bluuebunny/crossref_metadata_2025_split huggingface dataset:
One-day phenotypic drug susceptibility testing forMycobacterium tuberculosisvariantbovisBCG using single-cell imaging and a deep neural network
Authors: Tran Buu Minh , Larsson Jimmy , Grip Anastasia , Karempudi Praneeth , Elf Johan 
Published: May 2024

AbstractDrug-resistant tuberculosis (TB) kills approximately 200,000 people every year. A contributing factor is the slow turnaround time associated with anti-tuberculosis drug susceptibility diagnostics. The prevailing gold standard for phenotypic drug susceptibility testing (pDST) takes at least two weeks. In this study, we usedMycobacterium tuberculosisvariantbovisBCG (M. bovisBCG) andMycobacterium smegmatisas models for tuberculous and nontuberculous pathogens. The bacteria were loaded into a microfluidic chip, trapping them in microchambers, and allowing simultaneous tracking of single-cell growth with and without antibiotic exposure. A deep neural network image-segmentation algorithm was employed to quantify the growth rate over time and determine how the strains responded to the drugs compared to the untreated reference. We determined that the response time of the susceptible strains to isoniazid (INH), ethambutol (EMB), and linezolid (LZD) at MIC was within 3 hours and 1.5 hours forM. bovisBCG andM. smegmatis, respectively. Resistant strains ofM. smegmatiswere identifiable within 3 hours, suggesting that growth-based pDST can be conducted in less than 12 hours for slow-growingM. bovisBCG. The results obtained forM. bovisBCG are most likely comparable to what we expect forM. tuberculosisas these strains share 99.96% genetic identity.
p53 and TIGAR promote redox control to protect against metabolic dysfunction-associated steatohepatitis
Authors: Wittke Celine I , Cheung Eric C , Athineos Dimitris , Clements Nicola , Butler Liam , Hughes Mark , Morrison Vivienne , Watt Dale M , Blyth Karen , Vousden Karen H , Humpton Timothy J 
Published: May 2024

ABSTRACTTP53is a potent tumour suppressor that coordinates diverse stress response programmes within the cell. The activity of p53 is frequently context and cell type-dependent, and ranges from pro-survival activities, including the implementation of transient cell cycle arrest and metabolic rewiring, through to cell death. In addition to tumour suppressor functions, p53 also has established roles in the pathological response to stress that occurs during tissue damage and repair, including within the liver. Metabolic dysfunction-associated steatohepatitis (MASH) is a major driver of hepatocellular carcinoma (HCC), but our understanding of the molecular determinants of MASH development remains incomplete.Here, using a p53 reporter mouse, we report early and sustained activation of hepatic p53 in response to an obesogenic high fat and high sugar diet. In this context, liver-specific loss of p53 accelerates the progression of benign fatty liver disease to MASH that is characterised by high levels of reactive oxygen species (ROS), extensive fibrosis, and chronic inflammation. Using anin vitroculture system, we show that p53 functions to control ROS and protect against the development of MASH, in part through induction of the antioxidant gene TP53-induced glycolysis and apoptosis regulator (TIGAR). Our work demonstrates an important role for the p53-TIGAR axis in protecting against MASH, and identifies redox control as an essential barrier against liver disease progression.
Aligning protein generative models with experimental fitness via Direct Preference Optimization
Authors: Widatalla Talal , Rafailov Rafael , Hie Brian 
Published: May 2024

AbstractGenerative models trained on unlabeled protein datasets have demonstrated a remarkable ability to predict some biological functions without any task-specific training data. However, this capability does not extend to all relevant functions and, in many cases, the unsupervised model still underperforms task-specific, supervised baselines. We hypothesize that this is due to a fundamental “alignment gap” in which the rules learned during unsupervised training are not guaranteed to be related to the function of interest. Here, we demonstrate how to provide protein generative models with useful task-specific information without losing the rich, general knowledge learned during pretraining. Using an optimization task called Direct Preference Optimization (DPO), we align a structure-conditioned language model to generate stable protein sequences by encouraging the model to prefer stabilizing over destabilizing variants given a protein backbone structure. Our resulting model, ProteinDPO, is the first structure-conditioned language model preference-optimized to experimental data. ProteinDPO achieves competitive stability prediction and consistently outperforms both unsupervised and finetuned versions of the model. Notably, the aligned model also performs well in domains beyond its training data to enable absolute stability prediction of large proteins and binding affinity prediction of multi-chain complexes, while also enabling single-step stabilization of diverse backbones. These results indicate that ProteinDPO has learned generalizable information from its biophysical alignment data.
Sexual dimorphism in histamine regulation of striatal dopamine
Authors: Van Zandt Meghan , Pittenger Christopher 
Published: May 2024

AbstractDopamine modulation of the basal ganglia differs in males and females and is implicated in numerous neuropsychiatric conditions, including some, like Tourette Syndrome (TS) and attention deficit hyperactivity disorder (ADHD), that have marked sex differences in prevalence. Genetic studies in TS and subsequent work in animals suggest that a loss of histamine may contribute to dysregulation of dopamine. Motivated by this, we characterized the modulation of striatal dopamine by histamine, using microdialysis, targeted pharmacology, and siRNA knockdown of histamine receptors. Intracerebroventricular (ICV) histamine reduced striatal dopamine in male mice, replicating previous work. In contrast, and unexpectedly, ICV histamine increased striatal dopamine in females. ICV or targeted infusion of agonists revealed that the effect in males depends on H2R receptors in the substantia nigra pars compacta (SNc). Knockdown of H2R in SNc GABAergic neurons abrogated the effect, identifying these cells as a key locus of histamine’s regulation of dopamine in males. In females, however, H2R had no discernible role; instead, H3R agonists in the striatum increased striatal dopamine. Strikingly, the effect of histamine on dopamine in females was modulated by the estrous cycle, appearing only in estrus/proestrus, when estrogen levels are high. These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual dimorphism in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of sex differences in the striatal circuitry, and in several neuropsychiatric conditions.Significance StatementDysregulation of the basal ganglia contributes to the pathophysiology of numerous neuropsychiatric diseases, including several, such as Tourette syndrome (TS), that are characterized by sex differences. Previous genetic studies in humans identified histamine dysregulation as a potential to the development of TS; follow-up work in mice highlighted the role of histamine in regulating striatal dopamine tone. Striatal dopamine dysregulation has been implicated in numerous neuropsychiatric disorders, including TS, schizophrenia, and attention deficit-hyperactivity disorder. Here, we uncover novel and significant sex differences in histamine regulation of dopaminergic modulation of circuitry in the striatum. A better understanding of these inherent differences can provide insight into the mechanisms underlying sex-dependent outcomes in neuropsychiatric disease.
Compaction of Active Chromatin Domains and Promoters by H3S10 Phosphorylation during Mitosis Preserves Interphase-Specific Chromatin Structure and Function
Authors: Meel Sweety , Mishra Sachin , Mann Rajat , Najar Arif Hussain , Singh Anurag Kumar , Notani Dimple 
Published: May 2024

AbstractMitotic chromosomes lose interphase-specific genome organization and transcription but gain histone phosphorylation, specifically H3S10p. This phosphorylation event compacts chromosomes in early mitosis by reducing inter-nucleosomal distance before the loading of condensins. However, it is unclear if H3S10p in mitosis preserves the identity of lost chromatin domains and promoters, both physically and functionally. Here, using the pre- mitotic expression of histone H3S10 and its mutants H3S10A and H3S10D, we show that H3S10p hyper-phosphorylates active promoters and spreads into super-domains A in mitosis, causing compaction of these regions. By spreading into active domains in the absence of genome organization, H3S10p retains their identity physically. Functionally, H3S10p ensures optimal closing of promoters by stabilizing the nucleosomes, thereby protecting them from excess loading of transcription machinery post-mitosis. In the H3S10p phospho-mutants, these chromatin regions fail to condense properly during mitosis. As a result, they exhibit enhanced accessibility and transcription of active genes in the next interphase. We propose that the spreading of mitotic H3S10p into active domains preserves their identity during mitosis and, in subsequent interphase, acts as a rheostat to fine-tune transcription and chromatin domain re-formation.
MHConstructor: A high-throughput, haplotype-informed solution to the MHC assembly challenge
Authors: Wade Kristen J. , Suseno Rayo , Kizer Kerry , Williams Jacqueline , Boquett Juliano , Caillier Stacy , Pollock Nicholas R. , Renschen Adam , Santaniello Adam , Oksenberg Jorge R. , Norman Paul J. , Augusto Danillo G. , Hollenbach Jill A. 
Published: May 2024

AbstractThe extremely high levels of genetic polymorphism within the human major histocompatibility complex (MHC) limit the usefulness of reference-based alignment methods for sequence assembly. We incorporate a short readde novoassembly algorithm into a workflow for novel application to the MHC. MHConstructor is a containerized pipeline designed for high-throughput, haplotype-informed, reproducible assembly of both whole genome sequencing and target-capture short read data in large, population cohorts. To-date, no other self-contained tool exists for the generation ofde novoMHC assemblies from short read data. MHConstructor facilitates wide-spread access to high quality, alignment-free MHC sequence analysis.
Profiling Antibiotic Resistance Determinants in Ancient Permafrost Microbiomes
Authors: Gomathinayagam Sankaranarayanan , Muthukaliannan Gothandam Kodiveri 
Published: May 2024

AbstractAntimicrobial resistance presents a formidable challenge, yet its existence predates the introduction of antibiotics. Our study delves into the presence of antimicrobial resistance determinants (ARDs) in ancient permafrost microbiomes, comparing them with contemporary soil and pristine environments. Majority of the samples are from regions around Beringia, encompassing parts of Russia and Alaska, with only one sample originating from the Tien Shan Mountain range in Kyrgyzstan. From over 2.3 tera base pairs of raw metagenomic data, we assembled about 1.3 billion metagenomic contigs and explored the prevalence of ARDs in them. Our findings reveal a diverse array of ARDs in ancient microbiomes, akin to contemporary counterparts. On average, we identified 2 ARDs per ribosomal protein gene in ancient samples.Actinomycetota, Bacillota, and several thermophiles were prominent carriers of ARDs in Chukochi and Kamchatkan samples. Conversely, ancient permafrost from the Tien Shan Mountain range exhibited no Thermophiles orActinomycetotacarrying ARDs. Both ancient and contemporary microbiomes showcased numerous divergent ARDs, with approximately 40% identity to genes in antibiotic resistance gene databases. Antibiotic inactivation-type ARDs exhibited purifying selection with contemporary resistance genes, as estimated by dN/dS ratio. Importantly, we retrieved 359 putative complete viruses from ancient microbiomes and none of them harboured any ARDs.
Cellular cruise control: energy expenditure as a regulator of collective migration in epithelia
Authors: Breinyn Isaac B. , Martina-Perez Simon F. , Baker Ruth E. , Cohen Daniel J. 
Published: May 2024

AbstractEpithelial migration is implicit in processes ranging from gastrula development to the healing of skin, and involves the coordinated motion, force production, and resulting energy expenditure of thousands of constitutive cells. However, the spatiotemporal patterning and regulation of energy expenditure during epithelial migration remains poorly understood. Here, we propose a continuum mechan-ics framework and use it to explore how energy expenditure regulates epithelial migration. We use canonical mechanical metrics such as force, work and power to define what it means for a tissue to migrate ‘efficiently’ and show that freely expanding epithelia actively regulate themselves to operate within a maximally efficient regime. We then leverage electrotaxis (directed motion in response to an externally applied electric field) as a tool to study non-homeostatic migra-tion using this new framework. We show that regulation of migration is robust to external cues and acts to to attenuate a tissues response to stimuli.
Label-Free Electrochemical Imaging of Single Extracellular Vesicles
Authors: Zhang Yuanxin , Hong Zichen , Fu Xuan , Yao Bo , Ma Guangzhong 
Published: May 2024

AbstractExtracellular vesicles (EVs) are pivotal in various biological processes and diseases, yet their small size and heterogeneity pose challenges for single EV quantification. We introduce interferometric electrochemical microscopy (iECM), a sensitive label-free technique that combines interferometric scattering and electrochemical impedance imaging. This method enables the quantification of the impedance of single EVs, providing unique insights into their electrochemical properties, and allows for the simultaneous measurement of size and real-time monitoring of antibody binding. Notably, we discovered that the impedance spectra of EVs can serve as unique fingerprints to differentiate EVs from cancerous and healthy cells, offering potential advancements in clinical diagnostics and the profiling of extracellular biomarkers.
IK channel confers fine-tuning of rod bipolar cell excitation and synaptic transmission in the retina
Authors: Park Yong Soo , Sung Ki-Wug , Kim In-Beom 
Published: May 2024

AbstractDuring retinal visual processing, rod bipolar cells (RBCs) transfer scotopic signals from rods to AII amacrine cells as second-order neurons. Elucidation of the RBC excitation/inhibition is essential for understanding the visual signal transmission. Although excitation and extrinsic inhibitory mechanisms have been studied, intrinsic inhibitory mechanisms remain unclear. We focused on RBC’s prominent K+current, which exhibits voltage and Ca2+dependence. We isolated and confirmed intermediate-conductance Ca2+-activated K+channels (IK) and in RBCs using the patch-clamp method with IK inhibitors (clotrimazole and TRAM34). The regulation of the IK current primarily relies on Ca2+influx via low-threshold Ca2+channels during RBC excitation. It mediates RBC repolarization and oscillation, enabling fast and transient synaptic transmission to AII amacrine cells. Our findings highlight the unique role of the IK channel in RBC, suggesting that it plays a critical role in the scotopic pathway by fine-tuning RBC activity.
Developmental regulators drive DUX4 expression in facioscapulohumeral muscular dystrophy
Authors: Fox Amelia , Oliva Jonathan , Vangipurapu Rajanikanth , Sverdrup Francis M. 
Published: May 2024

AbstractFacioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle wasting disease caused by misexpression of the Double Homeobox 4 (DUX4) transcription factor in skeletal muscle. While epigenetic derepression of D4Z4 macrosatellite repeats is recognized to cause DUX4 misexpression in FSHD, the factors promotingDUX4transcription are unknown. Here, we show that SIX (sine oculis) transcription factors, critical during embryonic development, muscle differentiation, regeneration and homeostasis, are key regulators ofDUX4expression in FSHD muscle cells. In this study, we demonstrate SIX1, SIX2, and SIX4 to be necessary for induction ofDUX4transcription in differentiating FSHD myotubesin vitro, with SIX1 and SIX2 being the most critical in drivingDUX4expression. Interestingly, DUX4 downregulatesSIXRNA levels, suggesting negative feedback regulation. Our findings highlight the involvement of SIX transcription factors in driving the pathogenesis of FSHD by promotingDUX4and DUX4 target gene expression.TeaserWe identified a family of developmental regulators that promote aberrantDUX4expression in FSHD differentiating muscle cells.
First X-ray spectral ptychography and resonant ptychographic computed tomography experiments at the SWING beamline from Synchrotron SOLEIL
Authors: Kulow Anico , Pérez Javier , Boudjehem Redhouane , Gautier Eric , Pairis Sébastien , Ould-Chikh Samy , Hazemann Jean-Louis , da Silva Julio César 
Published: May 2024

X-ray ptychography and ptychographic computed tomography have seen a rapid rise since the advent of fourth-generation synchrotrons with a high degree of coherent radiation. In addition to quantitative multiscale structural analysis, ptychography with spectral capabilities has been developed, allowing for spatial-localized multiscale structural and spectral information of samples. The SWING beamline of Synchrotron SOLEIL has recently developed a nanoprobe setup where the endstation's first spectral and resonant ptychographic measurements have been successfully conducted. A metallic nickel wire sample was measured using 2D spectral ptychography in XANES mode and resonant ptychographic tomography. From the 2D spectral ptychography measurements, the spectra of the components of the sample's complex-valued refractive index, δ and β, were extracted, integrated along the sample thickness. By performing resonance ptychographic tomography at two photon energies, 3D maps of the refractive index decrement, δ, were obtained at the Ni K-edge energy and another energy above the edge. These maps allowed the detection of impurities in the Ni wire. The significance of accounting for the atomic scattering factor is demonstrated in the calculation of electron density near a resonance through the use of the δ values. These results indicate that at the SWING beamline it is possible to conduct state-of-the-art spectral and resonant ptychography experiments using the nanoprobe setup.
Guarantee or inoculate? Ex ante messages against service failures
Authors: Ma Ke , Sun Weizheng 
Published: May 2024

PurposeWhile many studies have focused on the effectiveness of service recovery after encountering service failure, few have considered for pre-recovery opportunities. Drawing on service guarantee research and the inoculation theory, this study examines the effect of pre-recovery strategy on customer’s satisfaction when faced with possible service failure. This study takes into consideration the uncertainty of service failure, including specific or unpredicted failures.Design/methodology/approachThree experimental studies were conducted to examine our research hypotheses, which include a total of 1203 subjects recruited from online and offline platforms.FindingsThe findings reveal that service guarantees and inoculation messages both effectively mitigate the negative consequences of a service failure. Specifically, the pre-recovery strategy is particularly effective for specific service failures. In addition, we thoroughly examined the mediating role of customer attribution.Originality/valueThis research significantly contributes to the existing literature on service research by delving into the potential positive impact of proactive measures undertaken by service enterprises. Furthermore, the findings of this research offer valuable insights for practitioners.
Emerging themes and future research directions in the cold supply chain: a bibliometric and co-citation analysis
Authors: Karanam Malleswari , Krishnanand Lanka , Manupati Vijaya Kumar , Nudurupati Sai Sudhakar 
Published: May 2024

PurposeThe primary goal of this review is to identify emerging themes in the cold supply chain (CSC) and their future research directions, methodologies, and theories.Design/methodology/approachThe review looks at CSC related articles from Scopus database published in the years 2000–2020. Thereafter, bibliometric and co-citation analyses have been conducted to identify emerging themes, methodologies, and theoretical perspectives related to CSC management.FindingsThis study revealed a clear research gap in CSC literature with emerging themes relevant to diverse aspects. Primarily, the most prominent authors, methodologies, and theories were identified from bibliometric analysis. Next, we generated clusters to identify the insights of each cluster using co-citation analysis. Consequently, the significance of clusters concerning the number of articles, theoretical frameworks, methodologies, and themes was recognized. Finally, a few future research questions regarding emerging themes have been identified.Practical implicationsThe importance of co-citation and bibliometric analyses in studying the evolution of research over a definite time is emphasized in this work. As per emerging themes, implementing digital technologies has increased the efficiency of traditional CSC and transformed it into digital CSC.Originality/valueAs per the authors' knowledge, this work is the first in literature to explore the significance of identifying emerging areas and future research directions in managing CSC through literature review based on bibliometric and co-citation analysis.
An integrated data-driven framework for vehicle quality analysis based on maintenance record mining and Bayesian network
Authors: Cheng Aoxiang , Bi Youyi 
Published: May 2024

PurposeThe purpose of this paper is to present an integrated data-driven framework for processing and analyzing large-scale vehicle maintenance records to get more comprehensive understanding on vehicle quality.Design/methodology/approachWe propose a framework for vehicle quality analysis based on maintenance record mining and Bayesian Network. It includes the development of a comprehensive dictionary for efficient classification of maintenance items, and the establishment of a Bayesian Network model for vehicle quality evaluation. The vehicle design parameters, price and performance of functional systems are modeled as node variables in the Bayesian Network. Bayesian Network reasoning is then used to analyze the influence of these nodes on vehicle quality and their respective importance.FindingsA case study using the maintenance records of 74 sport utility vehicle (SUV) models is presented to demonstrate the validity of the proposed framework. Our results reveal that factors such as vehicle size, chassis issues and engine displacement, can affect the chance of vehicle failures and accidents. The influence of factors such as price and performance of engine and chassis show explicit regional differences.Originality/valuePrevious research usually focuses on limited maintenance records from a single vehicle producer, while our proposed framework enables efficient and systematic processing of larger-scale maintenance records for vehicle quality analysis, which can support auto companies, consumers and regulators to make better decisions in purchase choice-making, vehicle design and market regulation.