Evidence for glutamate-mediated excitotoxic mechanisms during photoreceptor degeneration in the rd1 mouse retina

PURPOSE: Kinetic studies of photoreceptor cell death in the retinal degeneration (rd1) mouse model suggest that photoreceptor degeneration could result from cumulative damage. Since alterations in glutamate metabolism have been described in different models of retinitis pigmentosa, we investigated in the present work whether changes in glutamate turnover occur in the degenerating rd1 retina and whether glutamate-mediated excitotoxic mechanisms may contribute to rod photoreceptor death in this model. METHODS: Free amino acid levels were quantified in rd1 and wild-type retinas using an amino acid analyzer selecting times corresponding to early, intermediate, and terminal phases of rod photoreceptor degeneration. Reverse transcription-polymerase chain reaction (RT-PCR) was used to compare the mRNA expression levels of the glial L-glutamate/L-aspartate transporter GLAST, glutamine synthetase (GS), and vimentin, a marker for retinal glia, between rd1 and wild-type mouse retinas. 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of both AMPA and kainate subtypes of ionotropic glutamate receptors, was then daily administered from postnatal day 3 (PN3) to PN21 to rd1 mice while control rd1 mice received only physiological saline solution (7 per treatment). At PN22, the respective numbers of surviving rods i

Listening to limericks: a pupillometry investigation of perceivers’ expectancy

What features of a poem make it captivating, and which cognitive mechanisms are sensitive to these features? We addressed these questions experimentally by measuring pupillary responses of 40 participants who listened to a series of Limericks. The Limericks ended with either a semantic, syntactic, rhyme or metric violation. Compared to a control condition without violations, only the rhyme violation condition induced a reliable pupillary response. An anomaly-rating study on the same stimuli showed that all violations were reliably detectable relative to the control condition, but the anomaly induced by rhyme violations was perceived as most severe. Together, our data suggest that rhyme violations in Limericks may induce an emotional response beyond mere anomaly detection

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Invasion is a community affair: clandestine followers in the bacterial community associated to green algae, Caulerpa racemosa, track the invasion source

Biological invasions rank amongst the most deleterious components of global change inducing alterations from genes to ecosystems. The genetic characteristics of introduced pools of individuals greatly influence the capacity of introduced species to establish and expand. The recently demonstrated heritability of microbial communities associated to individual genotypes of primary producers makes them a potentially essential element of the evolution and adaptability of their hosts. Here, we characterized the bacterial communities associated to native and non-native populations of the marine green macroalga Caulerpa racemosa through pyrosequencing, and explored their potential role on the strikingly invasive trajectory of their host in the Mediterranean. The similarity of endophytic bacterial communities from the native Australian range and several Mediterranean locations confirmed the origin of invasion and revealed distinct communities associated to a second Mediterranean variety of C. racemosa long reported in the Mediterranean. Comparative analysis of these two groups demonstrated the stability of the composition of bacterial communities through the successive steps of introduction and invasion and suggested the vertical transmission of some major bacterial OTUs. Indirect inferences on the taxonomic identity and associated metabolism of bacterial lineages showed a striking consistency with sediment upheaval conditions associated to the expansion of their invasive host and to the decline of native species. These results demonstrate that bacterial communities can be an effective tracer of the origin of invasion and support their potential role in their eukaryotic host’s adaptation to new environments. They put forward the critical need to consider the 'meta-organism' encompassing both the host and associated micro-organisms, to unravel the origins, causes and mechanisms underlying biological invasions

Recruiting to a large-scale physical activity randomised controlled trial – experiences with the gift of hindsight

Background: Recruitment issues continue to impact a large number of trials. Sharing recruitment information is vital to support researchers to accurately predict recruitment and to manage the risk of poor recruitment during study design and implementation. The purpose of this paper is to build on the knowledge available to researchers on recruiting to community based trials. Methods: A critical commentary of the recruitment challenges encountered during the ‘Booster’ Study, a randomised controlled trial which investigated the effectiveness of a Motivational Interviewing style intervention on the maintenance of physical activity. An overview of recruitment is provided, as well as strategies employed to recruit prospective participants and possible barriers to recruitment. Results: Two hundred and eighty two people, 47% of the original target, were recruited through mail-outs with secondary recruitment pathways yielding no additional participants. The research team encountered problems re-contacting interested participants and providing study materials in non-English languages. A lower response rate to the mail-out and a greater number of non-contactable participants in the full study compared to the pilot study resulted in a smaller pool of eligible participants from the brief intervention eligible for recruitment into the RCT. Conclusion: Despite utilising widely accepted recruitment strategies and incorporating new recruitment tactics in response to challenges, the ‘Booster’ study failed to randomise a sufficient number of participants. Recruitment to community based, behavioural interventions may face different challenges than trials based in clinical or primary care pathways. Specific challenges posed by the complexity of the study design and problems with staffing and resources were exacerbated by the need to revise upwards the number of mailed invitations as a result of the pilot study. Researchers should ensure study design is facilitative to recruitment and consider the implications of changing recruitment on the operational aspects of the trial. Where possible the impact of new strategies should be measured, and recruitment successes and challenges shared with those planning similar studies. The study was a registered controlled trial (ISRCTN56495859 12 Feb 2009; NCT00836459 03 Feb 2009) KEYWORDS: Recruitment, Physical Activity, mail-outs, BOOSTER, behaviour maintenance

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Population‐based cohort study of outcomes following cholecystectomy for benign gallbladder diseases

Background The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all‐cause 30‐day readmissions and complications in a prospective population‐based cohort. Methods Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing all‐cause 30‐day readmissions and complications were analysed by means of multilevel, multivariable logistic regression modelling using a two‐level hierarchical structure with patients (level 1) nested within hospitals (level 2). Results Data were collected on 8909 patients undergoing cholecystectomy from 167 hospitals. Some 1451 cholecystectomies (16·3 per cent) were performed as an emergency, 4165 (46·8 per cent) as elective operations, and 3293 patients (37·0 per cent) had had at least one previous emergency admission, but had surgery on a delayed basis. The readmission and complication rates at 30 days were 7·1 per cent (633 of 8909) and 10·8 per cent (962 of 8909) respectively. Both readmissions and complications were independently associated with increasing ASA fitness grade, duration of surgery, and increasing numbers of emergency admissions with gallbladder disease before cholecystectomy. No identifiable hospital characteristics were linked to readmissions and complications. Conclusion Readmissions and complications following cholecystectomy are common and associated with patient and disease characteristics

White paper: Understanding, informing and defining the regulatory science of microneedle-based dosage forms that are applied to the skin

The COVID-19 pandemic has accelerated pre-clinical and clinical development of microneedle-based drug delivery technology. However the regulatory science of this emerging dosage form is immature and explicit regulatory guidance is limited. A group of international stakeholders has formed to identify and address key issues for the regulatory science of future products that combine a microneedle device and active pharmaceutical ingredient (in solid or semi-solid state) in a single entity that is designed for application to the skin. Guided by the principles of Quality by Design (QbD) and informed by consultation with wider stakeholders, this ‘White Paper’ describes fundamental elements of the work in an effort to harmonise understanding, stimulate discussion and guide innovation. The paper discusses classification of the dosage form (combination/medicinal product), the regulatory nomenclature that is likely to be adopted and the technical vocabulary that best describes its form and function. More than twenty potential critical quality attributes (CQAs) are identified for the dosage form, and a prioritisation exercise identifies those CQAs that are most pertinent to the dosage form and that will likely require bespoke test methods (delivered dose, puncture performance) or major adaptions to established compendial test methods (dissolution). Hopefully the work will provide a platform for the development of dosage form specific guidance (from regulatory authorities and/or international pharmacopoeias), that expedites clinical translation of safe and effective microneedle-based products

Perturbing Dynamin Reveals Potent Effects on the Drosophila Circadian Clock

BACKGROUND: Transcriptional feedback loops are central to circadian clock function. However, the role of neural activity and membrane events in molecular rhythms in the fruit fly Drosophila is unclear. To address this question, we expressed a temperature-sensitive, dominant negative allele of the fly homolog of dynamin called shibire(ts1) (shi(ts1)), an active component in membrane vesicle scission. PRINCIPAL FINDINGS: Broad expression in clock cells resulted in unexpectedly long, robust periods (>28 hours) comparable to perturbation of core clock components, suggesting an unappreciated role of membrane dynamics in setting period. Expression in the pacemaker lateral ventral neurons (LNv) was necessary and sufficient for this effect. Manipulation of other endocytic components exacerbated shi(ts1)'s behavioral effects, suggesting its mechanism is specific to endocytic regulation. PKA overexpression rescued period effects suggesting shi(ts1) may downregulate PKA pathways. Levels of the clock component PERIOD were reduced in the shi(ts1)-expressing pacemaker small LNv of flies held at a fully restrictive temperature (29 degrees C). Less restrictive conditions (25 degrees C) delayed cycling proportional to observed behavioral changes. Levels of the neuropeptide PIGMENT-DISPERSING FACTOR (PDF), the only known LNv neurotransmitter, were also reduced, but PERIOD cycling was still delayed in flies lacking PDF, implicating a PDF-independent process. Further, shi(ts1) expression in the eye also results in reduced PER protein and per and vri transcript levels, suggesting that shibire-dependent signaling extends to peripheral clocks. The level of nuclear CLK, transcriptional activator of many core clock genes, is also reduced in shi(ts1) flies, and Clk overexpression suppresses the period-altering effects of shi(ts1). CONCLUSIONS: We propose that membrane protein turnover through endocytic regulation of PKA pathways modulates the core clock by altering CLK levels and/or activity. These results suggest an important role for membrane scission in setting circadian period