bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of long repeat expansions from PCR-free whole-genome sequence data
Authors: Dolzhenko Egor , van Vugt Joke J.F.A. , Shaw Richard J. , Bekritsky Mitchell A. , van Blitterswijk Marka , Narzisi Giuseppe , Ajay Subramanian S. , Rajan Vani , Kingsbury Zoya , Humphray Sean J. , Schellevis Raymond D. , Brands William J. , Baker Matt , Rademakers Rosa , Kooyman Maarten , Tazelaar Gijs H.P. , van Es Michael A. , McLaughlin Russell , Sproviero William , Shatunov Aleksey , Jones Ashley , Al Khleifat Ahmad , Pittman Alan , Morgan Sarah , Hardiman Orla , Al-Chalabi Ammar , Shaw Chris , Smith Bradley , Neo Edmund J. , Morrison Karen , Shaw Pamela J. , Reeves Catherine , Winterkorn Lara , Wexler Nancy S. ,   The US-Venezuela Collaborative Research Group, Housman David E. , Ng Christopher , Li Alina , Taft Ryan J. , van den Berg Leonard H. , Bentley David R. , Veldink Jan H. , Eberle Michael A. 
Published: December 2016

AbstractIdentifying large repeat expansions such as those that cause amyotrophic lateral sclerosis (ALS) and Fragile X syndrome is challenging for short-read (100-150 bp) whole genome sequencing (WGS) data. A solution to this problem is an important step towards integrating WGS into precision medicine. We have developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3,001 ALS patients who have been tested for the presence of theC9orf72repeat expansion with repeat-primed PCR (RP-PCR). Taking the RP-PCR calls as the ground truth, our WGS-based method identified pathogenic repeat expansions with 98.1% sensitivity and 99.7% specificity. Further inspection identified that all 11 conflicts were resolved as errors in the original RP-PCR results. Compared against this updated result, ExpansionHunter correctly classified all (212/212) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2,786/2,789) of the wild type samples were correctly classified as wild type by this method with the remaining two identified as possible expansions. We further applied our algorithm to a set of 144 samples where every sample had one of eight different pathogenic repeat expansions including examples associated with fragile X syndrome, Friedreich’s ataxia and Huntington’s disease and correctly flagged all of the known repeat expansions. Finally, we tested the accuracy of our method for short repeats by comparing our genotypes with results from 860 samples sized using fragment length analysis and determined that our calls were >95% accurate. ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.
Silversword and lobeliad reintroduction linked to landscape restoration on Mauna Loa and Kīlauea, and its implications for plant adaptive radiation in Hawaiʻi
Authors: Robichaux Robert H. , Moriyasu Patrice Y. , Enoka Jaime H. , McDaniel Sierra , Loh Rhonda K. , Bio Kealiʻi F. , Bakutis Ane , Tunison J. Timothy , Bergfeld Steven T. , Perry J. Lyman , Warshauer Frederick R. , Wasser Mark , Cole T. Colleen , Agorastos Nicholas R. , Cole Ian W. , Camara J. Kualiʻi , Rubenstein Tanya , Whitehead A. Nāmaka , VanDeMark Joshua R. , Loo Reid , Bruegmann Marie M. 
Published: December 2016

AbstractThe endemic Hawaiian silversword and lobeliad lineages, which are two of the world’s premier examples of plant adaptive radiation, exemplify the severity of the threats confronting the Hawaiian flora, especially the threats posed by alien species. We have implemented collaborative reintroduction efforts with the endangered Kaʻū silversword (Argyroxiphium kauense) and Pele lobeliad (Clermontiapeleana)in Hawaiʻi Volcanoes National Park. The efforts with the Kaʻū silversword have involved rediscovery, helicopter assisted rescue of diminutive remnant founders, managed breeding, outplanting at two sites in the Park of more than 21,000 seedlings deriving from 169 founders, and facilitated achene dispersal following flowering. The efforts with the Pele lobeliad have involved rediscovery, air-layering of remnant founders while suspended on climbing ropes, managed breeding, and outplanting at two sites in the Park of more than 1,000 seedlings (to date) deriving from six of the seven known founders. We have linked the reintroduction efforts to landscape restoration at large scales in the Park and in adjacent State and private lands, thereby increasing the opportunities for substantial population growth and expansion of the Kaʻū silversword and Pele lobeliad in the future. Additionally, we have extended the reintroduction efforts, including the link to landscape restoration, to encompass all other endangered silversword and lobeliad taxa occurring historically on the eastern slopes of Mauna Loa or on Kīlauea. In so doing, we seek to restore the possibility of adaptive radiation of the silversword and lobeliad lineages going forward, especially on the youngest and most geologically active, and thus perhaps most evolutionarily dynamic, part of the Hawaiian archipelago.DedicationThis paper celebrates the centennial of Hawaiʻi Volcanoes National Park, which was founded in August 1916.
Environmental exposure does not explain putative maladaptation in road-adjacent populations
Authors: Brady Steven P. 
Published: December 2016

AbstractWhile the ecological consequences of roads are well described, little is known of their role as agents of natural selection, which can shape adaptive and maladaptive responses in populations influenced by roads. This is despite a growing appreciation for the influence of evolution in human-altered environments. There, insights indicate that natural selection typically results in local adaptation. Thus populations influenced by road-induced selection should evolve fitness advantages in their local environment. Contrary to this expectation, wood frog tadpoles from roadside populations show evidence of a fitness disadvantage, consistent with local maladaptation. Specifically, in reciprocal transplants, roadside populations survive at lower rates compared to populations away from roads. A key question remaining is whether roadside environmental conditions experienced by early-stage embryos induce this outcome. This represents an important missing piece in evaluating the evolutionary nature of this maladaptation pattern. Here, I address this gap using a reciprocal transplant experiment designed to test the hypothesis that embryonic exposure to roadside pond water induces a survival disadvantage. Contrary to this hypothesis, my results show that reduced survival persists when embryonic exposure is controlled. This indicates that the survival disadvantage is parentally mediated, either genetically and/or through inherited environmental effects. This result suggests that roadside populations are either truly maladapted or potentially locally adapted at later life stages. I discuss these interpretations, noting that regardless of mechanism, patterns consistent with maladaptation have important implications for conservation. In light of the pervasiveness of roads, further resolution explaining maladaptive responses remains a critical challenge in conservation.
Fetal therapy model of myelomeningocele with three-dimensional skin using amniotic fluid cell-derived induced pluripotent stem cells
Authors: Kajiwara Kazuhiro , Tanemoto Tomohiro , Wada Seiji , Karibe Jurii , Ihara Norimasa , Ikemoto Yu , Kawasaki Tomoyuki , Ohishi Yoshie , Samura Osamu , Okamura Kohji , Takada Shuji , Akutsu Hidenori , Sago Haruhiko , Okamoto Aikou , Umezawa Akihiro 
Published: December 2016

AbstractMyelomeningocele (MMC) is a congenital disease without genetic abnormalities. Neurological symptoms are irreversibly impaired after birth. No effective treatment has been reported to date. Only surgical repairs have reported so far. In this study, we performed antenatal treatment of MMC with an artificial skin using induced pluripotent stem cells (iPSCs) generated from a patient with Down syndrome (AF-T21-iPSCs) and twin–twin transfusion syndrome (AF-TTTS-iPSCs) to a rat model. We manufactured three-dimensional skin with epidermis generated from keratinocytes derived from AF-T21-iPSCs and AF-TTTS-iPSCs and dermis of human fibroblasts and collagen type I. For generation of epidermis, we developed a novel protocol using Y-27632 and epidermal growth factor. The artificial skin was successfully covered over MMC defect sites during pregnancy, implying a possible antenatal surgical treatment with iPSC technology.
Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease
Authors: Baillie J. Kenneth , Bretherick Andrew , Haley Christopher S. , Clohisey Sara , Gray Alan , Barret Jeffrey , Stahl Eli A. , Tenesa Albert , Andersson Robin , Brown J. Ben , Faulkner Geoffrey J. , Lizio Marina , Schaefer Ulf , Daub Carsten , Itoh Masayoshi , Kondo Naoto , Lassmann Timo , Kawai Jun ,   IIBDGC Consortium,   FANTOM5 Consortium, Bajic Vladimir B. , Heutink Peter , Rehli Michael , Kawaji Hideya , Sandelin Albin , Suzuki Harukazu , Satsangi Jack , Wells Christine A. , Hacohen Nir , Freeman Thomas C , Hayashizaki Yoshihide , Carninci Piero , Forrest Alistair R.R. , Hume David A. 
Published: December 2016

AbstractGenetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share patterns of transcriptional regulation. Accordingly, shared transcriptional regulation (coexpression) may help prioritise loci associated with a given trait, and help to identify the biological processes underlying it. Using cap analysis of gene expression (CAGE) profiles of promoter and enhancer-derived RNAs across 1824 human samples, we have quantified coexpression of RNAs originating from trait-associated regulatory regions using a novel analytical method (network density analysis; NDA). For most traits studied, sequence variants in regulatory regions were linked to tightly coexpressed networks that are likely to share important functional characteristics. These networks implicate particular cell types and tissues in disease pathogenesis; for example, variants associated with ulcerative colitis are linked to expression in gut tissue, whereas Crohn’s disease variants are restricted to immune cells. We show that this coexpression signal provides additional independent information for fine mapping likely causative variants. This approach identifies additional genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. This approach enables a deeper biological understanding of the causal basis of complex traits.ONE SENTENCE SUMMARYWe discover that variants associated with a specific disease share expression profiles across tissues and cell types, enabling fine mapping and identification of new disease-associated variants, illuminating key cell types involved in disease pathogenesis.
Incidental identification of maternal malignancies in two Asian women underwent noninvasive prenatal test
Authors: Ji Xing , Chen Fang , Zhou Yafeng , Li Jia , Yuan Yuying , Mo Yu , Liu Qiang , Tseng Jen-Yu , Lin Diego Shih-Chieh , Shen Shu-Huei , Liu Yu , Ye Weiping , Zhang Hongyun , Liu Na , Shen Li , Jin Xin , Sung Pi-Lin , Mao Mao 
Published: December 2016

AbstractNoninvasive prenatal test (NIPT) has been widely used as a screening test for trisomy 13, 18 and 21 worldwide. Recently, coexistence of maternal malignancy and pregnancy has drawn increasing attention in NIPT studies. Malignancy in pregnant women potentially affected NIPT results, which may cause false positive results or failed tests. However, no such case has ever been reported in Asian population. In this study, for the first time, we reported a stage III dysgerminoma and advanced gastric cancer during pregnancy accidentally identified during NIPT tests. These two women showed aberrant chromosome aneuploidies in NIPT results and concordant pattern of genome disruption found in tumor samples. The findings in this study further validate the effect of maternal malignancy on NIPT results and strengthen the possibility of detecting malignant tumors through NIPT in the future.
In situestimates of iron-oxidation and accretion rates for iron-oxidizing bacterial mats at Lō’ihi Seamount
Authors: Emerson David , Scott Jarrod J. , Leavitt Anna , Fleming Emily , Moyer Craig 
Published: December 2016

AbstractIt is increasingly recognized that diffuse, hydrothermal venting is an important source of iron to the deep-sea that can influence oceanic iron dynamics and abundance. Lithotrophic Fe-oxidizing bacteria (FeOB) are dominant at diffuse hydrothermal vent sites, producing microbial iron mats that are often centimeters or more thick. At present, little is known aboutin situFe-oxidation rates, or accretion rates for iron mats. Anin situproductivity chamber was developed that took advantage of the unique mineral morphotypes produced by FeOB to estimate rates of Fe-oxidation and accretion. Chambers were placed at two diffuse vents (1179 and 1300 mbsl) at Lō’ihi Seamount where they were colonized by FeOB for different amounts of time. From this analysis, it was estimated that Fe-oxidation rates could range from 8.2–51.9 × 10−6mol · hr−1, and that iron mats could accrete at around 2.2 cm · yr−1. Molecular analysis indicated that the relative abundance of Zetaproteobacteria, a group of known FeOB, accounted for 80–90% of the bacteria colonizing the chambers. There was a distinct difference between populations at the 1179m site (Pohaku), and the 1300m site (North Hiolo Ridge). Microscope slides placed within the productivity chambers were colonized by different morphotypes of FeOB. The cells responsible for one common morphotype that produces a Y-shaped filament were identified as Zetaproteobacteria by use of a small subunit rRNA probe. This work confirms the importance of FeOB in the formation of chemosynthetic iron mats, and provides the first estimates forin situFe-oxidation rates and mat accretion rates.HighlightsAnin-situproductivity chamber was developed to estimate rates of Fe-oxidation and understand colonization patterns at chemosynthetic iron mats at Lō’ihi Seamount.Fe-oxidation rates ranged from 8.2–51.9 × 10−6mol ˙ hr−1, and it was estimated that the iron mats could accrete at around 2.2 cm ˙ yr−1.The iron mat community was dominated by Zetaproteobacteria, whose relative abundance accounted for up to 89% of the microbial community.The community membership that grew during short-term incubations reflected the community composition of nearby microbial mats.
Malate-dependent Fe accumulation is a critical checkpoint in the root developmental response to low phosphate
Authors: Mora-Macías Javier , Ojeda-Rivera Jonathan Odilón , Gutiérrez-Alanís Dolores , Yong-Villalobos Lenin , Oropeza-Aburto Araceli , Raya González Javier , Jiménez-Domínguez Gabriel , Chávez-Calvillo Gabriela , Rellán-Álvarez Rubén , Herrera-Estrella Luis 
Published: December 2016

AbstractLow phosphate (Pi) availability constrains plant development and crop production in both natural and agricultural ecosystems. When Pi is scarce, modifications of root system architecture (RSA) enhance soil exploration ability and can lead to an increase in Pi uptake. InArabidopsis, an iron-dependent determinate developmental program that induces premature differentiation in the root apical meristem (RAM) begins when the root tip contacts low Pi media, resulting in a short-root phenotype. However, the mechanisms that enable the regulation of root growth in response to Pi-limiting conditions remain largely unknown. Cellular, genomic and transcriptomic analysis of low-Pi insensitive mutants revealed that the malate-exudation related genesSENSITIVE TO PROTON RHIZOTOXICITY(STOP1) andALUMINUM ACTIVATED MALATE TRANSPORTER 1(ALMT1) represent a critical checkpoint in the root developmental response to Pi starvation inArabidopsis thaliana.
Hardy Weinberg Exact Test In Large Scale Variant Calling Quality Control
Authors: Huang Zhuoyi , Rustagi Navin , Zhi Degui , Cupples L. Adrienne , Gibbs Richard , Boerwinkle Eric , Yu Fuli 
Published: December 2016

AbstractHardy Weinberg Equilibrium (HWE) test is widely used as a quality control measure to detect sequencing artifacts like mismapping, allelic dropout and biases. However, in the high throughput sequencing era, where the sample size is beyond a thousand scale, the utility of HWE test in reducing the false positive rate remains unclear. In this paper, we demonstrate that HWE test has limited power in identifying sequencing artifacts when the variant allele frequency is lower than 1% in a variant call set produced from more than five thousand whole genome sequenced samples from two homogeneous populations. We develop a novel strategy of implementing HWE filtering in which we incorporate site frequency spectrum information and determine the p-value cutoff which optimizes the tradeoff between sensitivity and specificity. The novel strategy is shown to outperform the exact test of HWE with an empirical constant p-value cutoff regardless of the sequencing sample size. We also present best practice recommendations for identifying possible sources of false positives from large sequencing datasets based on an analysis of intrinsic biases in the variant calling process. Our novel strategy of determining the HWE test p-value cutoff and applying the test to the common variants provides a practical approach for the variant level quality controls in the upcoming sequencing projects with tens to hundreds of thousand of samples.
Pravastatin attenuates the action of the ETS domain‐containing protein ELK1 to prevent atherosclerosis in apolipoprotein E‐knockout mice via modulation of extracellular signal‐regulated kinase 1/2 signal pathway
Authors: Yan Wei , Li Dan , Zhou Xiaoxu 
Published: December 2016

SummaryOxidative stress plays an important role in atherosclerosis, a vascular disease with high morbidity and mortality. The ETS domain‐containing protein ELK1 is an oxidative stress‐sensitive factor modulated by the extracellular signal‐regulated kinase (ERK) 1/2 pathway. However, the role of ELK1 in the prevention of atherosclerosis by pravastatin remains unclear. In the present study, male apolipoprotein E‐knockout (apoE−/−) mice fed a diet containing 1.25% cholesterol (w/w) were divided into two groups, one treated with pravastatin (80 mg/kg, 2‐2.4 mg/mouse per day) for 8 weeks and the other not. Male C57BL/6J mice fed with a normal diet were used as a control group. Human umbilical vein endothelial cells (HUVEC) were cultured and treated with pravastatin (10 μmol/L) for 18 hours before testing for the presence or absence of 100 μmol/L H2O2 (24 hours). Examination of pathological sections from mice aortas revealed that pravastatin treatment almost prevented atherosclerotic plaque formation. Pravastatin also inhibited increases in serum and aortic levels of oxidized low‐density lipoprotein and aortic malondialdehyde levels and decreases in aortic reduced glutathione, and the activities of superoxide dismutase, catalase and glutathione peroxidase. H2O2‐induced increases in reactive oxygen species in HUVECs were reversed by pravastatin by 48%. Pravastatin blocked the phosphorylation of ELK1 and ERK1/2 proteins and reduced mRNA levels of early growth response 1, a known atherogenic transcription factor upregulated by the ROS/ERK/ELK1 pathway, in mice. In conclusion, pravastatin attenuates the action of ELK1 induced by oxidative stress to prevent atherosclerosis, which is dependent partly on modulation of ERK1/2 signalling.
Sex differences in ischaemia/reperfusion‐induced acute kidney injury depends on the degradation of noradrenaline by monoamine oxidase
Authors: Tanaka Ryosuke , Yazawa Maki , Morikawa Yuri , Tsutsui Hidenobu , Ohkita Mamoru , Yukimura Tokihito , Matsumura Yasuo 
Published: December 2016

SummaryIschaemic acute kidney injury (AKI) is a leading killer of both sexes; however, resistance to this injury is higher among women than men. We found that renal venous noradrenaline (NAd) overflow after reperfusion played important roles in the development of ischaemic AKI, and that the attenuation of AKI observed in female rats may be dependent on depressing the renal sympathetic nervous system with endogenous oestrogen. In the present study, we used male and female Sprague‐Dawley rats to investigate whether sex differences in the pathogenesis of ischaemic AKI are related to the degradation of NAd by monoamine oxidase (MAO) in the kidney. Ischaemic AKI was achieved by clamping the left renal artery and vein for 45 minutes followed by reperfusion 2 weeks after contralateral nephrectomy. Renal injury was more severe in male rats than in female rats and renal venous plasma NAd levels after reperfusion were markedly elevated in males, but not in females. These sex differences were eliminated by a treatment with isatin, a non‐selective MAO inhibitor, and moclobemide, a selective MAOA inhibitor, but not by selegiline, a selective MAOB inhibitor. Ischaemia decreased the mRNA expression levels of both MAOs in the kidney 1 day after reperfusion; however, MAOA mRNA expression levels were higher in female rats than in male rats. These results suggest that the degradation of NAd by MAOA in the kidney contributes to sex differences in the pathogenesis of ischaemia/reperfusion‐induced AKI.
Effects of unilatral‐ and bilateral inhibition of rostral ventral tegmental area and central nucleus of amygdala on morphine‐induced place conditioning in male Wistar rat
Authors: Mohammadian Zahra , Sahraei Hedayat , Meftahi Gholam Hossein , Ali‐Beik Hengameh 
Published: December 2016

SummaryThe rostral ventral tegmental area (VTAR) and central nucleus of amygdala (CeA) are considered the main regions for induction of psychological dependence on abused drugs, such as morphine. The main aim of this study was to investigate the transient inhibition of each right and left side as well as both sides of the VTAR and the CeA by lidocaine (2%) on morphine reward properties using the conditioned place preference (CPP) method. Male Wistar rats (250±20 g) 7 days after recovery from surgery and cannulation were conditioned to morphine (7.5 mg/kg) in CPP apparatus. Five minutes before morphine injection in conditioning phase, lidocaine was administered either uni‐ or bilaterally into the VTAR (0.25 μL/site) or CeA (0.5 μL/site). The results revealed that lidocaine administration into the left side, but not the right side of the VTAR and the CeA reduced morphine CPP significantly. The reduction was potentiated when lidocaine was injected into both sides of the VTAR and the CeA. The number of compartment crossings was reduced when lidocaine was injected into both sides of the VTAR and the CeA as well as the left side. Rearing was reduced when lidocaine was injected into the right, but not the left side of the VTAR. Sniffing and rearing increased when animals received lidocaine in the right side and reduced in the group that received lidocaine in the left side of the CeA. It was concluded that the right and the left side of VTAR and the CeA play different roles in morphine‐induced activity and reward.