Ectopic cyclin E expression induces premature entry into S phase and disrupts pattern formation in the Drosophila eye imaginal disc

During animal development, cell proliferation is controlled in many cases by regulation of the G1 to S phase transition. Studies of mammalian tissue culture cells have shown that the G1-specific cyclin, cyclin E, can be rate limiting for progression from G1 to S phase. During Drosophila development, down-regulation of cyclin E is required for G1 arrest in terminally differentiating embryonic epidermal cells. Whether cyclin E expression limits progression into S phase in proliferating, as opposed to differentiating, cells during development has not been investigated. Here we show that Drosophila cyclin E (DmcycE) protein is absent in G1 phase cells but appears at the onset of S phase in proliferating cells of the larval optic lobe and eye imaginal disc. We have examined cells in the eye imaginal epithelium, where a clearly defined developmentally regulated G1 to S phase transition occurs. Ectopic expression of DmcycE induces premature entry of most of these G1 cells into S phase. Thus in these cells, control of DmcycE expression is required for regulated entry into S phase. Significantly, a band of eye imaginal disc cells in G1 phase was not induced to enter S phase by ectopic expression of DmcycE. This provides evidence for additional regulatory mechanisms that operate during G1 phase to limit cell proliferation during development. These results demonstrate that the role of cyclin E in regulating progression into S phase in mammalian tissue culture cells applies to some, but not all, cells during Drosophila development. Ectopic expression of DmcycE in the eye imaginal disc disrupts normal pattern formation, highlighting the importance of coordinating cell proliferation with developmental processes for correct patterning in the developing eye. These studies establish DmcycE as a target of regulatory mechanisms that coordinate cell proliferation with other developmental events

The Need for a Speech Corpus

This paper outlines the ongoing construction of a speech corpus for use by applied linguists and advanced EFL/ESL students. The first section establishes the need for improvements in the teaching of listening skills and pronunciation practice for EFL/ESL students. It argues for the need to use authentic native-to-native speech in the teaching/learning process so as to promote social inclusion and contextualises this within the literature, based mainly on the work of Swan, Brown and McCarthy. The second part addresses features of native speech flow which cause difficulties for EFL/ESL students (Brown, Cauldwell) and establishes the need for improvements in the teaching of listening skills. Examples are given of reduced forms characteristic of relaxed native speech, and how these can be made accessible for study using the Technological University Dublin’s slow-down technology, which gives students more time to study native speech features, without tonal distortion. The final section introduces a novel Speech Corpus being developed at DIT. It shows the limits of traditional corpora and outlines the general requirements of a Speech Corpus. This tool–which will satisfy the needs of teachers, learners and researchers–will link digitally recorded, natural, native-to-native speech so that each transcript segment will be linked to its associated sound file. Users will be able to locate desired speech strings, play, compare and contrast them—and slow them down for more detailed study

DIT’s Dynamic Speech Corpus and Dialogic Fluency

Monologic fluency is characterised by a lack of pauses and a smooth oral delivery. Dialogic fluency in L1-L1 unscripted speech, however, is characterized by seeming dis-fluency, hesitations, false starts etc. Yet the L1 speakers make perfect sense to each other. The Dynamic Speech Corpus (DSC) currently being developed under the FLUENT project at the Technological University Dublin (DIT). In dialogue, language represents only one of the communication channels at play in what is a dynamic, unscripted social interchange rather than a stand-alone linguistic performance. The language stream is supplemented by pragmatic considerations and a greater emphasis on prosody. DIT’s DSC is based on natural, native-to-native dialogues and recorded at a high level of audio quality and is being developed mainly for autonomous learners. It will afford access to a unique audio resource based on unscripted dialogues between friends and acquaintances, exemplifying informal, native-speaker speech and natural turn-taking, rather than scripted interactions. The presentation demonstrates how users can locate and study samples of L1-to-L1 speech, as well as various phonetic phenomena such as speed-induced elisions in their full, pragmatic, dialogic context. This will allow the learner user to focus on the manner in which native speakers produce reduced forms and slow them down for detailed study. The corpus will be a rich resource for users who wish to study the communicative value of prosody and formulaic sequences, and particular attention will be paid to turn-taking strategies, along with other forms of interaction, which some researchers see as a ‘fifth skill’

Mosquito repellents for malaria prevention

Background Malaria is an important cause of illness and death across endemic regions. Considerable success against malaria has been achieved within the past decade mainly through long-lasting insecticide-treated nets (LLINs). However, elimination of the disease is proving difficult as current control methods do not protect against mosquitoes biting outdoors and when people are active. Repellents may provide a personal protection solution during these times. Objectives To assess the impact of topical repellents, insecticide-treated clothing, and spatial repellents on malaria transmission. Search methods We searched the following databases up to 26 June 2017: the Cochrane Infectious Diseases Group Specialized Register; the Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; US AFPMB; CAB Abstracts; and LILACS. We also searched trial registration platforms and conference proceedings; and contacted organizations and companies for ongoing and unpublished trials. Selection criteria We included randomized controlled trials (RCTs) and cluster-randomized controlled trials of topical repellents proven to repel mosquitoes; permethrin-treated clothing; and spatial repellents such as mosquito coils. We included trials that investigated the use of repellents with or without LLINs, referred to as insecticide-treated nets. Data collection and analysis Two review authors independently reviewed trials for inclusion, extracted the data, and assessed the risk of bias. A third review author resolved any discrepancies. We analysed data by conducting meta-analysis and stratified by whether the trials had included LLINs. We combined results from cRCTs with individually RCTs by adjusting for clustering and presented results using forest plots. We used GRADE to assess the certainty of the evidence. Main results Eight cRCTs and two RCTs met the inclusion criteria. Six trials investigated topical repellents, two trials investigated insecticide-treated clothing, and two trials investigated spatial repellents. Topical repellents Six RCTS, five of them cluster-randomized, investigated topical repellents involving residents of malaria-endemic regions. Four trials used topical repellents in combination with nets, but two trials undertaken in displaced populations used topical repellents alone. It is unclear if topical repellents can prevent clinical malaria (RR 0.65, 95% CI 0.4 to 1.07, very low certainty evidence) or malaria infection (RR 0.84, 95% CI 0.64 to 1.12, low-certainty evidence) caused by P. falciparum. It is also unclear if there is any protection against clinical cases of P. vivax (RR 1.32, 95% CI 0.99 to 1.76, low-certainty evidence) or incidence of infections (RR 1.07, 95% CI 0.80 to 1.41, low-certainty evidence). Subgroup analysis of trials including insecticide-treated nets did not show a protective effect of topical repellents against malaria. Only two studies did not include insecticide-treated nets, and they measured different outcomes; one reported a protective effect against clinical cases of P. falciparum (RR 0.40, 95% CI 0.23 to 0.71); but the other study measured no protective effect against malaria infection incidence caused by either P. falciparum or P. vivax. Insecticide-treated clothing Insecticide-treated clothing were investigated in trials conducted in refugee camps in Pakistan and amongst military based in the Colombian Amazon. Neither study provided participants with insecticide-treated nets. In the absence of nets, treated clothing may reduce the incidence of clinical malaria caused by P. falciparum by approximately 50% (RR 0.49, 95% CI 0.29 to 0.83, low-certainty evidence) and P. vivax (RR 0.64, 95% CI 0.40 to 1.01, low-certainty evidence). Spatial repellents Two cluster-randomized RCTs investigated mosquito coils for malaria prevention. We do not know the effect of spatial repellents on malaria prevention (RR 0.24, 95% CI 0.03 to 1.72, very low certainty evidence). There was large heterogeneity between studies and one study had high risk of bias. Authors' conclusions There is insufficient evidence to conclude topical or spatial repellents can prevent malaria. There is a need for better designed trials to generate higher certainty of evidence before well-informed recommendations can be made. Adherence to daily compliance remains a major limitation. Insecticide-treated clothing may reduce risk of malaria infection in the absence of insecticide-treated nets; further studies on insecticide-treated clothing in the general population should be done to broaden the applicability of the results

HTML5 and the Learner of Spoken Languages

Traditional corpora are not renowned for being user friendly. If learners are to derive maximum benefit from speech corpora, then better interfaces are needed. This paper proposes such a role for HTML5. DIT’s dynamic speech corpus, FLUENT, contains a limited series of informal dialogues between friends and acquaintances. They are characterised by naturalness and their audio quality and marked-up using a schema which allows learners to retrieve features of spoken language, such as speaker intention, formulaicity and prosodic characteristics such as speed of delivery. The requirement to combine audio assets and synchronous text animation has in the past necessitated the use of browser ‘plug-in’ technologies, such as Adobe Flash. Plug-in-based systems all suffer from major drawbacks. They are not installed by default on deployed browsers. More critically they obscure the underlying speech corpus structure. Also proprietary UIs offer no standard way of dealing with accessibility or dynamic interface reconfiguration, e.g. moving from corpus playback to concordance views. This makes design of a unified interface framework, with audio playback, synchronous text and speech, more difficult. Given the profusion of plug-in architectures and plug-in types, it is clear that such an environment is unsustainable for building tools for speech corpus visualisation. In order to overcome these challenges, FLUENT drew heavily on the HTML5 specification coupled with a user-centred design for L2 learners to specify and develop scalable, reusable and accessible UIs for many devices.This paper describes the design of the corpus schema and its close integration with the UI model

Dialogic Fluency - Why it Matters

Speech as an LSP: Many dialogues presented to language learners could be better described as ‘interleaved mini-monologues’, their purpose being to provide examples of grammatical sentences in realistic settings. Real dialogues, on the other hand, are worked out ‘live’, with neither speaker knowing in detail where the conversation will lead. Speaker interaction is marked to a large extent by prosody and often even good communicators sound disfluent if their half of the dialogue is judged in isolation. Dialogic fluency: The objective of dialoguing L1 speakers, however, is to realise a social or personal goal, with language only part of effective communication. Possibly the bulk of the communication devolves to prosody, shared knowledge and body language. Whereas this might not be a mainstream production goal for language learners, all users of English as an international language likely to come into contact with native speakers should be sensitised to native-speaker prosody. Influence of live dialogue on speech production: Given that the aim of an L1-L1 dialogue is not to provide learners with sample sentences, but rather to use language as a key factor in a social encounter, learners need a tool which will allow them to study the interaction of real dialogues. Of particular interest is the turn-taking behaviour of speakers, which is often flagged prosodically and produces utterances which, on the surface seem disfluent, but which on further analysis are seen to have an interactive function. The production of such a tool is the aim of the Dynamic Speech Corpus (DSC)

Insecticide-treated nets for preventing malaria

BACKGROUND: A previous version of this Cochrane Review identified that insecticide-treated nets (ITNs) are effective at reducing child mortality, parasite prevalence, and uncomplicated and severe malaria episodes. Insecticide-treated nets have since become a core intervention for malaria control and have contributed greatly to the dramatic decline in disease incidence and malaria-related deaths seen since the turn of the millennium. However, this time period has also seen a rise in resistance to pyrethroids (the insecticide used in ITNs), raising questions over whether the evidence from trials conducted before resistance became widespread can be applied to estimate the impact of ITNs on malaria transmission today. OBJECTIVES: The primary objective of this review was to assess the impact of ITNs on mortality and malaria morbidity, incorporating any evidence published since the previous update into new and existing analyses, and assessing the certainty of the resulting evidence using GRADE. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) published in the Cochrane Library, MEDLINE, Embase, LILACS, the World Health Organization (WHO) International Clinical Trials Registry Platform, ClinicalTrials.gov, and the ISRCTN registry for new trials published since 2004 and up to 18 April 2018. SELECTION CRITERIA: We included individual randomized controlled trials (RCTs) and cluster RCTs comparing bed nets or curtains treated with a synthetic pyrethroid insecticide at a minimum target impregnation dose recommended by the WHO with no nets or untreated nets. DATA COLLECTION AND ANALYSIS: One review author assessed the identified trials for eligibility and risk of bias, and extracted data. We compared intervention and control data using risk ratios (RRs), rate ratios, and mean differences, and presented all results with their associated 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach. We drew on evidence from a meta-analysis of entomological outcomes stratified by insecticide resistance from 2014 to inform the GRADE assessments. MAIN RESULTS: Our updated search identified three new trials. A total of 23 trials met the inclusion criteria, enrolling more than 275,793 adults and children. The included studies were conducted between 1987 and 2001.ITN versus no netsInsecticide-treated nets reduce child mortality from all causes by 17% compared to no nets (rate ratio 0.83, 95% CI 0.77 to 0.89; 5 trials, 200,833 participants, high-certainty evidence). This corresponds to a saving of 5.6 lives (95% CI 3.6 to 7.6) each year for every 1000 children protected with ITNs. Insecticide-treated nets also reduce the incidence of uncomplicated episodes of Plasmodium falciparum malaria by almost a half (rate ratio 0.55, 95% CI 0.48 to 0.64; 5 trials, 35,551 participants, high-certainty evidence) and probably reduce the incidence of uncomplicated episodes of Plasmodium vivax malaria (risk ratio (RR) 0.61, 95% CI 0.48 to 0.77; 2 trials, 10,967 participants, moderate-certainty evidence).Insecticide-treated nets were also shown to reduce the prevalence of P falciparum malaria by 17% compared to no nets (RR 0.83, 95% CI 0.71 to 0.98; 6 trials, 18,809 participants, high-certainty evidence) but may have little or no effect on the prevalence of P vivax malaria (RR 1.00, 95% CI 0.75 to 1.34; 2 trials, 10,967 participants, low-certainty evidence). A 44% reduction in the incidence of severe malaria episodes was seen in the ITN group (rate ratio 0.56, 95% CI 0.38 to 0.82; 2 trials, 31,173 participants, high-certainty evidence), as well as an increase in mean haemoglobin (expressed as mean packed cell volume) compared to the no-net group (mean difference 1.29, 95% CI 0.42 to 2.16; 5 trials, 11,489 participants, high-certainty evidence).ITN versus untreated netsInsecticide-treated nets probably reduce child mortality from all causes by a third compared to untreated nets (rate ratio 0.67, 95% CI 0.36 to 1.23; 2 trials, 25,389 participants, moderate-certainty evidence). This corresponds to a saving of 3.5 lives (95% CI -2.4 to 6.8) each year for every 1000 children protected with ITNs. Insecticide-treated nets also reduce the incidence of uncomplicated P falciparum malaria episodes (rate ratio 0.58, 95% CI 0.44 to 0.78; 5 trials, 2036 participants, high-certainty evidence) and may also reduce the incidence of uncomplicated P vixax malaria episodes (rate ratio 0.73, 95% CI 0.51 to 1.05; 3 trials, 1535 participants, low-certainty evidence).Use of an ITN probably reduces P falciparum prevalence by one-tenth in comparison to use of untreated nets (RR 0.91, 95% CI 0.78 to 1.05; 3 trials, 2,259 participants, moderate-certainty evidence). However, based on the current evidence it is unclear whether or not ITNs impact on P vivax prevalence (1 trial, 350 participants, very low certainty evidence) or mean packed cell volume (2 trials, 1,909 participants, low certainty evidence). AUTHORS' CONCLUSIONS: Although there is some evidence that insecticide resistance frequency has some effects on mosquito mortality, it is unclear how quantitatively important this is. It appeared insufficient to downgrade the strong evidence of benefit on mortality and malaria illness from the trials conducted earlier

Drugs for treating Buruli ulcer (Mycobacterium ulcerans disease)

Background Buruli ulcer is a necrotizing cutaneous infection caused by infection with Mycobacterium ulcerans bacteria that occurs mainly in tropical and subtropical regions. The infection progresses from nodules under the skin to deep ulcers, often on the upper and lower limbs or on the face. If left undiagnosed and untreated, it can lead to lifelong disfigurement and disabilities. It is often treated with drugs and surgery. Objectives To summarize the evidence of drug treatments for treating Buruli ulcer. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (Ovid); and LILACS (Latin American and Caribbean Health Sciences Literature; BIREME). We also searched the US National Institutes of Health Ongoing Trials Register (clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en/). All searches were run up to 19 December 2017. We also checked the reference lists of articles identified by the literature search, and contacted leading researchers in this topic area to identify any unpublished data. Selection criteria We included randomized controlled trials (RCTs) that compared antibiotic therapy to placebo or alternative therapy such as surgery, or that compared different antibiotic regimens. We also included prospective observational studies that evaluated different antibiotic regimens with or without surgery. Data collection and analysis Two review authors independently applied the inclusion criteria, extracted the data, and assessed methodological quality. We calculated the risk ratio (RR) for dichotomous data with 95% confidence intervals (CI). We assessed the certainty of the evidence using the GRADE approach. Main results We included a total of 18 studies: five RCTs involving a total of 319 participants, ranging from 12 participants to 151 participants, and 13 prospective observational studies, with 1665 participants. Studies evaluated various drugs usually in addition to surgery, and were carried out across eight countries in areas with high Buruli ulcer endemicity in West Africa and Australia. Only one RCT reported adequate methods to minimize bias. Regarding monotherapy, one RCT and one observational study evaluated clofazimine, and one RCT evaluated sulfamethoxazole/trimethoprim. All three studies had small sample sizes, and no treatment effect was demonstrated. The remaining studies examined combination therapy. Rifampicin combined with streptomycin We found one RCT and six observational studies which evaluated rifampicin combined with streptomycin for different lengths of treatment (2, 4, 8, or 12 weeks) (941 participants). The RCT did not demonstrate a difference between the drugs added to surgery compared with surgery alone for recurrence at 12 months, but was underpowered (RR 0.12, 95% CI 0.01 to 2.51; 21 participants; very low‐certainty evidence). An additional five single‐arm observational studies with 828 participants using this regimen for eight weeks with surgery (given to either all participants or to a select group) reported healing rates ranging from 84.5% to 100%, assessed between six weeks and one year. Four observational studies reported healing rates for participants who received the regimen alone without surgery, reporting healing rates ranging from 48% to 95% assessed between eight weeks and one year. Rifampicin combined with clarithromycin Two observational studies administered combined rifampicin and clarithromycin. One study evaluated the regimen alone (no surgery) for eight weeks and reported a healing rate of 50% at 12 months (30 participants). Another study evaluated the regimen administered for various durations (as determined by the clinicians, durations unspecified) with surgery and reported a healing rate of 100% at 12 months (21 participants). Rifampicin with streptomycin initially, changing to rifampicin with clarithromycin in consolidation phase One RCT evaluated this regimen (four weeks in each phase) against continuing with rifampicin and streptomycin in the consolidation phase (total eight weeks). All included participants had small lesions, and healing rates were above 90% in both groups without surgery (healing rate at 12 months RR 0.94, 95% CI 0.87 to 1.03; 151 participants; low‐certainty evidence). One single‐arm observational study evaluating the substitution of streptomycin with clarithromycin in the consolidation phase (6 weeks, total 8 weeks) without surgery given to a select group showed a healing rate of 98% at 12 months (41 participants). Novel combination therapy Two large prospective studies in Australia evaluated some novel regimens. One study evaluating rifampicin combined with either ciprofloxacin, clarithromycin, or moxifloxacin without surgery reported a healing rate of 76.5% at 12 months (132 participants). Another study evaluating combinations of two to three drugs from rifampicin, ciprofloxacin, clarithromycin, ethambutol, moxifloxacin, or amikacin with surgery reported a healing rate of 100% (90 participants). Adverse effects were reported in only three RCTs (158 participants) and eight prospective observational studies (878 participants), and were consistent with what is already known about the adverse effect profile of these drugs. Paradoxical reactions (clinical deterioration after treatment caused by enhanced immune response to M ulcerans) were evaluated in six prospective observational studies (822 participants), and the incidence of paradoxical reactions ranged from 1.9% to 26%. Authors' conclusions While the antibiotic combination treatments evaluated appear to be effective, we found insufficient evidence showing that any particular drug is more effective than another. How different sizes, lesions, and stages of the disease may contribute to healing and which kind of lesions are in need of surgery are unclear based on the included studies. Guideline development needs to consider these factors in designing practical treatment regimens. Forthcoming trials using clarithromycin with rifampicin and other trials of new regimens that also address these factors will help to identify the best regimens

Discordant Immune Response with Antiretroviral Therapy in HIV-1: A Systematic Review of Clinical Outcomes.

BACKGROUND A discordant immune response (DIR) is a failure to satisfactorily increase CD4 counts on ART despite successful virological control. Literature on the clinical effects of DIR has not been systematically evaluated. We aimed to summarise the risk of mortality, AIDS and serious non-AIDS events associated with DIR with a systematic review. METHODS The protocol is registered with the Centre for Review Dissemination, University of York (registration number CRD42014010821). Included studies investigated the effect of DIR on mortality, AIDS, or serious non-AIDS events in cohort studies or cohorts contained in arms of randomised controlled trials for adults aged 16 years or older. DIR was classified as a suboptimal CD4 count (as defined by the study) despite virological suppression following at least 6 months of ART. We systematically searched PubMed, Embase, and the Cochrane Library to December 2015. Risk of bias was assessed using the Cochrane tool for assessing risk of bias in cohort studies. Two authors applied inclusion criteria and one author extracted data. Risk ratios were calculated for each clinical outcome reported. RESULTS Of 20 studies that met the inclusion criteria, 14 different definitions of DIR were used. Risk ratios for mortality in patients with and without DIR ranged between 1.00 (95% CI 0.26 to 3.92) and 4.29 (95% CI 1.96 to 9.38) with the majority of studies reporting a 2 to 3 fold increase in risk. CONCLUSIONS DIR is associated with a marked increase in mortality in most studies but definitions vary widely. We propose a standardised definition to aid the development of management options for DIR

Controlled Flowering Project for Lolium Perenne at Agresearch: an Overview

Ryegrass (Lolium perenne) is an important forage crop in New Zealand. The work presented here has the goal of developing a system for complete and arbitrary control of the transition from vegetative to floral development. For this, we have pursued an integrated approach utilising genomics with both forward and reverse genetics. Like other model plants, photoperiodic and vernalization pathways are presumed to be operating in ryegrass and control the activity of the meristem identity/floral patterning genes. The candidate gene approach targeting the photoperiodic pathway is described in an accompanying abstract (Gagic et al.). Other candidate genes include the meristem identity gene LEAFY and a range of the MADS box transcription factors. Relevant expression profiles are established for these genes, i.e. vernalization time course at weekly intervals, and daily and circadian collections during the secondary induction. A detailed genetic map of ryegrass has been developed at AgResearch (see abstract by Faville et al.) which we are using to map candidate genes. We are also conducting detailed phenotypic analysis of the flowering behaviour variation within this population in an effort to isolate relevant QTLs. Ryegrass transformation has been used to ascertain functions of the candidate genes and to manipulate flowering time control directly. We are developing a universal switch to turn on the flowering that consists of a cassette of the arabidopsis genes under a control of a chemically inducible promoter