The role of micronutrients in the infection and subsequent response to hepatitis C virus

Micronutrient deficiencies develop for a variety of reasons, whether geographic, socioeconomic, nutritional, or as a result of disease pathologies such as chronic viral infection. As micronutrients are essential for a strong immune response, deficiencies can significantly dampen both the innate and the adaptive arms of antiviral immunity. The innate immune response in particular is crucial to protect against hepatitis C virus (HCV), a hepatotropic virus that maintains chronic infection in up to 80% of individuals if left untreated. While many micronutrients are required for HCV replication, an overlapping group of micronutrients are also necessary to enact a potent immune response. As the liver is responsible for the storage and metabolism of many micronutrients, HCV persistence can influence the micronutrients’ steady state to benefit viral persistence both directly and by weakening the antiviral response. This review will focus on common micronutrients such as zinc, iron, copper, selenium, vitamin A, vitamin B12, vitamin D and vitamin E. We will explore their role in the pathogenesis of HCV infection and in the response to antiviral therapy. While chronic hepatitis C virus infection drives deficiencies in micronutrients such as zinc, selenium, vitamin A and B12, it also stimulates copper and iron excess; these micronutrients influence antioxidant, inflammatory and immune responses to HCV

The role of gut-derived microbial antigens on liver fibrosis initiation and progression

Intestinal dysbiosis has recently become known as an important driver of gastrointestinal and liver disease. It remains poorly understood, however, how gastrointestinal microbes bypass the intestinal mucosa and enter systemic circulation to enact an inflammatory immune response. In the context of chronic liver disease (CLD), insults that drive hepatic inflammation and fibrogenesis (alcohol, fat) can drastically increase intestinal permeability, hence flooding the liver with gut-derived microbiota. Consequently, this may result in exacerbated liver inflammation and fibrosis through activation of liver-resident Kupffer and stellate cells by bacterial, viral, and fungal antigens transported to the liver via the portal vein. This review summarizes the current understanding of microbial translocation in CLD, the cell-specific hepatic response to intestinal antigens, and how this drives the development and progression of hepatic inflammation and fibrosis. Further, we reviewed current and future therapies targeting intestinal permeability and the associated, potentially harmful anti-microbial immune response with respect to their potential in terms of limiting the development and progression of liver fibrosis and end-stage cirrhosis

The Influence of Eyelid Morphology on Normal Corneal Shape

PURPOSE. To investigate associations between the topography of the cornea and the morphology of the eyelids in a population of young adult subjects with a range of refractive errors. METHODS. Corneal topography data and digital images of the anterior eye were acquired for 100 young adult subjects. The corneal topography data and palpebral fissure images were analyzed to determine a range of parameters describing the shape of the cornea and the morphology of the palpebral fissure. Correlation analysis was carried out to investigate for significant associations between the parameters describing the topography of the cornea and the parameters describing the morphology of the palpebral fissure. RESULTS. A number of highly significant correlations were found between the best-fitting corneal spherocylinder and the eyelid morphology parameters. The corneal best-fit sphere (M) was significantly correlated with the horizontal palpebral fissure width (r ϭ -0.428; P Ͻ 0.001). Corneal astigmatism power vector J45 was significantly correlated with the angle of the palpebral fissure (r ϭ 0.392; P Ͻ 0.001). The axis of corneal astigmatism was also found to be significantly correlated with the angle of the palpebral fissure (r ϭ 0.317; P ϭ 0.005). CONCLUSIONS. A number of significant associations exist between the corneal spherocylinder and the morphology of the eyelids in a normal adult population. (Invest Ophthalmol Vis Sci

The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis

Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. Raw data have been deposited in the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE54810. Funding: This work was supported in part by grants to EMB from the MRC (G0501164) and BBSRC (BB/G009619/1), to EMB and NDR from the Wellcome Trust (WT093596MA), to MB from Imperial College London (Division of Investigative Sciences PhD Studentship), to HH from the ERA-NET PathoGenoMics project TRANSPAT, Austrian Science Foundation (FWF I282-B09), to SGF from the National Institutes of Health, USA (R01AI073829). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Immune-checkpoint inhibitors for metastatic colorectal cancer : a systematic review of clinical outcomes

Background. Colorectal cancer (CRC) is the fourth most deadly cancer worldwide. Unfortunately, a quarter of the patients are diagnosed at late stages, when surgical options are limited. Targeted therapies, particularly immune-checkpoint inhibitors (ICIs), are the latest addition and have been studied herein regarding their efficacy outcomes. Methods. Clinical studies were identified through the PubMed, Scopus and Cochrane databases. Any trial that evaluated ICIs in patients with metastatic CRC (mCRC) and reported the objective response rate was deemed eligible. Data analysis was performed by employing the random-effects model in STATA v.17. Results. A total of 461 articles were identified; 13 clinical trials were included, encompassing a total cohort of 1209 patients. Our study determined that a single PD-1/PD-L1 checkpoint blockade provides durable clinical response in mCRC patients with high microsatellite instability (MSI-H). The combinatorial therapy of CTLA-4 + PD-1 inhibitors also showed high response rates in pre-treated MSI-H patients. The single-arm REGONIVO trial reported durable clinical response in patients with microsatellite stable (MSS) status. Conclusions. Our study surmises that PD-1/PD-L1 inhibitors as well as combination therapy with CTLA-4 and PD-1 inhibitors show encouraging response rates in mCRC patients, albeit exclusively in patients with cancer that are of MSI-H status. A single study suggests that nivolumab + regorafenib can reach a durable response rate in MSS patients; however, further studies in larger randomized settings are required

A realtime observatory for laboratory simulation of planetary flows

Motivated by the large-scale circulation of the atmosphere and ocean, we develop a system that uses observations from a laboratory analog to constrain, in real time, a numerical simulation of the laboratory flow. This system provides a tool to rapidly prototype new methods for state and parameter estimation, and facilitates the study of prediction, predictability, and transport of geophysical fluids where observations or numerical simulations would not independently suffice. A computer vision system is used to extract measurements of the physical simulation. Observations are used to constrain the model-state of the MIT General Circulation Model in a probabilistic, ensemble based assimilation approach. Using a combination of parallelism, domain decomposition and an efficient scheme to select ensembles of model-states, we show that estimates that effectively track the fluid state can be produced. To the best of our knowledge this is the first such observatory for laboratory analogs of planetary circulation that functions in real time.National Science Foundation (U.S.) (CNS-0540259)National Science Foundation (U.S.) (grant CNS-0540248

Joint analysis of stressors and ecosystem services to enhance restoration effectiveness

With increasing pressure placed on natural systems by growing human populations, both scientists and resource managers need a better understanding of the relationships between cumulative stress from human activities and valued ecosystem services. Societies often seek to mitigate threats to these services through large-scale, costly restoration projects, such as the over one billion dollar Great Lakes Restoration Initiative currently underway. To help inform these efforts, we merged high-resolution spatial analyses of environmental stressors with mapping of ecosystem services for all five Great Lakes. Cumulative ecosystem stress is highest in near-shore habitats, but also extends offshore in Lakes Erie, Ontario, and Michigan. Variation in cumulative stress is driven largely by spatial concordance among multiple stressors, indicating the importance of considering all stressors when planning restoration activities. In addition, highly stressed areas reflect numerous different combinations of stressors rather than a single suite of problems, suggesting that a detailed understanding of the stressors needing alleviation could improve restoration planning. We also find that many important areas for fisheries and recreation are subject to high stress, indicating that ecosystem degradation could be threatening key services. Current restoration efforts have targeted high-stress sites almost exclusively, but generally without knowledge of the full range of stressors affecting these locations or differences among sites in service provisioning. Our results demonstrate that joint spatial analysis of stressors and ecosystem services can provide a critical foundation for maximizing social and ecological benefits from restoration investments. www.pnas.org/lookup/suppl/doi:10.1073/pnas.1213841110/-/DCSupplementa

Polar vortex formation in giant-planet atmospheres due to moist convection

A strong cyclonic vortex has been observed on each of Saturn’s poles, coincident with a local maximum in observed tropospheric temperature. Neptune also exhibits a relatively warm, although much more transient, region on its south pole. Whether similar features exist on Jupiter will be resolved by the 2016 Juno mission. Energetic, small-scale storm-like features that originate from the water-cloud level or lower have been observed on each of the giant planets and attributed to moist convection, suggesting that these storms play a significant role in global heat transfer from the hot interior to space. Nevertheless, the creation and maintenance of Saturn’s polar vortices, and their presence or absence on the other giant planets, are not understood. Here we use simulations with a shallow-water model to show that storm generation, driven by moist convection, can create a strong polar cyclone throughout the depth of a planet’s troposphere. We find that the type of shallow polar flow that occurs on a giant planet can be described by the size ratio of small eddies to the planetary radius and the energy density of its atmosphere due to latent heating from moist convection. We suggest that the observed difference in these parameters between Saturn and Jupiter may preclude a Jovian polar cyclone.National Science Foundation (U.S.). Graduate Research FellowshipNational Science Foundation (U.S.) (ATM-0850639)National Science Foundation (U.S.) (AGS-1032244)National Science Foundation (U.S.) (AGS-1136480)United States. Office of Naval Research (N00014-14-1-0062

The XMM-Newton serendipitous survey. VII. The third XMM-Newton serendipitous source catalogue

Thanks to the large collecting area (3 x ~1500 cm$^2$ at 1.5 keV) and wide field of view (30' across in full field mode) of the X-ray cameras on board the European Space Agency X-ray observatory XMM-Newton, each individual pointing can result in the detection of hundreds of X-ray sources, most of which are newly discovered. Recently, many improvements in the XMM-Newton data reduction algorithms have been made. These include enhanced source characterisation and reduced spurious source detections, refined astrometric precision, greater net sensitivity and the extraction of spectra and time series for fainter sources, with better signal-to-noise. Further, almost 50\% more observations are in the public domain compared to 2XMMi-DR3, allowing the XMM-Newton Survey Science Centre (XMM-SSC) to produce a much larger and better quality X-ray source catalogue. The XMM-SSC has developed a pipeline to reduce the XMM-Newton data automatically and using improved calibration a new catalogue version has been produced from XMM-Newton data made public by 2013 Dec. 31 (13 years of data). Manual screening ensures the highest data quality. This catalogue is known as 3XMM. In the latest release, 3XMM-DR5, there are 565962 X-ray detections comprising 396910 unique X-ray sources. For the 133000 brightest sources, spectra and lightcurves are provided. For all detections, the positions on the sky, a measure of the quality of the detection, and an evaluation of the X-ray variability is provided, along with the fluxes and count rates in 7 X-ray energy bands, the total 0.2-12 keV band counts, and four hardness ratios. To identify the detections, a cross correlation with 228 catalogues is also provided for each X-ray detection. 3XMM-DR5 is the largest X-ray source catalogue ever produced. Thanks to the large array of data products, it is an excellent resource in which to find new and extreme objects.Comment: 23 pages, version accepted for publication in A&