Protein phosphatase with EF-hand domains 2 (PPEF2) is a potent negative regulator of apoptosis signal regulating kinase-1 (ASK1)

The function of protein phosphatases with EF-hand domains (PPEF) in mammals is not known. Large-scale expression profiling experiments suggest that PPEF expression may correlate with stress protective responses, cell survival, growth, proliferation, or neoplastic transformation. Apoptosis signal regulating kinase-1 (ASK1) is a MAP kinase kinase kinase implicated in cancer, cardiovascular and neurodegenerative diseases. ASK1 is activated by oxidative stress and induces pro-apoptotic or inflammatory signalling, largely via sustained activation of MAP kinases p38 and/or JNK. We identify human PPEF2 as a novel interacting partner and a negative regulator of ASK1. In COS-7 or HEK 293A cells treated with H₂O₂, expression of PPEF2 abrogated sustained activation of p38 and one of the JNK p46 isoforms, and prevented ASK1-dependent caspase-3 cleavage and activation. PPEF2 efficiently suppressed H₂O₂-induced activation of ASK1. Overexpessed as well as endogenous ASK1 co-immunoprecipitated with PPEF2. PPEF2 was considerably more potent both as a suppressor of ASK1 activation and as its interacting partner as compared to protein phosphatase 5 (PP5), a well-known negative regulator of ASK1. PPEF2 was found to form complexes with endogenous Hsp70 and to a lesser extent Hsp90, which are also known interacting partners of PP5. These data identify, for the first time, a possible downstream signalling partner of a mammalian PPEF phosphatase, and suggest that, despite structural divergence, PPEF and PP5 phosphatases may share common interacting partners and functions.     

Design and synthesis of orally efficacious benzimidazoles as melanin-concentrating hormone receptor 1 antagonists

Biaryl urea lead compound 1 was discovered earlier in our MCH antagonist program. Novel benzimidazole analogues with increased chemical stability, devoid of the potential carcinogenic liability associated with a biarylamine moiety, were synthesized and evaluated to be potent MCH R1 antagonists. Two compounds in this series have demonstrated in vivo efficacy in a rodent obesity model.     

Hydroxylated analogues of the orally active broad spectrum antifungal, Sch 51048 (1), and the discovery of posaconazole [Sch 56592; 2 or (S,S)-5

As part of a detailed study, the syntheses, biological activities, and pharmacokinetic properties of hydroxylated analogues of the previously described broad spectrum antifungal agents, Sch 51048 (1), Sch 50001 (3), and Sch 50002 (4), are described. Based on an overall superior profile, one of the alcohols, Sch 56592 (2), was selected for clinical studies.     

Human impacts and the global distribution of extinction risk

Understanding the global geographical distribution of extinction risk is a key challenge in conservation biology. It remains controversial, however, to what extent areas become threat hotspots simply because of high human impacts or due to predisposing ecological conditions. Limits to the taxonomic and geographical extent, resolution and quality of previously available data have precluded a full global assessment of the relative roles of these factors. Here, we use a new global database on the geographical distributions of birds on continents and continental islands to show that, after controlling for species richness, the best predictors of the global pattern of extinction risk are measures of human impact. Ecological gradients are of secondary importance at a global scale. The converse is true for individual biogeographic realms, within which variation in human impact is reduced and its influence on extinction risk globally is therefore underestimated. These results underline the importance of a global perspective on the mechanisms driving spatial patterns of extinction risk, and the key role of anthropogenic factors in driving the current extinction crisis.     

The energy costs of sexual dimorphism in mole-rats are morphological not behavioural

Different reproductive strategies of males and females may lead to the evolution of differences in their energetic costs of reproduction, overall energetic requirements and physiological performances. Sexual dimorphism is often associated with costly behaviours (e.g. large males might have a competitive advantage in fighting, which is energetically expensive). However, few studies of mammals have directly compared the energy costs of reproductive activities between sexes. We compared the daily energy expenditure (DEE) and resting metabolic rate (RMR) of males and females of two species of mole-rat, Bathyergus janetta and Georychus capensis (the former is sexually dimorphic in body size and the latter is not) during a period of intense digging when males seek females. We hypothesized that large body size might be indicative of greater digging or fighting capabilities, and hence greater mass-independent DEE values in males of the sexually dimorphic species. In contrast to this prediction, although absolute values of DEE were greater in B. janetta males, mass-independent values were not. No differences were apparent between sexes in G. capensis. By comparison, although RMR values were greater in B. janetta than G. capensis, no differences were apparent between the sexes for either species. The energy cost of dimorphism is most likely to be the cost of maintenance of a large body size, and not the cost of behaviours performed when an individual is large.     

Epistasis among Drosophila persimilis factors conferring hybrid male sterility with D. pseudoobscura bogotana

The Bateson-Dobzhansky-Muller model posits that hybrid incompatibilities result from genetic changes that accumulate during population divergence. Indeed, much effort in recent years has been devoted to identifying genes associated with hybrid incompatibilities, often with limited success, suggesting that hybrid sterility and inviability are frequently caused by complex interactions between multiple loci and not by single or a small number of gene pairs. Our previous study showed that the nature of epistasis between sterility-conferring QTL in the Drosophila persimilis-D. pseudoobscura bogotana species pair is highly specific. Here, we further dissect one of the three QTL underlying hybrid male sterility between these species and provide evidence for multiple factors within this QTL. This result indicates that the number of loci thought to contribute to hybrid dysfunction may have been underestimated, and we discuss how linkage and complex epistasis may be characteristic of the genetics of hybrid incompatibilities. We further pinpoint the location of one locus that confers hybrid male sterility when homozygous, dubbed "mule-like", to roughly 250 kilobases.     

Barriers to insecticide-treated mosquito net possession 2 years after a mass free distribution campaign in Luangwa District, Zambia

Background and Methods

Roll Back Malaria set the goal of 100% of households in malaria endemic countries in Africa owning an insecticide-treated mosquito net (ITN) by 2010. Zambia has used mass free distribution campaigns and distribution through antenatal care (ANC) clinics to achieve high coverage.

Methodology and Principal Findings

We conducted a probability survey of 801 households in 2008 to assess factors associated with households that lacked an ITN after mass distribution. Community perceptions of barriers to ITN access were also obtained from in-depth interviews with household heads that reported not owning an ITN. Nearly 74% of households in Luangwa district reported owning ≥1 ITN. Logistic regression showed households without a child <5 years old during the ITN distribution campaigns were twice as likely to not have an ITN as those with a child <5 during distribution (Adjusted odds ratio (AOR)  = 2.43; 95% confidence interval (CI): 1.67–3.55). Households without a woman who attended an ANC in the past 2 years were more likely to be without ITNs compared to households with a woman who attended an ANC in the past 2 years (AOR  = 1.52; 95% CI: 1.04–2.21). In-depth interviews with heads of households without an ITN revealed that old age was a perceived barrier to receiving an ITN during distribution, and that ITNs wore out before they could be replaced.

Conclusions and Significance

Delivery of a large number of ITNs does not translate directly into 100% household coverage. Due to their design, current ITN distribution strategies may miss households occupied by the elderly and those without children or ANC access. ITN distribution strategies targeting the elderly, those with limited access to distribution points, and others most likely to be missed are necessary if 100% ITN coverage of households is to be achieved.     

Migration through a Major Andean Ecogeographic Disruption as a Driver of Genetic and Phenotypic Diversity in a Wild Tomato Species

Evolutionary dynamics at the population level play a central role in creating the diversity of life on our planet. In this study, we sought to understand the origins of such population-level variation in mating systems and defensive acylsugar chemistry in Solanum habrochaites—a wild tomato species found in diverse Andean habitats in Ecuador and Peru. Using Restriction-site-Associated-DNA-Sequencing (RAD-seq) of 50 S. habrochaites accessions, we identified eight population clusters generated via isolation and hybridization dynamics of 4–6 ancestral populations. Detailed characterization of mating systems of these clusters revealed emergence of multiple self-compatible (SC) groups from progenitor self-incompatible populations in the northern part of the species range. Emergence of these SC groups was also associated with fixation of deleterious alleles inactivating acylsugar acetylation. The Amotape-Huancabamba Zone—a geographical landmark in the Andes with high endemism and isolated microhabitats—was identified as a major driver of differentiation in the northern species range, whereas large geographical distances contributed to population structure and evolution of a novel SC group in the central and southern parts of the range, where the species was also inferred to have originated. Findings presented here highlight the role of the diverse ecogeography of Peru and Ecuador in generating population differentiation, and enhance our understanding of the microevolutionary processes that create biological diversity.