bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving Heritability Estimation by a Variable Selection Approach in Sparse High Dimensional Linear Mixed Models
Authors: Bonnet Anna , Lévy-Leduc Céline , Gassiat Elisabeth , Toro Roberto , Bourgeron Thomas 
Published: January 2018

SummaryMotivated by applications in neuroanatomy, we propose a novel methodology to estimate heritability, which corresponds to the proportion of phenotypic variance that can be explained by genetic factors. Since the phenotypic variations may be due to only a small fraction of the available genetic information, we propose an estimator of heritability that can be used in sparse linear mixed models. Since the real genetic architecture is in general unknown in practice, our method enables the user to determine whether the genetic effects are very sparse: in that case, we propose a variable selection approach to recover the support of these genetic effects before estimating heritability. Otherwise, we use a classical maximum likelihood approach. We apply our method, implemented in the R package EstHer that is available on the Comprehensive R Archive Network, on neuroanatomical data from the project IMAGEN.
Divergent functions of the GAGA‐binding transcription factor family in rice
Authors: Gong Rong , Cao Huasheng , Zhang Jianing , Xie Kun , Wang Dianwen , Yu Sibin 
Published: January 2018

SummaryOsGBPs are a small family of four genes in rice (Oryza sativa L.) that function as transcription factors recognizing the GAGA motif; however, their functions in plant growth and development remain unclear. Here we report the functions of OsGBPs in plant growth and grain development. Knock‐down and knock‐out of OsGBP1 promoted seedling growth and enhanced grain length, whereas overexpression of OsGBP1 exhibited the opposite effect on seedling growth and grain length, indicating that OsGBP1 repressed grain length and seedling growth. In addition, overexpression of OsGBP1 led to delayed flowering time and suppressed plant height. OsGBP1 could regulate OsLFL1 expression through binding to the (GA)12 element of its promoter. In contrast, OsGBP3 induced grain length and plant height. Grain length and plant height were decreased in OsGBP3RNAi lines and were increased in OsGBP3 overexpression lines. We also found a synergistic effect of these two genes on grain width and plant growth. RNAi of both OsGBP1 and OsGBP3 resulted in severe dwarfism, compared with RNAi of a single gene. These results suggest the presence of functional divergence of OsGBPs in the regulation of grain size and plant growth; these results enrich our understanding of the roles of GAGA‐binding transcription factors in the regulatory pathways of plant development.
Suppression of DELLA signaling induces procambial cell formation in culture
Authors: Yamazaki Kyoko , Kondo Yuki , Kojima Mikiko , Takebayashi Yumiko , Sakakibara Hitoshi , Fukuda Hiroo 
Published: January 2018

SummaryThe post‐embryonic growth of plants requires the activities of apical meristems and lateral meristems. In the meristems, self‐proliferation and differentiation of stem cells is tightly modulated by plant hormone signaling networks and specific transcription factors. Despite extensive studies on stem cell maintenance in plants, the mechanism by which stem cells are initially established is largely unknown. Vascular stem cells consisting of procambial/cambial cells give rise to xylem and phloem cells. In this study, we analyzed the establishment of procambial cells using the in vitro culture system VISUAL, in which mesophyll cells rapidly differentiate into xylem tracheary elements and phloem sieve elements via procambial cells. We found that procambial cell formation in VISUAL is initiated by light, which can be replaced by application of gibberellin (GA). Gibberellin was able to promote procambial cell formation through degradation of DELLA, whereas light did not elevate the endogenous GA content. Indeed, light in combination with bikinin reduced the accumulation of DELLA protein in VISUAL. Consistently, overexpression of a constitutively active DELLA protein repressed vascular cell differentiation even under light. These combined results suggest that DELLA signaling suppresses procambial cell formation during vascular development in VISUAL.
Increasing cardiac pyruvate dehydrogenase flux during chronic hypoxia improves acute hypoxic tolerance
Authors: Handzlik Michal K. , Constantin‐Teodosiu Dumitru , Greenhaff Paul L. , Cole Mark A. 
Published: January 2018

Key points
The cardiac metabolic reprogramming seen in heart diseases such as myocardial infarction and hypertrophy shares similarities with that seen in chronic hypoxia, but understanding of how the hypoxic heart responds to further hypoxic challenge – hypoxic tolerance – is limited.
The pyruvate dehydrogenase complex serves to control irreversible decarboxylation of pyruvate within mitochondria, and is a key regulator of substrate metabolism, potentially regulating hypoxic tolerance.
Acute activation of the pyruvate dehydrogenase complex did not improve cardiac function during acute hypoxia; however, simultaneous activation of the pyruvate dehydrogenase complex during chronic hypoxic exposure improved tolerance to subsequent acute hypoxia.
Activation of the pyruvate dehydrogenase complex during chronic hypoxia stockpiled cardiac acetylcarnitine, and this was used during acute hypoxia. This maintained cardiac ATP and glycogen, and improved hypoxic tolerance as a result.
These findings demonstrate that pyruvate dehydrogenase complex activation can improve cardiac function under hypoxia.
AbstractThe pattern of metabolic reprogramming in chronic hypoxia shares similarities with that following myocardial infarction or hypertrophy; however, the response of the chronically hypoxic heart to subsequent acute injury, and the role of metabolism is not well understood. Here, we determined the myocardial tolerance of the chronically hypoxic heart to subsequent acute injury, and hypothesised that activation of a key regulator of myocardial metabolism, the pyruvate dehydrogenase complex (PDC), could improve hypoxic tolerance. Mouse hearts, perfused in Langendorff mode, were exposed to 30 min of hypoxia, and lost 80% of pre‐hypoxic function (P = 0.001), with only 51% recovery of pre‐hypoxic function with 30 min of reoxygenation (P = 0.046). Activation of the PDC with infusion of 1 mm dichloroacetate (DCA) during hypoxia and reoxygenation did not alter function. Acute hypoxic tolerance was assessed in hearts of mice housed in hypoxia for 3 weeks. Chronic hypoxia reduced cardiac tolerance to subsequent acute hypoxia, with recovery of function 22% of pre‐acute hypoxic levels vs. 39% in normoxic control hearts (P = 0.012). DCA feeding in chronic hypoxia (per os, 70 mg kg−1 day−1) doubled cardiac acetylcarnitine content, and this fell following acute hypoxia. This acetylcarnitine use maintained cardiac ATP and glycogen content during acute hypoxia, with hypoxic tolerance normalised. In summary, chronic hypoxia renders the heart more susceptible to acute hypoxic injury, which can be improved by activation of the PDC and pooling of acetylcarnitine. This is the first study showing functional improvement of the chronically hypoxic heart with activation of the PDC, and offers therapeutic potential in cardiac disease with a hypoxic component.
Ca2+ signalling in mouse urethral smooth muscle in situ: role of Ca2+ stores and Ca2+ influx mechanisms
Authors: Drumm Bernard T. , Rembetski Benjamin E. , Cobine Caroline A. , Baker Salah A. , Sergeant Gerard P. , Hollywood Mark A. , Thornbury Keith D. , Sanders Kenton M. 
Published: January 2018

Key points
Contraction of urethral smooth muscle cells (USMCs) contributes to urinary continence. Ca2+ signalling in USMCs was investigated in intact urethral muscles using a genetically encoded Ca2+ sensor, GCaMP3, expressed selectively in USMCs.
USMCs were spontaneously active in situ, firing intracellular Ca2+ waves that were asynchronous at different sites within cells and between adjacent cells.
Spontaneous Ca2+ waves in USMCs were myogenic but enhanced by adrenergic or purinergic agonists and decreased by nitric oxide.
Ca2+ waves arose from inositol trisphosphate type 1 receptors and ryanodine receptors, and Ca2+ influx by store‐operated calcium entry was required to maintain Ca2+ release events.
Ca2+ release and development of Ca2+ waves appear to be the primary source of Ca2+ for excitation–contraction coupling in the mouse urethra, and no evidence was found that voltage‐dependent Ca2+ entry via L‐type or T‐type channels was required for responses to α adrenergic responses.
AbstractUrethral smooth muscle cells (USMCs) generate myogenic tone and contribute to urinary continence. Currently, little is known about Ca2+ signalling in USMCs in situ, and therefore little is known about the source(s) of Ca2+ required for excitation–contraction coupling. We characterized Ca2+ signalling in USMCs within intact urethral muscles using a genetically encoded Ca2+ sensor, GCaMP3, expressed selectively in USMCs. USMCs fired spontaneous intracellular Ca2+ waves that did not propagate cell‐to‐cell across muscle bundles. Ca2+ waves increased dramatically in response to the α1 adrenoceptor agonist phenylephrine (10 μm) and to ATP (10 μm). Ca2+ waves were inhibited by the nitric oxide donor DEA NONOate (10 μm). Ca2+ influx and release from sarcoplasmic reticulum stores contributed to Ca2+ waves, as Ca2+ free bathing solution and blocking the sarcoplasmic Ca2+‐ATPase abolished activity. Intracellular Ca2+ release involved cooperation between ryanadine receptors and inositol trisphosphate receptors, as tetracaine and ryanodine (100 μm) and xestospongin C (1 μm) reduced Ca2+ waves. Ca2+ waves were insensitive to L‐type Ca2+ channel modulators nifedipine (1 μm), nicardipine (1 μm), isradipine (1 μm) and FPL 64176 (1 μm), and were unaffected by the T‐type Ca2+ channel antagonists NNC‐550396 (1 μm) and TTA‐A2 (1 μm). Ca2+ waves were reduced by the store operated Ca2+ entry blocker SKF 96365 (10 μm) and by an Orai antagonist, GSK‐7975A (1 μm). The latter also reduced urethral contractions induced by phenylephrine, suggesting that Orai can function effectively as a receptor‐operated channel. In conclusion, Ca2+ waves in mouse USMCs are a source of Ca2+ for excitation–contraction coupling in urethral muscles.
Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Vaborbactam and Meropenem Alone and in Combination following Single and Multiple Doses in Healthy Adult Subjects
Authors: Rubino Christopher M. , Bhavnani Sujata M. , Loutit Jeffery S. , Morgan Elizabeth E. , White Dan , Dudley Michael N. , Griffith David C. 
Published: January 2018

ABSTRACT
Meropenem-vaborbactam is a fixed combination of the novel β-lactamase inhibitor vaborbactam and the carbapenem antibiotic meropenem, developed for the treatment of serious infections caused by drug-resistant Gram-negative bacteria. The safety, tolerability, and pharmacokinetics (PK) of vaborbactam and meropenem following single and multiple ascending doses of each study drug administered alone or combined were evaluated in 76 healthy adult subjects in a randomized, placebo-controlled, double-blind study. Subjects were enrolled in 1 of 5 dose cohorts (receiving 250 to 2,000 mg vaborbactam and/or 1,000 to 2,000 mg meropenem) alone or in combination. No subjects discontinued the study due to adverse events (AEs), and no serious AEs were observed. The pharmacokinetics of meropenem and vaborbactam were similar when given alone or in combination; all evaluated plasma PK exposure measures (peak plasma concentration, area under the plasma concentration-time curve [AUC] from time zero to the last measurable concentration area under the plasma concentration-time curve, and AUC from time zero to infinity) were similar for the study drugs alone versus those in combination, indicating no pharmacokinetic interaction between meropenem and vaborbactam. Across all treatments, 47 to 64% of an administered meropenem dose and 75 to 95% of vaborbactam was excreted unchanged in the urine over 48 h postdose. Meropenem and vaborbactam, when given alone or in combination, have similar pharmacokinetic properties, with no plasma or urine PK drug-drug interactions, and are well tolerated. These findings supported further clinical investigation of the combination product. (This study is registered at ClinicalTrials.gov under registration no. NCT01897779.)
Complete Genome Sequences of 44
Arthrobacter
Phages
Authors: Klyczek Karen K. , Jacobs-Sera Deborah , Adair Tamarah L. , Adams Sandra D. , Ball Sarah L. , Benjamin Robert C. , Bonilla J. Alfred , Breitenberger Caroline A. , Daniels Charles J. , Gaffney Bobby L. , Harrison Melinda , Hughes Lee E. , King Rodney A. , Krukonis Gregory P. , Lopez A. Javier , Monsen-Collar Kirsten , Pizzorno Marie C. , Rinehart Claire A. ,   SEA-PHAGES Program,   PHIRE Program, Staples Amanda K. , Stowe Emily L. , Garlena Rebecca A. , Russell Daniel A. , Cresawn Steven G. , Pope Welkin H. , Hatfull Graham F. 
Published: January 2018

ABSTRACT

We report here the complete genome sequences of 44 phages infecting
Arthrobacter
sp. strain ATCC 21022. These phages have double-stranded DNA genomes with sizes ranging from 15,680 to 70,707 bp and G+C contents from 45.1% to 68.5%. All three tail types (belonging to the families
Siphoviridae
,
Myoviridae
, and
Podoviridae
) are represented.
Draft Genome Sequence of the Wine Yeast Strain
Saccharomyces cerevisiae
I-328
Authors: Mardanov Andrey V. , Beletsky Alexey V. , Eldarov Mikhail A. , Tanashchuk Tatiana N. , Kishkovskaya Svetlana A. , Ravin Nikolai V. 
Published: January 2018

ABSTRACT

Saccharomyces cerevisiae
I-328 is a yeast strain used for production of sherry-like wine in Russia. Here we report the draft genome sequence of this strain, which will facilitate comparative genomic studies of yeast strains used for winemaking.
Draft Genome Sequence of
Zhihengliuella
sp. Strain ISTPL4, a Psychrotolerant and Halotolerant Bacterium Isolated from Pangong Lake, India
Authors: Mishra Arti , Jha Gopaljee , Thakur Indu Shekhar 
Published: January 2018

ABSTRACT

Zhihengliuella
sp. strain ISTPL4, a psychrotolerant bacterium, was isolated from brackish water of the high-altitude Pangong Lake in India. In this study, we report its draft genome sequence, which contains 3,529,629 bp with a G+C content of 69.84%. The genome is enriched in genes associated with cold adaptation and plant growth promotion.
Draft Genome Sequences of Two Thermotolerant Cyanobacterial Strains Isolated from Hot Springs
Authors: Mironov Kirill S. , Sinetova Maria A. , Kupriyanova Elena V. , Ustinova Vera V. , Kozlova Anna Y. , Messineva Ekaterina M. , Gabrielyan David A. , Bedbenov Vladimir S. , Zayadan Bolatkhan K. , Los Dmitry A. 
Published: January 2018

ABSTRACT

We report here two draft cyanobacterial genome sequences, those of
Cyanobacterium aponinum
IPPAS B-1201, isolated from a hot spring in the Turgen Gorge (Kazakhstan), and the uncharacterized cyanobacterium IPPAS B
-
1203, isolated from a hot spring in Karlovy Vary (Czech Republic). These two strains were deposited at the Collection of Microalgae (IPPAS) of the Timiryazev Institute of Plant Physiology.
Glucagon-like peptide-1 receptor agonists are not associated with retinal adverse events in the FDA Adverse Event Reporting System
Authors: Fadini Gian Paolo , Sarangdhar Mayur , Avogaro Angelo 
Published: January 2018

ObjectivesGlucagon-like peptide-1 receptor agonists (GLP-1RA) are widely used for the treatment of type 2 diabetes. In large trials, the GLP-1RAs liraglutide and semaglutide improved cardiovascular outcomes, but semaglutide was associated with an increased risk of retinopathy progression. We herein evaluated the association between GLP-1RA and retinal adverse events (AE) in the Food and Drug Administration Adverse Event Reporting System (FAERS).Research design and methodsWe mined the FAERS between 2004q1 and 2017q1 (for a total of 9 217 555 AE reports) to analyze disproportionality and evaluate the association between GLP-1RAs and AEs involving the retina. We compared the frequency of retinal AEs among reports including GLP-1RAs and in those including other glucose-lowering medications (GLMs) as suspect or concomitant drugs.ResultsWe retrieved 114 814 reports involving GLP-1RA and 694 725 reports involving other GLMs as suspect or concomitant drugs. The cumulative frequency of retinal AEs was 2.53/1000 for reports involving GLP-1RA vs 6.62/1000 for reports involving other GLMs, with a proportional reporting ratio of 0.38 (95% CI 0.34 to 0.43; P<0.0001). Reports involving GLP-1RAs listed significantly more comorbid conditions and concomitant medications. Findings were consistent after filtering the diabetes indication irrespective of concomitant GLM, in reports including and in those not including insulin, and for the various GLP-1RAs.ConclusionsIn the FAERS there is no evidence that GLP-1RAs are associated with AEs suggestive of retinopathy progression. Despite more comorbid conditions and concomitant medications, in reports with GLP-1RA the frequency of retinal AEs was significantly lower than in reports with other GLMs.
Tumour risks and genotype–phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD
Authors: Andrews Katrina A , Ascher David B , Pires Douglas Eduardo Valente , Barnes Daniel R , Vialard Lindsey , Casey Ruth T , Bradshaw Nicola , Adlard Julian , Aylwin Simon , Brennan Paul , Brewer Carole , Cole Trevor , Cook Jackie A , Davidson Rosemarie , Donaldson Alan , Fryer Alan , Greenhalgh Lynn , hodgson Shirley V , Irving Richard , Lalloo Fiona , McConachie Michelle , McConnell Vivienne P M , Morrison Patrick J , Murday Victoria , Park Soo-Mi , Simpson Helen L , Snape Katie , Stewart Susan , Tomkins Susan E , Wallis Yvonne , Izatt Louise , Goudie David , Lindsay Robert S , Perry Colin G , Woodward Emma R , Antoniou Antonis C , Maher Eamonn R 
Published: January 2018

BackgroundGermline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype–phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers.MethodsA retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses.ResultsTumour risks analysis provided novel penetrance estimates and genotype–phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%).ConclusionsOverall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype–tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.
Long Noncoding RNA LINC01234 Functions as a Competing Endogenous RNA to Regulate CBFB Expression by Sponging miR-204-5p in Gastric Cancer
Authors: Chen Xin , Chen Zhenyao , Yu Shanxun , Nie Fengqi , Yan Shuai , Ma Pei , Chen Qinnan , Wei Chenchen , Fu Hangjiang , Xu Tianwei , Ren Shengnan , Sun Ming , Wang Zhaoxia 
Published: January 2018

Abstract
Purpose: Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases, including cancers. However, the overall biological roles and clinical significance of most lncRNAs in gastric carcinogenesis are not fully understood. We investigated the clinical significance, biological function, and mechanism of LINC01234 in gastric cancer.
Experimental Design: First, we analyzed LINC01234 alterations in gastric cancerous and noncancerous tissues through an analysis of sequencing data obtained from The Cancer Genome Atlas. Next, we evaluated the effect of LINC01234 on the gastric cancer cell proliferation and apoptosis, and its regulation of miR-204-5p by acting as a competing endogenous RNA (ceRNA). The animal model was used to support the in vitro experimental findings.
Results: We found that LINC01234 expression was significantly upregulated in gastric cancer tissues and was associated with larger tumor size, advanced TNM stage, lymph node metastasis, and shorter survival time. Furthermore, knockdown of LINC01234-induced apoptosis and growth arrest in vitro and inhibited tumorigenesis in mouse xenografts. Mechanistic investigations indicated that LINC01234 functioned as a ceRNA for miR-204-5p, thereby leading to the derepression of its endogenous target core-binding factor β (CBFB).
Conclusions: LINC01234 is significantly overexpressed in gastric cancer, and LINC01234–miR-204-5p–CBFB axis plays a critical role in gastric cancer tumorigenesis. Our findings may provide a potential new target for gastric cancer diagnosis and therapy. Clin Cancer Res; 24(8); 2002–14. ©2018 AACR.