bluuebunny/crossref_metadata_2025_split huggingface dataset:
POT-3 preferentially binds the terminal DNA-repeat on the telomeric G-overhang
Authors: Yu Xupeng , Gray Sean , Ferreira Helder C 
Published: December 2022

Abstract
Eukaryotic chromosomes typically end in 3′ telomeric overhangs. The safeguarding of telomeric single-stranded DNA overhangs is carried out by factors related to the protection of telomeres 1 (POT1) protein in humans. Of the three POT1-like proteins in Caenorhabditis elegans, POT-3 was the only member thought to not play a role at telomeres. Here, we provide evidence that POT-3 is a bona fide telomere-binding protein. Using a new loss-of-function mutant, we show that the absence of POT-3 causes telomere lengthening and increased levels of telomeric C-circles. We find that POT-3 directly binds the telomeric G-strand in vitro and map its minimal DNA binding site to the six-nucleotide motif, GCTTAG. We further show that the closely related POT-2 protein binds the same motif, but that POT-3 shows higher sequence selectivity. Crucially, in contrast to POT-2, POT-3 prefers binding sites immediately adjacent to the 3′ end of DNA. These differences are significant as genetic analyses reveal that pot-2 and pot-3 do not function redundantly with each other in vivo. Our work highlights the rapid evolution and specialisation of telomere binding proteins and places POT-3 in a unique position to influence activities that control telomere length.
DNA–protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM)
Authors: Xu Wenyan , Tang Jin , Zhao Linlin 
Published: December 2022

Abstract
In higher eukaryotic cells, mitochondria are essential organelles for energy production, metabolism, and signaling. Mitochondrial DNA (mtDNA) encodes 13 protein subunits for oxidative phosphorylation and a set of tRNAs and rRNAs. mtDNA damage, sourced from endogenous chemicals and environmental factors, contributes to mitochondrial genomic instability, which has been associated with various mitochondrial diseases. DNA–protein cross-links (DPCs) are deleterious DNA lesions that threaten genomic integrity. Although much has been learned about the formation and repair of DPCs in the nucleus, little is known about DPCs in mitochondria. Here, we present in vitro and in cellulo data to demonstrate the formation of DPCs between a prevalent abasic (AP) DNA lesion and a DNA-packaging protein, mitochondrial transcription factor A (TFAM). TFAM cleaves AP-DNA and forms DPCs and single-strand breaks (SSB). Lys residues of TFAM are critical for the formation of TFAM-DPC and a reactive 3′-phospho-α,β-unsaturated aldehyde (3′pUA) residue on SSB. The 3′pUA residue reacts with two Cys of TFAM and contributes to the stable TFAM-DPC formation. Glutathione reacts with 3′pUA and competes with TFAM-DPC formation, corroborating our cellular experiments showing the accumulation of TFAM-DPCs under limiting glutathione. Our data point to the involvement of TFAM in AP-DNA turnover and fill a knowledge gap regarding the protein factors in processing damaged mtDNA.
Are Fatwas Dispensable? Examining the Contemporary Relevance and Authority of Fatwas in Australia
Authors: Whyte Shaheen 
Published: December 2022

Abstract
Fatwas play a central role in the articulation and contextualization of Islamic law. Despite its lofty status within Islam’s juristic tradition, the authoritative value and function of fatwas in contemporary Muslim societies is undergoing significant change. Whereas historical fatwas generated immense solidarity within Islam’s legal schools and traditional ulama (religious scholars), Muslims today are confronted with an unprecedented supply of fatwas from various religious actors, institutions and digital platforms vying to speak for Islam. Using Australia as a case study, this article investigates the role, demand, and relevance of fatwas in Australia. It draws on empirical fieldwork conducted between 2018 and 2019 with Muslim religious actors including imams/sheikhs, educators, academics and members of the Australian Muslim community. The findings show Australian Muslims are largely sceptical about the relevance and credibility behind fatwa-making in Australia. Among the findings, participants demand greater scholarly expertise, legal analysis, and institutional output in the production of fatwas. Participants additionally expressed desire to establish locally based fatwa councils with the ability to produce context-specific fatwas for Australian Muslims.
Risk factors for haemodynamic compromise in multisystem inflammatory syndrome in children: a multicentre retrospective study
Authors: Kaidar Kfir , Dizitzer Yotam , Hashkes Philip J , Wagner-Weiner Linda , Tesher Melissa , Butbul Aviel Yonatan , Inbar Kanteman , Berkun Yackov , Eisenstein Eli M , Saied Mohamad Hamad , Goldzweig Ofra , Heshin-Bekenstein Merav , Ling Eduard , Feldon Michal , Levinsky Yoel , Tal Rotem , Harel Liora , Amarilyo Gil 
Published: December 2022

Abstract

Objectives
To identify predictors of a severe clinical course of multisystem inflammatory syndrome in children (MIS-C), as defined by the need for inotropic support.

Methods
This retrospective study included patients diagnosed with MIS-C (according to the CDC definition) in nine Israeli and one US medical centre between July 2020 and March 2021. Univariate and multivariate regression models assessed odds ratio (OR) of demographic, clinical, laboratory and imaging variables during admission and hospitalization for severe disease.

Results
Of 100 patients, 61 (61%) were male; mean age 9.65 (4.48) years. Sixty-five patients were hypotensive, 44 required inotropic support. Eleven patients with MIS-C fulfilled Kawasaki disease diagnostic criteria; 87 had gastrointestinal symptoms on admission. Echocardiographic evaluation showed 10 patients with acute coronary ectasia or aneurysm, and 37 with left ventricular dysfunction. In a univariate model, left ventricular dysfunction was associated with severe disease [OR 4.178 (95% CI 1.760, 9.917)], while conjunctivitis [OR 0.403 (95% CI 0.173, 0.938)] and mucosal changes [OR 0.333 (95% CI 0.119, 0.931)] at admission were protective. Laboratory markers for a severe disease course were low values of haemoglobin, platelets, albumin and potassium; and high leukocytes, neutrophils, troponin and brain natriuretic peptide. In multivariate analysis, central nervous system involvement and fever &gt;39.5°C were associated with severe disease. Mucosal involvement showed 6.2-fold lower risk for severe disease. Low haemoglobin and platelet count, and elevated C-reactive protein and troponin levels were identified as risk factors for severe disease.

Conclusion
Key clinical and laboratory parameters of MIS-C were identified as risk factors for severe disease, predominantly during the disease course and not at the time of admission; and may prompt close monitoring, and earlier, more aggressive treatment decisions. Patients presenting with a Kawasaki-like phenotype were less likely to require inotropic support.
FAIRE‐MS reveals mitotic retention of transcriptional regulators on a proteome‐wide scale
Authors: Ye Bingyu , Shen Wenlong , Li Yanchang , Wang Dong , Zhang Yan , Li Ping , Yin Man , Wang Yahao , Xie Dejian , Shi Shu , Yao Tao , Chen Juncai , Xu Ping , Zhao Zhihu 
Published: December 2022

AbstractMitosis entails global and dramatic alterations, such as higher‐order chromatin organization disruption, concomitant with global transcription downregulation. Cells reliably re‐establishing gene expression patterns upon mitotic exit and maintaining cellular identities remain poorly understood. Previous studies indicated that certain transcription factors (TFs) remain associated with individual loci during mitosis and serve as mitotic bookmarkers. However, it is unclear which regulatory factors remain bound to the compacted mitotic chromosomes. We developed formaldehyde‐assisted isolation of regulatory elements‐coupled mass spectrometry (FAIRE‐MS) that combines FAIRE‐based open chromatin‐associated protein pull‐down and mass spectrometry (MS) to quantify the open chromatin‐associated proteome during the interphase and mitosis. We identified 189 interphase and mitosis maintained (IM) regulatory factors using FAIRE‐MS and found intrinsically disordered proteins and regions (IDP(R)s) are highly enriched, which plays a crucial role in liquid–liquid phase separation (LLPS) and chromatin organization during the cell cycle. Notably, in these IDP(R)s, we identified mitotic bookmarkers, such as CEBPB, HMGB1, and TFAP2A, and several factors, including MAX, HMGB3, hnRNP A2/B1, FUS, hnRNP D, and TIAL1, which are at least partially bound to the mitotic chromosome. Furthermore, it will be essential to study whether these IDP(R)s through LLPS helps cells transit from mitosis to the G1 phase during the cell cycle.
Single‐nucleus RNA and ATAC sequencing uncovers the molecular and cellular characteristics in the musk gland of Chinese forest musk deer (Moschus berezovskii)
Authors: Liu Chenmiao , Hong Tingting , Yu Lin , Chen Yuan , Wang Shuhui , Ren Zhanjun 
Published: December 2022

AbstractThe Chinese forest musk deer (FMD; Moschus berezovskii) is an endangered artiodactyl mammal. Musk secreted by the musk gland of male has extremely high economic and medicinal value. However, the molecular and cellular characteristics of the musk gland have not been studied. Here, we investigated the diversity and transcriptional composition of musk gland cell types and the effect of cell type‐specific chromatin accessibility on gene expression using single‐nucleus RNA sequencing (snRNA‐seq) and single‐nucleus ATAC sequencing (snATAC‐seq) association analysis. Based on uniform manifold approximation and projection (UMAP) analysis, we identified 13 cell types from the musk gland, which included two different acinar cells (cluster 0 and cluster 10). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that many pathways related to musk secretion were enriched in acinar cells. Our analysis also revealed acinar cell core transcription factors and core target genes, and further constructed acinar cell‐specific regulatory networks. In cluster 0, 11 core target genes (Nedd4l, Adcy9, Akr1c1, Vapb, Me1, Acsl1, Acss3, Srd5a1, Scnn1a, Acadm, and Nceh1) possibly related to musk secretion were regulated by 24 core transcription factors (SP3, NFIC, NR6A1, EHF, RUNX1, TFAP2A, RREB1, GRHL2, NFIB, ELF1, MAX, KLF5, REL, HES1, POU2F3, TFDP1, NR2C1, ATF7, MEIS1, NR4A2, NFIA, PBX1, ZNF652, and NFKB1). In cluster 10, four core target genes (Akr1c1, Pcca, Atp1b1, and Sgk1) possibly related to musk secretion were regulated by 10 core transcription factors (BARX2, EHF, PBX1, RUNX1, NFIB, FOXP1, KLF3, KLF6, ETV6, and NR3C2). Moreover, the credibility of snRNA‐seq and snATAC‐seq data was verified by fluorescence in situ hybridization and immunohistochemistry. Finally, cell communication analysis demonstrated that the two types of acinar cells mainly have communications in musk secretion‐related processes. In conclusion, we provided important insights and invaluable resources for the molecular and cellular characteristics of the musk gland, which will lay a foundation for the study of musk secretion mechanism in the future.
Modulation of TRPV4 protects against degeneration induced by sustained loading and promotes matrix synthesis in the intervertebral disc
Authors: Easson Garrett W. D. , Savadipour Alireza , Anandarajah Akila , Iannucci Leanne E. , Lake Spencer P. , Guilak Farshid , Tang Simon Y. 
Published: December 2022

AbstractWhile it is well known that mechanical signals can either promote or disrupt intervertebral disc (IVD) homeostasis, the molecular mechanisms for transducing mechanical stimuli are not fully understood. The transient receptor potential vanilloid 4 (TRPV4) ion channel activated in isolated IVD cells initiates extracellular matrix (ECM) gene expression, while TRPV4 ablation reduces cytokine production in response to circumferential stretching. However, the role of TRPV4 on ECM maintenance during tissue‐level mechanical loading remains unknown. Using an organ culture model, we modulated TRPV4 function over both short‐ (hours) and long‐term (days) and evaluated the IVDs' response. Activating TRPV4 with the agonist GSK101 resulted in a Ca2+ flux propagating across the cells within the IVD. Nuclear factor (NF)‐κB signaling in the IVD peaked at 6 h following TRPV4 activation that subsequently resulted in higher interleukin (IL)‐6 production at 7 days. These cellular responses were concomitant with the accumulation of glycosaminoglycans and increased hydration in the nucleus pulposus that culminated in higher stiffness of the IVD. Sustained compressive loading of the IVD resulted in elevated NF‐κB activity, IL‐6 and vascular endothelial growth factor A (VEGFA) production, and degenerative changes to the ECM. TRPV4 inhibition using GSK205 during loading mitigated the changes in inflammatory cytokines, protected against IVD degeneration, but could not prevent ECM disorganization due to mechanical damage in the annulus fibrosus. These results indicate TRPV4 plays an important role in both short‐ and long‐term adaptations of the IVD to mechanical loading. The modulation of TRPV4 may be a possible therapeutic for preventing load‐induced IVD degeneration.
Extracorporeal Membrane Oxygenation Cannulation Timing in the Pediatric Myocarditis Population: An Exploratory Analysis From the Extracorporeal Life Support Organization Registry
Authors: Gutierrez Maria E. , Anders Marc , Guffey Danielle , Denfield Susan W. , Deshpande Shriprasad R. , Rajagopal Satish K. , Thiagarajan Ravi R. , Alexander Peta M. A. , Lasa Javier J. 
Published: December 2022

OBJECTIVES:
Children presenting with acute myocarditis may experience rapid clinical deterioration requiring extracorporeal membrane oxygenation (ECMO); however, our understanding of best practices and timing of ECMO initiation are lacking. We explored the relationships between pre-cannulation factors and survival in this high-acuity patient population.

DESIGN:
Retrospective review of a large international registry. Primary outcome was survival to hospital discharge, stratified by incident cardiac arrest (CA) prior to ECMO and time to cannulation after intubation.

SETTING AND SUBJECTS:
The Extracorporeal Life Support Organization registry was queried for patients less than or equal to 18 years old receiving ECMO support for myocarditis between 2007 and 2018. Exclusion criteria included being nonindex runs, non-venoarterial ECMO or missing data points for main variables studied.

INTERVENTIONS:
None.

MEASUREMENTS AND MAIN RESULTS:
Population characteristics and survival were compared using t test, Wilcoxon rank-sum test, or Fisher exact test. Multivariable logistic regression was used for significant factors in the unadjusted logistic regression. Among 506 index ECMO runs in pediatric patients with myocarditis, survival for the cohort was 72%, with no difference between early and late eras (2007–2012 vs 2013–2018; p = 0.69). Survivors demonstrated higher pre-ECMO pH levels as well as shorter intubation-to-cannulation (ITC) times (3 hr [interquartile range (IQR)], 1–14 hr vs 6 hr [IQR, 2–20 hr]; p = 0.021). CA occurred within 24 hours prior to ECMO cannulation, including extracorporeal cardiopulmonary resuscitation, in 54% of ECMO runs (n = 273). Accounting for the interaction between pre-ECMO CA occurrence and ITC time, longer ITC time remained associated with lower survival for patients who did not experience a CA prior to ECMO, with adjusted odds ratio of 0.09 (IQR, 0.02–0.40; p = 0.002) for ITC time greater than or equal to 18 hours.

CONCLUSIONS:
The results of this multicenter analysis of ECMO utilization and outcomes for pediatric myocarditis suggest that patients approaching ECMO cannulation who have not experienced CA may have better survival outcomes if cannulated onto ECMO early after intubation.
Influence of severe neck angulation on hemodynamic and clinical outcomes following endovascular aneurysm repair: a hemodynamic analysis and a retrospective cohort study
Authors: Liu Yang , Qing Ming , Zhao Jichun , Huang Bin , Yang Yi , Zheng Tinghui , Yuan Ding 
Published: December 2022

Abstract

Background:
For patients with severe neck angulation (SNA), hemodynamic and clinical outcomes following endovascular aneurysm repair (EVAR) are still unclear. This study aimed to explore the influence of SNA on hemodynamic and clinical outcomes following EVAR.

Methods:
This study included a hemodynamic analysis and a retrospective cohort study from West China Hospital of Sichuan University between January 2011 and December 2020. The Cox regression model, inverse probability of treatment weighting (IPTW) analysis, sensitivity analysis, and subgroup analysis were applied. Primary outcome was type IA endoleak (T1AEL).

Results:
In this hemodynamic analysis, nine non-severe neck angulation (nSNA) and 16 SNA idealized models were constructed. We found a significant difference in drag force between SNA and nSNA models (7.016 ± 2.579 N vs. 4.283 ± 1.460 N, P = 0.008), and proximal neck angles were significantly associated with the magnitude of drag force (F = 0.082 × α–0.006 × β + 2.818, α: 95% confidence interval [CI] 0.070–0.094; P = 0.001; β: 95% CI −0.019 to 0.007; P = 0.319). In our cohort study, 514 nSNA patients (71.5 ± 8.5 years; 459 males) and 208 SNA patients (72.5 ± 7.8 years; 135 males) were included, with a median follow-up duration of 34 months (16–63 months). All baseline characteristics were well balanced after IPTW matching. We found that SNA was associated with a significant risk of adverse limb event (hazard ratio [HR] 2.18, 95% CI 1.09–3.12), yet was not associated with T1AEL, overall survival, or reintervention. In patients without proximal or distal additional procedures (DAP), subgroup analyses suggested a significant risk of T1AEL (Proximal: HR 5.25, 95% CI 1.51–18.23; Distal: HR 5.07, 95% CI 1.60–16.07) and adverse limb event (Proximal: HR 2.27, 95% CI 1.01–5.07; Distal: HR 2.91, 95% CI 1.30–6.54) in SNA patients. However, no noticeable difference was observed in patients with proximal or DAP.

Conclusions:
SNA has a critical influence on hemodynamic and clinical outcomes following EVAR. Appropriate additional procedures may be of great benefit to SNA patients.
Calcium-containing versus calcium-free replacement solution in regional citrate anticoagulation for continuous renal replacement therapy: a randomized controlled trial
Authors: Wei Tiantian , Tang Xin , Zhang Ling , Lin Li , Li Peiyun , Wang Fang , Fu Ping 
Published: December 2022

Abstract

Background:
A simplified protocol for regional citrate anticoagulation (RCA) using a commercial calcium-containing replacement solution, without continuous calcium infusion, is more efficient for use in continuous renal replacement therapy (CRRT). We aim to design a randomized clinical trial to compare the safety and efficacy between calcium-free and calcium-containing replacement solutions in CRRT with RCA.

Methods:
Of the 64 patients receiving RCA-based postdilution continuous venovenous hemodiafiltration (CVVHDF) enrolled from 2017 to 2019 in West China Hospital of Sichuan University, 35 patients were randomized to the calcium-containing group and 29 to the calcium-free replacement solution group. The primary endpoint was circuit lifespan and Kaplan–Meier survival analysis was performed. Secondary endpoints included hospital mortality, kidney function recovery rate, and complications. The amount of 4% trisodium citrate solution infusion was recorded. Serum and effluent total (tCa) and ionized (iCa) calcium concentrations were measured during CVVHDF.

Results:
A total of 149 circuits (82 in the calcium-containing group and 67 in the calcium-free group) and 7609 circuit hours (4335 h vs. 3274 h) were included. The mean circuit lifespan was 58.1 h (95% CI 53.8–62.4 h) in the calcium-containing group vs. 55.3 h (95% CI 49.7–60.9 h, log rank P = 0.89) in the calcium-free group. The serum tCa and iCa concentrations were slightly lower in the calcium-containing group during CRRT, whereas the postfilter iCa concentration was lower in the calcium-free group. Moreover, the mean amounts of 4% trisodium citrate solution infusion were not significantly different between the groups (171.1 ± 15.9 mL/h vs. 169.0 ± 15.1 mL/h, P = 0.49). The mortality (14/35 [40%] vs. 13/29 [45%], P = 0.70) and kidney function recovery rates of AKI patients (19/26, 73% vs. 14/24, 58%, P = 0.27) were comparable between the calcium-containing and calcium-free group during hospitalization, respectively. Six (three in each group) patients showed signs of citrate accumulation in this study.

Conclusions:
When compared with calcium-free replacement solution, RCA-based CVVHDF with calcium-containing replacement solution had a similar circuit lifespan, hospital mortality and kidney outcome. Since the calcium-containing solution obviates the need for a separate venous catheter and a large dose of intravenous calcium solution preparation for continuous calcium supplementation, it is more convenient to be applied in RCA-CRRT practice.

Registration:
Chinese Clinical Trial Registry (
www.chictr.org.cn
, ChiCTR-IPR-17012629)
Signaling pathways of adipose stem cell-derived exosomes promoting muscle regeneration
Authors: Zhu Aoxuan , Liu Na , Shang Yujia , Zhen Yonghuan , An Yang 
Published: December 2022

Abstract
Severe muscle injury is still a challenging clinical problem. Exosomes derived from adipose stem cells (ASC-exos) may be a potential therapeutic tool, but their mechanism is not completely clear. This review aims to elaborate the possible mechanism of ASC-exos in muscle regeneration from the perspective of signal pathways and provide guidance for further study. Literature cited in this review was acquired through PubMed using keywords or medical subject headings, including adipose stem cells, exosomes, muscle regeneration, myogenic differentiation, myogenesis, wingless/integrated (Wnt), mitogen-activated protein kinases, phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/Akt), Janus kinase/signal transducers and activators of transcription, and their combinations. We obtained the related signal pathways from proteomics analysis of ASC-exos in the literature, and identified that ASC-exos make different contributions to multiple stages of skeletal muscle regeneration by those signal pathways.