Identification of Human Islet Amyloid Polypeptide as a BACE2 Substrate

Pancreatic amyloid formation by islet amyloid polypeptide (IAPP) is a hallmark pathological feature of type 2 diabetes. IAPP is stored in the secretory granules of pancreatic beta-cells and co-secreted with insulin to maintain glucose homeostasis. IAPP is innocuous under homeostatic conditions but imbalances in production or processing of IAPP may result in homodimer formation leading to the rapid production of cytotoxic oligomers and amyloid fibrils. The consequence is beta-cell dysfunction and the accumulation of proteinaceous plaques in and around pancreatic islets. Beta-site APP-cleaving enzyme 2, BACE2, is an aspartyl protease commonly associated with BACE1, a related homolog responsible for amyloid processing in the brain and strongly implicated in Alzheimer’s disease. Herein, we identify two distinct sites of the mature human IAPP sequence that are susceptible to BACE2-mediated proteolytic activity. The result of proteolysis is modulation of human IAPP fibrillation and human IAPP protein degradation. These results suggest a potential therapeutic role for BACE2 in type 2 diabetes-associated hyperamylinaemia.     

Use of Mangroves by Lemurs

Despite an increasing recognition of the ecosystem services provided by mangroves, we know little about their role in maintaining terrestrial biodiversity, including primates. Madagascar’s lemurs are a top global conservation priority, with 94 % of species threatened with extinction, but records of their occurrence in mangroves are scarce. I used a mixed-methods approach to collect published and unpublished observations of lemurs in mangroves: I carried out a systematic literature search and supplemented this with a targeted information request to 1243 researchers, conservation and tourism professionals, and others who may have visited mangroves in Madagascar. I found references to, or observations of, at least 23 species in 5 families using mangroves, representing >20% of lemur species and >50% of species whose distributions include mangrove areas. Lemurs used mangroves for foraging, sleeping, and traveling between terrestrial forest patches, and some were observed as much as 3 km from the nearest permanently dry land. However, most records were anecdotal and thus tell us little about lemur ecology in this habitat. Mangroves are more widely used by lemurs than has previously been recognized and merit greater attention from primate researchers and conservationists in Madagascar.     

The constant philopater hypothesis: a new life history invariant for dispersal evolution

Surprising invariance relationships have emerged from the study of social interaction, whereby a cancelling‐out of multiple partial effects of genetic, ecological or demographic parameters means that they have no net impact upon the evolution of a social behaviour. Such invariants play a pivotal role in the study of social adaptation: on the one hand, they provide theoretical hypotheses that can be empirically tested; and, on the other hand, they provide benchmark frameworks against which new theoretical developments can be understood. Here we derive a novel invariant for dispersal evolution: the ‘constant philopater hypothesis’ (CPH). Specifically, we find that, irrespective of variation in maternal fecundity, all mothers are favoured to produce exactly the same number of philopatric offspring, with high‐fecundity mothers investing proportionally more, and low‐fecundity mothers investing proportionally less, into dispersing offspring. This result holds for female and male dispersal, under haploid, diploid and haplodiploid modes of inheritance, irrespective of the sex ratio, local resource availability and whether mother or offspring controls the latter's dispersal propensity. We explore the implications of this result for evolutionary conflict of interests – and the exchange and withholding of contextual information – both within and between families, and we show that the CPH is the fundamental invariant that underpins and explains a wider family of invariance relationships that emerge from the study of social evolution.     

Production of endothelial progenitor cells obtained from human Wharton's jelly using different culture conditions

Endothelial progenitor cells (EPC) participate in revascularization and angiogenesis. EPC can be cultured in vitro from mononuclear cells of peripheral blood, umbilical cord blood or bone marrow; they also can be transdifferentiated from mesenchymal stem cells (MSC). We isolated EPCs from Wharton's jelly (WJ) using two methods. The first method was by obtaining MSC from WJ and characterizing them by flow cytometry and their adipogenic and osteogenic differentiation, then applying endothelial growth differentiating media. The second method was by direct culture of cells derived from WJ into endothelial differentiating media. EPCs were characterized by morphology, Dil-LDL uptake/UEA-1 immunostaining and testing the expression of endothelial markers by flow cytometry and RT-PCR. We found that MSC derived from WJ differentiated into endothelial-like cells using simple culture conditions with endothelium induction agents in the medium.     

Early tetrapodomorph biogeography: Controlling for fossil record bias in macroevolutionary analyses

The fossil record provides direct empirical data for understanding macroevolutionary patterns and processes. Inherent biases in the fossil record are well known to confound analyses of this data. Sampling bias proxies have been used as covariates in regression models to test for such biases. Proxies, such as formation count, are associated with paleobiodiversity, but are insufficient for explaining species dispersal owing to a lack of geographic context. Here, we develop a sampling bias proxy that incorporates geographic information and test it with a case study on early tetrapodomorph biogeography. We use recently-developed Bayesian phylogeographic models and a new supertree of early tetrapodomorphs to estimate dispersal rates and ancestral habitat locations. We find strong evidence that geographic sampling bias explains supposed radiations in dispersal rate (potential adaptive radiations). Our study highlights the necessity of accounting for geographic sampling bias in macroevolutionary and phylogenetic analyses and provides an approach to test for its effect.     

Shining light on the alphaproteobacterial general stress response

The general stress response (GSR) allows many bacterial species to react to myriad different stressors. In Alphaproteobacteria, this signaling pathway proceeds through the partner‐switching PhyR‐EcfG sigma‐factor mechanism and is involved in multiple life processes, including virulence in Brucella abortus. To date, details of the alphaproteobacterial GSR signaling pathway have been determined using genetic and biochemical work on a diverse set of species distributed throughout the clade. Fiebig and co‐workers establish Erythrobacter litoralis DSM 8509 as a genetically tractable lab strain and use it to both directly and indirectly delineate photoresponsive GSR pathways mediated by multiple HWE/HisKA_2 histidine kinases. The existence of a new phototrophic lab strain allows researchers to compare the GSR across different Alphaproteobacteria, as well as study the interplay between the GSR and phototrophy. Additionally, the discovery of new HWE/HisKA_2 kinases regulating the GSR poses new questions about how different stimuli feed into this widespread stress pathway.     

Identification of flavonoids as regulators of YbeY activity in Liberibacter asiaticus

Liberibacter asiaticus is the prevalent causative pathogen of Huanglongbing or citrus greening disease, which has resulted in a devastating crisis in the citrus industry. A thorough understanding of this pathogen's physiology and mechanisms to control cell survival is critical in the identification of therapeutic targets. YbeY is a highly conserved bacterial RNase that has been implicated in multiple roles. In this study, we evaluated the biochemical characteristics of the L. asiaticus YbeY (CLIBASIA_01560) and assessed its potential as a target for antimicrobials. YbeY_Las was characterized as an endoribonuclease with activity on 3′ and 5′ termini of 16S and 23S rRNAs, and the capacity to suppress the E. coli ΔybeY phenotype. We predicted the YbeY_Las protein:ligand interface and subsequently identified a flavone compound, luteolin, as a selective inhibitor. Site-directed mutagenesis was subsequently used to identify key residues involved in the catalytic activity of YbeY_Las. Further evaluation of naturally occurring flavonoids in citrus trees indicated that both flavones and flavonols had potent inhibitory effects on YbeY_Las. Luteolin was subsequently examined for efficacy against L. asiaticus in Huanglongbing-infected citrus trees, where a significant reduction in L. asiaticus gene expression was observed.