bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating pharmacogenomics into the electronic health record by implementing genomic indicators
Authors: Caraballo Pedro J , Sutton Joseph A , Giri Jyothsna , Wright Jessica A , Nicholson Wayne T , Kullo Iftikhar J , Parkulo Mark A , Bielinski Suzette J , Moyer Ann M 
Published: September 2019

Abstract
Pharmacogenomics (PGx) clinical decision support integrated into the electronic health record (EHR) has the potential to provide relevant knowledge to clinicians to enable individualized care. However, past experience implementing PGx clinical decision support into multiple EHR platforms has identified important clinical, procedural, and technical challenges. Commercial EHRs have been widely criticized for the lack of readiness to implement precision medicine. Herein, we share our experiences and lessons learned implementing new EHR functionality charting PGx phenotypes in a unique repository, genomic indicators, instead of using the problem or allergy list. The Gen-Ind has additional features including a brief description of the clinical impact, a hyperlink to the original laboratory report, and links to additional educational resources. The automatic generation of genomic indicators from interfaced PGx test results facilitates implementation and long-term maintenance of PGx data in the EHR and can be used as criteria for synchronous and asynchronous CDS.
Dietary energy sources during late gestation and lactation of sows: effects on performance, glucolipid metabolism, oxidative status of sows, and their offspring1
Authors: Yang Yunyu , Hu Cheng Jun , Zhao Xichen , Xiao Kaili , Deng Ming , Zhang Lin , Qiu Xinggang , Deng Jinping , Yin Yulong , Tan Chengquan 
Published: September 2019

Abstract
In this study, the effects of maternal energy sources during late gestation and lactation on the performance, glucolipid metabolism, and oxidative status of sows and their offspring were investigated using a total of 75 (2 to 6 of parity) Landrace × Large White sows at day 85 of gestation under 3 different dietary treatments: SO diet (basal diet plus 3.0% and 5.0% soybean oil during late gestation and lactation, respectively), FO diet (basal diet plus 3.0%/5.0% fish oil during late gestation and lactation, respectively), and CS diet (basal diet plus 32%/42% corn starch during late gestation and lactation, respectively). All the 3 groups showed no obvious differences (P > 0.05) in the number of total piglets born, born alive, after cross-fostering, and at weaning, whereas the CS group exhibited a shorter farrowing duration (P < 0.05) and lower stillbirth rate (P < 0.05) when compared with the SO group. In addition, litter weight at birth was significantly higher in the CS group than in the SO or FO group (P < 0.05). Despite no notable differences in the ADG of suckling piglets among dietary treatments (P > 0.05), the CS group had greater feed intake than the SO group during the lactation period (P < 0.05). In neonatal piglets with normal birth weight (NBW, 1.3 to 1.5 kg), the CS group was lower than the SO group in the content of liver glycogen (P < 0.05) and the mRNA abundances of fatty acid synthase, acetyl-CoA carboxylase, fatty acid-binding protein 1, and acyl-CoA oxidase (P < 0.05). Interestingly, compared with the SO group, the FO group had a lower preweaning mortality rate (P < 0.05), but greater liver glycogen pools (P < 0.05) in neonatal piglets with low birth weight (LBW, <1.1 kg). Compared with the CS group, the FO group showed an increase in the plasma malondialdehyde levels (P < 0.05) of sows, as well as an increase of 8-hydroxy-deoxyguanosine (P < 0.05) and a decrease of ferric reducing ability of plasma (P < 0.05) in NBW piglets. Overall, the diet rich in starch decreased the stillbirth rate and increased the litter weight of neonatal piglets, the dietary supplementation with fish oil decreased preweaning mortality rate, and the diet with a low n6:n3 ratio increased the oxidative status of sows and their offspring.
The hRPC62 subunit of human RNA polymerase III displays helicase activity
Authors: Ayoubi Leyla El , Dumay-Odelot Hélène , Chernev Aleksandar , Boissier Fanny , Minvielle-Sébastia Lionel , Urlaub Henning , Fribourg Sébastien , Teichmann Martin 
Published: September 2019

AbstractIn Eukaryotes, tRNAs, 5S RNA and U6 RNA are transcribed by RNA polymerase (Pol) III. Human Pol III is composed of 17 subunits. Three specific Pol III subunits form a stable ternary subcomplex (RPC62-RPC39-RPC32α/β) being involved in pre-initiation complex formation. No paralogues for subunits of this subcomplex subunits have been found in Pols I or II, but hRPC62 was shown to be structurally related to the general Pol II transcription factor hTFIIEα. Here we show that these structural homologies extend to functional similarities. hRPC62 as well as hTFIIEα possess intrinsic ATP-dependent 3′-5′ DNA unwinding activity. The ATPase activities of both proteins are stimulated by single-stranded DNA. Moreover, the eWH domain of hTFIIEα can replace the first eWH (eWH1) domain of hRPC62 in ATPase and DNA unwinding assays. Our results identify intrinsic enzymatic activities in hRPC62 and hTFIIEα.
Altered Plant and Nodule Development and Protein S-Nitrosylation in Lotus japonicus Mutants Deficient in S-Nitrosoglutathione Reductases
Authors: Matamoros Manuel A , Cutrona Maria C , Wienkoop Stefanie , Begara-Morales Juan C , Sandal Niels , Orera Irene , Barroso Juan B , Stougaard Jens , Becana Manuel 
Published: September 2019

Abstract
Nitric oxide (NO) is a crucial signaling molecule that conveys its bioactivity mainly through protein S-nitrosylation. This is a reversible post-translational modification (PTM) that may affect protein function. S-nitrosoglutathione (GSNO) is a cellular NO reservoir and NO donor in protein S-nitrosylation. The enzyme S-nitrosoglutathione reductase (GSNOR) degrades GSNO, thereby regulating indirectly signaling cascades associated with this PTM. Here, the two GSNORs of the legume Lotus japonicus, LjGSNOR1 and LjGSNOR2, have been functionally characterized. The LjGSNOR1 gene is very active in leaves and roots, whereas LjGSNOR2 is highly expressed in nodules. The enzyme activities are regulated in vitro by redox-based PTMs. Reducing conditions and hydrogen sulfide-mediated cysteine persulfidation induced both activities, whereas cysteine oxidation or glutathionylation inhibited them. Ljgsnor1 knockout mutants contained higher levels of S-nitrosothiols. Affinity chromatography and subsequent shotgun proteomics allowed us to identify 19 proteins that are differentially S-nitrosylated in the mutant and the wild-type. These include proteins involved in biotic stress, protein degradation, antioxidant protection and photosynthesis. We propose that, in the mutant plants, deregulated protein S-nitrosylation contributes to developmental alterations, such as growth inhibition, impaired nodulation and delayed flowering and fruiting. Our results highlight the importance of GSNOR function in legume biology.
3,4-Dibromo-7-Azaindole Modulates Arabidopsis Circadian Clock by Inhibiting Casein Kinase 1 Activity
Authors: Ono Azusa , Sato Ayato , Fujimoto Kazuhiro J , Matsuo Hiromi , Yanai Takeshi , Kinoshita Toshinori , Nakamichi Norihito 
Published: September 2019

AbstractThe circadian clock is a timekeeping system for regulation of numerous biological daily rhythms. One characteristic of the circadian clock is that period length remains relatively constant in spite of environmental fluctuations, such as temperature change. Here, using the curated collection of in-house small molecule chemical library (ITbM chemical library), we show that small molecule 3,4-dibromo-7-azaindole (B-AZ) lengthened the circadian period of Arabidopsis thaliana (Arabidopsis). B-AZ has not previously been reported to have any biological and biochemical activities. Target identification can elucidate the mode of action of small molecules, but we were unable to make a molecular probe of B-AZ for target identification. Instead, we performed other analysis, gene expression profiling that potentially reveals mode of action of molecules. Short-term treatment of B-AZ decreased the expression of four dawn- and morning-phased clock-associated genes, CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1), LATE ELONGATED HYPOCOTYL (LHY), PSEUDO-RESPONSE REGULATOR 9 (PRR9) and PRR7. Consistently, amounts of PRR5 and TIMING OF CAB EXPRESSION 1 (TOC1) proteins, transcriptional repressors of CCA1, LHY, PRR9 and PRR7 were increased upon B-AZ treatment. B-AZ inhibited Casein Kinase 1 family (CK1) that phosphorylates PRR5 and TOC1 for targeted degradation. A docking study and molecular dynamics simulation suggested that B-AZ interacts with the ATP-binding pocket of human CK1 delta, whose amino acid sequences are highly similar to those of Arabidopsis CK1. B-AZ-induced period-lengthening effect was attenuated in prr5 toc1 mutants. Collectively, this study provides a novel and simple structure CK1 inhibitor that modulates circadian clock via accumulation of PRR5 and TOC1.
Outcomes of Nonsurgical Treatments for Symptomatic Adult Degenerative Scoliosis: A Systematic Review
Authors: Schoutens Carlijn , Cushman Daniel M , McCormick Zachary L , Conger Aaron , van Royen Barend J , Spiker William R 
Published: September 2019

AbstractObjectiveTo evaluate the effectiveness of nonsurgical treatments in symptomatic adult degenerative scoliosis (ADS).DesignA systematic literature review.MethodsPubMed, Web of Science, and The Cochrane Library were searched to identify research published since 1988. Randomized controlled trials (RCTs) and observational cohort studies were eligible if they featured symptomatic ADS patients aged ≥50 who received nonsurgical treatment. Minimum follow-up was six weeks, and outcomes of interest were pain, disability, quality of life, and Cobb angle. Evidence quality per intervention was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.ResultsSix studies were included. Of these, four focused specifically on injections, bracing, or yoga; two involved multiple treatments. One RCT provided evidence for greater effectiveness of transforaminal epidural steroid injection over anesthetic alone in reducing radiating pain and disability. Two single-group retrospective cohort studies lent support for bracing to slow curve progression. One retrospective single-group cohort study suggested an association between yoga and reduced curve progression. Evidence for injections to reduce ADS symptoms was rated as low quality; evidence for bracing and yoga was rated as very low quality. No specific evidence was identified regarding other treatments, including physical therapy and analgesics.ConclusionsLiterature describing the effectiveness of nonoperative treatments in symptomatic ADS is scarce. The quantity and quality of the evidence regarding injections, bracing, and yoga are insufficient to advise for or against the use of these methods to improve outcomes in symptomatic ADS. For these and other nonoperative treatment forms, further research is needed.
Measuring the Welfare Gains from Optimal Incentive Regulation
Authors: Abito Jose Miguel 
Published: September 2019

AbstractI empirically measure the welfare gains from optimal incentive regulation in the context of electric utilities facing both emissions and rate of return regulation (RORR). I provide evidence that RORR induces lower fuel efficiency, leading to greater coal consumption and higher emissions abatement costs. Replacing RORR with the optimal mechanism of Laffont and Tirole (1986) yields annual welfare gains of $686 million or a 11% reduction in electricity prices. I construct a much simpler two-contract menu that can achieve more than 65% of these welfare gains.
Symmetric and Asymmetric Market Betas and Downside Risk
Authors: Levi Yaron , Welch Ivo 
Published: September 2019

Abstract
Our paper explores whether a symmetric plain or an asymmetric down-beta is a better hedging measure (Roy 1952; Markowitz 1959). Unlike Ang, Chen, and Xing (2006) and Lettau, Maggiori, and Weber (2014), we find that the prevailing plain market beta is the better predictor, even for crashes. It also predicts the subsequent down-beta (i.e., beta measured only on days when the stock market had declined) better than down-beta itself. Stocks with higher down-betas ex ante also do not earn higher average rates of return ex post. Thus, down-betas are useful for neither hedging nor risk-pricing purposes.
2015 Glenn A. Fry Award Lecture: Driving toward a New Vision: Understanding the Role of Vision in Driving
Authors: Wood Joanne M. 
Published: September 2019

ABSTRACT
More than 90% of the sensory information that we use for driving is estimated to be visual. However, there is ongoing debate regarding the extent to which different ocular conditions and types of visual impairment affect driving performance and which visual functions are most important for safe driving. My program of research has sought to address these questions using a range of experimental approaches including measures of real-world driving performance on a closed-circuit driving course and under in-traffic conditions. This article provides a current overview of how visual impairment affects driving ability and safety and also highlights the visual challenges of nighttime driving, including the visibility of vulnerable road users, based on the wider research literature, as well as providing a snapshot of some of my own studies. Emphasis is placed on those studies that are relevant to assessing a patient's visual fitness to drive, as well as providing appropriate advice regarding the impact of common visual impairments on driving ability and safety.
Equivalent Change Enrichment Analysis: Assessing Equivalent and Inverse Change in Biological Pathways between Diverse Experiments
Authors: Thompson Jeffrey A. , Koestler Devin C. 
Published: September 2019

AbstractIn silico functional genomics have become a driving force in the way we interpret and use gene expression data, enabling researchers to understand which biological pathways are likely to be affected by the treatments or conditions being studied. There are many approaches to functional genomics, but a number of popular methods determine if a set of modified genes has a higher than expected overlap with genes known to function as part of a pathway (functional enrichment testing). Recently, researchers have started to apply such analyses in a new way: to ask if the data they are collecting show similar disruptions to biological functions compared to reference data. Examples include studying whether similar pathways are perturbed in smokers vs. users of e-cigarettes, or whether a new mouse model of schizophrenia is justified, based on its similarity in cytokine expression to a previously published model. However, there is a dearth of robust statistical methods for testing hypotheses related to these questions and most researchers resort to ad hoc approaches. In this work, we propose a statistical approach to answering such questions. First, we propose a statistic for measuring the degree of equivalent change in individual genes across different treatments. Using this statistic, we propose applying gene set enrichment analysis to identify pathways enriched in genes that are affected in similar or opposing ways across treatments. We evaluate this approach in comparison to ad hoc methods on a simulated dataset, as well as two biological datasets and show that it provides robust results.
Adeno-Associated Virus Technologies and Methods for Targeted Neuronal Manipulation
Authors: Haery Leila , Deverman Benjamin E. , Matho Katherine , Cetin Ali , Woodard Kenton , Cepko Connie , Guerin Karen I. , Rego Meghan A. , Ersing Ina , Bachle Susanna M. , Kamens Joanne , Fan Melina 
Published: September 2019

AbstractCell-type-specific expression of molecular tools and sensors is critical to construct circuit diagrams and to investigate the activity and function of neurons within the nervous system. Strategies for targeted manipulation include combinations of classical genetic tools such as Cre/loxP and Flp/FRT, use of cis-regulatory elements, targeted knock-in transgenic mice, and gene delivery by AAV and other viral vectors. The combination of these complex technologies with the goal of precise neuronal targeting is a challenge in the lab. This report will discuss the theoretical and practical aspects of combining current technologies and establish best practices for achieving targeted manipulation of specific cell types. Novel applications and tools, as well as areas for development, will be envisioned and discussed.
A single-cell and single-nucleus RNA-seq toolbox for fresh and frozen human tumors
Authors: Slyper Michal , Porter Caroline B. M. , Ashenberg Orr , Waldman Julia , Drokhlyansky Eugene , Wakiro Isaac , Smillie Christopher , Smith-Rosario Gabriela , Wu Jingyi , Dionne Danielle , Vigneau Sébastien , Jané-Valbuena Judit , Napolitano Sara , Su Mei-Ju , Patel Anand G. , Karlstrom Asa , Gritsch Simon , Nomura Masashi , Waghray Avinash , Gohil Satyen H. , Tsankov Alexander M. , Jerby-Arnon Livnat , Cohen Ofir , Klughammer Johanna , Rosen Yanay , Gould Joshua , Li Bo , Nguyen Lan , Wu Catherine J. , Izar Benjamin , Haq Rizwan , Hodi F. Stephen , Yoon Charles H. , Hata Aaron N. , Baker Suzanne J. , Suvà Mario L. , Bueno Raphael , Stover Elizabeth H. , Matulonis Ursula A. , Clay Michael R. , Dyer Michael A. , Collins Natalie B. , Wagle Nikhil , Rotem Asaf , Johnson Bruce E. , Rozenblatt-Rosen Orit , Regev Aviv 
Published: September 2019

AbstractSingle cell genomics is essential to chart the complex tumor ecosystem. While single cell RNA-Seq (scRNA-Seq) profiles RNA from cells dissociated from fresh tumor tissues, single nucleus RNA-Seq (snRNA-Seq) is needed to profile frozen or hard-to-dissociate tumors. Each strategy requires modifications to fit the unique characteristics of different tissue and tumor types, posing a barrier to adoption. Here, we developed a systematic toolbox for profiling fresh and frozen clinical tumor samples using scRNA-Seq and snRNA-Seq, respectively. We tested eight tumor types of varying tissue and sample characteristics (resection, biopsy, ascites, and orthotopic patient-derived xenograft): lung cancer, metastatic breast cancer, ovarian cancer, melanoma, neuroblastoma, pediatric sarcoma, glioblastoma, pediatric high-grade glioma, and chronic lymphocytic leukemia. Analyzing 212,498 cells and nuclei from 39 clinical samples, we evaluated protocols by cell quality, recovery rate, and cellular composition. We optimized protocols for fresh tissue dissociation for different tumor types using a decision tree to account for the technical and biological variation between clinical samples. We established methods for nucleus isolation from OCT embedded and fresh-frozen tissues, with an optimization matrix varying mechanical force, buffer, and detergent. scRNA-Seq and snRNA-Seq from matched samples recovered the same cell types and intrinsic expression profiles, but at different proportions. Our work provides direct guidance across a broad range of tumors, including criteria for testing and selecting methods from the toolbox for other tumors, thus paving the way for charting tumor atlases.
Generation and characterisation of an estrogen receptor-positive GEMM-derivedPten p53null transplantable breast tumour model for therapeutic testing
Authors: Davies E.J. , Morgan H. , Tornillo G. , Chabbert C.D. , Kendrick H. , Adhesmaki M.J. , Luke S. , Barry S.T. , Smalley M.J. 
Published: September 2019

AbstractAssessing the signalling pathway dependencies of tumours that arise autochthonously in genetically engineered mouse models (GEMMs) of breast cancer is particularly challenging due to the high degree of intra- and inter-tumour heterogeneity, as well as the long latency of tumour development in such models. Use of transplantable tumour lines derived from autochthonous tumours (‘Mouse Derived Xenografts’ or MDXs) is one possible solution and has been used successfully in models of BRCA1-associated triple negative breast cancer. However, their potential in ER+ breast cancer models has not been addressed. Here, we assess the utility of orthotopic transplantable tumour lines derived from an autochthonous ER+Blg-cre Ptenfl/flp53fl/flbreast cancer model. We show that initial tumour implantation and early passage results in the development of lines of progeny with heterogeneous histopathological phenotypes which is coincident with an accumulation of, or selection for,de novomutations. Importantly, these lines also display different dependencies on the key pathways that drive tumourigenesis, which can lead to inherent resistance to treatment with pharmacological agents targeting these pathways and makes them important models to test strategies to overcome such resistance.
Severity of Early Life Stress Moderates the Effect of Fine Particle Air Pollution on Adolescent Brain Development
Authors: Miller Jonas G. , Dennis Emily L. , Jo Booil , Gotlib Ian H. 
Published: September 2019

AbstractAir pollution is currently the greatest environmental threat to public health, but we know little about its effects on adolescent brain development. In this context, exposure to air pollution co-occurs, and could interact, with social factors that also affect brain development, such as early life stress (ELS). Here, we show that severity of ELS moderates the association between fine particle air pollution (particulate matter 2.5; PM2.5) and structural brain development. We interviewed adolescents about ELS, used census-tract data to characterize PM2.5 concentrations, and conducted longitudinal tensor-based morphometry to assess regional changes in brain volume over a two-year period. Across various cortical, thalamic, and white matter tract regions, there was a remarkably consistent effect of PM2.5 on volumetric change for adolescents who had experienced less, rather than more, severe ELS. Furthermore, exposure to higher levels of PM2.5 and experiencing moderate to severe ELS were associated with comparable volumetric changes in the brain in adolescence.
Systemic Infection Facilitates Transmission ofPseudomonas aeruginosa
Authors: Bachta Kelly E. R. , Allen Jonathan P. , Cheung Bettina H. , Chiu Cheng-Hsun , Hauser Alan R. 
Published: September 2019

ABSTRACTHealth care-associated infections such asPseudomonas aeruginosa(PA) bacteremia pose a major clinical risk for hospitalized patients, and efforts to limit them are a priority. The fitness pressures accounting for PA virulence factors that facilitate bloodstream infections are unclear, as these infections are presumed to be a “dead-end” and have no impact on transmission. Here, we used a mouse model to show that PA spreads from the bloodstream to the gallbladder, where it replicates to extremely high numbers. Bacteria in the gallbladder then seed the intestines and feces, leading to transmission to uninfected cage-mate mice. The findings demonstrate that the gallbladder is critical for spread of PA from the bloodstream to the feces during bacteremia, a process that promotes transmission.