bluuebunny/crossref_metadata_2025_split huggingface dataset:
In silicolearning of tumor evolution through mutational time series
Authors: Auslander Noam , Wolf Yuri I. , Koonin Eugene V. 
Published: March 2019

AbstractCancer arises through the accumulation of somatic mutations over time. Understanding the sequence of mutation occurrence during cancer progression can assist early and accurate diagnosis and improve clinical decision-making. Here we employ Long Short-Term Memory networks (LSTMs), a class of recurrent neural network, to learn the evolution of a tumor through an ordered sequence of mutations. We demonstrate the capacity of LSTMs to learn complex dynamics of the mutational time series governing tumor progression, allowing accurate prediction of the mutational burden and the occurrence of mutations in the sequence. Using the probabilities learned by the LSTM, we simulate mutational data and show that the simulation results are statistically indistinguishable from the empirical data. We identify passenger mutations that are significantly associated with established cancer drivers in the sequence and demonstrate that the genes carrying these mutations are substantially enriched in interactions with the corresponding driver genes. Breaking the network into modules consisting of driver genes and their interactors, we show that these interactions are associated with poor patient prognosis, thus likely conferring growth advantage for tumor progression. Thus, application of LSTM provides for prediction of numerous additional conditional drivers and to reveal hitherto unknown aspects of cancer evolution.SignificanceCancer is caused by the effects of somatic mutations known as drivers. Although a number of major cancer drivers have been identified, it is suspected that many more comparatively rare and conditional drivers exist, and the interactions between different cancer-associated mutations that might be relevant for tumor progression are not well understood. We applied an advanced neural network approach to learn the sequence of mutations and the mutational burden in colon and lung cancers, and to identify mutations that are associated with individual drivers. A significant ordering of driver mutations is demonstrated, and numerous, previously undetected conditional drivers are identified. These findings broaden the existing understanding of the mechanisms of tumor progression and have implications for therapeutic strategies.
Specific type 1 diabetes risk genes underpin age-at-diagnosis and indicate joint defects in immunity, beta-cell fragility and responses to viral infections in early-onset disease
Authors: Inshaw Jamie R.J. , Cutler Antony J. , Crouch Daniel J.M. , Wicker Linda S. , Todd John A. 
Published: March 2019

AbstractObjectiveImmunohistological analyses of pancreata from patients with type 1 diabetes suggest a stratification of islet pathology of both B and T lymphocyte islet inflammation common in children diagnosed at <7 years (<7 group), whereas B cells are rare in those diagnosed age ≥13 (≥13 group). Based on these observations, we sought to identify differences in genetic susceptibility between these age-at-diagnosis groups, to inform on the aetiology of the most aggressive form of type 1 diabetes that initiates in the first years of life.Research Design and MethodsUsing multinomial logistic regression models, we tested if known type 1 diabetes loci (17 within the HLA region and 55 non-HLA regions) had significantly stronger effect sizes in the <7 group compared to the ≥13 group, using genotype data from 27,075 individuals (18,488 controls, 3,109 cases diagnosed at <7, 3,754 at 7-13 and 1,724 at ≥13).ResultsSix HLA haplotypes/classical alleles and seven non-HLA regions, one of which functions specifically in beta cells (GLIS3), and the other six likely affecting key T cell (IL2RA, IL10, SIRPG, IKZF3, THEMIS), thymus (THEMIS) and B cell development/functions (IKZF3, IL10) or in both immune and beta cells (CTSH) had stronger effects in the <7 group.ConclusionsIn newborn children with the greatest load of certain risk alleles, dysregulated response of immune and beta cells to environmental stresses such as virus infection, combine to cause a rapid loss of insulin production, driving down the age of type 1 diabetes diagnosis.
Impact of 3-dimensional genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver
Authors: Matthews Bryan J. , Waxman David J. 
Published: March 2019

AbstractBackgroundSex differences in the transcriptome and epigenome are widespread in mouse liver and are associated with sex-bias in liver disease. Several thousand sex-differential distal enhancers have been identified; however, their links to sex-biased genes and the impact of any sex-differences in nuclear organization, DNA looping, and chromatin interactions are unknown.ResultsTo address these issues, we first characterized 1,847 mouse liver genomic regions showing significant sex differential occupancy by cohesin and CTCF, two key 3D nuclear organizing factors. These sex-differential binding sites were largely distal to sex-biased genes, but rarely generated sex-differential TAD (topologically associating domain) or intra-TAD loop anchors. A substantial subset of the sex-biased cohesin-non-CTCF binding sites, but not the sex-biased cohesin-and-CTCF binding sites, overlapped sex-biased enhancers. Cohesin depletion reduced the expression of male-biased genes with distal, but not proximal, sex-biased enhancers by >10-fold, implicating cohesin in long-range enhancer interactions regulating sex-biased genes. Using circularized chromosome conformation capture-based sequencing (4C-seq), we showed that sex differences in distal sex-biased enhancer-promoter interactions are common. Sex-differential chromatin interactions involving sex-biased gene promoters, enhancers, and lncRNAs were associated with sex-biased binding of cohesin and/or CTCF. Furthermore, intra-TAD loops with sex-independent cohesin-and-CTCF anchors conferred sex specificity to chromatin interactions indirectly, by insulating sex-biased enhancer-promoter contacts and by bringing sex-biased genes into closer proximity to sex-biased enhancers.ConclusionsThese findings elucidate how 3-dimensional genome organization contributes to sex differences in gene expression in a non-reproductive tissue through both direct and indirect effects of cohesin and CTCF looping on distal enhancer interactions with sex-differentially expressed genes.
Comparative Analysis of Electrostatic Models for Ligand Docking
Authors: Sartori Geraldo Rodrigues , Nascimento Alessandro S. 
Published: March 2019

AbstractThe precise modeling of molecular interactions remains an important goal among molecular modeling techniques. Some of the challenges in the field include the precise definition of a Hamiltonian for biomolecular systems, together with precise parameters derived from Molecular Mechanics Force Fields, for example. The problem is even more challenging when interaction energies from different species are computed, such as the interaction energy involving a ligand and a protein, given that small differences must be computed from large energies. Here we evaluated the effects of the electrostatic model for ligand binding energy evaluation in the context of ligand docking. For this purpose, a classical Coulomb potential with distance-dependent dielectrics was compared with a Poisson-Boltzmann (PB) model for electrostatic potential computation, based on DelPhi calculations. We found that, although the electrostatic energies were highly correlated for the Coulomb and PB models, the ligand pose and the enrichment of actual ligands against decoy compounds, were improved when binding energies were computed using PB as compared to the Coulomb model. We observed that the electrostatic energies computed with the Coulomb model were, on average, ten times larger than the energies computed with the PB model, suggesting a strong overestimation of the polar interactions in the Coulomb model. We also found that a slightly smoothed Lennard-Jones potential combined with the PB model resulted in a good compromise between ligand sampling and energetic scoring.
A rapid method to determine the bactericidal activity of compounds against non-replicatingMycobacterium tuberculosisat low pH
Authors: Early Julie V. , Mullen Steven , Parish Tanya 
Published: March 2019

AbstractThere is an urgent need for new anti-tubercular agents which can lead to a shortened treatment time by targeting persistent or non-replicating bacilli. In order to assess compound activity against non-replicatingMycobacterium tuberculosis, we developed a method to detect the bactericidal activity of novel compounds within 7 days. Our method uses incubation at low pH in order to induce a non-replicating state. We used a strain ofM. tuberculosisexpressing luciferase; we first confirmed the linear relationship between luminescence and viable bacteria (determined by colony forming units) under our assay conditions. We optimized the assay parameters in 96-well plates in order to achieve a reproducible assay. Our final assay usedM. tuberculosisin phosphate-citrate buffer, pH 4.5 exposed to compounds for 7 days; viable bacteria were determined by luminescence. We recorded the minimum bactericidal concentration at pH 4.5 (MBC4.5) representing >2 logs of kill. We confirmed the utility of the assay with control compounds. The ionophores monensin, niclosamide, and carbonyl cyanide 3-chlorophenylhydrazone and the anit-tubercular drugs pretomanid and rifampicin were active, while several other drugs such as isoniazid, ethambutol, and linezolid were not.
Short-time fractal analysis of biological autoluminescence
Authors: Dlask Martin , Kukal Jaromír , Poplová Michaela , Sovka Pavel , Cifra Michal 
Published: March 2019

AbstractBiological systems manifest continuous weak autoluminescence, which is present even in the absence of external stimuli. Since this autoluminescence arises from internal metabolic and physiological processes, several works suggested that it could carry information in the time series of the detected photon counts. However, there is little experimental work which would show any difference of this signal from random Poisson noise and some works were prone to artifacts due to lacking or improper reference signals. Here we apply rigorous statistical methods and advanced reference signals to test the hypothesis whether time series of autoluminescence from germinating mung beans display any intrinsic correlations. Utilizing the fractional Brownian bridge that employs short samples of time-series in the method kernel, we suggest that the detected autoluminescence signal from mung beans is not totally random, but it seems to involve a process with a negative memory. Our results contribute to the development of the rigorous methodology of signal analysis of photonic biosignals.
In the mother’s shadow: exploring power dynamics in family business succession
Authors: Ferrari Filippo 
Published: March 2019

Purpose
This paper aims to investigate and explain the power dynamics involving the mother (as the founder) and the daughter (as the successor) during the business transmission process.

Design/methodology/approach
This qualitative research was conducted on a sample of Italian family SMEs. The adopted approach is consistent with the narration paradigm, where the biographical features of the participant are investigated to highlight the culture, value systems and other background features.

Findings
This research suggests that if the founder is her mother, the daughter faces further challenges. Findings suggest that during business transmission, it is also important to consider the cultural and contextual factors, such as gender biases, both in the family and in the workplace. This paper seems to suggest that power is important in itself, regardless of the gender of those who exercise it.

Research limitations/implications
Future research should investigate, quantitatively, the same issues considered in this research, to assess the reliability and validity of the evidence discussed here.

Practical implications
This paper suggests how to overcome dysfunctional dynamics in mother–daughter business transmission.

Social implications
Family firms are the most widespread type of firm in the world; as a consequence, systematic failures in business transmission represent a prominent socio-economical problem for policymakers and institutions.

Originality/value
This research shows that in family business, power is not dynamic and does not shift among family members, as suggested by previous research. Even once the mother retires, a stable power hierarchy remains within the family firm.
Women’s ways of leading: the environmental effect
Authors: Dzubinski Leanne , Diehl Amy , Taylor Michelle 
Published: March 2019

PurposeThis paper aims to present a model describing how women enact executive leadership, taking into account gendered organizational patterns that may constrain women to perform leadership in context-specific ways.Design/methodology/approachThis paper discusses gendered organizations, role congruity theory and organizational culture and work context. These strands of theory are interwoven to construct a model describing ways in which executive-level women are constrained to self-monitor based on context.FindingsThe pressure on women to conform to an organization’s executive leadership culture is enormous. Executive women in strongly male-normed executive leadership contexts must exercise strong gendered self-constraint to break through the glass ceiling. Women in strongly male-normed contexts using lessened gendered self-constraint may encounter a glass cliff. Women in gender-diverse-normed contexts may still operate using strong gendered self-constraint due to internalized gender scripts. Only in gender-diverse-normed contexts with lessened gendered-self-restraint can executive women operate from their authentic selves.Practical implicationsOrganizational leaders should examine their leadership culture to determine levels of pressure on women to act with gendered self-constraint and to work toward creating change. Women may use the model to make strategic choices regarding whether or how much to self-monitor based on their career aspirations and life goals.Originality/valueLittle has been written on male-normed and gender-diverse-normed contexts as a marker for how executive-level women perform leadership. This paper offers a model describing how different contexts constrain women to behave in specific, gendered ways.
Lucky to reach the top?
Authors: Ottsen Christina Lundsgaard 
Published: March 2019

Purpose
As organizations aim to become increasingly diverse, it is important to understand how perspectives of potential future leaders vary across culture and gender. This study aims to advance the understanding of the persistent gender gap in management.

Design/methodology/approach
Samples from the gender-segregated Qatar and the co-ed Denmark present a unique opportunity to investigate the potential effects of gender. Here, 115 Middle Easterners and 121 Scandinavians rated perceived importance of job-related skills, networking upward and serendipity in leadership acquisition.

Findings
Effects of gender showed that compared to men, women across cultures expected that serendipity has less to do with leadership acquisition. Middle Eastern women also showed low expectations regarding networking with people in powerful positions. Nevertheless, both genders showed conviction of meritocracy by rating job-related skills as the most important factor in leadership acquisition. Cross-culturally, Scandinavians presumed job-related skills to be more important than Middle Easterners.

Research limitations/implications
Despite meritocracy beliefs, it appears that gender differences in perceived possibility of leadership acquisition contribute to the gender gap in management. Scandinavian women relied more on networking than Middle Eastern women, but still lacked faith in serendipitous opportunities compared to male peers. Perceived luck enhances achievement motivation. If men rely more on luck than women, then they are more confident in succeeding and more ambitious about pursuit of leadership. Women’s lack of faith in serendipity might affect their career ambitions negatively even in societies emphasizing equality.

Originality/value
This is the first study that directly focuses on gender differences in perception of opportunities for leadership acquisition through serendipity.
Numerical simulation of fatigue crack propagation in mixed-mode (I+II) using the program BemCracker2D
Authors: Leite Pedro G.P. , Gomes Gilberto 
Published: March 2019

Purpose
The purpose of this paper is to present the application of the boundary element method (BEM) in linear elastic fracture mechanics for analysis of fatigue crack propagation problems in mixed-mode (I+II) using a robust academic software named BemCracker2D and its graphical interface BemLab2D.

Design/methodology/approach
The methodology consists in calculating elastic stress by conventional BEM and to carry out an incremental analysis of the crack extension employing the dual BEM (DBEM). For each increment of the analysis, the stress intensity factors (SIFs) are computed by the J-Integral technique, the crack growth direction is evaluated by the maximum circumferential stress criterion and the crack growth rate is computed by a modified Paris equation, which takes into account an equivalent SIF to obtain the fracture Modes I and II. The numerical results are compared with the experimental and/or BEM values extracted from the open literature, aiming to demonstrate the accuracy and efficiency of the adopted methodology, as well as to validate the robustness of the programs.

Findings
The paper addresses the numerical simulation of fatigue crack growth. The main contribution of the paper is the introduction of a software for simulating two-dimensional fatigue crack growth problems in mixed-mode (I+II) via the DBEM. The software BemCracker2D coupled to the BemLab2D graphical user interface (GUI), for pre/post-processing, are very complete, efficient and versatile and its does make relevant contributions in the field of fracture mechanics.

Originality/value
The main contribution of the manuscript is the development of a GUI for pre/post-processing of 2D fracture mechanics problems, as well as the object oriented programming implementation. Finally, the main merit is of educational nature.
The effects of residual stresses and strains on lateral-torsional buckling behavior of cold-formed steel channel and built-up I-sections beams
Authors: Kabir Mohammad Zaman , Parvizi Mehdi 
Published: March 2019

Purpose
The purpose of this paper is to focus on the influences of residual stresses which were induced during roll-forming sections on lateral-torsional buckling of thin-walled cold-formed steel channel and built-up I-sections beams. Built-up I section is made up of two back-to-back cold-formed channel beams. In this direction, at the primary stage, the roll-forming process of a channel section was simulated in ABAQUS environment and the accuracy of the result was verified with those existing experiments. Residual stresses and strains in both longitudinal and circumferential transverse directions were extracted and considered in the lateral-torsional buckling analysis under uniform end moments. The contribution of the current research is devoted to the numerical simulation of the rolling process in ABAQUS software enabling to restore the remaining stresses and strains for the buckling analysis in the identical software. The results showed that the residual stresses decrease considerably the lateral-torsional buckling strength as they have a major impact on short-span beams for channel sections and larger span for built-up I sections. The obtained moment capacity from the buckling analysis was compared to the predictions by American Iron and Steel Institute design code and it is found to be conservative.

Design/methodology/approach
This paper has explained a numerical study on the roll-forming process of a channel section and member moment capacities related to the lateral-torsional buckling of the rolled form channel and built-up I-sections beams under uniform bending about its major axis. It has also investigated the effects of residual stresses and strains on the behaviour of this buckling mode.

Findings
The residuals decrease the moment capacities of the channel beams and have major effect on shorter spans and also increase the local buckling strength of compression flange. But the residuals have major effect on larger spans for built-up I sections. It could be seen that the ratio of moment (with residuals and without residuals) for singly symmetric sections is more pronounced than doubly symmetric sections. So it is recommended to use doubly symmetric section of cold-formed section beams.

Originality/value
The incorporation of residual stresses and strains in the process of numerical simulation of rolled forming of cold-formed steel sections under end moments is the main contribution of the current work. The effect of residual stresses and strains on the lateral-torsional buckling is, for the first time, addressed in the paper.
Wine attractions at hotels: study of online reviews
Authors: Hsieh Yu-Chin Jerrie , Lee Zui Chih , Yin Ping 
Published: March 2019

PurposeThe purpose of this study is to delineate the role of wine at hotels from the customer’s perspective by analyzing New York City hotel reviews posted on TripAdvisor.Design/methodology/approachThis study used content analysis to study 26,831 wine-relevant reviews that had been posted on TripAdvisor’s New York City hotels by April 12, 2018. Two trained coders quantified and tallied the presence of themes based on the pre-established coding scheme.FindingsWine was mentioned in the online reviews in expressing positive, negative or neutral hotel experiences. Of the 877,616 New York City hotel reviews, about 3 per cent contained the keyword “wine.” The three most frequently mentioned wine-related positive experiences were free happy hours, a surprise bottle of complimentary wine and the fun of pairing food and wine. The top three wine-related negative experiences were pricey/expensive/overpriced wine, poor wine list and poor quality of wine. The study found that hotel guests liked wine and that it had become a significant aspect of their lodging experience.Originality/valueThis study adds value to the literature of hotel wines by divulging hotel customers’ wine-related experiences through their online comments and by providing a snapshot of hotel guests’ wine-drinking behavior. The findings can provide an insight for hotels to further the use of wine as a means to enhance guest experience and to generate additional revenue.