Approximate Bayesian computation reveals the factors that influence genetic diversity and population structure of foxsnakes

Contemporary geographical range and patterns of genetic diversity within species reflect complex interactions between multiple factors acting across spatial and temporal scales, and it is notoriously difficult to disentangle causation. Here, we quantify patterns of genetic diversity and genetic population structure using mitochondrial DNA sequences (101 individuals, cytochrome b) and microsatellites (816 individuals, 12 loci) and use Approximate Bayesian computation methods to test competing models of the demographic history of eastern and western foxsnakes. Our analyses indicate that post-glacial colonization and past population declines, probably caused by the infilling of deciduous forest and cooler temperatures since the mid-Holocene, largely underpin large-scale genetic patterns for foxsnakes. At finer geographical scales, our results point to more recent anthropogenic habitat loss as having accentuated genetic population structure by causing further declines and fragmentation.     

Reproductive tract and spermatid abnormalities of hybrid males from reciprocal crosses between Drosophila mojavensis and D. arizonae

Hybrid males from reciprocal crosses of specific strains of the closely related species Drosophila mojavensis and Drosophila arizonae are sterile. The sterile hybrid males exhibit testis and seminal vesicle phenotypes that differ from their parental strains and from each other both in lengths of the organs and the development of the spermatids as seen in light and electron microscopy. Incompatibilities affecting spermiogenesis differ in reciprocal crosses, suggesting that hybrid male sterility may originate from a range of different underlying mechanisms.     

T cell profiling reveals high CD4+CTLA-4+ T cell frequency as dominant predictor for survival after Prostate GVAX/ipilimumab treatment

Immune checkpoint blockade enhances antitumor responses, but can also lead to severe immune-related adverse events (IRAE). To avoid unnecessary exposure to these potentially hazardous agents, it is important to identify biomarkers that correlate with clinical activity and can be used to select patients that will benefit from immune checkpoint blockade. To understand the consequences of CTLA-4 blockade and identify biomarkers for clinical efficacy and/or survival, an exploratory T cell monitoring study was performed in a phase I/II dose escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed striking differences between patients who benefited from therapy and patients that did not. Treatment-induced rises in absolute lymphocyte counts, CD4⁺ T cell differentiation, and CD4⁺ and CD8⁺ T cell activation were all associated with clinical benefit. Moreover, significantly prolonged overall survival (OS) was observed for patients with high pre-treatment frequencies of CD4⁺CTLA-4⁺, CD4⁺PD-1⁺, or differentiated (i.e., non-naive) CD8⁺ T cells or low pre-treatment frequencies of differentiated CD4⁺ or regulatory T cells. Unsupervised clustering of these immune biomarkers revealed cancer-related expression of CTLA-4⁺ in CD4⁺ T cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab therapy and to thus provide a putative and much-needed biomarker for patient selection prior to therapeutic CTLA4 blockade.     

Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors

Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC₅₀ = 8 nM) was made from a weak μM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed.     

Applying new inter-individual approaches to assess fine-scale population genetic diversity in a neotropical frog, Eleutherodactylus ockendeni

We assess patterns of genetic diversity of a neotropical leaflitter frog, Eleutherodactylus ockendeni, in the upper Amazon of Ecuador without a priori delineation of biological populations and with sufficiently intensive sampling to assess inter-individual patterns. We mapped the location of each collected frog across a 5.4 x 1 km landscape at the Jatun Sacha Biological Station, genotyped 185 individuals using five species-specific DNA microsatellite loci, and sequenced a fragment of mitochondrial cytochrome b for a subset of 51 individuals. The microsatellites were characterized by high allelic diversity and homozygote excess across all loci, suggesting that when pooled the sample is not a panmictic population. We conclude that the lack of panmixia is not attributable to the influence of null alleles or biased sampling of consanguineous family groups. Multiple methods of population cluster analysis, using both Bayesian and maximum likelihood approaches, failed to identify discrete genetic clusters across the sampled area. Using multivariate spatial autocorrelation, kinship coefficients and relatedness coefficients, we identify a continuous isolation by distance population structure, with a first patch size of ca. 260 m and apparently large population sizes. Analysis of mtDNA corroborates the observation of high genetic diversity at fine scales: there are multiple haplotypes, they are non-randomly distributed and a binary haplotype correlogram shows significant spatial genetic autocorrelation. We demonstrate the utility of inter-individual genetic methods and caution against making a priori assumptions about population genetic structure based simply on arbitrary or convenient patterns of sampling.     

First report of Phytopythium vexans causing the “Avocado sadness” in Michoacan,Mexico

Mexico is the main producer, consumer and exporter of avocado in the world, being Michoacan the main producer state contributing more than 80% of the national production. There are phytopathogens that decimate the production causing the death of the tree. Root samples were collected in avocado trees that showed the characteristic symptomatology of the disease known as avocado sadness, the sampling was carried out in four of the main avocado producing towns, in the state of Michoacan, Mexico. The isolation consisted in sowing root tissue in Petri dishes with V8^®-PARPH culture medium, subsequently they were identified morphologically and for species level it was determined by molecular biology, with the PCR-ITS technique. Pathogenicity tests were performed in triplicate with avocado seedlings with more than six leaves. After 24 hours, the inoculated plants expressed decay in the apical part, after 120 hours the leaves showed yellowing and after 15 days there was a generalized wilt on the stem and leaves, re-isolating the phytopathogen Phytopythium vexans. This study confirms the first report of the oomycete P. vexans affecting avocado trees in the most important producing region of the Mexican Republic.     

Modeling ion channel regulation

Remarkable recent successes in structure determinations of voltage-gated channels, ligand-gated channels, mechanosensitive channels and proton channels have advanced our understanding of the molecular basis of ion channel gating substantially. Models have helped to clarify aspects of this process and are now being designed as sophisticated biomimetics for various technological applications.     

Mating signal partitioning in multi-species assemblages: a null model test using frogs

Abstract Competitive partitioning of ‘community’ signal space has long been suggested to underlie diversification of mating signals. Selection or competitive exclusion is expected to reduce overlap of signals, minimizing destructive interference or reducing mismating. We used null models backed by simulation of type I and II error rates to test for evidence of structuring within 11 frog advertisement call assemblages. Within three assemblages, we found significant over‐dispersion and regularity‐of‐spacing in dominant frequency and in pulse rate, consistent with a signal interference hypothesis and signal confusion hypothesis, respectively. Observed partitioning could represent signal evolution or could result from selection on assemblage composition. Most assemblages showed no acoustic partitioning possibly because: (i) partitioning is more readily apparent in female preference, calling times or sites, rather than call attributes; (ii) assemblages have not yet accommodated recently arrived species, or are compositionally unstable so that acoustic accommodation cannot occur; and (iii) evidence of partitioning is only likely where the acoustic space is densely packed.