bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATR safeguards replication forks against APOBEC3B-induced toxic PARP1 trapping
Authors: Ortega Pedro , Bournique Elodie , Li Junyi , Sanchez Ambrocio , Santiago Gisselle , Harris Brooke R. , Green Abby M. , Buisson Rémi 
Published: November 2024

ABSTRACTATR is the master safeguard of genomic integrity during DNA replication. Acute inhibition of ATR with ATR inhibitor (ATRi) triggers a surge in origin firing, leading to increased levels of single-stranded DNA (ssDNA) that rapidly deplete all available RPA. This leaves ssDNA unprotected and susceptible to breakage, a phenomenon known as replication catastrophe. However, the mechanism by which unprotected ssDNA breaks remains unclear. Here, we reveal that APOBEC3B is the key enzyme targeting unprotected ssDNA at replication forks, triggering a reaction cascade that induces fork collapse and PARP1 hyperactivation. Mechanistically, we demonstrate that uracils generated by APOBEC3B at replication forks are removed by UNG2, creating abasic sites that are subsequently cleaved by APE1 endonuclease. Moreover, we demonstrate that APE1-mediated DNA cleavage is the critical enzymatic step for PARP1 trapping and hyperactivation in cells, regardless of how abasic sites are generated on DNA. Finally, we show that APOBEC3B-induced toxic PARP1 trapping in response to ATRi drives cell sensitivity to ATR inhibition, creating to a context of synthetic lethality when combined with PARP inhibitors. Together, these findings reveal the mechanisms that cause replication forks to break during replication catastrophe and explain why ATRi-treated cells are particularly sensitive to PARP inhibitors.
TUDCA modulates drug bioavailability to regulate resistance to acute ER stress inSaccharomyces cerevisiae
Authors: Chadwick Sarah R. , Stack-Couture Samuel , Berg Matthew D. , Gregorio Sonja Di , Lung Bryan , Genereaux Julie , Moir Robyn D. , Brandl Christopher J. , Willis Ian M. , Snapp Erik L. , Lajoie Patrick 
Published: November 2024

AbstractCells counter accumulation of misfolded secretory proteins in the endoplasmic reticulum (ER) through activation of the Unfolded Protein Response (UPR). Small molecules termed chemical chaperones can promote protein folding to alleviate ER stress. The bile acid tauroursodeoxycholic acid (TUDCA), has been described as a chemical chaperone. While promising in models of protein folding diseases, TUDCA’s mechanism of action remains unclear. Here, we found TUDCA can rescue growth of yeast treated with the ER stressor tunicamycin (Tm), even in the absence of a functional UPR. In contrast, TUDCA failed to rescue growth on other ER stressors. Nor could TUDCA attenuate chronic UPR associated with specific gene deletions or over-expression of a misfolded mutant secretory protein. Neither pretreatment with or delayed addition of TUDCA conferred protection against Tm. Importantly, attenuation of Tm-induced toxicity required TUDCA’s critical micelle forming concentration, suggesting a mechanism where TUDCA directly sequesters drugs. Indeed, in several assays, TUDCA treated cells closely resembled cells treated with lower doses of Tm. In addition, we found TUDCA can inhibit dyes from labeling intracellular compartments. Thus, our study challenges the model of TUDCA as a chemical chaperone and suggests that TUDCA decreases drug bioavailability, allowing cells to adapt to ER stress.
miRBench: novel benchmark datasets for microRNA binding site prediction that mitigate against prevalent microRNA Frequency Class Bias
Authors: Sammut Stephanie , Gresova Katarina , Tzimotoudis Dimosthenis , Marsalkova Eva , Cechak David , Alexiou Panagiotis 
Published: November 2024

MotivationMicroRNAs (miRNAs) are crucial regulators of gene expression, but the precise mechanisms governing their binding to target sites remain unclear. A major contributing factor to this is the lack of unbiased experimental datasets for training accurate prediction models. While recent experimental advances have provided numerous miRNA-target interactions, these are solely positive interactions. Generating negative examplesin silicois challenging and prone to introducing biases, such as the miRNA frequency class bias identified in this work. Biases within datasets can compromise model generalization, leading models to learn dataset-specific artifacts rather than true biological patterns.ResultsWe introduce a novel methodology for negative sample generation that effectively mitigates the miRNA frequency class bias. Using this methodology, we curate several new, extensive datasets and benchmark several state-of-the-art methods on them. We find that a simple convolutional neural network model, retrained on some of these datasets, is able to outperform state-of-the-art methods. This highlights the potential for leveraging unbiased datasets to achieve improved performance in miRNA binding site prediction. To facilitate further research and lower the barrier to entry for machine learning researchers, we provide an easily accessible Python package, miRBench, for dataset retrieval, sequence encoding, and the execution of state-of-the-art models.AvailabilityThe miRBench Python Package is accessible athttps://github.com/katarinagresova/miRBench/releases/tag/v1.0.0
Loss of the predicted cell adhesion molecule MPZL3 promotes EMT and chemoresistance in ovarian cancer
Authors: Cheng Ya-Yun , Worley Beth L. , Javed Zaineb , Elhaw Amal T. , Tang Priscilla W. , Al-Saad Sarah , Kamlapurkar Shriya , White Sierra , Uboveja Apoorva , Mythreye Karthikeyan , Aird Katherine M. , Czyzyk Traci A. , Hempel Nadine 
Published: November 2024

AbstractMyelin protein zero-like 3 (MPZL3) is an Immunoglobulin-containing transmembrane protein with predicted cell adhesion molecule function. Loss of 11q23, where theMPZL3gene resides, is frequently observed in cancer, andMPZL3copy number alterations are frequently detected in tumor specimens. Yet the role and consequences of altered MPZL3 expression have not been explored in tumor development and progression. We addressed this in ovarian cancer, where both MPZL3 amplification and deletions are observed in respective subsets of high-grade serous specimens. While high and low MPZL3 expressing populations were similarly observed in primary ovarian tumors from an independent patient cohort, metastatic omental tumors largely displayed decreased MPZL3 expression, suggesting that MPZL3 loss is associated with metastatic progression. MPZL3 knock-down leads to strong upregulation of vimentin and an EMT gene signature that is associated with poor patient outcomes. Moreover, MPZL3 is necessary for homotypic cancer cell adhesion, and decreasing MPZL3 expression enhances invasion and clearance of mesothelial cell monolayers. In addition, MPZL3 loss abrogated cell cycle progression and proliferation. This was associated with increased resistance to Cisplatin and Olaparib and reduced DNA damage and apoptosis in response to these agents. Enhanced Cisplatin resistance was further validatedin vivo. These data demonstrate for the first time that MPZL3 acts as an adhesion molecule and that MPZL3 loss results in EMT, decreased proliferation, and drug resistance in ovarian cancer. Our study suggests that decreased MPZL3 expression is a phenotype of ovarian cancer tumor progression and metastasis and may contribute to treatment failure in advanced-stage patients.
Novel CRITR-seq approach reveals influenza transcription is modulated by NELF and is a key event precipitating an interferon response
Authors: Vicary Alison C. , Jordan Sydney N.Z. , Mendes Marisa , Swaminath Sharmada , Castro Lennice K. , Porter Justin S. , Russell Alistair B. 
Published: November 2024

SummaryTranscription of interferons upon viral infection is critical for cell-intrinsic innate immunity. This process is influenced by many host and viral factors. To identify host factors that modulate interferon induction within cells infected by influenza A virus, we developed CRISPR with Transcriptional Readout (CRITR-seq). CRITR-seq is a method linking CRISPR guide sequence to activity at a promoter of interest. Employing this method, we find that depletion of the Negative Elongation Factor complex increases both flu transcription and interferon expression. We find that the process of flu transcription, both in the presence and absence of viral replication, is a key contributor to interferon induction. Taken together, our findings highlight innate immune ligand concentration as a limiting factor in triggering an interferon response, identify NELF as an important interface with the flu life cycle, and validate CRITR-seq as a tool for genome-wide screens for phenotypes of gene expression.
CLUEY enables knowledge-guided clustering and cell type detection from single-cell omics data
Authors: Kim Daniel , Chen Carissa , Yu Lijia , Yang Jean Yee Hwa , Yang Pengyi 
Published: November 2024

AbstractClustering is a fundamental task in single-cell omics data analysis and can significantly impact downstream analyses and biological interpretations. The standard approach involves grouping cells based on their gene expression profiles, followed by annotating each cluster to a cell type using marker genes. However, the number of cell types detected by different clustering methods can vary substantially due to several factors, including the dimension reduction method used and the choice of parameters of the chosen clustering algorithm. These discrepancies can lead to subjective interpretations in downstream analyses, particularly in manual cell type annotation. To address these challenges, we propose CLUEY, a knowledge-guided framework for cell type detection and clustering of single-cell omics data. CLUEY integrates prior biological knowledge into the clustering process, providing guidance on the optimal number of clusters and enhancing the interpretability of results. We apply CLUEY to both unimodal (e.g. scRNA-seq, scATAC-seq) and multimodal datasets (e.g. CITE-seq, SHARE-seq) and demonstrate its effectiveness in providing biologically meaningful clustering outcomes. These results highlight CLUEY on providing the much-needed guidance in clustering analyses of single-cell omics data. CLUEY package is available fromhttps://github.com/SydneyBioX/CLUEY.
Chlamydiaplasmid-encoded protein Pgp2 is a replication initiator with a unique β-hairpin necessary for iteron-binding and plasmid replication
Authors: Wan Danny , Pan Matthew , Zhong Guangming , Fan Huizhou 
Published: November 2024

ABSTRACTThe virulence plasmid of the obligate intracellular bacteriumChlamydiaencodes eight proteins. Among these, Pgp3 is crucial for pathogenicity, and Pgp4 functions as a transcriptional regulator of both plasmid and chromosomal genes. The remaining proteins, Pgp1, Pgp5, Pgp6, Pgp7, and Pgp8, are predicted to play various roles in plasmid replication or maintenance based on their amino acid sequences. However, the function of Pgp2 remains unknown, even though it is required for transformation. In this study, we utilized AlphaFold to predict the 3-dimensional (3-D) structure ofC. trachomatisPgp2. Despite a lack of apparent sequence homology, the AlphaFold structure exhibited high similarity to experimentally determined structures of several plasmid replication initiators. Notably, Pgp2 features a unique β-hairpin motif near the DNA-binding domain, absent in other plasmid replication initiators with overall 3-D structures similar to Pgp2. This β-hairpin motif was also present in AlphaFold models of Pgp2s across all 13Chlamydiaspecies. To assess its significance, we engineered a plasmid lacking the 11 amino acids constituting the β-hairpin motif inC. trachomatisPgp2. Although this deletion did not alter the overall structure of Pgp2, the mutated plasmid failed to transform plasmid-freeC. trachomatis. These findings reveal that Pgp2 is a plasmid replication initiator, with the β-hairpin motif playing a critical role in binding to its cognate iteron sequences in the replication origin of the chlamydial plasmid.
High-resolution imaging atlas reveals context-dependent role of pancreatic sympathetic innervation in diabetic mice
Authors: Xu Qingqing , Chen Yuxin , Ni Xinyan , Zhuang Hanying , Cao Shenxi , Zhao Liwei , Wang Leying , Chen Jianhui , Yang Wen Z , Zeng Wenwen , Li Xi , Sun Hongbin , Shen Wei L 
Published: November 2024

AbstractGaining a better understanding of how sympathetic nerves impact pancreatic function is helpful for understanding diabetes. However, there is still uncertainty and controversy surrounding the roles of sympathetic nerves within the pancreas. To address this, we utilize high-resolution imaging and advanced three-dimensional (3D) reconstruction techniques to study the patterns of sympathetic innervation and morphology in islets of adult WT and diabetic mice. Our data shows that more than ∼30% α/β-cells are innervated by sympathetic nerves in both WT and diabetic mice. Also, sympathetic innervated α/β-cells are reduced in DIO mice, whereas sympathetic innervated β-cells are increased indb/dbmice. Besides, in situ chemical pancreatic sympathetic denervation (cPSD) improves glucose tolerance in WT anddb/dbmice, but decreases in DIO mice. In situ cPSD also enhances insulin sensitivity in diabetic mice without affecting WT mice. Overall, our findings advance our comprehension of diabetes by highlighting the distinctive impact of pancreatic sympathetic innervation on glucose regulation.HighlightsPancreatic sympathetic innervation plays an important role in glucose homeostasis. In our study, we systematically investigate sympathetic innervation in the islets of WT and diabetic mice.45.9% α-cells and 31.8% β-cells are innervated by sympathetic nerves in 10-week-old WT mice.Sympathetic innervated α/β-cells are reduced in DIO mice, whereas sympathetic innervated β-cells are increased indb/dbmice.Unlike the core-mantle structure observed in WT and DIO mice, α-cells and β-cells are intermixed indb/dbmice.Pancreatic sympathetic denervation elicits varied responses across diabetic models, where it improves glucose tolerance and insulin sensitivity indb/dbmice, yet it increases insulin sensitivity but reduces glucose tolerance in DIO mice.Graphical abstractSummary of morphological and physiological phenotypes in diabetic mice.All data are normalized to that of WT-10 mice. The numbers of “+” refer to their relative numbers. ↑ or ↓ refers to increase or decrease, ns refers to “not significant”. “−” refers to the experiment has not been carried out.
Agentic AI for Streamlining Title and Abstract Screening: Addressing Precision and evaluating calibration of AI guardrails
Authors: Disher T , Janoudi G , Rada M 
Published: November 2024

1.AbstractBackgroundTitle and abstract (TiAb) screening in systematic literature reviews (SLRs) is labor-intensive. While agentic artificial intelligence (AI) platforms like Loon Lens 1.0 offer automation, lower precision can necessitate increased full-text review. This study evaluated the calibration of Loon Lens 1.0’s confidence ratings to prioritize citations for human review.MethodsWe conducted a post-hoc analysis of citations included in a previous validation of Loon Lens 1.0. The data set consists of records screened by both Loon Lens 1.0 and human reviewers (gold standard). A logistic regression model predicted the probability of discrepancy between Loon Lens and human decisions, using Loon Lens confidence ratings (Low, Medium, High, Very High) as predictors. Model performance was assessed using bootstrapping with 1000 resamples, calculating optimism-corrected calibration, discrimination (C-index), and diagnostic metrics.ResultsLow and Medium confidence citations comprised 5.1% of the sample but accounted for 60.6% of errors. The logistic regression model demonstrated excellent discrimination (C-index = 0.86) and calibration, accurately reflecting observed error rates. “Low” confidence citations had a predicted probability of error of 0.65 (95% CI: 0.56-0.74), decreasing substantially with higher confidence: 0.38 (95% CI 0.28-0.49) for “Medium”, 0.05 (95% CI 0.04-0.07) for “High”, and 0.01 (95% CI 0.007-0.01) for “Very High”. Human review of “Low” and “Medium” confidence abstracts would lead to improved overall precision from 62.97% to 81.4% while maintaining high sensitivity (99.3%) and specificity (98.1%).ConclusionsLoon Lens 1.0’s confidence ratings show good calibration used as the basis for a model predicting the probability of making an error. Targeted human review significantly improves precision while preserving recall and specificity. This calibrated model offers a practical strategy for optimizing human-AI collaboration in TiAb screening, addressing the challenge of lower precision in automated approaches. Further research is needed to assess generalizability across diverse review contexts.
Cross-sectional and Longitudinal Relationship between Sex Hormones and Six Epigenetic Clocks in Older Adults: Results of the Berlin Aging Study II (BASE-II)
Authors: Schmid Hannah , Vetter Valentin Max , Homann Jan , Bahr Vivien , Lill Christina M. , Regitz-Zagrosek Vera , Bertram Lars , Demuth Ilja 
Published: November 2024

AbstractBackgroundBeyond their essential roles in regulating reproduction and development, sex hormones play a crucial role in the aging processes. Observational studies have indicated that low sex hormone concentrations in older age are associated with adverse health events. DNA methylation age acceleration (DNAmAA) estimated from epigenetic clocks quantifies differences in biological aging. DNAmAA was previously shown to be associated with age at menopause, ovariectomy, hormone replacement therapy and testosterone level.MethodsWe analysed the relationship between estradiol, dehydroepiandrosterone sulfate (DHEAS) and the Free Androgen Index (FAI) with DNAmAA estimators from six epigenetic clocks (Horvath’s, Hannum’s, 7-CpG clock, PhenoAge, GrimAge, DunedinPACE) in 1,404 participants of the Berlin Aging Study II (BASE-II, mean age at baseline 68.7 ±3.7 years, 48% women). The relationship was investigated in multiple linear regression models cross- sectionally at two time points and longitudinally over on average 7.3 years of follow-up.ResultsWe did not observe any consistent associations between the sex hormones and DNAmAA estimators investigated. However, we found several nominal associations (alpha=0.05) of unclear relevance. For instance, we identified an inverse association between DHEAS and Horvath’s DNAmAA, i.e. a reduced biological age with higher DHEAS levels in men at baseline. In women we found an inverse association between estradiol and DunedinPACE (baseline) and a positive association with GrimAge (follow-up). In longitudinal analyses, ΔDHEAS and ΔDunedinPACE were inversely associated in both sexes.ConclusionsOur results suggest that sex hormones play at best a minor role with respect to biological aging in the older population studied here.
Appraised evidence and decision making in clinical practice
Authors: Leliopoulou Chrysi , Stroumpouki Theodora , Stafylarakis Emmanouil , Collins Linda 
Published: November 2024

AbstractBackgroundThe use of evidence in decision making in clinical practice may vary significantly from practice to practice. Research suggests that clinicians may ignore research-based evidence in their practice or useresearchevidence indirectly. The aim of this systematic review is to explore using an online independent learning approach for clinicians making evidence-based decisions using research and evidence.MethodologyThis systematic literature review was conducted across MEDLINE, PUBMED, SCIENCE Direct, APA PSYCINFO and CINHAL databases. The use of a search strategy employed to conduct searches on the individual database. Using the MMAT criteria by Hong et al., 2018) studies were screened and reviewed.ResultsThe findings from each study were thematically analysed and organised in the following thematic areas: (1) Searching for an answer to the clinical question or problem; (2) Expanding on the evidence to address the clinical question or problem; (3) Recording the available evidence to the clinical problem; (4) Validating the evidence, whether research-based or tacit knowledge; (5) Inspecting the evidence for its potential to improve current practice; (6) Cascading the evidence appropriately and possibly adopting the evidence in the decision; and (7) Evaluating the outcome of the clinical decision.ConclusionsThis systematic literature review found there is a lack of an online independent learning approach for clinicians making evidence-based decision using research and evidence which highlights a gap in the literature.
Risk Communication and Public Health Emergency Responses during COVID - 19 Pandemic in Rural Communities in Kenya: A Cross-sectional Study
Authors: Cholo Wilberforce , Njororai Fletcher , Amulla Walter Ogutu , Nyaranga Caleb Kogutu 
Published: November 2024

AbstractBackgroundCOVID-19 pandemic highlighted the crucial role of community preventive behaviors in controlling the virus’s spread. Studies show that people’s risk perceptions and awareness significantly contribute to containment and prevention of infections. However, limited studies focused on the influence of risk communication on Public Health Emergency Responses during g the peak of the COVID-19 pandemic in Kenya. This study aimed at assessing the role of risk communication on Public Health Emergency Responses during COVID - 19 Pandemic during the COVID-19 pandemic rural communities in Kenya.MethodsA descriptive cross-sectional study was conducted using a quantitative research approach, collecting data from 806 individuals across Kisumu, Vihiga, and Kakamega counties. Descriptive statistics were used to detail the demographic characteristics of the study population, while logistic regression analysis estimated the associations between risk communication and demographic characteristics on COVID-19 vaccine acceptance, compliance with mitigation behaviors, perceived severity, and perceived susceptibility.ResultsThe results showed that 55% of participants were male, and 45% were female, with an average moderate compliance with safety measures (Mean = 5.15). A significant portion of participants wore face masks (85.3%), practiced hand hygiene (78.9%), and avoided close contact behaviors (66.6%). Most respondents received information through mass media (86.1%) and health workers (72.9%). Compliance with COVID-19 mitigation measures was highest among those who trusted information from official institutions, health professionals, and mass media, compared to social media, with increased odds of 2.7 times and 2.5 times, respectively. Higher risk perception was significantly associated with older age groups (above 50 years), being male, and working in the private sector. Risk communication significantly influenced risk perception, compliance with COVID-19 measures, and vaccination.ConclusionThe findings suggest that effective risk communication strategies are essential during public health emergencies hence implications for future public health crises. The results underscore the importance of targeted communication and tailored interventions to improve compliance and vaccine acceptance among different demographic groups, ensuring a more robust public health response during outbreaks.