Search for new physics with same-sign isolated dilepton events with jets and missing transverse energy

A search for new physics is performed in events with two same-sign isolated leptons, hadronic jets, and missing transverse energy in the final state. The analysis is based on a data sample corresponding to an integrated luminosity of 4.98 inverse femtobarns produced in pp collisions at a center-of-mass energy of 7 TeV collected by the CMS experiment at the LHC. This constitutes a factor of 140 increase in integrated luminosity over previously published results. The observed yields agree with the standard model predictions and thus no evidence for new physics is found. The observations are used to set upper limits on possible new physics contributions and to constrain supersymmetric models. To facilitate the interpretation of the data in a broader range of new physics scenarios, information on the event selection, detector response, and efficiencies is provided.Comment: Published in Physical Review Letter

Reduced cAMP, Akt Activation and p65-c-Rel Dimerization: Mechanisms Involved in the Protective Effects of mGluR3 Agonists in Cultured Astrocytes

In recent decades, astrocytes have emerged as key pieces in the maintenance of normal functioning of the central nervous system. Any impairment in astroglial function can ultimately lead to generalized disturbance in the brain, thus pharmacological targets associated with prevention of astrocyte death are actually promising. Subtype 3 of metabotropic glutamate receptors (mGluR3) is present in astrocytes, its activation exerting neuroprotective roles. In fact, we have previously demonstrated that mGluR3 selective agonists prevent nitric oxide (NO)-induced astrocyte death. However, mechanisms responsible for that cytoprotective property are still subject to study. Although inhibition of adenylyl cyclase by mGluR3 activation was extensively reported, the involvement of reduced cAMP levels in the effects of mGluR3 agonists and the association between cAMP decrease and the downstream pathways activated by mGluR3 remain neglected. Thus, we studied intracellular signaling mediating anti-apoptotic actions of mGluR3 in cultured rat astrocytes exposed to NO. In the present work, we showed that the cytoprotective effect of mGluR3 agonists (LY379268 and LY404039) requires both the reduction of intracellular cAMP levels and activation of Akt, as assessed by MTT and TUNEL techniques. Moreover, dibutyryl-cAMP impairs Akt phosphorylation induced by LY404039, indicating a relationship between mGluR3-reduced cAMP levels and PI3K/Akt pathway activation. We also demonstrated, by co-immunoprecipitation followed by western-blot, that the mGluR3 agonists not only induce per se survival-linked interaction between members of the NF-κB family p65 and c-Rel, but also impede reduction of levels of p65-c-Rel dimers caused by NO, suggesting a possible anti-apoptotic role for p65-c-Rel. All together, these data suggest that mGluR3 agonists may regulate cAMP/Akt/p65-c-Rel pathway, which would contribute to the protective effect of mGluR3 against NO challenge in astrocytes. Our results widen the knowledge about mechanisms of action of mGluR3, potential targets for the treatment of neurodegenerative disorders where a pathophysiological role for NO has been established

Involvement of yeast HSP90 isoforms in response to stress and cell death induced by acetic acid

Acetic acid-induced apoptosis in yeast is accompanied by an impairment of the general protein synthesis machinery, yet paradoxically also by the up-regulation of the two isoforms of the heat shock protein 90 (HSP90) chaperone family, Hsc82p and Hsp82p. Herein, we show that impairment of cap-dependent translation initiation induced by acetic acid is caused by the phosphorylation and inactivation of eIF2 alpha by Gcn2p kinase. A microarray analysis of polysome-associated mRNAs engaged in translation in acetic acid challenged cells further revealed that HSP90 mRNAs are over-represented in this polysome fraction suggesting preferential translation of HSP90 upon acetic acid treatment. The relevance of HSP90 isoform translation during programmed cell death (PCD) was unveiled using genetic and pharmacological abrogation of HSP90, which suggests opposing roles for HSP90 isoforms in cell survival and death. Hsc82p appears to promote survival and its deletion leads to necrotic cell death, while Hsp82p is a pro-death molecule involved in acetic acid-induced apoptosis. Therefore, HSP90 isoforms have distinct roles in the control of cell fate during PCD and their selective translation regulates cellular response to acetic acid stress.This work was supported by Fundacao para a Ciencia e Tecnologia and COMPETE/QREN/EU (PTDC/BIA-MIC/114116/2009), and by the Canadian Institute for Health Research (MOP 89737 to MH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Identifying and Seeing beyond Multiple Sequence Alignment Errors Using Intra-Molecular Protein Covariation

BACKGROUND: There is currently no way to verify the quality of a multiple sequence alignment that is independent of the assumptions used to build it. Sequence alignments are typically evaluated by a number of established criteria: sequence conservation, the number of aligned residues, the frequency of gaps, and the probable correct gap placement. Covariation analysis is used to find putatively important residue pairs in a sequence alignment. Different alignments of the same protein family give different results demonstrating that covariation depends on the quality of the sequence alignment. We thus hypothesized that current criteria are insufficient to build alignments for use with covariation analyses. METHODOLOGY/PRINCIPAL FINDINGS: We show that current criteria are insufficient to build alignments for use with covariation analyses as systematic sequence alignment errors are present even in hand-curated structure-based alignment datasets like those from the Conserved Domain Database. We show that current non-parametric covariation statistics are sensitive to sequence misalignments and that this sensitivity can be used to identify systematic alignment errors. We demonstrate that removing alignment errors due to 1) improper structure alignment, 2) the presence of paralogous sequences, and 3) partial or otherwise erroneous sequences, improves contact prediction by covariation analysis. Finally we describe two non-parametric covariation statistics that are less sensitive to sequence alignment errors than those described previously in the literature. CONCLUSIONS/SIGNIFICANCE: Protein alignments with errors lead to false positive and false negative conclusions (incorrect assignment of covariation and conservation, respectively). Covariation analysis can provide a verification step, independent of traditional criteria, to identify systematic misalignments in protein alignments. Two non-parametric statistics are shown to be somewhat insensitive to misalignment errors, providing increased confidence in contact prediction when analyzing alignments with erroneous regions because of an emphasis on they emphasize pairwise covariation over group covariation

TRPA1 is essential for the vascular response to environmental cold exposure

This work was supported by the British Heart Foundation and a Capacity Building Award in Integrative Mammalian Biology. It was also supported by Arthritis Research UK and XK is supported by a British Pharmacological Society AJ Clark studentship

Validated spectrophotometric methods for determination of Alendronate sodium in tablets through nucleophilic aromatic substitution reactions

<p>Abstract</p> <p>Background</p> <p>Alendronate (ALD) is a member of the bisphosphonate family which is used for the treatment of osteoporosis, bone metastasis, Paget's disease, hypocalcaemia associated with malignancy and other conditions that feature bone fragility. ALD is a non-chromophoric compound so its determination by conventional spectrophotometric methods is not possible. So two derivatization reactions were proposed for determination of ALD through the reaction with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) and 2,4-dinitrofluorobenzene (DNFB) as chromogenic derivatizing reagents.</p> <p>Results</p> <p>Three simple and sensitive spectrophotometric methods are described for the determination of ALD. Method I is based on the reaction of ALD with NBD-Cl. Method II involved heat-catalyzed derivatization of ALD with DNFB, while, Method III is based on micellar-catalyzed reaction of the studied drug with DNFB at room temperature. The reactions products were measured at 472, 378 and 374 nm, for methods I, II and III, respectively. Beer's law was obeyed over the concentration ranges of 1.0-20.0, 4.0-40.0 and 1.5-30.0 μg/mL with lower limits of detection of 0.09, 1.06 and 0.06 μg/mL for Methods I, II and III, respectively. The proposed methods were applied for quantitation of the studied drug in its pure form with mean percentage recoveries of 100.47 ± 1.12, 100.17 ± 1.21 and 99.23 ± 1.26 for Methods I, II and III, respectively. Moreover the proposed methods were successfully applied for determination of ALD in different tablets. Proposals of the reactions pathways have been postulated.</p> <p>Conclusion</p> <p>The proposed spectrophotometric methods provided sensitive, specific and inexpensive analytical procedures for determination of the non-chromophoric drug alendronate either per se or in its tablet dosage forms without interference from common excipients.</p> <p>Graphical abstract</p> <p><display-formula><graphic file="1752-153X-6-25-i3.gif"/></display-formula></p

Genome-Wide Analysis Reveals a Major Role in Cell Fate Maintenance and an Unexpected Role in Endoreduplication for the Drosophila FoxA Gene Fork Head

Transcription factors drive organogenesis, from the initiation of cell fate decisions to the maintenance and implementation of these decisions. The Drosophila embryonic salivary gland provides an excellent platform for unraveling the underlying transcriptional networks of organ development because Drosophila is relatively unencumbered by significant genetic redundancy. The highly conserved FoxA family transcription factors are essential for various aspects of organogenesis in all animals that have been studied. Here, we explore the role of the single Drosophila FoxA protein Fork head (Fkh) in salivary gland organogenesis using two genome-wide strategies. A large-scale in situ hybridization analysis reveals a major role for Fkh in maintaining the salivary gland fate decision and controlling salivary gland physiological activity, in addition to its previously known roles in morphogenesis and survival. The majority of salivary gland genes (59%) are affected by fkh loss, mainly at later stages of salivary gland development. We show that global expression of Fkh cannot drive ectopic salivary gland formation. Thus, unlike the worm FoxA protein PHA-4, Fkh does not function to specify cell fate. In addition, Fkh only indirectly regulates many salivary gland genes, which is also distinct from the role of PHA-4 in organogenesis. Our microarray analyses reveal unexpected roles for Fkh in blocking terminal differentiation and in endoreduplication in the salivary gland and in other Fkh-expressing embryonic tissues. Overall, this study demonstrates an important role for Fkh in determining how an organ preserves its identity throughout development and provides an alternative paradigm for how FoxA proteins function in organogenesis

Change in physical activity level and clinical outcomes in older adults with knee pain: a secondary analysis from a randomised controlled trial

BACKGROUND: Exercise interventions improve clinical outcomes of pain and function in adults with knee pain due to osteoarthritis and higher levels of physical activity are associated with lower severity of pain and higher levels of physical functioning in older adults with knee osteoarthritis in cross-sectional studies. However, to date no studies have investigated if change in physical activity level during exercise interventions can explain clinical outcomes of pain and function. This study aimed to investigate if change in physical activity during exercise interventions is associated with future pain and physical function in older adults with knee pain. METHODS: Secondary longitudinal data analyses of a three armed exercise intervention randomised controlled trial. Participants were adults with knee pain attributed to osteoarthritis, over the age of 45 years old (n = 514) from Primary Care Services in the Midlands and Northwest regions of England. Crude and adjusted associations between absolute change in physical activity from baseline to 3 months (measured by the self-report Physical Activity Scale for the Elderly (PASE)) and i) pain ii) physical function (Western Ontario and McMaster Universities Osteoarthritis Index) and iii) treatment response (OMERACT-OARSI responder criteria) at 3 and 6 months follow-up were investigated using linear and logistic regression. RESULTS: Change in physical activity level was not associated with future pain, function or treatment response outcomes in crude or adjusted models at 3 or 6 months (P > 0.05). A 10 point increase in PASE was not associated with pain β = - 0.01 (- 0.05, 0.02), physical function β = - 0.09 (- 0.19, 0.02) or likelihood (odds ratio) of treatment response 1.02 (0.99, 1.04) at 3 months adjusting for sociodemographics, clinical covariates and the trial intervention arm. Findings were similar for 6 month outcome models. CONCLUSIONS: Change in physical activity did not explain future clinical outcomes of pain and function in this study. Other factors may be responsible for clinical improvements following exercise interventions. However, the PASE may not be sufficiently responsive to measure change in physical activity level. We also recommend further investigation into the responsiveness of commonly used physical activity measures. TRIAL REGISTRATION: ( ISRCTN93634563 ). Registered 29th September 2011

The influence of non-steroidal anti-inflammatory drugs and paracetamol used for pain control of orthodontic tooth movement: a systematic review

ABSTRACT The present study aimed to perform a systematic literature review to determine if there is a non-steroidal anti-inflammatory drug (NSAID) that interferes less within tooth movement. This research was performed according to the PRISMA statement. Articles were searched in eight electronic databases (PubMed, Scopus, Embase, Web of Science, LILACS, SciELO, Google Scholar, and Open Grey). Only experimental studies on male Wistar rats were selected, which included experiments related to the influence of NSAIDs on orthodontic movement. Studies in animals with pathological conditions, literature review articles, letters to the editor and/or editorials, case reports, abstracts, books, and book chapters were excluded. Each of the steps of this systematic literature review was performed by two examiners independently. Results: the total sample consisted of 505 articles, from which 6 studies were eligible after a qualitative analysis. From the drugs assessed, paracetamol was unanimous for not interfering within orthodontic movement when compared to the control group. However, drugs such as aspirin, ibuprofen, sodium diclofenac, and selective cyclooxygenase-2 inhibitors caused a reduction in tooth movement when compared to the control group. Conclusion: paracetamol could be considered the drug of choice for pain relief because it interferes less within tooth movement