bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational modeling of AMPK and mTOR crosstalk in glutamatergic synapse calcium signaling
Authors: Leung A. , Rangamani P. 
Published: August 2022

AbstractNeuronal energy consumption is vital for information processing and memory formation in synapses. The brain consists of just 2% of the human body’s mass, but consumes almost 20% of the body’s energy budget. Most of this energy is attributed to active transport in ion signaling, with calcium being the canonical second messenger of synaptic transmission. Here, we develop a computational model of synaptic signaling resulting in the activation of two protein kinases critical in metabolic regulation and cell fate, AMP-Activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) and investigate the effect of glutamate stimulus frequency on their dynamics. Our model predicts that frequencies of glutamate stimulus over 10 Hz perturb AMPK and mTOR oscillations at higher magnitudes by up to 70% and area under curve (AUC) by 10%. This dynamic difference in AMPK and mTOR activation trajectories potentially differentiates high frequency stimulus bursts from basal neuronal signaling leading to a downstream change in synaptic plasticity. Further, we also investigate the crosstalk between insulin receptor and calcium signaling on AMPK and mTOR activation and predict that the pathways demonstrate multistability dependent on strength of insulin signaling and metabolic consumption rate. Our predictions have implications for improving our understanding of neuronal metabolism, synaptic pruning, and synaptic plasticity.Key PointsNeurons consume disproportionate amounts of cellular energy relative to their mass, indicating the importance of energy regulation in information processing in the brain.AMP activated protein kinase (AMPK) is thought to be the biochemical link between energy consumption in neuronal information processing and synaptic plasticity.Computational model investigating the crosstalk between high-frequency glutamatergic calcium signaling and AMPK activation in neurons predicts multistability in AMPK and mammalian target of rapamycin (mTOR) activation.Our models predict a frequency-dependent response in AMPK and mTOR activation that also scales according to insulin signaling and energy consumption. The oscillatory behavior depends on both intracellular and extracellular factors, such as energy consumption and insulin signaling.This work elucidates the role of insulin and insulin resistance in regulating neuronal activity, through computational modeling the metabolic response of energy stress resulting from calcium signaling.
Anti-PF4 (heparin-independent)/PF4 complex induces allosteric activation of integrins αIIbβ3 and αvβ3, a potential mechanism of vaccine-induced thrombotic thrombocytopenia (VITT) and autoimmune diseases
Authors: Takada Yoko K , Wu Chun-Yi , Takada Yoshikazu 
Published: August 2022

AbstractThe classical immune-mediated heparin-induced thrombocytopenia (HIT) is induced by autoantibody against platelet-factor 4 (PF4)/heparin complex. Vaccine-induced thrombotic thrombocytopenia (VITT) and autoimmune HIT (aHIT) are induced by anti-PF4 in a heparin-independent manner. Activation of platelet integrin αIIbβ3 is a key event that leads to αIIbβ3 binding to fibrinogen and platelet aggregation, but is not involved in current models of HIT or VITT. Anti-PF4 (heparin-independent) is also detected in autoimmune diseases (e.g., SLE). However, the role of anti-PF4 in these diseases is unknown. Previous studies showed that several pro-inflammatory chemokines potently activated integrins by binding to the allosteric site (site 2). PF4 is known to be inhibitory since it inhibits angiogenesis and tumor growth. Here we describe that PF4 was predicted to bind to site 2 of αIIbβ3 by docking simulation, but did not activate it. However, PF4/anti-PF4 mAb (RTO, heparin-independent) complex potently activated it at biological concentrations of PF4 (<1 μg/ml), but anti-PF4/heparin (KKO) did not. This indicates that RTO changed the phenotype of PF4. We generated PF4 mutants defective in site 2 binding to integrin by introducing mutations in the predicted site 2 binding site of PF4. A PF4 mutant/RTO complex was defective in activating integrins. Furthermore, this PF4 mutant acted as an antagonist of PF4/RTO-induced integrin activation. We obtained similar results with vascular integrin αvβ3. We propose that a potential mechanism, in which PF4/RTO complex binds to site 2 and activates integrins and triggers thrombocytopenia or autoimmune diseases. The inhibitory PF4 mutant may have potential as a therapeutic.
Arrestin-3 agonism at D3 dopamine receptors defines a subclass of second generation antipsychotics that promotes drug tolerance
Authors: Schamiloglu Selin , Lewis Elinor , Hergarden Anne C. , Bender Kevin J. , Whistler Jennifer L. 
Published: August 2022

ABSTRACTSecond generation antipsychotics (SGAs) are front-line treatments for serious mental illness. Often, individual patients benefit only from some SGAs and not others. The mechanisms underlying this unpredictability in treatment efficacy remain unclear. All SGAs bind the D3 dopamine receptor (D3R) and are traditionally considered antagonists for dopamine receptor signaling. Here, we report that some clinically important SGAs function as arrestin-3 agonists at D3R, resulting in modulation of calcium channels localized to the site of action potential initiation in prefrontal cortex pyramidal neurons. We further show that chronic treatment with an arrestin-3 agonist-SGA, but not an antagonist-SGA, abolishes D3R function through post-endocytic receptor degradation by G-protein coupled receptor-associated sorting protein-1 (GASP1). These results implicate D3R-arrestin-3 signaling as a source of SGA variability, highlighting the importance of including arrestin-3 signaling in characterizations of drug action. Furthermore, they suggest that post-endocytic receptor trafficking that occurs during chronic SGA treatment may contribute to treatment efficacy.
Neural similarity between overlapping events at learning differentially affects reinstatement across the cortex
Authors: Hebscher Melissa , Bainbridge Wilma A. , Voss Joel L. 
Published: August 2022

AbstractEpisodic memory often involves high overlap between the actors, locations, and objects of everyday events. Under some circumstances, it may be beneficial to distinguish, or differentiate, neural representations of similar events to avoid interference at recall. Alternatively, forming overlapping representations of similar events, or integration, may aid recall by linking shared information between memories. It is currently unclear how the brain supports these seemingly conflicting functions of differentiation and integration. We used multivoxel pattern similarity analysis (MVPA) of fMRI data and neural-network analysis of visual similarity to examine how highly overlapping naturalistic events are encoded in patterns of cortical activity, and how the degree of differentiation versus integration at encoding affects later retrieval. Participants performed an episodic memory task in which they learned and recalled naturalistic video stimuli with high feature overlap. Visually similar videos were encoded in overlapping patterns of neural activity in temporal, parietal, and occipital regions, suggesting integration. We further found that encoding processes differentially predicted later reinstatement across the cortex. In visual processing regions in occipital cortex, greater differentiation at encoding predicted later reinstatement. Higher-level sensory processing regions in temporal and parietal lobes showed the opposite pattern, whereby highly integrated stimuli showed greater reinstatement. Moreover, integration in high-level sensory processing regions during encoding predicted greater accuracy and vividness at recall. These findings provide novel evidence that encoding-related differentiation and integration processes across the cortex have divergent effects on later recall of highly similar naturalistic events.
Geography, not lifestyle, explains the population structure of free-living and host-associated deep-sea hydrothermal vent snail symbionts
Authors: Hauer Michelle A. , Breusing Corinna , Trembath-Reichert Elizabeth , Huber Julie A. , Beinart Roxanne A. 
Published: August 2022

AbstractMarine symbioses are predominantly established through horizontal acquisition of microbial symbionts from the environment. However, genetic and functional comparisons of free-living populations of symbionts to their host-associated counterparts are sparse. Here, we assembled the first genomes of the chemoautotrophic gammaproteobacterial symbionts affiliated with the deep-sea snailAlviniconcha hesslerifrom two separate hydrothermal vent fields of the Mariana Back-Arc Basin. We used phylogenomic and population genomic methods to assess sequence and gene content variation between free-living and host-associated symbionts. Our phylogenomic analyses show that the free-living and host-associated symbionts ofA. hesslerifrom both vent fields are populations of monophyletic strains from a single species. Furthermore, genetic structure and gene content analyses indicate that these symbiont populations are differentiated by vent field rather than by lifestyle. Together, this work suggests that, despite the potential influence of host-mediated acquisition and release processes on horizontally transmitted symbionts, geographic isolation and/or adaptation to local habitat conditions are important determinants of symbiont population structure and intra-host composition.
Elemental stoichiometry and insect chill tolerance: Evolved and plastic changes in organismal Na+ and K+ content in Drosophila
Authors: Chalmer Sarah C. , Rudman Seth M. , Andersen Mads K. , Schmidt Paul , MacMillan Heath A. 
Published: August 2022

AbstractAcclimation and evolutionary adaptation can produce phenotypic change that allows organisms to cope with challenges like those associated with climate change. Determining the relative contributions of acclimation and adaptation is of central importance to understanding animal responses to change. Rates of evolution have traditionally been considered slow relative to ecological processes that shape biodiversity. Many organisms nonetheless show patterns of spatial genetic variation suggestive of adaptation and some evidence is emerging that adaptation can act sufficiently fast to allow phenotypic tracking in response to environmental change (‘adaptive tracking’). In Drosophila, both plastic and evolved differences in chill tolerance are associated with ionoregulation. Here we combine acclimation, latitudinal field collections, and a replicated field experiment to assess the effects of acclimation and adaptation on chill coma recovery and elemental (Na and K) stoichiometry in both sexes of Drosophila melanogaster. Acclimation and spatial adaptation both shape chill coma recovery, with acclimation producing the greatest magnitude response. Leveraging knowledge on the physiological mechanisms that underlie variation in chill tolerance traits, we find that the relationship between K content and chill tolerance differs among flies acclimated vs. adapted to cold. Taken together, these data reinforce the importance of acclimation in responses to abiotic challenges and illustrate that the mechanisms of phenotypic change can differ between acclimation and basal tolerance adaptation.
Comprehensive analyses of partially methylated domains and differentially methylated regions in esophageal cancer reveal both cell-type- and cancer-specific epigenetic regulation
Authors: Zheng Yueyuan , Ziman Benjamin , Ho Allen S. , Sinha Uttam K. , Xu Li-Yan , Li En-Min , Koeffler H Phillip , Berman Benjamin P. , Lin De-Chen 
Published: August 2022

AbstractAs one of the most common malignancies, esophageal cancer has two subtypes, squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), arising from distinct cells-of-origin. However, distinguishing cell-type-specific molecular features from cancer-specific characteristics has been challenging. Here, we analyze whole-genome bisulfite sequencing (WGBS) data on 45 esophageal tumor and nonmalignant samples from both subtypes. We develop a novel sequence-aware method to identify large partially methylated domains (PMDs), revealing profound heterogeneity at both the methylation level (depth) and genomic distribution (breadth) of PMDs across tumor samples. We identify subtype-specific PMDs, which are associated with repressive transcription, chromatin B compartments and high somatic mutation rate. While the genomic locations of these PMDs are pre-established in normal cells, the degree of loss is significantly higher in tumors. We find that cell-type-specific deposition of H3K36me2 may underlie the genomic distribution PMDs. At a smaller genomic scale, both cell-type- and cancer-specific differentially methylated regions (DMRs) are identified for each subtype. Using binding motif analysis within these DMRs, we show that a cell-type-specific transcription factor such as HNF4A can maintain the binding sites that it establishes in normal cells, while being recruited to new binding sites with novel partners such as FOSL1 in cancer. Finally, leveraging pan-tissue single-cell and pan-cancer epigenomic datasets, we demonstrate that a substantial fraction of the cell-type-specific PMDs and DMRs identified here in esophageal cancer, are actually markers that co-occur in other cancers originating from related cell types. These findings advance our understanding of the DNA methylation dynamics at various genomic scales in normal and malignant states, providing novel mechanistic insights into cell-type- and cancer-specific epigenetic regulations.
Recurrent mutation in the ancestry of a rare variant
Authors: Wakeley John , Fan Wai-Tong (Louis) , Koch Evan , Sunyaev Shamil 
Published: August 2022

AbstractRecurrent mutation produces multiple copies of the same allele which may be co-segregating in a population. Yet most analyses of allele-frequency or site-frequency spectra assume that all observed copies of an allele trace back to a single mutation. We develop a sampling theory for the number of latent mutations in the ancestry of a rare variant, specifically a variant observed in relatively small count in a large sample. Our results follow from the statistical independence of low-count mutations, which we show to hold for the standard neutral coalescent or diffusion model of population genetics as well as for more general coalescent trees. For populations of constant size, these counts are given by the Ewens sampling formula. We develop a Poisson sampling model for populations of varying size, and illustrate it using new results for site-frequency spectra in an exponentially growing population. We apply our model to a large data set of human SNPs and use it to explain dramatic differences in site-frequency spectra across the range of mutation rates in the human genome.
Insights for educators working with ethnically diverse youth in Hong Kong: a pilot positive youth development program
Authors: Arat Gizem , Wong Paul Wai-Ching 
Published: August 2022

PurposePositive youth development (PYD) among ethnic minorities is important to building a socially inclusive and rapidly aging Hong Kong. There are very limited empirically driven with evaluation among ethnic minorities in Hong Kong and in the region. This study aims to fill the research-to-practice gap by examining the implementation process and impacts of a school-based PYD school program for ethnic minorities in Hong Kong developed empirically based on the data of the larger sequential mixed-methods research project.Design/methodology/approachAlong with a non-governmental organization the authors co-developed, implemented and evaluated an eight-week pilot PYD program for youth from South Asia and newly arrival mainland Chinese backgrounds. Although a quasi-experimental mixed-methods research design was adopted and included 18 young people in the intervention group and 12 young people in the control group, this paper reported the qualitative interviews of three students, two of their teachers and two PYD interventionalists who commented about the content and process to further improve future PYD programs for ethnic minorities young people in Hong Kong.FindingsStudents stated their positive experience about the program while other participants (interventionalists and teachers) provided insights for further program effectiveness enhancement. This includes organizing social activities in the program, such as basketball or football matches would enhance the level of engagement of the participants. Teachers and interventionists suggested to develop age-appropriate programs as younger groups may have different needs or interests compared to their older counterparts.Originality/valueThis study provides insight into how to improve the implementation process, effectiveness and quality of evidence based PYD education research and practices from a culturally appropriate perspective, particularly for South Asian youth residing in Hong Kong and beyond.
Do boards practice what they preach on nonfinancial disclosure? Evidence from China on corporate water information disclosures
Authors: Liu Chengyun , Su Kun , Zhang Miaomiao 
Published: August 2022

PurposeThis study aims to examine whether and how gender diversity on corporate boards is associated with voluntary nonfinancial disclosures, particularly water disclosures.Design/methodology/approachThis study uses corporate water information disclosure data from Chinese listed firms between 2010 and 2018 to conduct regression analyses to examine the association between female directors and water information disclosure.FindingsEmpirical results show that female directors have a significantly positive association with corporate water information disclosure. Additionally, internal industry water sensitivity of firms moderates this significant relationship.Originality/valueThis study determined that female directors can promote not only water disclosure but also positive corporate water performance, reflecting the consistency of words and deeds of female directors in voluntary nonfinancial disclosures.
Property Assertion Constraints for ontologies and knowledge graphs
Authors: Dibowski Henrik 
Published: August 2022

PurposeThe curation of ontologies and knowledge graphs (KGs) is an essential task for industrial knowledge-based applications, as they rely on the contained knowledge to be correct and error-free. Often, a significant amount of a KG is curated by humans. Established validation methods, such as Shapes Constraint Language, Shape Expressions or Web Ontology Language, can detect wrong statements only after their materialization, which can be too late. Instead, an approach that avoids errors and adequately supports users is required.Design/methodology/approachFor solving that problem, Property Assertion Constraints (PACs) have been developed. PACs extend the range definition of a property with additional logic expressed with SPARQL. For the context of a given instance and property, a tailored PAC query is dynamically built and triggered on the KG. It can determine all values that will result in valid property value assertions.FindingsPACs can avoid the expansion of KGs with invalid property value assertions effectively, as their contained expertise narrows down the valid options a user can choose from. This simplifies the knowledge curation and, most notably, relieves users or machines from knowing and applying this expertise, but instead enables a computer to take care of it.Originality/valuePACs are fundamentally different from existing approaches. Instead of detecting erroneous materialized facts, they can determine all semantically correct assertions before materializing them. This avoids invalid property value assertions and provides users an informed, purposeful assistance. To the author's knowledge, PACs are the only such approach.
Federate learning on Web browsing data with statically and machine learning technique
Authors: Bhimanpallewar Ratnmala Nivrutti , Khan Sohail Imran , Raj K. Bhavana , Gulati Kamal , Bhasin Narinder , Raj Roop 
Published: August 2022

Purpose
Federation analytics approaches are a present area of study that has already progressed beyond the analysis of metrics and counts. It is possible to acquire aggregated information about on-device data by training machine learning models using federated learning techniques without any of the raw data ever having to leave the devices in the issue. Web browser forensics research has been focused on individual Web browsers or architectural analysis of specific log files rather than on broad topics. This paper aims to propose major tools used for Web browser analysis.

Design/methodology/approach
Each kind of Web browser has its own unique set of features. This allows the user to choose their preferred browsers or to check out many browsers at once. If a forensic examiner has access to just one Web browser's log files, he/she makes it difficult to determine which sites a person has visited. The agent must thus be capable of analyzing all currently available Web browsers on a single workstation and doing an integrated study of various Web browsers.

Findings
Federated learning has emerged as a training paradigm in such settings. Web browser forensics research in general has focused on certain browsers or the computational modeling of specific log files. Internet users engage in a wide range of activities using an internet browser, such as searching for information and sending e-mails.

Originality/value
It is also essential that the investigator have access to user activity when conducting an inquiry. This data, which may be used to assess information retrieval activities, is very critical. In this paper, the authors purposed a major tool used for Web browser analysis. This study's proposed algorithm is capable of protecting data privacy effectively in real-world experiments.
The social impacts of innovation: reproducing racial, gender and social class inequality
Authors: Dahlin Eric , Ammons Samantha K. , Rugh Jacob S. , Sumsion Rachel , Hebertson Justin 
Published: August 2022

PurposeWhile current scholarship on innovation typically examines its antecedents, the purpose of this paper is to provide a more complete account by advocating for social impacts as a critical component of the sociological study of innovation.Design/methodology/approachThis study adopts a conceptual approach to illustrate the ways in which innovation may generate unequitable outcomes. The authors illustrate the purpose of the paper by discussing strategically selected examples that are intended to reflect prominent themes and topics in the relevant literature.FindingsThe analysis suggests that while innovation yields many positive benefits, pervasive narratives about its virtues can be overstated when, in fact, innovation may generate adverse effects for particular social groups by reproducing or exacerbating inequality. The authors provide a more complete account of innovation by naming social impacts as a critical component of its sociological study and discussing examples that illustrate how innovation can produce disadvantageous effects by race, gender and social class. The authors move forward the discussion of social impacts by elaborating conditions in which innovation is likely to reproduce the status quo as well as ameliorate negative impacts.Originality/valueWhile many studies have explained the conditions that foster innovation, this study pushes the boundaries of the study of innovation – a timely topic for practitioners and scholars in the fields of not only sociology, but management, education and public policy. Accordingly, we move forward the discussion of the social impacts of innovation by identifying the ways in which innovation is likely to reproduce structural inequalities.