Home-based isometric exercise training induced reductions resting blood pressure

Purpose: Isometric exercise training (IET) reduces resting blood pressure (BP). Most previous protocols impose exercise barriers which undermine its effectiveness as a potential physical therapy for altering BP. An inexpensive, home-based programme would promote IET as a valuable tool in the fight against hypertension. The aims of this study were: (a) to investigate whether home-based wall squat training could successfully reduce resting BP, and (b) to explore the physiological variables that might mediate a change in resting BP. Methods: Twenty-eight healthy normotensive males were randomly assigned to a control and a 4 week home-based IET intervention using a crossover design with a 4 week ‘washout’ period in-between. Wall squat training was completed 3x weekly over 4 weeks with 48 hours between sessions. Each session comprised 4x 2 minute bouts of wall squat exercise performed at a participant-specific knee joint angle relative to a target HR of 95% HRpeak, with 2 minutes rest between bouts. Resting heart rate, BP, cardiac output, total peripheral resistance and stroke volume were taken at baseline and post each condition. Results: Resting BP (systolic = -4 ± 5, diastolic = -3 ± 3 and mean arterial = -3 ± 3 mmHg), cardiac output (-0.54 ± 0.66 L∙min-1) and heart rate (-5 ± 7 beats∙min-1) were all reduced following IET, with no change in total peripheral resistance or stroke volume compared to the control. Conclusion: These findings suggest the wall squat provides an effective method for reducing resting BP in the home resulting primarily from a reduction in resting heart rate

708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects:analysis for association with psychiatric disorder and cognitive traits

A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10-5, OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies. © 2014 Macmillan Publishers Limited

Climate-carbon cycle uncertainties and the Paris Agreement

The Paris Agreement aims to address the gap between existing climate policies and policies consistent with ‘holding the increase in global average temperature to well below 2C’. The feasibility of meeting the target has been questioned both in terms of the possible requirement for negative emissions, and ongoing debate on the sensitivity of the climate-carbon cycle system. Using a sequence of ensembles of a fully dynamic three-dimensional climate-carbon cycle model, forced by emissions from an integrated assessment model of regional-level climate policy, economy, and technological transformation, we show that a reasonable interpretation of the Paris Agreement is still technically achievable. Specifically, limiting peak (decadal) warming to less than 1.7°C, or end-century warming to less than 1.54°C, occurs in 50% of our simulations in a policy scenario without net negative emissions or excessive stringency in any policy domain. We evaluate two mitigation scenarios, with 200 GTC and 307 GTC post-2017 emissions, quantifying spatio-temporal variability of warming, precipitation, ocean acidification and marine productivity. Under rapid decarbonisation decadal variability dominates the mean response in critical regions, with significant implications for decision making, demanding impact methodologies that address non-linear spatio-temporal responses. Ignoring carbon-cycle feedback uncertainties (explaining 47% of peak warming uncertainty) becomes unreasonable under strong mitigation conditions.We acknowledge C-EERNG and Cambridge Econometrics for support, and funding from EPSRC (to J.-F.M., fellowship number EP/ K007254/1); the Newton Fund (to J.-F.M., P.S. and J.E.V., EPSRC grant number EP/N002504/1 and ESRC grant number ES/N013174/1), NERC (to N.R.E., P.H. and H.P., grant number NE/P015093/1), CONICYT (to P.S.), the Philomathia Foundation (to J.E.V.) and Horizon 2020 (to H.E.P. and J.-F.M., the Sim4Nexus project)

Rare disruptive variants in the DISC1 Interactome and Regulome : association with cognitive ability and schizophrenia

Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results identify altered regulation of schizophrenia candidate genes by DISC1 and its core Interactome as an alternate pathway for schizophrenia risk, consistent with the emerging effects of rare copy number variants associated with intellectual disability.Peer reviewe

Identification of functional differences between recombinant human α and β cardiac myosin motors

The myosin isoform composition of the heart is dynamic in health and disease and has been shown to affect contractile velocity and force generation. While different mammalian species express different proportions of α and β myosin heavy chain, healthy human heart ventricles express these isoforms in a ratio of about 1:9 (α:β) while failing human ventricles express no detectable α-myosin. We report here fast-kinetic analysis of recombinant human α and β myosin heavy chain motor domains. This represents the first such analysis of any human muscle myosin motor and the first of α-myosin from any species. Our findings reveal substantial isoform differences in individual kinetic parameters, overall contractile character, and predicted cycle times. For these parameters, α-subfragment 1 (S1) is far more similar to adult fast skeletal muscle myosin isoforms than to the slow β isoform despite 91% sequence identity between the motor domains of α- and β-myosin. Among the features that differentiate α- from β-S1: the ATP hydrolysis step of α-S1 is ~ten-fold faster than β-S1, α-S1 exhibits ~five-fold weaker actin affinity than β-S1, and actin·α-S1 exhibits rapid ADP release, which is >ten-fold faster than ADP release for β-S1. Overall, the cycle times are ten-fold faster for α-S1 but the portion of time each myosin spends tightly bound to actin (the duty ratio) is similar. Sequence analysis points to regions that might underlie the basis for this finding

Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia

Several polymorphisms in the Disrupted-in-Schizophrenia-1 (DISC1) gene are reported to be associated with schizophrenia. However, to date, there has been little effort to evaluate the evidence for association systematically. We carried out an imputation-driven meta-analysis, the most comprehensive to date, using data collected from 10 candidate gene studies and three genome-wide association studies containing a total of 11 626 cases and 15 237 controls. We tested 1241 single-nucleotide polymorphisms in total, and estimated that our power to detect an effect from a variant with minor allele frequency >5% was 99% for an odds ratio of 1.5 and 51% for an odds ratio of 1.1. We find no evidence that common variants at the DISC1 locus are associated with schizophrenia

The Glasgow Outcome Scale -- 40 years of application and refinement

The Glasgow Outcome Scale (GOS) was first published in 1975 by Bryan Jennett and Michael Bond. With over 4,000 citations to the original paper, it is the most highly cited outcome measure in studies of brain injury and the second most-cited paper in clinical neurosurgery. The original GOS and the subsequently developed extended GOS (GOSE) are recommended by several national bodies as the outcome measure for major trauma and for head injury. The enduring appeal of the GOS is linked to its simplicity, short administration time, reliability and validity, stability, flexibility of administration (face-to-face, over the telephone and by post), cost-free availability and ease of access. These benefits apply to other derivatives of the scale, including the Glasgow Outcome at Discharge Scale (GODS) and the GOS paediatric revision. The GOS was devised to provide an overview of outcome and to focus on social recovery. Since the initial development of the GOS, there has been an increasing focus on the multidimensional nature of outcome after head injury. This Review charts the development of the GOS, its refinement and usage over the past 40 years, and considers its current and future roles in developing an understanding of brain injury

Following the genes: a framework for animal modeling of psychiatric disorders

The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans

The Genetic Signatures of Noncoding RNAs

The majority of the genome in animals and plants is transcribed in a developmentally regulated manner to produce large numbers of non–protein-coding RNAs (ncRNAs), whose incidence increases with developmental complexity. There is growing evidence that these transcripts are functional, particularly in the regulation of epigenetic processes, leading to the suggestion that they compose a hitherto hidden layer of genomic programming in humans and other complex organisms. However, to date, very few have been identified in genetic screens. Here I show that this is explicable by an historic emphasis, both phenotypically and technically, on mutations in protein-coding sequences, and by presumptions about the nature of regulatory mutations. Most variations in regulatory sequences produce relatively subtle phenotypic changes, in contrast to mutations in protein-coding sequences that frequently cause catastrophic component failure. Until recently, most mapping projects have focused on protein-coding sequences, and the limited number of identified regulatory mutations have been interpreted as affecting conventional cis-acting promoter and enhancer elements, although these regions are often themselves transcribed. Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction. The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions. There is every possibility that many of these variations will alter the interactions between regulatory RNAs and their targets, a prospect that should be borne in mind in future functional analyses

On the typology and the worship status of sacred trees with a special reference to the Middle East

This article contains the reasons for the establishment of sacred trees in Israel based on a field study. It includes 97 interviews with Muslim and Druze informants. While Muslims (Arabs and Bedouins) consider sacred trees especially as an abode of righteous figures' (Wellis') souls or as having a connection to their graves, the Druze relate sacred trees especially to the events or deeds in the lives of prophets and religious leaders. A literary review shows the existence of 24 known reasons for the establishment of sacred trees worldwide, 11 of which are known in Israel one of these is reported here for the first time. We found different trends in monotheistic and polytheistic religions concerning their current worship of sacred trees