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Comment by Dr. Krishna Kumari Challa on December 31, 2024 at 10:37am

Although the researchers suspected estrogen would have an effect on drinking, they were surprised by its mechanism of action. This steroid hormone typically regulates behaviours by binding to receptors that then travel to the nucleus, where they alter the activity of specific genes—a process that could take hours.

However, researchers now realized that something else must be happening when estrogen infused directly into the BNST excited the neurons and triggered binge drinking within minutes.

So, the researchers tested estrogen that had been doctored so it could not enter cells and bind to nuclear receptors—a feat of chemical engineering performed by Dr. Jacob Geri, assistant professor of pharmacology at Weill Cornell Medicine. They determined that when estrogen promotes binging, the hormone is binding to receptors on the neurons' surface, where it directly modulates cell-cell communication.
This is the first time that anybody has shown that during a normal estrous cycle, endogenous estrogen made by the ovaries can use such a rapid mechanism to control behaviour.
The team identified the estrogen receptor that mediates this effect and determined that it is expressed in the excited BNST neurons and in neurons from other brain regions that excite them. The researchers are now investigating the signaling mechanisms for this effect, and they will also examine whether the same system regulates drinking in males.

 Lia J. Zallar et al, Rapid nongenomic estrogen signaling controls alcohol drinking behavior in mice, Nature Communications (2024). DOI: 10.1038/s41467-024-54737-6

Part 3

Comment by Dr. Krishna Kumari Challa on December 31, 2024 at 10:22am

In a 2021 study, researchers showed that a specific subpopulation of neurons in a brain region called the bed nucleus of the stria terminalis (BNST) were more excitable in female mice than in males. This enhanced activity correlated with their binge-drinking behaviour.

But what makes this neural circuit more excitable in females? Estrogen has such powerful effects on so many behaviors, particularly in females. So, it makes sense that it would also modulate drinking.

To assess estrogen's potential involvement, the researchers began by monitoring the hormone levels throughout the estrous cycle of female mice. Then, they served up the alcohol. They found that when a female has a high level of circulating estrogen, she drinks much more than on days when her estrogen is low.

That enhanced binging behaviour was reflected in heightened activity in those same neurons in the BNST. When a female takes her first sip from the bottle containing alcohol, those neurons go crazy. And if she's in a high-estrogen state, they go even crazier. That extra boost of neural activity means the mice hit the bottle even harder, particularly within the first 30 minutes after the alcohol was made available, a behavior researchers refer to as "front-loading."
part2

Comment by Dr. Krishna Kumari Challa on December 31, 2024 at 10:19am

Preclinical study finds surges in estrogen promote binge drinking in females

The hormone estrogen regulates binge drinking in females, causing them to "pregame," or consume large quantities of alcohol in the first 30 minutes after it's offered, according to a preclinical study led by scientists at Weill Cornell Medicine. The study establishes—for what is thought to be the first time—that circulating estrogen increases binge alcohol consumption in females and contributes to known sex differences in this behaviour.

The findings, published Dec. 30 in the journal Nature Communications, could lead to novel approaches for treating alcohol use disorder.

Comment by Dr. Krishna Kumari Challa on December 31, 2024 at 10:14am

Analysis of 160,000 films shows rise in 'murderous verbs' since 1970

The amount of murdering and killing in movies has increased overall over the past 50 years, according to a study that analyzed a massive database of film dialogue.

Researchers used machine learning to search a database of subtitles from more than 160,000 English-language movies produced from 1970 to 2000. They calculated the amount of dialogue from characters using variations of the words "murder" or "kill" in each of the films.

While the total use of these "murderous verbs" varied widely from year to year, there was a clear increasing trend over the five-decade period.

And not just in crime movies, where violence might be expected. Characters in noncrime movies are also talking more about killing and murdering today than they did 50 years ago.

It is still happening. Researchers found increases in violence cross all genres.

These findings suggest that references to killing and murder in movie dialogue not only occur far more frequently than in real life but are also increasing over time.

Movies are trying to compete for the audience's attention and research shows that violence is one of the elements that most effectively hooks audiences."

That means we need to promote "mindful consumption and media literacy to protect vulnerable populations, especially children," the researchers wrote in the study.

Why only in English movies, we find this trend in all Indian language movies too!

Trends of Violence in Movies During the Past Half Century, JAMA Pediatrics (2024). DOI: 10.1001/jamapediatrics.2024.5741

Comment by Dr. Krishna Kumari Challa on December 31, 2024 at 10:07am

what came first, the lesion or the microplastic," it is possible that MNPs contribute to inflammation, oxidative stress, and cellular damage, which can cause or worsen tissue lesions. But it is also possible that these lesions accumulate more MNPs in already damaged tissue areas. While the current findings do not provide a direct cause-and-effect relationship, they offer good targets for further study.
There are no conventional methods for removing microplastics from the environment or human tissues. While efforts are underway to discover methods of environmental mitigation, developing such strategies to handle diverse particle sizes and chemistries of the particles embedded in living tissues presents an immense and potentially unattainable challenge.

Yating Luo et al, Mapping micro(nano)plastics in various organ systems: Their emerging links to human diseases?, TrAC Trends in Analytical Chemistry (2024). DOI: 10.1016/j.trac.2024.118114

Part 2

Comment by Dr. Krishna Kumari Challa on December 31, 2024 at 10:07am

Microplastics found in multiple human organ tissues correlated with lesions

Researchers have recently performed a metadata investigation into the presence of microplastics in humans. They report a concerning relationship between micro and nanoplastic (MNP) concentrations in damaged tissues and links with multiple health conditions.

With the increased use in consumer products came elevated microscopic plastic pollution circulating in soil and waterways, eventually accumulating in the environment, food webs and human tissues.

In the study, "Mapping micro(nano)plastics in various organ systems: Their emerging links to human diseases?" published in TrAC Trends in Analytical Chemistry, investigators collected 61 available research articles for MNP detection in human tissues, plus 840 articles on MNP toxicological mechanisms.

Data came from spectroscopy, microscopy, and pyrolysis-gas chromatography/mass spectrometry investigations to identify polymer types in different tissues. Toxicological studies employed cell models and animal experiments to examine oxidative stress, inflammatory responses, and related signaling pathways.

The studies documented particles detected in skin, arteries, veins, thrombi, bone marrow, testes, semen, uterus, and placenta. MNPs were found in the digestive system, from saliva to feces, liver, and gallstones.

Within the respiratory system, MNPs were everywhere, including lung tissue, with microscopic fibers common in bronchoalveolar lavage fluid and sputum. Positive correlations emerged between particle abundance and specific disorders, such as inflammatory bowel disease, thrombosis, cervical cancer, and uterine fibroids.

Toxicological tests showed possible MNP-triggered oxidative stress, mitochondrial dysfunction, inflammatory responses, and apoptosis in various cell types, along with organ-level concerns like neurodegenerative disease onset when crossing the blood-brain barrier.

A critically important signal in the metadata discovered by the researchers was that measured levels of MNPs tended to be higher in tissues with lesions than in non-lesioned tissues. These included inflamed intestines, fibrotic lungs, or cancerous growths, suggesting a potential link between MNP buildup and local pathology.

Part 1

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.

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