Decline in lizard species diversity,abundance and ectoparasite load across an elevational gradient in the Australian alps

The rapid changes in altitude, and associated habitat, of mountain ecosystems make them ideal natural laboratories for testing the effect of environmental heterogeneity on species assemblage. Our understanding of the sensitivity of Australian reptiles to elevational clines is limited. We examined lizard distribution across three elevation zones (montane, subalpine and alpine), spanning from 900 to 1840 m above sea level, in the Australian alps. We aimed to examine how elevation influences species diversity and abundance, and ectoparasite load, and whether species alter their habitat use amongst different elevational zones. Active searches were conducted across the elevation zones to identify lizard community structure (at least 16 species) across elevational zones, along with skink habitat preferences and the ectoparasite load. Skink diversity and abundance were negatively correlated with increased elevation. The alpine zone had significantly lower diversity and abundance of skinks. Habitat use differed amongst both elevations and species. Ectoparasite prevalence was also significantly diminished in the alpine zone. Ectoparasites only infected a subset of the skink community, with ectoparasite load increasing as the active season progressed. This study provides evidence of the complex interplay between elevation and species diversity, as well as the differences in ectoparasite pressure along elevational gradients in the Australian alps.     

Discovery of a novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors

A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a–c and 12a–c from a weak-binding fragment-like structure 1 as a starting point.     

Design and characterization of novel dual Fc antibody with enhanced avidity for Fc receptors

Monoclonal antibodies (mAbs) have become an important class of therapeutics, particularly in the realm of anticancer immunotherapy. While the two antigen-binding fragments (Fabs) of an mAb allow for high-avidity binding to molecular targets, the crystallizable fragment (Fc) engages immune effector elements. mAbs of the IgG class are used for the treatment of autoimmune diseases and can elicit antitumor immune functions not only by several mechanisms including direct antigen engagement via their Fab arms but also by Fab binding to tumors combined with Fc engagement of complement component C1q and Fcγ receptors. Additionally, IgG binding to the neonatal Fc receptor (FcRn) allows for endosomal recycling and prolonged serum half-life. To augment the effector functions or half-life of an IgG1 mAb, we constructed a novel “2Fc” mAb containing two Fc domains in addition to the normal two Fab domains. Structural and functional characterization of this 2Fc mAb demonstrated that it exists in a tetrahedral-like geometry and retains binding capacity via the Fab domains. Furthermore, duplication of the Fc region significantly enhanced avidity for Fc receptors FcγRI, FcγRIIIa, and FcRn, which manifested as a decrease in complex dissociation rate that was more pronounced at higher densities of receptor. At intermediate receptor density, the dissociation rate for Fc receptors was decreased 6- to 130-fold, resulting in apparent affinity increases of 7- to 42-fold. Stoichiometric analysis confirmed that each 2Fc mAb may simultaneously bind two molecules of FcγRI or four molecules of FcRn, which is double the stoichiometry of a wild-type mAb. In summary, duplication of the IgG Fc region allows for increased avidity to Fc receptors that could translate into clinically relevant enhancement of effector functions or pharmacokinetics.     

The opening of the SPP1 bacteriophage tail, a prevalent mechanism in Gram-positive-infecting siphophages

The SPP1 siphophage uses its long non-contractile tail and tail tip to recognize and infect the Gram-positive bacterium Bacillus subtilis. The tail-end cap and its attached tip are the critical components for host recognition and opening of the tail tube for genome exit. In the present work, we determined the cryo-electron microscopic (cryo-EM) structure of a complex formed by the cap protein gp19.1 (Dit) and the N terminus of the downstream protein of gp19.1 in the SPP1 genome, gp21(1-552) (Tal). This complex assembles two back-to-back stacked gp19.1 ring hexamers, interacting loosely, and two gp21(1-552) trimers interacting with gp19.1 at both ends of the stack. Remarkably, one gp21(1-552) trimer displays a "closed" conformation, whereas the second is "open" delineating a central channel. The two conformational states dock nicely into the EM map of the SPP1 cap domain, respectively, before and after DNA release. Moreover, the open/closed conformations of gp19.1-gp21(1-552) are consistent with the structures of the corresponding proteins in the siphophage p2 baseplate, where the Tal protein (ORF16) attached to the ring of Dit (ORF15) was also found to adopt these two conformations. Therefore, the present contribution allowed us to revisit the SPP1 tail distal-end architectural organization. Considering the sequence conservation among Dit and the N-terminal region of Tal-like proteins in Gram-positive-infecting Siphoviridae, it also reveals the Tal opening mechanism as a hallmark of siphophages probably involved in the generation of the firing signal initiating the cascade of events that lead to phage DNA release in vivo.     

Chemoprevention of prostate cancer with selenium: an update on current clinical trials and preclinical findings

Prostate cancer is the most common cancer diagnosed and the second leading cause of cancer-related deaths in men in the United States. The etiological factors that give rise to prostate cancer are not known. Therefore, it is not possible to develop primary intervention strategies to remove the causative agents from the environment. However, secondary intervention strategies with selenium (Se) compounds and other agents represent a viable option to reduce the morbidity and mortality of prostate cancer. In this review, we discuss ongoing clinical trials. In addition, we discuss preclinical mechanistic studies that provide insights into the biochemical and molecular basis for the anti-carcinogenic activity of both inorganic and organic forms of Se.     

Human keratinocytes respond to direct current stimulation by increasing intracellular calcium: preferential response of poorly differentiated cells

A direct current (DC) endogenous electric field (EF) is induced in the wound following skin injury. It is potentially implicated in the wound healing process by attracting cells and altering their phenotypes as indicated by the response to an EF of keratinocytes cultured as individual cells. To better define the signalization induced by a direct current electric field (DCEF) in human keratinocytes, we took advantage of an in vitro model more representative of the in vivo situation since it promotes cell-cell interactions and stratification. Human keratinocytes were grown into colonies. Their exposure to a DCEF of physiological intensity induced an increase of intracellular calcium. This variation of intracellular calcium resulted from an extracellular calcium influx and was mediated, at least in part, by the L-type voltage-gated calcium channel. The increase in intracellular calcium in response to a DCEF was however not observed in all the cells composing the colonies. The intracellular calcium increase was only detected in keratinocytes that didn't express involucrin, a marker of differentiated cells. These results indicate that DCEF is able to induce a specific calcium response in poorly differentiated keratinocytes. This study brings a new perspective for the understanding of the signaling mechanism of endogenous EF in reepithelialization, a critical process during skin wound healing.     

Evaluating cognition and thermal physiology as components of the pace-of-life syndrome

The pace-of-life syndrome (POLS) suggests that behavioral traits are correlated and integrate within a fast–slow physiological continuum. At the fast extreme, individuals having higher metabolic rates are more active, exploratory, and bold with the opposite suite of traits characterizing those at the slow physiological extreme. A recent framework suggests that behavioral types may also differ consistently in their cognitive style. Accordingly, we propose that cognition could be further incorporated into the POLS framework comprised of behavioral and thermal physiological traits. Under this premise, fast behavioral types having high thermal traits are predicted to acquire a novel task faster but at the cost of accuracy while slow behavioral types with low thermal traits would be more attentive, responding to cues at a slower rate leading to higher accuracy and flexibility. This was tested by measuring physiological and behavioral traits in delicate skinks (Lampropholis delicata) and testing their learning ability. Correlations were detected between cognition and behavior but not thermal physiology. Contrary to our predictions, individual positioning along these axes opposed our predicted directions along the fast–slow continuum. Fast lizards preferring lower body temperatures expressed higher activity, exploration, sociality, and boldness levels, and learned the discrimination learning task at a slower rate but made the most errors. Additionally, modelling results indicated that neither thermal physiology, behavior, or their interaction influenced cognitive performance. Although the small number of animals completing the final stages of the learning assays limits the strength of these findings. Thus, we propose that future research involving a greater sample size and number of trials be conducted so as to enhance our understanding into how the integration of cognitive style, behavior, and physiology may influence individual fitness within natural populations.