Mast Cell Involvement in Fibrosis in Chronic Graft-versus-Host Disease

Allogeneic hematopoietic stem cell transplantation (HSCT) is most commonly a treatment for inborn defects of hematopoiesis or acute leukemias. Widespread use of HSCT, a potentially curative therapy, is hampered by onset of graft-versus-host disease (GVHD), classified as either acute or chronic GVHD. While the pathology of acute GVHD is better understood, factors driving GVHD at the cellular and molecular level are less clear. Mast cells are an arm of the immune system that are known for atopic disease. However, studies have demonstrated that they can play important roles in tissue homeostasis and wound healing, and mast cell dysregulation can lead to fibrotic disease. Interestingly, in chronic GVHD, aberrant wound healing mechanisms lead to pathological fibrosis, but the cellular etiology driving this is not well-understood, although some studies have implicated mast cells. Given this novel role, we here review the literature for studies of mast cell involvement in the context of chronic GVHD. While there are few publications on this topic, the papers excellently characterized a niche for mast cells in chronic GVHD. These findings may be extended to other fibrosing diseases in order to better target mast cells or their mediators for treatment of fibrotic disease

Assessing the Vulnerability of Monterey Bay Area Seniors to COVID-19

This paper assesses the vulnerability of seniors residing in the Monterey Bay Tri-County Region to the COVID-19 pandemic. Due to weakened immune systems, seniors are the most at-risk members of our community to COVID-19, and have a death rate that is three times higher than the overall death rate to COVID-19. Using standard ambulance response times from each hospital throughout the area, our objective is to determine what proportion of Tri-County seniors aged 65 and over, including those who are in nursing homes, are living independently, and cannot afford health care, were within an adequate travel time to the hospital. Additionally, we want to know which county is the most underprepared for a potential COVID-19 surge among its senior population. Using ArcGIS Online and Desktop, we addressed our research question by performing drive-time analysis on all Tri-County hospitals, determining the proportion of seniors and nursing homes that were within or outside the drive-time areas. We then compared the results to the number of active COVID-19 cases in each county. Our findings indicate that Monterey County had the most seniors and nursing homes completely outside of the hospital service zones, as well as the highest number of COVID-19 cases. Additionally, Santa Cruz County had the most seniors without health insurance living outside of the service zones, a figure that seems to agree logically with the astronomical cost of living in the area. We conclude that while Monterey County is by far the most at-risk, underprepared, and in need of resources, Santa Cruz could also have a potential problem with large proportions of uninsured (and homeless) seniors who are unable to access desperately needed medical attention

A blood RNA signature for tuberculosis disease risk: a prospective cohort study.

BACKGROUND: Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease might lead to interventions that combat the tuberculosis epidemic. We aimed to assess whether global gene expression measured in whole blood of healthy people allowed identification of prospective signatures of risk of active tuberculosis disease. METHODS: In this prospective cohort study, we followed up healthy, South African adolescents aged 12-18 years from the adolescent cohort study (ACS) who were infected with M tuberculosis for 2 years. We collected blood samples from study participants every 6 months and monitored the adolescents for progression to tuberculosis disease. A prospective signature of risk was derived from whole blood RNA sequencing data by comparing participants who developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex quantitative real-time PCR (qRT-PCR), the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. Participants of the independent cohorts were household contacts of adults with active pulmonary tuberculosis disease. FINDINGS: Between July 6, 2005, and April 23, 2007, we enrolled 6363 participants from the ACS study and 4466 from independent South African and Gambian cohorts. 46 progressors and 107 matched controls were identified in the ACS cohort. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% CI 63·2-68·9) and a specificity of 80·6% (79·2-82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA sequencing and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6-64·3) and a specificity of 82·8% (76·7-86) in the 12 months preceding tuberculosis. INTERPRETATION: The whole blood tuberculosis risk signature prospectively identified people at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease. FUNDING: Bill & Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union, and the South African Medical Research Council

Renewable Energy in the Context of Sustainable Development

Historically, economic development has been strongly correlated with increasing energy use and growth of greenhouse gas (GHG) emissions. Renewable energy (RE) can help decouple that correlation, contributing to sustainable development (SD). In addition, RE offers the opportunity to improve access to modern energy services for the poorest members of society, which is crucial for the achievement of any single of the eight Millennium Development Goals. Theoretical concepts of SD can provide useful frameworks to assess the interactions between SD and RE. SD addresses concerns about relationships between human society and nature. Traditionally, SD has been framed in the three-pillar model—Economy, Ecology, and Society—allowing a schematic categorization of development goals, with the three pillars being interdependent and mutually reinforcing. Within another conceptual framework, SD can be oriented along a continuum between the two paradigms of weak sustainability and strong sustainability. The two paradigms differ in assumptions about the substitutability of natural and human-made capital. RE can contribute to the development goals of the three-pillar model and can be assessed in terms of both weak and strong SD, since RE utilization is defined as sustaining natural capital as long as its resource use does not reduce the potential for future harvest. The relationship between RE and SD can be viewed as a hierarchy of goals and constraints that involve both global and regional or local considerations. Though the exact contribution of RE to SD has to be evaluated in a country specifi c context, RE offers the opportunity to contribute to a number of important SD goals: (1) social and economic development; (2) energy access; (3) energy security; (4) climate change mitigation and the reduction of environmental and health impacts. The mitigation of dangerous anthropogenic climate change is seen as one strong driving force behind the increased use of RE worldwide. The chapter provides an overview of the scientific literature on the relationship between these four SD goals and RE and, at times, fossil and nuclear energy technologies. The assessments are based on different methodological tools, including bottom-up indicators derived from attributional lifecycle assessments (LCA) or energy statistics, dynamic integrated modelling approaches, and qualitative analyses. Countries at different levels of development have different incentives and socioeconomic SD goals to advance RE. The creation of employment opportunities and actively promoting structural change in the economy are seen, especially in industrialized countries, as goals that support the promotion of RE. However, the associated costs are a major factor determining the desirability of RE to meet increasing energy demand and concerns have been voiced that increased energy prices might endanger industrializing countries’ development prospects; this underlines the need for a concomitant discussion about the details of an international burden-sharing regime. Still, decentralized grids based on RE have expanded and already improved energy access in developing countries. Under favorable conditions, cost savings in comparison to non-RE use exist, in particular in remote areas and in poor rural areas lacking centralized energy access. In addition, non-electrical RE technologies offer opportunities for modernization of energy services, for example, using solar energy for water heating and crop drying, biofuels for transportation, biogas and modern biomass for heating, cooling, cooking and lighting, and wind for water pumping. RE deployment can contribute to energy security by diversifying energy sources and diminishing dependence on a limited number of suppliers, therefore reducing the economy’s vulnerability to price volatility. Many developing countries specifically link energy access and security issues to include stability and reliability of local supply in their definition of energy security. Supporting the SD goal to mitigate environmental impacts from energy systems, RE technologies can provide important benefits compared to fossil fuels, in particular regarding GHG emissions. Maximizing these benefits often depends on the specific technology, management, and site characteristics associated with each RE project, especially with respect to land use change (LUC) impacts. Lifecycle assessments for electricity generation indicate that GHG emissions from RE technologies are, in general, considerably lower than those associated with fossil fuel options, and in a range of conditions, less than fossil fuels employing carbon capture and storage (CCS). The maximum estimate for concentrating solar power (CSP), geothermal, hydropower, ocean and wind energy is less than or equal to 100 g CO2eq/kWh, and median values for all RE range from 4 to 46 g CO2eq/kWh. The GHG balances of bioenergy production, however, have considerable uncertainties, mostly related to land management and LUC. Excluding LUC, most bioenergy systems reduce GHG emissions compared to fossil-fueled systems and can lead to avoided GHG emissions from residues and wastes in landfill disposals and co-products; the combination of bioenergy with CCS may provide for further reductions. For transport fuels, some first-generation biofuels result in relatively modest GHG mitigation potential, while most next-generation biofuels could provide greater climate benefits. To optimize benefits from bioenergy production, it is critical to reduce uncertainties and to consider ways to mitigate the risk of bioenergy-induced LUC. RE technologies can also offer benefits with respect to air pollution and health. Non-combustion-based RE power generation technologies have the potential to significantly reduce local and regional air pollution and lower associated health impacts compared to fossil-based power generation. Impacts on water and biodiversity, however, depend on local conditions. In areas where water scarcity is already a concern, non-thermal RE technologies or thermal RE technologies using dry cooling can provide energy services without additional stress on water resources. Conventional water-cooled thermal power plants may be especially vulnerable to conditions of water scarcity and climate change. Hydropower and some bioenergy systems are dependent on water availability, and can either increase competition or mitigate water scarcity. RE specific impacts on biodiversity may be positive or negative; the degree of these impacts will be determined by site-specific conditions. Accident risks of RE technologies are not negligible, but the technologies’ often decentralized structure strongly limits the potential for disastrous consequences in terms of fatalities. However, dams associated with some hydropower projects may create a specific risk depending on site-specific factors. The scenario literature that describes global mitigation pathways for RE deployment can provide some insights into associated SD implications. Putting an upper limit on future GHG emissions results in welfare losses (usually measured as gross domestic product or consumption foregone), disregarding the costs of climate change impacts. These welfare losses are based on assumptions about the availability and costs of mitigation technologies and increase when the availability of technological alternatives for constraining GHGs, for example, RE technologies, is limited. Scenario analyses show that developing countries are likely to see most of the expansion of RE production. Increasing energy access is not necessarily beneficial for all aspects of SD, as a shift to modern energy away from, for example, traditional biomass could simply be a shift to fossil fuels. In general, available scenario analyses highlight the role of policies and finance for increased energy access, even though forced shifts to RE that would provide access to modern energy services could negatively affect household budgets. To the extent that RE deployment in mitigation scenarios contributes to diversifying the energy portfolio, it has the potential to enhance energy security by making the energy system less susceptible to (sudden) energy supply disruption. In scenarios, this role of RE will vary with the energy form. With appropriate carbon mitigation policies in place, electricity generation can be relatively easily decarbonized through RE sources that have the potential to replace concentrated and increasingly scarce fossil fuels in the building and industry sectors. By contrast, the demand for liquid fuels in the transport sector remains inelastic if no technological breakthrough can be achieved. Therefore oil and related energy security concerns are likely to continue to play a role in the future global energy system; as compared to today these will be seen more prominently in developing countries. In order to take account of environmental and health impacts from energy systems, several models have included explicit representation of these, such as sulphate pollution. Some scenario results show that climate policy can help drive improvements in local air pollution (i.e., particulate matter), but air pollution reduction policies alone do not necessarily drive reductions in GHG emissions. Another implication of some potential energy trajectories is the possible diversion of land to support biofuel production. Scenario results have pointed at the possibility that climate policy could drive widespread deforestation if not accompanied by other policy measures, with land use being shifted to bioenergy crops with possibly adverse SD implications, including GHG emissions. 712 Renewable Energy in the Context of Sustainable Development Chapter 9 The integration of RE policies and measures in SD strategies at various levels can help overcome existing barriers and create opportunities for RE deployment in line with meeting SD goals. In the context of SD, barriers continue to impede RE deployment. Besides market-related and economic barriers, those barriers intrinsically linked to societal and personal values and norms will fundamentally affect the perception and acceptance of RE technologies and related deployment impacts by individuals, groups and societies. Dedicated communication efforts are therefore a crucial component of any transformation strategy and local SD initiatives can play an important role in this context. At international and national levels, strategies should include: the removal of mechanisms that are perceived to work against SD; mechanisms for SD that internalize environmental and social externalities; and RE strategies that support low-carbon, green and sustainable development including leapfrogging. The assessment has shown that RE can contribute to SD to varying degrees; more interdisciplinary research is needed to close existing knowledge gaps. While benefi ts with respect to reduced environmental and health impacts may appear more clear-cut, the exact contribution to, for example, social and economic development is more ambiguous. In order to improve the knowledge regarding the interrelations between SD and RE and to fi nd answers to the question of an effective, economically effi cient and socially acceptable transformation of the energy system, a much closer integration of insights from social, natural and economic sciences (e.g., through risk analysis approaches), refl ecting the different (especially intertemporal, spatial and intra-generational) dimensions of sustainability, is required. So far, the knowledge base is often limited to very narrow views from specifi c branches of research, which do not fully account for the complexity of the issue

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis.

Rationale: Contacts of patients with tuberculosis (TB) constitute an important target population for preventive measures because they are at high risk of infection with Mycobacterium tuberculosis and progression to disease.Objectives: We investigated biosignatures with predictive ability for incident TB.Methods: In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, PCR, and the pair ratio algorithm in a training/test set approach. Overall, 79 progressors who developed TB between 3 and 24 months after diagnosis of index case and 328 matched nonprogressors who remained healthy during 24 months of follow-up were investigated.Measurements and Main Results: A four-transcript signature derived from samples in a South African and Gambian training set predicted progression up to two years before onset of disease in blinded test set samples from South Africa, the Gambia, and Ethiopia with little population-associated variability, and it was also validated in an external cohort of South African adolescents with latent M. tuberculosis infection. By contrast, published diagnostic or prognostic TB signatures were predicted in samples from some but not all three countries, indicating site-specific variability. Post hoc meta-analysis identified a single gene pair, C1QC/TRAV27 (complement C1q C-chain / T-cell receptor-α variable gene 27) that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events.Conclusions: Collectively, we developed a simple whole blood-based PCR test to predict TB in recently exposed household contacts from diverse African populations. This test has potential for implementation in national TB contact investigation programs

Mapping local and global variability in plant trait distributions

Our ability to understand and predict the response of ecosystems to a changing environment depends on quantifying vegetation functional diversity. However, representing this diversity at the global scale is challenging. Typically, in Earth system models, characterization of plant diversity has been limited to grouping related species into plant functional types (PFTs), with all trait variation in a PFT collapsed into a single mean value that is applied globally. Using the largest global plant trait database and state of the art Bayesian modeling, we created fine-grained global maps of plant trait distributions that can be applied to Earth system models. Focusing on a set of plant traits closely coupled to photosynthesis and foliar respiration - specific leaf area (SLA) and dry mass-based concentrations of leaf nitrogen (Nm) and phosphorus (Pm), we characterize how traits vary within and among over 50,000 ∼50×50-km cells across the entire vegetated land surface. We do this in several ways - without defining the PFT of each grid cell and using 4 or 14 PFTs; each model's predictions are evaluated against out-of-sample data. This endeavor advances prior trait mapping by generating global maps that preserve variability across scales by using modern Bayesian spatial statistical modeling in combination with a database over three times larger than that in previous analyses. Our maps reveal that the most diverse grid cells possess trait variability close to the range of global PFT means

Immunometabolic Signatures Predict Risk of Progression to Active Tuberculosis and Disease Outcome.

There remains a pressing need for biomarkers that can predict who will progress to active tuberculosis (TB) after exposure to Mycobacterium tuberculosis (MTB) bacterium. By analyzing cohorts of household contacts of TB index cases (HHCs) and a stringent non-human primate (NHP) challenge model, we evaluated whether integration of blood transcriptional profiling with serum metabolomic profiling can provide new understanding of disease processes and enable improved prediction of TB progression. Compared to either alone, the combined application of pre-existing transcriptome- and metabolome-based signatures more accurately predicted TB progression in the HHC cohorts and more accurately predicted disease severity in the NHPs. Pathway and data-driven correlation analyses of the integrated transcriptional and metabolomic datasets further identified novel immunometabolomic signatures significantly associated with TB progression in HHCs and NHPs, implicating cortisol, tryptophan, glutathione, and tRNA acylation networks. These results demonstrate the power of multi-omics analysis to provide new insights into complex disease processes

Considerations for biomarker-targeted intervention strategies for tuberculosis disease prevention.

CAPRISA, 2018.Abstract available in pdf