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Molecular switches are not just ‘on’ or ‘off’

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The GTPases constitute a very large protein family, whose members are involved in the control of cell growth, transport of molecules, synthesis of other proteins, etc. Despite the many functions of the GTPases, they follow a common cyclic pattern (Figure 1). The activity of the GTPases is regulated by factors that control their ability to bind and hydrolyse guanosine triphosphate (GTP) to guanosine diphosphate (GDP). So far, it has been the general assumption that a GTPase is active or “on” when it is bound to GTP and inactive or “off” in complex with GDP. The GTPases are therefore sometimes referred to as molecular “switches.”

The bacterial translational elongation factor EF-Tu is a GTPase, which plays a crucial role during the synthesis of proteins in bacteria, as the factor transports the amino acids that build up a cell’s proteins to the cellular protein synthesis factory, the ribosome. Previous structural studies using X-ray crystallography have shown that EF-Tu occurs in two markedly different three-dimensional shapes depending on whether the factor is “on” (i.e. bound to GTP) or “off” (i.e. bound to GDP) (Figure 2). The binding of GTP/GDP have therefore always been thought to be decisive for the factor’s structural conformation.

However, a research collaboration between researchers from the Department of Molecular Biology and Genetics at Aarhus University and two American universities reveals that EF-Tu’s structure and function, and probably also those of other GTPases, are far more complex than previously assumed. In Søren Thirup’s group, X-ray crystallographic analysis of E. coli EF-Tu has shown that EF-Tu bound to a variant of GTP, GDPNP, can also occur in the “off” state, which is characterised by a more open structure. In collaboration with American researchers, Charlotte Knudsen’s Ph.D. student, Darius Kavaliauskas, conducted further studies using a special form of fluorescence microscopy that makes it possible to observe the spatial structure of individual EF-Tu molecules in solution.

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Switching Off ALPL Gene Contributes to Bone Aging

A recent open-access mouse study published by Xi’an Institute of Tissue Engineering and Regenerative Medicine scientists in the journal Bone Research describes how the ALPL gene affects bone aging and suggests that metformin might constitute a viable therapeutic option to prevent it [1].

Study abstract

Mutations in the liver/bone/kidney alkaline phosphatase (Alpl) gene cause hypophosphatasia (HPP) and early-onset bone dysplasia, suggesting that this gene is a key factor in human bone development. However, how and where Alpl acts in bone ageing is largely unknown. Here, we determined that ablation of Alpl induces prototypical premature bone ageing characteristics, including bone mass loss and marrow fat gain coupled with elevated expression of p16INK4A (p16) and p53 due to senescence and impaired differentiation in mesenchymal stem cells (MSCs). Mechanistically, Alpl deficiency in MSCs enhances ATP release and reduces ATP hydrolysis. Then, the excessive extracellular ATP is, in turn, internalized by MSCs and causes an elevation in the intracellular ATP level, which consequently inactivates the AMPKα pathway and contributes to the cell fate switch of MSCs.

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Genetic testing: Not a one-and-done deal

That conclusion is based on a study that reviewed genetic testing results from 1.45 million individuals and found that nearly 25 percent of “variants of uncertain significance” were subsequently reclassified — sometimes as less likely to be associated with cancer, sometimes as more likely.

The study appears in the Journal of the American Medical Association (JAMA).

When variations from the norm are discovered in a gene, the variants are classified as “benign,” “likely benign,” “variant of uncertain significance,” “likely pathogenic,” or “pathogenic.”

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An Interview with Mike Bonkowski

Today, we have an interview with Dr. Michael Bonkowski, an expert on NAD+ biology and aging from the David Sinclair Lab, Harvard Medical School.

Michael Bonkowski aims to advance our understanding of the links between metabolism, aging, and age-associated diseases. He has published 35 peer-reviewed journal articles and has conducted multiple successful longevity studies. In Dr. David Sinclair’s lab, his research efforts are focused on the role of nutrient sensors’ regulation of endocrine signaling and aging in the mouse. He is also working on direct and indirect ways to drive the activity of these nutrient sensors by using dietary manipulations, small molecules, and chemical treatments.

Michael is trained as a pharmacologist, physiologist, and animal scientist. Some of his areas of expertise include animal physiology, genetics, glucose, and insulin homeostasis, metabolism, assay development, protein biochemistry, and transmission electron microscopy imaging.

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Study of one million people leads to world’s biggest advance in blood pressure genetics

Over 500 new gene regions that influence people’s blood pressure have been discovered in the largest global genetic study of blood pressure to date, led by Queen Mary University of London and Imperial College London.

Involving more than one million participants, the results more than triple the number of gene regions to over 1,000 and means that almost a third of the estimated heritability for pressure is now explained.

The study, published in Nature Genetics and supported by the National Institute for Health Research (NIHR), Medical Research Council and British Heart Foundation, also reports a strong role of these genes, not only in blood vessels, but also within the adrenal glands above the kidney, and in body fat.

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Glimpse: On the Promise of a Future with Artificial Wombs, and Why It’s Being Stopped by the Present

Given the speed at which reproductive technology has advanced over the past few decades, it doesn’t feel all that far-fetched: A future in which anyone can have a baby, regardless of creed or need, whenever they feel like it. Already, in our present moment, one can buy or sell eggs and sperm; we can give embryos genetic tests to ensure the children they produce don’t have any life-threatening hereditary conditions; and babies can even be born, now, with the genetic information from three parents.

So it follows that we should soon be able to to have pregnancy outside the body — artificial wombs. R ight?

You’d think. Scientists have already figured out how to mimic many of the body’s processes for techniques like in-vitro fertilization and even hormonal birth control. But the ways mothers’ bodies support and signal fetuses is incredibly complicated — and the science isn’t yet at a point where we can simulate these processes. And because scientists are prohibited from studying embryos 14 days past their fertilization, that’s one sci-fi vision that is not likely to come to fruition.

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