Presynaptic actions of 4-Aminopyridine and γ-aminobutyric acid on rat sympathetic ganglia in vitro

Responses to bath-applications of 4-aminopyridine (4-AP) and -aminobutyric acid (GABA) were recorded intracellularly from neurones in the rat isolated superior cervical ganglion. 4-aminopyridine (0.1–1.0 mmol/l) usually induced spontaneous action potentials and excitatory postsynaptic potentials (EPSPs), which were blocked by hexamethonium. Membrane potential was unchanged; spike duration was slightly increased. Vagus nerve B-and C-fibre potentials were prolonged. In 4-AP solution (0.1–0.3 mmol/l), GABA (0.1 mmol/l), 3-aminopropanesulphonic acid or muscimol evoked bursts of spikes and EPSPs in addition to a neuronal depolarization. These bursts, which were not elicited by glycine, glutamate, taurine or (±)-baclofen, were completely antagonised by hexamethonium, tetrodotoxin or bicuculline methochloride. It is concluded that: (a) 4-AP has a potent presynaptic action on sympathetic ganglia; (b) presynaptic actions of GABA can be recorded postsynaptically in the presence of 4-AP; and (c) the presynaptic GABA-receptors revealed in this condition are similar to those on the postsynaptic membrane

Dopamine receptor D4 (DRD4) polymorphisms with reduced functional potency intensify atrophy in syndrome-specific sites of frontotemporal dementia.

ObjectiveWe aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD4 is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration.Methods337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD4 genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures.ResultsDRD4 dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity.ConclusionsWe conclude that DRD4 polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD

Introduction: Ideology, propaganda, and political discourse in the Xi Jinping era

The ideology, propaganda, and political discourse of the Communist Party of China (CPC) have continued to function as key elements of the political system of the People’s Republic of China (PRC) in the post-Maoist period since 1978. In the first term of the Xi Jinping leadership (2012–2017), the CPC, for instance, elaborated on its guiding ideological concepts, devised inventive ideational framings of phenomena usually perceived as tangible (such as the BNew Normal^), engaged in complex intellectual debates on crucial topics (such as Beco-civilization^), intensified and diversified its argumentation patterns and discursive strategies, and consolidated ideational governance over some citizens’ individual values, beliefs, and loyalties. Furthermore, it is often no longer possible to differentiate between the CPC’s internal and external propaganda, as seemingly exclusively domestic ideational and discursive issues increasingly correlate with international phenomena. However, the trends in the Xi era do not present paradigmatic shifts, but rather an overall reassertion-cuminnovation of previous Maoist and post-Maoist uses of ideology, propaganda, and political discourse, primarily aiming at strengthening one-party rule

The writing on the wall: the concealed communities of the East Yorkshire horselads

This paper examines the graffiti found within late nineteenth and early-twentieth century farm buildings in the Wolds of East Yorkshire. It suggests that the graffiti were created by a group of young men at the bottom of the social hierarchy - the horselads – and was one of the ways in which they constructed a distinctive sense of communal identity, at a particular stage in their lives. Whilst it tells us much about changing agricultural regimes and social structures, it also informs us about experiences and attitudes often hidden from official histories and biographies. In this way, the graffiti are argued to inform our understanding, not only of a concealed community, but also about their hidden histor

Organisational participation and women - an attitude problem?

Employee participation is a dynamic and contested area of organisational behaviour, attracting continuing academic, practitioner and policy interest and debate. This chapter focuses on organisational participation and women

Pharmacological levels of withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells

Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer

Construct-level predictive validity of educational attainment and intellectual aptitude tests in medical student selection: meta-regression of six UK longitudinal studies

Background: Measures used for medical student selection should predict future performance during training. A problem for any selection study is that predictor-outcome correlations are known only in those who have been selected, whereas selectors need to know how measures would predict in the entire pool of applicants. That problem of interpretation can be solved by calculating construct-level predictive validity, an estimate of true predictor-outcome correlation across the range of applicant abilities. Methods: Construct-level predictive validities were calculated in six cohort studies of medical student selection and training (student entry, 1972 to 2009) for a range of predictors, including A-levels, General Certificates of Secondary Education (GCSEs)/O-levels, and aptitude tests (AH5 and UK Clinical Aptitude Test (UKCAT)). Outcomes included undergraduate basic medical science and finals assessments, as well as postgraduate measures of Membership of the Royal Colleges of Physicians of the United Kingdom (MRCP(UK)) performance and entry in the Specialist Register. Construct-level predictive validity was calculated with the method of Hunter, Schmidt and Le (2006), adapted to correct for right-censorship of examination results due to grade inflation. Results: Meta-regression analyzed 57 separate predictor-outcome correlations (POCs) and construct-level predictive validities (CLPVs). Mean CLPVs are substantially higher (.450) than mean POCs (.171). Mean CLPVs for first-year examinations, were high for A-levels (.809; CI: .501 to .935), and lower for GCSEs/O-levels (.332; CI: .024 to .583) and UKCAT (mean = .245; CI: .207 to .276). A-levels had higher CLPVs for all undergraduate and postgraduate assessments than did GCSEs/O-levels and intellectual aptitude tests. CLPVs of educational attainment measures decline somewhat during training, but continue to predict postgraduate performance. Intellectual aptitude tests have lower CLPVs than A-levels or GCSEs/O-levels. Conclusions: Educational attainment has strong CLPVs for undergraduate and postgraduate performance, accounting for perhaps 65% of true variance in first year performance. Such CLPVs justify the use of educational attainment measure in selection, but also raise a key theoretical question concerning the remaining 35% of variance (and measurement error, range restriction and right-censorship have been taken into account). Just as in astrophysics, ‘dark matter’ and ‘dark energy’ are posited to balance various theoretical equations, so medical student selection must also have its ‘dark variance’, whose nature is not yet properly characterized, but explains a third of the variation in performance during training. Some variance probably relates to factors which are unpredictable at selection, such as illness or other life events, but some is probably also associated with factors such as personality, motivation or study skills

(Micro)evolutionary changes and the evolutionary potential of bird migration

Seasonal migration is the yearly long-distance movement of individuals between their breeding and wintering grounds. Individuals from nearly every animal group exhibit this behavior, but probably the most iconic migration is carried out by birds, from the classic V-shape formation of geese on migration to the amazing nonstop long-distance flights undertaken by Arctic Terns Sterna paradisaea. In this chapter, we discuss how seasonal migration has shaped the field of evolution. First, this behavior is known to turn on and off quite rapidly, but controversy remains concerning where this behavior first evolved geographically and whether the ancestral state was sedentary or migratory (Fig. 7.1d, e). We review recent work using new analytical techniques to provide insight into this topic. Second, it is widely accepted that there is a large genetic basis to this trait, especially in groups like songbirds that migrate alone and at night precluding any opportunity for learning. Key hypotheses on this topic include shared genetic variation used by different populations to migrate and only few genes being involved in its control. We summarize recent work using new techniques for both phenotype and genotype characterization to evaluate and challenge these hypotheses. Finally, one topic that has received less attention is the role these differences in migratory phenotype could play in the process of speciation. Specifically, many populations breed next to one another but take drastically different routes on migration (Fig. 7.2). This difference could play an important role in reducing gene flow between populations, but our inability to track most birds on migration has so far precluded evaluations of this hypothesis. The advent of new tracking techniques means we can track many more birds with increasing accuracy on migration, and this work has provided important insight into migration's role in speciation that we will review here

Phylogenetic Codivergence Supports Coevolution of Mimetic Heliconius Butterflies

The unpalatable and warning-patterned butterflies _Heliconius erato_ and _Heliconius melpomene_ provide the best studied example of mutualistic Müllerian mimicry, thought – but rarely demonstrated – to promote coevolution. Some of the strongest available evidence for coevolution comes from phylogenetic codivergence, the parallel divergence of ecologically associated lineages. Early evolutionary reconstructions suggested codivergence between mimetic populations of _H. erato_ and _H. melpomene_, and this was initially hailed as the most striking known case of coevolution. However, subsequent molecular phylogenetic analyses found discrepancies in phylogenetic branching patterns and timing (topological and temporal incongruence) that argued against codivergence. We present the first explicit cophylogenetic test of codivergence between mimetic populations of _H. erato_ and _H. melpomene_, and re-examine the timing of these radiations. We find statistically significant topological congruence between multilocus coalescent population phylogenies of _H. erato_ and _H. melpomene_, supporting repeated codivergence of mimetic populations. Divergence time estimates, based on a Bayesian coalescent model, suggest that the evolutionary radiations of _H. erato_ and _H. melpomene_ occurred over the same time period, and are compatible with a series of temporally congruent codivergence events. This evidence supports a history of reciprocal coevolution between Müllerian co-mimics characterised by phylogenetic codivergence and parallel phenotypic change

All clinically-relevant blood components transmit prion disease following a single blood transfusion: a sheep model of vCJD

Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. Whilst the epidemic appears to be waning, there is much concern that vCJD infection may be perpetuated in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported and linked to blood collected from pre-clinically affected donors. Using an animal model in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components are vectors for prion disease transmission, and highlight the importance of multiple control measures to minimise the risk of human to human transmission of vCJD by blood transfusion