853 resultados para Karen Lieberman
Resumo:
Robotic multiwell planar patch-clamp has become common in drug development and safety programs because it enables efficient and systematic testing of compounds against ion channels during voltage-clamp. It has not, however, been adopted significantly in other important areas of ion channel research, where conventional patch-clamp remains the favored method. Here, we show the wider potential of the multiwell approach with the ability for efficient intracellular solution exchange, describing protocols and success rates for recording from a range of native and primary mammalian cells derived from blood vessels, arthritic joints and the immune and central nervous systems. The protocol involves preparing a suspension of single cells to be dispensed robotically into 4-8 microfluidic chambers each containing a glass chip with a small aperture. Under automated control, giga-seals and whole-cell access are achieved followed by preprogrammed routines of voltage paradigms and fast extracellular or intracellular solution exchange. Recording from 48 chambers usually takes 1-6 h depending on the experimental design and yields 16-33 cell recordings.
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Some proponents of local knowledge, such as Sillitoe (2010), have expressed second thoughts about its capacity to effect development on the ‘revolutionary’ scale once predicted. Our argument in this article follows a similar route. Recent research into the management of livestock in South Africa makes clear that rural African livestock farmers experience uncertainty in relation to the control of stock diseases. State provision of veterinary services has been significantly reduced over the past decade. Both white and African livestock owners are to a greater extent left to their own devices. In some areas of animal disease management, African livestock owners have recourse to tried-and-tested local remedies, which are largely plant-based. But especially in the critical sphere of tick control, efficacious treatments are less evident, and livestock owners struggle to find adequate solutions to high tickloads. This is particularly important in South Africa in the early twenty-first century because land reform and the freedom to purchase land in the post-apartheid context affords African stockowners opportunities to expand livestock holdings. Our research suggests that the limits of local knowledge in dealing with ticks is one of the central problems faced by African livestock owners. We judge this not only in relation to efficacy but also the perceptions of livestock owners themselves. While confidence and practice varies, and there is increasing resort of chemical acaricides we were struck by the uncertainty of livestock owners over the best strategies.
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Activity within caves provides an important element of the later prehistoric and historic settlement pattern of western Scotland. This contribution reports on a small-scale excavation within Croig Cave, on the coast of north-west Mull, that exposed a 1.95m sequence of midden deposits and cave floors that dated bewteen c 1700 BC and AD 1400. Midden analysis indicated the processing of a .... 950 BC, a penannular copper bracelet a discrete ritual episode within the cycle of otherwise potentially mundane activities. Lead isotope analysis indicates an Irish origin for the copper ore. A piece of iron slag within later midden deposits, dated to c 400 BC, along with high frequencies of wood charcoal, suggest that smithing or smelting may have occurred within the cave. High zinc levels in the historic levels of the midden c AD 1200 might indicate intensive processing of seaweed.
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Recently there has been considerable concern about declines in bee communities in agricultural and natural habitats. The value of pollination to agriculture, provided primarily by bees, is >$200 billion/year worldwide, and in natural ecosystems it is thought to be even greater. However, no monitoring program exists to accurately detect declines in abundance of insect pollinators; thus, it is difficult to quantify the status of bee communities or estimate the extent of declines. We used data from 11 multiyear studies of bee communities to devise a program to monitor pollinators at regional, national, or international scales. In these studies, 7 different methods for sampling bees were used and bees were sampled on 3 different continents. We estimated that a monitoring program with 200–250 sampling locations each sampled twice over 5 years would provide sufficient power to detect small (2–5%) annual declines in the number of species and in total abundance and would cost U.S.$2,000,000. To detect declines as small as 1% annually over the same period would require >300 sampling locations. Given the role of pollinators in food security and ecosystem function, we recommend establishment of integrated regional and international monitoring programs to detect changes in pollinator communities.
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The global atmospheric electric circuit is driven by thunderstorms and electrified rain/shower clouds and is also influenced by energetic charged particles from space. The global circuit maintains the ionosphere as an equipotential at∼+250 kV with respect to the good conducting Earth (both land and oceans). Its “load” is the fair weather atmosphere and semi-fair weather atmosphere at large distances from the disturbed weather “generator” regions. The main solar-terrestrial (or space weather) influence on the global circuit arises from spatially and temporally varying fluxes of galactic cosmic rays (GCRs) and energetic electrons precipitating from the magnetosphere. All components of the circuit exhibit much variability in both space and time. Global circuit variations between solar maximum and solar minimum are considered together with Forbush decrease and solar flare effects. The variability in ion concentration and vertical current flow are considered in terms of radiative effects in the troposphere, through infra-red absorption, and cloud effects, in particular possible cloud microphysical effects from charging at layer cloud edges. The paper identifies future research areas in relation to Task Group 4 of the Climate and Weather of the Sun-Earth System (CAWSES-II) programme.
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Variability in the strength of the stratospheric Lagrangian mean meridional or Brewer-Dobson circulation and horizontal mixing into the tropics over the past three decades are examined using observations of stratospheric mean age of air and ozone. We use a simple representation of the stratosphere, the tropical leaky pipe (TLP) model, guided by mean meridional circulation and horizontal mixing changes in several reanalyses data sets and chemistry climate model (CCM) simulations, to help elucidate reasons for the observed changes in stratospheric mean age and ozone. We find that the TLP model is able to accurately simulate multiyear variability in ozone following recent major volcanic eruptions and the early 2000s sea surface temperature changes, as well as the lasting impact on mean age of relatively short-term circulation perturbations. We also find that the best quantitative agreement with the observed mean age and ozone trends over the past three decades is found assuming a small strengthening of the mean circulation in the lower stratosphere, a moderate weakening of the mean circulation in the middle and upper stratosphere, and a moderate increase in the horizontal mixing into the tropics. The mean age trends are strongly sensitive to trends in the horizontal mixing into the tropics, and the uncertainty in the mixing trends causes uncertainty in the mean circulation trends. Comparisons of the mean circulation and mixing changes suggested by the measurements with those from a recent suite of CCM runs reveal significant differences that may have important implications on the accurate simulation of future stratospheric climate.
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Learned helplessness is a maladaptive response to uncontrollable stress characterized by impaired motor escape responses, reduced motivation and learning deficits. There are important individual differences in the likelihood of becoming helpless following exposure to uncontrollable stress but little is known about the neural mechanisms underlying these individual differences. Here we used structural MRI to measure gray and white matter in individuals with chronic pain, a population at high risk for helplessness due to prolonged exposure to a poorly controlled stressor (pain). Given that self-reported helplessness is predictive of treatment outcomes in chronic pain, understanding such differences might provide valuable clinical insight. We found that the magnitude of self-reported helplessness correlated with cortical thickness in the supplementary motor area (SMA) and midcingulate cortex, regions implicated in cognitive aspects of motor behavior. We then examined the white matter connectivity of these regions and found that fractional anisotropy of connected white matter tracts along the corticospinal tract was associated with helplessness and mediated the relationship between SMA cortical thickness and helplessness. These data provide novel evidence that links individual differences in the motor output pathway with perceived helplessness over a chronic and poorly controlled stressor.
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Lord Kelvin (William Thomson) made important contributions to the study of atmospheric elec- tricity during a brief but productive period from 1859–1861. By 1859 Kelvin had recognised the need for “incessant recording” of atmospheric electrical parameters, and responded by inventing both the water dropper equaliser for measuring the atmospheric potential gradient (PG), and photographic data logging. The water dropper equaliser was widely adopted internationally and is still in use today. Following theoretical consid- erations of electric field distortion by local topography, Kelvin developed a portable electrometer, using it to investigate the PG on the Scottish island of Arran. During these environmental measurements, Kelvin may have unwittingly detected atmospheric PG changes during solar activity in August / September 1859 associated with the “Carrington event”, which is interesting in the context of his later statements that solar magnetic influ- ence on the Earth was impossible. Kelvin’s atmospheric electricity work presents an early representative study in quantitative environmental physics, through the application of mathematical principles to an environmental problem, the design and construction of bespoke instrumentation for real world measurements and recognising the limitations of the original theoretical view revealed by experimental work
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We undertook a study to investigate the views of both students and staff in our department towards assessment in mathematics, as a precursor to considering increasing the diversity of assessment types. In a survey and focus group there was reasonable agreement amongst the students with regards major themes such as mode of assessment. However, this level of agreement was not seen amongst the staff, where discussions regarding diversity in mathematics assessment definitely revealed a difference of opinion. As a consequence, we feel that the greatest barriers to increasing diversity may be with staff, and so more efforts are needed to communicate to staff the advantages and disadvantages, in order to give them greater confidence in trying a range of assessment types.
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The plume from the 2011 eruption of Grímsvötn was highly electrically charged, as shown by the considerable lightning activity measured by the United Kingdom Met Office’s low-frequency lightning detection network. Previous measurements of volcanic plumes have shown that ash particles are electrically charged up to hundreds of kilometers away from the vent, which indicates that the ash continues to charge in the plume [R. G. Harrison, K. A. Nicoll, Z. Ulanowski, and T. A. Mather, Environ. Res. Lett. 5 024004 (2010); H. Hatakeyama J. Meteorol. Soc. Jpn. 27 372 (1949)]. In this Letter, we study triboelectric charging of different size fractions of a sample of volcanic ash experimentally. Consistently with previous work, we find that the particle size distribution is a determining factor in the charging. Specifically, our laboratory experiments demonstrate that the normalized span of the particle size distribution plays an important role in the magnitude of charging generated. The influence of the normalized span on plume charging suggests that all ash plumes are likely to be charged, with implications for remote sensing and plume lifetime through scavenging effects.
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The character of settlement patterns within the late Mesolithic communities of north-west Europe is a topic of substantial debate. An important case study concerns the five shell middens on the island of Oronsay, Inner Hebrides, western Scotland. Two conflicting interpretations have been proposed: the evidence from seasonality indicators and stable isotope analysis of human bones has been used to support a model of year-round settlement on this small island; alternatively, the middens have been interpreted as resulting from short-term intermittent visits to Oronsay within a regionally mobile settlement pattern. We contribute to this debate by describing Storakaig, a newly discovered site on the nearby island of Islay, undertaking a Bayesian chronological analysis and providing evidence for technological continuity between Oronsay and sites elsewhere in the region. While this new evidence remains open to alternative interpretation, we suggest that it makes regional mobility rather than year-round settlement on Oronsay a more viable interpretation for the Oronsay middens. Our analysis also confirms the likely overlap of the late Mesolithic with the earliest Neolithic within western Scotland.
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BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
Resumo:
The INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I(2) measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I(2) measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI> or =32.5, 35.0, 37.5, 40.0 kg/m(2) versus BMI<25 kg/m(2)) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.