bluuebunny/crossref_metadata_2025_split huggingface dataset:
British Oncology Pharmacy Association Delphi Consensus Guidelines: co-infusion of trometamol-containing calcium folinate (Leucovorin) with Systemic Anti-Cancer Treatments
Authors: Polwart Calum , Root Tim , Tezcan Songül , Meehan Sharon , Wetherill Bill , Waterson Chloë , Burnett Bruce , Chauhan Rena , Al-Modaris Ibrahim , Walters-Davies Rhiannon 
Published: February 2024

AbstractDrug stability and compatibility are critical factors influencing cost and logistics of treatment delivery, therapeutic effectiveness, and patient safety. This is particularly significant in the realm of cancer chemotherapeutics, where stability and compatibility studies play a vital role in ensuring rational and safe medicine administration. Oxaliplatin, fluorouracil, and irinotecan, commonly used in various combination for gastrointestinal cancers, are complemented by co-administration of folinic acid in certain protocols. Notably, some folinic acid preparations include trometamol as an excipient, potentially impacting the stability of the chemotherapeutic agentsif infused concomitantly. This study seeks to establish guidelines for oncology multidisciplinary teams, addressing potential risks associated with the combination of trometamol-containing folinic acid and chemotherapeutics. To achieve this, a quantitative questionnaire was distributed to members of the British Oncology Pharmacy Association (BOPA) and non-BOPA members through an online survey. Nineteen healthcare professionals with oncology experience, comprising 18 pharmacists and 1 nurse, completed the questionnaires. Each participant rated the validity and clarity of statements on a 5-point scale. The Delphi process concluded after the fourth round, consolidating the findings and recommendations from the multidisciplinary team. Twelve recommendations for safe practice have been made.
Clinical prediction model performance in differentiating septic arthritis from transient synovitis: A multi-center study
Authors: Qiu Xin , Deng Han-Sheng , Tang Gen , Su Yu-Xi , Chen Xiao-Liang , Liu Yao-Xi , Li Jing-Chun , Wu Xin-Wu , Guo Jia-Chao , Jiang Fei , Su Qi-Ru , Tang Sheng-Ping , Xiong Zhu ,   Chinese Multi-center Pediatric Orthopedic Study Group (CMPOS)
Published: February 2024

AbstractObjectiveDifferentiating septic arthritis from transient synovitis in children is challenging. This study aimed to determine the diagnostic value for distinguishing these two conditions and to develop an effective clinical prediction model based on multi-center clinical data.MethodsWe retrospectively analyzed data of children aged under 18 years who were hospitalized in eight specialized children’s hospitals in China from 2013 to 2021. To ensure the prediction model’s reliability, we established three clinical prediction models.ResultsThis study collected data of 819 children from 8 tertiary children’s hospitals, including 265 patients with septic arthritis and 554 patients with transient synovitis.We established three clinical prediction models. For septic hip arthritis, a retrospective study based on six clinical predictors was a history of prodromal respiratory tract infection (HRTI), temperature>37.5 °C, ESR>20 mm/h, CRP>10 mg/L, red blood cell distribution width (RDW)>50%, and WBC>11×109 /L. When these six factors were present, the probability of septic hip arthritis was 99.99%.For septic knee arthritis, a retrospective study based on three clinical predictors, the predictors were ESR>20 mm/h, CRP>10 mg/L, and absolute monocyte count (AMONO)>0.74×109/L. When these three factors were present, the probability of having septic knee arthritis was 94.68%. For septic arthritis (septic hip arthritis or septic knee arthritis), a retrospective study based on six clinical predictors, the predictors were male children, history of HRTI), temperature>37.5 °C, ESR>20 mm/hr, PC > 407 × 109/L and CRP>10 mg/L. When these six factors were present, the probability of septic arthritis was 99.65%.ConclusionThis study used multi-center clinical data to construct a new clinical prediction model for children with septic arthritis. In addition we identified new clinical predictors such as sex, history of HRTI, RDW, PC and AMONO.Translational potentialA clinical prediction model, built on multi-center data, is capable of effectively making high-precision predictions for septic arthritis. Furthermore, based on the microbial characteristics of septic arthritis in children, we aim to develop diagnostic kits that can accurately and quickly detect infections caused by pathogens such as bacteria.
Improving research transparency with individualized report cards: A feasibility study in clinical trials at a large university medical center
Authors: Franzen Delwen L. , Salholz-Hillel Maia , Müller-Ohlraun Stephanie , Strech Daniel 
Published: February 2024

ABSTRACTResearch transparency is crucial for ensuring the relevance, integrity, and reliability of scientific findings. However, previous work indicates room for improvement across transparency practices. The primary objective of this study was to develop an extensible tool to provide individualized feedback and guidance for improved transparency across phases of a study. Our secondary objective was to assess the feasibility of implementing this tool to improve transparency in clinical trials.We developed study-level “report cards” that combine tailored feedback and guidance to investigators across several transparency practices, including prospective registration, availability of summary results, and open access publication. The report cards were generated through an automated pipeline for scalability. We also developed an infosheet to summarize relevant laws, guidelines, and resources relating to transparency. To assess the feasibility of using these tools to improve transparency, we conducted a single-arm intervention study at Berlin’s university medical center, the Charité – Universitätsmedizin Berlin. Investigators (n = 92) of 155 clinical trials were sent individualized report cards and the infosheet, and surveyed to assess their perceived usefulness. We also evaluated included trials for improvements in transparency following the intervention.Survey responses indicated general appreciation for the report cards and infosheet, with a majority of participants finding them helpful to build awareness of the transparency of their trial and transparency requirements. However, improvement on transparency practices was minimal and largely limited to linking publications in registries. Investigators also commented on various challenges associated with implementing transparency, including a lack of clarity around best practices and institutional hurdles.This study demonstrates the potential of developing and using tools, such as report cards, to provide individualized feedback at scale to investigators on the transparency of their study. While these tools were positively received by investigators, the limited improvement in transparency practices suggests that awareness alone is likely not sufficient to drive improvement. Future research and implementation efforts may adapt the tools to further practices or research areas, and explore integrated approaches that combine the report cards with incentives and institutional support to effectively strengthen transparency in research.
Caregiver ECHO: A Model for Delivering Virtual Behavior Management Education to Families of Children with Developmental Disabilities
Authors: Nevill Rose E. , Lovette Gail E. , Bateman Katherine J. , Badgett Natalie M. , Lyons Genevieve R. , Fuhrmann Emily C. , Bohac Genevieve E. , Orlando Karen G. , Page Keith D. 
Published: February 2024

AbstractChildren with developmental disabilities are at high risk of challenging behavior, yet their families experience consistent barriers to affordable parent education in behavior management. The present study tested the efficacy of a caregiver-focused Extensions of Community Health Outcomes program for delivering virtual parent education and support to familial caregivers of children with DD in behavior management. A pre-post quasi-experimental design was used to evaluate the effect of Caregiver ECHO on caregiver participants’ (n = 30) knowledge of behavior modification strategies, self-efficacy in managing challenging behavior, empowerment, and negative emotional reactions to challenging behavior. Participating in Caregiver ECHO resulted in significant increases in caregiver knowledge, self-efficacy, and empowerment, and significant reductions in certain negative emotional reactions to challenging behavior. The Caregiver ECHO model offers advantages over other parent education programs in that it emphasizes peer learning, active problem-solving, and community building as core components of its approach while using low-cost methodologies.
Macrolactin A Is an Inhibitor of Protein Biosynthesis in Bacteria
Authors: Vasilchenko Alexey S. , Lukyanov Dmitry A. , Dilbaryan Diana S. , Usachev Konstantin S. , Poshvina Darya V. , Nikandrova Arina A. , Imamutdinova Arina N. , Garaeva Natalia S. , Bikmullin Aydar G. , Klochkova Evelina A. , Taldaev Amir , Rusanov Alexander L. , Romashin Daniil D. , Luzgina Natalia G. , Osterman Ilya A. , Sergiev Petr V. , Teslya Anastasia V. 
Published: February 2024

ABSTRACTThe macrolide antibiotic, macrolactin A (McA), has been known for its antimicrobial properties since the late 1980s, but the mechanism of its antibacterial activity is still unknown. In this study, we investigated the microbiological and molecular characteristics of McA antimicrobial activity. McA effect on bacteria was found to be both bacteriostatic and bactericidal, depending on species and strains. Regarding the mechanism of action of McA, the following important results were obtained: 1) usingin vivoandin vitrosystems, we showed that McA is an inhibitor of protein synthesis in bacteria; 2) the concentration of McA required to inhibit protein synthesis in theE. colicell-free model was found to be 50 times lower than the concentration required in theS. aureuscell-free model; 3) the toe-printing assay revealed that McA inhibits the first step of elongation stage of protein synthesis; 4) we identified single and multiple nucleotide polymorphisms in the gene encoding the translation elongation factor Tu (EF-Tu) by annotating the genomes of McA-resistantBacillus pumilusMcARand its parental strain. Molecular modeling showed that the McA molecule can form non-covalent bonds with amino acids at the interface of domains 1 and 2 of EF-Tu, characterized by a relatively high docking score. Overall, our study demonstrated that McA acts as an elfamycin-like antibiotic (targeting EF-Tu), addressing a substantial gap in our understanding of the mechanism of action of macrolactin A, a representative member of macrolides.
A genome wide CRISPR/Cas9 screen identifies calreticulin as a selective repressor of ATF6α
Authors: Tung Joanne , Huang Lei , George Ginto , Harding Heather P. , Ron David , Ordóñez Adriana 
Published: February 2024

AbstractActivating transcription factor 6 (ATF6) is one of three endoplasmic reticulum (ER) transmembrane stress sensors that mediate the unfolded protein response (UPR). Despite its crucial role in long-term ER stress adaptation, regulation of ATF6 alpha (α) signalling remains poorly understood, possibly because its activation involves ER-to-Golgi and nuclear trafficking. Here, we generated an ATF6α/IRE1 dual UPR reporter CHO-K1 cell line and performed an unbiased genome-wide CRISPR/Cas9 mutagenesis screen to systematically profile genetic factors that specifically contribute to ATF6α signalling in the presence and absence of ER stress. The screen identified both anticipated and new candidate genes that regulate ATF6α activation. Among these, calreticulin (CRT), a key ER luminal chaperone, selectively repressed ATF6α signalling: Cells lacking CRT constitutively activated a BiP::sfGFP ATF6α-dependent reporter, had higher BiP levels and an increased rate of trafficking and processing of ATF6α. Purified CRT interacted with the luminal domain of ATF6αin vitroand the two proteins co-immunoprecipitated from cell lysates. CRT depletion exposed a negative feedback loop implicating ATF6α in repressing IRE1 activity basally and overexpression of CRT reversed this repression. Our findings indicate that CRT, beyond its known role as a chaperone, also serves as an ER repressor of ATF6α to selectively regulate one arm of the UPR.
Critical Differential Expression Assessment for Individual Bulk RNA-Seq Projects
Authors: Warden Charles D. , Wu Xiwei 
Published: February 2024

AbstractFinding the right balance of quality and quantity can be important, and it is essential that project quality does not drop below the level where important main conclusions are missed or misstated. We use knock-out and over-expression studies as a simplification to test recovery of a known causal gene in RNA-Seq cell line experiments. When single-end RNA-Seq reads are aligned with STAR and quantified with htseq-count, we found potential value in testing the use of the Generalized Linear Model (GLM) implementation of edgeR with robust dispersion estimation more frequently for either single-variate or multi-variate 2-group comparisons (with the possibility of defining criteria less stringent than |fold-change| > 1.5 and FDR < 0.05). When considering a limited number of patient sample comparisons with larger sample size, there might be some decreased variability between methods (except for DESeq1). However, at the same time, the ranking of the gene identified using immunohistochemistry (for ER/PR/HER2 in breast cancer samples from The Cancer Genome Atlas) showed as possible shift in performance compared to the cell line comparisons, potentially highlighting utility for standard statistical tests and/or limma-based analysis with larger sample sizes. If this continues to be true in additional studies and comparisons, then that could be consistent with the possibility that it may be important to allocate time for potential methods troubleshooting for genomics projects.Analysis of public data presented in this study does not consider all experimental designs, and presentation of downstream analysis is limited. So, any estimate from this simplification would be an underestimation of the true need for some methods testing for every project. Additionally, this set of independent cell line experiments has a limitation in being able to determine the frequency of missing a highly important gene if the problem is rare (such as 10% or lower). For example, if there was an assumption that only one method can be tested for “initial” analysis, then it is not completely clear to the extent that using edgeR-robust might perform better than DESeq2 in the cell line experiments.Importantly, we do not wish to cause undue concern, and we believe that it should often be possible to define a gene expression differential expression workflow that is suitable for some purposes for many samples. Nevertheless, at the same time, we provide a variety of measures that we believe emphasize the need to critically assess every individual project and maximize confidence in published results.
Extracellular disposal of nuclear waste by APP: a protective mechanism impaired in Alzheimer’s disease
Authors: Dougnon Godfried , Otsuka Takayoshi , Nakamura Yuka , Sakai Akiko , Yamanaka Tomoyuki , Matsui Noriko , Nakahara Asa , Ito Ai , Hatano Atsushi , Matsumoto Masaki , Igarashi Hironaka , Kakita Akiyoshi , Ueno Masaki , Matsui Hideaki 
Published: February 2024

AbstractAlthough the amyloid beta (Aβ) hypothesis1has long been central to Alzheimer’s disease (AD) research, effective therapeutic strategies remain elusive2,3. Here we re-evaluate the functions of amyloid precursor protein (APP) and reveal its critical function in protecting against nuclear impairment-induced cell death and inflammation4,5. Overexpression of APP mitigated etoposide or lamin A knockdown-induced nuclear damage, while APP removal or mutations exacerbated these effects. Interestingly, neurons differentiated from induced pluripotent stem cells (iPSCs) exhibited similar patterns, and notably, familial AD-associated mutant APP failed to confer protection against nuclear impairment. We identify APP’s interaction with a cytoplasmic structure of nuclear origin, termed “nuclear waste”, and propose its role in extracellular waste disposal. Intriguingly, cells lacking APP showed impaired nuclear waste clearance, leading to abnormal cytoplasmic accumulation of the nuclear waste. Similarly, neuron-specific APP overexpression using adeno-associated virus (AAV) in mice reduced neuronal death and inflammation caused by nuclear damage. Conversely, shRNA-mediated APP exacerbated these effects, and mutant APP associated with familial AD lacked protective effects. Moreover, postmortem analysis of AD brains revealed accumulation of abnormal nuclear waste in the neurocytoplasm, irregular nuclear morphology, and reduced APP levels per neuron. Our data underscore APP’s crucial role in disposing of nuclear waste, maintaining cellular homeostasis, and suggest its dysregulation as a potential contributor to AD pathogenesis. Restoring APP waste clearance in AD could be a promising target for disease-modifying therapies.
Conformational basis of subtype-specific allosteric control of NMDA receptor gating
Authors: Bleier Julia , Ribeiro Furtado de Mendonca Philipe , Habrian Chris , Stanley Cherise , Vyklicky Vojtech , Isacoff Ehud Y. 
Published: February 2024

SummaryN-methyl-D-aspartate receptors are ionotropic glutamate receptors that are integral to synaptic transmission and plasticity. Variable GluN2 subunits in diheterotetrameric receptors with identical GluN1 subunits set very different functional properties, which support their individual physiological roles in the nervous system. To understand the conformational basis of this diversity, we assessed the conformation of the common GluN1 subunit in receptors with different GluN2 subunits using single-molecule fluorescence resonance energy transfer (smFRET). We established smFRET sensors in the ligand binding domain and modulatory amino-terminal domain to study an apo-like state and partially liganded activation intermediates, which have been elusive to structural analysis. Our results demonstrate a strong, subtype- specific influence of apo and glutamate-bound GluN2 subunits on GluN1 rearrangements, suggesting a conformational basis for the highly divergent levels of receptor activity, desensitization and agonist potency. Chimeric analysis reveals structural determinants that contribute to the subtype differences. Our study provides a framework for understanding GluN2-dependent functional properties and could open new avenues for subtype-specific modulation.
Aligning with the predecessors and counterarguments: A systematic review of the anatomical correlates for the newly discovered meningeal layer in the existing literature
Authors: Kumar Ashutosh , Kumar Rajesh , Narayan Ravi K. , Nath Banshi , Datusalia Ashok K. , Rastogi Ashok K. , Jha Rakesh K. , Kumar Pankaj , Pareek Vikas , Prasoon Pranav , Faiq Muneeb A. , Agrawal Prabhat , Prasad Surya Nandan , Kumari Chiman , Asghar Adil 
Published: February 2024

AbstractA recent study reported the existence of a subarachnoid lymphatic-like membrane (SLYM) –an intermediate leptomeningeal layer between the arachnoid and pia mater in mice and human brains – dividing the subarachnoid space (SAS) into two functional compartments. Despite being a macroscopic structure, how it missed detection in previous studies is surprising. We systematically reviewed the published reports in animals and humans to explore whether prior descriptions of this meningeal layer have existed. An electronic search was conducted in PubMed/Medline, EMBASE, Google Scholar, Science Direct, and Web of Science databases using combinations of MeSH terms and keywords with Boolean operators from inception until 31stDec 2023. We found at least eight studies that provided structural evidence of an intermediate leptomeningeal layer in the brain or spinal cord. However, unequivocal descriptions for this layer all along the central nervous system were scarce. Obscured names were used to describe it, i.e., the epipial layer, intermediate meningeal layer, intermediate lamella, and outer pial layer. Its microscopic/ultrastructural details closely resembled the SLYM. Further, we examined the counterarguments in current literature that are skeptical of this layer’s existence. Considering the significant physiological/clinical implications, exploring further structural and functional details of the new meningeal layer is a need of the hour.
Zebrafish reveal new roles for Fam83f in hatching and the DNA damage-mediated autophagic response
Authors: Jones Rebecca A. , Cooper Fay , Kelly Gavin , Barry David , Renshaw Matthew J. , Sapkota Gopal , Smith James C. 
Published: February 2024

AbstractThe FAM83 (Family with sequence similarity83) family is highly conserved in vertebrates, but little is known of the functions of these proteins beyond their association with oncogenesis. Of the family, FAM83F is of particular interest because it is the only membrane-targeted FAM83 protein. When over-expressed, FAM83F activates the canonical Wnt signalling pathway and binds to and stabilizes p53; it therefore interacts with two pathways often dysregulated in disease. Insights into gene function can often be gained by studying the roles they play during development, and here we report the generation offam83fknock-out (KO) zebrafish, which we have used to study the role of Fam83f in vivo. We show that endogenousfam83fis most strongly expressed in the hatching gland of developing zebrafish embryos, and thatfam83fKO embryos hatch earlier than their wild-type (WT) counterparts, despite developing at a comparable rate. We also demonstrate thatfam83fKO embryos are more sensitive to ionizing radiation than WT embryos—an unexpected finding, bearing in mind the previously-reported ability of FAM83F to stabilize p53. Transcriptomic analysis shows that loss offam83fleads to downregulation of phosphatidylinositol-3-phosphate (PI(3)P) binding proteins and impairment of cellular degradation pathways, particularly autophagy, a crucial component of the DNA damage response. Finally, we show that Fam83f protein is itself targeted to the lysosome when over-expressed in HEK293T cells, and that this localization is dependent upon a C’ terminal signal sequence. The zebrafish lines we have generated suggest that Fam83f plays an important role in autophagic/lysosomal processes, resulting in dysregulated hatching and increased sensitivity to genotoxic stress in vivo.