bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic plasticity via adaptive DNA hypermethylation and clonal expansion underlie resistance to oncogenic pathway inhibition in pancreatic cancer
Authors: Godfrey Laura K. , Forster Jan , Liffers Sven-Thorsten , Schröder Christopher , Köster Johannes , Henschel Leonie , Ludwig Kerstin U. , Trajkovic-Arsic Marija , Behrens Diana , Scarpa Aldo , Lawlor Rita T. , Witzke Kathrin E. , Sitek Barbara , Johnsen Steven A. , Rahmann Sven , Horsthemke Bernhard , Zeschnigk Michael , Siveke Jens T. 
Published: May 2022

AbstractPancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis. Drug resistance is the major cause for therapeutic failure in PDAC patients with progressive disease. The mechanisms underlying resistance formation are complex and remain poorly understood.To gain insights into molecular changes during the formation of resistance to oncogenic MAPK pathway inhibition we utilized short-term passaged primary tumor cells from ten PDACs of genetically engineered mice. We followed gain and loss of resistance upon MEKiexposure and withdrawal by longitudinal integrative analysis of whole genome sequencing, whole genome bisulfite sequencing, RNA-sequencing and mass spectrometry data.We found that resistant cell populations under increasing MEKitreatment evolved by the expansion of a single clone but were not a direct consequence of known resistance-conferring mutations. Rather, resistant cells showed adaptive DNA hypermethylation of 209 and hypomethylation of 8 genomic sites, most of which overlap with regulatory elements known to be active in murine PDAC cells. Both DNA methylation changes and MEKiresistance were transient and reversible upon drug withdrawal. The effector caspaseCASP3is one of the 114 genes for which transcriptional downregulation inversely correlated with the methylation status of the associated DNA region. CASP3 inactivation in resistant cells led to attenuation of drug-induced apoptosis which could be reversed by DNA methyltransferase inhibition with remarkable sensitivity exclusively in the resistant cells.Overall, our data provide a context for characterization and targeting of epigenetically mediated resistance mechanisms in PDAC.
Scientific hypothesis generation process in clinical research: a secondary data analytic tool versus experience study protocol
Authors: Jing Xia , Patel Vimla L. , Cimino James J. , Shubrook Jay H. , Zhou Yuchun , Liu Chang , De Lacalle Sonsoles 
Published: May 2022

AbstractBackgroundScientific hypothesis generation is a critical step in scientific research that determines the direction and impact of any investigation. Despite its vital role, we have limited knowledge of the process itself, hindering our ability to address some critical questions.ObjectiveTo what extent can secondary data analytic tools facilitate scientific hypothesis generation during clinical research? Are the processes similar in developing clinical diagnoses during clinical practice and developing scientific hypotheses for clinical research projects? We explore the process of scientific hypothesis generation in the context of clinical research. The study is designed to compare the role of VIADS, our web-based interactive secondary data analysis tool, and the experience levels of study participants during their scientific hypothesis generation processes.MethodsInexperienced and experienced clinical researchers are recruited. In this 2×2 study design, all participants use the same data sets during scientific hypothesis-generation sessions, following pre-determined scripts. The inexperienced and experienced clinical researchers are randomly assigned into groups with and without using VIADS. The study sessions, screen activities, and audio recordings of participants are captured. Participants use the think-aloud protocol during the study sessions. After each study session, every participant is given a follow-up survey, with participants using VIADS completing an additional modified System Usability Scale (SUS) survey. A panel of clinical research experts will assess the scientific hypotheses generated based on pre-developed metrics. All data will be anonymized, transcribed, aggregated, and analyzed.ResultsThis study is currently underway. Recruitment is ongoing via a brief online survey 1. The preliminary results show that study participants can generate a few to over a dozen scientific hypotheses during a 2-hour study session, regardless of whether they use VIADS or other analytic tools. A metric to assess scientific hypotheses within a clinical research context more accurately, comprehensively, and consistently has also been developed.ConclusionThe scientific hypothesis-generation process is an advanced cognitive activity and a complex process. Clinical researchers can quickly generate initial scientific hypotheses based on data sets and prior experience based on our current results. However, refining these scientific hypotheses is much more time-consuming. To uncover the fundamental mechanisms of generating scientific hypotheses, we need breakthroughs that capture thinking processes more precisely.
Shared genetic etiology and causality between COVID-19 and venous thromboembolism: evidence from genome-wide cross trait analysis and bi-directional Mendelian randomization study
Authors: Huang Xin , Yao Minhao , Tian Peixin , Wong Jason Y.Y. , Li Zilin , Liu Zhonghua , Zhao Jie V. 
Published: May 2022

AbstractVenous thromboembolism (VTE) occurs in up to one third patients with COVID-19. VTE and COVID-19 may share a common genetic architecture, which has not been clarified yet. To fill this gap, we leveraged summary-level genetic data from the latest COVID-19 host genetics consortium and UK Biobank and examined the shared genetic etiology and causal relationship between COVID-19 and VTE. The cross-trait analysis identified 8, 11, and 7 shared loci between VTE and severe COVID-19, COVID-19 hospitalization, SARS-CoV-2 infection respectively, in 13 genes involved in coagulation and immune function and enriched in the lung. Co-localization analysis identified eight shared loci in ABO, ADAMTS13 and FUT2 genes. Bi-direction Mendelian randomization suggested that VTE was associated with higher risks of all COVID-19 related traits, and SARS-CoV-2 infection was associated with higher risk of VTE. Our study provided timely evidence and novel insights into the genetic etiology between COVID-19 and VTE.
Somatic hypermutation patterns in immunoglobulin variable regions are established independently of the local transcriptional landscape
Authors: Schoeberl Ursula E. , Fitz Johanna , Froussios Kimon , Valieris Renan , Ourailidis Iordanis , Makharova Marina , Bauer Bernd , Neumann Tobias , Wiedemann Eva-Maria , Steininger Monika , Garcia Adriana Cantoran , Mastrovito Marialaura , Mouquet Hugo , Da Silva Israel Tojal , Pavri Rushad 
Published: May 2022

AbstractSomatic hypermutation (SHM) of immunoglobulin variable (V) regions modulates antibody-antigen affinity is initiated by activation-induced cytidine deaminase (AID) on single-stranded DNA (ssDNA). Transcription is essential for SHM and AID target genes harbor activating chromatin marks and RNA polymerase II (Pol II) stalling, leading to the model that these features favor higher rates of mutagenesis. However, whether such relationships exist within V regions is undetermined. Here, we directly compared SHM and nascent transcription across four V regions and 275 non-immunoglobulin SHM targets at single-nucleotide resolution using precision run-on sequencing (PRO-seq). Although locales of Pol II enrichment and zones of Pol II stalling were detected within V regions, their correlation with SHM was not statistically significant. Moreover, SHM was robust against major reductions of activating epigenetic marks and transcription. This data suggests that SHM patterns and spectra are established independently of specific local nascent transcriptional features.
The Survival Analysis of Veterans’ Administration Lung Cancer Dataset
Authors: Amaka Ewuru Deborah , Etikan İlker 
Published: May 2022

ABSTRACTAIMThis study will describe the notion about survival analysis and the variability between diverse methods and test statistics used in analyzing survival data.METHODSThis study will be using the Veterans’ Administrative Lung Cancer dataset(R Dataset) of 137 patients having advanced inoperable Lung cancer, carried out by the US Veterans Administration. Out of 137 male patients, 69 patients received the Standard test while 68 patients received Chemotherapy test and 64 patients died in each treatment group while only 9 patients were alive (censored) at the end of the study. This dataset will be analyzed using the SPSS version to determine whether there is a statistically remarkable difference between the survival distributions of the cell types of Lung cancer using Life tables, and also between the Standard test and Chemotherapy test treatment groups using Kaplan Meier method. Various covariates were also analyzed to find out if they have any effect on the death of the male patients with advanced inoperable lung cancer using Cox-Regression.RESULTSThe Wilcoxon (Gehan) statistic from Life table method shows a p-value of 0.000 less than the 95% confidence level indicating that there is a statistical significance between the Lung cancer cell types. The three statistical tests of Kaplan-Meier method which include Log Rank (Mantel-Cox) test, Breslow (Generalized Wilcoxon) and Tarone Ware tests showed that the survival distribution between the two Lung cancer treatment groups are equal using an alpha level of 0.05.The Standard test and the Chemotherapy test drug treatment show the same effect on the survival time of the patients, no treatment is more beneficial than the other. Cox Regression result showed that Squamous cell type2(4), Adeno-carcinoma cell type (1), Small cell type (3) and karnofsky score are statistically significant while Large cell type2 (2), prior therapy, age, diagnosis time and the treatment group were found not significant.CONCLUSIONThe treatment difference does not show any remarkable effect on the survival time of male patients with Lung Cancer.
Male mate preference against tail-elongated females in the barn swallow
Authors: Hasegawa Masaru , Arai Emi 
Published: May 2022

AbstractThe function of female ornamentation in the context of (inter)sexual selection attracts keen attention these days, but empirical field studies are mostly based on indirect measures such as mating patterns; direct evidence of male mate preference on female ornamentation while controlling for confounding factors is needed. Here we performed model presentation experiments to study male mate preference in the barn swallowHirundo rustica, a model species of sexual selection. Female barn swallows have somewhat shorter tails than males, but their tails are still long and costly. Although many correlational and experimental studies of live females have focused on long tails in female barn swallows over the last three decades, direct behavioral tests of male mate preference are lacking. By using a sequential model presentation experiment, in which we repeated the trials with the same males, we found that males significantly reduced the number of pairing displays when they were presented with tail-elongated female models compared to control female models. Interaction between treatment and male tail length was far from significant. The observed pattern is inconsistent with the prevailing view that costly female ornamentation is maintained via male preference for more ornamented females. Rather, the observed pattern is consistent with the sexual mimicry hypothesis, in which females can avoid sexual (and social) harassment by mimicking males.
The 5-Hydroxytryptaminergic Neurons in the Dorsal Raphe Nucleus and Different 5-HT Receptors are Implicated in Mediating the Awakening from Sevoflurane Anesthesia
Authors: Ma HaiXiang , Gu LeYuan , Wang YuLing , Xu Qing , Yu Qian , Lian XiTing , Shao WeiHui , Liu Lu , Gu JiaXuan , Shen Yue , Zhang HongHai 
Published: May 2022

AbstractIn order to explore the mechanism of general anesthesia emergence, based on the common clinical phenomenon-delayed emergence, we explore the role of 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus in promoting awakening from sevoflurane anesthesia in mice model. In this study, C57BL/6J male mice were selected to specifically activate or inhibit 5-HT neurons in the dorsal raphe nucleus (DRN) and different 5-HT receptors by intraperitoneal, lateral ventricle, intranuclear or DRN injection of agonists/antagonists and optogenetics during the sevoflurane anesthesia to record and observe the anesthesia induction and emergence time of mice. Through intraventricular infusion and intranuclear microinjection of 5-HT and the agonists or antagonists of different 5-HT receptors, our data showed that 5-HT and 5-HT1A and 2A/C receptors, especially 5-HT1A receptor, are involved in the regulation of delayed awakening mediated by DRN 5-HT neurons. This can provide a reliable theoretical basis as well as potential targets for clinical intervention to prevent delayed emergence and some postoperative risks.Graphical Abstract
Single-Cell Transcriptome Analyses Reveal the Cell Diversity and Developmental Features of Human Gastric and Metaplastic Mucosa
Authors: Tsubosaka Ayumu , Komura Daisuke , Katoh Hiroto , Kakiuchi Miwako , Onoyama Takumi , Yamamoto Asami , Abe Hiroyuki , Seto Yasuyuki , Ushiku Tetsuo , Ishikawa Shumpei 
Published: May 2022

AbstractThe stomach is an important digestive organ with a variety of biological functions. However, due to the complexity of its cellular and glandular composition, the precise cellular biology has yet to be elucidated. In this study, we conducted single-cell RNA sequence analysis of the human stomach and constructed a 137,610-cell dataset, the largest cell atlas reported to date. By integrating this single-cell analysis with spatial cellular distribution analysis, we were able to clarify novel aspects of the developmental and tissue homeostatic ecosystems in the human stomach. We identified LEFTY1+ as a potential stem cell marker in both gastric and intestinal metaplastic glands. We also revealed skewed distribution patterns for PDGFRA+BMP4+WNT5A+ fibroblasts that play pivotal roles in, or even precede, the phenotypic changes from gastric to metaplastic mucosa. Our extensive dataset will function as a fundamental resource in investigations of the stomach, including studies on development, aging, and carcinogenesis.
Subtle cognitive impairments in memory, attention, and executive functioning in patients with post-COVID syndrome and their relationships with clinical variables and subjective complaints
Authors: Kozik V. , Reuken P. , Utech I. , Gramlich J. , Stallmach Z. , Demeyere N. , Rakers F. , Schwab M. , Stallmach A. , Finke K. 
Published: May 2022

AbstractBackground and objectivesCognitive symptoms persisting beyond three months following COVID-19 present a considerable disease burden. We aimed to establish a domain-specific cognitive profile of post-COVID syndrome (PCS) and relationships with subjective cognitive complaints and clinical variables to provide relevant information for the understanding of cognitive dysfunction and its predictors in a clinical cohort with PCS.MethodsIn this cross-sectional study, we compared cognitive performance on the clinically viable Oxford Cognitive Screen-Plus between a large post-COVID cohort (n= 282) and a socio-demographically matched healthy control group (n= 52). We assessed group differences in terms of fatigue and depression as well as relationships between cognitive dysfunction and clinical and patient-reported outcomes.ResultsOn a group-level, patients scored significantly lower on delayed verbal memory (non-parametric effect sizer= .13), attention (r= .1), and executive functioning (r=.1) than healthy controls. In each of these domains, 10-20% of patients performed more than 1.5 SD below the healthy control mean. Delayed Memory was particularly affected and a small proportion of its variance was explained by hospitalisation (β= -.72,p< .01) and age (β= -.03,p< .05; R2adj. = .08). Attention scores were significantly predicted by hospitalisation (β= -.78,p< .01) and fatigue (β= -.04,p< .05; R2adj. = .06).DiscussionPCS is associated with long-term cognitive dysfunction, particularly in delayed verbal memory, attention, and executive functioning. Deficits in delayed memory performance seem to be of particular relevance to patients’ subjective experience of impairment. Initial disease severity, current level of fatigue, and age seem to predict cognitive performance, while time since infection, depression, and pre-existing conditions do not. Longitudinal data are needed to map long-term course of cognitive dysfunction in PCS.
Involvement of nucleus accumbens D2-MSN projections to the ventral pallidum in anxious-like behavior
Authors: Correia Raquel , Domingues Ana Verónica , Coimbra Bárbara , Vieitas-Gaspar Natacha , Sousa Nuno , Pinto Luísa , Rodrigues Ana João , Soares-Cunha Carina 
Published: May 2022

AbstractThe nucleus accumbens (NAc) is a crucial brain region for emotionally-relevant behaviors. The NAc is mainly composed of medium spiny neurons (MSN) expressing either dopamine receptor D1 (D1-MSNs) or D2 (D2-MSNs). D1-MSNs project to the ventral tegmental area (VTA) and ventral pallidum (VP), while D2-MSNs project only to the VP. In this work, we selectively manipulated D1-MSN projections to the VP and VTA, and D2-MSN projections to the VP during classical anxiety behavioral paradigms in naïve mice.We found that optogenetic activation of D1-MSN to VP or VTA did not trigger significant anxious-like behaviors. Interestingly, optical activation of D2-MSN-VP projections significantly increased anxious-like behavior in all of the tests performed. This phenotype was associated with a decrease in the activity of VP putative GABAergic neurons. Importantly, pre-treating D2-MSN-VP animals with the GABA modulator diazepam prevented the optically-triggered anxious-like behavior.Overall, our results suggest that D2-MSN-VP projections contribute for the development of anxious-like behavior, through modulation of GABAergic activity in the VP.
Lactate supply overtakes glucose when neural computational and cognitive loads scale up
Authors: Dembitskaya Yulia , Piette Charlotte , Perez Sylvie , Berry Hugues , Magistretti Pierre J , Venance Laurent 
Published: May 2022

SUMMARYThe neural computational power is determined by neuroenergetics, but how and which energy substrates are allocated to various forms of memory engram is unclear. To solve this question, we asked whether neuronal fueling by glucose or lactate scales differently upon increasing neural computation and cognitive loads. Here, using electrophysiology, two-photon imaging, cognitive tasks and mathematical modeling, we show that both glucose and lactate are involved in engram formation, with lactate supporting long-term synaptic plasticity evoked by high stimulation load activity patterns and high attentional load in cognitive tasks, and glucose being sufficient for less demanding neural computation and learning tasks. Overall, these results demonstrate that glucose and lactate metabolisms are differentially engaged in neuronal fueling depending on the complexity of the activity-dependent plasticity and behavior.One sentence summaryNeuronal fueling by lactate versus glucose scales differently according to engram level and memory load.
Customer power, perceived behavioral control, and life insurance salespeople's reactions to customer sexual harassment
Authors: Lin Yi-Ling , Tseng Lu-Ming 
Published: May 2022

PurposeSexual harassment is often the result of the abuse of power by perpetrators over victims. This study investigated the effects of customer reward power, customer coercive power, perceived behavioral control (PBC), and personal factors on full-time life insurance salespeople's intentions to report customer sexual harassment.Design/methodology/approachThis study collected quantitative data through questionnaire surveys. A total of 743 valid questionnaires were collected.FindingsTwo types of customer sexual harassment (quid pro quo and hostile work environment) were evaluated. PBC was found to be the most influential factor affecting whistleblowing intentions. Regression analysis indicated that customer reward power significantly affected whistleblowing intentions toward quid pro quo customer sexual harassment. The male salespeople experienced stronger customer coercive power than did the female salespeople.Originality/valueNot every society views customer power and customer sexual harassment in the same manner. By examining Taiwan's life insurance salespeople and including the concept of customer power, this study broadens the understanding of whistleblowing intentions toward the two types of customer sexual harassment.
NoPaperForms: enrolment engine for the education sector
Authors: Mital Amita , Panwar Archana , Jawalgi Yuvaraj 
Published: May 2022

Learning outcomesDiscussion of the case will enable students to identify the cornerstones of industry development using simple frameworks like PESTLE and five forces that shape strategy. They will be able to identify critical success factors and evaluate how a firm gets competitive advantage. They will also be able to assess whether the advantage is sustainable for the firms and along which dimensions they have only competitive parity. The issues of contemporary firms growing through the use of network strategies is also highlighted and students will learn to appreciate the role of platforms and connectivity for gaining sustainable advantage.Case overview/synopsisThis case describes the growth strategy of NoPaperForms, a start-up in the domain of enrolment automation for higher education in India. Naveen Goyal, the founder CEO sensed an opportunity in this growing industry segment and acquired it from the founder, Vishal Shah in 2017. The ultimate objective of an educational institute was to attract talent, Goyal evolved a comprehensive enrolment solution starting with the time a prospective student made an inquiry for enrolment till the time he/she paid for enrolment. It was a complete panel, bundled and packaged in a single system taking care of lead management, lead nurturing, application management, fee payment, post-application management and enrolment. He developed it into a unique blend of a customer relationship management (CRM), which was unique in the country. At this juncture, Goyal was exploring growth avenues. On the client side, he had the alternatives of focusing on the B2C segment or diversifying from B2B to B2C. Geographically, he had the options of expanding to tier II and tier III cities, which were the next growth hubs. The option of growing internationally was also on the cards. The purpose of the case is to analyse the opportunities in the education technology sector, specific to student enrolment and leverage the competencies of the firm to detail the future strategy of the firm.Complexity academic levelThe case can be used in a MBA program for a course in Strategic Management in the module of strategy formulation after fundamental concepts and theories of Strategic Management have been discussed.Supplementary materialsTeaching notes are available for educators only.Subject codeCSS 11: Strategy.