UV solar irradiance in observations and the NRLSSI and SATIRE-S models

Total solar irradiance and UV spectral solar irradiance have been monitored since 1978 through a succession of space missions. This is accompanied by the development of models aimed at replicating solar irradiance by relating the variability to solar magnetic activity. The NRLSSI and SATIRE-S models provide the most comprehensive reconstructions of total and spectral solar irradiance over the period of satellite observation currently available. There is persistent controversy between the various measurements and models in terms of the wavelength dependence of the variation over the solar cycle, with repercussions on our understanding of the influence of UV solar irradiance variability on the stratosphere. We review the measurement and modelling of UV solar irradiance variability over the period of satellite observation. The SATIRE-S reconstruction is consistent with spectral solar irradiance observations where they are reliable. It is also supported by an independent, empirical reconstruction of UV spectral solar irradiance based on UARS/SUSIM measurements from an earlier study. The weaker solar cycle variability produced by NRLSSI between 300 and 400 nm is not evident in any available record. We show that although the method employed to construct NRLSSI is principally sound, reconstructed solar cycle variability is detrimentally affected by the uncertainty in the SSI observations it draws upon in the derivation. Based on our findings, we recommend, when choosing between the two models, the use of SATIRE-S for climate studies

Bicyclic Boronate β-Lactamase Inhibitors: The Present Hope against Deadly Bacterial Pathogens

The use of β-lactamase inhibitors in combination with β-lactam antibiotics is an emerging area in drug discovery. This strategy allows the restoration of the therapeutic efficacy of these antibiotics in clinical use against multiresistant bacteria. These pathogens are drug resistant because they express β-lactamase enzymes, which prevent the antibiotic therapeutic action by catalyzing the hydrolysis of the β-lactam ring. These enzymes are quite diverse in both their structural architecture and hydrolytic capability, as well as in the mechanism of action. The ever-increasing emergence of pathogens that are capable of coproducing different types of β-lactamases has triggered the search for ultrabroad-spectrum inhibitors capable of deactivating both serine- and metallo-β-lactamases. A recent breakthrough in this long-pursued and unmet need is the discovery of bicyclic boronate inhibitors, specifically taniborbactam, VNRX-7145, and QPX7728, which are currently under clinical development in combination with cefepime, ceftibuten, and QPX2014, respectively. The present article highlights the therapeutic potential of these inhibitors and their spectrum of efficacy is compared with those of other β-lactam/β-lactamase inhibitor combinations recently approved by the food and drug administration. The molecular basis of the ultrabroad-spectrum of activity of boron-based inhibitors is also discussed, on the basis of the available crystal structures and the results of computational studiesinancial support from the Spanish Ministry of Economy and Competiveness (SAF2016-75638-R, PID2019-105512RB-I00), the Xunta de Galicia [ED431B 2018/04 and Centro singular de investigación de Galicia accreditation 2019–2022 (ED431G 2019/03)], and the European Regional Development Fund (ERDF) is gratefully acknowledgedS

Are non-allergic drug reactions commonly documented as medication “allergies”? A national cohort of Veterans\u27 admissions from 2000 to 2014

Purpose: Adverse drug reactions (ADRs) including medication allergies are not well-described among large national cohorts. This study described the most common documented medication allergies and their reactions among a national cohort of Veterans Affairs (VA) inpatients. Methods: We evaluated inpatient admissions in any VA Medical Center from 1 January 2000 to 31 December 2014. Each admission was linked with allergy history preceding or upon admission. Individual drugs were aggregated into drug class category including: penicillins, sulfonamides, angiotensin converting enzyme (ACE) inhibitors, opiates, HMG-CoA reductase inhibitors (“statins”) and non-steroidal anti-inflammatory inhibitors (NSAID). Results were reported in aggregate and over time. Results: Approximately ~10.8 million inpatient admissions occurred from 2000 to 2014. We found the most commonly reported allergy drug classes were penicillins (13%, n = 1 410 080), opiates (9.1%, n = 984 978), ACE inhibitors (5.7%, n = 618 075) sulfonamides (5.1%, n = 558 653), NSAIDs (5.1%, n = 551 216) and statins (3.6%, n  = 391 983). Several allergy histories increased over time including opiates (6.2 to 11.2%), ACE inhibitors (1.3 to 10.2%), statins (0.3 to 7.3%) and NSAIDs (3.9 to 6.0%). Rash was the most commonly documented reaction on reports for penicillins (25.5%, n = 371 825), sulfonamides (25.6%, n = 165 954) and NSAIDs (10.3%, n = 65 741). The most common reaction for opiates was nausea/vomiting (17.9%, n = 211 864), cough/coughing for ACE inhibitors (41.0%, n = 270 537) and muscle pain/myalgia for statins (34.1%, n = 186 565). Conclusions: We report that penicillins and opiates are the most commonly documented drug allergies among VA inpatients, but other drug classes such as ACE inhibitors, statins and NSAIDs are becoming increasingly common. Clinicians also commonly document non-allergic ADRs in the allergy section such as cough or myalgia. Copyright © 2016 John Wiley & Sons, Ltd

Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders that exist on a symptomological spectrum and share both genetic underpinnings and pathophysiological hallmarks. Functional abnormality of TAR DNA-binding protein 43 (TDP-43), an aggregation-prone RNA and DNA binding protein, is observed in the vast majority of both familial and sporadic ALS cases and in ~40% of FTLD cases, but the cascade of events leading to cell death are not understood. We have expressed human TDP-43 (hTDP-43) in Drosophila neurons and glia, a model that recapitulates many of the characteristics of TDP-43-linked human disease including protein aggregation pathology, locomotor impairment, and premature death. We report that such expression of hTDP-43 impairs small interfering RNA (siRNA) silencing, which is the major post-transcriptional mechanism of retrotransposable element (RTE) control in somatic tissue. This is accompanied by de-repression of a panel of both LINE and LTR families of RTEs, with somewhat different elements being active in response to hTDP-43 expression in glia versus neurons. hTDP-43 expression in glia causes an early and severe loss of control of a specific RTE, the endogenous retrovirus (ERV) gypsy. We demonstrate that gypsy causes the degenerative phenotypes in these flies because we are able to rescue the toxicity of glial hTDP-43 either by genetically blocking expression of this RTE or by pharmacologically inhibiting RTE reverse transcriptase activity. Moreover, we provide evidence that activation of DNA damage-mediated programmed cell death underlies both neuronal and glial hTDP-43 toxicity, consistent with RTE-mediated effects in both cell types. Our findings suggest a novel mechanism in which RTE activity contributes to neurodegeneration in TDP-43-mediated diseases such as ALS and FTLD

Spatial segregation measures: a methodological review

Quantitative indices of segregation are powerful tools for summarising the spatial relationships between population groups and thereby providing the basis for analysis and public policy intervention. While the broad concept of segregation may be intuitive, measurement is challenging because of the complexity of varied dimensions and spatial arrangements. Many traditional measures can be criticised for over-simplification or over-reduction, not least in their treatment of geographical space. Over the last several decades, however, a series of measures has been developed to explicitly incorporate the spatial arrangement of population groups as well as their interactions. This paper reviews the development of spatial segregation measures, particularly focusing on the mathematical formulation of spatial arrangement/relations. In addition, several related issues are discussed, including representation of spatial interaction, spatial scale and statistical inferences. Also, this paper presents an overview of existing software tools that are readily available for calculating some of the reviewed measures. Finally, discussions on challenges and future research are provided

Manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols via alkoxy radicals

A manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols has been developed. This electrochemical method provides access to alkoxy radicals from alcohols and exhibits a broad substrate scope, with various cyclopropanols and cyclobutanols converted into synthetically useful β- and γ-chlorinated ketones (40 examples). Furthermore, the combination of recirculating flow electrochemistry and continuous inline purification was employed to access products on a gram scale

Nonequilibrium clumped isotope signals in microbial methane

Methane is a key component in the global carbon cycle with a wide range of anthropogenic and natural sources. Although isotopic compositions of methane have traditionally aided source identification, the abundance of its multiply-substituted “clumped” isotopologues, e.g., 13CH3D, has recently emerged as a proxy for determining methane-formation temperatures; however, the impact of biological processes on methane’s clumped isotopologue signature is poorly constrained. We show that methanogenesis proceeding at relatively high rates in cattle, surface environments, and laboratory cultures exerts kinetic control on 13CH3D abundances and results in anomalously elevated formation temperature estimates. We demonstrate quantitatively that H2 availability accounts for this effect. Clumped methane thermometry can therefore provide constraints on the generation of methane in diverse settings, including continental serpentinization sites and ancient, deep groundwaters.National Science Foundation (U.S.) (EAR-1250394)National Science Foundation (U.S.) (EAR-1322805)Deep Carbon Observatory (Program)Natural Sciences and Engineering Research Council of CanadaDeutsche Forschungsgemeinschaft (Gottfried Wilhelm Leibniz Program)United States. Dept. of Defense (National Defense Science and Engineering Graduate Fellowship)Neil & Anna Rasmussen FoundationGrayce B. Kerr Fund, Inc. (Fellowship)MIT Energy Initiative (Shell-MITEI Graduate Fellowship)Shell International Exploration and Production B.V. (N. Braunsdorf and D. Smit of Shell PTI/EG grant

In-situ 3D Micro-sensor Model using Embedded Plasmonic Island for Biosensors

The design of the microsensor system for biosensors using the plasmonic island is proposed. The sensor head is formed by the stacked layers of silicon-graphene-gold materials. The dual-mode operations of the sensor can be performed using the relationship of the changes between the electron mobility and optical phase, where the exciting environment can be light intensity (phase), electrical transient, heat, pressure, flavour and smoke, The change in light phase (intensity) in silicon and conductivity (mobility) in gold layers cause change in the output measurands. The design and simulation interpretation of the sensor is presented. The sensor manipulation using the MCM arrangement is simulated and interpreted for biosensor applications 3D imaging can also be applied to the MCM function, where the 3D in situ sensor function is possible. The sensor sensitivity of 2.0 × 10−21 cm2 V−1 s−1 (mW)−1 via simulation is obtained