New research points to malfunctioning tau, not amyloid-beta (Abeta) plaque, as the seminal event that spurs neuron death in disorders such as Alzheimer’s disease. The finding, which dramatically alters the prevailing theory of Alzheimer’s development, also explains why some people with plaque build-up in their brains don’t have dementia.

Neuronal death happens when tau, found inside neurons, fails to function. Tau’s role is to provide a structure — like a train track —inside brain neurons that allows the cells to clear accumulation of unwanted and toxic proteins.

“When tau is abnormal, these proteins, which include Abeta, accumulate inside the neurons,” explains the study’s senior investigator, Charbel E-H Moussa, MB, PhD, assistant professor of neuroscience at Georgetown University Medical Center. “The cells start to spit the proteins out, as best they can, into the extracellular space so that they cannot exert their toxic effects inside the cell. Because Abeta is ‘sticky,’ it clumps together into plaque,” Moussa says.

He says his study suggests the remaining Abeta inside the neuron (that isn’t pushed out) destroys the cells, not the plaques that build up outside. “When tau does not function, the cell cannot remove the garbage, which at that point includes Abeta as well as tangles of non-functioning tau, and the cell dies. The Abeta released from the dead neuron then sticks to the plaque that had been forming.”

Moussa’s experiments in animal models also show less plaques accumulate outside the cell when tau is functioning; when tau was reintroduced into neurons that did not have it, plaques did not grow.

Malfunctioning tau can occur due to errant genes or through aging. As individuals grow older, some tau can malfunction while enough normal tau remains to help clear the garbage. In these cases, the neurons don’t die, he says. “That explains the confusing clinical observations of older people who have plaque build-up, but no dementia,” Moussa says.

Moussa has long sought a way to force neurons to clean up their garbage. In this study, he shows that nilotinib, a drug approved to treat cancer, can aid in that process. Nilotinib helps the neuron clear garbage, but requires some functional tau, he says.

“This drug can work if there is a higher percentage of good to bad tau in the cell,” Moussa says. “There are many diseases of dementia that have malfunctioning tau and no plaque accumulation, such as frontal temporal dementia linked to Parkinsonism,” Moussa says. “The common culprit is tau, so a drug that helps tau do its job may help protect against progression of these diseases.” Georgetown University Medical Center

Brown University biologists have determined how the loss of a gene in male mice results in the premature exhaustion of their fertility. Their fundamental new insights into the complex process of sperm generation may have direct applications to a similar loss of fertility in men.

What the team discovered is that the loss of the gene that makes the protein TAF4b causes a deficit in the number of progenitor cells at an embryonic stage of a male mouse’s reproductive development. Lacking those important precursor cells means that the mice struggle to develop a robust stem cell infrastructure to sustain sperm production for the long term. The affected mice are fertile at first, but quickly deplete the limited sperm supply that they can generate.

“What’s fascinating about these mice is they can reproduce,” said Richard Freiman, senior author of the new study in the journal Stem Cells. “Mice can usually reproduce until they are two years old, but these mice can only reproduce until they are four months old.”

TAF4b is a protein that affects how genes are regulated and transcribed, and its absence has profound impacts on the reproductive system. In previous work, Freiman’s research group has shown that female mice without TAF4b are totally infertile and that their ovaries age prematurely. But in experiments with males, led by lab members Lindsay Lovasco and Eric Gustafson, the effect proved more subtle.

Sperm generation follows from a complex chain of events that the research shows begins before a male mouse is even born. In their experiments, the team compared the development of mice with and without the TAF4b gene. In mice with TAF4b, progenitor cells for sperm in the male embryo arise and proliferate normally, laying the groundwork in the testes for a robust pool of spermatogonial stem cells to develop. Those stem cells are the ones that produce a renewable supply of sperm. Without TAF4b, there were fewer progenitor cells and consequently fewer stem cells. They still produce sperm at first, but they can’t renew production for the long haul. Ultimately the testes, which develop normally, become unproductive and atrophy.

What’s not yet clear from the research is why the process fades out rather than just continuing, albeit at a very low level of productivity. One possibility is the low supply of spermatogonial stem cells drives the body to invest all its meagre resources in immediate sperm production, leaving none of the stem cells in a more flexible state that can perpetually renew the supply. Another possibility is that regardless of supply, TAF4b is simply needed to see the renewal process through, for instance by maintaining some stem cells in their regenerative state.

Not only do humans have a gene for TAF4b, but a coincidental study last year in the Journal of Medical Genetics provides evidence that it also matters for sperm count. That research reported that four Turkish brothers who carried a mutation in the TAF4b gene had low sperm counts. Their mutation was in the same region of their gene as the one Freiman’s team generated in the mice.

“The human implications are very exciting,” he said. “It is possible that those men, as teenagers, were able to make functional sperm.”

Certainly more research is needed, Freiman said, but if TAF4b mutation plays out in men the way it plays out in mice, his hope is that detecting the mutation in teenage boys could allow doctors to freeze their sperm so that when they are older and want to have children, they could draw on that banked supply. Brown University

An international research collaboration led by UC San Francisco researchers has identified a genetic variant common in Latina women that protects against breast cancer.

The variant, a difference in just one of the three billion “letters” in the human genome known as a single-nucleotide polymorphism (SNP), originates from indigenous Americans and confers significant protection from breast cancer, particularly the more aggressive oestrogen receptor–negative forms of the disease, which generally have a worse prognosis.

 “The effect is quite significant,” said Elad Ziv, MD, professor of medicine and senior author of the study. “If you have one copy of this variant, which is the case for approximately 20 percent of U.S. Latinas, you are about 40 percent less likely to have breast cancer. If you have two copies, which occurs in approximately 1 percent of the US Latina population, the reduction in risk is on the order of 80 percent.”

The new study showed that women who carry the variant have breast tissue that appears less dense on mammograms. High “mammographic density” is a known risk factor for breast cancer.

 “We have detected something that is definitely relevant to the health of Latinas, who represent a large percentage of the population in California, and of other states such as Texas,” said first author Laura Fejerman, PhD, assistant professor of medicine and a member of UCSF’s Institute of Human Genetics. “This work was done as a collaboration of multiple investigators, many of us originally from Latin America. As a Latina myself, I am gratified that there are representatives of that population directly involved in research that concerns them.” University of California – San Francisco

One of the central questions in human biology is to understand how our genes determine which diseases we get and how severe they might be. Knowing just the DNA sequence, or the blueprint, is not enough. We must figure out how proteins, the genes’ products, work too.

Now an international team of researchers, jointly led by Dr. Fritz Roth (at Mount Sinai Hospital’s Lunenfeld-Tanenbaum Research Institute and the Donnelly Centre of the University of Toronto), and Dr. Marc Vidal (with the Dana-Farber Cancer Institute and Harvard Medical School in Boston), have produced the largest ever map of human protein interactions. This publicly available resource will be invaluable to anyone trying to understand complex genetic traits and develop new disease therapies.

“It is realistic to think that many of the people reading this will have their genomes sequenced within their lifetimes. The next challenge is to figure out what their genomes mean,” says Dr. Roth. “You cannot figure out how the car works based on the parts list. You have to know how they fit together.”

This is because genes do not do the work in a cell. Rather, the work is usually done by the proteins that genes provide the plans for. Some pairs of proteins stick together, or ‘interact’ when they are in close contact with each other. These interactions underlie all of cell’s biology and mediate processes such as gene expression, cell metabolism, and transporting other molecules within a cell.

Having a detailed map of protein interactions bring us one step closer to understanding the relationship between our genes (genotype) and our physiology in health and disease (phenotype).

Drs. Roth and Vidal, and their colleagues, analysed direct interactions in pairwise combinations between 13,000 proteins. Out of 85 million possible interactions they found 14,000 directly-interacting protein pairs. This more than doubles the previous set of known interactions, making it the largest ever experimentally determined human protein interaction map.

“We’ve managed to peer into the car and connect a fraction of the parts,” says Dr. Roth.

The study reveals several important findings. The new map can be used to identify novel genes involved in diseases. If a novel protein, which we know nothing about, interacts with a known protein that has a role in a disease, then the novel protein is highly likely to be involved in that same disease. Dr. Roth and colleagues illustrate this point by identifying a novel cancer gene STAT3 based on its interactions with known cancer genes. Their finding was confirmed when STAT3 subsequently became included into the cancer gene database based on independent evidence.
 Further unbiased analyses identified 100 strong cancer candidate genes, 60 of which were connected to known cancer molecular pathways. Some of these genes are completely novel. This shows the potential of the human interaction map in revealing new disease genes and promising therapeutic targets.

Mapping all human protein interactions is a colossal task and will require several different approaches. This is because not every method can find every protein interaction. Dr. Roth estimates that they found, using a yeast two hybrid method, 5-10% of all protein interactions, a substantial increase from their previous paper that reported 1% of interactions.

“Although much sweat and some tears were put into analysing this new map, it is clear that we have only scratched the surface of what these interactions can tell us about human disease. It is personally very exciting to anticipate the discoveries to come, as it passes from our hands into the research community,” says Dr. Roth. Lunenfeld-Tanenbaum Research Institute

HORIBA Medical and NoemaLife announced in January a non-exclusive agreement, for the worldwide distribution of Halia, the web-based Laboratory Automation System by NoemaLife which allows central management of all pre-analytical, analytical and post-analytical instruments, making it possible to connect multiple sites, multiple Laboratory Information Systems and multiple instruments of various disciplines of the laboratory. “The addition of Halia to HORIBA Medical ’s Hematology product line makes it possible for a wide range of clinical laboratories to realize efficiencies resulting from a powerful yet very user friendly data management. NoemaLife is pleased to serve as HORIBA Medical‘s middleware provider in this effort” said Piero Tassoni, Diagnostic Marketing & Alliance Director NoemaLife, “HORIBA Medical equips more than 30,000 laboratories throughout the world, distributed in 110 countries in 5 continents. Not only we are proud to work with a partner who holds world records in its industry, but we are confident that this agreement has huge potential.” The specific version of the Halia middleware distributed by HORIBA Medical will soon integrate all the Hematology Expert validation station features that HORIBA Medical so far proposed exclusively in its “ABX Pentra ML” Work Station, the all-in-one validation system entirely dedicated to whole blood. “Halia is an important evolution to our hematology solution’s offer” said Olivier Pou, Corporate Marketing Director, HORIBA Medical. “The addition of a specific version of the Halia middleware to our product offer makes it possible for HORIBA Medical to provide a complete solution to our worldwide base of customers around the hematology expertise but also to facilitate the integrated management of hematology within the global IVD laboratory”.

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