Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs

Data availability. The RNA sequencing dataset is available at EBI (www.ebi.ac.uk/arrayexpress/) under accession number E-MTAB-5990. Other data that support the findings of this study are available from the corresponding author upon reasonable request. ACKNOWLEDGMENTS We thank Debbie Smith for constructing the strains JC41 and JC310, Arnab Pradhan for help with DHE control experiments, and our colleagues in the Aberdeen Fungal Group and Newcastle Yeast Group for insightful discussions. We are also grateful to Mike Gustin for his advice. We are grateful to the Centre for Genome Enabled Biology and Medicine, Aberdeen Proteomics, the Iain Fraser Cytometry Centre, the Microscopy and Histology Facility, and the qPCR facility at the University of Aberdeen for their help, advice, and support. This work was funded by the UK Biotechnology and Biological Research Council (http://www.bbsrc.ac.uk) (grants BB/K017365/1 and BB/F00513X/1 to A.J.P.B. and grant BB/K016393/1 to J.Q.). This work was also supported by the European Research Council (http://erc.europa.eu/) (STRIFE advanced grant C-2009-AdG-249793 to A.J.P.B.), the UK Medical Research Council (http://www.mrc.ac.uk) (grant MR/M026663/1 to A.J.P.B. and grant MR/M000923/1 to P.S.S.), the Wellcome Trust (https://wellcome.ac.uk) (grant 097377 to A.J.P.B. and J.Q.), the MRC Centre for Medical Mycology and the University of Aberdeen (grant MR/M026663/1 to A.J.P.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Barriers to Treatment Access for Chagas Disease in Mexico

Background: According to World Health Organization (WHO) prevalence estimates, 1.1 million people in Mexico are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease (CD). However, limited information is available about access to antitrypanosomal treatment. This study assesses the extent of access in Mexico, analyzes the barriers to access, and suggests strategies to overcome them. Methods and Findings: Semi-structured in-depth interviews were conducted with 18 key informants and policymakers at the national level in Mexico. Data on CD cases, relevant policy documents and interview data were analyzed using the Flagship Framework for Pharmaceutical Policy Reform policy interventions: regulation, financing, payment, organization, and persuasion. Data showed that 3,013 cases were registered nationally from 2007–2011, representing 0.41% of total expected cases based on Mexico's national prevalence estimate. In four of five years, new registered cases were below national targets by 11–36%. Of 1,329 cases registered nationally in 2010–2011, 834 received treatment, 120 were pending treatment as of January 2012, and the treatment status of 375 was unknown. The analysis revealed that the national program mainly coordinated donation of nifurtimox and that important obstacles to access include the exclusion of antitrypanosomal medicines from the national formulary (regulation), historical exclusion of CD from the social insurance package (organization), absence of national clinical guidelines (organization), and limited provider awareness (persuasion). Conclusions: Efforts to treat CD in Mexico indicate an increased commitment to addressing this disease. Access to treatment could be advanced by improving the importation process for antitrypanosomal medicines and adding them to the national formulary, increasing education for healthcare providers, and strengthening clinical guidelines. These recommendations have important implications for other countries in the region with similar problems in access to treatment for CD

The effects of peptide modified gellan gum and olfactory ensheathing glia cells on neural stem/progenitor cell fate

The regenerative capacity of injured adult central nervous system (CNS) tissue is very limited. Specifically, traumatic spinal cord injury (SCI) leads to permanent loss of motor and sensory functions below the site of injury, as well as other detrimental complications. A potential regenerative strategy is stem cell transplantation; however, cell survival is typically less than 1%. To improve cell survival, stem cells can be delivered in a biomaterial matrix that provides an environment conducive to survival after transplantation. One major challenge in this approach is to define the biomaterial and cell strategies in vitro. To this end, we investigated both peptide-modification of gellan gum and olfactory ensheathing glia (OEG) on neural stem/progenitor cell (NSPC) fate. To enhance cell adhesion, the gellan gum (GG) was modified using Diels–Alder click chemistry with a fibronectin-derived synthetic peptide (GRGDS). Amino acid analysis demonstrated that approximately 300 nmol of GRGDS was immobilized to each mg of GG. The GG–GRGDS had a profound effect on NSPC morphology and proliferation, distinct from that of NSPCs in GG alone, demonstrating the importance of GRGDS for cell-GG interaction. To further enhance NSPC survival and outgrowth, they were cultured with OEG. Here NSPCs interacted extensively with OEG, demonstrating significantly greater survival and proliferation relative to monocultures of NSPCs. These results suggest that this co-culture strategy of NSPCs with OEG may have therapeutic benefit for SCI repair.: Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BD/40684/2007, Science 2007 Programe, PTDC/SAU-BMA/114059/2009).Ontario Ministry of Research and Innovation (Ontario Neurotrauma FoundationCanadian Institute of Health Research (MSS)Stem Cell Network (MJC

Is Thermosensing Property of RNA Thermometers Unique?

A large number of studies have been dedicated to identify the structural and sequence based features of RNA thermometers, mRNAs that regulate their translation initiation rate with temperature. It has been shown that the melting of the ribosome-binding site (RBS) plays a prominent role in this thermosensing process. However, little is known as to how widespread this melting phenomenon is as earlier studies on the subject have worked with a small sample of known RNA thermometers. We have developed a novel method of studying the melting of RNAs with temperature by computationally sampling the distribution of the RNA structures at various temperatures using the RNA folding software Vienna. In this study, we compared the thermosensing property of 100 randomly selected mRNAs and three well known thermometers - rpoH, ibpA and agsA sequences from E. coli. We also compared the rpoH sequences from 81 mesophilic proteobacteria. Although both rpoH and ibpA show a higher rate of melting at their RBS compared with the mean of non-thermometers, contrary to our expectations these higher rates are not significant. Surprisingly, we also do not find any significant differences between rpoH thermometers from other -proteobacteria and E. coli non-thermometers

Lambda and Antilambda polarization from deep inelastic muon scattering

We report results of the first measurements of Lambda and Antilambda polarization produced in deep inelastic polarized muon scattering on the nucleon. The results are consistent with an expected trend towards positive polarization with increasing x_F. The polarizations of Lambda and Antilambda appear to have opposite signs. A large negative polarization for Lambda at low positive x_F is observed and is not explained by existing models.A possible interpretation is presented.Comment: 9 pages, 2 figure

Shadowing in Inelastic Scattering of Muons on Carbon, Calcium and Lead at Low XBj

Nuclear shadowing is observed in the per-nucleon cross-sections of positive muons on carbon, calcium and lead as compared to deuterium. The data were taken by Fermilab experiment E665 using inelastically scattered muons of mean incident momentum 470 GeV/c. Cross-section ratios are presented in the kinematic region 0.0001 < XBj <0.56 and 0.1 < Q**2 < 80 GeVc. The data are consistent with no significant nu or Q**2 dependence at fixed XBj. As XBj decreases, the size of the shadowing effect, as well as its A dependence, are found to approach the corresponding measurements in photoproduction.Comment: 22 pages, incl. 6 figures, to be published in Z. Phys.

Spectroscopic and Mechanistic Studies of Heterodimetallic Forms of Metallo-β-lactamase NDM-1

In an effort to characterize the roles of each metal ion in metallo-β-lactamase NDM-1, heterodimetallic analogues (CoCo-, ZnCo-, and CoCd-) of the enzyme were generated and characterized. UV–vis, 1H NMR, EPR, and EXAFS spectroscopies were used to confirm the fidelity of the metal substitutions, including the presence of a homogeneous, heterodimetallic cluster, with a single-atom bridge. This marks the first preparation of a metallo-β-lactamase selectively substituted with a paramagnetic metal ion, Co(II), either in the Zn1 (CoCd-NDM-1) or in the Zn2 site (ZnCo-NDM-1), as well as both (CoCo-NDM-1). We then used these metal-substituted forms of the enzyme to probe the reaction mechanism, using steady-state and stopped-flow kinetics, stopped-flow fluorescence, and rapid-freeze-quench EPR. Both metal sites show significant effects on the kinetic constants, and both paramagnetic variants (CoCd- and ZnCo-NDM-1) showed significant structural changes on reaction with substrate. These changes are discussed in terms of a minimal kinetic mechanism that incorporates all of the data