A computational investigation of kinetoplastid trans-splicing

Trans-splicing is an unusual process in which two separate RNA strands are spliced together to yield a mature mRNA. We present a novel computational approach which has an overall accuracy of 82% and can predict 92% of known trans-splicing sites. We have applied our method to chromosomes 1 and 3 of Leishmania major, with high-confidence predictions for 85% and 88% of annotated genes respectively. We suggest some extensions of our method to other systems

Influence of long-range dipolar interactions on the phase stability and hysteresis shapes of ferroelectric and antiferroelectric multilayers

Phase transition and field driven hysteresis evolution of a two-dimensional Ising grid consisting of ferroelectric-antiferroelectric multilayers that take into account the long range dipolar interactions were simulated by a Monte-Carlo method. Simulations were carried out for a 1+1 bilayer and a 5+5 superlattice. Phase stabilities of components comprising the structures with an electrostatic-like coupling term were also studied. An electrostatic-like coupling, in the absence of an applied field, can drive the ferroelectric layers towards 180º domains with very flat domain interfaces mainly due to the competition between this term and the dipole-dipole interaction. The antiferroelectric layers do not undergo an antiferroelectric-to-ferroelectric transition under the influence of an electrostatic-like coupling between layers as the ferroelectric layer splits into periodic domains at the expense of the domain wall energy. The long-range interactions become significant near the interfaces. For high periodicity structures with several interfaces, the interlayer long-range interactions substantially impact the configuration of the ferroelectric layers while the antiferroelectric layers remain quite stable unless these layers are near the Neel temperature. In systems investigated with several interfaces, the hysteresis loops do not exhibit a clear presence of antiferroelectricity that could be expected in the presence of anti-parallel dipoles, i. e., the switching takes place abruptly. Some recent experimental observations in ferroelectric-antiferroelectric multilayers are discussed where we conclude that the different electrical properties of bilayers and superlattices are not only due to strain effects alone but also long-range interactions. The latter manifests itself particularly in superlattices where layers are periodically exposed to each other at the interfaces

Observation of discrete time-crystalline order in a disordered dipolar many-body system

Understanding quantum dynamics away from equilibrium is an outstanding challenge in the modern physical sciences. It is well known that out-of-equilibrium systems can display a rich array of phenomena, ranging from self-organized synchronization to dynamical phase transitions. More recently, advances in the controlled manipulation of isolated many-body systems have enabled detailed studies of non-equilibrium phases in strongly interacting quantum matter. As a particularly striking example, the interplay of periodic driving, disorder, and strong interactions has recently been predicted to result in exotic "time-crystalline" phases, which spontaneously break the discrete time-translation symmetry of the underlying drive. Here, we report the experimental observation of such discrete time-crystalline order in a driven, disordered ensemble of $\sim 10^6$ dipolar spin impurities in diamond at room-temperature. We observe long-lived temporal correlations at integer multiples of the fundamental driving period, experimentally identify the phase boundary and find that the temporal order is protected by strong interactions; this order is remarkably stable against perturbations, even in the presence of slow thermalization. Our work opens the door to exploring dynamical phases of matter and controlling interacting, disordered many-body systems.Comment: 6 + 3 pages, 4 figure

BRain health and healthy AgeINg in retired rugby union players, the BRAIN Study: study protocol for an observational study in the UK.

INTRODUCTION: Relatively little is known about the long-term health of former elite rugby players, or former sportspeople more generally. As well as the potential benefits of being former elite sportspersons, there may be potential health risks from exposures occurring during an individual's playing career, as well as following retirement. Each contact sport has vastly different playing dynamics, therefore exposing its players to different types of potential traumas. Current evidence suggests that these are not necessarily comparable in terms of pathophysiology, and their potential long-term adverse effects might also differ. There is currently limited but increasing evidence that poorer age-related and neurological health exists among former professional sportsmen exposed to repetitive concussions; however the evidence is limited on rugby union players, specifically. METHODS AND ANALYSIS: We present the protocol for a cross-sectional study to assess the association between self-reported history of concussion during a playing career, and subsequent measures of healthy ageing and neurological and cognitive impairment. We are recruiting a sample of approximately 200 retired rugby players (former Oxford and Cambridge University rugby players and members of the England Rugby International Club) aged 50 years or more, and collecting a number of general and neurological health-related outcome measures though validated assessments. Biomarkers of neurodegeneration (neurofilaments and tau) will be also be measured. Although the study is focusing on rugby union players specifically, the general study design and the methods for assessing neurological health are likely to be relevant to other studies of former elite sportspersons. ETHICS AND DISSEMINATION: The study has been approved by the Ethical Committee of London School of Hygiene and Tropical Medicine (reference: 11634-2). It is intended that results of this study will be published in peer-reviewed medical journals, communicated to participants, the general public and all relevant stakeholders

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial : study protocol for a randomized controlled trial

Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI

A pivotal role for starch in the reconfiguration of 14C-partitioning and allocation in Arabidopsis thaliana under short-term abiotic stress.

Plant carbon status is optimized for normal growth but is affected by abiotic stress. Here, we used 14C-labeling to provide the first holistic picture of carbon use changes during short-term osmotic, salinity, and cold stress in Arabidopsis thaliana. This could inform on the early mechanisms plants use to survive adverse environment, which is important for efficient agricultural production. We found that carbon allocation from source to sinks, and partitioning into major metabolite pools in the source leaf, sink leaves and roots showed both conserved and divergent responses to the stresses examined. Carbohydrates changed under all abiotic stresses applied; plants re-partitioned 14C to maintain sugar levels under stress, primarily by reducing 14C into the storage compounds in the source leaf, and decreasing 14C into the pools used for growth processes in the roots. Salinity and cold increased 14C-flux into protein, but as the stress progressed, protein degradation increased to produce amino acids, presumably for osmoprotection. Our work also emphasized that stress regulated the carbon channeled into starch, and its metabolic turnover. These stress-induced changes in starch metabolism and sugar export in the source were partly accompanied by transcriptional alteration in the T6P/SnRK1 regulatory pathway that are normally activated by carbon starvation

Variations in the detection of anorectal anomalies at birth amongst European cities

Aim: The diagnosis of anorectal malformations (ARM) is made at birth by perineal examination of the newborn, yet small series reported late diagnosis in almost 13%. No large series to date have looked into the magnitude of missed ARM cases in the neonatal period across Europe. This study aimed to define the rate of missed ARM at birth across four UK and EU centers. Methods: All ARM cases treated at two UK tertiary centers in the past 15 years were compared to two tertiary European centers. Demographic and relevant clinical data were collected. Late diagnosis was defined as any diagnosis made after discharge from the birth unit. Factors associated with late diagnosis were explored with descriptive statistics. Results: Across the four centers (117/1350, 8.7%) were sent home from the birth unit without recognizing the anorectal anomaly. Missed cases showed a slight female predominance (1.3:1), and the majority (113/117, 96.5%) were of the low anomaly with a fistula to the perineum. The rate of missed ARM cases was significantly higher in the UK centers combined (74/415, 17.8%) compared to those in the EU (43/935, 4.6%), (p<0.00001), and this was independent of individual center and year of birth. Conclusion: Significant variation exist between the UK and other European countries in the detection of ARM at birth. We recommend raising the awareness of accurate perineal examination at time of newborn physical examination. We feel this highlights an urgent need for a national initiative to assess and address the timely diagnosis of ARM in the UK

Post-polypectomy surveillance interval and advanced neoplasia detection rates: a multicenter, retrospective cohort study

Background Longer post-polypectomy surveillance intervals are associated with increased colorectal neoplasia detection at surveillance in some studies. We investigated this association to inform optimal surveillance intervals. Methods Patients who underwent colonoscopy and post-polypectomy surveillance at 17 UK hospitals were classified as low/high risk by baseline findings. We compared detection rates of advanced adenomas (≥ 10 mm, tubulovillous/villous, high grade dysplasia), high risk findings (HRFs: ≥ 2 serrated polyps/[adenomas] of which ≥ 1 is ≥ 10 mm or has [high grade] dysplasia; ≥ 5 serrated polyps/adenomas; or ≥ 1 nonpedunculated polyp ≥ 20 mm), or colorectal cancer (CRC) at surveillance colonoscopy by surveillance interval (< 18 months, 2, 3, 4, 5, 6 years). Risk ratios (RRs) were estimated using multivariable regression. Results Of 11 214 patients, 7216 (64 %) were low risk and 3998 (36 %) were high risk. Among low risk patients, advanced adenoma, HRF, and CRC detection rates at first surveillance were 7.8 %, 3.7 %, and 1.1 %, respectively. Advanced adenoma detection increased with increasing surveillance interval, reaching 9.8 % with a 6-year interval (P trend < 0.001). Among high risk patients, advanced adenoma, HRF, and CRC detection rates at first surveillance were 15.3 %, 10.0 %, and 1.5 %, respectively. Advanced adenoma and CRC detection rates (P trends < 0.001) increased with increasing surveillance interval; RRs (95 % confidence intervals) for CRC were 1.54 (0.68–3.48), 4.44 (1.95–10.08), and 5.80 (2.51–13.40) with 3-, 4-, and 5-year intervals, respectively, versus an interval of < 18 months. Conclusions Metachronous neoplasia was uncommon among low risk patients, even with long surveillance intervals, supporting recommendations for no surveillance in these patients. For high risk patients, a 3-year surveillance interval would ensure timely CRC detection