MERS antibodies isolated
Two independent teams of scientists, one from the Chinese Tsinghua University and one from the Dana-Farber Cancer Institute and the University of North Carolina, have identified antibodies to the Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) that may form the basis of prophylactic or therapeutic treatments against the virus. MERS-CoV is a similar, albeit more highly fatal, virus to the SARS-CoV that came uncomfortably close to causing a major pandemic in 2002/2003. The virus appears to have originated in Saudi Arabia, and last week, the king of Saudi Arabia replaced his minister of health amidst a spike in cases. In their work, the authors identified antibodies that bind to the spike region of the virus and could prevent the virus from binding to its receptor. In cell culture experiments, the virus was able to develop resistance to the antibodies. One paper appeared in the April 28, 2014, issue of the Proceedings of the National Academy of Sciences, while the other was published in the May 1, 2014, issue of Science Translational Medicine.
Heart regeneration hits snag in macaques
Researchers from the University of Washington have been able to induce heart regeneration by transplanting macaques with stem cells, showing that the procedure can induce regeneration in primates. However, some of the animals developed arrhythmias – a side effect that had not been seen in earlier experiments in rodents. The authors induced experimental heart failure in seven macaques, and then transplanted the animals with a billion embryonic stem cell-derived heart muscle cells which had been previously frozen. The cells engrafted and synchronized their beating to those of the host. But all animals also showed electrical evidence of arrhythmias, although the animals did not pass out during such episodes, nor did they show behavioral signs of distress. The authors said their study showed that cell replacement therapy can be scaled up to work in large animals, and concluded that "comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome." Their work appeared in the May 2, 2014, issue of Nature.
Brain diseases: New role of interneurons . . .
Researchers from Columbia University and Weill Cornell Medical College have shown that targeting inhibitory interneurons in the hippocampus may be a useful therapeutic approach for psychosis. The hippocampus is best known for its importance in learning and memory, but is also involved in many other higher cognitive functions, as well as psychological illnesses including depression and psychosis. In psychosis, the hippocampus is overly active, and in their work the authors transplanted inhibitory neurons into the hippocampus in mice lacking the cyclin D2 gene, which do not develop such neurons in the hippocampus. The transplants formed functional circuits, improved the animals' ability to learn, and normalized dopamine transmission. "The sustained efficacy of the transplants supports a rationale for targeting hippocampal GABA interneurons with novel therapies for psychosis," the authors said. Their findings appeared in the April 28, 2014, issue of the Proceedings of the National Academy of Sciences.
. . . cortical neurons . . .
Huntington's disease leads to the degeneration of neurons in two areas of the brain, the cerebral cortex and a midbrain area called the striatum. Although the striatum has received more attention from researchers, a group from the University of California at Los Angeles has now shown that both damage to cortical and striatal neurons contribute to the disease. The authors studied transgenic mice that expressed mutant huntingtin protein in the cortex, the striatum, or both brain areas. Although reducing the levels of mutant huntingtin in either the cortex or the striatum alone did improve the animals' symptoms, animals fared much better if the protein was reduced in both brain areas. They found that high cortical levels of mutant huntingtin were responsible for motor as well as psychiatric-like symptoms, but it was expression in the striatum that led to neurodegeneration. The authors concluded that optimal strategies for targeting Huntington's disease will likely require targeting both brain areas. Their work appeared in the April 28, 2014, issue of Nature Medicine.
. . . and astrocytes
Scientists from the University of California at San Francisco have demonstrated that a type of brain cells called astrocytes are important for maintaining the integrity of brain circuits, suggesting they could play a role in multiple brain disorders from amyotrophic lateral sclerosis to schizophrenia. Astrocytes play important support roles in maintaining synapses, but it had not been clear whether astrocytes in different parts of the brain had different functions. In their work, the authors showed that astrocytes in the spinal cord expressed several genes that were not expressed by astrocytes in other brain regions, and that expression of one gene in particular, semaphorin 3a, was required for the proper development of synapses in the spinal cord. When astrocytes did not express semaphorin 3a, it set off a cascade of events whose net result was the death of alpha motor neurons in the spinal cord. The authors published their work in the April 28, 2014, advance online issue of Nature.
Blood stem cells decide when to call it quits
Researchers from the Canadian Princess Margret Cancer Center have gained new insights into how blood-forming or hematopoietic stem cells balance health and longevity in response to stressors. Because stem cells are long-lived, they necessarily accumulate damage over the course of their existence, and need to strike a middle path that allows most of them to keep dividing, while responding to mutations that are likely to be serious enough to leukemia through inducing cell death pathways. In their work, the authors showed that blood-forming stem cells tend to go into apoptosis in response to mutations that activated one form of the unfolded protein response, the PERK branch. Similar mutations that did not lead to PERK branch activation allowed the cells to survive. "Because the unfolded protein response is a focal point where different sources of stress converge, our study provides a framework for understanding how stress signaling is coordinated within tissue hierarchies and integrated with stemness. Broadly, these findings reveal that the [hematopoietic stem cell] pool maintains clonal integrity by clearance of individual [hematopoietic stem cells] after stress to prevent propagation of damaged stem cells." The paper appeared in the April 28, 2014, advance online issue of Nature.
Sperm from stem cells
Scientists from Stanford University have made sperm precursor cells from induced pluripotent stem cells (iPSCs) of infertile men with a genetic mutation that prevents them from making sperm. In their work, the authors generated iPSCs from the skin cells of men with azoospermic infertility, meaning that they did not produce sperm, and transplanted them into the reproductive system of mice. Aided by the anatomy of the male mouse reproductive tract, such iPSCs were able to form sperm cells. The findings, while they are not intended to be a roadmap for direct fertility treatment, give new insights into certain types of male infertility, and suggest that males with some forms of infertility may have sperm progenitor cells at a young age, which could be banked. The work appeared in the May 1, 2014, advance online edition of Cell Reports.
Another reason to watch your cholesterol
Scientists from the University of Pittsburgh have shown that the ability of some HIV-infected individuals to fend off AIDS is related to cholesterol levels in their antigen-presenting cells. In so-called nonprogressors, T-cell levels can remain high for years without treatment with antiretroviral therapy (ART). In their experiments, the authors showed that such nonprogression was due to the fact that HIV could not be spread from antigen-presenting cells – specifically, from dendritic cells and B cells – to T cells, which are the viruses' main reservoir. The antigen-presenting cells that did not pass on HIV had low levels of cholesterol and high levels of a transporter that shuttled cholesterol out of cells. In cell culture studies, inhibiting the activity of the cholesterol transporter restored the ability of antigen-presenting cells to infect T cells with HIV. The authors concluded that "these results provide a basis for therapeutic interventions to control of HIV-1 infection through modulation of cholesterol metabolism." Their work appeared in the April 29, 2014, edition of the online journal mBio.
Nanoparticles target cancer stem cells
Researchers from Johns Hopkins University have developed nanoparticles that specifically targeted glioblastoma stem cells, and the genes delivered by the particles were expressed preferentially in cancer cells in a mouse model of glioblastoma. In their experiments, the authors used biodegradable poly(beta-amino ester)s (PBAEs) to deliver a reporter gene. They found that the PBAEs preferentially entered tumor initiating cells over regular brain stem cells. Importantly, the genes were still expressed from PBAE/DNA nanoparticles that had been fabricated two years earlier and stored, "increasing the translational relevance of this technology." The findings appeared in the April 26, 2014, online issue of ACS Nano.
The shape of celiac disease
Researchers from the Australian Monash University and the Dutch Leiden University Medical Center have reported structural data that could help develop treatments for celiac disease, which arises from intolerance to the wheat protein gluten and related proteins in barley and rye. More than 90 percent of celiac disease sufferers have a specific variant of an antigen-presenting HLA molecule, HLA-DQ2. In their studies, the authors used crystallography to look at the structure of the complex between HLA-DQ2, T-cell receptors, and different epitopes of gliadin, a peptide that is part of gluten. The authors said their findings "not only offer key insight into the pathogenesis of CD and antigen-specific immunotherapy to treat CD40 but also may be of relevance for our understanding of the involvement of biased T-cell repertoire selection in other HLA-associated disorders." They appeared in the April 28, 2014, issue of Nature Structural & Molecular Biology.
By Anette Breindl, Science Editor.