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In an in vitro model of human tuberculosis, monocyte-microglial networks regulate matrix metalloproteinase-1 and -3 gene expression and secretion via a p38 mitogen activated protein kinase-dependent pathway.

BACKGROUND: Tuberculosis (TB) of the central nervous system (CNS) is characterized by extensive tissue inflammation, driven by molecules that cleave extracellular matrix such as matrix metalloproteinase (MMP)-1 and MMP-3. However, relatively little is known about the regulation of these MMPs in the CNS. METHODS: Using a cellular model of CNS TB, we stimulated a human microglial cell line (CHME3) with conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb). MMP-1 and MMP-3 secretion was detected using ELISAs confirmed with casein zymography or western blotting. Key results of a phospho-array profile that detects a wide range of kinase activity were confirmed with phospho-Western blotting. Chemical inhibition (SB203580) of microglial cells allowed investigation of expression and secretion of MMP-1 and MMP-3. Finally we used promoter reporter assays employing full length and MMP-3 promoter deletion constructs. Student's t-test was used for comparison of continuous variables and multiple intervention experiments were compared by one-way ANOVA with Tukey's correction for multiple pairwise comparisons. RESULTS: CoMTb up-regulated microglial MMP-1 and MMP-3 secretion in a dose- and time-dependent manner. The phospho-array profiling showed that the major increase in kinase activity due to CoMTb stimulation was in p38 mitogen activated protein kinase (MAPK), principally the α and γ subunits. p38 phosphorylation was detected at 15 minutes, with a second peak of activity at 120 minutes. High basal extracellular signal-regulated kinase activity was further increased by CoMTb. Secretion and expression of MMP-1 and MMP-3 were both p38 dependent. CoMTb stimulation of full length and MMP-3 promoter deletion constructs demonstrated up-regulation of activity in the wild type but a suppression site between -2183 and -1612 bp. CONCLUSIONS: Monocyte-microglial network-dependent MMP-1 and MMP-3 gene expression and secretion are dependent upon p38 MAPK in tuberculosis. p38 is therefore a potential target for adjuvant therapy in CNS TB

Science Goals and Overview of the Radiation Belt Storm Probes (RBSP) Energetic Particle, Composition, and Thermal Plasma (ECT) Suite on NASA’s Van Allen Probes Mission

The Radiation Belt Storm Probes (RBSP)-Energetic Particle, Composition, and Thermal Plasma (ECT) suite contains an innovative complement of particle instruments to ensure the highest quality measurements ever made in the inner magnetosphere and radiation belts. The coordinated RBSP-ECT particle measurements, analyzed in combination with fields and waves observations and state-of-the-art theory and modeling, are necessary for understanding the acceleration, global distribution, and variability of radiation belt electrons and ions, key science objectives of NASA’s Living With a Star program and the Van Allen Probes mission. The RBSP-ECT suite consists of three highly-coordinated instruments: the Magnetic Electron Ion Spectrometer (MagEIS), the Helium Oxygen Proton Electron (HOPE) sensor, and the Relativistic Electron Proton Telescope (REPT). Collectively they cover, continuously, the full electron and ion spectra from one eV to 10’s of MeV with sufficient energy resolution, pitch angle coverage and resolution, and with composition measurements in the critical energy range up to 50 keV and also from a few to 50 MeV/nucleon. All three instruments are based on measurement techniques proven in the radiation belts. The instruments use those proven techniques along with innovative new designs, optimized for operation in the most extreme conditions in order to provide unambiguous separation of ions and electrons and clean energy responses even in the presence of extreme penetrating background environments. The design, fabrication and operation of ECT spaceflight instrumentation in the harsh radiation belt environment ensure that particle measurements have the fidelity needed for closure in answering key mission science questions. ECT instrument details are provided in companion papers in this same issue. In this paper, we describe the science objectives of the RBSP-ECT instrument suite on the Van Allen Probe spacecraft within the context of the overall mission objectives, indicate how the characteristics of the instruments satisfy the requirements to achieve these objectives, provide information about science data collection and dissemination, and conclude with a description of some early mission results

Condom Use Trajectories in Adolescence and the Transition to Adulthood: The Role of Mother and Father Support

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92028/1/jora775.pd

Gender-dependent differences in plasma matrix metalloproteinase-8 elevated in pulmonary tuberculosis.

Tuberculosis (TB) remains a global health pandemic and greater understanding of underlying pathogenesis is required to develop novel therapeutic and diagnostic approaches. Matrix metalloproteinases (MMPs) are emerging as key effectors of tissue destruction in TB but have not been comprehensively studied in plasma, nor have gender differences been investigated. We measured the plasma concentrations of MMPs in a carefully characterised, prospectively recruited clinical cohort of 380 individuals. The collagenases, MMP-1 and MMP-8, were elevated in plasma of patients with pulmonary TB relative to healthy controls, and MMP-7 (matrilysin) and MMP-9 (gelatinase B) were also increased. MMP-8 was TB-specific (p<0.001), not being elevated in symptomatic controls (symptoms suspicious of TB but active disease excluded). Plasma MMP-8 concentrations inversely correlated with body mass index. Plasma MMP-8 concentration was 1.51-fold higher in males than females with TB (p<0.05) and this difference was not due to greater disease severity in men. Gender-specific analysis of MMPs demonstrated consistent increase in MMP-1 and -8 in TB, but MMP-8 was a better discriminator for TB in men. Plasma collagenases are elevated in pulmonary TB and differ between men and women. Gender must be considered in investigation of TB immunopathology and development of novel diagnostic markers

Investigation of current perspectives for NHS Wales sustainable development through procurement policies

Public sector procurement has to operate under the pressure of policies and strict budgets. This paper examines the current perspectives of NHS Wales Shared Services Partnership (NWSSP) on sustainable procurement policies through the environmental, social and economic dimensions. In particular, it investigates the adoption levels of the sustainable procurement policies of buyers (NHS Wales), examines the level of engagement of SMEs to NHS Wales, and explores the support for the existing sustainable procurement function through order-processing analysis of catalogue coverage

Substance Use Prevention Services in Juvenile Justice and Behavioral Health: Results from a National Survey

BACKGROUND: This study examined the national availability of substance use prevention (SUP) within juvenile justice (JJ) and their primary behavioral health (BH) providers, and the relationships between the availability of SUP and agency-level measures of organizational structure, staffing, and youth characteristics. A three-stage national probability sampling process was used to select participants for a national survey that included, among other facets of community supervision (CS) and BH practices, questions on agency characteristics, youth characteristics, whether the agency/provider directly provided SUP services, and whether the agency/provider directly provided substance use and/or mental health treatment. This paper focuses on SUP services along with agency/provider and youth characteristics related to providing SUP. RESULTS: The response rate for both CS agencies (n = 195) and BH providers (n = 271) was 96%. Complex samples logistic regression initially examined univariate associations of each variable and identified candidates for a final multivariate model. Overall, only one-third of CS and BH providers reported offering SUP services, with BH providers being significantly more likely than CS agencies to provide SUP services. In addition, likelihood of SUP was significantly lower among agencies where the substance use distribution of the caseload was below the median. Controlling for master\u27s level staff and the substance use distribution, CS agencies were about 67% less likely to offer SUP when compared to BH providers. CONCLUSIONS: Given the high rates of substance use among justice-involved youth and that substance use is an established risk for several negative behaviors, outcomes, and health conditions, these findings suggest that evidence-based prevention services should likely be expanded in justice settings, and perhaps included as part of CS programs, even when youth do not initially present with SU service needs

Event-specific chorus wave and electron seed population models in DREAM3D using the Van Allen Probes

Abstract The DREAM3D diffusion model is applied to Van Allen Probes observations of the fast dropout and strong enhancement of MeV electrons during the October 2012 double-dip storm. We show that in order to explain the very different behavior in the two dips, diffusion in all three dimensions (energy, pitch angle, and Lo) coupled with data-driven, event-specific inputs, and boundary conditions is required. Specifically, we find that outward radial diffusion to the solar wind-driven magnetopause, an event-specific chorus wave model, and a dynamic lower-energy seed population are critical for modeling the dynamics. In contrast, models that include only a subset of processes, use statistical wave amplitudes, or rely on inward radial diffusion of a seed population, perform poorly. The results illustrate the utility of the high resolution, comprehensive set of Van Allen Probes\u27 measurements in studying the balance between source and loss in the radiation belt, a principal goal of the mission. Key Points DREAM3D uses event-specific driving conditions measured by Van Allen Probes Electron dropout is due to outward radial diffusion to compressed magnetopause Event-specific chorus and seed electrons are necessary for the enhancement

Nonstorm time dynamics of electron radiation belts observed by the Van Allen Probes

Abstract Storm time electron radiation belt dynamics have been widely investigated for many years. Here we present a rarely reported nonstorm time event of electron radiation belt evolution observed by the Van Allen Probes during 21-24 February 2013. Within 2 days, a new belt centering around L=5.8 formed and gradually merged with the original outer belt, with the enhancement of relativistic electron fluxes by a factor of up to 50. Strong chorus waves (with power spectral density up to 10-4nT2/Hz) occurred in the region L\u3e5. Taking into account the local acceleration driven by these chorus waves, the two-dimensional STEERB can approximately reproduce the observed energy spectrums at the center of the new belt. These results clearly illustrate the complexity of electron radiation belt behaviors and the importance of chorus-driven local acceleration even during the nonstorm times

Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an <i>in vitro</i> model of CNS tuberculosis

Central nervous system tuberculosis (CNS TB) has a high mortality and morbidity associated with severe inflammation. The blood-brain barrier (BBB) protects the brain from inflammation but the mechanisms causing BBB damage in CNS TB are uncharacterized. We demonstrate that Mycobacterium tuberculosis (Mtb) causes breakdown of type IV collagen and decreases tight junction protein (TJP) expression in a co-culture model of the BBB. This increases permeability, surface expression of endothelial adhesion molecules and leukocyte transmigration. TJP breakdown was driven by Mtb-dependent secretion of matrix metalloproteinase (MMP)-9. TJP expression is regulated by Sonic hedgehog (Shh) through transcription factor Gli-1. In our model, the hedgehog pathway was downregulated by Mtb-stimulation, but Shh levels in astrocytes were unchanged. However, Scube2, a glycoprotein regulating astrocyte Shh release was decreased, inhibiting Shh delivery to brain endothelial cells. Activation of the hedgehog pathway by addition of a Smoothened agonist or by addition of exogenous Shh, or neutralizing MMP-9 activity, decreased permeability and increased TJP expression in the Mtb-stimulated BBB co-cultures. In summary, the BBB is disrupted by downregulation of the Shh pathway and breakdown of TJPs, secondary to increased MMP-9 activity which suggests that these pathways are potential novel targets for host directed therapy in CNS TB