DNA-induced spatial entrapment of general transcription machinery can stabilize gene expression in a nondividing cell.

Funder: Wellcome TrustAn important characteristic of cell differentiation is its stability. Only rarely do cells or their stem cell progenitors change their differentiation pathway. If they do, it is often accompanied by a malfunction such as cancer. A mechanistic understanding of the stability of differentiated states would allow better prospects of alleviating the malfunctioning. However, such complete information is yet elusive. Earlier experiments performed in Xenopus oocytes to address this question suggest that a cell may maintain its gene expression by prolonged binding of cell type-specific transcription factors. Here, using DNA competition experiments, we show that the stability of gene expression in a nondividing cell could be caused by the local entrapment of part of the general transcription machinery in transcriptionally active regions. Strikingly, we found that transcriptionally active and silent forms of the same DNA template can stably coexist within the same nucleus. Both DNA templates are associated with the gene-specific transcription factor Ascl1, the core factor TBP2, and the polymerase II (Pol-II) ser5 C-terminal domain (CTD) phosphorylated form, while Pol-II ser2 CTD phosphorylation is restricted to the transcriptionally dominant template. We discover that the active and silent DNA forms are physically separated in the oocyte nucleus through partition into liquid-liquid phase-separated condensates. Altogether, our study proposes a mechanism of transcriptional regulation involving a spatial entrapment of general transcription machinery components to stabilize the active form of a gene in a nondividing cell

Repeated Sprint Ability in Young Basketball Players (Part 2): The Chronic Effects of Multidirection and of One Change of Direction Are Comparable in Terms of Physiological and Performance Responses

The aim of this study was to examine the effects of a 5-week training program, consisting of repeated 30-m sprints, on two repeated sprint ability (RSA) test formats: one with one change of direction (RSA) and the other with multiple changes of direction (RSM). Thirty-six young male and female basketball players (age 16.1 ± 0.9 years), divided into two experimental groups, were tested for RSA, RSM, squat jump, counter-movement jump, and the Yo-Yo Intermittent Recovery-Level-1 (Yo-Yo IR1) test, before and after a 4-week training program and 1 week of tapering. One group performed 30-m sprints with one change of direction (RSA group, RSAG), whereas the other group performed multidirectional 30-m sprints (RSM group, RSMG). Both groups improved in all scores in the post-intervention measurements (P < 0.05), except for the fatigue index in the RSM test. However, when comparing the two groups, similar effects were found for almost all parameters of the tests applied, except for RPE in the RSA test, which had a greater decrease in the RSAG (from 8.7 to 5.9) than in the RSMG (from 8.5 to 6.6, P = 0.021). We can conclude that repeated 30-m sprints, either with one change of direction or multidirectional, induce similar physiological and performance responses in young basketball players, but have a different psycho-physiological impact

The Hypermultiplet with Heisenberg Isometry in N=2 Global and Local Supersymmetry

The string coupling of N=2 supersymmetric compactifications of type II string theory on a Calabi-Yau manifold belongs to the so-called universal dilaton hypermultiplet, that has four real scalars living on a quaternion-Kaehler manifold. Requiring Heisenberg symmetry, which is a maximal subgroup of perturbative isometries, reduces the possible manifolds to a one-parameter family that describes the tree-level effective action deformed by the only possible perturbative correction arising at one-loop level. A similar argument can be made at the level of global supersymmetry where the scalar manifold is hyper-Kaehler. In this work, the connection between global and local supersymmetry is explicitly constructed, providing a non-trivial gravity decoupled limit of type II strings already in perturbation theory.Comment: 24 page

Repeated Sprint Ability in Young Basketball Players: Multi-direction vs. One-Change of Direction (Part 1)

The aim of the present study was to examine the reliability of a novel multi-direction repeated sprint ability (RSA) test [RSM; 10 7 (6 7 5-m)] compared with a RSA with one change of direction [10 7 (2 7 15-m)], and the relationship of the RSM and RSA with Yo-Yo intermittent recovery test level 1 (Yo-Yo IR1) and jump performances [squat jump (SJ) and counter-movement-jump (CMJ)]. Thirty-six (male, n = 14, female n = 22) young basketball players (age 16.0 \ub1 0.9 yrs) performed the RSM, RSA, Yo-Yo IR1, SJ, and CMJ, and were re-tested only for RSM and RSA after 1 week. The absolute error of reliability (standard error of the measurement) was lower than 0.212 and 0.617-s for the time variables of the RSA and RSM test, respectively. Performance in the RSA and RSM test significantly correlated with CMJ and SJ. The best time, worst time, and total time of the RSA and RSM test were negatively correlated with Yo-Yo IR1 distance. Based on these findings, consistent with previously published studies, it was concluded that the novel RSM test was valid and reliable

Repeated Sprint Ability in Young Basketball Players (Part 2): The Chronic Effects of Multidirection and of One Change of Direction Are Comparable in Terms of Physiological and Performance Responses

The aim of this study was to examine the effects of a 5-week training program, consisting of repeated 30-m sprints, on two repeated sprint ability (RSA) test formats: one with one change of direction (RSA) and the other with multiple changes of direction (RSM). Thirty-six young male and female basketball players (age 16.1 \ub1 0.9 years), divided into two experimental groups, were tested for RSA, RSM, squat jump, counter-movement jump, and the Yo-Yo Intermittent Recovery-Level-1 (Yo-Yo IR1) test, before and after a 4-week training program and 1 week of tapering. One group performed 30-m sprints with one change of direction (RSA group, RSAG), whereas the other group performed multidirectional 30-m sprints (RSM group, RSMG). Both groups improved in all scores in the post-intervention measurements (P &lt; 0.05), except for the fatigue index in the RSM test. However, when comparing the two groups, similar effects were found for almost all parameters of the tests applied, except for RPE in the RSA test, which had a greater decrease in the RSAG (from 8.7 to 5.9) than in the RSMG (from 8.5 to 6.6, P = 0.021). We can conclude that repeated 30-m sprints, either with one change of direction or multidirectional, induce similar physiological and performance responses in young basketball players, but have a different psycho-physiological impact

Model-based parametric study of frontostriatal abnormalities in schizophrenia patients

<p>Abstract</p> <p>Background</p> <p>Several studies have suggested that the activity of the prefrontal cortex (PFC) and the dopamine (DA) release in the striatum has an inverse relationship. One would attribute this relationship primarily to the circuitry comprised of the glutamatergic projection from the PFC to the striatum and the GABAergic projection from the striatum to the midbrain DA nucleus. However, this circuitry has not characterized satisfactorily yet, so that no quantitative analysis has ever been made on the activities of the PFC and the striatum and also the DA release in the striatum.</p> <p>Methods</p> <p>In this study, a system dynamics model of the corticostriatal system with dopaminergic innervations is constructed to describe the relationships between the activities of the PFC and the striatum and the DA release in the striatum. By taking published receptor imaging data from schizophrenia patients and healthy subjects into this model, this article analyzes the effects of striatal D2 receptor activation on the balance of the activity and neurotransmission in the frontostriatal system of schizophrenic patients in comparison with healthy controls.</p> <p>Results</p> <p>The model predicts that the suppressive effect by D2 receptors at the terminals of the glutamatergic afferents to the striatum from the PFC enhances the hypofrontality-induced elevation of striatal DA release by at most 83%. The occupancy-based estimation of the 'optimum' D2 receptor occupancy by antipsychotic drugs is 52%. This study further predicts that patients with lower PFC activity tend to have greater improvement of positive symptoms following antipsychotic medication.</p> <p>Conclusion</p> <p>This model-based parametric study would be useful for system-level analysis of the brains with psychiatric diseases. It will be able to make reliable prediction of clinical outcome when sufficient data will be available.</p

Beyond the Global Brain Differences:Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and globalbrain differences compared with noncarriers. However, interpreting regional differences is challenging if a globaldifference drives the regional brain differences. Intraindividual variability measures can be used to test for regionaldifferences beyond global differences in brain structure.METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n =30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matchednoncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual’sregional difference and global difference, were used to test for regional differences that diverge from the globaldifference.RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differedmore than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thicknessin regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal andsomatosensory cortex differed more than the global difference in cortical thickness.CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distaland 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distaland 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanismsinvolved in altered neurodevelopment

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe