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Comment by Dr. Krishna Kumari Challa on May 6, 2024 at 10:32am

In translational patient-based studies, the team also analyzed human tissue, blood and stool samples from Weill Cornell Medicine's Jill Roberts Institute for Research in Inflammatory Bowel Disease Live Cell Bank. This analysis revealed that patients with inflammatory bowel disease, like the mice fed inulin, had higher levels of bile acids in their blood and stool and excessive levels of eosinophils in their intestine compared with people without the condition.

The results suggest that the inflammation cascade similar to that in the mice fed inulin is already primed in humans with inflammatory bowel disease, and dietary uptake of inulin may further exacerbate the disease.
These unexpected discoveries may help explain why high-fiber diets often exacerbate inflammatory bowel disease in patients. It may also help scientists develop therapeutic diets to reduce symptoms and gut damage in patients with inflammatory bowel disease or related conditions.

New therapies are urgently needed for these increasingly common gut conditions. Existing biologic therapies can increase the risk of developing infections or autoimmune diseases, which cause the immune system to attack the body. 
The present study shows that not all fibers are the same in how they influence the microbiota and the body's immune system.
These findings could have broader implications for the delivery of precision nutrition to individual patients to promote their overall health based on their unique symptoms, microbiota composition and dietary needs.

Mohammad Arifuzzaman et al, Dietary fiber is a critical determinant of pathologic ILC2 responses and intestinal inflammation, Journal of Experimental Medicine (2024). DOI: 10.1084/jem.20232148

Part 2

Comment by Dr. Krishna Kumari Challa on May 6, 2024 at 10:31am

A common type of fiber may trigger bowel inflammation

Inulin, a type of fiber found in certain plant-based foods and fiber supplements, causes inflammation in the gut and exacerbates inflammatory bowel disease in a preclinical model, according to a new study by  investigators. The surprising findings could pave the way for therapeutic diets that may help ease symptoms and promote gut health. 

The study, published March 20 in the Journal of Experimental Medicine, shows that inulin, which is found in foods such as garlic, leeks and sunchoke, as well as commonly used fiber supplements and foods with added fiber, stimulates microbes in the gut to release bile acids that increase the production of molecules that promote intestinal inflammation.

One such protein, IL-33, causes immune cells called group 2 innate lymphoid cells (ILC2s) to become activated, triggering an excessive immune response similar to an allergic reaction. That excessive immune response then exacerbates intestinal damage and symptoms in an animal model of inflammatory bowel disease.
Dietary fiber, including inulin, is considered an essential part of a healthy diet for most people. Gut microbes turn inulin and other types of dietary fiber into short-chain fatty acids that turn on immune cells called regulatory T cells, which help reduce inflammation and have other beneficial effects throughout the body. This led to a remarkable rise in use of dietary fiber as an additive in both foods and supplements, and purified inulin or inulin-rich chicory root is often the main source of the fiber.
Inulin is now everywhere, from clinical trials to prebiotic sodas.
Feeding inulin to mice in the context of a model of inflammatory bowel disease increased the production of certain bile acids by specific groups of gut bacteria. The increased bile acids boosted the production of an inflammatory protein called IL-5 by ILC2s. The ILC2s also failed to produce a tissue-protecting protein called amphiregulin.

In response to these changes, the immune system promotes the production of immune cells called eosinophils, which further ramp up inflammation and tissue damage. Previously, a 2022 study by the same team of investigators showed that this flood of eosinophils may help protect against parasite infections. However, in the inflammatory bowel disease model, this chain reaction exacerbated intestinal inflammation, weight loss and other symptoms like diarrhea. 
Part 1

Comment by Dr. Krishna Kumari Challa on May 6, 2024 at 10:03am

A 'cosmic glitch' in gravity: New model may explain strange behaviour on a cosmic scale

A group of researchers  have discovered a potential "cosmic glitch" in the universe's gravity, explaining its strange behavior on a cosmic scale.

The paper is published in the Journal of Cosmology and Astroparticle Physics.
For the last 100 years, physicists have relied upon Albert Einstein's theory of "general relativity" to explain how gravity works throughout the universe. General relativity, proven accurate by countless tests and observations, suggests that gravity impacts not simply three physical dimensions but also a fourth dimension: time.

This model of gravity has been essential for everything from theorizing the Big Bang to photographing black holes.
But when we try to understand gravity on a cosmic scale, at the scale of galaxy clusters and beyond, we encounter apparent inconsistencies with the predictions of general relativity. It's almost as if gravity itself stops perfectly matching Einstein's theory. We are calling this inconsistency a 'cosmic glitch': gravity becomes around one percent weaker when dealing with distances in the billions of light years.
For more than twenty years, physicists and astronomers have been trying to create a mathematical model that explains the apparent inconsistencies of the theory of general relativity. Many of those efforts have taken place at Waterloo, which has a long history of cutting-edge gravitational research resulting from ongoing interdisciplinary collaboration between applied mathematicians and astrophysicists.

"Almost a century ago, astronomers discovered that our universe is expanding.
The farther away galaxies are, the faster they are moving, to the point that they seem to be moving at nearly the speed of light, the maximum allowed by Einstein's theory. Our finding suggests that, on those very scales, Einstein's theory may also be insufficient.
The research team's new model of a "cosmic glitch" modifies and extends Einstein's mathematical formulas in a way that resolves the inconsistency of some of the cosmological measurements without affecting existing successful uses of general relativity.

"Think of it as being like a footnote to Einstein's theory," the researchers say. "Once you reach a cosmic scale, terms and conditions apply."

"This new model might just be the first clue in a cosmic puzzle we are starting to solve across space and time".

Robin Y. Wen et al, A cosmic glitch in gravity, Journal of Cosmology and Astroparticle Physics (2024). DOI: 10.1088/1475-7516/2024/03/045

Comment by Dr. Krishna Kumari Challa on May 6, 2024 at 9:52am

New mRNA cancer vaccine triggers fierce immune response to fight malignant brain tumour

Glioblastoma is among the most devastating diagnoses, with median survival around 15 months. The current standard of care involves surgery, radiation and some combination of chemotherapy.

In a first-ever human clinical trial of four adult patients, an mRNA cancer vaccine developed by scientists quickly reprogrammed the immune system to attack glioblastoma, the most aggressive and lethal brain tumour.

The results mirror those in 10 pet dog patients suffering from naturally occurring brain tumors whose owners approved of their participation, as they had no other treatment options, as well as results from preclinical mouse models. The breakthrough now will be tested in a Phase I pediatric clinical trial for brain cancer.

Reported May 1 in the journal Cell, the discovery represents a potential new way to recruit the immune system to fight notoriously treatment-resistant cancers using an iteration of mRNA technology and lipid nanoparticles, similar to COVID-19 vaccines, but with two key differences: use of a patient's own tumor cells to create a personalized vaccine, and a newly engineered complex delivery mechanism within the vaccine.

In less than 48 hours, the researchers could see these tumours shifting from what they refer to as 'cold'—immune cold, very few immune cells, very silenced immune response—to 'hot,' very active immune response.

The 10 pet dogs on which trials were done lived a median of 139 days, compared with a median survival of 30 to 60 days typical for dogs with the condition.

 RNA aggregates harness the danger response for potent cancer immunotherapy, Cell (2024). DOI: 10.1016/j.cell.2024.04.003. www.cell.com/cell/fulltext/S0092-8674(24)00398-2

Comment by Dr. Krishna Kumari Challa on May 4, 2024 at 11:38am

Most amniotic fluid cells are epithelial, but scientists knew very little about these cell populations. Everything changed when researchers started to look at the single cell level at what happened in the amniotic fluid.
used single-cell RNA sequencing to characterize the amniotic fluid of 12 patients and discovered subpopulations of epithelial cells that expressed markers typical of progenitors for the lung, kidney, and small intestine. The researchers cultured the tissue-specific progenitor cells, fed them a chemical cocktail to support growth, and watched as they proliferated, differentiated, and self-organized into 3D epithelial organoids. The mini-organs shared some transcriptomic and protein features found in their tissues of origin. For example, lung epithelial cells that developed and differentiated in culture had elevated expression of airway markers compared to their nondifferentiated counterparts. Similarly, kidney epithelial organoids expressed markers associated with renal tubules, which are integral components of the kidneys’ filtration system.

Although the amniotic fluid contained cells from other tissues, the researchers could not grow them into organoids, suggesting that they lack progenitor capabilities. Other research groups have successfully grown fetal organoids from somatic cells floating around the amniotic fluid, and the mini-organs generated using this approach are more complex.
reprogramming methods take up to 20 weeks to generate organoids. If the goal is to use organoids to inform prenatal interventions, timing is critical.
Part 3

Researchers re using these to study various diseases and find solutions to them.

More here: https://www.the-scientist.com/fetal-organoids-generated-from-human-...

Comment by Dr. Krishna Kumari Challa on May 4, 2024 at 11:35am

Scientists use patient cells to generate organoids that possess certain features and functions of the modeled organ while retaining the individual's genetic fingerprint. However, many of these platforms require lengthy dedifferentiation protocols to revert somatic cells into a state of pluripotency and then reprogram them to develop as another cell type. In contrast to organoids generated from pluripotent stem cells, primary organoids use tissue-specific stem cells or progenitor cells and therefore require minimal manipulation.3 While the organoid field is relatively advanced in terms of using adult tissues, researchers can only generate primary fetal organoids using tissue from terminated pregnancies. “This made it basically impossible to [generate organoids] compatible with the continuation of pregnancy, and therefore in a personalized medicine fashion”.
During gestation, the fetus floats in a protective pool of amniotic fluid.6 The yellowish liquid contains a concoction of nutrients and antibodies produced by the parent as well as less glamorous contributions from the fetus, including urine. It also includes fetal cells sloughed off during development, which doctors can extract and analyze for signs of disease.

“Those cells historically have been thought to be dead cells or cells that were shed from the lining of the amniotic fluid cavity.
Part 2

Comment by Dr. Krishna Kumari Challa on May 4, 2024 at 11:32am

Fetal Organoids Generated From Human Amniotic Fluid

A minimally invasive strategy for creating fetal organoids could facilitate precision medicine in the womb.

Moments after birth, a baby takes a first breath as the placenta, which has served as the fetus’ lungs during gestation, transfers responsibility to the baby's own organs. However, for patients born with congenital diaphragmatic hernia (CDH), a rare condition where the diaphragm fails to close, causing impaired lung development, entry into the world is more precarious. More severe cases of the disease lead to multiorgan damage, and approximately thirty percent of infants diagnosed with CDH never leave the hospital.

Diagnostic imaging and genetic screens help clinicians catch congenital fetal diseases in utero, but models for studying organ development and disease progression are limited. Over the last decade, organoids have become an increasingly popular platform for modeling organ function and disease. However, the generation of fetal organoids is complicated by ethical and legal restrictions on the harvesting of the human tissues needed to generate the mini-organs.

Now, reporting in Nature Medicine, researchers generated fetal organoids using cells derived from human amniotic and tracheal fluids. These mini-organs offer a minimally invasive approach for disease modeling during an active pregnancy and may eventually inform the development of personalized prenatal interventions.

Part 1

Comment by Dr. Krishna Kumari Challa on May 4, 2024 at 10:40am

Ice shelves fracture under weight of meltwater lakes, study shows

When air temperatures in Antarctica rise and glacier ice melts, water can pool on the surface of floating ice shelves, weighing them down and causing the ice to bend. Now, for the first time in the field, researchers have shown that ice shelves don't just buckle under the weight of meltwater lakes—they fracture.

As the climate warms and melt rates in Antarctica increase, this fracturing could cause vulnerable ice shelves to collapse, allowing inland glacier ice to spill into the ocean and contribute to sea level rise.

Ice shelves are important for the Antarctic Ice Sheet's overall health as they act to buttress or hold back the glacier ice on land. Scientists have predicted and modeled that surface meltwater loading could cause ice shelves to fracture, but no one had observed the process in the field, until now.

The new study, published in the Journal of Glaciology, may help explain how the Larsen B Ice Shelf abruptly collapsed in 2002. In the months before its catastrophic breakup, thousands of meltwater lakes littered the ice shelf's surface, which then drained over just a few weeks.

 Alison F. Banwell et al, Observed meltwater-induced flexure and fracture at a doline on George VI Ice Shelf, Antarctica, Journal of Glaciology (2024). DOI: 10.1017/jog.2024.31

Comment by Dr. Krishna Kumari Challa on May 4, 2024 at 10:24am

Mantle movements shape Earth's surface

The movement of tectonic plates shapes the rocky features of Earth's surface. Plates' convergence can form mountain ranges or ocean trenches, and their divergence can form oceanic ridges. But it's not just the plates themselves that influence Earth's topography. The mantle layer underneath exerts its own subtle influence, which can be seen even in places located far from tectonic plate edges, and is referred to as residual topography.

To better understand how the mantle affects topography,  researchers building on previous work focused on the oceans, created two new databases. The paper is published in the Journal of Geophysical Research: Solid Earth.

One compiles 26,725 measurements of crust thickness around the globe, the largest such database to date, along with estimates of seismic velocity. The other contains laboratory analysis of seismic velocity as a function of temperature, density, and pressure. Together these measurements helped disentangle crustal influences on topography from mantle influences to identify residual topography.

The researchers found that differences in the temperature and chemical structure of the mantle can cause swells and basins in the landscape distinct from those that form at the edges of tectonic plates. These features can rise or fall by up to 2 kilometers and stretch for hundreds to thousands of kilometers—all within the interior of plates.

Some of the highest swells (about 2 kilometers), which are thought to correspond to locations where the mantle is particularly hot, can be found in the Afar–Yemen–Red Sea region, western North America, and Iceland. Some of the deepest basins (deeper than about 1.5 kilometers), where the mantle is thought to be cooler, are in areas near the Black, Caspian, and Aral seas, as well as in the East European Plain. This pattern of swells and basins may control—to some extent—the locations where significant erosion and sedimentary deposition occur.

These topographical features can develop slowly over millions of years, but they nonetheless control important geological processes. According to the researchers, these findings could help explain the existence of magmatism found far from plate boundaries. They also could help scientists understand the elusive effects of flow in Earth's mantle on the surface through geologic time.

Simon N. Stephenson et al, Continental Residual Topography Extracted From Global Analysis of Crustal Structure, Journal of Geophysical Research: Solid Earth (2024). DOI: 10.1029/2023JB026735

Comment by Dr. Krishna Kumari Challa on May 4, 2024 at 10:02am

Genetics, not lack of oxygen, causes cerebral palsy in quarter of cases: Study

The world's largest study of cerebral palsy (CP) genetics has discovered genetic defects are most likely responsible for more than a quarter of cases in Chinese children, rather than a lack of oxygen at birth as previously thought.

The study, published in Nature Medicine, used modern genomic sequencing and found mutations were significantly higher in CP cases with birth asphyxia, indicating a lack of oxygen could be secondary to the underlying genetic defect. The results are consistent with smaller studies globally.

More than 1,500 Chinese children with CP were involved in this research project. 

24.5% of Chinese children in the study had rare genetic variations linked to cerebral palsy. This revelation mirrors  earlier findings in  Australian cerebral palsy cohort, where up to one-third of cases have genetic causes.

This research shows at least some babies who experience birth asphyxia and are diagnosed with CP may have improper brain development as a result of the underlying genetic variants rather than a lack of oxygen.

Crucially, clinically actionable treatments were found in 8.5% of cases with a genetic cause. It is exciting to see how genetic pathways to cerebral palsy inform tailored treatments for these individuals.

Cerebral palsy affects movement and posture and is the most common motor disability in children. The disorder is diagnosed in up to 2 per 1,000 children globally and is sometimes in association with epilepsy, autism and intellectual difficulties. Symptoms often emerge during infancy and early childhood and can range from mild to severe.

The research team identified 81 genes with causation mutations in the children with CP. These genes are known to play important roles in neural and embryonic development and may affect the molecular pathways responsible for respiration.

These results highlight the need for early genetic testing in children with cerebral palsy, especially those with risk factors like birth asphyxia, to ensure they receive the right medical care and treatment.

Yangong Wang et al, Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy, Nature Medicine (2024). DOI: 10.1038/s41591-024-02912-z

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