nature Microbiology, 2024; DOI: 10.1038/s41564-024-01786-8

Courtesy:

Northwestern University. "Spike mutations help SARS-CoV-2 infect the brain." ScienceDaily. ScienceDaily, 23 August 2024. <www.sciencedaily.com/releases/2024/08/240823120055.htm>.

Mitochondria are flinging their DNA into our brain cells

 As direct descendants of ancient bacteria, mitochondria have always been a little alien.

Now a study shows that mitochondria are possibly even stranger than we thought.

Mitochondria in our brain cells frequently fling their DNA into the nucleus, the study found, where the DNA becomes integrated into the cells' chromosomes. And these insertions may be causing harm: Among the study's nearly 1,200 participants, those with more mitochondrial DNA insertions in their brain cells were more likely to die earlier than those with fewer insertions.

"We used to think that the transfer of DNA from mitochondria to the human genome was a rare occurrence," says Martin Picard, mitochondrial psychobiologist and associate professor of behavioral medicine at Columbia University Vagelos College of Physicians and Surgeons and in the Robert N. Butler Columbia Aging Center. Picard led the study with Ryan Mills of the University of Michigan.

"It's stunning that it appears to be happening several times during a person's lifetime, Picard adds. "We found lots of these insertions across different brain regions, but not in blood cells, explaining why dozens of earlier studies analyzing blood DNA missed this phenomenon."

Mitochondrial DNA behaves like a virus

Mitochondria live inside all our cells, but unlike other organelles, mitochondria have their own DNA, a small circular strand with about three dozen genes. Mitochondrial DNA is a remnant from the organelle's forebears: ancient bacteria that settled inside our single-celled ancestors about 1.5 billion years ago.

In the past few decades, researchers discovered that mitochondrial DNA has occasionally "jumped" out of the organelle and into human chromosomes.

"The mitochondrial DNA behaves similar to a virus in that it makes use of cuts in the genome and pastes itself in, or like jumping genes known as retrotransposons that move around the human genome," says Mills.

The insertions are called nuclear-mitochondrial segments -- NUMTs ("pronounced new-mites") -- and have been accumulating in our chromosomes for millions of years.

"As a result, all of us are walking around with hundreds of vestigial, mostly benign, mitochondrial DNA segments in our chromosomes that we inherited from our ancestors," Mills says.

Mitochondrial DNA insertions are common in the human brain

Research in just the past few years has shown that "NUMTogenesis" is still happening today.

"Jumping mitochondrial DNA is not something that only happened in the distant past," says Kalpita Karan, a postdoc in the Picard lab who conducted the research with Weichen Zhou, a research investigator in the Mills lab. "It's rare, but a new NUMT becomes integrated into the human genome about once in every 4,000 births. This is one of many ways, conserved from yeast to humans, by which mitochondria talk to nuclear genes."

The realization that new inherited NUMTs are still being created made Picard and Mills wonder if NUMTs could also arise in brain cells during our lifespan.

"Inherited NUMTs are mostly benign, probably because they arise early in development and the harmful ones are weeded out," says Zhou. But if a piece of mitochondrial DNA inserts itself within a gene or regulatory region, it could have important consequences on that person's health or lifespan. Neurons may be particularly susceptible to damage caused by NUMTs because when a neuron is damaged, the brain does not usually make a new brain cell to take its place.

To examine the extent and impact of new NUMTs in the brain, the team worked with Hans Klein, assistant professor in the Center for Translational and Computational Neuroimmunology at Columbia, who had access to DNA sequences from participants in the ROSMAP aging study (led by David Bennett at Rush University). The researchers looked for NUMTs in different regions of the brain using banked tissue samples from more than 1,000 older adults.

Their analysis showed that nuclear mitochondrial DNA insertion happens in the human brain -- mostly in the prefrontal cortex -- and likely several times over during a person's lifespan.

They also found that people with more NUMTs in their prefrontal cortex died earlier than individuals with fewer NUMTs. "This suggests for the first time that NUMTs may have functional consequences and possibly influence lifespan," Picard says. "NUMT accumulation can be added to the list of genome instability mechanisms that may contribute to aging, functional decline, and lifespan."

Stress accelerates NUMTogenesis

What causes NUMTs in the brain, and why do some regions accumulate more than others?

To get some clues, the researchers looked at a population of human skin cells that can be cultured and aged in a dish over several months, enabling exceptional longitudinal "lifespan" studies.

These cultured cells gradually accumulated several NUMTs per month, and when the cells' mitochondria were dysfunctional from stress, the cells accumulated NUMTs four to five times more rapidly.

"This shows a new way by which stress can affect the biology of our cells," Karan says. "Stress makes mitochondria more likely to release pieces of their DNA and these pieces can then 'infect' the nuclear genome," Zhou adds. It's just one way mitochondria shape our health beyond energy production.

"Mitochondria are cellular processors and a mighty signaling platform," Picard says. "We knew they can control which genes are turned on or off. Now we know mitochondria can even change the nuclear DNA sequence itself."

Story Source:

Materials provided by Columbia University Irving Medical Center. Note: Content may be edited for style and length.

Journal Reference:

1. Weichen Zhou, Kalpita R. Karan, Wenjin Gu, Hans-Ulrich Klein, Gabriel Sturm, Philip L. De Jager, David A. Bennett, Michio Hirano, Martin Picard, Ryan E. Mills. Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts. PLOS Biology, 2024; 22 (8): e3002723 DOI: 10.1371/journal.pbio.3002723

Courtesy:

Columbia University Irving Medical Center. "Mitochondria are flinging their DNA into our brain cells." ScienceDaily. ScienceDaily, 22 August 2024. <www.sciencedaily.com/releases/2024/08/240822142624.htm>.

Researchers call for genetically diverse models to drive innovation in drug discovery

Researchers at The Jackson Laboratory (JAX) have unveiled a new approach to drug discovery that could revolutionize how we understand and treat diseases. Their recent commentary in the Aug.14 issue of Nature Biotechnology explains the limitations of studies using traditional mouse models and proposes using genetically diverse mice and mouse and human cells to better predict human responses to drugs and diseases.

For decades, scientists have relied on inbred mice to study human diseases and test new drugs. However, these mice often fail to accurately replicate human conditions, especially for complex diseases like cancer and diabetes. The FDA's recent decision to allow alternatives to animal testing through the Modernization Act 2.0 highlights the urgency of finding more reliable solutions.

JAX Mammalian Genetics Scientific Director Nadia Rosenthal, Ph.D., F.Med.Sci, and colleagues make a bold claim: it's not the mice that are the problem, but the lack of genetic diversity in the models used. Reliance on a single inbred strain can lead to inconsistent and often unreliable results, creating unnecessary obstacles to finding better therapies for a variety of diseases.

A new, more accurate approach

The researchers propose an integrative solution: combine the use of genetically diverse mouse models with cell-based assays to more accurately match data from mice and humans. This approach takes full advantage of the rich genetic resources already available in diverse mouse and human populations to create more accurate and relevant disease models.

"Using diverse mouse models has already shown remarkable improvements in mimicking human diseases," said Rosenthal. "This method could revolutionize our understanding of disease progression and patients' responses to different treatments."

Real-world impact

Studies using diverse mice have already provided valuable insights into diseases like heart disease, cancer, and diabetes. For example, recent research on chemotherapy side effects identified genetic factors that influence how patients respond to treatment, leading to more personalized and effective therapies for cancer patients. And heart attacks in humans can lead to variable severity and different kinds of damage to the heart, such as scarring or dilation, driven by complex genetics that a single inbred mouse strain is unable to replicate. A genetically diverse mouse panel showed a human-like variety of outcomes, however.

This new framework stresses the importance of combining mouse and human data. While human cell-based tests are useful, they often fall short in capturing the full complexity of human diseases. Cells from genetically diverse mouse models help fill this gap, ensuring that findings are directly applicable to real-world patients.

A call to action

The authors advocate for a new, balanced approach that respects ethical concerns while maximizing scientific benefits. They urge the community to embrace experimental designs that account for genetic diversity and environmental factors, moving away from standardized but limited mouse and cellular models. By combining the strengths of both in vitro and in vivo systems, researchers will be able to develop more effective, humane methods for studying human diseases and testing new treatments.

 

Journal Reference:

1. Martin Pera, Andy Greene, Lon Cardon, Gregory W. Carter, Elissa J. Chesler, Gary Churchill, Vivek Kumar, Cathleen Lutz, Steven Munger, Steve Murray, Kristen O’Connell, Laura Reinholdt, Nadia A. Rosenthal. Improving the predictive power of mouse models. Nature Biotechnology, 2024; 42 (8): 1175 DOI: 10.1038/s41587-024-02349-2 

Source:

Jackson Laboratory. "Researchers call for genetically diverse models to drive innovation in drug discovery." ScienceDaily. ScienceDaily, 14 August 2024. <www.sciencedaily.com/releases/2024/08/240814124440.htm>.

 

 

 

 

Memory loss in aging and dementia: Dendritic spine head diameter predicts memory in old age : This finding suggests that therapy to remodel synapses could help memory in old age and dementia patients.

Over the course of life, memory fades with varying degrees, robbing older people of the ability to recollect personal experiences. This progressive, nearly inevitable process has long been hypothesized as a consequence of nature's removal of dendritic spines, a key component of synapses, from brain neurons as they age.

A study published in Science Advances led by researchers at the University of Alabama at Birmingham and Rush University Medical Center, Chicago, Illinois, now provides evidence that the preservation of past life experiences is maintained by the quality -- not the quantity -- of synapses in old age.

"This is a paradigm breaker," said Jeremy Herskowitz, Ph.D., associate professor in the UAB Department of Neurology and corresponding author of the study. "For 35 years, the predominant dogma was that memory decline is mediated predominantly by loss of dendritic spine, which are a surrogate for synapses. As we age from 40 through 85, there is natural loss of dendritic spines and synapses, which is completely normal. This natural loss can contribute to the lack of cognitive sharpness that we all feel as we age. However, we demonstrate that, even though there is synapse loss, the ones that are left can compensate for that loss."

Herskowitz says this has an enormous implication. "Even in older individuals, people age 80, 90 or 95, there is still enough plasticity in synapse formation to retain memory. This means a therapy to remodel dendritic spines and synapses could dramatically facilitate memory as you age or if you are experiencing memory impairment due to Alzheimer's disease dementia."

The study was made possible by the Religious Orders Study and Rush Memory and Aging Project, or ROSMAP, at Rush University. ROSMAP enrolls Catholic nuns, priests and brothers age 65 or older, who are without known dementia at time of enrollment. Participants receive medical and psychological evaluations each year and agree to donate their brains after death.

Herskowitz and colleagues studied postmortem brain samples from 128 ROSMAP participants. The participants had an average age of 90.5 years at the time of death, with variable cognitive performance scores and Alzheimer's disease-related neuropathology. They all had undergone yearly cognitive testing for episodic memory, visuospatial ability/perceptual orientation, perceptual speed, semantic memory, and working memory. The study included two samples from each brain, one from the temporal cortex, which has structures vital for long-term memory, and one from the frontal premotor cortex.

After staining the brain samples, photographing thin slices and building three-dimensional digital reconstructions of 55,521 individual dendritic spines on 2,157 neurons, researchers used two statistical methods, one employing innovative machine learning, to see if any of 16 different spine morphology measurements correlated with any of 17 different measures of brain function, age and Alzheimer's disease neuropathology. One of the brain function measures was episodic memory -- the ability to remember everyday events and past personal experiences.

For neurons from the temporal cortex, researchers found that dendritic spine head diameter, but not the quantity of spines, improved prediction of episodic memory in models containing β-amyloid plaque scores, neurofibrillary tangle pathology and sex. Larger head diameters were associated with better episodic memory performance, supporting the emerging hypothesis that, in the temporal cortex, synaptic strength is more critical than quantity for memory in old age.

"Targeting pathways that maintain spine head diameter or synaptic strength, rather than pathways that maintain or generate new spines or synapses, could potentially yield greater therapeutic benefits for older adults in preclinical phases of Alzheimer's disease," Herskowitz said.

A dendrite is a branched extension from a neuron body that receives impulses from other neurons. Each dendrite can have thousands of small protrusions called spines. The head of each spine can form a contact point called a synapse to receive an impulse sent from the axon of another neuron. Dendritic spines can rapidly change shape or volume while forming new synapses, part of the process called brain plasticity. Creating or eliminating synapses is a fundamental mechanism of brain function.

Collecting the tens of thousands of spine measurements took two and a half years. This painstaking work started in 2019 and continued through the COVID-19 pandemic, as UAB researchers worked under COVID restrictions, Herskowitz says.

Co-first authors of the study, "Dendritic spine head diameter predicts episodic memory performance in older adults," are Courtney K. Walker and Evan Liu, UAB Department of Neurology.

Other authors are Kelsey M. Greathouse, Ashley B. Adamson, Julia P. Wilson, Emily H. Poovey, Kendall A. Curtis, Hamad M. Muhammad and Audrey J. Weber, UAB Department of Neurology; David A. Bennett, Rush University Medical Center; Nicholas T. Seyfried, Emory University School of Medicine; and Christopher Gaiteri, SUNY Upstate Medical University, Syracuse, New York.

Support came from National Institutes of Health grants NS061788, AG067635, AG061800, AG054719, AG063755, AG068024, AG10161, AG72975, AG15819, AG17917, AG46152 and AG61356.

At UAB, Neurology is a department in the Marnix E. Heersink School of Medicine.

Journal Reference:

1. Courtney K. Walker, Evan Liu, Kelsey M. Greathouse, Ashley B. Adamson, Julia P. Wilson, Emily H. Poovey, Kendall A. Curtis, Hamad M. Muhammad, Audrey J. Weber, David A. Bennett, Nicholas T. Seyfried, Christopher Gaiteri, Jeremy H. Herskowitz. Dendritic spine head diameter predicts episodic memory performance in older adults. Science Advances, 2024; 10 (32) DOI: 10.1126/sciadv.adn5181

Source: 

University of Alabama at Birmingham. "Memory loss in aging and dementia: Dendritic spine head diameter predicts memory in old age." ScienceDaily. ScienceDaily, 7 August 2024. <www.sciencedaily.com/releases/2024/08/240807225459.htm>.

New biomaterial regrows damaged cartilage in joints: A crucial component in joints, cartilage is notoriously difficult to repair

Northwestern University scientists have developed a new bioactive material that successfully regenerated high-quality cartilage in the knee joints of a large-animal model.

Although it looks like a rubbery goo, the material is actually a complex network of molecular components, which work together to mimic cartilage's natural environment in the body.

In the new study, the researchers applied the material to damaged cartilage in the animals' knee joints. Within just six months, the researchers observed evidence of enhanced repair, including the growth of new cartilage containing the natural biopolymers (collagen II and proteoglycans), which enable pain-free mechanical resilience in joints.

With more work, the researchers say the new material someday could potentially be used to prevent full knee replacement surgeries, treat degenerative diseases like osteoarthritis and repair sports-related injuries like ACL tears.

The study will be published in the Proceedings of the National Academy of Sciences.

"Cartilage is a critical component in our joints," said Northwestern's Samuel I. Stupp, who led the study. "When cartilage becomes damaged or breaks down over time, it can have a great impact on people's overall health and mobility. The problem is that, in adult humans, cartilage does not have an inherent ability to heal. Our new therapy can induce repair in a tissue that does not naturally regenerate. We think our treatment could help address a serious, unmet clinical need."

A pioneer of regenerative nanomedicine, Stupp is Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern, where he is founding director of the Simpson Querrey Institute for BioNanotechnology and its affiliated center, the Center for Regenerative Nanomedicine. Stupp has appointments in the McCormick School of Engineering, Weinberg College of Arts and Sciences and Feinberg School of Medicine. Jacob Lewis, a former Ph.D. student in Stupp's laboratory, is the paper's first author.

What's in the material?

The new study follows recently published work from the Stupp laboratory, in which the team used "dancing molecules" to activate human cartilage cells to boost the production of proteins that build the tissue matrix. Instead of using dancing molecules, the new study evaluates a hybrid biomaterial also developed in Stupp's lab. The new biomaterial comprises two components: a bioactive peptide that binds to transforming growth factor beta-1 (TGFb-1) -- an essential protein for cartilage growth and maintenance -- and modified hyaluronic acid, a natural polysaccharide present in cartilage and the lubricating synovial fluid in joints.

"Many people are familiar with hyaluronic acid because it's a popular ingredient in skincare products," Stupp said. "It's also naturally found in many tissues throughout the human body, including the joints and brain. We chose it because it resembles the natural polymers found in cartilage."

Stupp's team integrated the bioactive peptide and chemically modified hyaluronic acid particles to drive the self-organization of nanoscale fibers into bundles that mimic the natural architecture of cartilage. The goal was to create an attractive scaffold for the body's own cells to regenerate cartilage tissue. Using bioactive signals in the nanoscale fibers, the material encourages cartilage repair by the cells, which populate the scaffold.

Clinically relevant to humans

To evaluate the material's effectiveness in promoting cartilage growth, the researchers tested it in sheep with cartilage defects in the stifle joint, a complex joint in the hind limbs similar to the human knee. This work was carried out in the laboratory of Mark Markel in the School of Veterinary Medicine at the University of Wisconsin-Madison.

According to Stupp, testing in a sheep model was vital. Much like humans, sheep cartilage is stubborn and incredibly difficult to regenerate. Sheep stifles and human knees also have similarities in weight bearing, size and mechanical loads.

"A study on a sheep model is more predictive of how the treatment will work in humans," Stupp said. "In other smaller animals, cartilage regeneration occurs much more readily."

In the study, researchers injected the thick, paste-like material into cartilage defects, where it transformed into a rubbery matrix. Not only did new cartilage grow to fill the defect as the scaffold degraded, but the repaired tissue was consistently higher quality compared to the control.

A lasting solution

In the future, Stupp imagines the new material could be applied to joints during open-joint or arthroscopic surgeries. The current standard of care is microfracture surgery, during which surgeons create tiny fractures in the underlying bone to induce new cartilage growth.

"The main issue with the microfracture approach is that it often results in the formation of fibrocartilage -- the same cartilage in our ears -- as opposed to hyaline cartilage, which is the one we need to have functional joints," Stupp said. "By regenerating hyaline cartilage, our approach should be more resistant to wear and tear, fixing the problem of poor mobility and joint pain for the long term while also avoiding the need for joint reconstruction with large pieces of hardware."

The study, "A bioactive supramolecular and covalent polymer scaffold for cartilage repair in a sheep model," was supported by the Mike and Mary Sue Shannon Family Fund for Bio-Inspired and Bioactive Materials Systems for Musculoskeletal Regeneration.

Journal Reference:

1. Jacob A. Lewis, Brett Nemke, Yan Lu, Nicholas A. Sather, Mark T. McClendon, Michael Mullen, Shelby C. Yuan, Sudheer K. Ravuri, Jason A. Bleedorn, Marc J. Philippon, Johnny Huard, Mark D. Markel, Samuel I. Stupp. A bioactive supramolecular and covalent polymer scaffold for cartilage repair in a sheep model. Proceedings of the National Academy of Sciences, 2024; 121 (33) DOI: 10.1073/pnas.2405454121

Source:

Northwestern University. "New biomaterial regrows damaged cartilage in joints." ScienceDaily. ScienceDaily, 5 August 2024. <www.sciencedaily.com/releases/2024/08/240805164407.htm>.

Glimpse into the nanoworld: Microscope reveals tiniest cell processes Research team develops high-resolution fluorescence microscope

 What does the inside of a cell really look like? In the past, standard microscopes were limited in how well they could answer this question. Now, researchers from the Universities of Göttingen and Oxford, in collaboration with the University Medical Center Göttingen (UMG), have succeeded in developing a microscope with resolutions better than five nanometres (five billionths of a metre). This is roughly equivalent to the width of a hair split into 10,000 strands. Their new method was published in Nature Photonics.

Many structures in cells are so small that standard microscopes can only produce fragmented images.

Their resolution only begins at around 200 nanometres. However, human cells for instance contain a kind of scaffold of fine tubes that are only around seven nanometres wide.

The synaptic cleft, meaning the distance between two nerve cells or between a nerve cell and a muscle cell, is just 10 to 50 nanometres -- too small for conventional microscopes.

The new microscope, which researchers at the University of Göttingen have helped to develop, promises much richer information.

It benefits from a resolution better than five nanometres, enabling it to capture even the tiniest cell structures.

It is difficult to imagine something so tiny, but if we were to compare one nanometre with one metre, it would be the equivalent of comparing the diameter of a hazelnut with the diameter of the Earth.

This type of microscope is known as a fluorescence microscope.

Their function relies on "single-molecule localization microscopy," in which individual fluorescent molecules in a sample are switched on and off and their individual positions are then determined very precisely.

The entire structure of the sample can then be modelled from the positions of these molecules.

The current process enables resolutions of around 10 to 20 nanometres.

Professor Jörg Enderlein's research group at the University of Göttingen's Faculty of Physics has now been able to double this resolution again -- with the help of a highly sensitive detector and special data analysis.

This means that even the tiniest details of protein organization in the connecting area between two nerve cells can be very precisely revealed.

"This newly developed technology is a milestone in the field of high-resolution microscopy. It not only offers resolutions in the single-digit nanometre range, but it is also particularly cost-effective and easy to use compared to other methods," explains Enderlein. The scientists also developed an open-source software package for data processing in the course of publishing their findings. This means that this type of microscopy will be available to a wide range of specialists in the future.

Journal Reference:

1. Niels Radmacher, Oleksii Nevskyi, José Ignacio Gallea, Jan Christoph Thiele, Ingo Gregor, Silvio O. Rizzoli, Jörg Enderlein. Doubling the resolution of fluorescence-lifetime single-molecule localization microscopy with image scanning microscopy. Nature Photonics, 2024; DOI: 10.1038/s41566-024-01481-4

Source: University of Göttingen. "Glimpse into the nanoworld: Microscope reveals tiniest cell processes." ScienceDaily. ScienceDaily, 7 August 2024. <www.sciencedaily.com/releases/2024/08/240807225708.htm>.

IGNTU Neuroscience Project Scientist Post