Solving rate equations for electron tunneling via discrete quantum states

We consider the form of the current-voltage curves generated when tunneling spectroscopy is used to measure the energies of individual electronic energy levels in nanometer-scale systems. We point out that the voltage positions of the tunneling resonances can undergo temperature-dependent shifts, leading to errors in spectroscopic measurements that are proportional to temperature. We do this by solving the set of rate equations that can be used to describe electron tunneling via discrete quantum states, for a number of cases important for comparison to experiments, including (1) when just one spin-degenerate level is accessible for transport, (2) when 2 spin-degenerate levels are accessible, with no variation in electron-electron interactions between eigenstates, and (3) when 2 spin-degenerate levels are accessible, but with variations in electron-electron interactions. We also comment on the general case with an arbitrary number of accessible levels. In each case we analyze the voltage-positions, amplitudes, and widths of the current steps due to the quantum states.Comment: REVTeX 4, 10 pages, 12 figures, submitted to Phys. Rev. B. Associated programs available at http://www.ccmr.cornell.edu/~ralph

Targeted interventions of the Avahan program and their association with intermediate outcomes among female sex workers in Maharashtra, India

<p>Abstract</p> <p>Background</p> <p>Avahan, the India AIDS Initiative has been a partner supporting targeted interventions of high risk populations under India’s National AIDS Control Organisation (NACO) since 2004 in the state of Maharashtra. This paper presents an assessment of the Avahan program among female sex workers (FSWs) in Maharashtra, its coverage, outcomes achieved and their association with Avahan program.</p> <p>Methods</p> <p>An analytical framework based on the Avahan evaluation design was used, addressing assessment questions on program implementation, intermediate outcomes and association of outcomes with Avahan. Data from routine program monitoring, two rounds of cross-sectional Integrated Behavioural and Biological Assessments (IBBAs) conducted in 2006 (Round 1- R1) and 2009 (Round 2 – R2) and quality assessments of program clinics were used. Bi-variate and multivariate analysis were conducted using the complex samples module in SPSS 15® (IBM, Somers NY).</p> <p>Results</p> <p>The Avahan program achieved coverage of over 66% of FSWs within four years of implementation. The IBBA data showed increased contact by peers in R2 compared to R1 (AOR:2.34; p=0.001). Reported condom use with clients increased in R2 and number of FSWs reporting zero unprotected sex acts increased from 76.2% (R1) to 94.6% (R2) [AOR: 5.1, p=0.001].</p> <p>Significant declines were observed in prevalence of syphilis (RPR) (15.8% to 10.8%; AOR:0.54; p=0.001), chlamydia (8% to 6.2%; AOR:.0.65; p=0.010) and gonorrohoea (7.4% to 3.9; AOR:.0.60; p=0.026) between R1 and R2. HIV prevalence increased (25.8% to 27.5%; AOR:1.29; p=0.04). District-wise analysis showed decline in three districts and increase in Mumbai and Thane districts.</p> <p>FSWs exposed to Avahan had higher consistent condom use with occasional (94.3% vs. 90.6%; AOR: 1.55; p=0.04) and regular clients (92.5% vs. 86.0%; AOR: 1.95, p=0.001) compared to FSWs unexposed to Avahan. Decline in high titre syphilis was associated with Avahan exposure.</p> <p>Conclusion</p> <p>The Avahan program was scaled up and achieved high coverage of FSWs in Maharashtra amidst multiple intervention players. Avahan coverage of FSWs was associated with improved safe sexual practices and declines in STIs. Prevalence of HIV increased requiring more detailed understanding of the data and, if confirmed, new approaches for HIV control.</p

PDBe: towards reusable data delivery infrastructure at protein data bank in Europe

© 2017 The Authors. Published by OUP. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1093/nar/gkx1070The Protein Data Bank in Europe (PDBe, pdbe.org) is actively engaged in the deposition, annotation, remediation, enrichment and dissemination of macromolecular structure data. This paper describes new developments and improvements at PDBe addressing three challenging areas: data enrichment, data dissemination and functional reusability. New features of the PDBe Web site are discussed, including a context dependent menu providing links to raw experimental data and improved presentation of structures solved by hybrid methods. The paper also summarizes the features of the LiteMol suite, which is a set of services enabling fast and interactive 3D visualization of structures, with associated experimental maps, annotations and quality assessment information. We introduce a library of Web components which can be easily reused to port data and functionality available at PDBe to other services. We also introduce updates to the SIFTS resource which maps PDB data to other bioinformatics resources, and the PDBe REST API.Wellcome Trust [104948]; UK Biotechnology and Biological Sciences Research Council [BB/M011674/1, BB/N019172/1, BB/M020347/1]; European Union [284209]; European Molecular Biology Laboratory (EMBL). Funding for open access charge: EMBL.Published versio

PDBe: improved accessibility of macromolecular structure data from PDB and EMDB

© 2015 The Authors. Published by OUP. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1093/nar/gkv1047The Protein Data Bank in Europe (http://pdbe.org) accepts and annotates depositions of macromolecular structure data in the PDB and EMDB archives and enriches, integrates and disseminates structural information in a variety of ways. The PDBe website has been redesigned based on an analysis of user requirements, and now offers intuitive access to improved and value-added macromolecular structure information. Unique value-added information includes lists of reviews and research articles that cite or mention PDB entries as well as access to figures and legends from full-text open-access publications that describe PDB entries. A powerful new query system not only shows all the PDB entries that match a given query, but also shows the 'best structures' for a given macromolecule, ligand complex or sequence family using data-quality information from the wwPDB validation reports. A PDBe RESTful API has been developed to provide unified access to macromolecular structure data available in the PDB and EMDB archives as well as value-added annotations, e.g. regarding structure quality and up-to-date cross-reference information from the SIFTS resource. Taken together, these new developments facilitate unified access to macromolecular structure data in an intuitive way for non-expert users and support expert users in analysing macromolecular structure data.The Wellcome Trust [88944, 104948]; UK Biotechnology and Biological Sciences Research Council [BB/J007471/1, BB/K016970/1, BB/M013146/1, BB/M011674/1]; National Institutes of Health [GM079429]; UK Medical Research Council [MR/L007835/1]; European Union [284209]; CCP4; European Molecular Biology Laboratory (EMBL). Funding for open access charge: The Wellcome Trust.Published versio

PDBe-KB: a community-driven resource for structural and functional annotations.

The Protein Data Bank in Europe-Knowledge Base (PDBe-KB, https://pdbe-kb.org) is a community-driven, collaborative resource for literature-derived, manually curated and computationally predicted structural and functional annotations of macromolecular structure data, contained in the Protein Data Bank (PDB). The goal of PDBe-KB is two-fold: (i) to increase the visibility and reduce the fragmentation of annotations contributed by specialist data resources, and to make these data more findable, accessible, interoperable and reusable (FAIR) and (ii) to place macromolecular structure data in their biological context, thus facilitating their use by the broader scientific community in fundamental and applied research. Here, we describe the guidelines of this collaborative effort, the current status of contributed data, and the PDBe-KB infrastructure, which includes the data exchange format, the deposition system for added value annotations, the distributable database containing the assembled data, and programmatic access endpoints. We also describe a series of novel web-pages-the PDBe-KB aggregated views of structure data-which combine information on macromolecular structures from many PDB entries. We have recently released the first set of pages in this series, which provide an overview of available structural and functional information for a protein of interest, referenced by a UniProtKB accession

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial

Background. Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. Methods. TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). Results. Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01). Conclusions. In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial. Clinical Trials Registration. NCT02958709

Mitochondrial DNA (mtDNA) damage in diabetic heart: 4-hydroxy-2-nonenal (4HNE) inhibits mtDNA repair enzyme, 8-oxoguanine glycosylase 1

Background: Diabetes mellitus (DM) affects a variety of organs including myocardium. 8-oxoguanine glycosylase 1 (OGG-1) repairs mitochondrial DNA (mtDNA) by base excision repair process. We hypothesize that DM mediated 4-hydroxy-2-nonenal (4HNE) contributes to mtDNA damage by forming adducts with mtOGG-1 and thus inhibiting its activity and thereby contributing to cardiac dysfunction in the diabetic heart. Methods and results: First of all, we treated 4HNE (1, 10 and 100 μM) directly to recombinant OGG-1, analyzed the 4HNE adduction on specific amino acids in OGG-1 and measured its activity, in vitro. 4HNE dose-dependently inhibited the activity of OGG-1 by forming adducts. We identified that several amino acids on OGG-1 such as Cys241, His237, Lys238, Cys163, His282, and Lys249 were 4HNE adducted. A type-2 diabetic model, db/db mice were sacrificed at six months when they exhibit cardiac dysfunction. We found a decrease in myocardial OGG-1 activity in db/db mouse hearts compared to db/dm hearts. We observed an increase in 4HNE adducts on OGG-1 in db/db mouse hearts. We also found increased mtDNA damage. The activity of aldehyde dehydrogenase (ALDH) 2 which detoxifies 4HNE was decreased in db/db mouse hearts which may have led to increases in the 4HNE levels. Before the 4HNE challenge, pre-incubation with recombinant ALDH2 decreased the 4HNE-mediated reduction in OGG-1 activity, in vitro. Therefore, we treated db/db mice with Alda-1, an ALDH2 activator and found a decrease in 4HNE adducts and thus decreased mtDNA damage along with improved cardiac function. Conclusion: Increased 4HNE formed adducts with OGG-1 and inhibited its activity and thus led to mtDNA damage in a type-2 diabetic heart. ALDH2 decreased the 4HNE adduction on OGG-1 and thereby improved mtDNA repair and cardiac function

Decreased aldehyde dehydrogenase (aldh)2 activity contributes to coronary endothelial dysfunction in diabetic cardiomyopathy

Background: Around 8% of Americans acquire diabetes mellitus (DM). Diabetics cause micro and macrovascular complications to develop, that lead to end-organ damage. However, microvascular damage is understudied in diabetic cardiomyopathy (DCM), despite needing extensive coronary perfusion. Hyperglycemia-mediated reactive aldehydes, like 4-hydroxy-2-nonenal (4HNE) are associated with cardiac damage. Aldehyde dehydrogenase (ALDH) 2, a mitochondrial enzyme which detoxifies 4HNE, is implicated in endothelial cell function in vasculature

Precision medicine approach: Empagliflozin for diabetic cardiomyopathy in mice with aldehyde dehydrogenase (ALDH) 2 * 2 mutation, a specific genetic mutation in millions of East Asians

A vast majority of type-2 diabetic patients (~65%) die of cardiovascular complications including heart failure (HF). In diabetic hearts, levels of 4-hydroxy-2-nonenal (4HNE), a reactive aldehyde that is produced upon lipid peroxidation, were increased. We also demonstrated that in diabetic hearts, there is a decrease in the activity of aldehyde dehydrogenase (ALDH) 2, a primary detoxifying enzyme present in cardiac mitochondria. A single point mutation at E487K of ALDH2 in East Asians known as ALDH2 * 2 intrinsically lowers ALDH2 activity. We hypothesize that Empagliflozin (EMP), a sodium-glucose cotransporter (SGLT) 2 inhibitor, can ameliorate diabetic cardiomyopathy by decreasing hyperglycemia-mediated 4HNE protein adducts in ALDH2 * 2 mutant mice which serve as a precision medicine tool as they mimic ALDH2 * 2 carriers. We induced type-2 diabetes in 11-14 month-old male and female ALDH2 * 2 mice through a high-fat diet. Chow-fed ALDH2 * 2 mice served as controls. At the end of 4 months, we treated the diabetic ALDH2 * 2 mice with EMP (3 mg/kg/d) or its vehicle (Veh). After 2 months of EMP treatment, cardiac function was assessed by conscious echocardiography after treadmill exercise stress. EMP improved the cardiac function and running distance and duration significantly compared to Veh-treated ALDH2 * 2 diabetic mice. These beneficial effects can be attributed to the EMP-mediated decrease in cardiac mitochondrial 4HNE adducts and increase in the levels of phospho AKT, AKT, phospho Akt substrate of 160 kDa (pAS160), AS160 and GLUT-4 in the skeletal muscle tissue of the ALDH2*2 mutant diabetic mice, respectively. Finally, our data implicate EMP can ameliorate diabetic cardiomyopathy in diabetic ALDH2 * 2 mutant patients

ALDH2 Inhibition Potentiates High Glucose Stress-Induced Injury in Cultured Cardiomyocytes

Aldehyde dehydrogenase (ALDH) gene superfamily consists of 19 isozymes. They are present in various organs and involved in metabolizing aldehydes that are biologically generated. For instance, ALDH2, a cardiac mitochondrial ALDH isozyme, is known to detoxify 4-hydroxy-2-nonenal, a reactive aldehyde produced upon lipid peroxidation in diabetic conditions. We hypothesized that inhibition of ALDH leads to the accumulation of unmetabolized 4HNE and consequently exacerbates injury in cells subjected to high glucose stress. H9C2 cardiomyocyte cell lines were pretreated with 1