bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accurate Therapeutic Response Assessment of Pancreatic Ductal Adenocarcinoma Using Quantitative Dynamic Contrast-Enhanced Magnetic Resonance Imaging With a Point-of-Care Perfusion Phantom
Authors: Kim Harrison , Morgan Desiree E. , Schexnailder Patrick , Navari Rudolph M. , Williams Grant R. , Bart Rose J. , Li Yufeng , Paluri Ravikumar 
Published: August 2018

Objectives
The aim of this study was to test the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with concurrent perfusion phantom for monitoring therapeutic response in patients with pancreatic ductal adenocarcinoma (PDAC).

Materials and Methods
A prospective pilot study was conducted with 8 patients (7 men and 1 woman) aged 46 to 78 years (mean age, 66 years). Participants had either locally advanced (n = 7) or metastatic (n = 1) PDAC, and had 2 DCE-MRI examinations: one before and one 8 ± 1 weeks after starting first-line chemotherapy. A small triplicate perfusion phantom was imaged with each patient, serving as an internal reference for accurate quantitative image analysis. Tumor perfusion was measured with Ktrans using extended Tofts model before and after phantom-based data correction. Results are presented as mean ± SD and 95% confidence intervals (CIs). Statistical difference was evaluated with 1-way analysis of variance.

Results
Tumor-size change of responding group (n = 4) was −12% ± 4% at 8 weeks of therapy, while that of nonresponding group (n = 4) was 18% ± 15% (P = 0.0100). Before phantom-based data correction, the Ktrans change of responding tumors was 69% ± 23% (95% CI, 32% to 106%) at 8 weeks, whereas that of nonresponding tumors was −1% ± 41% (95% CI, −65% to 64%) (P = 0.0247). After correction, the data variation in each group was significantly reduced; the Ktrans change of responding tumors was 73% ± 6% (95% CI, 64% to 82%) compared with nonresponding tumors of −0% ± 5% (95% CI, −7% to 8%) (P < 0.0001).

Conclusions
Quantitative DCE-MRI measured the significant perfusion increase of PDAC tumors responding favorably to chemotherapy, with decreased variability after correction using a perfusion phantom.
Impact of a Novel Preoperative Patient-centered Surgical Wellness Program
Authors: Kelley Kristen E. , Fajardo Alyssa D. , Strange Nancy M. , Harmon Carol A. , Pawlecki Kim , Sieber Marnie , Walke Nikki , Fadel William F. , Wooden William A. , Sadowski Josh , Birdas Thomas J. , Stevens Larry H. , Rozycki Grace S. , Schmidt C. Max 
Published: August 2018

Objective:
The objective of this study was to evaluate if a preoperative wellness bundle significantly decreases the risk of hospital acquired infections (HAI).

Background:
HAI threaten patient outcomes and are a significant burden to the healthcare system. Preoperative wellness efforts may significantly decrease the risk of infections.

Methods:
A group of 12,396 surgical patients received a wellness bundle in a roller bag during preoperative screening at an urban academic medical center. The wellness bundle consisted of a chlorhexidine bath solution, immuno-nutrition supplements, incentive spirometer, topical mupirocin for the nostrils, and smoking cessation information. Study staff performed structured patient interviews, observations, and standardized surveys at key intervals throughout the perioperative period. Statistics compare HAI outcomes of patients in the wellness program to a nonintervention group using the Fisher's exact test, logistic regression, and Poisson regression.

Results:
Patients in the nonintervention and intervention groups were similar in demographics, comorbidity, and type of operations. Compliance with each element was high (80% mupirocin, 72% immuno-nutrition, 71% chlorhexidine bath, 67% spirometer). The intervention group had statistically significant reductions in surgical site infections, Clostridium difficile, catheter associated urinary tract infections, and patient safety indicator 90.

Conclusions:
A novel, preoperative, patient-centered wellness program dramatically reduced HAI in surgical patients at an urban academic medical center.
Hearing through lip-reading: the brain synthesizes features of absent speech
Authors: Bourguignon Mathieu , Baart Martijn , Kapnoula Efthymia C. , Molinaro Nicola 
Published: August 2018

AbstractLip-reading is crucial to understand speech in challenging conditions. Neuroimaging investigations have revealed that lip-reading activates auditory cortices in individuals covertly repeating absent—but known—speech. However, in real-life, one usually has no detailed information about the content of upcoming speech. Here we show that during silent lip-reading ofunknownspeech, activity in auditory cortices entrains more to absent speech than to seen lip movements at frequencies below 1 Hz. This entrainment to absent speech was characterized by a speech-to-brain delay of 50–100 ms as when actually listening to speech. We also observed entrainment to lip movements at the same low frequency in the right angular gyrus, an area involved in processing biological motion. These findings demonstrate that the brain can synthesize high-level features of absent unknown speech sounds from lip-reading that can facilitate the processing of the auditory input. Such a synthesis process may help explain well-documented bottom-up perceptual effects.
Splice variants of DOMINO controlDrosophilacircadian behavior and pacemaker neuron maintenance
Authors: Liu Zhenxing , Niu Ye , Lam Vu H. , Chiu Joanna C. , Zhang Yong 
Published: August 2018

AbstractCircadian clocks control daily rhythms in physiology. InDrosophila, the small ventral lateral neurons (sLNvs) expressing PIGMENT DISPERSING FACTOR (PDF) are the master pacemaker neurons. Despite the importance of sLNvs and PDF in circadian behavior, little is known about factors that control sLNvs maintenance and PDF accumulation. Here, we identify theDrosophilaSWI2/SNF2 protein DOMINO (DOM) as a key regulator of circadian behavior. Depletion of DOM eliminates morning anticipation and impairs rhythmicity. Interestingly, the two splice variants of DOM, DOM-A and DOM-B have distinct circadian functions. DOM-A depletion leads to arrhythmic behavior, while DOM-B knockdown lengthens circadian period. Both DOM-A and DOM-B bind to the promotor regions of key pacemaker genesperiodandtimeless, and regulate their protein expression. Furthermore, we identify that DOM-A is required for the maintenance of sLNvs and transcription ofpdf. Lastly, constitutive activation of PDF-receptor signaling rescued the arrhythmia and period lengthening of DOM downregulation. Taken together, our findings reveal that splice variants of DOM play distinct roles in circadian rhythms through regulating abundance of pacemaker proteins and sLNvs maintenance.
SNP Variable Selection by Generalized Graph Domination
Authors: Sun Shuzhen , Miao Zhuqi , Ratcliffe Blaise , Campbell Polly , Pasch Bret , El-Kassaby Yousry A. , Balasundaram Balabhaskar , Chen Charles 
Published: August 2018

AbstractHigh-throughput sequencing technology has revolutionized both medical and biological research by generating exceedingly large numbers of genetic variants. The resulting datasets share a number of common characteristics that might lead to poor generalization capacity. Concerns include noise accumulated due to the large number of predictors, sparse information regarding thep≫nproblem, and overfitting and model mis-identification resulting from spurious collinearity. Additionally, complex correlation patterns are present among variables. As a consequence, reliable variable selection techniques play a pivotal role in predictive analysis, generalization capability, and robustness in clustering, as well as interpretability of the derived models.K-dominating set, a parameterized graph-theoretic generalization model, was used to model SNP (single nucleotide polymorphism) data as a similarity network and searched for representative SNP variables. In particular, each SNP was represented as a vertex in the graph, (dis)similarity measures such as correlation coefficients or pairwise linkage disequilibrium were estimated to describe the relationship between each pair of SNPs; a pair of vertices are adjacent, i.e. joined by an edge, if the pairwise similarity measure exceeds a user-specified threshold. A minimumK-dominating set in the SNP graph was then made as the smallest subset such that every SNP that is excluded from the subset has at leastkneighbors in the selected ones. The strength ofk-dominating set selection in identifying independent variables, and in culling representative variables that are highly correlated with others, was demonstrated by a simulated dataset. The advantages ofk-dominating set variable selection were also illustrated in two applications: pedigree reconstruction using SNP profiles of 1,372 Douglas-fir trees, and species delineation for 226 grasshopper mouse samples. A C++ source code that implements SNP-SELECT and uses Gurobi™ optimization solver for thek-dominating set variable selection is available (https://github.com/transgenomicsosu/SNP-SELECT).
A population of stress-like cancer cells in melanoma promotes tumorigenesis and confers drug resistance
Authors: Baron Maayan , Tagore Mohita , Hunter Miranda V. , Kim Isabella S. , Moncada Reuben , Yan Yun , Campbell Nathaniel R. , White Richard M. , Yanai Itai 
Published: August 2018

SUMMARYTranscriptional profiling has revealed a diverse range of cancer cell states, however an understanding of their function has remained elusive. Using a combination of zebrafish melanoma modeling and human validation, we have identified a conserved stress-like state that confers intrinsic drug resistance. The stress-like state expresses genes such asfos,hsp70andubb, all required for adaptation to diverse cellular stresses, and we confirmed its existence using immunofluorescence and spatial transcriptomics. We provide evidence that this state has a higher tumor seeding capabilities compared to non-stressed cells, and confers intrinsic resistance to MEK inhibitors, a commonly used melanoma therapeutic. Furthermore, the stress-like program can be induced by extrinsic processes such as heat shock, and confers resistance to both MEK and BRAF inhibitors in both zebrafish and human melanomas. Collectively, our study suggests that the transcriptional states associated with therapeutic failure are established during the earliest steps of tumorigenesis.
A de novoEDA-variant in a litter of shorthaired standard Dachshunds with X-linked hypohidrotic ectodermal dysplasia
Authors: Vasiliadis Danae , Hewicker-Trautwein Marion , Klotz Daniela , Fehr Michael , Ruseva Stefka , Arndt Jennifer , Metzger Julia , Distl Ottmar 
Published: August 2018

AbstractIn this study, we present a detailed phenotype description and genetic elucidation of the first case of X-linked hypohidrotic ectodermal dysplasia in the shorthaired standard Dachshund. This condition is characterized by partial alopecia, missing and malformed teeth and a lack of eccrine sweat glands. Clinical signs including dental X-raying and histopathological findings were consistent with an ectodermal dysplasia. Pedigree analysis supported an X-recessive mode of inheritance. Whole-genome sequencing of one affected puppy and his dam identified a 1-basepair deletion within theectodysplasin-Agene (CM000039.3:g.54509504delT, PRJEB27789). Sanger sequencing of further family members confirmed the PRJEB27789-variant. Validation in all available family members, 37 unrelated shorthaired standard Dachshunds, 128 Dachshunds from all other breeds and samples from 34 dog breeds revealed the PRJEB27789 variant to be private for this family. Two heterozygous females showed very mild alopecia but normal dentition. Since the dam is demonstrably the only heterozygous animal in the ancestry of the affected animals, we assume that the PRJEB27789-variant arose in the germline of the granddam or in an early embryonic stage of the dam. In conclusion, we detected a very recent de-novoEDAmutation causing X-linked hypohidrotic ectodermal dysplasia in the shorthaired standard Dachshund.
Gene target discovery with network analysis inToxoplasma gondii
Authors: Alonso Andres M. , Corvi Maria M. , Diambra Luis 
Published: August 2018

ABSTRACTInfectious diseases are of great relevance for global health, but needed drugs and vaccines have not been developed yet or are not effective in many cases. In fact, traditional scientific approaches with intense focus on individual genes or proteins have not been successful in providing new treatments. Hence, innovations in technology and computational methods provide new tools to further understand complex biological systems such as pathogens biology. In this work, we propose a system biology approach to analyze transcriptomic data of the parasiteToxoplasma gondii. By means of an optimization procedure, the phenotypic transitions between the stages associated with the life cycle of the parasite were embedded into the dynamics of a gene network model. Thus, through this methodology we were able to reconstruct a gene regulatory network able to emulate the life cycle of the pathogen. The community network analysis has revealed that nodes of the network can be organized in seven communities which allow us to assign putative functions to 339 previously uncharacterized genes, 25 of which are predicted as new pathogenic factors. Furthermore, we identified a small subnetwork module that controls the parasite’s life cycle. These new findings can contribute to understand of parasite pathogenesis.
Zero-preserving imputation of scRNA-seq data using low-rank approximation
Authors: Linderman George C. , Zhao Jun , Kluger Yuval 
Published: August 2018

ABSTRACTSingle cell RNA-sequencing (scRNA-seq) methods have revolutionized the study of gene expression but are plagued by dropout events, a phenomenon where genes actually expressed in a given cell are incorrectly measured as unexpressed. We present a method based on low-rank approximation which successfully replaces these dropouts (zero expression levels of unobserved expressed genes) by nonzero values, while preserving biologically non-expressed genes (true biological zeros) at zero expression levels. We validate our approach and compare it to two state-of-the-art methods. We show that it recovers true expression of marker genes while preserving biological zeros, increases separation of known cell types and improves correlation of simulated cells to their true profiles. Furthermore, our method is dramatically more scalable, allowing practitioners to quickly and easily recover expression of even the largest scRNA-seq datasets.
Genome Scale Epigenetic Profiling Reveals Five Distinct Subtypes of Colorectal Cancer
Authors: Fennell Lochlan , Dumenil Troy , Hartel Gunter , Nones Katia , Bond Catherine , McKeone Diane , Bowdler Lisa , Montgomery Grant , Wockner Leesa , Klein Kerenaftali , Hoffmann Isabell , Patch Ann-Marie , Kazakoff Stephen , Pearson John , Waddell Nicola , Wirapati Pratyaksha , Lochhead Paul , Imamura Yu , Ogino Shuji , Shao Renfu , Tejpar Sabine , Leggett Barbara , Whitehall Vicki 
Published: August 2018

AbstractBACKGROUND:Colorectal cancer is an epigenetically heterogeneous disease, however the extent and spectrum of the CpG Island Methylator Phenotype (CIMP) is not clear.RESULTSAn unselected cohort of 216 colorectal cancers clustered into five clinically and molecularly distinct subgroups using Illumina 450K DNA methylation arrays. CIMP-High cancers were most frequent in the proximal colons of female patients. These dichotomised into CIMP-Hl and CIMP-H2 based on methylation profile which was supported by over representation ofBRAF(74%, P<0.0001) orKRAS(55%, P<0.0001) mutation, respectively. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CI MP-Negative subgroup to 75 years in the CIMP-Hl subgroup (P<0.0001). There was a striking association between PRC2-marked loci and those subjected to significant gene body methylation in CIMP-type cancers (P<1.6xl078). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster specific mutations were observed for genes involved in chromatin remodelling, such as in the SWI/SNF and NuRD complexes, suggesting synthetic lethality.CONCLUSIONThere are five clinically and molecularly distinct subgroups of colorectal cancer based on genome wide epigenetic profiling. These analyses highlighted an unidentified role for gene body methylation in progression of serrated neoplasia. Subgroup-specific mutation of distinct epigenetic regulator genes revealed potentially druggable vulnerabilities for these cancers, which may provide novel precision medicine approaches.
GxEMM: Extending linear mixed models to general gene-environment interactions
Authors: Dahl Andy , Cai Na , Flint Jonathan , Zaitlen Noah 
Published: August 2018

AbstractGene-environment interaction (GxE) is a well-known source of non-additive inheritance. GxE can be important in applications ranging from basic functional genomics to precision medical treatment. Further, GxE effects elude inherently-linear LMMs and may explain missing heritability. We propose a simple, unifying mixed model for polygenic interactions (GxEMM) to capture the aggregate effect of small GxE effects spread across the genome. GxEMM extends existing LMMs for GxE in two important ways. First, it extends to arbitrary environmental variables, not just categorical groups. Second, GxEMM can estimate and test for environment-specific heritability. In simulations where the assumptions of existing methods do not hold, we show that GxEMM improves estimates of ordinary and GxE heritability and increases power to test for polygenic GxE. We then use GxEMM to prove that the heritability of major depression (MD) is reduced by stress, which we previously conjectured but could not prove with prior methods, and that a tail of polygenic GxE effects remains unexplained by MD GWAS.
Systematic evaluation of the causal relationship between DNA methylation and C-reactive protein
Authors: Walton Esther , Hemani Gibran , Dehghan Abbas , Relton Caroline , Smith George Davey 
Published: August 2018

AbstractElevated C-reactive protein (CRP) levels are an indicator of chronic low-grade inflammation. Epigenetic modifications, including DNA methylation, have been linked to CRP, but systematic investigations into potential underlying causal relationships have not yet been performed.We systematically performed two-sample Mendelian randomization and colocalization analysis between CRP and DNA methylation levels, using GWAS and EWAS summary statistics as well as individual level data available through the ARIES subset of the Avon Longitudinal Study of Parents and Children (ALSPAC; 1,616 participants).We found no convincing examples for a causal association from CRP to DNA methylation. Testing for the reverse (a putative causal effect of DNA methylation on CRP), we found three CpG sites that had shared genetic effects with CRP levels after correcting for multiple testing (cg26470501 (offspring: beta=0.07 [0.03, 0.11]; mothers: beta=0.08 [0.04, 0.13]), cg27023597 (offspring: beta=0.18 [0.10, 0.25]; mothers: beta=0.20 [0.12, 0.28]) and cg12054453 (offspring: beta=0.09 [0.05, 0.13])) influenced CRP levels. For all three CpG sites, linked to the genes TMEM49, BCL3 and MIR21, increased methylation related to an increase in CRP levels. Two CpGs (cg27023597 and cg12054453) were influenced by SNPs in genomic regions that had not previously been implicated in CRP GWASs, implicating them as novel genetic associations.Overall, our findings suggest that CRP associations with DNA methylation are more likely to be driven by either confounding or causal influences of DNA methylation on CRP levels, rather than the reverse.
Combinatorial recognition of clustered RNA elements by a multidomain RNA-binding protein, IMP3
Authors: Schneider Tim , Hung Lee-Hsueh , Aziz Masood , Wilmen Anna , Thaum Stephanie , Wagner Jacqueline , Janowski Robert , Müller Simon , Hüttelmaier Stefan , Niessing Dierk , Sattler Michael , Schlundt Andreas , Bindereif Albrecht 
Published: August 2018

AbstractHow multidomain RNA-binding proteins recognize their specific target sequences, based on a combinatorial code, represents a fundamental unsolved question and has not been studied systematically so far. Here we focus on a prototypical multidomain RNA-binding protein, IMP3 (also called IGF2BP3), which contains six RNA-binding domains (RBDs): four KH and two RRM domains. We have established an integrative systematic strategy, combining single-domain-resolved SELEX-seq, motif-spacing analyses,in vivoiCLIP, functional validation assays, and structural biology. This approach identifies the RNA-binding specificity and RNP topology of IMP3, involving all six RBDs and a cluster of up to five distinct and appropriately spaced CA-rich and GGC-core RNA elements, covering a >100 nucleotide-long target RNA region. Our generally applicable approach explains both specificity and flexibility of IMP3-RNA recognition, providing a paradigm for the function of multivalent interactions with multidomain RNA-binding proteins in gene regulation.
LION/web: a web-based ontology enrichment tool for lipidomic data analysis
Authors: Molenaar Martijn R. , Jeucken Aike , Wassenaar Tsjerk A. , van de Lest Chris H. A. , Brouwers Jos F. , Helms J. Bernd 
Published: August 2018

SUMMARYA major challenge for lipidomic analyses is the handling of the large amounts of data and the translation of results to interpret the involvement of lipids in biological systems. We built a new lipid ontology (LION) that associates over 50,000 lipid species to biophysical, chemical and cell biological features. By making use of enrichment algorithms, we used LION to develop a web-based interface (LION/web, www.lipidontology.com) that allows identification of lipid-associated terms in lipidomes. LION/web was validated by analyzing a lipidomic dataset derived from well-characterized sub-cellular fractions of RAW 264.7 macrophages. Comparison of isolated plasma membranes with the microsomal fraction showed a significant enrichment of relevant LION-terms including ‘plasma membrane’, ‘headgroup with negative charge, ‘glycerophosphoserines’, ‘above average bilayer thickness’, and ‘below average lateral diffusion’. A second validation was performed by analyzing the membrane fluidity of CHO cells incubated with arachidonic acid. An increase in membrane fluidity was observed both experimentally by using pyrene decanoic acid and by using LION/web, showing significant enrichment of terms associated with high membrane fluidity ('above average’, 'very high’ and 'high lateral diffusion’, and 'below average transition temperature’). The results demonstrate the functionality of LION/web, which is freely accessible in a platform-independent way.