In vivo manipulation of the extracellular matrix induces vascular regression in a basal chordate.

We investigated the physical role of the extracellular matrix (ECM) in vascular homeostasis in the basal chordate Botryllus schlosseri, which has a large, transparent, extracorporeal vascular network encompassing an area >100 cm2 We found that the collagen cross-linking enzyme lysyl oxidase is expressed in all vascular cells and that in vivo inhibition using β-aminopropionitrile (BAPN) caused a rapid, global regression of the entire network, with some vessels regressing >10 mm within 16 h. BAPN treatment changed the ultrastructure of collagen fibers in the vessel basement membrane, and the kinetics of regression were dose dependent. Pharmacological inhibition of both focal adhesion kinase (FAK) and Raf also induced regression, and levels of phosphorylated FAK in vascular cells decreased during BAPN treatment and FAK inhibition but not Raf inhibition, suggesting that physical changes in the vessel ECM are detected via canonical integrin signaling pathways. Regression is driven by apoptosis and extrusion of cells through the basal lamina, which are then engulfed by blood-borne phagocytes. Extrusion and regression occurred in a coordinated manner that maintained vessel integrity, with no loss of barrier function. This suggests the presence of regulatory mechanisms linking physical changes to a homeostatic, tissue-level response

Increasing interest in social studies: Social perspective taking and self-efficacy in stimulating simulations

This study examined the potential of simulations to bolster interest in middle school social studies classrooms. Using a pre-post design, we examined 305 middle school students (49% female) who participated in the web-based GlobalEd simulation. Unlike the motivation declines middle school students usually experience, participants in this simulation became more interested in social studies. We investigated four hypotheses as to why these increases may have occurred. We found no support for the possibility that, (a) students’ interest in a particular issue area or (b) their increased valuing of the subject matter, were related to their increased interest. However, results suggested that, (c) the challenging nature of the activity may have bolstered their interest in social studies and (d) students’ increased propensity to engage in social perspective taking. The discussion explores future research directions and whether implications for classroom teachers are warranted given the correlational nature of the research

Abordaxe fisioterápico no asma infantil

[Resumen] Objetivo: analizar qué intervenciones se están llevando a cabo por parte de la fisioterapia en la patología del asma. Material y métodos: revisión de artículos en los cuales se lleven a cabo intervenciones de fisioterapia en niños asmáticos. La búsqueda se efectuó en las bases de datos Pubmed, PEDro, Web of Science y Scopus, seleccionando artículos publicados entre 2013 y 2017 en lengua inglesa, portuguesa y española. Resultados: se seleccionaron 6 artículos, la mayoría de calidad intermedia, con variabilidad en el número de sujetos en cada estudio. La población que se seleccionó comprende desde el nacimiento hasta los 18 años. Las terapias fisioterápicas empleadas son variables. Se realiza en todos los casos un tratamiento enfocado al abordaje de las capacidades físicas por medio de diferentes programas de entrenamiento que cada estudio enfocó de forma diferente. Los aspectos más evaluados han sido la función pulmonar, la calidad de vida y la disnea, medidos a través de diferentes test y pruebas funcionales. Se obtienen resultados positivos en el manejo del asma con cada uno de estos programas de entrenamiento físico. Conclusiones: existen múltiples programas de intervención fisioterápica sobre el asma. Se llevan a cabo programas de entrenamiento de la musculatura inspiratoria, entrenamiento aeróbico, anaeróbico, de fuerza y equilibrio por parte de la fisioterapia en el abordaje de esta patología y todos presentan beneficio sobre ella. Asimismo, se objetivó que el programa de tratamiento que engloba un entrenamiento basado en ejercicio aeróbico y ejercicios respiratorios presenta una mayor eficacia.[Abstract] Objective: to analyze what interventions are being carried out by physiotherapy in the pathology of asthma. Material and methods: review of articles in which physiotherapy interventions are carried out in asthmatic children. The search was carried out in the Pubmed, PEDro, Web of Science and Scopus databases, selecting articles published between 2013 and 2017 in English, Portuguese and Spanish. Results: Six articles were selected, most of intermediate quality, with variability in the number of subjects in each study. The population that was selected comprises from birth to 18 years. The physiotherapeutic therapies used are variable. In all cases, a treatment focused on addressing physical abilities is carried out through different training programs that each study focused on differently. The most evaluated aspects have been pulmonary function, quality of life and dyspnea, measured through different tests and functional tests. Positive results are obtained in the management of asthma with each of these physical training programs. Conclusions: There are multiple programs of physiotherapy intervention on asthma. Training programs for inspiratory musculature, aerobic, anaerobic, strength and balance training are carried out by physiotherapy in the approach to this pathology and all have benefit over it. Likewise, it was found that the treatment program that includes a training based on aerobic exercise and breathing exercises is more effective.[Resumo] Obxectivo: analizar que intervencións se están a facer por parte da fisioterapia na patoloxía da asma. Material e metodoloxía: revisión de artículos nos que se fagan intervencións de fisioterapia en nenos asmáticos. A búsqueda efectuouse nas bases de datos Pubmed, PEDro, Web of Science y Scopus, seleccionando artículos publicados entre 2013 y 2017 en lingua inglesa, portuguesa e española. Resultados: seleccionáronse 6 artigos, a maioría de calidade intermedia, con variabilidade no número de suxeitos en cada estudo. A poboación que se seleccionou comprende dende o nacemento ata os 18 anos. As terapias fisioterápicas empregadas son variables. Realizouse en todos os casos un tratamento enfocado á abordaxe das capacidades físicas por medio de diferentes programas de entrenamento que cada estudo enfocou de forma diferente. Os aspectos máis avaliados foron a función pulmonar, a calidade da vida e a disnea, medidos a través de diferentes test e probas funcionais. Obtéñense resultados positivos no manexo do asma con cada un destes programas de entrenamento físico. Conclusións: existen múltiples programas de intervención fisioterápica sobre a asma infantil. Lévanse a cabo programas de entrenamento da musculatura inspiratoria, entrenamiento aeróbico, anaeróbico, de forza e equilibrio por parte da fisioterapia no abordaxe desta patoloxía e todos presentan beneficio sobre ela. Así mesmo obxectivouse que o programa de tratamento que engloba un entrenamento baseado no exercicio aeróbico e exercicios respiratorios presenta unha maior eficacia.Traballo fin de grao (UDC.FCS). Fisioterapia. Curso 2017/201

Deconvoluting kinase inhibitor induced cardiotoxicity

Many drugs designed to inhibit kinases have their clinical utility limited by cardiotoxicity-related label warnings or prescribing restrictions. While this liability is widely recognized, designing safer kinase inhibitors (KI) requires knowledge of the causative kinase(s). Efforts to unravel the kinases have encountered pharmacology with nearly prohibitive complexity. At therapeutically relevant concentrations, KIs show promiscuity distributed across the kinome. Here, to overcome this complexity, 65 KIs with known kinome-scale polypharmacology profiles were assessed for effects on cardiomyocyte (CM) beating. Changes in human iPSC-CM beat rate and amplitude were measured using label-free cellular impedance. Correlations between beat effects and kinase inhibition profiles were mined by computation analysis (Matthews Correlation Coefficient) to identify associated kinases. Thirty kinases met criteria of having (1) pharmacological inhibition correlated with CM beat changes, (2) expression in both human-induced pluripotent stem cell-derived cardiomyocytes and adult heart tissue, and (3) effects on CM beating following single gene knockdown. A subset of these 30 kinases were selected for mechanistic follow up. Examples of kinases regulating processes spanning the excitation–contraction cascade were identified, including calcium flux (RPS6KA3, IKBKE) and action potential duration (MAP4K2). Finally, a simple model was created to predict functional cardiotoxicity whereby inactivity at three sentinel kinases (RPS6KB1, FAK, STK35) showed exceptional accuracy in vitro and translated to clinical KI safety data. For drug discovery, identifying causative kinases and introducing a predictive model should transform the ability to design safer KI medicines. For cardiovascular biology, discovering kinases previously unrecognized as influencing cardiovascular biology should stimulate investigation of underappreciated signaling pathways

Species-Specific Responses of Juvenile Rockfish to Elevated pCO2: From Behavior to Genomics

In the California Current ecosystem, global climate change is predicted to trigger large-scale changes in ocean chemistry within this century. Ocean acidification—which occurs when increased levels of atmospheric CO2 dissolve into the ocean—is one of the biggest potential threats to marine life. In a coastal upwelling system, we compared the effects of chronic exposure to low pH (elevated pCO2) at four treatment levels (i.e., pCO2 = ambient [500], moderate [750], high [1900], and extreme [2800 μatm]) on behavior, physiology, and patterns of gene expression in white muscle tissue of juvenile rockfish (genus Sebastes), integrating responses from the transcriptome to the whole organism level. Experiments were conducted simultaneously on two closely related species that both inhabit kelp forests, yet differ in early life history traits, to compare high-CO2 tolerance among species. Our findings indicate that these congeners express different sensitivities to elevated CO2 levels. Copper rockfish (S. caurinus) exhibited changes in behavioral lateralization, reduced critical swimming speed, depressed aerobic scope, changes in metabolic enzyme activity, and increases in the expression of transcription factors and regulatory genes at high pCO2 exposure. Blue rockfish (S. mystinus), in contrast, showed no significant changes in behavior, swimming physiology, or aerobic capacity, but did exhibit significant changes in the expression of muscle structural genes as a function of pCO2, indicating acclimatization potential. The capacity of long-lived, late to mature, commercially important fish to acclimatize and adapt to changing ocean chemistry over the next 50–100 years is likely dependent on species-specific physiological tolerances

Joint analysis of stressors and ecosystem services to enhance restoration effectiveness

With increasing pressure placed on natural systems by growing human populations, both scientists and resource managers need a better understanding of the relationships between cumulative stress from human activities and valued ecosystem services. Societies often seek to mitigate threats to these services through large-scale, costly restoration projects, such as the over one billion dollar Great Lakes Restoration Initiative currently underway. To help inform these efforts, we merged high-resolution spatial analyses of environmental stressors with mapping of ecosystem services for all five Great Lakes. Cumulative ecosystem stress is highest in near-shore habitats, but also extends offshore in Lakes Erie, Ontario, and Michigan. Variation in cumulative stress is driven largely by spatial concordance among multiple stressors, indicating the importance of considering all stressors when planning restoration activities. In addition, highly stressed areas reflect numerous different combinations of stressors rather than a single suite of problems, suggesting that a detailed understanding of the stressors needing alleviation could improve restoration planning. We also find that many important areas for fisheries and recreation are subject to high stress, indicating that ecosystem degradation could be threatening key services. Current restoration efforts have targeted high-stress sites almost exclusively, but generally without knowledge of the full range of stressors affecting these locations or differences among sites in service provisioning. Our results demonstrate that joint spatial analysis of stressors and ecosystem services can provide a critical foundation for maximizing social and ecological benefits from restoration investments. www.pnas.org/lookup/suppl/doi:10.1073/pnas.1213841110/-/DCSupplementa

Factors Associated with Opioid Overdose after an Initial Opioid Prescription

Importance: The opioid epidemic continues to be a public health crisis in the US. Objective: To assess the patient factors and early time-varying prescription-related factors associated with opioid-related fatal or nonfatal overdose. Design, Setting, and Participants: This cohort study evaluated opioid-naive adult patients in Oregon using data from the Oregon Comprehensive Opioid Risk Registry, which links all payer claims data to other health data sets in the state of Oregon. The observational, population-based sample filled a first (index) opioid prescription in 2015 and was followed up until December 31, 2018. Data analyses were performed from March 1, 2020, to June 15, 2021. Exposures: Overdose after the index opioid prescription. Main Outcomes and Measures: The outcome was an overdose event. The sample was followed up to identify fatal or nonfatal opioid overdoses. Patient and prescription characteristics were identified. Prescription characteristics in the first 6 months after the index prescription were modeled as cumulative, time-dependent measures that were updated monthly through the sixth month of follow-up. A time-dependent Cox proportional hazards regression model was used to assess patient and prescription characteristics that were associated with an increased risk for overdose events. Results: The cohort comprised 236921 patients (133 839 women [56.5%]), of whom 667 (0.3%) experienced opioid overdose. Risk of overdose was highest among individuals 75 years or older (adjusted hazard ratio [aHR], 3.22; 95% CI, 1.94-5.36) compared with those aged 35 to 44 years; men (aHR, 1.29; 95% CI, 1.10-1.51); those who were dually eligible for Medicaid and Medicare Advantage (aHR, 4.37; 95% CI, 3.09-6.18), had Medicaid (aHR, 3.77; 95% CI, 2.97-4.80), or had Medicare Advantage (aHR, 2.18; 95% CI, 1.44-3.31) compared with those with commercial insurance; those with comorbid substance use disorder (aHR, 2.74; 95% CI, 2.15-3.50), with depression (aHR, 1.26; 95% CI, 1.03-1.55), or with 1 to 2 comorbidities (aHR, 1.32; 95% CI, 1.08-1.62) or 3 or more comorbidities (aHR, 1.90; 95% CI, 1.42-2.53) compared with none. Patients were at an increased overdose risk if they filled oxycodone (aHR, 1.70; 95% CI, 1.04-2.77) or tramadol (aHR, 2.80; 95% CI, 1.34-5.84) compared with codeine; used benzodiazepines (aHR, 1.06; 95% CI, 1.01-1.11); used concurrent opioids and benzodiazepines (aHR, 2.11; 95% CI, 1.70-2.62); or filled opioids from 3 or more pharmacies over 6 months (aHR, 1.38; 95% CI, 1.09-1.75). Conclusions and Relevance: This cohort study used a comprehensive data set to identify patient and prescription-related risk factors that were associated with opioid overdose. These findings may guide opioid counseling and monitoring, the development of clinical decision-making tools, and opioid prevention and treatment resources for individuals who are at greatest risk for opioid overdose

The classification of static vacuum space-times containing an asymptotically flat spacelike hypersurface with compact interior

We prove non-existence of static, vacuum, appropriately regular, asymptotically flat black hole space-times with degenerate (not necessarily connected) components of the event horizon. This finishes the classification of static, vacuum, asymptotically flat domains of outer communication in an appropriate class of space-times, showing that the domains of outer communication of the Schwarzschild black holes exhaust the space of appropriately regular black hole exteriors.Comment: This version includes an addendum with a corrected proof of non-existence of zeros of the Killing vector at degenerate horizons. A problem with yet another Lemma is pointed out; this problem does not arise if one assumes analyticity of the metric. An alternative solution, that does not require analyticity, has been given in arXiv:1004.0513 [gr-qc] under appropriate global condition

Benefits, Barriers and Enablers of Breastfeeding: Factor Analysis of Population Perceptions in Western Australia

Objective: The objective of this study was to investigate knowledge and community perceptions of breastfeeding in Western Australia using a factor analysis approach. Methods: Data were pooled from five Nutrition Monitoring Survey Series which included information on breastfeeding from 4,802 Western Australian adults aged 18–64 years. Tetrachoric factor analysis was conducted for data reduction and significant associations identified using logistic, ordinal and poisson regression analyses. Results: Four factors were derived for benefits (it’s natural, good nutrition, good for the baby, and convenience), barriers (breastfeeding problems, poor community acceptability, having to go back to work, and inconvenience) and for enablers (breastfeeding education, community support, family support and not having to work).As assessed by standardized odds ratios the most important covariates across benefit factors were: importance of breastfeeding (ORs range from 1.22–1.44),female gender (ORs range from 0.80 to 1.46), being able to give a time for how long a baby should be breastfed (ORs range from 0.96 to 1.27) and education (less than high school to university completion) (ORs range from 0.95 to 1.23); the most important covariate across barrier factors was being able to give a time for how long a baby should be breastfed (ORs range from 0.89 to 1.93); and the most important covariates across all enabling factors were education (ORs range from 1.14 to1.32) and being able to give a time for how long a baby should be breastfed (ORs range from 1.17 to 1.42).Conclusions: Being female, rating breastfeeding as important, believing that babies should be breastfed for a period of time and education accounted for most of the statistically significant associations. The differences between male and female perceptions require investigation particularly in relation to returning to work

Relative energetics and structural properties of zirconia using a self-consistent tight-binding model

We describe an empirical, self-consistent, orthogonal tight-binding model for zirconia, which allows for the polarizability of the anions at dipole and quadrupole levels and for crystal field splitting of the cation d orbitals. This is achieved by mixing the orbitals of different symmetry on a site with coupling coefficients driven by the Coulomb potentials up to octapole level. The additional forces on atoms due to the self-consistency and polarizabilities are exactly obtained by straightforward electrostatics, by analogy with the Hellmann-Feynman theorem as applied in first-principles calculations. The model correctly orders the zero temperature energies of all zirconia polymorphs. The Zr-O matrix elements of the Hamiltonian, which measure covalency, make a greater contribution than the polarizability to the energy differences between phases. Results for elastic constants of the cubic and tetragonal phases and phonon frequencies of the cubic phase are also presented and compared with some experimental data and first-principles calculations. We suggest that the model will be useful for studying finite temperature effects by means of molecular dynamics.Comment: to be published in Physical Review B (1 march 2000