Common variation at 10p12.31 near MLLT10 influences meningioma risk

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.     

Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.     

Early SIV and HIV infection promotes the LILRB2/MHC-I inhibitory axis in cDCs

Classical dendritic cells (cDCs) play a pivotal role in the early events that tip the immune response toward persistence or viral control. In vitro studies indicate that HIV infection induces the dysregulation of cDCs through binding of the LILRB2 inhibitory receptor to its MHC-I ligands and the strength of this interaction was proposed to drive disease progression. However, the dynamics of the LILRB2/MHC-I inhibitory axis in cDCs during early immune responses against HIV are yet unknown. Here, we show that early HIV-1 infection induces a strong and simultaneous increase of LILRB2 and MHC-I expression on the surface of blood cDCs. We further characterized the early dynamics of LILRB2 and MHC-I expression by showing that SIVmac251 infection of macaques promotes coordinated up-regulation of LILRB2 and MHC-I on cDCs and monocytes/macrophages, from blood and lymph nodes. Orientation towards the LILRB2/MHC-I inhibitory axis starts from the first days of infection and is transiently induced in the entire cDC population in acute phase. Analysis of the factors involved indicates that HIV-1 replication, TLR7/8 triggering, and treatment by IL-10 or type I IFNs increase LILRB2 expression. Finally, enhancement of the LILRB2/MHC-I inhibitory axis is specific to HIV-1 and SIVmac251 infections, as expression of LILRB2 on cDCs decreased in naturally controlled chikungunya virus infection of macaques. Altogether, our data reveal a unique up-regulation of LILRB2 and its MHC-I ligands on cDCs in the early phase of SIV/HIV infection, which may account for immune dysregulation at a critical stage of the anti-viral response.     

ATP-induced Ca<Superscript>2+</Superscript>-signalling mechanisms in the regulation of mesenchymal stem cell migration

The ability of cells to migrate to the destined tissues or lesions is crucial for physiological processes from tissue morphogenesis, homeostasis and immune responses, and also for stem cell-based regenerative medicines. Cytosolic Ca²⁺ is a primary second messenger in the control and regulation of a wide range of cell functions including cell migration. Extracellular ATP, together with the cognate receptors on the cell surface, ligand-gated ion channel P2X receptors and a subset of G-protein-coupled P2Y receptors, represents common autocrine and/or paracrine Ca²⁺ signalling mechanisms. The P2X receptor ion channels mediate extracellular Ca²⁺ influx, whereas stimulation of the P2Y receptors triggers intracellular Ca²⁺ release from the endoplasmic reticulum (ER), and activation of both type of receptors thus can elevate the cytosolic Ca²⁺ concentration ([Ca²⁺]_c), albeit with different kinetics and capacity. Reduction in the ER Ca²⁺ level following the P2Y receptor activation can further induce store-operated Ca²⁺ entry as a distinct Ca²⁺ influx pathway that contributes in ATP-induced increase in the [Ca²⁺]_c. Mesenchymal stem cells (MSC) are a group of multipotent stem cells that grow from adult tissues and hold promising applications in tissue engineering and cell-based therapies treating a great and diverse number of diseases. There is increasing evidence to show constitutive or evoked ATP release from stem cells themselves or mature cells in the close vicinity. In this review, we discuss the mechanisms for ATP release and clearance, the receptors and ion channels participating in ATP-induced Ca²⁺ signalling and the roles of such signalling mechanisms in mediating ATP-induced regulation of MSC migration.     

Effects of cobble embeddedness on the microdistribution of the sculpin Cottus beldingi and its stonefly prey

Laboratory experiments were undertaken to assess the effects of three levels of cobble embeddedness on the microdistribution of the sculpin Cottus beldingi and its stonefly prey, Skwala Americana . Experiments were conducted separately and together as predator and prey in temperature- and flow-controlled artificial streams. When tested either separately or together, both the predator sculpin and its stonefly prey occurred in significantly greater numbers on substrata having unembedded cobbles than substrata having half- or completely embedded cobbles. Stonefly densities were greater in substrata having unembedded cobbles even though predator densities within the more embedded cobble patches were significantly lower. These findings support the hypothesis that higher predator densities influence prey densities less than the structural habitat quality of unembedded-cobble patches.     

Controlling performance of bluebunch wheatgrass and spotted knapweed using nitrogen and sucrose amendments

Range- and wildlands are being invaded by nonindigenous plants, resulting in an unprecedented, rapid change in plant community composition across the United States. Successional management predicts that species performance may be modified by resource availability. The objective of this study was to determine whether species performance could be altered by modifying soil nitrate (NO 3 – ) and ammonium (NH 4 + ) concentrations within an Idaho fescue ( Festuca idahoensis )/bluebunch wheatgrass ( Pseudoroegneria spicata ) plant association. We planted bluebunch wheatgrass and spotted knapweed ( Centaurea maculosa ) in an addition series at 2 sites in southwestern Montana. Each plot in the addition series matrix was divided into thirds, and we applied nitrogen (N) to a subplot and sucrose to a 2nd subplot. The remaining subplot was not amended and considered a control. Nitrogen amendment tended to enhance the performance of spotted knapweed, while sucrose amendment had no effect. Bluebunch wheatgrass performance was not affected by either amendment. Sucrose treatments only decreased soil NO 3 – at the more productive site. Regression models for predicting bluebunch wheatgrass and spotted knapweed biomass accounted for only about 30% of the variation, suggesting other processes in addition to interference were responsible for explaining relative plant perfor - mance. We recommend that land managers prevent activities that increase soil N concentration while the effectiveness of carbon amendments as a means to decrease soil N concentrations and shift interference relationships is further investigated.     

Denning chronology of black bears in eastern Rocky Mountain National Park, Colorado

Understanding factors influencing the timing of den entrance and emergence of black bears ( Ursus americanus ) provides insight for bear management. We determined den entrance and emergence dates for bears in Rocky Mountain National Park (RMNP) and related these dates to vegetative productivity, weather, habitat, and demographic factors to assess the influence of these factors on denning chronology. Date of den entrance was most strongly influenced by age class, precipitation, and proportion of human-use areas in annual home ranges. Den entrance was typically later for adult bears during wetter years and when annual home ranges contained a greater proportion of human-use areas. Sex and presence of human-use areas were most strongly related to den emergence. Male bears typically emerged from dens before females, and bears emerged from dens earlier when human-use areas composed a greater proportion of annual home ranges. Collectively, our results suggest that denning behavior of black bears in RMNP was strongly influenced by presence of human-use areas, likely because of foods associated with such areas. Managers of black bears in RMNP can use precipitation to predict relative dates of den entrance, thereby allowing for more efficient strategies to combat potentially negative human&ndash;black bear encounters.     

Forecast comparisons of four models of U.S. interest rates

In this paper we compare the out of sample forecasts from four alternative interest rate models based on expanding information sets. The random walk model is the most restrictive. The univariate time series model allows for a richer dynamic pattern and more conditioning information on own rates. The multivariate time series model permits a flexible dynamic pattern with own- and cross-series information. Finally, the forecasts from the MPS econometric model depend on the full model structure and information set. In theory, more information is preferred to less. In practice, complicated misspecified models can perform much worse than simple (also probably misspecified) models. For forecasts evaluated over the volatile 1970s the multivariate time series model forecasts are considerably better than those from simpler models which use less conditioning information, as well as forecasts from the MPS model which uses substantially more conditioning information but also imposes ‘structural’ economic restrictions.     

An extant cichlid fish radiation emerged in an extinct Pleistocene lake

The haplochromine cichlid fish of the East African Great Lakes represent some of the fastest and most species-rich adaptive radiations known, but rivers in most of Africa accommodate only a few morphologically similar species of haplochromine cichlid fish. This has been explained by the wealth of ecological opportunity in large lakes compared with rivers. It is therefore surprising that the rivers of southern Africa harbour many, ecologically diverse haplochromines. Here we present genetic, morphological and biogeographical evidence suggesting that these riverine cichlids are products of a recent adaptive radiation in a large lake that dried up in the Holocene. Haplochromine species richness peaks steeply in an area for which geological data reveal the historical existence of Lake palaeo-Makgadikgadi. The centre of this extinct lake is now a saltpan north of the Kalahari Desert, but it once hosted a rapidly evolving fish species radiation, comparable in morphological diversity to that in the extant African Great Lakes. Importantly, this lake seeded all major river systems of southern Africa with ecologically diverse cichlids. This discovery reveals how local evolutionary processes operating during a short window of ecological opportunity can have a major and lasting effect on biodiversity on a continental scale.