Process-Informed Subsampling Improves Subseasonal Rainfall Forecasts in Central America.

Subseasonal rainfall forecast skill is critical to support preparedness for hydrometeorological extremes. We assess how a process-informed evaluation, which subsamples forecasting model members based on their ability to represent potential predictors of rainfall, can improve monthly rainfall forecasts within Central America in the following month, using Costa Rica and Guatemala as test cases. We generate a constrained ensemble mean by subsampling 130 members from five dynamic forecasting models in the C3S multimodel ensemble based on their representation of both (a) zonal wind direction and (b) Pacific and Atlantic sea surface temperatures (SSTs), at the time of initialization.

Global terrestrial drought and its projected socioeconomic implications under different warming targets.

Droughts are increasingly frequent as the Earth warms, presenting adaptation challenges for ecosystems and human communities worldwide. A strategic environmental assessment (SEA) and the integration of adaptation strategies into policies, plans, and programs (PPP) are two important approaches for enhancing climate resilience and fostering sustainable development. This study developed an innovative approach to strengthen the SEA of droughts by quantifying the impacts of future temperature increases.

A high-resolution daily global dataset of statistically downscaled CMIP6 models for climate impact analyses.

A large number of historical simulations and future climate projections are available from Global Climate Models, but these are typically of coarse resolution, which limits their effectiveness for assessing local scale changes in climate and attendant impacts. Here, we use a novel statistical downscaling model capable of replicating extreme events, the Bias Correction Constructed Analogues with Quantile mapping reordering (BCCAQ), to downscale daily precipitation, air-temperature, maximum and minimum temperature, wind speed, air pressure, and relative humidity from 18 GCMs from the Coupled Model Intercomparison Project Phase 6 (CMIP6). BCCAQ is calibrated using high-resolution reference datasets and showed a good performance in removing bias from GCMs and reproducing extreme events.

Large anomalies in future extreme precipitation sensitivity driven by atmospheric dynamics.

Increasing atmospheric moisture content is expected to intensify precipitation extremes under climate warming. However, extreme precipitation sensitivity (EPS) to temperature is complicated by the presence of reduced or hook-shaped scaling, and the underlying physical mechanisms remain unclear. Here, by using atmospheric reanalysis and climate model projections, we propose a physical decomposition of EPS into thermodynamic and dynamic components (i.

Constrained CMIP6 projections indicate less warming and a slower increase in water availability across Asia.

Climate projections are essential for decision-making but contain non-negligible uncertainty. To reduce projection uncertainty over Asia, where half the world's population resides, we develop emergent constraint relationships between simulated temperature (1970-2014) and precipitation (2015-2100) growth rates using 27 CMIP6 models under four Shared Socioeconomic Pathways. Here we show that, with uncertainty successfully narrowed by 12.

A sensitive and affordable multiplex RT-qPCR assay for SARS-CoV-2 detection.

With the ongoing COVID-19 (Coronavirus Disease 2019) pandemic, caused by the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), there is a need for sensitive, specific, and affordable diagnostic tests to identify infected individuals, not all of whom are symptomatic. The most sensitive test involves the detection of viral RNA using RT-qPCR (quantitative reverse transcription PCR), with many commercial kits now available for this purpose. However, these are expensive, and supply of such kits in sufficient numbers cannot always be guaranteed.

Structural and functional characterization of C0021158, a high-affinity monoclonal antibody that inhibits Arginase 2 function via a novel non-competitive mechanism of action.

Arginase 2 (ARG2) is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine. The dysregulated expression of ARG2 within specific tumor microenvironments generates an immunosuppressive niche that effectively renders the tumor 'invisible' to the host's immune system. Increased ARG2 expression leads to a concomitant depletion of local L-arginine levels, which in turn leads to suppression of anti-tumor T-cell-mediated immune responses.

Extensive sequence and structural evolution of Arginase 2 inhibitory antibodies enabled by an unbiased approach to affinity maturation.

Affinity maturation is a powerful technique in antibody engineering for the in vitro evolution of antigen binding interactions. Key to the success of this process is the expansion of sequence and combinatorial diversity to increase the structural repertoire from which superior binding variants may be selected. However, conventional strategies are often restrictive and only focus on small regions of the antibody at a time.

Substance use in pregnancy.

The increase in substance use which occurred in the 1980s was disproportionately large among women of reproductive age, so both the numbers of women who use drugs and the duration of drug use have increased (Hepburn 2004). While drug use occurs throughout society, the type and pattern of drug use that is associated with medical and social problems is closely associated with socio-economic deprivation. Socio-economic deprivation is in turn associated with unhealthy lifestyles and behaviours such as smoking and poor diet.

Bacterial toxins and small molecules elucidate endosomal trafficking.

Bacterial toxins and small molecules are useful tools for studying eukaryotic cell biology. In a recent issue of PNAS, Gillespie and colleagues describe a novel small molecule inhibitor of bacterial toxins and virus trafficking through the endocytic pathway, 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone (EGA), that prevents transport from early to late endosomes.

CCT chaperonin complex is required for efficient delivery of anthrax toxin into the cytosol of host cells.

Bacterial toxins have evolved successful strategies for coopting host proteins to access the cytosol of host cells. Anthrax lethal factor (LF) enters the cytosol through pores in the endosomal membrane formed by anthrax protective antigen. Although in vitro models using planar lipid bilayers have shown that translocation can occur in the absence of cellular factors, recent studies using intact endosomes indicate that host factors are required for translocation in the cellular environment.

Chemical genetics reveals a kinase-independent role for protein kinase R in pyroptosis.

Formation of the inflammasome, a scaffolding complex that activates caspase-1, is important in numerous diseases. Pyroptotic cell death induced by anthrax lethal toxin (LT) is a model for inflammasome-mediated caspase-1 activation. We discovered 7-desacetoxy-6,7-dehydrogedunin (7DG) in a phenotypic screen as a small molecule that protects macrophages from LT-induced death.

Identification of novel host-targeted compounds that protect from anthrax lethal toxin-induced cell death.

Studying how pathogens subvert the host to cause disease has contributed to the understanding of fundamental cell biology. Bacillus anthracis, the causative agent of anthrax, produces the virulence factor lethal toxin to disarm host immunity and cause pathology. We conducted a phenotypic small molecule screen to identify inhibitors of lethal toxin-induced macrophage cell death and used an ordered series of secondary assays to characterize the hits and determine their effects on cellular function.

Defining critical roles for NF-κB p65 and type I interferon in innate immunity to rhinovirus.

The importance of NF-κB activation and deficient anti-viral interferon induction in the pathogenesis of rhinovirus-induced asthma exacerbations is poorly understood. We provide the first in vivo evidence in man and mouse that rhinovirus infection enhanced bronchial epithelial cell NF-κB p65 nuclear expression, NF-κB p65 DNA binding in lung tissue and NF-κB-regulated airway inflammation. In vitro inhibition of NF-κB reduced rhinovirus-induced pro-inflammatory cytokines but did not affect type I/III interferon induction.

GRP78(BiP) facilitates the cytosolic delivery of anthrax lethal factor (LF) in vivo and functions as an unfoldase in vitro.

Anthrax toxin is an A/B bacterial protein toxin which is composed of the enzymatically active Lethal Factor (LF) and/or Oedema Factor (EF) bound to Protective Antigen 63 (PA63) which functions as both the receptor binding and transmembrane domains. Once the toxin binds to its cell surface receptors it is internalized into the cell and traffics through Rab5- and Rab7-associated endosomal vesicles. Following acidification of the vesicle lumen, PA63 undergoes a dynamic change forming a beta-barrel that inserts into and forms a pore through the endosomal membrane.

Co-ordinated role of TLR3, RIG-I and MDA5 in the innate response to rhinovirus in bronchial epithelium.

The relative roles of the endosomal TLR3/7/8 versus the intracellular RNA helicases RIG-I and MDA5 in viral infection is much debated. We investigated the roles of each pattern recognition receptor in rhinovirus infection using primary bronchial epithelial cells. TLR3 was constitutively expressed; however, RIG-I and MDA5 were inducible by 8-12 h following rhinovirus infection.

Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation.

Rationale: Respiratory virus infections are associated with chronic obstructive pulmonary disease (COPD) exacerbations, but a causative relationship has not been proven. Studies of naturally occurring exacerbations are difficult and the mechanisms linking virus infection to exacerbations are poorly understood. We hypothesized that experimental rhinovirus infection in subjects with COPD would reproduce the features of naturally occurring COPD exacerbations and is a valid model of COPD exacerbations.

Signalling pathways mediating type I interferon gene expression.

Type I interferon-alpha/beta play an essential role in immunity to viruses. While interferon-beta has been used as a model of a complex promoter, many of the signalling pathways leading to interferon-beta gene expression remain controversial. Recent milestones include the discovery of Toll-like receptors and RNA helicases that signal via a novel kinase complex composed of I kappa B kinase-iota/epsilon or TANK binding kinase-1.

Role of deficient type III interferon-lambda production in asthma exacerbations.

Rhinoviruses are the major cause of asthma exacerbations, and asthmatics have increased susceptibility to rhinovirus and risk of invasive bacterial infections. Here we show deficient induction of interferon-lambdas by rhinovirus in asthmatic primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus-induced asthma exacerbation and virus load in experimentally infected human volunteers. Induction by lipopolysaccharide in asthmatic macrophages was also deficient and correlated with exacerbation severity.