bluuebunny/crossref_metadata_2025 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

ATR 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

Cells 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

Motivation

MicroRNAs (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.

Results

We 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.

Availability

The 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

Myelin 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

Transcription 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

Clustering 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

The 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

Gaining 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.

Highlights

Pancreatic 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 abstract

Summary 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.

Background

Title 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.

Methods

We 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.

Results

Low 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%).

Conclusions

Loon 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

Background

Beyond 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.

Methods

We 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.

Results

We 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.

Conclusions

Our 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

Background

The 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.

Methodology

This 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.

Results

The 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.

Conclusions

This 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

Background

COVID-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.

Methods

A 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.

Results

The 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.

Conclusion

The 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.
Sleep disorders as risk factors for calcific aortic stenosis
Authors: El Jamal Nadim , Brooks Thomas G. , Skarke Carsten , FitzGerald Garret A.
Published: November 2024

Background

Circadian disruption and sleep disorders have been shown to increase the risk for many cardiovascular diseases. Their association specifically with valvular heart disease, however, is inconclusive.

Methods

We leveraged large electronic health record datasets (the TriNetX network and the AllofUs study) to test whether sleep disorders are a risk factor for calcific aortic stenosis (AS). We fitted Cox proportional hazards models to quantify the risk of future incidence of AS in patients with sleep disorders. We also explored clinical laboratory test datasets for biochemical signals that might explain the association, running mediation analyses.

Results

In our fully adjusted Cox models, we find that having any sleep disorder increases the risk for the future incidence of AS (HR: 1.15 95% CI: 1.13-1.18). Changes in lipid profile mediate a proportion of that association.

Conclusion

Sleep disorders are associated with an increased risk of AS incidence. That association is independent of classical cardiovascular risk factors even though dyslipidemia plays a large role in mediating this risk.
Monogenic Parkinson’s Disease and the Impact ofAPOEE4: A Case-Control Study
Authors: Kmiecik Matthew J. , Holmes Michael V. , Fontanillas Pierre , Riboldi Giulietta M. , Schneider Ruth B. , Shi Jingchunzi , Guan Anna , Tat Susana , Stagaman Keaton , Gottesman Josh , Hinds David A. , Tung Joyce Y. ,   23andMe Research Team, Aslibekyan Stella , Norcliffe-Kaufmann Lucy
Published: November 2024

Importance

The lack of information on progression, phenoconversion, and risk of dementia in a large genotyped sample impedes reliable enrichment for early interventional trials in Parkinson’s disease (PD).

Objective

To investigate PD penetrance, risk, motor/non-motor phenotypes, andAPOEallele effects inLRRK2G2019S andGBAN370S carriers.

Design

Observational longitudinal case-control self-report survey study.

Setting

A US population-based study cohort enrolled in the 23andMe, Inc. and Fox Insight Genetic Substudy (FIGS) databases.

Participants

The total cohort included 7,586,842 participants (n=35,163 PD; 27% of PD cases from FIGS); 8,791LRRK2G2019S carriers (565 with PD), 37,427GBAN370S carriers (524 with PD), 244 dual carriers (37 with PD), and 7.5 million non-carriers (34,037 with PD).

Exposure(s)

LRRK2G2019S,GBAN370S,APOEE2/E3/E4 alleles and PD polygenic risk scores (PRS).

Main Outcome(s) and Measure(s)

Cumulative incidence of PD was estimated using Kaplan-Meier and accelerated failure time models. Relative odds of developing motor and non-motor symptoms were calculated using logistic regression models according to genetic exposure. Impact of theAPOEalleles was estimated in a dose-dependent analysis.

Results

By the age of 80 years, the cumulative incidence of PD was 43% for dual carriers, 32% forLRRK2G2019S carriers, 6% forGBAN370S carriers, and 3% for non-carriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis. Motor symptoms were similar inLRRK2G2019S,GBAN370S, and non-carriers with PD.GBAN370S PD was associated with the highest burden of non-motor symptoms, including REM sleep behavior disorder and cognitive/memory deficits, andLRRK2G2019S the lowest.APOEE4 dosage was associated with greater odds of developing hallucinations and cognitive decline in addition to carrier status.

Conclusions and Relevance

Our findings support the use of genetic screening—includingLRRK2G2019S,GBAN370S,APOEE4, and PRS—to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetic risk factors.
Study on the Intervention of α-Lipoic Acid in Patients with Type 2 Diabetes Mellitus after CAG or PCI Compared with Contrast-Induced Nephropathy
Authors: Wu Aijie , Li Chunyao , Wang Pingping , Shi Wenlu , Zhu Jiaojiao , Zhang Zhengjun , Chen Dapeng , Zhang Ting
Published: November 2024

Objective

To investigate the effect of α-lipoic acid on contrast-induced nephropathy (CIN) in diabetic patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI).

Methods

Patients diagnosed with type 2 diabetes mellitus and coronary heart disease scheduled for CAG or PCI treatment at the Department of Cardiovascular Medicine, General Hospital of Ningxia Medical University from February 1, 2021, to August 30, 2023, were recruited. After obtaining informed consent, patients were allocated into three groups: α-lipoic acid group (38 cases), adequate hydration group (60 cases), and routine hydration group (104 cases).The primary outcome observed was the incidence of CIN, and secondary endpoints included changes in SCr, TBiL, and GGT 72 hours after contrast agent administration.

Results

The incidence of CIN in the α-lipoic acid group was 2.63% (1/38), 1.67% (1/60) in the adequate hydration group, and 4.81% (5/104) in the routine hydration group, with no statistically significant difference among the three groups (p=0.544). After PCI or CAG, SCr levels decreased slightly more in the α-lipoic acid group compared to the adequate hydration group, while the routine hydration group showed an increase, but the differences were not statistically significant (p> 0.05).

Conclusion

α-Lipoic acid has a certain improvement effect on renal function indicators (Scr) after CAG or PCI, but it did not demonstrate a significant preventive effect on CIN. Adequate hydration showed greater reduction in oxidative stress damage after CAG or PCI compared to α-lipoic acid and routine hydration.
Inflammation-associated monocytes express ACOD1 to curtail inflammatory behaviour in IBD and experimental colitis
Authors: Jones Gareth-Rhys , Drury Broc , Alegbe Tobi , Krzak Monika , Hegarty Lizi M , Raine Tim , Bryne Adam , Anderson Carl A , Ho Gwo-Tzer , Bain Calum C
Published: November 2024

Monocytes are essential for replenishing homeostatic macrophages in the intestine. However, they also accumulate in significant numbers when intestinal homeostasis is disrupted in diseases, such as inflammatory bowel disease (IBD). The molecular pathways governing monocyte behaviour across these different contexts remain poorly understood. Here, we profile the monocyte / macrophage compartment in human IBD using single-cell RNA sequencing and identify a discrete population of monocytes that accumulate in IBD, which we term inflammation associated monocytes (IAMs). These can be identified by the expression of CD319, CD274 and CCRL2, and demonstrate increased expression of IBD susceptibility genes. By performing cross-species analysis, we show an analogous population of IAMs accumulate during chemically induced colitis in mice. Using transgenic fate mapping approaches, we show these cells likely derive from a discrete precursor in the bone marrow (BM) and are locally imprinted to produce heightened IL-1β and TNF in mouse and humans. Importantly, we show that co-incident with a hyper-inflammatory phenotype, these same cells uniquely and specifically express aconitate decarboxylase (ACOD1) in response to local Toll-like receptor (TLR) and interferon (IFN) receptor signalling, to limit unrestricted cytokine production. Thus, the intestinal environment after injury instructs both inflammation and recovery specifically within a transitioning population of monocytes that are absent in health.
Dynamic change of calcium-rich compartments during coccolithophore biomineralization
Authors: Triccas Alexander , Chevrier Daniel M. , Verezhak Mariana , Ihli Johannes , Guizar-Sicairos Manuel , Holler Mirko , Scheffel Andre , Ozaki Noriaki , Chamard Virginie , Wood Rachel , Grünewald Tilman , Nudelman Fabio
Published: November 2024

Coccolithophores are abundant marine phytoplankton that produce biomineralized calcite scales, called coccoliths, which sequester substantial amounts of carbon and play a significant role in biogeochemical cycles. However, mechanisms underlying the storage and transport of ions essential for calcification remain unresolved. We used ptychographic X-ray computed tomography under cryogenic conditions to visualize intracellular calcium-rich structures involved in the storage of calcium ions in the coccolithophore speciesChrysotila carterae. During calcification, we observed a range of structures, from small electron-dense bodies within larger compartments, to denser and distributed globular compartments, before returning to small bodies once scale formation is complete. Nanobeam-scanning X-ray fluorescence measurements further revealed these electron-dense bodies are rich in P and Ca (molar ratio of ∼4:1). We infer from the dynamic nature of structures that these bodies are part of required cellular calcium ion transport pathways, a fundamental process critical for understanding the response of coccolithophores to climate change.
Pro-inflammatory Pathways Contribute to Pathogenesis ofClostridioides difficileInfection in a Murine Model - A Spatial Transcriptomics Study
Authors: Ghahari Niloufar , AbdelKhalek Ahmed , Narayanan Sanjeev , Pillai Deepti
Published: November 2024

Clostridioides difficile(C. difficile) is a common cause of antibiotic-induced diarrhea and causes the highest number of nosocomial infections. Only two antibiotics are currently recommended for treatingC. difficileinfection (CDI), which may contribute to unsatisfactory treatment outcomes and an increased likelihood of recurrence.Clostridioides difficileexists as a non-pathogenic member of the human intestinal microbiome in 10-20% of the population, a phenomenon observed in mouse models after infection with bacterial spores. In this study, we aim to evaluate the difference in gene expression between symptomatic and asymptomatic mice after infection withC. difficileusing spatial transcriptomics analysis. We also aim to evaluate the spatial aspect of altered genes between different layers of intestinal mucosa (superficial vs deep) and identify the key pathways. Formalin-fixed paraffin-embedded (FFPE) intestinal sections were utilized for analysis using NanoString™platform to evaluate differential gene expressions in the caecum and colon. The IL-17 pathway, includingLcn2, Cxcl2, andS100a8genes, was significantly upregulated in symptomatic mice. The IL-17 signaling pathway activated downstream signaling through NF-κB and MAPK pathways. Gene expression was significantly altered between the intestinal superficial and deep mucosal layers, highlighting layer-specific differences in gene expression patterns in the intestines of symptomatic and asymptomatic mice. Gene expression patterns in the enteric mucosa explain several clinical signs and lesions in CDI mice.
Illumina Complete Long Read Assay yields contiguous bacterial genomes from human gut metagenomes
Authors: Maghini Dylan G , Darling Aaron E , Monahan Leigh G , Halpern Aaron L , Burke Catherine M , Jaeger Erich , Statham Aaron , Truong Tiffany , Ying Kevin , Schroth Gary P , Bhatt Ami S.
Published: November 2024

Metagenomics enables direct investigation of the gene content and potential functions of gut bacteria without isolation and culture. However, metagenome-assembled genomes are often incomplete and have low contiguity due to challenges in assembling repeated genomic elements. Long-read sequencing approaches have successfully yielded circular bacterial genomes directly from metagenomes, but these approaches are low throughput, have high DNA input requirements, and can have high error rates. Illumina has recently launched the Illumina Complete Long Read (ICLR) assay, a new approach for generating kilobase-scale reads with low DNA input requirements and high accuracy. Here, we evaluate the performance of ICLR sequencing for gut metagenomics. We sequenced a microbial mock community and ten human gut microbiome samples with standard, shotgun 2×150 paired-end sequencing, ICLR sequencing, and nanopore long-read sequencing and compared performance in read lengths, assembly contiguity, and bin quality. We find that ICLR human metagenomic assemblies have higher N50 (119.5 ± 24.8 kilobases) than short read assemblies (9.9 ± 4.5 kilobases; p = 0.002), and comparable N50 to nanopore assemblies (91.0 ± 43.8 kilobases; p = 0.32). Additionally, we find that ICLR draft microbial genomes are more complete (94.0% ± 20.6%) than nanopore draft genomes (85.9% ± 23.0%; p≤0.001), and that nanopore draft genomes have truncated gene lengths (924.6 ± 114.7 base pairs) relative to ICLR genomes (954.6 ± 71.5 base pairs; p≤0.001). Overall, we find that ICLR sequencing is a promising method for high-throughput and accurate assembly of microbial genomes from gut metagenomes.

Importance

Metagenomic sequencing allows scientists to directly measure the genome content and structure of microbes residing in complex microbial communities. Traditional short-read metagenomic sequencing methods often yield fragmented genomes, whereas advanced long-read sequencing methods improve genome assembly quality but often suffer from high error rates and are logistically limited due to low throughput and high input requirements. A new method, the Illumina Complete Long Read Assay (ICLR), is capable of generating highly-accurate kilobase-scale sequencing reads with minimal input material. To evaluate the utility of ICLR in metagenomic contexts, we applied short-read, long-read, and ICLR methods to simple and complex microbial communities. We found that ICLR outperforms short-read methods, and yields comparable metagenomic assemblies to standard long-read approaches while requiring less input material. Overall, ICLR represents a high-throughput and efficient solution for assembling complete genomes from complex metagenomes.
Structural basis for growth factor and nutrient signal integration on the lysosomal membrane by mTORC1
Authors: Cui Zhicheng , Esposito Alessandra , Napolitano Gennaro , Ballabio Andrea , Hurley James H.
Published: November 2024

Mechanistic target of rapamycin complex 1 (mTORC1), which consists of mTOR, Raptor, and mLST8, receives signaling inputs from growth factor signals and nutrients. These signals are mediated by the Rheb and Rag small GTPases, respectively, which activate mTORC1 on the cytosolic face of the lysosome membrane. We biochemically reconstituted the activation of mTORC1 on membranes by physiological submicromolar concentrations of Rheb, Rags, and Ragulator. We determined the cryo-EM structure and found that Raptor and mTOR directly interact with the membrane at anchor points separated by up to 230 Å across the membrane surface. Full engagement of the membrane anchors is required for maximal activation, which is brought about by alignment of the catalytic residues in the mTOR kinase active site. The observations show at the molecular and atomic scale how converging signals from growth factors and nutrients drive mTORC1 recruitment to and activation on the lysosomal membrane in a three-step process, consisting of (1) Rag-Ragulator-driven recruitment to within ∼100 Å of the lysosomal membrane, (2) Rheb-driven recruitment to within ∼40 Å, and finally (3) direct engagement of mTOR and Raptor with the membrane. The combination of Rheb and membrane engagement leads to full catalytic activation, providing a structural explanation for growth factor and nutrient signal integration at the lysosome.
Anubis: a multi-level authentication scale for ancient proteins using random forest classification
Authors: Chiang Yun , Nair Bharath Anila Bhuvanendran , Ramsøe Max Emil Ermter , Ravnsborg Tina , Jensen Ole Nørregaard , Collins Matthew James
Published: November 2024

Deamidation is a time-dependent, post-translational modification with wide applications in clinical proteomics and palaeoproteomics as ageing indicators and authentication markers. Despite its significance, the use of deamidation for authenticating ancient proteins remains controversial, primarily due to variability in deamidation kinetics and context-specific protein preservation. We proposeAnubis, an open-source, Python-based pipeline to evaluate relative deamidation patterns and authenticate ancient proteins.Anubisleverages random forest classification based on a range of tandem mass spectrometry-based features and physico-chemical characteristics. We use a combination of ancient and experimentally degraded beta-lactoglobulin to demonstrate thatAnubiscan authenticate a putative ancient dairy protein using position-specific deamidation patterns, relative deamidation (asparagine vs. glutamine), and overall modification patterns using trypsin processed in the same batch as a baseline. This multi-level approach addresses the complexities of ancient protein deamidation and paves the way for automated, reliable authentication across different archaeological substrates.
Neutrino roof: Single-scatter cross section ceilings in dark matter direct detection experiments
Authors: Raj Nirmal , Mondal Biprajit
Published: November 2024

We identify the maximum cross sections probed by single-scatter weakly interacting massive particle (WIMP) searches in dark matter direct detection. Owing to Poisson fluctuations in scatter multiplicity, these ceilings scale logarithmically with mass for heavy dark matter and often lie in regions probed by multiscatter searches. Using a generalized formula for single-scatter event rates we recast WIMP searches by the quintal-to-tonne scale detectors XENON1T, XENONnT, LZ, PANDAX-II, PANDAX-4T, DarkSide-50, and DEAP-3600 to obtain ceilings and floors up to a few 1017  GeV mass and 10−22  cm2 per nucleus cross section. We do this for coherent, geometric, isospin-violating xenophobic and argophobic spin-independent scattering, and neutron-only and proton-only spin-dependent scattering. Future large-exposure detectors would register an almost irreducible background of atmospheric neutrinos that would determine a dark matter sensitivity ceiling that we call the “neutrino roof,” in analogy with the well-studied “neutrino floor.” Accounting for this background, we estimate the reaches of the 10–100 tonne scale DarkSide-20k, DARWIN/XLZD, PANDAX-xT, and Argo, which would probe many decades of unconstrained parameter space up to the Planck mass, as well as of 103–104  tonne scale noble liquid detectors that have been proposed in synergy with neutrino experiments.

Published by the American Physical Society
2024
Social media usage and job performance: a sequential mediation analysis with social capital, self-efficacy, job satisfaction and knowledge sharing
Authors: Kumar Satinder , Rani Pooja
Published: November 2024

Purpose

Social media use is prevalent today, but there is a possibility that it might go out of control and cause negative consequences. Furthermore, by using social media at work, businesses may develop their networks, communicate in a productive manner and ultimately expand the efficiency. The purpose of this study is to investigate the effect of social media use (SMU) on job performance (JP) through sequential mediators such as social capital dimensions (SC), self-efficacy (SE), job satisfaction (JS) and knowledge sharing (KS) in Indian Public Universities.

Design/methodology/approach

Serial mediation model has been used in the study to analyse the relationship. Data is collected from teaching faculty (n = 702) who use social media in Indian public universities. The study has assessed the association between variables using structural equation modelling.

Findings

The findings suggest that the dimensions of SC, SE, JS and KS sequentially mediated the effect of SMU on JP. In light of the results, the SMU specifies prerequisites for the development of various dimensions of SC. Similarly, the rest of the mediating constructs further affect the other constructs, which ultimately positively affect JP. The final result shows that the indirect effect between social media use and job performance is positive and significant.

Practical implications

The study provides practical suggestions for university administration regarding the use of social media for teaching faculty.

Originality/value

No research has been done regarding social media use affecting the job performance of teaching faculty through serial mediation in public universities. In this respect, this study represents an original attempt to conduct such research.
Variation theory as a teaching theory in the theatre classroom
Authors: Ahlstrand Pernilla , Andersson Ninnie
Published: November 2024

Purpose

The paper presents and discusses an example of findings from a research project. Filmed material from teaching situations in theatre has been the starting point for analysing and planning similar teaching situations in research lessons, where variation theory was used. The aim of using variation theory is to develop teaching practices in the school subject of theatre at upper secondary school level in Sweden.

Design/methodology/approach

In the article, one example from the last part of a three-step research project design is discussed. In the third part of the design five research lessons, based on variation theory, were conducted. The starting point for planning the research lessons was teaching situations called didactic interventions, when the teacher interrupts the theatre rehearsals of a stage production and gives response on the student´s acting. The specific situations are used when planning five research lessons based on variation theory. In this paper, one example from one of the research lessons is presented, exemplifying how variation theory has been applied.

Findings

The example shows how variation theory was used in analysing and facilitating teaching in the classroom. The findings suggest that teachers can use variation theory as a way to strengthen the student’s experience of specified objects of learning, in this case, interplay in acting. Another conclusion is that variation theory is helpful when planning whole class teaching situations in the school subject of theatre.

Originality/value

This paper fulfils an identified need to study how to develop teaching practices in the school subject of theatre.
Combined oxygen and glucose oscillations distinctly change the transcriptional and physiological state of Escherichia coli
Authors: Bafna‐Rührer Jonas , Orth Jean V. , Sudarsan Suresh
Published: November 2024

Escherichia coli, a common microbial host for industrial bioproduction, experiences a highly dynamic environment in industrial‐scale bioreactors due to significant glucose and oxygen gradients. In this study, we mimic the combined gradients of glucose and oxygen in high‐throughput bioreactors to study the transcriptional response of E. coli to industrial‐scale conditions. Under oscillating oxygen conditions, E. coli formed less biomass and accumulated the anaerobic by‐product acetate. With respect to oxygen‐responsive genes, we found that genes of the TCA cycle and of different electron transport chain complexes were differentially expressed. A global analysis of the expression data revealed that oxygen oscillations had caused a transition towards a catabolite‐repressed state and upregulation of several stress‐related regulatory programs. Interestingly, the transcriptional changes persisted after oxygen limitation stopped. In contrast, the changes we observed due to glucose starvation, such as induction of the stringent response, were primarily transient. Most importantly, we found that effects of combined oxygen and glucose oscillations were distinct from the ones of oxygen and substrate oscillations alone, suggesting an important interplay between the different metabolic regimes in industrial‐scale bioreactors.
Bacterial Catabolism of Phthalates With Estrogenic Activity Used as Plasticisers in the Manufacture of Plastic Products
Authors: Dhar Rinita , Basu Suman , Bhattacharyya Mousumi , Acharya Debarun , Dutta Tapan K.
Published: November 2024

Phthalic acid esters (PAEs), the pervasive and ubiquitous endocrine‐disrupting chemicals of environmental concern, generated annually on a million‐ton scale, are primarily employed as plasticisers in the production of a variety of plastic products and as additives in a large number of commercial supplies. The increased awareness of various adverse effects on the ecosystem and human health including reproductive and developmental disorders has led to a striking increase in research interest aimed at managing these man‐made oestrogenic chemicals. In these circumstances, microbial metabolism appeared as the major realistic process to neutralise the toxic burdens of PAEs in an ecologically accepted manner. Among a wide variety of microbial species capable of degrading/transforming PAEs reported so far, bacteria‐mediated degradation has been studied most extensively. The main purpose of this review is to provide current knowledge of metabolic imprints of microbial degradation/transformation of PAEs, a co‐contaminant of plastic pollution. In addition, this communication illustrates the recent advancement of the structure–functional aspects of the key metabolic enzyme phthalate hydrolase, their inducible regulation of gene expression and evolutionary relatedness, besides prioritising future research needs to facilitate the development of new insights into the bioremediation of PAE in the environment.