bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclin D-CDK4 Disulfide Bond Attenuates Pulmonary Vascular Cell Proliferation
Authors: Knight Hannah , Abis Giancarlo , Kaur Manpreet , Green Hannah L.H. , Krasemann Susanne , Hartmann Kristin , Lynham Steven , Clark James , Zhao Lan , Ruppert Clemens , Weiss Astrid , Schermuly Ralph T. , Eaton Philip , Rudyk Olena 
Published: November 2023

BACKGROUND:
Pulmonary hypertension (PH) is a chronic vascular disease characterized, among other abnormalities, by hyperproliferative smooth muscle cells and a perturbed cellular redox and metabolic balance. Oxidants induce cell cycle arrest to halt proliferation; however, little is known about the redox-regulated effector proteins that mediate these processes. Here, we report a novel kinase-inhibitory disulfide bond in cyclin D-CDK4 (cyclin-dependent kinase 4) and investigate its role in cell proliferation and PH.

METHODS:
Oxidative modifications of cyclin D-CDK4 were detected in human pulmonary arterial smooth muscle cells and human pulmonary arterial endothelial cells. Site-directed mutagenesis, tandem mass-spectrometry, cell-based experiments, in vitro kinase activity assays, in silico structural modeling, and a novel redox-dead constitutive knock-in mouse were utilized to investigate the nature and definitively establish the importance of CDK4 cysteine modification in pulmonary vascular cell proliferation. Furthermore, the cyclin D-CDK4 oxidation was assessed in vivo in the pulmonary arteries and isolated human pulmonary arterial smooth muscle cells of patients with pulmonary arterial hypertension and in 3 preclinical models of PH.

RESULTS:
Cyclin D-CDK4 forms a reversible oxidant-induced heterodimeric disulfide dimer between C7/8 and C135, respectively, in cells in vitro and in pulmonary arteries in vivo to inhibit cyclin D-CDK4 kinase activity, decrease Rb (retinoblastoma) protein phosphorylation, and induce cell cycle arrest. Mutation of CDK4 C135 causes a kinase-impaired phenotype, which decreases cell proliferation rate and alleviates disease phenotype in an experimental mouse PH model, suggesting this cysteine is indispensable for cyclin D-CDK4 kinase activity. Pulmonary arteries and human pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension display a decreased level of CDK4 disulfide, consistent with CDK4 being hyperactive in human pulmonary arterial hypertension. Furthermore, auranofin treatment, which induces the cyclin D-CDK4 disulfide, attenuates disease severity in experimental PH models by mitigating pulmonary vascular remodeling.

CONCLUSIONS:
A novel disulfide bond in cyclin D-CDK4 acts as a rapid switch to inhibit kinase activity and halt cell proliferation. This oxidative modification forms at a critical cysteine residue, which is unique to CDK4, offering the potential for the design of a selective covalent inhibitor predicted to be beneficial in PH.
Intracranial Atherosclerosis Disease Associated With Cognitive Impairment and Dementia: Systematic Review and Meta‐Analysis
Authors: Sabayan Behnam , Goudarzi Roham , Ji Yuekai , Borhani‐Haghighi Afshin , Olson‐Bullis Barbara A. , Murray Anne M. , Sedaghat Sanaz 
Published: November 2023

Background
Intracranial atherosclerosis disease (ICAD) alters cerebrovascular hemodynamics and brain structural integrity. Multiple studies have evaluated the link between ICAD and cognitive impairment, with mixed results. This study aims to systematically review and summarize the current evidence on this link.

Methods and Results
PubMed, EMBASE, PsycInfo, and Web of Science were searched from 2000 to 2023 without language restriction. Cross‐sectional and prospective cohort studies as well as postmortem studies were included. Studies containing data on the link between ICAD, defined as at least 50% stenosis in 1 intracranial vessel, and cognitive impairment and dementia were screened by 2 independent reviewers. A total of 22 (17 observational and 5 postmortem) unique studies, comprising 11 184 individuals (average age range, 59.8–87.6 years; 45.7% women; 36.5% Asian race), were included in the systematic review. Seven of 10 cross‐sectional studies and 5 of 7 prospective studies showed a significant association between ICAD and cognitive impairment. In the pooled analysis, ICAD was associated with greater cognitive impairment (measure of association, 1.87 [95% CI, 1.49–2.35]). Meta‐regression analyses did not show a significant impact of age, sex, and race. All postmortem studies showed that patients with Alzheimer disease and vascular dementia had a higher burden of ICAD compared with controls.

Conclusions
This study shows that ICAD is associated with cognitive impairment and dementia across age, sex, and race groups. Our findings may underscore the need to develop individualized dementia preventive care plans in patients with ICAD.
“Wars without Gun Smoke”: Global Supply Chains, Power Transitions, and Economic Statecraft
Authors: Chen Ling S. , Evers Miles M. 
Published: November 2023

Abstract
Conventional wisdom holds that conflict is highly likely during a power transition between declining and rising powers. The spread of global supply chains has provided new economic weapons for great powers waging these conflicts, but the businesses that constitute global supply chains can make it harder or easier for them to do so. A structural theory of business-state relations shows how power transitions affect a state's ability to exercise economic statecraft. As a dominant power and a rising power approach parity, they face structural incentives to use economic statecraft to decouple their economies. The resulting threat to businesses’ profits changes business-state relations: high-value businesses within the dominant power tend to oppose their state's use of economic statecraft, whereas low-value businesses within the rising power tend to cooperate with their state's use of economic statecraft. The Anglo-German power transition from 1890 to 1914 and the U.S.-China power transition since 1990 illustrate the theory. The findings shift scholarly debates on the use of economic statecraft in modern great power competition and have policy implications for weaponizing supply chains against rising powers like China.
Potential prognostic biomarkers of hepatocellular carcinoma based on 4D label-free quantitative proteomics analysis pilot investigation
Authors: Suo Lida , Liang Xiangnan , Zhang Weibin , Gao Mingwei , Ma Taiheng , Hu Daosheng , Song Yilin , Gao Zhenming 
Published: November 2023

Background Hepatocellular carcinoma carries a poor prognosis and poses a serious threat to global health. Currently, there are few potential prognostic biomarkers available for the prognosis of hepatocellular carcinoma. Methods This pilot study used 4D label-free quantitative proteomics to compare the proteomes of hepatocellular carcinoma and adjacent non-tumor tissue. A total of 66,075 peptides, 6363 identified proteins, and 772 differentially expressed proteins were identified in specimens from three hepatocellular carcinoma patients. Through functional enrichment analysis of differentially expressed proteins by Gene Ontology, KEGG pathway, and protein domain, we identified proteins with similar functions. Results Twelve differentially expressed proteins (RPL17, RPL27, RPL27A, RPS5, RPS16, RSL1D1, DDX18, RRP12, TARS2, YARS2, MARS2, and NARS1) were selected for identification and validation by parallel reaction monitoring. Subsequent Western blotting confirmed overexpression of RPL27, RPS16, and TARS2 in hepatocellular carcinoma compared to non-tumor tissue in 16 pairs of clinical samples. Analysis of The Cancer Genome Atlas datasets associated the increased expression of these proteins with poor prognosis. Tissue microarray revealed a negative association between high expression of RPL27 and TARS2 and the prognosis of hepatocellular carcinoma patients, although RPS16 was not significant. Conclusions These data suggest that RPL27 and TARS2 play an important role in hepatocellular carcinoma progression and may be potential prognostic biomarkers of overall survival in hepatocellular carcinoma patients.
Correlation analysis between cytokines’ profile, autoimmune antibodies and the duration of type 1 diabetes: A case control study in a specialized children’s centre in Riyadh
Authors: Al-Dubayee Mohammed , Babiker Amir , Alkewaibeen Abdulaziz , Alkhalifah Abdulrahman , Alanazi Tammam , Nogoud Maysa , Alotaibi Anas , Alotaibi Faisal , Almetairi Firas , Alrowaily Mohammed A , Masuadi Emad , Nasr Amre 
Published: November 2023

Objective: The aim of this study was to investigate the role of cytokines in children with T1D living in Saudi Arabia and their correlation with disease duration and autoimmune antibody markers. Methods: A case-control study was conducted in the endocrine clinic of King Abdullah Specialized Children’s Hospital in Riyadh. A total of 274 T1D and healthy control children were enrolled in the study. 5 mL of venous blood samples were collected in the morning after 9 to 12 h of fasting in BD Vacutainer® EDTA tubes and centrifuged at 250 g for 15 min at. Plasma was then stored at −20°C for detection of anti-islet, anti-GAD antibodies (Abs), and C-peptide using commercial ELISA kits from Thermo Fisher Scientific. The levels of cytokines were measured using commercial sandwich ELISA kits from Abcam. Results: Median differences in cytokine levels (IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-13, IL-18, IL-21, IL-35, and IL-37) were significantly higher in T1D patients compared with healthy controls ( p-value < .001). Spearman’s Rho correlation indicated that TNFα, IL-1β, IL-4, IL-10, IL-13, and IL-21 correlated significantly with T1D Abs ( p-value = .01). HbA1C correlated negatively with IL-35 and IL-37, and positively with IL-18 ( p-value = .01). Linear regression analysis showed a significant increase in anti-glutamic acid antibodies (GAD) in patients with >3 years of T1D duration. Conclusion: Autoantibodies remained positive at high levels in our patients over a 3-year duration of the disease and correlated with specific cytokines. The clear correlations with disease duration and profile of specific cytokines could be targets for future therapeutic interventions.
Using Patient-Centered Dissemination and Implementation Frameworks and Strategies in Palliative Care Settings for Improved Quality of Life and Health Outcomes: A Scoping Review
Authors: Sacca Lea , Lobaina Diana , Burgoa Sara , Rao Meera , Jhumkhawala Vama , Zapata Sheena M. , Issac Michelle , Medina Suleyki 
Published: November 2023

Background There is a need for patient-provider dissemination and implementation frameworks, strategies, and protocols in palliative care settings for a holistic approach when it comes to addressing pain and other distressing symptoms affecting the quality of life, function, and independence of patients with chronic illnesses. The purpose of this scoping review is to explore patient-centered D&I frameworks and strategies that have been adopted in PC settings to improve behavioral and environmental determinants influencing health outcomes through evidence-based programs and protocols. Methods The five step Arksey and O’Malley’s (2005) York methodology was adopted as a guiding framework: (1) identifying research questions; (2) searching for relevant studies; (3) selecting studies relevant to the research questions; (4) charting the data; and (5) collating, summarizing, and reporting results. Results Only 6 out of the 38 (16%) included studies applied a D&I theory and/or framework. The RE-AIM framework was the most prominently cited (n = 3), followed by the Diffusion of Innovation Model (n = 2), the CONNECT framework (n = 1), and the Transtheoretical Stages of Change Model (n = 1). The most frequently reported ERIC strategy was strategy #6 “Develop and organize quality monitoring systems”, as it identified in all 38 of the included studies. Conclusion This scoping review identifies D&I efforts to translate research into practice in U.S. palliative care settings. Results may contribute to enhancing future D&I initiatives for dissemination/adaptation, implementation, and sustainability efforts aiming to improve patient health outcomes and personal satisfaction with care received.
Results of a hemodialysis vascular access routine ultrasound surveillance protocol and frequency of surveillance guided pre-emptive access maintenance interventions
Authors: Giannikouris Ioannis E. , Georgiadis George S. , Giannakopoulos Triantafyllos , Passadakis Ploumis , Spiliopoulos Stavros 
Published: November 2023

Background: To evaluate the implementation of routine surveillance using ultrasound on hemodialysis vascular access (VA) outcomes and determine the number and frequency of corrective, surveillance-guided procedures performed. Methods: Multicenter, prospective, observational study that includes consecutive hemodialysis patients receiving therapy from native arteriovenous fistulae (AVF) or grafts (AVG). Participants were assigned to a routine VA Color Doppler ultrasound surveillance (DUS) protocol from January 2019 to December 2021. Patients were referred for corrective procedures (endovascular or surgical) based on clinical or DUS findings (pre-emptive procedures; PEP). Primary endpoint was the estimation of primary unassisted (PUP) and secondary patency (SP) rates. Secondary endpoints were the determination of the number and frequency of PEP and VA survival rates. Results: In total, 223 patients with 243 VA (192 AVF and 51 AVG) were included. Access PUP and SP rates were 83% and 93% at 12 months, 75% and 88% at 24 months, and 72% and 83% at 36 months follow-up. Autologous fistulae PUP and SP were 89% and 96% at 12 months, 81% and 93% at 24 months, and 80% and 89% at 36 months, respectively. Graft PUP and SP were 56% and 80% at 12 months, 44% and 65% at 24 months, and 39% and 54% at 36 months, respectively. In total, 56 corrective procedures (38/56 PEP; 65.5%) were performed (0.13 procedures/year), of which 34 were in AVF patients (0.09 procedures/year) and 22 in AVG patients (0.40 procedures/year). Overall, 33 VA losses occurred (0.06 failures/year), 17 in AVF (0.04 failures/year), and 16 in AVG patients (0.20 failures/year). Conclusion: The use of DUS resulted in the timely diagnosis of dysfunction, satisfactory overall VA survival, and patency rates, with a low PEP frequency. Randomized controlled trials are required to establish the value of DUS surveillance on access patency and whether DUS-guided interventions could improve VA outcomes.
Contrast-Enhanced MRI in Women with Endometrial Cancer: Dynamic Versus Single-Phase Acquisitions
Authors: Lee Myoung Seok , Moon Min Hoan , Kim Taek Min , Jang Siwon , Oh Sohee , Cho Jeong Yeon 
Published: November 2023

Background: The 2019 European Society of Urogenital Radiology (ESUR) guidelines for endometrial cancer recommend performing either dynamic contrast-enhanced magnetic resonance imaging (CE MRI) or single-phase CE MRI. However, no study has directly compared these options. Therefore, this study compared dynamic versus single-phase CE MRI for the evaluation of myometrial invasion in women with endometrial cancer. Methods: This retrospective, single-institution comparative study was conducted among women with surgically proven endometrial cancer, including 30 consecutive women with single-phase CE MRI and 30 age- and pathologic stage-matched women with dynamic CE MRI. Three readers independently compared dynamic and single-phase CE MRI in terms of the tumor-myometrium signal intensity (SI) difference ratio, depth of myometrial invasion, image quality, and image number. Pathologic findings served as a reference standard for the depth of myometrial invasion. Results: The estimated mean SI difference ratios of dynamic CE MRI and single-phase CE MRI fell within an equivalence margin of 0.05 (90% confidence intervals [CIs] = [−0.0497 to −0.0165], [−0.0226 to −0.0403], and [−0.0429 to −0.0433], respectively, for readers A, B, and C). The area under the receiver operating characteristic curve for the detection of deep myometrial invasion was not significantly different between the acquisitions ( P = .3315, P = .3345, and P = .8593, respectively). Single-phase CE MRI showed significantly better image quality than dynamic CE MRI ( P = .0143, P = .0042, and P = .0066, respectively), while the median number of images for dynamic CE MRI was 2.4 times higher than that for single-phase CE MRI. Conclusion: Single-phase acquisition may be a better option for CE MRI in women with endometrial cancer than dynamic acquisition.
Bilingual children display comparative strength using prosodic cues for pragmatic word learning
Authors: Lorge Isabelle , Katsos Napoleon 
Published: November 2023

Aims/objectives/research questions: Previous studies indicate differences in the way children who grow up with two languages use socio-pragmatic cues to help them identify referents and learn new words, yet the nature of these differences (executive control, better attention to social cues, or pragmatic reasoning) has not been investigated. Design/methodology/approach: This study examined 270 monolingual and bilingually exposed 4–6-year-old children’s performance in 2 tasks using different prosodic cues (contrastive stress and emotional affect) for fast mapping. It avoids a design where children have to inhibit an irrelevant cue, which would enhance the role of differences in executive control. Data/analysis: We performed statistical analyses using a logistic regression mixed model. Findings/conclusions: The bilingually exposed group performed lower than monolinguals in a control condition involving structural language (0.83 vs. 0.92). However, they performed on par with monolinguals in a pragmatic condition when considering only semantically correct answers in both groups (0.55 vs. 0.58), and even displayed significant comparative strength in the task once control performance and demographic variables were taken into account. This effect appeared when the task required reasoning about the speaker’s communicative intentions (contrastive stress) but not when children merely had to recognise a communicative cue (emotional affect). Originality: No study has so far investigated the socio-pragmatic abilities of bilingual children using a task that did not require inhibiting an irrelevant cue. Implications: These findings have implications for bilingual education and a better understanding of the impact of being educated in two languages. We also draw attention to implications regarding the existence of different types of pragmatic skills which may have differing developmental timelines and rely on different sets of abilities.
Non-participation in a health examination survey in a rural-provincial area of Denmark – results from the Lolland-Falster Health Study (LOFUS)
Authors: Lyngsøe Signe , Lophaven Søren , Jepsen Randi , Holmager Therese , Janssens Astrid , Lynge Elsebeth 
Published: November 2023

Background: Lolland-Falster Health Study (LOFUS) was a health examination survey that included self-administered questionnaires, clinical examinations, and the collection of biological samples, undertaken in 2016–2020 in a rural, socioeconomically deprived area with the lowest life expectancy in Denmark. The aim of this study was to examine the determinants of non-participation in LOFUS to evaluate the extent to which LOFUS data reflected the general population of the area. Methods: LOFUS invited randomly selected subjects together with their entire household. As determinants of non-participation, we analyzed age, sex, municipality of residency, citizenship, residency status, socioeconomic status, invitation type, and year of invitation. Relative risk regression was used to estimate the association between determinants and non-participation rate, mutually adjusted for other determinants. Results: In total, 53,313 subjects were invited of whom 18,949 (36%) participated. In the multivariable analysis, men had a 3% higher non-participation rate than women; subjects with citizenship other than Danish had a 3% higher non-participation rate than Danes. In-migrants had 6% higher non-participation than long-term residents. Compared with self-supported subjects aged 30–64, both publicly supported subjects of this age and younger and older subjects had higher non-participation rates: 16%, 16%, and 13%, respectively. Compared with self-supported, long-term residents, publicly supported in-migrants had 23% higher non-participation. Conclusions: Only about one third of subjects invited to LOFUS participated. Yet, this is a relatively high participation rate compared with other recent health examination surveys in Denmark. Furthermore, there was a relatively flat social gradient in the non-participation rate across the studied determinants.
Effects of Hypericin on Cultured Primary Normal Human Dermal Fibroblasts Under Increased Oxidative Stress
Authors: Anastasiou Ioanna A. , Sarantis Panagiotis , Eleftheriadou Ioanna , Tentolouris Konstantinos N. , Mourouzis Iordanis , Karamouzis Michalis V. , Pantos Konstantinos , Tentolouris Nikolaos 
Published: November 2023

Introduction Wound healing is a dynamic process that begins with inflammation, proliferation, and cell migration of a variety of fibroblast cells. As a result, identifying possible compounds that may improve fibroblast cell wound healing capacity is crucial. Hypericin is a natural quinine that has been reported to possess a wide range of pharmacological profiles, including antioxidant and anti-inflammatory, activities. Herein we examined for the first time the effect of hypericin on normal human dermal fibroblasts (NHDFs) under oxidative stress. Methods NHDF were exposed to different concentrations of hypericin (0-20 μg/mL) for 24 h. For the oxidative stress evaluation, H2O2 was used as a stressor factor. Cell viability and proliferation levels were evaluated. Immunohistochemistry and flow cytometry were performed to assess cell apoptosis levels and with confocal microscopy we identified the mitochondrial superoxide production under oxidative stress and after the treatment with hypericin. Scratch assay was performed under oxidative stress to evaluate the efficacy of hypericin in wound closure. To gain an insight into the molecular mechanisms of hypericin bioactivity, we analyzed the relative expression levels of genes involved in oxidative response and in wound healing process. Results We found that the exposure of NHDF to hypericin under oxidative stress resulted in an increase in cell viability and ATP levels. We found a decrease in apoptosis and mitochondrial superoxide levels after treatment with hypericin. Moreover, treatment with hypericin reduced wound area and promoted wound closure. The levels of selected genes showed that hypericin upregulated the levels of antioxidants genes. Moreover, treatment with hypericin in wound under oxidative stress downregulated the levels of proinflammatory cytokines, and metalloproteinases; and upregulated transcription factors and extracellular matrix genes. Conclusion These findings indicated that hypericin possesses significant in vitro antioxidant activity on NHDF and provide new insights into its potential beneficial role in the management of diabetic ulcers.