bluuebunny/crossref_metadata_2025_split huggingface dataset:
Definition of Fiducial Points in the Normal Seismocardiogram
Authors: Sørensen Kasper , Schmidt Samuel E. , Jensen Ask S. , Søgaard Peter , Struijk Johannes J. 
Published: October 2018

AbstractThe purpose of this work is to define fiducial points in the seismocardiogram (SCG) and to correlate them with physiological events identified in ultrasound images. For 45 healthy subjects the SCG and the electrocardiogram (ECG) were recorded simultaneously at rest. Immediately following the SCG and ECG recordings ultrasound images of the heart were also obtained at rest. For all subjects a mean SCG signal was calculated and all fiducial points (peaks and valleys) were identified and labeled in the same way across all signals. Eight physiologic events, including the valve openings and closings, were annotated from ultrasound as well and the fiducial points were correlated with those physiologic events. A total of 42 SCG signals were used in the data analysis. The smallest mean differences (±SD) between the eight events found in the ultrasound images and the fiducial points, together with their correlation coefficients (r) were: atrial systolic onset: −2 (±16) ms, r = 0.75 (p < 0.001); peak atrial inflow: 13 (±19) ms, r = 0.63 (p < 0.001); mitral valve closure: 4 (±11) ms, r = 0.71 (p < 0.01); aortic valve opening: −3 (±11) ms, r = 0.60 (p < 0.001); peak systolic outflow: 13 (±23) ms, r = 0.42 (p < 0.01); aortic valve closure: −5 (±12) ms, r = 0.94 (p < 0.001); mitral valve opening: −7 (±19) ms, r = 0.87 (p < 0.001) and peak early ventricular filling: −18 (±28 ms), r = 0.79 (p < 0.001). In conclusion eight physiologic events characterizeing the cardiac cycle, are associated with reproducible, well-defined fiducial points in the SCG.
Plasmid-normalized quantification of relative mitochondrial DNA copy number
Authors: Fazzini Federica , Schöpf Bernd , Blatzer Michael , Coassin Stefan , Hicks Andrew A. , Kronenberg Florian , Fendt Liane 
Published: October 2018

AbstractAlterations of mitochondrial DNA (mtDNA) copy number have been associated with a wide variety of phenotypes and diseases. Unfortunately, the literature provides scarce methodical information about duplex targeting of nuclear and mtDNA that meets the quality criteria for qPCR. Therefore, we established a method for mtDNA copy number quantification using a quantitative PCR assay that allows for simultaneous targeting of a single copy nuclear gene (beta-2-microglobulin) and the t-RNALeu gene on the mtDNA. We include a plasmid containing both targets in order to normalize against differences in emission intensities of the fluorescent dyes Yakima Yellow and FAM. Applying the plasmid calibrator on an internal control reduced the intra-assay variability from 21% (uncorrected) to 7% (plasmid-corrected). Moreover, we noted that DNA samples isolated with different methods revealed different numbers of mtDNA copies, thus highlighting an important influence of the pre-analytical procedures. In summary, we developed a precise assay for mitochondrial copy number detection relative to nuclear DNA. Our method is applicable to comparative mitochondrial DNA copy number studies since the use of the dual insert plasmid allows correcting for the unequal emission intensities of the different fluorescent labels of the two targets.
In-season performance of European Union wheat forecasts during extreme impacts
Authors: van der Velde M. , Baruth B. , Bussay A. , Ceglar A. , Garcia Condado S. , Karetsos S. , Lecerf R. , Lopez R. , Maiorano A. , Nisini L. , Seguini L. , van den Berg M. 
Published: October 2018

AbstractHere we assess the quality and in-season development of European wheat (Triticum spp.) yield forecasts during low, medium, and high-yielding years. 440 forecasts were evaluated for 75 wheat forecast years from 1993–2013 for 25 European Union (EU) Member States. By July, years with median yields were accurately forecast with errors below ~2%. Yield forecasts in years with low yields were overestimated by ~10%, while yield forecasts in high-yielding years were underestimated by ~8%. Four-fifths of the lowest yields had a drought or hot driver, a third a wet driver, while a quarter had both. Forecast accuracy of high-yielding years improved gradually during the season, and drought-driven yield reductions were anticipated with lead times of ~2 months. Single, contrasting successive in-season, as well as spatially distant dry and wet extreme synoptic weather systems affected multiple-countries in 2003, ’06, ’07, ’11 and 12’, leading to wheat losses up to 8.1 Mt (>40% of total EU loss). In these years, June forecasts (~ 1-month lead-time) underestimated these impacts by 10.4 to 78.4%. To cope with increasingly unprecedented impacts, near-real-time information fusion needs to underpin operational crop yield forecasting to benefit from improved crop modelling, more detailed and frequent earth observations, and faster computation.
MicroRNA induction by copy number gain is associated with poor outcome in squamous cell carcinoma of the lung
Authors: Xia Endi , Kanematsu Sotaro , Suenaga Yusuke , Elzawahry Asmaa , Kondo Hitomi , Otsuka Noriko , Moriya Yasumitsu , Iizasa Toshihiko , Kato Mamoru , Yoshino Ichiro , Yokoi Sana 
Published: October 2018

AbstractCopy number gains in cancer genomes have been shown to induce oncogene expression and promote carcinogenesis; however, their role in regulating oncogenic microRNAs (onco-miRNAs) remains largely unknown. Our aim was to identify onco-miRNAs induced by copy number gains in human squamous cell carcinoma (Sq) of the lung. We performed a genome-wide screen of onco-miRNAs from 245 Sqs using data sets from RNA-sequencing, comparative genomic hybridization, and the corresponding clinical information from The Cancer Genome Atlas. Among 1001 miRNAs expressed in the samples, 231 were correlated with copy number alternations, with only 11 of these being highly expressed in Sq compared to adenocarcinoma and normal tissues. Notably, miR-296-5p, miR-324-3p, and miR-3928-3p expression was significantly associated with poor prognosis. Multivariate analysis using the Cox proportional hazards model showed that miRNA expression and smoking were independent prognostic factors and were associated with poor prognosis. Furthermore, the three onco-miRNAs inhibited FAM46C to induce MYC expression, promoting proliferation of Sq cells. We found that copy number gains in Sq of the lung induce onco-miRNA expression that is associated with poor prognosis.
Variants in the 14q32 miRNA cluster are associated with osteosarcoma risk in the Spanish population
Authors: Martin-Guerrero Idoia , Bilbao-Aldaiturriaga Nerea , Gutierrez-Camino Angela , Santos-Zorrozua Borja , Dolžan Vita , Patiño-Garcia Ana , Garcia-Orad Africa 
Published: October 2018

AbstractAssociation studies in osteosarcoma risk found significant results in intergenic regions, suggesting that regions which do not codify for proteins could play an important role. The deregulation of microRNAs (miRNAs) has been already associated with osteosarcoma. Consequently, genetic variants affecting miRNA function could be associated with risk. This study aimed to evaluate the involvement of all genetic variants in pre-miRNAs described so far in relationship to the risk of osteosarcoma. We analyzed a total of 213 genetic variants in 206 pre-miRNAs in two cohorts of osteosarcoma patients (n = 100) and their corresponding controls (n = 256) from Spanish and Slovenian populations, using Goldengate Veracode technology (Illumina). Four polymorphisms in pre-miRNAs at 14q32 miRNA cluster were associated with osteosarcoma risk in the Spanish population (rs12894467, rs61992671, rs58834075 and rs12879262). Pathway enrichment analysis including target genes of these miRNAs pointed out the WNT signaling pathways overrepresented. Moreover, different single nucleotide polymorphism (SNP) effects between the two populations included were observed, suggesting the existence of population differences. In conclusion, 14q32 miRNA cluster seems to be a hotspot for osteosarcoma susceptibility in the Spanish population, but not in the Slovenian, which supports the idea of the existence of population differences in developing this disease.
Genetic enhancement of Ras-ERK pathway does not aggravate L-DOPA-induced dyskinesia in mice but prevents the decrease induced by lovastatin
Authors: Ruiz-DeDiego Irene , Fasano Stefania , Solís Oscar , Garcia-Montes José-Rubén , Brea José , Loza María I. , Brambilla Riccardo , Moratalla Rosario 
Published: October 2018

AbstractIncreasing evidence supports a close relationship between Ras-ERK1/2 activation in the striatum and L-DOPA-induced dyskinesia (LID). ERK1/2 activation by L-DOPA takes place through the crosstalk between D1R/AC/PKA/DARPP-32 pathway and NMDA/Ras pathway. Compelling genetic and pharmacological evidence indicates that Ras-ERK1/2 inhibition prevents LID onset and may even revert already established dyskinetic symptoms. However, it is currently unclear whether exacerbation of Ras-ERK1/2 activity in the striatum may further aggravate dyskinesia in experimental animal models. Here we took advantage of two genetic models in which Ras-ERK1/2 signaling is hyperactivated, the Nf1+/− mice, in which the Ras inhibitor neurofibromin is reduced, and the Ras-GRF1 overexpressing (Ras-GRF1 OE) transgenic mice in which a specific neuronal activator of Ras is enhanced. Nf1+/− and Ras-GRF1 OE mice were unilaterally lesioned with 6-OHDA and treated with an escalating L-DOPA dosing regimen. In addition, a subset of Nf1+/− hemi-parkinsonian animals was also co-treated with the Ras inhibitor lovastatin. Our results revealed that Nf1+/− and Ras-GRF1 OE mice displayed similar dyskinetic symptoms to their wild-type counterparts. This observation was confirmed by the lack of differences between mutant and wild-type mice in striatal molecular changes associated to LID (i.e., FosB, and pERK1/2 expression). Interestingly, attenuation of Ras activity with lovastatin does not weaken dyskinetic symptoms in Nf1+/− mice. Altogether, these data suggest that ERK1/2-signaling activation in dyskinetic animals is maximal and does not require further genetic enhancement in the upstream Ras pathway. However, our data also demonstrate that such a genetic enhancement may reduce the efficacy of anti-dyskinetic drugs like lovastatin.
A Real-Time PCR based assay for determining parasite to host ratio and parasitaemia in the clinical samples of Bovine Theileriosis
Authors: Dandasena Debabrata , Bhandari Vasundhra , Sreenivasamurthy G. S. , Murthy Shweta , Roy Sonti , Bhanot Vandna , Arora Jaspreet Singh , Singh Satparkash , Sharma Paresh 
Published: October 2018

AbstractTheileria annulatais an intracellular parasite that causes active and latent forms of bovine theileriosis. Diagnosis of the disease is primarily based on traditional methods such as microscopy, however, PCR based methods have proven to be superior in the absence of clear disease symptoms. However, diagnosis is difficult in cases of lower parasitaemia by conventional PCR. Hence, a rapid and sensitive method which can detect early infection and low parasite load is required. Therefore, we have developed an absolute quantification based real-time PCR (qPCR) assay. Reference standard curve using recombinant plasmids of a host (hprt) and a parasite gene (tasp) was constructed, and the assay was initially standardised usingin vitro T. annulatacell lines. Further, 414 blood samples from suspected theileriosis cases were also evaluated using qPCR. The assay can estimate host to parasite ratios, calculate parasitaemia and treatment effectiveness in the clinical cases of theileriosis. In comparison with the conventional PCR results, 44 additional positive cases were found. Therefore, the assay holds importance in a clinical setting due to its ability to quantify the parasite load in clinical samples. It may be further used in distinguishing active and latent theileriosis infections and detection of drug resistance in the field.
Integrating standardized whole genome sequence analysis with a global Mycobacterium tuberculosis antibiotic resistance knowledgebase
Authors: Ezewudo Matthew , Borens Amanda , Chiner-Oms Álvaro , Miotto Paolo , Chindelevitch Leonid , Starks Angela M. , Hanna Debra , Liwski Richard , Zignol Matteo , Gilpin Christopher , Niemann Stefan , Kohl Thomas Andreas , Warren Robin M. , Crook Derrick , Gagneux Sebastien , Hoffner Sven , Rodrigues Camilla , Comas Iñaki , Engelthaler David M. , Alland David , Rigouts Leen , Lange Christoph , Dheda Keertan , Hasan Rumina , McNerney Ruth , Cirillo Daniela M. , Schito Marco , Rodwell Timothy C. , Posey James 
Published: October 2018

AbstractDrug-resistant tuberculosis poses a persistent public health threat. The ReSeqTB platform is a collaborative, curated knowledgebase, designed to standardize and aggregate global Mycobacterium tuberculosis complex (MTBC) variant data from whole genome sequencing (WGS) with phenotypic drug susceptibility testing (DST) and clinical data. We developed a unified analysis variant pipeline (UVP) (https://github.com/CPTR-ReSeqTB/UVP) to identify variants and assign lineage from MTBC sequence data. Stringent thresholds and quality control measures were incorporated in this open source tool. The pipeline was validated using a well-characterized dataset of 90 diverse MTBC isolates with conventional DST and DNA Sanger sequencing data. The UVP exhibited 98.9% agreement with the variants identified using Sanger sequencing and was 100% concordant with conventional methods of assigning lineage. We analyzed 4636 publicly available MTBC isolates in the ReSeqTB platform representing all seven major MTBC lineages. The variants detected have an above 94% accuracy of predicting drug based on the accompanying DST results in the platform. The aggregation of variants over time in the platform will establish confidence-graded mutations statistically associated with phenotypic drug resistance. These tools serve as critical reference standards for future molecular diagnostic assay developers, researchers, public health agencies and clinicians working towards the control of drug-resistant tuberculosis.
smarce1 mutants have a defective endocardium and an increased expression of cardiac transcription factors in zebrafish
Authors: Castillo-Robles Jorge , Ramírez Laura , Spaink Herman P. , Lomelí Hilda 
Published: October 2018

AbstractSWI/SNF or BAF chromatin-remodeling complexes are polymorphic assemblies of homologous subunit families that remodel nucleosomes and facilitate tissue-specific gene regulation during development. BAF57/SMARCE1 is a BAF complex subunit encoded in animals by a single gene and is a component of all mammalian BAF complexes. In vivo, the loss of SMARCE1 would lead to the formation of deficient combinations of the complex which might present limited remodeling activities. To address the specific contribution of SMARCE1 to the function of the BAF complex, we generated CRISPR/Cas9 mutations of smarce1 in zebrafish. Smarce1 mutants showed visible defects at 72 hpf, including smaller eyes, abnormal body curvature and heart abnormalities. Gene expression analysis revealed that the mutant embryos displayed defects in endocardial development since early stages, which led to the formation of a misshapen heart tube. The severe morphological and functional cardiac problems observed at 4 dpf were correlated with the substantially increased expression of different cardiac transcription factors. Additionally, we showed that Smarce1 binds to cis-regulatory regions of the gata5 gene and is necessary for the recruitment of the BAF complex to these regions.
Stem cell enriched-epithelial spheroid cultures for rapidly assaying small intestinal radioprotectors and radiosensitizers in vitro
Authors: de la Cruz Bonilla Marimar , Stemler Kristina M. , Taniguchi Cullen M. , Piwnica-Worms Helen 
Published: October 2018

AbstractRadiation therapy is one of the main treatment options for many cancer patients. Although high doses of radiation may maximize tumor cell killing, dose escalation is limited by toxicity to neighboring normal tissues. This limitation applies particularly to the small intestine, the second most radiosensitive organ in the body. Identifying small intestinal (SI) radioprotectors could enable dose escalation in the treatment of abdominopelvic malignancies. However, the only assay currently available to identify effects of radiomodulating drugs on the regenerating capacity of SI stem cells is the Withers-Elkind microcolony assay, which requires large numbers of mice, making it a costly and low throughput method. Here, we describe a novel spheroid formation assay (SFA) that utilizes SI stem cell-enriched three-dimensional epithelial spheroid cultures to identify gastrointestinal radiomodulators ex vivo. The SFA is scalable for high throughput screening and can be used to identify both radioprotectors and radiosensitizers.
Genetic diversities and phylogenetic analyses of three Chinese main ethnic groups in southwest China: A Y-Chromosomal STR study
Authors: Chen Pengyu , He Guanglin , Zou Xing , Zhang Xin , Li Jida , Wang Zhisong , Gao Hongyan , Luo Li , Zhang Zhongqing , Yu Jian , Han Yanyan 
Published: October 2018

AbstractShort tandem repeats (STRs) located on the Y chromosome with the properties of male-specific inheritance and haploidy are widely used in forensics to analyze paternal genealogies and match male trace donors to evidence. Besides, Y-chromosomal haplotypes play an important role in providing breathtaking insights into population genetic history. However, the genetic diversity and forensic characteristics of Y-STRs in Guizhou main ethnic groups (Hans, Miaos and Bouyeis) remain uncharacterized. Here, we obtained Y-chromosomal 23-marker haplotypes in three Guizhou populations and submitted the first batch of Y-STR haplotype data to the YHRD. The HD in the aforementioned three populations are 0.99990, 0.99983, and 0.99979, respectively, and DC values are 0.9902, 0.9908, and 0.97959, respectively. Subsequently, genetic differentiation between our newly studied populations and reference groups along ethnic/administrative divisions, as well as national/continental boundaries were investigated via AMOVA, MDS, and phylogenetic relationship reconstruction. Significant genetic differentiations from our subjects and other groups are identified in ethnically, linguistically and geographically diverse populations, including most prominently Tibetans and Uyghurs among 30 mainland Chinese populations, Taiwanese groups and others among 58 Asian populations, as well as African groups and others among 89 worldwide populations. Qiannan Bouyei has a close genetic relationship with Guangxi Zhuang, and Zunyi Han and Qiandongnan Miao have close genetic affinity with Hunan Han and Guizhou Shui, respectively. Collectively, this new-generation Y-STR amplification system can be used as a supplementary tool in forensic identification and male parentage testing and even pedigree search.
The pathogenic mechanisms of Tilletia horrida as revealed by comparative and functional genomics
Authors: Wang Aijun , Pang Linxiu , Wang Na , Ai Peng , Yin Desuo , Li Shuangcheng , Deng Qiming , Zhu Jun , Liang Yueyang , Zhu Jianqing , Li Ping , Zheng Aiping 
Published: October 2018

AbstractTilletia horrida is a soil-borne, mononucleate basidiomycete fungus with a biotrophic lifestyle that causes rice kernel smut, a disease that is distributed throughout hybrid rice growing areas worldwide. Here we report on the high-quality genome sequence of T. horrida; it is composed of 23.2 Mb that encode 7,729 predicted genes and 6,973 genes supported by RNA-seq. The genome contains few repetitive elements that account for 8.45% of the total. Evolutionarily, T. horrida lies close to the Ustilago fungi, suggesting grass species as potential hosts, but co-linearity was not observed between T. horrida and the barley smut Ustilago hordei. Genes and functions relevant to pathogenicity were presumed. T. horrida possesses a smaller set of carbohydrate-active enzymes and secondary metabolites, which probably reflect the specific characteristics of its infection and biotrophic lifestyle. Genes that encode secreted proteins and enzymes of secondary metabolism, and genes that are represented in the pathogen-host interaction gene database genes, are highly expressed during early infection; this is consistent with their potential roles in pathogenicity. Furthermore, among the 131 candidate pathogen effectors identified according to their expression patterns and functionality, we validated two that trigger leaf cell death in Nicotiana benthamiana. In summary, we have revealed new molecular mechanisms involved in the evolution, biotrophy, and pathogenesis of T. horrida.
Intra- and inter-protein couplings of backbone motions underlie protein thiol-disulfide exchange cascade
Authors: Zhang Wenbo , Niu Xiaogang , Ding Jienv , Hu Yunfei , Jin Changwen 
Published: October 2018

AbstractThe thioredoxin (Trx)-coupled arsenate reductase (ArsC) is a family of enzymes that catalyzes the reduction of arsenate to arsenite in the arsenic detoxification pathway. The catalytic cycle involves a series of relayed intramolecular and intermolecular thiol-disulfide exchange reactions. Structures at different reaction stages have been determined, suggesting significant conformational fluctuations along the reaction pathway. Herein, we use two state-of-the-art NMR methods, the chemical exchange saturation transfer (CEST) and the CPMG-based relaxation dispersion (CPMG RD) experiments, to probe the conformational dynamics of B. subtilis ArsC in all reaction stages, namely the enzymatic active reduced state, the intra-molecular C10–C82 disulfide-bonded intermediate state, the inactive oxidized state, and the inter-molecular disulfide-bonded protein complex with Trx. Our results reveal highly rugged energy landscapes in the active reduced state, and suggest global collective motions in both the C10–C82 disulfide-bonded intermediate and the mixed-disulfide Trx-ArsC complex.
Dual Inhibition of Bcl-2/Bcl-xL and XPO1 is synthetically lethal in glioblastoma model systems
Authors: Shang Enyuan , Zhang Yiru , Shu Chang , Ishida Chiaki Tsuge , Bianchetti Elena , Westhoff Mike-Andrew , Karpel-Massler Georg , Siegelin Markus D. 
Published: October 2018

AbstractXPO1 has recently emerged as a viable treatment target for solid malignancies, including glioblastoma (GBM), the most common primary malignant brain tumor in adults. However, given that tumors become commonly resistant to single treatments, the identification of combination therapies is critical. Therefore, we tested the hypothesis that inhibition of anti-apoptotic Bcl-2 family members and XPO1 are synthetically lethal. To this purpose, two clinically validated drug compounds, the BH3-mimetic, ABT263, and the XPO1 inhibitor, Selinexor, were used in preclinical GBM model systems. Our results show that inhibition of XPO1 reduces cellular viability in glioblastoma cell cultures. Moreover, addition of ABT263 significantly enhances the efficacy of XPO1 inhibition on the reduction of cellular viability, which occurs in a synergistic manner. While selinexor inhibits the proliferation of glioblastoma cells, the combination treatment of ABT263 and selinexor results in substantial induction of cell death, which is accompanied by activation of effector- initiator caspases and cleavage of PARP. Mechanistically we find that XPO1 inhibition results in down-regulation of anti-apoptotic Mcl-1 and attenuates ABT263 driven Mcl-1 up-regulation. Consistently, siRNA mediated silencing of Mcl-1 sensitizes for ABT263 mediated cell death and partially for the combination treatment. By using a human patient-derived xenograft model of glioblastoma in mice, we demonstrate that the combination treatment of ABT263 and Selinexor reduces tumor growth significantly more than each compound alone. Collectively, these results suggest that inhibition of XPO1 and Bcl-2/Bcl-xL might be a potential strategy for the treatment of malignant glial tumors.