Pacifist Dendritic Cells

Antigen-presenting dendritic cells can generally set off two types of reaction in T cells: an immune reaction when an antigen is recognized as part of an infectious threat – or tolerance, when that antigen is recognized as harmless. The general belief has been that any dendritic cell can either rev up or calm down T cells, depending on the sorts of activating signals it receives. But researchers at the Australian Centenary Institute of Cancer Medicine and Cell Biology describe a subset of dendritic cells – Langerhans cells that reside on the skin that induced tolerance in T cells no matter what. The authors believe their results may explain why commensal microorganisms expressing Toll-like receptor (TLR) ligands – though confined to the skin epithelium are tolerated – whereas invading pathogens that breach the epithelial basement membrane and activate dermal (dendritic) cells stimulate a strong immune response. Their findings were published in the Oct. 17, 2011, issue of the Proceedings of the National Academy of Sciences

Hedgehogs Tell Humans What it All Means

One concern about genome sequencing is that while sequencing costs may have come down, the ability to understand what all those base pairs mean lags ever further behind the ability to read them. Sequencing the genome of 29 mammals and comparing it to that of humans, scientists from the Broad Institute have applied comparative genomics to help with such interpretation. By using all eutherian mammals for their comparison – roughly speaking, mammals that have a placenta – the authors were able to identify relatively recent genomic innovations. They note that such comparison of relatively closely related species is particularly important for identifying genome elements that control transcription, which, they say, "can be subject to rapid turnover." Their estimate of the proportion of the genome that is under active selective pressure, at 5 percent, does not differ markedly from previous estimates; but they were able to identify the specific elements that are under active selection much more precisely than previous studies using fewer species. The work appeared in the Oct. 12, 2011, advance online edition of Nature.

Gut Bacteria Influence Statin Response

People vary considerably in how well they respond to cholesterol-lowering statins, and genetics can explain only part of that variability. Or, at least, human genetics. Researchers from Children's Hospital Oakland Research Institute and Duke University have shown that part of the variation is due to the composition of gut microbes that an individual has. In the study, the researchers tested for levels of different bile acids which are the metabolic products of gut bacteria. They found that individuals who responded well to statins had high levels of certain bile acids, while those who responded poorly had higher levels of a distinct group of bile acids. The metabolites use similar transporters to statins, basically competing for transport, which may be why they influence statin effectiveness. The authors said their results "indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease." Findings were published in the Oct. 13, 2011, issue of PLoS ONE.

When C. Difficile Can't Leave Well Enough Alone

A team from the University of Edinburgh has identified a mutation that may be the reason that some Clostridium difficile strains have mutated into superbugs, and infections with those strains have shot up sharply in the past decade. By introducing a naturally found mutation into a strain and comparing it to a strain that was otherwise genetically identical, the authors showed that mutations in an inhibitor of toxin production allowed C. difficile to produce much more of the toxin. The authors said their findings could lead to improved surveillance of C. difficile superbug strains, as well as strains that are at risk of becoming superbug strains. Some other strains of C. difficile are not currently superbugs, but have mutations in the same gene as the superbug strain does. The findings appeared in the Oct. 13, 2011, issue of PLoS Pathogens.

GWAS Finds New Liver Metabolism Genes

A group of multiple individuals and consortia, led by scientists from Imperial College London in the UK, has identified more than 30 new genetic variants that correlate with liver enzyme levels, which in turn can be used to predict – and in some cases, presumably, treat – liver disease. The study also replicated 10 previously established associations. Using a combination of methods, the scientists went on to identify candidate genes that might be responsible for the association, and identified 69 such genes. While many of the genes they found are known to play a role in liver physiology – such as bile acid transporters, metabolism, glycoprotein synthesis and immune functions – others have no known function to date. The authors said their results "provide the basis for further studies investigating the biological mechanisms involved in liver injury." They appeared in the Oct. 16, 2011, issue of Nature Genetics.

Pulmonary Hypertension: Calpain Culprit

Researchers from the University of Georgia have identified a new target that could be useful for treating pulmonary hypertension, or high blood pressure in the lungs, which is a precursor to chronic obstructive pulmonary disease (COPD) and emphysema: calpain, an enzyme that cuts other proteins. The authors looked at a potential role for calpain in pulmonary hypertension because the enzyme is activated by several growth factor receptors that play a role in the disease, and itself activates the production of TGF-beta. They found that in both knockout mice and rats treated with a calpain inhibitor, symptoms of pulmonary hypertension decreased. They also looked at lung samples from patients with pulmonary hypertension, and found that calpain levels were high in those samples. Calpain may work by multiple mechanisms, including increasing the synthesis of collagen and influencing the production of nitric oxide synthase, which is critical for letting blood vessels relax. The authors conclude that calpain "plays an important role" in pulmonary hypertension, and the changes in blood vessels that precede it. Their findings were published in the Oct. 17, 2011, issue of the Journal of Clinical Investigation.

HER3 Joins its Sisters

Antibodies against both HER2 and HER1, which is better known as epidermal growth factor receptor (EGFR), are used as cancer therapeutics. Now, researchers from Genentech Inc. have made an antibody that inhibits both HER1 or EGFR, and HER3. HER3, in contrast to HER1 and HER2, has not been found to be amplified in any cancers to date; but indirect evidence suggested it might play a role in some cancers. The scientists made an antibody that blocks both EGFR and HER3, and found that the dual antibody, but not antibodies blocking either receptor by itself, completely blocked signaling of the oncogenic Map kinase and AKT. Compared to its component antibodies, the combination antibody was also more active in xenografted tumors, and potentiated the effects of the chemotherapy gemcitabine. The authors called that latter result "particularly intriguing" because combining chemotherapy with antibodies targeting EGFR only have been repeatedly unsuccessful in clinical trials. The findings appeared in the Oct. 18, 2011, issue of Cancer Cell.

New Neurotransmitter, at Least in Flies

Researchers from the University of California at Los Angeles have identified what they believe is a new neurotransmitter system in the fruit fly drosophila. Classical amino acid transmitters are stored in so-called vesicular transporters. Some cells in the fly mushroom body, however, (a part of the fly brain that is essential for complex behaviors) do not have any known vesicular transporter. The authors searched for genes that are similar to known vesicular transporter genes, and identified the gene "portabella" as a candidate transmitter gene. Knocking out portabella caused problems in olfactory learning and sexual behaviors. The authors say the fact that portabella has not previously been recognized as a transmitter may suggest that it is unique to insects, but also point out that many human neurotransmitters were not identified until relatively recently and that "the identification of most neurotransmitters has lagged far behind the physiological and behavioral characterization of their attendant cells and circuits," implying that an analogous transmitter in mammals may yet be identified. The work appeared in the Oct. 20, 2011, issue of Neuron.

Transcription Factor Revs Up T Cells

Scientists at Albany Medical Center have discovered a new target for fighting inflammatory bowel disease. The authors showed that T cells lacking the transcription factor Bcl11b left T cells unable to take the developmental path toward regulatory T cells, which inhibit other T cell responses. In cells that were already regulatory T cells, removing Bcl11b turned the cells back from inhibitory cells to cells that mounted an immune response. Mice with T cells lacking the transcription factor developed inflammatory bowel disease. The authors concluded that their work demonstrates that Bcl11b is indispensable for the function of inhibitory T cells. The work appeared in the Sept. 26, 2011, print edition of the Journal of Experimental Medicine.

New Roles for VEGF in Skin Cancer

Part of the reason that vascular endothelial growth factor (VEGF) promotes cancer is that it stimulates the formation of new blood vessels. But scientists have long realized that it has additional effects on tumor growth, as well. Now, researchers at the Belgian University of Brussels have identified two new roles for VEGF in squamous cell carcinoma, a type of skin cancer. First, VEGF is important for allowing squamous cell cancer stem cells to maintain their stem cell characteristics, or ability to self-renew. VEGF was also important for creating a niche where these stem cells thrive. The authors concluded that their findings, which were published in the Oct. 19, 2011, issue of Nature, "may have important implications for the prevention and treatment of skin cancers."

– Anette Breindl, Science Editor