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Comment by Dr. Krishna Kumari Challa on September 2, 2021 at 11:20am

Scientists  discover a rare, aggressive form of Alzheimer's that begins in the early 40s

A newly discovered gene mutation linked to early onset Alzheimer's disease has been discovered by an international team of scientists, who traced the DNA flaw through multiple members of a single family.

Alzheimer's has long been known as a mind-robbing disease that that wipes out memories and destroys one's sense of self. Most cases of arise sporadically, emerging after age of 65—transmuting one's golden years into a nightmare marked by an incurable brain disease.

Aside from Alzheimer's dementia that begins sporadically in old age, are insidious familial forms that begin years to decades earlier. Early onset refers Alzheimer's that begins before age 65.

Now, an international team of scientists—led by neurobiologists in Sweden—have identified an extraordinarily rare form of the disease that so far has been found only in one family. This form of Alzheimer's is aggressive, rapid and steals its victims' most productive years along their cognitive functions.

Researchers in Sweden have named this form of Alzheimer's—the Uppsala APP deletion—after the family that's endowed with this notorious DNA miscue. It invariably causes descent into dementia at a young age.

Affected individuals have an age at symptom onset  in their early forties, and suffer from a rapidly progressing disease course.

Researchers found that the mutation accelerates the formation of brain-damaging protein plaques, known as amyloid beta, or more simply as Aβ. The gooey plaques destroy neurons and, as a result, annihilate the executive functions of the brain itself. Neuroscientists basically define executive functions as working memory, mental flexibility and self control.

María Pagnon de la Vega et al, The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid β fibril formation, Science Translational Medicine (2021). DOI: 10.1126/scitranslmed.abc6184

https://medicalxpress.com/news/2021-09-scientists-sweden-rare-aggre...

Comment by Dr. Krishna Kumari Challa on September 1, 2021 at 12:33pm

 Winners from the Wellcome Photography Prize 2021: 

Fighting Infections

Comment by Dr. Krishna Kumari Challa on September 1, 2021 at 10:57am

The team was particularly interested in the role of sugar molecules on the spike protein, which are called glycans. To see whether the number, type and position of glycans play a role in the membrane fusion stage of viral cell entry by mediating these intermediate spike formations, they performed thousands of simulations using an all-atom structure-based model. Such models allow prediction of the trajectory of atoms over time, taking into account steric forces—that is, how neighboring atoms affect the movement of others.

The simulations revealed that glycans form a "cage" that traps the "head" of the S2 subunit, causing it to pause in an intermediate form between when it detaches from the S1 subunit and when the viral and cell membranes are fused. When the glycans were not there, the S2 subunit spent much less time in this conformation.

The simulations also suggest that holding the S2 head in a particular position helps the S2 subunit recruit human host cells and fuse with their membranes, by allowing the extension of short proteins called fusion peptides from the virus. Indeed, glycosylation of S2 significantly increased the likelihood that a fusion peptide would extend to the host cell membrane, whereas when glycans were absent, there was only a marginal possibility that this would occur.

 simulations indicate that glycans can induce a pause during the spike protein transition. This provides a critical opportunity for the fusion peptides to capture the host cell.

In the absence of glycans, the viral particle would likely fail to enter the host. Our study reveals how sugars can control infectivity, and it provides a foundation for experimentally investigating factors that influence the dynamics of this pervasive and deadly pathogen.

Esteban Dodero-Rojas et al, Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion, eLife (2021). DOI: 10.7554/eLife.70362

https://phys.org/news/2021-08-sars-cov-dynamics-reveals-opportunity...

part 2 **

Comment by Dr. Krishna Kumari Challa on September 1, 2021 at 10:56am

Model of SARS-CoV-2 dynamics reveals opportunity to prevent COVID-19 transmission

Scientists have simulated the transition of the SARS-CoV-2 spike protein structure from when it recognizes the host cell to when it gains entry, according to a study published today in eLife.

The research shows that a structure enabled by sugar molecules on the spike protein could be essential for cell entry and that disrupting this structure could be a strategy to halt virus transmission.
An essential aspect of SARS-CoV-2's lifecycle is its ability to attach to host cells and transfer its genetic material. It achieves this through its spike protein, which is made up of three separate components—a transmembrane bundle that anchors the spike to the virus, and two S subunits (S1 and S2) on the exterior of the virus. To infect a human cell, the S1 subunit binds to a molecule on the surface of human cells called ACE2, and the S2 subunit detaches and fuses the viral and human cell membranes. Although this process is known, the exact order in which it occurs is as yet undiscovered. Yet, understanding the microsecond-scale and atomic-level movements of these protein structures could reveal potential targets for COVID-19 treatment.
Most of the current SARS-CoV-2 treatments and vaccines have focused on the ACE2 recognition step of virus invasion, but an alternative strategy is to target the structural change that allows the virus to fuse with the human host cell.
But probing these intermediate, transient structures experimentally is extremely difficult, and so researchers now  used a computer simulation sufficiently simplified to investigate this large system but that maintains sufficient physical details to capture the dynamics of the S2 subunit as it transitions between pre-fusion and post-fusion shapes.
part 1

Comment by Dr. Krishna Kumari Challa on September 1, 2021 at 10:35am

Cadherins need calcium ions to complete their connections, so Shim grew the cells with different amounts of calcium and measured their response to electrical stimulation. She saw that the less calcium the cells had, the more fluid they became and the quicker they moved. "It goes really fast.

Calcium has many effects on living tissues, however, so Shim had to confirm that the handshakes were to blame for the slow movement. She grew cells with an antibody that attaches to cadherins. With blocked handshakes, these cells moved more quickly.

After working out the ground rules of cell adhesiveness, the researchers developed a solution to their sticky cell problem. Shim grew a layer of skin cells in a high calcium solution so they made their normal connections. Then she treated the cells with a chemical that grabs up calcium ions to break up the cellular handshakes. When Shim lowered the calcium level and applied the electric field, the cells moved on command. Finally, she restored the high calcium level to reinstate the handshakes, resulting in a healthy and cohesive layer of skin cells.

To demonstrate that this approach has the potential to accelerate healing, Shim performed the above experiment using an electrobioreactor developed in the Cohen lab that mimics the closing of a wound. Unlike other models of electrotaxis where the electric field moves cells in one direction, their new system exposes cells to an electric field focused on the center of the injury. Shim showed that the stimulated tissues successfully came together while the unstimulated ones remained largely separate. Cohen's group described their electrobioreactor in a new paper in Biosensors and Bioelectronics.

part3

Comment by Dr. Krishna Kumari Challa on September 1, 2021 at 10:34am

In their previous work, Cohen's group used electric fields to program thousands of individual cells to move in circles and around corners. Their new study used a model of more mature skin—a single layer of mouse skin cells all latched together—which is harder to control. Instead of moving with the speed and precision of a marching band in response to an electric current, the mature skin cells inched along like a crowd of people holding hands with their neighbors.

The mature skin also posed another problem: Once the leading edge of cells advanced, it would peel away from the petri dish and die. "If you apply a command that differs from what the cells naturally 'want' to do, you get a tug-of-war. The result was the tissues ripped themselves apart.

Cohen and Shim suspected that the "handshakes" between cells prevented the tissue from fluidly following the electrical commands. These handshakes are proteins called cadherins that anchor neighboring cells together. They make tissues cohesive so they can move together but can also create traffic jams when cells don't have space to move.

 Gawoon Shim et al, Overriding native cell coordination enhances external programming of collective cell migration, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2101352118

https://phys.org/news/2021-08-cellular-motion-wound.html?utm_source...

part 2

Comment by Dr. Krishna Kumari Challa on September 1, 2021 at 10:33am

Researchers take step toward using cellular motion to help wound healing

With a technique that overcomes cells' innate social behaviors, researchers have taken an important step in directing skin cells to migrate en masse to close wounds—"literally making skin crawl".

In a new study, the researchers overcame the inertia typical of mature skin tissue by breaking the molecular connections between cells, applying an electrical field to direct their migration and then rebuilding the connections. This novel approach improves the controllability of tissues and may one day help optimize wound healing through electrical stimulation.

Research showed that cells in the body can sense and follow an electric field, a process called electrotaxis. Electric fields generated in the body promote healing by directing cells to move toward the wound and are also vital for growth and development.

Despite promising clinical evidence from decades of use in patients, scientists have yet to work out how cells detect and respond to electric fields or how electrical stimulation can best be applied therapeutically. "It's kind of a black box

 Gawoon Shim et al, Overriding native cell coordination enhances external programming of collective cell migration, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2101352118

part1

Comment by Dr. Krishna Kumari Challa on September 1, 2021 at 10:29am

The right mixture of salts to get life started

In modern organisms, the hereditary material DNA encodes the instructions for the synthesis of proteins—the versatile nanomachines that enable modern cells to function and replicate. But how was this functional linkage between DNA and proteins established? According to the "RNA world" hypothesis, primordial living systems were based on self-replicating RNA molecules. Chemically speaking, RNA is closely related to DNA. However, in addition to storing information, RNA can fold into complex structures that have catalytic activity, similar to the protein nanomachines that catalyze chemical reactions in cells. These properties suggest that RNA molecules should be capable of catalyzing the replication of other RNA strands, and initiating self-sustaining evolutionary processes. Hence, RNA is of particular interest in the context of the origin of life as a promising candidate for the first functional biopolymer.

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New options for sustainable antibiotic therapy

Public health is coming under increasing pressure worldwide due to the antibiotic crisis: the rapid increase in resistance of bacterial pathogens could mean that in the near future bacterial infections that are usually harmless will be difficult or impossible to treat. The spread of antibiotic resistance is based on the ability of pathogens to adapt quickly to the drugs. In principle, evolutionary theory assumes that this adaptation is more difficult when environmental conditions change rapidly. Sequential antibiotic therapy, which involves switching between different antibiotics in a short time, could therefore lead to a reduction in the spread of resistance. This therapeutic approach is usually not considered in medical treatment and is also hardly investigated in basic research—despite the possible long-term benefits.

Comment by Dr. Krishna Kumari Challa on September 1, 2021 at 9:51am

High virus count in the lungs drives COVID-19 deaths

A buildup of coronavirus in the lungs is likely behind the steep mortality rates seen in the pandemic, a new study finds. The results contrast with previous suspicions that simultaneous infections, such as bacterial pneumonia or overreaction of the body's immune defense system, played major roles in heightened risk of death, the investigators say.

the new study showed that people who died of COVID-19 had on average 10 times the amount of virus, or viral load, in their lower airways as did severely ill patients who survived their illness. Meanwhile, the investigators found no evidence implicating a secondary bacterial infection as the cause of the deaths, although they cautioned that this may be due to the frequent course of antibiotics given to critically ill patients.

These findings suggest that the body's failure to cope with the large numbers of virus infecting the lungs is largely responsible for COVID-19 deaths in the pandemic.

Despite previous concerns that the virus may prompt the immune system to attack the body's own lung tissue and lead to dangerous levels of inflammation, the investigators found no evidence that this was a major contributor to COVID-19 deaths in the group studied. In fact,  this study notes that the strength of the immune response appeared proportionate to the amount of virus in the lungs.

The new study, publishing online Aug. 31 in the journal Nature Microbiology, was designed to clarify the role of secondary infections, viral load, and immune cell populations in COVID-19 mortality.

1. Imran Sulaiman, Matthew Chung, Luis Angel, Jun-Chieh J. Tsay, Benjamin G. Wu, Stephen T. Yeung, Kelsey Krolikowski, Yonghua Li, Ralf Duerr, Rosemary Schluger, Sara A. Thannickal, Akiko Koide, Samaan Rafeq, Clea Barnett, Radu Postelnicu, Chang Wang, Stephanie Banakis, Lizzette Pérez-Pérez, Guomiao Shen, George Jour, Peter Meyn, Joseph Carpenito, Xiuxiu Liu, Kun Ji, Destiny Collazo, Anthony Labarbiera, Nancy Amoroso, Shari Brosnahan, Vikramjit Mukherjee, David Kaufman, Jan Bakker, Anthony Lubinsky, Deepak Pradhan, Daniel H. Sterman, Michael Weiden, Adriana Heguy, Laura Evans, Timothy M. Uyeki, Jose C. Clemente, Emmie de Wit, Ann Marie Schmidt, Bo Shopsin, Ludovic Desvignes, Chan Wang, Huilin Li, Bin Zhang, Christian V. Forst, Shohei Koide, Kenneth A. Stapleford, Kamal M. Khanna, Elodie Ghedin, Leopoldo N. Segal. Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome. Nature Microbiology, 2021; DOI: 10.1038/s41564-021-00961-5

https://medicalxpress.com/news/2021-08-high-virus-lungs-covid-death...

Comment by Dr. Krishna Kumari Challa on September 1, 2021 at 8:54am

Genes can respond to coded information in signals—or filter them out entirely

New research demonstrates that genes are capable of identifying and responding to coded information in light signals, as well as filtering out some signals entirely. The study shows how a single mechanism can trigger different behaviours from the same gene—and has applications in the biotechnology sector.

The fundamental idea here is that you can encode information in the dynamics of a signal that a gene is receiving. So, rather than a signal simply being present or absent, the way in which the signal is being presented matters.

For this study, researchers modified a yeast cell so that it has a gene that produces fluorescent proteins when the cell is exposed to blue light.

Here's how that works. A region of the gene called the promoter is responsible for controlling the gene's activity. In the modified yeast cells, a specific protein binds to the promoter region of the gene. When researchers shine blue light on that protein, it becomes receptive to a second protein. When the second protein binds to the first protein, the gene becomes active. And that's easy to detect, since the activated gene produces proteins that glow in the dark.

The researchers then exposed these yeast cells to 119 different light patterns. Each light pattern differed in terms of the intensity of the light, how long each pulse of light was, and how frequently the pulses occurred. The researchers then mapped out the amount of fluorescent protein that the cells produced in response to each light pattern.

People talk about genes being turned on or off, but it's less like a light switch and more like a dimmer switch—a gene can be activated a little bit, a lot, or anywhere in between. If a given light pattern led to the production of a lot of fluorescent protein, that means the light pattern made the gene very active. If the light pattern led to the production of just a little fluorescent protein, that means the pattern only triggered mild activity of the gene.

The researchers found that different light patterns can produce very different outcomes in terms of gene activity, that all three light pattern variables—intensity of the light, frequency of the light pulses, and how long each pulse lasted—could influence gene activity, but found that controlling the frequency of light pulses gave them the most precise control over gene activity.

Mapping the Dynamic Transfer Functions of Eukaryotic Gene Regulation, Cell Systems (2021).

1. Jessica B. Lee et al. Mapping the dynamic transfer functions of eukaryotic gene regulation. Cell Systems, 2021 DOI: 10.1016/j.cels.2021.08.003

https://phys.org/news/2021-08-genes-coded-signalsor-filter.html?utm...

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