Binding and phosphorylation of par-4 by akt is essential for cancer cell survival

Activation of the PI3K-Akt pathway by loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, increased growth factor signaling, or oncogene expression renders cancer cells resistant to apoptotic signals and promotes tumor growth. Although Akt acts as a global survival signal, the molecular circuits of this pathway have not been completely established. We report that Akt physically binds to the pro-apoptotic protein Par-4 via the Par-4 leucine zipper domain and phosphorylates Par-4 to inhibit apoptosis. Suppression of Akt activation by the PI3K-inhibitor PTEN or LY294002, Akt expression by RNA-interference, or Akt function by dominant-negative Akt caused apoptosis in cancer cells. Apoptosis induced by inhibiting Akt was blocked by inhibition of Par-4 expression, but not by inhibition of other apoptosis agonists that are Akt substrates, suggesting that inhibition of the PI3K-Akt pathway leads to Par-4-dependent apoptosis. Thus, Par-4 is essential for PTEN-inducible apoptosis, and inactivation of Par-4 by Akt promotes cancer cell survival.     

Modeling Spatial Trends in Estimated Species Richness using Breeding Bird Survey Data: A Valuable Tool in Biodiversity Assessment

We used data from the French breeding bird survey to estimate local bird species richness within sampled sites, using capture–recapture models. We investigated the possible effects of habitat structure and composition (landscape fragmentation, habitat cover and diversity) on estimated species richness at a local scale, and used the identified trends to help with modeling species richness at a large spatial scale. We performed geostatistical analyses based on spatial autocorrelation – cokriging models – to interpolate estimated species richness over the entire country, providing an opportunity to predict species-rich areas. We further compared species richness obtained with this method to species and rarity richness obtained using a national atlas of breeding birds. Estimated species richness was higher in species richness hotspots identified by the atlas. Combining informations on rare species from Atlas and species richness estimates from sound sampling based schemes should help with identifying species-rich areas for various taxa and locating biodiversity hotspots to be protected as high conservation value areas, especially in temperate zones where diversity hotspots are likely to match centers of high species richness because of very few centers of true endemicity.     

A high‐resolution genetic map of the cereal crown rot pathogen Fusarium pseudograminearum provides a near‐complete genome assembly

Fusarium pseudograminearum is an important pathogen of wheat and barley, particularly in semi‐arid environments. Previous genome assemblies for this organism were based entirely on short read data and are highly fragmented. In this work, a genetic map of F. pseudograminearum has been constructed for the first time based on a mapping population of 178 individuals. The genetic map, together with long read scaffolding of a short read‐based genome assembly, was used to give a near‐complete assembly of the four F. pseudograminearum chromosomes. Large regions of synteny between F. pseudograminearum and F. graminearum, the related pathogen that is the primary causal agent of cereal head blight disease, were previously proposed in the core conserved genome, but the construction of a genetic map to order and orient contigs is critical to the validation of synteny and the placing of species‐specific regions. Indeed, our comparative analyses of the genomes of these two related pathogens suggest that rearrangements in the F. pseudograminearum genome have occurred in the chromosome ends. One of these rearrangements includes the transposition of an entire gene cluster involved in the detoxification of the benzoxazolinone (BOA) class of plant phytoalexins. This work provides an important genomic and genetic resource for F. pseudograminearum, which is less well characterized than F. graminearum. In addition, this study provides new insights into a better understanding of the sexual reproduction process in F. pseudograminearum, which informs us of the potential of this pathogen to evolve.     

Differential plasticity of size and mass to environmental change in a hibernating mammal

Morphological changes following changes in species' distribution and phenology have been suggested to be the third universal response to global environmental change. Although structural size and body mass result from different genetic, physiological, and ecological mechanisms, they are used interchangeably in studies evaluating population responses to environmental change. Using a 22‐year (1991–2013) dataset including 1768 individuals, we investigated the coupled dynamics of size and mass in a hibernating mammal, the Alpine marmot (Marmota marmota), in response to local environmental conditions. We (i) quantified temporal trends in both traits, (ii) determined the environmental drivers of trait dynamics, and (iii) identified the life‐history processes underlying the observed changes. Both phenotypic traits were followed through life: we focused on the initial trait value (juvenile size and mass) and later‐life development (annual change in size [Δsize] and mass [Δmass]). First, we demonstrated contrasting dynamics between size and mass over the study period. Juvenile size and subsequent Δsize showed significant declines, whereas juvenile mass and subsequent Δmass remained constant. As a consequence of smaller size associated with a similar mass, individuals were in better condition in recent years. Second, size and mass showed different sensitivities to environmental variables. Both traits benefited from early access to resources in spring, whereas Δmass, particularly in early life, also responded to summer and winter conditions. Third, the interannual variation in both traits was caused by changes in early life development. Our study supports the importance of considering the differences between size and mass responses to the environment when evaluating the mechanisms underlying population dynamics. The current practice of focusing on only one trait in population modeling can lead to misleading conclusions when evaluating species' resilience to contemporary climate change.     

High Throughput Sequential ELISA for Validation of Biomarkers of Acute Graft-Versus-Host Disease

Unbiased discovery proteomics strategies have the potential to identify large numbers of novel biomarkers that can improve diagnostic and prognostic testing in a clinical setting and may help guide therapeutic interventions. When large numbers of candidate proteins are identified, it may be difficult to validate candidate biomarkers in a timely and efficient fashion from patient plasma samples that are event-driven, of finite volume and irreplaceable, such as at the onset of acute graft-versus-host disease (GVHD), a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT).Here we describe the process of performing commercially available ELISAs for six validated GVHD proteins: IL-2Rα⁵, TNFR1⁶, HGF⁷, IL-8⁸, elafin², and REG3α³ (also known as PAP1) in a sequential fashion to minimize freeze-thaw cycles, thawed plasma time and plasma usage. For this procedure we perform the ELISAs in sequential order as determined by sample dilution factor as established in our laboratory using manufacturer ELISA kits and protocols with minor adjustments to facilitate optimal sequential ELISA performance. The resulting plasma biomarker concentrations can then be compiled and analyzed for significant findings within a patient cohort. While these biomarkers are currently for research purposes only, their incorporation into clinical care is currently being investigated in clinical trials.This technique can be applied to perform ELISAs for multiple proteins/cytokines of interest on the same sample(s) provided the samples do not need to be mixed with other reagents. If ELISA kits do not come with pre-coated plates, 96-well half-well plates or 384-well plates can be used to further minimize use of samples/reagents.     

CUBN and NEBL common variants in the chromosome 10p13 linkage region are associated with multibacillary leprosy in Vietnam

Leprosy is caused by infection with Mycobacterium leprae and is classified clinically into paucibacillary (PB) or multibacillary (MB) subtypes based on the number of skin lesions and the bacillary index detected in skin smears. We previously identified a major PB susceptibility locus on chromosome region 10p13 in Vietnamese families by linkage analysis. In the current study, we conducted high-density association mapping of the 9.5 Mb linkage peak on chromosome region 10p13 covering 39 genes. Using leprosy per se and leprosy subtypes as phenotypes, we employed 294 nuclear families (303 leprosy cases, 63 % MB, 37 % PB) as a discovery sample and 192 nuclear families (192 cases, 55 % MB, 45 % PB) as a replication sample. Replicated significant association signals were revealed in the genes for cubilin (CUBN) and nebulette (NEBL). In the combined sample, the C allele (frequency 0.26) at CUBN SNP rs10904831 showed association [p = 1 × 10^?5; OR 0.52 (0.38–0.7)] with MB leprosy only. Likewise, allele T (frequency 0.42) at NEBL SNP rs11012461 showed association [p = 4.2 × 10^?5; OR 2.51 (1.6–4)] with MB leprosy only. These associations remained valid for the CUBN signal when taking into account the effective number of tests performed (type I error significance threshold = 2.4 × 10^?5). We used the results of our analyses to propose a new model for the genetic control of polarization of clinical leprosy.