The Potential of Antimicrobial Peptides as Biocides

Antimicrobial peptides constitute a diverse class of naturally occurring antimicrobial molecules which have activity against a wide range of pathogenic microorganisms. Antimicrobial peptides are exciting leads in the development of novel biocidal agents at a time when classical antibiotics are under intense pressure from emerging resistance, and the global industry in antibiotic research and development stagnates. This review will examine the potential of antimicrobial peptides, both natural and synthetic, as novel biocidal agents in the battle against multi-drug resistant pathogen infections

Oral abstracts of the 21st International AIDS Conference 18-22 July 2016, Durban, South Africa

The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n=122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression.Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed.Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants.Expression of ‘exhaustion’ or ‘immune checkpoint’ markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches

PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus

Mellado-Gil, José Manuel et al.[Aims/hypothesis]: A strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7.1 mouse model background and to characterise putative cellular mechanisms associated with preserved BCM. [Methods]: Two groups of RIP-B7.1 mice were genetically engineered to: (1) conditionally express either PAX4 (BPTL) or its diabetes-linked mutant variant R129W (mutBPTL) using doxycycline (DOX); and (2) constitutively express luciferase in beta cells through the use of RIP. Mice were treated or not with DOX, and EAD was induced by immunisation with a murine preproinsulin II cDNA expression plasmid. The development of hyperglycaemia was monitored for up to 4 weeks following immunisation and alterations in the BCM were assessed weekly by non-invasive in vivo bioluminescence intensity (BLI). In parallel, BCM, islet cell proliferation and apoptosis were evaluated by immunocytochemistry. Alterations in PAX4- and PAX4R129W-mediated islet gene expression were investigated by microarray profiling. PAX4 preservation of endoplasmic reticulum (ER) homeostasis was assessed using thapsigargin, electron microscopy and intracellular calcium measurements. [Results]: PAX4 overexpression blunted EAD, whereas the diabetes-linked mutant variant PAX4R129W did not convey protection. PAX4-expressing islets exhibited reduced insulitis and decreased beta cell apoptosis, correlating with diminished DNA damage and increased islet cell proliferation. Microarray profiling revealed that PAX4 but not PAX4R129W targeted expression of genes implicated in cell cycle and ER homeostasis. Consistent with the latter, islets overexpressing PAX4 were protected against thapsigargin-mediated ER-stress-related apoptosis. Luminal swelling associated with ER stress induced by thapsigargin was rescued in PAX4-overexpressing beta cells, correlating with preserved cytosolic calcium oscillations in response to glucose. In contrast, RNA interference mediated repression of PAX4-sensitised MIN6 cells to thapsigargin cell death. [Conclusions/interpretation]: The coordinated regulation of distinct cellular pathways particularly related to ER homeostasis by PAX4 not achieved by the mutant variant PAX4R129W alleviates beta cell degeneration and protects against diabetes mellitus. The raw data for the RNA microarray described herein are accessible in the Gene Expression Omnibus database under accession number GSE62846.This work was funded by grants from the Consejeria de Salud, Fundacion Publica Andaluza Progreso y Salud, Junta de Andalucia (PI-0727-2010 to BRG and PI-0085-2013 to PIL), Consejeria de Economia, Innovacion y Ciencia (P10.CTS.6359 to BRG), Ministerio de Ciencia e Innovacion (BFU2013-42789-P to IQ) and the Ministerio de Economia y Competidividad, Instituto de Salud Carlos III co-funded by Fondos FEDER (PI10/00871 and PI13/00593 to BRG). NC-V is supported by a JDRF subsidy (17-2013-372 to BRG.). AM-M is a recipient of a Miguel Servet grant (CP14/00105) from the Instituto de Salud Carlos III co-funded by Fondos FEDER and EF-M is a recipient of a Juan de la Cierva Fellowship. PM is supported by Swiss National Science Foundation grant 310030-141162, and the European Union grant IMIDIA, C2008-T7. BOB is supported by grants from the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Republic of Singapore.Peer Reviewe

Assessment of the Performance of Three Dynamical Climate Downscaling Methods Using Different Land Surface Information over China

This study aims to assess the performance of different dynamical downscaling methods using updated land surface information. Particular attention is given to obtaining high-resolution climate information over China by the combination of an appropriate dynamical downscaling method and updated land surface information. Two group experiments using two land surface datasets are performed, including default Weather Research and Forecasting (WRF) land surface data (OLD) and accurate dynamically accordant MODIS data (NEW). Each group consists of three types of experiments for the summer of 2014, including traditional continuous integration (CT), spectral nudging (SN), and re-initialization (Re) experiments. The Weather Research and Forecasting (WRF) model is used to dynamically downscale ERA-Interim (reanalysis of the European Centre for Medium-Range Weather Forecast, ECMWF) data with a grid spacing of 30 km over China. The simulations are evaluated via comparison with observed conventional meteorological variables, showing that the CT method, which notably overestimates 2 m temperature and underestimates 2 m relative humidity across China, performs the worst; the SN and Re runs outperform the CT method, and the Re shows the smallest RMSE (root means square error). A comparison of observed and simulated precipitation shows that the SN simulation is closest to the observed data, while the CT and Re simulations overestimate precipitation south of the Yangtze River. Compared with the OLD group, the RMSE values of temperature and relative humidity are significantly improved in CT and SN, and there is smaller improved in Re. However, obvious improvements in precipitation are not evident

Assessment and Reduction of the Physical Parameterization Uncertainty for Noah‐MP Land Surface Model

The community Noah land surface model with multiparameterization options (Noah-MP) provides a plethora of model configurations with varying complexity for land surface modeling. The practical application of this model requires a basic understanding of the relative abilities of its various parameterization configurations in representing spatiotemporal variability and hydrologic connectivity. We designed an ensemble of 288 experiments from multiparameterization schemes of six physical processes to assess and reduce the structural uncertainty for land surface modeling over 10 hydrologic regions in China for the period 2001–2010. The observed latent heat (LH) was well reproduced by the ensemble. Meanwhile, most experiments underestimated sensible heat (SH) throughout the year and overestimated the cold season but underestimated the warm season terrestrial water storage anomaly (TWSA). The sensitive processes and best-performing schemes varied not only with regions but also among variables. The LH and SH were most sensitive to runoff-groundwater (RUN), surface heat exchange coefficient (SFC), and radiation transfer (RAD). The TWSA was dominated by RUN and RAD while largely influenced by soil moisture factor for stomatal resistance (BTR) and frozen soil permeability (INF) over some limited regions. By contrast, supercooled liquid water (FRZ) had little influence on all variables. Our optimization for individual variables produced high mean Taylor skill scores that ranged from 0.95–0.99 for LH, 0.82–0.99 for SH, and 0.63–0.95 for TWSA depending on regions. The simultaneous optimization made trade-off among the three variables, which improved TWSA performance at the cost of reducing the skill for LH and SH over a few regions. ©2019. The Authors