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Comment by Dr. Krishna Kumari Challa on December 6, 2024 at 11:38am

Researchers reprogram immune cells to decrease rejection of medical implants

Researchers have discovered that using a drug that is a metabolic inhibitor  makes the body more receptive to medical devices such as pacemakers, replacement joints and dental implants.

When doctors surgically place an implant into a human, there will always be an immune response and there's a chance the implant will be rejected.

Scientists used a drug that signals the body to boost or inhibit a particular reaction, called a metabolic modulator. This drug was incorporated into an amorphous polylactide—a biomaterial used to make medical implants—and then the material was implanted in mice.

Using intravital microscopy—a technique that allows us to look inside a living subject under a microscope—the researchers imaged different kinds of immune cells around the implant site for up to 10 weeks.

Their paper is published in the journal Nature Biomedical Engineering.

These findings have significant implications for improving patient recovery times, reducing postsurgical complications like chronic inflammation and implant rejection and potentially saving costs. And they may eventually affect the way medical device manufacturers and pharmaceutical scientists approach medical implants.

Chima V. Maduka et al, Immunometabolic cues recompose and reprogram the microenvironment around implanted biomaterials, Nature Biomedical Engineering (2024). DOI: 10.1038/s41551-024-01260-0

Comment by Dr. Krishna Kumari Challa on December 6, 2024 at 11:33am

Researchers studied the flocculus and paraflocculus' role in the brain to better understand how their malformation could influence behavior. They found that the neural circuits within the flocculus and paraflocculus are dysfunctional.
The regions also control a reflex that ensures stable vision during head movements and is crucial for face recognition. The researchers found that this reflex is impaired in 22q. This may be a valuable lead for schizophrenia research because patients with schizophrenia have a deficit in face recognition.
The paraflocculus is also connected to the auditory cortex.

Tae-Yeon Eom et al, Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome, Nature Communications (2024). DOI: 10.1038/s41467-024-54837-3

Part 2

Comment by Dr. Krishna Kumari Challa on December 6, 2024 at 11:31am

Genetic risk for schizophrenia linked to a malformed skull

The chromosomal disorder 22q11.2 deletion syndrome (22q) has emerged as one of the strongest risks for schizophrenia. Scientists at St. Jude Children's Research Hospital identified malformed regions of the cerebellum in laboratory models and patients with 22q and found that these malformations were caused by improper skull formation. Further, the researchers linked the skull malformation to the loss of one gene: Tbx1.

The research shows that neurological disorders can stem from sources beyond the nervous system, such as improper skull development. The findings were published today in Nature Communications.

Gene removal blocks skull pocket from forming.

Previous work from scientists found that the deletion of only one 22q gene, Dgcr8, disrupts the flow of auditory information from a lower brain region called the thalamus to the auditory cortex, where sounds are interpreted. This region of the brain is also associated with auditory hallucinations, which are a hallmark symptom of schizophrenia. The researchers called this breakdown in information flow "thalamocortical disruption."

Although thalamocortical disruption occurs late in development, which is consistent with the onset of schizophrenia symptoms, it stays and doesn't go away. However, hallucinations are transient in nature—they come and go.

It seemed that this was just one of the hits that triggered symptoms.

The researchers noticed a part of the brain, the cerebellum, malformed in 22q animal models, specifically, the cerebellum's small lobules called the flocculus and paraflocculus. Most neurodevelopmental disorders arise from defects in genes that play a role in the brain, but the 22q gene the researchers linked to this malformation, Tbx1, was unexpected.

What is interesting about Tbx1 is that it is not very well expressed in the brain, especially the adolescent or adult brain. Rather, it's expressed in the surrounding tissues, namely bone, cartilage and vasculature tissues. It is very unlikely that Tbx1 directly affects the brain at all.

Instead, removing Tbx1 has an indirect but significant effect on brain development. Bone formation relies on immature osteoblast cells correctly growing into mature osteocytes. Tbx1 removal disrupted this cycle, resulting in an underdeveloped pocket in the skull which normally houses the flocculus and paraflocculus.

For a neurological syndrome, the findings are strikingly unusual—with no pocket in the skull for these structures to develop, they appear substantially smaller than normal. The reduction of the flocculus and paraflocculus was validated through magnetic resonance imaging studies of dozens of patients with 22q and a comparative control group.

Part 1

Comment by Dr. Krishna Kumari Challa on December 6, 2024 at 11:16am

Scientists have data representing genetic material from 50,000 E. coli samples gathered from four continents. When they studied these, they saw that the ability to produce the toxin is very limited and is primarily found in two particular genotypes of E. coli bacteria. Both of these circulate frequently in Norway and they are also the main genotypes causing infections in the bloodstream in the country.
In contrast, these genotypes of bacteria are rarely found in countries of South Asia.
The scientists involved in this study have therefore put forward a number of hypotheses on which ecological conditions drive these unwanted bacterial families away from certain population groups.
If scientists can succeed in developing vaccines against the harmful type of E. coli that produces colibactin, or a form of probiotics, this would result in notable public health benefits. These measures could eliminate the unwanted colibactin-producing bacteria from the intestines.

Tommi Mäklin et al, Geographical variation in the incidence of colorectal cancer and urinary tract cancer is associated with population exposure to colibactin-producing Escherichia coli, The Lancet Microbe (2024). DOI: 10.1016/j.lanmic.2024.101015. www.sciencedirect.com/science/ … ii/S2666524724002830

Part 2

Comment by Dr. Krishna Kumari Challa on December 6, 2024 at 11:09am

Scientists explore role of intestinal bacteria in cancer prevention

The link between intestinal bacteria and cancer

Certain intestinal bacteria are found more frequently in some countries such as Norway than in a number of other countries and there is also a higher incidence of bladder cancer, bowel cancer and prostate cancer. These findings may lead to new opportunities for preventing these types of cancer, according to a new study.

Previous studies have shown that a toxin produced by certain bacteria in order to dominate inside the intestine, causes damage to healthy cells and increases the risk of developing bowel cancer.

In a new study, scientists examined the incidence of bladder, colon, rectal and prostate cancer and compared this to the prevalence of two toxin-producing E. coli bacteria in the countries concerned. E. coli is the most common cause of urinary tract infections and bacterial infections in the bloodstream worldwide. Norway has a higher incidence of bladder cancer and colorectal cancer compared with many other countries.

In the course of the study, scientists also found that the prevalence of these two E. coli bacteria was higher in Norway. When they compared equivalent data from several different countries, they discovered a clear pattern: the fewer of these E. coli bacteria that circulate in the population, the lower the incidence of these types of cancer, and vice versa, and the study recently published in The Lancet Microbe confirms this.

In recent years, intense research has been carried out internationally on the link between the toxin produced by these bacteria, called colibactin, and several types of cancer. The research was initiated after groundbreaking studies revealed that colibactin damages DNA in intestinal cells and scientists produced models of intestinal organs and saw that the toxin-producing E. coli resulted in cancer in the models.

Part 1

Comment by Dr. Krishna Kumari Challa on December 6, 2024 at 10:37am

How hummingbirds fly and feed

Comment by Dr. Krishna Kumari Challa on December 6, 2024 at 9:42am

Engineered immune cells to tame inflammation

When the immune system overreacts and starts attacking the body, the only option may be to shut the entire system down and risk developing infections or cancer. But now, scientists  may have found a more precise way to dial the immune system down.

The technology uses engineered T cells that act as immune "referees" to soothe overreacting immune responses. They also can mop up inflammatory molecules.

The new approach could be used to stop the body from rejecting transplanted organs and tissues, such as pancreatic islet cells, which are sometimes used to treat type 1 diabetes. That way, recipients would not need to take harsh immunosuppressant drugs.

This technology can put the immune system back into balance.

The research The team adapted the suppressor cells' anti-inflammatory abilities to work in CD4 immune cells. These are the same cells that are used to make cancer-killing CAR T cells. They also gave these cells a molecular sensor to guide them to their target tissue in the body.

Proof of principle in type 1 diabetes :

The scientists tailored a batch of immune referees to search for human pancreatic islet cells and then produce TGF-Beta and CD25, molecules that can muzzle killer T cells.

They introduced the engineered referee cells into mice that had received a transplant of human islet cells, modeling the treatment for type 1 diabetes.

The referee cells found the vulnerable islet cells and stopped the killer T cells from attacking, and the islet cells survived.

 Nishith R. Reddy et al, Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs, Science (2024). DOI: 10.1126/science.adl4793. www.science.org/doi/10.1126/science.adl4793

Comment by Dr. Krishna Kumari Challa on December 5, 2024 at 2:19pm

To get the cell to use homology-directed repair, the researchers recently began using a molecule called AZD7648, which blocks fast repair and forces the cell to use homology-directed repair. This approach is expected to accelerate the development of more efficient gene therapies. Initial studies with these new therapies have been good. Too good to be true, as it turned out.

A research group led by Corn has discovered that the use of AZD7648 has serious side effects. The study has been published in the journal Nature Biotechnology.

Although AZD7648 promotes precise repair and thus precise gene editing using the CRISPR-Cas9 system as hoped, in a significant proportion of cells this has led to massive genetic changes in a part of the genome that was expected to be modified without scarring.

The ETH researchers found that these changes resulted in the simple deletion of thousands and thousands of DNA building blocks, known as bases. Even whole chromosome arms broke off. This makes the genome unstable, with unpredictable consequences for the cells edited by the technique.

When the researchers analyzed the genome at the sites where it had been edited, it looked correct and precise. But when they analyzed the genome more broadly, they saw massive genetic changes. These are not seen when you only analyze the short, edited section and its immediate neighborhood.

The extent of the negative effects surprised the researchers. In fact, they suspect that they do not yet have a complete picture of the full extent of the damage because they did not look at the entire genome when analyzing the modified cells, only partial regions.

New tests, approaches and regulations are therefore needed to clarify the extent and potential of the damage.

The development of any new technology is a rocky road. One stumble does not mean we give up on the technology, say the researchers.

Gene therapies based on the CRISPR-Cas system have already been successfully used in clinical practice. In recent years, for example, a hundred patients suffering from the hereditary disease sickle cell anemia have been treated with CRISPR-Cas-based therapeutics—without AZD7648.

"All patients are considered cured and have no side effects".

Grégoire Cullot et al, Genome editing with the HDR-enhancing DNA-PKcs inhibitor AZD7648 causes large-scale genomic alterations, Nature Biotechnology (2024). DOI: 10.1038/s41587-024-02488-6

Part 2

Comment by Dr. Krishna Kumari Challa on December 5, 2024 at 2:15pm

Serious side effect of using CRISPR-Cas gene scissors uncovered: AZD7648 molecule can destroy parts of genome

Genome editing with various CRISPR-Cas molecule complexes has progressed rapidly in recent years. Hundreds of labs around the world are now working to put these tools to clinical use and are continuously advancing them.

CRISPR-Cas tools allow researchers to modify individual building blocks of genetic material in a precise and targeted manner. Gene therapies based on such gene editing are already being used to treat inherited diseases, fight cancer and create drought- and heat-tolerant crops.

The CRISPR-Cas9 molecular complex, also known as genetic scissors, is the most widely used tool by scientists around the world. It cuts the double-stranded DNA at the exact site where the genetic material needs to be modified. This contrasts with newer gene-editing methods, which do not cut the double strand.

The cut activates two natural repair mechanisms that the cell uses to repair such damage: a fast but imprecise one that reconnects only the ends of the cut DNA, and a slow and precise one that is not activated in every case. The latter requires a copyable template for repair to accurately rejoin the DNA at the cut site.

The slow variant is called homology-directed repair. Researchers want to use this method of repair because it allows the precise integration of individual DNA segments into a desired gene region. The approach is very flexible and can be used to repair different disease genes.

In principle, it could be used to cure any disease.

Part 1

Comment by Dr. Krishna Kumari Challa on December 5, 2024 at 11:29am

Interestingly, the cancer cells themselves were unable to use fructose readily as a nutrient because they do not express the right biochemical machinery. Liver cells do. This allows them to convert fructose into LPCs, which they can secrete to feed tumors.

Gary Patti, Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer, Nature (2024). DOI: 10.1038/s41586-024-08258-3. www.nature.com/articles/s41586-024-08258-3

Part 2

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