bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effective Tyrosine Kinase Inhibitors result in the intracellular accumulation of EGFR and allows response prediction in patients
Authors: de Wit Maurice , Gao Ya , Mercieca Darlene , de Heer Iris , Valkenburg Bart , van Royen Martin , Aerts Joachim , Smitt Peter Sillevis , French Pim 
Published: October 2019

AbstractClinical responses to EGFR tyrosine kinase inhibitors are restricted only to tumors harboring specific activating mutations and even then, not all tyrosine kinase inhibitors provide clinical benefit. We here show that the addition of EGFR-TKIs results in a strong and rapid intracellular accumulation of the protein. However, this accumulation was observed only in the context of a combination of a TKI-sensitive mutation with a clinically effective TKI: TKI-insensitive mutations did not show this accumulation nor did clinically ineffective TKIs induce accumulation. All TKIs effectively inhibited EGFR phosphorylation and downstream pathway activation, irrespective of the mutation present in EGFR. The discrepancy between molecular activity of TKIs and their efficacy in patients therefore is mimicked by the mutation- and TKI-specificity of intracellular accumulation. Using this intracellular accumulation as assay, we were able to predict response to gefitinib in a panel of cell-lines (harboring different EGFR mutations) and predicted clinical benefit to EGFR TKIs on a cohort of unselected pulmonary adenocarcinoma patients (hazard ratio 0.21, P=0.0004). Even in patients harboring rare mutations with unknown TKI-sensitivity, intracellular accumulation was predictive of the clinical response. The intracellular accumulation depended on a continued presence of TKI indicating that TKIs exert a continued effect on the protein even after its dephosphorylation. It is therefore possible that accumulation is caused by conformational changes induced by both the mutation and the TKI and this change induces a block in intracellular trafficking. Interestingly, intracellular accumulation was observed independent of the genetic background of the cell, indicating that accumulation is almost entirely dictated by the combination of mutation and TKI. Our results therefore suggest that TKI-sensitivity is tumor-type independent.
qDRIP: Quantitative differential RNA:DNA hybrid immunoprecipitation sequencing
Authors: Crossley Madzia P , Bocek Michael J , Hamperl Stephan , Swigut Tomek , Cimprich Karlene A. 
Published: October 2019

AbstractR-loops are dynamic, co-transcriptional nucleic acid structures that facilitate physiological processes and cause DNA damage in certain contexts. Perturbations of transcription or R-loop resolution are expected to change their genomic distribution. Next-generation sequencing approaches to map RNA:DNA hybrids, a component of R-loops, have so far not allowed quantitative comparisons between such conditions. Here we describe quantitative differential RNA:DNA immunoprecipitation (qDRIP), a method combining synthetic RNA:DNA-hybrid internal standards with high-resolution, strand-specific sequencing. We show that qDRIP avoids biases inherent to read-count normalization by accurately profiling signal in regions unaffected by transcription inhibition in human cells, and by facilitating accurate differential peak calling between conditions. Finally, we use these quantitative comparisons to make the first estimates of the absolute count of RNA:DNA hybrids per cell and their half-lives genome-wide. Overall, qDRIP allows for accurate normalization in conditions where R-loops are perturbed and for quantitative measurements that provide previously unattainable biological insights.
Systematic identification of A-to-I editing associated regulators from multiple human cancers
Authors: Gu Tongjun , Fu Audrey Qiuyan , Bolt Michael J. , Zhao Xiwu 
Published: October 2019

AbstractA-to-I editing is the most common editing type in human that is catalyzed by ADAR family members (ADARs), ADAR1 and ADAR2. Millions of A-to-I editing sites have been discovered recently, however, the regulation mechanisms of the RNA editing process are still not clear. Here we developed a two-step logistic regression model to identify genes that are potentially involved in RNA editing process in four human cancers. The first step by classifying the editing sites into different categories assists the analysis at the second step. In the first step, ADAR1 was identified as the enzyme that associated with the majority of the A-to-I editing sites. Thus, ADAR1 was taken as a control gene in the second step to identify genes that have a stronger effect on editing sites than ADAR1. In addition, the detectable interferons and their receptors were used as covariates in the both steps to account for potential association caused by interferons. Using our advanced method, we successfully found a set of genes that were significantly positively or negatively associated (PA or NA) with specific sets of RNA editing sites. We highlighted two genes, SRSF5 and MIR22HG which were supported by multiple evidences. Most PA and NA genes were unique to each cancer, and only a few shared across two cancers. Pathway enrichment analysis showed that the PA genes from the four cancer types were enriched in Immune System, while the NA genes were enriched in two pathways: Metabolism of RNA, and Metabolism. The functional similarity of the PA and NA genes across all the four cancers indicates that even though most of the editing associated genes were unique to each cancer, they may impact on editing process through common pathways. Interestingly, the PA genes from kidney cancer were enriched for survival-associated genes while the NA genes were depleted of these genes, indicating that the PA genes may play more important roles in kidney cancer development.
RNAfamProb Plus NeoFold: Estimations of Posterior Probabilities on RNA Structural Alignment and RNA Secondary Structures with Incorporating Homologous-RNA Sequences
Authors: Tagashira Masaki , Asai Kiyoshi 
Published: October 2019

AbstractMotivationThe simultaneous optimization of the sequence alignment and secondary structures among RNAs, structural alignment, has been required for the more appropriate comparison of functional ncRNAs than sequence alignment. Pseudo-probabilities given RNA sequences on structural alignment have been desired for more-accurate secondary structures, sequence alignments, consensus secondary structures, and structural alignments. However, any algorithms have not been proposed for these pseudo-probabilities.ResultsWe invented the RNAfamProb algorithm, an algorithm for estimating these pseudo-probabilities. We performed the application of these pseudo-probabilities to two biological problems, the visualization with these pseudo-probabilities and maximum-expected-accuracy secondary-structure (estimation). The RNAfamProb program, an implementation of this algorithm, plus the NeoFold program, a maximum-expected-accuracy secondary-structure program with these pseudo-probabilities, demonstrated prediction accuracy better than three state-of-the-art programs of maximum-expected-accuracy secondary-structure while demanding running time far longer than these three programs as expected due to the intrinsic serious problem-complexity of structural alignment compared with independent secondary structure and sequence alignment. Both the RNAfamProb and NeoFold programs estimate matters more accurately with incorporating homologous-RNA sequences.AvailabilityThe source code of each of these two programs is available on each of “https://github.com/heartsh/rnafamprob” and “https://github.com/heartsh/neofold”.Contact“tagashira_masaki_17@stu-cbms.k.u-tokyo.ac.jp” and “asai@k.u-tokyo.ac.jp”.Supplementary informationSupplementary data are available at Bioinformatics online.
InterPep2: Global Peptide-Protein Docking with Structural Templates
Authors: Johansson-Åkhe Isak , Mirabello Claudio , Wallner Björn 
Published: October 2019

AbstractMotivationInteractions between proteins and peptides or peptide-like intrinsically disordered regions are involved in many important biological processes, such as gene expression and cell life-cycle regulation. Experimentally determining the structure of such interactions is time-consuming, and because of the disordered nature of the ligand, the interactions are especially difficult to predict through software, requiring specialized solutions. Although several prediction-methods exist, most are limited in performance or availability.ResultsInterPep2 is a freely available method for predicting the structure of peptide-protein interactions. We have previously shown that structural templates can be used to accurately predict peptide-protein binding sites, and that using templates from regular protein-protein interactions will increase the number of sites found. Here, we show that the same principle can be extended to dock the peptide to the binding surface using InterPep2. A key component of InterPep2 is the ability to score plausible interaction templates using a RandomForest trained to predict the DockQ-score using sequence and structural features. InterPep2 is tested on a difficult dataset of 251 peptide-protein complexes, where it correctly positions 136 (54%) at the correct site compared to 114 (45%) for the second best method. Analyzing the confidence score InterPep2 recalls more true positives across all specificity levels compared to the second best method, for example at 10% False Positive Rate it correctly identifies 59% of the complexes compared to 44% for the second best method.AvailabilityThe program is available from:http://wallnerlab.org/InterPepContactBjörn Wallnerbjorn.wallner@liu.se
Dysregulation of temporal dynamics of synchronous neural activity in adolescents on autism spectrum
Authors: Malaia Evie A. , Ahn Sungwoo , Rubchinsky Leonid L 
Published: October 2019

AbstractAutism spectrum disorder is increasingly understood to be based on atypical signal transfer among multiple interconnected networks in the brain. Relative temporal patterns of neural activity have been shown to underlie both the altered neurophysiology and the altered behaviors in a variety of neurogenic disorders. We assessed brain network dynamics variability in Autism Spectrum Disorders (ASD) using measures of synchronization (phase-locking) strength, and timing of synchronization and desynchronization of neural activity (desynchronization ratio) across frequency bands of resting state EEG. Our analysis indicated that fronto-parietal synchronization is higher in ASD, but with more short periods of desynchronization. It also indicates that the relationship between the properties of neural synchronization and behavior is different in ASD and typically developing populations. Recent theoretical studies suggest that neural networks with high desynchronization ratio have increased sensitivity to inputs. Our results point to the potential significance of this phenomenon to autistic brain. This sensitivity may disrupt production of an appropriate neural and behavioral responses to external stimuli. Cognitive processes dependent on integration of activity from multiple networks may be, as a result, particularly vulnerable to disruption.Lay SummaryParts of the brain can work together by synchronizing activity of the neurons. We recorded electrical activity of the brain in adolescents with autism spectrum disorder, and then compared the recording to that of their peers without the diagnosis. We found that in participants with autism, there were a lot of very short time periods of non-synchronized activity between frontal and parietal parts of the brain. Mathematical models show that the brain system with this kind of activity is very sensitive to external events.
Amino and PEG-Amino Graphene Oxide Grids Enrich and Protect Samples for High-resolution Single Particle Cryo-electron Microscopy
Authors: Wang Feng , Yu Zanlin , Betegon Miguel , Campbell Melody , Aksel Tural , Zhao Jianhua , Li Sam , Douglas Shawn M. , Cheng Yifan , Agard David A. 
Published: October 2019

AbstractCryo-EM samples prepared using the traditional methods often suffer from too few particles, poor particle distribution, or strongly biased orientation, or damage from the air-water interface. Here we report that functionalization of graphene oxide (GO) coated grids with amino groups concentrates samples on the grid with improved distribution and orientation. By introducing a PEG spacer, particles are kept away from both the GO surface and the air-water interface, protecting them from potential denaturation.
Cryptococcus neoformansChitin Synthase 3 (Chs3) Plays a Critical Role in Dampening Host Inflammatory Responses
Authors: Hole Camaron R. , Lam Woei C. , Upadhya Rajendra , Lodge Jennifer K. 
Published: October 2019

ABSTRACTCryptococcus neoformansinfections are significant causes of morbidity and mortality among AIDS patients and the third most common invasive fungal infection in organ transplant recipients. One of the main interfaces between the fungus and the host is the fungal cell wall. The cryptococcal cell wall is unusual among human pathogenic fungi in that the chitin is predominantly deacetylated to chitosan. Chitosan deficient strains ofC. neoformanswere found to be avirulent and rapidly cleared from the murine lung. Moreover, infection with a chitosan deficientC. neoformanslacking three chitin deacetylases (cda1Δ2Δ3Δ) was found to confer protective immunity to a subsequent challenge with a virulent wild type counterpart. In addition to the chitin deacetylases, it was previously shown that chitin synthase 3 (Chs3) is also essential for chitin deacetylase mediated formation of chitosan. Mice inoculated withchs3Δat a dose previously shown to induce protection with cda1Δ2Δ3Δdie within 36 hours after installation of the organism. Mortality was not dependent on viable fungi as mice inoculated with heat-killed preparation ofchs3Δdied at the same rate as mice inoculated with livechs3Δ, suggesting the rapid onset of death was host mediated likely caused by an over exuberant immune response. Histology, cytokine profiling, and flow cytometry indicates a massive neutrophil influx in the mice inoculated withchs3Δ. Mice depleted of neutrophils survivedchs3Δinoculation indicating that death was neutrophil mediated. Altogether, these studies lead us to conclude that Chs3, along with chitosan, plays critical roles in dampening cryptococcal induced host inflammatory responses.IMPORTANCECryptococcus neoformansis the most common disseminated fungal pathogen in AIDS patients, resulting in ∼200,000 deaths each year. There is a pressing need for new treatments for this infection, as current antifungal therapy is hampered by toxicity and/or the inability of the host’s immune system to aid in resolution of the disease. An ideal target for new therapies is the fungal cell wall. The cryptococcal cell wall is different than many other pathogenic fungi in that it contains chitosan. Strains that have decreased chitosan are less pathogenic and strains that are deficient in chitosan are avirulent and can induce protective responses. In this study we investigated the host responses tochs3Δ, a chitosan-deficient strain, and found mice inoculated withchs3Δ all died within 36 hours and death was associated with an aberrant hyperinflammatory immune response driven by neutrophils, indicating that chitosan is critical in modulating the immune response toCryptococcus.
The Dynamics of Influenza A H3N2 Defective Viral Genomes from a Human Challenge Study
Authors: Martin Michael A. , Kaul Drishti , Tan Gene S. , Woods Christopher W. , Koelle Katia 
Published: October 2019

AbstractThe rapid evolution of influenza is an important contributing factor to its high worldwide incidence. The emergence and spread of genetic point mutations has been thoroughly studied both within populations and within individual hosts. In addition, influenza viruses are also known to generate genomic variation during their replication in the form of defective viral genomes (DVGs). These DVGs are formed by internal deletions in at least one gene segment that render them incapable of replication without the presence of wild-type virus. DVGs have previously been identified in natural human infections and may be associated with less severe clinical outcomes. These studies have not been able to address how DVG populations evolvein vivoin individual infections due to their cross-sectional design. Here we present an analysis of DVGs present in samples from two longitudinal influenza A H3N2 human challenge studies. We observe the generation of DVGs in almost all subjects. Although the genetic composition of DVG populations was highly variable, identical DVGs were observed both between multiple samples within single hosts as well as between hosts. Most likely due to stochastic effects, we did not observe clear instances of selection for specific DVGs or for shorter DVGs over the course of infection. Furthermore, DVG presence was not found to be associated with peak viral titer or peak symptom scores. Our analyses highlight the diversity of DVG populations within a host over the course of infection and the apparent role that genetic drift plays in their population dynamics.ImportanceThe evolution of influenza virus, in terms of single nucleotide variants and the reassortment of gene segments, has been studied in detail. However, influenza is known to generate defective viral genomes (DVGs) during replication, and little is known about how these genomes evolve both within hosts and at the population level. Studies in animal models have indicated that prophylactically or therapeutically administered DVGs can impact patterns of disease progression. However, the formation of naturally-occurring DVGs, their evolutionary dynamics, and their contribution to disease severity in human hosts is not well understood. Here, we identify the formation ofde novoDVGs in samples from human challenge studies throughout the course of infection. We analyze their evolutionary trajectories, revealing the important role of genetic drift in shaping DVG populations during acute infections with well-adapted viral strains.
Crystal structure, Hirshfeld surface analysis and interaction energy and DFT studies of (2Z)-4-benzyl-2-(2,4-dichlorobenzylidene)-2H-1,4-benzothiazin-3(4H)-one
Authors: Sebbar Nada Kheira , Hni Brahim , Hökelek Tuncer , Labd Taha Mohamed , Mague Joel T. , El Ghayati Lhoussaine , Essassi El Mokhtar 
Published: October 2019

The title compound, C22H15Cl2NOS, contains 1,4-benzothiazine and 2,4-dichlorobenzylidene units, where the dihydrothiazine ring adopts a screw-boat conformation. In the crystal, intermolecular C—HBnz...OThz(Bnz = benzene and Thz = thiazine) hydrogen bonds form corrugated chains extending along theb-axis direction which are connected into layers parallel to thebcplane by intermolecular C—HMethy...SThz(Methy = methylene) hydrogen bonds, enclosingR44(22) ring motifs. Offset π-stacking interactions between 2,4-dichlorophenyl rings [centroid–centroid = 3.7701 (8) Å] and π-interactions which are associated by C—HBnz...π(ring) and C—HDchlphy...π(ring) (Dchlphy = 2,4-dichlorophenyl) interactions may be effective in the stabilization of the crystal structure. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H...H (29.1%), H...C/C...H (27.5%), H...Cl/Cl...H (20.6%) and O...H/H...O (7.0%) interactions. Hydrogen-bonding and van der Waals interactions are the dominant interactions in the crystal packing. Computational chemistry indicates that in the crystal, the C—HBnz...OThzand C—HMethy...SThzhydrogen-bond energies are 55.0 and 27.1 kJ mol−1, respectively. Density functional theory (DFT) optimized structures at the B3LYP/6-311G(d,p) level are compared with the experimentally determined molecular structure in the solid state. The HOMO–LUMO behaviour was elucidated to determine the energy gap.
Corporate governance and internal audit: an institutional theory perspective
Authors: Vadasi Christina , Bekiaris Michalis , Andrikopoulos Andreas 
Published: October 2019

PurposeThis paper aims to explore internal audit effectiveness through its contribution to corporate governance. Namely, the authors attempt to investigate the impact of internal audit professionalization on internal audit’s contribution to corporate governance.Design/methodology/approachUsing a research framework informed by institutional theory, the authors predict that internal audit’s contribution to corporate governance is associated with factors related to internal audit professionalization. To investigate the arguments, the authors combine data from a survey of 49 listed companies in the Athens Stock Exchange with publicly available information from annual reports.FindingsEmpirical results indicate that internal audit professionalization affects internal audit effectiveness, as internal audit’s contribution to corporate governance is improved for organizations where internal audit function complies with internal auditing standards and internal auditors hold professional certifications. The findings also suggest that internal audit’s contribution to corporate governance is shaped by some company-specific characteristics, namely, CEO duality and audit committee quality.Practical implicationsThe results have implications for internal auditors who wish to increase the efficiency of their work, corporate governance mechanisms such as the board of directors and the audit committee, which can use the findings of this study to better respond to their responsibilities concerning internal audit and regulators who can also benefit to strengthen areas with substantial impact on internal audit’s contribution to corporate governance.Originality/valueThis paper contributes to the academic discussion on the role of internal audit in corporate governance and complements the work of other researchers in the field of internal audit professionalization. This study tries to fill a gap in the literature on the effect of internal audit professionalization elements on internal audit’s contribution to corporate governance.
Use of Koha-integrated library system by higher education institutions in Malawi
Authors: Chaputula Aubrey , Kanyundo Allan 
Published: October 2019

Purpose
The purpose of this paper is to study the use of Koha integrated library system by higher education institutions in Malawi.

Design/methodology/approach
The study made use of the diffusion of innovation theory as an anchoring model. Data were collected using a survey questionnaire that was administered to library managers of higher education institutions registered with the National Council for Higher Education in Malawi. The data collected were analyzed using SPPS version 21 to generate descriptive statistics.

Findings
The findings revealed that 84.2 per cent of libraries in higher education institutions in Malawi are automated, and 81.3 per cent of them are using Koha ILS and the rest were using proprietary and other open source software. Cost and technical aspects have been discovered to be the primary factors that have assisted in the rapid diffusion of Koha. The study also exposed some factors that negatively impacted the use of Koha in the adopting institutions. The main ones included lack of information and communication technology infrastructure, unreliable Internet connectivity and limited finances.

Originality/value
Previously, some small-scale case studies have been performed to examine implementation of Koha in some higher education institutions in Malawi. However, this is the first large-scale attempt to investigate use of Koha among higher education institutions in the country. Findings that have shown that Koha can be installed easily and used at minimal cost could assist in its rapid adoption in the higher education institutions, a majority of whom face a myriad of financial challenges.