The Role of Hyaluronan in Innate Defense Responses of the Intestine

Hyaluronan is an abundant extracellular matrix component prevalent in the vertebrate intestinal tract. Here we discuss what is known about hyaluronan distribution during homeostasis and inflammatory diseases of the gut and discuss ways in which this glycosaminoglycan can participate in regulating innate host defense mechanisms. These natural responses include mechanisms promoting rapid leukocyte recruitment after bacterial challenge/colon tissue damage as well as promoting epithelial defense mechanisms in the intestine

Treatment interventions to maintain abstinence from alcohol in primary care:Systematic review and network meta-analysis

OBJECTIVE: To determine the most effective interventions in recently detoxified, alcohol dependent patients for implementation in primary care. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, PsycINFO, Cochrane CENTRAL, ClinicalTrials.gov, and the World Health Organization's International Clinical Trials Registry Platform. STUDY SELECTION: Randomised controlled trials comparing two or more interventions that could be used in primary care. The population was patients with alcohol dependency diagnosed by standardised clinical tools and who became detoxified within four weeks. DATA EXTRACTION: Outcomes of interest were continuous abstinence from alcohol (effectiveness) and all cause dropouts (as a proxy for acceptability) at least 12 weeks after start of intervention. RESULTS: 64 trials (43 interventions) were included. The median probability of abstinence across placebo arms was 25%. Compared with placebo, the only intervention associated with increased probability of abstinence and moderate certainty evidence was acamprosate (odds ratio 1.86, 95% confidence interval 1.49 to 2.33, corresponding to an absolute probability of 38%). Of the 62 included trials that reported all cause dropouts, interventions associated with a reduced number of dropouts compared with placebo (probability 50%) and moderate certainty of evidence were acamprosate (0.73, 0.62 to 0.86; 42%), naltrexone (0.70, 0.50 to 0.98; 41%), and acamprosate-naltrexone (0.30, 0.13 to 0.67; 17%). Acamprosate was the only intervention associated with moderate confidence in the evidence of effectiveness and acceptability up to 12 months. It is uncertain whether other interventions can help maintain abstinence and reduce dropouts because of low confidence in the evidence. CONCLUSIONS: Evidence is lacking for benefit from interventions that could be implemented in primary care settings for alcohol abstinence, other than for acamprosate. More evidence from high quality randomised controlled trials is needed, as are strategies using combined interventions (combinations of drug interventions or drug and psychosocial interventions) to improve treatment of alcohol dependency in primary care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016049779

Elemental ratio measurements of organic compounds using aerosol mass spectrometry: characterization, improved calibration, and implications

Elemental compositions of organic aerosol (OA) particles provide useful constraints on OA sources, chemical evolution, and effects. The Aerodyne high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS) is widely used to measure OA elemental composition. This study evaluates AMS measurements of atomic oxygen-to-carbon (O : C), hydrogen-to-carbon (H : C), and organic mass-to-organic carbon (OM : OC) ratios, and of carbon oxidation state ([bar over OS][subscript C]) for a vastly expanded laboratory data set of multifunctional oxidized OA standards. For the expanded standard data set, the method introduced by Aiken et al. (2008), which uses experimentally measured ion intensities at all ions to determine elemental ratios (referred to here as "Aiken-Explicit"), reproduces known O : C and H : C ratio values within 20% (average absolute value of relative errors) and 12%, respectively. The more commonly used method, which uses empirically estimated H[subscript 2]O[superscript +] and CO[superscript +] ion intensities to avoid gas phase air interferences at these ions (referred to here as "Aiken-Ambient"), reproduces O : C and H : C of multifunctional oxidized species within 28 and 14% of known values. The values from the latter method are systematically biased low, however, with larger biases observed for alcohols and simple diacids. A detailed examination of the H[subscript 2]O[superscript +], CO[superscript +], and CO[subscript 2][superscript +] fragments in the high-resolution mass spectra of the standard compounds indicates that the Aiken-Ambient method underestimates the CO[superscript +] and especially H[subscript 2]O[superscript +] produced from many oxidized species. Combined AMS–vacuum ultraviolet (VUV) ionization measurements indicate that these ions are produced by dehydration and decarboxylation on the AMS vaporizer (usually operated at 600 °C). Thermal decomposition is observed to be efficient at vaporizer temperatures down to 200 °C. These results are used together to develop an "Improved-Ambient" elemental analysis method for AMS spectra measured in air. The Improved-Ambient method uses specific ion fragments as markers to correct for molecular functionality-dependent systematic biases and reproduces known O : C (H : C) ratios of individual oxidized standards within 28% (13%) of the known molecular values. The error in Improved-Ambient O : C (H : C) values is smaller for theoretical standard mixtures of the oxidized organic standards, which are more representative of the complex mix of species present in ambient OA. For ambient OA, the Improved-Ambient method produces O : C (H : C) values that are 27% (11%) larger than previously published Aiken-Ambient values; a corresponding increase of 9% is observed for OM : OC values. These results imply that ambient OA has a higher relative oxygen content than previously estimated. The [bar over OS][subscript C] values calculated for ambient OA by the two methods agree well, however (average relative difference of 0.06 [bar over OS][subscript C] units). This indicates that [bar over OS][subscript C] is a more robust metric of oxidation than O : C, likely since [bar over OS][subscript C] is not affected by hydration or dehydration, either in the atmosphere or during analysis.National Science Foundation (U.S.) (CHE-1012809)National Science Foundation (U.S.) (ATM-1238109

Therapeutic interventions for alcohol dependence in non-inpatient settings:a systematic review and network meta-analysis (protocol)

BACKGROUND: Alcohol dependence is common and serious cause of social and physical harm. However, the optimal management of those with moderate and severe alcohol dependence in primary and community care after detoxification remains unclear. The aim of this review is to evaluate the effectiveness of interventions for maintaining abstinence in people with alcohol dependence following detoxification. METHODS: We will systematically search electronic databases and clinical trial registries for randomized controlled trials (RCTs) examining the effectiveness of pharmacological and/or psychosocial interventions for maintaining abstinence in recently detoxified, alcohol-dependent adults. The searches will be complemented by checking references and citations from included studies and other relevant systematic reviews. No limitation on language, year, or publication status will be applied. RCTs will be selected using prespecified criteria. Descriptive information, study characteristics, and results of eligible RCTs will be extracted. A revised version of the Cochrane Risk of Bias tool (RoB 2.0) will be used to assess the risk of bias in eligible RCTs. Results will be synthesized and analyzed using network meta-analysis (NMA). Overall strength of the evidence and publication bias will be evaluated. Subgroup and sensitivity analysis will also be performed. DISCUSSION: This network meta-analysis aims to appraise and summarize the total evidence of therapeutic interventions for alcohol-dependent patients that require support for detoxification and can be treated in the community. The evidence will determine which combination of interventions are most promising for current practice and further investigation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016049779

Development of the chronic obstructive pulmonary disease morning symptom diary (COPD-MSD).

BACKGROUND: The morning tends to be the most difficult time of day for many patients with chronic obstructive pulmonary disease (COPD) when symptoms can limit one's ability to perform even simple activities. Morning symptoms have been linked to higher levels of work absenteeism, thereby increasing the already substantial economic burden associated with COPD. A validated patient-reported outcome (PRO) instrument designed to capture morning symptoms will allow for a more comprehensive approach to the evaluation of treatment benefit in COPD clinical trials. METHODS: A qualitative interview study was conducted among a sample of symptomatic adults with COPD. Concept elicitation interviews (n = 35) were conducted to identify COPD morning symptoms, followed by cognitive interviews (n = 21) to ensure patient comprehension of the items, instructions and response options of the draft COPD Morning Symptom Diary (COPD-MSD). All interview transcript data were coded using ATLAS.ti software for content analysis. RESULTS: Mean age of the concept elicitation and cognitive interview sample was 65.0 years (±7.5) and 62.3 years (±8.3), respectively. The study sample represented the full range of COPD severity (Global Initiative for Chronic Lung Disease [GOLD] classifications I-IV) and included a mix of racial backgrounds, employment status and educational achievement. During the concept elicitation interviews, the three most frequently reported morning symptoms were shortness of breath (n = 35/35; 100 %), phlegm/mucus (n = 31/35; 88.6 %), and cough (n = 30/35; 85.7 %). A group of clinical and instrument development experts convened to review the concept elicitation data and develop the initial 32-item draft COPD-MSD. Cognitive interviews indicated subjects found the draft COPD-MSD to be comprehensive, clear, and easy to understand. The COPD-MSD underwent minor editorial revisions and streamlining based on cognitive interviews and input from the experts to yield the final 19-item daily diary. CONCLUSIONS: This study supports the content validity of the new COPD-MSD and positions the diary for quantitative psychometric testing

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Retraction Notice to: Suppressors of Cytokine Signaling 2 and 3 Diametrically Control Macrophage Polarization

Friday, 8th December 1916

Treatment success for overactive bladder with urinary urge incontinence refractory to oral antimuscarinics: a review of published evidence

<p>Abstract</p> <p>Background</p> <p>Treatment options for overactive bladder (OAB) with urinary urge incontinence (UUI) refractory to oral antimuscarinics include: botulinum toxin type A (BoNTA), sacral neuromodulation (SNM), and augmentation cystoplasty (AC). A standard treatment success metric that can be used in both clinical and economic evaluations of the above interventions has not emerged. Our objective was to conduct a literature review and synthesis of published measures of treatment success for OAB with UUI interventions and to identify a treatment success outcome.</p> <p>Methods</p> <p>We performed a literature review of primary studies that used a definition of treatment success in the OAB with UUI population receiving BoNTA, SNM, or AC. The recommended success outcome was compared to generic and disease-specific health-related quality-of-life (HRQoL) measures using data from a BoNTA treatment study of neurogenic incontinent patients.</p> <p>Results</p> <p>Across all interventions, success outcomes included: complete continence (n = 23, 44%), ≥ 50% improvement in incontinence episodes (n = 16, 31%), and subjective improvement (n = 13, 25%). We recommend the OAB with UUI treatment success outcome of ≥ 50% improvement in incontinence episodes from baseline. Using data from a neurogenic BoNTA treatment study, the average change in the Incontinence Quality of Life questionnaire was 8.8 (95% CI: -4.7, 22.3) higher for those that succeeded (N = 25) versus those that failed (N = 26). The average change in the SF-6D preference score was 0.07 (95% CI: 0.02, 0.12) higher for those that succeeded versus those that failed.</p> <p>Conclusion</p> <p>A treatment success definition that encompasses the many components of underlying OAB with UUI symptoms is currently not practical as a consequence of difficulties in measuring urgency. The treatment success outcome of ≥ 50% improvement in incontinence episodes was associated with a clinically meaningful improvement in disease-specific HRQoL for those with neurogenic OAB with UUI. The recommended success definition is less restrictive than a measure such as complete continence but includes patients who are satisfied with treatment and experience meaningful improvement in symptoms. A standardized measure of treatment success will be useful in clinical and health economic applications.</p

Diverse RNA-Binding Proteins Interact with Functionally Related Sets of RNAs, Suggesting an Extensive Regulatory System

RNA-binding proteins (RBPs) have roles in the regulation of many post-transcriptional steps in gene expression, but relatively few RBPs have been systematically studied. We searched for the RNA targets of 40 proteins in the yeast Saccharomyces cerevisiae: a selective sample of the approximately 600 annotated and predicted RBPs, as well as several proteins not annotated as RBPs. At least 33 of these 40 proteins, including three of the four proteins that were not previously known or predicted to be RBPs, were reproducibly associated with specific sets of a few to several hundred RNAs. Remarkably, many of the RBPs we studied bound mRNAs whose protein products share identifiable functional or cytotopic features. We identified specific sequences or predicted structures significantly enriched in target mRNAs of 16 RBPs. These potential RNA-recognition elements were diverse in sequence, structure, and location: some were found predominantly in 3′-untranslated regions, others in 5′-untranslated regions, some in coding sequences, and many in two or more of these features. Although this study only examined a small fraction of the universe of yeast RBPs, 70% of the mRNA transcriptome had significant associations with at least one of these RBPs, and on average, each distinct yeast mRNA interacted with three of the RBPs, suggesting the potential for a rich, multidimensional network of regulation. These results strongly suggest that combinatorial binding of RBPs to specific recognition elements in mRNAs is a pervasive mechanism for multi-dimensional regulation of their post-transcriptional fate

Brevicoryne brassicae aphids interfere with transcriptome responses of Arabidopsis thaliana to feeding by Plutella xylostella caterpillars in a density‑dependent manner

Plants are commonly attacked by multiple herbivorous species. Yet, little is known about transcriptional patterns underlying plant responses to multiple insect attackers feeding simultaneously. Here, we assessed= transcriptomic responses of Arabidopsis thaliana plants to simultaneous feeding by Plutella xylostella caterpillars and Brevicoryne brassicae aphids in comparison to plants infested by P. xylostella caterpillars alone, using microarray analysis. We particularly investigated how aphid feeding interferes with the transcriptomic response to P. xylostella caterpillars and whether this interference is dependent on aphid density and time since aphid attack. Various JA-responsive genes were up-regulated in response to feeding by P. xylostella caterpillars. The additional presence of aphids, both at low and high densities, clearly affected the transcriptional plant response to caterpillars. Interestingly, some important modulators of plant defense signalling, including WRKY transcription factor genes and ABA-dependent genes, were differentially induced in response to simultaneous aphid feeding at low or high density compared with responses to P. xylostella caterpillars feeding alone. Furthermore, aphids affected the P. xylostella-induced transcriptomic response in a density dependent manner, which caused an acceleration in plant response against dual insect attack at high aphid density compared to dual insect attack at low aphid density. In conclusion, our study provides evidence that aphids influence the caterpillar-induced transcriptional response of A. thaliana in a density-dependent manner. It highlights the importance of addressing insect density to understand how plant responses to single attackers interfere with responses to other attackers and thus underlines the importance of the dynamics of transcriptional plant responses to multiple herbivory