bluuebunny/crossref_metadata_2025_split huggingface dataset:
The enzyme glutamate-cysteine ligase (GCL) is a target for ferroptosis induction in cancer
Authors: Eaton John K. , Chatterji Priya , Furst Laura , Basak Sneha , Patel Ayesha M. , Sweat Yan Y. , Cai Luke L. , Dave Krishna , Victorio Rachelle A. , Pizzi Elizabeth , Noorbakhsh Javad , Tian Gaochao , Roth Jennifer A. , Hynes John , Xing Gang , Wawer Mathias J. , Viswanathan Vasanthi S. 
Published: April 2024

AbstractDespite glutathione’s long-recognized role as a major cellular antioxidant and its central role in ferroptosis defense, inhibition of glutathione biosynthetic enzymes has received little attention as a target for the therapeutic induction of ferroptosis. Here, we report that small-molecule inhibition of glutamate–cysteine ligase (GCL), the rate-limiting enzyme of glutathione biosynthesis, selectively and potently kills cancer cells by ferroptosis. We further describe novel GCL inhibitors including KOJ-1 and KOJ-2, compounds with excellent cellular potency and pharmacological properties, representing valuable tools to study the biology of ferroptosis and glutathione.
Validation of ferroptosis in canine cancer cells to enable comparative oncology and translational medicine
Authors: Chatterji Priya , Xing Gang , Furst Laura , Dave Krishna , Zhou Qiong , LaBarbera Daniel V. , Thamm Douglas H. , Eaton John K. , Wawer Mathias J. , Viswanathan Vasanthi S. 
Published: April 2024

AbstractFerroptosis is a cell death mechanism that has attracted significant attention as a potential basis for the development of new cancer therapies. Validation of ferroptosis biology in species commonly used in translation and pre-clinical development is a necessary foundation for enabling the advancement of such ferroptosis modulating drugs. Here, we demonstrate that canine cancer cells exhibit sensitivity to a wide range of ferroptosis-inducing perturbations in a manner indistinguishable from human cancer cells, and recapitulate characteristic patterns of ferroptotic response across tumor types seen in the human setting. The foundation provided herein establishes the dog as a relevant efficacy and toxicology model for ferroptosis and creates new opportunities to leverage the canine comparative oncology paradigm to accelerate the development of ferroptosis-inducing drugs for human cancer patients.
Variant electrical activation and recovery in normal human hearts revealed by noninvasive electrocardiographic imaging
Authors: Stoks Job , Patel Kiran , van Rees Bianca , Nguyen Uyen Chau , Mihl Casper , Deissler Peter M , ter Bekke Rachel MA , Peeters Ralf , Vijgen Johan , Dendale Paul , Ng Fu , Cluitmans Matthijs JM , Volders Paul GA 
Published: April 2024

AbstractBackground and aimsAlthough electrical activity of the normal human heart is well-characterized by the 12-lead electrocardiogram, detailed insights into within-subject and between-subject variations of ventricular activation and recovery by noninvasive electroanatomic mapping are lacking. We characterized human epicardial activation and recovery within and between normal subjects using noninvasive electrocardiographic imaging (ECGI) as a basis to better understand pathology.MethodsEpicardial activation and recovery were assessed by ECGI in 22 normal subjects, 4 subjects with bundle branch block (BBB) and 4 with long-QT syndrome (LQTS). We compared characteristics between the ventricles (LV versus RV), sexes and age groups (<50y/≥50y (years)). Pearson’s correlation coefficient (CC) was used for within-subject and between- subject comparisons.ResultsAge of normal subjects averaged 49±14 years, 6/22 were male, and no structural/electrical heart disease was present. Average activation time was longer in LV than in RV, but not different by sex or age. Electrical recovery was similar for the ventricles, but started earlier and was on average shorter in males than females. Median CCs of between-subject comparisons of the ECG signals, activation and recovery patterns were 0.61, 0.32 and 0.19, respectively. Within-subject beat-to-beat comparisons yielded higher CCs (0.98, 0.89 and 0.82, respectively). Activation and/or recovery patterns of patients with BBB or LQTS contrasted significantly with those found in the normal population.ConclusionActivation and recovery patterns vary profoundly between normal subjects, but are stable individually beat to beat, with a male preponderance to shorter recovery. Individual characterization by ECGI at baseline serves as reference to better understand the emergence, progression and treatment of electrical heart disease.Graphical abstractCentral illustration.Application of electrocardiographic imaging (ECGI) in healthy controls allows to study normal epicardial activation and recovery patterns. Top: Although all subjects had a normal ECG, we found that their underlying activation time (AT) and recovery time (RT) patterns could be profoundly different. Still, beat-to-beat AT and RT patterns within one subject were relatively similar. Bottom: On a population level, we found that average right-ventricular (RV) AT was lower than left-ventricular (LV) AT, and both first and average RT were lower in males than in females.
The prognostic, predictive and clinicopathological impact of KRT81 / HNF1A- and GATA6- based transcriptional subtyping in pancreatic cancer
Authors: Guenther Michael , Surendran Sai Agash , Heinemann Volker , Haas Michael , Boeck Stefan , Ormanns Steffen 
Published: April 2024

ABSTRACTBACKGROUNDTranscriptional subtypes of pancreatic ductal adenocarcinoma (PDAC) have prognostic implications and potential predictive functions. This study aimed to determine their clinicopathological impact in large cohorts of advanced and resected PDAC and their evolution during disease progression.METHODSThe clinicopathological and prognostic implications of transcriptional subtypes determined by the expression of KRT81, HNF1A and GATA6 were examined using immunohistochemistry in advanced (n=139) and resected (n=411) PDAC samples as well as in 57 matched primary tumors and corresponding metastases. RNAseq data of 316 resected PDAC patients was analyzed for validation.RESULTSBoth subtyping systems were highly interrelated. Subtypes switched during disease progression in up to 31.6% of patients. Transcriptional subtyping had a modest prognostic impact in both unstratified cohorts, but strongly improved outcomes in patients with KRT81 positive / GATA6 negative tumors treated with palliative or adjuvant gemcitabine-based chemotherapy. RNAseq expression data confirmed the findings.CONCLUSIONSTranscriptional subtypes have differential responses on palliative and adjuvant gemcitabine- based chemotherapy, but they may change during disease progression. Both employed subtyping systems are equivalent and can be used to inform clinical therapy decisions.CLINICAL TRIAL REGISTRYThe clinical trial registry identifier isNCT00440167.
Derivation and Internal Validation of Prediction Models for Pulmonary Hypertension Risk Assessment in a Cohort Inhabiting Tibet, China
Authors: Tang Junhui , Yang Rui , Li Hui , Wei Xiaodong , Yang Zhen , Cai Wenbin , Jiang Yao , Zhuo Ga , Meng Li , Xu Yali 
Published: April 2024

AbstractBackgroundDue to exposure to hypoxic environments, individuals residing in plateau regions are susceptible to pulmonary hypertension (PH). Consequently, there is an urgent need for a simple and efficient nomogram to assess the risk of PH in this population.MethodsThis study included a total of 6,603 subjects, who were randomly divided into a validation set and a derivation set at a ratio of 7:3. Optimal predictive features were identified through the least absolute shrinkage and selection operator regression technique, and nomograms were constructed using multivariate logistic regression. The performance of these nomograms was evaluated and validated using the area under the curve (AUC), calibration curves, the Hosmer-Lemeshow test, and decision curve analysis. Comparisons between nomograms were conducted using the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices.ResultsNomogramIwas established based on independent risk factors, including gender, Tibetan ethnicity, age, incomplete right bundle branch block (IRBBB), atrial fibrillation (AF), sinus tachycardia (ST), and T wave changes (TC). The AUCs for NomogramIwere 0.716 in the derivation set and 0.718 in the validation set. NomogramIIwas established based on independent risk factors, including Tibetan ethnicity, age, right axis deviation (RAD), high voltage in the right ventricle (HVRV), IRBBB, AF, pulmonary P waves, ST, and TC. The AUCs for NomogramIIwere 0.844 in the derivation set and 0.801 in the validation set. Both nomograms demonstrated satisfactory clinical consistency. The IDI and NRI indices confirmed that NomogramIIoutperformed NomogramI. Therefore, the online dynamic NomogramIIwas established.ConclusionsA reliable and straightforward nomogram was developed to predict the risks of PH in the plateau population.
Incidence rate, risk factors and patient reported outcome in patients with a dislocation following hip hemiarthroplasty after acute femoral neck fracture; a scoping review
Authors: Närhi Susanne C. Faurholt , Rasmussen Louise I. E. Ø. , Overgaard Søren , Viberg Bjarke L. , Hermansen Lars L. 
Published: April 2024

AbstractObjectiveThe objective of this scoping review of the literature is to find the incidence rate and risk factors for dislocation of hip hemiarthroplasties (HAs) after acute femoral neck fractures (FNFs). Additionally we aim to determine the subjectively reported experience and/or Patient Reported Outcomes (PROs) minimum six months after a dislocation of a hip HA after acute FNF.IntroductionThe existing literature suggests a dislocation rate of 1 – 12%(1-8), and we aim to evaluate the dislocation rates reported in the literature, and explain the differences in the reportings. Some of the suggested risk factors ranging from surgical approach(1, 5, 6), cognitive impairment(2, 5-8), prosthesis type(4) and uncemented vs cemented implant(3). There are no studies summarizing all risk factors for dislocating the hip HA. The patient’s subjective experience after dislocation of a hip HA after acute FNF is not well known. The literature lacks direct information of the patients’ subjective experience after dislocation of the hip HA after acute FNF.Inclusion criteriaPublished articles on the incidence of patients with HA, who develop dislocation. Risk factors for dislocation and patient reported outcomes after reposition of dislocation. Register studies, clinical prospective studies and case-control studies will be included. The lower limit for inclusion of a risk factor will be minimum 5 studies that have minimum 10 patients with dislocation(s).MethodsThis scoping review will be conducted in accordance with the JBI methodology for scoping reviews(9). We will develop a full search strategy for Embase, MEDLINE, PubMed and Cochrane Library. Studies published in English, Swedish, Danish and Norwegian will be included. Studies with other languages will be considered if an appropriate translator is available. The three research questions will be analyzed separately and reported narratively. Despite this being a scoping review, we shall include some risk of bias elements in the analysis.
Location of phosphorylation sites within long polypeptide chains by binder-assisted nanopore detection
Authors: Lan Wei-Hsuan , He Hanxiao , Bayley Hagan , Qing Yujia 
Published: April 2024

AbstractThe detection and mapping of protein phosphorylation sites are essential for understanding the mechanisms of various cellular processes and for identifying targets for drug development. The study of biopolymers at the single-molecule level has been revolutionized by nanopore technology. In this study, we detect protein phosphorylation within long polypeptides (>600 amino acids), after the attachment of binders that interact with phosphate monoesters; electro-osmosis is used to drive the tagged chains through engineered protein nanopores. By monitoring the ionic current carried by a nanopore, phosphorylation sites are located within individual polypeptide chains, providing a valuable step toward nanopore proteomics.
A pervasive large conjugative plasmid mediates multispecies biofilm formation in the intestinal microbiota increasing resilience to perturbations
Authors: García-Bayona Leonor , Said Nathania , Coyne Michael J. , Flores Katia , Elmekki Nazik M. , Sheahan Madeline L. , Camacho Adriana Gutierrez , Hutt Kathryn , Yildiz Fitnat H. , Kovács Ákos T. , Waldor Matthew K. , Comstock Laurie E. 
Published: April 2024

SUMMARYAlthough horizontal gene transfer is pervasive in the intestinal microbiota, we understand only superficially the roles of most exchanged genes and how the mobile repertoire affects community dynamics. Similarly, little is known about the mechanisms underlying the ability of a community to recover after a perturbation. Here, we identified and functionally characterized a large conjugative plasmid that is one of the most frequently transferred elements among Bacteroidales species and is ubiquitous in diverse human populations. This plasmid encodes both an extracellular polysaccharide and fimbriae, which promote the formation of multispecies biofilms in the mammalian gut. We use a hybridization-based approach to visualize biofilms in clarified whole colon tissue with unprecedented 3D spatial resolution. These biofilms increase bacterial survival to common stressors encountered in the gut, increasing strain resiliency, and providing a rationale for the plasmid’s recent spread and high worldwide prevalence.
Fungi activate Toll-1 dependent immune evasion to induce cell loss in the host brain
Authors: Singh Deepanshu N.D. , Roberts Abigail R.E. , Moraga Enrique Quesada , Alliband David , Ballou Elizabeth , Tsai Hung-Ji , Hidalgo Alicia 
Published: April 2024

AbstractFungi evolve within the host, ensuring their own nutrition and reproduction, at the expense of host health. They intervene in hosts’ brain function, to alter host behaviour and induce neurodegeneration. In humans, fungal infections are emerging as drivers of neuroinflammation, neurodegenerative diseases and psychiatric disorders. However, how fungi alter the host brain is unknown. Fungi trigger an innate immune response mediated by the Toll-1/TLR receptor, the adaptor MyD88 and the transcription factor Dif/NFκB, that induce the expression of antimicrobial peptides (AMPs). However, in the nervous system, Toll-1/TLR could also drive an alternative pathway involving the adaptor Sarm, which causes cell death instead. Sarm is the universal inhibitor of MyD88 and could drive immune evasion. The entomopathogenic fungusBeauveria bassianais well-known to activate Toll-1 signalling in innate immunity inDrosophila. In fruit-flies, the adaptor Wek links Toll-1 to Sarm. Thus, here we asked whetherB. bassianacould damage theDrosophilabrain via Toll-1, Wek and Sarm. We show that exposure toB. bassianareduced fly lifespan and impaired locomotion.B. bassianaentered the brain and induced the up-regulation ofAMPs,as well aswekandsarm,within the brain. Exposure toB. bassianacaused neuronal and glial loss in the adultDrosophilabrain. Importantly, RNAi knockdown ofToll-1, wekorsarmconcomitantly with infection preventedB. bassianainduced cell loss. By contrast, over-expression ofwekorsarmwas sufficient to cause dopaminergic neuron loss in the absence of infection. These data show thatB. bassianacaused cell loss in the host brain via Toll-1/Wek/Sarm signalling driving immune evasion. We conclude that pathogens can benefit from an innate immunity receptor to damage the host brain. A similar activation of Sarm downstream of TLRs in response to fungal infections could underlie psychiatric and neurodegenerative diseases in humans.
Communication between DNA polymerases and Replication Protein A within the archaeal replisome
Authors: Martínez-Carranza Markel , Vialle Léa , Madru Clément , Cordier Florence , Tekpinar Ayten Dizkirici , Haouz Ahmed , Legrand Pierre , Le Meur Rémy A. , England Patrick , Dulermo Rémi , Iñaki Guijarro J. , Henneke Ghislaine , Sauguet Ludovic 
Published: April 2024

ABSTRACTReplication Protein A (RPA) plays a pivotal role in DNA replication by coating and protecting exposed single-stranded DNA, and acting as a molecular hub that recruits additional replication factors. We demonstrated that archaeal RPA hosts a winged-helix domain (WH) that interacts with two key actors of the replisome: the DNA primase (PriSL) and the replicative DNA polymerase (PolD). Using an integrative structural biology approach, combining nuclear magnetic resonance, X-ray crystallography and cryo-electron microscopy, we unveiled how RPA interacts with PriSL and PolD through two distinct surfaces of the WH domain: an evolutionarily conserved interface and a novel binding site. Finally, RPA was shown to stimulate the activity of PriSL in a WH-dependent manner. This study provides a molecular understanding of the WH-mediated regulatory activity in conserved central replication factors such as RPA, which regulate genome maintenance in Archaea and Eukaryotes.
Investigating NovelStreptomycesBacteriophage Endolysins as Potential Antimicrobial Agents
Authors: Maneekul Jindanuch , Chiaha Amanda , Hughes Rachel , Labry Faith , Saito Joshua , Almendares Matthew , Banda Brenda N. , Lopez Leslie , McGaskey Nyeomi , Miranda Melizza , Rana Jenil , Zadeh Brandon R. , Hughes Lee E. 
Published: April 2024

AbstractBackgroundAs antibiotic resistance has become a major global threat; the World Health Organization (WHO) has urgently called for alternative strategies for control of bacterial infections. Endolysin, a phage-encoded protein, can degrade bacterial peptidoglycan (PG) and disrupt bacterial growth. According to the WHO, there are only three endolysin products currently in clinical phase development. In this study we explore novel endolysins fromStreptomycesphages as only a few of them have been experimentally characterized. Using several bioinformatics tools, we identified nine different functional domain combinations from 250Streptomycesphages putative endolysins. LazerLemon gp35 (CHAP; LL35lys), Nabi gp26 (amidase; Nb26lys), and Tribute gp42 (PGRP/amidase; Tb42lys) were selected for experimental studies. We hypothesized that (1) the proteins of interest will have the ability to degrade purified PG, and (2) the proteins will have potential antimicrobial activity against bacteria from families of importance in antibiotic resistance, such as ESKAPE safe relatives (Enterococcus raffinosus, Staphylococcus epidermidis,Klebsiella aerogenes,Acinetobacter baylyi,Pseudomonas putida, andEscherichia coli).ResultsLL35lys, Nb26lys, and Tb42lys exhibit PG-degrading activity on zymography and hydrolysis assay. The enzymes (100 µg/mL) can reduce PG turbidity to 32-40%. The killing assay suggests that Tb42lys has a broader range (E. coli,P. putida,A. baylyiandK. aerogenes). While Nb26lys better attacks Gram-negative than Gram-positive bacteria, LL35lys can only reduce the growth of the Gram-positive ESKAPE strains but does so effectively with a low MIC90of 2 µg/mL. A higher concentration (≥300 µg/mL) of Nb26lys is needed to inhibitP. putidaandK. aerogenes.ConclusionFrom 250 putative endolysins, bioinformatic methods were used to select three putative endolysins for cloning and study: LL35lys, Nb26lys, and Tb42lys. All have shown PG-degrading activity, a critical function of endolysin. With a low MIC, LL35lys shows activity for the Gram-positive ESKAPE strains, while Nb26lys and Tb42lys are active against the Gram-negatives. Therefore, endolysins fromStreptomycesphage have potential as possible antimicrobial agents against ESKAPE bacteria.
Heat tolerance, oxidative stress response tuning, and robust gene activation in early-stageDrosophila melanogasterembryos
Authors: Mikucki Emily E. , O’Leary Thomas S. , Lockwood Brent L. 
Published: April 2024

ABSTRACTIn organisms with complex life cycles, life stages that are most susceptible to environmental stress may determine species persistence in the face of climate change. Early embryos ofDrosophila melanogasterare particularly sensitive to acute heat stress, yet tropical embryos have higher heat tolerance than temperate embryos, suggesting adaptive variation in embryonic heat tolerance. We compared transcriptomic responses to heat stress among tropical and temperate embryos to elucidate the gene regulatory basis of divergence in embryonic heat tolerance. The transcriptomes of tropical and temperate embryos were differentiated by the expression of relatively few genes, including genes involved in oxidative stress. But most of the transcriptomic response to heat stress was shared among all embryos. Further, embryos shifted the expression of thousands of genes and showed robust gene activation, demonstrating that, contrary to previous reports, early embryos are not transcriptionally silent. The involvement of oxidative stress genes in embryonic heat tolerance corroborates recent reports on the critical role of redox homeostasis in coordinating developmental transitions. By characterizing adaptive variation in the transcriptomic basis of embryonic heat tolerance, this study is a novel contribution to the literature on developmental physiology and genetics, which often lacks ecological and evolutionary context.
Evaluation of extraction solvents for untargeted metabolomics to decipher the dissolved organic matter of Antarctic cryoconite holes
Authors: Mundhe Swapnil , Maiti Saborni , Sanyal Aritri , Kadoo Narendra Y , Dhotre Dhiraj , Barvkar Vitthal T , Shaikh Shamim A. , Antony Runa , Paul Dhiraj 
Published: April 2024

AbstractCryoconite holes are biological hotspots with a high biogeochemical turnover rate, contributing significantly to the glacial ecosystem’s overall carbon cycles and net fluxes. Unfortunately, the information about the composition of low molecular weight molecules formed through the metabolic processes of cryoconite-dwelling microbes is scanty. These molecules constitute a substantial portion of the dissolved organic matter (DOM) within cryoconite holes. The present study investigated the composition of DOM in cryoconite holes using reverse-phase liquid chromatography (RP-LC) coupled with high-resolution tandem mass spectrometry. We evaluated various solvent combinations of water, methanol, and acetonitrile to extract chemically diverse polar and non-polar metabolites from the cryoconite holes. Among the single solvents, organic-rich MeOH: Water (70:30 v/v) and in parallel 2-single solvent combinations of MeOH: Water (70:30 v/v) and Acetonitrile: Methanol: Water (40:40:20 v/v) provided increased number and chemical diversity of extracted metabolites. Combining RP with the hydrophilic interaction liquid chromatography (HILIC) technique provided the highest number of unique metabolites. This dual-LC and ionization polarity combination increased the detection of metabolic features by 46.96% and 24.52% in single- and two-solvent combinations compared to RP alone. This study developed a simple untargeted metabolomics workflow that is highly sensitive and robust, detecting and potentially identifying a large number of chemically diverse molecules present in the DOM (extracellular) and microbes (intracellular) from the cryoconite holes environment. This method can better characterize DOM’s chemical composition and, after integrating with other ‘omics’ approaches, can be used to examine the link between metabolic pathways and microbial communities in global cryoconite holes or other similar ecosystems, revealing how these earthy systems and their microbial flora control carbon or nutrient storage or release in response to global climate change. Overall, the study presents a valuable methodology for studying the biogeochemistry of cryoconite holes.