bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct IDH1/2-associated Methylation Profile and Enrichment ofTP53andTERTMutations Distinguish Dedifferentiated Chondrosarcoma from Conventional Chondrosarcoma
Authors: Dermawan Josephine Kam Tai , Nafa Khedoujia , Mohanty Abhinita , Xu Yingjuan , Rijo Ivelise , Casanova Jacklyn , Villafania Liliana , Benhamida Jamal , Kelly Ciara M. , Tap William D. , Boland Patrick J. , Fabbri Nicola , Healey John H. , Ladanyi Marc , Lu Chao , Hameed Meera 
Published: February 2023

Dedifferentiated chondrosarcoma (DDCS) is a rare high-grade chondrosarcoma characterized by a well-differentiated chondrosarcoma (WDCS) component that abruptly transitions to a high-grade, noncartilaginous sarcomatous component. To date, the molecular pathogenesis of DDCS and its distinction from conventional chondrosarcoma remain poorly understood. By targeted sequencing, we examined the mutational and copy-number profiles of 18 DDCS, including macrodissected WDCS components, compared with 55 clinically sequenced conventional chondrosarcomas. In conjunction with publicly available external data, we analyzed the methylation and expression profiles of 34 DDCS and 94 conventional chondrosarcomas. Isocitrate dehydrogenase 1/isocitrate dehydrogenase 2 (IDH1/IDH2) mutations were present in 36% conventional chondrosarcomas and 71% DDCS. Compared with conventional chondrosarcomas, DDCS had higher frequencies of TP53 and TERT promoter mutations and CDKN2A/B copy-number losses. Paired analysis of macrodissected WDCS and the high-grade components revealed TERT promoter mutations as early events. Despite phenotypic similarities, the percentage of genome with copy-number alterations in DDCS was significantly lower than that in other high-grade sarcomas. Differential methylation analysis revealed reduction of IDH1/IDH2-associated global hypermethylation characteristically seen in conventional chondrosarcoma and a distinct methylation profile in DDCS. The WDCS and high-grade components in DDCS showed similar methylation profiles. These CpG sites were associated with upregulated expression of genes involved in G2–M checkpoints and E2F targets. Genomic profiling revealed enrichment of TP53, TERT promoter, and CDKN2A/B alterations in DDCS. Integrated methylation and gene expression analysis revealed distinct IDH1/IDH2-associated methylation and transcriptional profiles as early events in DDCS, which may underlie the pathogenesis of dedifferentiation in chondrosarcomas.Significance:DDCS is a rare, high-grade chondrosarcoma with a dismal prognosis. About 50%–80% of DDCS harbor IDH1/IDH2 mutations. We uncover a significant alteration of IDH-associated methylation profile in DDCS, which we propose is key to the progression to dedifferentiation. In this context, the potential effect of the use of IDH inhibitors is unclear but important to address, as clinical trials of selective IDH1 inhibitors showed worse outcome in DDCS.
Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Studies
Authors: Naito Tatsuhiko , Inoue Kosuke , Sonehara Kyuto , Baba Ryuta , Kodama Takaya , Otagaki Yu , Okada Akira , Itcho Kiyotaka , Kobuke Kazuhiro , Kishimoto Shinji , Yamamoto Kenichi ,   BioBank Japan, Morisaki Takayuki , Higashi Yukihito , Hinata Nobuyuki , Arihiro Koji , Hattori Noboru , Okada Yukinori , Oki Kenji 
Published: February 2023

Background:
Hypertension imposes substantial health and economic burden worldwide. Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, causing cardiovascular events at higher risk compared with essential hypertension. However, the germline genetic contribution to the susceptibility of PA has not been well elucidated.

Method:
We conducted a genome-wide association analysis of PA in the Japanese population and a cross-ancestry meta-analysis combined with UK Biobank and FinnGen cohorts (816 PA cases and 425 239 controls) to identify genetic variants that contribute to PA susceptibility. We also performed a comparative analysis for the risk of 42 previously established blood pressure–associated variants between PA and hypertension with the adjustment of blood pressure.

Results:

In the Japanese genome-wide association study, we identified 10 loci that presented suggestive evidence for the association with the PA risk (
P
<1.0×10
−6
). In the meta-analysis, we identified 5 genome-wide significant loci (1p13, 7p15, 11p15, 12q24, and 13q12;
P
<5.0×10
−8
), including 3 of the suggested loci in the Japanese genome-wide association study. The strongest association was observed at rs3790604 (1p13), an intronic variant of
WNT2B
(odds ratio, 1.50 [95% CI, 1.33−1.69];
P
=5.2×10
−11
). We further identified 1 nearly genome-wide significant locus (8q24,
CYP11B2
), which presented a significant association in the gene-based test (
P
=7.2×10
−7
). Of interest, all of these loci were known to be associated with blood pressure in previous studies, presumably because of the prevalence of PA among individuals with hypertension. This assumption was supported by the observation that they had a significantly higher risk effect on PA than on hypertension. We also revealed that 66.7% of the previously established blood pressure–associated variants had a higher risk effect for PA than for hypertension.

Conclusions:

This study demonstrates the genome-wide evidence for a genetic predisposition to PA susceptibility in the cross-ancestry cohorts and its significant contribution to the genetic background of hypertension. The strongest association with the
WNT2B
variants reinforces the implication of the Wnt/β-catenin pathway in the PA pathogenesis.
Krüppel‐Like Factors Orchestrate Endothelial Gene Expression Through Redundant and Non‐Redundant Enhancer Networks
Authors: Sweet David R. , Padmanabhan Roshan , Liao Xudong , Dashora Himanshu R. , Tang Xinmiao , Nayak Lalitha , Jain Rajan , De Val Sarah , Vinayachandran Vinesh , Jain Mukesh K. 
Published: February 2023

Background
Proper function of endothelial cells is critical for vascular integrity and organismal survival. Studies over the past 2 decades have identified 2 members of the KLF (Krüppel‐like factor) family of proteins, KLF2 and KLF4, as nodal regulators of endothelial function. Strikingly, inducible postnatal deletion of both KLF2 and KLF4 resulted in widespread vascular leak, coagulopathy, and rapid death. Importantly, while transcriptomic studies revealed profound alterations in gene expression, the molecular mechanisms underlying these changes remain poorly understood. Here, we seek to determine mechanisms of KLF2 and KLF4 transcriptional control in multiple vascular beds to further understand their roles as critical endothelial regulators.

Methods and Results
We integrate chromatin occupancy and transcription studies from multiple transgenic mouse models to demonstrate that KLF2 and KLF4 have overlapping yet distinct binding patterns and transcriptional targets in heart and lung endothelium. Mechanistically, KLFs use open chromatin regions in promoters and enhancers and bind in context‐specific patterns that govern transcription in microvasculature. Importantly, this occurs during homeostasis in vivo without additional exogenous stimuli.

Conclusions
Together, this work provides mechanistic insight behind the well‐described transcriptional and functional heterogeneity seen in vascular populations, while also establishing tools into exploring microvascular endothelial dynamics in vivo.
Impact of Concomitant Mitral Regurgitation on the Hemodynamic Indicators of Aortic Stenosis
Authors: Šeman Michael , Stephens Andrew F. , Walton Antony , Duffy Stephen J. , McGiffin David , Nanayakkara Shane , Kaye David M. , Gregory Shaun D. , Stub Dion 
Published: February 2023

Background
In patients with aortic stenosis (AS), the presence of mitral regurgitation (MR) can lead to underestimation of AS severity and worse clinical outcomes. The objective of this study was to characterize the magnitude of the effects of concomitant MR on hemodynamic indicators of AS severity using clinical data and a computational cardiovascular simulation.

Methods and Results

Echocardiographic data from 1427 patients with severe AS were used to inform a computational cardiovascular system model, and varying degrees of MR and AS were simulated. Hemodynamic data, including left ventricular and aortic pressure waveforms, were generated for all simulations. Simulated reduction in mean transaortic pressure gradient (MPG) associated with MR was then used to calculate the adjusted MPG in the clinical cohort. MR was present in 861 (60%) patients. Compared with patients without MR, patients with MR had a lower aortic‐valve area (0.83±0.2 cm
2
versus 0.75±0.2;
P
<0.001) and were more likely to have a low‐gradient pattern (MPG <40 mm Hg) (45% versus 54%;
P
<0.001). Simulations showed that the presence of concomitant mild, moderate, and severe MR with AS was accompanied by a mean reduction in MPG of 10%, 29%, and 40%, respectively. For patients with MR, their calculated adjusted MPG was on average 24% higher than their MPG (52±22 versus 42±16 mm Hg). Of the 467 patients with low‐gradient AS and MR, 240 (51%) would reclassify as high gradient based on their adjusted MPG.

Conclusions
Concomitant MR results in lower MPG and reduced forward flow compared with isolated AS. Careful quantitation of MR should be factored into the assessment of AS severity to mitigate for potential underestimation.
Examining the Real‐Life Journey of Individuals and Families Affected by Single‐Ventricle Congenital Heart Disease
Authors: Mery Carlos M. , Well Andrew , Taylor Kate , Carberry Kathleen , Colucci José , Ulack Christopher , Zeiner Adam , Mizrahi Michelle , Stewart Eileen , Dillingham Christine , Cook Taylor , Hartounian Arotin , McCullum Elizabeth , Affolter Jeremy T. , Van Diest Heather , Lamari‐Fisher Alexandra , Chang Stacey , Wallace Scott , Teisberg Elizabeth , Fraser Charles D. 
Published: February 2023

Background
The lifetime journey of patients with single‐ventricle congenital heart disease is characterized by long‐term challenges that are incompletely understood and still unfolding. Health care redesign requires a thorough understanding of this journey to create and implement solutions that improve outcomes. This study maps the lifetime journey of individuals with single‐ventricle congenital heart disease and their families, identifies the most meaningful outcomes to them, and defines significant challenges in the journey.

Methods and Results
This qualitative research study involved experience group sessions and 1:1 interviews of patients, parents, siblings, partners, and stakeholders. Journey maps were created. The most meaningful outcomes to patients and parents and significant gaps in care were identified across the life journey.

A total of 142 participants from 79 families and 28 stakeholders were included. Lifelong and life‐stage specific journey maps were created. The most meaningful outcomes to patients and parents were identified and categorized using a “
capability (doing the things in life you want to), comfort (experience of physical/emotional pain/distress), and calm (experiencing health care with the least impact on daily life)
” framework. Gaps in care were identified and classified into areas of ineffective communication, lack of seamless transitions, lack of comprehensive support, structural deficiencies, and insufficient education.

Conclusions
There are significant gaps in care during the lifelong journey of individuals with single‐ventricle congenital heart disease and their families. A thorough understanding of this journey is a critical first step in developing initiatives to redesign care around their needs and priorities. This approach can be used for people with other forms of congenital heart disease and other chronic conditions.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04613934.
High Burden of Premature Ventricular Complex Increases the Risk of New‐Onset Atrial Fibrillation
Authors: Lee Po‐Tseng , Huang Mu‐Hsian , Huang Ting‐Chung , Hsu Chi‐Hui , Lin Sheng‐Hsian , Liu Ping‐Yen 
Published: February 2023

Background
High burden of premature ventricular complex (PVC) leads to increased cardiovascular mortality. A recent nationwide population‐based study demonstrated that PVC is associated with an increased risk of atrial fibrillation (AF). However, the relationship between PVC burden and new‐onset AF has not been investigated. The purpose of the study is to elucidate whether PVC burden is associated with new‐onset AF.

Methods and Results

We designed a single‐center, retrospective, large population‐based cohort study to evaluate the role of PVC burden and new‐onset AF in Taiwan. Patients who were AF naïve with PVC were divided into the low burden group (<1000/day) and moderate‐to‐high burden group (≥1000/day) based on the 24‐h Holter ECG report. New‐onset AF was defined as a new or first detectable event of either a persistent or paroxysmal AF. A total of 16 030 patients who were AF naïve and underwent 24‐h Holter ECG monitoring were enrolled in this study, with a mean follow‐up time of 973 days. A propensity score‐matched analysis demonstrated that the moderate‐to‐high burden PVC group had a higher risk of developing new‐onset AF than that of the low burden PVC group (4.91% versus 2.73%,
P
<0.001). Multivariate Cox regression analysis showed that moderate‐to‐high burden of PVC is an independent risk factor for new‐onset AF. The Kaplan–Meier analysis demonstrated that patients with moderate‐to‐high PVC burden were associated with higher risk of new‐onset AF (log‐rank
P
<0.001).

Conclusions
PVC burden is associated with new‐onset AF. Patients with moderate‐to‐high PVC burden are at a higher risk of new‐onset AF.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03877614.
Social Determinants, Cardiovascular Disease, and Health Care Cost: A Nationwide Study in the United States Using Machine Learning
Authors: Sun Feinuo , Yao Jie , Du Shichao , Qian Feng , Appleton Allison A. , Tao Cui , Xu Hua , Liu Lei , Dai Qi , Joyce Brian T. , Nannini Drew R. , Hou Lifang , Zhang Kai 
Published: February 2023

Background
Existing studies on cardiovascular diseases (CVDs) often focus on individual‐level behavioral risk factors, but research examining social determinants is limited. This study applies a novel machine learning approach to identify the key predictors of county‐level care costs and prevalence of CVDs (including atrial fibrillation, acute myocardial infarction, congestive heart failure, and ischemic heart disease).

Methods and Results

We applied the extreme gradient boosting machine learning approach to a total of 3137 counties. Data are from the
Interactive Atlas of Heart Disease and Stroke
and a variety of national data sets. We found that although demographic composition (eg, percentages of Black people and older adults) and risk factors (eg, smoking and physical inactivity) are among the most important predictors for inpatient care costs and CVD prevalence, contextual factors such as social vulnerability and racial and ethnic segregation are particularly important for the total and outpatient care costs. Poverty and income inequality are the major contributors to the total care costs for counties that are in nonmetro areas or have high segregation or social vulnerability levels. Racial and ethnic segregation is particularly important in shaping the total care costs for counties with low poverty rates or social vulnerability level. Demographic composition, education, and social vulnerability are consistently important across different scenarios.

Conclusions
The findings highlight the differences in predictors for different types of CVD cost outcomes and the importance of social determinants. Interventions directed toward areas that have been economically and socially marginalized may aid in reducing the impact of CVDs.
Collagen‐Specific HSP47
+
Myofibroblasts and CD163
+
Macrophages Identify Profibrotic Phenotypes in Deceased Hearts With SARS‐CoV‐2 Infections
Authors: Puzyrenko Andrii , Jacobs Elizabeth R. , Padilla Nathan , Devine Adam , Aljadah Michael , Gantner Benjamin N. , Pan Amy Y. , Lai Shuping , Dai Qiang , Rubenstein Jason C. , North Paula E. , Simpson Pippa M. , Willoughby Rodney E. , O'Meara Caitlin C. , Flinn Michael A. , Lough John W. , Ibrahim El‐Sayed H. , Zheng Ze , Sun Yunguang , Felix Juan , Hunt Bryan C. , Ross Gracious , Rui Hallgeir , Benjamin Ivor J. 
Published: February 2023

Background
Cardiac fibrosis complicates SARS‐CoV‐2 infections and has been linked to arrhythmic complications in survivors. Accordingly, we sought evidence of increased HSP47 (heat shock protein 47), a stress‐inducible chaperone protein that regulates biosynthesis and secretion of procollagen in heart tissue, with the goal of elucidating molecular mechanisms underlying cardiac fibrosis in subjects with this viral infection.

Methods and Results

Using human autopsy tissue, immunofluorescence, and immunohistochemistry, we quantified Hsp47
+
cells and collagen α 1(l) in hearts from people with SARS‐CoV‐2 infections. Because macrophages are also linked to inflammation, we measured CD163
+
cells in the same tissues. We observed irregular groups of spindle‐shaped HSP47
+
and CD163
+
cells as well as increased collagen α 1(I) deposition, each proximate to one another in “hot spots” of ≈40% of hearts after SARS‐CoV‐2 infection (HSP47
+
P
<0.05 versus nonfibrotics and
P
<0.001 versus controls). Because HSP47
+
cells are consistent with myofibroblasts, subjects with hot spots are termed “profibrotic.” The remaining 60% of subjects dying with COVID‐19 without hot spots are referred to as “nonfibrotic.” No control subject exhibited hot spots.

Conclusions

Colocalization of myofibroblasts, M2(CD163
+
) macrophages, and collagen α 1(l) may be the first evidence of a COVID‐19–related “profibrotic phenotype” in human hearts in situ. The potential public health and diagnostic implications of these observations require follow‐up to further define mechanisms of viral‐mediated cardiac fibrosis.
Consonance Perception in Congenital Amusia: Behavioral and Brain Responses to Harmonicity and Beating Cues
Authors: Graves Jackson E. , Pralus Agathe , Fornoni Lesly , Oxenham Andrew J. , Tillmann Barbara , Caclin Anne 
Published: February 2023

Abstract
Congenital amusia is a neurodevelopmental disorder characterized by difficulties in the perception and production of music, including the perception of consonance and dissonance, or the judgment of certain combinations of pitches as more pleasant than others. Two perceptual cues for dissonance are inharmonicity (the lack of a common fundamental frequency between components) and beating (amplitude fluctuations produced by close, interacting frequency components). Amusic individuals have previously been reported to be insensitive to inharmonicity, but to exhibit normal sensitivity to beats. In the present study, we measured adaptive discrimination thresholds in amusic participants and found elevated thresholds for both cues. We recorded EEG and measured the MMN in evoked potentials to consonance and dissonance deviants in an oddball paradigm. The amplitude of the MMN response was similar overall for amusic and control participants; however, in controls, there was a tendency toward larger MMNs for inharmonicity than for beating cues, whereas the opposite tendency was observed for the amusic participants. These findings suggest that initial encoding of consonance cues may be intact in amusia despite impaired behavioral performance, but that the relative weight of nonspectral (beating) cues may be increased for amusic individuals.
Behavioral and Neural Trajectories of Risk Taking for Peer and Parent in Adolescence
Authors: Kwon Seh-Joo , Flannery Jessica E. , Turpyn Caitlin C. , Prinstein Mitchell J. , Lindquist Kristen A. , Telzer Eva H. 
Published: February 2023

Abstract
One feature of adolescence is a rise in risk-taking behaviors, whereby the consequences of adolescents' risky action often impact their immediate surrounding such as their peers and parents (vicarious risk taking). Yet, little is known about how vicarious risk taking develops, particularly depending on who the risk affects and the type of risky behavior. In a 3-wave longitudinal fMRI study, 173 adolescents completed 1–3 years of a risky decision-making task where they took risks to win money for their best friend and parent (n with behavioral and fMRI data ranges from 139–144 and 100–116 participants, respectively, per wave). Results of this preregistered study suggest that adolescents did not differentially take adaptive (sensitivity to the expected value of reward during risk taking) and general (decision-making when the expected values of risk taking and staying safe are equivalent) risks for their best friend and parent from sixth to ninth grade. At the neural level, preregistered ROI analyses revealed no differences in the ventral striatum and ventromedial pFC during general nor adaptive risk taking for best friend versus parent over time. Furthermore, exploratory longitudinal whole-brain analyses revealed subthreshold differences between best friend and parent trajectories within regulatory regions during general vicarious risk taking and social-cognitive regions during adaptive vicarious risk taking. Our findings demonstrate that brain regions implicated in cognitive control and social-cognitive processes may distinguish behaviors involving peers and parents over time.
Heading Direction Tracks Internally Directed Selective Attention in Visual Working Memory
Authors: Thom Jude L. , Nobre Anna C. , van Ede Freek , Draschkow Dejan 
Published: February 2023

Abstract
We shift our gaze even when we orient attention internally to visual representations in working memory. Here, we show the bodily orienting response associated with internal selective attention is widespread as it also includes the head. In three virtual reality experiments, participants remembered 2 visual items. After a working memory delay, a central color cue indicated which item needed to be reproduced from memory. After the cue, head movements became biased in the direction of the memorized location of the cued memory item—despite there being no items to orient toward in the external environment. The heading-direction bias had a distinct temporal profile from the gaze bias. Our findings reveal that directing attention within the spatial layout of visual working memory bears a strong relation to the overt head orienting response we engage when directing attention to sensory information in the external environment. The heading-direction bias further demonstrates common neural circuitry is engaged during external and internal orienting of attention.
First record of Parasquilla ferussaci (Roux, 1828) (Stomatopoda, Parasquillidae) in the Adriatic Sea with notes on its morphology and molecular identification
Authors: Dulčić Jakov , Dragičević Branko , Kirinčić Marin , Ugarković Pero , Žužul Iva , Šegvić-Bubić Tanja 
Published: February 2023

Abstract
The first record of the little known stomatopod Parasquilla ferussaci (Roux, 1828) in the Adriatic Sea is documented. One specimen was captured near islet Blitvenica in the eastern Adriatic (Croatian coast) on 26 January 2021 with a bottom trawl. This record indicates the extension of the known distributional range of this species in the Mediterranean Sea. Here we also provide the first data on the molecular identification of Parasquilla ferussaci supported by the detailed morphological description of the investigated specimen. Parasquilla is derived as a sister group to Faughnia, which together are sister to the genus Pseudosquillopsis.