Trade in the balance: reconciling trade and climate policy: report of the Working Group on Trade, Investment, and Climate Policy

This repository item contains a report published by the Working Group on Trade, Investment, and Climate Policy at The Frederick S. Pardee Center for the Study of the Longer-Range Future at Boston University, and the Global Economic Governance Initiative at Boston University.This report outlines the general tensions between the trade and investment regime and climate policy, and outlines a framework toward making trade and investment rules more climate friendly. Members of the working group have contributed short pieces addressing a range of issues related to the intersection of trade and climate policy. The first two are by natural scientists. Anthony Janetos discusses the need to address the effects of international trade on efforts to limit the increase in global annual temperature to no more than 2oC over preindustrial levels. James J. Corbett examines the failure of the Trans Pacific Partnership (TPP) and the Transatlantic Trade and Investment Partnership (TTIP) to adequately address the environmental implications of shipping and maritime transport. The next two pieces are by economists who examine economic aspects of the trade-climate linkage. Irene Monasterolo and Marco Raberto discuss the potential impacts of including fossil fuel subsidies reduction under the TTIP. Frank Ackerman explores the economic costs of efforts to promote convergence of regulatory standards between the United States and the European Union under the TTIP. The following two contributions are by legal scholars. Brooke Güven and Lise Johnson explore the potential for international investment treaties to redirect investment flows to support climate change mitigation and adaptation, particularly with regard to China and India. Matt Porterfield provides an overview of the ways in which both existing and proposed trade and investment agreements could have either “climate positive” or “climate negative” effects on mitigation policies. The final article is by Tao Hu, a former WTO trade and environment expert advisor for China and currently at the World Wildlife Fund, arguing that the definition of environmental goods and services’ under the WTO negotiations needs to be expanded to better incorporate climate change

Trade in the balance: reconciling trade and climate policy: report of the Working Group on Trade, Investment, and Climate Policy

This repository item contains a report published by the Working Group on Trade, Investment, and Climate Policy at The Frederick S. Pardee Center for the Study of the Longer-Range Future at Boston University, and the Global Economic Governance Initiative at Boston University.This report outlines the general tensions between the trade and investment regime and climate policy, and outlines a framework toward making trade and investment rules more climate friendly. Members of the working group have contributed short pieces addressing a range of issues related to the intersection of trade and climate policy. The first two are by natural scientists. Anthony Janetos discusses the need to address the effects of international trade on efforts to limit the increase in global annual temperature to no more than 2oC over preindustrial levels. James J. Corbett examines the failure of the Trans Pacific Partnership (TPP) and the Transatlantic Trade and Investment Partnership (TTIP) to adequately address the environmental implications of shipping and maritime transport. The next two pieces are by economists who examine economic aspects of the trade-climate linkage. Irene Monasterolo and Marco Raberto discuss the potential impacts of including fossil fuel subsidies reduction under the TTIP. Frank Ackerman explores the economic costs of efforts to promote convergence of regulatory standards between the United States and the European Union under the TTIP. The following two contributions are by legal scholars. Brooke Güven and Lise Johnson explore the potential for international investment treaties to redirect investment flows to support climate change mitigation and adaptation, particularly with regard to China and India. Matt Porterfield provides an overview of the ways in which both existing and proposed trade and investment agreements could have either “climate positive” or “climate negative” effects on mitigation policies. The final article is by Tao Hu, a former WTO trade and environment expert advisor for China and currently at the World Wildlife Fund, arguing that the definition of environmental goods and services’ under the WTO negotiations needs to be expanded to better incorporate climate change

Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes

X-linked neutropenia (XLN) is caused by activating mutations in the Wiskott-Aldrich syndrome protein (WASP) that result in aberrant autoinhibition. Although patients with XLN appear to have only defects in myeloid lineages, we hypothesized that activating mutations of WASP are likely to affect the immune system more broadly. We generated mouse models to assess the role of activating WASP mutations associated with XLN (XLN-WASP) in lymphocytes. XLN-WASP is expressed stably in B and T cells and induces a marked increase in polymerized actin. XLN-WASP–expressing B and T cells migrate toward chemokines but fail to adhere normally. In marked contrast to WASP-deficient cells, XLN-WASP–expressing T cells proliferate normally in response to cell-surface receptor activation. However, XLN-WASP–expressing B cells fail to proliferate and secrete lower amounts of antibodies. Moreover, XLN-WASP expression in lymphocytes results in modestly increased apoptosis associated with increased genomic instability. These data indicate that there are unique requirements for the presence and activation status of WASP in B and T cells and that WASP-activating mutations interfere with lymphocyte cell survival and genomic stability

The Grizzly, April 29, 2010

Active Minds Hosts Art Fair to Benefit Mental Health • Students Say Farewell Through Presidential Celebration • UCDC Hosts Spring Concert in Lenfest Theater • Dr. Spencer Foreman: Counting Down the Reasons • Workout and Have Fun at Ursinus Zumba-Thon! • Music and Diplomacy Converge to Help Alleviate HIV and AIDS • Professor Mudd\u27s CIE III Class Explores Happiness and the UC Student Body • Class of 2010 Spotlight: Seniors Reflect on UC Memories • Ursinus College Mourns the Loss of a Legend • Senior Spotlight: Mark Worrilow, Footballhttps://digitalcommons.ursinus.edu/grizzlynews/1813/thumbnail.jp

Replication competent retrovirus testing (RCR) in the National Gene Vector Biorepository: No evidence of RCR in 1,595 post-treatment peripheral blood samples obtained from 60 clinical trials

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy

Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells.

Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott-Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells. In ex vivo models of enteropathogenic Escherichia coli and Shigella flexneri infection, WASp deficiency causes defective bacterial clearance, excessive inflammasome activation and host cell death that are associated with dysregulated septin cage-like formation, impaired autophagic p62/LC3 recruitment and defective formation of canonical autophagosomes. Taken together, we propose that dysregulation of autophagy and inflammasome activities contribute to the autoinflammatory manifestations of WAS, thereby identifying potential targets for therapeutic intervention

Computational and Serologic Analysis of Novel and Known Viruses in Species Human Adenovirus D in Which Serology and Genomics Do Not Correlate

In November of 2007 a human adenovirus (HAdV) was isolated from a bronchoalveolar lavage (BAL) sample recovered from a biopsy of an AIDS patient who presented with fever, cough, tachycardia, and expiratory wheezes. To better understand the isolated virus, the genome was sequenced and analyzed using bioinformatic and phylogenomic analysis. The results suggest that this novel virus, which is provisionally named HAdV-D59, may have been created from multiple recombination events. Specifically, the penton, hexon, and fiber genes have high nucleotide identity to HAdV-D19C, HAdV-D25, and HAdV-D56, respectively. Serological results demonstrated that HAdV-D59 has a neutralization profile that is similar yet not identical to that of HAdV-D25. Furthermore, we observed a two-fold difference between the ability of HAdV-D15 and HAdV-D25 to be neutralized by reciprocal antiserum indicating that the two hexon proteins may be more similar in epitopic conformation than previously assumed. In contrast, hexon loops 1 and 2 of HAdV-D15 and HAdV-D25 share 79.13 and 92.56 percent nucleotide identity, respectively. These data suggest that serology and genomics do not always correlate

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre