bluuebunny/crossref_metadata_2025_split huggingface dataset:
mTOR Signaling Promotes Rapid m6A mRNA Methylation to Regulate NK-Cell Activation and Effector Functions
Authors: Meng Meng , Zhong Zhaoyang , Song Liang , Zhang Zhaohui , Yin Xiaofeng , Xie Xiqiang , Tian Lei , Wu Wei , Yang Yao , Deng Yafei , Peng Hongyan , Wu Shuting , Ran Guanghe , Lin Yuqing , Lai Qiangqiang , Bi Qinghua , Yan Fulin , Ji Yan , Wang Yang , Li Xiaohui , Yi Ping , Yu Jianhua , Deng Youcai 
Published: April 2024

Abstract
NK cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of a large number of genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment (TME). Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double-knockout of METTL3/14 more significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing, we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTOR complex 1–S-adenosylmethionine signal axis in regulating NK-cell activation and effector functions.
Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis
Authors: Mocci Giuseppe , Sukhavasi Katyayani , Örd Tiit , Bankier Sean , Singha Prosanta , Arasu Uma Thanigai , Agbabiaje Olayinka Oluwasegun , Mäkinen Petri , Ma Lijiang , Hodonsky Chani J. , Aherrahrou Redouane , Muhl Lars , Liu Jianping , Gustafsson Sonja , Byandelger Byambajav , Wang Ying , Koplev Simon , Lendahl Urban , Owens Gary K. , Leeper Nicholas J. , Pasterkamp Gerard , Vanlandewijck Michael , Michoel Tom , Ruusalepp Arno , Hao Ke , Ylä-Herttuala Seppo , Väli Marika , Järve Heli , Mokry Michal , Civelek Mete , Miller Clint J. , Kovacic Jason C. , Kaikkonen Minna U. , Betsholtz Christer , Björkegren Johan L.M. 
Published: April 2024

BACKGROUND:
While our understanding of the single-cell gene expression patterns underlying the transformation of vascular cell types during the progression of atherosclerosis is rapidly improving, the clinical and pathophysiological relevance of these changes remains poorly understood.

METHODS:

Single-cell RNA sequencing data generated with SmartSeq2 (≈8000 genes/cell) in 16 588 single cells isolated during atherosclerosis progression in
Ldlr

−/−

Apob

100/100

mice with human-like plasma lipoproteins and from humans with asymptomatic and symptomatic carotid plaques was clustered into multiple subtypes. For clinical and pathophysiological context, the advanced-stage and symptomatic subtype clusters were integrated with 135 tissue-specific (atherosclerotic aortic wall, mammary artery, liver, skeletal muscle, and visceral and subcutaneous, fat) gene-regulatory networks (GRNs) inferred from 600 coronary artery disease patients in the STARNET (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task) study.

RESULTS:

Advanced stages of atherosclerosis progression and symptomatic carotid plaques were largely characterized by 3 smooth muscle cells (SMCs), and 3 macrophage subtype clusters with extracellular matrix organization/osteogenic (SMC), and M1-type proinflammatory/Trem2-high lipid-associated (macrophage) phenotypes. Integrative analysis of these 6 clusters with STARNET revealed significant enrichments of 3 arterial wall GRNs: GRN33 (macrophage), GRN39 (SMC), and GRN122 (macrophage) with major contributions to coronary artery disease heritability and strong associations with clinical scores of coronary atherosclerosis severity. The presence and pathophysiological relevance of GRN39 were verified in 5 independent RNAseq data sets obtained from the human coronary and aortic artery, and primary SMCs and by targeting its top-key drivers,
FRZB
and
ALCAM
in cultured human coronary artery SMCs.

CONCLUSIONS:
By identifying and integrating the most gene-rich single-cell subclusters of atherosclerosis to date with a coronary artery disease framework of GRNs, GRN39 was identified and independently validated as being critical for the transformation of contractile SMCs into an osteogenic phenotype promoting advanced, symptomatic atherosclerosis.
Mitochondrial CypD Acetylation Promotes Endothelial Dysfunction and Hypertension
Authors: Dikalova Anna , Fehrenbach Daniel , Mayorov Vladimir , Panov Alexander , Ao Mingfang , Lantier Louise , Amarnath Venkataraman , Lopez Marcos G. , Billings Frederic T. , Sack Michael N. , Dikalov Sergey 
Published: April 2024

BACKGROUND:
Nearly half of adults have hypertension, a major risk factor for cardiovascular disease. Mitochondrial hyperacetylation is linked to hypertension, but the role of acetylation of specific proteins is not clear. We hypothesized that acetylation of mitochondrial CypD (cyclophilin D) at K166 contributes to endothelial dysfunction and hypertension.

METHODS:
To test this hypothesis, we studied CypD acetylation in patients with essential hypertension, defined a pathogenic role of CypD acetylation in deacetylation mimetic CypD-K166R mutant mice and endothelial-specific GCN5L1 (general control of amino acid synthesis 5 like 1)–deficient mice using an Ang II (angiotensin II) model of hypertension.

RESULTS:
Arterioles from hypertensive patients had 280% higher CypD acetylation coupled with reduced Sirt3 (sirtuin 3) and increased GCN5L1 levels. GCN5L1 regulates mitochondrial protein acetylation and promotes CypD acetylation, which is counteracted by mitochondrial deacetylase Sirt3. In human aortic endothelial cells, GCN5L1 depletion prevents superoxide overproduction. Deacetylation mimetic CypD-K166R mice were protected from vascular oxidative stress, endothelial dysfunction, and Ang II-induced hypertension. Ang II-induced hypertension increased mitochondrial GCN5L1 and reduced Sirt3 levels resulting in a 250% increase in GCN5L1/Sirt3 ratio promoting CypD acetylation. Treatment with mitochondria-targeted scavenger of cytotoxic isolevuglandins (mito2HOBA) normalized GCN5L1/Sirt3 ratio, reduced CypD acetylation, and attenuated hypertension. The role of mitochondrial acetyltransferase GCN5L1 in the endothelial function was tested in endothelial-specific GCN5L1 knockout mice. Depletion of endothelial GCN5L1 prevented Ang II-induced mitochondrial oxidative stress, reduced the maladaptive switch of vascular metabolism to glycolysis, prevented inactivation of endothelial nitric oxide, preserved endothelial-dependent relaxation, and attenuated hypertension.

CONCLUSIONS:
These data support the pathogenic role of CypD acetylation in endothelial dysfunction and hypertension. We suggest that targeting cytotoxic mitochondrial isolevuglandins and GCN5L1 reduces CypD acetylation, which may be beneficial in cardiovascular disease.
Association Between Hemoglobin A1c and Development of Cardiovascular Disease in Canadian Men and Women Without Diabetes at Baseline: A Population‐Based Study of 608 474 Adults
Authors: Butalia Sonia , Chu Luan Manh , Dover Douglas C. , Lau Darren , Yeung Roseanne O. , Eurich Dean T. , Senior Peter , Kaul Padma 
Published: April 2024

Background
We examined the association between hemoglobin A1c (HbA1c) and the development of cardiovascular disease (CVD) in men and women, without diabetes or CVD at baseline.

Methods and Results
This retrospective cohort study included adults aged 40 to <80 years in Alberta, Canada. Men and women were divided into categories based on a random HbA1c during a 3‐year enrollment period. The primary outcome of CVD hospitalization and secondary outcome of combined CVD hospitalization/mortality were examined during a 5‐year follow‐up period until March 31, 2021. A total of 608 474 individuals (55.2% women) were included. Compared with HbA1c 5.0% to 5.4%, men with HbA1c of 5.5% to 5.9% had an increased risk of CVD hospitalization (adjusted hazard ratio [aHR], 1.12 [95% CI, 1.07–1.19]) whereas women did not (aHR, 1.01 [95% CI, 0.95–1.08]). Men and women with HbA1c of 6.0% to 6.4% had a 38% and 17% higher risk and men and women with HbA1c ≥6.5% had a 79% and 51% higher risk of CVD hospitalization, respectively. In addition, HbA1c of 6.0% to 6.4% and HbA1c ≥6.5% were associated with a higher risk (14% and 41%, respectively) of CVD hospitalization/death in men, but HbA1c ≥6.5% was associated with a 24% higher risk only among women.

Conclusions
In both men and women, HbA1c ≥6.0% was associated with an increased risk of CVD and mortality outcomes. The association between CVD and HbA1c levels of 5.5% to 5.9%, considered to be in the “normal” range, highlights the importance of optimizing cardiovascular risk profiles at all levels of glycemia, especially in men.
Impact of Vaccination Status on Outcome of Patients With COVID‐19 and Acute Ischemic Stroke Undergoing Mechanical Thrombectomy
Authors: Deuschl Cornelius , Goertz Lukas , Kabbasch Christoph , Köhrmann Martin , Kleinschnitz Christoph , Berlis Ansgar , Maurer Christoph Johannes , Mühlen Iris , Kallmünzer Bernd , Gawlitza Matthias , Kaiser Daniel P. O. , Klisch Joachim , Lobsien Donald , Behme Daniel , Thormann Maximilian , Flottmann Fabian , Winkelmeier Laurens , Gizewski Elke Ruth , Mayer‐Suess Lukas , Holtmannspoetter Markus , Moenninghoff Christoph , Schlunz‐Hendann Martin , Grieb Dominik , Arendt Christophe T. , Bohmann Ferdinand O. , Altenbernd Jens , Li Yan , Sure Ulrich , Mühl‐Benninghaus Ruben , Rodt Thomas , Kallenberg Kai , Durutya Alexandru , Elsharkawy Mohamed , Stracke Christian‐Paul , Schumann Mathias Gerhard , Bock Alexander , Nikoubashman Omid , Wiesmann Martin , Henkes Hans , Dolff Sebastian , Demircioglu Aydin , Forsting Michael , Styczen Hanna 
Published: April 2024

Background
Data on impact of COVID‐19 vaccination and outcomes of patients with COVID‐19 and acute ischemic stroke undergoing mechanical thrombectomy are scarce. Addressing this subject, we report our multicenter experience.

Methods and Results

This was a retrospective analysis of patients with COVID‐19 and known vaccination status treated with mechanical thrombectomy for acute ischemic stroke at 20 tertiary care centers between January 2020 and January 2023. Baseline demographics, angiographic outcome, and clinical outcome evaluated by the modified Rankin Scale score at discharge were noted. A multivariate analysis was conducted to test whether these variables were associated with an unfavorable outcome, defined as modified Rankin Scale score >3. A total of 137 patients with acute ischemic stroke (48 vaccinated and 89 unvaccinated) with acute or subsided COVID‐19 infection who underwent mechanical thrombectomy attributable to vessel occlusion were included in the study. Angiographic outcomes between vaccinated and unvaccinated patients were similar (modified Thrombolysis in Cerebral Infarction ≥2b: 85.4% in vaccinated patients versus 86.5% in unvaccinated patients;
P
=0.859). The rate of functional independence (modified Rankin Scale score, ≤2) was 23.3% in the vaccinated group and 20.9% in the unvaccinated group (
P
=0.763). The mortality rate was 30% in both groups. In the multivariable analysis, vaccination status was not a significant predictor for an unfavorable outcome (
P
=0.957). However, acute COVID‐19 infection remained significant (odds ratio, 1.197 [95% CI, 1.007–1.417];
P
=0.041).

Conclusions
Our study demonstrated no impact of COVID‐19 vaccination on angiographic or clinical outcome of COVID‐19–positive patients with acute ischemic stroke undergoing mechanical thrombectomy, whereas worsening attributable to COVID‐19 was confirmed.
Impact of New‐Onset Right Bundle‐Branch Block After Transcatheter Aortic Valve Replacement on Permanent Pacemaker Implantation
Authors: Kikuchi Shinnosuke , Minamimoto Yugo , Matsushita Kensuke , Cho Tomoki , Terasaka Kengo , Hanajima Yohei , Nakahashi Hidefumi , Gohbara Masaomi , Kimura Yuichiro , Yasuda Shota , Okada Kozo , Matsuzawa Yasushi , Iwahashi Noriaki , Kosuge Masami , Ebina Toshiaki , Morel Olivier , Ohlmann Patrick , Uchida Keiji , Hibi Kiyoshi 
Published: April 2024

Background
A delayed and recurrent complete atrioventricular block (CAVB) is a life‐threatening complication of transcatheter aortic valve replacement (TAVR). Post‐TAVR evaluation may be important in predicting delayed and recurrent CAVB requiring permanent pacemaker implantation (PPI). The impact of new‐onset right bundle‐branch block (RBBB) after TAVR on PPI remains unknown.

Methods and Results

In total, 407 patients with aortic stenosis who underwent TAVR were included in this analysis. Intraprocedural CAVB was defined as CAVB that occurred during TAVR. A 12‐lead ECG was evaluated at baseline, immediately after TAVR, on postoperative days 1 and 5, and according to the need to identify new‐onset bundle‐branch block (BBB) and CAVB after TAVR. Forty patients (9.8%) required PPI, 17 patients (4.2%) had persistent intraprocedural CAVB, and 23 (5.7%) had delayed or recurrent CAVB after TAVR. The rates of no new‐onset BBB, new‐onset left BBB, and new‐onset RBBB were 65.1%, 26.8%, and 4.7%, respectively. Compared with patients without new‐onset BBB and those with new‐onset left BBB, the rate of PPI was higher in patients with new‐onset RBBB (3.4% versus 5.6% versus 44.4%,
P
<0.0001). On post‐TAVR evaluation in patients without persistent intraprocedural CAVB, the multivariate logistic regression analysis showed that new‐onset RBBB was a statistically significant predictor of PPI compared with no new‐onset BBB (odds ratio [OR], 18.0 [95% CI, 5.94–54.4]) in addition to the use of a self‐expanding valve (OR, 2.97 [95% CI, 1.09–8.10]).

Conclusions
Patients with new‐onset RBBB after TAVR are at high risk for PPI.
Association Between Diagnosis‐to‐Limb Revascularization Time and Clinical Outcomes in Outpatients With Chronic Limb‐Threatening Ischemia: Insights From the CLIPPER Cohort
Authors: Fanaroff Alexander C. , Dayoub Elias J. , Yang Lin , Schultz Kaitlyn , Ramadan Omar I. , Wang Grace J. , Damrauer Scott M. , Genovese Elizabeth A. , Secemsky Eric A. , Parikh Sahil A. , Nathan Ashwin S. , Kohi Maureen P. , Weinberg Mitchell D. , Jaff Michael R. , Groeneveld Peter W. , Giri Jay S. 
Published: April 2024

Background
The extent and consequences of ischemia in patients with chronic limb‐threatening ischemia (CLTI) may change rapidly, and delays from diagnosis to revascularization may worsen outcomes. We sought to describe the association between time from diagnosis to endovascular lower extremity revascularization (diagnosis‐to‐limb revascularization [D2L] time) and clinical outcomes in outpatients with CLTI.

Methods and Results
In the CLIPPER cohort, comprising patients between 66 and 86 years old diagnosed with CLTI betweeen 2010 and 2019, we used Medicare claims data to identify patients who underwent outpatient endovascular revascularization within 180 days of diagnosis. We described the risk‐adjusted association between D2L time and clinical outcomes. Among 1 130 065 patients aged between 66 and 86 years with CLTI, 99 221 (8.8%) underwent outpatient endovascular lower extremity revascularization within 180 days of their CLTI diagnosis. Among patients with D2L time <30 days, there was no association between D2L time and all‐cause death or major lower extremity amputation. However, among patients with D2L time >30 days, each additional 10‐day increase in D2L time was associated with a 2.5% greater risk of major amputation (hazard ratio, 1.025 [95% CI, 1.014–1.036]). There was no association between D2L time and all‐cause death.

Conclusions
A delay of >30 days from CLTI diagnosis to lower extremity endovascular revascularization was associated with an increased risk of major lower extremity amputation among patients undergoing outpatient endovascular revascularization. Improving systems of care to reduce D2L time could reduce amputations.
Implementing Telestroke in the Inpatient Setting: Identifying Factors for Success
Authors: Pestka Deborah L. , Boes Samuel , Ramezani Solmaz , Peters Maya , Usher Michael G. , Koopmeiners Joseph S. , Beebe Timothy J. , Melton Genevieve B. , Streib Christopher D. 
Published: April 2024

BACKGROUND:
Inpatient telestroke programs have emerged as a solution to provide timely stroke care in underserved areas, but their successful implementation and factors influencing their effectiveness remain underexplored. This study aimed to qualitatively evaluate the perspectives of inpatient clinicians located at spoke hospitals participating in a newly established inpatient telestroke program to identify implementation barriers and facilitators.

METHODS:
This was a formative evaluation relying on semistructured qualitative interviews with 16 inpatient providers (physicians and nurse practitioners) at 5 spoke sites of a hub-and-spoke inpatient telestroke program. The Integrated-Promoting Action on Research Implementation in Health Services framework guided data analysis, focusing on the innovation, recipients, context, and facilitation aspects of implementation. Interviews were transcribed and coded using thematic analysis.

RESULTS:
Fifteen themes were identified in the data and mapped to the Integrated-Promoting Action on Research Implementation in Health Services framework. Themes related to the innovation (the telestroke program) included easy access to stroke specialists, the benefits of limiting patient transfers, concerns about duplicating tests, and challenges of timing inpatient telestroke visits and notes to align with discharge workflow. Themes pertaining to recipients (care team members and patients) were communication gaps between teams, concern about the supervision of inpatient telestroke advanced practice providers and challenges with nurse empowerment. With regard to the context (hospital and system factors), providers highlighted familiarity with telehealth technologies as a facilitator to implementing inpatient telestroke, yet highlighted resource limitations in smaller facilities. Facilitation (program implementation) was recognized as crucial for education, standardization, and buy-in.

CONCLUSIONS:
Understanding barriers and facilitators to implementation is crucial to determining where programmatic changes may need to be made to ensure the success and sustainment of inpatient telestroke services.
The effect of deep brain stimulation on cortico-subcortical networks in Parkinson’s disease patients with freezing of gait: Exhaustive exploration of a basic model
Authors: Popova Mariia , Messé Arnaud , Gulberti Alessandro , Gerloff Christian , Pötter-Nerger Monika , Hilgetag Claus C. 
Published: April 2024

Abstract
Current treatments of Parkinson’s disease (PD) have limited efficacy in alleviating freezing of gait (FoG). In this context, concomitant deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) has been suggested as a potential therapeutic approach. However, the mechanisms underlying this approach are unknown. While the current rationale relies on network-based hypotheses of intensified disinhibition of brainstem locomotor areas to facilitate the release of gait motor programs, it is still unclear how simultaneous high-frequency DBS in two interconnected basal ganglia nuclei affects large-scale cortico-subcortical network activity. Here, we use a basic model of neural excitation, the susceptible-excited-refractory (SER) model, to compare effects of different stimulation modes of the network underlying FoG based on the mouse brain connectivity atlas. We develop a network-based computational framework to compare subcortical DBS targets through exhaustive analysis of the brain attractor dynamics in the healthy, PD, and DBS states. We show that combined STN+SNr DBS outperforms STN DBS in terms of the normalization of spike propagation flow in the FoG network. The framework aims to move toward a mechanistic understanding of the network effects of DBS and may be applicable to further perturbation-based therapies of brain disorders.
Conditional Loyalty and Exit
Authors: Chau Grace W.F. , Gherghina Sergiu 
Published: April 2024

Abstract
This article aims to explain the emigration of wealthy Chinese citizens after the 2012 political leadership change, with reference to Hirschman’s model. It builds on the concepts of loyalty and exit in the context of an authoritarian regime with rapid economic growth, to offer insights into the self-declared reasons behind the emigration of these people from China. Based on evidence from 25 semi-structured interviews conducted in 2021 with Chinese emigrants, the analysis outlines the intricate interplay between economic opportunities and the level of control within an authoritarian regime as a cause for emigration.
Locating Premigration as a Critical Stage in the Migration Value Chain
Authors: Sibanda Sehlaphi , Hlatshwayo Mondli 
Published: April 2024

Abstract
This article draws on the narratives of 29 Zimbabwean migrant women employed in the Johannesburg restaurant industry. It uses qualitative methods through in-depth interviews. Although there is a growing amount of research on the migration experiences of Zimbabwean migrant women, the paper argues that there is a need to deepen the examination of the premigration phase because it is the foundation of the migration process. A thorough examination of premigration in this paper offers a crucial understanding of the circumstances behind migration choices, encompassing incentives, decision-making procedures and premigration arrangements and plans. Some women incorporate menstruation as part of their migration plan and strategy. Menstruation may occasionally shield women from sexual assault by men when they travel to Johannesburg.
Introduction: Globalizing Protestantisms
Authors: McGhee Patrick Seamus , Hill Kat 
Published: April 2024

Abstract
The articles in this Special Issue shed new light on the global dimensions of the Protestant Reformation from the sixteenth century to the nineteenth century. Drawing upon a range of historiographical debates and methodological approaches, they examine the variety of identities and perspectives that made up post-Reformation religious cultures. Contributions uncover the ways in which multiple forms of Protestantism shaped and responded to global patterns of knowledge and practice, movement and migration, colonization and empire, commercial ventures, and cultural encounters. They reveal the role of Protestant beliefs and practices in expressing and recalibrating changing attitudes towards race, gender, and sexuality, as well as shifting cultural perceptions of the world and its history. This Introduction frames the articles featured in the Special Issue and situates them in historical context. It also reflects upon key themes and concepts as well as recent historiographical developments.
Hans Staden and the Protestant Captivity Narrative: The Origins and Fractured Legacy of a New Literary Genre
Authors: Harrington Joel F. 
Published: April 2024

Abstract
Virtually all discussions of Hans Staden’s famous True History (1557) have focused on the cannibalistic aspects of his tale. This article argues that 1) the religious language throughout his account is not incidental but rather indicative of the main purpose of his writing: proselytizing about personal conversion and divine providence; 2) the profound similarity of this early version of the Protestant captivity narrative to its much better known New England version a century later suggests a hitherto hidden influence, either direct or indirect; 3) in this focus on individual conversion, the New World descriptions of non-colonizing German Lutherans differed considerably from the imperially-driven missionary agendas of other European Protestants abroad.