In Pilot Study, a Blood Test for Depression

Early onset major depression is surprisingly prevalent. But its diagnosis, like that of most psychiatric disorders, is subjective, based on patients reports of their syndrome and clinician observations. Scientists from Northwestern University's Feinberg School of Medicine have identified transcriptomic markers that could lead to a blood test for depression. The authors began by analyzing gene expression profiles in the brain and blood of two animal models of depression – one genetic and one stress-induced – and comparing them to their respective controls to arrive at candidate transcripts. With that technique, they identified 11 transcripts whose levels were changed in genetically depressed animals, and another 15 in animals depressed due to repeated stress. Those transcripts were then measured in the blood of teenagers with a major depression diagnosis and controls. The authors found that an 11-marker signature differentiated depressed teens from nondepressed peers, and an overlapping 18-marker signature could differentiate depression co-occurring with anxiety from depression without anxiety. The authors plan to test the gene signature in a larger cohort. The paper detailing their findings appeared in the April 17, 2012, issue of Translational Psychiatry.

Neural Guidance Molecule Helps Build Bone

Researchers at the Japanese Tokyo Medical and Dental University found that semaphorin 3A, a protein with roles in neural development, affects both types of bone-remodeling cells to promote bone formation. Bone is the only tissue with a cell type of its own – osteoclasts – dedicated to its destruction. In healthy individuals, that is balanced by bone-forming osteoblasts. But as people age, the osteoclasts can gain the upper hand, and after an injury to the bone, it is advantageous if the osteoblasts can put in overtime for repair. Other studies have shown that proteins with a role in neural development may also mediate the balance between osteoclasts and osteoblasts, so the authors tested semaphorin 3A's effects on bone in animal studies. Administering semaphorin 3A to mice resulted in increased bone density and faster repair of bones after injury, leading the authors to conclude that it is "a promising new therapeutic agent in bone and joint diseases." Their work was published in the April 18, 2012, advance online edition of Nature.

Healthy Heart Cells from Scar Tissue . . .

Researchers at the Gladstone Institutes have managed to coax cardiac fibroblasts, which would normally form scar tissue, to turn into beating heart cells in mice after the animals suffered a heart attack. After a heart attack, assuming it does not kill its victim outright, the heart is no longer beating at full capacity because cardiac muscle cells die and set off the formation of scar tissue. The authors were able to transform fibroblasts, which are part of such scar tissue, into beating cardiac cells by delivering three genes that control the development of heart muscle cells during development. Adding a peptide that stimulates the formation of blood vessels further increased their success rate. "These findings demonstrate," the authors wrote, "that cardiac fibroblasts can be reprogrammed into cardiomyocyte-like cells in their native environment for potential regenerative purposes." The same team had previously demonstrated they could manage the transition in vitro. Their findings appeared in the April 18, 2012, advance online edition of Nature.

. . . And Diseased Heart Cells from iPSCs

Another team, this one lead by researchers from Stanford University, transformed skin fibroblasts from patients with the heart condition familial dilated cardiomyopathy into induced pluripotent stem cells, and from there into heart cells. Such cells recapitulated some of the known problems of patients with dilated cardiomyopathy, which is the most common form of heart disease, and the most common diagnosis leading to a heart transplant. The authors also showed that overexpression of Serca2a, which, in the form of Mydicar (AAV1/Serca2a, Celladon Corp.) is in clinical trials as a genetically targeted enzyme replacement therapy for advanced heart failure, improved the function of the cells. The cells, the authors said, "may serve as a useful platform for exploring disease mechanisms and for drug screening." The work appeared in the April 19, 2012, issue of Science Translational Medicine.

Ten Breast Cancer Subtypes Identified

A team led by scientists from the Canadian University of Vancouver and the British Cambridge Research Institute have developed a new classification system for breast cancer that divides the disease into 10 distinct subtypes. The authors looked at both genes and transcripts of nearly 2,000 women with breast cancer. They found that copy number aberrations – that is, changes in copy number that were not inherited, but acquired during a patient's lifetime – accounted for the most extreme changes in transcripts, though copy number variants – inherited changes in copy numbers – and single-nucleotide polymorphism also played a role. As part of their study the team identified three new breast cancer genes, as well as signatures that correlated with survival differences. The results "provide a novel molecular stratification of the breast cancer population," the authors said. The paper appeared in the April 18, 2012, advance online edition of Nature.

Antibiotics Final Common Pathway

Researchers at the Massachusetts Institute of Technology have shown that many antibiotics kill bacteria through a common molecular mechanism regardless of their initial target. That common mechanism is the oxidation of guanine, one of the four bases that make up DNA. In their experiments, when oxidized guanine was incorporated into DNA, it led to double-stranded DNA breaks which ultimately killed bacteria. Such double-stranded DNA breaks have been seen in bacteria, but were assumed to occur after cell death. But the team showed that double-stranded DNA breaks increased quickly after bacteria were exposed to several different classes of antibiotics, and preceded cell death. The authors said their findings had two broad implications. First, in addition to how permeable a bacterium is to antibiotics, and how good it is at pumping them back out of the cell, susceptibility to antibiotics is also determined by its DNA repair capacities. Secondly, those DNA repair capacities could be targeted to develop adjuvants to existing antibiotics, which might extend their utility. The work appeared in the April 20, 2012, issue of Science.

Aspirin: Metabolic Drug?

Scientists at the Scottish University of Dundee have discovered that aspirin, at high but still clinically realistic doses, directly activates AMP kinase, which is a key cellular energy sensor. Aspirin exerts its painkiller effects through its actions on the COX enzymes and NF-kappaB pathways, but knockout mice still benefit to an extent from aspirin, suggesting it must affect other pathways as well. In their work, the authors showed that aspirin, as well as the related drug salsalate, directly inhibited AMP kinase. Normal mice treated with the drugs, but not AMP kinase knockouts, had increased fat metabolism and lower levels of liver fat than controls. The drug's effect on AMP kinase parallels that of metformin, and so suggests a mechanism for recent epidemiology studies that show aspirin protects against cancer. The paper describing the drug's actions on AMP kinase appeared in the April 19, 2012, advance online edition of Science.

Three Night-Blind Mice

Scientists at the British University College London have demonstrated that blind mice were able to see after they were transplanted with rod photoreceptor cells, which mediate vision under conditions of low light. Such transplantations have been done before, but none of the studies have been able to show unequivocally that the recipient animals could actually see afterward. The team first optimized the procedure to enable the transplantation of greater numbers of cells than previous experiments, and transplanted mice that lack cones and so are night blind. After transplantation, the animals showed head-tracking and navigated in a maze under low light. Visual stimuli were transmitted to higher areas of the brain, including the visual cortex. The authors concluded that their findings "demonstrate the feasibility of photoreceptor transplantation as a therapeutic strategy for restoring vision after retinal degeneration." They published their study in the April 19, 2012, issue of Nature.

The Form of Proteins You Can't See

Using a combination of high-resolution imaging and bioinformatics techniques, scientists at the University of Toronto have been able to deduce the structure of an intermediate form of amyloid protein that is prone to forming fibrils – the protein clumps that are a feature of many neurodegenerative diseases. The authors showed that in this state, four amino acids near the end of the protein become disordered and leave a part of the protein that is prone to aggregating exposed. When the team engineered a form of amyloid precursor protein that lacked the four amino acids, it was also prone to aggregating. The researchers hope their methods, which can deduce the structure of intermediates that appear too rarely in cells to measure their shape directly, will help the development of rational therapeutics against such proteins. Their work appeared in the April 20, 2012, issue of Science.

Preshrunk Brains & Neurodegenerative Disease?

Four separate papers from researchers at hundreds of institutions overall have identified genetic loci that are related to intracranial size, head circumference and the size of the hippocampus, which is a brain structure critical for forming new memories. Brain size is highly genetically determined, but identifying the underlying genes has been difficult. Success came in the form of meta analyses combining previous studies to look at more than 10,000 individuals in each study. The authors did not directly look at whether the genes they have identified correlate with disease. But the hippocampus in particular shrinks in Alzheimer's disease, and so genes that also cause such shrinkage could hasten Alzheimer's onset. All four studies were published in the April 15, 2012, online edition of Nature Genetics.

– Anette Breindl, Science Editor