bluuebunny/crossref_metadata_2025_split huggingface dataset:
GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources
Authors: Pándy-Szekeres Gáspár , Caroli Jimmy , Mamyrbekov Alibek , Kermani Ali A , Keserű György M , Kooistra Albert J , Gloriam David E 
Published: November 2022

Abstract
G protein-coupled receptors (GPCRs) are physiologically abundant signaling hubs routing hundreds of extracellular signal substances and drugs into intracellular pathways. The GPCR database, GPCRdb supports &gt;5000 interdisciplinary researchers every month with reference data, analysis, visualization, experiment design and dissemination. Here, we present our fifth major GPCRdb release setting out with an overview of the many resources for receptor sequences, structures, and ligands. This includes recently published additions of class D generic residue numbers, a comparative structure analysis tool to identify functional determinants, trees clustering GPCR structures by 3D conformation, and mutations stabilizing inactive/active states. We provide new state-specific structure models of all human non-olfactory GPCRs built using AlphaFold2-MultiState. We also provide a new resource of endogenous ligands along with a larger number of surrogate ligands with bioactivity, vendor, and physiochemical descriptor data. The one-stop-shop ligand resources integrate ligands/data from the ChEMBL, Guide to Pharmacology, PDSP Ki and PubChem database. The GPCRdb is available at https://gpcrdb.org.
PDCM Finder: an open global research platform for patient-derived cancer models
Authors: Perova Zinaida , Martinez Mauricio , Mandloi Tushar , Gomez Federico Lopez , Halmagyi Csaba , Follette Alex , Mason Jeremy , Newhauser Steven , Begley Dale A , Krupke Debra M , Bult Carol , Parkinson Helen , Groza Tudor 
Published: November 2022

Abstract
PDCM Finder (www.cancermodels.org) is a cancer research platform that aggregates clinical, genomic and functional data from patient-derived xenografts, organoids and cell lines. It was launched in April 2022 as a successor of the PDX Finder portal, which focused solely on patient-derived xenograft models. Currently the portal has over 6200 models across 13 cancer types, including rare paediatric models (17%) and models from minority ethnic backgrounds (33%), making it the largest free to consumer and open access resource of this kind. The PDCM Finder standardises, harmonises and integrates the complex and diverse data associated with PDCMs for the cancer community and displays over 90 million data points across a variety of data types (clinical metadata, molecular and treatment-based). PDCM data is FAIR and underpins the generation and testing of new hypotheses in cancer mechanisms and personalised medicine development.
METTL3-mediated m6A modification stabilizes TERRA and maintains telomere stability
Authors: Chen Liping , Zhang Canfeng , Ma Wenbin , Huang Junjiu , Zhao Yong , Liu Haiying 
Published: November 2022

Abstract
Telomeric repeat-containing RNA (TERRA) is a type of long non-coding RNA transcribed from telomeres, and it forms R-loops by invasion into telomeric DNA. Since either an excessive or inadequate number of R-loops leads to telomere instability, the TERRA levels need to be delicately modulated. In this study, we found that m6A modification presents on the subtelomeric regions of TERRA and stabilizes it, and the loss of METTL3 impacts telomere stability. Mechanically, the m6A modification on TERRA is catalyzed by METTL3, recognized and stabilized by the m6A reader YTHDC1. Knockdown of either METTL3 or YTHDC1 enhances TERRA degradation. The m6A-modified TERRA forms R-loops and promotes homologous recombination which is essential for the alternative lengthening of telomeres (ALT) pathway in cancer cells. METTL3 depletion leads to R-loop reduction, telomere shortening and instability. Altogether, these findings reveal that METTL3 protects telomeres by catalyzing m6A modification on TERRA, indicating that inhibition or deletion of METTL3 is potentially a new avenue for ALT cancer therapy.
Glucocorticoids unmask silent non-coding genetic risk variants for common diseases
Authors: Nguyen Thanh Thanh L , Gao Huanyao , Liu Duan , Philips Trudy Janice , Ye Zhenqing , Lee Jeong-Heon , Shi Geng-xian , Copenhaver Kaleigh , Zhang Lingxin , Wei Lixuan , Yu Jia , Zhang Huan , Barath Abhijeet , Luong Maggie , Zhang Cheng , Gaspar-Maia Alexandre , Li Hu , Wang Liewei , Ordog Tamas , Weinshilboum Richard M 
Published: November 2022

Abstract
Understanding the function of non-coding genomic sequence variants represents a challenge for biomedicine. Many diseases are products of gene-by-environment interactions with complex mechanisms. This study addresses these themes by mechanistic characterization of non-coding variants that influence gene expression only after drug or hormone exposure. Using glucocorticoid signaling as a model system, we integrated genomic, transcriptomic, and epigenomic approaches to unravel mechanisms by which variant function could be revealed by hormones or drugs. Specifically, we identified cis-regulatory elements and 3D interactions underlying ligand-dependent associations between variants and gene expression. One-quarter of the glucocorticoid-modulated variants that we identified had already been associated with clinical phenotypes. However, their affected genes were ‘unmasked’ only after glucocorticoid exposure and often with function relevant to the disease phenotypes. These diseases involved glucocorticoids as risk factors or therapeutic agents and included autoimmunity, metabolic and mood disorders, osteoporosis and cancer. For example, we identified a novel breast cancer risk gene, MAST4, with expression that was repressed by glucocorticoids in cells carrying the risk genotype, repression that correlated with MAST4 expression in breast cancer and treatment outcomes. These observations provide a mechanistic framework for understanding non-coding genetic variant-chemical environment interactions and their role in disease risk and drug response.
IntroVerse: a comprehensive database of introns across human tissues
Authors: García-Ruiz Sonia , Gustavsson Emil K , Zhang David , Reynolds Regina H , Chen Zhongbo , Fairbrother-Browne Aine , Gil-Martínez Ana Luisa , Botia Juan A , Collado-Torres Leonardo , Ryten Mina 
Published: November 2022

Abstract
Dysregulation of RNA splicing contributes to both rare and complex diseases. RNA-sequencing data from human tissues has shown that this process can be inaccurate, resulting in the presence of novel introns detected at low frequency across samples and within an individual. To enable the full spectrum of intron use to be explored, we have developed IntroVerse, which offers an extensive catalogue on the splicing of 332,571 annotated introns and a linked set of 4,679,474 novel junctions covering 32,669 different genes. This dataset has been generated through the analysis of 17,510 human control RNA samples from 54 tissues provided by the Genotype-Tissue Expression Consortium. IntroVerse has two unique features: (i) it provides a complete catalogue of novel junctions and (ii) each novel junction has been assigned to a specific annotated intron. This unique, hierarchical structure offers multiple uses, including the identification of novel transcripts from known genes and their tissue-specific usage, and the assessment of background splicing noise for introns thought to be mis-spliced in disease states. IntroVerse provides a user-friendly web interface and is freely available at https://rytenlab.com/browser/app/introverse.
ChIPBase v3.0: the encyclopedia of transcriptional regulations of non-coding RNAs and protein-coding genes
Authors: Huang Junhong , Zheng Wujian , Zhang Ping , Lin Qiao , Chen Zhirong , Xuan Jiajia , Liu Chang , Wu Di , Huang Qiaojuan , Zheng Lingling , Liu Shurong , Zhou Keren , Qu Lianghu , Li Bin , Yang Jianhua 
Published: November 2022

Abstract
Non-coding RNAs (ncRNAs) are emerging as key regulators of various biological processes. Although thousands of ncRNAs have been discovered, the transcriptional mechanisms and networks of the majority of ncRNAs have not been fully investigated. In this study, we updated ChIPBase to version 3.0 (https://rnasysu.com/chipbase3/) to provide the most comprehensive transcriptional regulation atlas of ncRNAs and protein-coding genes (PCGs). ChIPBase has identified ∼151 187 000 regulatory relationships between ∼171 600 genes and ∼3000 regulators by analyzing ∼55 000 ChIP-seq datasets, which represent a 30-fold expansion. Moreover, we de novo identified ∼29 000 motif matrices of transcription factors. In addition, we constructed a novel ‘Enhancer’ module to predict ∼1 837 200 regulation regions functioning as poised, active or super enhancers under ∼1300 conditions. Importantly, we constructed exhaustive coexpression maps between regulators and their target genes by integrating expression profiles of ∼65 000 normal and ∼15 000 tumor samples. We built a ‘Disease’ module to obtain an atlas of the disease-associated variations in the regulation regions of genes. We also constructed an ‘EpiInter’ module to explore potential interactions between epitranscriptome and epigenome. Finally, we designed ‘Network’ module to provide extensive and gene-centred regulatory networks. ChIPBase will serve as a useful resource to facilitate integrative explorations and expand our understanding of transcriptional regulation.
ViLoN—a multi-layer network approach to data integration demonstrated for patient stratification
Authors: Kańduła Maciej M , Aldoshin Alexander D , Singh Swati , Kolaczyk Eric D , Kreil David P 
Published: November 2022

AbstractWith more and more data being collected, modern network representations exploit the complementary nature of different data sources as well as similarities across patients. We here introduce the Variation of information fused Layers of Networks algorithm (ViLoN), a novel network-based approach for the integration of multiple molecular profiles. As a key innovation, it directly incorporates prior functional knowledge (KEGG, GO). In the constructed network of patients, patients are represented by networks of pathways, comprising genes that are linked by common functions and joint regulation in the disease. Patient stratification remains a key challenge both in the clinic and for research on disease mechanisms and treatments. We thus validated ViLoN for patient stratification on multiple data type combinations (gene expression, methylation, copy number), showing substantial improvements and consistently competitive performance for all. Notably, the incorporation of prior functional knowledge was critical for good results in the smaller cohorts (rectum adenocarcinoma: 90, esophageal carcinoma: 180), where alternative methods failed.
Roxadustat (FG-4592) protects against ischaemia-induced acute kidney injury via improving CD73 and decreasing AIM2 inflammasome activation
Authors: Yang Huan , Wu Yong , Cheng Ming , Zhang Ming , Qiu Xiaoyan , Liu Shaojun , Zhang Minmin 
Published: November 2022

ABSTRACTBackgroundHypoxia-mediated inflammation plays a crucial role in renal ischaemia–reperfusion (IR)-induced acute kidney injury (AKI) and may influence renal graft survival, with no available pharmacological treatments. Here we investigate the protective effects and mechanism of roxadustat (FG-4592), a hypoxia-inducible factor stabilizer, against renal IR injury.MethodsThe protein expression levels of CD73 and AIM2 inflammasome complex were examined in kidney biopsy specimens of AKI and post-renal transplantation (PRT) patients. The effects of FG-4592 on CD73 and absent in melanoma 2 (AIM2) inflammasome components were examined in IR mice (right nephrectomy, followed by 30 min of unilateral renal ischaemia and reperfusion for 24 h), and some of the model mice received intraperitoneal administrations of adenosine 5′-(α,β-methylene)diphosphate sodium salt, which is an inhibitor of CD73. The function of FG-4592 was also investigated in vitro with HK-2 cells.ResultsIn the AKI and PRT patients, the protein expression of AIM2 complex [AIM2–apoptosis-associated speck-like protein (ASC)–cleaved caspase-1) increased and the activation of CD73 signalling pathway was detected as well. The pretreatment of FG-4592 improved the creatinine elevation and renal tubular injuries induced by ischaemia. What's more, the administration of FG-4592 significantly enhanced CD73 synthesis in mouse kidney but suppressed the activation of the AIM2 inflammasome [decreased AIM2, ASC, caspase-1, interleukin (IL)-1β and IL-18 levels]. Notably, the renoprotection of FG-4592 and the inhibition of AIM2 were abolished by the CD73 inhibitor.ConclusionFG-4592-conveyed protection against AKI might be mediated by the induction of CD73 and the suppression of the AIM2 inflammasome, which may provide a novel therapeutic method for the treatment of AKI.
VrMYB90Functions Synergistically withVrbHLHAandVrMYB3to Regulate Anthocyanin Biosynthesis in Mung Bean
Authors: Chen Jiahui , Zhan Junyi , Wang Haixia , Zhao Yingdi , Zhang Derui , Chen Xin , Su Nana , Cui Jin 
Published: November 2022

AbstractMung bean is an important grain-legume crop and its sprout is an economical and nutrient vegetable for the public, but the genetic regulation of anthocyanin production, which is an antioxidant in mung bean, remains elusive. In our study, we characterized a subgroup (SG) 6 R2R3-MYB anthocyanin activator VrMYB90 and a SG 4 R2R3-MYB anthocyanin repressor VrMYB3, which synergistically function in regulating anthocyanin synthesis with VrbHLHA transcription factor. The overexpressed VrMYB90 protein activates the expression of VrMYB3 and VrbHLHA in mung bean hair roots, and also promotes VrDFR and VrANS transcript levels by directly binding to the corresponding promoters at specific motifs (CAACTG and CCGTTG). VrMYB90 interacts with VrbHLHA to enhance its regulatory activities on VrDFR and VrANS. Furthermore, the interaction between VrMYB3 with VrMYB90 and VrbHLHA could result in the restriction of anthocyanin synthesis to prevent excessive anthocyanin accumulation. Our results demonstrate that the VrMYB90 protein, in conjunction with VrMYB3 and VrbHLHA, forms a key regulatory module to fine-tune anthocyanin synthesis in mung bean.
UV-B-Induced CPD Photolyase Gene Expression is Regulated by UVR8-Dependent and -Independent Pathways in Arabidopsis
Authors: Li Nan , Teranishi Mika , Yamaguchi Hiroko , Matsushita Tomonao , Watahiki Masaaki K , Tsuge Tomohiko , Li Shao-Shan , Hidema Jun 
Published: November 2022

Abstract
Plants have evolved various mechanisms that protect against the harmful effects of UV-B radiation (280–315 nm) on growth and development. Cyclobutane pyrimidine dimer (CPD) photolyase, the repair enzyme for UV-B-induced CPDs, is essential for protecting cells from UV-B radiation. Expression of the CPD photolyase gene (PHR) is controlled by light with various wavelengths including UV-B, but the mechanisms of this regulation remain poorly understood. In this study, we investigated the regulation of PHR expression by light with various wavelengths, in particular low-fluence UV-B radiation (280 nm, 0.2 µmol m–2 s –1), in Arabidopsis thaliana seedlings grown under light–dark cycles for 7 d and then adapted to the dark for 3 d. Low-fluence UV-B radiation induced CPDs but not reactive oxygen species. AtPHR expression was effectively induced by UV-B, UV-A (375 nm) and blue light. Expression induced by UV-A and blue light was predominantly regulated by the cryptochrome-dependent pathway, whereas phytochromes A and B played a minor but noticeable role. Expression induced by UV-B was predominantly regulated by the UVR8-dependent pathway. AtPHR expression was also mediated by a UVR8-independent pathway, which is correlated with CPD accumulation induced by UV-B radiation. These results indicate that Arabidopsis has evolved diverse mechanisms to regulate CPD photolyase expression by multiple photoreceptor signaling pathways, including UVR8-dependent and -independent pathways, as protection against harmful effects of UV-B radiation.
Attributing Increases in Ozone to Accelerated Oxidation of Volatile Organic Compounds at Reduced Nitrogen Oxides Concentrations
Authors: Zhang Zekun , Jiang Jiakui , Lu Bingqing , Meng Xue , Herrmann Hartmut , Chen Jianmin , Li Xiang 
Published: November 2022

AbstractSurface ozone (O3) is an important secondary pollutant affecting climate change and air quality in the atmosphere. Observations during the COVID-19 lockdown in urban China show that the co-abatement of nitrogen oxides (NOx) and volatile organic compounds (VOCs) caused winter ground-level O3 increases, but the chemical mechanisms involved are unclear. Here we report field observations in the Shanghai lockdown that reveals increasing photochemical formation of O3 from VOC oxidation with decreasing NOx. Analyses of the VOC profiles and NO/NO2 indicate that the O3 increases by the NOx reduction counteracted the O3 decreases through the VOC emission reduction in the VOC-limited region, and this may have been the main mechanism for this net O3 increase. The mechanism may have involved accelerated OH–HO2–RO2 radical cycling. The NOx reductions for increasing O3 production could explain why O3 increased from 2014 to 2020 in response to NOx emission reduction even as VOC emissions have essentially remained unchanged. Model simulations suggest that aggressive VOC abatement, particularly for alkenes and aromatics, should help reverse the long-term O3 increase under current NOx abatement conditions.
The Hierarchy of Care Work: How Immigrants Influence the Gender-Segregated Labor Market
Authors: Østbakken Kjersti Misje , Orupabo Julia , Nadim Marjan 
Published: November 2022

Abstract
The devaluation of care work is regarded as a main explanation for the dominance of women in care work. However, less attention has been paid to how such devaluation affects not only the gender balance of jobs but also their ethnic and racial composition. This article examines patterns of gender and ethnic segregation and inequality within different types of care work. Using high-quality linked administrative register data covering the period 2004–2017, the analysis shows that although the strong female dominance in care work is relatively stable, a shift in the composition of workers has occurred. While native women are leaving the most devalued types of care work, they are replaced by immigrants—both women and men. The findings underscore how patterns of gender segregation are influenced by immigration, and that not all men benefit from being men in female-dominated occupations.
The Puzzle of Lionel Robbins: How a Neoliberal Economist Expanded Public University Education in 1960s Britain
Authors: Patel Josh 
Published: November 2022

Abstract
Lionel Robbins (1898–1984) has been identified as one of the leading ‘neoliberal’ economists of his day. However, his name remains irrevocably linked with the massive state-funded ‘social democratic’ expansion of higher education recommended by the Robbins Report (1963). This article explores this paradox. Examining Robbins’s writings on higher education in the context of his economic thought shows how he blended the liberalism of Adam Smith and J. S. Mill, neoliberal economics, and growing demands for personal choice. For Robbins, the atrocities of the Nazi and Soviet regimes demonstrated how the state armed with new modern technologies could endanger freedom and prosperity. But the ‘good society’ might wield technology to secure conditions of freedom and choice. Robbins advocated a system of state-subsidized universities based on ‘student demand’ and which generated social and individual returns. This system would perpetuate what Robbins called the ‘creed of freedom’: a reimagined interdisciplinary liberal education through which students would understand the importance of their specialism to liberal capitalism. His thought on higher education indicates something of the dynamism of post-war British liberalism and the range of support for higher education expansion. It further counters the impression of the British universities as sites of a static and conservative liberal education.
Strategies for successfully completing a DNP final project
Authors: Reid Kimone Racquel Yolanda , DeGennaro Regina 
Published: November 2022

Abstract:
Completion of a final project is an essential component of Doctor of Nursing Practice programs. Strategies for successful project planning, implementation, and evaluation are outlined, from identifying an evidence-based practice or quality improvement project, advisor, and practice mentor through completion, presentation, and dissemination of your work.
Evidence-based updates to the 2021 Surviving Sepsis Campaign guidelines Part 2
Authors: Lehman Karen D. 
Published: November 2022

Abstract:
NPs should be prepared to screen for sepsis, initiate treatment, and optimize care for sepsis survivors. The 2021 Surviving Sepsis Campaign guidelines offer best practices for identification and management of sepsis and septic shock. This article, second in a 2-part series, presents evidence updates and discusses implications for NPs.
Predictive Models for Length of Stay and Discharge Disposition in Elective Spine Surgery: Development, Validation, and Comparison to the ACS NSQIP Risk Calculator
Authors: Arora Ayush , Lituiev Dmytro , Jain Deeptee , Hadley Dexter , Butte Atul J. , Berven Sigurd , Peterson Thomas A. 
Published: November 2022

Study Design.
A retrospective study at a single academic institution.

Objective.
The purpose of this study is to utilize machine learning to predict hospital length of stay (LOS) and discharge disposition following adult elective spine surgery, and to compare performance metrics of machine learning models to the American College of Surgeon’s National Surgical Quality Improvement Program’s (ACS NSQIP) prediction calculator.

Summary of Background Data.
A total of 3678 adult patients undergoing elective spine surgery between 2014 and 2019, acquired from the electronic health record.

Methods.
Patients were divided into three stratified cohorts: cervical degenerative, lumbar degenerative, and adult spinal deformity groups. Predictive variables included demographics, body mass index, surgical region, surgical invasiveness, surgical approach, and comorbidities. Regression, classification trees, and least absolute shrinkage and selection operator (LASSO) were used to build predictive models. Validation of the models was conducted on 16% of patients (N=587), using area under the receiver operator curve (AUROC), sensitivity, specificity, and correlation. Patient data were manually entered into the ACS NSQIP online risk calculator to compare performance. Outcome variables were discharge disposition (home vs. rehabilitation) and LOS (days).

Results.
Of 3678 patients analyzed, 51.4% were male (n=1890) and 48.6% were female (n=1788). The average LOS was 3.66 days. In all, 78% were discharged home and 22% discharged to rehabilitation. Compared with NSQIP (Pearson R
2=0.16), the predictions of poisson regression (R
2=0.29) and LASSO (R
2=0.29) models were significantly more correlated with observed LOS (P=0.025 and 0.004, respectively). Of the models generated to predict discharge location, logistic regression yielded an AUROC of 0.79, which was statistically equivalent to the AUROC of 0.75 for NSQIP (P=0.135).

Conclusion.
The predictive models developed in this study can enable accurate preoperative estimation of LOS and risk of rehabilitation discharge for adult patients undergoing elective spine surgery. The demonstrated models exhibited better performance than NSQIP for prediction of LOS and equivalent performance to NSQIP for prediction of discharge location.