IDO1 is an Integral Mediator of Inflammatory Neovascularization.

The immune tolerogenic effects of IDO1 (indoleamine 2,3-dioxygenase 1) have been well documented and genetic studies in mice have clearly established the significance of IDO1 in tumor promotion. Dichotomously, the primary inducer of IDO1, the inflammatory cytokine IFNγ (interferon-γ), is a key mediator of immune-based tumor suppression. One means by which IFNγ can exert an anti-cancer effect is by decreasing tumor neovascularization. We speculated that IDO1 might contribute to cancer promotion by countering this anti-neovascular effect of IFNγ, possibly through IDO1-potentiated elevation of the pro-tumorigenic inflammatory cytokine IL6 (interleukin-6). In this study, we investigated how genetic loss of IDO1 affects neovascularization in mouse models of oxygen-induced retinopathy and lung metastasis. Neovascularization in both models was significantly reduced in mice lacking IDO1, was similarly reduced with loss of IL6, and was restored in both cases by concomitant loss of IFNγ. Likewise, the lack of IDO1 or IL6 resulted in reduced metastatic tumor burden and increased survival, which the concomitant loss of IFNγ abrogated. This insight into IDO1\u27s involvement in pro-tumorigenic inflammatory neovascularization may have important ramifications for IDO1 inhibitor development, not only in cancer where clinical trials are currently ongoing, but in other disease indications associated with neovascularization as well

Utah\u27s Water Future: Perspectives on Water Issues in Utah\u27s Wasatch Range Metropolitan Area

The iUTAH Household Survey was conducted in 2014 during a time when the State of Utah was initiating various activities aimed at charting a long-term strategy for securing Utah’s water future. Water is currently high on the state’s public policy agenda due to Utah’s rapid population growth and urbanization, future water supply uncertainties related to climate change, and the political challenges of allocating increasingly limited regional water supplies. In order to provide information relevant to water policy, planning and management, the survey focused on understanding residents’ water management practices, water experiences and concerns, as well as their support for various state and local water policies and programs. The iUTAH Household Survey gathered data from over 2,300 residents in 23 different neighborhoods that represent the diverse types of urban development occurring in the Wasatch Range Metropolitan Area of Northern Utah. The survey was successful in capturing the views, experiences, and priorities of a representative cross-section of adults living in Utah’s urban areas. Study neighborhoods were selected based upon development of a detailed urban neighborhood typology. Using a drop-off/pick-up method, the research team received responses from over 62% of the randomly selected households within study neighborhoods. This report summarizes overall findings from the survey research effort, with an emphasis on comparing the four broad study locations of Salt Lake City, other parts of the Salt Lake Valley, the Cache Valley, and the Heber Valley. Our analysis presents some overarching themes that appear across our entire study area, but also highlights differences across these four locations

The Lamprey Genome: Illuminating Genomic Change across Eons and Embryogenesis

The lamprey genome provides unique insights into both the deep evolutionary history of vertebrate genomes and the maintenance of genome structure/integrity over development. The lamprey lineage diverged from all other vertebrates approximately 500 million years ago. As such, comparisons between lamprey and other vertebrates permit reconstruction of ancient duplication and rearrangement events that defined the fundamental architecture and gene content of all extant vertebrate genomes. Lamprey also undergoes programmatic changes genome structure that result in the physical elimination of ~20% of its genomic DNA (~0.5Gb from a ~2 Gb genome) from all somatic cell lineages during early embryonic development. Here, we outline recent progress in assembly and analysis of the lamprey germline genome, and progress in the development of methods for characterizing the cellular events that mediate DNA elimination. We have integrated information from several sampling approaches and sequencing technologies to achieve a highly contiguous assembly of lamprey genome (including: Illumina fragments/mate pairs, 20X coverage in Pacific Biosciences reads, dense meiotic maps and optical mapping data). This genome assembly has dramatically improved our ability to dissect the molecular basis and genetic outcomes of programmed genome rearrangements (PGRs), and has improved our understanding of the tempo and mode of large-­scale duplications and translocations within the ancestral vertebrate lineage. Analysis of the germline genome identifies several genes that are expressed in germline but physically eliminated from all somatic tissues. These eliminated genes correspond to several known oncogenes and appear to identify several other novel oncogene candidates. Complementing this assembly, the development of approaches to in situ analysis of 3D preserved cells has revealed that PGR unfolds through a series of dramatic cellular events that involve the programmatic alteration of several fundamental mechanisms of genome maintenance, including: alignment of chromosomes at metaphase, chromatid cohesion, separation and segregation, and nuclear envelope formation

Perspectives of patients and healthcare professionals on mHealth for asthma self-management

Copyright ©ERS 2017. Mobile healthcare (mHealth) has the potential to revolutionise the self-management of long-term medical conditions such as asthma. A user-centred design is integral if mHealth is to be embraced by patients and healthcare professionals. The aim of this study was to determine the perspectives of individuals with asthma and healthcare professionals on the use of mHealth for asthma self-management. We used a sequential exploratory mixed methods design; focus groups informed the development of questionnaires, which were disseminated to individuals with asthma and healthcare professionals. Focus group participants (18 asthma patients and five healthcare professionals) identified 12 potential uses of mHealth. Questionnaire results showed that individuals with asthma (n=186) most frequently requested an mHealth system to monitor asthma over time (72%) and to collect data to present to healthcare teams (70%). In contrast, healthcare professionals (n=63) most frequently selected a system alerting patients to deteriorating asthma control (86%) and advising them when to seek medical attention (87%). Individuals with asthma were less likely than healthcare professionals (p < 0.001) to believe that assessing medication adherence and inhaler technique could improve asthma control. Our data provide strong support for mHealth for asthma self-management, but highlight fundamental differences between the perspectives of patients and healthcare professionals

CRISPR/Cas9 DNA cleavage at SNP-derived PAM enables both in vitro and in vivo KRT12 mutation-specific targeting

CRISPR/Cas9-based therapeutics hold the possibility for permanent treatment of genetic disease. The potency and specificity of this system has been used to target dominantly inherited conditions caused by heterozygous missense mutations through inclusion of the mutated base in the short-guide RNA (sgRNA) sequence. This research evaluates a novel approach for targeting heterozygous single-nucleotide polymorphisms (SNPs) using CRISPR/Cas9. We determined that a mutation within KRT12, which causes Meesmann's epithelial corneal dystrophy (MECD), leads to the occurrence of a novel protospacer adjacent motif (PAM). We designed an sgRNA complementary to the sequence adjacent to this SNP-derived PAM and evaluated its potency and allele specificity both in vitro and in vivo. This sgRNA was found to be highly effective at reducing the expression of mutant KRT12 mRNA and protein in vitro. To assess its activity in vivo we injected a combined Cas9/sgRNA expression construct into the corneal stroma of a humanized MECD mouse model. Sequence analysis of corneal genomic DNA revealed non-homologous end-joining repair resulting in frame-shifting deletions within the mutant KRT12 allele. This study is the first to demonstrate in vivo gene editing of a heterozygous disease-causing SNP that results in a novel PAM, further highlighting the potential for CRISPR/Cas9-based therapeutics

Impacts of Climate Change on Multiple Use Management of Bureau of Land Management Land in the Intermountain West, USA

Although natural resource managers are concerned about climate change, many are unable to adequately incorporate climate change science into their adaptation strategies or management plans, and are not always aware of or do not employ the most current scientific knowledge. One of the most prominent natural resource management agencies in the United States is the Bureau of Land Management (BLM), which is tasked with managing over 248 million acres (\u3e1 million km2) of public lands for multiple, often conflicting, uses. Climate change will affect the sustainability of many of these land uses and could further increase conflicts between them. As such, the purpose of our study was to determine the extent to which climate change will affect public land uses, and whether the BLM is managing for such predicted effects. To do so, we first conducted a systematic review of peer-reviewed literature that discussed potential impacts of climate change on the multiple land uses the BLM manages in the Intermountain West, USA, and then expanded these results with a synthesis of projected vegetation changes. Finally, we conducted a content analysis of BLM Resource Management Plans in order to determine how climate change is explicitly addressed by BLM managers, and whether such plans reflect changes predicted by the scientific literature. We found that active resource use generally threatens intrinsic values such as conservation and ecosystem services on BLM land, and climate change is expected to exacerbate these threats in numerous ways. Additionally, our synthesis of vegetation modeling suggests substantial changes in vegetation due to climate change. However, BLM plans rarely referred to climate change explicitly and did not reflect the results of the literature review or vegetation model synthesis. Our results suggest there is a disconnect between management of BLM lands and the best available science on climate change. We recommend that the BLM actively integrates such research into on-the-ground management plans and activities, and that researchers studying the effects of climate change make a more robust effort to understand the practices and policies of public land management in order to effectively communicate the management significance of their findings

An exploration of concomitant psychiatric disorders in children with autism spectrum disorder

Objective We explored patterns of concomitant psychiatric disorders in a large sample of treatment-seeking children and adolescents with autism spectrum disorder (ASD). Methods Participants were 658 children with ASD (age 3–17 years; mean = 7.2 years) in one of six federally-funded multisite randomized clinical trials (RCT) between 1999 and 2014. All children were referred for hyperactivity or irritability. Study designs varied, but all used the Child and Adolescent Symptom Inventory or Early Childhood Inventory to assess Attention Deficit Hyperactivity Disorder (ADHD), Oppositional-Defiant Disorder (ODD), Conduct Disorder (CD), Anxiety Disorders, and Mood Disorders. In addition, several measures in common were used to assess demographic and clinical characteristics. Results Of the 658 children, 73% were Caucasian and 59% had an IQ >70. The rates of concomitant disorders across studies were: ADHD 81%, ODD 46%, CD 12%, any anxiety disorder 42%, and any mood disorder 8%. Two or more psychiatric disorders were identified in 66% of the sample. Of those who met criteria for ADHD, 50% also met criteria for ODD and 46% for any anxiety disorder. Associations between types of concomitant disorders and a number of demographic and clinical characteristics are presented. Conclusion In this well-characterized sample of treatment-seeking children with ASD, rates of concomitant psychiatric disorders were high and the presence of two or more co-occurring disorders was common. Findings highlight the importance of improving diagnostic practice in ASD and understanding possible mechanisms of comorbidity

The Science Case for an Extended Spitzer Mission

Although the final observations of the Spitzer Warm Mission are currently scheduled for March 2019, it can continue operations through the end of the decade with no loss of photometric precision. As we will show, there is a strong science case for extending the current Warm Mission to December 2020. Spitzer has already made major impacts in the fields of exoplanets (including microlensing events), characterizing near Earth objects, enhancing our knowledge of nearby stars and brown dwarfs, understanding the properties and structure of our Milky Way galaxy, and deep wide-field extragalactic surveys to study galaxy birth and evolution. By extending Spitzer through 2020, it can continue to make ground-breaking discoveries in those fields, and provide crucial support to the NASA flagship missions JWST and WFIRST, as well as the upcoming TESS mission, and it will complement ground-based observations by LSST and the new large telescopes of the next decade. This scientific program addresses NASA's Science Mission Directive's objectives in astrophysics, which include discovering how the universe works, exploring how it began and evolved, and searching for life on planets around other stars.Comment: 75 pages. See page 3 for Table of Contents and page 4 for Executive Summar

Understanding and measuring child welfare outcomes

The new Children\u27s and Family Services Reviews (CFSR) process focuses on the effectiveness of services to children and families by measuring client outcomes. This article reviews the research literature related to child welfare outcomes in order to provide a context for federal accountability efforts. It also summarizes the 2001 federal mandate to hold states accountable for child welfare outcomes and describes California\u27s response to this mandate. Implications of the outcomes literature review and measurement problems in the CFSR process suggest CSFR measures do not always capture meaningful outcomes. Recommendations for change are made