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Category: biotech/medical – Page 2,512

DNA capture by a CRISPR-Cas9–guided adenine base editor

CRISPR-Cas9 base editors comprise RNA-guided Cas proteins fused to an enzyme that can deaminate a DNA nucleoside. No natural enzyme deaminates adenine in DNA, and so a breakthrough came when a natural transfer RNA deaminase was fused to Cas9 and evolved to give an adenine base editor (ABE) that works on DNA. Further evolution provided the enzyme ABE8e, which catalyzes deamination more than 1000 times faster than early ABEs. Lapinaite et al. now present a 3.2-angstrom resolution structure of ABE8e bound to DNA in which the target adenine is replaced with an analog designed to trap the catalytic conformation. The structure, together with kinetic data comparing ABE8e to earlier ABEs, explains how ABE8e edits DNA bases and could inform future base-editor design.

Science, this issue p. 566

CRISPR-Cas–guided base editors convert A•T to G•C, or C•G to T•A, in cellular DNA for precision genome editing. To understand the molecular basis for DNA adenosine deamination by adenine base editors (ABEs), we determined a 3.2-angstrom resolution cryo–electron microscopy structure of ABE8e in a substrate-bound state in which the deaminase domain engages DNA exposed within the CRISPR-Cas9 R-loop complex. Kinetic and structural data suggest that ABE8e catalyzes DNA deamination up to ~1100-fold faster than earlier ABEs because of mutations that stabilize DNA substrates in a constrained, transfer RNA–like conformation. Furthermore, ABE8e’s accelerated DNA deamination suggests a previously unobserved transient DNA melting that may occur during double-stranded DNA surveillance by CRISPR-Cas9. These results explain ABE8e-mediated base-editing outcomes and inform the future design of base editors.

Challenging a central tenet of chemistry

Steve Granick, Director of the IBS Center for Soft and Living Matter and Dr. Huan Wang, Senior Research Fellow, report together with 5 interdisciplinary colleagues in the July 31 issue of the journal Science that common chemical reactions accelerate Brownian diffusion by sending long-range ripples into the surrounding solvent.

The findings violate a central dogma of chemistry, that and chemical reaction are unrelated. To observe that molecules are energized by chemical reaction is “new and unknown,” said Granick. “When one substance transforms to another by breaking and forming bonds, this actually makes the molecules move more rapidly. It’s as if the chemical reactions stir themselves naturally.”

“Currently, nature does an excellent job of producing molecular machines but in the natural world scientists have not understood well enough how to design this property,” said Wang. “Beyond curiosity to understand the world, we hope that practically this can become useful in guiding thinking about transducing chemical energy for molecular motion in liquids, for nanorobotics, precision medicine and greener material synthesis.”

New understanding of CRISPR-Cas9 tool could improve gene editing

Within a mere eight years, CRISPR-Cas9 has become the go-to genome editor for both basic research and gene therapy. But CRISPR-Cas9 also has spawned other potentially powerful DNA manipulation tools that could help fix genetic mutations responsible for hereditary diseases.

Researchers at the University of California, Berkeley, have now obtained the first 3D structure of one of the most promising of these tools: base , which bind to DNA and, instead of cutting, precisely replace one nucleotide with another.

First created four years ago, base editors are already being used in attempts to correct single-nucleotide mutations in the human genome. Base editors now available could address about 60% of all known genetic diseases—potentially more than 15,000 inherited disorders—caused by a mutation in only one nucleotide.

U.S. banks are ‘swimming in money’ as deposits increase

It’s the banking world’s version of the rich getting richer.

A record $2 trillion surge in cash hit the deposit accounts of U.S. banks since the coronavirus first struck the U.S. in January, according to FDIC data.

The wall of money flowing into banks has no precedent in history: in April alone, deposits grew by $865 billion, more than the previous record for an entire year.

Scientists find new way to kill tuberculosis

The toxin can block the use of important amino acids required by the bacteria to produce essential proteins needed for survival.

An international team of researchers, led by Durham University, UK, and the Laboratory of Molecular Microbiology and Genetics/Centre Integrative Biology in Toulouse, France, are aiming to exploit this to develop new anti-TB drugs.

Their findings are published in the journal Science Advances.

Getting Gene Therapy to the Brain

Summary: Researchers successfully applied a gene therapy platform to completely correct brain defects in a large animal model of a human genetic disease.

Source: University of Pennsylvania

A lone genetic mutation can cause a life-changing disorder with effects on multiple body systems. Lysosomal storage diseases, for example, of which there are dozens, arise due to single mutations that affect production of critical enzymes required to metabolize large molecules in cells. These disorders affect multiple organs including, notably, the brain, causing intellectual disability of varying degrees.

Trial data support dexamethasone, but not hydroxychloroquine, for COVID-19

According to the University of Minnesota trial data supports dexamethasone over Hydroxychloroquine:

Data from a large randomized controlled trial in the United Kingdom showing a benefit from use of the steroid dexamethasone in hospitalized COVID-19 patients was released today in the New England Journal of Medicine (NEJM), while two more studies show no benefit for the malaria drug hydroxychloroquine.

The NEJM data, which were originally reported in a press release in mid-June by the chief investigators of the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial after an interim analysis, show that in patients needing mechanical ventilation, dexamethasone reduced deaths by 36% compared with usual care. In patients receiving oxygen, the incidence of death was 18% lower for patients on dexamethasone.

“The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support,” investigators with the RECOVERY Collaborative Group, which is led by scientists from the University of Oxford, wrote.

Some scientists are taking a DIY coronavirus vaccine, and nobody knows if it’s legal or if it works

Nearly 200 covid-19 vaccines are in development and some three dozen are at various stages of human testing. But in what appears to be the first “citizen science” vaccine initiative, Estep and at least 20 other researchers, technologists, or science enthusiasts, many connected to Harvard University and MIT, have volunteered as lab rats for a do-it-yourself inoculation against the coronavirus. They say it’s their only chance to become immune without waiting a year or more for a vaccine to be formally approved.

Preston Estep was alone in a borrowed laboratory, somewhere in Boston. No big company, no board meetings, no billion-dollar payout from Operation Warp Speed, the US government’s covid-19 vaccine funding program. No animal data. No ethics approval.

What he did have: ingredients for a vaccine. And one willing volunteer.

Estep swirled together the mixture and spritzed it up his nose.

CES, the world’s largest tech conference, will be online-only in 2021

The Consumer Electronics Show (CES), long the world’s largest tech trade show, will be all-digital in January 2021, the Consumer Technology Association (CTA) announced on Monday. The CTA cited the COVID-19 pandemic and concerns about the spread of the virus as its reasoning for canceling the in-person event.

CES usually takes place in Las Vegas and involves many large gatherings in tightly packed convention halls, as well as smaller meetings between retailers, manufacturers, and other industry professionals.

Per the CTA, the digital CES will be a “new immersive experience.” The organization did not provide many details about what the online event will look like, but it claims it will be “highly personalized.” The organization still plans to hold CES 2022 in Las Vegas.

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