Progressive Visceral Leishmaniasis Is Driven by Dominant Parasite-induced STAT6 Activation and STAT6-dependent Host Arginase 1 Expression

The clinicopathological features of the hamster model of visceral leishmaniasis (VL) closely mimic active human disease. Studies in humans and hamsters indicate that the inability to control parasite replication in VL could be related to ineffective classical macrophage activation. Therefore, we hypothesized that the pathogenesis of VL might be driven by a program of alternative macrophage activation. Indeed, the infected hamster spleen showed low NOS2 but high arg1 enzyme activity and protein and mRNA expression (p<0.001) and increased polyamine synthesis (p<0.05). Increased arginase activity was also evident in macrophages isolated from the spleens of infected hamsters (p<0.05), and arg1 expression was induced by L. donovani in primary hamster peritoneal macrophages (p<0.001) and fibroblasts (p<0.01), and in a hamster fibroblast cell line (p<0.05), without synthesis of endogenous IL-4 or IL-13 or exposure to exogenous cytokines. miRNAi-mediated selective knockdown of hamster arginase 1 (arg1) in BHK cells led to increased generation of nitric oxide and reduced parasite burden (p<0.005). Since many of the genes involved in alternative macrophage activation are regulated by Signal Transducer and Activator of Transcription-6 (STAT6), and because the parasite-induced expression of arg1 occurred in the absence of exogenous IL-4, we considered the possibility that L. donovani was directly activating STAT6. Indeed, exposure of hamster fibroblasts or macrophages to L. donovani resulted in dose-dependent STAT6 activation, even without the addition of exogenous cytokines. Knockdown of hamster STAT6 in BHK cells with miRNAi resulted in reduced arg1 mRNA expression and enhanced control of parasite replication (p<0.0001). Collectively these data indicate that L. donovani infection induces macrophage STAT6 activation and STAT6-dependent arg1 expression, which do not require but are amplified by type 2 cytokines, and which contribute to impaired control of infection

Seasonality in Human Zoonotic Enteric Diseases: A Systematic Review

BACKGROUND: Although seasonality is a defining characteristic of many infectious diseases, few studies have described and compared seasonal patterns across diseases globally, impeding our understanding of putative mechanisms. Here, we review seasonal patterns across five enteric zoonotic diseases: campylobacteriosis, salmonellosis, vero-cytotoxigenic Escherichia coli (VTEC), cryptosporidiosis and giardiasis in the context of two primary drivers of seasonality: (i) environmental effects on pathogen occurrence and pathogen-host associations and (ii) population characteristics/behaviour. METHODOLOGY/PRINCIPAL FINDINGS: We systematically reviewed published literature from 1960-2010, resulting in the review of 86 studies across the five diseases. The Gini coefficient compared temporal variations in incidence across diseases and the monthly seasonality index characterised timing of seasonal peaks. Consistent seasonal patterns across transnational boundaries, albeit with regional variations was observed. The bacterial diseases all had a distinct summer peak, with identical Gini values for campylobacteriosis and salmonellosis (0.22) and a higher index for VTEC (Gini  0.36). Cryptosporidiosis displayed a bi-modal peak with spring and summer highs and the most marked temporal variation (Gini = 0.39). Giardiasis showed a relatively small summer increase and was the least variable (Gini = 0.18). CONCLUSIONS/SIGNIFICANCE: Seasonal variation in enteric zoonotic diseases is ubiquitous, with regional variations highlighting complex environment-pathogen-host interactions. Results suggest that proximal environmental influences and host population dynamics, together with distal, longer-term climatic variability could have important direct and indirect consequences for future enteric disease risk. Additional understanding of the concerted influence of these factors on disease patterns may improve assessment and prediction of enteric disease burden in temperate, developed countries

Ossification of the femur in thyroxine-treated tadpoles of Rana pipiens

Tadpoles of Rana pipiens at Taylor-Kollros stage IX were treated by immersion in a thyroxine solution at a concentration of 6.25 x 10-8 M. Hindlimbs developed precociously, and alizarin-stained specimens showed that treatment with thyroxine induced accelerated ossification of limb bones.Light microscopy of thick Epon sections showed that cartilage and perichondrium were beginning to organize in the femur of normal animals at stage IX and had become separated by a narrow zone of osteoid matrix by stage XI. After 4 days of exposure to thyroxine, inner perichondrial cells had enlarged to become osteoblasts bordering a prominent zone of osteoid matrix. By 9 days of treatment some inner osteoblasts were entirely surrounded by bone matrix and thus had become osteocytes.Electron microscopy revealed that rough endoplasmic reticulum began to accumulate in osteoblasts by the second day of treatment. Fusion of collagen fibrils was observed in the osteoid matrix of a specimen treated for 5 days. Deposition of hydroxyapatite crystals along collagen protofibrils in scattered mineralization sites began after 6 days of treatment. Mineralized sites grew and became confluent, so that by 9 days the lower two-thirds of the bone matrix was almost completely mineralized. Enlarged mineralization sites at 9 days usually were organized with collagen protofibrils in the interior and hydroxyapatite crystals clustered around the periphery of the mineralizing mass.Thyroxine appears to stimulate differentiation of osteoblasts from perichondrial cells. The hormone may stimulate osteoblasts to secrete depolymerases which prepare osteoid matrix for mineralization along collagen fibrils.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32873/1/0000251.pd

Accelerating Cost-Effective Green Stormwater Infrastructure: Learning From Local Implementation

Although green stormwater infrastructure (GSI) is critical to solving stormwater management challenges, GSI is evolving technology with inconsistent performance and uncertain costs. Our report recommends enhancing learning from local implementation efforts to address knowledge gaps and speed cost-effective deployment. We identify key actions the EPA and state water quality authorities can take to help drive data collection and sharing

Accelerating Cost-Effective Green Stormwater Infrastructure: Learning From Local Implementation

Although green stormwater infrastructure (GSI) is critical to solving stormwater management challenges, GSI is evolving technology with inconsistent performance and uncertain costs. Our report recommends enhancing learning from local implementation efforts to address knowledge gaps and speed cost-effective deployment. We identify key actions the EPA and state water quality authorities can take to help drive data collection and sharing

California Groundwater Management, Science-Policy Interfaces, and the Legacies of Artificial Legal Distinctions

California water law has traditionally treated groundwater and surface water as separate resources. The 2014 Sustainable Groundwater Management Act (SGMA) broke with this tradition by requiring groundwater managers to avoid significant and unreasonable adverse impacts to beneficial uses of surface water. This paper considers the trajectory of this partial integration of science, law, and resource management policy. Drawing on legal analysis and participatory workshops with subject area experts, we describe the challenges of reconciling the separate legal systems that grew out of an artificial legal distinction between different aspects of the same resource. Our analysis offers two main contributions. First, it demonstrates that laws that subdivide an interconnected resource can have legacy effects that linger long after lawmakers begin dismantling the artificial divides. Using SGMA as a case study, the article illustrates the complexities of reconciling law with science, showing that reconciliation is a process that does not end with updating statutes, or with any other single intervention. Second, we introduce a framework for evaluating the elements of an effort to reconcile law with scientific understanding, whether that reform effort involves groundwater or some other resource. Applying that framework helps reveal where lingering legacy effects still need to be addressed. More generally, it reveals the need for literature addressing science-policy interactions to devote more attention to the multifaceted nature of law and policy reform. Much of that literature describes policy-making in broad and undifferentiated terms, often referring simply to the science-policy interface. But as the SGMA case study illustrates, the complex and multi-layered nature of policy-making means that a successful reform effort may need to address many science-policy interfaces

Learning from California’s Experience with Small Water System Consolidations: A Workshop Synthesis

California recognizes a human right to safe, affordable drinking water. However, small and disadvantaged communities can find it especially challenging to fund the water systems necessary to achieve this goal. Small water systems are responsible for the bulk of the state’s drinking water quality violations, and an estimated 300 disadvantaged communities in California are served by systems that fail to meet state drinking water standards.Water system consolidations can create economies of scale that help address persistent water system inadequacies in small and disadvantaged communities. More than 100 consolidation projects have been completed or are ongoing in California, and many more communities are likely to pursue consolidations in the future. While consolidation offers many potential benefits for communities served by unreliable water systems, the costs and benefits associated with different consolidation options have not been well documented. During the current legislative session, legislators have introduced several legislative proposals to address perceived needs related to consolidation.This project begins to take stock of past and current consolidation efforts—and the lessons they provide—with the goal of helping to accelerate cost-effective solutions for near-term water needs and long-term water system resilience. A daylong workshop held at UC Berkeley in March 2018 aimed to identify key lessons learned and emerging issues from California’s experience to date with small water system consolidations. This document synthesizes that facilitated dialogue, exploring the factors that drive and influence consolidations. It enumerates barriers to effective consolidations and identifies potential solutions for overcoming those barriers, highlighting which entities may be best situated to implement them.In addition to laying the foundation for further constructive and inclusive dialogue, this work aims to inform the development of legislative and administrative policy proposals and a future research agenda