Intolerant Hosts Can Damage Themselves

One of the major reasons that influenza is dangerous is that it softens the body up for pneumonia, which can deliver a fatal blow to weakened individuals and is, in fact, responsible for the majority of the deaths that start with a flu infection. But why the flu should predispose to pneumonia to the extent that it does has remained unclear. Infected individuals cope in two different ways: by controlling infections via resistance, and via adapting to the damage the infections do via tolerance. A team from Yale University and the Austrian University of Vienna studied animals simultaneously afflicted with a viral and a bacterial infection and found infection with the flu virus made the animals less able to cope with tissue damage due to simultaneous bacterial infection, even though the immune system was able to control the bacterial infection. The authors concluded that in viral and bacterial co-infection, the "failure of host defense is due to impaired ability to tolerate tissue damage." Their work appeared in the April 25, 2013, advance online edition of Science.

Producing Brain Cells from Bone Marrow

Researchers from the Scripps Research Institute have discovered an antibody that can cause bone marrow cells to differentiate into neural progenitor cells, rather than the blood cells they normally produce. The authors were testing a method they have developed to genetically engineer an entire antibody library and its receptor into different cell types. In the current set of experiments, they discovered that antibodies to the receptor for the growth factor G-CSF caused bone marrow cells to turn into brain cells. G-CSF itself causes cells to differentiate into blood cells, and so the authors concluded that "antibody agonists and the natural ligand that bind to the same receptor can induce different cell fates from an identical starting cell population." Such antibodies might be useful for controlling cell fate. The findings appeared in the April 22, 2013, online edition of the Proceedings of the National Academy of Sciences.

Specific Anti-Anti-Apoptotic Drug

Scientists from the Australian Walter and Eliza Hall Institute of Medical Research have engineered an inhibitor that is specific to the anti-apoptotic protein Bcl-xL, a member of the Bcl-2 family of proteins, which are critical for orchestrating programmed cell death. Different Bcl-2 family members can have either pro- or anti-apoptotic functions, and Bcl-xL is anti-apoptotic and overexpressed in many solid tumors, so that a compound that could inhibit the protein "will most likely have widespread utility in cancer treatment" combined with limited toxicity. In their studies, the authors identified such a compound though screening followed by structure-guided drug design. The authors contended that the compound they engineered using their approach, WEHI-539 "will be an invaluable tool for distinguishing the roles of BCL-XL from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-XL for their sustained growth." They described their findings in the April 21, 2013, issue of Nature Chemical Biology.

Remember H5N1?

Scientists from the British MRC National Institute for Medical Research have gained new insights into the structural changes that the highly pathogenic H5N1 needs to undergo to become transmissible between ferrets, which are the best model for human-to-human transmission. Infections with H5N1 have a high fatality rate, but to date at least, the virus does not spread easily between humans. Studies published last year, however, showed that the virus could become more easily transmissible through acquiring fewer than 10 mutations. In the new work, the authors looked at the biophysical properties of the easily transmissible H5N1 mutant's hemagglutinin protein – one of two key proteins that determine that viruses' binding capability. They found that while it was only slightly more likely to bind to human hemagglutinin receptor, it was far less likely to bind to the bird hemagglutinin receptor, leading to an overall strong preference for human over bird protein. The mutant hemagglutinin protein was also able to bind to the human receptor in a shape that is similar to that of previous pandemic strains, including both the 1918/19 "Spanish flu" pandemic and the most recent, milder pandemic of 2009. The findings appeared in the April 24, 2013, advance online edition of Nature.

Secreted Proteins' Secrets Revealed

A team from the German Max-Planck-Institute for Biophysical Chemistry has developed a method to identify proteins that are secreted in response to immune cell activation. Secreted proteins are important messengers in the body, but precisely because they are secreted, they have been harder to identify and quantify than those proteins that stay put within cells. The authors used mass spectrometry to measure peptides from culture medium after stimulating immune cells, and combined it with computational and statistical methods. The method allowed the measurement of all secreted proteins, rather than labeling specific candidates with antibodies, and allowed the identification of proteins that were secreted from pre-existing stores after cell stimulation, which could not be identified by looking at transcriptional changes. The approach was published in the April 26, 2013, issue of Science.

Kinase Has 2 Distinct Roles in Inflammation

Researchers from Harvard Medical School have discovered a compound that can be used to gain new insights into how the inflammasome is activated. The authors discovered the compound, 7DG, while screening for drugs that can protect immune cells from anthrax toxin. They found that 7FG affects protein kinase R, and that protein kinase R has two different roles in inflammation and apoptosis that are stimulated by distinct toxins. The authors contended that "7DG has the potential to serve as a useful new small molecule for studying diseases where caspase-1 activation through inflammasome stimulation results in IL-1β and IL-18 release and inflammatory damage associated with a diverse set of diseases." Their work appeared in the April 21, 2013, issue of Nature Chemical Biology.

Mitochondrial Cleanup Protein Identified

Researchers from Washington University in St. Louis have found a new protein that is involved in getting rid of damaged mitochondria, which need to be removed from cells to avoid killing their hosts by the overproduction of reactive oxygen species. Two proteins important in the removal are Pink and Parkin, both of which malfunction in Parkinson's disease. In their studies, the authors showed that Pink and Parkin need to interact with a third protein, Mitofusin-2, to properly target damaged mitochondria and tag them for destruction. Cells deficient in Mitofusin-2 accumulated dysfunctional mitochondria, which in turn damaged cultured heart cells of both mice and fruit flies. They concluded that Mitofusin-2 "functions as a mitochondrial receptor for Parkin and is required for quality control of cardiac mitochondria." The findings establish Mitofusin as a target for mitochondrial diseases, and might explain the so-far puzzling link between Parkinson's disease and heart problems. The work appeared in the April 26, 2013, issue of Science.

Targeting Processing Protein Gets at MiRNAs

The expression level of many noncoding RNAs is changed in cancer, and such changes can drive disease. But targeting such RNAs directly to fight cancer has been difficult. Now, researchers from the Ohio State University Comprehensive Cancer Center have shown that they could indirectly target such miRNAs by inhibiting nucleolin, a protein that is involved in the processing of microRNAs. In their work, the authors showed that treating cells with AS1411, an aptamer drug, inhibited the processing of several cancer-associated microRNAs. Inhibiting nucleolin in cells that are resistant to the breast cancer drug Faslodex (fulvestrant, AstraZeneca plc) restored sensitivity to the drug both in cell culture and in animal studies. The findings appeared in the April 22, 2013, issue of the Journal of Experimental Medicine.

Alzheimer's Findings May Help Lighten LOAD

Researchers from the Mount Sinai School of Medicine and the University of Iceland have studied gene expression patterns in the brain autopsy samples from nearly 400 patients with late-onset Alzheimer's disease (LOAD), as well as nearly 200 healthy elderly controls, to identify a gene network that is deregulated in individuals with LOAD. The authors used a bioinformatics approach to identify the most critical gene networks that were different between patients and controls, and identified a gene circuit more commonly identified with the immune system that is up-regulated in patients with Alzheimer's disease. Many genes in the network have to date been associated with phagocytosis, or the "eating" of pathogens by immune system cells. More generally, they anticipate their approach might be used to decrypt the molecular causes of many complex diseases, which "arise from the downstream interplay of DNA-sequence variants and nongenetic factors that act through molecular networks to confer disease risk." The findings appeared in the April 26, 2013, issue of Cell.

Beta Cells Breeding Like Bunnies

Scientists from the Harvard Stem Cell Institute have identified a new hormone, betatrophin, that caused insulin-producing pancreatic beta cells to divide when it was injected into animals. The researchers discovered the hormone while screening for genes and compounds that induce beta cells to replicate. Betatrophin expression correlated with the proliferation of beta cells both in animals models of insulin resistance and during pregnancy. In animals, betatrophin injections caused beta cells to proliferate, and improved glucose control. The authors contended that betatrophin injections could ultimately replace insulin injections for the treatment of Type II diabetes, and may also have some utility in Type I diabetes. They also said that such injections would be necessary only rarely, in contrast to the frequent injections of insulin that patients with advanced diabetes often need. Their findings appeared in the April 25, 2013, advance online edition of Cell.

– Anette Breindl, Science Editor