bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Significance of Uneven Walking Transitory Modulations in Walking Momentum Regulation and Active Work
Authors: Hosseini Yazdi Seyed Saleh 
Published: August 2024

AbstractUneven walking presents challenges such as balance maintenance and increased energetics. Beyond average step parameter variations, humans may employ transient strategies to conserve mechanical work or enhance momentum with minimal metabolic costs. Thus, we quantified mid-flight positive mechanical work induction, step length, and effective leg length modulation from four steps before to four steps after a specific encounter for young and older adults with normal and restricted lookaheads. Simulations were also conducted to assess the impact of step length or effective leg length changes on step-to-step transition or post-transition speed. We observed that young adults’ mid-flight energy inducements were focused around the encounter, influenced by lookahead state affecting modulation based on feedback or feedforward control. While with the restricted lookahead, older adults showed similar regulation, their anticipatory modulation was poorer and extended over the evaluation interval. With normal lookahead, young adults reduced step length just before the encounter, potentially increasing momentum with less heel-strike energy dissipation. Step length changes around and after the perturbation may have been passive. Older adults exhibited longer modulation periods than young adults. We also noted active leg length modulation, likely influenced by tactile sensory information. For up-steps, effective leg lengths were shorter, while for down-steps, they were longer, potentially compensatory actions to minimize COM vertical fluctuations and associated work against gravity. The amplitude of leg length modulation may have been constrained by the flexed legs walking energetic cost or and ankle range of motion. With restricted lookahead, older adults showed larger leg length modulation amplitudes.
Machine learning-based proteogenomic data modeling identifies circulating plasma biomarkers for early detection of lung cancer
Authors: Johnson Marcela A. , Hou Liping , Huang Bevan Emma , Saadatpour Assieh , Torshizi Abolfazl Doostparast 
Published: August 2024

AbstractIdentifying genetic variants associated with lung cancer (LC) risk and their impact on plasma protein levels is crucial for understanding LC predisposition. The discovery of risk biomarkers can enhance early LC screening protocols and improve prognostic interventions. In this study, we performed a genome-wide association analysis using the UK Biobank and FinnGen. We identified genetic variants associated with LC and protein levels leveraging the UK Biobank Pharma Proteomics Project. The dysregulated proteins were then analyzed in pre-symptomatic LC cases compared to healthy controls followed by training machine learning models to predict future LC diagnosis. We achieved median AUCs ranging from 0.79 to 0.88 (0-4 years before diagnosis/YBD), 0.73 to 0.83 (5-9YBD), and 0.78 to 0.84 (0-9YBD) based on 5-fold cross-validation. Conducting survival analysis using the 5-9YBD cohort, we identified eight proteins, including CALCB, PLAUR/uPAR, and CD74 whose higher levels were associated with worse overall survival. We also identified potential plasma biomarkers, including previously reported candidates such as CEACAM5, CXCL17, GDF15, and WFDC2, which have shown associations with future LC diagnosis. These proteins are enriched in various pathways, including cytokine signaling, interleukin regulation, neutrophil degranulation, and lung fibrosis. In conclusion, this study generates novel insights into our understanding of the genome-proteome dynamics in LC. Furthermore, our findings present a promising panel of non-invasive plasma biomarkers that hold potential to support early LC screening initiatives and enhance future diagnostic interventions.
Which Components of the Haemodynamic Response to Active Stand Predict Cardiovascular Disease and Mortality? Data From The Irish Longitudinal Study on Ageing
Authors: Hernández Belinda , Dyer Adam H. , McCrory Cathal , Newman Louise , Finucane Ciaran , Kenny Rose Anne 
Published: August 2024

AbstractBackgroundAn integrated haemodynamic response during standing may serve as an integrative marker of neuro-cardiovascular function. Individual components of both heart rate (HR) and blood pressure (BP) responses to active stand (AS) have been linked with cardiovascular disease (CVD) and mortality. We assessed longitudinal associations between entire HR/BP response curves during AS, incident CVD and mortality over 12 years.MethodsBeat-to-beat measurements of dynamic HR/BP responses to AS were conducted in 4,336 individuals (61.5±8.2 years; 53.7% female). Functional Principal Components Analysis was applied to HR/BP response curves and their association with CVD and mortality assessed. We hypothesised that integrating BP/HR information from the entire haemodynamic response curve may uncover novel associations with both CVD and mortality.ResultsHigher systolic BP (SBP) before AS and blunted recovery of SBP during AS was associated with all-cause mortality over 12-years (Hazard Ratio [HR]: 1.14; 1.04, 1.26; p=0.007). Higher baseline/peak HR and lower HR from 30 seconds post stand onwards were associated with lower mortality due to circulatory causes (HR: 0.78; 0.64, 0.95; p = 0.013). Higher HR throughout AS was associated with mortality from other causes (HR: 1.48; 1.22, 1.80; p<0.001). Findings persisted on robust covariate adjustment.ConclusionsWe observed distinct relationships between HR/BP responses to AS and 12-year incident CVD and mortality. Integrating the entire haemodynamic response may reveal more nuanced relationships between HR/BP responses to AS, CVD and mortality - serving as an integrative marker of neuro-cardiovascular health in midlife and beyond.
A phase Ib/IIa randomized trial of Enoxacin in patients with ALS
Authors: Magen Iddo , Kaneb Hannah Marlene , Masnata Maria , Pulimood Nisha , Emde Anna , Genge Angela , Hornstein Eran 
Published: August 2024

AbstractBackground and ObjectivesThe RNAse III DICER is essential for miRNA biogenesis. DICER activity is downregulated in sporadic and genetic forms of ALS. Accordingly, hundreds of miRNAs are broadly downregulated, and their mRNA targets are de-repressed. Enoxacin is a fluoroquinolone, which increases DICER activity and miRNA biogenesis. In an investigator-initiated, first-in-patient phase Ib/IIa study, we tested Enoxacin safety and tolerability in patients with ALS and explored pharmacodynamic biomarkers for Enoxacin target engagement.Trial designREALS1 was a randomized, double-blind, parallel group study.MethodsPatients with sporadic ALS who met inclusion criteria were dosed with 200mg, 400mg or 600mg oral Enoxacin twice daily for 30 days. Randomization was conducted as per a randomization sequence generated by the study statistician. The study participants, care givers, and those assessing outcomes were blinded to dose assignment throughout the study. The main objective of this trial was safety and tolerability, and primary outcomes were the number and severity of adverse events and number of patients completing dosing. Other objective was pharmacodynamic biomarkers for Enoxacin target engagement, measured by profiling miRNAs by RNA-seq.ResultsA total of eight patients were randomized to either 200mg x 2/day (n=3), 400mg x 2/day (n=3) or 600mg x 2/day (n=2). Patients did not experience any serious adverse events. One patient in the 600 mg x 2/day group discontinued the study early, due to adverse events that were not life-threatening. Molecular analysis of cell-free miRNA in plasma and CSF was performed in the 200mg x 2/day and 400mg x 2/day groups, in which all patients completed dosing. This analysis revealed a global increase in plasma and CSF miRNA levels in all post-treatment time points, compared to baseline.ConclusionEnoxacin is safe and tolerable and provides important evidence for in-patient target engagement. These results encourage testing Enoxacin efficacy in larger trials.Trial Registration informationClinicalTrials.govidentifier:NCT04840823. Submitted on March 29, 2021. First patient enrolled on April 8, 2021.FundingALS Association, ALS Canada, eRARE FP7, Israel Ministry of Health, Muscular Dystrophy Canada, Canadian Institutes of Health Research and Fonds de recherche du Québec - Santé.
The oxytocin system in patients with craniopharyngioma: A systematic review
Authors: Mann Amy , Kalitsi Jennifer , Jani Khushali , Martins Daniel , Kapoor Ritika R , Paloyelis Yannis 
Published: August 2024

AbstractCraniopharyngioma is a benign tumour affecting the hypothalamic and pituitary regions, which are involved in the production and secretion of oxytocin. We conducted a systematic review to assess dysregulation of the oxytocin system in craniopharyngioma and associations with neurobehavioural, eating, and metabolic abnormalities. Eight studies (n=72 patients) were included. Evidence for dysfunction of the endogenous oxytocin system in craniopharyngioma is limited and mixed. While no significant differences in baseline salivary oxytocin concentrations were reported between patients with craniopharyngioma and controls, patients with craniopharyngioma were found to have blunted salivary oxytocin response following exercise stimulation and this was associated with greater state anxiety and higher BMI. Studies administering exogenous oxytocin are sparse and do not meet required standards. Hypothalamic damage may pose an additional mechanism of oxytocin dysregulation. Improving understanding of the oxytocin system in craniopharyngioma could be pivotal for exploring the potential therapeutic role of exogenous oxytocin in this condition.
Indications and Outcome of Intravitreal Bevacizumab Injection in a Community Eye Hospital, Nepal
Authors: Thakali Sunil , Shrestha Mohini , Gauchan Aleena , Gurung Hom Bahadur , Poudel Manish 
Published: August 2024

AbstractIntravitreal bevacizumab(IVB) injection, is a humanized monoclonal antibody that has been in use for the treatment of retinal diseases, very cheaply, especially for developing countries like Nepal. This is a retrospective study designed to evaluate the indications and outcomes of IVB at Hetauda Community Eye Hospital from 2019 to 2022. In this study, among 247 patients including 260 eyes with a follow-up rate of 221 patients involving 234 eyes, the mean patient age was 64.4 years, with male predominance of 56.1%. Thus, IVB was used principally in the treatment of diabetic retinopathy, neovascular age-related macular degeneration, and branch retinal vein occlusion. The results indicated significant improvements in central macular thickness and visual acuity with respect to diabetic retinopathy, nAMD, and BRVO. The study thus puts forth the effectiveness of IVB in improving visual outcomes and reducing CMT in a resource-constrained setting; hence, its use should be implemented as a viable treatment option within such an environment.
Imputing abundance of over 2500 surface proteins from single-cell transcriptomes with context-agnostic zero-shot deep ensembles
Authors: Chen Ruoqiao , Zhou Jiayu , Chen Bin 
Published: August 2024

AbstractCell surface proteins serve as primary drug targets and cell identity markers. The emergence of techniques like CITE-seq has enabled simultaneous quantification of surface protein abundance and transcript expression for multimodal data analysis within individual cells. The published data have been utilized to train machine learning models for predicting surface protein abundance based solely from transcript expression. However, the small scale of proteins predicted and the poor generalization ability for these computational approaches across diverse contexts, such as different tissues or disease states, impede their widespread adoption. Here we propose SPIDER (surface protein prediction using deep ensembles from single-cell RNA-seq), a context-agnostic zero-shot deep ensemble model, which enables the large-scale prediction of cell surface protein abundance and generalizes better to various contexts. Comprehensive benchmarking shows that SPIDER outperforms other state-of-the-art methods. Using the predicted surface abundance of >2500 proteins from single-cell transcriptomes, we demonstrate the broad applications of SPIDER including cell type annotation, biomarker/target identification, and cell-cell interaction analysis in hepatocellular carcinoma and colorectal cancer.
Metabolic modelling reveals increased autonomy and antagonism in type 2 diabetic gut microbiota
Authors: Kadibalban A. Samer , Künstner Axel , Schröder Torsten , Zauleck Julius , Witt Oliver , Marinos Georgios , Kaleta Christoph 
Published: August 2024

1.AbstractType 2 diabetes presents a growing global health concern, with emerging evidence highlighting the pivotal role of the human gut microbiome in metabolic diseases. This study employs metabolic modelling to elucidate changes in host-microbiome interactions in type 2 diabetes. Glucose levels, dietary intake, 16S sequences and metadata were estimated and collected for a cohort of 1,866 individuals. In addition, microbial community models, as well as ecological interactions were simulated for the gut microbiomes of the cohort participants. Our findings revealed a significant decrease in the fluxes of metabolites provided by the host to the microbiome through the diet in patients with type 2 diabetes, accompanied by an increase in within-community exchanges. Moreover, the diabetic microbial community shifts towards increased exploitative ecological interactions among its member species at the expense of collaborative interactions. The reduced butyrate flux from the community to the host and reduced tryptophan acquired by the microbiome from the host’s diet further highlight the dysregulation in microbial-host interactions in diabetes. Additionally, microbiomes of type 2 diabetes patients exhibit enrichment in energy metabolism pathways, indicative of increased metabolic activity and antagonism. This study provides insights into the metabolic dynamics of the diabetic gut microbiome, shedding light on its increased autonomy and altered ecological interactions accompanying diabetes, and provides candidate metabolic targets for intervention studies and experimental validations, such as butyrate, tryptophan, H2S, several nucleotides, amino acids, and B vitamins.
Extensive mutual influences of SMC complexes shape 3D genome folding
Authors: Zhao Han , Shu Lirong , Liu Fuhai , Lin En , Xia Sijian , Wang Baiyue , Wang Manzhu , Shan Fengnian , Lin Yinzhi , Zhang Lin , Gu Yufei , Blobel Gerd A. , Zhang Haoyue 
Published: August 2024

AbstractMammalian genomes are folded by the distinct actions of SMC complexes which include the chromatin loop-extruding cohesin, the sister-chromatid cohesive cohesin, and the mitotic chromosome-associated condensins. While these complexes function at different stages of the cell cycle, they co-exist on chromatin during the G2/M-phase transition, when genome structure undergoes a dramatic reorganization. Yet, how distinct SMC complexes affect each other and how their mutual interplay orchestrates the dynamic folding of 3D genome remains elusive. Here, we engineered all possible cohesin/condensin configurations on mitotic chromosomes to delineate the concerted, mutual influential action of SMC complexes. We find that: (i) The mitotic SMC complex condensin disrupts the focal accumulation of extrusive-cohesin at CTCF binding sites, thereby promoting the disassembly of interphase TADs and chromatin loops during mitotic progression. Conversely, extrusive-cohesin can impair condensin activity and alter mitotic chromosome helicity. (ii) Condensin diminishes cohesive-cohesin focal enrichment and, conversely, cohesive-cohesin can counteract condensin function and impede mitotic chromosome longitudinal shortening. (iii) The co-presence of extrusive- and cohesive-cohesin synergistically antagonizes condensin function and dramatically delays mitotic chromosome condensation. (iv) Extrusive-cohesin positions cohesive-cohesin at CTCF binding sites. However, cohesive-cohesin by itself is insufficient to mediate the formation of TADs or chromatin loop, implying non-overlapping function with extrusive-cohesin. Instead, cohesive-cohesin restricts chromatin loop expansion, potentially by limiting extrusive-cohesin movement. Collectively, our data describe a comprehensive three-way interplay among major SMC complexes that dynamically sculpts chromatin architecture during cell cycle progression.
DNA stimulates SIRT6 to mono-ADP-ribosylate proteins within histidine repeats
Authors: Pederson Nicholas J. , Diehl Katharine L. 
Published: August 2024

AbstractSirtuins are the NAD+-dependent class III lysine deacylases (KDACs). Members of this family have been linked to longevity and a wide array of different diseases, motivating the pursuit of sirtuin modulator compounds. Sirtuin 6 (SIRT6) is a primarily nuclear KDAC that deacetylates histones to facilitate gene repression. In addition to this canonical post-translational modification (PTM) “eraser” function, SIRT6 can use NAD+instead to “write” mono-ADP-ribosylation (mARylation) on target proteins. This enzymatic function has been primarily associated with SIRT6’s role in the DNA damage response. This modification has been challenging to study because it is not clear under what precise cellular contexts it occurs, only a few substrates are known, and potential interference from other ADP-ribosyltransferases in cells, among other reasons. In this work, we used commercially available ADP-ribosylation detection reagents to investigate the mARylation activity of SIRT6 in a reconstituted system. We observed that SIRT6 is activated in its mARylation activity by binding to dsDNA ends. We further identified a surprising target motif within biochemical substrates of SIRT6, polyhistidine (polyHis) repeat tracts, that are present in several previously identified SIRT6 mARylation substrates and binding partners. This work provides important context for SIRT6 mARylation activity, in contrast to its KDAC activity, and proposes that SIRT6 is a histidine mARyltransferase enzyme.
Be overworked: after-hours electronic communication expectations and emotional exhaustion
Authors: Du Jingwen 
Published: August 2024

PurposeThis study aimed to explore two questions. The first is why employees become emotionally exhausted when faced with after-hours electronic communication. The second is how can emotional exhaustion caused by after-hours electronic communication be alleviated?Design/methodology/approachOur research was based on conservation of resources theory, social exchange theory, and relative deprivation theory. We surveyed 241 employees using three waves of data collection to examine the impact of after-hours electronic communication expectations on their emotional exhaustion. We also explored the mediating effects of relative deprivation and obsessive passion from a cognitive-affective perspective and the moderating effect of leader-member exchange.FindingsThe results indicate that after-hours electronic communication expectations lead to employee emotional exhaustion, which is mediated by obsessive passion and relative deprivation. The leader-member exchange negatively moderated after-hours electronic communication expectations and relative deprivation but positively moderated after-hours electronic communication expectations and obsessive passion, thereby alleviating employee emotional exhaustion.Originality/valueIn exploring the influence mechanism of after-hours electronic communication expectations on emotional exhaustion from a cognitive-affective perspective, our study went beyond the limitations of analysis from a single perspective. A comparison of the two pathways indicated that cognition (relative deprivation) is more likely to lead to emotional exhaustion, which validates the view that individuals can ultimately analyse their behaviours rationally. By exploring the moderating effect of leader-member exchange, we provide a theoretical basis for organisations to take measures to alleviate the negative emotions caused by after-hours electronic communication.
Why is digital transformation so slow? The shadow of dehumanization 2.0
Authors: Czakon Wojciech , Meyer Natanya 
Published: August 2024

PurposeIn recent years we have seen major technological advancements including the launch of large language models such as ChatGPT and the popularity of the digital transformation topic among professionals and academics. Despite this, the pace of digital transformation is surprisingly slow. We aimed to identify behavioral antecedents of an organization’s sluggish digital transformation.Design/methodology/approachWe adopted the organizational level of analysis, which differs from prior analyses of technological revolutions that looked at the phenomenon from an aggregate labor market or society level of analysis.FindingsWe identified dehumanization as a key construct useful in examining the behavioral impediments to digital transformation. We indicated that the traditionally dual understanding of dehumanization needs to incorporate the actual involvement of non-human agents in operational and decision-making processes in organizations.Originality/valueWe complemented the predominant approach of digital transformation, which focuses on technology and related business model development, with a behavioral approach. We considered digital transformation as an extreme degree of change, similar to the Industrial Revolution. We paved the way for the conceptual development of dehumanization in the digital world and for developing managerial practices useful in alleviating concerns that impede the pace of digital transformation.
Knowledge distance and business model reconfiguration: the moderating role of tie strength
Authors: Karoui Badr Eddine , Chtourou Wafi 
Published: August 2024

PurposeThe purpose of this paper is to determine how knowledge distance, which encompasses cognitive and geographic distance, influences efficiency-centered and novelty-centered business model reconfiguration (BMR), and the moderating role of tie strength.Design/methodology/approachThe authors analyze a sample of 132 Tunisian incumbent firms by multiple hierarchical regressions.FindingsFirst, the effect of knowledge distance on novelty-centered BMR may differ depending on whether the firm introduces novelty within or outside its organizational boundaries. Specifically, the authors introduce two new types of novelty-centered BMR: intra-novelty and extra-novelty, which respectively take into account whether the reconfigured activities are governed within or outside the focal firm’s boundaries. Second, cognitive distance has an inverted U-shaped effect on efficiency-centered and intra-novelty-centered BMR. Third, tie strength has a moderating role, with varying effects depending on the type of BMR pursued.Practical implicationsThis study provides guidance for managers on structuring alliances and collaborations when pursuing BMR. It provides recommendations on partner characteristics, as well as relationship tie strength, that are most beneficial for different types of BMR.Originality/valueThis paper answers the call for research on how knowledge obtained from distant sources can contribute to BMR. Additionally, the paper introduces a previously absent distinction in the BMR literature. The findings suggest that studying the antecedents of BMR should not be limited to the level of design themes but also encompass the level of design elements such as governance.