When will unusual heat waves become normal in a warming Africa?

n/

A CGRP receptor antagonist peptide formulated for nasal administration to treat migraine

Objectives: To investigate the formulation of the peptide‐based antagonist (34Pro,35Phe)CGRP27–37, of the human calcitonin gene‐related peptide (CGRP) receptor as a potential nasally delivered migraine treatment. Methods: Peptide sequences were prepared using automated methods and purified by preparative HPLC. Their structure and stability were determined by LC‐MS. Antagonist potency was assessed by measuring CGRP‐stimulated cAMP accumulation in SK‐N‐MC, cells and in CHO cells overexpressing the human CGRP receptor. In vivo activity was tested in plasma protein extravasation (PPE) studies using Evans blue dye accumulation. Peptide‐containing chitosan microparticles were prepared by spray drying. Key findings: (34Pro,35Phe)CGRP27–37 exhibited a 10‐fold increased affinity compared to αCGRP27–37. Administration of (34Pro,35Phe)CGRP27–37 to mice led to a significant decrease in CGRP‐induced PPE confirming antagonistic properties in vivo . There was no degradation of (34Pro,35Phe)CGRP27–37 and no loss of antagonist potency during formulation and release from chitosan microparticles. Conclusions: (34Pro,35Phe)CGRP27–37 is a potent CGRP receptor antagonist both in vitro and in vivo, and it can be formulated as a dry powder with no loss of activity indicating its potential as a nasally formulated anti‐migraine medicine

Pregnancy-induced changes in cell-fate in the mammary gland

The protective effect of an early full-term pregnancy is a well established phenomenon; in contrast, the molecular and cell-specific mechanisms that govern parity-specific changes in the mammary gland have not been well described. Recent studies signify a dramatic advance in our understanding of this phenomenon, and indicate a 'cell fate' model for parity-related changes that lead to protection against breast cancer

The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission

1Infection of red blood cells (RBC) subjects the malaria parasite to oxidative stress. Therefore, efficient antioxidant and redox systems are required to prevent damage by reactive oxygen species. Plasmodium spp. have thioredoxin and glutathione (GSH) systems that are thought to play a major role as antioxidants during blood stage infection. In this report, we analyzed a critical component of the GSH biosynthesis pathway using reverse genetics. Plasmodium berghei parasites lacking expression of gamma-glutamylcysteine synthetase (γ-GCS), the rate limiting enzyme in de novo synthesis of GSH, were generated through targeted gene disruption thus demonstrating, quite unexpectedly, that γ-GCS is not essential for blood stage development. Despite a significant reduction in GSH levels, blood stage forms of pbggcs− parasites showed only a defect in growth as compared to wild type. In contrast, a dramatic effect on development of the parasites in the mosquito was observed. Infection of mosquitoes with pbggcs− parasites resulted in reduced numbers of stunted oocysts that did not produce sporozoites. These results have important implications for the design of drugs aiming at interfering with the GSH redox-system in blood stages and demonstrate that de novo synthesis of GSH is pivotal for development of Plasmodium in the mosquito

HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease

Background&Aims: Hepatocellular carcinoma (HCC) is a main cause of morbidity and mortality in patients with advanced chronic liver disease (ACLD) due to chronic hepatitis C and who have achieved sustained virologic response (SVR). We elaborated risk stratification algorithms for de-novo-HCC-development after SVR and validated them in an independent cohort. Methods: Derivation cohort: 527 patients with pre-treatment ACLD and SVR to interferon-free therapy were evaluated for de-novo-HCC-development. Among others, alpha-fetoprotein (AFP) and non-invasive surrogates of portal hypertension including liver stiffness measurement (LSM) were assessed pre-/post-treatment. Validation cohort: 1500 patients with compensated ACLD (cACLD) from other European centers. Results: During a median follow-up (FU) of 41 months, 22/475 cACLD (4.6%) (1.45/100patient-years)vs.12/52 decompensated patients (23.1%, 7.00/100patient-years, p<0.001) developed de-novo-HCC. Since decompensated patients were at substantial HCC-risk, we focused on cACLD for all further analyses. In cACLD, post-treatment-values showed a higher discriminative ability for patients with/without de-novo-HCC-development during FU than pre-treatment-values or absolute/relative changes. Models based on post-treatment AFP≥4.6ngxmL-1-3points, alcohol consumption (males:>30g/d/females:>20g/d)-2points (optional), age≥59year-2points, LSM≥19.0kPa-1point, and albumin<42gxL-1-1point, accurately predicted de-novo-HCC-development (bootstrapped Harrel’s C with and without considering alcohol:0.893 and 0.836). Importantly, these parameters also provided independent prognostic information in competing risk analysis and accurately stratified patients into low-(0-3points; ≈2/3 of patients) and high-risk (≥4points; ≈1/3) groups in the derivation (algorithm with alcohol consumption; 4-year HCC-risk:0%vs.16.5%) and validation (3.3%/17.5%) cohorts. An alternative approach based on age/alcohol (optional)/FU-LSM/FU-albumin (i.e., without FU-AFP) also showed a robust performance. Conclusions: Simple algorithms based on post-treatment age/albumin/LSM, and optionally, AFP and alcohol, accurately stratified de-novo-HCC-risk in cACLD patients with SVR. Approximately 2/3 were identified as having an HCC-risk <1%/y in both the derivation and validation cohort, thereby clearly falling below the cost-effectiveness threshold for HCC-surveillance. LAY SUMMARY: Simple algorithms based on age, alcohol consumption, results of blood tests (albumin and α-fetoprotein), as well as liver stiffness measurement after the end of hepatitis C treatment identify a large proportion (approximately 2/3) of patients with advanced but still asymptomatic liver disease who are at very low risk (<1%/year) of liver cancer development, and thus, might not need to undergo 6-monthly liver ultrasound

A Josephson Quantum Electron Pump

A macroscopic fluid pump works according to the law of Newtonian mechanics and transfers a large number of molecules per cycle (of the order of 10^23). By contrast, a nano-scale charge pump can be thought as the ultimate miniaturization of a pump, with its operation being subject to quantum mechanics and with only few electrons or even fractions of electrons transfered per cycle. It generates a direct current in the absence of an applied voltage exploiting the time-dependence of some properties of a nano-scale conductor. The idea of pumping in nanostructures was discussed theoretically a few decades ago [1-4]. So far, nano-scale pumps have been realised only in system exhibiting strong Coulombic effects [5-12], whereas evidence for pumping in the absence of Coulomb-blockade has been elusive. A pioneering experiment by Switkes et al. [13] evidenced the difficulty of modulating in time the properties of an open mesoscopic conductor at cryogenic temperatures without generating undesired bias voltages due to stray capacitances [14,15]. One possible solution to this problem is to use the ac Josephson effect to induce periodically time-dependent Andreev-reflection amplitudes in a hybrid normal-superconducting system [16]. Here we report the experimental detection of charge flow in an unbiased InAs nanowire (NW) embedded in a superconducting quantum interference device (SQUID). In this system, pumping may occur via the cyclic modulation of the phase of the order parameter of different superconducting electrodes. The symmetry of the current with respect to the enclosed magnetic flux [17,18] and bias SQUID current is a discriminating signature of pumping. Currents exceeding 20 pA are measured at 250 mK, and exhibit symmetries compatible with a pumping mechanism in this setup which realizes a Josephson quantum electron pump (JQEP).Comment: 7+ pages, 6 color figure

Blocking representation in the ERA-Interim driven EURO-CORDEX RCMs

While Regional Climate Models (RCMs) have been shown to yield improved simulations compared to General Circulation Model (GCM), their representation of large-scale phenomena like atmospheric blocking has been hardly addressed. Here, we evaluate the ability of RCMs to simulate blocking situations present in their reanalysis driving data and analyse the associated impacts on anomalies and biases of European 2-m air temperature (TAS) and precipitation rate (PR). Five RCM runs stem from the EURO-CORDEX ensemble while three RCMs are WRF models with different nudging realizations, all of them driven by ERA-Interim for the period 1981?2010. The detected blocking systems are allocated to three sectors of the Euro-Atlantic region, allowing for a characterization of distinctive blocking-related TAS and PR anomalies. Our results indicate some misrepresentation of atmospheric blocking over the EURO-CORDEX domain, as compared to the driving reanalysis. Most of the RCMs showed fewer blocks than the driving data, while the blocking misdetection was negligible for RCMs strongly conditioned to the driving data. A higher resolution of the RCMs did not improve the representation of atmospheric blocking. However, all RCMs are able to reproduce the basic anomaly structure of TAS and PR connected to blocking. Moreover, the associated anomalies do not change substantially after correcting for the misrepresentation of blocking in RCMs. The overall model bias is mainly determined by pattern biases in the representations of surface parameters during non-blocking situations. Biases in blocking detections tend to have a secondary influence in the overall bias due to compensatory effects of missed blockings and non-blockings. However, they can lead to measurable effects in the presence of a strong blocking underestimation.This work was funded by the Austrian Science Fund (FWF) under the project: Understanding Contrasts in high Mountain hydrology in Asia (UNCOMUN: I 1295-N29). This research was supported by the Faculty of Environmental, Regional and Educational Sciences (URBI), University of Graz, as well as the Federal Ministry of Science, Research and Economy (BMWFW) by funding the OeAD Grant Marietta Blau. This work was partially supported (JMG and SH) by the project MULTI-SDM (CGL2015-66583- R, MINECO/FEDER). DB was supported by the PALEOSTRAT (CGL2015-69699-R) project funded by the Spanish Ministry of Economy and Competitiveness (MINECO)

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns