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Pregnancy outcome relies on the maintenance of immune and metabolic homeostasis at the maternal fetal interface. Maternal and perinatal morbidity and mortality is associated with impaired placental development. Multiple regulatory effects of the endogenous-produced vasoactive intestinal peptide (VIP) on vascular, metabolic and immune functions at the maternal-fetal interface have been reported. Here we studied the involvement of the two primary high affinity receptors for VIP (VPAC1 and VPAC2) on maternal immune response, placental homeostasis and pregnancy outcome. Targeted disruption of each receptor gene led to altered placental structure, vascular and trophoblast functional markers and shaped the functional profiles of macrophages and neutrophils towards a proinflammatory state. Several changes in pregnant mice were receptor specific: ROS production elicited by VIP on neutrophils was selectively dependent on the presence of VPAC1 whereas apoptosis rate was associated with the VPAC2 deletion. In peritoneal macrophages from pregnant mice, levels of MHC-II, TLR2, and IL-10 were selectively altered in VPAC2 receptor-deficient mice, whereas IL-6 gene expression was reduced only in mice lacking VPAC1 receptors. Additionally, MMP9 mRNA in isolated TGCs was reduced in VPAC2 receptor deleted mice, while the percentage of IL-12 cells in post-phagocytosis macrophage cultures was selectively reduced in VPAC2 receptor deficient mice. The results indicate that manipulation of VPAC1 and VPAC2 receptor affects immune, vascular and metabolic environment at the maternal fetal interface. These mouse models offer new approaches to study pregnancy complications adding new perspectives to the development of VPAC receptor-selective drugs.

BACKGROUND & AIMS: The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of digestive manifestations in patients hospitalized with COVID-19. METHODS: Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were abstracted manually from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19. RESULTS: A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least 1 gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were increased to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio, 0.93; 95% CI, 0.76-1.15) or liver test abnormalities on admission (odds ratio, 1.31; 95% CI, 0.80-2.12) were not associated independently with mechanical ventilation or death. CONCLUSIONS: Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common, but the majority were mild and their presence was not associated with a more severe clinical course.

In the face of rapidly advancing climate change, biodiversity loss, and water scarcity, it is clear that global agriculture must swiftly and decisively shift toward sustainability. Fortunately, farmers and researchers have developed a thoroughly studied pathway to this transition: agroecological farming systems that mimic natural ecosystems, creating tightly coupled cycles of energy, water, and nutrients. A critical and underappreciated feature of agroecological systems is that they replace fossil fuel- and chemical -intensive management with knowledge-intensive management. Hence, the greatest sustainability challenge for agriculture may well be that of replacing non-renewable resources with ecologically-skilled people, and doing so in ways that create and support desirable rural livelihoods. Yet over the past century, US agriculture has been trending in the opposite direction, rapidly replacing knowledgeable people with non-renewable resources and eroding rural economies in the process. Below, we suggest how US policy could pivot to enable and support the ecologically skilled workforce needed to achieve food security in the face of climate change.

In the face of rapidly advancing climate change, biodiversity loss, and water scarcity, it is clear that global agriculture must swiftly and decisively shift toward sustainability. Fortunately, farmers and researchers have developed a thoroughly studied pathway to this transition: agroecological farming systems that mimic natural ecosystems, creating tightly coupled cycles of energy, water, and nutrients. A critical and underappreciated feature of agroecological systems is that they replace fossil fuel- and chemical -intensive management with knowledge-intensive management. Hence, the greatest sustainability challenge for agriculture may well be that of replacing non-renewable resources with ecologically-skilled people, and doing so in ways that create and support desirable rural livelihoods. Yet over the past century, US agriculture has been trending in the opposite direction, rapidly replacing knowledgeable people with non-renewable resources and eroding rural economies in the process. Below, we suggest how US policy could pivot to enable and support the ecologically skilled workforce needed to achieve food security in the face of climate change.

Introduction: Mobile health (mHealth) has the potential to change how patients make healthcare decisions. We sought to determine the readiness to use mHealth technology in underserved communities.Methods: We conducted a cross-sectional survey of patients presenting with low-acuity complaints to an urban emergency department (ED) with an underserved population. Patients over the age of two who presented with low-acuity complaints were included. We conducted  structured interview with each patient or parent (for minors) about willingness to use mHealth tools for guidance. Analysis included descriptive statistics and univariate analysis based on age and gender.Results: Of 560 patients included in the survey, 80% were adults, 64% female, and 90% Black. The mean age was 28 ± 9 years for adults and 9 ± 5 years for children. One-third of patients reported no primary care physician, and 55% reported no access to a nurse or clinician for medical advice. Adults were less likely to have access to phone consultation than parents of children (odds ratio [OR] 0.49, 95% confidence interval [CI], 0.32 – 0.74), as were males compared to females (OR 0.52, 95% CI, 0.37– 0.74). Most patients (96%) reported cellular internet access. Two-thirds of patients reported using online references. When asked how they would behave if an mHealth tool advised them that their current health problem was low risk, 69% of patients responded that they would seek care in an outpatient clinic instead of the ED (30%), stay home and not seek urgent medical care (28%), or use telehealth (11%).Conclusion: In this urban community we found a large capacity and willingness to use mHealth technology in medical triage.

Sustainable agriculture is among the most urgently needed work in the United States, for at least three reasons: we face an environmental crisis, a health crisis, and a rural economic crisis. Addressing these pressing crises through sustainability transition will require growing our agricultural workforce: both because the current farm population is aging, and because sustainable agriculture is knowledge-intensive work that substitutes experiential knowledge of farm ecosystems for harmful industrial inputs. Given its social value, sustainable agriculture ought to be a welcoming profession. But at present, US agriculture is decidedly unwelcoming for nearly all who work in it – and it puts new entry and sustainable farmers at a distinct disadvantage. In this paper, we first examine why it is so hard to enter and succeed in sustainable farming. We find that new entrants struggle to gain critical access, assets, and assistance, encountering substantial barriers that stand between them and the land, capital, markets, equipment, water, labor, and training and technical assistance they need to succeed. Secondly, we review promising policy and civil society interventions targeted at addressing these barriers, nearly all of which have already been piloted at the local and state levels or through modest public funding. These interventions are most effective, we find, when they are linked up through robustly governed networks to provide “wraparound” coverage for new entry sustainable farmers. Such networks can help patch together complementary sources of support (e.g. federal, state, local, NGO, cooperative) and synergistically address multiple barriers at once. Finally, we propose additional interventions that are more aspirational today, but that could offer important pathways to support new sustainable farmers in the longer term.

Sustainable agriculture is among the most urgently needed work in the United States, for at least three reasons: we face an environmental crisis, a health crisis, and a rural economic crisis. Addressing these pressing crises through sustainability transition will require growing our agricultural workforce: both because the current farm population is aging, and because sustainable agriculture is knowledge-intensive work that substitutes experiential knowledge of farm ecosystems for harmful industrial inputs. Given its social value, sustainable agriculture ought to be a welcoming profession. But at present, US agriculture is decidedly unwelcoming for nearly all who work in it – and it puts new entry and sustainable farmers at a distinct disadvantage. In this paper, we first examine why it is so hard to enter and succeed in sustainable farming. We find that new entrants struggle to gain critical access, assets, and assistance, encountering substantial barriers that stand between them and the land, capital, markets, equipment, water, labor, and training and technical assistance they need to succeed. Secondly, we review promising policy and civil society interventions targeted at addressing these barriers, nearly all of which have already been piloted at the local and state levels or through modest public funding. These interventions are most effective, we find, when they are linked up through robustly governed networks to provide “wraparound” coverage for new entry sustainable farmers. Such networks can help patch together complementary sources of support (e.g. federal, state, local, NGO, cooperative) and synergistically address multiple barriers at once. Finally, we propose additional interventions that are more aspirational today, but that could offer important pathways to support new sustainable farmers in the longer term.

BackgroundScientists and practitioners alike need reliable, valid measures of contextual factors that influence implementation. Yet, few existing measures demonstrate reliability or validity. To meet this need, we developed and assessed the psychometric properties of measures of several constructs within the Inner Setting domain of the Consolidated Framework for Implementation Research (CFIR).MethodsWe searched the literature for existing measures for the 7 Inner Setting domain constructs (Culture Overall, Culture Stress, Culture Effort, Implementation Climate, Learning Climate, Leadership Engagement, and Available Resources). We adapted items for the healthcare context, pilot-tested the adapted measures in 4 Federally Qualified Health Centers (FQHCs), and implemented the revised measures in 78 FQHCs in the 7 states (N = 327 respondents) with a focus on colorectal cancer (CRC) screening practices. To psychometrically assess our measures, we conducted confirmatory factor analysis models (CFA; structural validity), assessed inter-item consistency (reliability), computed scale correlations (discriminant validity), and calculated inter-rater reliability and agreement (organization-level construct reliability and validity).ResultsCFAs for most constructs exhibited good model fit (CFI > 0.90, TLI > 0.90, SRMR

BackgroundScientists and practitioners alike need reliable, valid measures of contextual factors that influence implementation. Yet, few existing measures demonstrate reliability or validity. To meet this need, we developed and assessed the psychometric properties of measures of several constructs within the Inner Setting domain of the Consolidated Framework for Implementation Research (CFIR).MethodsWe searched the literature for existing measures for the 7 Inner Setting domain constructs (Culture Overall, Culture Stress, Culture Effort, Implementation Climate, Learning Climate, Leadership Engagement, and Available Resources). We adapted items for the healthcare context, pilot-tested the adapted measures in 4 Federally Qualified Health Centers (FQHCs), and implemented the revised measures in 78 FQHCs in the 7 states (N = 327 respondents) with a focus on colorectal cancer (CRC) screening practices. To psychometrically assess our measures, we conducted confirmatory factor analysis models (CFA; structural validity), assessed inter-item consistency (reliability), computed scale correlations (discriminant validity), and calculated inter-rater reliability and agreement (organization-level construct reliability and validity).ResultsCFAs for most constructs exhibited good model fit (CFI > 0.90, TLI > 0.90, SRMR

The Concise Guide to PHARMACOLOGY 2017/18 is the third in this series of biennial publications. This version provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13882/full. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are eight areas of focus: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13347/full. This compilation of the major pharmacological targets is divided into eight areas of focus: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.

DEAD-box RNA helicases are vital for the regulation of various aspects of the RNA life cycle, but the molecular underpinnings of their involvement, particularly in mammalian cells, remain poorly understood. Here we show that the DEAD-box RNA helicase DDX21 can sense the transcriptional status of both RNA polymerase (Pol) I and II to control multiple steps of ribosome biogenesis in human cells. We demonstrate that DDX21 widely associates with Pol I- and Pol II-transcribed genes and with diverse species of RNA, most prominently with non-coding RNAs involved in the formation of ribonucleoprotein complexes, including ribosomal RNA, small nucleolar RNAs (snoRNAs) and 7SK RNA. Although broad, these molecular interactions, both at the chromatin and RNA level, exhibit remarkable specificity for the regulation of ribosomal genes. In the nucleolus, DDX21 occupies the transcribed rDNA locus, directly contacts both rRNA and snoRNAs, and promotes rRNA transcription, processing and modification. In the nucleoplasm, DDX21 binds 7SK RNA and, as a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, is recruited to the promoters of Pol II-transcribed genes encoding ribosomal proteins and snoRNAs. Promoter-bound DDX21 facilitates the release of the positive transcription elongation factor b (P-TEFb) from the 7SK snRNP in a manner that is dependent on its helicase activity, thereby promoting transcription of its target genes. Our results uncover the multifaceted role of DDX21 in multiple steps of ribosome biogenesis, and provide evidence implicating a mammalian RNA helicase in RNA modification and Pol II elongation control.

This paper describes the scientific aims and potentials as well as the preliminary technical design of IRIDE, an innovative tool for multi-disciplinary investigations in a wide field of scientific, technological and industrial applications. IRIDE will be a high intensity "particles factory", based on a combination of high duty cycle radio-frequency superconducting electron linacs and of high energy lasers. Conceived to provide unique research possibilities for particle physics, for condensed matter physics, chemistry and material science, for structural biology and industrial applications, IRIDE will open completely new research possibilities and advance our knowledge in many branches of science and technology. IRIDE is also supposed to be realized in subsequent stages of development depending on the assigned priorities. © 2013 Elsevier B.V.

This paper describes the scientific aims and potentials as well as the preliminary technical design of IRIDE, an innovative tool for multi-disciplinary investigations in a wide field of scientific, technological and industrial applications. IRIDE will be a high intensity "particles factory", based on a combination of high duty cycle radio-frequency superconducting electron linacs and of high energy lasers. Conceived to provide unique research possibilities for particle physics, for condensed matter physics, chemistry and material science, for structural biology and industrial applications, IRIDE will open completely new research possibilities and advance our knowledge in many branches of science and technology. IRIDE is also supposed to be realized in subsequent stages of development depending on the assigned priorities. © 2013 Elsevier B.V.

Lichen sclerosus (LS) is a mucocutaneous disease with uncommon oral involvement. The etiology is not yet well understood, but LS has been associated with autoimmune, genetic, and immunological factors. We report a 47-year-old man with LS that exhibited an asymptomatic white plaque with red patches on the maxillary alveolar mucosa extending to the labial mucosa. He had no other skin disease. Positive immunostaining for tenascin and scarcity of fibronectin suggested extracellular matrix reorganization. Elastin immunostaining indicated a reduction of elastic fibers. Immunoexpression of collagen IV in blood vessels and its absence in the epithelial basement membrane, together with diffuse MMP-9 immunoexpression, suggested altered proteolytic activity. Mast cell staining bordering areas of sclerosis indicated a possible role in the synthesis of collagen. IgG4 positivity in plasma cells suggested a role in the fibrogenesis. This is an unusual presentation of oral LS and we discuss immunohistochemical findings regarding cellular and extracellular matrix components.