Identification of gene targets against dormant phase Mycobacterium tuberculosis infections

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium tuberculosis</it>, the causative agent of tuberculosis (TB), infects approximately 2 billion people worldwide and is the leading cause of mortality due to infectious disease. Current TB therapy involves a regimen of four antibiotics taken over a six month period. Patient compliance, cost of drugs and increasing incidence of drug resistant <it>M. tuberculosis </it>strains have added urgency to the development of novel TB therapies. Eradication of TB is affected by the ability of the bacterium to survive up to decades in a dormant state primarily in hypoxic granulomas in the lung and to cause recurrent infections.</p> <p>Methods</p> <p>The availability of <it>M. tuberculosis </it>genome-wide DNA microarrays has lead to the publication of several gene expression studies under simulated dormancy conditions. However, no single model best replicates the conditions of human pathogenicity. In order to identify novel TB drug targets, we performed a meta-analysis of multiple published datasets from gene expression DNA microarray experiments that modeled infection leading to and including the dormant state, along with data from genome-wide insertional mutagenesis that examined gene essentiality.</p> <p>Results</p> <p>Based on the analysis of these data sets following normalization, several genome wide trends were identified and used to guide the selection of targets for therapeutic development. The trends included the significant up-regulation of genes controlled by <it>devR</it>, down-regulation of protein and ATP synthesis, and the adaptation of two-carbon metabolism to the hypoxic and nutrient limited environment of the granuloma. Promising targets for drug discovery were several regulatory elements (<it>devR/devS</it>, <it>relA</it>, <it>mprAB</it>), enzymes involved in redox balance and respiration, sulfur transport and fixation, pantothenate, isoprene, and NAD biosynthesis. The advantages and liabilities of each target are discussed in the context of enzymology, bacterial pathways, target tractability, and drug development.</p> <p>Conclusion</p> <p>Based on our bioinformatics analysis and additional discussion of in-depth biological rationale, several novel anti-TB targets have been proposed as potential opportunities to improve present therapeutic treatments for this disease.</p

What Do Community Benefits Agreements Deliver? Evidence From Los Angeles

Problem, research strategy, and findings: Advocates of community benefits agreements (CBAs) between coalitions of nongovernmental organizations (NGOs) and real estate developers contend that CBAs promote public accountability and responsiveness to community concerns. This study assesses the Los Angeles Sports and Entertainment District (LASED) CBA, which scholars and practitioners have described as a model for such agreements. I assess compliance with key provisions of the agreement related to jobs, affordable housing, and parks and recreational facilities. I also assess whether compliance with these provisions has yielded benefits beyond those required under existing laws and regulations. I find that the parties to the agreement have technically complied with many, although arguably not all, of its provisions. But some of the provisions in the CBA are not legally binding, other provisions overlap with requirements that the developer would have had to satisfy even without the CBA, and some reports required by the CBA are unavailable. As a result, outcomes such as living wage jobs and funding for affordable housing units are not clearly attributable to the CBA; other outcomes, such as targeted hiring, are unknown due to a lack of relevant information.Takeaway for practice: Although CBAs may not fulfill all the claims that advocates make on their behalf, they can play important roles in community development by directing public and private spending to underserved neighborhoods. But collecting and verifying the relevant data may be challenging, even if reporting requirements are clearly spelled out in the CBA. As the complexity of a CBA increases, so do the challenges of assessing outcomes and assigning responsibility for those outcomes

Data from: Multi-scalar drivers of biodiversity: local management mediates wild bee community response to regional urbanization

It is critical to understand the specific drivers of biodiversity across multiple spatial scales, especially within rapidly urbanizing areas, given the distinct management recommendations that may result at each scale. However, drivers of biodiversity patterns and interactions between drivers are often only measured and modeled at a single scale. In this study, we assessed bee community composition at three time periods in 20 grassland and 20 agriculture sites located across two major metroplexes. We examined how local environmental variables and surrounding landscape composition impact bee abundance, richness, and evenness, including comparisons between groups with different nesting strategies and body sizes. We collected nearly 13,000 specimens and identified 172 species. We found that levels of regional land-use differentially impacted bee abundance and diversity depending on local habitat management. Specifically, within agriculture sites, bee richness was greater with increasing landscape-level semi-natural habitat, while in grassland sites, bee richness was similar across landscapes regardless of semi-natural habitat cover. Bee evenness at both site types declined with increasing landscape-level habitat heterogeneity, due to an increase of rare species at the grassland sites, but not in the agricultural sites; further indicating that diversity is driven by the interaction of local habitat quality and landscape-level habitat composition. We additionally found that agriculture sites supported higher abundances, but not richness, of small-bodied and below-ground nesting bees, while grassland sites supported higher abundances of above-ground nesting bees, and higher richness of large-bodied species. Increased levels of local bare ground were significantly related to multiple metrics of bee diversity, including greater below-ground nesting bee abundance and richness. Local floral richness was also significantly related to increases of overall bee abundance, as well as the abundance and richness of small bees. Overall, we suggest that local land managers can support bee abundance and diversity by conserving areas of bare soil and promoting native floral diversity, the latter especially critical in highly urban agricultural spaces. Our results provide the first documentation of significant interactions between local habitat management and landscape composition impacting insect communities in urban systems, indicating that bee conservation practices depend critically on land-use interactions across multiple spatial scales