Platelet Immunoreceptor Tyrosine-Based Activation Motif (ITAM) Signaling and Vascular Integrity

Platelets are well-known for their critical role in hemostasis, i.e. the prevention of blood loss at sites of mechanical vessel injury. Inappropriate platelet activation and adhesion, however, can lead to thrombotic complications, such as myocardial infarction and stroke. To fulfill its role in hemostasis, the platelet is equipped with various G protein-coupled receptors (GPCRs) that mediate the response to soluble agonists such as thrombin, ADP, and thromboxane A2. In addition to GPCRs, platelets express three glycoproteins (GP) that belong to the family of immunoreceptor tyrosine-based activation motif (ITAM) receptors: Fc receptor (FcR) γ chain, which is non-covalently associated with the GPVI collagen receptor, C-type lectin 2 (CLEC2), the receptor for podoplanin, and FcγRIIA, a low-affinity receptor for immune complexes. While both genetic and chemical approaches have documented a critical role for platelet GPCRs in hemostasis, the contribution of ITAM receptors to this process is less defined. Studies performed over the last decade, however, have identified new roles for platelet ITAM signaling in vascular integrity in utero and at sites of inflammation. The purpose of this review is to summarize recent findings on how platelet ITAM signaling controls vascular integrity, both in the presence and absence of mechanical injury

Molecular Dynamics Simulations

A tutorial introduction to the technique of Molecular Dynamics (MD) is given, and some characteristic examples of applications are described. The purpose and scope of these simulations and the relation to other simulation methods is discussed, and the basic MD algorithms are described. The sampling of intensive variables (temperature T, pressure p) in runs carried out in the microcanonical (NVE) ensemble (N= particle number, V = volume, E = energy) is discussed, as well as the realization of other ensembles (e.g. the NVT ensemble). For a typical application example, molten SiO2, the estimation of various transport coefficients (self-diffusion constants, viscosity, thermal conductivity) is discussed. As an example of Non-Equilibrium Molecular Dynamics (NEMD), a study of a glass-forming polymer melt under shear is mentioned.Comment: 38 pages, 11 figures, to appear in J. Phys.: Condens. Matte

Ancillary health effects of climate mitigation scenarios as drivers of policy uptake: a review of air quality, transportation and diet co-benefits modeling studies

Background: Significant mitigation efforts beyond the Nationally Determined Commitments (NDCs) coming out of the 2015 Paris Climate Agreement are required to avoid warming of 2 °C above pre-industrial temperatures. Health co-benefits represent selected near term, positive consequences of climate policies that can offset mitigation costs in the short term before the beneficial impacts of those policies on the magnitude of climate change are evident. The diversity of approaches to modeling mitigation options and their health effects inhibits meta-analyses and syntheses of results useful in policy-making. Methods/Design: We evaluated the range of methods and choices in modeling health co-benefits of climate mitigation to identify opportunities for increased consistency and collaboration that could better inform policy-making. We reviewed studies quantifying the health co-benefits of climate change mitigation related to air quality, transportation, and diet published since the 2009 Lancet Commission 'Managing the health effects of climate change' through January 2017. We documented approaches, methods, scenarios, health-related exposures, and health outcomes. Results/Synthesis: Forty-two studies met the inclusion criteria. Air quality, transportation, and diet scenarios ranged from specific policy proposals to hypothetical scenarios, and from global recommendations to stakeholder-informed local guidance. Geographic and temporal scope as well as validity of scenarios determined policy relevance. More recent studies tended to use more sophisticated methods to address complexity in the relevant policy system. Discussion: Most studies indicated significant, nearer term, local ancillary health benefits providing impetus for policy uptake and net cost savings. However, studies were more suited to describing the interaction of climate policy and health and the magnitude of potential outcomes than to providing specific accurate estimates of health co-benefits. Modeling the health co-benefits of climate policy provides policy-relevant information when the scenarios are reasonable, relevant, and thorough, and the model adequately addresses complexity. Greater consistency in selected modeling choices across the health co-benefits of climate mitigation research would facilitate evaluation of mitigation options particularly as they apply to the NDCs and promote policy uptake

Estimating the health effects of greenhouse gas mitigation strategies: addressing parametric, model, and valuation challenges.

BACKGROUND: Policy decisions regarding climate change mitigation are increasingly incorporating the beneficial and adverse health impacts of greenhouse gas emission reduction strategies. Studies of such co-benefits and co-harms involve modeling approaches requiring a range of analytic decisions that affect the model output. OBJECTIVE: Our objective was to assess analytic decisions regarding model framework, structure, choice of parameters, and handling of uncertainty when modeling health co-benefits, and to make recommendations for improvements that could increase policy uptake. METHODS: We describe the assumptions and analytic decisions underlying models of mitigation co-benefits, examining their effects on modeling outputs, and consider tools for quantifying uncertainty. DISCUSSION: There is considerable variation in approaches to valuation metrics, discounting methods, uncertainty characterization and propagation, and assessment of low-probability/high-impact events. There is also variable inclusion of adverse impacts of mitigation policies, and limited extension of modeling domains to include implementation considerations. Going forward, co-benefits modeling efforts should be carried out in collaboration with policy makers; these efforts should include the full range of positive and negative impacts and critical uncertainties, as well as a range of discount rates, and should explicitly characterize uncertainty. We make recommendations to improve the rigor and consistency of modeling of health co-benefits. CONCLUSION: Modeling health co-benefits requires systematic consideration of the suitability of model assumptions, of what should be included and excluded from the model framework, and how uncertainty should be treated. Increased attention to these and other analytic decisions has the potential to increase the policy relevance and application of co-benefits modeling studies, potentially helping policy makers to maximize mitigation potential while simultaneously improving health

Medical School Without Walls: 50 Years of Regional Campuses at Indiana University School of Medicine

The history of Indiana University School of Medicine (IUSM) dates to 1871, when Indiana Medical College entered into an affiliation with Indiana University in Bloomington to offer medical education. In 1971, the Indiana General Assembly passed a bill to create and fund a distributed model for medical education for which IUSM was responsible, an innovative approach to implementing a statewide medical education program. IUSM became one of the first U.S. medical schools to implement what is today known as a regional medical campus model. This regional medical campus system has permitted IUSM to expand enrollment based on national and local concerns about physician shortages, increase access to care locally, support expansion of graduate medical education, and provide opportunities for research and scholarship by faculty and students statewide. This effort was made possible by partnerships with other universities and health care systems across the state and the support of local community and state leaders. The model is a forward-thinking and cost-effective way to educate physicians for service in the state of Indiana and is applicable to others. This article highlights milestones in IUSM’s 50-year history of regional medical education, describes the development of the regional medical campus model, recognizes significant achievements over the years, shares lessons learned, and discusses considerations for the future of medical education

Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life

Mammals transport blood through a high-pressure, closed vascular network and lymph through a low-pressure, open vascular network. These vascular networks connect at the lymphovenous (LV) junction, where lymph drains into blood and an LV valve (LVV) prevents backflow of blood into lymphatic vessels. Here we describe an essential role for platelets in preventing blood from entering the lymphatic system at the LV junction. Loss of CLEC2, a receptor that activates platelets in response to lymphatic endothelial cells, resulted in backfilling of the lymphatic network with blood from the thoracic duct (TD) in both neonatal and mature mice. Fibrin-containing platelet thrombi were observed at the LVV and in the terminal TD in wild-type mice, but not Clec2-deficient mice. Analysis of mice lacking LVVs or lymphatic valves revealed that platelet-mediated thrombus formation limits LV backflow under conditions of impaired valve function. Examination of mice lacking integrin-mediated platelet aggregation indicated that platelet aggregation stabilizes thrombi that form in the lymphatic vascular environment to prevent retrograde blood flow. Collectively, these studies unveil a newly recognized form of hemostasis that functions with the LVV to safeguard the lymphatic vascular network throughout life

Novel multiparameter correlates of \u3cem\u3eCoxiella burnetii\u3c/em\u3e infection and vaccination identified by longitudinal deep immune profiling

Q-fever is a flu-like illness caused by Coxiella burnetii (Cb), a highly infectious intracellular bacterium. There is an unmet need for a safe and effective vaccine for Q-fever. Correlates of immune protection to Cb infection are limited. We proposed that analysis by longitudinal high dimensional immune (HDI) profiling using mass cytometry combined with other measures of vaccination and protection could be used to identify novel correlates of effective vaccination and control of Cb infection. Using a vaccine-challenge model in HLA-DR transgenic mice, we demonstrated significant alterations in circulating T-cell and innate immune populations that distinguished vaccinated from naïve mice within 10 days, and persisted until at least 35 days post-vaccination. Following challenge, vaccinated mice exhibited reduced bacterial burden and splenomegaly, along with distinct effector T-cell and monocyte profiles. Correlation of HDI data to serological and pathological measurements was performed. Our data indicate a Th1-biased response to Cb, consistent with previous reports, and identify Ly6C, CD73, and T-bet expression in T-cell, NK-cell, and monocytic populations as distinguishing features between vaccinated and naïve mice. This study refines the understanding of the integrated immune response to Cb vaccine and challenge, which can inform the assessment of candidate vaccines for Cb