Allelic segregation and independent assortment in <i>T. brucei</i> crosses: proof that the genetic system is Mendelian and involves meiosis

The genetic system on Trypanosoma brucei has been analysed by generating large numbers of independent progeny clones from two crosses, one between two cloned isolates of Trypanosoma brucei brucei and one between cloned isolates of T. b. brucei and Trypanosoma brucei gambiense, Type 2. Micro and minisatellite markers (located on each of the 11 megabase housekeeping chromosomes) were identified, that are heterozygous in one or more of the parental strains and the segregation of alleles at each locus was then determined in each of the progeny clones. The results unequivocally show that alleles segregate in the predicted ratios and that alleles at loci on different chromosomes segregate independently. These data provide statistically robust proof that the genetic system is Mendelian and that meiosis occurs. Segregation distortion is observed with the minisatellite locus located on chromosome I of T. b. gambiense Type 2 and neighboring markers, but analysis of markers further along this chromosome did not show distortion leading to the conclusion that this is due to selection acting on one part of this chromosome. The results obtained are discussed in relation to previously proposed models of mating and support the occurrence of meiosis to form haploid gametes that then fuse to form the diploid progeny in a single round of mating

A Description of Quasar Variability Measured Using Repeated SDSS and POSS Imaging

We provide a quantitative description and statistical interpretation of the optical continuum variability of quasars. The Sloan Digital Sky Survey (SDSS) has obtained repeated imaging in five UV-to-IR photometric bands for 33,881 spectroscopically confirmed quasars. About 10,000 quasars have an average of 60 observations in each band obtained over a decade along Stripe 82 (S82), whereas the remaining ~25,000 have 2-3 observations due to scan overlaps. The observed time lags span the range from a day to almost 10 years, and constrain quasar variability at rest-frame time lags of up to 4 years, and at rest-frame wavelengths from 1000A to 6000A. We publicly release a user-friendly catalog of quasars from the SDSS Data Release 7 that have been observed at least twice in SDSS or once in both SDSS and the Palomar Observatory Sky Survey, and we use it to analyze the ensemble properties of quasar variability. Based on a damped random walk (DRW) model defined by a characteristic time scale and an asymptotic variability amplitude that scale with the luminosity, black hole mass, and rest wavelength for individual quasars calibrated in S82, we can fully explain the ensemble variability statistics of the non-S82 quasars such as the exponential distribution of large magnitude changes. All available data are consistent with the DRW model as a viable description of the optical continuum variability of quasars on time scales of ~5-2000 days in the rest frame. We use these models to predict the incidence of quasar contamination in transient surveys such as those from PTF and LSST.Comment: 33 pages, 19 figures, replaced with accepted version. Catalog is available at http://www.astro.washington.edu/users/ivezic/macleod/qso_dr7

The genetic map and comparative analysis with the physical map of Trypanosoma brucei

Trypanosoma brucei is the causative agent of African sleeping sickness in humans and contributes to the debilitating disease ‘Nagana’ in cattle. To date we know little about the genes that determine drug resistance, host specificity, pathogenesis and virulence in these parasites. The availability of the complete genome sequence and the ability of the parasite to undergo genetic exchange have allowed genetic investigations into this parasite and here we report the first genetic map of T.brucei for the genome reference stock TREU 927, comprising of 182 markers and 11 major linkage groups, that correspond to the 11 previously identified chromosomes. The genetic map provides 90% probability of a marker being 11 cM from any given locus. Its comparison to the available physical map has revealed the average physical size of a recombination unit to be 15.6 Kb/cM. The genetic map coupled with the genome sequence and the ability to undertake crosses presents a new approach to identifying genes relevant to the disease and its prevention in this important pathogen through forward genetic analysis and positional cloning

Modifiable and fixed factors predicting quality of life in people with colorectal cancer

BACKGROUND: People with colorectal cancer have impaired quality of life (QoL). We investigated what factors were most highly associated with it. METHODS: Four hundred and ninety-six people with colorectal cancer completed questionnaires about QoL, functioning, symptoms, co-morbidity, cognitions and personal and social factors. Disease, treatment and co-morbidity data were abstracted from case notes. Multiple linear regression identified modifiable and unmodifiable factors independently predictive of global quality of life (EORTC-QLQ-C30). RESULTS: Of unmodifiable factors, female sex (P<0.001), more self-reported co-morbidities (P=0.006) and metastases at diagnosis (P=0.036) significantly predicted poorer QoL, but explained little of the variability in the model (R(2)=0.064). Adding modifiable factors, poorer role (P<0.001) and social functioning (P=0.003), fatigue (P=0.001), dyspnoea (P=0.001), anorexia (P<0.001), depression (P<0.001) and worse perceived consequences (P=0.013) improved the model fit considerably (R(2)=0.574). Omitting functioning subscales resulted in recent diagnosis (P=0.002), lower perceived personal control (P=0.020) and travel difficulties (P<0.001) becoming significant predictors. CONCLUSION: Most factors affecting QoL are modifiable, especially symptoms (fatigue, anorexia, dyspnoea) and depression. Beliefs about illness are also important. Unmodifiable factors, including metastatic (or unstaged) disease at diagnosis, have less impact. There appears to be potential for interventions to improve QoL in patients with colorectal cancer

Self-guided trails – a route to more responsible tourism?

In recent years, the tourism industry has faced criticism by turning its attention to the development of more responsible tourism. This is a form of tourism that is mindful of the diverse needs of host communities, local business and the visitor. This paper investigates the development of more responsible tourism from the perspective of a popular tourist product – the self-guided trail or route. The trail or route provides a themed and interpreted journey through the urban or rural landscape, creating links between sites, attractions and other tourism businesses by providing information and storytelling along the way. These products have a global appeal and are becoming more prolific. Through a literature review on trails, the paper analyses their key characteristics and the rationales of developers and concludes that trails have the potential to contribute to more responsible tourism development. The paper proposes a series of planning principles which are derived from the literature and examples of good practice therein which may assist trail developers in creating more responsible tourism routes and trails. The discussion concludes with a case study of a project in Cornwall in the south-west of the UK, where responsible planning has underpinned recent trail development

Language and anxiety: an ethnographic study of international postgraduate students

This paper presents some findings from an ethnographic study of international postgraduate students at a university in the South of England, which involved interviews and participant observation over a twelve-month academic year. One of the major themes that emerged from this research was students’ anxiety over their level of English language. Although all students entered their course with a minimum level of IELTS 6, the majority felt disadvantaged by particularly poor spoken English, and suffered feelings of anxiety, shame and inferiority. Low self-confidence meant that they felt ill-equipped to engage in class discussion and in social interaction which used English as the medium of communication. A common reaction to stress caused by language problems was to retreat into monoethnic communication with students from the same country, further inhibiting progress in language. Whilst some linguistic progress was made by nearly all students during the academic sojourn, the anxiety suffered by students in the initial stage must not be underestimated, and appropriate support systems must be put in place to alleviate their distress

The TRACTISS protocol: a randomised double blind placebo controlled clinical trial of anti-B-cell therapy in patients with primary Sjögren's Syndrome.

Background: Primary Sjögren's Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 - 0.6% of adult women. For patients with PSS there is currently no effective therapy that can alter the progression of the disease. The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes. Methods/design: TRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS. Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks. The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness. Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition. Discussion: The TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity. Trial registration: UKCRN Portfolio ID: 9809 ISRCTN65360827

Effect of flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor

Background and Purpose Flecainide is a use-dependent blocker of cardiac Na+ channels. Mechanistic analysis of this block showed that the cationic form of flecainide enters the cytosolic vestibule of the open Na+ channel. Flecainide is also effective in the treatment of catecholaminergic polymorphic ventricular tachycardia but, in this condition, its mechanism of action is contentious. We investigated how flecainide derivatives influence Ca2+-release from the sarcoplasmic reticulum through the ryanodine receptor channel (RyR2) and whether this correlates with their effectiveness as blockers of Na+ and/or RyR2 channels. Experimental Approach We compared the ability of fully charged (QX-FL) and neutral (NU-FL) derivatives of flecainide to block individual recombinant human RyR2 channels incorporated into planar phospholipid bilayers, and their effects on the properties of Ca2+ sparks in intact adult rat cardiac myocytes. Key Results Both QX-FL and NU-FL were partial blockers of the non-physiological cytosolic to luminal flux of cations through RyR2 channels but were significantly less effective than flecainide. None of the compounds influenced the physiologically relevant luminal to cytosol cation flux through RyR2 channels. Intracellular flecainide or QX-FL, but not NU-FL, reduced Ca2+ spark frequency. Conclusions and Implications Given its inability to block physiologically relevant cation flux through RyR2 channels, and its lack of efficacy in blocking the cytosolic-to-luminal current, the effect of QX-FL on Ca2+ sparks is likely, by analogy with flecainide, to result from Na+ channel block. Our data reveal important differences in the interaction of flecainide with sites in the cytosolic vestibules of Na+ and RyR2 channels

Mortality after discharge from long-term psychiatric care in Scotland, 1977 – 94: a retrospective cohort study

BACKGROUND: Recent United Kingdom strategies focus on preventable suicide deaths in former psychiatric in-patients, but natural causes of death, accidents and homicide may also be important. This study was intended to find the relative importance of natural and unnatural causes of death in people discharged from long-term psychiatric care in Scotland in 1977 –1994. METHODS: People discharged alive from psychiatric hospitals in Scotland in 1977 – 94 after a stay of one year or longer were identified using routine hospital records. Computer record linkage was used to link hospital discharges to subsequent death records. Mortality was described using a person-years analysis, and compared to the general population rates. RESULTS: 6,776 people were discharged in the time period. 1,994 people (29%) died by the end of follow-up, 732 more deaths than expected. Deaths from suicide, homicide, accident and undetermined cause were increased, but accounted for only 197 of the excess deaths. Deaths from respiratory disease were four times higher than expected, and deaths from other causes, including cardiovascular disease, were also elevated. CONCLUSION: Suicide is an important cause of preventable mortality, but natural causes account for more excess deaths. Prevention activities should not focus only on unnatural causes of death

The impact of the COVID-19 pandemic on self-harm and suicidal behaviour: update of living systematic review

Background: The COVID-19 pandemic has caused considerable morbidity, mortality and disruption to people’s lives around the world. There are concerns that rates of suicide and suicidal behaviour may rise during and in its aftermath. Our living systematic review synthesises findings from emerging literature on incidence and prevalence of suicidal behaviour as well as suicide prevention efforts in relation to COVID-19, with this iteration synthesising relevant evidence up to 19th October 2020.Method: Automated daily searches feed into a web-based database with screening and data extraction functionalities. Eligibility criteria include incidence/prevalence of suicidal behaviour, exposure-outcome relationships and effects of interventions in relation to the COVID-19 pandemic. Outcomes of interest are suicide, self-harm or attempted suicide and suicidal thoughts. No restrictions are placed on language or study type, except for single-person case reports. We exclude one-off cross-sectional studies without either pre-pandemic measures or comparisons of COVID-19 positive vs. unaffected individuals.Results: Searches identified 6,226 articles. Seventy-eight articles met our inclusion criteria. We identified a further 64 relevant cross-sectional studies that did not meet our revised inclusion criteria. Thirty-four articles were not peer-reviewed (e.g. research letters, pre-prints). All articles were based on observational studies.There was no consistent evidence of a rise in suicide but many studies noted adverse economic effects were evolving. There was evidence of a rise in community distress, fall in hospital presentation for suicidal behaviour and early evidence of an increased frequency of suicidal thoughts in those who had become infected with COVID-19.Conclusions: Research evidence of the impact of COVID-19 on suicidal behaviour is accumulating rapidly. This living review provides a regular synthesis of the most up-to-date research evidence to guide public health and clinical policy to mitigate the impact of COVID-19 on suicide risk as the longer term impacts of the pandemic on suicide risk are researched