An interaction network of mental disorder proteins in neural stem cells

Mental disorders (MDs) such as intellectual disability (ID), autism spectrum disorders (ASD) and schizophrenia have a strong genetic component. Recently, many gene mutations associated with ID, ASD or schizophrenia have been identified by high-throughput sequencing. A substantial fraction of these mutations are in genes encoding transcriptional regulators. Transcriptional regulators associated with different MDs but acting in the same gene regulatory network provide information on the molecular relation between MDs. Physical interaction between transcriptional regulators is a strong predictor for their cooperation in gene regulation. Here, we biochemically purified transcriptional regulators from neural stem cells, identified their interaction partners by mass spectrometry and assembled a protein interaction network containing 206 proteins, including 68 proteins mutated in MD patients and 52 proteins significantly lacking coding variation in humans. Our network shows molecular connections between established MD proteins and provides a discovery tool for novel MD genes. Network proteins preferentially co-localize on the genome and cooperate in disease-relevant gene regulation. Our results suggest that the observed transcriptional regulators associated with ID, ASD or schizophrenia are part of a transcriptional network in neural stem cells. We find that more severe mutations in network proteins are associated with MDs that include lower intelligence quotient (IQ), suggesting that the level of disruption of a shared transcriptional network correlates with cognitive dysfunction

Instability, Intermixing and Electronic Structure at the Epitaxial LaAlO3/SrTiO3(001) Heterojunction

The question of stability against diffusional mixing at the prototypical LaAlO3/SrTiO3(001) interface is explored using a multi-faceted experimental and theoretical approach. We combine analytical methods with a range of sensitivities to elemental concentrations and spatial separations to investigate interfaces grown using on-axis pulsed laser deposition. We also employ computational modeling based on the density function theory as well as classical force fields to explore the energetic stability of a wide variety of intermixed atomic configurations relative to the idealized, atomically abrupt model. Statistical analysis of the calculated energies for the various configurations is used to elucidate the relative thermodynamic stability of intermixed and abrupt configurations. We find that on both experimental and theoretical fronts, the tendency toward intermixing is very strong. We have also measured and calculated key electronic properties such as the presence of electric fields and the value of the valence band discontinuity at the interface. We find no measurable electric field in either the LaAlO3 or SrTiO3, and that the valence band offset is near zero, partitioning the band discontinuity almost entirely to the conduction band edge. Moreover, we find that it is not possible to account for these electronic properties theoretically without including extensive intermixing in our physical model of the interface. The atomic configurations which give the greatest electrostatic stability are those that eliminate the interface dipole by intermixing, calling into question the conventional explanation for conductivity at this interface - electronic reconstruction. Rather, evidence is presented for La indiffusion and doping of the SrTiO3 below the interface as being the cause of the observed conductivity

Effects of Cooling During Exercise on Thermoregulatory Responses of Men With Paraplegia.

BACKGROUND: People with spinal cord injury (SCI) have an altered afferent input to the thermoregulatory center, resulting in a reduced efferent response (vasomotor control and sweating capacity) below the level of the lesion. Consequently, core body temperature rises more rapidly during exercise in individuals with SCI compared with people who are able-bodied. Cooling strategies may reduce the thermophysiological strain in SCI. OBJECTIVE: The aim of this study was to examine the effects of a cooling vest on the core body temperature response of people with a thoracic SCI during submaximal exercise. METHODS: Ten men (mean age=44 years, SD=11) with a thoracic lesion (T4-T5 or below) participated in this randomized crossover study. Participants performed two 45-minute exercise bouts at 50% maximal workload (ambient temperature 25°C), with participants randomized to a group wearing a cooling vest or a group wearing no vest (separate days). Core body temperature and skin temperature were continuously measured, and thermal sensation was assessed every 3 minutes. RESULTS: Exercise resulted in an increased core body temperature, skin temperature, and thermal sensation, whereas cooling did not affect core body temperature. The cooling vest effectively decreased skin temperature, increased the core-to-trunk skin temperature gradient, and tended to lower thermal sensation compared with the control condition. LIMITATIONS: The lack of differences in core body temperature among conditions may be a result of the relative moderate ambient temperature in which the exercise was performed. CONCLUSIONS: Despite effectively lowering skin temperature and increasing the core-to-trunk skin temperature gradient, there was no impact of the cooling vest on the exercise-induced increase in core body temperature in men with low thoracic SCI

Extrinsic CPT Violation in Neutrino Oscillations in Matter

We investigate matter-induced (or extrinsic) CPT violation effects in neutrino oscillations in matter. Especially, we present approximate analytical formulas for the CPT-violating probability differences for three flavor neutrino oscillations in matter with an arbitrary matter density profile. Note that we assume that the CPT invariance theorem holds, which means that the CPT violation effects arise entirely because of the presence of matter. As special cases of matter density profiles, we consider constant and step-function matter density profiles, which are relevant for neutrino oscillation physics in accelerator and reactor long baseline experiments as well as neutrino factories. Finally, the implications of extrinsic CPT violation on neutrino oscillations in matter for several past, present, and future long baseline experiments are estimated.Comment: 47 pages, 7 figures, RevTeX4. Final version to be published in Phys. Rev.

Predictors of cardiac troponin release after a marathon

Objectives: Exercise leads to an increase in cardiac troponin I in healthy, asymptomatic athletes after a marathon. Previous studies revealed single factors to relate to post-race cardiac troponin I levels. Integrating these factors into our study, we aimed to identify independent predictors for the exercise-induced cardiac troponin I release. Design: Observational study. Methods: Ninety-two participants participated in a marathon at a self-selected speed. Demographic data, health status, physical activity levels and marathon experience were obtained. Before and immediately after the marathon fluid intake was recorded, body mass changes were measured to determine fluid balance and venous blood was drawn for analysis of high-sensitive cardiac troponin I. Exercise intensity was examined by recording heart rate. We included age, participation in previous marathons, exercise duration, exercise intensity and hydration status (relative weight change) in our model as potential determinants to predict post-exercise cardiac troponin I level. Results: Cardiac troponin I increased significantly from 14. ±. 12. ng/L at baseline to 94. ±. 102. ng/L post-race, with 69% of the participants demonstrating cardiac troponin I levels above the clinical cut-off value (40. ng/L) for an acute myocardial infarction. Linear backward regression analysis identified younger age (β=. -0.27) and longer exercise duration (β=. 0.23) as significant predictors of higher post-race cardiac troponin I levels (total r=. 0.31, p<. 0.05), but not participation in previous marathons, relative weight change and exercise intensity. Conclusions: We found that cardiac troponin I levels significantly increased in a large heterogeneous group of athletes after completing a marathon. The magnitude of this response could only be partially explained, with a lower age and longer exercise duration being related to higher post-race cardiac troponin I levels

Proteins that bind regulatory regions identified by histone modification chromatin immunoprecipitations and mass spectrometry

The locations of transcriptional enhancers and promoters were recently mapped in many mammalian cell types. Proteins that bind those regulatory regions can determine cell identity but have not been systematically identified. Here we purify native enhancers, promoters or heterochromatin from embryonic stem cells by chromatin immunoprecipitations (ChIP) for characteristic histone modifications and identify associated proteins using mass spectrometry (MS). 239 factors are identified and predicted to bind enhancers or promoters with different levels of activity, or heterochromatin. Published genome-wide data indicate a high accuracy of location prediction by ChIP-MS. A quarter of the identified factors are important for pluripotency and includes Oct4, Esrrb, Klf5, Mycn and Dppa2, factors that drive reprogramming to pluripotent stem cells. We determined the genome-wide binding sites of Dppa2 and find that Dppa2 operates outside the classical pluripotency network. Our ChIP-MS method provides a detailed read-out of the transcriptional landscape representative of the investigated cell type

The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently results in renal fallure due to progressive cyst development. The major locus, PKD1, maps to 16p13.3. We identified a chromosome translocation associated with ADPKD that disrupts a gene (PBP) encoding a 14 kb transcript in the PKD1 candidate region. Further mutations of the PBP gene were found in PKD1 patients, two deletions (one a de novo event) and a splicing defect, confirming that PBP is the PKD1 gene. This gene is located adjacent to the TSC2 locus in a genomic region that is reiterated more proximally on 16p. The duplicate area encodes three transcripts substantially homologous to the PKD1 transcript. Partial sequence analysis of the PKD1 transcript shows that it encodes a novel protein whose function is at present unknown

Rehabilitation and outcomes after complicated vs uncomplicated mild TBI:results from the CENTER-TBI study

Background: Despite existing guidelines for managing mild traumatic brain injury (mTBI), evidence-based treatments are still scarce and large-scale studies on the provision and impact of specific rehabilitation services are needed. This study aimed to describe the provision of rehabilitation to patients after complicated and uncomplicated mTBI and investigate factors associated with functional outcome, symptom burden, and TBI-specific health-related quality of life (HRQOL) up to six months after injury. Methods: Patients (n = 1379) with mTBI from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study who reported whether they received rehabilitation services during the first six months post-injury and who participated in outcome assessments were included. Functional outcome was measured with the Glasgow Outcome Scale – Extended (GOSE), symptom burden with the Rivermead Post Concussion Symptoms Questionnaire (RPQ), and HRQOL with the Quality of Life after Brain Injury – Overall Scale (QOLIBRI-OS). We examined whether transition of care (TOC) pathways, receiving rehabilitation services, sociodemographic (incl. geographic), premorbid, and injury-related factors were associated with outcomes using regression models. For easy comparison, we estimated ordinal regression models for all outcomes where the scores were classified based on quantiles. Results: Overall, 43% of patients with complicated and 20% with uncomplicated mTBI reported receiving rehabilitation services, primarily in physical and cognitive domains. Patients with complicated mTBI had lower functional level, higher symptom burden, and lower HRQOL compared to uncomplicated mTBI. Rehabilitation services at three or six months and a higher number of TOC were associated with unfavorable outcomes in all models, in addition to pre-morbid psychiatric problems. Being male and having more than 13 years of education was associated with more favorable outcomes. Sustaining major trauma was associated with unfavorable GOSE outcome, whereas living in Southern and Eastern European regions was associated with lower HRQOL. Conclusions: Patients with complicated mTBI reported more unfavorable outcomes and received rehabilitation services more frequently. Receiving rehabilitation services and higher number of care transitions were indicators of injury severity and associated with unfavorable outcomes. The findings should be interpreted carefully and validated in future studies as we applied a novel analytic approach. Trial registration: ClinicalTrials.gov NCT02210221.</p