bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure of a HIV-1 IN-Allosteric Inhibitor Complex at 2.93 Å Resolution: Routes to Inhibitor Optimization
Authors: Eilers Grant , Gupta Kushol , Allen Audrey , Montermoso Saira , Murali Hemma , Sharp Robert , Hwang Young , Bushman Frederic D. , Van Duyne Gregory 
Published: June 2022

AbstractHIV integrase (IN) inserts viral DNA into the host genome and is the target of the strand transfer inhibitors (STIs), a class of small molecules currently in clinical use. Another potent class of antivirals is the allosteric inhibitors of integrase, or ALLINIs. ALLINIs promote IN aggregation by stabilizing an interaction between the catalytic core domain (CCD) and carboxy -terminal domain (CTD) that undermines viral particle formation in late replication. Ongoing challenges with inhibitor potency, toxicity, and viral resistance motivate research to understand their mechanism. Here, we report a 2.93 Å X-ray crystal structure of the minimal ternary complex between CCD, CTD, and the ALLINI BI-224436. This structure reveals an asymmetric ternary complex with a prominent network of π-mediated interactions that suggest specific avenues for future ALLINI development and optimization.
Dysregulation of ADAM10 shedding activity in naked mole-rat fibroblasts is due to deficient phosphatidylserine externalisation
Authors: Urriola-Muñoz Paulina , Pattison Luke A. , Smith Ewan St. John. 
Published: June 2022

ABSTRACTThe naked mole-rat (NMR,Heterocephalus glaber) is of significant interest to biogerontological research, rarely developing age-associated diseases, such as cancer. The transmembrane glycoprotein CD44 is upregulated in certain cancers and CD44 cleavage by a disintegrin and metalloproteinase 10 (ADAM10) regulates cellular migration. Here we provide evidence that mature ADAM10 is expressed in NMR primary skin fibroblasts (NPSF), and that ionomycin increases cell surface ADAM10 localization. However, we observed an absence of ADAM10 mediated CD44 cleavage, as well as shedding of exogenous and overexpressed betacellulin in NPSF, whereas in mouse primary skin fibroblasts (MPSF) ionomycin induced ADAM10-dependent cleavage of both CD44 and betacellulin. Overexpressing a hyperactive form of the Ca2+-dependent phospholipid scramblase ANO6 in NPSF increased phosphatidylserine (PS) externalization, which rescued the ADAM10 sheddase activity and promoted wound closure in NPSF in an ADAM10-dependent manner. These findings suggest that dysregulation of ADAM10 shedding activity is due to a deficient PS externalization in NMR.
G-Trap Assay I: Small GTPases as sensitive immune response biomarkers for active bacteremia
Authors: Clark Ross , Bondu Virginie , Simons Peter , Shevy Laura , Young Stephen , Castillo Eliseo F. , Kanagy Nancy L. , Wandinger-Ness Angela , Howdieshell Thomas , Buranda Tione 
Published: June 2022

AbstractThe annual toll of sepsis is a 33% mortality rate for hospitalized patients with a cost of greater than 60 billion dollars in the U.S. There is a correlation between sepsis mortality rates and time to treatment with broad-spectrum antibiotics. Consequently, antibiotics are prescribed to nearly every patient suspected of bacteremia. However, once determined that broad-spectrum antibiotics are not required, it is unclear how to optimize the de-escalation of the antibiotics. There is an urgent need for methods to distinguish bacteremia from sterile inflammation and to assess antibiotic efficacy. Rho (Rac1 and RhoA) and Ras (Rap1) family GTPases are dynamic nodes of signaling convergence used by immune-activated leukocytes migrating to sites of infection. This study targeted the onset of GTPase activation as a biomarker of infection-induced immune activation in trauma patients. GTP binding assays were performed using a novel GTPase effector trap flow cytometry assay (G-Trap). Here, we demonstrate increased GTP binding to small GTPases (Rac1, Rap1, and RhoA) of resting cells serially exposed to plasma samples from bacteremic trauma patients. Responses to the serial samples showed that GTPase activation was influenced by the concentration of circulating pro- and anti-inflammatory mediators, in tandem with synergy or antagonism from the cytokines and the antibiotic treatment.
G-Trap Assay II: Characterization of blood Leukocyte Functionality differentiates immune activation and immune suppression in bacteremia patient samples
Authors: Simons Peter , Shevy Laura , Bondu Virginie , Wandinger-Ness Angela , Young Stephen , Buranda Tione 
Published: June 2022

AbstractSepsis is a severe organ dysfunction syndrome caused by a dysregulation of the immune system’s response to infection. Unfortunately, most infection-causing pathogens aren’t routinely detectable in real-time to enable targeted and lifesaving treatment. Thus, clinicians frequently have limited data on which to base treatment decisions. A complete blood count with differential is available within 24 h, and positive culture is only available in ~30% of cases. Furthermore, a blood culture, the traditional gold standard for accurate diagnosis of bacteremia, may take up to five days for results, long after a clinical decision for sepsis management is required. Circulating leukocytes can sense chemotactic signals released by bloodborne pathogens or focal infections not in the bloodstream. Our earlier study showed that pathogen and host immune factors released in the bloodstream stimulated GTP binding of Ras homology (Rho) GTPases (guanosine triphosphatase) such as Rac1 in quiescent endothelial and human leukocytes after exposure to blood plasma from infected patients.[1] In this study, we measured Rac1•GTP as a biomarker of immune functionality of peripheral blood monocytes and polymorphonuclear cells extracted from blood samples drawn for diagnostic use in blood culture assays; from 120 non-infected control patients and serial blood test samples from 28 patients with a confirmed diagnosis of bloodstream infection. 18 cases presented with Rac1•GTP elevation of ≥3 fold above that of control samples. Ten patients with normal or below-normal GTPase activity, accompanied by neutrophilia or pancytopenia. We used Principal Component Analysis to differentiate the 2D spatial distribution of infected patients and negative controls. Measuring differential leukocyte functionality in infected and control patients’ blood samples with the G-Trap assay may provide an innovative process for a real-time distinction between infection and non-infectious etiologies.
A single cell spatial temporal atlas of skeletal muscle reveals cellular neighborhoods that orchestrate regeneration and become disrupted in aging
Authors: Wang Yu Xin , Holbrook Colin A. , Hamilton James N. , Garoussian Jasmin , Afshar Mohsen , Su Shiqi , Schürch Christian M. , Lee Michael Y. , Goltsev Yury , Kundaje Anshul , Nolan Garry P. , Blau Helen M. 
Published: June 2022

AbstractOur mobility requires muscle regeneration throughout life. Yet our knowledge of the interplay of cell types required to rebuild injured muscle is lacking, because most single cell assays require tissue dissociation. Here we use multiplexed spatial proteomics and neural network analyses to resolve a single cell spatiotemporal atlas of 34 cell types during muscle regeneration and aging. This atlas maps interactions of immune, fibrogenic, vascular, nerve, and myogenic cells at sites of injury in relation to tissue architecture and extracellular matrix. Spatial pseudotime mapping reveals sequential cellular neighborhoods that mediate repair and a nodal role for immune cells. We confirm this role by macrophage depletion, which triggers formation of aberrant neighborhoods that obstruct repair. In aging, immune dysregulation is chronic, cellular neighborhoods are disrupted, and an autoimmune response is evident at sites of denervation. Our findings highlight the spatial cellular ecosystem that orchestrates muscle regeneration, and is altered in aging.HighlightsSingle cell resolution spatial atlas resolves a cellular ecosystem of 34 cell types in multicellular neighborhoods that mediate efficient skeletal muscle repairHighly multiplexed spatial proteomics, neural network and machine learning uncovers temporal dynamics in the spatial crosstalk between immune, fibrogenic, vascular, nerve, and muscle stem cells and myofibers during regenerationSpatial pseudotime mapping reveals coherent formation of multicellular neighborhoods during efficacious repair and the nodal role of immune cells in coordinating muscle repairIn aged muscle, cellular neighborhoods are disrupted by a chronically inflamed state and autoimmunity
Whole blood transcriptome profiles of trypanotolerant and trypanosusceptible cattle highlight a differential modulation of metabolism and immune response during infection byTrypanosoma congolense
Authors: Peylhard Moana , Berthier David , Dayo Guiguigbaza-Kossigan , Chantal Isabelle , Sylla Souleymane , Nidelet Sabine , Dubois Emeric , Martin Guillaume , Sempéré Guilhem , Flori Laurence , Thévenon Sophie 
Published: June 2022

AbstractAnimal African trypanosomosis, caused by blood protozoan parasites transmitted mainly by tsetse flies, represents a major constraint for millions of cattle in sub-Saharan Africa. Exposed cattle include trypanosusceptible indicine breeds, severely affected by the disease, and West African taurine breeds called trypanotolerant owing to their ability to control parasite development, survive and grow in enzootic areas. Until now the genetic basis of trypanotolerance remains unclear. Here, to improve knowledge of the biological processes involved in trypanotolerance versus trypanosusceptibility, we identified bovine genes differentially expressed in five West African cattle breeds during an experimental infection byTrypanosoma congolenseand their biological functions. To this end, whole blood genome-wide transcriptome of three trypanotolerant taurine breeds (N’Dama, Lagune and Baoulé), one susceptible zebu (Zebu Fulani) and one African taurine x zebu admixed breed (Borgou) were profiled by RNA sequencing at four time points, one before and three during infection. As expected, infection had a major impact on cattle blood transcriptome regardless of the breed. The functional analysis of differentially expressed genes over time in each breed confirmed an early activation of the innate immune response, followed by an activation of the humoral response and an inhibition of T cell functions at the chronic stage of infection. More importantly, we highlighted overlooked features, such as a strong disturbance in host metabolism and cellular energy production that differentiates trypanotolerant and trypanosusceptible breeds. N’Dama breed showed the earliest regulation of immune response, associated with a strong activation of cellular energy production, also observed in Lagune, and to a lesser extent in Baoulé. Susceptible Zebu Fulani breed differed from other breeds by the strongest modification in lipid metabolism regulation. Overall, this study provides a better understanding of the biological mechanisms at work during infection, especially concerning the interplay between immunity and metabolism that seems differentially regulated depending on the cattle breeds.
Requirement for specific bacterial genome maintenance pathways in repair of C8-linked pyrrolobenzodiazepine (PBD) bi-aryl monomer-mediated DNA damage
Authors: Joseph Asha Mary , Nahar Kazi , Daw Saheli , Hasan Md. Mahbub , Lo Rebecca , Le Tung B. K. , Rahman Khondaker Miraz , Badrinarayanan Anjana 
Published: June 2022

AbstractPyrrolobenzodiazepines (PBDs) are naturally occurring DNA binding compounds that possess anti-tumor and anti-bacterial activity. Chemical modifications of PBDs can result in improved DNA binding, sequence specificity and enhanced efficacy. More recently, synthetic PBD monomers have shown promise as payloads for antibody drug conjugates and antibacterial agents. The precise mechanism of action of these PBD monomers and their role in causing DNA damage remains to be elucidated. Here we characterized the damage-inducing potential of two C8-linked PBD bi-aryl monomers in Caulobacter crescentus and investigated the strategies employed by cells to repair the same. We show that these compounds cause DNA damage and efficiently kill bacteria, in a manner comparable to the extensively used DNA cross-linking agent mitomycin-C (MMC). However, in stark contrast to MMC which employs a mutagenic lesion tolerance pathway, we implicate essential functions for error-free mechanisms in repairing PBD monomer-mediated damage. We find that survival is severely compromised in cells lacking nucleotide excision repair and to a lesser extent, in cells with impaired recombination-based repair. Loss of nucleotide excision repair leads to significant increase in double-strand breaks, underscoring the critical role of this pathway in mediating repair of PBD-induced DNA lesions. Together, our study provides comprehensive insights into how mono-alkylating DNA-targeting therapeutic compounds like PBD monomers challenge cell growth, and identifies the specific mechanisms employed by the cell to counter the same.
SARS-CoV-2 minor variant genomes at the start of the pandemic contained markers of VoCs
Authors: Dong Xiaofeng , Hiscox Julian A. 
Published: June 2022

AbstractSARS-CoV-2 emerged through limited zoonotic spillovers and was predicted to have constrained sequence diversity. The dominant consensus and minor variant genomes were determined from the earliest samples associated with the Huanan market and the start of the pandemic. The sequence data confirmed that the dominant consensus genomes shared very close homology. However, there were minor variant genomes present in each sample, which encompassed synonymous and non-synonymous changes. Fusion sequences characteristic of defective RNAs were identified that could be linked between patients. Several substitutions (but not deletions) associated with much later variants of concern (VoCs) were already present as minor variant genomes. This suggests it may be possible to predict futures variants at the start of a pandemic by examining where variability in sequence occurs.
The sets of kinesins and dynein transporting endocytic cargoes determine the effect of tau on their motility
Authors: Beaudet Daniel , Berger Christopher L. , Hendricks Adam G. 
Published: June 2022

SummaryThe misregulation of tau, a neuronal microtubule-associated protein, is linked to defective axonal transport and neurodegenerative disease. We reconstituted the motility of isolated phagosomes along microtubules to ask how the sets of motors transporting a cargo determine its motility and response to tau. Using quantitative photobleaching, we find that early phagosomes (EPs) and late phagosomes (LPs) are associated with different sets of kinesin-1, -2, -3, and dynein. While EPs exhibit unidirectional retrograde transport, LPs move bidirectionally. Previously, we found that tau biases LP transport towards the microtubule minus-end. Here, we find that tau strongly inhibits long-range retrograde EP motility. Tau impedes the forces generated by multi-dynein teams and accelerates dynein unbinding under load. Thus, specific cargoes differentially respond to tau, where dynein-complexes on EPs are more sensitive to tau than those on LPs.
NISNet3D: Three-Dimensional Nuclear Synthesis and Instance Segmentation for Fluorescence Microscopy Images
Authors: Wu Liming , Chen Alain , Salama Paul , Dunn Kenneth , Delp Edward 
Published: June 2022

AbstractThe primary step in tissue cytometry is the automated distinction of individual cells (segmentation). Since cell borders are seldom labeled, researchers generally segment cells by their nuclei. While effective tools have been developed for segmenting nuclei in two dimensions, segmentation of nuclei in three-dimensional volumes remains a challenging task for which few tools have been developed. The lack of effective methods for three-dimensional segmentation represents a bottleneck in the realization of the potential of tissue cytometry, particularly as methods of tissue clearing present researchers with the opportunity to characterize entire organs. Methods based upon deep-learning have shown enormous promise, but their implementation is hampered by the need for large amounts of manually annotated training data. In this paper we describe 3D Nuclei Instance Segmentation Network (NISNet3D), a deep learning-based approach in which training is accomplished using synthetic data, profoundly reducing the effort required for network training. We compare results obtained from NISNet3D with results obtained from eight existing techniques.
Degenerate exponential integral function and its properties
Authors: Nantomah Kwara 
Published: June 2022

PurposeIn this paper, the author introduces a degenerate exponential integral function and further studies some of its analytical properties. The new function is a generalization of the classical exponential integral function and the properties established are analogous to those satisfied by the classical function.Design/methodology/approachThe methods adopted in establishing the results are theoretical in nature.FindingsA degenerate exponential integral function which is a generalization of the classical exponential integral function has been introduced and its properties investigated. Upon taking some limits, the established results reduce to results involving the classical exponential integral function.Originality/valueThe results obtained in this paper are new and have the potential of inspiring further research on the subject.
Physics-informed neural networks for consolidation of soils
Authors: Zhang Sheng , Lan Peng , Li Hai-Chao , Tong Chen-Xi , Sheng Daichao 
Published: June 2022

PurposePrediction of excess pore water pressure and estimation of soil parameters are the two key interests for consolidation problems, which can be mathematically quantified by a set of partial differential equations (PDEs). Generally, there are challenges in solving these two issues using traditional numerical algorithms, while the conventional data-driven methods require massive data sets for training and exhibit negative generalization potential. This paper aims to employ the physics-informed neural networks (PINNs) for solving both the forward and inverse problems.Design/methodology/approachA typical consolidation problem with continuous drainage boundary conditions is firstly considered. The PINNs, analytical, and finite difference method (FDM) solutions are compared for the forward problem, and the estimation of the interface parameters involved in the problem is discussed for the inverse problem. Furthermore, the authors also explore the effects of hyperparameters and noisy data on the performance of forward and inverse problems, respectively. Finally, the PINNs method is applied to the more complex consolidation problems.FindingsThe overall results indicate the excellent performance of the PINNs method in solving consolidation problems with various drainage conditions. The PINNs can provide new ideas with a broad application prospect to solve PDEs in the field of geotechnical engineering, and also exhibit a certain degree of noise resistance for estimating the soil parameters.Originality/valueThis study presents the potential application of PINNs for the consolidation of soils. Such a machine learning algorithm helps to obtain remarkably accurate solutions and reliable parameter estimations with fewer and average-quality data, which is beneficial in engineering practice.
Field models for the electromagnetic compatibility of wireless power transfer systems for electric vehicles
Authors: Bertoluzzo Manuele , Di Barba Paolo , Forzan Michele , Mognaschi Maria Evelina , Sieni Elisabetta 
Published: June 2022

PurposeThe paper presents the Finite Element (FE) evaluation of the magnetic field emitted by a Wireless Power Transfer Systems used to charge the battery of electrical vehicles. An original approach for reducing the mesh size of the 3D FE model is used.Design/methodology/approachA minicar equipped with a circular coil is considered, while the transmitting coil is coherent with the Society of Automotive Engineers (SAE) standard. The different shape of the coils and a possible misalignment are considered as possible sources of emitted magnetic field, which a person could be exposed to. To this end, a FE model is implemented. Because of the complexity of the mesh, a suitable 3D model is used. This model is previously validated and then used for evaluating the magnetic field around the Wireless Power Transfer Systems (WPTS).FindingsThe magnetic flux density around the WPTS is calculated and compared with the International Commission on Non-Ionizing Radiation Protection (ICNIRP) limits.Originality/valueThe proposed 3D model, whose validation is shown in the paper, is able to compute the magnetic field with high accuracy despite the presence of a conductive and ferromagnetic thin structure, the steel layer related to the car frame, which would need a very fine mesh with a large number of elements to solve Maxwell equations.
Emotion in teams: a scoping literature review
Authors: Xie Lei , Wilson Jonathan , Sherron Todd 
Published: June 2022

PurposeThe empirical findings of the roles of emotions in teams are mixed. This study, a scoping literature review, aims to synthesize extant research on the roles of emotions in work teams and offers future research directions.Design/methodology/approachSixty-nine empirical studies from the past ten years (2012 to 2021) were identified and reviewed. The authors then analyzed these 69 papers based on their research design, focus and nomological network of emotions.FindingsThe authors found that there is a clear increasing research trend of studying emotions in a team setting. In the extant literature, team emotions were studied from three major perspectives: emotions, emotional management and emotion measurement. The authors also summarized findings into the nomological network of team emotions. Last but not least, future research directions regarding the research context, focus and design and analysis were recommended.Originality/valueThe role of emotions in teams has not been extensively reviewed or synthesized, and the empirical findings are mixed. This paper synthesized the role of emotions in teams and critical factors that affect emotions in teams. In particular, the research recommendations for critical human resource development scholars cover three aspects: research context advancement, research focus advancement and research design and analysis advancement.
Antecedents and consequences of co-creation value with a resolution of complex P2P relationships
Authors: Foroudi Pantea , Marvi Reza , Colmekcioglu Nazan 
Published: June 2022

PurposeThis study aims to address the following three questions: What are the main factors influencing co-creation behaviour among peers in a peer-to-peer (P2P) platform? What are the key consequences of such behaviour? and What are the main factors that positively influence a sense of commitment among peers in a P2P platform?Design/methodology/approachThis study used a positivist paradigm to scrutinise the causal associations between the scale validation and causal configurations of influential factors by using fuzzy set qualitative comparative analysis.FindingsFindings indicate that the significance of co-creation behaviour in enhancing the sense of commitment in a P2P platform. The implications for hospitality managers and researchers are discussed.Practical implicationsThe findings of this research provide interesting insights for peer providers in a peer platform on how to enhance co-creation. They also offer guidelines on how to build a positive sense of commitment in the peer platform.Originality/valueBy investigating co-creation behaviour at the peer level, this research offers a unique theoretical contribution. Drawing on complexity theory, the research also proposes two tenets supporting the managerial contribution by identifying and clarifying how co-creation behaviour and related constructs can lead to a sense of commitment between peers in a P2P platform.