bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporal Dynamics of Genetically Heterogeneous Extended-Spectrum Cephalosporin ResistantEscherichia coliBloodstream Infections
Authors: Shropshire William C , Strope Benjamin , Anand Selvalakshmi Selvaraj , Bremer Jordan , McDaneld Patrick , Bhatti Micah M , Flores Anthony R , Kalia Awdhesh , Shelburne Samuel A 
Published: February 2023

ABSTRACTExtended-spectrum cephalosporin resistantEscherichia coli(ESC-R-Ec) is an urgent public health threat with sequence type clonal complex 131 (STc131), phylogroup B2 strains being particularly concerning as the dominant cause of ESC-R-Ecinfections. To address the paucity of recent ESC-R-Ecmolecular epidemiology data in the United States, we used whole genome sequencing (WGS) to fully characterize a large cohort of invasive ESC-R-Ecat a tertiary care cancer center in Houston, Texas collected from 2016-2020. During the study timeframe, there were 1154 indexE. colibloodstream infections (BSIs) of which 389 (33.7%) were ESC-R-Ec. Using time series analyses, we identified a temporal dynamic of ESC-R-Ecdistinct from ESC-susceptibleE. coli(ESC-S-Ec), with cases peaking in the last six months of the calendar year. WGS of 297 ESC-R-Ecstrains revealed that while STc131 strains accounted for ∼45% of total BSIs, the proportion of STc131 strains remained stable across the study time frame with infection peaks driven by genetically heterogeneous ESC-R-Ecclonal complexes.BlaCTX-Mvariants accounted for most β-lactamases conferring the ESC-R phenotype (89%; 220/248 index ESC-R-Ec), and amplification ofblaCTX-Mgenes was widely detected in ESC-R-Ecstrains, particularly in carbapenem non-susceptible, recurrent BSI strains.BlaCTX-M-55was significantly enriched within phylogroup A strains, and we identifiedblaCTX-M-55plasmid-to-chromosome transmission occurring across non-B2 strains. Our data provide important information regarding the current molecular epidemiology of invasive ESC-R-Ecinfections at a large tertiary care cancer center and provide novel insights into the genetic basis of observed temporal variability for these clinically important pathogens.IMPORTANCEGiven thatE. coliis the leading cause of worldwide ESC-REnterobacteralesinfections, we sought to assess the current molecular epidemiology of ESC-R-Ecusing a WGS analysis of many BSIs over a five-year period. We identified fluctuating temporal dynamics of ESC-R-Ecinfections, which has also recently been identified in other geographical regions such as Israel. Our WGS data allowed us to visualize the stable nature of STc131 over the study period and demonstrate a limited, but genetically diverse group of ESC-R-Ecclonal complexes are detected during infection peaks. Additionally, we provide a widespread assessment of β-lactamase gene copy number in ESC-R-Ecinfections and delineate mechanisms by which such amplifications are achieved in a diverse array of ESC-R-Ecstrains. These data suggest that serious ESC-R-Ecinfections are driven by a diverse array of strains in our cohort and impacted by environmental factors suggesting that community-based monitoring could inform novel preventative measures.
Multiplicity ofAgrobacteriuminfection ofNicotiana benthamianafor transient DNA delivery
Authors: Carlson Erik D. , Rajniak Jakub , Sattely Elizabeth S. 
Published: February 2023

AbstractBiological DNA transfer into plant cells mediated byAgrobacteriumrepresents one of the most powerful tools for the engineering and study of plant systems. Transient expression of transfer DNA (T-DNA) in particular enables rapid testing of gene products and has recently been harnessed for facile combinatorial expression of multiple genes. In analogous mammalian cell-based gene expression systems, a clear sense of the multiplicity of infection (MOI) allows users to predict and control viral transfection frequencies for applications requiring single vs. multiple transfection events per cell. Despite the value ofAgrobacterium-mediated transient transformation of plants, MOI has not been quantified. Establishing MOI forAgrobacteriumT-DNA delivery at the level of single plant cells would allow users to design genomic library delivery conditions (at most 1 event/cell), or maximize co-delivery of T-DNA loads from separateAgrobacterium(>1 event/cell). Here, we analyze the Poisson probability distribution of T-DNA transfer in leaf pavement cells to determine the MOI for the widely used model systemAgrobacteriumGV3101/Nicotiana benthamiana. These data delineate the relationship between an individualAgrobacteriumstrain infiltration OD600, plant cell perimeter and leaf age, as well as plant cell co-infection rates. Our analysis also establishes experimental regimes where the probability of near-simultaneous delivery of >20 unique T-DNAs to a given plant cell remains high throughout the leaf. We anticipate that these data will enable users to develop new approaches to in-leaf library development usingAgrobacteriumtransient expression and the reliable combinatorial assaying of multiple heterologous proteins in a single plant cell.
Junctophilin-2 Regulates Mitochondrial Metabolism
Authors: Prisco Sasha Z. , Hartweck Lynn M. , Kazmirczak Felipe , Mendelson Jenna B. , Deng Stephanie L. , Lahiri Satadru K. , Wehrens Xander H.T. , Prins Kurt W. 
Published: February 2023

AbstractRight ventricular dysfunction (RVD) is a risk factor for mortality in multiple cardiovascular diseases, but approaches to combat RVD are lacking. Therapies used for left heart failure are largely ineffective in RVD, and thus the identification of molecules that augment RV function could improve outcomes in a wide-array of cardiac limitations. Junctophilin-2 (JPH2) is an essential protein that plays important roles in cardiomyocytes, including calcium handling/maintenance of t-tubule structure and gene transcription. Additionally, JPH2 may regulate mitochondrial function asJph2knockout mice exhibit cardiomyocyte mitochondrial swelling and cristae derangements. Moreover, JPH2 knockdown in embryonic stem cell-derived cardiomyocytes induces downregulation of the mitochondrial protein mitofusin-2 (MFN2), which disrupts mitochondrial cristae structure and transmembrane potential. Impaired mitochondrial metabolism drives RVD, and here we evaluated the mitochondrial role of JPH2. We showed JPH2 directly interacts with MFN2, ablation of JPH2 suppresses mitochondrial biogenesis, oxidative capacity, and impairs lipid handling in iPSC-CM. Gene therapy with AAV9-JPH2 corrects RV mitochondrial morphological defects, mitochondrial fatty acid metabolism enzyme regulation, and restores the RV lipidomic signature in the monocrotaline rat model of RVD. Finally, AAV-JPH2 improves RV function without altering PAH severity, showing JPH2 provides an inotropic effect to the dysfunction RV.
The clock-modulatory activity of Nobiletin suppresses adipogenesis via Wnt signaling
Authors: Xiong Xuekai , Kiperman Tali , Li Weini , Dhawan Sangeeta , Lee Jeongkyung , Yechoor Vijay , Ma Ke 
Published: February 2023

AbstractThe circadian clock machinery exerts transcriptional control to modulate adipogenesis and its disruption leads to the development of obesity. Here we report that Nobiletin, a clock amplitude-enhancing molecule, displays anti-adipogenic properties via activating a clock-controlled Wnt signaling pathway that suppresses adipocyte differentiation. Nobiletin augmented clock oscillation with period length shortening in the adipogenic mesenchymal precursor cells and preadipocytes, accompanied by an induction of Bmal1 and core clock components. Consistent with its circadian clock-modulatory activity, Nobiletin inhibited the lineage commitment and terminal differentiation of adipogenic progenitors. Mechanistically, we show that Nobiletin induced the re-activation of Wnt signaling during adipogenic differentiation via transcriptional up-regulation of key components of this pathway. Furthermore, Nobiletin administration in mice markedly reduced adipocyte hypertrophy, leading to a significant loss of fat mass and body weight reduction. Lastly, Nobiletin inhibited the maturation of primary preadipocytes and this effect was dependent on a functional clock regulation. Collectively, our findings uncover a novel activity of Nobiletin in suppressing adipocyte development, implicating its potential therapeutic application in countering obesity and its associated metabolic consequences.
Protein Crowding and Cholesterol Increase Cell Membrane Viscosity in a Temperature Dependent Manner
Authors: Fábián Balázs , Vattulainen Ilpo , Javanainen Matti 
Published: February 2023

AbstractShear viscosity of lipid membranes dictates how fast lipids, proteins, and other membrane constituents travel along the membrane and rotate around their principal axis, thus governing the rates of diffusion-limited reactions taking place at membranes. In this framework, the heterogeneity of biomembranes indicates that cells could regulate these ratesviavarying local viscosities. Unfortunately, experiments to probe membrane viscosity at various conditions are tedious and error prone. Molecular dynamics simulations provide a luring alternative, especially now that recent theoretical developments enable the elimination of finite-size effects in simulations. Here, we use different equilibrium methods to extract the shear viscosities of lipid membranes from both coarse-grained and all-atom molecular dynamics simulations. We systematically probe the variables relevant for cellular membranes, namely membrane protein crowding, cholesterol concentration, and the length and saturation level of the lipid acyl chains, as well as temperature. Our results highlight that in their physiologically relevant ranges, cholesterol concentration, protein concentration, and temperature have significantly larger effects on membrane viscosity than lipid acyl chain length and unsaturation level. Our work also provides the largest collection of membrane viscosity values from simulation to date, which can be used by the community to predict the diffusion coefficients or their trendsviathe Saffman–Delbrück description. Additionally, diffusion coefficients extracted from simulations exploiting periodic boundary conditions must be corrected for the finite-size effects prior to comparison with experiment, for which the present collection of viscosity values can readily be used. Finally, our thorough comparison to experiments suggests that there is some room for improvement in the description of bilayer dynamics provided by the present force fields.
MiR-4521 perturbs FOXM1-mediated DNA damage response in breast cancer
Authors: Kuthethur Raviprasad , Adiga Divya , Kandettu Amoolya , Jerome Maria Sona , Mallya Sandeep , Mumbrekar Kamalesh Dattaram , Kabekkodu Shama Prasada , Chakrabarty Sanjiban 
Published: February 2023

AbstractForkhead (FOX) transcription factors are involved in cell cycle control, cellular differentiation, maintenance of tissues, and aging. Mutation or aberrant expression of FOX proteins is associated with developmental disorders and cancers. FOXM1, an oncogenic transcription factor, is a promoter of cell proliferation and accelerated development of breast adenocarcinomas, squamous carcinoma of the head, neck, and cervix, and nasopharyngeal carcinoma. High FOXM1 expression is correlated with chemoresistance in patients treated with doxorubicin and Epirubicin by enhancing the DNA repair in breast cancer cells. Here, we showed that FOXM1 is a direct target of miR-4521 in breast cancer. Overexpression of miR-4521 significantly downregulated FOXM1 expression in breast cancer cells. FOXM1 regulates cell cycle progression and DNA damage response in breast cancer. We showed that miR-4521 expression leads to increased ROS levels and DNA damage in breast cancer cells. FOXM1 plays a critical role in ROS scavenging and promotes stemness which contributes to drug resistance in breast cancer. We observed that breast cancer cells stably expressing miR-4521 lead to cell cycle arrest, impaired FOXM1 mediated DNA damage response leading to increased cell death in breast cancer cells. Additionally, miR-4521-mediated FOXM1 downregulation perturbs cell proliferation, invasion, cell cycle progression, and epithelial-to-mesenchymal progression (EMT) in breast cancer. High FOXM1 expression has been associated with radio and chemoresistance contributing to poor patient survival in multiple cancers, including breast cancer. Our study showed that FOXM1 mediated DNA damage response could be targeted using miR-4521 mimics as a novel therapeutic for breast cancer.
CD38 promotes hematopoietic stem cell dormancy via c-Fos
Authors: Ibneeva Liliia , Singh Sumeet Pal , Sinha Anupam , Eski Sema Elif , Wehner Rebekka , Rupp Luise , Pérez-Valencia Juan Alberto , Gerbaulet Alexander , Reinhardt Susanne , Wobus Manja , von Bonin Malte , Sancho Jaime , Lund Frances , Dahl Andreas , Schmitz Marc , Bornhäuser Martin , Chavakis Triantafyllos , Wielockx Ben , Grinenko Tatyana 
Published: February 2023

AbstractA subpopulation of deeply quiescent, so-called dormant hematopoietic stem cells (dHSCs) resides at the top of the hematopoietic hierarchy and serves as a reserve pool for HSCs possessing the greatest long-term blood repopulation capacity. The state of dormancy protects the HSC pool from exhaustion throughout life, however excessive dormancy may block an efficient response to hematological stresses. The mechanisms of HSC dormancy remain elusive, mainly due to the absence of surface markers that allow dHSC prompt isolation. Here, we identify CD38 as a novel surface marker for murine dHSCs that is broadly applicable. Moreover, we demonstrate that cyclic adenosine diphosphate ribose (cADPR), the product of CD38 cyclase activity, regulates the expression of the transcription factor c-Fos by increasing cytoplasmic Ca2+concentration. Strikingly, we uncover that c-Fos drives HSCs dormancy through the induction of the cell cycle inhibitor p57Kip2. Moreover, we found that CD38 ecto-enzymatic activity at the neighboring CD38-positive cells can promote human HSC quiescence. Together, CD38/cADPR/Ca2+/cFos/p57Kip2axis maintains HSC dormancy. Pharmacological manipulations of this pathway can provide new strategies to expand dHSCs for transplantation or to activate them during hematological stresses.
Catalytic antibodies in arrhythmogenic cardiomyopathy patients cleave desmoglein 2 and N-cadherin and impair cardiomyocyte cohesion
Authors: Yeruva Sunil , Stangner Konstanze , Jungwirth Anna , Hiermaier Matthias , Shoykhet Maria , Kugelmann Daniela , Hertl Michael , Egami Shohei , Ishii Norito , Koga Hiroshi , Hashimoto Takashi , Weis Michael , Beckmann Britt Maria , Biller Ruth , Schüttler Dominik , Kääb Stefan , Waschke Jens 
Published: February 2023

AbstractAimsArrhythmogenic cardiomyopathy (AC) is a severe heart disease predisposing to ventricular arrhythmias and sudden cardiac death caused by mutations affecting intercalated disc (ICD) proteins and aggravated by physical exercise. Recently, autoantibodies targeting ICD proteins, including the desmosomal cadherin desmoglein 2 (DSG2), were reported in AC patients and were considered relevant for disease development and progression, particularly in patients without underlying pathogenic mutations. However, it is unclear at present whether these autoantibodies are pathogenic and by which mechanisms show specificity for DSG2 and thus can be used as a diagnostic tool.Methods and ResultsIgG fractions were purified from 15 AC patients and 4 healthy controls. Immunostainings dissociation assays, atomic force microscopy (AFM), western blot analysis and Triton-X-100 assays were performed utilizing human heart left ventricle tissue, HL-1 cells, and murine cardiac slices. Immunostainings revealed that autoantibodies against ICD proteins are prevalent in AC and most autoantibody fractions have catalytic properties and cleave the ICD adhesion molecules DSG2 and N-cadherin, thereby reducing cadherin interactions as revealed by AFM. Furthermore, most of the AC-IgG fractions causing loss of cardiomyocyte cohesion activated p38MAPK, which is known to contribute to a loss of desmosomal adhesion in different cell types, including cardiomyocytes. In addition, p38MAPK inhibition rescued the loss of cardiomyocyte cohesion induced by AC-IgGs.ConclusionOur study demonstrates that catalytic autoantibodies play a pathogenic role by cleaving ICD cadherins and thereby reducing cardiomyocyte cohesion by a mechanism involving p38MAPK activation. Finally, we conclude that DSG2 cleavage by autoantibodies could be used as a diagnostic tool for AC.
Evaluation of efficiency and ranking of Indian hotels and restaurants: a bootstrap DEA approach
Authors: Mahajan Varun , Mogha Sandeep Kumar , Pannala R.K.Pavan Kumar 
Published: February 2023

PurposeThe main purpose of this paper is to determine the bias-corrected efficiencies and rankings of the selected hotels and restaurants (H&Rs) in India.Design/methodology/approachThe data for the Indian H&R sector are collected from the Prowess database. The bootstrap data envelopment analysis (DEA) based on a constant return to scale (CRS), variable return to scale-input oriented (VRS-IP) and variable return to scale-output oriented (VRS-OP) are applied on H&Rs to obtain the bias-corrected efficiencies.FindingsIt is found that relative efficiencies using basic DEA methods of all the 45 H&Rs of India are overestimated. These efficiencies are corrected using bias correction through bootstrap DEA methods. The bounds for the efficiencies of each H&R are computed using all the adopted methods. All H&Rs are ranked using bias-corrected efficiencies, and the linear trend between ranks suggests that the H&Rs are ranked almost similarly by all the adopted methods.Practical implicationsTo improve efficiency, Indian H&R companies must rethink their personnel needs by enhancing their workforce management capabilities. The government needs to extend more support to this sector by introducing a liberal legislation framework and supporting infrastructure policies.Originality/valueThere is a paucity of studies on H&Rs in India. The current study focused on measuring bias-corrected efficiencies of the selected H&Rs of India. This study is one of the few initiatives to explore bias-corrected efficiencies extensively using the bootstrap DEA method.
Does the transcultural problem really matter? An integrated approach to analyze barriers to eHealth SMEs’ development
Authors: Zhao Guoqing , Suklan Jana , Liu Shaofeng , Lopez Carmen , Hunter Lise 
Published: February 2023

PurposeIn a competitive environment, eHealth small and medium-sized enterprises’ (SMEs’) barriers to survival differ from those of large enterprises. Empirical research on barriers to eHealth SMEs in less prosperous areas has been largely neglected. This study fills this gap by employing an integrated approach to analyze barriers to the development of eHealth SMEs. The purpose of this paper is to address this issue.Design/methodology/approachThe authors collected data through semi-structured interviews and conducted thematic analysis to identify 16 barriers, which were used as inputs into total interpretive structural modeling (TISM) to build interrelationships among them and identify key barriers. Cross-impact matrix multiplication applied to classification (MICMAC) was then applied validate the TISM model and classify the 16 barriers into four categories.FindingsThis study makes significant contributions to theory by identifying new barriers and their interrelationships, distinguishing key barriers and classifying the barriers into four categories. The authors identify that transcultural problems are the key barrier and deserve particular attention. eHealth SMEs originating from regions with cultural value orientations, such as hierarchy and embeddedness, that differ from the UK’s affective autonomy orientation should strengthen their transcultural awareness when seeking to expand into UK markets.Originality/valueBy employing an integrated approach to analyze barriers that impede the development of eHealth SMEs in a less prosperous area of the UK, this study raises entrepreneurs’ awareness of running businesses in places with different cultural value orientations.
Wimp out or take off? Temporal dynamics in new venture effort after exposure to entrepreneurial obstacles
Authors: Li Ci-Rong , Yang Yanyu , Liu Jing , Lee Allan 
Published: February 2023

PurposeThe present research integrates conservation of resources theory (COR) and adaptation theory to investigate the dynamics of entrepreneurs' reactions to obstacles. Furthermore, this research explores whether entrepreneurs' effort allocations following an obstacle influence how entrepreneurs appraise subsequent loss-related events. Finally, this research seeks to understand why some entrepreneurs handle obstacles better than others by considering the role of optimism.Design/methodology/approachThis research utilized a longitudinal survey with 130 nascent entrepreneurs across 4 time periods. This research used a multivariate latent change analysis model to examine the temporal dynamics of new venture effort after exposure to obstacles.FindingsThe results indicated that entrepreneurial obstacles at time t were associated with decreased effort in new ventures at time t+1. Furthermore, new venture effort at time t was associated with decreased effort in new ventures at time t+1. The results also demonstrated that the allocation of greater effort may lead to a decrease in subsequent obstacle appraisals, a relationship that also varies as a function of nascent entrepreneurs' optimism.Originality/valueThis research extends the understanding of the dynamic pattern of reactions following exposure to entrepreneurial obstacles. The findings suggest that, rather than being straightforward, reactions are likely to ebb and flow over time.
The incentive effect of government subsidies on the digital transformation of manufacturing enterprises
Authors: Zhao Xueqi , Zhao Longwen , Sun Xiaozhe , Xing Yibing 
Published: February 2023

PurposeChina's digital economy is flourishing and playing a pivotal role in the national economy. Government subsidies, as an important tool for the national treasury, are a “reassurance” for the digital transformation of manufacturing enterprises. The purpose of this paper is to investigate the relations between the digital transformation of manufacturing enterprises and government subsidies to provide inspiration for promoting the digitization and upgrading of China's manufacturing industry and facilitate enterprises' innovative development.Design/methodology/approachBased on the panel data of 2,928 manufacturing listed companies in China from 2016 to 2020, this paper empirically tests the effect of subsidies on the digital transformation of manufacturing enterprises using fixed-effect econometric regression.FindingsThe results illustrate that subsidies effectively incentivize digital transformation in manufacturing enterprises, and verify different situations through heterogeneity. Further analysis of the moderating effect shows that the innovation level and servitization level of manufacturing enterprises positively moderated the relationship between government subsidies and the enterprise's digital transformation.Originality/valueBased on Chinese manufacturing enterprise samples, this paper empirically tests the incentive effect of government subsidies on the digital transformation of manufacturing enterprises, therefore clarifying the main regulatory effects. This paper could provide enlightenment for manufacturing enterprises to make good use of government subsidies to improve their digital ability, thereby enhancing competitiveness in the digital economy era.