bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of the three-test genetic toxicology battery for groundwater metabolites
Authors: Fowler Paul , Bearzatto Alessandra , Beevers Carol , Booth Ewan D , Donner E Maria , Gan Lin , Hartmann Kerstin , Meurer Krista , Schutte Maaike E , Settivari Raja S 
Published: January 2024

Abstract
The two-test in vitro battery for genotoxicity testing (Ames and micronucleus) has in the majority of cases replaced the three-test battery (as two-test plus mammalian cell gene mutation assay) for the routine testing of chemicals, pharmaceuticals, cosmetics, and agrochemical metabolites originating from food and feed as well as from water treatment. The guidance for testing agrochemical groundwater metabolites, however, still relies on the three-test battery. Data collated in this study from 18 plant protection and related materials highlights the disparity between the often negative Ames and in vitro chromosome aberration data and frequently positive in vitro mammalian cell gene mutation assays. Sixteen of the 18 collated materials with complete datasets were Ames negative, and overall had negative outcomes in in vitro chromosome damage tests (weight of evidence from multiple tests). Mammalian cell gene mutation assays (HPRT and/or mouse lymphoma assay (MLA)) were positive in at least one test for every material with this data. Where both MLA and HPRT tests were performed on the same material, the HPRT seemed to give fewer positive responses. In vivo follow-up tests included combinations of comet assays, unscheduled DNA synthesis, and transgenic rodent gene mutation assays, all gave negative outcomes. The inclusion of mammalian cell gene mutation assays in a three-test battery for groundwater metabolites is therefore not justified and leads to unnecessary in vivo follow-up testing.
Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome
Authors: Li Shijun , Liu Bing , Tan Min , Juillard Franceline , Szymula Agnieszka , Álvarez Ángel L , Van Sciver Nicholas , George Athira , Ramachandran Akshaya , Raina Komal , Tumuluri Vinayak Sadasivam , Costa Catarina N , Simas J Pedro , Kaye Kenneth M 
Published: January 2024

Abstract
To establish lifelong, latent infection, herpesviruses circularize their linear, double-stranded, DNA genomes through an unknown mechanism. Kaposi's sarcoma (KS) herpesvirus (KSHV), a gamma herpesvirus, is tightly linked with KS, primary effusion lymphoma, and multicentric Castleman's disease. KSHV persists in latently infected cells as a multi-copy, extrachromosomal episome. Here, we show the KSHV genome rapidly circularizes following infection, and viral protein expression is unnecessary for this process. The DNA damage response (DDR) kinases, ATM and DNA-PKcs, each exert roles, and absence of both severely compromises circularization and latency. These deficiencies were rescued by expression of ATM and DNA-PKcs, but not catalytically inactive mutants. In contrast, γH2AX did not function in KSHV circularization. The linear viral genomic ends resemble a DNA double strand break, and non-homologous DNA end joining (NHEJ) and homologous recombination (HR) reporters indicate both NHEJ and HR contribute to KSHV circularization. Last, we show, similar to KSHV, ATM and DNA-PKcs have roles in circularization of the alpha herpesvirus, herpes simplex virus-1 (HSV-1), while γH2AX does not. Therefore, the DDR mediates KSHV and HSV-1 circularization. This strategy may serve as a general herpesvirus mechanism to initiate latency, and its disruption may provide new opportunities for prevention of herpesvirus disease.
Intein-based thermoregulated meganucleases for containment of genetic material
Authors: Foo Gary W , Leichthammer Christopher D , Saita Ibrahim M , Lukas Nicholas D , Batko Izabela Z , Heinrichs David E , Edgell David R 
Published: January 2024

Abstract
Limiting the spread of synthetic genetic information outside of the intended use is essential for applications where biocontainment is critical. In particular, biocontainment of engineered probiotics and plasmids that are excreted from the mammalian gastrointestinal tract is needed to prevent escape and acquisition of genetic material that could confer a selective advantage to microbial communities. Here, we built a simple and lightweight biocontainment system that post-translationally activates a site-specific DNA endonuclease to degrade DNA at 18°C and not at higher temperatures. We constructed an orthogonal set of temperature-sensitive meganucleases (TSMs) by inserting the yeast VMA1 L212P temperature-sensitive intein into the coding regions of LAGLIDADG homing endonucleases. We showed that the TSMs eliminated plasmids carrying the cognate TSM target site from laboratory strains of Escherichia coli at the permissive 18°C but not at higher restrictive temperatures. Plasmid elimination is dependent on both TSM endonuclease activity and intein splicing. TSMs eliminated plasmids from E. coli Nissle 1917 after passage through the mouse gut when fecal resuspensions were incubated at 18°C but not at 37°C. Collectively, our data demonstrates the potential of thermoregulated meganucleases as a means of restricting engineered plasmids and probiotics to the mammalian gut.
CADD v1.7: using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide variant predictions
Authors: Schubach Max , Maass Thorben , Nazaretyan Lusiné , Röner Sebastian , Kircher Martin 
Published: January 2024

Abstract
Machine Learning-based scoring and classification of genetic variants aids the assessment of clinical findings and is employed to prioritize variants in diverse genetic studies and analyses. Combined Annotation-Dependent Depletion (CADD) is one of the first methods for the genome-wide prioritization of variants across different molecular functions and has been continuously developed and improved since its original publication. Here, we present our most recent release, CADD v1.7. We explored and integrated new annotation features, among them state-of-the-art protein language model scores (Meta ESM-1v), regulatory variant effect predictions (from sequence-based convolutional neural networks) and sequence conservation scores (Zoonomia). We evaluated the new version on data sets derived from ClinVar, ExAC/gnomAD and 1000 Genomes variants. For coding effects, we tested CADD on 31 Deep Mutational Scanning (DMS) data sets from ProteinGym and, for regulatory effect prediction, we used saturation mutagenesis reporter assay data of promoter and enhancer sequences. The inclusion of new features further improved the overall performance of CADD. As with previous releases, all data sets, genome-wide CADD v1.7 scores, scripts for on-site scoring and an easy-to-use webserver are readily provided via https://cadd.bihealth.org/ or https://cadd.gs.washington.edu/ to the community.
Cystic phenotype and chronic kidney disease in autosomal dominant Alport syndrome
Authors: Bada-Bosch Teresa , Sevillano Angel M , Sánchez-Calvin María Teresa , Palma-Milla Carmen , Alba de Cáceres Ignacio , Díaz-Crespo Francisco , Trujillo Hernando , Alonso Marina , Cases-Corona Clara , Shabaka Amir , Quesada-Espinosa Juan Francisco , Lezana-Rosales José Miguel , Gutiérrez Eduardo , Fernández-Juárez Gema , Caravaca-Fontán Fernando , Praga Manuel 
Published: January 2024

ABSTRACT

Background
Autosomal dominant Alport Syndrome (ADAS), also known as thin basement membrane disease (TBMD), is caused by pathogenic variants in the COL4A3 and COL4A4 genes. A cystic phenotype has been described in some patients with TBMD, but no genetic studies have been performed. We conducted a genetic and radiologic investigation in a cohort of ADAS patients to analyze the prevalence of multicystic kidney disease (MKD) and its association with chronic kidney disease (CKD).

Methods
This was a retrospective single-center cohort study. Thirty-one patients showing pathogenic or likely pathogenic variants in COL4A3 or COL4A4 from a cohort of 79 patients with persistent microscopic hematuria were included. Mean follow-up was 9.4 ± 9.6 years. The primary objective of the study was to determine the prevalence of MKD in the cohort of ADAS patients. Secondary objectives were to determine risk factors associated with an estimated glomerular filtration rate (eGFR) &lt;45 mL/min/1.73 m2 at the time of genetic and radiologic evaluation and to investigate the coexistence of other genetic abnormalities associated with familial hematuria and cystic kidney disease.

Results
MKD was found in 16 patients (52%). Mean number of cysts per kidney was 12.7 ± 5.5. No genetic abnormalities were found in a panel of 101 other genes related to familial hematuria, focal segmental glomerulosclerosis and cystic kidney disease. A greater number of patients with MKD had an eGFR &lt;45 mL/min/1.73 m2 (63% vs 7%, P = .006) and more advanced CKD than patients without MKD. The annual rate of eGFR decline was greater in patients with MKD: –1.8 vs 0.06 mL/min/1.73 m2/year (P = .009). By multivariable linear regression analysis, the main determinants of eGFR change per year were time-averaged proteinuria (P = .002) and MKD (P = .02).

Conclusion
MKD is commonly found in ADAS and is associated with a worse kidney outcome. No pathogenic variants were found in genes other than COL4A3/COL4A4.
Comparative Analysis of Shikonin and Alkannin Acyltransferases Reveals Their Functional Conservation in Boraginaceae
Authors: Oshikiri Haruka , Li Hao , Manabe Misaki , Yamamoto Hirobumi , Yazaki Kazufumi , Takanashi Kojiro 
Published: January 2024

Abstract
Shikonin and its enantiomer, alkannin, are bioactive naphthoquinones produced in several plants of the family Boraginaceae. The structures of these acylated derivatives, which have various short-chain acyl moieties, differ among plant species. The acylation of shikonin and alkannin in Lithospermum erythrorhizon was previously reported to be catalyzed by two enantioselective BAHD acyltransferases, shikonin O-acyltransferase (LeSAT1) and alkannin O-acyltransferase (LeAAT1). However, the mechanisms by which various shikonin and alkannin derivatives are produced in Boraginaceae plants remain to be determined. In the present study, evaluation of six Boraginaceae plants identified 23 homologs of LeSAT1 and LeAAT1, with 15 of these enzymes found to catalyze the acylation of shikonin or alkannin, utilizing acetyl-CoA, isobutyryl-CoA or isovaleryl-CoA as an acyl donor. Analyses of substrate specificities of these enzymes for both acyl donors and acyl acceptors and determination of their subcellular localization using Nicotiana benthamiana revealed a distinct functional differentiation of BAHD acyltransferases in Boraginaceae plants. Gene expression of these acyltransferases correlated with the enantiomeric ratio of produced shikonin/alkannin derivatives in L. erythrorhizon and Echium plantagineum. These enzymes showed conserved substrate specificities for acyl donors among plant species, indicating that the diversity in acyl moieties of shikonin/alkannin derivatives involved factors other than the differentiation of acyltransferases. These findings provide insight into the chemical diversification and evolutionary processes of shikonin/alkannin derivatives.
The Function of Florigen in the Vegetative-to-Reproductive Phase Transition in and around the Shoot Apical Meristem
Authors: Tsuji Hiroyuki , Sato Moeko 
Published: January 2024

Abstract
Plants undergo a series of developmental phases throughout their life-cycle, each characterized by specific processes. Three critical features distinguish these phases: the arrangement of primordia (phyllotaxis), the timing of their differentiation (plastochron) and the characteristics of the lateral organs and axillary meristems. Identifying the unique molecular features of each phase, determining the molecular triggers that cause transitions and understanding the molecular mechanisms underlying these transitions are keys to gleaning a complete understanding of plant development. During the vegetative phase, the shoot apical meristem (SAM) facilitates continuous leaf and stem formation, with leaf development as the hallmark. The transition to the reproductive phase induces significant changes in these processes, driven mainly by the protein FT (FLOWERING LOCUS T) in Arabidopsis and proteins encoded by FT orthologs, which are specified as ‘florigen’. These proteins are synthesized in leaves and transported to the SAM, and act as the primary flowering signal, although its impact varies among species. Within the SAM, florigen integrates with other signals, culminating in developmental changes. This review explores the central question of how florigen induces developmental phase transition in the SAM. Future research may combine phase transition studies, potentially revealing the florigen-induced developmental phase transition in the SAM.
The interrelationships between sleep regularity, obstructive sleep apnea, and hypertension in a middle-aged community population
Authors: Sansom Kelly , Reynolds Amy , Windred Daniel , Phillips Andrew , Dhaliwal Satvinder S , Walsh Jennifer , Maddison Kathleen , Singh Bhajan , Eastwood Peter , McArdle Nigel 
Published: January 2024

Abstract

Study Objectives
Little is known about the interrelationships between sleep regularity, obstructive sleep apnea (OSA) and important health markers. This study examined whether irregular sleep is associated with OSA and hypertension, and if this modifies the known association between OSA and hypertension.

Methods
Six hundred and two adults (age mean(SD) = 56.96(5.51) years, female = 60%) from the Raine Study who were not evening or night shift workers were assessed for OSA (in-laboratory polysomnography; apnea–hypopnea index ≥ 15 events/hour), hypertension (doctor diagnosed, or systolic blood pressure ≥140 mmHg and/or diastolic ≥90 mmHg) and sleep (wrist actigraphy for ≥5 days). A sleep regularity index (SRI) was determined from actigraphy. Participants were categorized by tertiles as severely irregular, mildly irregular, or regular sleepers. Logistic regression models examined the interrelationships between SRI, OSA and hypertension. Covariates included age, sex, body mass index, actigraphy sleep duration, insomnia, depression, activity, alcohol, smoking, and antihypertensive medication.

Results
Compared to regular sleepers, participants with mildly irregular (OR 1.97, 95% confidence intervals [CI] 1.20 to 3.27) and severely irregular (OR 2.06, 95% CI: 1.25 to 3.42) sleep had greater odds of OSA. Compared to those with no OSA and regular sleep, OSA and severely irregular sleep combined had the highest odds of hypertension (OR 2.34 95% CI: 1.07 to 5.12; p for interaction = 0.02) while those with OSA and regular/mildly irregular sleep were not at increased risk (p for interaction = 0.20).

Conclusions
Sleep irregularity may be an important modifiable target for hypertension among those with OSA.
Effect of Baseline Veterans RAND-12 Mental Composite Score on Postoperative Patient-Reported Outcome Measures for Cervical Disk Replacement
Authors: Nie James W. , Hartman Timothy J. , Oyetayo Omolabake O. , Zheng Eileen , MacGregor Keith R. , Anwar Fatima N. , Roca Andrea M. , Federico Vincent P. , Massel Dustin H. , Lopez Gregory D. , Sayari Arash J. , Singh Kern 
Published: January 2024

Study Design:
Retrospective review.

Objective:
To examine the effect of baseline Veterans RAND-12 (VR-12) Mental Composite Score (MCS) on clinical outcomes in patients undergoing cervical disk replacement (CDR) for herniated disk.

Background:
Few studies in spine surgery have evaluated the impact of preoperative VR-12 MCS on postoperative outcomes in patients undergoing CDR.

Methods:
Patients undergoing CDR for herniated disk were separated into 2 cohorts based on the VR-12 MCS standardized mean: VR-12 MCS<50 (worse mental health) and VR-12 MCS≥50 (better mental health). Patient-reported outcome measures of VR-12 MCS, VR-12 Physical Composite Score, Short Form-12 (SF-12) MCS, SF-12 Physical Composite Score, Patient-Reported Outcomes Measurement Information System Physical Function, Patient Health Questionnaire-9 (PHQ-9), Visual Analog Scale (VAS) Neck Pain, VAS Arm Pain, and Neck Disability Index were collected at preoperative and up to 2-year postoperative time points.

Results:
In all, 109 patients were identified, with 50 patients in the worse mental health cohort. The worse mental health cohort reported inferior patient-reported outcome measures in all domains at preoperative, 6-week postoperative, and final postoperative time points. For 6-week postoperative improvement, the worse mental health cohort reported greater improvement for VR-12 MCS, SF-12 MCS, and PHQ-9. For final postoperative improvement, the worse mental health cohort reported greater improvement in VR-12 MCS and SF-12 MCS. Minimum clinically important difference achievement rates were higher in the worse mental health cohort for VR-12 MCS, SF-12 MCS, and PHQ-9.

Conclusion:
Patients undergoing cervical disk replacement for herniated disk with worse baseline mental health reported inferior clinical outcomes in mental health, physical function, pain, and disability outcomes throughout the postoperative period. Patients with worse baseline mental health demonstrated greater clinically meaningful improvement in mental health. In cervical disk replacement patients, those with worse baseline mental health may report inferior postoperative clinical outcomes but experience greater rates of tangible improvement in mental health.
Perspectives of ICU Patients on Deferred Consent in the Context of Post-ICU Quality of Life: A Substudy of a Randomized Clinical Trial*
Authors: van der Wal L. Imeen , Grim Chloe C.A. , del Prado Michael R. , van Westerloo David J. , Schultz Marcus J. , Helmerhorst Hendrik J.F. , de Vries Martine C. , de Jonge Evert ,   for the ICONIC Investigators
Published: January 2024

OBJECTIVES:
Deferred consent enables research to be conducted in the ICU when patients are unable to provide consent themselves, and there is insufficient time to obtain consent from surrogates before commencing (trial) treatment. The aim of this study was to evaluate how former ICU patients reflect on their participation in a study with deferred consent and examine whether their opinions are influenced by the quality of life (QoL) following hospital discharge.

DESIGN:
Survey study by questionnaire.

SETTING:
Eight ICUs in The Netherlands.

PATIENTS:
Former ICU patients who participated in the ICONIC trial, a multicenter randomized clinical trial that evaluated oxygenation targets in mechanically ventilated ICU patients.

INTERVENTIONS:
Participants enrolled in the ICONIC trial in one of the eight participating centers in The Netherlands received a questionnaire 6 months after randomization. The questionnaire included 12 close-ended questions on their opinion about the deferred consent procedure. QoL was measured using the EQ-5D-5L questionnaire. By calculating the EQ-5D index, patients were divided into four QoL quartiles, where Q1 reflects the lowest and Q4 is the highest.

MEASUREMENTS AND MAIN RESULTS:
Of 362 participants who were contacted, 197 responded (54%). More than half of the respondents (59%) were unaware of their participation in the ICONIC study. In total 61% were content with the deferred consent procedure, 1% were not content, 25% neutral, 9% did not know, and 9% answered “other.” Those with a higher QoL were more likely to be content (p = 0.02). In all QoL groups, the legal representative was the most often preferred individual to provide consent.

CONCLUSIONS:
Former ICU patients who participated in the ICONIC study often did not remember their participation but were predominantly positive regarding the use of deferred consent. Those with a higher QoL were most likely to be content.
Circulating biomarker- and magnetic resonance-based nomogram predicting long-term outcomes in dilated cardiomyopathy
Authors: Liu Yupeng , Wang Wenyao , Song Jingjing , Wang Jiancheng , Fu Yi , Tang Yida 
Published: January 2024

AbstractBackground:Dilated cardiomyopathy (DCM) has a high mortality rate and is the most common indication for heart transplantation. Our study sought to develop a multiparametric nomogram to assess individualized all-cause mortality or heart transplantation (ACM/HTx) risk in DCM patients.Methods:The present study is a retrospective cohort study. The demographic, clinical, blood test, and cardiac magnetic resonance imaging (CMRI) data of DCM patients in the tertiary center (Fuwai Hospital) were collected. The primary endpoint was ACM/HTx. The least absolute shrinkage and selection operator (LASSO) Cox regression model was applied for variable selection. Multivariable Cox regression was used to develop a nomogram. The concordance index (C-index), area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance of the nomogram.Results:A total of 218 patients were included in the present study. They were randomly divided into a training cohort and a validation cohort. The nomogram was established based on eight variables, including mid-wall late gadolinium enhancement, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, left ventricular end-diastolic diameter, left ventricular end-diastolic volume index, free triiodothyronine, and N-terminal pro-B type natriuretic peptide. The AUCs regarding 1-year, 3-year, and 5-year ACM/HTx events were 0.859, 0.831, and 0.840 in the training cohort and 0.770, 0.789, and 0.819 in the validation cohort, respectively. The calibration curve and DCA showed good accuracy and clinical utility of the nomogram.Conclusions:We established and validated a circulating biomarker- and CMRI-based nomogram that could provide a personalized prediction of ACM/HTx for DCM patients, which might help risk stratification and decision-making in clinical practice.