Developmental seizures and mortality result from reducing GABAᴀ receptor α2-subunit interaction with collybistin

Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABAARs) that are enriched at functionally diverse synapses via mechanisms that remain unclear. Using isothermal titration calorimetry and complementary methods we demonstrate an exclusive low micromolar binding of collybistin to the α2-subunit of GABAARs. To explore the biological relevance of collybistin-α2-subunit selectivity, we generate mice with a mutation in the α2-subunit-collybistin binding region (Gabra2-1). The mutation results in loss of a distinct subset of inhibitory synapses and decreased amplitude of inhibitory synaptic currents. Gabra2–1 mice have a striking phenotype characterized by increased susceptibility to seizures and early mortality. Surviving Gabra2-1 mice show anxiety and elevations in electroencephalogram δ power, which are ameliorated by treatment with the α2/α3-selective positive modulator, AZD7325. Taken together, our results demonstrate an α2-subunit selective binding of collybistin, which plays a key role in patterned brain activity, particularly during development

Effects of air pollution and the introduction of the London Low Emission Zone on the prevalence of respiratory and allergic symptoms in schoolchildren in East London: a sequential cross-sectional study

The adverse effects of traffic-related air pollution on children’s respiratory health have been widely reported, but few studies have evaluated the impact of traffic-control policies designed to reduce urban air pollution. We assessed associations between traffic-related air pollutants and respiratory/allergic symptoms amongst 8–9 year-old schoolchildren living within the London Low Emission Zone (LEZ). Information on respiratory/allergic symptoms was obtained using a parent-completed questionnaire and linked to modelled annual air pollutant concentrations based on the residential address of each child, using a multivariable mixed effects logistic regression analysis. Exposure to traffic-related air pollutants was associated with current rhinitis: NOx (OR 1.01, 95% CI 1.00–1.02), NO2 (1.03, 1.00–1.06), PM10 (1.16, 1.04–1.28) and PM2.5 (1.38, 1.08–1.78), all per μg/m3 of pollutant, but not with other respiratory/allergic symptoms. The LEZ did not reduce ambient air pollution levels, or affect the prevalence of respiratory/allergic symptoms over the period studied. These data confirm the previous association between traffic-related air pollutant exposures and symptoms of current rhinitis. Importantly, the London LEZ has not significantly improved air quality within the city, or the respiratory health of the resident population in its first three years of operation. This highlights the need for more robust measures to reduce traffic emissions

Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation

Body Segment Differences in Surface Area, Skin Temperature and 3D Displacement and the Estimation of Heat Balance during Locomotion in Hominins

The conventional method of estimating heat balance during locomotion in humans and other hominins treats the body as an undifferentiated mass. This is problematic because the segments of the body differ with respect to several variables that can affect thermoregulation. Here, we report a study that investigated the impact on heat balance during locomotion of inter-segment differences in three of these variables: surface area, skin temperature and rate of movement. The approach adopted in the study was to generate heat balance estimates with the conventional method and then compare them with heat balance estimates generated with a method that takes into account inter-segment differences in surface area, skin temperature and rate of movement. We reasoned that, if the hypothesis that inter-segment differences in surface area, skin temperature and rate of movement affect heat balance during locomotion is correct, the estimates yielded by the two methods should be statistically significantly different. Anthropometric data were collected on seven adult male volunteers. The volunteers then walked on a treadmill at 1.2 m/s while 3D motion capture cameras recorded their movements. Next, the conventional and segmented methods were used to estimate the volunteers' heat balance while walking in four ambient temperatures. Lastly, the estimates produced with the two methods were compared with the paired t-test. The estimates of heat balance during locomotion yielded by the two methods are significantly different. Those yielded by the segmented method are significantly lower than those produced by the conventional method. Accordingly, the study supports the hypothesis that inter-segment differences in surface area, skin temperature and rate of movement impact heat balance during locomotion. This has important implications not only for current understanding of heat balance during locomotion in hominins but also for how future research on this topic should be approached

Tales of the unexpected: the selection of British party leaders since 1963

Jeremy Corbyn’s election as Leader of the Labour Party in 2015 stunned observers and practitioners of British politics alike. In this article, we first outline a theoretical framework that purports to explain why political parties operating in parliamentary systems choose the leaders they do. We then examine 32 leadership successions involving five major British parties since 1963, and note that many of these were unexpected, in that they were triggered by unforeseen circumstances, such as the sudden death or resignation of the incumbent. Examining each party in turn, we briefly explain why the winners won and identify at least eight cases (a quarter of our sample) where a candidate widely expected to prevail at the outset was ultimately defeated by a ‘dark horse’, ‘second favourite’ or even ‘rank outsider’. Of these, Corbyn’s election in 2015 was the most unexpected and, consistent with the findings of studies of party leadership conventions in other parliamentary systems, namely Canada and Spain, suggests that ideological and policy concerns are sometimes more important than considerations of party unity and electability, especially when a leadership contest is dominated by party activists

Sialyl Residues Modulate LPS-Mediated Signaling through the Toll-Like Receptor 4 Complex

We previously reported that neuraminidase (NA) pretreatment of human PBMCs markedly increased their cytokine response to lipopolysaccharide (LPS). To study the mechanisms by which this occurs, we transfected HEK293T cells with plasmids encoding TLR4, CD14, and MD2 (three components of the LPS receptor complex), as well as a NFκB luciferase reporting system. Both TLR4 and MD2 encoded by the plasmids are α-2,6 sialylated. HEK293T cells transfected with TLR4/MD2/CD14 responded robustly to the addition of LPS; however, omission of the MD2 plasmid abrogated this response. Addition of culture supernatants from MD2 (sMD2)-transfected HEK293T cells, but not recombinant, non-glycosylated MD2 reconstituted this response. NA treatment of sMD2 enhanced the LPS response as did NA treatment of the TLR4/CD14-transfected cell supplemented with untreated sMD2, but optimal LPS-initiated responses were observed with NA-treated TLR4/CD14-transfected cells supplemented with NA-treated sMD2. We hypothesized that removal of negatively charged sialyl residues from glycans on the TLR4 complex would hasten the dimerization of TLR4 monomers required for signaling. Co-transfection of HEK293T cells with separate plasmids encoding either YFP- or FLAG-tagged TLR4, followed by treatment with NA and stimulation with LPS, led to an earlier and more robust time-dependent dimerization of TLR4 monomers on co-immunoprecipitation, compared to untreated cells. These findings were confirmed by fluorescence resonance energy transfer (FRET) analysis. Overexpression of human Neu1 increased LPS-initiated TLR4-mediated NFκB activation and a NA inhibitor suppressed its activation. We conclude that (1) sialyl residues on TLR4 modulate LPS responsiveness, perhaps by facilitating clustering of the homodimers, and that (2) sialic acid, and perhaps other glycosyl species, regulate MD2 activity required for LPS-mediated signaling. We speculate that endogenous sialidase activity mobilized during cell activation may play a role in this regulation

The impact of personalisation on people from Chinese backgrounds: accounts of social care experience

The limited research that considers people from black and minority ethnic communities experiences of personalisation tends to focus on personal budgets rather than personalisation per se. This article provides an opportunity to hear the voices of people from Chinese backgrounds and their experiences of personalisation. The study used individual semi-structured interviews and focus groups to collect data from people from Chinese backgrounds who lived in England, were aged between 18 and 70 and received social care for a physical disability. Data were analysed using an iterative and thematic approach, with early analysis informing the subsequent analytical rounds. The findings reveal that personalisation has the potential to transform the lives of people from Chinese backgrounds, especially when tailored support is available for people to understand and access personal budgets and put them to creative use. However, the impact of personalisation is barely evident because few eligible individuals access personal budgets or participate in co-production. This is related to a lack of encouragement for service users to become genuine partners in understanding, designing, commissioning and accessing a diverse range of social care services to meet their cultural and social care needs

Molecular measurement of BCR-ABL transcript variations in chronic myeloid leukemia patients in cytogenetic remission

<p>Abstract</p> <p>Background</p> <p>The monitoring of <it>BCR-ABL </it>transcript levels by real-time quantitative polymerase chain reaction (RT-qPCR) has become important to assess minimal residual disease (MRD) and standard of care in the treatment of chronic myeloid leukemia (CML). In this study, we performed a prospective, sequential analysis using RT-qPCR monitoring of <it>BCR-ABL </it>gene rearrangements in blood samples from 91 CML patients in chronic phase (CP) who achieved complete cytogenetic remission (CCyR) and major molecular remission (MMR) throughout imatinib treatment.</p> <p>Methods</p> <p>The absolute level of <it>BCR-ABL </it>transcript from peripheral blood was serially measured every 4 to 12 weeks by RT-qPCR. Only level variations > 0.5%, according to the international scale, was considered positive. Sequential cytogenetic analysis was also performed in bone marrow samples from all patients using standard protocols.</p> <p>Results</p> <p>Based on sequential analysis of <it>BCR-ABL </it>transcripts, the 91 patients were divided into three categories: (A) 57 (62.6%) had no variation on sequential analysis; (B) 30 (32.9%) had a single positive variation result obtained in a single sample; and (C) 4 (4.39%) had variations of <it>BCR-ABL </it>transcripts in at least two consecutive samples. Of the 34 patients who had elevated levels of transcripts (group B and C), 19 (55.8%) had a < 1% of <it>BCR-ABL/BCR </it>ratio, 13 (38.2%) patients had a 1% to 10% increase and 2 patients had a >10% increase of RT-qPCR. The last two patients had lost a CCyR, and none of them showed mutations in the <it>ABL </it>gene. Transient cytogenetic alterations in Ph-negative cells were observed in five (5.5%) patients, and none of whom lost CCyR.</p> <p>Conclusions</p> <p>Despite an increase levels of <it>BCR-ABL/BCR </it>ratio variations by RT-qPCR, the majority of CML patients with MMR remained in CCyR. Thus, such single variations should neither be considered predictive of subsequent failure and nor an indication for altering imatinib dose or switching to second generation therapy. Changing of imatinib on the basis of <it>BCR-ABL/BCR</it>% sustained increase and mutational studies is a prudent approach for preserving other therapeutic options in imatinib-resistant patients.</p

Experiences of integrated care for dementia from family and carer perspectives: A framework analysis of massive open online course discussion board posts

Background Integrated Care for dementia is an increasingly popular approach to supporting people with dementia, bringing services together to form a single cohesive provision for service users. This approach is still in its infancy but has the potential to improve the management of dementia, social care and to enhance the patient experience. Aims To understand views and experiences of integrated health and social care for dementia from the perspective of carers, families, healthcare professionals and researchers. Methods Crowdsourcing views and experiences from 'Bridging the Dementia Divide', a massive open online course at the University of Derby, provide a rich source of qualitative data from carers, families and healthcare professionals. We analysed 847 massive open online course discussion board posts using a Framework Analysis approach. Results Participants described how Integrated Care for dementia should be person-centred and holistic, involving a multidisciplinary team of health and social care practitioners, as well as the patient, the family and the wider community. The establishment of Integrated Care for dementia was viewed positively.N/

Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project

<p>Abstract</p> <p>Background</p> <p>There is a lack of knowledge regarding the frequency of disease associated polymorphisms in populations and population attributable risk for many populations remains unknown. Factors that could affect the association of the allele with disease, either positively or negatively, such as race, ethnicity, and gender, may not be possible to determine without population based allele frequencies.</p> <p>Here we used a panel of 51 polymorphisms previously associated with at least one disease and determined the allele frequencies within the entire Personalized Medicine Research Project population based cohort. We compared these allele frequencies to those in dbSNP and other data sources stratified by race. Differences in allele frequencies between self reported race, region of origin, and sex were determined.</p> <p>Results</p> <p>There were 19544 individuals who self reported a single racial category, 19027 or (97.4%) self reported white Caucasian, and 11205 (57.3%) individuals were female. Of the 11,208 (57%) individuals with an identifiable region of origin 8337 or (74.4%) were German.</p> <p>41 polymorphisms were significantly different between self reported race at the 0.05 level. Stratification of our Caucasian population by self reported region of origin revealed 19 polymorphisms that were significantly different (p = 0.05) between individuals of different origins. Further stratification of the population by gender revealed few significant differences in allele frequencies between the genders.</p> <p>Conclusions</p> <p>This represents one of the largest population based allele frequency studies to date. Stratification by self reported race and region of origin revealed wide differences in allele frequencies not only by race but also by region of origin within a single racial group. We report allele frequencies for our Asian/Hmong and American Indian populations; these two minority groups are not typically selected for population allele frequency detection. Population wide allele frequencies are important for the design and implementation of studies and for determining the relevance of a disease associated polymorphism for a given population.</p