An integrated environmental and human systems modeling framework for Puget Sound restoration planning

Local, state, federal, tribal and private stakeholders have committed significant resources to restoring Puget Sound’s terrestrial-marine ecosystem. Though jurisdictional issues have promoted a fragmented approach to restoration planning, there is growing recognition that a more coordinated systems-based restoration approach is needed to achieve recovery goals. This presentation describes our collaborative effort to develop and apply an integrated environmental and human systems modeling framework for the Puget Sound Basin, inclusive of all marine and land areas (1,020 and 12,680 sq. mi.). Our goal is to establish a whole-basin systems modeling framework that dynamically simulates biophysical interactions and transfers (water, nutrients, contaminants, biota) across terrestrial-marine boundaries. The core environmental models include a terrestrial ecohydrological model (VELMA), an ocean circulation and biogeochemistry model (Salish Sea Model), and an ocean food web model (Atlantis). This environmental subsystem will be linked with an agent-based modeling subsystem (e.g., Envision) that allows human decision-makers to be represented in whole-basin simulations. The integrated environmental and human systems framework aims to facilitate discourse among different stakeholders and decision makers (agents) and enable them play out the ecological, social and economic consequences of alternative ecosystem restoration choices. All of these models are currently being applied in Puget Sound, but they have not yet been integrated. The linked models will better capture the propagation of human impacts throughout the terrestrial-marine ecosystem, and thereby provide a more effective decision support tool for addressing restoration of high priority environmental endpoints, such as the Vital Signs identified by the Puget Sound Partnership (http://www.psp.wa.gov/vitalsigns/). Our overview will include examples of existing stand-alone model applications, and conceptual plans for linking models across terrestrial-marine boundaries. The Puget Sound multi-model framework described here can potentially be expanded to address the entire Salish Sea transboundary ecosystem (https://www.eopugetsound.org/maps/salish-sea-basin-and-water-boundaries)

WNT signalling control by KDM5C during development affects cognition

Although KDM5C is one of the most frequently mutated genes in X-linked intellectual disability, the exact mechanisms that lead to cognitive impairment remain unknown. Here we use human patient-derived induced pluripotent stem cells and Kdm5c knockout mice to conduct cellular, transcriptomic, chromatin and behavioural studies. KDM5C is identified as a safeguard to ensure that neurodevelopment occurs at an appropriate timescale, the disruption of which leads to intellectual disability. Specifically, there is a developmental window during which KDM5C directly controls WNT output to regulate the timely transition of primary to intermediate progenitor cells and consequently neurogenesis. Treatment with WNT signalling modulators at specific times reveal that only a transient alteration of the canonical WNT signalling pathway is sufficient to rescue the transcriptomic and chromatin landscapes in patient-derived cells and to induce these changes in wild-type cells. Notably, WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice. Conversely, a single injection of WNT3A into the brains of wild-type embryonic mice cause anxiety and memory alterations. Our work identifies KDM5C as a crucial sentinel for neurodevelopment and sheds new light on KDM5C mutation-associated intellectual disability. The results also increase our general understanding of memory and anxiety formation, with the identification of WNT functioning in a transient nature to affect long-lasting cognitive function

Comparison of heterosubtypic protection in ferrets and pigs induced by a single-cycle influenza vaccine

Influenza is a major health threat, and a broadly protective influenza vaccine would be a significant advance. Signal Minus FLU (S-FLU) is a candidate broadly protective influenza vaccine that is limited to a single cycle of replication, which induces a strong cross-reactive T cell response but a minimal Ab response to hemagglutinin after intranasal or aerosol administration. We tested whether an H3N2 S-FLU can protect pigs and ferrets from heterosubtypic H1N1 influenza challenge. Aerosol administration of S-FLU to pigs induced lung tissue-resident memory T cells and reduced lung pathology but not the viral load. In contrast, in ferrets, S-FLU reduced viral replication and aerosol transmission. Our data show that S-FLU has different protective efficacy in pigs and ferrets, and that in the absence of Ab, lung T cell immunity can reduce disease severity without reducing challenge viral replication

Prioritization of zoonotic diseases in Kenya, 2015

INTRODUCTION:Zoonotic diseases have varying public health burden and socio-economic impact across time and geographical settings making their prioritization for prevention and control important at the national level. We conducted systematic prioritization of zoonotic diseases and developed a ranked list of these diseases that would guide allocation of resources to enhance their surveillance, prevention, and control. METHODS:A group of 36 medical, veterinary, and wildlife experts in zoonoses from government, research institutions and universities in Kenya prioritized 36 diseases using a semi-quantitative One Health Zoonotic Disease Prioritization tool developed by Centers for Disease Control and Prevention with slight adaptations. The tool comprises five steps: listing of zoonotic diseases to be prioritized, development of ranking criteria, weighting criteria by pairwise comparison through analytical hierarchical process, scoring each zoonotic disease based on the criteria, and aggregation of scores. RESULTS:In order of importance, the participants identified severity of illness in humans, epidemic/pandemic potential in humans, socio-economic burden, prevalence/incidence and availability of interventions (weighted scores assigned to each criteria were 0.23, 0.22, 0.21, 0.17 and 0.17 respectively), as the criteria to define the relative importance of the diseases. The top five priority diseases in descending order of ranking were anthrax, trypanosomiasis, rabies, brucellosis and Rift Valley fever. CONCLUSION:Although less prominently mentioned, neglected zoonotic diseases ranked highly compared to those with epidemic potential suggesting these endemic diseases cause substantial public health burden. The list of priority zoonotic disease is crucial for the targeted allocation of resources and informing disease prevention and control programs for zoonoses in Kenya

Aerosol Delivery of a Candidate Universal Influenza Vaccine Reduces Viral Load in Pigs Challenged with Pandemic H1N1 Virus

Influenza A viruses are a major health threat to livestock and humans, causing considerable mortality, morbidity, and economic loss. Current inactivated influenza vaccines are strain specific and new vaccines need to be produced at frequent intervals to combat newly arising influenza virus strains, so that a universal vaccine is highly desirable. We show that pandemic H1N1 influenza virus in which the hemagglutinin signal sequence has been suppressed (S-FLU), when administered to pigs by aerosol can induce CD4 and CD8 T cell immune responses in blood, bronchoalveolar lavage (BAL), and tracheobronchial lymph nodes. Neutralizing Ab was not produced. Detection of a BAL response correlated with a reduction in viral titer in nasal swabs and lungs, following challenge with H1N1 pandemic virus. Intratracheal immunization with a higher dose of a heterologous H5N1 S-FLU vaccine induced weaker BAL and stronger tracheobronchial lymph node responses and a lesser reduction in viral titer. We conclude that local cellular immune responses are important for protection against influenza A virus infection, that these can be most efficiently induced by aerosol immunization targeting the lower respiratory tract, and that S-FLU is a promising universal influenza vaccine candidate

Evaluation of a web-based intervention to reduce antibiotic prescribing for LRTI in six European countries: quantitative process analysis of the GRACE/INTRO randomised controlled trial.

To reduce the spread of antibiotic resistance, there is a pressing need for worldwide implementation of effective interventions to promote more prudent prescribing of antibiotics for acute LRTI. This study is a process analysis of the GRACE/INTRO trial of a multifactorial intervention that reduced antibiotic prescribing for acute LRTI in six European countries. The aim was to understand how the interventions were implemented and to examine effects of the interventions on general practitioners' (GPs') and patients' attitudes

Short RNAs Are Transcribed from Repressed Polycomb Target Genes and Interact with Polycomb Repressive Complex-2

Polycomb proteins maintain cell identity by repressing the expression of developmental regulators specific for other cell types. Polycomb repressive complex-2 (PRC2) catalyzes trimethylation of histone H3 lysine-27 (H3K27me3). Although repressed, PRC2 targets are generally associated with the transcriptional initiation marker H3K4me3, but the significance of this remains unclear. Here, we identify a class of short RNAs, ~50–200 nucleotides in length, transcribed from the 5′ end of polycomb target genes in primary T cells and embryonic stem cells. Short RNA transcription is associated with RNA polymerase II and H3K4me3, occurs in the absence of mRNA transcription, and is independent of polycomb activity. Short RNAs form stem-loop structures resembling PRC2 binding sites in Xist, interact with PRC2 through SUZ12, cause gene repression in cis, and are depleted from polycomb target genes activated during cell differentiation. We propose that short RNAs play a role in the association of PRC2 with its target genes.National Institutes of Health (U.S.) (Grant HG002668)National Institutes of Health (U.S.) (Grant NS055923

Recognition and control of neutrophil extracellular trap formation by MICL

Acknowledgements We thank the staff of the animal facilities at the University of Aberdeen and the University of Exeter for support and care for animals; C. Paterson from the University of Glasgow for assistance in establishing a Material Transfer Agreement; C. Parkin and D. Thompson for support with microscopy; and M. Stacey for valuable input. We acknowledge funding from the Wellcome Trust (102705 and 097377), Versus Arthritis (21164, 20775 and 21156), the US National Institutes of Health (R01DK121977 and R01AI163007), Versus Arthritis Centre of Excellence, Medical Research Council (MR/L020211/1) and the MRC Centre for Medical Mycology (MR/N006364/1). SLE tissue samples were provided by the Imperial College Healthcare Tissue Bank funded by the National Institute for Health Research (NIHR), Biomedical Research Centre based at the Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.Peer reviewe

A Histone Methylation Network Regulates Transgenerational Epigenetic Memory in C. elegans

How epigenetic information is transmitted from generation to generation remains largely unknown. Deletion of the C. elegans Histone H3 lysine 4 dimethyl (H3K4me2) demethylase spr-5 leads to inherited accumulation of the euchromatic H3K4me2 mark and progressive decline in fertility. Here we identified multiple chromatin-modifying factors, including novel H3K4me1/me2 and H3K9me3 methyltransferases, an H3K9me3 demethylase and an H3K9me reader, which either suppress or accelerate the progressive transgenerational phenotypes of spr-5 mutant worms. Our findings uncover a network of chromatin regulators that control the trans-generational flow of epigenetic information, and suggest that the balance between euchromatic H3K4 and heterochromatic H3K9 methylation regulates trans-generational effects on fertility

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist