bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inference of drug off-target effects on cellular signaling using Interactome-Based Deep Learning
Authors: Meimetis Nikolaos , Lauffenburger Douglas A. , Nilsson Avlant 
Published: October 2023

AbstractMany diseases emerge from dysregulated cellular signaling, and drugs are often designed to target specific nodes in cellular networks e.g. signaling proteins, or transcription factors. However, off-target effects are common and may ultimately result in failed clinical trials. Computational modeling of the cell’s transcriptional response to drugs could improve our understanding of their mechanisms of action. Here we develop such an approach based on ensembles of artificial neural networks, that simultaneously infer drug-target interactions and their downstream effects on intracellular signaling. Applied to gene expression data from different cell lines, it outperforms basic machine learning approaches in predicting transcription factors’ activity, while recovering most known drug-target interactions and inferring many new, which we validate in an independent dataset. As a case study, we explore the inferred interactions of the drug Lestaurtinib and its effects on downstream signaling. Beyond its intended target FLT3 the model predicts an inhibition of CDK2 that enhances downregulation of the cell cycle-critical transcription factor FOXM1, corroborating literature findings. Our approach can therefore enhance our understanding of drug signaling for therapeutic design.
Socio-demographic and genetic risk factors for drug adherence and persistence: a retrospective nationwide and biobank study across 5 medication classes and 1 845 665 individuals
Authors: Cordioli M. , Corbetta A. , Kariis H.M. , Jukarainen S. , Vartiainen P. , Kiiskinen T. , Ferro M. ,   FinnGen, Estonian Biobank Research Team, Niemi M. , Ripatti S. , Lehto K. , Milani L. , Ganna A. 
Published: October 2023

AbstractLow drug adherence is a major obstacle to the benefits of pharmacotherapies and it is therefore important to identify factors associated with discontinuing or being poorly adherent to a prescribed treatment regimen. Using high-quality nationwide health registry data and genome-wide genotyping, we evaluate the impact of socio-demographic and genetic risk factors on adherence and persistence for 5 common medication classes that require long-term, regular therapy (N = 1 814 591 individuals from Finnish nationwide registries, 217 005 with genetic data from Finland and Estonia).Need for social assistance and immigration status showed a notable negative effect on persistence and adherence across the examined medications (odd ratios between 0.48 and 0.82 for persistence and between 1.1% to 4.3% decrease in adherence) while demographic and health factors showed comparably modest or inconsistent effects. A genome-wide scan did not identify genetic variants associated with the two phenotypes, while some pharmacogenes (i.e.CYP2C9andSLCO1B1) were modestly associated with persistence, but not with adherence. We observed significant genetic correlations between medication adherence and participation in research studies. Overall, our findings suggest that socio-economically disadvantaged groups would benefit from targeted interventions to improve the dispensing and uptake of pharmacological treatments.
Rumination Induction Task in fMRI: Test-Retest Reliability in Youth and Potential Mechanisms of Change with Intervention
Authors: Schreiner Mindy Westlund , Miller Raina H. , Jacobsen Anna M. , Crowell Sheila E. , Kaufman Erin A. , Farstead Brian , Feldman Daniel A. , Thomas Leah , Bessette Katie L. , Welsh Robert C. , Watkins Edward R. , Langenecker Scott A. 
Published: October 2023

AbstractBackgroundRumination is a transdiagnostic problem that is common in major depressive disorder (MDD). Rumination Focused Cognitive Behavioral Therapy (RF-CBT) explicitly targets the ruminative habit. This study examined changes in brain activation during a rumination induction task in adolescents with remitted MDD following RF-CBT. We also evaluated the reliability of the rumination task among adolescents who received treatment as usual (TAU).MethodFifty-five adolescents ages 14-17 completed a self-relevant rumination induction fMRI task and were then randomized to either RF-CBT (n = 30) or TAU (n = 25). Participants completed the task a second time either following 10-14 sessions of RF-CBT or the equivalent time delay for the TAU group. We assessed activation change in the RF-CBT group using paired-samples t-tests and reliability by calculating intraclass correlation coefficients (ICCs) of five rumination-related ROIs during each of three blocks for the TAU and RF-CBT groups separately (Rumination Instruction, Rumination Prompt, and Distraction).ResultsFollowing treatment, participants in the RF-CBT group demonstrated an increase in activation of the left precuneus during Rumination Instruction and the left angular and superior temporal gyri during Rumination Prompt (p< .01). The TAU group demonstrated fair to excellent reliability (M= .52, range = .27-.86) across most ROIs and task blocks. In contrast, the RF-CBT group demonstrated poor reliability across most ROIs and task blocks (M= .21, range = -.19-.69).ConclusionRF-CBT appears to lead to rumination-related brain change. We demonstrated that the rumination induction task has fair to excellent reliability among individuals who do not receive an intervention that explicitly targets the ruminative habit, whereas reliability of this task is largely poor in the context of RF-CBT. This has meaningful implications in longitudinal and intervention studies, particularly when conceptualizing it as an important target for intervention. It also suggests one of many possible mechanisms for why fMRI test-retest reliability can be low that appears unrelated to the methodology itself.
Percent Thrombus Outperforms Size in Predicting Popliteal Artery Aneurysm Related Thromboembolic Events
Authors: Bellomo Tiffany R. , Goudot Guillaume , Lella Srihari K. , Gaston Brandon , Sumetsky Natalie , Patel Shiv , Brunson Ashley , Beardsley Jenna , Zacharias Nikolaos , Dua Anahita 
Published: October 2023

ABSTRACTIntroductionPopliteal artery aneurysms (PAAs) are associated with high morbidity and mortality and current Society for Vascular Surgery (SVS) recommend operative repair for PAAs with a diameter greater than 20 mm, which is based on limited evidence. To help risk stratify patients for surgery, our aim was to identify anatomic characteristics of PAA associated with limb threatening and thromboembolic events (TEs).MethodsA retrospective multi-institutional cohort was queried for all patients with a PAA from 2008 to 2022. Symptom status at the time of presentation was divided into three categories: symptomatic PAA with documented claudication or chronic limb ischemia (CLI), limb threatening PAA with a TE, acute limb ischemia, or rupture, and asymptomatic PAA without symptoms or limb threatening events. Patient and anatomic factors based on duplex ultrasound (DUS) were evaluated as potential predictors of symptom groups and thresholds of anatomic variables were identified using receiver operating characteristic curves.ResultsThere were 470 PAAs identified in 331 patients. The mean age was 74 years at diagnosis, 94% of patients were white, and 97% of patients were male. Cardiovascular comorbidities were prevalent in and similar between all patient groups studied, and almost all patients were on anticoagulation or antiplatelet therapy at the time of diagnosis, at 96%. The most common concurrent aneurysm was abdominal aortic aneurysm (62%). Patient comorbidities were not associated with symptom status. PAAs with a higher percent thrombus burden were 18 times more likely to experience a limb threatening event and 24 times more likely to experience a TE. A largest diameter threshold of 20.4 mm was predictive of a TE (sensitivity 78.1%, specificity 40.5%), but percent thrombus threshold of 62% outperformed largest diameter as a predictor of a TE (sensitivity of 81.3%, specificity 52.0%). Percent thrombus threshold of 73% also predicted limb threatening events (sensitivity 65.7%, specificity 69.7%).ConclusionA PAA diameter greater than 20.4 mm was predictive of TEs, which is in agreement with clinical practice guidelines. However, percent thrombus greater than 62% outperformed largest diameter as a predictor of a TE. This analysis supports the use of size greater than 20.4 mm and 62% thrombus in identifying high risk PAAs that warrant repair.
Characterization of Cancer Evolution Landscape Based on Accurate Detection of Somatic Mutations in Single Tumor Cells
Authors: Niu Muchun , Zhang Yang , Luo Jiayi , Sinson Jefferson C. , Thompson Alastair M. , Zong Chenghang 
Published: October 2023

AbstractAccurate detection of somatic mutations in single tumor cells is greatly desired as it allows us to quantify the single-cell mutation burden and construct the mutation-based phylogenetic tree. Here we developed scNanoSeq chemistry and profiled 842 single cells from 21 human breast cancer samples. The majority of the mutation-based phylogenetic trees comprise a characteristic stem evolution followed by the clonal sweep. We observed the subtype-dependent lengths in the stem evolution. To explain this phenomenon, we propose that the differences are related to different reprogramming required for different subtypes of breast cancer. Furthermore, we reason that the time that the tumor-initiating cell took to acquire the critical clonal-sweep-initiating mutation by random chance set the time limit for the reprogramming process. We refer to this model as a reprogramming and critical mutation co-timing (RCMC) subtype model. Next, in the sweeping clone, we observed that tumor cells undergo a branched evolution with rapidly decreasing selection. In the most recent clades, effectively neutral evolution has been reached, resulting in a substantially large number of mutational heterogeneities. Integrative analysis with 522-713X ultra-deep bulk whole genome sequencing (WGS) further validated this evolution mode. Mutation-based phylogenetic trees also allow us to identify the early branched cells in a few samples, whose phylogenetic trees support the gradual evolution of copy number variations (CNVs). Overall, the development of scNanoSeq allows us to unveil novel insights into breast cancer evolution.
Role of Dynamin-Related Proteins 2 and SH3P2 in Clathrin-Mediated Endocytosis in Plants
Authors: Gnyliukh Nataliia , Johnson Alexander , Nagel Marie-Kristin , Monzer Aline , Hlavata Annamaria , Isono Erika , Loose Martin , Friml Jiří 
Published: October 2023

AbstractClathrin-mediated endocytosis (CME) is vital for the regulation of plant growth and development by controlling plasma membrane protein composition and cargo uptake. CME relies on the precise recruitment of regulators for vesicle maturation and release. Homologues of components of mammalian vesicle scission are strong candidates to be part of the scissin machinery in plants, but the precise roles of these proteins in this process is not fully understood. Here, we characterised the roles of Plant Dynamin-Related Proteins 2 (DRP2s) and SH3-domain containing protein 2 (SH3P2), the plant homologue to Dynamins’ recruiters, like Endophilin and Amphiphysin, in the CME by combining high-resolution imaging of endocytic eventsin vivoand characterisation of the purified proteinsin vitro. Although DRP2s and SH3P2 arrive similarly late during CME and physically interact, genetic analysis of the Dsh3p1,2,3triple-mutant and complementation assays with non-SH3P2-interacting DRP2 variants suggests that SH3P2 does not directly recruit DRP2s to the site of endocytosis. These observations imply that despite the presence of many well-conserved endocytic components, plants have acquired a distinct mechanism for CME.One Sentence SummaryIn contrast to predictions based on mammalian systems, plant Dynamin-related proteins 2 are recruited to the site of Clathrin-mediated endocytosis independently of BAR-SH3 proteins.
IL-33-binding HpARI family homologues with divergent effects in suppressing or enhancing Type 2 immune responses
Authors: Colomb Florent , Ogunkanbi Adefunke , Jamwal Abhishek , Dong Beverley , Maizels Rick M. , Finney Constance A. M. , Wasmuth James D. , Higgins Matthew , McSorley Henry J. 
Published: October 2023

AbstractHpARI is an immunomodulatory protein secreted by the intestinal nematodeHeligmosomoides polygyrus bakeri, which binds and blocks IL-33. Here, we find that theH. polygyrus bakerigenome contains 3 HpARI family members, and that these have different effects on IL-33-dependent responses in vitro and in vivo, with HpARI1+2 suppressing, and HpARI3 amplifying these responses. All HpARIs have sub-nanomolar affinity for mouse IL-33, however HpARI3 does not block IL-33-ST2 interactions. Instead, HpARI3 stabilises IL-33, increasing the half-life of the cytokine and amplifying responses to it in vivo. Together these data show thatH. polygyrus bakerisecretes a family of HpARI proteins with both overlapping and distinct functions, comprising a complex immunomodulatory arsenal of host-targeted proteins.
Nascent Chain Ubiquitination is Uncoupled from Degradation to Enable Protein Maturation
Authors: Li Xia , Mariappan Malaiyalam 
Published: October 2023

SUMMARYA significant proportion of nascent proteins undergo polyubiquitination on ribosomes in mammalian cells, yet the fate of these proteins remains elusive. The ribosome-associated quality control (RQC) is a mechanism that mediates the ubiquitination of nascent chains on stalled ribosomes. Here, we find that nascent proteins ubiquitinated on stalled ribosomes by the RQC E3 ligase LTN1 are insufficient for proteasomal degradation. Our biochemical reconstitution studies reveal that ubiquitinated nascent chains are promptly deubiquitinated in the cytosol upon release from stalled ribosomes, as they are no longer associated with LTN1 E3 ligase for continuous ubiquitination to compete with cytosolic deubiquitinases. These deubiquitinated nascent chains can mature into stable proteins. However, if they misfold and expose a degradation signal, the cytosolic quality control recognizes them for re-ubiquitination and subsequent proteasomal degradation. Thus, our findings suggest that cycles of ubiquitination and deubiquitination spare foldable nascent proteins while ensuring the degradation of terminally misfolded proteins.
Research on ecological evaluation of an enterprise open innovation community website
Authors: Xie Renqiang 
Published: October 2023

PurposeWhile providing users with important innovation resources, an enterprise's open innovation community also encounters numerous challenges. The purpose of this study is to develop and implement a set of evaluation systems that can identify the ecological characteristics of open innovation communities. The ultimate goal is to provide guidance for the construction and establishment of these communities.Design/methodology/approachFirstly, from the perspective of information ecology, according to the connotation requirements of the four information elements of “people, information, technology and environment” in the information ecosystem, this paper determines the evaluation indicators of enterprise's open innovation community from the aspects of integrity and dynamics. Then, based on the improved analytic hierarchy process, the weight of each index is calculated, and a complete evaluation system of open innovation community is established. Finally, the fuzzy comprehensive evaluation method is used to conduct empirical research on Haier Open Partnership (HOPE) platform, analyze its ecological situation and existing problems and put forward the corresponding construction recommendations.FindingsThe application of HOPE platform shows that the evaluation index system built in this study has good applicability, and the whole research process and research method have certain reference value for future studies. At the same time, the study found that the HOPE platform has good ecological characteristics, but there are also some problems. This study can directly promote the construction of the platform.Originality/valueThis paper, for the first time, combines the information ecology theory with the open innovation community. The results demonstrate that the open innovation community is an information ecosystem, which can be evaluated ecologically. Furthermore, to ensure the calculation's scientific accuracy, the index weight is determined by constructing a judgment matrix based on expert questionnaires.
Fake news detection using machine learning: an adversarial collaboration approach
Authors: DSouza Karen M. , French Aaron M. 
Published: October 2023

PurposePurveyors of fake news perpetuate information that can harm society, including businesses. Social media's reach quickly amplifies distortions of fake news. Research has not yet fully explored the mechanisms of such adversarial behavior or the adversarial techniques of machine learning that might be deployed to detect fake news. Debiasing techniques are also explored to combat against the generation of fake news using adversarial data. The purpose of this paper is to present the challenges and opportunities in fake news detection.Design/methodology/approachFirst, this paper provides an overview of adversarial behaviors and current machine learning techniques. Next, it describes the use of long short-term memory (LSTM) to identify fake news in a corpus of articles. Finally, it presents the novel adversarial behavior approach to protect targeted business datasets from attacks.FindingsThis research highlights the need for a corpus of fake news that can be used to evaluate classification methods. Adversarial debiasing using IBM's Artificial Intelligence Fairness 360 (AIF360) toolkit can improve the disparate impact of unfavorable characteristics of a dataset. Debiasing also demonstrates significant potential to reduce fake news generation based on the inherent bias in the data. These findings provide avenues for further research on adversarial collaboration and robust information systems.Originality/valueAdversarial debiasing of datasets demonstrates that by reducing bias related to protected attributes, such as sex, race and age, businesses can reduce the potential of exploitation to generate fake news through adversarial data.
Can digital service trade promote the high-quality development of global manufacturing? – existence and mechanism
Authors: Qiu Ailian , Yu Yingchun , McCollough John 
Published: October 2023

PurposeThis thesis deeply studies the impact mechanism of digital service trade on the high-quality development of the manufacturing industry from the aspects of technological innovation and industrial structure.Design/methodology/approachIn this thesis, 40 countries from 2010 to 2020 were selected as samples, and the panel fixed-effect model and intermediary effect model were used to empirically analyze the impact path of digital service trade on the high-quality development of global manufacturing.FindingsOverall, digital service trade has a positive impact on the high-quality development of the global manufacturing industry. Through the analysis of the intermediary effect mechanism, it is found that digital service trade can further positively affect the high-quality development of the global manufacturing industry by promoting technological innovation and industrial structure upgrading.Research limitations/implicationsBased on the empirical results, targeted countermeasures and suggestions are given in this paper.Practical implicationsThrough the test of national heterogeneity, it is found that in developing countries, digital service trade mainly acts on the high-quality development of the manufacturing industry by promoting industrial structure upgrading.Social implicationsIn developed countries, digital service trade mainly promotes the high-quality development of manufacturing through technological innovation; from the perspective of industry heterogeneity, the three service industries of information and communication technology (ICT), other business services and property have the intermediary effect of technological innovation and industrial structure.Originality/valueThis manuscript suggests that trade in digital services should be promoted as a national trade priority.
“We do it but they don't” unveiling the impact of differentiation-oriented content on purchase intentions through mediation of SM engagement and moderation of social media skills
Authors: Khan Shahid , Rehman Sumaira , Kashif Uzma 
Published: October 2023

PurposeThis research aimed to investigate the mediating role of social media engagement in the relationship between differentiation-oriented content and purchase intentions. Additionally, this research studies the moderating impact of entrepreneurial social media skills in the relationship between social media engagement and purchase intentions.Design/methodology/approachThe research proposes a positivist research philosophy, deductive research approach and survey research strategy. Data were collected from followers of social media pages of small and medium businesses operating in the fields of groceries, food items, apparel and supplies in Pakistan. Respondents were selected randomly. The descriptive statistics were calculated first, followed by reliability and validity analysis as part of the measurement model. Finally, mediation and moderation analyses were run by using structural equation modeling.FindingsResults of the study confirm that differentiation-oriented content has a positive relationship with purchase intentions and social media engagement mediates this relationship. Results further confirm that the social media skills of entrepreneurs moderate the relationship between social media engagement and purchase intentions.Practical implicationsFrom a practical point of view, this study will potentially help entrepreneurs in Pakistan unveil the undiscovered potential of social media and understand the importance of social media marketing campaigns in crisis situations. It will unlock the importance of entrepreneurial training and development to better adapt to the dynamic and vibrant world of social media.Originality/valueThis is the first study that investigates the relationship between differentiation-oriented content and purchase intentions. Additionally, the current study adds to existing knowledge by proposing entrepreneurial social media skills as moderators in the relationship of social media engagement with purchase intentions.