bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of inhibitor size and flexibility on the binding pathways to c-Src kinase
Authors: Shinobu Ai , Re Suyong , Sugita Yuji 
Published: October 2022

ABSTRACTConsidering dynamical aspects of protein-drug binding processes is inevitable in current drug compound design. Conformational plasticity of protein kinases poses a challenge for the design of their inhibitors, and therefore, atomistic molecular dynamics (MD) simulations have often been utilized. While protein conformational changes have been increasingly discussed, a fundamental yet non-trivial question remains for the effect of drug compound flexibility, which is hardly detectable from experiments. In this study, we apply two-dimensional replica-exchange MD simulations as enhanced sampling to investigate how c-Src kinase can bind PP1, a small inhibitor, and dasatinib, a larger inhibitor with greater flexibility. 600 microseconds simulations in total sample binding and unbinding events of these inhibitors much more frequently than conventional MD simulation, resulting in statistically converged binding pathways. While the two inhibitors adopt a similar mechanism of multiple binding pathways, the non-canonical binding poses become less feasible for dasatinib. A notable difference is apparent in their energetics where dasatinib stabilizes at intermediate states more than PP1 to raise the barrier toward the canonical pose. Conformational analysis shows that dasatinib adopts linear and bent forms for which relative populations are altered upon binding. We further find hidden conformations of dasatinib at intermediate regions, and unexpectedly one of them could efficiently bypasses the intermediate-to-bound state transition. The results demonstrate that inhibitor size and flexibility impact the binding mechanism, which could potentially modulate inhibitor residence time.
Smoother: A Unified and Modular Framework for Incorporating Structural Dependency in Spatial Omics Data
Authors: Su Jiayu , Reynier Jean-Baptiste , Fu Xi , Zhong Guojie , Jiang Jiahao , Escalante Rydberg Supo , Wang Yiping , Aparicio Luis , Izar Benjamin , Knowles David A , Rabadan Raul 
Published: October 2022

AbstractSpatial omics technologies can help identify spatially organized biological processes, but existing computational approaches often overlook structural dependencies in the data. Here, we introduce Smoother, a unified framework that integrates positional information into non-spatial models via modular priors and losses. In simulated and real datasets, Smoother enables accurate data imputation, cell-type deconvolution, and dimensionality reduction with remarkable efficiency. In colorectal cancer, Smoother-guided deconvolution revealed plasma cell and fibroblast subtype localizations linked to tumor microenvironment restructuring. Additionally, joint modeling of spatial and single-cell human prostate data with Smoother allowed for spatial mapping of reference populations with significantly reduced ambiguity.
Nonlinear microscale mechanics of actin networks governed by coupling of filament crosslinking and stabilization
Authors: Dwyer Mike , Robertson-Anderson Rae M. , Gurmessa Bekele J. 
Published: October 2022

AbstractActin plays a vital role in maintaining the stability and rigidity of biological cells while allowing for cell motility and shape change. The semiflexible nature of actin filaments – along with the myriad actin-binding proteins (ABPs) that serve to crosslink, bundle, and stabilize filaments – are central to this multifunctionality. The effect of ABPs on the structural and mechanical properties of actin network mechanics has been the topic of fervent investigation over the past few decades, revealing diverse structures from isotropic percolated networks to heterogeneous bundles that depend on the crosslinker type and concentration. Yet, the impact of filament stabilization and stiffening via ABPs on the nonlinear response of crosslinked networks has yet to be explored. Here, we perform optical tweezers microheology measurements to characterize the nonlinear force response and relaxation dynamics of actin networks in the presence of varying concentrations ofα-actinin, which transiently crosslinks actin filaments, and phalloidin, which stabilizes filamentous actin and increases its persistence length. We show that crosslinking and stabilization can act both synergistically and antagonistically to tune the network resistance to nonlinear straining. For example, phalloidin-stabilization leads to enhanced elastic response and reduced dissipation at large strains and timescales, while the initial microscale force response is reduced compared to networks without phalloidin. Moreover, we find that stabilization switches this initial response from that of stress-stiffening to softening despite the increased filament stiffness that phalloidin confers. Finally, we show that both crosslinking and stabilization are necessary to elicit these emergent features, while the effect of stabilization on networks without crosslinkers is much more subdued. We suggest that these intriguing mechanical properties arise from the competition and cooperation between filament connectivity, bundling, and rigidification, shedding light on how ABPs with distinct roles can act in concert to mediate diverse mechanical properties of the cytoskeleton and bio-inspired polymeric materials.
Homotopic local-global parcellation of the human cerebral cortex from resting-state functional connectivity
Authors: Yan Xiaoxuan , Kong Ru , Xue Aihuiping , Yang Qing , Orban Csaba , An Lijun , Holmes Avram J. , Qian Xing , Chen Jianzhong , Zuo Xi-Nian , Zhou Juan Helen , Fortier Marielle V , Tan Ai Peng , Gluckman Peter , Chong Yap Seng , Meaney Michael J , Bzdok Danilo , Eickhoff Simon B. , Yeo B.T. Thomas 
Published: October 2022

AbstractResting-state fMRI is commonly used to derive brain parcellations, which are widely used for dimensionality reduction and interpreting human neuroscience studies. We previously developed a model that integrates local and global approaches for estimating areal-level cortical parcellations. The resulting local-global parcellations are often referred to as the Schaefer parcellations. However, the lack of homotopic correspondence between left and right Schaefer parcels has limited their use for brain lateralization studies. Here, we extend our previous model to derive homotopic areal-level parcellations. Using resting-fMRI and task-fMRI across diverse scanners, acquisition protocols, preprocessing and demographics, we show that the resulting homotopic parcellations are as homogeneous as the Schaefer parcellations, while being more homogeneous than five publicly available parcellations. Furthermore, weaker correlations between homotopic parcels are associated with greater lateralization in resting network organization, as well as lateralization in language and motor task activation. Finally, the homotopic parcellations agree with the boundaries of a number of cortical areas estimated from histology and visuotopic fMRI, while capturing sub-areal (e.g., somatotopic and visuotopic) features. Overall, these results suggest that the homotopic local- global parcellations represent neurobiologically meaningful subdivisions of the human cerebral cortex and will be a useful resource for future studies. Multi-resolution parcellations estimated from 1479 participants are publicly available (GITHUB_LINK).
Visual awareness during the attentional blink is determined by representational similarity
Authors: Tang Matthew F. , Shapiro Kimron L. , Enns James T. , Visser Troy A.W. , Mattingley Jason B. , Arabzadeh Ehsan 
Published: October 2022

AbstractOur visual perception seems effortless, but the brain has a limited processing capacity which curtails the amount of sensory information that can be brought into conscious awareness at any moment in time. A widely studied exemplar of this limitation is the ‘attentional blink’ (AB), in which observers are unable to report the second of two rapidly sequential targets if it appears within 200-500 ms of the first. Despite the apparent ubiquity of the AB effect, its computational and neurophysiological underpinnings have remained elusive. Here we propose a simple computational model of temporal attention that unifies the AB with spatial and feature-based attention. We took a novel, integrative approach involving human psychophysics and functional brain imaging, along with neuronal recordings in mice to test this model. Specifically, we demonstrate that the AB only arises when visual targets have dissimilar representations in the brain but is absent when both targets have the same representation. Similarity in this context can be determined either by elementary features such as edge orientation, or by acquired, high-level factors such as numerical or alphabetical order. In this parsimonious model of the AB, attention to an initial target establishes a perceptual filter that is tuned to its unique representation in the brain. Subsequent items that match the filter remain available for conscious report, whereas those that do not match elude awareness altogether.
A novel non-invasive biomarker based on oral microbiome dysbiosis for detection of Community-Acquired Pneumonia
Authors: Sun Ni , Zhang Xuhan , Hou Yating , Zhong Ting 
Published: October 2022

AbstractBackgroundEarly diagnosis of pathogenic bacteria is crucial for the treatment of community-acquired pneumonia (CAP), but conventional diagnostics are limited by sampling difficulties. Oral microbiota has also been explored as a noninvasive biomarker of lung diseases, but it’s role in CAP has been neglected. We aimed to investigate whether the oral bacteria can be novel non-invasive biomarkers for CAP.MethodsOral swab samples were collected from 29 patients with CAP and 26 healthy volunteers and characterized based on clinical parameters and 16S rRNA profiling of oral bacteria. A predict functional profiling was performed for the functional and metabolic changes in oral microbial communities.ResultsOral microbial of patients with CAP had a lower diversity than healthy group. And the dominant bacteria wereStreptococcus, PrevotellaandNeisseriain CAP. Higher abundance ofPrevotella(particularlyPrevotella_melaninogenica),VeillonellaandCampylobacter, and lower abundance ofNeisseriaandFusobacteriumwere detected in CAP group. Analysis of the functional potential of oral microbiota demonstrated that the pathway involving infectious disease was overrepresented in the CAP groups relative to that in the healthy controls.ConclusionsOral microbial dysbiosis was found in patients with CAP, supporting the use of this non-invasive specimen for biomarkers of CAP.HighlightsOral microbial diversity was significantly lower in community-acquired pneumonia (CAP) patients than healthy controls.GeneraNeisseriaandFusobacteriumwere decreased, while generaPrevotella, VeillonellaandCampylobacterwere increased in CAP versus healthy controls.Oral microbiota-based biomarkers can serve as a promising non-invasive tool for the detection of CAP.
Detecting Heart Failure using novel bio-signals and a Knowledge Enhanced Neural Network
Authors: Nogueira Marta Afonso , Calcagno Simone , Campbell Niall , Zaman Azfar , Koulaouzidis Georgios , Jalil Anwar , Alam Firdous , Stankovic Tatjana , Szabo Erzsebet , Szabo Aniko B. , Kecskes Istvan 
Published: October 2022

1AbstractBackgroundClinical decisions about Heart Failure (HF) are frequently based on measurements of left ventricular ejection fraction (LVEF), relying mainly on echocardiography measurements for evaluating structural and functional abnormalities of heart disease. As echocardiography is not available in primary care, this means that HF cannot be detected on initial patient presentation. Instead, physicians in primary care must rely on a clinical diagnosis that can take weeks, even months of costly testing and clinical visits. As a result, the opportunity for early detection of HF is lost.Methods and resultsThe standard 12-Lead ECG provides only limited diagnostic evidence for many common heart problems. ECG findings typically show low sensitivity for structural heart abnormalities and low specificity for function abnormalities, e.g., systolic dysfunction. As a result, structural and functional heart abnormalities are typically diagnosed by echocardiography in secondary care, effectively creating a diagnostic gap between primary and secondary care. This diagnostic gap was successfully reduced by an AI solution, the Cardio-HART™ (CHART), which uses Knowledge-enhanced Neural Networks to process novel bio-signals. Cardio-HART reached higher performance in prediction of HF when compared to the best ECG-based criteria: sensitivity increased from 53.5% to 82.8%, specificity from 85.1% to 86.9%, positive predictive value from 57.1% to 70.0%, the F-score from 56.4% to 72.2%, and area under curve from 0.79 to 0.91. The sensitivity of the HF-indicated findings is doubled by the AI compared to the best rule-based ECG-findings with a similar specificity level: from 38.6% to 71%.ConclusionUsing an AI solution to process ECG and novel bio-signals, the CHART algorithms are able to predict structural, functional, and valve abnormalities, effectively reducing this diagnostic gap, thereby allowing for the early detection of most common heart diseases and HF in primary care.
Augmenting CAR NK cell Anti-tumor Activity by Synapse Tuning
Authors: Chockley Peter J , Ibanez-Vega Jorge , Krenciute Giedre , Talbot Lindsay J , Gottschalk Stephen 
Published: October 2022

Introductory ParagraphChimeric antigen receptor (CAR) technologies have been clinically implemented for the treatment of hematological malignancies; however, solid tumors remain resilient to CAR therapeutics1-3. Natural Killer (NK) cells may provide an optimal class of immune cells for CAR-based approaches due to their inherent anti-tumor functionality. We sought to tune CAR synapses in NK cells by adding an intracellular scaffolding protein binding site to the CAR. We employed a PDZ binding motif (PDZbm) that specifically binds Scribble4resulting in additional scaffolding crosslinking to enhance synapse formation and cell polarization5,6. Combined effects of this novel CAR design resulted in increased effector cell functionalityin vitroandin vivo. Synapse-tuned CAR-NK cells exhibited amplified synaptic strength, number and abundance of secreted cytokines, enhanced killing of tumor cells, and prolonged survival with tumor clearance in two solid tumor models. Thus, synapse tuning has the potential to improve the efficacy of CAR-based cell therapeutics.
Limited Defense of Liver Energy Status in Rats Susceptible to Diet-induced Obesity
Authors: Friedman Mark I , Ji Hong 
Published: October 2022

AbstractRats that are susceptible to diet-induced obesity have a preexisting reduced capacity for hepatic fatty acid oxidation compared with those resistant to diet-induced obesity. The eating response to administration of a fatty acid oxidation inhibitor is more closely associated with low liver energy status than it is with reduced hepatic fatty acid oxidation, a finding consistent with studies showing that lowered liver energy status stimulates food intake. To evaluate whether susceptibility to diet-induced obesity is associated with a preexisting impairment in liver energy status, we conducted two experiments in obesity-prone (OP) and -resistant (OR) outbred rats. In one experiment, OP rats increased food intake more than did OR rats during refeeding after a 24 h fast. When fasted and refed again, liver energy status (i.e., liver ATP content, ATP:ADP ratio and phosphorylation index) was lower in OP rats after a fast. When OP animals were refed fixed rations of food, liver energy status increased more slowly during refeeding than it did in OR rats. The delay in restoration of liver energy status during refeeding corresponded to the interval during which OP rats ate significantly more food in the intake test. In a second experiment, liver energy status was lower in OP than it was in OR rats after injection of the fructose analogue, 2,5-anhydro-D-mannitol, which depletes liver ATP. These results suggest that liver energy status is more vulnerable in rats susceptible to diet-induced obesity.
Development and Validation of theVanderbilt PRS-KS, an Instrument to Quantify Polygenic Risk Score Knowledge
Authors: Stubbs Doug , Hooker Gillian , Le Yajing , Richter Lucas , Bick Alexander 
Published: October 2022

AbstractPurposeAs polygenic risk scores (PRS) enter clinical practice, healthcare providers’ and the publics’ comprehension of PRS results are of great importance, yet poorly understood. We present the Vanderbilt Polygenic Risk Scores Knowledge Score (Vanderbilt PRS-KS), a tool to quantify PRS knowledge.MethodsThe Vanderbilt PRS-KS was developed by a team of genetic counselors and physicians to cover key conceptual facts pertaining to PRSs. We recruited (n=500) individuals with demographics representative of a U.S. sample and graduate-level healthcare students (n=74) at a large academic medical center to participate in this validation study. We evaluated the Vanderbilt PRS-KS’s psychometric properties using confirmatory factor analysis (CFA) and item response theory (IRT).ResultsThe 7-item Vanderbilt PRS-KS correlated to a single latent construct on CFA (Λ=0.31-0.61). The scale showed promising reliability (Cronbach’s α=0.66) with IRT summed scores of ≥2 to ≤5, demonstrating reliability > 0.70. The Vanderbilt PRS-KS significantly correlated with genetic knowledge and applied PRS knowledge (r=0.55, r=0.29), and graduate-level healthcare students had significantly higher scores compared to the representative sample (p<0.01).ConclusionsThe Vanderbilt PRS-KS is a rigorously validated measure to quantify PRS knowledge.
Exploring the potential of using simulation games for engaging with sheep farmers about lameness recognition
Authors: Jones Matt L. , Barnish Maxwell S. , Hughes Robert R. , Murray Aimee , Mansour Omid , Loni Tiziana , Vickery Holly , Evans Myfanwy Lloyd , Green Laura , Verdezoto Nervo 
Published: October 2022

AbstractIntroductionComputer simulation games are increasingly being used in agriculture as a promising tool to study, support and influence real-life farming practices. We explored the potential of using simulation games to engage with sheep farmers on the ongoing challenge of reducing lameness. Working with UK stakeholders, we developed a game in which players are challenged with identifying all the lame sheep in a simulated flock. Here, we evaluate the game’s potential to act as a tool for to help assess, train and understand farmers’ ability to recognise the early signs of lameness.MethodsParticipants in the UK were invited to play the game in an online study, sharing with us their in-game scores alongside information relating to their real-life farming experience, how they played the game, and feedback on the game. Mixed methods were used to analyse this information in order to evaluate the game. Quantitative analyses consisted of linear modelling to test for statistical relationships between participants’ in-game recall (% of the total number of lame sheep that were marked as lame), and the additional information they provided. Qualitative analyses of participants’ feedback on the game consisted of thematic analysis and a Likert Scale questionnaire to contextualise the quantitative results and identify additional insights from the study.ResultsQuantitative analyses identified no relationships between participants’ (n = 63) recall scores and their real life farming experience, or the lameness signs they looked for when playing the game. The only relationship identified was a relationship between participants’ recall score and time spent playing the game. Qualitative analyses identified that participants did not find the game sufficiently realistic or engaging, though several enjoyed playing it and saw potential for future development. Qualitative analyses also identified several interesting and less-expected insights about real-life lameness recognition practices that participants shared after playing the game.DiscussionSimulation games have potential as a tool in livestock husbandry education and research, but achieving the desired levels of realism and/or engagingness may be an obstacle to realising this. Future research should explore this potential further, aided by larger budgets and closer collaboration with farmers, stockpeople and veterinarians.
Amount of antigen, T follicular helper cells and quality of seeder cells shape the diversity of germinal center B cells
Authors: Garg Amar K. , Mitra Tanmay , Schips Marta , Bandyopadhyay Arnab , Meyer-Hermann Michael 
Published: October 2022

ABSTRACTA variety of B cell clones seed the germinal centers, where a selection stringency expands the fitter clones to generate higher affinity antibodies. However, recent experiments suggest that germinal centers often retain a diverse set of B cell clones with a range of affinities and concurrently carry out affinity maturation. Amid a tendency to flourish germinal centers with fitter clones, how several B cell clones with differing affinities can be concurrently selected remains poorly understood. Such a permissive selection may allow non-immunodominant clones, which are often rare and of low-affinity, to somatically hypermutate and result in a broad and diverse B cell response. How the constituent elements of germinal centers, their quantity and kinetics may modulate diversity of B cells, has not been addressed well. By implementing a state-of-the-art agent-based model of germinal center, here, we study how these factors impact temporal evolution of B cell clonal diversity and its underlying balance with affinity maturation. While we find that the extent of selection stringency dictates clonal dominance, limited antigen availability on follicular dendritic cells is shown to expedite the loss of diversity of B cells as germinal centers mature. Intriguingly, the emergence of a diverse set of germinal center B cells depends on high affinity founder cells. Our analysis also reveals a substantial number of T follicular helper cells to be essential in balancing affinity maturation with clonal diversity, as a low number of T follicular helper cells impedes affinity maturation and also contracts the scope for a diverse B cell response. Our results have implications for eliciting antibody responses to non-immunodominant specificities of the pathogens by controlling the regulators of the germinal center reaction, thereby pivoting a way for vaccine development to generate broadly protective antibodies.