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Comment by Dr. Krishna Kumari Challa on December 30, 2024 at 9:25am

The researchers looked at how CRISPR sequences changed over time in two different datasets obtained by sequencing microbes from the human digestive tract. One of these datasets contained 6,275 genomic sequences representing 52 bacterial species, and the other contained 388 longitudinal "metagenomes," that is, sequences from many microbes found in a sample, taken from four healthy people.
By analyzing those two datasets, the researchers found out that spacer acquisition is really slow in human gut microbiome: On average, it would take 2.7 to 2.9 years for a bacterial species to acquire a single spacer in our gut, which is super surprising because our gut is challenged with viruses almost every day from the microbiome itself and in our food.
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The researchers then built a computational model to help them figure out why the acquisition rate was so slow. This analysis showed that spacers are acquired more rapidly when bacteria live in high-density populations. However, the human digestive tract is diluted several times a day, whenever a meal is consumed. This flushes out some bacteria and viruses and keeps the overall density low, making it less likely that the microbes will encounter a virus that can infect them.
Another factor may be the spatial distribution of microbes, which the researchers think prevents some bacteria from encountering viruses very frequently.

Sometimes one population of bacteria may never or rarely encounter a phage because the bacteria are closer to the epithelium in the mucus layer and farther away from a potential exposure to viruses.
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Among the populations of bacteria that they studied, the researchers identified one species—Bifidobacteria longum—that had gained spacers much more recently than others. The researchers found that in samples from unrelated people, living on different continents, B. longum had recently acquired up to six different spacers targeting two different Bifidobacteria bacteriophages.
This acquisition was driven by horizontal gene transfer—a process that allows bacteria to gain new genetic material from their neighbors. The findings suggest that there may be evolutionary pressure on B. longum from those two viruses.
Analyzing microbes' immune defenses may offer a way for scientists to develop targeted treatments that will be most effective in a particular patient, the researchers say. For example, they could design therapeutic microbes that are able to fend off the types of bacteriophages that are most prevalent in that person's microbiome, which would increase the chances that the treatment would succeed.

An-Ni Zhang et al. CRISPR-Cas spacer acquisition is a rare event in human gut microbiome, Cell Genomics (2024). DOI: 10.1016/j.xgen.2024.100725. www.cell.com/cell-genomics/ful … 2666-979X(24)00354-9

Part 2

Comment by Dr. Krishna Kumari Challa on December 30, 2024 at 9:20am

 Bacteria in human gut rarely update their CRISPR defense systems

Within the human digestive tract are trillions of bacteria from thousands of different species. These bacteria form communities that help digest food, fend off harmful microbes, and play many other roles in maintaining human health.

These bacteria can be vulnerable to infection from viruses called bacteriophages. One of bacterial cells' most well-known defenses against these viruses is the CRISPR system, which evolved in bacteria to help them recognize and chop up viral DNA.

A new study  has yielded new insight into how bacteria in the gut microbiome adapt their CRISPR defenses as they encounter new threats. The researchers found that while bacteria grown in the lab can incorporate new viral recognition sequences as quickly as once a day, bacteria living in human gut add new sequences at a much slower rate—on average, one every three years.

The findings suggest that the environment within the digestive tract offers many fewer opportunities for bacteria and bacteriophages to interact than in the lab, so bacteria don't need to update their CRISPR defenses very often. It also raises the question of whether bacteria have more important defense systems than CRISPR.

This finding is significant because we use microbiome-based therapies like fecal microbiota transplant to help treat some diseases, but efficacy is inconsistent because new microbes do not always survive in patients. Learning about microbial defenses against viruses helps us to understand what makes a strong, healthy microbial community.

In bacteria, CRISPR serves as a memory immune response. When bacteria encounter viral DNA, they can incorporate part of the sequence into their own DNA. Then, if the virus is encountered again, that sequence produces a guide RNA that directs an enzyme called Cas9 to snip the viral DNA, preventing infection.

These virus-specific sequences are called spacers, and a single bacterial cell may carry more than 200 spacers. These sequences can be passed onto offspring, and they can also be shared with other bacterial cells through a process called horizontal gene transfer.

Previous studies have found that spacer acquisition occurs very rapidly in the lab, but the process appears to be slower in natural environments.

Part 1

Comment by Dr. Krishna Kumari Challa on December 28, 2024 at 12:40pm

The researchers quickly homed in on a gene called H2-Aa. Mice carrying two mutated copies of this gene, causing them to completely lack the H2-Aa protein, often showed no tumor growth after exposure to melanoma cells. Those carrying one mutant copy had significantly reduced growth compared with mice carrying strictly the "wild type" form of the gene. H2-Aa is responsible for producing part of an immune protein called MHC class II, which helps the immune system distinguish self-proteins from non-self-proteins, readying it to attack potential invaders.
Using genetic engineering, the researchers narrowed H2-Aa's cancer-supporting function to its presence on the surface of a subclass of immune cells called dendritic cells. Eliminating H2-Aa in only these cells was enough to mimic having the absence of H2-Aa throughout the body. When the researchers compared tumors that developed in wild-type mice and those in mice lacking H2-Aa, the tumors in mutant mice were infiltrated with more dendritic cells as well as more tumor-fighting CD8 T cells, and far fewer regulatory T cells that suppress anticancer immune activity.

Seeking a pharmaceutical that could produce the same effects as mutant H2-Aa, the researchers developed a monoclonal antibody—a protein that blocks the effects of other proteins—against H2-Aa. Although the antibody had a considerable anticancer effect when delivered to mice with melanoma tumors, its effect was greatly enhanced when the researchers also treated the same mice with a checkpoint inhibitor drug, a type of immunotherapy. On the other hand, without monoclonal antibodies against H2-Aa, checkpoint inhibitors had no effect on cancer growth.
Monoclonal antibodies targeting the human form of this and other closely related proteins could have a similar effect, serving as a viable cancer treatment on its own or as a boost to immunotherapy treatments. This idea might eventually be tested in clinical trials.

Hexin Shi et al, Suppression of melanoma by mice lacking MHC-II: Mechanisms and implications for cancer immunotherapy, Journal of Experimental Medicine (2024). DOI: 10.1084/jem.20240797

Part 2

Comment by Dr. Krishna Kumari Challa on December 28, 2024 at 12:38pm

New genetic mutation found to suppress cancer growth

 Researchers have identified a genetic mutation that slows the growth of melanoma and potentially other cancers by harnessing the power of the immune system. Their findings, published in the Journal of Experimental Medicine, could lead to new treatments that improve outcomes from existing cancer immunotherapies.

Researchers have identified many genes, known as oncogenes, that initiate and drive cancer when mutated. Although scientists have long speculated that mutations protecting against cancer also exist in the human genome but finding them by studying human subjects has been difficult because people carrying these genetic variants don't show any obvious differences compared to others.

To search for genes that confer tumor resistance, researchers created mouse models with various genetic mutations and then searched for mice that didn't develop tumors or had limited cancer growth. Next, they used a method recently developed  called automated meiotic mapping (AMM), which traces unusual features of interest in mutant mice to the causative mutations.

Part 1

Comment by Dr. Krishna Kumari Challa on December 27, 2024 at 12:07pm

Applying short-term interventions with drugs that clear senescent cells, including venetoclax, navitoclax, fisetin and luteolin, as well as transgenic clearance methods targeting p16-positive senescent cells, mice were examined for changes in plasma proteins and tissue transcripts.

Analyses showed that three of the tested plasma proteins, IL-23R, CCL5 and CA13, displayed age-related alterations in circulation and tissues, indicating potential biomarker marker viability.

Age-dependent increases in IL-23R and CCL5 were reversed by senolytic treatment, and CA13 levels, which normally decline with age, were restored to more youthful levels.

Researchers identified IL-23R as the most promising plasma protein biomarker due to its obvious and consistent association with aging across multiple tissue parameters. IL-23R increased with age in both mice and humans and had a robust change response to senolytic interventions.

The strong correlation between IL-23R and other well-defined senescence tissue markers makes it a potential reliable biomarker of systemic senescent cell burden, offering an important new tool for probing and possibly preventing age-related diseases.

Chase M. Carver et al, IL-23R is a senescence-linked circulating and tissue biomarker of aging, Nature Aging (2024). DOI: 10.1038/s43587-024-00752-7

Part 2

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Comment by Dr. Krishna Kumari Challa on December 27, 2024 at 12:06pm

Novel biomarker catches aging cells in the act

Researchers have identified interleukin-23 receptor (IL-23R) as a significant biomarker of cellular senescence and aging in both mice and humans. Experiments show that IL-23R levels in the bloodstream increase with age and can decrease, reflecting senescent cell clearing, with senolytic therapies.

Cellular senescence occurs when cells stop dividing but do not trigger apoptosis mechanisms that would allow them to die naturally. Instead, they are stuck in a zombie-like state, where they still have the urge to feed and carry out metabolic activities, but with increasingly incoherent cell signaling and increased pro-inflammatory cytokine secretions.

Senescent cell activity has been linked to several age-related diseases, including those of the immune, cardiovascular, metabolic, pulmonary, musculoskeletal and neurological systems.
Scientists have been searching for a biomarker that reliably estimates the levels of active senescent cells in the body. If found, this biomarker could inform clinical interventions, potentially intervening before disease conditions present themselves.

In the study "IL-23R is a senescence-linked circulating and tissue biomarker of aging," published in Nature Aging, researchers sought to identify senescence-related biomarkers and measure their responsiveness to different therapeutics in mice of various ages.

The team tested 92 plasma proteins through the Olink Target 96 Mouse Exploratory panel and ultimately analyzed 67 (25 were excluded due to low or no detection).

Tissues, including kidney, liver, spleen, cerebral cortex, adipose and lung, were examined with real-time PCR for 21 gene expressions related to senescence secretions and inflammation markers.
Part 1

Comment by Dr. Krishna Kumari Challa on December 26, 2024 at 1:34pm

The Risk of Cancer Fades as We Get Older

Aging brings two opposing trends in cancer risk: first, the risk climbs in our 60s and 70s, as decades of genetic mutations build up in our bodies. But then, past the age of around 80, the risk drops again – and a new study may explain a key reason why.

The international team of scientists behind the study analyzed lung cancer in mice, tracking the behavior of alveolar type 2 (AT2) stem cells. These cells are crucial for lung regeneration, and are also where many lung cancers get started.

What emerged was higher levels of a protein called NUPR1 in the older mice. This caused cells to act as if they were deficient in iron, which in turn limited their regeneration rates – putting restrictions on both healthy growth and cancerous tumors.

The aging cells actually have more iron, but for reasons we don't yet fully understand, they function like they don't have enough. Aging cells lose their capacity for renewal and therefore for the runaway growth that happens in cancer.

The same processes were found to be happening in human cells too: more NUPR1 leads to a drop in the amount of iron available to cells. When NUPR1 was artificially lowered or iron was artificially increased, cell growth capabilities were boosted again.

That potentially gives researchers a way of exploring treatments that target iron metabolism – especially in older people. 

These findings also have implications for cancer treatments based on a type of cell death called ferroptosis, which is triggered by iron. This cell death is less common in older cells, the researchers found, because of their functional iron deficiency.

This perhaps also makes them more resistant to cancer treatments based on ferroptosis that are in development– so the earlier a ferroptosis treatment can be tried, the better it's likely to work.

https://www.nature.com/articles/s41586-024-08285-0

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Comment by Dr. Krishna Kumari Challa on December 26, 2024 at 10:26am

Scientists discover a 'Goldilocks' zone for DNA organization, opening new doors for drug development

In a discovery that could redefine how we understand cellular resilience and adaptability, scientists  have unlocked the secret interactions between a primordial inorganic polymer of phosphate known as polyphosphate (polyP), and two basic building blocks of life: DNA and the element magnesium. These components formed clusters of tiny liquid droplets–also known as condensates–with flexible and adaptable structures.

PolyP and magnesium are involved in many biological processes. Thus, the findings could lead to new methods for tuning cellular responses, which could have impactful applications in translational medicine.

The ensuing study, published in Nature Communications on October 26, 2024, reveals a delicate "Goldilocks" zone—a specific magnesium concentration range—where DNA wraps around polyP-magnesium ion condensates. Similar to a thin eggshell covering a liquid-like interior, this seemingly simple structure may help cells organize and protect their genetic material.

The microscopy images revealed that DNA wraps itself around a condensate, creating a thin eggshell-like barrier. This shell could affect molecule transportation and also slow down fusion: the process where two condensates merge into one. Without DNA shells, polyP-magnesium ion condensates readily fused—like how oil drops and vinegar fuse in a salad dressing bottle when shaken. However, careful examination showed that fusion overall slowed to varying extents, depending on DNA length. Longer DNA, the researchers suspected, caused greater entanglement on condensate surfaces—similar to how long hair tangles more than short hair.

Another crucial discovery: DNA shell formation only occurred within a specific magnesium concentration range—too much or too little, and the shell wouldn't materialize. This "Goldilocks" effect highlights how cells can regulate condensate structure, size and function simply by tuning control parameters.

 Ravi Chawla et al, Reentrant DNA shells tune polyphosphate condensate size, Nature Communications (2024). DOI: 10.1038/s41467-024-53469-x

Comment by Dr. Krishna Kumari Challa on December 26, 2024 at 10:03am

From Earth to alien worlds: The fundamental limits to life

Extraterrestrial and artificial life have long captivated the human mind. Knowing only the building blocks of our own biosphere, can we predict how life may exist on other planets? What factors will rein in the Frankensteinian life forms we hope to build in laboratories here on Earth?

An open-access paper published in Interface Focus and co-authored by several SFI researchers takes these questions out of the realm of science fiction and into scientific laws.

Reviewing case studies from thermodynamics, computation, genetics, cellular development, brain science , ecology and evolution, the paper concludes that certain fundamental limits prevent some forms of life from ever existing.

Requirements include entropy reduction (which includes, for instance, the ability to heal and repair), closed-compartment cells as the inevitable units of life, and a system—such as brains—that integrates information and makes decisions using neuron-like units.

The authors point to historical examples where people predicted some complex feature of life that biologists later confirmed. Examples include the Schrodinger view of information molecules as "aperiodic crystals," or mid-century simulations predicting that parasites are inevitable when complex life evolves.

That such correct predictions were possible with almost no available evidence suggests all living systems follow an underlying universal logic.

 Ricard Solé et al, Fundamental constraints to the logic of living systems, Interface Focus (2024). DOI: 10.1098/rsfs.2024.0010

Comment by Dr. Krishna Kumari Challa on December 26, 2024 at 9:56am

Gold is present in Earth's mantle above the subducting ocean plate. But when the conditions are just right that a fluid containing the trisulfur ion is added from the subducting plate to the mantle, gold strongly prefers to bond with trisulfur to form a gold-trisulfur complex. This complex is highly mobile in magma.

Scientists have previously known that gold complexes with various sulfur ions, but this study is the first to present a robust thermodynamic model for the existence and importance of the gold-trisulfur complex.

To identify this new complex, the researchers developed a thermodynamic model based on lab experiments in which the researchers control pressure and temperature of the experiment, then measure the results of the experiment. Then, the researchers developed a thermodynamic model that predicts the results of the experiment. This thermodynamic model can then be applied to real-world conditions.

These results provide a really robust understanding of what causes certain subduction zones to produce very gold-rich ore deposits.

Deng-Yang He et al, Mantle oxidation by sulfur drives the formation of giant gold deposits in subduction zones, Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2404731121

Part 2

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