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Comment by Dr. Krishna Kumari Challa on January 8, 2023 at 10:50am

How liver cancer hijacks circadian clock machinery inside cells

The most common type of liver cancer, hepatocellular carcinoma (HCC), is already the third leading cause of cancer-related deaths globally—and cases are on the rise worldwide. While chemotherapy, surgery and liver transplants can help some patients, targeted treatments for HCC could save millions more lives.

Recent studies have offered clues about one potential target: the circadian clock proteins inside cells, which help coordinate changes in the body's functioning over the course of a day. But most of this research only hints at an indirect link between circadian clock function and HCC, for instance the observation that cells collected from patients with liver cancer have disrupted circadian rhythms. Now, a study by researchers not only directly links circadian clock proteins to liver cancer, but also shows precisely how cancer cells hijack circadian clock machinery to divide and spread. The research, just published in the journal Proceedings of the National Academy of Sciences, also found that inhibiting key clock proteins can prevent cancer cells from multiplying.

By targeting the circadian clock, we are not only targeting tumour cells but also the area around the tumor, which can help increase the efficacy of other targeted treatments.

The researchers showed that two key clock proteins, known as CLOCK and BMAL1, are critical for the replication of liver cancer cells in cell culture. When CLOCK and BMAL1 are suppressed, cancer cells' replication process was interrupted—ultimately causing cell death, or apoptosis. Triggering apoptosis, during which a cell stops dividing, then self-destructs, is the goal of many modern cancer treatments.

Among other findings, they showed that eliminating the clock proteins reduced levels of the enzyme Wee1 and increased levels of the enzyme inhibitor P21. That's exactly what you want, because when it comes to cancer cell proliferation, P21 is a brake and Wee1 is a gas pedal.

Finally, the researchers tested their findings in vivo. Mice injected with unmodified human liver cancer cells grew large tumors, but those injected with cells modified to suppress CLOCK and BMAL1 showed little to no tumour growth.

 Meng Qu et al, Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2214829120

Comment by Dr. Krishna Kumari Challa on January 7, 2023 at 11:44am

After transplantation, the follicles continued to produce hair and induced restoration across skin layers. Scarring causes the outermost layer of skin—the epidermis—to thin out, leaving it vulnerable to tears. At six months post-transplant, the epidermis had doubled in thickness alongside increased cell growth, bringing it to around the same thickness as uninjured skin. The next skin layer down, the dermis, is populated with connective tissue, blood vessels, sweat glands, nerves, and hair follicles. Scar maturation leaves the dermis with fewer cells and blood vessels, but after transplantation the number of cells had doubled at six months, and the number of vessels had reached nearly healthy-skin levels by four months. This demonstrated that the follicles inspired the growth of new cells and blood vessels in the scars, which are unable to do this unaided. Scarring also increases the density of collagen fibers—a major structural protein in skin—which causes them to align such that scar tissue is stiffer than healthy tissue. The hair transplants reduced the density of the fibers, which allowed them to form a healthier "basket weave" pattern, reducing stiffness—a key factor in tears and discomfort. The authors also found that after transplantation, the scars expressed 719 genes differently than before. Genes that promoted cell and blood vessel growth were expressed more, while genes that promoted scar-forming processes were expressed less.

Anagen hair follicles transplanted into mature human scars remodel fibrotic tissue, npj Regenerative Medicine (2023). DOI: 10.1038/s41536-022-00270-3 , www.nature.com/articles/s41536-022-00270-3

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Comment by Dr. Krishna Kumari Challa on January 7, 2023 at 11:43am

Scars mended using transplanted hair follicles in new study

In a new  study involving three volunteers, skin scars began to behave more like uninjured skin after they were treated with hair follicle transplants. The scarred skin harbored new cells and blood vessels, remodeled collagen to restore healthy patterns, and even expressed genes found in healthy unscarred skin.

The findings could lead to better treatments for scarring both on the skin and inside the body, leading to hope for patients with extensive scarring, which can impair organ function and cause disability.

After scarring, the skin never truly regains its pre-wound functions, and until now all efforts to remodel scars have yielded poor results. The new  findings lay the foundation for exciting new therapies that can rejuvenate even mature scars and restore the function of healthy skin.

Scar tissue in the skin lacks hair, sweat glands, blood vessels and nerves, which are vital for regulating body temperature and detecting pain and other sensations. Scarring can also impair movement as well as potentially cause discomfort and emotional distress.

Compared to scar tissue, healthy skin undergoes constant remodeling by the hair follicle. Hairy skin heals faster and scars less than non-hairy skin—and hair transplants had previously been shown to aid wound healing. Inspired by this, the researchers hypothesized that transplanting growing hair follicles into scar tissue might cause scars to remodel themselves. To test their hypothesis,  researchers  transplanted hair follicles into the mature scars on the scalps of three participants in 2017. The researchers selected the most common type of scar, called normotrophic scars, which usually form after surgery. They took and microscope-imaged 3 mm-thick biopsies of the scars just before transplantation, and then again at two, four, and six months afterwards. The researchers found that the follicles inspired profound architectural and genetic shifts in the scars towards a profile of healthy, uninjured skin.

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Comment by Dr. Krishna Kumari Challa on January 7, 2023 at 11:35am

The researchers built a model that uses de novo mutations—a genetic alteration that is present for the first time in one family member as a result of a variant or mutation in a germ cell of one of the parents or that arises in the fertilized egg during early embryogenesis—to separately estimate the male and female generation times at many different points throughout the past 250,000 years.

The story of human history is pieced together from a diverse set of sources: written records, archaeological findings, fossils, etc. Our genomes, the DNA found in every one of our cells, offer a kind of manuscript of human evolutionary history. The findings from our genetic analysis confirm some things we knew from other sources (such as the recent rise in parental age), but also offer a richer understanding of the demography of ancient humans. These findings contribute to a better understanding of our shared history.

Richard Wang, Human generation times across the past 250,000 years, Science Advances (2023). DOI: 10.1126/sciadv.abm7047. www.science.org/doi/10.1126/sciadv.abm7047

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Comment by Dr. Krishna Kumari Challa on January 7, 2023 at 11:35am

Study reveals average age at conception for men versus women over past 250,000 years

The length of a specific generation can tell us a lot about the biology and social organization of humans. Now, researchers  can determine the average age that women and men had children throughout human evolutionary history with a new method they developed using DNA mutations.

The researchers said this work can help us understand the environmental challenges experienced by our ancestors and may also help us in predicting the effects of future environmental change on human societies.

Through this research on  modern humans, researchers noticed that they could predict the age at which people had children from the types of DNA mutations they left to their children.They  then applied this model to our human ancestors to determine what age our ancestors procreated.

According to the study, published recently in Science Advances, the average age that humans had children throughout the past 250,000 years is 26.9. Furthermore, fathers were consistently older, at 30.7 years on average, than mothers, at 23.2 years on average, but the age gap has shrunk in the past 5,000 years, with the study's most recent estimates of maternal age averaging 26.4 years. The shrinking gap seems to largely be due to mothers having children at older ages. Other than the recent uptick in maternal age at childbirth, the researchers found that parental age has not increased steadily from the past and may have dipped around 10,000 years ago because of population growth coinciding with the rise of civilization. These mutations from the past accumulate with every generation and exist in humans today. Researchers  can now identify these mutations, see how they differ between male and female parents, and how they change as a function of parental age. Children's DNA inherited from their parents contains roughly 25 to 75 new mutations, which allows scientists to compare the parents and offspring, and then to classify the kind of mutation that occurred. When looking at mutations in thousands of children, the researchers noticed a pattern: The kinds of mutations that children get depend on the ages of the mother and the father. Previous genetic approaches to determining historical generation times relied on the compounding effects of either recombination or mutation of modern human DNA sequence divergence from ancient samples. But the results were averaged across both males and females and across the past 40,000 to 45,000 years.

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Comment by Dr. Krishna Kumari Challa on January 6, 2023 at 9:57am

The study documents three types of discoveries from a genotype-first approach.

First, the researchers found that this approach helped discover new relationships between genomic variants and specific clinical traits. For example, one NIH study found that having more than two copies of the TPSAB1 gene was associated with symptoms related to the gastrointestinal tract, connective tissues, and the nervous system.

Second, this approach helped researchers find novel symptoms related to a disorder that clinicians previously missed because the patient did not have the typical symptoms. NHGRI researchers identified a person with a genomic variant associated with a known metabolic disorder. Further testing found that the individual had high levels of certain chemicals in their body associated with the disorder, despite having only minor symptoms.

Third, this approach allowed researchers to determine the function of specific genomic variants, which has the potential to help clinicians understand newly described disorders. For example, in one study, NHGRI researchers and their collaborators found that a genomic variant was associated with immune dysfunction at the molecular level in blood cells.

Leslie G. Biesecker, Genotype First: Clinical Genomics Research Through a Reverse Phenotyping Approach, The American Journal of Human Genetics (2023). DOI: 10.1016/j.ajhg.2022.12.004. www.cell.com/ajhg/fulltext/S0002-9297(22)00538-9

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Comment by Dr. Krishna Kumari Challa on January 6, 2023 at 9:56am

New approach successfully traces genomic variants back to genetic disorders

Researchers have published an assessment of 13 studies that took a genotype-first approach to patient care. This approach contrasts with the typical phenotype-first approach to clinical research, which starts with clinical findings. A genotype-first approach to patient care involves selecting patients with specific genomic variants and then studying their traits and symptoms; this finding uncovered new relationships between genes and clinical conditions, broadened the traits and symptoms associated with known disorders, and offered insights into newly described disorders. The study was published in the American Journal of Human Genetics.

Genotype-first research can work, especially for identifying people with rare disorders who otherwise might not have been brought to clinical attention.

Typically, to treat genetic conditions, researchers first identify patients who are experiencing symptoms, then they look for variants in the patients' genomes that might explain those findings. However, this can lead to bias because the researchers are studying clinical findings based on their understanding of the disorder. The phenotype-first approach limits researchers from understanding the full spectrum of symptoms of the disorders and the associated genomic variants.

Genomics has the potential to change reactive medicine into preventative medicine. Studying how taking a genotype-first approach to research can help us learn how to model predictive and precision medicine in the future.

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Comment by Dr. Krishna Kumari Challa on January 6, 2023 at 9:02am

The brain's ability to perceive space expands like the universe

Young children sometimes believe that the moon is following them, or that they can reach out and touch it. It appears to be much closer than is proportional to its true distance. As we move about our daily lives, we tend to think that we navigate space in a linear way. But  scientists have discovered that time spent exploring an environment causes neural representations to grow in surprising ways.

The findings, published in Nature Neuroscience on December 29, 2022, show that neurons in the hippocampus essential for spatial navigation, memory, and planning represent space in a manner that conforms to a nonlinear hyperbolic geometry—a three-dimensional expanse that grows outward exponentially. (In other words, it's shaped like the interior of an expanding hourglass.) The researchers also found that the size of that space grows with time spent in a place. And the size is increasing in a logarithmic fashion that matches the maximal possible increase in information being processed by the brain.

This discovery provides valuable methods for analyzing data on neurocognitive disorders involving learning and memory, such as Alzheimer's disease.

This new study demonstrates that the brain does not always act in a linear manner. Instead, neural networks function along an expanding curve, which can be analyzed and understood using hyperbolic geometry and information theory.It is exciting to see that neural responses in this area of the brain formed a map that expanded with experience based on the amount of time devoted in a given place. The effect even held for miniscule deviations in time when animal ran more slowly or faster through the environment.

In the current study, the scientists found that hyperbolic geometry guides neural responses as well. Hyperbolic maps of sensory molecules and events are perceived with hyperbolic neural maps. The space representations dynamically expanded in correlation with the amount of time the rat spent exploring each environment. And, when a rat moved more slowly through an environment, it gained more information about the space, which caused the neural representations to grow even more.

The findings provide a novel perspective on how neural representations can be altered with experience. The geometric principles identified in our study can also guide future endeavors in understanding neural activity in various brain systems.

You would think that hyperbolic geometry only applies on a cosmic scale, but that is not true. Our brains work much slower than the speed of light, which could be a reason that hyperbolic effects are observed on graspable spaces instead of astronomical ones.

Huanqiu Zhang et al, Hippocampal spatial representations exhibit a hyperbolic geometry that expands with experience, Nature Neuroscience (2022). DOI: 10.1038/s41593-022-01212-4

Comment by Dr. Krishna Kumari Challa on January 5, 2023 at 10:02am

An Organism That Can Dine Exclusively on Viruses Has Been Found in a World First

A type of freshwater plankton has become the first organism seen thriving on a diet of viruses, according to a new study by researchers.

Viruses are often consumed incidentally by a range wide of organisms, and may even season the diets of certain marine protists. But to qualify as a true step in the food chain – described as virovory – viruses ought to contribute a significant amount of energy or nutrients to their consumer.

The microbe Halteria is a common genus of protist known to flit about as its hair-like cilia propel it through the water. Not only did laboratory samples of the ciliate consume chloroviruses added to its environment, the giant virus fueled Halteria's growth and increased its population size.

The knock-on effects of widespread consumption of chloroviruses in the wild could have a profound impact on the carbon cycle. Known to infect microscopic green algae, chloroviruses cause their hosts to burst apart, releasing carbon and other nutrients into the environment – a process that serious amounts of virus-eating could be limiting.

There's some good stuff inside viruses if you're an organism looking to feed, including amino acids, nucleic acids, lipids, nitrogen, and phosphorus. Surely something would want to make a meal out of that.

While the Paramecium snacked on the viruses, its sizes and numbers barely budged. Halteria, on the other hand, dined on them, using the chlorovirus as a source of nutrients. The ciliate's population grew about 15 times larger in two days, while the virus population dropped a hundredfold.

Fluorescent green dye was used to tag chlorovirus DNA before it was introduced to the two types of plankton. This confirmed that the viruses were being eaten: the vacuoles – microbial equivalent of stomachs – were glowing green from the feeding.

Further analysis revealed that the growth of Halteria in comparison to the decline of the chlorovirus matched the ratios seen in other microscopic predator vs prey relationships in aquatic environments, giving the team more evidence of what was happening.

https://www.pnas.org/doi/10.1073/pnas.2215000120

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Comment by Dr. Krishna Kumari Challa on January 5, 2023 at 9:07am

Insulin has changed little throughout evolution

Do the results allow conclusions to be drawn about humans? Probably.

Although the release of insulin in fruit flies is mediated by different cells than in humans, the insulin molecule and its function have hardly changed in the course of evolution.

In the past 20 years, using Drosophila as a model organism, many fundamental questions have already been answered that could also contribute to a better understanding of metabolic defects in humans and associated diseases, such as diabetes or obesity.

Less insulin means longevity

One exciting point is that reduced insulin activity contributes to healthy aging and longevity. This has already been shown in flies, mice, humans and other species. The same applies to an active lifestyle. Our work shows a possible link explaining how physical activity could positively affect insulin regulation via neuronal signaling pathways.

Sander Liessem et al, Behavioral state-dependent modulation of insulin-producing cells in Drosophila, Current Biology (2022). DOI: 10.1016/j.cub.2022.12.005

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