Inhibition of a viral enzyme by a small-molecule dimer disruptor.

We identified small-molecule dimer disruptors that inhibit an essential dimeric protease of human Kaposi's sarcoma-associated herpesvirus (KSHV) by screening an alpha-helical mimetic library. Next, we synthesized a second generation of low-micromolar inhibitors with improved potency and solubility. Complementary methods including size exclusion chromatography and 1H-13C HSQC titration using selectively labeled 13C-Met samples revealed that monomeric protease is enriched in the presence of inhibitor. 1H-15N HSQC titration studies mapped the inhibitor binding site to the dimer interface, and mutagenesis studies targeting this region were consistent with a mechanism where inhibitor binding prevents dimerization through the conformational selection of a dynamic intermediate. These results validate the interface of herpesvirus proteases and other similar oligomeric interactions as suitable targets for the development of small-molecule inhibitors

Site fidelity of Hippocampus guttulatus Cuvier, 1829 at Mar Piccolo of Taranto (Southern Italy; Ionian Sea)

Lack of detailed knowledge on ecological niche, life cycles, spatial distribution, reproductive biology and space use strongly affects the selection of useful tools and measures in the conservation of threatened marine species. Especially for sedentary and slow species, behaviour and movement capacities are supposed to be the most important functional traits. Indeed, behavioural variability concerning available space and the close presence of individuals is considered a crucial trait for the population dynamics assessments, especially when disturbances of various causes are present in the environment. The present study aimed to investigate the site fidelity and degree of movement of Hippocampus guttulatus, an emblematic and threatened Mediterranean seahorse species. With this aim, a number of seahorses were tagged and monitored throughout two years within a limited area of the lagoon of Mar Piccolo of Taranto (Southern Italy). The studied individuals were initially morphometrically measured for size, sex and life-cycle stage and subsequently monitored through repeated four-month surveys each year. Obtained results indicated high site fidelity regardless of habitat type. Movement pattern was in line with the data on congeneric species, although values were slightly higher. The analyses showed differences in movement degree among different sexes and life-cycle stages and indicated greater mobility of adult females compared to males and juveniles. The investigated parameters showed a great variability suggesting that even small-scale environmental factors can influence the species mobility. Finally, a change in the population structure has been observed, with the loss of large individuals in 2016 and reduced recruitment in 2017. These findings indicated the possible presence of stressors that could lead to the alteration of the seahorse population at Mar Piccolo of Taranto

On the electromagnetic energy resolution of Cherenkov-fiber calorimeters

Electromagnetic calorimeters which sample the Cherenkov radiation of shower particles in optical fibers operate in a markedly different manner from calorimeters which rely on the dE/dx of shower particles. The well-understood physics of electromagnetic shower development is applied to the case of Cherenkov-fiber calorimetry (also known as quartz fiber calorimetry) and the results of systematically performed studies are considered in detail to derive an understanding of the critical parameters involved in energy measurement using such calorimeters. A quantitative parameterization of Cherenkov-fiber calorimetry electromagnetic energy resolution is proposed and compared with existing experimental results

Genetic structure of the long-snouted seahorse, Hippocampus guttulatus, in the Central-Western Mediterranean Sea

The seahorse Hippocampus guttulatus reaches its highest abundance in confined environments, where it has unique biological and ecological traits that suggest significant genetic differentiation among populations. In the present study, we aimed to reveal the genetic structure of this species by analysing eight microsatellite loci and a mitochondrial DNA region (cytochrome b) of eight populations from the Central-Western Mediterranean Sea, including lagoon sites. Levels of genetic diversity, as measured by the total number of alleles, number of private alleles, allelic richness and heterozygosity, ranged from low to moderate. The overall value of inbreeding was high, indicating a deficiency in heterozygotes. The haplotype network had a star-like construction, with the most common haplotype present in all populations. Data from the two molecular markers congruently displayed a similar pattern and revealed low genetic differentiation, notwithstanding predictions based on species traits. The observed genetic structure is probably the result of both historical population demographic events and current gene flow. The investigated lagoons, however, revealed a unique genetic profile, which is especially highlighted by the Taranto population. At this site, the results also showed altered values of observed/expected heterozygosity and allelic richness, a characteristic of marginal populations. Our study suggests that lagoon populations should be managed as distinct genetic units

Lipid-Induced Toxicity Stimulates Hepatocytes to Release Angiogenic Microparticles That Require Vanin-1 for Uptake by Endothelial Cells.

Angiogenesis is a key pathological feature of experimental and human steatohepatitis, a common chronic liver disease that is associated with obesity. We demonstrated that hepatocytes generated a type of membrane-bound vesicle, microparticles, in response to conditions that mimicked the lipid accumulation that occurs in the liver in some forms of steatohepatitis and that these microparticles promoted angiogenesis. When applied to an endothelial cell line, medium conditioned by murine hepatocytes or a human hepatocyte cell line exposed to saturated free fatty acids induced migration and tube formation, two processes required for angiogenesis. Medium from hepatocytes in which caspase 3 was inhibited or medium in which the microparticles were removed by ultracentrifugation lacked proangiogenic activity. Isolated hepatocyte-derived microparticles induced migration and tube formation of an endothelial cell line in vitro and angiogenesis in mice, processes that depended on internalization of microparticles. Microparticle internalization required the interaction of the ectoenzyme Vanin-1 (VNN1), an abundant surface protein on the microparticles, with lipid raft domains of endothelial cells. Large quantities of hepatocyte-derived microparticles were detected in the blood of mice with diet-induced steatohepatitis, and microparticle quantity correlated with disease severity. Genetic ablation of caspase 3 or RNA interference directed against VNN1 protected mice from steatohepatitis-induced pathological angiogenesis in the liver and resulted in a loss of the proangiogenic effects of microparticles. Our data identify hepatocyte-derived microparticles as critical signals that contribute to angiogenesis and liver damage in steatohepatitis and suggest a therapeutic target for this condition

Immune genotypes, immune responses, and survival in a wild bird population

ACKNOWLEDGEMENTS We thank the Tsawout and Tseycum bands for allowing us to conduct research on Mandarte Island, and to the many contributors to long-term monitoring, especially L. Keller, P. Nietlisbach, and J. Krippel. We also thank C. Ritland, A. Miscampbell, and G. Huber for their assistance in the laboratory. All work was conducted under permit of the Canadian Wildlife Service and UBC Animal Care Committee. Funding Information: This study was generously supported by the Natural Sciences and Engineering Research Council of Canada via a Post‐doctoral Fellowship award to MJNF (PDF‐2014–454522) and a Discovery Grant to EAMS.Peer reviewedPublisher PD

Digitally enabled health service for the integrated management of hypertension: A participatory user-centred design process

This article describes a user-centred approach taken by a group of five procurers to set specifications for the procurement of value-based research and development services for IT-sup-ported integrated hypertension management. The approach considered the unmet needs of patients and health systems of the involved regions. The procurers established a framework for requirements and a solution design consisting of nine building blocks, divided into three domains: service delivery, devices and integration, and health care organisation. The approach included the development of questionnaires, capturing patients’ and professionals’ views on possible system functionalities, and a template collecting information about the organisation of healthcare, professionals involved and existing IT systems at the procurers’ premises. A total of 28 patients diagnosed with hypertension and 26 professionals were interviewed. The interviewees identified 98 functional requirements, grouped in the nine building blocks. A total of nine use cases and their corresponding process models were defined by the procurers’ working group. As result, a digitally enabled integrated approach to hypertension has been designed to allow citizens to learn how to prevent the development of hypertension and lead a healthy lifestyle, and to receive comprehensive, individualised treatment in close collaboration with healthcare professionals

Large-area epitaxial monolayer MoS2

Two-dimensional semiconductors such as MoS2 are an emerging material family with wide-ranging potential applications in electronics, optoelectronics, and energy harvesting. Large-area growth methods are needed to open the way to applications. Control over lattice orientation during growth remains a challenge. This is needed to minimize or even avoid the formation of grain boundaries, detrimental to electrical, optical, and mechanical properties of MoS2 and other 2D semiconductors. Here, we report on the growth of high-quality monolayer MoS2 with control over lattice orientation. We show that the monolayer film is composed of coalescing single islands with limited numbers of lattice orientation due to an epitaxial growth mechanism. Optical absorbance spectra acquired over large areas show significant absorbance in the high-energy part of the spectrum, indicating that MoS2 could also be interesting for harvesting this region of the solar spectrum and fabrication of UV-sensitive photodetectors. Even though the interaction between the growth substrate and MoS2 is strong enough to induce lattice alignment via van der Waals interaction, we can easily transfer the grown material and fabricate devices. Local potential mapping along channels in field-effect transistors shows that the single-crystal MoS2 grains in our film are well connected, with interfaces that do not degrade the electrical conductivity. This is also confirmed by the relatively large and length-independent mobility in devices with a channel length reaching 80um

Quartz fiber calorimetry

The fundamentals of a new electromagnetic and hadronic sampling calorimetry based on the detection of Cherenkov light generated in quartz optical fibers are presented. Optical fibers transport light only in a selected angular range which results in a non-obvious and absolutely unique characteristic for this new technique: showers of very narrow visible energy. In addition, the technique is characterized by radiation resistance measured in Gigarads and nanosecond signal duration. Combined, these properties make quartz fiber calorimetry a very promising technique for high intensity heavy ion experiments and for the high pseudorapidity regions of high intensity collider experiments. The results of beam tests and simulations are used to illustrate the basic properties and peculiar characteristics of this recent development