Transplacental innate immune training via maternal microbial exposure: role of XBP1-ERN1 axis in dendritic cell precursor programming

We recently reported that offspring of mice treated during pregnancy with the microbial-derived immunomodulator OM-85 manifest striking resistance to allergic airways inflammation, and localized the potential treatment target to fetal conventional dendritic cell (cDC) progenitors. Here, we profile maternal OM-85 treatment-associated transcriptomic signatures in fetal bone marrow, and identify a series of immunometabolic pathways which provide essential metabolites for accelerated myelopoiesis. Additionally, the cDC progenitor compartment displayed treatment-associated activation of the XBP1-ERN1 signalling axis which has been shown to be crucial for tissue survival of cDC, particularly within the lungs. Our forerunner studies indicate uniquely rapid turnover of airway mucosal cDCs at baseline, with further large-scale upregulation of population dynamics during aeroallergen and/or pathogen challenge. We suggest that enhanced capacity for XBP1-ERN1-dependent cDC survival within the airway mucosal tissue microenvironment may be a crucial element of OM-85-mediated transplacental innate immune training which results in postnatal resistance to airway inflammatory disease

Preliminary uncertainty and sensitivity analysis for basic transport parameters at the Horonobe Site, Hokkaido, Japan.

Incorporating results from a previously developed finite element model, an uncertainty and parameter sensitivity analysis was conducted using preliminary site-specific data from Horonobe, Japan (data available from five boreholes as of 2003). Latin Hypercube Sampling was used to draw random parameter values from the site-specific measured, or approximated, physicochemical uncertainty distributions. Using pathlengths and groundwater velocities extracted from the three-dimensional, finite element flow and particle tracking model, breakthrough curves for multiple realizations were calculated with the semi-analytical, one-dimensional, multirate transport code, STAMMT-L. A stepwise linear regression analysis using the 5, 50, and 95% breakthrough times as the dependent variables and LHS sampled site physicochemical parameters as the independent variables was used to perform a sensitivity analysis. Results indicate that the distribution coefficients and hydraulic conductivities are the parameters responsible for most of the variation among simulated breakthrough times. This suggests that researchers and data collectors at the Horonobe site should focus on accurately assessing these parameters and quantifying their uncertainty. Because the Horonobe Underground Research Laboratory is in an early phase of its development, this work should be considered as a first step toward an integration of uncertainty and sensitivity analyses with decision analysis

Public release of optimization of metallization scheme for thin emitter wrap-through solar cells for higher efficiency, reduced precious metal costs, and reduced stress.

Back-contact crystalline-silicon photovoltaic solar cells and modules offer a number of advantages, including the elimination of grid shadowing losses, reduced cost through use of thinner silicon substrates, simpler module assembly, and improved aesthetics. While the existing edge tab method for interconnecting and stringing edge-connected back contact cells is acceptably straightforward and reliable, there are further gains to be exploited when you have both contact polarities on one side of the cell. In this work, we produce 'busbarless' emitter wrap-through solar cells that use 41% of the gridline silver (Ag) metallization mass compared to the edge tab design. Further, series resistance power losses are reduced by extraction of current from more places on the cell rear, leading to a fill factor improvement of about 6% (relative) on the module level. Series resistance and current-generation losses associated with large rear bondpads and busbars are eliminated. Use of thin silicon (Si) wafers is enabled because of the reduced Ag metallization mass and by interconnection with conductive adhesives leading to reduced bow. The busbarless cell design interconnected with conductive adhesives passes typical International Electrotechnical Commission damp heat and thermal cycling test

The Red Sea, Coastal Landscapes, and Hominin Dispersals

This chapter provides a critical assessment of environment, landscape and resources in the Red Sea region over the past five million years in relation to archaeological evidence of hominin settlement, and of current hypotheses about the role of the region as a pathway or obstacle to population dispersals between Africa and Asia and the possible significance of coastal colonization. The discussion assesses the impact of factors such as topography and the distribution of resources on land and on the seacoast, taking account of geographical variation and changes in geology, sea levels and palaeoclimate. The merits of northern and southern routes of movement at either end of the Red Sea are compared. All the evidence indicates that there has been no land connection at the southern end since the beginning of the Pliocene period, but that short sea crossings would have been possible at lowest sea-level stands with little or no technical aids. More important than the possibilities of crossing the southern channel is the nature of the resources available in the adjacent coastal zones. There were many climatic episodes wetter than today, and during these periods water draining from the Arabian escarpment provided productive conditions for large mammals and human populations in coastal regions and eastwards into the desert. During drier episodes the coastal region would have provided important refugia both in upland areas and on the emerged shelves exposed by lowered sea level, especially in the southern sector and on both sides of the Red Sea. Marine resources may have offered an added advantage in coastal areas, but evidence for their exploitation is very limited, and their role has been over-exaggerated in hypotheses of coastal colonization

Industry in Motion: Using Smart Phones to Explore the Spatial Network of the Garment Industry in New York City

Industrial agglomerations have long been thought to offer economic and social benefits to firms and people that are only captured by location within their specified geographies. Using the case study of New York City’s garment industry along with data acquired from cell phones and social media, this study set out to understand the discrete activities underpinning the economic dynamics of an industrial agglomeration. Over a two week period, data was collected by employing the geo-locative capabilities of Foursquare, a social media application, to record every movement of fashion workers employed at fashion design firms located both inside and outside the geographical boundaries of New York City’s Garment District. This unique method of studying worker activity exposed the day-to-day dynamics of an industrial district with a precision thus far undocumented in literature. Our work suggests that having access to the cluster provides almost the same agglomeration economies as residing within its borders.Rockefeller Foundatio

A Policy-Ready Public Health Guidebook of Strategies and Indicators to Promote Financial Well-Being and Address Financial Strain in Response to COVID-19

Introduction The COVID-19 pandemic has adversely affected the financial well-being of populations globally, escalating concerns about links with health care and overall well-being. Governments and organizations need to act quickly to protect population health relative to exacerbated financial strain. However, limited practice and policy-relevant resources are available to guide action, particularly from a public health perspective, that is, targeting equity, social determinants of health, and health-in-all policies. Our study aimed to create a public health guidebook of strategies and indicators for multisectoral action on financial well-being and financial strain by decision makers in high-income contexts. Methods We used a multimethod approach to create the guidebook. We conducted a targeted review of existing theoretical and conceptual work on financial well-being and strain. By using rapid review methodology informed by principles of realist review, we collected data from academic and practice-based sources evaluating financial well-being or financial strain initiatives. We performed a critical review of these sources. We engaged our research–practice team and government and nongovernment partners and participants in Canada and Australia for guidance to strengthen the tool for policy and practice. Results The guidebook presents 62 targets, 140 evidence-informed strategies, and a sample of process and outcome indicators. Conclusion The guidebook supports action on the root causes of poor financial well-being and financial strain. It addresses a gap in the academic literature around relevant public health strategies to promote financial well-being and reduce financial strain. Community organizations, nonprofit organizations, and governments in highincome countries can use the guidebook to direct initiative design, implementation, and assessmen

Mendelian randomization for studying the effects of perturbing drug targets [version 2; peer review: 3 approved, 1 approved with reservations]

Drugs whose targets have genetic evidence to support efficacy and safety are more likely to be approved after clinical development. In this paper, we provide an overview of how natural sequence variation in the genes that encode drug targets can be used in Mendelian randomization analyses to offer insight into mechanism-based efficacy and adverse effects. Large databases of summary level genetic association data are increasingly available and can be leveraged to identify and validate variants that serve as proxies for drug target perturbation. As with all empirical research, Mendelian randomization has limitations including genetic confounding, its consideration of lifelong effects, and issues related to heterogeneity across different tissues and populations. When appropriately applied, Mendelian randomization provides a useful empirical framework for using population level data to improve the success rates of the drug development pipeline

Designing programs for eliminating canine rabies from islands: Bali, Indonesia as a case study

<p>Background: Canine rabies is one of the most important and feared zoonotic diseases in the world. In some regions rabies elimination is being successfully coordinated, whereas in others rabies is endemic and continues to spread to uninfected areas. As epidemics emerge, both accepted and contentious control methods are used, as questions remain over the most effective strategy to eliminate rabies. The Indonesian island of Bali was rabies-free until 2008 when an epidemic in domestic dogs began, resulting in the deaths of over 100 people. Here we analyze data from the epidemic and compare the effectiveness of control methods at eliminating rabies.</p> <p>Methodology/Principal Findings: Using data from Bali, we estimated the basic reproductive number, R0, of rabies in dogs, to be ~1·2, almost identical to that obtained in ten–fold less dense dog populations and suggesting rabies will not be effectively controlled by reducing dog density. We then developed a model to compare options for mass dog vaccination. Comprehensive high coverage was the single most important factor for achieving elimination, with omission of even small areas (<0.5% of the dog population) jeopardizing success. Parameterizing the model with data from the 2010 and 2011 vaccination campaigns, we show that a comprehensive high coverage campaign in 2012 would likely result in elimination, saving ~550 human lives and ~$15 million in prophylaxis costs over the next ten years.</p> <p>Conclusions/Significance: The elimination of rabies from Bali will not be achieved through achievable reductions in dog density. To ensure elimination, concerted high coverage, repeated, mass dog vaccination campaigns are necessary and the cooperation of all regions of the island is critical. Momentum is building towards development of a strategy for the global elimination of canine rabies, and this study offers valuable new insights about the dynamics and control of this disease, with immediate practical relevance.</p&gt

Borrelia recurrentis employs a novel multifunctional surface protein with anti-complement, anti-opsonic and invasive potential to escape innate immunity

Borrelia recurrentis, the etiologic agent of louse-borne relapsing fever in humans, has evolved strategies, including antigenic variation, to evade immune defence, thereby causing severe diseases with high mortality rates. Here we identify for the first time a multifunctional surface lipoprotein of B. recurrentis, termed HcpA, and demonstrate that it binds human complement regulators, Factor H, CFHR-1, and simultaneously, the host protease plasminogen. Cell surface bound factor H was found to retain its activity and to confer resistance to complement attack. Moreover, ectopic expression of HcpA in a B. burgdorferi B313 strain, deficient in Factor H binding proteins, protected the transformed spirochetes from complement-mediated killing. Furthermore, HcpA-bound plasminogen/plasmin endows B. recurrentis with the potential to resist opsonization and to degrade extracellular matrix components. Together, the present study underscores the high virulence potential of B. recurrentis. The elucidation of the molecular basis underlying the versatile strategies of B. recurrentis to escape innate immunity and to persist in human tissues, including the brain, may help to understand the pathological processes underlying louse-borne relapsing fever