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Comment by Dr. Krishna Kumari Challa on January 9, 2024 at 9:02am

Around the time that they made their breakthrough, these researchers caught wind of an intriguing study in the journal Blood. This paper found that three unrelated people suffering from recurrent infections had the exact same mutation, which hyperactivates Rac2, a Rac protein produced in blood cells. They suspected their lab's recent revelation in fruit flies might shed light on this enigma.

The patients' mutation was just mildly activating, and yet it was enough that they all suffered from multiple infections and ultimately needed bone marrow transplants. Blood tests revealed that these patients had nearly no T cells, a specialized kind of white blood cells crucial to the immune system. The team at the National Institutes of Health inserted the Rac2 mutation into mice and found the same mysterious loss of T cells. They also found that the T cells with hyperactive Rac developed normally in the animals' bone marrow, and migrated to the thymus, where they continued to mature without incident. But then they just seemed to disappear. So, the paper ended with a mystery: what was causing the T cells to disappear?

The authors of that journal study had noticed that many of the patients' neutrophils—another type of white blood cell—were enlarged. They seemed to be consuming quite a lot of material, unusual behavior in an otherwise healthy person.
The researchers wondered if the patients' T cells were disappearing because their innate immune cells like neutrophils with active Rac2 were eating them, much like the fruit fly border cells with active Rac were eating the egg chamber. So they turned their attention to macrophages—the neutrophil's more voracious counterpart—to investigate. They cultured human macrophages with and without hyperactive Rac2 together with T cells. They observed that macrophages with hyperactive Rac consumed more cells, confirming the group's hypothesis from their work with fruit flies.

To test whether this might cause the observed immunodeficiency, co-author Melanie Rodriguez (a graduate student in Montell's lab) took bone marrow samples from mice with the same hyperactive Rac2 mutation found in the patients. She then grew the marrow stem cells into macrophages, and performed a similar experiment to earlier researchers' work , but this time mixing both macrophages and T cells with and without the Rac2 mutation.

She found that macrophages with active Rac2 consumed significantly more T-cells than their normal counterparts. However, T-cells with active Rac2 were also more vulnerable to consumption from either kind of macrophage. So the most likely explanation for the patients' missing T cells was a combination of increased consumption by macrophages as well as increased vulnerability of the T cells themselves. A human medical mystery was solved based on fundamental observations in fruit flies.
part 2

Comment by Dr. Krishna Kumari Challa on January 9, 2024 at 8:58am

When bad cells go good: Harnessing cellular cannibalism for cancer treatment

Scientists have solved a cellular murder mystery nearly 25 years after the case went cold. Following a trail of evidence from fruit flies to mice to humans revealed that cannibalistic cells likely cause a rare human immunodeficiency. Now the discovery shows promise for enhancing an up-and-coming cancer treatment.

This paper takes us from very fundamental cell biology in a fly, to explaining a human disease and harnessing that knowledge for a cancer therapy.

The primary character in this story is a gene, Rac2, and the protein it encodes. Rac2 is one of three Rac genes in humans. Rac is very ancient in evolution, so it must serve a fundamental function.

Rac proteins help build a cell's scaffolding, called the cytoskeleton. The cytoskeleton is made of dynamic filaments that allow cells to maintain their shape or deform, as needed. In 1996, while studying a small group of cells in the fruit fly ovary, scientists determined that Rac proteins are instrumental in cell movement. Since then, it has become clear that Rac is a nearly universal regulator of cell motility in animal.

In nineties, they also noticed that a hyperactive form of the Rac1 protein, expressed in only a few cells in a fly's egg chamber, destroyed the whole tissue. Just expressing this active Rac in six to eight cells kills the entire tissue, which is composed of about 900 cells.

A few years ago, evidence began to mount implicating cell eating, also known as cannibalism, in tissue destruction. There's a step in normal fly egg development where certain cells similar to the border cells consume their neighbors because they are no longer needed. Indeed, cellular cannibalism is not as rare as you might expect: Millions of old red blood cells are eliminated from the human body this way every second.

Rac2 is one component of the complex eating process. Rac helps the eating cell to envelop its target. The researchers were curious if a hyperactive form of the protein was causing border cells to prematurely consume their neighbours.

For this to occur, the border cells need to recognize their targets, which requires a particular receptor. Indeed, when  this receptor was blocked by scientists, the border cells expressing activated Rac didn't consume their neighbors, and the egg chamber remained alive and healthy.

Part 1

Comment by Dr. Krishna Kumari Challa on January 9, 2024 at 8:45am

Renal macrophages observed playing crucial role in preventing kidney stones

Researchers have investigated how the body's innate immune system of renal macrophages works to prevent kidney stones. In a paper, "Renal macrophages monitor and remove particles from urine to prevent tubule obstruction," published in Immunity, the authors detail their findings of mechanistic actions and strategic positioning of macrophages to surveil epithelial cells and intratubular environments.

When urine passes through the tubular system of the kidneys, it generates various microscopic sediment particles, including mineral crystals, from the concentrated urine. Pathological conditions can lead to the presence of proteins and inflammatory cells. These particles can become lodged in the tubules, blocking urine flow and causing renal dysfunction.

The researchers observed renal macrophages adjacent to the tubules in real-time, using high-resolution microscopy, live recordings and two-photon microscopy techniques. They were able to record macrophages extending transepithelial protrusions and interacting with intratubular particles, as well as their migration to assist in the excretion of urine particles.

These techniques captured the association of macrophages with particles in urine and demonstrated the role of macrophages in particle removal. Renal macrophages located near medullary tubules display specific behaviors, extending transepithelial protrusions and constantly sampling urine contents. The macrophages were then seen to migrate and surround intratubular particles, aiding in their removal from the tubular system.

To confirm the role of the macrophages, the latex bead experiment was repeated with mice lacking renal macrophages. Macrophage-depleted mice showed increased retention of the fluorescent beads even after 36 hours despite the more prolonged exposure to natural urine flushing.

This result suggests that normal urine flushing alone could not efficiently remove big particles in the renal tubule system without the macrophage pre-disposal assistance.

 Jian He et al, Renal macrophages monitor and remove particles from urine to prevent tubule obstruction, Immunity (2023). DOI: 10.1016/j.immuni.2023.12.003

Comment by Dr. Krishna Kumari Challa on January 8, 2024 at 11:59am

Study Discovers Novel Biomarker for Vascular Aging and Neurodegeneration

Comment by Dr. Krishna Kumari Challa on January 8, 2024 at 11:46am

They found that some gene families never turned up in a genome when a particular other gene family was already there, and on other occasions, some genes were very much dependent on a different gene family being present.
In effect, the researchers discovered an invisible ecosystem where genes can cooperate or can be in conflict with one another.

"These interactions between genes make aspects of evolution somewhat predictable and furthermore, we now have a tool that allows us to make those predictions
The implications of the research are far-reaching and could lead to:

Novel Genome Design—allowing scientists to design synthetic genomes and providing a roadmap for the predictable manipulation of genetic material.
Combating Antibiotic Resistance—Understanding the dependencies between genes can help identify the 'supporting cast' of genes that make antibiotic resistance possible, paving the way for targeted treatments.
Climate Change Mitigation—Insights from the study could inform the design of microorganisms engineered to capture carbon or degrade pollutants, thereby contributing to efforts to combat climate change.
Medical Applications—The predictability of gene interactions could revolutionize personalized medicine by providing new metrics for disease risk and treatment efficacy.

Alan Beavan et al, Contingency, repeatability, and predictability in the evolution of a prokaryotic pangenome, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2304934120

Part 2

Comment by Dr. Krishna Kumari Challa on January 8, 2024 at 11:45am

Evolution is not as random as previously thought, finds new study

A new study has found that evolution is not as unpredictable as previously thought, which could allow scientists to explore which genes could be useful to tackle real-world issues such as antibiotic resistance, disease, and climate change.

The study, which is published in the Proceedings of the National Academy of Sciences (PNAS), challenges the long-standing belief about the unpredictability of evolution and has found that the evolutionary trajectory of a genome may be influenced by its evolutionary history, rather than determined by numerous factors and historical accidents.

By demonstrating that evolution is not as random as scientists once thought, they've opened the door to an array of possibilities in synthetic biology, medicine, and environmental science.

The team carried out an analysis of the pangenome—the complete set of genes within a given species, to answer a critical question of whether evolution is predictable or whether the evolutionary paths of genomes are dependent on their history and so not predictable today.

Using a machine learning approach known as Random Forest, along with a dataset of 2,500 complete genomes from a single bacterial species, the team carried out several hundred thousand hours of computer processing to address the question.

After feeding the data into their high-performance computer, the team first made "gene families" from each of the gene of each genome.

In this way, they could compare like-with-like across the genomes.

Once the families had been identified, the team analyzed the pattern of how these families were present in some genomes and absent in others.

Part 1

Comment by Dr. Krishna Kumari Challa on January 6, 2024 at 12:26pm

HIV vaccine takes step forward with confirmation of neutralizing antibodies

The path to a successful HIV vaccine depends on a critical first step—activating specific immune cells that induce broadly neutralizing antibodies.

Reporting Jan. 4 in the journal Cell, a research team has achieved that requisite initial step in a study using monkeys. The next phase of the work will now move to testing in humans. This study confirms that the antibodies are, at the structural and genetic levels, similar to the human antibody that we need as the foundation for a protective HIV vaccine.

 In earlier work, the research team had isolated naturally occurring broadly neutralizing antibodies from an individual, and then back-tracked through all the changes the antibody and the virus underwent to reach a point of origin for the native antibody and its binding site on the HIV envelope.
With that knowledge, they engineered a molecule that elicits antibodies that mimic the native antibody and its binding site on the HIV envelope.

Four years ago, they published a  study in Science in which they established that monkeys made neutralizing antibodies when vaccinated with the engineered immunogen, but it was uncertain if those antibodies were like the broadly neutralizing antibody that is needed for a human vaccine.

In the current study, the researchers made a new, more potent formulation of the vaccine and delivered it to monkeys. This time, their goal was to determine whether the neutralizing antibodies generated in the animals were structurally and genetically similar to the antibodies needed in humans. They were.

Kevin O. Saunders et al, Vaccine induction of CD4-mimicking HIV-1 broadly neutralizing antibody precursors in macaques, Cell (2024). DOI: 10.1016/j.cell.2023.12.002

Comment by Dr. Krishna Kumari Challa on January 6, 2024 at 12:18pm

Scientists discover why chicken farms are a breeding ground for antibiotic resistant bacteria

Scientists  are one step closer to understanding how bacteria, such as E. coli and Salmonella enterica, share genetic material which makes them resistant to antibiotics.

Antimicrobial resistance (AMR), the capability of organisms to be resistant to treatment with antibiotics and other antimicrobials, is now one of the most threatening issues worldwide. Livestock farms, their surrounding environments and food products generated from husbandry, have been highlighted as potential sources of resistant infections for animals and humans.

In livestock farming, the misuse and overuse of broad-spectrum antimicrobials administered to reduce production losses is a major known contribution to the large increase and spread of AMR.

In this latest study, scientists provide a significant contribution to demonstrating that different bacteria species, co-existing within the same microbial community (for example, within the chicken gut), are able to share AMR-associated genetic material and end-up implementing similar resistance mechanisms. The discovery has important implications as it affects our understanding of AMR and poses further challenges to the implementation of solutions for surveillance and treatment/control.

This study, published in Nature Communications, looks at two important bacteria found in food animals—Escherichia coli and Salmonella enterica, which both show high levels of drug resistance, are common in farming settings, have high levels of transmissibility to humans and cause food poisoning.

These species of bacteria can share genetic material both within, and potentially between species, a way in which AMR is spread. That is why understanding the extent to which these bacteria within the same environment, and importantly, the same host, can co-evolve and share their genome could help the development and more efficient treatments to fight AMR.

The insurgence and spread of AMR in livestock farming is a complex phenomenon arising from an entangled network of interactions happening at multiple spatial and temporal scales and involving interchanges between bacteria, animals and humans over a multitude of connected microbial environments.

Michelle Baker et al, Convergence of resistance and evolutionary responses in Escherichia coli and Salmonella enterica co-inhabiting chicken farms in China, Nature Communications (2024). DOI: 10.1038/s41467-023-44272-1

Comment by Dr. Krishna Kumari Challa on January 5, 2024 at 9:46am

Why are bees making less honey?

Honey yields  have been declining since the 1990s, with honey producers and scientists unsure why, but a new study by  researchers has uncovered clues in the mystery of the missing honey.

Using five decades of data from across the U.S., the researchers analyzed the potential factors and mechanisms that might be affecting the number of flowers growing in different regions—and, by extension, the amount of honey produced by honey bees.

The study, recently published in the journal Environmental Research Letters, found that changes in honey yields over time were connected to herbicide application and land use, such as fewer land conservation programs that support pollinators. Annual weather anomalies also contributed to changes in yields.

Overall, researchers found that climate conditions and soil productivity—the ability of soil to support crops based on its physical, chemical and biological properties—were some of the most important factors in estimating honey yields. States in both warm and cool regions produced higher honey yields when they had productive soils.

The eco-regional soil and climate conditions set the baseline levels of honey production, while changes in land use, herbicide use and weather influenced how much is produced in a given year, the researchers summarized.

Gabriela M Quinlan et al, Examining spatial and temporal drivers of pollinator nutritional resources: evidence from five decades of honey bee colony productivity data, Environmental Research Letters (2023). DOI: 10.1088/1748-9326/acff0c

Comment by Dr. Krishna Kumari Challa on January 5, 2024 at 9:38am

Scientists use high-tech brain stimulation to make people more hypnotizable

How deeply someone can be hypnotized—known as hypnotizability—appears to be a stable trait that changes little throughout adulthood, much like personality and IQ. But now, for the first time,  researchers have demonstrated a way to temporarily heighten hypnotizablity—potentially allowing more people to access the benefits of hypnosis-based therapy.

In the new study, published Jan. 4 in Nature Mental Health, the researchers found that less than two minutes of electrical stimulation targeting a precise area of the brain could boost participants' hypnotizability for about one hour.

Approximately two-thirds of adults are at least somewhat hypnotizable, and 15% are considered highly hypnotizable, meaning they score 9 or 10 on a standard 10-point measure of hypnotizability.

Hypnosis is a state of highly focused attention, and higher hypnotizability improves the odds of your doing better with techniques using hypnosis.

Earlir researchers found that highly hypnotizable people had stronger functional connectivity between the left dorsolateral prefrontal cortex, which is involved in information processing and decision making; and the dorsal anterior cingulate cortex, involved in detecting stimuli.

It made sense that people who naturally coordinate activity between these two regions would be able to concentrate more intently. It's because you're coordinating what you are focusing on with the system that distracts you.

Clinically, a transient bump in hypnotizability may be enough to allow more people living with chronic pain to choose hypnosis as an alternative to long-term opioid use.

The new results could have implications beyond hypnosis. Neurostimulation may be able to temporarily shift other stable traits or enhance people's response to other forms of psychotherapy.

Stanford Hypnosis Integrated with Functional Connectivity-targeted Transcranial Stimulation (SHIFT): a preregistered randomized controlled trial, Nature Mental Health DOI: 10.1038/s44220-023-00184-z www.nature.com/articles/s44220-023-00184-z

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