Optimization of fluorophores for chemical tagging and immunohistochemistry of Drosophila neurons.

The use of genetically encoded 'self-labeling tags' with chemical fluorophore ligands enables rapid labeling of specific cells in neural tissue. To improve the chemical tagging of neurons, we synthesized and evaluated new fluorophore ligands based on Cy, Janelia Fluor, Alexa Fluor, and ATTO dyes and tested these with recently improved Drosophila melanogaster transgenes. We found that tissue clearing and mounting in DPX substantially improves signal quality when combined with specific non-cyanine fluorophores. We compared and combined this labeling technique with standard immunohistochemistry in the Drosophila brain.This work was supported by Howard Hughes Medical Institute (https://www.hhmi.org), the Medical Research Council (https://mrc.ukri.org; MRC file reference U105188491) and a European Research Council (https://erc.europa.eu) Consolidator grant (649111) to G.S.X.E.J., and a Royal Society (https://royalsociety.org) Dorothy Hodgkin Fellowship to S.C

Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios

Purpose: Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene–disease associations. Methods: We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients. Results: We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice (P = 3.4 × 10−8). This enrichment is only partially explained by mutations found in known disease-causing genes. Conclusion: This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications

REALISTIC MODELS WITH A LIGHT U(1) GAUGE BOSON COUPLED TO BARYON NUMBER

We recently showed that a new gauge boson $\gamma_B$ coupling only to baryon number is phenomenologically allowed, even if $m_B<m_Z$ and $\alpha_B \approx 0.2$. In our previous work we assumed that kinetic mixing between the baryon number and hypercharge gauge bosons (via an $F^{\mu\nu}_B F_{\mu\nu}^Y$ term) was small enough to evade constraints from precision electroweak measurements. In this paper we propose a class of models in which this term is naturally absent above the electroweak scale. We show that the generation of a mixing term through radiative corrections in the low-energy effective theory does not lead to conflict with precision electroweak measurements and may provide a leptonic signal for models of this type at an upgraded Tevatron.Comment: 21 pages, LaTeX, 4 figures in a uuencoded compressed postscript file

Noncoding deletions reveal a gene that is critical for intestinal function.

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes

Medication errors in the Middle East countries: a systematic review of the literature

Background: Medication errors are a significant global concern and can cause serious medical consequences for patients. Little is known about medication errors in Middle Eastern countries. The objectives of this systematic review were to review studies of the incidence and types of medication errors in Middle Eastern countries and to identify the main contributory factors involved. Methods: A systematic review of the literature related to medication errors in Middle Eastern countries was conducted in October 2011 using the following databases: Embase, Medline, Pubmed, the British Nursing Index and the Cumulative Index to Nursing & Allied Health Literature. The search strategy included all ages and languages. Inclusion criteria were that the studies assessed or discussed the incidence of medication errors and contributory factors to medication errors during the medication treatment process in adults or in children. Results: Forty-five studies from 10 of the 15 Middle Eastern countries met the inclusion criteria. Nine (20%) studies focused on medication errors in paediatric patients. Twenty-one focused on prescribing errors, 11 measured administration errors, 12 were interventional studies and one assessed transcribing errors. Dispensing and documentation errors were inadequately evaluated. Error rates varied from 7.1% to 90.5% for prescribing and from 9.4% to 80% for administration. The most common types of prescribing errors reported were incorrect dose (with an incidence rate from 0.15% to 34.8% of prescriptions), wrong frequency and wrong strength. Computerised physician rder entry and clinical pharmacist input were the main interventions evaluated. Poor knowledge of medicines was identified as a contributory factor for errors by both doctors (prescribers) and nurses (when administering drugs). Most studies did not assess the clinical severity of the medication errors. Conclusion: Studies related to medication errors in the Middle Eastern countries were relatively few in number and of poor quality. Educational programmes on drug therapy for doctors and nurses are urgently needed

Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1?year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn?s disease or ulcerative colitis who have achieved clinical remission for ?6?months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1?year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-1

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV