bluuebunny/crossref_metadata_2025_split huggingface dataset:
Death pluralism: a proposal
Authors: Díaz-Cobacho Gonzalo , Molina-Pérez Alberto , Rodríguez-Arias David 
Published: August 2023

AbstractThe debate over the determination of death has been raging for more than fifty years. Since then, objections against the diagnosis of brain death from family members of those diagnosed as dead-have been increasing and are causing some countries to take novel steps to accommodate people’s beliefs and preferences in the determination of death. This, coupled with criticism by some academics of the brain death criterion, raises some questions about the issues surrounding the determination of death. In this paper, we discuss some of the main approaches to death determination that have been theoretically proposed or currently put into practice and propose a new approach to death determination called "weak pluralism" as a reasonable ethical and political alternative to respect diversity in death determination.
Ten fraction hypofractionated stereotactic body radiotherapy for the management of ultracentral lung tumors: a retrospective analysis of dosimetry, outcomes, and toxicity
Authors: Rock Crosby , Sood Sumit , Cao Ying , Shelton Shary , Chen Ronald C. , Wang Fen 
Published: August 2023

Abstract
Background
The management of ultracentral thoracic tumors with ablative dose of radiotherapy remains challenging given proximity to critical central structures. We report patient outcomes, toxicity, and dosimetry for ultracentrally located tumors with hypofractionated stereotactic body radiotherapy (hfSBRT).

Methods
Seventy-eight individuals (50 initial radiotherapy, 28 re-irradiation) undergoing 10 fraction hfSBRT for ultracentrally located thoracic tumors treated between 2009 and 2020 at a single institution were retrospectively reviewed. Overall survival (OS), progression free survival (PFS), and local control (LC) were calculated. Incidence and grade of treatment related toxicity were evaluated. Dosimetric analysis of treatment plans and critical adjacent OARs was performed.

Results
At a median follow up time of 13 months, 1- and 3-year OS, PFS, and LC were 89%/63%, 37%/18%, and 84%/65%, respectively. Median dose was 65 Gy (BED10 = 107.25 Gy). Median primary bronchial tree maximum dose (Dmax) was 60 Gy (V50 = 0.96 cc). Median esophageal Dmax was 38 Gy (V40 = 0 cc). Median great vessel Dmax was 68 Gy (V50 = 3.53 cc). The most common ≥ grade 2 adverse event was pneumonitis, in 15 individuals (20%). Grade 3 or higher toxicity was observed in 9 individuals (12%): three cases of grade 3 pneumonitis (two re-irradiation, one initial radiotherapy), one grade 3 esophageal stricture following re-irradiation, two grade 3 endobronchial obstructions both following initial radiotherapy, and three grade 5 hemoptysis events (two re-irradiation, one initial radiotherapy). One hemoptysis event was categorized as “possibly” related to treatment, while the remaining two events were categorized as “unlikely” related to treatment in patients with clear evidence of disease progression.

Conclusions
hfSBRT to ultracentral lung tumors delivered over 10 fractions is a safe and effective treatment option, with acceptable rates of toxicity and good rates of tumor control.
Trial registration: IRB registration number 12573.
Discovery and evaluation of active compounds from Xuanfei Baidu formula against COVID-19 via SARS-CoV-2 Mpro
Authors: Zhang Min , Liu Liting , Zhao Yao , Cao Yipeng , Zhu Yan , Han Lifeng , Yang Qi , Wang Yu , Wang Changjian , Zhang Han , Wang Yuefei , Zhang Junhua 
Published: August 2023

Abstract
Background
The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) is still a widespread concern. As one of the effective traditional Chinese medicine (TCM) formulae, Xuanfei Baidu formula (XFBD) shows significant efficacy for treatment of COVID-19 patients. However, its antiviral active compounds and mechanism are still unclear.

Purpose
In this study, we explored the bioactive compounds of XFBD and its antiviral mechanism by integrating computational analysis and experimental testing.

Methods
Focusing on the SARS-CoV-2 main protease (Mpro), as a key target in virus transcription and replication, the fluorescence resonance energy transfer (FRET) assay was built to screen out satisfactory natural inhibitors in XFBD. The surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) were undertaken to verify the binding affinity of ligand-Mpro. Omicron BA.1.1 and BA.2.3 variants were used to evaluate the antiviral activity of the focused compounds in non-cytotoxicity concentrations. For introducing the molecular mechanism, computational modeling and NMR spectra were employed to characterize the ligand-binding modes and identify the ligand-binding site on Mpro.

Results
From a library of 83 natural compounds, acteoside, licochalcone B, licochalcone D, linoleic acid, and physcion showed the satisfactory inhibition effects on Mpro with IC50 ranging from 1.93 to 42.96 µM, which were further verified by SPR. Showing the excellent binding affinity, acteoside was witnessed to gain valuable insights into the thermodynamic signatures by ITC and presented antiviral activity on Omicron BA.1.1 and BA.2.3 variants in vitro. The results revealed that acteoside inhibited Mpro via forming the hydrogen bond between 7-H of acteoside and Mpro.

Conclusion
Acteoside is regarded as a representative active natural compound in XFBD to inhibit replication of SARS-CoV-2, which provides the antiviral evidence and some insights into the identification of SARS-CoV-2 Mpro natural inhibitors.

Graphical Abstract
ZEB1-mediated biogenesis of circNIPBL sustains the metastasis of bladder cancer via Wnt/β-catenin pathway
Authors: Li Yuanlong , Kong Yao , An Mingjie , Luo Yuming , Zheng Hanhao , Lin Yan , Chen Jiancheng , Yang Jin , Liu Libo , Luo Baoming , Huang Jian , Lin Tianxin , Chen Changhao 
Published: August 2023

Abstract
Background
Circular RNAs (circRNAs) circularized by back-splicing of pre-mRNA are widely expressed and affected the proliferation, invasion and metastasis of bladder cancer (BCa). However, the mechanism underlying circRNA biogenesis in mediating the distant metastasis of BCa still unexplored.

Methods
RNA sequencing data between BCa and normal adjacent tissues was applied to identify the differentially expressed circRNAs. The functions of circNIPBL in BCa were investigated via a series of biochemical experiments. The Clinical significance of circNIPBL was examined in a cohort of larger BCa tissues.

Results
In the present study, we identified a novel circRNA (hsa_circ_0001472), circNIPBL, which was significantly upregulated and had great influence on the poor prognosis of patients with BCa. Functionally, circNIPBL promotes BCa metastasis in vitro and in vivo. Mechanistically, circNIPBL upregulate the expression of Wnt5a and activated the Wnt/β-catenin signaling pathway via directly sponged miR-16-2-3p, leading to the upregulation of ZEB1, which triggers the EMT of BCa. Moreover, we revealed that ZEB1 interacted with the flanking introns of exons 2–9 on NIPBL pre-mRNA to trigger circNIPBL biogenesis, thus forming a positive feedback loop. Importantly, circNIPBL overexpression significantly facilitated the distant metastasis of BCa in the orthotopic bladder cancer model, while silencing ZEB1 remarkably blocked the effects of metastasis induced by circNIPBL overexpression.

Conclusions
Our study highlights that circNIPBL-induced Wnt signaling pathway activation triggers ZEB1-mediated circNIPBL biogenesis, which forms a positive feedback loop via the circNIPBL/miR-16-2-3p/Wnt5a/ZEB1 axis, supporting circNIPBL as a novel therapeutic target and potential biomarker for BCa patients.

Graphical Abstract
Acriflavine: an efficient green fluorescent probe for sensitive analysis of aceclofenac in pharmaceutical formulations
Authors: El-Masry Amal A. , Zeid Abdallah M. 
Published: August 2023

AbstractAcriflavine is a multipurpose drug that shows antibacterial, antiviral, antimalarial, and antifungal activities. The remarkable native fluorescence of acriflavine is exploited in analytical chemistry field as an efficient probe for analysis of pharmaceutical and biological compounds. The fluorescent probe action of acriflavine is based on the remarkable fluorescence turning-off via formation of ion-pair complexes with acidic drugs at a specific pH. Herein, the acidic drug aceclofenac is analysed for the first time using acriflavine as a fluorescent probe. Aceclofenac can form an ion-pair complex with acriflavine at pH 8.5, and hence it partially turns off the fluorescence intensity of acriflavine over a concentration range of 1–20 µg/mL. The fluorescence quenching was monitored at 502 nm following an excitation at 265 or 451 nm. The reaction stoichiometry between acriflavine and aceclofenac was found to be 1:1 using limiting logarithmic method. The type of quenching was confirmed to be static using Stern–Volmer plot. The method showed low values of quantitation limit (0.89 µg/mL) and detection limit (0.29 µg/mL). Moreover, the method was linear (r = 0.9999), accurate, precise (RSD < 1.7%), robust, and specific. The proposed method was successfully employed to analyse aceclofenac in its dosage forms with high %recovery (98–101%). Additionally, GAPI and AGREE approaches were used to guarantee the suggested techniques' greenness, and the findings showed an excellent level of greenness.
Unravelling and engineering an operon involved in the side-chain degradation of sterols in Mycolicibacterium neoaurum for the production of steroid synthons
Authors: Zhao Yun-Qiu , Liu Yong-Jun , Song Lu , Yu Dingyan , Liu Kun , Liu Ke , Gao Bei , Tao Xin-Yi , Xiong Liang-Bin , Wang Feng-Qing , Wei Dong-Zhi 
Published: August 2023

Abstract
Background
Harnessing engineered Mycolicibacteria to convert cheap phytosterols into valuable steroid synthons is a basic way in the industry for the production of steroid hormones. Thus, C-19 and C-22 steroids are the two main types of commercial synthons and the products of C17 side chain degradation of phytosterols. During the conversion process of sterols, C-19 and C-22 steroids are often produced together, although one may be the main product and the other a minor byproduct. This is a major drawback of the engineered Mycolicibacteria for industrial application, which could be attributed to the co-existence of androstene-4-ene-3,17-dione (AD) and 22-hydroxy-23,24-bisnorchol-4-ene-3-one (HBC) sub-pathways in the degradation of the sterol C17 side chain. Since the key mechanism underlying the HBC sub-pathway has not yet been clarified, the above shortcoming has not been resolved so far.

Results
The key gene involved in the putative HBC sub-pathway was excavated from the genome of M. neoaurum by comparative genomic analysis. Interestingly, an aldolase- encoding gene, atf1, was identified to be responsible for the first reaction of the HBC sub-pathway, and it exists as a conserved operon along with a DUF35-type gene chsH4, a reductase gene chsE6, and a transcriptional regulation gene kstR3 in the genome. Subsequently, atf1 and chsH4 were identified as the key genes involved in the HBC sub-pathway. Therefore, an updated strategy was proposed to develop engineered C-19 or C-22 steroid-producing strains by simultaneously modifying the AD and HBC sub-pathways. Taking the development of 4-HBC and 9-OHAD-producing strains as examples, the improved 4-HBC-producing strain achieved a 20.7 g/L production titer with a 92.5% molar yield and a 56.4% reduction in byproducts, and the improved 9-OHAD producing strain achieved a 19.87 g/L production titer with a 94.6% molar yield and a 43.7% reduction in byproduct production.

Conclusions
The excellent performances of these strains demonstrated that the primary operon involved in the HBC sub-pathway improves the industrial strains in the conversion of phytosterols to steroid synthons.
DNA methylation as a triage marker for colposcopy referral in HPV-based cervical cancer screening: a systematic review and meta-analysis
Authors: Salta Sofia , Lobo João , Magalhães Bruno , Henrique Rui , Jerónimo Carmen 
Published: August 2023

Abstract
Background
Screening plays a key role in secondary prevention of cervical cancer. High-risk human papillomavirus (hrHPV) testing, a highly sensitive test but with limited specificity, has become the gold standard frontline for screening programs. Thus, the importance of effective triage strategies, including DNA methylation markers, has been emphasized. Despite the potential reported in individual studies, methylation markers still require validation before being recommended for clinical practice. This systematic review and meta-analysis aimed to evaluate the performance of DNA methylation-based biomarkers for detecting high-grade intraepithelial lesions (HSIL) in hrHPV-positive women.

Methods
Hence, PubMed, Scopus, and Cochrane databases were searched for studies that assessed methylation in hrHPV-positive women in cervical scrapes. Histologically confirmed HSIL was used as endpoint and QUADAS-2 tool enabled assessment of study quality. A bivariate random-effect model was employed to pool the estimated sensitivity and specificity as well as positive (PPV) and negative (NPV) predictive values.

Results
Twenty-three studies were included in this meta-analysis, from which cohort and referral population-based studies corresponded to nearly 65%. Most of the women analyzed were Dutch, and CADM1, FAM19A4, MAL, and miR124-2 were the most studied genes. Pooled sensitivity and specificity were 0.68 (CI 95% 0.63–0.72) and 0.75 (CI 95% 0.71–0.80) for cervical intraepithelial neoplasia (CIN) 2+ detection, respectively. For CIN3+ detection, pooled sensitivity and specificity were 0.78 (CI 95% 0.74–0.82) and 0.74 (CI 95% 0.69–0.78), respectively. For pooled prevalence, PPV for CIN2+ and CIN3+ detection were 0.514 and 0.392, respectively. Furthermore, NPV for CIN2+ and CIN3+ detection were 0.857 and 0.938, respectively.

Conclusions
This meta-analysis confirmed the great potential of DNA methylation-based biomarkers as triage tool for hrHPV-positive women in cervical cancer screening. Standardization and improved validation are, however, required. Nevertheless, these markers might represent an excellent alternative to cytology and genotyping for colposcopy referral of hrHPV-positive women, allowing for more cost-effective screening programs.
DNA methylation and 28-year cardiovascular disease risk in type 1 diabetes: the Epidemiology of Diabetes Complications (EDC) cohort study
Authors: Miller Rachel G. , Mychaleckyj Josyf C. , Onengut-Gumuscu Suna , Feingold Eleanor , Orchard Trevor J. , Costacou Tina 
Published: August 2023

Abstract
Background
The potential for DNA methylation (DNAm) as an early marker for cardiovascular disease (CVD) and how such an association might differ by glycemic exposure has not been examined in type 1 diabetes, a population at increased CVD risk. We thus performed a prospective epigenome-wide association study of blood leukocyte DNAm (EPIC array) and time to CVD incidence over 28 years in a childhood-onset (< 17 years) type 1 diabetes cohort, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (n = 368 with DNA and no CVD at baseline), both overall and separately by glycemic exposure, as measured by HbA1c at baseline (split at the median: < 8.9% and ≥ 8.9%). We also assessed whether DNAm-CVD associations were independent of established cardiometabolic risk factors, including body mass index, estimated glucose disposal rate, cholesterol, triglycerides, blood pressure, pulse rate, albumin excretion rate, and estimated glomerular filtration rate.

Results
CVD (first instance of CVD death, myocardial infarction, coronary revascularization, ischemic ECG, angina, or stroke) developed in 172 participants (46.7%) over 28 years. Overall, in Cox regression models for time to CVD, none of the 683,597 CpGs examined reached significance at a false discovery rate (FDR) ≤ 0.05. In participants with HbA1c < 8.9% (n = 180), again none reached FDR ≤ 0.05, but three were associated at the a priori nominal significance level FDR ≤ 0.10: cg07147033 in MIB2, cg12324048 (intergenic, chromosome 3), and cg15883830 (intergenic, chromosome 1). In participants with HbA1c ≥ 8.9% (n = 188), two CpGs in loci involved in calcium channel activity were significantly associated with CVD (FDR ≤ 0.05): cg21823999 in GPM6A and cg23621817 in CHRNA9; four additional CpGs were nominally associated (FDR ≤ 0.10). In participants with HbA1c ≥ 8.9%, DNAm-CVD associations were only modestly attenuated after cardiometabolic risk factor adjustment, while attenuation was greater in those with HbA1c < 8.9%. No pathways were enriched in those with HbA1c < 8.9%, while pathways for calcium channel activity and integral component of synaptic membrane were significantly enriched in those with HbA1c ≥ 8.9%.

Conclusions
These results provide novel evidence that DNAm at loci involved in calcium channel activity and development may contribute to long-term CVD risk beyond known risk factors in type 1 diabetes, particularly in individuals with greater glycemic exposure, warranting further study.
Total transcriptome analysis of Candida auris planktonic cells exposed to tyrosol
Authors: Balla Noémi , Jakab Ágnes , Kovács Fruzsina , Ragyák Ágota , Tóth Zoltán , Balázsi Dávid , Forgács Lajos , Bozó Aliz , Al Refai Farah , Borman Andrew M , Majoros László , Kovács Renátó 
Published: August 2023

AbstractTyrosol, a secondary metabolite of Candida species, regulates fungal morphogenesis, and its application may represent a novel innovative therapy against emerging multi-resistant fungal superbug such as Candida auris. In the current study, the effects of tyrosol on growth, redox homeostasis, intracellular microelement contents and activities of virulence-related enzymes released by C. auris were examined. To gain further information about the effect of tyrosol exposure, we revealed gene transcriptional changes using total transcriptome sequencing (RNA-Seq). At a concentration of 15 mM, tyrosol significantly decrease the growth of fungal cells within 2 h of its addition (5.6 × 107±1.2 × 107 and 2.5 × 107±0.6 × 107 colony forming unit/mL for control and tyrosol-treated cells, respectively). Furthermore, it enhanced the release of reactive oxygen species as confirmed by a dichlorofluorescein (DCF) assay (7.3 ± 1.8 [nmol DCF (OD640)−1] versus 16.8 ± 3.9 [nmol DCF (OD640)−1]), which was coincided with elevated superoxide dismutase, catalase and glutathione peroxidase activities. Tyrosol exerted in a 37%, 25%, 34% and 55% decrease in intracellular manganese, iron, zinc and copper contents, respectively, compared to control cells. The tyrosol treatment led to a 142 and 108 differentially transcripted genes with at least a 1.5-fold increase or decrease in transcription, respectively. Genes related to iron and fatty acid metabolism as well as nucleic acid synthesis were down-regulated, whereas those related to the antioxidative defence, adhesion and oxoacid metabolic processes were up-regulated. This study shows that tyrosol significantly influences growth, intracellular physiological processes and gene transcription in C. auris, which could highly support the development of novel treatment approaches against this important pathogen.
APP family member dimeric complexes are formed predominantly in synaptic compartments
Authors: Schilling Sandra , August Alexander , Meleux Mathieu , Conradt Carolin , Tremmel Luisa M. , Teigler Sandra , Adam Virginie , Müller Ulrike C. , Koo Edward H. , Kins Stefan , Eggert Simone 
Published: August 2023

AbstractBackgroundThe amyloid precursor protein (APP), a key player in Alzheimer’s disease (AD), is part of a larger gene family, including the APP like proteins APLP1 and APLP2. They share similar structures, form homo- and heterotypic dimers and exhibit overlapping functions.ResultsWe investigated complex formation of the APP family members via two inducible dimerization systems, the FKBP-rapamycin based dimerization as well as cysteine induced dimerization, combined with co-immunoprecipitations and Blue Native (BN) gel analyses. Within the APP family, APLP1 shows the highest degree of dimerization and high molecular weight (HMW) complex formation. Interestingly, only about 20% of APP is dimerized in cultured cells whereas up to 50% of APP is dimerized in mouse brains, independent of age and splice forms. Furthermore, we could show that dimerized APP originates mostly from neurons and is enriched in synaptosomes. Finally, BN gel analysis of human cortex samples shows a significant decrease of APP dimers in AD patients compared to controls.ConclusionsTogether, we suggest that loss of full-length APP dimers might correlate with loss of synapses in the process of AD.
In-situ monitoring of 3He/4He in summit gases of Kilauea Volcano (Hawaii) prior to the 2020 eruption
Authors: McMurtry Gary M. , Dasilveira Luis A. 
Published: August 2023

AbstractWe present He isotope (3He/4He) data from a fumarole and near-ground gases measured in-situ at the Sulfur Banks solfatara field at the summit of Kilauea Volcano, Hawaii. We used a field-deployable mass-spectrometer-based system: the Helium Isotope Monitor (HIM) previously described in McMurtry et al. (2019a, b). The in-situ instrument was deployed using solar power for the first time and results were ground-truthed against data determined using conventional gas analytical and noble gas mass spectrometry techniques. The HIM instrumentation, associated Vent Gas Purification System (VGPS), and related sampling equipment and strategy are described. Cloudy and rainy weather conditions hampered the deployment, which was reorganized to reduce power loads and resulted in less sampling than planned. Nevertheless, we obtained daily sampling of the volcanic vent gas. Results from the Old Well fumarole indicate a ~ 2 RA increase in 3He/4He on the day of the December 20th, 2020 eruption of nearby Halema‘uma‘u Crater, reaching 17.0 RA using the in-situ instrument and 16.0 ± 0.67 RA using conventional techniques. This finding suggests that a new 3He-enriched magma source is driving the current, ongoing eruption phase of Kilauea and, if so, confirms that the deep summit caldera fault system that hosts the Sulfur Banks field is connected to the Halema‘uma‘u Crater magmatic system. Overall, these findings illustrate how time-series helium isotope data, which are well established by ongoing discrete monitoring at low temporal resolution, can help forecast forthcoming eruptive events that may not be foreseen by other volcanic monitoring methods.