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Category: genetics – Page 403

  • Spherical nucleic acids are a class of personalized medicines for treating cancer and other diseases
  • SNAs are challenging to optimize because their structures can vary in many ways
  • Northwestern University team developed a library approach and machine learning to rapidly synthesize, analyze and select for potent SNA medicines

EVANSTON, Ill.— With their ability to treat a wide a variety of diseases, (SNAs) are poised to revolutionize medicine. But before these digitally designed nanostructures can reach their full potential, researchers need to optimize their various components.

A Northwestern University team led by nanotechnology pioneer Chad A. Mirkin has developed a direct route to optimize these challenging particles, bringing them one step closer to becoming a viable treatment option for many forms of cancer, , neurological disorders and more.

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LA JOLLA—(February 18, 2019) Aging is a leading risk factor for a number of debilitating conditions, including heart disease, cancer and Alzheimer’s disease, to name a few. This makes the need for anti-aging therapies all the more urgent. Now, Salk Institute researchers have developed a new gene therapy to help decelerate the aging process.

The findings, published on February 18, 2019 in the journal Nature Medicine, highlight a novel CRISPR/Cas9 genome-editing that can suppress the accelerated aging observed in mice with Hutchinson-Gilford progeria syndrome, a rare genetic disorder that also afflicts humans. This treatment provides important insight into the molecular pathways involved in accelerated aging, as well as how to reduce toxic proteins via .

“Aging is a complex process in which cells start to lose their functionality, so it is critical for us to find effective ways to study the molecular drivers of aging,” says Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory and senior author of the paper. “Progeria is an ideal aging model because it allows us to devise an intervention, refine it and test it again quickly.”

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There are 1.4 billion insects for each one of us. Though you often need a microscope to see them, insects are “the lever pullers of the world,” says David MacNeal, author of Bugged. They do everything from feeding us to cleaning up waste to generating $57 billion for the U.S. economy alone.

Today, many species are faced with extinction. When National Geographic caught up with MacNeal in Los Angeles, he explained why this would be catastrophic for life on Earth and why a genetically engineered bee could save hives—and our food supply—worldwide.

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Scientists have discovered that grasses are able to short cut evolution by taking genes from their neighbours. The findings suggest wild grasses are naturally genetically modifying themselves to gain a competitive advantage.

Understanding how this is happening may also help scientists reduce the risk of genes escaping from GM crops and creating so called super-weeds—which can happen when genes from GM crops transfer into local wild plants, making them herbicide resistant.

Since Darwin, much of the theory of evolution has been based on common descent, where natural selection acts on the genes passed from parent to offspring. However, researchers from the Department of Animal and Plant Sciences at the University of Sheffield have found that grasses are breaking these rules. Lateral gene transfer allows organisms to bypass evolution and skip to the front of the queue by using genes that they acquire from distantly related species.

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UC San Francisco scientists have used the CRISPR-Cas9 gene-editing system to create the first pluripotent stem cells that are functionally “invisible” to the immune system, a feat of biological engineering that, in laboratory studies, prevented rejection of stem cell transplants. Because these “universal” stem cells can be manufactured more efficiently than stem cells tailor-made for each patient—the individualized approach that dominated earlier efforts—they bring the promise of regenerative medicine a step closer to reality.

“Scientists often tout the therapeutic potential of pluripotent stem cells, which can mature into any adult tissue, but the immune system has been a major impediment to safe and effective stem cell therapies,” said Tobias Deuse, MD, the Julien I.E. Hoffman, MD, Endowed Chair in Cardiac Surgery at UCSF and lead author of the new study, published Feb. 18 in the journal Nature Biotechnology.

The immune system is unforgiving. It’s programmed to eradicate anything it perceives as alien, which protects the body against infectious agents and other invaders that could wreak havoc if given free rein. But this also means that transplanted organs, tissues or cells are seen as a potentially dangerous foreign incursion, which invariably provokes a vigorous immune response leading to transplant rejection. When this occurs, donor and recipient are said to be—in medical parlance—” histocompatibility mismatched.”

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The genetic and cellular alterations that define cancer provide the immune system with the means to generate T cell responses that recognize and eradicate cancer cells. However, elimination of cancer by T cells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell T cell inhibitory signals, including PD-L1, has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer.

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Genetic, epidemiologic, and biochemical evidence suggests that predisposition to Alzheimer’s disease (AD) may arise from altered cholesterol metabolism, although the molecular pathways that may link cholesterol to AD phenotypes are only partially understood. Here, we perform a phenotypic screen for pTau accumulation in AD-patient iPSC-derived neurons and identify cholesteryl esters (CE), the storage product of excess cholesterol, as upstream regulators of Tau early during AD development. Using isogenic induced pluripotent stem cell (iPSC) lines carrying mutations in the cholesterol-binding domain of APP or APP null alleles, we found that while CE also regulate Aβ secretion, the effects of CE on Tau and Aβ are mediated independent pathways. Efficacy and toxicity screening in iPSC- derived astrocytes and neurons showed that allosteric activation of CYP46A1 lowers CE specifically in neurons and is well tolerated by astrocytes. These data reveal that CE independently regulate Tau and Aβ and identify a druggable CYP46A1-CE-Tau axis in AD.

Van der Kant et al. performed a repurposing drug screen in iPSC-derived AD neurons and identified compounds that reduce aberrant accumulation of phosphorylated Tau (pTau). Reduction of cholesteryl ester levels or allosteric activation of CYP46A1 by lead compounds enhanced pTau degradation independently of APP and Aβ.

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Scientists at the University of Virginia School of Medicine have identified a potential explanation for the mysterious death of specific brain cells seen in Alzheimer’s, Parkinson’s and other neurodegenerative diseases.

The new research suggests that the may die because of naturally occurring in brain cells that were, until recently, assumed to be genetically identical. This variation – called “somatic mosaicism” – could explain why in the are the first to die in Alzheimer’s, for example, and why are the first to die in Parkinson’s.

“This has been a big open question in neuroscience, particularly in various neurodegenerative diseases,” said neuroscientist Michael McConnell of UVA’s Center for Brain Immunology and Glia, or BIG. “What is this selective vulnerability? What underlies it? And so now, with our work, the hypotheses moving forward are that it could be that different regions of the brain actually have a different garden of these [variations] in and that sets up different regions for decline later in life.”

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