A Statistical Analysis of RNA Folding Algorithms Through Thermodynamic Parameter Perturbation

Computational RNA secondary structure prediction is rather well established. However, such prediction algorithms always depend on a large number of experimentally measured parameters. Here, we study how sensitive structure prediction algorithms are to changes in these parameters. We find that already for changes corresponding to the actual experimental error to which these parameters have been determined 30% of the structure are falsly predicted and the ground state structure is preserved under parameter perturbation in only 5% of all cases. We establish that base pairing probabilities calculated in a thermal ensemble are a viable though not perfect measure for the reliability of the prediction of individual structure elements. A new measure of stability using parameter perturbation is proposed, and its limitations discussed.Comment: 6 pages, 3 figures, 1 table submitted to Nucleic Acids Researc

Philanthropy and the Third Sector in Mexico: The Enabling Environment and Its Limitations

Why is Mexico's third sector underdeveloped? Despite the importance of this question, there is no persuasive answer. The usual mono-causal explanations –such as historical trajectory or lack of civic culture– are inadequate. A better way to address this question is applying the concept of an enabling environment for civil society. This encompasses empowering legal and fiscal frameworks, an effective accountability system, adequate institutional capacity of organizations, and availability of resources. The article offers an assessment of where Mexico stands in relation to these five components and argues that on each count they are unfavorable and/or underdeveloped. In addition, the author argues for including a sixth element: the cultural context for philanthropy and civil society. Based on original survey results, he demonstrates that key values and habits inhibit efforts to strengthen civil society and must be taken into account in any effort to understand or change the status quo. The article concludes with a reflection on how Mexican civil society can begin to change its unfavorable context, beginning with the need for stronger mechanisms for greater accountability on the part of organizations

Safety profile of oxcarbazepine: results from a prescription-event monitoring study

Purpose: To monitor safety of oxcarbazepine, prescribed in primary care in England, using prescription-event monitoring (PEM). Methods: Postmarketing surveillance using observational cohort technique of PEM. Exposure data were obtained from dispensed British National Health Service prescriptions issued by general practitioners (GPs) March 2000–July 2003. Demographic, drug utilization, and clinical event data were collected from questionnaires posted to GPs at least 6 months after first prescription date for each patient. Incidence densities (IDs) (number of first reports per 1,000 patient-months of treatment) were calculated and differences for events reported in month 1 (ID1) and months 2–6 (ID2–6) (99% confidence intervals) were examined for changes in event rates. Follow-up and causality assessment of medically significant events were undertaken. Results: The cohort comprised 2,243 patients [mean age 40.4 years; range 2–99 years; standard deviation (SD) 18.8; 46.3% (n = 1,038) male]. Most frequently reported primary indications were epilepsy, convulsion (n = 1,111; 49.5%, n = 209; 9.3%, respectively). GPs recorded 932 reasons for stopping medication in 698 (31.1%) patients; most frequent clinical reason “drowsiness/sedation” (n = 57; 2.5% of cohort). Clinical events (excluding indication) associated with starting treatment (lower 99% CI > 0) included: “drowsiness/sedation” (ID1-ID2–6 = 14.2), “nausea/vomiting” (ID1-ID2–6 = 13.0), and dizziness (ID1-ID2–6 = 11.6). Events followed up and assessed as probably related to oxcarbazepine use included rash (7 of 11) and hyponatremia (15 of 38). Discussion:  There were no serious adverse drug reactions reported during this study. Results of the study should be taken in context with other epidemiologic studies

New concept in brazing metallic honeycomb panels

Aluminum oxide coating provides surface which will not be wetted by brazing alloy and which stops metallic diffusion welding of tooling materials to part being produced. This method eliminates loss of tooling materials and parts from braze wetting and allows fall-apart disassembly of tooling after brazing

Characterisation of the effects of salicylidene acylhydrazide compounds on type three secretion in Escherichia coli O157:H7

Recent work has highlighted a number of compounds that target bacterial virulence by affecting gene regulation. In this work, we show that small-molecule inhibitors affect the expression of the type III secretion system (T3SS) of <i>Escherichia coli</i> O157:H7 in liquid culture and when the bacteria are attached to bovine epithelial cells. The inhibition of T3SS expression resulted in a reduction in the capacity of the bacteria to form attaching and effacing lesions. Our results show a marked variation in the ability of four structurally-related compounds to inhibit the T3SS of a panel of isolates. Using transcriptomics, we provide a comprehensive analysis of the conserved- and inhibitor-specific transcriptional responses to the four compounds. These analyses of gene expression show that numerous virulence genes, located on horizontally-acquired DNA elements, are affected by the compounds but the number of genes significantly affected varied markedly between the compounds. Overall, we highlight the importance of assessing the effect of such "anti-virulence" agents on a range of isolates and discuss the possible mechanisms which may lead to the co-ordinate down-regulation of horizontally acquired virulence genes

Drugs and life-threatening ventricular arrhythmia risk: results from the DARE study cohort.

OBJECTIVES: To establish a unique sample of proarrhythmia cases, determine the characteristics of cases and estimate the contribution of individual drugs to the incidence of proarrhythmia within these cases. SETTING: Suspected proarrhythmia cases were referred by cardiologists across England between 2003 and 2011. Information on demography, symptoms, prior medical and drug histories and data from hospital notes were collected. PARTICIPANTS: Two expert cardiologists reviewed data for 293 referred cases: 130 were included. Inclusion criteria were new onset or exacerbation of pre-existing ventricular arrhythmias, QTc >500 ms, QTc >450 ms (men) or >470 ms (women) with cardiac syncope, all secondary to drug administration. Exclusion criteria were acute ischaemia and ischaemic polymorphic ventricular tachycardia at presentation, structural heart disease, consent withdrawn or deceased prior to study. Descriptive analysis of Caucasian cases (95% of included cases, n=124) and culpable drug exposures was performed. RESULTS: Of the 124 Caucasian cases, 95 (77%) were QTc interval prolongation-related; mean age was 62 years (SD 15), and 63% were female. Cardiovascular comorbidities included hypertension (53%) and patient-reported 'heart rhythm problems' (73%). Family history of sudden death (36%) and hypokalaemia at presentation (27%) were common. 165 culpable drug exposures were reported, including antiarrhythmics (42%), of which amiodarone and flecainide were the most common. Sotalol, a beta-blocking agent with antiarrhythmic activity, was also common (15%). 26% reported multiple drugs, of which 84% reported at least one cytochrome (CYP) P450 inhibitor. Potential pharmacodynamics interactions identified were mainly QT prolongation (59%). CONCLUSIONS: Antiarrhythmics, non-cardiac drugs and drug combinations were found to be culpable in a large cohort of 124 clinically validated proarrhythmia cases. Potential clinical factors that may warn the prescriber of potential proarrhythmia include older women, underlying cardiovascular comorbidity, family history of sudden death and hypokalaemia

Differential Disease Susceptibilities in Experimentally Reptarenavirus-Infected Boa Constrictors and Ball Pythons.

Inclusion body disease (IBD) is an infectious disease originally described in captive snakes. It has traditionally been diagnosed by the presence of large eosinophilic cytoplasmic inclusions and is associated with neurological, gastrointestinal, and lymphoproliferative disorders. Previously, we identified and established a culture system for a novel lineage of arenaviruses isolated from boa constrictors diagnosed with IBD. Although ample circumstantial evidence suggested that these viruses, now known as reptarenaviruses, cause IBD, there has been no formal demonstration of disease causality since their discovery. We therefore conducted a long-term challenge experiment to test the hypothesis that reptarenaviruses cause IBD. We infected boa constrictors and ball pythons by cardiac injection of purified virus. We monitored the progression of viral growth in tissues, blood, and environmental samples. Infection produced dramatically different disease outcomes in snakes of the two species. Ball pythons infected with Golden Gate virus (GoGV) and with another reptarenavirus displayed severe neurological signs within 2 months, and viral replication was detected only in central nervous system tissues. In contrast, GoGV-infected boa constrictors remained free of clinical signs for 2 years, despite high viral loads and the accumulation of large intracellular inclusions in multiple tissues, including the brain. Inflammation was associated with infection in ball pythons but not in boa constrictors. Thus, reptarenavirus infection produces inclusions and inclusion body disease, although inclusions per se are neither necessarily associated with nor required for disease. Although the natural distribution of reptarenaviruses has yet to be described, the different outcomes of infection may reflect differences in geographical origin.IMPORTANCE New DNA sequencing technologies have made it easier than ever to identify the sequences of microorganisms in diseased tissues, i.e., to identify organisms that appear to cause disease, but to be certain that a candidate pathogen actually causes disease, it is necessary to provide additional evidence of causality. We have done this to demonstrate that reptarenaviruses cause inclusion body disease (IBD), a serious transmissible disease of snakes. We infected boa constrictors and ball pythons with purified reptarenavirus. Ball pythons fell ill within 2 months of infection and displayed signs of neurological disease typical of IBD. In contrast, boa constrictors remained healthy over 2 years, despite high levels of virus throughout their bodies. This difference matches previous reports that pythons are more susceptible to IBD than boas and could reflect the possibility that boas are natural hosts of these viruses in the wild

Time evolution, cyclic solutions and geometric phases for general spin in an arbitrarily varying magnetic field

A neutral particle with general spin and magnetic moment moving in an arbitrarily varying magnetic field is studied. The time evolution operator for the Schr\"odinger equation can be obtained if one can find a unit vector that satisfies the equation obeyed by the mean of the spin operator. There exist at least $2s+1$ cyclic solutions in any time interval. Some particular time interval may exist in which all solutions are cyclic. The nonadiabatic geometric phase for cyclic solutions generally contains extra terms in addition to the familiar one that is proportional to the solid angle subtended by the closed trace of the spin vector.Comment: revtex4, 8 pages, no figur

Geometric Phases and Mielnik's Evolution Loops

The cyclic evolutions and associated geometric phases induced by time-independent Hamiltonians are studied for the case when the evolution operator becomes the identity (those processes are called {\it evolution loops}). We make a detailed treatment of systems having equally-spaced energy levels. Special emphasis is made on the potentials which have the same spectrum as the harmonic oscillator potential (the generalized oscillator potentials) and on their recently found coherent states.Comment: 11 pages, harvmac, 2 figures available upon request; CINVESTAV-FIS GFMR 11/9