bluuebunny/crossref_metadata_2025_split huggingface dataset:
The bacterial genetic determinants ofEscherichia colicapacity to cause bloodstream infections in humans
Authors: Burgaya Judit , Marin Julie , Royer Guilhem , Condamine Bénédicte , Gachet Benoit , Clermont Olivier , Jaureguy Françoise , Burdet Charles , Lefort Agnès , de Lastours Victoire , Denamur Erick , Galardini Marco , Blanquart François ,   the Colibafi/Septicoli and Coliville groups
Published: January 2023

AbstractEscherichia coliis both a highly prevalent commensal and a major opportunistic pathogen causing bloodstream infections (BSI). A systematic analysis characterizing the genomic determinants of extra-intestinal pathogenic vs. commensal isolates in human populations, which could inform mechanisms of pathogenesis, diagnostics, prevention and treatment is still lacking. We used a collection of 1282 BSI and commensalE. coliisolates collected in France over a 17-year period (2000-2017) and we compared their pangenomes, genetic backgrounds (phylogroups, STs, O groups), presence of virulence-associated genes (VAGs) and antimicrobial resistance genes, finding significant differences in all comparisons between commensal and BSI isolates. A machine learning linear model trained on all the genetic variants derived from the pangenome and controlling for population structure reveals similar differences in VAGs, discovers new variants associated with pathogenicity (capacity to cause BSI), and accurately classifies BSI vs. commensal strains. Pathogenicity is a highly heritable trait, with up to 69% of the variance explained by bacterial genetic variants. Lastly, complementing our commensal collection with an older collection from 1980, we predict that pathogenicity increased steadily from 23% in 1980 to 46% in 2010. Together our findings imply thatE. coliexhibit substantial genetic variation contributing to the transition between commensalism and pathogenicity and that this species evolved towards higher pathogenicity.
Implementation of a flavin biosynthesis operon improves extracellular electron transfer in bioengineered Escherichia coli
Authors: Mouhib Mohammed , Reggente Melania , Boghossian Ardemis A. 
Published: January 2023

AbstractBioelectrochemical systems (BES) are promising for energy, sensing, environmental, and synthesis applications.Escherichia coliwere previously bioengineered for application in BES by introduction of extracellular electron transfer (EET) pathways. Inspired by the metal-reducing (Mtr) pathway ofShewanella oneidensisMR-1, several of its cytochromes were heterologously expressed inE. coli, leading to increased EET rates and successful application in BES. Besides direct electron transfer, S. oneidensisMR-1 is known to secrete flavins that act as redox mediators and are crucial for high EET rates.Here we co-express the Mtr pathway and a flavin biosynthesis pathway inE. coli, to enhance EET in engineered strains. The secretion of both flavin mononucleotide and riboflavin was increased up to 3-fold in engineered strains. Chronoamperometry revealed an up to ~3.4-fold increase in current over the wild type when co-expressing cytochromes and flavin biosynthesis genes, and a ~2.3-fold increase when expressing flavin biosynthesis genes on their own. Thus, the introduction of flavin biosynthesis genes yields in a distinct, yet complementary EET mechanism, and holds promise for application in BES.
Development of digital Hi-C assay
Authors: Mori Akihiro , Schweikert Gabriele 
Published: January 2023

AbstractsEnhancers are genomic elements and contain all necessary cis-regulatory contexts. Such enhancers are convened to the appropriate promoter of target genes for gene regulations even though the enhancers and the promoters are apart a few mega-base pairs away from each other. In addition to physical distance, nucleotide mutations in enhancers influence a partial group of the target genes. Those make it more complicated to reveal the paired relationship between enhancer and promoter of target genes. Recently, advanced computational approaches are employed to predict such interactions. One approach requires a large number of different high-throughput datasets to predict such interactions; however, in practical aspects, all datasets for tissues and conditions of interest are not available. Whereas the alternative approach requires only genome sequences for particular predictions, their predictions are insufficient for practical applications. We address those issues by developing the digital Hi-C assay with a transformer-algorithm basis. This assay allows us to create models from simple/small/limited sequence-based datasets only. We apply the trained models to be able to identify long-distance interactions of genomic loci and three-dimensional (3D) genomic architectures in any other tissue/cell datasets; additionally, we demonstrated the predictions of genomic contexts by analysing the prediction patterns around the target locus in the three following genomic-context problems: enhancer-promoter interactions (i.e., promoter-capture Hi-C), the CTCF-enriched regions, and TAD-boundary regions. Because our approach adopted a sequence-based approach, we can predict the long-distance interactions of genomic loci by using the genomic sequences of the user’s interest (e.g., input sequences from high-throughput assay datasets such as ATAC-seq and ChIP-seq assays). Consequently, we provide an opportunity to predict interactions of genomic loci from a minimum dataset.
ERBB4-mediated signaling is a mediator of resistance to BTK and PI3K inhibitors in B cell lymphoid neoplasms
Authors: Arribas Alberto J. , Napoli Sara , Cascione Luciano , Barnabei Laura , Sartori Giulio , Cannas Eleonora , Gaudio Eugenio , Tarantelli Chiara , Mensah Afua A. , Spriano Filippo , Zucchetto Antonella , Rossi Francesca M. , Rinaldi Andrea , de Moura Manuel Castro , Jovic Sandra , Pittau Roberta Bordone , Stathis Anastasios , Stussi Georg , Gattei Valter , Brown Jennifer R. , Esteller Manel , Zucca Emanuele , Rossi Davide , Bertoni Francesco 
Published: January 2023

AbstractBTK and PI3K inhibitors are among the drugs approved for the treatment of patients with lymphoid neoplasms. Although active, their ability to lead as single agents to long-lasting complete remission is rather limited especially in the lymphoma setting. This indicates that tumor cells often develop resistance to the drugs. Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors and that targeted pharmacological interventions can restore sensitivity to the small molecules.We started from a marginal zone lymphoma (MZL) cell line, Karpas-1718, kept under prolonged exposure to the PI3Kδ inhibitor idelalisib until acquisition of resistance, or with no drug. Cells underwent transcriptome, miRNA and methylation profiling, whole exome sequencing, and pharmacological screening which led to the identification of the overexpression of ERBB4 and its ligands HBEGF and NRG2 in the resistant cells. Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting. Addition of recombinant HBEGF induced resistance to BTK and PI3K inhibitors in parental cells but also in additional lymphoma models. Combination with the ERBB inhibitor lapatinib was beneficial in resistant cells and in other lymphoma models already expressing the identified resistance factors. Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors, and pretreatment with demethylating agents or EZH2 inhibitors overcame the resistance. Resistance factors were shown to be expressed in clinical samples, further extending the findings of the study.In conclusions, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors and treatments that appear to overcome it.Key pointsA mechanism of secondary resistance to the PI3Kδ and BTK inhibitors in B cell neoplasms driven by secreted factors.Resistance can be reverted by targeting ERBB signaling.
KLRG1 marks tumor-infiltrating CD4 T cell subsets associated with tumor progression and immunotherapy response
Authors: Ager Casey R. , Zhang Mingxuan , Chaimowitz Matthew , Bansal Shruti , Obradovic Aleksandar , Rogava Meri , Melms Johannes C. , McCann Patrick , Spina Catherine , Drake Charles G. , Dallos Matthew C. , Izar Benjamin 
Published: January 2023

AbstractCurrent methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow cytometry panel and performed high-throughput analyses in critical contexts. We leveraged two distinct preclinical models that recapitulate cancer immunoediting (NPK-C1) and immune checkpoint blockade (ICB) response (MC38), respectively, and profiled multiple relevant tissues at and around key inflection points of immune surveillance and escape and/or ICB response. Machine learning-driven data analysis revealed a pattern of KLRG1 expression that uniquely identified intratumoral effector CD4 T cell populations that constitutively associate with tumor burden across tumor models, and are lost in tumors undergoing regression in response to ICB. Similarly, a Helios-KLRG1+subset of tumor-infiltrating regulatory T cells (Tregs) was associated with tumor progression from immune equilibrium to escape, and were also lost in tumors responding to ICB. Validation studies confirmed KLRG1 signatures in human tumorinfiltrating CD4 T cells associate with disease progression in renal cancer. These findings nominate KLRG1+CD4 T cell populations as subsets for further investigation in cancer immunity and demonstrate the utility of longitudinal spectral flow profiling as an engine of dynamic biomarker and/or target discovery.
Screening of herbal molecules for the management of Alzheimer’s Disorder through molecular docking andin-vitroinvestigation
Authors: Nagu Priyanka , Pathan Amjad Khan A , Mehta Vineet 
Published: January 2023

AbstractAt present, there is not a single disease-modifying drug available for the management of Alzheimer’s disease (AD) pathogenesis. The exact pathology of AD is still not known, which opens up the wide scope of research for developing some novel therapeutic strategies for AD management. In the present study, 100 herbal molecules were identified through the literature survey which could be beneficial for Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), β-Secretase inhibition, and neurodegeneration. AutoDock Tools-1.5.6 docking software is used to screen the herbal molecules against AChE, BChE, and β-Secretase with Protein Data Bank (PDB) ID 1B41, 1P0I, and 1FKN respectively. Based on the docking parameters quercetin, rutin, vitisinol-C, dihydrotanshinone-I, and β-carotene were found to be the best molecules against their respective proteins receptors. Moreover,in-vitroAChE and BChE assay demonstrated that quercetin and rutin could modulate cholinergic pathways during AD and thereby could impart beneficial effects during AD. Further, our results forin-vitroneurodegeneration studies also support the neuroprotective effect of quercetin and rutin against HgCl2-induced neurodegeneration and suggested the protective role of these molecules against neurodegeneration during AD. However, a preclinical investigation is required to support the potential effect on AD pathogenesis.
Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively
Authors: Raina Kanak , Forbes Chris D. , Stronk Rebecca , Rappi Jonathan P. , Eastman Kyle J. , Gerritz Samuel W. , Yu Xinheng , Li Hao , Bhardwaj Amit , Forgione Mia , Hundt Abigail , King Madeline P. , Posner Zoe M. , Denny Allison , McGovern Andrew , Puleo David E. , Garvin Ethan , Chenard Rebekka , Zaware Nilesh , Mousseau James J. , Macaluso Jennifer , Martin Michael , Bassoli Kyle , Jones Kelli , Garcia Marco , Howard Katia , Smith Levi M. , Chen Jinshan M. , De Leon Cesar A. , Hines John , Kayser-Bricker Katherine J. , Crews Craig M. 
Published: January 2023

AbstractWhile specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities.Here, we describe a proof-of-concept study using novel heterobifunctional small molecules calledRegulatedInducedProximityTargetingChimeras or RIPTACs, which elicit a stable ternary complex between a target protein selectively expressed in cancer tissue and a pan-expressed protein essential for cell survival. The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to cell death selectively in cells expressing the target protein. This approach not only opens new target space by leveraging differentially expressed intracellular proteins but also has the advantage of not requiring the target to be a driver of disease. Thus, RIPTACs can address non-target mechanisms of resistance given that cell killing is driven by inactivation of the essential protein.Using the HaloTag7-FKBP model system as a target protein, we describe RIPTACs that incorporate a covalent or non-covalent target ligand connected via a linker to effector ligands such as JQ1 (BRD4), BI2536 (PLK1), or multi-CDK inhibitors such as TMX3013 or dinaciclib. We show that these RIPTACs exhibit positive co-operativity, accumulate selectively in cells expressing HaloTag7-FKBP, form stable target:RIPTAC:effector trimers in cells, and induce an anti-proliferative response in target-expressing cells. We propose that RIPTACs are a novel heterobifunctional therapeutic modality to treat cancers that are known to selectively express a specific intracellular protein.
HSV-1 Oncolytic Virus Targeting CEACAM6-Expressing Tumors Using a Bispecific T-Cell Engager
Authors: Murad Yanal M. , Lee I-Fang , Liu Xiaohu , Delwar Zahid , Ding Jun , Liu Guoyu , Tatsiy Olga , Chouljenko Dmitry , Hussack Gregory , Van Faassen Henk , Jia William Wei-Guo 
Published: January 2023

AbstractVG21306 is a novel oncolytic virus (OV) that encodes a secretable bispecific T-cell engager targeting Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6)-expressing tumors. Delivering a T-cell engager locally to a tumor mass will circumvent physical barriers that prevent antibodies from penetrating the tumor, and will mitigate the off-tumor, on-target toxicity risk. Both in vitro and in vivo testing demonstrated the expression of a functional T-cell engager capable of binding both targets. The efficacy of the engager was demonstrated in vitro, where addition of the engager payload to the OV enhanced anti-tumor efficacy against tumor cells overexpressing CEACAM6. Moreover, we have demonstrated the engager’s ability to induce bystander killing in cells lacking CEACAM6 expression, as well as engaging exhausted T cells and inducing tumor cell death. The safety of the engager was demonstrated by the lack of binding to normal human tissue or normal tissue adjacent to tumors, as well as the absence of any measurable leakage of the expressed engager into the blood of mice treated by intratumoral OV injection.
Extracellular succinate induces spatially organized biofilm formation inClostridioides difficile
Authors: Auria Emile , Deschamps Julien , Briandet Romain , Dupuy Bruno 
Published: January 2023

AbstractClostridioides difficileis the major cause of nosocomial diarrhea, which are associated with gut microbiome dysbiosis. Biofilms ofC. difficilehave been progressively linked to the pathogenesis of this bacterium and the recurrences of its infections. Though the number of conditions in whichC. difficilebiofilms are being produced is increasing, little is known about how and when biofilms are formed in the gut. Here we report that succinate, a metabolite abundantly produced by the dysbiotic gut microbiota, inducesin vitrobiofilm formation ofC. difficilestrains. We characterized the morphology and spatial composition of succinate-induced biofilms, and compared to non-induced or deoxycholate-induced biofilms, biofilms induced by succinate are significantly thicker, structurally more complex, and poorer in proteins and exopolysaccharides (EPS). We then applied transcriptomics and genetics to characterize the early stages of succinate-induced biofilm formation and we showed that succinate-induced biofilm results from major metabolic shifts and cell-wall composition changes. Similar to deoxycholate-induced biofilms, biofilms induced by succinate depend on the presence of a rapidly metabolized sugar. Finally, although succinate can be consumed by the bacteria, we found that the extracellular succinate is in fact responsible for the induction of biofilm formation through complex regulation involving global metabolic regulators and the osmotic stress response. In the context of human gut dysbiosis, succinate can limit bacterial infections through the control of innate immune responses. Collectively, our results suggest that succinate is an intestinal signal which can drive the biofilm formation and persistence ofC. difficilein the gut and increase the risk of relapse.
Regulation of replication origin licensing by ORC phosphorylation reveals a two-step mechanism for Mcm2-7 ring closing
Authors: Amasino Audra , Gupta Shalini , Friedman Larry J. , Gelles Jeff , Bell Stephen P 
Published: January 2023

AbstractEukaryotic DNA replication must occur exactly once per cell cycle to maintain cell ploidy. This outcome is ensured by temporally separating replicative helicase loading (G1 phase) and activation (S phase). In budding yeast, helicase loading is prevented outside of G1 by cyclin-dependent kinase (CDK) phosphorylation of three helicase-loading proteins: Cdc6, the Mcm2-7 helicase, and the origin recognition complex (ORC). CDK inhibition of Cdc6 and Mcm2-7 are well understood. Here we use single-molecule assays for multiple events during origin licensing to determine how CDK phosphorylation of ORC suppresses helicase loading. We find that phosphorylated ORC recruits a first Mcm2-7 to origins but prevents second Mcm2-7 recruitment. Phosphorylation of the Orc6, but not of the Orc2 subunit, increases the fraction of first Mcm2-7 recruitment events that are unsuccessful due to the rapid and simultaneous release of the helicase and its associated Cdt1 helicase-loading protein. Real-time monitoring of first Mcm2-7 ring closing reveals that either Orc2 or Orc6 phosphorylation prevents Mcm2-7 from stably encircling origin DNA. Consequently, we assessed formation of the MO complex, an intermediate that requires the closed-ring form of Mcm2-7. We found that ORC phosphorylation fully inhibits MO-complex formation and provide evidence that this event is required for stable closing of the first Mcm2-7. Our studies show that multiple steps of helicase loading are impacted by ORC phosphorylation and reveal that closing of the first Mcm2-7 ring is a two-step process started by Cdt1 release and completed by MO-complex formation.Significance StatementEach time a eukaryotic cell divides (by mitosis) it must duplicate its chromosomal DNA exactly once to ensure that one full copy is passed to each resulting cell. Both under-replication or over-replication result in genome instability and disease or cell death. A key mechanism to prevent over-replication is the temporal separation of loading of the replicative DNA helicase at origins of replication and activation of these same helicases during the cell division cycle. Here we define the mechanism by which phosphorylation of the primary DNA binding protein involved in these events inhibits helicase loading. Our studies identify multiple steps of inhibition and provide new insights into the mechanism of helicase loading in the uninhibited condition.
Analysis of the rate of growth of intellectual capital ability in predicting present and future profitability of Sharia commercial banks in Indonesia
Authors: Wahyuni Sri , Pujiharto Pujiharto , Pratama Bima Cinintya , Azizah Siti Nur 
Published: January 2023

PurposeThis research examines the growth of intellectual assets in Islamic banking (IB) in Indonesia and intellectual capital (IC) growth to predict Islamic commercial banks' (ICBs) current and future profitability.Design/methodology/approachThis research is a quantitative descriptive research, a study that emphasizes theory testing by measuring research variables with numbers that aim to test the hypothesis. The object of this research is sharia banking companies listed on the Indonesia Stock Exchange during 2014–2019. This study takes IB companies as an object because IB has its types of relatively different transactions from conventional banking or commercial banks.FindingsThe results show that the rate of growth of IC (ROGIC) for ICBs in Indonesia can predict the current year's financial performance but has not been able to predict the profitability of the future year.Originality/valueThis study examines the predictive value rate of IC return in predicting current and next three years’ earnings, which previous researchers have never done.
User perception on the utilisation of artificial intelligence for the management of records at the council for scientific and industrial research
Authors: Modiba Mashilo 
Published: January 2023

Purpose
This study aims to investigate the users’ perception on the utilisation of artificial intelligence (AI) for the management of records at the Council for Scientific and Industrial Research (CSIR) in South Africa. User perception plays a crucial role in the utilisation of AI for the management of records at the CSIR. It is important to know the views of the users, especially how they think AI can be used for effective and efficient management of records.

Design/methodology/approach
The convergent mixed methods research was applied, and data was collected using interviews and questionnaires. Data was analysed thematically and statistically and presented using tables and figures.

Findings
This study reveals that the users were not aware of the application of AI for the management of records until the workshops, which were facilitated by the researcher. The users are of the view that AI can be used to provide efficient storage of records, quick retrieval of records and adequate security. This study further reveals that the CSIR is not yet ready to use AI for the management of records because of the lack of knowledge and resources to implement AI.

Originality/value
This study also proposes a framework regarding the users’ perception on the utilisation of AI for the management of records at the CSIR. It is hoped that the framework proposed will serve as a benchmark and guideline for user perception regarding the use of AI for the management of records in the archives and records management industry.