Molecular Determinants of PQBP1 Binding to the HIV-1 Capsid Lattice.

Human immunodeficiency virus type 1 (HIV-1) stimulates innate immune responses upon infection, including cyclic GMP-AMP synthase (cGAS) signaling that results in type I interferon production. HIV-1-induced activation of cGAS requires the host cell factor polyglutamine binding protein 1 (PQBP1), an intrinsically disordered protein that bridges capsid recognition and cGAS recruitment. However, the molecular details of PQBP1 interactions with the HIV-1 capsid and their functional implications remain poorly understood. Here, we show that PQBP1 binds to HIV-1 capsids through charge complementing contacts between acidic residues in the N-terminal region of PQBP1 and an arginine ring in the central channel of the HIV-1 CA hexamer that makes up the viral capsid. These studies reveal the molecular details of PQBP1's primary interaction with the HIV-1 capsid and suggest that additional elements are likely to contribute to stable capsid binding.

Differential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes resulting in inflammation.

Dysregulated secretion in neutrophil leukocytes associates with human inflammatory disease. The exocytosis response to triggering stimuli is sequential; gelatinase granules modulate the initiation of the innate immune response, followed by the release of pro-inflammatory azurophilic granules, requiring stronger stimulation. Exocytosis requires actin depolymerization which is actively counteracted under non-stimulatory conditions. Here we show that the actin nucleator, WASH, is necessary to maintain azurophilic granules in their refractory state by granule actin entrapment and interference with the Rab27a-JFC1 exocytic machinery. On the contrary, gelatinase granules of WASH-deficient neutrophil leukocytes are characterized by decreased Rac1, shortened granule-associated actin comets and impaired exocytosis. Rac1 activation restores exocytosis of these granules. In vivo, WASH deficiency induces exacerbated azurophilic granule exocytosis, inflammation, and decreased survival. WASH deficiency thus differentially impacts neutrophil granule subtypes, impairing exocytosis of granules that mediate the initiation of the neutrophil innate response while exacerbating pro-inflammatory granule secretion.

Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue.

Targeting the delivery of therapeutics specifically to diseased tissue enhances their efficacy and decreases their side effects. Here we show that mesenchymal stromal cells with their nuclei removed by density-gradient centrifugation following the genetic modification of the cells for their display of chemoattractant receptors and endothelial-cell-binding molecules are effective vehicles for the targeted delivery of therapeutics. The enucleated cells neither proliferate nor permanently engraft in the host, yet retain the organelles for energy and protein production, undergo integrin-regulated adhesion to inflamed endothelial cells, and actively home to chemokine gradients established by diseased tissues. In mouse models of acute inflammation and of pancreatitis, systemically administered enucleated cells expressing two types of chemokine receptor and an endothelial adhesion molecule enhanced the delivery of an anti-inflammatory cytokine to diseased tissue (with respect to unmodified stromal cells and to exosomes derived from bone-marrow-derived stromal cells), attenuating inflammation and ameliorating disease pathology. Enucleated cells retain most of the cells' functionality, yet acquire the cargo-carrying characteristics of cell-free delivery systems, and hence represent a versatile delivery vehicle and therapeutic system.

Simulating lightning NO production in CMAQv5.2: performance evaluations.

This study assesses the impact of the lightning nitric oxide (LNO) production schemes in the Community Multiscale Air Quality (CMAQ) model on ground-level air quality as well as aloft atmospheric chemistry through detailed evaluation of model predictions of nitrogen oxides (NO x ) and ozone (O3) with corresponding observations for the US. For ground-level evaluations, hourly O3 and NO x values from the U.S. EPA Air Quality System (AQS) monitoring network are used to assess the impact of different LNO schemes on model prediction of these species in time and space. Vertical evaluations are performed using ozonesonde and P-3B aircraft measurements during the Deriving Information on Surface Conditions from Column and Vertically Resolved Observations Relevant to Air Quality (DISCOVER-AQ) campaign conducted in the Baltimore- Washington region during July 2011. The impact on wet deposition of nitrate is assessed using measurements from the National Atmospheric Deposition Program's National Trends Network (NADP NTN). Compared with the Base model (without LNO), the impact of LNO on surface O3 varies from region to region depending on the Base model conditions. Overall statistics suggest that for regions where surface O3 mixing ratios are already overestimated, the incorporation of additional NO from lightning generally increased model overestimation of mean daily maximum 8 h (DM8HR) O3 by 1-2 ppb. In regions where surface O3 is underestimated by the Base model, LNO can significantly reduce the underestimation and bring model predictions close to observations. Analysis of vertical profiles reveals that LNO can significantly improve the vertical structure of modeled O3 distributions by reducing underestimation aloft and to a lesser degree decreasing overestimation near the surface. Since the Base model underestimates the wet deposition of nitrate in most regions across the modeling domain with the exception of the Pacific Coast, the inclusion of LNO leads to reduction in biases and errors and an increase in correlation coefficients at almost all the NADP NTN sites. Among the three LNO schemes described in Kang et al. (2019), the hNLDN scheme, which is implemented using hourly observed lightning flash data from National Lightning Detection Network (NLDN), performs best for comparisons with ground-level values, vertical profiles, and wet deposition of nitrate; the mNLDN scheme (the monthly NLDN-based scheme) performed slightly better. However, when observed lightning flash data are not available, the linear regression-based parameterization scheme, pNLDN, provides an improved estimate for nitrate wet deposition compared to the base simulation that does not include LNO.

Simulating lightning NO production in CMAQv5.2: evolution of scientific updates.

This work describes the lightning nitric oxide (LNO) production schemes in the Community Multiscale Air Quality (CMAQ) model. We first document the existing LNO production scheme and vertical distribution algorithm. We then describe updates that were made to the scheme originally based on monthly National Lightning Detection Network (mNLDN) observations. The updated scheme uses hourly NLDN (hNLDN) observations. These NLDN-based schemes are good for retrospective model applications when historical lightning data are available. For applications when observed data are not available (i.e., air quality forecasts and climate studies that assume similar climate conditions), we have developed a scheme that is based on linear and log-linear parameters derived from regression of multiyear historical NLDN (pNLDN) observations and meteorological model simulations. Preliminary assessment for total column LNO production reveals that the mNLDN scheme overestimates LNO by over 40% during summer months compared with the updated hNLDN scheme that reflects the observed lightning activity more faithfully in time and space. The pNLDN performance varies with year, but it generally produced LNO columns that are comparable to hNLDN and mNLDN, and in most cases it outperformed mNLDN. Thus, when no observed lightning data are available, pNLDN can provide reasonable estimates of LNO emissions over time and space for this important natural NO source that influences air quality regulations.

Global O3-CO Correlations in a Chemistry and Transport Model During July-August: Evaluation with TES Satellite Observations and Sensitivity to Input Meteorological Data and Emissions.

We examine the capability of the Global Modeling Initiative (GMI) chemistry and transport model to reproduce global mid-tropospheric (618hPa) O3-CO correlations determined by the measurements from Tropospheric Emission Spectrometer (TES) aboard NASA's Aura satellite during boreal summer (July-August). The model is driven by three meteorological data sets (fvGCM with sea surface temperature for 1995, GEOS4-DAS for 2005, and MERRA for 2005), allowing us to examine the sensitivity of model O3-CO correlations to input meteorological data. Model simulations of radionuclide tracers (222Rn, 210Pb, and 7Be) are used to illustrate the differences in transport-related processes among the meteorological data sets. Simulated O3 values are evaluated with climatological ozone profiles from ozonesonde measurements and satellite tropospheric O3 columns. Despite the fact that three simulations show significantly different global and regional distributions of O3 and CO concentrations, all simulations show similar patterns of O3-CO correlations on a global scale. These patterns are consistent with those derived from TES observations, except in the tropical easterly biomass burning outflow regions. Discrepancies in regional O3-CO correlation patterns in the three simulations may be attributed to differences in convective transport, stratospheric influence, and subsidence, among other processes. To understand how various emissions drive global O3-CO correlation patterns, we examine the sensitivity of GMI/MERRA model-calculated O3 and CO concentrations and their correlations to emission types (fossil fuel, biomass burning, biogenic, and lightning NOx emissions). Fossil fuel and biomass burning emissions are mainly responsible for the strong positive O3-CO correlations over continental outflow regions in both hemispheres. Biogenic emissions have a relatively smaller impact on O3-CO correlations than other emissions, but are largely responsible for the negative correlations over the tropical eastern Pacific, reflecting the fact that O3 is consumed and CO generated during the atmospheric oxidation process of isoprene under low NOx conditions. We find that lightning NOx emissions degrade both positive correlations at mid-/high- latitudes and negative correlations in the tropics because ozone production downwind of lightning NOx emissions is not directly related to the emission and transport of CO. Our study concludes that O3-CO correlations may be used effectively to constrain the sources of regional tropospheric O3 in global 3-D models, especially for those regions where convective transport of pollution plays an important role.

Personalized medicine for osteoarthritis: where are we now?

Personalized medicine is a much talked about subject that is a timely and important development to healthcare in general and also specifically for patients affected by osteoarthritis. This review uses biomarker examples pertinent to osteoarthritis to highlight the current status of the field, while also highlighting probable future developments. It is not meant to be an exhaustive account. The BIPED(s) [Burden of disease, Investigative, Prognosis, Efficacy, Diagnosis (safety)] classification system is used to organize the discussion of examples. Biomarkers pertaining to burden, investigation, prognosis, efficacy, diagnosis and safety are highlighted. The examples are followed by a discussion of issues related to interpretation and application of biomarker results and approaches to solve the challenges interpretation faces, including graphical, mathematical and synthetic representations. Through this review, it is hoped that a better appreciation can be gained of the potential and pitfalls of personal medicine in the care of patients with osteoarthritis.

Report from The International Society for Nomenclature of Paediatric and Congenital Heart Disease: cardiovascular catheterisation for congenital and paediatric cardiac disease (Part 2 - Nomenclature of complications associated with interventional cardiology).

Interventional cardiology for paediatric and congenital cardiac disease is a relatively young and rapidly evolving field. As the profession begins to establish multi-institutional databases, a universal system of nomenclature is necessary for the field of interventional cardiology for paediatric and congenital cardiac disease. The purpose of this paper is to present the results of the efforts of The International Society for Nomenclature of Paediatric and Congenital Heart Disease to establish a system of nomenclature for cardiovascular catheterisation for congenital and paediatric cardiac disease, focusing both on procedural nomenclature and the nomenclature of complications associated with interventional cardiology. This system of nomenclature for cardiovascular catheterisation for congenital and paediatric cardiac disease is a component of The International Paediatric and Congenital Cardiac Code. This manuscript is the second part of the two-part series. Part 1 covered the procedural nomenclature associated with interventional cardiology as treatment for paediatric and congenital cardiac disease. Part 2 will cover the nomenclature of complications associated with interventional cardiology as treatment for paediatric and congenital cardiac disease.

Report from The International Society for Nomenclature of Paediatric and Congenital Heart Disease: cardiovascular catheterisation for congenital and paediatric cardiac disease (Part 1 - Procedural nomenclature).

Interventional cardiology for paediatric and congenital cardiac disease is a relatively young and rapidly evolving field. As the profession begins to establish multi-institutional databases, a universal system of nomenclature is necessary for the field of interventional cardiology for paediatric and congenital cardiac disease. The purpose of this paper is to present the results of the efforts of The International Society for Nomenclature of Paediatric and Congenital Heart Disease to establish a system of nomenclature for cardiovascular catheterisation for congenital and paediatric cardiac disease, focusing both on procedural nomenclature and on the nomenclature of complications associated with interventional cardiology. This system of nomenclature for cardiovascular catheterisation for congenital and paediatric cardiac disease is a component of The International Paediatric and Congenital Cardiac Code. This manuscript is the first part of a two-part series. Part 1 will cover the procedural nomenclature associated with interventional cardiology as treatment for paediatric and congenital cardiac disease. This procedural nomenclature of The International Paediatric and Congenital Cardiac Code will be used in the IMPACT Registry™ (IMproving Pediatric and Adult Congenital Treatment) of the National Cardiovascular Data Registry® of The American College of Cardiology. Part 2 will cover the nomenclature of complications associated with interventional cardiology as treatment for paediatric and congenital cardiac disease.

An exploratory study of factors influencing glaucoma treatment adherence.

PURPOSE: To understand the factors that influence glaucoma treatment adherence with medication taking, prescription refills, and appointment keeping to develop an intervention for a specific population. PATIENTS AND METHODS: In-depth interviews were conducted with 80 individuals diagnosed with open-angle glaucoma, glaucoma suspect, or ocular hypertension. Additional eligibility requirements were that all participants were: between the ages of 18 to 80; white or African American; spoke and understood English; and were taking daily doses of topical glaucoma treatments for at least the past year. Cross-tabulations and chi2 tests were conducted to compare adherent and nonadherent individuals, classified as such based on self-report and medical chart/pharmacy data. RESULTS: Compared with adherent participants, nonadherent participants were less likely to: believe their eye doctors spent sufficient time with them; ask their eye doctor if they had any questions; know of benefits to taking their glaucoma medication regularly; and have someone help them take their glaucoma medications or drive them to eye appointments. Conversely, compared with adherent individuals, nonadherent participants were more likely to have difficulty remembering to take their medications and to believe their glaucoma would affect their eye sight in the future. CONCLUSIONS: Nonadherent glaucoma patients struggle with a variety of issues related to consistent use of glaucoma medicine and routine eye care. Interventions are needed to address these modifiable factors related to glaucoma treatment adherence.