bluuebunny/crossref_metadata_2025_split huggingface dataset:
Actomyosin contractility modulates Wnt signaling through adherens junction stability
Authors: Hall Eric T. , Hoesing Elizabeth , Sinkovics Endre , Verheyen Esther M. 
Published: November 2017

AbstractMechanical forces can influence the canonical Wnt signaling pathway in processes like mesoderm differentiation and tissue stiffness during tumorigenesis, but a molecular mechanism involving both in a developing epithelium and its homeostasis is lacking. We identified that increased non-muscle myosin II activation and cellular contraction inhibited Wnt target gene transcription in developingDrosophila. Genetic interactions studies identified this effect was due to myosin-induced accumulation of cortical F-actin resulting in clustering and accumulation of E-cadherin to the adherens junctions. E-cadherin titrates any available β-catenin, the Wnt pathway transcriptional co-activator, to the adherens junctions in order to maintain cell-cell adhesion under contraction. We show that decreased levels of cytoplasmic β-catenin result in insufficient nuclear translocation for full Wnt target gene transcription. Our work elucidates a mechanism in which the dynamic activation of actomyosin contractility refines patterning of Wnt transcription during development and maintenance of epithelial tissue in organisms.
Impaired Cu-Zn superoxide dismutase (SOD1) and calcineurin (Cn) interaction in ALS: A presumed consequence for TDP-43 and zinc aggregation in Tg SOD1G93A rodent spinal cord tissue
Authors: Kim Jolene M. , Billington Elizabeth , Reyes Ada , Notarianni Tara , Sage Jessica , Agbas Emre , Taylor Michael , Monast Ian , Stanford John A. , Agbas Abdulbaki 
Published: November 2017

ABSTRACTImpaired interactions between Calcineurin (Cn) and (Cu/Zn) superoxide dismutase (SOD1) are suspected to be responsible for the formation of hyperphosphorylated protein aggregation in amyotrophic lateral sclerosis (ALS). Serine (Ser)-enriched TDP-43 protein aggregation appears in the spinal cord of ALS animal models, and may be linked to the reduced phosphatase activity of Cn. The mutant overexpressed SOD1G93A protein does not properly bind zinc (Zn) in animal models; hence, mutant SOD1G93A - Cn interaction weakens. Consequently, unstable Cn fails to dephosphorylate TDP-43 that yields hyperphosphorylated TDP-43 aggregates. Our previous studies had suggested that Cn and SOD1 interaction was necessary to keep Cn enzyme functional. We have observed low Cn level, increased Zn concentrations, and increased TDP-43 protein levels in cervical, thoracic, lumbar, and sacral regions of the spinal cord tissue homogenates. This study further supports our previous published work indicating that Cn stability depends on functional Cn-SOD1 interaction because Zn metal is crucial for maintaining the Cn stability. Less active Cn did not efficiently dephosphorylate TDP-43; hence TDP-43 aggregations appeared in the spinal cord tissue.
Enterococcus faecalisstrains with compromised CRISPR-Cas defense emerge under antibiotic selection for a CRISPR-targeted plasmid
Authors: Huo Wenwen , Price Valerie J. , Sharifi Ardalan , Zhang Michael Q. , Palmer Kelli L. 
Published: November 2017

AbstractEnterococcus faecalisis a Gram-positive bacterium that natively colonizes the human gastrointestinal tract and opportunistically causes life-threatening infections. Multidrug-resistant (MDR)E. faecalisstrains have emerged that are replete with mobile genetic elements (MGEs). Non-MDRE. faecalisstrains frequently possess CRISPR-Cas systems, which reduce the frequency of mobile genetic element (MGE) acquisition. We demonstrated in previous studies thatE. faecalispopulations can transiently maintain both a functional CRISPR-Cas system and a CRISPR-Cas target. In this study, we used serial passage and deep sequencing to analyze these populations. In the presence of antibiotic selection for the plasmid, mutants with compromised CRISPR-Cas defense and enhanced ability to acquire a second antibiotic resistance plasmid emerged. Conversely, in the absence of selection, the plasmid was lost from wild-typeE. faecalispopulations, but notE. faecalispopulations that lacked thecas9gene. Our results indicate thatE. faecalisCRISPR-Cas can become compromised under antibiotic selection, generating populations with enhanced abilities to undergo horizontal gene transfer.ImportanceEnterococcus faecalisis a leading cause of hospital-acquired infections and disseminator of antibiotic resistance plasmids among Gram-positive bacteria. We have previously shown thatE. faecalisstrains with an active CRISPR-Cas system can prevent plasmid acquisition and thus limit the transmission of antibiotic resistance determinants. Yet, CRISPR-Cas was not a perfect barrier. In this study, we observed populations ofE. faecaliswith transient co-existence of CRISPR-Cas and one of its plasmid targets. Our experimental data demonstrate that antibiotic selection results in compromisedE. faecalisCRISPR-Cas function, thereby facilitating the acquisition of additional resistance plasmids byE. faecalis.
Differential Representation of Articulatory Gestures and Phonemes in Motor, Premotor, and Inferior Frontal Cortices
Authors: Mugler Emily M. , Tate Matthew C. , Livescu Karen , Templer Jessica W. , Goldrick Matthew A. , Slutzky Marc W. 
Published: November 2017

ABSTRACTSpeech is a critical form of human communication and is central to our daily lives. Yet, despite decades of study, an understanding of the fundamental neural control of speech production remains incomplete. Current theories model speech production as a hierarchy from sentences and phrases down to words, syllables, speech sounds (phonemes) and the movements of speech articulator muscles used to produce these sounds (articulatory gestures). Here, we investigate the cortical representation of articulatory gestures and phonemes in speech motor, premotor, and inferior frontal cortices. Our results indicate that primary motor and premotor areas represent gestures to a greater extent than phonemes, while inferior frontal cortex represents both gestures and phonemes. These findings suggest that the cortical control of speech production shares a common representation with that of other types of movement, such as arm and hand movements.
Origin and evolution of the nuclear auxin response system
Authors: Mutte Sumanth K. , Kato Hirotaka , Rothfels Carl , Melkonian Michael , Wong Gane Ka-Shu , Weijers Dolf 
Published: November 2017

AbstractThe small signaling molecule auxin controls numerous developmental processes in land plants, acting mostly by regulating gene expression. Auxin response proteins are represented by large families of diverse functions, but neither their origin nor their evolution is understood. Here we use a deep phylogenomics approach to reconstruct both the origin and the evolutionary trajectory of all nuclear auxin response protein families. We found that, while all subdomains are ancient, a complete auxin response mechanism is limited to land plants. Functional phylogenomics predicts defined steps in the evolution of response system properties, and comparative transcriptomics across six ancient lineages revealed how these innovations shaped a sophisticated response mechanism. Genetic analysis in a basal land plant revealed unexpected contributions of ancient non-canonical proteins in auxin response as well as auxin-unrelated function of core transcription factors. Our study provides a functional evolutionary framework for understanding diverse functions of the auxin signal.
Paternal germ line aging: DNA methylation age prediction from human sperm
Authors: Jenkins Timothy G , Aston Kenneth I , Smith Andrew , Carrell Douglas T 
Published: November 2017

AbstractBackgroundThe relationship between aging and epigenetic profiles has been highlighted in many recent studies. Models using somatic cell methylomes to predict age have been successfully constructed. However, gamete aging is quite distinct and as such age prediction using sperm methylomes is ineffective with current techniques.ResultsWe have produced a model that utilizes human sperm DNA methylation signatures to predict chronological age by utilizing methylation array data from a total of 329 samples. The dataset used for model construction includes infertile patients, sperm donors, and individuals from the general population. Our model is capable of accurately predicting age with an R2 of 0.928 in our test data set. We additionally investigated the repeatability of prediction by processing the same sample on 6 different arrays and found very robust age prediction with an average standard deviation of only 0.877 years. Additionally, we found that smokers have approximately 5% increased age profiles compared to ‘never smokers.’ConclusionsThe predictive model described herein was built to offer researchers the ability to assess “germ line age” by accessing sperm DNA methylation signatures at genomic regions affected by age. Our data suggest that this model can predict an individual’s chronological age with a high degree of accuracy regardless of fertility status and with a high degree of repeatability. Additionally, our data appear to show age acceleration patterns as a result of smoking suggesting that the aging process in sperm may be impacted by environmental factors, though this effect appears to be quite subtle.
A map of constrained coding regions in the human genome
Authors: Havrilla James M. , Pedersen Brent S. , Layer Ryan M. , Quinlan Aaron R. 
Published: November 2017

ABSTRACTDeep catalogs of genetic variation collected from many thousands of humans enable the detection of intraspecies constraint by revealing coding regions with a scarcity of variation. While existing techniques summarize constraint for entire genes, single metrics cannot capture the fine-scale variability in constraint within each protein-coding gene. To provide greater resolution, we have created a detailed map of constrained coding regions (CCRs) in the human genome by leveraging coding variation observed among 123,136 humans from the Genome Aggregation Database (gnomAD). The most constrained coding regions in our map are enriched for both pathogenic variants in ClinVar and de novo mutations underlying developmental disorders. CCRs also reveal protein domain families under high constraint, suggest unannotated or incomplete protein domains, and facilitate the prioritization of previously unseen variation in studies of disease. Finally, a subset of CCRs with the highest constraint likely exist within genes that cause yet unobserved human phenotypes owing to strong purifying selection.
Recurrent Neural Networks with Interpretable Cells Predict and Classify Worm Behaviour
Authors: Li Kezhi , Javer Avelino , Keaveny Eric E. , Brown Andre E.X. 
Published: November 2017

AbstractAn important goal in behaviour analytics is to connect disease state or genome variation with observable differences in behaviour. Despite advances in sensor technology and imaging, informative behaviour quantification remains challenging. The nematode worm C. elegans provides a unique opportunity to test analysis approaches because of its small size, compact nervous system, and the availability of large databases of videos of freely behaving animals with known genetic differences. Despite its relative simplicity, there are still no reports of generative models that can capture essential differences between even well-described mutant strains. Here we show that a multilayer recurrent neural network (RNN) can produce diverse behaviours that are difficult to distinguish from real worms’ behaviour and that some of the artificial neurons in the RNN are interpretable and correlate with observable features such as body curvature, speed, and reversals. Although the RNN is not trained to perform classification, we find that artificial neuron responses provide features that perform well in worm strain classification.
Leveraging polygenic functional enrichment to improve GWAS power
Authors: Kichaev Gleb , Bhatia Gaurav , Loh Po-Ru , Gazal Steven , Burch Kathryn , Freund Malika , Schoech Armin , Pasaniuc Bogdan , Price Alkes L 
Published: November 2017

AbstractFunctional genomics data has the potential to increase GWAS power by identifying SNPs that have a higher prior probability of association. Here, we introduce a method that leverages polygenic functional enrichment to incorporate coding, conserved, regulatory and LD-related genomic annotations into association analyses. We show via simulations with real genotypes that the method, Functionally Informed Novel Discovery Of Risk loci (FINDOR), correctly controls the false-positive rate at null loci and attains a 9–38% increase in the number of independent associations detected at causal loci, depending on trait polygenicity and sample size. We applied FINDOR to 27 independent complex traits and diseases from the interim UK Biobank release (average N=130K). Averaged across traits, we attained a 13% increase in genome-wide significant loci detected (including a 20% increase for disease traits) compared to un-weighted raw p-values that do not use functional data. We replicated the novel loci in independent UK Biobank and non-UK Biobank data, yielding a highly statistically significant replication slope (0.66–0.69) in each case. Finally, we applied FINDOR to the full UK Biobank release (average N=416K), attaining smaller relative improvements (consistent with simulations) but larger absolute improvements, detecting an additional 583 GWAS loci. In conclusion, leveraging functional enrichment using our method robustly increases GWAS power.
Decoding of neural data using cohomological learning
Authors: Rybakken Erik , Baas Nils , Dunn Benjamin 
Published: November 2017

AbstractWe introduce a novel data-driven approach to discover and decode features in the neural code coming from large population neural recordings with minimal assumptions, using cohomological learning. We apply our approach to neural recordings of mice moving freely in a box, where we find a circular feature. We then observe that the decoded value corresponds well to the head direction of the mouse. Thus we capture head direction cells and decode the head direction from the neural population activity without having to process the behaviour of the mouse. Interestingly, the decoded values convey more information about the neural activity than the tracked head direction does, with differences that have some spatial organization. Finally, we note that the residual population activity, after the head direction has been accounted for, retains some low-dimensional structure which is correlated with the speed of the mouse.
Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases
Authors: Li Yingmei , Liu Boxiang , Connollyt Ian David , Kakusa Bina Wasunga , Pan Wenying , Nagpal Seema , Montgomery Stephen B. , Gephart Melanie Hayden 
Published: November 2017

AbstractPurposeBrain metastases from non-small cell lung cancer (NSCLC) engraft and grow either within the brain (solid) or diffusely on its surface (leptomeningeal disease; LMD). Routine clinical diagnostics have low sensitivity and provide no information about the underlying mutations. A recurrent mutation analysis of LMD and a comparison between solid and LMD NSCLC brain metastases have yet to be explored.Experimental DesignWe performed whole-exome sequencing (WES) on eight cerebrospinal fluid (CSF) specimens from NSCLC LMD patients. We compared our LMD sequencing data with a published data set of 26 NSCLC solid brain metastases to determine the relative mutation frequency. We then performed a retrospective chart review of an additional set of 44 NSCLC LMD patients to further evaluate LMD mutations and clinical prognosis.ResultsSix (75%) LMD cases had mutations inEGFR, while none hadKRASmutations. Retrospective chart review revealed only 4 LMD cases (7.7%) withKRASmutations, but 33 cases (63.5%) withEGFRmutations.TP53was mutated in 4/8 LMD (50%) cases and 13/26 of solid metastasis (50%). The median interval for developing LMD from NSCLC was shorter in EGFR-mutant (16.3 mo) than wild-type (23.9 mo) patients (p = 0.017).ConclusionsEGFRandTP53mutations were frequent in LMD exomes (combined frequency 87.5%), suggesting that PCR-based mutation detection assays towards these two genes could be a useful complement to current diagnostics. Correlations ofEGFRin LMD andKRASin solid metastases suggest molecular distinctions or systemic treatment pressure underpinning differences in growth patterns within the brain.Translational RelevanceLeptomeningeal disease is a diffuse, malignant, and incurable metastatic brain tumor that accounts for 5-10% of brain metastases. Patients with LMD do not undergo biopsy and their overall prognosis is poor (median survival 3 to 27 months), making it difficult to collect sufficient samples for recurrent mutation analysis. Standard diagnostic procedures (MRI and cytology) for LMD provide no genetic information. To understand the mutation landscape of LMD, we performed whole-exome sequencing on eight lung-derived LMD cases. We showed that mutations inEGFRoccurred more frequently in LMD than solid brain metastases, butKRASmutations were not present in LMD. Further, mutations in recurrent genes such asEGFRandTP53could be reliably detected in CSF via droplet digital PCR. Targeted analysis of recurrent mutations thus presents a useful complement to the existing diagnostic toolkit, and differences in mutations between LMD and solid brain metastases suggest distinct molecular mechanisms for growth.
Integrated analysis of single-cell embryo data yields a unified transcriptome signature for the human preimplantation epiblast
Authors: Stirparo Giuliano G , Boroviak Thorsten , Guo Ge , Nichols Jennifer , Smith Austin , Bertone Paul 
Published: November 2017

AbstractSingle-cell profiling techniques create opportunities to delineate cell fate progression in mammalian development. Recent studies provide transcriptome data from human preimplantation embryos, in total comprising nearly 2000 individual cells. Interpretation of these data is confounded by biological factors such as variable embryo staging and cell-type ambiguity, as well as technical challenges in the collective analysis of datasets produced with different sample preparation and sequencing protocols. Here we address these issues to assemble a complete gene expression time course spanning human preimplantation embryogenesis. We identify key transcriptional features over developmental time and elucidate lineage-specific regulatory networks. We resolve post hoc cell-type assignment in the blastocyst, and define robust transcriptional prototypes that capture epiblast and primitive endoderm lineages. Examination of human pluripotent stem cell transcriptomes in this framework identifies culture conditions that sustain a naïve state pertaining to the inner cell mass. Our approach thus clarifies understanding both of lineage segregation in the early human embryo and of in vitro stem cell identity, and provides an analytical resource for comparative molecular embryology.
Evaluation and comparison the effect of heat treatment on mechanical properties of NiCrBSi thermally sprayed coatings
Authors: Shabanlo Mohsen , Amini Najafabadi Reza , Meysami Amirhossein 
Published: November 2017

Purpose
This study aims to investigate the effect of post heat treatment on mechanical properties of NiCrBSi coatings, which were applied on 316L stainless steel using high-velocity oxygen-fuel (HVOF) and flame spray techniques.

Design/methodology/approach
The properties of coatings were investigated by metallographic characterizations as well as wear, micro-hardness and adhesion tests.

Findings
The micro-hardness results showed that the coatings considerably increased the sub-layer hardness. In addition, regarding the wear test results, it can be seen that heat treatment increased wear resistance of the coatings. These thermal sprayed coatings are usually re-melted by post heat treatment, leading to improvement in tribological properties. The results obtained revealed that re-melting procedure improved the metallurgical bonding in the substrate\coating interface.

Originality/value
Microstructure defects resulting from thermal spraying such as pores and unmelted particles can be eliminated by post heat treatment. This process can considerably improve the corrosion and wear resistances of the thermal sprayed coatings.
Consumers’ wine preferences in a changing scenario
Authors: Escobar Cristina , Kallas Zein , Gil José M. 
Published: November 2017

Purpose
Important socioeconomic changes have been undergone due to the international economic crisis. In Catalonia (Spain), political changes towards independentism also occurred within the same period. The purpose of this paper is to explore the consumers’ wine preferences in Catalonia in two different scenarios. In particular, the authors have focussed the interest in those preferences regarding the regional origin of the wine.

Design/methodology/approach
Data were elicited from two identical discrete choice experiments performed in two times: before (2008) and during the economic crisis (2010) in Catalonia, Spain.

Findings
The results imply that the external common circumstances may have had a homogenising influence in consumer choices by decreasing the level of randomness of consumers’ selection. Consumers’ preferences for a Catalan origin were enhanced during the crisis, while price became the most important attribute.

Research limitations/implications
Ideally, the participants involved in both experiments would have been the same. Unfortunately, this was not possible to maintain and it is one of the limitations of this study. The authors are also aware that other non-controlled variables may have also played a role and the conclusions that are driven should be taken carefully.

Originality/value
This paper contributes to the literature of the discrete choice modelling using the recently developed Generalized Multinomial Logit Model. To the knowledge this is the first application in the literature of wine preferences to measure the impact of the contextual changes (economic and political) in Catalonia (Spain).