bluuebunny/crossref_metadata_2025_split huggingface dataset:
An mTOR Inhibitor Discovery System Using the Growth of Drug-Sensitized Yeast Strains
Authors: Breen Anna K. , Thomas Sarah , Beckett David , Agsalud Matthew , Gingras Graham , Williams Judd , Wasko Brian M. 
Published: January 2025

AbstractInhibition of the target of rapamycin (TOR/mTOR) protein kinase by the drug rapamycin extends lifespan and healthspan across diverse species. However, rapamycin has potential off-target and side effects that warrant the discovery of additional TOR inhibitors. TOR was initially discovered inSaccharomyces cerevisiae(yeast) which contains two TOR paralogs,TOR1andTOR2. Yeast lacking functional Tor1 are viable but are hypersensitive to growth inhibition by TORC1 inhibitors, which is a property of yeast that can be exploited to identify TOR inhibitors. Additionally, yeast lacking FK506-sensitive proline rotamase (FPR1) or containing ator1-1allele (a mutation in the Fpr1-rapamycin binding domain of Tor1) are robustly and selectively resistant to rapamycin and analogs that allosterically inhibit TOR activity via anFPR1-dependent mechanism.To facilitate the identification of TOR inhibitors, we generated a panel of yeast strains with mutations in TOR pathway genes combined with the removal of 12 additional genes involved in drug efflux. This creates a drug sensitive strain background that can sensitively and effectively identify TOR inhibitors.In a wildtype yeast strain background, 25 µM of Torin1 and 100 µM of GSK2126458 (omipalisib) are necessary to observeTOR1-dependent growth inhibition by these known TOR inhibitors. In contrast, 100 nM Torin1 and 500 nM GSK2126458 (omipalisib) are sufficient to identifyTOR1-dependent growth inhibition in the drug sensitized background. This represents a 200-fold and 250-fold increase in detection sensitivity for Torin1 and GSK2126458, respectively. Additionally, for the TOR inhibitor AZD8055, the drug sensitive system resolves that the compound results inTOR1-dependent growth sensitivity at 100 µM, whereas no growth inhibition is observed in a wildtype yeast strain background. Our platform also identifies the caffeine analog aminophylline as aTOR1-dependent growth inhibitor via selectivetor1growth sensitivity. We also tested nebivolol, isoliquiritigenin, canagliflozin, withaferin A, ganoderic acid A, and taurine, and found no evidence for TOR inhibition using our yeast growth-based model.Our results demonstrate that this system is highly effective at identifying compounds that inhibit the TOR pathway. It offers a rapid, cost-efficient, and sensitive tool for drug discovery, with the potential to expedite the identification of new TOR inhibitors that could serve as geroprotective and/or anti-cancer agents.
Structural basis of lipopolysaccharide translocon assembly mediated by the small lipoprotein LptM
Authors: Miyazaki Ryoji , Kimoto Mai , Kohga Hidetaka , Tsukazaki Tomoya 
Published: January 2025

AbstractGram-negative bacteria possess an outer membrane (OM) that acts as a barrier against toxic compounds. Lipopolysaccharide (LPS) in the outer leaflet of the OM is crucial for barrier function. After its synthesis in the cytoplasm and translocation to the periplasm, LPS is transported to the OM by the LPS transport system. The LPS translocon, composed of an OM protein LptD and a lipoprotein LptE, mediates LPS assembly into the OM. Recently, the small lipoprotein LptM (YifL) was identified as a novel LptD/E-interactor that facilitates LptD maturation. However, its mechanism remains unclear. Here, we investigated the detailed interaction between LptM and LptD. We found that LptM interacts with the folded LptD intermediate at the late stage of its maturation. Mutational analyses demonstrated that the N-terminal conserved region (C20GLKGPLYF28) of LptM is essential for its function. Cryo-EM structural analysis of theE. coliLptD/E/M complex, combined with biochemical analyses, revealed the molecular basis of the LptM–LptD interaction and its functional importance. Thus, we propose that LptM functions as a “barrel-rivet,” stabilizing LptD for its proper assembly.
Identification and Characterization of Novel Outer Membrane Proteins ofBrachyspira pilosicoli
Authors: Panda Amisha , Kapoor Jahnvi , Hareramadas B. , Naqvi Ilmas , Chhabra Ravindresh , Kumar Sanjiv , Bandyopadhyay Anannya 
Published: January 2025

AbstractBrachyspira pilosicoliis a pathogenic, Gram-negative, spirochete bacterium that causes intestinal spirochetosis (IS) in birds, pigs, and humans and is distributed worldwide. This anaerobic intestinal bacterium colonizes the large intestine, potentially leading to colitis, diarrhoea, and decreased growth rate. Outer membrane proteins of Gram-negative bacteria play crucial roles in adhesion and host-pathogen interaction, helping the bacteria to evade the host immune system, and enhancing their virulence. However,B. pilosicoliouter membrane proteins are yet to be identified and characterized. Here, we report the computational discovery of 42 outer membrane β-barrel (OMBB) proteins inB. pilosicoliproteome predicted using a consensus-based computational framework. β-barrel architectures of the predicted proteins were confirmed by generating AlphaFold 3-based structural models. Structure-based functional annotation predicted putative functions for the identified OMBB proteins, including BamA homolog involved in folding and membrane insertion of OMPs, LptD homolog involved in transport of lipopolysaccharides into the OM, efflux pumps, transporters, enzymes, diffusion channels, and porins. Sequence variations across nine strains ofB. pilosicoliwere identified and mapped onto structural models, revealing that many of the variations were present on the surface exposed loop regions of the β-barrel structures. Ourin-silicoanalysis has identified 42 OMBB proteins, including homologs of BamA, LptD, TolC, TonB-dependent receptors, CsgG. Seven of these were identified as hypothetical proteins. Computational characterization of the predicted OMBB proteins offer insights into their potential roles in physiology, virulence, and disease pathogenesis, highlighting their potential for applications in diagnostics, vaccine development, or therapeutic interventions.
T Lymphocyte-Specific Deletion of SHP1 and SHP2 Promotes Activation-Induced Cell Death of CD4+ T Cells and Impairs Antitumor Response
Authors: Foster Connor J.R. , Du Jasper , Pundel Oscar , Geer Mitchell J. , Ripert Ryan C. , Liu Jia , Heim Taylor A. , Araki Kiyomi Y. , Lund Amanda W. , Wang Jun , Neel Benjamin G. 
Published: January 2025

ABSTRACTSHP1 (PTPN6) and SHP2 (PTPN11) are closely related protein-tyrosine phosphatases (PTPs), which are autoinhibited until their SH2 domains bind paired tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory/switch motifs (ITIMs/ITSMs). These PTPs bind overlapping sets of ITIM/ITSM-bearing proteins, suggesting that they might have some redundant functions. By studying T cell-specific single and double knockout mice, we found that SHP1 and SHP2 redundantly restrain naïve T cell differentiation to effector and central memory phenotypes, with SHP1 playing the dominant role. Surprisingly, loss of SHP2 alone in T cells enhanced the antitumor effects of anti-PD-1 antibodies, whereas there was no effect of SHP1 deletion. Also unexpectedly, the absence of both PTPs resulted in poorer tumor control and failure to respond to PD-1 blockade, associated with reduced frequency and activation of T cells and dendritic cells. Mechanistic studies revealed that CD4+, but not CD8+ T cells lacking SHP1 and SHP2 show increased activation-induced cell death upon anti-CD3/CD28 stimulation. Adoptive transfer of antigen-specific CD4+ T cells restored normal levels of tumor control in mice lacking both PTPs. Together, our results demonstrate that SHP1 or SHP2 is required to prevent activation-induced cell death of CD4+ T cells and is critical for tumor immunity, raising the possibility that inhibition of SHP2 might augment the therapeutic efficacy of PD-1-based immune therapy.SIGNIFICANCE STATEMENTSHP1 and SHP2 are related protein tyrosine phosphatases that associate with several of the same ITIM/ITSM-containing receptors or T cell receptor (TCR) signaling molecules. The individual roles of SHP1 and SHP2 in T cells have been reported previously, but potentially redundant functions are less well understood. Here we uncover an essential function in CD4+ T cells that is manifest only in the absence of both enzymes and is critical for the control of tumors.
Altered brain-ventricle coupling modes over Alzheimer’s disease progression detected with fMRI
Authors: Campo Fulvia Francesca , Brattico Elvira , Magalhães Vicente , Nigro Salvatore , Tafuri Benedetta ,   the Alzheimer’s Disease Neuroimaging Initiative, Logroscino Giancarlo , Cabral Joana 
Published: January 2025

AbstractThe origins of resting-state functional MRI (rsfMRI) signal fluctuations remain debated. Recent evidence shows coupling between global cortical rsfMRI signals and cerebrospinal fluid inflow in the fourth ventricle, increasing during sleep and decreasing with Alzheimer’s disease (AD) progression, potentially reflecting brain clearance mechanisms. However, the existence of more complex brain-ventricle coupling modes and their relationship to cognitive decline remains unexplored.Analyzing 599 minimally-preprocessed rsfMRI scans from 163 elderly participants across the AD spectrum, we identified distinct brain-ventricle coupling modes that differentiate across groups and correlate with cognitive scores. Beyond the known anti-phase coupling between global brain signals and ventricles —more frequent in cognitively normal controls— we discovered additional modes where specific brain areas temporarily align with ventricle signals. At the cortical level, these modes form canonical resting-state networks, such as the Default Mode Network, which occurs less in AD or the Frontoparietal Network, which correlates positively with memory scores.The direct link between ventricle and brain signals challenges the common practice of removing CSF components from rsfMRI analyses and questions the origin of cortical signal fluctuations forming functional networks, which may reflect region-specific fluid inflow patterns. These findings provide new insights into the relationship between brain clearance mechanisms and network dysfunction in neurodegenerative diseases.
How do auditors price financial secrecy culture? An international study
Authors: Sun Xuan Sean , Houqe Muhammad Nurul , Bhuiyan Md. Borhan Uddin , Zaman Mahbub 
Published: January 2025

PurposeThis research examines the influence of financial secrecy culture on audit fees. Additionally, we investigate the potential moderating effect of adopting International Financial Reporting Standards (IFRS) on the relationship between financial secrecy culture and audit fees.Design/methodology/approachWe use an international dataset comprising 249,217 firm-year observations from 30 countries/regions listed between 1996 and 2022. Our analysis includes regression analysis, the Heckman self-selection bias test, change analysis and various robustness tests.FindingsOur results reveal a significant positive association between audit fees and firms listed in secretive jurisdictions, suggesting that auditors charge higher fees to accommodate additional audit effort or risk premiums. Furthermore, our empirical findings indicate that implementing IFRS in countries/regions with higher levels of secrecy introduces complexities or ambiguities in audit procedures, leading to increased audit fees. These results hold up under rigorous endogeneity tests and remain consistent across alternative measures and tests.Research limitations/implicationsOur findings establish a direct link between financial secrecy and audit fees, demonstrating higher costs for firms with greater secrecy. Additionally, they show that implementing IFRS in secretive jurisdictions intensifies audit complexities, resulting in higher fees. These findings emphasize the critical importance of transparency, regulatory compliance and risk management in financial reporting, with implications for investor confidence and regulatory strategies.Originality/valueThis study contributes to the literature by exploring the previously unexamined relationship between financial secrecy culture and audit fees while also assessing the moderating effect of IFRS adoption. By utilizing a comprehensive international dataset spanning multiple jurisdictions and years, our research provides valuable insights into cross-border variations in audit practices and their broader implications.
Am I making a difference? A scoping review of the consultant’s individual characteristics fostering organizational consulting effectiveness
Authors: Lallier Beaudoin Marie-Claude , Samson Irène , Dionne Émilie , Kusion Pierre-Yves 
Published: January 2025

PurposeThe field of organizational consulting is often criticized for the lack of data supporting the practice and limited understanding of individual characteristics required for consultants to make a positive impact on organizations. The aims of this study were (1) to identify existing evidence on consultants’ knowledge, skills, abilities and other personal attributes (KSAO) related to organizational consulting effectiveness and (2) to lay the foundation of an empirically derived competency framework for effective consulting.Design/methodology/approachA scoping review of scientific peer-reviewed papers published between 1973 and 2023 and exploring attributes of the consultant related to consulting effectiveness was carried out among three academic databases and one consulting-specific journal. Content analysis was conducted in NVivo using an inductive/deductive approach.FindingsIn total, 32 single individual characteristics were extracted from 13 empirical papers and organized into 3 broad categories: (1) knowledge, (2) skills and abilities, and (3) other personal attributes. Results showed that skills and abilities have received the most attention from scholars, emphasizing the importance for consulting training programs to focus on the development of process-related and relational skills. Knowledge and personal attributes, including personality traits, were marked by a paucity of research.Originality/valueThe findings laid the foundation of a first data-based competency model for consulting effectiveness, useful for both researchers and practitioners. The current review identified gaps in the literature and highlighted opportunities for consolidating research in the field of organizational consulting.
CuMg2GaS4: a novel photocatalyst with promising properties
Authors: Hocine Hayat , Khelfaoui Friha , Al-Douri Y. , Boudia Keltouma , Fontaine-Vive Fabien , Sadouki Ouafaa , Slamani Amel , Amara Kadda , Belabbas Mawloud , Belkharroubi Fadila , Ameri M. 
Published: January 2025

PurposeThe mechanical properties, including elastic constants and moduli, indicate the material’s stiffness and stability. Our calculations reveal that CuMg2GaS4 is a direct bandgap semiconductor, 2.18 eV. A detailed analysis of the electronic structure provides an insight into the bonding characteristics and charge distribution within the material.Design/methodology/approachThis work presents a comprehensive investigation of the structural, electronic, optical, mechanical properties of the CuMg2GaS4 compound using density functional theory (DFT) calculations. Unlike its counterpart CuMg2InS4, which exhibits a tetragonal WS structure, CuMg2GaS4 is found to be an energetically stable in the monoclinic phase.FindingsThe calculated effective masses of electrons (0.38 m0) and holes (1.28 m0) suggest promising charge carrier mobility within the compound. Furthermore, based on the evaluation of electronic structure and optical absorption properties of CuMg2GaS4 in relation with the redox potentials of water, this demonstrates its potential as a promising candidate for efficient photocatalytic water splitting under visible light irradiation. These findings contribute to the understanding of the structural and functional properties of CuMg2GaS4 and pave the way for its potential applications in optoelectronic and energy conversion devices.Originality/valueThe prime novelty is to employ ab initio self-consistent Full-Potential Linearized augmented plane wave + local orbital method (FP-LAPW + lo) and investigate the properties of CuMg2GaS4 of structural, mechanical, thermodynamic stabilities, linear optical response.
Navigating new threats: Prey naïveté in native mammals
Authors: McKee Rebecca K. , Hart Kristen M. , Zeitoune Spencer , McCleery Robert A. 
Published: January 2025

Abstract

Invasive predators pose a substantial threat to global biodiversity. Native prey species frequently exhibit naïveté to the cues of invasive predators, and this phenomenon may contribute to the disproportionate impact of invasive predators on prey populations. However, not all species exhibit naïveté, which has led to the generation of many hypotheses to explain patterns in prey responses. These hypotheses primarily fall into two categories: system‐centric hypotheses related to biogeographic isolation (BIH) and species‐centric hypotheses, like the archetype similarity hypothesis (ASH).

We tested the predictions of these hypotheses by assessing the response of the common raccoon (Procyon lotor) and hispid cotton rat (Sigmodon hispidus), two native mammal species with divergent snake predation histories, to the cues of the invasive Burmese python (Python bivittatus) in the Florida Everglades (USA). Using giving‐up densities (GUDs), we assessed the responses of both cotton rats and raccoons to life‐size replicas of Burmese pythons and two North American predators—eastern diamondback rattlesnakes (Crotalus adamanteus) and coyotes (Canis latrans).

Although cotton rats increased their GUD in the presence of all three predators relative to the novel‐object control, raccoons only increased their GUD in coyote treatments.

These results align with the predictions of the ASH but not the BIH, and mirror observed patterns of population declines in invaded areas of the Florida Everglades.

More broadly, our findings suggest that naïveté may contribute to the vulnerability of some species to invasive predators even in large continental systems.
Evaluation of the effect of therapeutic plasma exchange on serum cytokine levels in pediatric intensive care unit
Authors: Cakmak Selen Ceren , Tugrul Hazal Ceren , Akgun Unlu Dilan , Albayrak Rasit Alkan , Atay Gurkan , Erdogan Seher , Sozeri Betul 
Published: January 2025

AbstractIntroductionTherapeutic plasma exchange (TPE) is crucial for saving lives when used appropriately. This study aimed to assess TPE's impact on tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) protein and IL‐6 levels in critically ill pediatric patients.MethodsConducted between May 2022 and December 2022, the study observed pediatric intensive care unit (PICU) patients undergoing TPE, recording demographics, lab results, TWEAK, and IL‐6 levels pre‐ and post‐procedure.ResultsOf 41 patients, 53.7% were male, 51.2% had underlying conditions, and 39% showed sepsis symptoms. IL‐6 levels significantly rose post‐TPE (p: 0.006), while TWEAK protein levels dropped (p: 0.030). Positive correlations were found between interleukin‐6 (IL‐6) pre‐TPE and ventilation duration, ferritin levels (p <0.05), and TWEAK pre‐TPE and organ failure indicators, D‐Dimer levels (p <0.05). Prognosis showed no significant difference in IL‐6/TWEAK levels (p >0.05).ConclusionSerum IL‐6 and TWEAK can indicate disease severity and inflammation level, but may not predict prognosis accurately.Clinical Trial RegistrationOur study has clinical study registration number B.10.1.TKH.4.34.H.GP.0.01/154 of the University of Health Sciences Ümraniye Training and Research Hospital.
Morphological Features of the Pecten Oculi in the Common Kestrel (Falco tinnunculus)
Authors: Kilinç Bahadır , Toprak Burhan , Yüksel Süleyman , Kandir Emine Hesna , Koçak Gökhan 
Published: January 2025

ABSTRACTThis study aimed to investigate the macroscopic, light microscopic (LM) and scanning electron microscopic (SEM) characteristics of the pecten oculi in common kestrels (Falco tinnunculus). A total of six eyeballs from three common kestrels were used as the study material. The examination revealed that the bulbus oculi was spherical in shape and its diameter exceeded the axial‐global length. In the equatorial section of the eyeball, the pecten oculi were observed to be situated on the retina layer where the optic nerve enters the eyeball, showing a posterior‐to‐anterior distribution. The pecten oculi appeared dark brown, with a convoluted structure, comprising approximately 15–17 vascular folds. Scanning electron microscopic examination revealed dense capillary vascular folds on the surface of the pecten oculi. Within these capillary vessels, a few hyalocytes were noted, and melanocytes were found at the edges of the folds. Light microscopic examination detected numerous large, medium and small diameter vessels within the folds of the pecten oculi, especially at the periphery of the folds and the apical parts of the pecten oculi. The findings of this study were compared with the morphological characteristics of the pecten oculi in other bird species, revealing both similarities and differences.
The Adelaide Score: prospective implementation of an artificial intelligence system to improve hospital and cost efficiency
Authors: Kovoor Joshua G. , Stretton Brandon , Gupta Aashray K. , Beath Alexander , Jacob Mathew O. , Kefalianos John M. , Carmichael Gavin J. , Zaka Ammar , O'Callaghan Gerry , Satheakeerthy Shrirajh , Booth Andrew , Delloso Thomson , Hugh Thomas J. , Chan Weng Onn , Maddern Guy J. , Balan‐Vnuk Eva , Cusack Michael , Gilbert Toby , Maddison John , Bacchi Stephen ,   the Adelaide Score Advisory Group
Published: January 2025

AbstractBackgroundThe Adelaide Score is an artificial intelligence system that integrates objective vital signs and laboratory tests to predict likelihood of hospital discharge.MethodsA prospective implementation trial was conducted at the Lyell McEwin Hospital in South Australia. The Adelaide Score was added to existing human, artificial intelligence, and other technological infrastructure for the first 28 days of April 2024 (intervention), and outcomes were compared using parametric, non‐parametric and health economic analyses, to those in the first 28 days of April 2023 (control). Artificial intelligence evaluated inpatients admitted under 18 surgical and medical teams, and patients of high likelihood of discharge were provided, on working shifts between Thursday to Sunday, to the Supportive Weekend Interprofessional Flow Team (SWIFT) comprising a senior nurse and pharmacist.ResultsTwo thousand nine hundred and sixty‐eight admissions were included across intervention and control periods. Relative to the control group, use of the Adelaide Score in the intervention group resulted in significantly shorter median length of stay (3.1 versus 2.9 days, P = 0.028) and significantly lower seven‐day readmission rate (7.1 versus 5.0%, p = 0.02). The 0.2 bed‐day reduction in median length of stay produced a cost saving of $735 708.60 across the 28‐day period, or $9 564 211.80 across a 52‐week year. There was no significant difference between intervention and control groups in median length of stay for patients discharged on weekends, in‐hospital mortality, or discharge to non‐home destinations.ConclusionsThe prospective implementation of the Adelaide Score was associated with improved hospital and cost efficiency, alongside lower readmissions, for patients across surgical and medical services.