Y women live longer
Men whose blood cells had lost the Y chromosome were at higher risk of developing Alzheimer's disease in three independent case-control and prospective studies. Most genetic risk studies focus on specific mutations or structural variations in the genome, but men can develop a far more wholesale genomic change loss of the Y chromosome in specific cells. Recent studies have shown that roughly 15 percent of men over the age of 70 have lost the Y chromosome in at least 10 percent of their blood cells. Previous work had correlated loss of Y (LOY) with an increased risk of both all-cause mortality and cancer, and in their current study, the authors showed that men with LOY were also more likely to develop Alzheimer's disease. The molecular link between LOY and increased disease risk is unknown, but the authors suggested that disturbed immune system function "could link the increased risk of AD as well as the risk of various tumor types. Another and non-mutually exclusive hypothesis is that LOY in blood cells could be a mirror of parallel processes of chromosomal instability also present in other cell types, such as neurons." The team from the Swedish Uppsala University published its results in the May 23, 2016, online issue of the American Journal of Human Genetics.
Platelets aggregate amyloids
Platelets play a role in the vascular disease that is one feature of Alzheimer's and contributes to dementia by restricting blood flow. Amyloid beta plaques are the anatomical hallmark of Alzheimer's disease, and cerebral amyloid angiopathy occurs when amyloid beta accumulates in blood vessels. The authors showed that non-aggregated amyloid beta peptides bound to an extracellular matrix protein that subsequently stimulated the release of clusterin from platelets, leading to amyloid beta aggregation. The team from the German Heinrich Heine University published its results, which suggest that antiplatelet therapy may be helpful for preventing cerebral amyloid angiopathy in Alzheimer's disease, in the May 24, 2016, online issue of Science Signaling.
Innate immune system has checkpoints, too
Cytokine-inducible SH2-containing protein (CIS) is a checkpoint protein for natural killer (NK) cells, and mice lacking the gene that encodes for CIS were resistant to melanoma and prostate cancer metastasis after injection of tumor cells. Immune checkpoint blockade of T cells targeting either CTLA-4 or PD-1 has been the biggest breakthrough in cancer treatment in recent years. But T cells are not the only tumor-fighting cells, and the team investigated immune checkpoints in NK cells, one of the major cell types of the innate immune system. They identified CIS as a major checkpoint that responded to interleukin-15 and activated the JAK/STAT pathway. The team from the Australian Walter and Eliza Hall Institute of Medical Research said that "our data uncover a potent intracellular checkpoint in NK cellmediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function." Their results appeared in the May 23, 2016, online issue of Nature Immunology.
Fungi and breath
Bacteria have gotten most of the attention in research on the gut microbiome, but fungal commensals, too, have effects on health that reach beyond the gut. Prolonged treatment of mice with oral antifungals disrupted the fungal microbiome, and made the animals more susceptible to both colitis and allergic airway disease. Microbiome profiling showed that antifungal treatment disrupted both the fungal and bacterial commensal communities. Its effect on fungi was to decrease the presence of Candida spp. and to increase the presence of three other species Aspergillus, Wallemia and Epicoccum spp. Supplementing mice with those three species was sufficient by itself to exacerbate allergic airway disease. The team from Cedars Mount Sinai Center concluded that "disruption of commensal fungal populations can influence local and peripheral immune responses and enhance relevant disease states." They published their work in the May 26, 2016, online issue of Cell Host & Microbe.
Intermittent fasting reduces autoimmunity
Intermittent fasting suppressed autoimmune attacks on the myelin sheath and induced remyelination in multiple mouse models of multiple sclerosis (MS). Fasting has many health benefits, including being the only treatment that has been reliably shown to increase lifespan. But it is not always a feasible option for those with either chronic or severe illnesses, who often need to hang on to every pound they can. In their work, the scientists investigated the effects of a fasting-mimicking diet intermittent three-day periods of low calories and protein and showed that such a diet not only reduced T-cell attacks on the insulating neuronal myelin sheath that is damaged in MS, but also stimulated regeneration of that sheath by oligodendrocytes. The team from the University of Southern California had previously demonstrated a beneficial effect of intermittent fasting as an adjuvant cancer treatment. (See BioWorld Today, Feb. 9, 2012.) Their new results showed, they said, that intermittent fasting "is a safe, feasible, and possibly a potentially effective treatment for patients with relapsing-remitting MS." Their work appeared in the May 26, 2016, online issue of Cell Reports.
Glioblastoma immune signature
The relative expression levels of eight immune system genes could be used to predict high or low levels of disease progression in glioblastoma multiforme. Glioblastoma has dismal survival rates, and is not one of the tumor types that tends to respond to immune checkpoint blockade, likely due to the brain's unique immune system. In their experiments, the authors profiled a set of roughly 300 glioblastoma tumors taken from the Chinese Glioma Genome Atlas database and analyzed expression levels of more than 200 immune-related genes. They identified a group of eight genes that predicted a roughly 50 percent longer time to progression when their collective signature indicated low risk, though even the "favorable" group had a median time to progression of only a year. The Cancer Genome Atlas database was used to validate the findings. The researchers, who are at The First Hospital of China Medical University, concluded that their signature has independent prognostic significance. Their work appeared in the May 25, 2016, online issue of Neurology.
How Zika virus gets to the fetus
Zika virus can infect human placental macrophages and, to a lesser extent, cytotrophoblasts, giving it a route to the fetus. The strain of Zika virus currently spreading in the Americas has been directly linked to fetal brain abnormalities, including microcephaly. But how the virus crosses the placenta to gain access to the fetus is unclear, as recent studies have shown that during early pregnancy placental cells were resistant to Zika infection. In their work, the authors showed that human placental macrophages, which are called Hofbauer cells, were susceptible to Zika virus infection. They also found that mature trophoblasts could be infected, though they were less susceptible than Hofbauer cells. The team, from Emory University, concluded that their findings stress the importance of developing antiviral therapies that could prevent Zika replication in placental cells "as a means to reduce vertical transmission in the mother-infant dyad and the incidence of adverse pregnancy outcomes and fetal abnormalities." Their work appeared in the May 27, 2016, online issue of Cell Host & Microbe.
Cystic fibrosis interactome probed
Knocking down the ribosomal protein RPL12 increased levels of cystic fibrosis transmembrane conductance regulator (CFTR) with the delta 508 mutation (delF508-CFTR), the most frequent mutation in cystic fibrosis patients. The authors used yeast to test proteins, previously identified through a genomewide screen, that they predicted would interact with delF508-CFTR. CFTR encodes a chloride channel, and the authors found that RPL12 silencing in combination with lumacaftor (VX-809, Vertex Pharmaceuticals Inc.), increased the mutant function to 50 percent of the wild-type channel, which is well above the threshold of 10 percent that is necessary to restore lung function, "suggesting that the ribosomal stalk perturbation may represent a therapeutic target for rescuing the [delF508-CFTR] biogenesis defect," the authors from the University of Alabama at Birmingham wrote. The work is also evidence that it is possible to accurately predict human disease-modifying proteins through studies in yeast. The findings appeared in the May 11, 2016, issue of PLoS Biology.
Salt, fat make malaria grow up too fast
Increasing sodium levels kill the malaria parasite Plasmodium falciparum by increasing cholesterol content of its membrane and subsequently enticing it to divide too early. Several experimental malaria agents raise intracellular sodium levels in P. falciparum, but how that ultimately kills the parasite had not been worked out. Researchers showed that after treatment with the experimental antimalarials KAE609 or PA21A050, a rise in sodium levels was rapidly followed by increases of the normally very low cholesterol content of the parasite's membrane. The team from Drexel University College of Medicine published its findings in the May 26, 2016, online issue of PLoS Pathogens.
Mitochondrial fine-tuning affects flu susceptibility
Methylation-controlled J protein (MCJ) is a regulator of mitochondrial metabolism in T cells and affects how well killer T cells are able to fight influenza virus. The metabolic demands of T cells change a great deal as they fight infections, because their activity increases and their numbers expand. One way cells cope with changing energy demands is by adjusting the number of mitochondria, which are the energy powerhouses of the cell. But adjusting the number of mitochondria is a slow and cumbersome process for cells, as well as taking a fair amount of energy itself. In their study, the authors looked for factors that could modify mitochondrial activity, and showed that MCJ slowed down energy generation by mitochondria, as well as enhancing cytokine secretion. Mice with killer T cells that lacked MCJ had an improved ability to resist infection with influenza virus. The authors, from the University of Vermont, concluded that "MCJ could be a therapeutic target to enhance [killer] T cell responses." They published their work in the May 24, 2016, online issue of Immunity.