Comment

Comment by Dr. Krishna Kumari Challa 10 hours ago

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 10 hours ago

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 yesterday

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 yesterday

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 yesterday

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 yesterday

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

Comment by Dr. Krishna Kumari Challa yesterday

How gold reaches Earth's surface

A research team has discovered a new gold-sulfur complex that helps researchers understand how gold deposits are formed.

Gold in ore deposits associated with volcanoes around the Pacific Ring of Fire originates in Earth's mantle and is transported by magma to its surface. But how that gold is brought to the surface has been a subject of debate. Now, the research team has used numerical modeling to reveal the specific conditions that lead to the enrichment of gold in magmas that rise from the Earth's mantle to its surface.

Specifically, the model reveals the importance of a gold-trisulfur complex whose existence has been vigorously debated.

The presence of this gold-trisulfur complex under a very specific set of pressures and temperatures in the mantle 30 to 50 miles beneath active volcanoes causes gold to be transferred from the mantle into magmas that eventually move to the Earth's surface. The team's results are published in the Proceedings of the National Academy of Sciences.

This offers the most plausible explanation for the very high concentrations of gold in some mineral systems in subduction zone environments.

Gold deposits associated with volcanoes form in what are called subduction zones. Subduction zones are regions where a continental plate—the Pacific plate, which lies under the Pacific Ocean—is diving under the continental plates that surround it. In these seams where continental plates meet each other, magma from Earth's mantle has the opportunity to rise to the surface.

On all of the continents around the Pacific Ocean, from New Zealand to Indonesia, the Philippines, Japan, Russia, Alaska, the western United States and Canada, all the way down to Chile, we have lots of active volcanoes. All of those active volcanoes form over or in a subduction zone environment. The same types of processes that result in volcanic eruptions are processes that form gold deposits.

Part 1

Comment by Dr. Krishna Kumari Challa on Tuesday

Unclogging the immune system: Scientists use immunotherapy to remove aging cell buildup

 As we age, our bodies are flooded by aging, or senescent cells, which have stopped dividing but, instead of dying, remain active and build up in body tissues. Recent studies have shown that getting rid of these cells might delay age-related diseases, reduce inflammation and extend lives. Despite the great potential, however, there is currently no drug that can target these cells directly and efficiently.

researchers suggest an alternative approach. In a new study published in Nature Cell Biology, they reveal that senescent cells  build up in the body by clogging up the immune system, thereby preventing their own removal.

The scientists demonstrated in mice how to unclog this blockage using immunotherapy, the new generation of treatments that is revolutionizing cancer therapy.  These findings could pave the way for innovative treatment of age-related diseases and other chronic disorders.

Julia Majewska et al, p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells, Nature Cell Biology (2024). DOI: 10.1038/s41556-024-01465-0

Comment by Dr. Krishna Kumari Challa on Tuesday

Salt-seeking behavior traced to specific brain neurons

Salt, or more precisely the sodium it contains, is very much a "Goldilocks" nutrient. Low sodium levels cause a drop in blood volume, which can have serious, sometimes deadly, health consequences. Conversely, too much salt can lead to high blood pressure and cardiovascular disease.

Given the critical importance of sodium for body and brain functions, evolution has developed a powerful drive to consume salt in situations where there is a deficiency.

Aldosterone triggers salt-appetite neurons.

Researchers made their discovery by teasing out the actions of aldosterone, a key hormone for controlling sodium levels.

Normally, aldosterone is produced when body fluid volume (including blood volume) is low, for example, after sweating without drinking enough fluid, or blood loss, or during an illness with vomiting or diarrhea. Aldosterone tells the kidney and other organs to retain sodium, which helps maintain the existing fluid in the body.

However, when aldosterone is inappropriately high, a condition called primary aldosteronism, blood pressure can rise to dangerous levels. Aldosteronism is the cause of hypertension in as many as 10-30% of all patients with high blood pressure, and the risk of stroke, heart failure, and abnormal heart rhythms is three times higher in these patients than in other patients with hypertension, although it is not clear why.

The research team focused on an unappreciated aspect of aldosteronism—a tendency to eat more salt. Almost a century ago, studies showed that aldosterone and related hormones cause salt appetite to go up in rats. More recent human studies have also found that patients with aldosteronism consume more salt than other patients with hypertension.

The team first confirmed that lack of sodium in the diet of mice increases aldosterone production and salt intake. It also increases the activity of a tiny group of neurons in the brainstem known as HSD2 neurons. The researchers had previously discovered these HSD2 neurons and had circumstantial evidence suggesting they were responsible for salt appetite.

Researchers used genetically targeted cell deletion to show that the HSD2 neurons were required for aldosterone-driven salt consumption. Moreover, they showed that humans also have a small population of HSD2 neurons in the same part of the brainstem, indicating that the same neural circuit may be relevant to people with elevated aldosterone.

Overall, the findings suggest that aldosterone acts on the tiny population of HSD2 neurons (there are roughly 200 HSD2 neurons in mice and 1,000 in humans) to induce the highly specific behavior of seeking and consuming sodium. The team's findings suggest that boosting sodium appetite may be the only central function of HSD2 neurons.

Silvia Gasparini et al, Aldosterone-induced salt appetite requires HSD2 neurons, JCI Insight (2024). DOI: 10.1172/jci.insight.175087

Comment by Dr. Krishna Kumari Challa on Tuesday

Perceptein, a protein-based artificial neural network in living cells

Researchers have designed a protein-based system inside living cells that can process multiple signals and make decisions based on them.

The researchers have also introduced a unique term, "perceptein," as a combination of protein and perceptron. Perceptron is a foundational artificial neural network concept, effectively solving binary classification problems by mapping input features to an output decision.

By merging concepts from neural network theory with protein engineering, "perceptein" represents a biological system capable of performing classification computations at the protein level, similar to a basic artificial neural network. This "perceptein" circuit can classify different signals and respond accordingly, such as deciding to stay alive or undergo programmed cell death.

In the study, "A synthetic protein-level neural network in mammalian cells," published in Science, researchers showed that perceptein circuits could distinguish signal inputs with tunable decision boundaries, offering the possibility of controlling complex cellular responses without transcriptional regulation.

 Zibo Chen et al, A synthetic protein-level neural network in mammalian cells, Science (2024). DOI: 10.1126/science.add8468

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