bluuebunny/crossref_metadata_2025_split huggingface dataset:
Revealing allostery in PTPN11 SH2 domains from MD simulations
Authors: Anselmi Massimiliano , Hub Jochen S. 
Published: July 2022

AbstractSrc-homology 2 (SH2) domains are protein interaction domains that bind to specific peptide motifs containing phosphotyrosine. SHP2, a tyrosine phosphatase encoded by PTPN11 gene, which has been emerged as positive or negative modulator in multiple signaling pathways, contains two SH2 domains, respectively called N-SH2 and C-SH2. These domains play a relevant role in regulating SHP2 activity, either by recognizing its binding partners or by blocking its catalytic site. Considering the multiple functions that these domains carry out in SHP2, N-SH2 and C-SH2 represent an interesting case of study. Here, we present a methodology that permits, by means of the principal component analysis (PCA), to study and to rationalize the structures adopted by the SH2 domains, in terms of the conformations of their binding sites. The structures can be distinguished, grouped, classified and reported in a diagram. This approach permits to identify the accessible conformations of the SH2 domains in different binding conditions and to eventually reveal allosteric interactions. The method further reveals that the conformation dynamics of N-SH2 and C- SH2 strongly differ, which likely reflects their distinct functional roles.
From Molecular Dynamics to Supramolecular Organization: The Role of PIM Lipids in the Originality of theMycobacterialPlasma Membrane
Authors: Brown Chelsea M. , Corey Robin A. , Gao Ya , Choi Yeol Kyo , Gilleron Martine , Destainville Nicolas , Fullam Elizabeth , Im Wonpil , Stansfeld Phillip J. , Chavent Matthieu 
Published: July 2022

AbstractMycobacterium tuberculosis(Mtb) is the causative agent of tuberculosis, a disease that claims ~1.5 million lives annually. The current treatment regime is long and expensive, and missed doses contribute to drug resistance. There is much to be understood about theMtbcell envelope, a complicated barrier that antibiotics need to negotiate to enter the cell. Within this envelope, the plasma membrane is the ultimate obstacle and is proposed to be comprised of over 50% mannosylated phosphatidylinositol lipids (phosphatidyl-myoinositol mannosides, PIMs), whose role in the membrane structure remains elusive. Here we used multiscale molecular dynamics (MD) simulations to understand the structure-function relationship of the PIM lipid family and decipher how they self-organize to drive biophysical properties of theMycobacterialplasma membrane. To validate the model, we tested known anti-tubercular drugs and replicated previous experimental results. Our results shed new light into the organization of theMycobacterialplasma membrane and provides a working model of this complex membrane to use forin silicostudies. This opens the door for new methods to probe potential antibiotic targets and further understand membrane protein function.Abstract Figure
Development of esterase-resistant and highly active ghrelin analogs via thiol-ene click chemistry
Authors: Li Hao-Zheng , Shao Xiao-Xia , Shou Li-Li , Li Ning , Liu Ya-Li , Xu Zeng-Guang , Guo Zhan-Yun 
Published: July 2022

AbstractThe orexigenic peptide ghrelin exerts important functions in energy metabolism and cellular homeostasis by activating the growth hormone secretagogue receptor type 1a (GHSR1a), and thus has therapeutic potential to treat certain diseases. Native ghrelin carries an essentialO-fatty acyl moiety at the side-chain of its third Ser residue; however, this posttranslational modification is susceptible to hydrolysis by certain esterases in circulation, representing a major route ofin vivoinactivation of ghrelin. In the present study, we developed a novel approach to prepare various esterase-resistant ghrelin analogs via photo-induced thiol-ene click chemistry. A recombinant unacylated human ghrelin mutant carrying a unique Cys residue at the third position was reacted with commercially available end alkenes, thus various alkyl moieties were introduced to the side-chain of its unique Cys residue via a thioether bond. Among elevenS-alkylated ghrelin analogs, analog11, generated by reacting with 2-methyl-1-octene, not only acquired much higher stability in human serum and fetal bovine serum, but also acquired moderately higher activity compared with native human ghrelin. Thus, the present study not only provided an efficient approach to prepare various esterase-resistant ghrelin analogs, but also produced a novel highly stable and highly active ghrelin analog with therapeutic potential.
Avian and Human Influenza Viruses Exhibit Distinct Glycoconjugate Receptor Specificities in Human Lung Cells
Authors: Liang Chieh-Yu , Huang Iris , Han Julianna , Manivasagam Senthamizharasi , Plung Jesse , Strutz Miranda , Yu Yolanda , Kandasamy Matheswaran , Gourronc Francoise A. , Klingelhutz Aloysius J. , Choudhury Biswa , Rong Lijun , Perez Jasmine T. , Neelamegham Sriram , Manicassamy Balaji 
Published: July 2022

AbstractIAV utilize sialic acid (Sia) containing cell surface glycoconjugates for host cell infection, and IAV strains from different host species show preferences for structurally distinct Sia at the termini of glycoconjugates. Various types of cell surface glycoconjugates (N-glycans, O-glycans, glycolipids) display significant diversity in both structure and carbohydrate composition. To define the types of glycoconjugates that facilitate IAV infection, we utilized the CRISPR/Cas9 technique to truncate different types of glycoconjugates, either individually or in combination, by targeting glycosyltransferases essential to glycan biosynthesis in a human lung epithelial cell line. Our studies show that both human and avian IAV strains do not display strict preferences for a specific type of glycoconjugate. Interestingly, truncation of all three types of glycoconjugates significantly decreased the replication of human IAV strains, yet did not impact the replication of avian IAV strains. Taken together, our studies demonstrate that avian IAV strains utilize a broader repertoire of glycoconjugates for host cell infection as compared to human IAV strains.Author SummaryIt is well known that influenza A viruses (IAV) initiate host cell infection by binding to sialic acid, a sugar molecule present at the ends of various sugar chains called glycoconjugates. These glycoconjugates can vary in chain length, structure, and composition. However, it remains unknown if IAV strains preferentially bind to sialic acid on specific glycoconjugates for host cell infection. Here, we utilized CRISPR gene editing to abolish sialic acid on different glycoconjugate types in human lung cells, and evaluated human versus avian IAV infections. Our studies show that both human and avian IAV strains can infect human lung cells by utilizing any of the three major sialic acid-containing glycoconjugate types, specifically N-glycans, O-glycans, and glycolipids. Interestingly, simultaneous elimination of sialic acid on all three glycoconjugate types in human lung cells dramatically decreased human IAV infection, yet had little effect on avian IAV infection. Our studies indicate that avian IAV strains can utilize a wide variety of glycoconjugates for infection, whereas human IAV strains display restrictions in glycoconjugate type usage. These novel studies show distinct differences in host glycoconjugate preferences between human and avian IAV strains.
Influenza and pneumococcal vaccination and the risk of COVID-19: A systematic review and meta-analysis
Authors: Kapoula Georgia G. , Vennou Konstantina E. , Bagos Pantelis G. 
Published: July 2022

ABSTRACTA number of studies have investigated the potential non-specific effects of some routinely administered vaccines (e.g. influenza, pneumococcal) on COVID-19 related outcomes, with contrasting results. In order to elucidate this discrepancy, we conducted a systematic review and meta-analysis to assess the association between seasonal influenza vaccination and pneumococcal vaccination with SARS-CoV-2 infection and its clinical outcomes. PubMed and medRxiv databases were searched, up until November 2021. Random effects model was used in the meta-analysis to pool odds ratio (OR) and adjusted estimates with their 95% confidence intervals (CIs). Heterogeneity was quantitatively assessed using the Cohran’sQand theI2index. Sub-group analysis, sensitivity analysis and assessment of publication bias were performed for all outcomes. In total 38 observational studies were included in the meta-analysis and there was substantial heterogeneity. Influenza and pneumococcal vaccination were associated with lower risk of SARS-Cov-2 infection (OR: 0.80, 95% CI: 0.75-0.86 and OR: 0.70, 95% CI: 0.57-0.88, respectively). Regarding influenza vaccination, it seems that the majority of studies did not properly adjust for all potential confounders, so when the analysis was limited to studies that adjusted for age, sex, comorbidities and socioeconomic indices, the association diminished. This is not the case regarding the pneumococcal vaccination, for which even after adjustment for such factors the association persisted. Regarding harder endpoints such as ICU admission and death, current data do not support the association. Possible explanations are discussed, including trained immunity, inadequate matching for socioeconomic indices and possible coinfection.
Scanning ion-conductance microscopy for studying β-amyloid aggregate formation on living cell surface
Authors: Kolmogorov Vasilii S. , Erofeev Alexander S. , Barykin Evgeny P. , Timoshenko Roman V. , Lopatukhina Elena V. , Kozin Sergey A. , Salikhov Sergey V. , Klyachko Natalia L. , Mitkevich Vladimir A. , Edwards Christopher R.W. , Korchev Yuri E. , Makarov Alexander A. , Gorelkin Petr V. 
Published: July 2022

AbstractAlzheimer’s disease (AD) is the most common form of dementia, a progressive neurological disorder characterized by short and long-term memory loss, including cognitive and functional impairment, which is refractory to current therapy. It is suggested that the aggregation of β-amyloid (Aβ) peptide on neuronal cell surface leads to various deviations of its vital function due to myriad pathways defined by internalization of calcium ions, apoptosis promotion, reduction of membrane potential, synaptic activity loss etc. These are associated with structural reorganizations and pathologies of the cell cytoskeleton mainly involving actin filaments and microtubules, and consequently – alterations of cell mechanical properties. Thus, the effect of amyloid oligomers on cells’ Young’s modulus has been observed in a variety of studies. However, the precise connection between the formation of amyloid aggregates on cell membranes and their effects on local mechanical properties of living cells is still unresolved. In this work, we have used correlative scanning ion-conductance microscopy (SICM) to study cell topography, Young’s modulus mapping and confocal imaging of Aβ aggregates formation on living cell surfaces with subsequent assessment of the reactive oxygen species levels inside single cells using platinum nanoelectrodes. We showed that correlative SICM technique, in conjunction with topography mapping and confocal imaging, can be used for Patch-Clamp recordings from living cells with evidently formed FAM-labeled Aβ aggregates on its surface. As we demonstrated, SICM can be successfully applied to studying cytotoxicity mechanisms of Aβ aggregates on living cell surface.
High resolution studies of DNA lesion bypass by human DNA polymerase δ holoenzymes
Authors: Dannenberg Rachel L. , Cardina Joseph A. , Pytko Kara G. , Hedglin Mark 
Published: July 2022

ABSTRACTDuring DNA replication, DNA lesions present in lagging strand templates are initially encountered by DNA polymerase δ (pol δ). The historical view for what transpires from these encounters is that replication of the afflicted lagging strand template abruptly stops, activating DNA damage tolerance (DDT) pathways that replicate the offending lesion and adjacent DNA sequence, allowing pol δ to resume downstream. However, qualitative studies observed that human pol δ is capable of replicating various DNA lesions, albeit to unknown extents, which raises issues regarding the roles of pol δ and DDT in the replication of DNA lesions. To address these issues, we re-constituted human lagging strand replication to quantitatively characterize initial encounters of pol δ holoenzymes with DNA lesions. The results indicate that pol δ holoenzymes support stable dNTP incorporation opposite and beyond multiple lesions and the extent of these activities depends on the lesion and pol δ proofreading. Furthermore, after encountering a given DNA lesion, subsequent dissociation of pol δ is distributed around the lesion and a portion of pol δ does not dissociate at all. The distributions of these events are dependent on the lesion and pol δ proofreading. These results challenge our understanding of DNA lesion replication and DDT.
Small CD4 mimetics sensitize HIV-1-infected macrophages to antibody-dependent cellular cytotoxicity
Authors: Laumaea Annemarie , Marchitto Lorie , Beaudoin-Bussières Guillaume , Ding Shilei , Gasser Romain , Chatterjee Debashree , Gendron-Lepage Gabrielle , Medjahed Halima , Chen Hung-Ching , Smith Amos B , Ding Haitao , Kappes John C. , Hahn Beatrice H. , Kirchhoff Frank , Richard Jonathan , Duerr Ralf , Finzi Andrés 
Published: July 2022

SummaryHIV-1 Envelope (Env) conformation determines the susceptibility of infected CD4+T cells to Antibody Dependent Cellular Cytotoxicity (ADCC). Upon interaction with CD4, Env adopts more “open” conformations, exposing ADCC epitopes. HIV-1 limits Env-CD4 interaction and protects infected cells against ADCC by downregulating CD4 via Nef, Vpu and Env. Limited data exists however of the role of these proteins in downmodulating CD4 on infected macrophages and how this impacts Env conformation. While Nef, Vpu and Env are all required to efficiently downregulate CD4 on infected CD4+T cells, we show here that any one of these proteins is sufficient to downmodulate most CD4 from the surface of infected macrophages. Consistent with this finding, Nef and Vpu have a lesser impact on Env conformation and ADCC sensitivity in infected macrophages compared to CD4+T cells. However, treatment of infected macrophages with small CD4-mimetics expose vulnerable CD4-induced Env epitopes and sensitize them to ADCC.
Wnt7a Suppresses Adipogenesis of Skeletal Muscle Mesenchymal Stem Cells and Fatty Infiltration Through the Alternative Wnt-Rho-YAP/TAZ Signaling Axis
Authors: Fu Chengcheng , Guzmán-Seda Mariana , Laudier Damien , Han Woojin M. 
Published: July 2022

ABSTRACTIntramuscular fatty infiltration in muscle injuries and diseases, caused by aberrant adipogenesis of fibro-adipogenic progenitors, negatively impacts function. Intramuscular delivery of Wnt7a offers a promising strategy to stimulate muscle regeneration but its effects on adipogenic conversion of fibro-adipogenic progenitors remain unknown. Here we show that Wnt7a inhibits adipogenesis of FAPs through the alternative Wnt-Rho-YAP/TAZ signaling that subsequently upregulates the canonical Wnt pathway. Furthermore, intramuscular injection of Wnt7a in vivo effectively suppresses fatty infiltration in mice. Our results collectively suggest Wnt7a as a potential protein-based therapeutic for inhibiting adipogenesis of FAPs and intramuscular fatty infiltration in pathological muscle injuries or diseases.
Nanopore-only assemblies for genomic surveillance of the global priority drug-resistant pathogen, Klebsiella pneumoniae
Authors: Foster-Nyarko Ebenezer , Cottingham Hugh , Wick Ryan R. , Judd Louise M. , Lam Margaret M. C. , Wyres Kelly L. , Stanton Thomas D. , Tsang Kara K. , David Sophia , Aanensen David M. , Brisse Sylvain , Holt Kathryn E. 
Published: July 2022

BackgroundOxford Nanopore Technologies (ONT) sequencing has rich potential for genomic epidemiology and public health investigations of bacterial pathogens, particularly in low-resource settings and at the point of care, due to its portability and affordability. However, low base-call accuracy has limited the reliability of ONT data for critical tasks such as antimicrobial resistance (AMR) and virulence gene detection and typing, serotype prediction and cluster identification. Thus, Illumina sequencing remains the standard for genomic surveillance despite higher capital and running costs.MethodsWe tested the accuracy of ONT-only assemblies for common applied bacterial genomics tasks (genotyping and cluster detection, implemented via Kleborate, Kaptive and Pathogenwatch), using data from 54 unique Klebsiella pneumoniae isolates. ONT reads generated via MinION with R9.4 flowcells were basecalled using three alternative models (Fast, High-accuracy (HAC) and Super-accuracy (SUP), available within ONT’s Guppy software), assembled with Flye and polished using Medaka. Accuracy of typing using ONT-only assemblies was compared with that of Illumina-only and hybrid ONT+Illumina assemblies, constructed from the same isolates as reference standards.ResultsThe most resource-intensive ONT-assembly approach (SUP basecalling, with or without Medaka polishing) performed best, yielding reliable capsule (K) type calls for all strains (100% exact or best matching locus), reliable multi-locus sequence type (MLST) assignment (98.3% exact match or single-locus variants), and good detection of acquired AMR genes and mutations (88% – 100% correct identification across the various drug classes). Distance-based trees generated from SUP+Medaka assemblies accurately reflected overall genetic relationships between isolates; however, the definition of outbreak clusters from ONT-only assemblies was problematic. HAC basecalling + Medaka polishing performed similarly to SUP basecalling without polishing, and polishing introduced errors into HAC- or Fast-basecalled assemblies. Therefore, we recommend investing compute resources into basecalling (SUP model) over polishing, where compute resources and/or time are limiting.ConclusionsOverall, our results show that MLST, K type and AMR determinants can be reliably identified with ONT-only data. However, cluster detection remains challenging with this technology.
Elastic properties and shape of the Piezo dome underlying its mechanosensory function
Authors: Haselwandter Christoph A. , Guo Yusong R. , Fu Ziao , MacKinnon Roderick 
Published: July 2022

AbstractIn a companion paper we show that the free membrane shape of lipid bilayer vesicles containing the mechanosensitive ion channel Piezo can be predicted, with no free parameters, from membrane elasticity theory together with measurements of the protein geometry and vesicle size (accompanying paper). Here we use these results to determine the force that Piezo exerts on the free membrane and, hence, that the free membrane exerts on Piezo, for a range of vesicle sizes. From vesicle shape measurements alone, we thus obtain a force-distortion relationship for Piezo, from which we deduce Piezo’s intrinsic radius of curvature, 42 ± 12 nm, and bending stiffness, 18 ± 2.1 kBT, in free-standing lipid bilayer membranes mimicking cell membranes. Applying these estimates to a spherical cap model of Piezo embedded in a lipid bilayer, we suggest that Piezo’s intrinsic curvature, surrounding membrane footprint, small stiffness, and large area are the key properties of Piezo that give rise to low-threshold, high-sensitivity mechanical gating.
Examining the effects of strategic orientation and motivation on performance and innovation in the production sector of automobile spare parts
Authors: Adiguzel Zafer , Sonmez Cakir Fatma 
Published: July 2022

PurposeThe aim of this study is to evaluate the relationship between innovative climate, strategic orientation, work motivation, business performance and job performance.Design/methodology/approachWithin the scope of the research, a survey was conducted with 400 engineers working in organizations operating within companies producing spare parts for automobile companies. IBM SPSS 25, IBM SPSS AMOS and LISREL programs were gradually used, and the data obtained were evaluated and analyzed.FindingsThe importance of strategic orientation and work motivation for organizations can be seen in the analysis results in terms of their positive effects.Practical implicationsIn the production sector, where innovation and competition activities take place, not only strategic decisions but also motivation for employees must be realized within the organizational culture in order for the organizations to be successful. Strategic orientation is effective in achieving innovation and creation to the extent that employees are motivated.Originality/valueIn terms of successful performance, it is very important to manage companies with the right strategic understanding and to involve the employees. In order to realize the innovation climate and to be successful in performance criteria, motivation is considered a key factor, in particular for the automobile sector. Automobile companies are now turning to electric vehicle production using new generation technologies. However, they also attach importance to the use of smart technologies in cars. For this reason, the effects of strategic orientation and work motivation on performance and innovation are investigated in companies producing automobile spare parts.
Recognition and rewards as moderators in the relationships between antecedents and performance of women teachers: evidence from India
Authors: Balakrishnan Sashi Rekha , Soundararajan Vasanthi , Parayitam Satyanarayana 
Published: July 2022

PurposeAs teachers are considered “knowledge workers,” the present study explores teacher performance in schools. A particular emphasis is given to assessing the performance of female teachers in the rural part of South India.Design/methodology/approachAfter collecting data from 563 female teachers from four blocks in Nilgiris District (Ooty, Kotagiri, Coonoor and Gudalur) consisting of 37 government schools in the southern part of India, all the female teachers were surveyed, and the data were analyzed after checking the instrument's psychometric properties by performing confirmatory factor analysis. Hierarchical regression was employed to test the hypotheses.FindingsThe findings revealed that (1) empowerment, organizational communication and work–life balance (WLB) and recognition and rewards are positively and significantly related to teacher performance; (2) recognition and rewards moderate the relationship between (a) empowerment and performance, (b) organizational communication and performance, (c) WLB and performance, (d) organizational culture and performance and (e) quality of work-life (QWL) and performance.Research limitations/implicationsAs with any survey research, common method bias and social desirability bias may be potential limitations. However, proper care is taken to minimize these biases. The findings from this study contribute to the growing literature on education and training. In addition, the study highlights the importance of creating a climate for empowerment, recognition and rewards to foster teacher performance.Practical implicationsThe study helps administrators and policymakers to understand the antecedents of teacher performance and take necessary steps to motivate the teachers for superior performance.Originality/valueThe conceptual model the authors developed and tested is, according to the authors' knowledge, the first of the model's kind. A clear understanding of the predictors of teacher performance may guide the administrators and teaches in fostering performance in schools. The exclusive focus on female teachers is considered in this study because of the several problems the female teachers encounter in rural areas. Despite the disadvantages, female teachers perform well and contribute to students and the country as a whole.