Physiology and Pharmacology Feedback via Ca 2þ -Activated Ion Channels Modulates Endothelin 1 Signaling in Retinal Arteriolar Smooth Muscle

PURPOSE. To investigate the role of feedback by Ca 2þ -sensitive plasma-membrane ion channels in endothelin 1 (Et1) signaling in vitro and in vivo. METHODS. Et1 responses were imaged from Fluo-4-loaded smooth muscle in isolated segments of rat retinal arteriole using two-dimensional (2-D) confocal laser microscopy. Vasoconstrictor responses to intravitreal injections of Et1 were recorded in the absence and presence of appropriate ion channel blockers using fluorescein angiograms imaged using a confocal scanning laser ophthalmoscope. RESULTS. Et1 (10 nM) increased both basal [Ca 2þ ] i and the amplitude and frequency of Ca 2þ -waves in retinal arterioles. The Ca 2þ -activated Cl --channel blockers DIDS and 9-anthracene carboxylic acid (9AC) blocked Et1-induced increases in wave frequency, and 9AC also inhibited the increase in amplitude. Iberiotoxin, an inhibitor of large conductance (BK) Ca 2þ -activated K þ -channels, increased wave amplitude in the presence of Et1 but had no effect on frequency

Early childhood epilepsies:epidemiology, classification, aetiology, and socio-economic determinants

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials. We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review. Capture-recapture methodology was then used to improve the accuracy of incidence estimates. Socio-demographic and clinical details were obtained at presentation, and 24 months later. Children were extensively investigated for aetiology. Whole genome sequencing was offered for all patients with drug-resistant epilepsy for whom no aetiology could yet be identified. Multivariate logistic regression modelling was used to determine associations between clinical features, aetiology, and outcome. Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100 000 live births [95% confidence interval (CI) 216–263]. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100 000 live births, 95% CI 251–357) compared with the least deprived quintile (182 per 100 000 live births, 95% CI 139–233), χ2 odds ratio = 1.7 (95% CI 1.3–2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD. In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations

An Extragalactic HI Cloud with No Optical Counterpart?

We report the discovery, from the HI Parkes All-Sky Survey (HIPASS), of an isolated cloud of neutral hydrogen which we believe to be extragalactic. The HI mass of the cloud (HIPASS J1712-64) is very low, 1.7 x 10^7 Msun, using an estimated distance of ~3.2 Mpc. Most significantly, we have found no optical companion to this object to very faint limits (mu(B)~ 27 mag arcsec^-2). HIPASS J1712-64 appears to be a binary system similar to, but much less massive than, HI 1225+01 (the Virgo HI Cloud) and has a size of at least 15 kpc. The mean velocity dispersion, measured with the Australia Telescope Compact Array (ATCA), is only 4 km/s for the main component and because of the weak or non-existent star-formation, possibly reflects the thermal linewidth (T<2000 K) rather than bulk motion or turbulence. The peak column density for HIPASS J1712-64, from the combined Parkes and ATCA data, is only 3.5 x 10^19 cm^-2, which is estimated to be a factor of two below the critical threshold for star formation. Apart from its significantly higher velocity, the properties of HIPASS J1712-64 are similar to the recently recognised class of Compact High Velocity Clouds. We therefore consider the evidence for a Local Group or Galactic origin, although a more plausible alternative is that HIPASS J1712-64 was ejected from the interacting Magellanic Cloud/Galaxy system at perigalacticon ~ 2 x 10^8 yr ago.Comment: 23 pages, 7 figures, AJ accepte

Isolation and fine mapping of Rps6: An intermediate host resistance gene in barley to wheat stripe rust

A plant may be considered a nonhost of a pathogen if all known genotypes of a plant species are resistant to all known isolates of a pathogen species. However, if a small number of genotypes are susceptible to some known isolates of a pathogen species this plant maybe considered an intermediate host. Barley (Hordeum vulgare) is an intermediate host for Puccinia striiformis f. sp. tritici (Pst), the causal agent of wheat stripe rust. We wanted to understand the genetic architecture underlying resistance to Pst and to determine whether any overlap exists with resistance to the host pathogen, Puccinia striiformis f. sp. hordei (Psh). We mapped Pst resistance to chromosome 7H and show that host and intermediate host resistance is genetically uncoupled. Therefore, we designate this resistance locus Rps6. We used phenotypic and genotypic selection on F2:3 families to isolate Rps6 and fine mapped the locus to a 0.1 cM region. Anchoring of the Rps6 locus to the barley physical map placed the region on two adjacent fingerprinted contigs. Efforts are now underway to sequence the minimal tiling path and to delimit the physical region harbouring Rps6. This will facilitate additional marker development and permit identification of candidate genes in the region

Spontaneously broken neutral symmetry in an ecological system

Spontaneous symmetry breaking plays a fundamental role in many areas of condensed matter and particle physics. A fundamental problem in ecology is the elucidation of the mechanisms responsible for biodiversity and stability. Neutral theory, which makes the simplifying assumption that all individuals (such as trees in a tropical forest)-regardless of the species they belong to-have the same prospect of reproduction, death, etc., yields gross patterns that are in accord with empirical data. We explore the possibility of birth and death rates that depend on the population density of species, treating the dynamics in a species-symmetric manner. We demonstrate that dynamical evolution can lead to a stationary state characterized simultaneously by both biodiversity and spontaneously broken neutral symmetry

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

Impact of Transmammary-Delivered Meloxicam on Biomarkers of Pain and Distress in Piglets after Castration and Tail Docking

To investigate a novel route for providing analgesia to processed piglets via transmammary drug delivery, meloxicam was administered orally to sows after farrowing. The objectives of the study were to demonstrate meloxicam transfer from sows to piglets via milk and to describe the analgesic effects in piglets after processing through assessment of pain biomarkers and infrared thermography (IRT). Ten sows received either meloxicam (30 mg/kg) (n = 5) or whey protein (placebo) (n = 5) in their daily feedings, starting four days after farrowing and continuing for three consecutive days. During this period, blood and milk samples were collected at 12-hour intervals. On Day 5 after farrowing, three boars and three gilts from each litter were castrated or sham castrated, tail docked, and administered an iron injection. Piglet blood samples were collected immediately before processing and at predetermined times over an 84-hour period. IRT images were captured at each piglet blood collection point. Plasma was tested to confirm meloxicam concentrations using a validated high-performance liquid chromatography-mass spectrometry method. Meloxicam was detected in all piglets nursing on medicated sows at each time point, and the mean (± standard error of the mean) meloxicam concentration at castration was 568.9±105.8 ng/mL. Furthermore, ex-vivo prostaglandin E2(PGE2) synthesis inhibition was greater in piglets from treated sows compared to controls (p = 0.0059). There was a time-by-treatment interaction for plasma cortisol (p = 0.0009), with meloxicam-treated piglets demonstrating lower cortisol concentrations than control piglets for 10 hours after castration. No differences in mean plasma substance P concentrations between treatment groups were observed (p = 0.67). Lower cranial skin temperatures on IRT were observed in placebo compared to meloxicam-treated piglets (p = 0.015). This study demonstrates the successful transfer of meloxicam from sows to piglets through milk and corresponding analgesia after processing, as evidenced by a decrease in cortisol and PGE2levels and maintenance of cranial skin temperature

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Improving girls’ perception of computer science as a viable career option through game playing and design: Lessons from a systematic literature review

The objective of exposing girls to Computer Science as a career option has led to research directed towards gaming activities for girls. These activities include both game play and game design. Research about gaming activities for increasing girls’ interest in computer science has gained much attention over the past few years and has resulted in a number of contributions. We follow up with an overview of the status of research through a Systematic Literature Review. We investigate the relation between the various game playing or designing activities and their impact on girls’ perception of Computer Science as a career choice. We further present the design consideration for the games and related activities to potentially improve the perception of girls towards a Computer Science career. The applied method is a Systematic Literature Review through which we investigate which contributions were made, which knowledge areas were most explored, and which research facets have been used. We identify 25 papers to distill a common understanding of the state-of-the-art. Specifically, we investigate the effects that the game play/design activities had on girls’ perception about Computer Science; and what are the key design factors to be kept in mind while designing a serious game to improve girls’ perception about Computer Science. The results of this systematic literature review show that game playing or designing could indeed improve how girls perceive having a career in CS. The key aspects that such activities require are personalizing, opportunity for collaboration and the presence of a female lead characterThis work has been done during the tenure of an ERCIM Alain Bensoussan fellowshi

Buried Versus Exposed Kirschner Wires Following Fixation of Hand Fractures: l Clinician and Patient Surveys

Background: Fractures of the metacarpals and phalanges are common. Placement of Kirschner wires (K-wires) is the most common form of surgical fixation. After placement, a key decision is whether to bury the end of a K-wire or leave it protruding from the skin (exposed). A recent systematic review found no evidence to support either approach. The aim of study was to investigate current clinical practice, understand the key factors influencing clinician decision-making, and explore patient preferences to inform the design of a randomized clinical trial. Methods: The steering group developed surveys for hand surgeons, hand therapists, and patients. Following piloting, they were distributed across the United Kingdom hand surgery units using the Reconstructive Surgery Trials Network. Results: A total of 423 hand surgeons, 187 hand therapists, and 187 patients completed the surveys. Plastic surgeons and junior surgical trainees preferred to leave K-wires not buried. Ease of removal correlated with a decision to leave wires exposed, whereas perceived risk of infection correlated with burying wires. Cost did not affect the decision. Hand therapists were primarily concerned about infection and patient-related outcomes. Patients were most concerned about wire-related problems and pain. Conclusion: This national survey provides a new understanding of the use of K-wires to manage hand fractures in the United Kingdom. A number of nonevidence-based factors seem to influence the decision to bury or leave K-wires exposed. The choice has important clinical and health economic implications that justify a randomized controlled trial