Identification of a 200-kD, brefeldin-sensitive protein on Golgi membranes

A mAb AD7, raised against canine liver Golgi membranes, recognizes a novel, 200-kD protein (p200) which is found in a wide variety of cultured cell lines. Immunofluorescence staining of cultured cells with the AD7 antibody produced intense staining of p200 in the juxtanuclear Golgi complex and more diffuse staining of p200 in the cytoplasm. The p200 protein in the Golgi complex was colocalized with other Golgi proteins, including mannosidase II and beta-COP, a coatomer protein. Localization of p200 by immunoperoxidase staining at the electron microscopic level revealed concentrations of p200 at the dilated rims of Golgi cisternae. Biochemical studies showed that p200 is a peripheral membrane protein which partitions to the aqueous phase of Triton X-114 solutions and is phosphorylated. The p200 protein is located on the cytoplasmic face of membranes, since it was accessible to trypsin digestion in microsomal preparations. and is recovered in approximately equal amounts in membrane pellets and in the cytosol of homogenized cells. Immunofluorescence staining of normal rat kidney cells exposed to the toxin brefeldin A (BFA), showed that there was very rapid redistribution of p200, which was dissociated from Golgi membranes in the presence of this drug. The effect of BFA was reversible, since upon removal of the toxin, AD7 rapidly reassociated with the Golgi complex. In the BFA-resistant cell line PtK1, BFA failed to cause redistribution of p200 from Golgi membranes. Taken together, these results indicate that the p200 Golgi membrane-associated protein has many properties in common with the coatomer protein, beta-COP

Changes over time in the health and functioning of older people moving into care homes: analysis of data from the English Longitudinal Study of Ageing

Background: the number of people requiring care home support is projected to rise in future years, but little information is available on the needs of new care home residents. Objective: to measure the health and functioning of people moving into care homes and how they have changed between 2002 and 2015. Setting: English Longitudinal Study of Ageing. Participants: two hundred fifty-four of the 313 (1.99%) individuals who moved from the community into a care home, and were interviewed in the survey wave prior to entry. Main outcome measures: changes over time for number of health conditions and functional deficits (deficits in activities of daily living (ADL), and instrumental ADLs (IADLs)), assessed in the survey wave prior to admission. Results: over time there were significant increases in the total number of health conditions and functional deficits amongst soon to be care home entrants (P = 0.0011), the proportion with high blood pressure (OR 1.37, 95% CI: 1.17-1.62, P < 0.0001), memory problems (OR 1.33, 95% CI: 1.11-1.61, P = 0.0021) or total number of IADL deficits (P = 0.008). Non-significant increases were observed in the proportion of care home entrants with cancer (OR 1.23, 95% CI: 0.93-1.65, P = 0.15), lung disease (OR 1.21, 95% CI: 0.85-1.75), heart disease (OR 1.12, 95% CI: 0.95-1.30) and arthritis (OR 1.11, 95% CI: 0.95-1.30). Stroke and ADL deficits did not increase. No differential ageing effect was observed. Conclusions: the support needs of care home entrants in England appear to be increasing over time. This has important implications for the provision and funding of care home places and community services.FM was supported by the Medical Research Council [Grant: MC_U105292687]. DS was funded by the National Institute for Health Research School for Primary Care Research (NIHR SPCR)

Epidemiology of Subpatent Plasmodium Falciparum Infection: Implications for Detection of Hotspots with Imperfect Diagnostics.

At the local level, malaria transmission clusters in hotspots, which may be a group of households that experience higher than average exposure to infectious mosquitoes. Active case detection often relying on rapid diagnostic tests for mass screen and treat campaigns has been proposed as a method to detect and treat individuals in hotspots. Data from a cross-sectional survey conducted in north-western Tanzania were used to examine the spatial distribution of Plasmodium falciparum and the relationship between household exposure and parasite density. Dried blood spots were collected from consenting individuals from four villages during a survey conducted in 2010. These were analysed by PCR for the presence of P. falciparum, with the parasite density of positive samples being estimated by quantitative PCR. Household exposure was estimated using the distance-weighted PCR prevalence of infection. Parasite density simulations were used to estimate the proportion of infections that would be treated using a screen and treat approach with rapid diagnostic tests (RDT) compared to targeted mass drug administration (tMDA) and Mass Drug Administration (MDA). Polymerase chain reaction PCR analysis revealed that of the 3,057 blood samples analysed, 1,078 were positive. Mean distance-weighted PCR prevalence per household was 34.5%. Parasite density was negatively associated with transmission intensity with the odds of an infection being subpatent increasing with household exposure (OR 1.09 per 1% increase in exposure). Parasite density was also related to age, being highest in children five to ten years old and lowest in those > 40 years. Simulations of different tMDA strategies showed that treating all individuals in households where RDT prevalence was above 20% increased the number of infections that would have been treated from 43 to 55%. However, even with this strategy, 45% of infections remained untreated. The negative relationship between household exposure and parasite density suggests that DNA-based detection of parasites is needed to provide adequate sensitivity in hotspots. Targeting MDA only to households with RDT-positive individuals may allow a larger fraction of infections to be treated. These results suggest that community-wide MDA, instead of screen and treat strategies, may be needed to successfully treat the asymptomatic, subpatent parasite reservoir and reduce transmission in similar settings

Contourite depositional system after the exit of a strait: Case study from the late Miocene South Rifian Corridor, Morocco

Idealized facies of bottom current deposits (contourites) have been established for fine-grained contourite drifts in modern deep-marine sedimentary environments. Their equivalent facies in the ancient record however are only scarcely recognized due to the weathered nature of most fine-grained deposits in outcrop. Facies related to the erosional elements (i.e. contourite channels) of contourite depositional systems have not yet been properly established and related deposits in outcrop appear non-existent. To better understand the sedimentary facies and facies sequences of contourites, the upper Miocene contourite depositional systems of the South Rifian Corridor (Morocco) is investigated. This contourite depositional system formed by the dense palaeo-Mediterranean Outflow Water. Foraminifera assemblages were used for age-constraints (7.51 to 7.35 Ma) and to determine the continental slope depositional domains. Nine sedimentary facies have been recognized based on lithology, grain-size, sedimentary structures and biogenic structures. These facies were subsequently grouped into five facies associations related to the main interpreted depositional processes (hemipelagic settling, contour currents and gravity flows). The vertical sedimentary facies succession records the tectonically induced, southward migration of the contourite depositional systems and the intermittent behaviour of the palaeo-Mediterranean Outflow Water, which is mainly driven by precession and millennial-scale climate variations. Tides substantially modulated the palaeo-Mediterranean Outflow Water on a sub-annual scale. This work shows exceptional examples of muddy and sandy contourite deposits in outcrop by which a facies distribution model from the proximal continental slope, the contourite channel to its adjacent contourite drift, is proposed. This model serves as a reference for contourite recognition both in modern environments and the ancient record. Furthermore, by establishing the hydrodynamics of overflow behaviour a framework is provided that improves process-based interpretation of deep-water bottom current deposits

social laughter is correlated with an elevated pain threshold

Although laughter forms an important part of human non-verbal communication, it has received rather less attention than it deserves in both the experimental and the observational literatures. Relaxed social (Duchenne) laughter is associated with feelings of wellbeing and heightened affect, a proximate explanation for which might be the release of endorphins. We tested this hypothesis in a series of six experimental studies in both the laboratory (watching videos) and naturalistic contexts (watching stage performances), using change in pain threshold as an assay for endorphin release. The results show that pain thresholds are significantly higher after laughter than in the control condition. This pain-tolerance effect is due to laughter itself and not simply due to a change in positive affect. We suggest that laughter, through an endorphin-mediated opiate effect, may play a crucial role in social bonding

Efficient delivery of RNA Interference to peripheral neurons in vivo using herpes simplex virus

Considerable interest has been focused on inducing RNA interference (RNAi) in neurons to study gene function and identify new targets for disease intervention. Although small interfering RNAs (siRNAs) have been used to silence genes in neurons, in vivo delivery of RNAi remains a major challenge limiting its applications. We have developed a highly efficient method for in vivo gene silencing in dorsal root ganglia (DRG) using replication-defective herpes simplex viral (HSV-1) vectors. HSV-mediated delivery of short-hairpin RNA (shRNA) targeting reporter genes resulted in highly effective and specific silencing in neuronal and non-neuronal cells in culture and in the DRG of mice in vivo including in a transgenic mouse model. We further establish proof of concept by demonstrating in vivo silencing of the endogenous trpv1 gene. These data are the first to show silencing in DRG neurons in vivo by vector-mediated delivery of shRNA. Our results support the utility of HSV vectors for gene silencing in peripheral neurons and the potential application of this technology to the study of nociceptive processes and in pain gene target validation studies

A Rapid, Strong, and Convergent Genetic Response to Urban Habitat Fragmentation in Four Divergent and Widespread Vertebrates

Urbanization is a major cause of habitat fragmentation worldwide. Ecological and conservation theory predicts many potential impacts of habitat fragmentation on natural populations, including genetic impacts. Habitat fragmentation by urbanization causes populations of animals and plants to be isolated in patches of suitable habitat that are surrounded by non-native vegetation or severely altered vegetation, asphalt, concrete, and human structures. This can lead to genetic divergence between patches and in turn to decreased genetic diversity within patches through genetic drift and inbreeding.We examined population genetic patterns using microsatellites in four common vertebrate species, three lizards and one bird, in highly fragmented urban southern California. Despite significant phylogenetic, ecological, and mobility differences between these species, all four showed similar and significant reductions in gene flow over relatively short geographic and temporal scales. For all four species, the greatest genetic divergence was found where development was oldest and most intensive. All four animals also showed significant reduction in gene flow associated with intervening roads and freeways, the degree of patch isolation, and the time since isolation.Despite wide acceptance of the idea in principle, evidence of significant population genetic changes associated with fragmentation at small spatial and temporal scales has been rare, even in smaller terrestrial vertebrates, and especially for birds. Given the striking pattern of similar and rapid effects across four common and widespread species, including a volant bird, intense urbanization may represent the most severe form of fragmentation, with minimal effective movement through the urban matrix

Bolus characteristics based on Magnetic Resonance Angiography

BACKGROUND: A detailed contrast bolus propagation model is essential for optimizing bolus-chasing Computed Tomography Angiography (CTA). Bolus characteristics were studied using bolus-timing datasets from Magnetic Resonance Angiography (MRA) for adaptive controller design and validation. METHODS: MRA bolus-timing datasets of the aorta in thirty patients were analyzed by a program developed with MATLAB. Bolus characteristics, such as peak position, dispersion and bolus velocity, were studied. The bolus profile was fit to a convolution function, which would serve as a mathematical model of bolus propagation in future controller design. RESULTS: The maximum speed of the bolus in the aorta ranged from 5–13 cm/s and the dwell time ranged from 7–13 seconds. Bolus characteristics were well described by the proposed propagation model, which included the exact functional relationships between the parameters and aortic location. CONCLUSION: The convolution function describes bolus dynamics reasonably well and could be used to implement the adaptive controller design

Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease.

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases

Risk aversion in a performativity culture – what can we learn from teachers’ curriculum decision making in history?

Using the notion of risk aversion, this study explores the decisions teachers make when constructing a curriculum. Adopting a qualitative, grounded approach, this study used semi-structured interviews with nine history teachers to examine the decisions they were making during a period of considerable curriculum change in England. Five key categories were identified, which were then defined as risk averse or high risk. The findings show that teachers largely adopt a low risk approach when constructing a curriculum. In particular choice of content, pedagogical and assessment approaches are affected. Also, changes to the curriculum in high stakes examination courses have a major distorting impact on the curriculum choices for the phase of schooling prior to the examination course. This study would suggest that teachers generally aim to maximise examination outcomes through adopting a low risk approach to curriculum change. However, according to the literature, these low risk approaches appear unlikely to improve examination outcomes, whilst at the same time narrowing students’ experience of the curriculum