Global diversity and evidence for coevolution of KIR and HLA

The killer immunoglobulin-like receptor (KIR) gene cluster shows extensive genetic diversity, as do the HLA class I loci, which encode ligands for KIR molecules. We genotyped 1,642 individuals from 30 geographically distinct populations to examine population-level evidence for coevolution of these two functionally related but unlinked gene clusters. We observed strong negative correlations between the presence of activating KIR genes and their corresponding HLA ligand groups across populations, especially KIR3DS1 and its putative HLA-B Bw4-80I ligands (r = -0.66, P = 0.038). In contrast, we observed weak positive relationships between the various inhibitory KIR genes and their ligands. We observed a negative correlation between distance from East Africa and frequency of activating KIR genes and their corresponding ligands, suggesting a balance between selection on HLA and KIR loci. Most KIR-HLA genetic association studies indicate a primary influence of activating KIR-HLA genotypes in disease risk; concomitantly, activating receptor-ligand pairs in this study show the strongest signature of coevolution of these two complex genetic systems as compared with inhibitory receptor-ligand pairs.     

A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.     

Explosive volcanism on the ultraslow-spreading Gakkel ridge, Arctic Ocean

Roughly 60% of the Earth's outer surface is composed of oceanic crust formed by volcanic processes at mid-ocean ridges. Although only a small fraction of this vast volcanic terrain has been visually surveyed or sampled, the available evidence suggests that explosive eruptions are rare on mid-ocean ridges, particularly at depths below the critical point for seawater (3,000 m). A pyroclastic deposit has never been observed on the sea floor below 3,000 m, presumably because the volatile content of mid-ocean-ridge basalts is generally too low to produce the gas fractions required for fragmenting a magma at such high hydrostatic pressure. We employed new deep submergence technologies during an International Polar Year expedition to the Gakkel ridge in the Arctic Basin at 85 degrees E, to acquire photographic and video images of 'zero-age' volcanic terrain on this remote, ice-covered ridge. Here we present images revealing that the axial valley at 4,000 m water depth is blanketed with unconsolidated pyroclastic deposits, including bubble wall fragments (limu o Pele), covering a large (>10 km(2)) area. At least 13.5 wt% CO(2) is necessary to fragment magma at these depths, which is about tenfold the highest values previously measured in a mid-ocean-ridge basalt. These observations raise important questions about the accumulation and discharge of magmatic volatiles at ultraslow spreading rates on the Gakkel ridge and demonstrate that large-scale pyroclastic activity is possible along even the deepest portions of the global mid-ocean ridge volcanic system.     

Zoogeography of Great Basin butterflies: patterns of distribution and differentiation

The butterflies of the Great Basin exhibit general patterns of distribution and speciation similar to those found for other taxa, particularly birds. Two major centers of infraspecific differentiation and coinciding distribution limits of taxa are identified, each with three subregions. Great Basin butterflies are characterized by pallidity and substantial endemism below the species level.     

Hindia sphaeroidalis Duncan from the Devonian of Nevada (Porifera)

The small, spherical, lithistid sponge, Hindia sphaeroidalis Duncan, 1879, is reported from the Devonian and Silurian of the Great Basin for the first time. Devonian specimens came from the Emsian Bartine Member of the McColley Formation from near Roberts Creek, Roberts Mountains, and from the Eifelian part of the Nevada Group near Bishops Creek, north of Wells, Nevada. The Silurian occurrence, questioned because of poor preservation, is from the Laketown Dolomite, on Tunnel Spring Mountain in western Millard County, Utah.     

Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure

Ferroptosis is a recently recognized caspase-independent form of regulated cell death that is characterized by the accumulation of lethal lipid ROS produced through iron-dependent lipid peroxidation. Considering that regulation of fatty acid metabolism is responsible for the membrane-resident pool of oxidizable fatty acids that undergo lipid peroxidation in ferroptotic processes, we examined the contribution of the key fatty acid metabolism enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), in regulating ferroptosis. By using CRISPR/Cas9 technology, we found that knockout of Acsl4 in ferroptosis-sensitive murine and human cells conferred protection from erastin- and RSL3-induced cell death. In the same cell types, deletion of mixed lineage kinase domain-like (Mlkl) blocked susceptibility to necroptosis, as expected. Surprisingly, these studies also revealed ferroptosis and necroptosis are alternative, in that resistance to one pathway sensitized cells to death via the other pathway. These data suggest a mechanism by which one regulated necrosis pathway compensates for another when either ferroptosis or necroptosis is compromised. We verified the synergistic contributions of ferroptosis and necroptosis to tissue damage during acute organ failure in vivo. Interestingly, in the course of pathophysiological acute ischemic kidney injury, ACSL4 was initially upregulated and its expression level correlated with the severity of tissue damage. Together, our findings reveal ACSL4 to be a reliable biomarker of the emerging cell death modality of ferroptosis, which may also serve as a novel therapeutic target in preventing pathological cell death processes.     

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.     

Comparative genomic analysis of three Leishmania species that cause diverse human disease

Leishmania parasites cause a broad spectrum of clinical disease. Here we report the sequencing of the genomes of two species of Leishmania: Leishmania infantum and Leishmania braziliensis. The comparison of these sequences with the published genome of Leishmania major reveals marked conservation of synteny and identifies only approximately 200 genes with a differential distribution between the three species. L. braziliensis, contrary to Leishmania species examined so far, possesses components of a putative RNA-mediated interference pathway, telomere-associated transposable elements and spliced leader-associated SLACS retrotransposons. We show that pseudogene formation and gene loss are the principal forces shaping the different genomes. Genes that are differentially distributed between the species encode proteins implicated in host-pathogen interactions and parasite survival in the macrophage.