Phenotypic Characterization of PNPase Mutation and Overexpression in C. elegans

PNPase, polynucleotide phosphorylase, is a multifunctional exoribonuclease protein with 3` terminal oligonucleotide polymerase activity. Coded by the PNPT1 gene, the protein is associated with mitochondrial homeostasis and functions as a possible target for cancer therapy. In this study, C. elegans was used to investigate the effect of mutation and overexpression of pnpt-1, the gene that encodes PNPase. It was determined that two specific mutations in pnpt-1 did not affect PNPase expression nor did they produce deleterious phenotypes that affected polycistronic transcript accumulation or ROS production. Creation of a stable overexpression model was achieved through Fusion PCR. However, different transgenic strains overexpressing PNPase produced opposite results for polycistronic transcript accumulation while ROS production saw no significant change, suggesting a mosaic overexpression model. In a cancer model, exogenous PNPase was present in the pachytene region of the germline and where expressed the cells were in non-germline cells suggesting differentiation mechanisms associated with overexpression of PNPase. However, further analysis of different mutations in pnpt-1 or optimizations to the overexpression model are necessary to provide a better understanding of PNPase function with mitochondria homeostasis and in a cancer model setting

Incident and long-term opioid therapy among patients with psychiatric conditions and medications: a national study of commercial health care claims

There is growing evidence that opioid prescribing in the United States follows a pattern in which patients who are at the highest risk of adverse outcomes from opioids are more likely to receive long-term opioid therapy. These patients include, in particular, those with substance use disorders (SUDs) and other psychiatric conditions. This study examined health insurance claims among 10,311,961 patients who filled prescriptions for opioids. Specifically, we evaluated how opioid receipt differed among patients with and without a wide range of preexisting psychiatric and behavioral conditions (ie, opioid and nonopioid SUDs, suicide attempts or other self-injury, motor vehicle crashes, and depressive, anxiety, and sleep disorders) and psychoactive medications (ie, antidepressants, benzodiazepines, hypnotics, mood stabilizers, antipsychotics, and medications used for SUD, tobacco cessation, and attention-deficit/hyperactivity disorder). Relative to those without, patients with all assessed psychiatric conditions and medications had modestly greater odds of subsequently filling prescriptions for opioids and, in particular, substantially greater risk of long-term opioid receipt. Increases in risk for long-term opioid receipt in adjusted Cox regressions ranged from approximately 1.5-fold for prior attention-deficit/hyperactivity disorder medication prescriptions (hazard ratio [HR] = 1.53; 95% confidence interval [CI], 1.48-1.58) to approximately 3-fold for prior nonopioid SUD diagnoses (HR = 3.15; 95% CI, 3.06-3.24) and nearly 9-fold for prior opioid use disorder diagnoses (HR = 8.70; 95% CI, 8.20-9.24). In sum, we found evidence of greater opioid receipt among commercially insured patients with a breadth of psychiatric conditions. Future studies assessing behavioral outcomes associated with opioid prescribing should consider preexisting psychiatric conditions

Association of Mental Health Conditions and Treatments With Long-term Opioid Analgesic Receipt Among Adolescents

Importance: Adults with mental health conditions are more likely than those without to receive long-term opioid therapy. Less is known about opioid therapy among adolescents, especially those with mental health conditions. Objective: To examine associations between preexisting mental health conditions and treatments and initiation of any opioid and long-term opioid therapy among adolescents. Design, Setting, and Participants: A cohort of 1 224 520 incident opioid recipients without cancer diagnoses aged 14 to 18 years at first receipt was extracted from nationwide commercial health care claims data from January 1, 2003, to December 31, 2014. Analysis was conducted from August 19, 2016, to November 16, 2017. Associations between preexisting mental health conditions and treatments and any opioid receipt were examined by comparing recipients with nonrecipients matched on sex, calendar year and years of age of first enrollment, and months of enrollment (prior to the index month for recipients, ever for nonrecipients). Associations between preexisting mental health conditions and treatments and subsequent long-term opioid therapy were examined among recipients with at least 6 months' follow-up using Cox proportional hazards regressions adjusted for demographics. Exposures: Mental health condition diagnoses and treatments recorded in inpatient, outpatient, and filled-prescription claims prior to opioid receipt. Main Outcomes and Measures: Opioid receipt, defined as any opioid analgesic prescription claim, and long-term opioid therapy, defined as more than 90 days' supply within a 6-month window having no gaps in supply of more than 32 days. Results: Of the 1 224 520 new opioid recipients included, the median age at first receipt was 17 years (interquartile range, 16-18 years), and 51.1% were female. Median follow-up after first receipt was 625 days (interquartile range, 255-1268 days). Adolescents with anxiety, mood, neurodevelopmental, sleep, and nonopioid substance use disorders and most mental health treatments were significantly more likely to receive any opioid (odds ratios from 1.13 [95% CI, 1.10-1.16] for nonopioid substance use disorders to 1.69 [95% CI, 1.58-1.81] for nonbenzodiazepine hypnotics). Among the 1 000 453 opioid recipients (81.7%) who had at least 6 months' follow-up, the cumulative incidence of long-term opioid therapy was 3.0 (95% CI, 2.8-3.1) per 1000 recipients within 3 years after first opioid receipt. All preexisting mental health conditions and treatments were strongly associated with higher rates of long-term opioid therapy (adjusted hazard ratios from 1.73 [95% CI 1.54-1.95] for attention-deficit/hyperactivity disorder to 8.90 [95% CI, 5.85-13.54] for opioid use disorder). Conclusions and Relevance: Commercially insured adolescents with many types of preexisting mental health conditions and treatments were modestly more likely to receive any opioid and were substantially more likely to subsequently transition to long-term opioid therapy relative to those without, although overall rates of long-term opioid therapy were low

Selective Trihydroxyazepane NagZ Inhibitors Increase Sensitivity of Pseudomonas Aeruginosa to β-lactams

AmpC β-lactamase confers resistance to β-lactam antibiotics in many Gram negative bacteria. Inducible expression of AmpC requires an N-acetylglucosaminidase termed NagZ. Here we describe the synthesis and characterization of hydroxyazepane inhibitors of NagZ. We find that these inhibitors enhance the susceptibility of clinically relevant Pseudomonas aeruginosa to β-lactams

The influence of taxonomy and environment on leaf trait variation along tropical abiotic gradients

Deconstructing functional trait variation and co-variation across a wide range of environmental conditions is necessary to increase the mechanistic understanding of community assembly processes and improve current parameterization of dynamic vegetation models. Here, we present a study that deconstructs leaf trait variation and co-variation into within-species, taxonomic-, and plot-environment components along three tropical environmental gradients in Peru, Brazil, and Ghana. To do so, we measured photosynthetic, chemical, and structural leaf traits using a standardized sampling protocol for more than 1,000 individuals belonging to 367 species. Variation associated with the taxonomic component (species + genus + family) for most traits was relatively consistent across environmental gradients, but within-species variation and plot-environment variation was strongly dependent on the environmental gradient. Trait-trait co-variation was strongly linked to the environmental gradient where traits were measured, although some traits had consistent co-variation components irrespective of gradient. Our results demonstrate that filtering along these tropical gradients is mostly expressed through trait taxonomic variation, but that trait co-variation is strongly dependent on the local environment, and thus global trait co-variation relationships might not always apply at smaller scales and may quickly change under future climate scenarios.Fil: Oliveras, Imma. University of Oxford; Reino UnidoFil: Bentley, Lisa. Sonoma State University; Estados UnidosFil: Fyllas, Nikolaos M.. University Of The Aegean; GreciaFil: Gvozdevaite, Agne. University of Oxford; Reino UnidoFil: Shenkin, Alexander Frederick. University of Oxford; Reino UnidoFil: Peprah, Theresa. Forestry Research Institute Of Ghana; GhanaFil: Morandi, Paulo. Universidade Federal do Mato Grosso do Sul; BrasilFil: Peixoto, Karine Silva. Universidade Federal do Mato Grosso do Sul; BrasilFil: Boakye, Mickey. Forestry Research Institute Of Ghana; GhanaFil: Adu-Bredu, Stephen. Csir - Forestry Research Institute Of Ghana; GhanaFil: Schwantes Marimon, Beatriz. Universidade Do Estado de Mato Grosso; BrasilFil: Marimon Junior, Ben Hur. Universidade Do Estado de Mato Grosso; BrasilFil: Salinas, Norma. Pontificia Universidad Católica de Perú; PerúFil: Martin, Roberta. Arizona State University; Estados UnidosFil: Asner, Gregory. Arizona State University; Estados UnidosFil: Díaz, Sandra Myrna. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Enquist, Brian J.. University of Arizona; Estados UnidosFil: Malhi, Yadvinder. University of Oxford; Reino Unid

Microbial Community and Chemical Characteristics of Swine Manure during Maturation

Swine diet formulations have the potential to lower animal emissions, including odor and ammonia (NH3). The purpose of this study was to determine the impact of manure storage duration on manure chemical and microbial properties in swine feeding trials. Three groups of 12 pigs were fed a standard corn–soybean meal diet over a 13-wk period. Urine and feces were collected at each feeding and transferred to 12 manure storage tanks. Manure chemical characteristics and headspace gas concentrations were monitored for NH3, hydrogen sulfide (H2S), volatile fatty acids, phenols, and indoles. Microbial analysis of the stored manure included plate counts, community structure (denaturing gradient gel electrophoresis), and metabolic function (Biolog). All odorants in manure and headspace gas concentrations were significantly (p \u3c 0.01) correlated for length of storage using quadratic equations, peaking after Week 5 for all headspace gases and most manure chemical characteristics. Microbial community structure and metabolic utilization patterns showed continued change throughout the 13-wk trial. Denaturing gradient gel electrophoresis species diversity patterns declined significantly (p \u3c 0.01) with time as substrate utilization declined for sugars and certain amino acids, but functionality increased in the utilization of short chain fatty acids as levels of these compounds increased in manure. Studies to assess the effect of swine diet formulations on manure emissions for odor need to be conducted for a minimum of 5 wk. Efforts to determine the impact of diets on greenhouse gas emissions will require longer periods of study (\u3e13 wk)

Pantropical modelling of canopy functional traits using Sentinel-2 remote sensing data

Funding Information: This work is a product of the Global Ecosystems Monitoring (GEM) network (gem.tropicalforests.ox.ac.uk). J.A.G. was funded by the Natural Environment Research Council (NERC; NE/T011084/1 and NE/S011811/1) and the Netherlands Organisation for Scientific Research (NWO) under the Rubicon programme with project number 019.162LW.010. The traits field campaign was funded by a grant to Y.M. from the European Research Council (Advanced Grant GEM-TRAIT: 321131) under the European Union‘s Seventh Framework Programme (FP7/2007-2013), with additional support from NERC Grant NE/D014174/1 and NE/J022616/1 for traits work in Peru, NERC Grant ECOFOR (NE/K016385/1) for traits work in Santarem, NERC Grant BALI (NE/K016369/1) for plot and traits work in Malaysia and ERC Advanced Grant T-FORCES (291585) to Phillips for traits work in Australia. Plot setup in Ghana and Gabon were funded by a NERC Grant NE/I014705/1 and by the Royal Society-Leverhulme Africa Capacity Building Programme. The Malaysia campaign was also funded by NERC GrantNE/K016253/1. Plot inventories in Peru were supported by funding from the US National Science Foundation Long-Term Research in Environmental Biology program (LTREB; DEB 1754647) and the Gordon and Betty Moore Foundation Andes-Amazon Program. Plots inventories in Nova Xavantina (Brazil) were supported by the National Council for Scientific and Technological Development (CNPq), Long Term Ecological Research Program (PELD), Proc. 441244/2016-5, and the Foundation of Research Support of Mato Grosso (FAPEMAT), Project ReFlor, Proc. 589267/2016. During data collection, I.O. was supported by a Marie Curie Fellowship (FP7-PEOPLE-2012-IEF-327990). GEM trait data in Gabon was collected under authorisation to Y.M. and supported by the Gabon National Parks Agency. D.B. was funded by the Fondation Wiener-Anspach. W.D.K. acknowledges support from the Faculty Research Cluster ‘Global Ecology’ of the University of Amsterdam. M.S. was funded by a grant from the Ministry of Education, Youth and Sports of the Czech Republic (INTER-TRANSFER LTT19018). Y.M. is supported by the Jackson Foundation. We thank the two anonymous reviewers and Associate Editor G. Henebry for their insightful comments that helped improved this manuscript.Peer reviewedPostprin

Phosphoprotein Associated with Glycosphingolipid-Enriched Microdomains Differentially Modulates Src Kinase Activity in Brain Maturation

Src family kinases (SFK) control multiple processes during brain development and function. We show here that the phosphoprotein associated with glycosphigolipid-enriched microdomains (PAG)/Csk binding protein (Cbp) modulates SFK activity in the brain. The timing and localization of PAG expression overlap with Fyn and Src, both of which we find associated to PAG. We demonstrate in newborn (P1) mice that PAG negatively regulates Src family kinases (SFK). P1 Pag1-/- mouse brains show decreased recruitment of Csk into lipid rafts, reduced phosphorylation of the inhibitory tyrosines within SFKs, and an increase in SFK activity of >/ = 50%. While in brain of P1 mice, PAG and Csk are highly and ubiquitously expressed, little Csk is found in adult brain suggesting altered modes of SFK regulation. In adult brain Pag1-deficiency has no effect upon Csk-distribution or inhibitory tyrosine phosphorylation, but kinase activity is now reduced (−20–30%), pointing to the development of a compensatory mechanism that may involve PSD93. The distribution of the Csk-homologous kinase CHK is not altered. Importantly, since the activities of Fyn and Src are decreased in adult Pag1-/- mice, thus presenting the reversed phenotype of P1, this provides the first in vivo evidence for a Csk-independent positive regulatory function for PAG in the brain

A Genome-Wide Linkage and Association Scan Reveals Novel Loci for Hypertension and Blood Pressure Traits

Hypertension is caused by the interaction of environmental and genetic factors. The condition which is very common, with about 18% of the adult Hong Kong Chinese population and over 50% of older individuals affected, is responsible for considerable morbidity and mortality. To identify genes influencing hypertension and blood pressure, we conducted a combined linkage and association study using over 500,000 single nucleotide polymorphisms (SNPs) genotyped in 328 individuals comprising 111 hypertensive probands and their siblings. Using a family-based association test, we found an association with SNPs on chromosome 5q31.1 (rs6596140; P<9×10−8) for hypertension. One candidate gene, PDC, was replicated, with rs3817586 on 1q31.1 attaining P = 2.5×10−4 and 2.9×10−5 in the within-family tests for DBP and MAP, respectively. We also identified regions of significant linkage for systolic and diastolic blood pressure on chromosomes 2q22 and 5p13, respectively. Further family-based association analysis of the linkage peak on chromosome 5 yielded a significant association (rs1605685, P<7×10−5) for DBP. This is the first combined linkage and association study of hypertension and its related quantitative traits with Chinese ancestry. The associations reported here account for the action of common variants whereas the discovery of linkage regions may point to novel targets for rare variant screening