Basal Signaling Through Death Receptor 5 And Caspase 3 Activates P38 Kinase To Regulate Serum Response Factor - Mediated Myod Transcription

The formation of functional skeletal muscle is the consequence of both the differentiation and apoptosis of skeletal myoblasts. Ex vivo culture of skeletal myoblasts provides a tractable model for the study of these two coordinately regulated processes. We have previously reported that 23A2 myoblasts stably expressing a dominant negative Death Receptor 5 (A2:dnDR5 myoblasts) exhibit decreased basal mRNA and protein expression of the master muscle regulatory transcription factor MyoD. This decrease at the mRNA level is not a consequence of altered stability. Binding of the transcription factor SRF to a non-canonical CArG box within a serum response element (SRE) in the distal regulatory region (DRR) of the MyoD gene is required for basal MyoD expression. Herein, we report that A2:dnDR5 myoblasts exhibit a decrease in the amount of SRF bound at this CArG box. Additionally, in A2:dnDR5 myoblasts, we observe a decrease in the phosphorylation indicative of activation of SRF as well as a decrease in the phosphorylation indicative of activation of the mitogen-activated protein kinase p38, which is known to activate SRF. Pharmacological inhibition of p38, or of caspase-3, in parental 23A2 myoblasts mimics the decreased activation of SRF and p38, the decreased binding of SRF to the MyoD CArG box, and the decreased levels of MyoD mRNA and protein detected in the A2:dnDR5 myoblasts. Taken together, these results suggest that v basal signaling through DR5 to caspase 3 leads to the activation of p38 and subsequently SRF to maintain basal expression of Myo

Static and dynamic XY-like short-range order in a frustrated magnet with exchange disorder

A single crystal of the Co2+ based pyrochlore NaCaCo2F7 was studied by inelastic neutron scattering. This frustrated magnet with quenched exchange disorder remains in a strongly correlated paramagnetic state down to one 60th of the Curie-Weiss temperature. Below T_f = 2.4 K, diffuse elastic scattering develops and comprises 30 +/- 10% of the total magnetic scattering, as expected for J_{eff} = 1/2 moments frozen on a time scale that exceeds \hbar/\delta E=3.8 ps. The diffuse scattering is consistent with short range XY antiferromagnetism with a correlation length of 16 \AA. The momentum (Q) dependence of the inelastic intensity indicates relaxing XY-like antiferromagnetic clusters at energies below ~ 5.5 meV, and collinear antiferromagnetic fluctuations above this energy. The relevant XY configurations form a continuous manifold of symmetry-related states. Contrary to well-known models that produce this continuous manifold, order-by-disorder does not select an ordered state in NaCaCo2F7 despite evidence for weak (~12 %) exchange disorder. Instead, NaCaCo2F7 freezes into short range ordered clusters that span this manifold.Comment: 9 pages, 9 figures. This updated version features modified figures and some new discussio

Research Priorities for Eight Areas of Adolescent Health in Low- and Middle-Income Countries.

PURPOSE: To conduct an expert-led process for identifying research priorities for eight areas of adolescent health in low- and middle-income countries. Specific adolescent health areas included communicable diseases prevention and management, injuries and violence, mental health, noncommunicable diseases management, nutrition, physical activity, substance use, and health policy. METHODS: We used a modified version of the Child Health and Nutrition Research Initiative methodology for reaching consensus on research priorities. In a three phase process, we (1) identified research and program experts with wide-ranging backgrounds and experiences from all geographic regions through systematic searches and key informants; (2) invited these experts to propose research questions related to descriptive epidemiology, interventions (discovery, development/testing, and delivery/implementation), and health policy/systems; and (3) asked the experts to prioritize the research questions based on five criteria: clarity, answerability, importance or impact, implementation, and equity. RESULTS: A total of 142 experts submitted 512 questions which were edited and reduced to 303 for scoring. Overall, the types of the top 10 research questions in each of the eight health areas included descriptive epidemiology (26%), interventions: discovery (11%), development/testing (25%), delivery (33%), and policy, health and social systems (5%). Across health areas, the top questions highlighted integration of health services, vulnerable populations, and different health platforms (such as primary care, schools, families/parents, and interactive media). CONCLUSIONS: Priority questions have been identified for research in eight key areas of adolescent health in low- and middle-income countries. These expert-generated questions may be used by donors, program managers, and researchers to prioritize and stimulate research in adolescent health

Development and application of an antibiotic spectrum index for benchmarking antibiotic selection patterns across hospitals

Standard metrics for antimicrobial use consider volume but not spectrum of antimicrobial prescribing. We developed an antibiotic spectrum index (ASI) to classify commonly used antibiotics based on activity against important pathogens. The application of this index to hospital antibiotic use reveals how this tool enhances current antimicrobial stewardship metrics.Infect Control Hosp Epidemiol 2017;38:993–997</jats:p

Attenuation of neural responses in primary visual cortex during the attentional blink

Information-processing bottlenecks are characteristic of many cognitive and neural systems. One such bottleneck is revealed by tasks in which rapidly successive stimulus events must be reported. Here, observers missed the second of two visual targets if it occurred within 700 ms of the first [an "attentional blink" (AB)], even though this second target could be reported accurately when the first item was ignored. Isolating neural responses to such rapid events has proven difficult because current magnetic resonance imaging methods rely on relatively sluggish changes in the brain's physiological response to sensory inputs. Here, we overcame this limitation by presenting successive visual targets at different spatial locations, thereby exploiting the retinotopic organization of early cortical visual areas to distinguish neural activity associated with successive target events. We show that neural activity in primary visual cortex is significantly modulated during the AB, and that this activity mirrors behavioral measures of target identification accuracy. The findings suggest that the neural signature of perceptual suppression during processing of rapidly successive stimuli is evident at the earliest stages of cortical sensory processing

Real-space investigation of short-range magnetic correlations in fluoride pyrochlores NaCaCo2_2F7_7 and NaSrCo2_2F7_7 with magnetic pair distribution function analysis

We present time-of-flight neutron total scattering and polarized neutron scattering measurements of the magnetically frustrated compounds NaCaCo$_2$F$_7$ and NaSrCo$_2$F$_7$, which belong to a class of recently discovered pyrochlore compounds based on transition metals and fluorine. The magnetic pair distribution function (mPDF) technique is used to analyze and model the total scattering data in real space. We find that a previously-proposed model of short-range XY-like correlations with a length scale of 10-15 \AA, combined with nearest-neighbor collinear antiferromagnetic correlations, accurately describes the mPDF data at low temperature, confirming the magnetic ground state in these materials. This model is further verified by the polarized neutron scattering data. From an analysis of the temperature dependence of the mPDF and polarized neutron scattering data, we find that short-range correlations persist on the nearest-neighbor length scale up to 200 K, approximately two orders of magnitude higher than the spin freezing temperatures of these compounds. These results highlight the opportunity presented by these new pyrochlore compounds to study the effects of geometric frustration at relatively high temperatures, while also advancing the mPDF technique and providing a novel opportunity to investigate a genuinely short-range-ordered magnetic ground state directly in real space

Drivers of long-distance spotting during wildfires in south-eastern Australia

We analysed the influence of wildfire area, topography, fuel, surface weather and upper-level weather conditions on long-distance spotting during wildfires. The analysis was based on a large dataset of 338 observations, from aircraft-acquired optical line scans, of spotting wildfires in south-east Australia between 2002 and 2018. Source fire area (a measure of fire activity) was the most important predictor of maximum spotting distance and the number of long-distance spot fires produced (i.e. >500 m from a source fire). Weather (surface and upper-level), vegetation and topographic variables had important secondary effects. Spotting distance and number of long-distance spot fires increased strongly with increasing source fire area, particularly under strong winds and in areas containing dense forest and steep slopes. General vegetation descriptors better predicted spotting compared with bark hazard and presence variables, suggesting systems that measure and map bark spotting potential need improvement. The results from this study have important implications for the development of predictive spotting and wildfire behaviour models

Basal Signalling Through Death Receptor 5 and Caspase 3 Activates p38 Kinase To Regulate Serum Response Factor (SRF)-Mediated Myod Transcription

We have previously reported that stable expression of a dominant negative Death Receptor 5 (dnDR5) in skeletal myoblasts results in decreased basal caspase activity and decreased mRNA and protein expression of the muscle regulatory transcription factor MyoD in growth medium (GM), resulting in inhibited differentation when myoblasts are then cultured in differentiation media (DM). Further, this decreased level of MyoD mRNA was not a consequence of altered message stability, but rather correlated with decreased acetylation of histones in the distal regulatory region (DRR) of the MyoD extended promoter known to control MyoD transcription. As serum response factor (SRF) is the transcription factor known to be responsible for basal MyoD expression in GM, we compared the level of SRF binding to the non-canonical serum response element (SRE) within the DRR in parental and dnDR5 expressing myoblasts. Herein, we report that stable expression of dnDR5 resulted in decreased levels of serum response factor (SRF) binding to the CArG box in the SRE of the DRR. Total SRF expression levels were not affected, but phosphorylation indicative of SRF activation was impaired. This decreased SRF phosphorylation correlated with decreased phosphorylation-induced activation of p38 kinase. Moreover, the aforementioned signaling events affected by expression of dnDR5 could be appropriately recapitulated using either a pharmacological inhibitor of caspase 3 or p38 kinase. Thus, our results have established a signaling pathway from DR5 through caspases to p38 kinase activation, to SRF activation and the basal expression of MyoD

Duration of Posttraumatic Amnesia Predicts Neuropsychological and Global Outcome in Complicated Mild Traumatic Brain Injury.

OBJECTIVES: Examine the effects of posttraumatic amnesia (PTA) duration on neuropsychological and global recovery from 1 to 6 months after complicated mild traumatic brain injury (cmTBI). PARTICIPANTS: A total of 330 persons with cmTBI defined as Glasgow Coma Scale score of 13 to 15 in emergency department, with well-defined abnormalities on neuroimaging. METHODS: Enrollment within 24 hours of injury with follow-up at 1, 3, and 6 months. MEASURES: Glasgow Outcome Scale-Extended, California Verbal Learning Test II, and Controlled Oral Word Association Test. Duration of PTA was retrospectively measured with structured interview at 30 days postinjury. RESULTS: Despite all having a Glasgow Coma Scale Score of 13 to 15, a quarter of the sample had a PTA duration of greater than 7 days; half had PTA duration of 1 of 7 days. Both cognitive performance and Extended Glasgow Outcome Scale outcomes were strongly associated with time since injury and PTA duration, with those with PTA duration of greater than 1 week showing residual moderate disability at 6-month assessment. CONCLUSIONS: Findings reinforce importance of careful measurement of duration of PTA to refine outcome prediction and allocation of resources to those with cmTBI. Future research would benefit from standardization in computed tomographic criteria and use of severity indices beyond Glasgow Coma Scale to characterize cmTBI

Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability.

Thrombospondins (Thbs) are a family of five secreted matricellular glycoproteins in vertebrates that broadly affect cell-matrix interaction. While Thbs4 is known to protect striated muscle from disease by enhancing sarcolemmal stability through increased integrin and dystroglycan attachment complexes, here we show that Thbs3 antithetically promotes sarcolemmal destabilization by reducing integrin function, augmenting disease-induced decompensation. Deletion of Thbs3 in mice enhances integrin membrane expression and membrane stability, protecting the heart from disease stimuli. Transgene-mediated overexpression of α7β1D integrin in the heart ameliorates the disease predisposing effects of Thbs3 by augmenting sarcolemmal stability. Mechanistically, we show that mutating Thbs3 to contain the conserved RGD integrin binding domain normally found in Thbs4 and Thbs5 now rescues the defective expression of integrins on the sarcolemma. Thus, Thbs proteins mediate the intracellular processing of integrin plasma membrane attachment complexes to regulate the dynamics of cellular remodeling and membrane stability