Toward an effective protocol on land-based marine pollution in the wider Caribbean Region

This study was undertaken to advance the basis for discussions among Contracting Parties to the Cartagena Convention concerning a protocol on land-based marine pollution (LBMP) in the Wider Caribbean Region (WCR). The study has four principal objectives: (1) a review and summary of LBMP problems to determine common problems and priority areas; (2) a survey of broadly defined environmental infrastructure to help identify national commitments and national capacities to prevent, reduce, or control LBMP; (3) a survey and analysis of subregional differences in commitment or interest in regional control of LBMP; and (4) a comparison of program approaches from other regions, providing lessons from which an effective program for the Caribbean might be designed. The study argues that the environmental, economic, and institutional diversity of the region as a whole suggests (1) an incremental approach to international resolution of LBMP problems, one that builds upon successful arangements among states that have appropriate incentives for solving real transboundary pollution problems; and (2) a subregional approach to the control of localized but widely occurring pollution problems, in which the "umbrella" function of a regional protocol would concentrate on the need to ensure uniform access to all clearinghouse products and on the internal allocation of financial and technical assistance to individual states and subregions.Funding provided by the United States Environmental Protection Agency, Office of International Activities under Co-operative Agreement No. CX82IS40-01-0

Marine area governance and management in the Gulf of Maine : a case study

This case study provides a description and evaluation of marine area governance and management in the Gulf of Maine. On the advice of the Oversight Committee, we began the study at a broad level by identifying marine resources, uses of the resources, existing management regimes, and conflicts among users of the resources. The results of these initial reviews are collected in the tables in Appendix A. The Oversight Committee also suggested that we develop a chronology of important events relating to marine area governance and management in the Gulf of Maine, which is included as Appendix B. As is clear from even a quick scan of the material in Appendix A, almost every conceivable use of the marine environment occurs in the Gulf of Maine at some scale. However, some of these uses are more problematic than others in terms of the governance and management problems they engender. Rather than take a broadbrush approach that might not have done justice to any of the region's many ocean resources and uses, we decided to focus the case study on one or more of its most difficult and consequential governance and management issues. The initial survey enabled us to focus in on a subset of resources, use conflicts, and governance issues, namely those associated mainly with marine fisheries governance and management. Several considerations support the argument for a focus on fisheries governance and management. The marine fisheries are a regional-scale resource and industry, due to the mobility of the fish stocks, the geographic distribution of the users of the resource, and the fact that governance institutions have been designed to have regionwide authority. Thus fisheries mismanagement has the potential to inflict widespread social detriment and significant economic losses. Indeed, the net cost of depleted groundfish stocks under the current management structure, relative to the condition of stocks in an optimally managed fishery, has been estimated at about $139 million annually, or just under one-fifth the landed value of the entire Gulf of Maine commercial catch. Other ocean resources with potentially regional impacts, such as offshore energy, are not being pursued in the Gulf of Maine region at levels that pose significant concerns. Consequently, non-fishery resource management problems in the Gulf of Maine are, for the most part, local in scale, of comparatively minor economic significance, and not unique to the region. There is no evidence, for example, of "system-wide degradation of marine environmental quality in the Gulf of Maine. . . . The Gulf as a whole remains relatively clean, although the deep central basins appear to be accumulating several pollutants, including PAHs and PCBs" (GOMCME 1994; see also Dow and Braasch 1996 and Gould, Clark, and Thurberg 1994). Given that most pollutants of concern are concentrated in inshore waters near urban areas and in the mouths of industrialized rivers, it is not at all clear that they could be dealt with more effectively or efficiently at the regional level. In sum, our focus on fisheries reflects our judgment that the greatest net benefits might be obtained from improvements in the governance and management of these marine resources within the Gulf of Maine region.This case study was produced for the purposes of the Committee on Marine Area Governance and Management of the National Research Council (NRC), Agreement No. DOT -3830-96-002

Qubit Channels Can Require More Than Two Inputs to Achieve Capacity

We give examples of qubit channels that require three input states in order to achieve the Holevo capacity.Comment: RevTex, 5 page, 4 figures

Psychosocial functioning in pediatric heart transplant recipients and their families

Across pediatric organ transplant populations, patient and family psychosocial functioning is associated with important health‐related outcomes. Research has suggested that pediatric heart transplant recipients and their families are at increased risk for adverse psychosocial outcomes; however, recent investigation of psychosocial functioning in this population is lacking. This study aimed to provide a contemporary characterization of psychosocial functioning in pediatric heart transplant recipients and their families. Associations between psychosocial function, demographic variables, and transplant‐related variables were investigated. Fifty‐six parents/guardians of pediatric heart transplant recipients completed a comprehensive psychosocial screening measure during transplant follow‐up clinic visits. Descriptive statistics, correlational analyses, and independent samples t tests were performed. Forty percent of pediatric heart transplant recipients and their families endorsed clinically meaningful levels of total psychosocial risk. One‐third of patients presented with clinically significant psychological problems per parent report. Psychosocial risk was unassociated with demographic or transplant‐related factors. Despite notable improvements in the survival of pediatric heart transplant recipients over the past decade, patients and families present with sustained psychosocial risks well beyond the immediate post‐transplant period, necessitating mental health intervention to mitigate adverse impact on health‐related outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142422/1/petr13110.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142422/2/petr13110_am.pd

Estimating the global burden of endemic canine rabies

Background: Rabies is a notoriously underreported and neglected disease of lowincome countries. This study aims to estimate the public health and economic burden of rabies circulating in domestic dog populations, globally and on a country-by-country basis, allowing an objective assessment of how much this preventable disease costs endemic countries.<p></p> Methodology/Principal Findings: We established relationships between rabies mortality and rabies prevention and control measures, which we incorporated into a model framework. We used data derived from extensive literature searches and questionnaires on disease incidence, control interventions and preventative measures within this framework to estimate the disease burden. The burden of rabies impacts on public health sector budgets, local communities and livestock economies, with the highest risk of rabies in the poorest regions of the world. This study estimates that globally canine rabies causes approximately 59,000 (95% Confidence Intervals: 25- 159,000) human deaths, over 3.7 million (95% CIs: 1.6-10.4 million) disability-adjusted life years (DALYs) and 8.6 billion USD (95% CIs: 2.9-21.5 billion) economic losses annually. The largest component of the economic burden is due to premature death (55%), followed by direct costs of post-exposure prophylaxis (PEP, 20%) and lost income whilst seeking PEP (15.5%), with only limited costs to the veterinary sector due to dog vaccination (1.5%), and additional costs to communities from livestock losses (6%).<p></p> Conclusions/Significance: This study demonstrates that investment in dog vaccination, the single most effective way of reducing the disease burden, has been inadequate and that the availability and affordability of PEP needs improving. Collaborative investments by medical and veterinary sectors could dramatically reduce the current large, and unnecessary, burden of rabies on affected communities. Improved surveillance is needed to reduce uncertainty in burden estimates and to monitor the impacts of control efforts.<p></p&gt

HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells

Objective Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activating NK-cell receptor NKp44, we investigated the role of HLA-DP/NKp44-interactions in PSC. Design Liver tissue, intrahepatic and peripheral blood lymphocytes of individuals with PSC and control individuals were characterised using flow cytometry, immunohistochemical and immunofluorescence analyses. HLA-DPA1 and HLA-DPB1 imputation and association analyses were performed in 3408 individuals with PSC and 34 213 controls. NK cell activation on NKp44/HLA-DP interactions was assessed in vitro using plate-bound HLA-DP molecules and HLA-DPB wildtype versus knock-out human cholangiocyte organoids. Results NKp44+NK cells were enriched in livers, and intrahepatic bile ducts of individuals with PSC showed higher expression of HLA-DP. HLA-DP haplotype analysis revealed a highly elevated PSC risk for HLA-DPA1*02:01~B1*01:01 (OR 1.99, p=6.7×10-50). Primary NKp44+NK cells exhibited significantly higher degranulation in response to plate-bound HLA-DPA1*02:01-DPB1*01:01 compared with control HLA-DP molecules, which were inhibited by anti-NKp44-blocking. Human cholangiocyte organoids expressing HLA-DPA1*02:01-DPB1*01:01 after IFN-γ-exposure demonstrated significantly increased binding to NKp44-Fc constructs compared with unstimulated controls. Importantly, HLA-DPA1*02:01-DPB1*01:01-expressing organoids increased degranulation of NKp44+NK cells compared with HLA-DPB1-KO organoids. Conclusion Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01~DPB1*01:01 and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

Background & aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.Methods: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.Results: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.Conclusions: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts