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Comment by Dr. Krishna Kumari Challa on January 31, 2025 at 2:18pm

Future antibiotics face early bacterial resistance challenges, studies show

Researchers have made a concerning discovery about the future of antibiotics. Two recent studies, published just days apart in Nature Microbiology and Science Translational Medicine found that resistance can develop against new antibiotics even before they are widely used, compromising their effectiveness from the start. The studies focused on five critical bacterial species that cause major hospital infections and examined 18 new antibiotics, some already on the market and others still in development.

New antibiotics are often marketed as resistance-free, but this claim relies on limited data. 

This new work  highlights a major issue: antibiotic development tends to prioritize broad-spectrum activity - that is the number of bacterial species a drug targets- over long-term sustainability. While many new antibiotics indeed offer a broader spectrum, this doesn't guarantee they will remain effective in the long run in clinical use.

The studies found that resistance developed rapidly against nearly all the tested antibiotics, defying earlier expectations. For example, teixobactin, once hailed as a revolutionary drug, was believed to be less prone to resistance. However, the research revealed that bacteria can adapt to it with this adaptation resulting in cross-resistance to other critical antibiotics.

Alarmingly, the team also found that resistance mutations may already exist in bacterial populations, likely due to the overuse of older antibiotics and the shared resistance mechanisms between those and new drugs. These pre-existing mutations could render even the newest drugs ineffective shortly after they are introduced into clinical use.

Rethinking antibiotic development:  The studies call for a fundamental shift in how antibiotics are developed. Drug companies must incorporate resistance studies early in the development process to anticipate and mitigate risks before antibiotics are released. Integrating resistance prediction and genetic surveillance into drug design could reduce the chances of failure.

Some new antibiotics show more promise than others, as resistance develops more slowly or only in specific bacterial species. Understanding why these drugs perform better is the next crucial step.

The studies emphasize the importance of prioritizing antibiotics with novel modes of action to bypass existing resistance. In cases where only certain bacterial species are prone to resistance, narrow-spectrum therapy could provide an effective alternative. Finally, the studies stress the urgency of responsible antibiotic use to slow down the evolution of resistance and ensure the prolonged efficacy of new treatments in the future.

 Lejla Daruka et al, ESKAPE pathogens rapidly develop resistance against antibiotics in development in vitro, Nature Microbiology (2025). DOI: 10.1038/s41564-024-01891-8

Ana Martins et al, Antibiotic candidates for Gram-positive bacterial infections induce multidrug resistance, Science Translational Medicine (2025). DOI: 10.1126/scitranslmed.adl2103

Comment by Dr. Krishna Kumari Challa on January 31, 2025 at 2:06pm

Scientists replicate bone marrow

Hidden within our bones, marrow sustains life by producing billions of blood cells daily, from oxygen-carrying red cells to immune-boosting white cells. This vital function is often disrupted in cancer patients undergoing chemotherapy or radiation, which can damage the marrow and lead to dangerously low white cell counts, leaving patients vulnerable to infection.

Now researchers have developed a platform that emulates human marrow's native environment. This breakthrough addresses a critical need in medical science, as animal studies often fail to fully replicate the complexities of human marrow.

The team's new device is a small plastic chip whose specially designed chambers are filled with human blood stem cells and the surrounding support cells with which they interact in a hydrogel to mimic the intricate process of bone marrow development in the human embryo. This biologically inspired platform makes it possible to build living human marrow tissue that can generate functional human blood cells and release them into culture media flowing in engineered capillary blood vessels.

The bone marrow-on-a-chip allows researchers to simulate and study common side effects of medical treatments, such as radiotherapy and chemotherapy for cancer patients. When connected to another device, it can even model how the bone marrow communicates with other organs, like the lungs, to protect them from infections and other potentially life-threatening conditions.

Described in a new paper published in Cell Stem Cell, the bone marrow model and the demonstration of its large-scale production and automation could advance fields as diverse as drug development by enabling automated, high-throughput preclinical screening of marrow toxicity of anticancer drugs) and space travel (by allowing researchers to study the effects of prolonged radiation exposure and microgravity on the immune system of astronauts).  

Andrei Georgescu et al, Self-organization of the hematopoietic vascular niche and emergent innate immunity on a chip, Cell Stem Cell (2024). DOI: 10.1016/j.stem.2024.11.003

Comment by Dr. Krishna Kumari Challa on January 31, 2025 at 2:01pm

The team then studied the impacts of the structural variation on the human cell lines. Using genomic sequencing, the team was able to take 'snapshots' of the human cells and their 'shuffled' genomes over the course of a few weeks, watching which cells survived and which died.

As expected, they found that when structural variation deleted essential genes, this was heavily selected against and the cells died. However, they found that groups of cells with large-scale deletions in the genomes that avoided essential genes survived.

The team also conducted RNA sequencing of the human cell lines, which measures gene activity, known as gene expression. This revealed that large-scale deletions of the genetic code, especially in non-coding regions, did not seem to impact the gene expression of the rest of the cell.

The researchers suggest that human genomes are extremely tolerant of structural variation, including variants that change the position of hundreds of genes, as long as essential genes are not deleted.

In another study related to this  another research  team used a different approach, adding recombinase sites to transposons—mobile genetic elements—that randomly integrated in the genomes of human cell lines and mouse embryonic stem cells.

Using their method, they demonstrated that the effects of the induced structural variants can be read out using single-cell RNA sequencing. This advance paves the way for large screens of structural variant impact, potentially improving the classification of structural variants found in human genomes as benign or clinically significant.

Both studies came to similar conclusions that human genomes are surprisingly tolerant to some substantial structural changes, although the full extent of this tolerance remains to be explored in future studies enabled by these technologies.

Jonas Koeppel et al, Randomizing the human genome by engineering recombination between repeat elements, Science (2025). DOI: 10.1126/science.ado3979. www.science.org/doi/10.1126/science.ado3979

Science (2025). DOI: 10.1126.science.ado5978

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Comment by Dr. Krishna Kumari Challa on January 31, 2025 at 2:00pm

Complex engineering of human cell lines reveals genome's unexpected resilience to structural changes

The most complex engineering of human cell lines ever has been achieved by scientists, revealing that our genomes are more resilient to significant structural changes than was previously thought.

Researchers used CRISPR prime editing to create multiple versions of human genomes in cell lines, each with different structural changes. Using genome sequencing, they were able to analyze the genetic effects of these structural variations on cell survival .

The research, published in Science, shows that as long as essential genes remain intact, our genomes can tolerate significant structural changes, including large deletions of the genetic code. The work opens the door to studying and predicting the role of structural variation in disease.

Structural variation is a change in the structure of an organism's genome, such as deletions, duplications and inversions of the genetic sequence. These structural changes to the genome can be significant, sometimes affecting hundreds to many thousands of nucleotides—the basic building blocks of DNA and RNA.

Structural variants are associated with developmental diseases and cancer. However, our ability to study the effects of structural variation in the genomes of mammals, and the role they play in disease, has been difficult due to the inability to engineer these genetic changes.

To overcome this challenge,  researchers  set out to develop new approaches for creating and studying structural variation.

In a new study, the team used a combination of CRISPR prime editing and human cell lines—groups of human cells in a dish—to generate thousands of structural variants in human genomes within a single experiment.

To do this, researchers used prime editing to insert a recognition sequence into the genomes of the human cell lines to target with recombinase—an enzyme that enabled the team to 'shuffle' the genome.

By inserting these recombinase handles into repetitive sequences, which are hundreds and thousands of identical sequences in the genome, with a single prime editor they were able to integrate up to almost 1,700 recombinase recognition sites into each cell line.

This resulted in more than 100 random large-scale genetic structural changes per cell. This is the first time that it's been possible to 'shuffle' a mammalian genome, especially at this scale.

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Comment by Dr. Krishna Kumari Challa on January 31, 2025 at 1:40pm

Your fridge still uses tech from the 50s, but scientists have an update

Researchers report on Jan. 30 in the journal Joule that a more efficient and environmentally friendly form of refrigeration might be on the horizon. The new technology is based on thermogalvanic cells that produce a cooling effect by way of a reversible electrochemical reaction.

Thermogalvanic refrigeration is cheaper and more environmentally friendly than other cooling methods because it requires a far lower energy input, and its scalability means that it could be used for various applications—from wearable cooling devices to industrial-grade scenarios.

Thermogalvanic cells use the heat produced by reversible electrochemical reactions to create electrical power. In theory, reversing this process—applying an external electrical current to drive electrochemical reactions—enables cooling power to be generated.

Previous studies have shown that thermogalvanic cells have a limited potential to produce cooling power, but  this new work was able to dramatically increase this potential by optimizing the chemicals used in the technology.

By tweaking the solutes and solvents used in the electrolyte solution, the researchers were able to improve the hydrogalvanic cell's cooling power. They used a hydrated iron salt containing perchlorate, which helped the iron ions dissolve and dissociate more freely compared to other previously tested iron-containing salts such as ferricyanide.
By dissolving the iron salts in a solvent containing nitriles rather than pure water, the researchers were able to improve the hydrogalvanic cell's cooling power by 70%.

The optimized system was able to cool the surrounding electrolyte by 1.42 K, which is a big improvement compared to the 0.1 K cooling capacity reported by previously published thermogalvanic systems.

Looking ahead, the team plans to continue optimizing their system's design and is also investigating potential commercial applications.

Solvation entropy engineering of thermogalvanic electrolytes for efficient electrochemical refrigeration, Joule (2025). DOI: 10.1016/j.joule.2025.101822. www.cell.com/joule/fulltext/S2542-4351(25)00003-0

Comment by Dr. Krishna Kumari Challa on January 31, 2025 at 1:35pm

Mast cells are culprits in a range of inflammatory skin conditions and allergic reactions, but they're also important for protecting against bacteria and other pathogens. As such, the researchers wondered if scratching-induced activation of mast cells could affect the skin microbiome.
The researchers showed that scratching reduced the amount of Staphylococcus aureus, the most common bacteria involved in skin infections, on the skin.
The finding that scratching improves defense against Staphylococcus aureus suggests that it could be beneficial in some contexts. But the damage that scratching does to the skin probably outweighs this benefit when itching is chronic.

Andrew W. Liu et al, Scratching promotes allergic inflammation and host defense via neurogenic mast cell activation, Science (2025). DOI: 10.1126/science.adn9390. www.science.org/doi/10.1126/science.adn9390

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Comment by Dr. Krishna Kumari Challa on January 31, 2025 at 1:33pm

Why you shouldn't scratch an itchy rash

New research published in the journal Science uncovers how scratching aggravates inflammation and swelling in a mouse model of a type of eczema called allergic contact dermatitis.

Scratching is often pleasurable, which suggests that, in order to have evolved, this behaviour must provide some kind of benefit. This new study helps resolve this paradox by providing evidence that scratching also provides defense against bacterial skin infections.

Allergic contact dermatitis is an allergic reaction to allergens or skin irritants—including poison ivy and certain metals such as nickel—leading to an itchy, swollen rash. Succumbing to the often-irresistible urge to scratch triggers further inflammation that worsens symptoms and slows healing.

To figure out what drives this vicious cycle,  researchers used itch-inducing allergens to induce eczema-like symptoms on the ears of normal mice and those that don't get itchy because they lack an itch-sensing neuron.

When normal mice were allowed to scratch, their ears became swollen and filled with inflammatory immune cells called neutrophils. In contrast, inflammation and swelling were much milder in normal mice that couldn't scratch because they wore tiny Elizabethan collars, similar to a cone that a dog might sport after a visit to the vet, and in animals that lacked the itch-sensing neuron. This experiment confirmed that scratching further aggravates the skin.

Next, the researchers showed that scratching causes pain-sensing neurons to release a compound called substance P. In turn, substance P activates mast cells, which are key coordinators of inflammation that drive itchiness and inflammation via recruitment of neutrophils.

In contact dermatitis, mast cells are directly activated by allergens, which drives minor inflammation and itchiness.

In response to scratching, the release of substance P activates mast cells through a second pathway, so the reason that scratching triggers more inflammation in the skin is because mast cells have been synergistically activated through two pathways.

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Comment by Dr. Krishna Kumari Challa on January 31, 2025 at 1:26pm

Successfully treating sepsis would be a multipurpose life-saver, preventing mortality regardless of the illness that triggered it. Viral sepsis is a major cause of deaths triggered by severe COVID-19, while many deaths in historical pandemics like the 1919 influenza pandemic and the bubonic plague are thought to have resulted from sepsis.

If we can tackle sepsis, we might be able to protect ourselves against the worst consequences and the highest death tolls in future pandemics, no matter what kind of infection causes them. Since immune dysregulation linked to sepsis can linger, causing symptoms similar to post-viral syndromes like long COVID-19, learning to treat this could also benefit some chronic illness patients.

But to make this happen, the researchers caution, more funding and larger studies will be needed.
The omics methods that underlie systems immunology are relatively expensive on a per patient basis. It will require a concerted drive from stakeholders to generate the data needed for further insights. We need to invest in larger omics studies of patients, develop new animal and organoid models that reflect sepsis heterogeneity, and invest in early diagnostics for sepsis and treatments that correct or supplement defective immunity in sepsis patients.

Deciphering sepsis: transforming diagnosis and treatment through systems immunology, Frontiers in Science (2025). DOI: 10.3389/fsci.2024.1469417

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Comment by Dr. Krishna Kumari Challa on January 31, 2025 at 1:24pm

How tackling sepsis can save millions of lives—and prevent future pandemic deaths

Sepsis is an underestimated killer. Nearly a quarter of patients treated for sepsis in hospital will die, but because so many different illnesses can predispose patients to experiencing it, it's overlooked as a direct cause of death. Yet approximately 20% of deaths worldwide are caused by sepsis, and currently we have no treatments that tackle it directly.

Now researchers writing in Frontiers in Science explain how systems immunology can help us understand and treat sepsis—and how this could cut the death toll of future pandemics, no matter what disease causes them.

One of the reasons it's so hard to understand and treat sepsis is that it is multifaceted. Sepsis arises when the immune system fails to control an infection and malfunctions, causing multi-organ failure. Many different infections can cause sepsis, and its symptoms and progression vary between patients and over time in the same patient. Its early symptoms are similar to those of many other illnesses, which makes it difficult to diagnose quickly and initiate timely treatment, contributing to high mortality.

Systems immunology offers a potential solution to this diagnosis problem by using mathematical and computational modeling to study the immune system in the context of all the body's other systems. It does this by using different types of clustering analysis to identify patterns in large volumes of omics data, ranging from transcriptomic data (what genes show altered expression) to proteomic and metabolomic data—data that tell us about the body's reaction to its physical circumstances, in this case sepsis, in incredibly fine-grained detail.

These patterns help us work out the patterns and basis for the immune dysregulation that drives sepsis, come up with new hypotheses that we can research and use to develop new treatments, and identify diagnostic markers that we can use to catch sepsis early.

For instance, using these clustering analyses, scientists have identified changes to gene expression that act as early warnings for sepsis. They've also been able to identify five different subtypes of sepsis which are caused by different kinds of immune dysregulation and have different prognoses. In the future, we could build on these advances to diagnose different subtypes of sepsis earlier and treat them with the right drugs when we do.

However, systems immunology analysis is not yet in widespread use, because it is expensive and demands significant volumes of data—so we don't yet know how these diagnostics could translate into clinical results. The researchers call urgently for targeted funding and greater data availability.

"In sepsis we lack the depth of information required to enable more effective systems immunology and machine learning approaches.

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Comment by Dr. Krishna Kumari Challa on January 31, 2025 at 1:19pm

Essentially, explainable AI approximates the flexibility of expert clinical judgment while avoiding its pitfalls. The researchers' model is also especially well-suited to judging risk for rare pregnancy scenarios, accurately estimating outcomes for people with unique combinations of risk factors. This kind of tool could ultimately help personalize care by guiding informed decisions for people whose situations are one-of-a-kind.
AI models can essentially estimate a risk that is specific to a given person's context and they can do it transparently and reproducibly, which is what human brains can't do.

 AI-based analysis of fetal growth restriction in a prospective obstetric cohort quantifies compound risks for perinatal morbidity and mortality and identifies previously unrecognized high risk clinical scenarios, BMC Pregnancy and Childbirth (2025). DOI: 10.1186/s12884-024-07095-6

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