Showing papers by "Medical Research Council published in 2008"

TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

A systematic review of mental disorder, suicide, and deliberate self harm in lesbian, gay and bisexual people

Abstract: Lesbian, gay and bisexual (LGB) people may be at higher risk of mental disorders than heterosexual people. We conducted a systematic review and meta-analysis of the prevalence of mental disorder, substance misuse, suicide, suicidal ideation and deliberate self harm in LGB people. We searched Medline, Embase, PsycInfo, Cinahl, the Cochrane Library Database, the Web of Knowledge, the Applied Social Sciences Index and Abstracts, the International Bibliography of the Social Sciences, Sociological Abstracts, the Campbell Collaboration and grey literature databases for articles published January 1966 to April 2005. We also used Google and Google Scholar and contacted authors where necessary. We searched all terms related to homosexual, lesbian and bisexual people and all terms related to mental disorders, suicide, and deliberate self harm. We included papers on population based studies which contained concurrent heterosexual comparison groups and valid definition of sexual orientation and mental health outcomes. Of 13706 papers identified, 476 were initially selected and 28 (25 studies) met inclusion criteria. Only one study met all our four quality criteria and seven met three of these criteria. Data was extracted on 214,344 heterosexual and 11,971 non heterosexual people. Meta-analyses revealed a two fold excess in suicide attempts in lesbian, gay and bisexual people [pooled risk ratio for lifetime risk 2.47 (CI 1.87, 3.28)]. The risk for depression and anxiety disorders (over a period of 12 months or a lifetime) on meta-analyses were at least 1.5 times higher in lesbian, gay and bisexual people (RR range 1.54–2.58) and alcohol and other substance dependence over 12 months was also 1.5 times higher (RR range 1.51–4.00). Results were similar in both sexes but meta analyses revealed that lesbian and bisexual women were particularly at risk of substance dependence (alcohol 12 months: RR 4.00, CI 2.85, 5.61; drug dependence: RR 3.50, CI 1.87, 6.53; any substance use disorder RR 3.42, CI 1.97–5.92), while lifetime prevalence of suicide attempt was especially high in gay and bisexual men (RR 4.28, CI 2.32, 7.88). LGB people are at higher risk of mental disorder, suicidal ideation, substance misuse, and deliberate self harm than heterosexual people.

Inflammatory and coagulation biomarkers and mortality in patients with HIV infection.

Abstract: Background In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]). We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.

HITS-CLIP yields genome-wide insights into brain alternative RNA processing

Abstract: Protein-RNA interactions have critical roles in all aspects of gene expression. However, applying biochemical methods to understand such interactions in living tissues has been challenging. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova revealed extremely reproducible RNA-binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3' untranslated regions, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.

Conducting a meta-ethnography of qualitative literature: Lessons learnt

Abstract: Qualitative synthesis has become more commonplace in recent years. Meta-ethnography is one of several methods for synthesising qualitative research and is being used increasingly within health care research. However, many aspects of the steps in the process remain ill-defined. We utilized the seven stages of the synthesis process to synthesise qualitative research on adherence to tuberculosis treatment. In this paper we discuss the methodological and practical challenges faced; of particular note are the methods used in our synthesis, the additional steps that we found useful in clarifying the process, and the key methodological challenges encountered in implementing the meta-ethnographic approach. The challenges included shaping an appropriate question for the synthesis; identifying relevant studies; assessing the quality of the studies; and synthesising findings across a very large number of primary studies from different contexts and research traditions. We offer suggestions that may assist in undertaking meta-ethnographies in the future. Meta-ethnography is a useful method for synthesising qualitative research and for developing models that interpret findings across multiple studies. Despite its growing use in health research, further research is needed to address the wide range of methodological and epistemological questions raised by the approach.

Combined Impact of Health Behaviours and Mortality in Men and Women: The EPIC-Norfolk Prospective Population Study

Abstract: Background There is overwhelming evidence that behavioural factors influence health, but their combined impact on the general population is less well documented. We aimed to quantify the potential combined impact of four health behaviours on mortality in men and women living in the general community.

Impact of Stepping Stones on incidence of HIV and HSV-2 and sexual behaviour in rural South Africa: cluster randomised controlled trial.

Abstract: Objective To assess the impact of Stepping Stones, a HIV prevention programme, on incidence of HIV and herpes simplex type 2 (HSV-2) and sexual behaviour. Design Cluster randomised controlled trial. Setting 70 villages (clusters) in the Eastern Cape province of South Africa. Participants 1360 men and 1416 women aged 15-26 years, who were mostly attending schools. Intervention Stepping Stones, a 50 hour programme, aims to improve sexual health by using participatory learning approaches to build knowledge, risk awareness, and communication skills and to stimulate critical reflection. Villages were randomised to receive either this or a three hour intervention on HIV and safer sex. Interviewers administered questionnaires at baseline and 12 and 24 months and blood was tested for HIV and HSV-2. Main outcome measures Primary outcome measure: incidence of HIV. Other outcomes: incidence of HSV-2, unwanted pregnancy, reported sexual practices, depression, and substance misuse. Results There was no evidence that Stepping Stones lowered the incidence of HIV (adjusted incidence rate ratio 0.95, 95% confidence interval 0.67 to 1.35). The programme was associated with a reduction of about 33% in the incidence of HSV-2 (0.67, 0.46 to 0.97; P=0.036)—that is, Stepping Stones reduced the number of new HSV-2 infections over a two year period by 34.9 (1.6 to 68.2) per 1000 people exposed. Stepping Stones significantly improved a number of reported risk behaviours in men, with a lower proportion of men reporting perpetration of intimate partner violence across two years of follow-up and less transactional sex and problem drinking at 12 months. In women desired behaviour changes were not reported and those in the Stepping Stones programme reported more transactional sex at 12 months. Conclusion Stepping Stones did not reduce incidence of HIV but had an impact on several risk factors for HIV—notably, HSV-2 and perpetration of intimate partner violence. Trial Registration Clinical Trials NCT00332878.

Reducing Uncertainties About the Effects of Chemoradiotherapy for Cervical Cancer: A Systematic Review and Meta-Analysis of Individual Patient Data From 18 Randomized Trials

Abstract: Background After a 1999 National Cancer Institute (NCI) clinical alert was issued, chemoradiotherapy has become widely used in treating women with cervical cancer. Two subsequent systematic reviews found that interpretation of the benefits was complicated, and some important clinical questions were unanswered. Patients and Methods We initiated a meta-analysis seeking updated individual patient data from all randomized trials to assess the effect of chemoradiotherapy on all outcomes. We prespecified analyses to investigate whether the effect of chemoradiotherapy differed by trial or patient characteristics. Results On the basis of 13 trials that compared chemoradiotherapy versus the same radiotherapy, there was a 6% improvement in 5-year survival with chemoradiotherapy (hazard ratio [HR] = 0.81, P <.001). A larger survival benefit was seen for the two trials in which chemotherapy was administered after chemoradiotherapy. There was a significant survival benefit for both the group of trials that used platinum-based (HR = 0.83, P = .017) and non-platinum-based (HR = 0.77, P <.009) chemoradiotherapy, but no evidence of a difference in the size of the benefit by radiotherapy or chemotherapy dose or scheduling was seen. Chemoradiotherapy also reduced local and distant recurrence and progression and improved disease-free survival. There was a suggestion of a difference in the size of the survival benefit with tumor stage, but not across other patient subgroups. Acute hematologic and GI toxicity was increased with chemoradiotherapy, but data were too sparse for an analysis of late toxicity. Conclusion These results endorse the recommendations of the NCI alert, but also demonstrate their applicability to all women and a benefit of non-platinum-based chemoradiotherapy. Furthermore, although these results suggest an additional benefit from adjuvant chemotherapy, this requires testing in randomized trials.

Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review.

Abstract: Background The relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two populationbased cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context. Methods and Findings Measurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The yearto-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28–0.53, over 4 y, and 0.35, 95% CI 0.23–0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29–1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45–3.15) with long-term average (‘‘usual’’) IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42–1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45–4.56] per 2 SD increase in usual [long-term average] IL-6 levels).

Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo.

Abstract: Resident macrophages are an integral component of many tissues and are important in homeostasis and repair. This study examines the contribution of resident tissue macrophages to bone physiology. Using immunohistochemistry, we showed that a discrete population of resident macrophages, OsteoMacs, was intercalated throughout murine and human osteal tissues. OsteoMacs were distributed among other bone lining cells within both endosteum and periosteum. Furthermore, OsteoMacs were coisolated with osteoblasts in murine bone explant and calvarial preparations. OsteoMacs made up 15.9% of calvarial preparations and persisted throughout standard osteoblast differentiation cultures. Contrary to previous studies, we showed that it was OsteoMacs and not osteoblasts within these preparations that responded to pathophysiological concentrations of LPS by secreting TNF. Removal of OsteoMacs from calvarial cultures significantly decreased osteocalcin mRNA induction and osteoblast mineralization in vitro. In a Transwell coculture system of enriched osteoblasts and macrophages, we demonstrated that macrophages were required for efficient osteoblast mineralization in response to the physiological remodeling stimulus, elevated extracellular calcium. Notably, OsteoMacs were closely associated with areas of bone modeling in situ, forming a distinctive canopy structure covering >75% of mature osteoblasts on diaphyseal endosteal surfaces in young growing mice. Depletion of OsteoMacs in vivo using the macrophage-Fas-induced apoptosis (MAFIA) mouse caused complete loss of osteoblast bone-forming surface at this modeling site. Overall, we have demonstrated that OsteoMacs are an integral component of bone tissues and play a novel role in bone homeostasis through regulating osteoblast function. These observations implicate OsteoMacs, in addition to osteoclasts and osteoblasts, as principal participants in bone dynamics.

Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data from 16 randomized controlled trials

Abstract: PURPOSE Since our individual patient data (IPD) meta-analysis (MA) of supportive care and chemotherapy for non-small-cell lung cancer (NSCLC), published in 1995, many trials have been completed. An updated, IPD MA has been carried out to assess newer regimens and determine conclusively the effect of chemotherapy. METHODS Systematic searches for randomized controlled trials (RCTs) were undertaken, followed by central collection, checking, and reanalysis of updated IPD. Results from RCTs were combined to calculate individual and pooled hazard ratios (HRs). RESULTS Data were obtained from 2,714 patients from 16 RCTs. There were 1,293 deaths among 1,399 patients assigned supportive care and chemotherapy and 1,240 among 1,315 assigned supportive care alone. Results showed a significant benefit of chemotherapy (HR, 0.77; 95% CI, 0.71 to 0.83; P

Baseline Serum 25-Hydroxy Vitamin D Is Predictive of Future Glycemic Status and Insulin Resistance: The Medical Research Council Ely Prospective Study 1990–2000

Abstract: OBJECTIVE— Accumulating epidemiological evidence suggests that hypovitaminosis D may be associated with type 2 diabetes and related metabolic risks. However, prospective data using the biomarker serum 25-hydroxyvitamin D [25(OH)D] are limited and therefore examined in the present study. RESEARCH DESIGN AND METHODS— A total of 524 randomly selected nondiabetic men and women, aged 40–69 years at baseline, with measurements for serum 25(OH)D and IGF-1 in the population-based Ely Study, had glycemic status (oral glucose tolerance), lipids, insulin, anthropometry, and blood pressure measured and metabolic syndrome risk (metabolic syndrome z score) derived at baseline and at 10 years of follow-up. RESULTS— Age-adjusted baseline mean serum 25(OH)D was greater in men (64.5 nmol/l [95% CI 61.2–67.9]) than women (57.2 nmol/l [54.4,60.0]) and varied with season (highest late summer). Baseline 25(OH)D was associated inversely with 10-year risk of hyperglycemia (fasting glucose: β = −0.0023, P = 0.019; 2-h glucose: β = −0.0097, P = 0.006), insulin resistance (fasting insulin β = −0.1467, P = 0.010; homeostasis model assessment of insulin resistance [HOMA-IR]: β = −0.0059, P = 0.005), and metabolic syndrome z score (β = −0.0016, P = 0.048) after adjustment for age, sex, smoking, BMI, season, and baseline value of each metabolic outcome variable. Associations with 2-h glucose, insulin, and HOMA-IR remained significant after further adjustment for IGF-1, parathyroid hormone, calcium, physical activity, and social class. CONCLUSIONS— This prospective study reports inverse associations between baseline serum 25(OH)D and future glycemia and insulin resistance. These associations are potentially important in understanding the etiology of abnormal glucose metabolism and warrant investigation in larger, specifically designed prospective studies and randomized controlled trials of supplementation.

Promoting coherent minimum reporting guidelines for biological and biomedical investigations: the MIBBI project

Abstract: The Minimum Information for Biological and Biomedical Investigations (MIBBI) project aims to foster the coordinated development of minimum-information checklists and provide a resource for those exploring the range of extant checklists.

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

Abstract: Gene-environmental interaction (G x E) between a common functional polymorphism in the promoter region of the serotonin transporter gene (5-HTT) and environmental adversity on the onset of depression in humans has been found in fifteen independent studies. It is supported by evidence from animal experiments, pharmacological challenge and neuroimaging investigations. However, negative findings have been reported in two large samples. We explore reasons for the inconsistencies and suggest means to their resolution. Sample age and gender composition emerge as important factors. While the G x E has been consistently detected in young adult samples, there are contradictory findings in adolescent boys and elderly people. The method of assessment of environmental adversity is also important with detailed interview-based approaches being associated with positive G x E findings. Unresolved issues in the definition of the genotype include the dominance of alleles and influence of other polymorphisms, both in 5-HTT and other genes. Assessment of multiple adverse outcomes, including depression, substance use and self-destructive behaviour is needed to clarify the generalisability of the G x E pathogenic mechanisms. Biological and behavioural intermediate phenotypes are yet to be exploited to understand the mechanisms underlying the G x E.

Vitamin D deficiency: a global perspective

Abstract: The prevalence of clinical vitamin D deficiency (rickets and osteomalacia) is high in many parts of the world, and there is a resurgence of rickets among children of ethnic minority groups in Europe and Australasia. Plasma 25-hydroxyvitamin D concentration (25OHD) is a useful risk marker of clinical vitamin D deficiency. This review summarizes the factors that contribute to differences in 25OHD among populations and provides an overview of the prevalence of low vitamin D status worldwide. It discusses the controversies that surround the interpretation of 25OHD, other proposed indices of vitamin D adequacy and dietary reference values for vitamin D, and describes the emerging evidence that a very low calcium intake may contribute to the etiology of rickets in Africa and Asia. There is an urgent need for action to address the global burden of rickets and osteomalacia.

Changes in the risk of death after HIV seroconversion compared with mortality in the general population.

Abstract: Context Mortality among human immunodeficiency virus (HIV)–infected individuals has decreased dramatically in countries with good access to treatment and may now be close to mortality in the general uninfected population. Objective To evaluate changes in the mortality gap between HIV-infected individuals and the general uninfected population. Design, Setting, and Population Mortality following HIV seroconversion in a large multinational collaboration of HIV seroconverter cohorts (CASCADE) was compared with expected mortality, calculated by applying general population death rates matched on demographic factors. A Poisson-based model adjusted for duration of infection was constructed to assess changes over calendar time in the excess mortality among HIV-infected individuals. Data pooled in September 2007 were analyzed in March 2008, covering years at risk 1981-2006. Main Outcome Measure Excess mortality among HIV-infected individuals compared with that of the general uninfected population. Results Of 16 534 individuals with median duration of follow-up of 6.3 years (range, 1 day to 23.8 years), 2571 died, compared with 235 deaths expected in an equivalent general population cohort. The excess mortality rate (per 1000 person-years) decreased from 40.8 (95% confidence interval [CI], 38.5-43.0; 1275.9 excess deaths in 31 302 person-years) before the introduction of highly active antiretroviral therapy (pre-1996) to 6.1 (95% CI, 4.8-7.4; 89.6 excess deaths in 14 703 person-years) in 2004-2006 (adjusted excess hazard ratio, 0.05 [95% CI, 0.03-0.09] for 2004-2006 vs pre-1996). By 2004-2006, no excess mortality was observed in the first 5 years following HIV seroconversion among those infected sexually, though a cumulative excess probability of death remained over the longer term (4.8% [95% CI, 2.5%-8.6%] in the first 10 years among those aged 15-24 years). Conclusions Mortality rates for HIV-infected persons have become much closer to general mortality rates since the introduction of highly active antiretroviral therapy. In industrialized countries, persons infected sexually with HIV now appear to experience mortality rates similar to those of the general population in the first 5 years following infection, though a mortality excess remains as duration of HIV infection lengthens.

Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis.

Abstract: Posttranscriptional gene regulation by microRNAs (miRNAs) is important for many aspects of development, homeostasis, and disease. Here, we show that reduction of endothelial miRNAs by cell-specific inactivation of Dicer, the terminal endonuclease responsible for the generation of miRNAs, reduces postnatal angiogenic response to a variety of stimuli, including exogenous VEGF, tumors, limb ischemia, and wound healing. Furthermore, VEGF regulated the expression of several miRNAs, including the up-regulation of components of the c-Myc oncogenic cluster miR-17-92. Transfection of endothelial cells with components of the miR-17-92 cluster, induced by VEGF treatment, rescued the induced expression of thrombospondin-1 and the defect in endothelial cell proliferation and morphogenesis initiated by the loss of Dicer. Thus, endothelial miRNAs regulate postnatal angiogenesis and VEGF induces the expression of miRNAs implicated in the regulation of an integrated angiogenic response.

Prediction of human errors by maladaptive changes in event-related brain networks.

Abstract: Humans engaged in monotonous tasks are susceptible to occasional errors that may lead to serious consequences, but little is known about brain activity patterns preceding errors. Using functional MRI and applying independent component analysis followed by deconvolution of hemodynamic responses, we studied error preceding brain activity on a trial-by-trial basis. We found a set of brain regions in which the temporal evolution of activation predicted performance errors. These maladaptive brain activity changes started to evolve ≈30 sec before the error. In particular, a coincident decrease of deactivation in default mode regions of the brain, together with a decline of activation in regions associated with maintaining task effort, raised the probability of future errors. Our findings provide insights into the brain network dynamics preceding human performance errors and suggest that monitoring of the identified precursor states may help in avoiding human errors in critical real-world situations.

Environmental determinants of active travel in youth: A review and framework for future research

Abstract: Many youth fail to meet the recommended guidelines for physical activity. Walking and cycling, forms of active travel, have the potential to contribute significantly towards overall physical activity levels. Recent research examining the associations between physical activity and the environment has shown that environmental factors play a role in determining behaviour in children and adolescents. However, links between the environment and active travel have received less attention. Twenty four studies were identified which examined the associations between the environment (perceived or objectively measured) and active travel among youth aged 5–18 years. Findings were categorised according to the location of the environmental measure examined; attributes of the neighbourhood, destination and the route between home and destination. Results from the reviewed studies indicated that youth active travel is positively associated with social interactions, facilities to assist active travel and urban form in the neighbourhood as well as shorter route length and road safety en-route. A conceptual framework is presented which highlights the associations between active travel behaviours and environmental factors, drawing upon both existing and hypothesised relationships. We provide a review of the available literature and present a novel theoretical framework that integrates the environment into the wider decision making process around travel choices for children and adolescents. Further work should explore associations where gaps in understanding have been identified, and account for the main moderators of behaviour so hypothesised associations can be confirmed.

Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia

Abstract: Understanding cancer pathogenesis requires knowledge of not only the specific contributory genetic mutations but also the cellular framework in which they arise and function. Here we explore the clonal evolution of a form of childhood precursor-B cell acute lymphoblastic leukemia that is characterized by a chromosomal translocation generating a TEL-AML1 fusion gene. We identify a cell compartment in leukemic children that can propagate leukemia when transplanted in mice. By studying a monochorionic twin pair, one preleukemic and one with frank leukemia, we establish the lineal relationship between these "cancer-propagating" cells and the preleukemic cell in which the TEL-AML1 fusion first arises or has functional impact. Analysis of TEL-AML1-transduced cord blood cells suggests that TEL-AML1 functions as a first-hit mutation by endowing this preleukemic cell with altered self-renewal and survival properties.

HP1-β mobilization promotes chromatin changes that initiate the DNA damage response

Abstract: The earliest known response to chromosomal DNA breakage is the phosphorylation of the histone H2AX. Ayoub et al. have now identified a dynamic change in chromatin that promotes this phosphorylation step. DNA breaks swiftly mobilize the chromatin factor HP1-β, and via a previously unrecognized signalling cascade involving a phosphorylation step carried out by casein kinase 2, H2AX becomes phosphorylated and the DNA damage response is under way. A phosphorylation step carried out by casein kinase 2, coupled with mobilization of the chromatin factor HP1-β, helps to initiate the DNA damage response by promoting phosphorylation of histone H2AX. Minutes after DNA damage, the variant histone H2AX is phosphorylated by protein kinases of the phosphoinositide kinase family, including ATM, ATR or DNA-PK1. Phosphorylated (γ)-H2AX—which recruits molecules that sense or signal the presence of DNA breaks, activating the response that leads to repair2,3—is the earliest known marker of chromosomal DNA breakage. Here we identify a dynamic change in chromatin that promotes H2AX phosphorylation in mammalian cells. DNA breaks swiftly mobilize heterochromatin protein 1 (HP1)-β (also called CBX1), a chromatin factor bound to histone H3 methylated on lysine 9 (H3K9me). Local changes in histone-tail modifications are not apparent. Instead, phosphorylation of HP1-β on amino acid Thr 51 accompanies mobilization, releasing HP1-β from chromatin by disrupting hydrogen bonds that fold its chromodomain around H3K9me. Inhibition of casein kinase 2 (CK2), an enzyme implicated in DNA damage sensing and repair4,5,6, suppresses Thr 51 phosphorylation and HP1-β mobilization in living cells. CK2 inhibition, or a constitutively chromatin-bound HP1-β mutant, diminishes H2AX phosphorylation. Our findings reveal an unrecognized signalling cascade that helps to initiate the DNA damage response, altering chromatin by modifying a histone-code mediator protein, HP1, but not the code itself.

cAMP-dependent signaling as a core component of the mammalian circadian pacemaker.

Abstract: The mammalian circadian clockwork is modeled as transcriptional and posttranslational feedback loops, whereby circadian genes are periodically suppressed by their protein products. We show that adenosine 3',5'-monophosphate (cAMP) signaling constitutes an additional, bona fide component of the oscillatory network. cAMP signaling is rhythmic and sustains the transcriptional loop of the suprachiasmatic nucleus, determining canonical pacemaker properties of amplitude, phase, and period. This role is general and is evident in peripheral mammalian tissues and cell lines, which reveals an unanticipated point of circadian regulation in mammals qualitatively different from the existing transcriptional feedback model. We propose that daily activation of cAMP signaling, driven by the transcriptional oscillator, in turn sustains progression of transcriptional rhythms. In this way, clock output constitutes an input to subsequent cycles.

Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study

Abstract: BACKGROUND: The SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts 250 cells/microL may reduce both OD and serious non-AIDS events These findings require validation in a large, randomized clinical trial