2,316 research outputs found
Constraining the Twomey effect from satellite observations: issues and perspectives
The Twomey effect describes the radiative forcing
associated with a change in cloud albedo due to an increase
in anthropogenic aerosol emissions. It is driven by the perturbation
in cloud droplet number concentration (1Nd; ant)
in liquid-water clouds and is currently understood to exert
a cooling effect on climate. The Twomey effect is the key
driver in the effective radiative forcing due to aerosol–cloud
interactions, but rapid adjustments also contribute. These
adjustments are essentially the responses of cloud fraction
and liquid water path to 1Nd; ant and thus scale approximately
with it. While the fundamental physics of the influence
of added aerosol particles on the droplet concentration
(Nd) is well described by established theory at the particle
scale (micrometres), how this relationship is expressed at the
large-scale (hundreds of kilometres) perturbation, 1Nd; ant,
remains uncertain. The discrepancy between process understanding
at particle scale and insufficient quantification at
the climate-relevant large scale is caused by co-variability of
aerosol particles and updraught velocity and by droplet sink
processes. These operate at scales on the order of tens of metres at which only localised observations are available and at
which no approach yet exists to quantify the anthropogenic
perturbation. Different atmospheric models suggest diverse
magnitudes of the Twomey effect even when applying the
same anthropogenic aerosol emission perturbation. Thus, observational
data are needed to quantify and constrain the
Twomey effect. At the global scale, this means satellite data.
There are four key uncertainties in determining 1Nd; ant,
namely the quantification of (i) the cloud-active aerosol – the
cloud condensation nuclei (CCN) concentrations at or above
cloud base, (ii) Nd, (iii) the statistical approach for inferring
the sensitivity of Nd to aerosol particles from the satellite
data and (iv) uncertainty in the anthropogenic perturbation
to CCN concentrations, which is not easily accessible from
observational data. This review discusses deficiencies of current
approaches for the different aspects of the problem and
proposes several ways forward: in terms of CCN, retrievals
of optical quantities such as aerosol optical depth suffer from
a lack of vertical resolution, size and hygroscopicity information,
non-direct relation to the concentration of aerosols,
difficulty to quantify it within or below clouds, and the problem
of insufficient sensitivity at low concentrations, in addition
to retrieval errors. A future path forward can include
utilising co-located polarimeter and lidar instruments, ideally
including high-spectral-resolution lidar capability at two
wavelengths to maximise vertically resolved size distribution
information content. In terms of Nd, a key problem is the lack
of operational retrievals of this quantity and the inaccuracy of
the retrieval especially in broken-cloud regimes. As for the
Nd-to-CCN sensitivity, key issues are the updraught distributions
and the role of Nd sink processes, for which empirical
assessments for specific cloud regimes are currently the best
solutions. These considerations point to the conclusion that past studies using existing approaches have likely underestimated
the true sensitivity and, thus, the radiative forcing due
to the Twomey effect
Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2.
AIMS
Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2.
METHODS AND RESULTS
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM.
CONCLUSION
A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS
Minimum requirements for publishing hydrogen, carbon, nitrogen, oxygen and sulfur stable-isotope delta results (IUPAC Technical Report)
Stable hydrogen, carbon, nitrogen, oxygen and sulfur (HCNOS) isotope compositions expressed as isotope-delta values are typically reported relative to international standards such as Vienna Standard Mean Ocean Water (VSMOW), Vienna Peedee belemnite (VPDB) or Vienna Cañon Diablo Troilite (VCDT). These international standards are chosen by convention and the calibration methods used to realise them in practice undergo occasional changes. To ensure longevity and reusability of published data, a comprehensive description of (1) analytical procedure, (2) traceability, (3) data processing, and (4) uncertainty evaluation is required. Following earlier International Union of Pure and Applied Chemistry documents on terminology and notations, this paper proposes minimum requirements for publishing HCNOS stable-isotope delta results. Each of the requirements are presented with illustrative example
Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs
Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 \u3bcM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 \u3bcM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability
Saliva Proteins of Vector Culicoides Modify Structure and Infectivity of Bluetongue Virus Particles
Bluetongue virus (BTV) and epizootic haemorrhagic disease virus (EHDV) are related orbiviruses, transmitted between their ruminant hosts primarily by certain haematophagous midge vectors (Culicoides spp.). The larger of the BTV outer-capsid proteins, ‘VP2’, can be cleaved by proteases (including trypsin or chymotrypsin), forming infectious subviral particles (ISVP) which have enhanced infectivity for adult Culicoides, or KC cells (a cell-line derived from C. sonorensis). We demonstrate that VP2 present on purified virus particles from 3 different BTV strains can also be cleaved by treatment with saliva from adult Culicoides. The saliva proteins from C. sonorensis (a competent BTV vector), cleaved BTV-VP2 more efficiently than those from C. nubeculosus (a less competent / non-vector species). Electrophoresis and mass spectrometry identified a trypsin-like protease in C. sonorensis saliva, which was significantly reduced or absent from C. nubeculosus saliva. Incubating purified BTV-1 with C. sonorensis saliva proteins also increased their infectivity for KC cells ∼10 fold, while infectivity for BHK cells was reduced by 2–6 fold. Treatment of an ‘eastern’ strain of EHDV-2 with saliva proteins of either C. sonorensis or C. nubeculosus cleaved VP2, but a ‘western’ strain of EHDV-2 remained unmodified. These results indicate that temperature, strain of virus and protein composition of Culicoides saliva (particularly its protease content which is dependent upon vector species), can all play a significant role in the efficiency of VP2 cleavage, influencing virus infectivity. Saliva of several other arthropod species has previously been shown to increase transmission, infectivity and virulence of certain arboviruses, by modulating and/or suppressing the mammalian immune response. The findings presented here, however, demonstrate a novel mechanism by which proteases in Culicoides saliva can also directly modify the orbivirus particle structure, leading to increased infectivity specifically for Culicoides cells and, in turn, efficiency of transmission to the insect vector
Reception Test of Petals for the End Cap TEC+ of the CMS Silicon Strip Tracker
The silicon strip tracker of the CMS experiment has been completed and was inserted into the CMS detector in late 2007. The largest sub system of the tracker are its end caps, comprising two large end caps (TEC) each containing 3200 silicon strip modules. To ease construction, the end caps feature a modular design: groups of about 20 silicon modules are placed on sub-assemblies called petals and these self-contained elements are then mounted onto the TEC support structures. Each end cap consists of 144 such petals, which were built and fully qualified by several institutes across Europe. Fro
Integration of the End Cap TEC+ of the CMS Silicon Strip Tracker
The silicon strip tracker of the CMS experiment has been completed and inserted into the CMS detector in late 2007. The largest sub-system of the tracker is its end cap system, comprising two large end caps (TEC) each containing 3200 silicon strip modules. To ease construction, the end caps feature a modular design: groups of about 20 silicon modules are placed on sub-assemblies called petals and these self-contained elements are then mounted into the TEC support structures. Each end cap consists of 144 petals, and the insertion of these petals into the end cap structure is referred to as TEC integration. The two end caps were integrated independently in Aachen (TEC+) and at CERN (TEC--). This note deals with the integration of TEC+, describing procedures for end cap integration and for quality control during testing of integrated sections of the end cap and presenting results from the testing
Comment letters to the National Commission on Commission on Fraudulent Financial Reporting, 1987 (Treadway Commission) Vol. 1
https://egrove.olemiss.edu/aicpa_sop/1661/thumbnail.jp
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