bluuebunny/crossref_metadata_2025_split huggingface dataset:
A high-sensitivity low-nanoflow LC-MS configuration for high-throughput sample-limited proteomics
Authors: Zheng Runsheng , Matzinger Manuel , Mayer Rupert , Valenta Alec , Sun Xuefei , Mechtler Karl 
Published: April 2023

AbstractThis study demonstrates how optimized liquid chromatography-mass spectrometry (LC-MS) conditions combined with a 50 µm internal diameter (I.D.) column operated at 100 nL/min enables high-sensitivity and high-throughput sample-limited proteomics analysis, including single-cell proteomics (SCP). Through systematic parameter evaluation, an optimized method was developed, capable of identifying ∼3,000 protein groups from 250 pg of HeLa protein digest using a 10-min gradient in the direct injection workflow using data-independent acquisition (DIA) from a library-free search method. Further improvements reduced the cycle time from 20 to 14.4 min by employing a trap-and-elute workflow, permitting 100 runs/day with 70% MS utilization. A proof of principle study indicated thatca. 1,700 protein groups were identified from single-cell samples without a library for label-free quantification (LFQ). In conclusion, we demonstrate a high-sensitivity LC-MS/MS configuration that serves the needs for limited sample analysis, permitting 100 runs/day throughout.
Swi/Snf Chromatin Remodeling Regulates Transcriptional Interference and Gene Repression
Authors: Morse Kaitlin , Swerdlow Sarah , Ünal Elçin 
Published: April 2023

SUMMARYAlternative transcription start sites can affect transcript isoform diversity and translation levels. In a recently described form of gene regulation, coordinated transcriptional and translational interference results in transcript isoform-dependent changes in protein expression. Specifically, a long undecoded transcript isoform (LUTI) is transcribed from a gene-distal promoter, interfering with expression of the gene-proximal promoter. While transcriptional and chromatin features associated with LUTI expression have been described, the mechanism underlying LUTI-based transcriptional interference is not well understood. Using an unbiased genetic approach followed by integrated genomic analysis, we uncovered that the Swi/Snf chromatin remodeling complex is required for co-transcriptional nucleosome remodeling that leads to LUTI-based repression. We identified genes with tandem promoters that rely on Swi/Snf function for transcriptional interference during protein folding stress, including LUTI-regulated genes. To our knowledge, this study is the first to observe Swi/Snf’s direct involvement in gene repression via acistranscriptional interference mechanism.
Deciphering the Differential Impact of Thrombopoietin/MPL Signaling on Hematopoietic Stem Cell Function in Bone Marrow and Spleen
Authors: Lee Sandy , Zhan Huichun 
Published: April 2023

SUMMARYThrombopoietin (TPO) and its receptor MPL play crucial roles in hematopoietic stem cell (HSC) function and platelet production. However, the precise effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches remain unclear. Here, we investigated the effects of TPO/MPL ablation on marrow and splenic hematopoiesis in TPO-/-and MPL-/-mice during aging. Despite severe thrombocytopenia, TPO-/-and MPL-/-mice did not develop marrow failure during a 2-year follow-up. Marrow and splenic HSCs exhibited different responses to TPO/MPL ablation and exogenous TPO treatment. Splenic niche cells compensated for marrow HSC loss in TPO-/-and MPL-/-mice by upregulating CXCL12 levels. These findings provide new insights into the complex regulation of HSCs by TPO/MPL and reveal a previously unknown link between TPO and CXCL12, two key growth factors for HSC maintenance. Understanding the distinct regulatory mechanisms between marrow and spleen hematopoiesis will help develop novel therapeutic approaches for hematopoietic disorders.
Receptor endocytosis orchestrates the spatiotemporal bias of β-arrestin signaling
Authors: Tóth András Dávid , Szalai Bence , Kovács Orsolya Tünde , Garger Dániel , Prokop Susanne , Balla András , Inoue Asuka , Várnai Péter , Turu Gábor , Hunyady László 
Published: April 2023

AbstractThe varying efficacy of biased and balanced agonists is generally explained by the stabilization of different active receptor conformations. In this study, systematic profiling of transducer activation of AT1angiotensin receptor agonists revealed that the extent and kinetics of β-arrestin binding exhibit substantial ligand-dependent differences, which however completely disappear upon the inhibition of receptor internalization. Even weak partial agonists for the β- arrestin pathway acted as full or near full agonists, if receptor endocytosis was prevented, indicating that receptor conformation is not an exclusive determinant of β-arrestin recruitment. The ligand-dependent variance in β-arrestin translocation at endosomes was much larger than it was at the plasma membrane, showing that ligand efficacy in the β-arrestin pathway is spatiotemporally determined. Experimental investigations and mathematical modeling demonstrated how multiple factors concurrently shape the effects of agonists on endosomal receptor–β-arrestin binding and thus determine the extent of bias. Among others, ligand dissociation rate and G protein activity have particularly strong impact on receptor–β-arrestin interaction, and their effects are integrated at endosomes. Our results highlight that endocytosis forms a key spatiotemporal platform for biased GPCR signaling and can aid the development of more efficacious functionally-selective compounds.One Sentence summaryAgonist-specific differences in β-arrestin recruitment are mainly determined by the ligand dissociation rate and G protein activation at the endosomes.
Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape
Authors: Ratnasinghe Brian D. , Haque Neshatul , Wagenknecht Jessica B. , Jensen Davin R. , Esparza Guadalupe V. , Leverence Elise N. , Milech De Assuncao Thiago , Mathison Angela J. , Lomberk Gwen , Smith Brian C. , Volkman Brian F. , Urrutia Raul , Zimmermann Michael T. 
Published: April 2023

ABSTRACTCurrent capabilities in genomic sequencing outpace functional interpretations. Our previous work showed that 3D protein structure calculations enhance mechanistic understanding of genetic variation in sequenced tumors and patients with rare diseases. The KRAS GTPase is among the critical genetic factors driving cancer and germline conditions. Because KRAS-altered tumors frequently harbor one of three classic hotspot mutations, nearly all studies have focused on these mutations, leaving significant functional ambiguity across the broader KRAS genomic landscape observed in cancer and non-cancer diseases. Herein, we extend structural bioinformatics with molecular simulations to study an expanded landscape of 86 KRAS mutations. We identify multiple coordinated changes strongly associated with experimentally established KRAS biophysical and biochemical properties. The patterns we observe span hotspot and non-hotspot alterations, which can all dysregulate Switch regions, producing mutation-restricted conformations with different effector binding propensities. We experimentally measured mutation thermostability and identified shared and distinct patterns with simulations. Our results indicate mutation-specific conformations which show potential for future research into how these alterations reverberate into different molecular and cellular functions. The data we present is not predictable using current genomic tools, demonstrating the added functional information derived from molecular simulations for interpreting human genetic variation.Key PointsPlease provide 3 bullet points summarizing the manuscript’s contribution to the field (100 characters max per point)1)We functionally grouped 86 distinct KRAS mutations using MD scores, demonstrating scalability for genomics2)MD-based groups explain experimental differences and mechanistic information about mutant proteins3)Demonstrated added functional information from simulations for interpreting human genetic variation
A novel resistance reversion mechanism in a vancomycin-variableEnterococcus faeciumstrain
Authors: McInnes Ross S. , Snaith Ann E. , Dunn Steven J. , Papangeli Maria , Hardy Katherine J. , Hussain Abid , van Schaik Willem 
Published: April 2023

AbstractObjectivesTo investigate an outbreak ofEnterococcus faeciumin a hospital haematology ward and uncover the mechanism of a vancomycin resistance phenotype-genotype disparity in an isolate from this outbreak.MethodsWhole genome shotgun sequencing was used for the phylogenetic analysis ofE. faeciumisolates (n = 39) and to identify the carriage of antibiotic resistance genes. A long-read sequencing approach was adopted to identify structural variations in the vancomycin resistance region of a vancomycin-variableE. faecium(VVE) and to uncover the resistance reversion mechanism in this isolate. RT-qPCR and RT-PCR were used to determine differences in the expression ofvanRSandvanHAXamong strains.ResultsTheE. faeciumstrains isolated in the hospital haematology ward were extensively drug resistant and highly diverse. The notable expansion of ST262 among patients was the likely driver of a VRE outbreak. A VVE isolate was identified that could rapidly revert to a vancomycin-resistant state in the presence of vancomycin. Disruption of thevanRgene in this isolate by an IS6-family element impaired its response to vancomycin. However, when the isolate was evolved to vancomycin resistance, it could constitutively express thevanHAXgenes at levels up to 36,000-fold greater than the parent isolate via co-transcription with a ribosomal RNA operon.ConclusionIn this study, we report a VVE isolate that was isolated during a VRE outbreak. This strain was capable of rapidly reverting to a resistant phenotype through a novel mechanism involving integration ofvanHAXdownstream of a ribosomal RNA operon. During VRE outbreaks, attention should be paid to contemporaneous vancomycin-susceptible strains as these may carry silent vancomycin resistance genes that can be activated through genomic rearrangements upon exposure to vancomycin.
Rapid Synthesis of Cryo-ET Data for Training Deep Learning Models
Authors: Purnell Carson , Heebner Jessica , Swulius Michael T. , Hylton Ryan , Kabonick Seth , Grillo Michael , Grigoryev Sergei , Heberle Fred , Waxham M. Neal , Swulius Matthew T. 
Published: April 2023

AbstractDeep learning excels at cryo-tomographic image restoration and segmentation tasks but is hindered by a lack of training data. Here we introduce cryo-TomoSim (CTS), a MATLAB-based software package that builds coarse-grained models of macromolecular complexes embedded in vitreous ice and then simulates transmitted electron tilt series for tomographic reconstruction. We then demonstrate the effectiveness of these simulated datasets in training different deep learning models for use on real cryotomographic reconstructions. Computer-generated ground truth datasets provide the means for training models with voxel-level precision, allowing for unprecedented denoising and precise molecular segmentation of datasets. By modeling phenomena such as a three-dimensional contrast transfer function, probabilistic detection events, and radiation-induced damage, the simulated cryo-electron tomograms can cover a large range of imaging content and conditions to optimize training sets. When paired with small amounts of training data from real tomograms, networks become incredibly accurate at segmentingin situmacromolecular assemblies across a wide range of biological contexts.SummaryBy pairing rapidly synthesized Cryo-ET data with computed ground truths, deep learning models can be trained to accurately restore and segment real tomograms of biological structures bothin vitroandin situ.
The duplication of genomes and gene regulatory networks and its potential for evolutionary adaptation and survival
Authors: Ebadi Mehrshad , Bafort Quinten , Mizrachi Eshchar , Audenaert Pieter , Simoens Pieter , Van Montagu Marc , Bonte Dries , Van de Peer Yves 
Published: April 2023

AbstractThe importance of whole genome duplication (WGD), or polyploidy, for evolution, is controversial. Whereas some view WGD mainly as detrimental and an evolutionary dead end, there is growing evidence that (the establishment of) polyploidy can help overcome environmental change, stressful conditions, or periods of extinction. However, despite much research, the mechanistic underpinnings of why and how polyploids might be able to outcompete or outlive non-polyploids at times of environmental upheaval remain elusive, especially for autopolyploids, in which heterosis effects are limited. On the longer term, WGD might increase both mutational and environmental robustness due to redundancy and increased genetic variation, but on the short – or even immediate – term, selective advantages of WGDs are harder to explain. Here, by duplicating artificially generated Gene Regulatory Networks (GRNs), we show that duplicated GRNs – and thus duplicated genomes – show higher signal output variation than non-duplicated GRNs. This increased variation leads to niche expansion and can provide polyploid populations with substantial advantages to survive environmental turmoil. In contrast, under stable environments, GRNs might be maladaptive to changes, a phenomenon that is exacerbated in duplicated GRNs. We believe that these results provide new insights into how genome duplication and (auto)polyploidy might help organisms to adapt quickly to novel conditions and to survive ecological uproar or even cataclysmic events.
Mapping problem-solving competencies and talent management strategies for universities
Authors: Ábrahám Zsolt , Szőgyényi Dániel , Eckert Bálint , Németh Szilárd 
Published: April 2023

PurposeThe paper aims to clarify the relationship between problem-solving skills and socialization of first-year university students and propose talent management strategies for university management, course instructors and administrators. Thus, this paper identifies three student clusters among the first-year bachelor students. This paper aims to propose a talent management framework and makes recommendations for course instructors and administrators.Design/methodology/approachIn this paper, a Simulated Work Experience is applied to collect data on problem-solving skills and demographics of first-year business students. Based on the anonymous competency and demographic data of 546 students, 3 clusters were identified with a hierarchical K-means clustering method and linked with talent management and curriculum design strategies.FindingsThe paper provides empirical insights about how the demographic background of the first-year students affects the students' problem-solving skills. This paper identifies three clusters – laggers, unpolished diamonds and drivers – and proposes a talent management framework to support the students' personal and professional development. The proposed talent management framework is based on the direction of upskilling and type of talent management incentives and outlines four distinct categories: extracurricular reward, tutoring and catching up, perform-or-punish and up-or-out systems. This paper makes suggestions to course administrators and instructors how to incorporate talent management and competency mapping aspects into the curriculum and syllabus design activities.Research limitations/implicationsThe research is limited to problem-solving skills and focused only on first-year business students.Practical implicationsThe paper includes practical implications for business school management, course administrators and instructors about competency mapping, talent management strategies, curriculum and syllabus design.Originality/valueThe research is based on the competency mapping of 546 first-year students at Budapest Business School. The data were collected via a Simulated Work Experience, where the students were participating in a virtual business project.
How supplier concentration impacts a buyer firm's R&D intensity: testing a mediation and moderation model
Authors: Yang Jinyu , Zhang Shanshan , Wang Zhiqiang , Zhao Xiande 
Published: April 2023

PurposeThe purpose of this paper is to investigate how supplier concentration influences a buyer firm's R&D intensity. This study proposes a mediation and moderation model to test this relationship in the Chinese household appliance industry. Specifically, this study tests the mediation effect of operational slack on the relationship between supplier concentration and R&D intensity and the moderation effect of financial constraints on this relationship.Design/methodology/approachDrawing upon real options theory and resource dependence theory, the proposed relationships are tested with the Chinese household appliance market using financial data from listed companies over a ten-year span from 2012 to 2021. Fixed effects (within-group) panel regression models are used to test the hypotheses. In addition, the authors use the bias-corrected bootstrap method to test the mediation effect.FindingsThe authors find that supplier concentration negatively affects a buyer firm's R&D intensity and that internal operational slack mediates this relationship. Interestingly, financial constraints from the external financing organization weaken the negative relationship between the buyer firm's supplier concentration and R&D intensity.Originality/valueBased on the argument of real options theory and resource dependence theory, this study provides novel insights into the issue of how concentration on several major suppliers may reduce buyer firms' R&D intensity. First, this study introduces operational slack as a form of internal uncertainty that mediates the supplier concentration–R&D intensity relationship. Second, this study suggests that the effect of supplier concentration on R&D intensity is contingent upon firms' financial constraints from external financial organizations, disclosing a synergetic interactive effect of supplier concentration and financial constraints on firms' R&D activities. Third, this study is conducted in the unique institutional context of China, providing meaningful insights into the relationship between supplier concentration and R&D intensity.
The role of organizational attributes on the marketing performance of Asian telecommunication companies: mediating effect of the Chief Marketing Officers’ political skill
Authors: Mustafi Mohitul Ameen Ahmed , Dong Ya-juan , Hosain Md Sajjad 
Published: April 2023

PurposeAt present, for any product, smooth marketing has become a major challenge due to the novel market challenges as well as sudden and extended changes. Thus, the concerns for the marketers are essential to consider the choice of buyers and also to satisfy them. The purpose of this empirical research is to focus on the role of three organizational attributes (OA): job satisfaction (JS), organizational commitment (OC) and extrinsic motivation (EM) on the marketing performance (MP) mediated by the Chief Marketing Officers' (CMOs') political skill (CPS) in the telecommunication industries of China, Singapore, Vietnam, Malaysia, Indonesia, India, Pakistan, Bangladesh, United Arab Emirates (UAE) and Sri Lanka.Design/methodology/approachIn this paper, based on 132 survey responses collected from CMOs, the authors conducted descriptive statistics using Statistical Package for Social Science (SPSS-25) and tested the assumed hypotheses through covariance-based structural equation modeling (CB-SEM) using AMOS software (version 25).FindingsThe authors found that JS has an insignificant role on MP while OC and EM have significant positive roles over the dependent variable. CPS has also a significant positive influence over MP. Further, the authors identified that CPS can fully mediate the relationship between JS and MP while it can partially mediate the relationship between OC and MP. On the other hand, CPS cannot mediate the relationship between EM and MP at all.Originality/valueAccording to authors’ knowledge, this is one of the very limited initial attempts that have investigated the role of three important OA on the MP testing the mediating effect of CPS. The authors expect that the study outcomes will have an enormous impact on marketing academia as a torch-bearing research as well as for CMOs for formulating an effective marketing policy.
Empowering leadership: role of organizational culture of self-esteem and emotional intelligence on creativity
Authors: Ahmad Tufail , Hamid Ali Raza , Abbas Ansar , Anwar Aisha , Ekowati Dian , Fenitra Rakototoarisoa Maminirina , Suhariadi Fendy 
Published: April 2023

PurposeThe changing workplace and the disruption and transformation of business processes brought on by modern technology make it difficult for a firm to maintain its existing plans. A management's ability to succeed is related to sustaining and developing its employees to be innovative workers. The idea is to empower subordinates and share authority with them, which increases efficiency.Design/methodology/approachIn this study, it was anticipated that there is a definite relationship between leadership empowerment and workplace cultures of self-esteem, emotional intelligence and creative thinking. Data were obtained using random sample techniques to confirm the hypothesis. A total of 291 Pakistani private-sector employees were surveyed for this study.FindingsThere were positive and substantial links between empowered leadership and creativity, while emotional intelligence and organizational self-esteem have an inverse relationship. For psychological appeal and inventiveness at work, empowerment alone is sufficient. Intellectual stimulus or culture of excessively positive self-esteem may cause numerous limits at work. Hence, management should avoid situations where leaders are predisposed to developing empowering techniques.Research limitations/implicationsThis study yields an additional understanding of organizational behavior literature. It was concluded from this study that empowering leaders should avoid using emotional intelligence when scaling up creative strategies. As an alternative, they should develop a culture of self-esteem through emotional intelligence.Practical implicationsLeaders may want to consider demographic values while developing empowerment strategies. It is not recommended to use emotional intelligence and empowerment simultaneously. As a result, this framework suggests a realistic and candid approach that is simple to implement.Originality/valueLeaders make people aware of the ongoing importance of innovative processes to encourage staff to be creative. Successful leaders may use either empowering culture or leadership empowerment strategies for a more significant appeal. Self-esteem culture may provide a structure of interaction buffer against the other emotions that could counter disruption.