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Comment by Dr. Krishna Kumari Challa on May 1, 2023 at 11:46am

'Deletions' from the human genome may be what made us human

 What the human genome is lacking compared with the genomes of other primates might have been as crucial to the development of humankind as what has been added during our evolutionary history, according to a new study led by researchers.

The new findings, published April 28 in the journal Science, fill an important gap in what is known about historical changes to the human genome. While a revolution in the capacity to collect data from genomes of different species has allowed scientists to identify additions that are specific to the human genome — such as a gene that was critical for humans to develop the ability to speak — less attention has been paid to what’s missing in the human genome.

For the new study researchers used an even deeper genomic dive into primate DNA to show that the loss of about 10,000 bits of genetic information — most as small as a few base pairs of DNA — over the course of our evolutionary history differentiate humans from chimpanzees, our closest primate relative. Some of those “deleted” pieces of genetic information are closely related to genes involved in neuronal and cognitive functions, including one associated with the formation of cells in the developing brain.

These 10,000 missing pieces of DNA — which are present in the genomes of other mammals — are common to all humans, the researchers found.

The fact that these genetic deletions became conserved in all humans, the authors say, attests to their evolutionary importance, suggesting that they conferred some biological advantage.

Often we think new biological functions must require new pieces of DNA, but this work shows us that deleting genetic code can result in profound consequences for traits make us unique as a species.

Researchers found that some genetic sequences found in the genomes of most other mammal species, from mice to whales, vanished in humans. But rather than disrupt human biology, they say, some of these deletions created new genetic encodings that eliminated elements that would normally turn genes off.

The deletion of this genetic information had an effect that was the equivalent of removing three characters — “n’t” — from the word “isn’t” to create a new word, “is.”
Such deletions can tweak the meaning of the instructions of how to make a human slightly, helping explain our bigger brains and complex cognition.

The researchers used a technology called Massively Parallel Reporter Assays (MPRA), which can simultaneously screen and measure the function of thousands of genetic changes among species.

“These tools have the capability to allow us to start to identify the many small molecular building blocks that make us unique as a species.

https://news.yale.edu/2023/04/27/deletions-human-genome-may-be-what...,'Deletions'%20from%20the%20human%20genome%20may%20be%20what%20made%20us,team%20of%20Yale%20researchers%20found.

The functional and evolutionary impacts of human-specific deletions in conserved elements. Science, 2023; 380 (6643) DOI: 10.1126/science.abn2253

Comment by Dr. Krishna Kumari Challa on May 1, 2023 at 11:20am

This protein only worked in conjunction with Cas13b, which suggested the two were coordinating with each other to disarm the virus.

When both Cas13b and Csx28 were present, the proportion of infected bacteria that released infectious viral particles decreased from around 19 percent to roughly 3 percent, and there was a significant reduction of phage numbers per milliliter. In other words, the virus wasn't able to replicate as much as it usually would.

The researchers examined the structure of the Csx28 protein using a technique called cryogenic electron microscopy and found that it resembled a funnel with a hole in the center.

This raised the possibility that the protein formed a membrane pore and was disrupting the metabolism of the cell to make it an inhospitable environment for the virus.

The researchers tested this hypothesis using a technique that makes cells fluorescent after they have lost their membrane potential, a small electrical charge caused by the difference in the concentration of ions inside and outside the cell.

They found that the two proteins together caused the membrane to depolarize, sending in a rush of charged atoms that radically altered the cell's internal environment. After 90 minutes, 40 percent of the bacterial population was depolarized in this fashion.

It is really impressive that the research team identified this pore-like protein that doesn't resemble anything else we've seen before.

https://www.science.org/doi/10.1126/science.abm1184

Part 2

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Comment by Dr. Krishna Kumari Challa on May 1, 2023 at 11:17am

CRISPR Protects Bacteria From Invading Viruses in a Completely Unexpected Way

The acronym CRISPR has become synonymous with editing DNA in recent years, taking center stage in the molecular geneticist's toolbox as a means of identifying genetic codes and then cutting into them with uncanny precision.
In its original function as a means of immunity in bacteria, the CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated endonuclease) system seeks out known genes of invading viruses and renders them dysfunctional.

Scientists  have discovered that the famous gene-editing tool does more in bacteria than just spot DNA for chopping up; it coordinates with other proteins to bulk up defenses against invading viruses as well.

Activating the funnel-shaped proteins – called Csx28 – scrambles the permeability of the bacteria's membrane, making it difficult for invading viral DNA to hijack the cell's machinery and replicate.

The study involved a series of experiments where Escherichia coli bacteria were infected with a virus that infects bacteria, or bacteriophage, called enterobacteria phage λ. This phage latches onto the bacteria cell surface like a lunar module and injects its DNA into the cell to create copies of itself. The E. coli fight back, using CRISPR to identify the threat by matching repetitive DNA sections from previously encountered phages, and then using an enzyme called Cas13b to snip the invading DNA into pieces.

The researchers found that the virus replicated sluggishly when Csx28 was present inside the bacteria.

part1

Comment by Dr. Krishna Kumari Challa on April 29, 2023 at 11:55am

A Bacterial Culprit for Rheumatoid Arthritis

Scientists identified a species of Subdoligranulum that may drive disease.

heumatoid arthritis (RA) is a debilitating autoimmune condition that affects millions of people across the globe (1). The ultimate cause of RA is largely mysterious. While researchers have long suspected that the microbiome influenced development of the disease, the specific microbe (or microbes) has eluded identification.

Now, in a recent Science Translational Medicine paper, researchers reported a strain of Subdoligranulum bacteria that may drive RA development . Some people at risk for the disease have antibodies against this bacteria, and Subdoligranulum activation of T cells was more prevalent in people with RA than in healthy controls. Perhaps even more intriguingly, mice given this bacterium developed a condition similar to human RA.

Identifying this bacterium was no simple task. First, the research team, a collaboration between scientists at the University of Colorado, Stanford University, and the Benaroya Research Institute, screened blood donated by people at risk for RA or with early-stage RA for RA-related autoantibodies.

Then researchers tested whether any of these autoantibodies also targeted human intestinal bacteria. They mixed the antibodies with bacteria from stool samples donated by healthy people and people with RA. They then sequenced the bacterial species to which the autoantibodies attached. These RA antibodies cross-reacted with many species of bacteria, largely from Lachnospiraceae or Ruminococcaceae, two closely related families.

To study these species in more detail, researchers cultured bacteria from the stool of an individual who had high levels of these two bacterial families present. Two types of Subdoligranulum bacteria, which they called isolates 1 and 7, emerged as potential candidates for driving RA development. Compared to isolate 1, isolate 7 was a more potent activator of T cells in blood from RA patients.

To find out if isolate 7 bacteria actually caused disease, scientists fed the bacteria to mice. After a couple of weeks,  the mice got swollen paws. This is similar to the swollen hand and finger joints experienced by people with RA.

The similarities between the mice and human RA patients extended beyond what could be seen with the naked eye. There were antibodies getting into the joints, much like we see in rheumatoid arthritis.

1. Chriswell, M. E. et al. Clonal IgA and IgG autoantibodies from individuals at risk for rheumatoid arthritis identify an arthritogenic strain of Subdoligranulum. Science Translational Medicine  14, eabn5166 (2022).
2. Scher, J. U. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife  2, e01202 (2013).

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Comment by Dr. Krishna Kumari Challa on April 29, 2023 at 10:42am

Getting a mission to the Moon, around 384,000 kilometres from Earth, is much more challenging than lofting a satellite into low-Earth orbit — and failures can occur early on, even for missions that don't plan to land. This happened with NASA’s Lunar Flashlight mission, a small spacecraft that launched in December and was supposed to map the Moon’s ice. Its propulsion system malfunctioned soon after launch and may keep it from reaching an orbit from which it can do the intended science.

Even if a lander makes it to the vicinity of the Moon, it still has to navigate its way down to the surface with no global-positioning satellites for guidance and virtually no atmosphere to help to slow it down. Once it gets within the crucial last few kilometres, its software has to deal quickly and autonomously with any last-minute challenges, such as its sensors potentially becoming confused by large amounts of dust kicked up from the surface by exhaust plumes.

Both of the 2019 landing failures probably stemmed from software and sensor issues during these final moments. And early indications suggest that this week’s ispace failure could have been caused by the lander running out of propellant just before it touched down.

Comment by Dr. Krishna Kumari Challa on April 29, 2023 at 10:36am

What makes landing on the Moon very difficult ?

Compared with Earth,  the Moon has reduced gravity, very little atmosphere and lots of dust.

To pull off a successful landing, engineers need to anticipate how a spacecraft will interact with this environment — and spend money testing how things might go wrong. Tests, tests and more tests are needed to prove out the landing system in as many scenarios as possible.And even then, nothing is guaranteed.

 In the 1960s, when the United States and the Soviet Union were racing to land there, they crashed spacecraft after spacecraft before each finally succeeded in 1966.

The government space agencies were able to learn from each landing attempt. Today, by contrast, private companies are expected to repeat these successes, without government resources and without lessons gleaned from many failed and successful missions. That’s a lot to ask of a private enterprise to get it right on the first attempt.

In 2013, China landed successfully on the Moon on its first try with its Chang’e 3 mission. China also accomplished the first-ever landing on the far side of the Moon, and brought back samples of Moon rocks. But India, for its part, crashed during its attempt to land on the Moon in 2019; it will try again later this year.

Comment by Dr. Krishna Kumari Challa on April 29, 2023 at 10:19am

A new treatment for multidrug-resistant bacteria

Comment by Dr. Krishna Kumari Challa on April 29, 2023 at 10:14am

Near-universal T cell immunity towards a broad range of bacteria discovered

 Typically T cells of the immune system respond to a specific feature (antigen) of a microbe, thereby generating protective immunity. As reported in the journal Immunity, an international team of scientists have discovered an exception to this rule. Namely, a group of divergent bacterial pathogens, including pneumococci, all share a small highly conserved protein sequence, which is both presented and recognized by human T cells in a conserved population-wide manner.

The study set out to understand immune mechanisms that protect against pneumococcus, a bacterial pathobiont that can reside harmlessly in the upper respiratory mucosae but can also cause infectious disease, especially in infants and older adults, which can range from middle ear and sinus infections to pneumococcal pneumonia and invasive bloodstream infections.

The researchers identified a crucial fragment of the pneumococcal toxin pneumolysin that was commonly presented by a particular class of human antigen presenting molecules and recognized by T cells from most people who naturally develop specific immunity to pneumococcal proteins.

The study further found that the uniformly presented and broadly recognized bacterial protein fragment was not unique for the pneumococcal pneumolysin but was shared by a large family of bacterial so-called cholesterol dependent cytolysins (CDCs). These are produced by divergent bacterial pathogens mostly affecting humans and cause a range of respiratory, gastro-intestinal, or vaginal infectious diseases.

Jamie Rossjohn, CD4+ T cell-mediated recognition of a conserved cholesterol-dependent cytolysin epitope generates broad antibacterial immunity, Immunity (2023). DOI: 10.1016/j.immuni.2023.03.020. www.cell.comimmunity/fulltext/ … 1074-7613(23)00140-1

Comment by Dr. Krishna Kumari Challa on April 29, 2023 at 9:45am

Newly discovered electrical activity within cells could change the way researchers think about biological chemistry

The human body relies heavily on electrical charges. Lightning-like pulses of energy fly through the brain and nerves and most biological processes depend on electrical ions traveling across the membranes of each cell in our body.

These electrical signals are possible, in part, because of an imbalance in electrical charges that exists on either side of a cellular membrane. Until recently, researchers thought the membrane was an essential component to creating this imbalance. But that thought was turned on its head when researchers discovered that similar imbalanced electrical charges can exist between microdroplets of water and air.

Now, researchers have discovered that these types of electric fields also exist within and around another type of cellular structure called biological condensates. Like oil droplets floating in water, these structures exist because of differences in density. They form compartments inside the cell without needing the physical boundary of a membrane.

Inspired by previous research demonstrating that microdroplets of water interacting with air or solid surfaces create tiny electrical imbalances, the researchers decided to see if the same was true for small biological condensates. They also wanted to see if these imbalances sparked reactive oxygen, "redox," reactions like these other systems.

Appearing on April 28 in the journal Chem, their foundational discovery could change the way researchers think about biological chemistry. It could also provide a clue as to how the first life on Earth harnessed the energy needed to arise.

Yifan Dai et al, Interface of biomolecular condensates modulates redox reactions, Chem (2023). DOI: 10.1016/j.chempr.2023.04.001

Comment by Dr. Krishna Kumari Challa on April 29, 2023 at 9:38am

Scientists design new bio-inspired molecules to promote bone regeneration

People's ability to regenerate bones declines with age and is further decreased by diseases such as osteoporosis. To help the aging population, researchers are looking for new therapies that improve bone regeneration.

Now, an interdisciplinary team of researchers  developed novel bio-inspired molecules that enhance bone regeneration in mice. The results were published in the journal Biomaterials.

As people age, their ability to regenerate bones decreases. Fractures take longer to heal and diseases like osteoporosis only add to it. This represents a serious health challenge to the aging population and an increasing socioeconomic burden for the society. To help combat this issue, researchers are looking for new therapeutic approaches that can improve bone regeneration.

A team of scientists  used computer modeling and simulations to design novel bio-inspired molecules to enhance bone regeneration in mice. The new molecules can be incorporated into biomaterials and applied locally to bone defects. These new molecules are based on glycosaminoglycans, which are long-chained sugars such as hyaluronic acid or heparin.

 Gloria Ruiz-Gómez et al, Rational engineering of glycosaminoglycan-based Dickkopf-1 scavengers to improve bone regeneration, Biomaterials (2023). DOI: 10.1016/j.biomaterials.2023.122105

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