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Comment by Dr. Krishna Kumari Challa yesterday

Depriving mice of iron can increase the chance of intersex offspring

Iron deficiency in pregnant mice may lead to the development of ovaries in a small proportion of offspring carrying XY chromosomes, which typically determine male sex. The findings, published in Nature this week, reveal a link between iron metabolism and sex determination in mammals.

A key gene responsible for male sex determination in mammals is Sry, which controls the development of the testes and is found on the Y chromosome. An enzyme called KDM3A that is essential for regulating Sry gene expression is known to rely on Fe²⁺ for its activity. However, how iron levels may influence sex determination remains unclear.

To explore the potential connection between iron metabolism and sex determination in mammals,  researchers conducted a series of experiments using cultured cells and mice. They found that genes favoring accumulation of Fe²⁺ are upregulated in developing mouse embryonic gonads during the crucial period of sex determination.

When the researchers reduced iron levels in cultured cells to approximately 40% of normal levels, expression of the Sry gene was largely suppressed, and the XY gonads began to show genetic markers associated with ovary development.

The researchers then tested the effects of both short-term and long-term iron deficiency in pregnant mice. Short-term iron deficiency was induced by administering an iron-removing drug to pregnant mice for about five days around the time of embryonic sex determination. Among 72 XY offspring born to these mothers, four developed two ovaries and one developed an ovary and a testis. Long-term iron deficiency was induced through a low-iron diet starting four weeks before pregnancy and continuing for six weeks.

This long-term low-iron diet showed no effect on sex determination until a loss-of-function mutation in the gene that encodes KDM3A was introduced in the mothers. This resulted in male-to-female sex reversal in two of 43 XY offspring. No abnormalities were observed in offspring born to mothers with normal iron levels in either of the experiments.

The findings demonstrate a key role of iron in mammalian sex determination, although the effects of iron deficiency on human pregnancies were not investigated.

 Makoto Tachibana, Maternal iron deficiency causes male-to-female sex reversal in mouse embryos, Nature (2025). DOI: 10.1038/s41586-025-09063-2. www.nature.com/articles/s41586-025-09063-2

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Comment by Dr. Krishna Kumari Challa yesterday

In animal experiments with SARS‑CoV‑2‑infected hamsters, phenformin significantly reduced the viral load in the respiratory tract. In cell cultures, phenformin also inhibited the multiplication of dengue viruses, for which there is currently no approved treatment.

Extensive clinical studies on the use of phenformin as an antidiabetic agent have already established its safety in humans. Further clinical studies are needed to determine if phenformin has an antiviral effect in humans. In contrast, atpenin A5 is an experimental substance that demonstrates the feasibility of the methodological approach in cell culture.

Further studies must be conducted to determine whether variants of the substance can be used in animal models where they are both tolerated and have an antiviral effect.

According to the scientists, the developed methods and identified drug candidates are an important step in the rapid development of potential treatments for future pandemics.

Alina Renz et al, Metabolic modeling elucidates phenformin and atpenin A5 as broad-spectrum antiviral drugs against RNA viruses, Communications Biology (2025). DOI: 10.1038/s42003-025-08148-y

Part 2

Comment by Dr. Krishna Kumari Challa yesterday

Broad-spectrum antiviral compounds discovered

An interdisciplinary research team has identified two antiviral drug candidates effective against a wide range of viruses. The study demonstrates how combining computer-aided modeling with laboratory validation can speed up the development of new antiviral drugs.

The researchers used computer simulations to search for specific metabolic processes necessary for viral reproduction but not vital for the cell itself. Using this method, the team identified two active agents that successfully combated various viruses in initial laboratory tests. The study was published in Communications Biology.

Using data from virus-infected tissues, the international research team developed computer models representing the complex metabolism of cells.

The team then used these tissue-specific models to simulate the replication of various RNA viruses, which are of particular importance due to their pandemic potential. The modeling revealed metabolic processes that the viruses require for replication but that are not essential for cellular survival.

Using these models, the researchers have predicted specific metabolic pathways essential for viral replication, which represent potential targets for antiviral therapies.

They then searched existing drug databases for substances that inhibit precisely these metabolic processes.

Since most viruses have similar basic replication requirements, the international research team from Germany, France, Italy, Greece, and Australia suspected that this strategy could be used to inhibit a wide variety of viruses.

They  tested this hypothesis experimentally and found various substances with broad antiviral activity against very different virus families.

Infection experiments in cell cultures confirmed that two drug candidates—phenformin and atpenin A5—effectively inhibit viral replication.

Phenformin interferes with the metabolism of the cell and was therefore previously used as a drug in type 2 diabetes. Since phenformin is well-characterized for use in humans, their findings could be used to establish supportive therapy against corona or flavivirus infections in the relatively short term.

Part 1

Comment by Dr. Krishna Kumari Challa yesterday

Nanoparticle smart spray helps crops block infection before it starts

As climate change fuels the spread of plant diseases worldwide, a new nanoparticle smart spray could help crops defend themselves by blocking harmful bacteria from entering through tiny pores in their leaves.

The spray is made of nano-sized particles which are designed to deliver antibacterial compounds directly to the plant's stomata—the pores on a plant's leaves that let it breathe, but which can also act as gateways for infection.

The particles, which we've called 'SENDS'—short for stomata-targeting engineered nanoparticles—are designed to stick precisely to these pores, like a lock finding its key. Once in place, they release natural antibacterial agents that stop pathogens from getting inside and infecting the plant.

Suppanat Puangpathumanond et al, Stomata-targeted nanocarriers enhance plant defense against pathogen colonization, Nature Communications (2025). DOI: 10.1038/s41467-025-60112-w

Comment by Dr. Krishna Kumari Challa yesterday

The team now plans to explore the efficacy of the nanozyme in preventing ischemic stroke, which is also caused by clogging of blood vessels.

Their experiments with human platelets worked well too.

G. R. Sherin et al, Vanadia Nanozymes Inhibit Platelet Aggregation, Modulate Signaling Pathways and Prevent Pulmonary Embolism in Mice, Angewandte Chemie International Edition (2025). DOI: 10.1002/anie.202503737

Part 2

Comment by Dr. Krishna Kumari Challa yesterday

Novel nanozyme prevents excess clotting

Researchers at the Indian Institute of Science (IISc) have developed an artificial metal-based nanozyme that can potentially be used to clamp down on abnormal blood clotting caused by conditions like pulmonary thromboembolism (PTE).

The work is published in the journal Angewandte Chemie International Edition.

Under normal circumstances, when a blood vessel is injured, specialized blood cells called platelets get activated and cluster together around the vessel to form protective blood clots. This process, known as the blood clotting cascade (hemostasis), involves a complex series of protein interactions triggered by signals from physiological agonists (chemicals) such as collagen and thrombin.

However, when these signals go haywire in conditions like PTE or diseases like COVID-19, oxidative stress and levels of toxic reactive oxygen species (ROS) increase, leading to over-activation of platelets. This triggers the formation of excess clots in the blood vessel, contributing to thrombosis, a major cause of morbidity and mortality.

To tackle this challenge, researchers  have developed nanomaterials that mimic the activity of natural antioxidant enzymes, which scavenge reactive oxidative molecules.

These "nanozymes" work by controlling ROS levels, thereby preventing the over-activation of platelets that leads to excess clot formation or thrombosis.

The team synthesized redox active nanomaterials of different sizes, shapes, and morphologies via a series of controlled chemical reactions starting from small building blocks. They then isolated platelets from human blood, activated them using physiological agonists, and tested how effectively the different nanozymes could prevent excess platelet aggregation.

The team found that spherical-shaped vanadium pentoxide (V₂O₅) nanozymes were the most efficient—these materials mimic a natural antioxidant enzyme called glutathione peroxidase to reduce oxidative stress.

It was challenging to get the pure form of the nano enzyme with only the +5 oxidation state of vanadium oxide. This was important because the +4 oxidation state is toxic to the cells.

The unique chemistry of the vanadium metal is crucial because the redox reactions that reduce ROS levels are happening on the surface of the vanadium nanomaterial.

The team injected the nanozyme in a mouse model of PTE and found that it significantly reduced thrombosis and increased the animals' survival rates. They also observed the weight, behavior, and blood parameters of the animal for up to five days after injecting the nanozyme, and did not find any toxic effects.

Anti-platelet drugs that target thrombosis sometimes have side effects such as increased bleeding.

Unlike conventional anti-platelet drugs that interfere with physiological hemostasis, the nanozymes modulate the redox signaling and do not interfere with normal blood clotting. This means that they won't cause bleeding complications that are a major concern with current therapies.

Part 1

Comment by Dr. Krishna Kumari Challa yesterday

The researchers also examined whether eating a portion of fiber, protein or fat before carbohydrates reduced blood sugar spikes. The participants ate pea fiber powder, protein from boiled egg whites or fat in the form of crème fraîche 10 minutes before eating rice.

Eating fiber or protein before the rice lowered the glucose spike, and eating fat before the rice delayed the peak of the spike. But these changes in blood glucose response occurred only in the metabolically healthy participants who were insulin-sensitive or had normal beta cell function.

Though eating fat, protein or fiber before carbohydrates had minimal impact on the blood glucose response patterns in participants with insulin resistance or beta cell dysfunction.
Eating carbohydrates later in a meal is still a good idea even though it has not yet been sorted out whether it is best to eat protein, fat or fiber before carbohydrates. Eat your salad or hamburger before your French fries, the researchers recommend.

Individual variations in glycemic responses to carbohydrates and underlying metabolic physiology, Nature Medicine (2025). DOI: 10.1038/s41591-025-03719-2

Part 3

Comment by Dr. Krishna Kumari Challa yesterday

The study participants wore continuous glucose monitors and ate same-sized portions of different carbohydrates that were delivered to their homes. There were seven foods tested: jasmine rice; buttermilk bread; shredded potato; pasta; canned black beans; grapes; and a berry mix containing blackberries, strawberries and blueberries.

The participants consumed the food first thing in the morning, after fasting for 10 to 12 hours. Each participant ate each food type twice, and the research team tracked their blood sugar response during the three hours after their meal.

Many participants had a blood glucose spike after eating rice or grapes, regardless of their metabolic health status. The blood glucose responses to foods containing the highest amounts of resistant starch—potatoes and pasta—varied depending on the participants' metabolic dysfunction.

Starchy foods were not equal; there was a lot of individual variability in which foods produced the highest glucose spike.
The highest blood sugar spikes after eating pasta occurred in participants who had insulin resistance, and the highest spikes after eating potatoes occurred in participants who were either insulin resistant or had beta cell dysfunction.

The multi-omics profiling showed that the potato-spiking participants also had high levels of triglycerides, fatty acids and other metabolites commonly seen in people with insulin resistance.

Glucose spikes to beans were associated with histidine and keto metabolism, a state in which the body primarily uses fat for energy. Participants whose blood sugar spiked after eating bread were more likely to have hypertension, or high blood pressure.
The highest blood glucose spikes after eating potatoes occurred in the participants who were the most insulin resistant and had the lowest beta cell function. Everyone spiked to some extent after eating grapes. The comparison of the blood glucose responses to potatoes versus grapes was associated with having insulin resistance, suggesting that this ratio could serve as a real-world biomarker for insulin resistance in the future.

"Such a biomarker would be useful because insulin resistance is amenable to lifestyle and medication interventions that can reduce risk for diabetes in high- risk individuals. At present there is no easy way to diagnose it in the clinic.
Part 2

Comment by Dr. Krishna Kumari Challa yesterday

Blood sugar response to various carbohydrates may point to metabolic health subtypes

A study  by researchers shows that differences in blood sugar responses to certain carbohydrates depend on details of an individual's metabolic health status.

The differences in blood sugar response patterns among individuals were associated with specific metabolic conditions such as insulin resistance or beta cell dysfunction, both of which can lead to diabetes. The study findings suggest that this variability in blood sugar response could lead to personalized prevention and treatment strategies for prediabetes and diabetes.

Right now, the Diabetes Associations' dietary guidelines do not work that well because they lump everyone together. This study suggests that not only are there subtypes within prediabetes, but also that your subtype could determine the foods you should and should not eat.

A paper explaining the research was published in Nature Medicine.

There is more than one pathway to diabetes, which is currently diagnosed based on elevated blood sugar levels, called hyperglycemia. Beta cells in the pancreas make the hormone insulin, which is then distributed to cells throughout the body to help convert glucose, or sugar, in the blood into energy.

Beta cell dysfunction occurs when the pancreas fails to make or to release enough insulin, and insulin resistance occurs when cells in the body do not respond fully to insulin. Both beta cell dysfunction and insulin resistance can contribute to the high blood sugar levels that define prediabetes and type 2 diabetes.

In the study, 55 participants without a history of type 2 diabetes underwent metabolic testing for insulin resistance and beta cell dysfunction in addition to multi-omics profiling, which included tests for triglyceride levels, metabolites in plasma of the blood, measures of liver function and gut microbiome data.

Just under half of the participants, 26 in total, had prediabetes.

Part 1

Comment by Dr. Krishna Kumari Challa yesterday

Why AI can't understand a flower the way humans do

Even with all its training and computer power, an artificial intelligence (AI) tool like ChatGPT can't represent the concept of a flower the way a human does, according to a new study.

That's because the large language models (LLMs) that power AI assistants are usually based on language alone, and sometimes with images.

A large language model can't smell a rose, touch the petals of a daisy or walk through a field of wildflowers. Without those sensory and motor experiences, it can't truly represent what a flower is in all its richness. The same is true of some other human concepts.

The findings have implications for how AI and humans relate to each other.

If AI construes the world in a fundamentally different way from humans, it could affect how it interacts with us.

Researcher found that overall, the LLMs did very well compared to humans in representing words that didn't have any connection to the senses and to motor actions. But when it came to words that have connections to things we see, taste or interact with using our body, that's where AI failed to capture human concepts.

"From the intense aroma of a flower, the vivid silky touch when we caress petals, to the profound joy evoked, human representation of 'flower' binds these diverse experiences and interactions into a coherent category," the researchers say in the paper they published on the topic.

The issue is that most LLMs are dependent on language, and "language by itself can't fully recover conceptual representation in all its richness".

Even though LLMs can approximate some human concepts, particularly when they don't involve senses or motor actions, this kind of learning is not efficient.

"They obtain what they know by consuming vast amounts of text—orders of magnitude larger than what a human is exposed to in their entire lifetimes—and still can't quite capture some concepts the way humans do.

"The human experience is far richer than words alone can hold."

 Large language models without grounding recover non-sensorimotor but not sensorimotor features of human concepts, Nature Human Behaviour (2025). DOI: 10.1038/s41562-025-02203-8

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