The inflammatory microenvironment in colorectal neoplasia

Peer reviewedPublisher PD

Expression of neutrophil gelatinase-associated lipocalin in colorectal neoplastic progression:A marker of malignant potential?

Peer reviewedPublisher PD

Attribution of 2012 extreme climate events: does air-sea interaction matter?

In 2012, extreme anomalous climate conditions occurred around the globe. Large areas of North America experienced an anomalously hot summer, with large precipitation deficits inducing severe drought. Over Europe, the summer of 2012 was marked by strong precipitation anomalies with the UK experiencing its wettest summer since 1912 while Spain suffered severe drought. What caused these extreme climate conditions in various regions in 2012? This study compares attribution conclusions for 2012 climate anomalies relative to a baseline period (1964–1981) based on two sets of parallel experiments with different model configurations (with coupling to an ocean mixed layer model or with prescribed sea surface temperatures) to assess whether attribution conclusions concerning the climate anomalies in 2012 are sensitive to the representation of air-sea interaction. Modelling results indicate that attribution conclusions for large scale surface air temperature (SAT) changes in both boreal winter and summer are generally robust and not very sensitive to air-sea interaction. This is especially true over southern Europe, Eurasia, North America, South America, and North Africa. Some other responses also appear to be insensitive to air-sea interaction: for example, forced increases in precipitation over northern Europe and Sahel, and reduced precipitation over North America and the Amazon in boreal summer. However, the attribution of circulation and precipitation changes for some other regions exhibits a sensitivity to air-sea interaction. Results from the experiments including coupling to an ocean mixed layer model show a positive NAO-like circulation response in the Atlantic sector in boreal winter and weak changes in the East Asian summer monsoon and precipitation over East Asia. With prescribed sea surface temperatures, some different responses arise over these two regions. Comparison with observed changes indicates that the coupled simulations generally agree better with observations, demonstrating that attribution methods based on atmospheric general circulation models have limitations and may lead to erroneous attribution conclusions for regional anomalies in circulation, precipitation and surface air temperature

Ecology and Transmission of Buruli Ulcer Disease: A Systematic Review

Buruli ulcer is a neglected emerging disease that has recently been reported in some countries as the second most frequent mycobacterial disease in humans after tuberculosis. Cases have been reported from at least 32 countries in Africa (mainly west), Australia, Southeast Asia, China, Central and South America, and the Western Pacific. Large lesions often result in scarring, contractual deformities, amputations, and disabilities, and in Africa, most cases of the disease occur in children between the ages of 4–15 years. This environmental mycobacterium, Mycobacterium ulcerans, is found in communities associated with rivers, swamps, wetlands, and human-linked changes in the aquatic environment, particularly those created as a result of environmental disturbance such as deforestation, dam construction, and agriculture. Buruli ulcer disease is often referred to as the “mysterious disease” because the mode of transmission remains unclear, although several hypotheses have been proposed. The above review reveals that various routes of transmission may occur, varying amongst epidemiological setting and geographic region, and that there may be some role for living agents as reservoirs and as vectors of M. ulcerans, in particular aquatic insects, adult mosquitoes or other biting arthropods. We discuss traditional and non-traditional methods for indicting the roles of living agents as biologically significant reservoirs and/or vectors of pathogens, and suggest an intellectual framework for establishing criteria for transmission. The application of these criteria to the transmission of M. ulcerans presents a significant challenge

Climate simulations for 1880-2003 with GISS modelE

We carry out climate simulations for 1880-2003 with GISS modelE driven by ten measured or estimated climate forcings. An ensemble of climate model runs is carried out for each forcing acting individually and for all forcing mechanisms acting together. We compare side-by-side simulated climate change for each forcing, all forcings, observations, unforced variability among model ensemble members, and, if available, observed variability. Discrepancies between observations and simulations with all forcings are due to model deficiencies, inaccurate or incomplete forcings, and imperfect observations. Although there are notable discrepancies between model and observations, the fidelity is sufficient to encourage use of the model for simulations of future climate change. By using a fixed well-documented model and accurately defining the 1880-2003 forcings, we aim to provide a benchmark against which the effect of improvements in the model, climate forcings, and observations can be tested. Principal model deficiencies include unrealistically weak tropical El Nino-like variability and a poor distribution of sea ice, with too much sea ice in the Northern Hemisphere and too little in the Southern Hemisphere. The greatest uncertainties in the forcings are the temporal and spatial variations of anthropogenic aerosols and their indirect effects on clouds.Comment: 44 pages; 19 figures; Final text accepted by Climate Dynamic

Isozyme-Specific Ligands for O-acetylserine sulfhydrylase, a Novel Antibiotic Target

Conceived and designed the experiments: FS PC BC ES AM. Performed the experiments: FS RS ES PF SR. Analyzed the data: FS BC ES PF GEK PFC AM. Contributed reagents/materials/analysis tools: PC PB GC. Wrote the paper: FS GEK BC AM.The last step of cysteine biosynthesis in bacteria and plants is catalyzed by O-acetylserine sulfhydrylase. In bacteria, two isozymes, O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B, have been identified that share similar binding sites, although the respective specific functions are still debated. O-acetylserine sulfhydrylase plays a key role in the adaptation of bacteria to the host environment, in the defense mechanisms to oxidative stress and in antibiotic resistance. Because mammals synthesize cysteine from methionine and lack O-acetylserine sulfhydrylase, the enzyme is a potential target for antimicrobials. With this aim, we first identified potential inhibitors of the two isozymes via a ligand- and structure-based in silico screening of a subset of the ZINC library using FLAP. The binding affinities of the most promising candidates were measured in vitro on purified O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B from Salmonella typhimurium by a direct method that exploits the change in the cofactor fluorescence. Two molecules were identified with dissociation constants of 3.7 and 33 µM for O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B, respectively. Because GRID analysis of the two isoenzymes indicates the presence of a few common pharmacophoric features, cross binding titrations were carried out. It was found that the best binder for O-acetylserine sulfhydrylase-B exhibits a dissociation constant of 29 µM for O-acetylserine sulfhydrylase-A, thus displaying a limited selectivity, whereas the best binder for O-acetylserine sulfhydrylase-A exhibits a dissociation constant of 50 µM for O-acetylserine sulfhydrylase-B and is thus 8-fold selective towards the former isozyme. Therefore, isoform-specific and isoform-independent ligands allow to either selectively target the isozyme that predominantly supports bacteria during infection and long-term survival or to completely block bacterial cysteine biosynthesis.Yeshttp://www.plosone.org/static/editorial#pee

Influence of Resistance Training Proximity-to-Failure, Determined by Repetitions-in-Reserve, on Neuromuscular Fatigue in Resistance-Trained Males and Females

Background This study examined the influence of proximity-to-failure in resistance training (RT), using subjective repetitions-in-reserve (RIR) prediction, on neuromuscular fatigue and perceptual responses. Methods Twenty-four resistance-trained males (n = 12) and females (n = 12) completed three experimental trials in a randomised order, each involving six RT sets (barbell bench press) with 75% 1-RM performed to either momentary muscular failure (FAIL), 1-RIR, or 3-RIR. Changes in lifting velocity with a fixed load were assessed from pre-exercise to post-exercise with the aim of quantifying acute neuromuscular fatigue (4 min post-exercise) and the associated time course of recovery (24 and 48 h post-exercise), and from the first to final set performed. Perceptual responses to RT were assessed at multiple time points during and following RT. Results Decreases in lifting velocity at 4 min post-exercise were greater for FAIL ( − 25%) versus 1-RIR ( − 13%) and 3-RIR ( − 8%), with greater decreases for male ( − 29%) versus female ( − 21%) participants following FAIL. At 24 h post-exercise, decreases in lifting velocity were greater for FAIL ( − 3%) and 1-RIR ( − 3%) versus 3-RIR (+ 2%), with all between-protocol differences diminishing at 48 h post-exercise. Loss of lifting velocity from the first to final set was greater for FAIL ( − 22%) versus 1-RIR ( − 9%) and 3-RIR ( − 6%), with a greater lifting velocity loss from the first to final set for males ( − 15%) versus females ( − 9%). As proximity-to-failure neared, ratings of perceived discomfort, exertion, and muscle soreness increased, general feelings worsened, and perceived recovery decreased. Conclusion These findings support a linear relationship between RT proximity-to-failure and both acute neuromuscular fatigue and negative perceptual responses, which may influence long-term physiological adaptations and adherence to RT