bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clingen Cancer Somatic Working Group – standardizing and democratizing access to cancer molecular diagnostic data to drive translational research
Authors: Madhavan Subha , Ritter Deborah , Micheel Christine , Rao Shruti , Roy Angshumoy , Sonkin Dmitriy , Mccoy Matthew , Griffith Malachi , Griffith Obi L , Mcgarvey Peter , Kulkarni Shashikant ,   On Behalf Of The Clingen Somatic Working Group
Published: November 2017

AbstractA growing number of academic and community clinics are conducting genomic testing to inform treatment decisions for cancer patients (1). In the last 3–5 years, there has been a rapid increase in clinical use of next generation sequencing (NGS) based cancer molecular diagnostic (MolDx) testing (2). The increasing availability and decreasing cost of tumor genomic profiling means that physicians can now make treatment decisions armed with patient-specific genetic information. Accumulating research in the cancer biology field indicates that there is significant potential to improve cancer patient outcomes by effectively leveraging this rich source of genomic data in treatment planning (3). To achieve truly personalized medicine in oncology, it is critical to catalog cancer sequence variants from MolDx testing for their clinical relevance along with treatment information and patient outcomes, and to do so in a way that supports large-scale data aggregation and new hypothesis generation. One critical challenge to encoding variant data is adopting a standard of annotation of those variants that are clinically actionable. Through the NIH-funded Clinical Genome Resource (ClinGen) (4), in collaboration with NLM’s ClinVar database and >50 academic and industry based cancer research organizations, we developed the Minimal Variant Level Data (MVLD) framework to standardize reporting and interpretation of drug associated alterations (5). We are currently involved in collaborative efforts to align the MVLD framework with parallel, complementary sequence variants interpretation clinical guidelines from the Association of Molecular Pathologists (AMP) for clinical labs (6). In order to truly democratize access to MolDx data for care and research needs, these standards must be harmonized to support sharing of clinical cancer variants. Here we describe the processes and methods developed within the ClinGen’s Somatic WG in collaboration with over 60 cancer care and research organizations as well as CLIA-certified, CAP-accredited clinical testing labs to develop standards for cancer variant interpretation and sharing.
A simulation and comparison of dynamic functional connectivity methods
Authors: Thompson William Hedley , Richter Craig Geoffrey , Plavén-Sigray Pontus , Fransson Peter 
Published: November 2017

AbstractThere is a current interest in quantifying brain dynamic functional connectivity (DFC) based on neuroimaging data such as fMRI. Many methods have been proposed, and are being applied, revealing new insight into the brain’s dynamics. However, given that the ground truth for DFC in the brain is unknown, many concerns remain regarding the accuracy of proposed estimates. Since there exists many DFC methods it is difficult to assess differences in dynamic brain connectivity between studies. Here, we evaluate five different methods that together represent a wide spectrum of current approaches to estimating DFC (sliding window, tapered sliding window, temporal derivative, spatial distance and jackknife correlation). In particular, we were interested in each methods’ ability to track changes in covariance over time, which is a key property in DFC analysis. We found that all tested methods correlated positively with each other, but there were large differences in the strength of the correlations between methods. To facilitate comparisons with future DFC methods, we propose that the described simulations can act as benchmark tests for evaluation of methods. In this paper, we present dfcbenchmarker, which is a Python package where researchers can easily submit and compare their own DFC methods to evaluate its performance.
Effects of mutating α-tubulin lysine 40 on sensory dendrite development
Authors: Jenkins Brian V. , Saunders Harriet A. J. , Record Helena L. , Johnson-Schlitz Dena M. , Wildonger Jill 
Published: November 2017

ABSTRACTMicrotubules are essential to neuronal structure and function. Axonal and dendritic microtubules are enriched in post-translational modifications that impact microtubule dynamics, transport, and microtubule-associated proteins. Acetylation of α-tubulin lysine 40 (K40) is a prominent, conserved modification of neuronal microtubules. However, the cellular role of microtubule acetylation remains controversial. To resolve how microtubule acetylation might affect neuronal morphogenesis we mutated endogenous α-tubulin in vivo using a new fly strain that facilitates the rapid knock-in of designerα-tubulinalleles. Leveraging our new strain, we found that microtubule acetylation, as well as polyglutamylation and (de)tyrosination, is not essential for survival. However, we found that dendrite branch refinement in sensory neurons relies on α-tubulin K40. Mutagenesis of K40 reveals moderate yet significant changes in dendritic lysosome transport, microtubule polymerization, and Futsch distribution in dendrites but not axons. Our studies point to an unappreciated role for α-tubulin K40 and acetylation in dendrite morphogenesis. While our results are consistent with the idea that microtubule acetylation patterns microtubule function within neurons, they also suggest there may be a structural requirement for α-tubulin K40.Summary StatementNeurons are enriched in post-translationally modified microtubules. Targeted mutagenesis of endogenous α-tubulin in flies reveals that dendrite branch refinement is altered by acetylation-blocking mutations.
Genetic variation across the human olfactory receptor repertoire alters odor perception
Authors: Trimmer Casey , Keller Andreas , Murphy Nicolle R. , Snyder Lindsey L. , Willer Jason R. , Nagai Maira , Katsanis Nicholas , Vosshall Leslie B. , Matsunami Hiroaki , Mainland Joel D. 
Published: November 2017

ABSTRACTThe human olfactory receptor repertoire is characterized by an abundance of genetic variation that affects receptor response, but the perceptual effects of this variation are unclear. To address this issue, we sequenced the OR repertoire in 332 individuals and examined the relationship between genetic variation and 276 olfactory phenotypes, including the perceived intensity and pleasantness of 68 odorants at two concentrations, detection thresholds of three odorants, and general olfactory acuity. Genetic variation in a single OR frequently associated with odorant perception, and we validated 10 cases in which in vitro OR function correlated with in vivo odorant perception using a functional assay. This more than doubles the published examples of this phenomenon. For eight of these 10 cases, reduced receptor function associated with reduced intensity perception. In addition, we used participant genotypes to quantify genetic ancestry and found that, in combination with single OR genotype, age and gender, we can explain between 10 and 20% of the perceptual variation in 15 olfactory phenotypes, highlighting the importance of single OR genotype, ancestry, and demographic factors in variation of olfactory perception.
Variation in traction forces during cell cycle progression
Authors: Vianay Benoit , Senger Fabrice , Alamos Simon , Anjur-Dietrich Maya , Bearce Elizabeth , Cheeseman Bevan , Lee Lisa , Théry Manuel 
Published: November 2017

AbstractTissue morphogenesis results from the interplay between cell growth and mechanical forces. While the impact of forces on cell proliferation has been fairly well characterized, the inverse relationship is much less understood. Here we investigated how traction forces vary during cell cycle progression. Cell shape was constrained on micropatterned substrates in order to distinguish variations in cell contractility from cell size increase. We performed traction force measurements of asynchronously dividing cells expressing a cell-cycle reporter, to obtain measurements of contractile forces generated during cell division. We found that forces tend to increase as cells progress through G1, before reaching a plateau in S phase, and then decline during G2. This biphasic behaviour revealed a previously undocumented specific and opposite regulation of cell contractility during each cell cycle stage.
Context of Psychotropic Drug Delivery Modulates its Neurobehavioral Effects: the Case of Methylphenidate
Authors: Sar-El Roy , Raz Gal , Lubianiker Nitzan , Sharon Haggai , Hendler Talma 
Published: November 2017

AbstractPharmacotherapy is substantially hindered by poor drug targeting, resulting in low specificity and efficacy. Here, we tested a novel, non-invasive targeting approach (termed functional-pharmacology), which couples drug administration with a task that activates the drug’s sites-of-action in the brain, thus possibly improving absorption and efficacy. Methylphenidate (MPH) or Placebo were administered to healthy subjects, which then performed a cognitive induction or a control task. N-Back fMRI before and after drug-task coupling measured therapeutic effects. Only following MPH, subjects that performed better in the cognitive induction task showed greater improvements in N-back performance. Moreover, only under MPH-Cognitive induction condition, there existed a significant correlation between improved recruitment of N-Back rDLPFC activation, and a concurrent improvement in task performance. Importantly, mediation analysis suggested a causal role of rDLPFC activation in these coupling effects. Our results support the functional-pharmacology concept feasibility and efficacy, hence opening a new horizon for patient-tailored, context-driven drug therapy.
Evaluation of protein-ligand docking methods on peptide-ligand complexes for docking small ligands to peptides
Authors: Singh Sandeep , Srivastava Hemant Kumar , Kishor Gaurav , Singh Harinder , Agrawal Piyush , Raghava G.P.S. 
Published: November 2017

ABSTRACTIn the past, many benchmarking studies have been performed on protein-protein and protein-ligand docking however there is no study on peptide-ligand docking. In this study, we evaluated the performance of seven widely used docking methods (AutoDock, AutoDock Vina, DOCK 6, PLANTS, rDock, GEMDOCK and GOLD) on a dataset of 57 peptide-ligand complexes. Though these methods have been developed for docking ligands to proteins but we evaluate their ability to dock ligands to peptides. First, we compared TOP docking pose of these methods with original complex and achieved average RMSD from 4.74Å for AutoDock to 12.63Å for GEMDOCK. Next we evaluated BEST docking pose of these methods and achieved average RMSD from 3.82Å for AutoDock to 10.83Å for rDock. It has been observed that ranking of docking poses by these methods is not suitable for peptide-ligand docking as performance of their TOP pose is much inferior to their BEST pose. AutoDock clearly shows better performance compared to the other six docking methods based on their TOP docking poses. On the other hand, difference in performance of different docking methods (AutoDock, AutoDock Vina, PLANTS and DOCK 6) was marginal when evaluation was based on their BEST docking pose. Similar trend has been observed when performance is measured in terms of success rate at different cut-off values. In order to facilitate scientific community a web server PLDbench has been developed (http://webs.iiitd.edu.in/raghava/pldbench/).
Perturbed Mitochondrial Metabolism in Islets from Donors with Type-2 Diabetes
Authors: Sun Jiangming , Jain Ruchi , Andersson Lotta E. , Medina Anya , Storm Petter , Spégel Peter , Mulder Hindrik 
Published: November 2017

ABSTRACTThere is a preponderance for genes involved in ß-cell function among gene variants associated with future risk of type-2 diabetes (T2D). ß-cell function is controlled by metabolism of glucose, yielding signals triggering and amplifying insulin secretion. Perturbed ß-cell metabolism is a likely, albeit not proven, cause of T2D. We profiled metabolites in islets from T2D and non-diabetic donors, and found altered levels of mitochondrial metabolites in T2D. Analysis of genes encoding proteins localized to mitochondria (MitoCarta) by RNA-seq in an extended sample of islets revealed genes whose expression was associated with glycaemia- and/or BMI. Expression of two of these, α-methylacyl-CoA racemase(AMACR)and methylmalonyl-CoA mutase(MUT),was influenced by genetic variation (cis-eQTL). Silencing ofAMACRandMUTin insulin-secreting cells reduced hormone secretion by 40-50%. In conclusion, by linking the metabolome to the transcriptome, we showed that perturbed mitochondrial metabolism is a feature of ß-cell dysfunction in T2D.[Supplementary material is available for this article.]
Duplication and divergence of Sox genes in spiders
Authors: Paese Christian L. B. , Leite Daniel J. , Schoenauer Anna , McGregor Alistair P. , Russell Steven 
Published: November 2017

AbstractBackgroundThe Sox family of transcription factors are present and conserved in the genomes of all metazoans examined to data and are known to play important developmental roles in vertebrates and insects. However, outside the commonly studiedDrosophilamodel little is known about the extent or conservation of the Sox family in other arthropod species. Here we characterise the Sox family in two chelicerate species, the spidersParasteatoda tepidariorumandStegodyphus mimosarum, which have experienced a whole genome duplication (WGD) in their evolutionary history.ResultsWe find that virtually all of the duplicate Sox genes have been retained in these spiders after the WGD. Analysis of the expression of Sox genes inP. tepidariorumembryos indicates that it is likely that some of these genes have neofunctionalised after duplication. Our expression analysis also strengthens the view that an orthologue of vertebrate Group B1 genes,SoxNeuro, is implicated in the earliest events of CNS specification in both vertebrates and invertebrates. In addition, a gene in theDichaete/Sox21bclass is dynamically expressed in the spider segment addition zone, suggestive of an ancient regulatory mechanism controlling arthropod segmentation as recently suggested for flies and beetles. Together with the recent analysis of Sox gene expression in the embryos of other arthropods, our findings are also indicative of conserved functions for some of these genes, including a role forSoxCandSoxDgenes in CNS development,SoxFin limb development and a tantalising suggestion thatSoxEgenes may be involved in gonadogenesis across the metazoa.ConclusionsOur study provides a new chelicerate perspective to understanding the evolution and function of Sox genes and how the retention of duplicates of such important tool-box genes after WGD has contributed to different aspects of spider embryogenesis. Future characterisation of the function of these genes in spiders will help us to better understand the evolution of the regulation of important developmental processes in arthropods and other metazoans including neurogenesis and segmentation.
Enhanced JBrowse plugins for epigenomics data visualization
Authors: Hofmeister Brigitte T. , Schmitz Robert J. 
Published: November 2017

ABSTRACTNew sequencing techniques require new visualization strategies, as is the case for epigenomics data such as DNA base modifications, small non-coding RNAs, and histone modifications. We present a set of plugins for the genome browser JBrowse that are targeted for epigenomics visualizations. Specifically, we have focused on visualizing DNA base modifications, small non-coding RNAs, stranded read coverage, and sequence motif density. Additionally, we present several plugins for improved user experience such as configurable, high-quality screenshots. In visualizing epigenomics with traditional genomics data, we see these plugins improving scientific communication and leading to discoveries within the field of epigenomics.
Coordination between discrete Mitotic Arrest Deficient 1 (MAD1) domains is required for efficient mitotic checkpoint signaling
Authors: Ji Wenbin , Luo Yibo , Ahmad Ejaz , Liu Song-Tao 
Published: November 2017

ABSTRACTAs a sensitive signaling system, the mitotic checkpoint ensures faithful chromosome segregation by delaying anaphase onset when even a single kinetochore is unattached. The key signal amplification reaction for the checkpoint is the conformational conversion of open MAD2 (O-MAD2) into closed MAD2 (C-MAD2). The reaction was suggested to be catalyzed by an unusual catalyst, a MAD1:C-MAD2 tetramer, but how the catalysis is executed and regulated remains elusive. Here we report that in addition to the well-characterized middle region (MIM), both amino- and carboxyl-terminal domains (NTD and CTD) of MAD1 also contribute to the mitotic checkpoint. In contrast to MIM that stably associates with C-MAD2, MAD1-NTD and CTD surprisingly bind to both O-MAD2 and C-MAD2, suggesting their interactions with substrates and products of the O-C conversion. MAD1-NTD also interacts with CTD. MPS1 kinase interacts with and phosphorylates both NTD and CTD. The phosphorylation reduces the NTD:CTD interaction and CTD interaction with MPS1. Mutating CTD phosphorylation sites including Thr716 compromises MAD2 binding and the checkpoint responses. Ser610 and Tyr634 also contribute to the checkpoint. Our results have uncovered previously unknown interactions of MAD1-NTD and CTD with MAD2 conformers and their regulation by MPS1 kinase, providing novel insights into the mitotic checkpoint signaling.
An automated statistical technique for counting distinct multiple sclerosis lesions can recover aspects of lesion history and provide relevant disease information
Authors: Dworkin Jordan D. , Linn Kristin A. , Oguz Ipek , Fleishman Greg M. , Bakshi Rohit , Nair Govind , Calabresi Peter A. , Henry Roland G. , Oh Jiwon , Papinutto Nico , Pelletier Daniel , Rooney William , Stern William , Sicotte Nancy L. , Reich Daniel S. , Shinohara Russell T. ,   the NAIMS Cooperative
Published: November 2017

AbstractBackgroundLesion load is a common biomarker in multiple sclerosis, yet it has historically shown modest associations with clinical outcomes. Lesion count, which encapsulates the natural history of lesion formation and is thought to provide complementary information, is difficult to assess in patients with confluent (i.e. spatially overlapping) lesions. We introduce a statistical technique for cross-sectionally counting pathologically distinct lesions.MethodsMRI is used to assess the probability of lesion at each location. The texture of this map is quantified using a novel technique, and clusters resembling the center of a lesion are counted.ResultsValidity was demonstrated by comparing the proposed count to a gold-standard count in 60 subjects observed longitudinally. The counts were highly correlated (r = .97, p < .001) and not significantly different (t59 = −0.83, p > .40). Reliability was determined using 14 scans of a clinically stable subject acquired at 7 sites, and variability of lesion count was equivalent to that of lesion load. Accounting for lesion load and age, lesion count was negatively associated (t58 = −2.73, p < .01) with the Expanded Disability Status Scale (EDSS). Average lesion size had a higher association with EDSS (r =.35, p < .01) than lesion load (r = .10, p > .40) or lesion count (r = −.12, p > .30) alone.ConclusionThese findings demonstrate that it is possible to recover important aspects of the natural history of lesion formation without longitudinal data, and suggest that lesion size provides complementary information about disease.Grant SupportThe project described was supported in part by the NIH grants R01 NS085211, R21 NS093349, and R01 NS094456 from the National Institute of Neurological Disorders and Stroke (NINDS). The study was also supported by the Intramural Research Program of NINDS and the Race to Erase MS Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Gene network analysis identifies a central post-transcriptional regulator of cellular stress survival
Authors: Tien Matthew Z. , Fiebig Aretha , Crosson Sean 
Published: November 2017

SUMMARYCells adapt to shifts in their environment by remodeling transcription. Measuring changes in transcription at the genome scale is now routine, but defining the functional significance of individual genes within large gene expression datasets remains a major challenge. We applied a network-based algorithm to interrogate publicly available transcription data to predict genes that serve major functional roles inCaulobacter crescentusstress survival. This approach identified GsrN, a conserved small RNA that is directly controlled by the general stress sigma factor, στ, and functions as a potent post-transcriptional regulator of survival under multiple stress conditions. GsrN expression is both necessary and sufficient to protect cells from hydrogen peroxide, where it functions by base pairing with the leader ofkatGmRNA and promoting catalase/peroxidase expression. We conclude that GsrN convenes a post-transcriptional layer of gene expression that serves a central functional role in stress physiology.
“Corps” leadership: a cadet perspective on shared leadership
Authors: Martin Ira H. , Prophet Trevor , Owens Christopher , Martin JennyMae , Plummer Gabe 
Published: November 2017

PurposeThe purpose of this paper is to enhance understanding of shared leadership in a military academy setting.Design/methodology/approachA qualitative methodology was selected to ask senior cadets about a shared leadership concept at the United States Coast Guard Academy, known as the “corps leading the corps.” Cadets responded to, “what does the corps leading the corps mean to you?” via a paper and pencil survey. Cadet responses were coded using content analysis.FindingsThree higher-order dimensions emerged from the data: autonomy and empowerment, developing self and others, and role modeling.Originality/valueThe paper provides emerging leaders’ commentary to incorporating a shared leadership concept within an educational environment.
Mother-child disagreements on child anxiety: associated factors
Authors: Giuseppone Kathryn R. , Brumariu Laura E. 
Published: November 2017

Purpose
Previous literature demonstrated low-to-moderate rates of agreement between children and mothers regarding child anxiety. The purpose of this paper is to evaluate factors related to differences between mother-child dyads who disagreed vs agreed in their reports of child anxiety symptoms.

Design/methodology/approach
In total, 87 children aged 9-12 years old and their mothers completed questionnaires regarding maternal perceptions of child behavior, maternal separation anxiety about the child’s individuation, and mother-child relationship characteristics.

Findings
The results showed that mothers in mother-child dyads who disagreed on child anxiety symptoms, compared to those in dyads who agreed on child anxiety symptoms, perceived their children as showing higher affect intensity and behavioral problems. They also expressed greater anxiety about the children’s individuation process, characterized in part by children’s increased autonomy and decline of reliance on them. Further, children in dyads who disagreed, compared to those in dyads who agreed, reported lower mother-child attachment security.

Originality/value
The results extend the literature by identifying specific factors related to the discrepancy between mothers’ and children’s reports of childhood anxiety in early adolescence. The results highlight the need to consider both mothers’ and children’s views when assessing childhood anxiety. Importantly, the results also indicate that specific factors investigated in this study, including maternal perception of children’s behavioral problems and their affect intensity, maternal anxiety about child individuation, and mother-child attachment security, could be used to inform clinical decisions regarding informant discrepancies.