bluuebunny/crossref_metadata_2025_split huggingface dataset:
Somatic Mutations inMCOLN3in Aldosterone-Producing Adenomas cause Primary Aldosteronism
Authors: van Rooyen Desmaré , Bandulik Sascha , Coon Grace , Laukemper Miriam , Kumar-Sinha Chandan , Udager Aaron M. , Lee Chaelin , Wachtel Heather , Cohen Debbie L. , Luther James M. , Giordano Thomas , Turcu Adina , Warth Richard , Rainey William E. , Rege Juilee 
Published: October 2024

AbstractPrimary aldosteronism is characterized by renin-independent hyperaldosteronism that originates from aldosterone-producing lesions in the adrenal glands. Under physiological conditions, aldosterone synthase (CYP11B2) expression is confined to the adrenal zona glomerulosa where it catalyzes the final reaction yielding aldosterone. The regulation ofCYP11B2transcription depends on the control of cellular membrane potential and cytosolic calcium activity. In primary aldosteronism, aldosterone-producing adenomas (APAs) are characterized by disrupted regulation of CYP11B2 expression resulting in autonomous biosynthesis of aldosterone. These lesions often harbor aldosterone-driver somatic mutations in genes encoding ion transporters/channels/pumps that increase cytosolic calcium activity causing increasedCYP11B2expression and aldosterone biosynthesis. We investigated APAs devoid of known somatic mutations and detected a missense mutation and a deletion-insertion variant inMCOLN3which encodes for mucolipin-3 (TRPML3) — a highly conserved inwardly-rectifying, cation-permeable channel. TheseMCOLN3mutations were identified in three APAs derived from male patients with primary aldosteronism: p. Y391D and p.N411_V412delinsI. Both mutations are located near the ion pore and selectivity filter of TRPML3. This is the first report of disease-causingMCOLN3mutations in humans. Functional studies suggestMCOLN3Y391Dmight directly or indirectly via membrane depolarization alter calcium influx of transfected adrenocortical cells, resulting in increasedCYP11B2transcription and aldosterone production. This study implicates mutatedMCOLN3as a driver of aldosterone excess in primary aldosteronism.Significance StatementPrimary aldosteronism is a common but under-diagnosed endocrine disease that contributes to global hypertension burden and cardiovascular mortality and morbidity. Hyperaldosteronism in primary aldosteronism is mainly caused by adrenal lesions harboring somatic mutations that disrupt intracellular calcium levels and consequently aldosterone synthase expression and aldosterone production. Majority of these mutations have been identified in genes encoding ion transporters/channels/pumps. Herein, we report the first disease-causing somatic mutations in humanMCOLN3in aldosterone-producing adenomas (APAs) devoid of known mutations.In vitroinvestigations showed theMCOLN3variant (p.Y391D) caused an influx of cytosolic calcium in adrenocortical cells and the subsequent increase in aldosterone synthase and aldosterone biosynthesis.
Genetic testing forSCA27Bin Korean Multiple System Atrophy
Authors: Laß Joshua , Berselli Michele , Rioux Doug , Schaake Susen , Follett Jordan , Bravo Jonathan E. , Veit Alexander D. , Ronchetti William , Reiff Sarah B. , Huentelman Matthew J. , Vuzman Dana , Bower Pamela , Park Peter J. , Khurana Vikram , Trinh Joanne , Jeon Beomseok , Kim Han-Joon , Farrer Matthew J. 
Published: October 2024

ABSTRACTFGF14(GAA)nrepeat expansions are a common cause of idiopathic late-onset ataxia (SCA27B). The cerebellar form of multiple system atrophy (MSA) has comparable clinical features, albeit faster progression. Hence, we performed an analysis ofFGF14genomic variability in a South Korean cohort of 199 patients with ‘probable’ MSA, compared with 1,048 ethnically-matched controls. All whole genome sequences (WGS) are depicted on a computational genome analysis platform, CGAP, to enable storage, visualization and analysis for partners of the International MSA Coalition. The size of theFGF14(GAA)nrepeat was also assessed by genomic PCR, and by interrogating WGS data using Expansion Hunter (EH) with an extensive catalogue of potential repeats. However, MSA samples were not significantly different to matched Korean controls, and only three MSA patients showed possible abnormalFGF14(GAA)nexpansions >300bp. Nevertheless, as PCR and EH findings were often discordant, a subset of samples with expansions was validated by long-read sequencing. Some intermediate expansions (>150 bp) were found in 6.9% (27/392) of controls compared to 13.4% (46/344) in MSA, though overall our results suggestFGF14(GAA)nrepeat expansions do not influence susceptibility to MSA in Korean patients and highlight challenges inherent in this genetic testing.
Transcriptomic profiling of unmethylated full mutation carriers implicates TET3 in FMR1 CGG repeat expansion methylation dynamics in Fragile X syndrome
Authors: Farmiloe Grace , Bejczy Veronika , Tabolacci Elisabetta , Willemsen Rob , Jacobs Frank 
Published: October 2024

BackgroundFragile X syndrome (FXS) is a neurodevelopmental disorder caused by the expansion of a CGG repeat in the 5’UTR of the FMR1 (fragile X messenger ribonucleoprotein 1) gene. Healthy individuals possess a repeat 30-55 CGG units in length. Once the CGG repeat exceeds 200 copies it triggers methylation at the locus. This methylation covers the FMR1 promoter region and silences expression of the gene and the production of FMRP (fragile X messenger ribonucleoprotein). The loss of FMRP is responsible for a number of pathologies including neurodevelopmental delay and autism spectrum disorder. Methylation of the expanded repeat in the FMR1 locus is the causal factor for FXS, however it is not known why the expanded repeat triggers this epigenetic change or how exactly DNA methylation is established. Intriguingly, genetic engineering of expanded CGG repeats of over 300x in the FMR1 locus in mice remains unmethylated. Also in humans, in very rare cases, individuals can have an FMR1 CGG expansion >200x but the locus remains unmethylated. These unmethylated full mutation individuals give us a rare opportunity to investigate the mechanism of FMR1 promoter methylation.MethodsFibroblasts were obtained from a healthy control, an FXS patient and two unmethylated full expansion carriers. RNA was extracted and comparative transcriptomic analysis was performed on all samples. Whole genome sequencing was carried out on DNA from the two UFM carriers and the results analysed to investigate DNA variants that could explain the observed differences in gene expression.ResultsOur analyses focused on genes involved in epigenetic modification. We show that Tet methylcytosine dioxygenase 3 (TET3), a gene involved in DNA methylation, is significantly downregulated in UFM carriers compared to healthy controls or FXS patient derived cells. Genomic analyses reveal a number of rare variants present in the TET3 locus in UFM carriers when compared to the reference genome. No single variant has a significant predicted effect, raising the possibility that a trans acting variant could be driving the differential gene expression.ConclusionOur results suggest that TET3 is a candidate factor responsible for the lack of methylation of the expanded FMR1 locus. Further analyses are needed to further elucidate this relationship, however given its potential to directly interact with CGG repeats and its ambiguous role in 5-hydroxy-methylation of CG containing sequences, TET3 is a strong candidate for further exploration.
Human short association fibers are thinner and less myelinated than long fibers
Authors: Ruthig Philip , Edler v.d. Planitz David , Morozova Maria , Reimann Katja , Jäger Carsten , Reinert Tilo , Mohammadi Siawoosh , Weiskopf Nikolaus , Kirilina Evgeniya , Morawski Markus 
Published: October 2024

AbstractThe size and complexity of the human brain requires optimally sized and myelinated fibers. White matter fibers facilitate fast communication between distant areas, but also connect adjacent cortical regions via short association fibers. The fundamental questions of i) how thick these fibers are and ii) how strongly they are myelinated, however, remain unanswered. We present a comprehensive analysis of ∼400,000 fibers of human white matter regions with long (corpus callosum) and short fibers (superficial white matter). We demonstrate a substantially smaller fiber diameter and lower myelination in superficial white matter than in the corpus callosum. Surprisingly, we do not find a difference in the ratio between axon diameter and myelin thickness (g-ratio), which is close to the theoretically optimal value of ∼0.6 in both areas. For the first time, to our knowledge, we shed light on a fundamental principle of brain organization that will be essential to understand the human brain.
A Comprehensive Statistical Analysis of COVID-19 Trends: Global and U.S. Insights through ARIMA, Regression, and Spatial Models
Authors: Lei Zhihao 
Published: October 2024

AbstractThe COVID-19 pandemic has driven the need for accurate data analysis and forecasting to guide public health decisions. In this study, we utilized ARIMA and ARIMAX models to predict short-term trends in confirmed COVID-19 cases across different regions, including the United States, Asia, Europe, Africa, and the Americas. Comparisons were made between ARIMA and auto.arima models, and anomaly detection was performed to investigate discrepancies between predictions and actual data. The study also explored the relationship between vaccination rates and new case numbers, and examined how socioeconomic factors such as GDP per capita, HDI, and healthcare resources influenced COVID-19 incidence rates across countries. Our findings provide insights into the effectiveness of predictive models and the significant impact of socioeconomic factors on the spread of the virus, contributing valuable information for future epidemic prevention and control strategies.
Prolonged dry seasons lengthen coccidioidomycosis transmission seasons: implications for a changing California
Authors: Camponuri Simon K. , Head Jennifer R. , Collender Philip A. , Weaver Amanda K. , Heaney Alexandra K. , Colvin Kate A. , Bhattachan Abinash , Sondermeyer-Cooksey Gail , Vugia Duc J. , Jain Seema , Remais Justin V. 
Published: October 2024

AbstractCoccidioidomycosis, a fungal disease caused by soil-borneCoccidioidesspp., exhibits pronounced seasonal transmission, with incidence in California typically peaking in the fall. However, the influence of climate on the timing and duration of transmission seasons remains poorly understood. Using weekly data on reported coccidioidomycosis cases in California from 2000-2023, we developed a distributed-lag Markov state-transition model to estimate the effects of temperature and precipitation on the timing of transmission season onset and end. We found that transitions from cooler, wetter conditions to hotter, drier conditions accelerate season onset. Dry conditions (10thpercentile of precipitation) in the spring shifted season onset an average of 2.8 weeks (95% CI: 0.43-3.58) earlier compared to wet conditions (90thpercentile of precipitation). Conversely, transitions back to cooler, wetter conditions hastened season end, with dry fall conditions extending the season by an average of 0.69 weeks (95% CI: 0.37-1.41) compared to wet conditions. When dry conditions occurred in the spring and fall, the transmission season extended by 3.70 weeks (95% CI: 1.23-4.22). As California is expected to experience prolonged dry seasons with climate change, our findings suggest this shift may lengthen the time at which populations are at elevated coccidioidomycosis risk.
Genomic Landscape and Molecular Subtypes of Primary Central Nervous System Lymphoma
Authors: Li Shengjie , Li Danhui , Xia Zuguang , Wu Jianing , Ren Jun , Li Yingzhu , Cao Jiazhen , Sun Ying , Zhang Liyang , Ye Hongwei , Zhou Xingtao , Li Chengxun , Cao Wenjun , Mao Ying 
Published: October 2024

AbstractPrimary central nervous system lymphoma (PCNSL) is a rare and aggressive brain tumor with a poor prognosis and almost exclusively comprises diffuse large B-cell lymphoma (DLBCL). Its genetic characteristics and molecular subtypes in Chinese patients remain poorly understood, which in turn makes developing effective new therapies challenging. In our study, 140 Chinese patients with PCNSL that was newly diagnosed at one of three tertiary care centers and who underwent extensive follow-up were included. With this sample, we performed a genomic study aimed at expanding the genomic landscape and identifying new molecular subtypes. We first confirmed that the molecular subtype categories of DLBCL, as previously published, are not applicable to PCNSLs in Chinese patients. We then identified (n = 58) and validated (n = 82) three prominent genetic subtypes related to different clinical and molecular features of PCNSL and further confirmed them in an independent external Chinese PCNSL cohort (n = 36). We called these BMIs (from the co-occurrence of mutations in two genes among BTG1, MYD88, and IRF4), which are associated with favorable outcomes; E3s (so-called EP300 mutations), which are associated with unfavorable outcomes; and UCs (unclassified, without characteristic mutations). Importantly, EP300 was mutated in more PCNSLs from Asian patients (16.88%) than from Western patients (< 5.26%), resulting in unfavorable outcomes independent of the specific mutation site. Our analysis comprehensively reveals the genomic landscape of PCNSL in Chinese patients and emphasizes the clinical value of molecular classification for improving precision medicine strategies.Abstract FigureHighlightsIn this study, the genomic landscape of 140 Chinese patients with primary central nervous system lymphomas (PCNSLs) was evaluated.Chinese PCNSL patients have a defining genetic signature that differs from that of both PCNSL patients in other racial groups and DLBCL patients.Three robust molecular subtypes of PCNSL related to clinical and molecular features were identified and validated.The rate of EP300 mutation in PCNSLs was approximately three times higher among Asians than among Western patients, resulting in unfavorable outcomes independent of the specific mutation site.
A comprehensive survey of RNA modifications in a human transcriptome
Authors: Mulroney Logan , Coscujuela Tarrero Lucia , Maragno Paola , Rubolino Carmela , Maestri Simone , Furlan Mattia , Marzi Matteo Jacopo , Fitzgerald Tom , Leonardi Tommaso , Pelizzola Mattia , Birney Ewan , Nicassio Francesco 
Published: October 2024

ABSTRACTRNA modifications are critical for transcript function and regulation. Direct RNA nanopore sequencing offers a unique advantage by observing these modifications through characteristic alterations in ionic current signals. Various computational tools have been developed to detect RNA modifications, typically by comparing a sample of interest with a control lacking the target modification, often achieved through enzyme knockdown or knockout. We have developed a robustin vitrotranscription protocol to generate a modification-free copy of any input RNA to detect all modifications that alter the raw ionic current signal relative to the canonical nucleotides during nanopore sequencing. We generated anin vitrotranscribed sample from K562 cells and used Nanocompore to detect 26,619 modified RNA sites across 2,520 transcript isoforms from 1,742 genes. Of these, 56% are consistent with the well-characterized m6A modification. By inferring the identities of these modifications, we assessed differential usage and correlation patterns, revealing a significant co-occurrence between m6A and m5C modifications within the same transcripts. Additionally, some modifications were non-randomly associated with alternative splicing events. This study provides a comprehensive survey of RNA modifications across the transcriptome, demonstrating the utility ofin vitrotranscription coupled with direct RNA nanopore sequencing to simultaneously detect multiple modifications without the need for additional independent biochemical assays. The protocol is consistent in the future with more complex experimental designs, for example for differential modification usage between samples.
Oxytocin neurons signal state-dependent transitions to thermogenesis and behavioral arousal in social and non-social settings
Authors: Vandendoren Morgane , Rogers Joseph F. , Landen Jason G. , Killmer Samantha , Alimiri Baizar , Pohlman Celeste , Tattersall Glenn J. , Bedford Nicole L. , Nelson Adam C. 
Published: October 2024

AbstractMammalian thermoregulatory behaviors such as thermal comfort seeking, physical activity, nesting, and huddling operate alongside autonomic responses such as brown fat thermogenesis and peripheral vasodilation to defend core body temperature (Tb)1–4. The defended Tb is not held constant, but alternates across active/rest and behavioral cycles5–9. Although the thermoregulatory behaviors facilitating these alternations are controlled by the brain, the underlying neural populations are poorly understood. The oxytocin system has been proposed to contribute to behavioral thermoregulation10,11, yet evidence for how activity within oxytocin neurons relates to such pathways is lacking. Here, we identify neuronal dynamics underlying behavioral thermoregulation in mice. We show that the paraventricular hypothalamus (PVN) and PVN oxytocin (PVNOT) neurons are selectively activated during two thermoregulatory states: active and quiescent huddling. Next, activation and inhibition of PVNOTneurons reveals effects on Tb, peripheral vasodilation, and warm seeking, establishing a role in thermoeffector pathways. We then demonstrate thatin vivoPVNOTcalcium activity tracks the patterning of thermoregulatory behaviors. Across social contexts, PVNOTpeaks occur during low Tb (∼36.0°C) and during transitions towards physical activity and thermogenesis. In the solo context, PVNOTpeaks predict the offset of quiescence and onset of post-quiescence nesting. In the paired context, PVNOTpeaks predict the offset of quiescent huddling and onset of post-quiescent active huddling. Our study provides evidence for a role of PVNOTneurons during the offset of rest and the onset of behavioral arousal and thermogenesis and provides a foundation for understanding the coordination between thermal homeostasis and animal behavior.Graphical Abstract
Limitations of grouping subjects based on biological sex (males versus females) and a new approach: insights from intra-nucleus accumbens core dopamine-induced psychostimulant activity
Authors: Job Martin O. 
Published: October 2024

AbstractBackgroundIn the field of substance use disorder research, sex-as-a-biological-variable (SABV) is employed to determine the mechanisms governing sex differences. Based on our recently developed MISSING (Mapping Intrinsic Sex Similarities as an Integral quality of Normalized Groups) model, we hypothesized that grouping subjects by biological sex does not represent the most effective way to group behavioral data objectively. To test our hypothesis, we conducted experiments to compare the psychostimulant effect of intra-nucleus accumbens (NAc) dopamine on groups based on 1) biological sex (current model) and 2) behavioral clustering (MISSING model) for effectiveness in identifying groups of subjects that a) are distinct with regards to behavioral variables, and b) confirm NAc dopamine neurochemical expression/activity topography (NEAT).MethodsFor the current model, we separated subjects (n = 37 Sprague Dawley rats, male n = 20, female n = 17) by biological sex prior to all assessments. For the MISSING model, we conducted normal mixtures clustering of baseline activity, dopamine activity (as distance traveled in cm over 60 min) and dopamine activity normalized-to-baseline activity (NBA) of all subjects to identify behavioral clusters.ResultsSeparating groups by biological sex revealed groups (males and females) that were not clearly distinct with regards to behavioral variables and do not confirm NAc dopamine NEAT. Separating groups using the MISSING model revealed groups (behavioral clusters) that were clearly distinct with regards to behavior and confirm NAc dopamine NEAT.ConclusionsOur results reveal the limitations of grouping subjects based on biological sex. We discuss a new approach.
Linking work meaningfulness, engagement and job crafting to career commitment
Authors: Kim Eun-Jee , Park Sunyoung 
Published: October 2024

PurposeThe purpose of this study is to examine the relationships among meaningful work, employee engagement, job crafting and career commitment.MethodsThe study primarily employed structural equation modeling to test the proposed research model and hypotheses. Data were collected through an online questionnaire from employees working at multiple companies.FindingsThe findings indicated that meaningful work affected employee engagement, job crafting and career commitment. In addition, employee engagement and job crafting mediated the relationships between meaningful work and career commitment.OriginalityThis study identifies three important antecedents (meaningful work, employee engagement and job crafting) that improve employees’ level of career commitment. Based on previous findings indicating that career commitment can promote behavioral and attitudinal outcomes, this study focuses on contributors of career commitment, which ultimately may link to the positive outcomes of career commitment.
Gendered workplace as a double-loop social construct: the case of Japanese women professionals
Authors: Zhang-Zhang Yingying 
Published: October 2024

Purpose
This paper aims to critically examine the role of women in the Japanese workplace and discusses its implications for gender studies within the context of diversity, equity and inclusion in international business (IB). Employing a social constructivism approach, this paper moves beyond conventional economic typologies and specific cases to offer an integrative and socially embedded perspective for understanding gender dynamics in the Japanese workplace.

Design/methodology/approach
This viewpoint paper critiques existing research on Japanese women professionals, drawing on factual evidence and literature to propose a double-loop gendering framework. This framework explores the socially constructed phenomenon of women in the Japanese workplace at multiple levels, providing a holistic interpretation of gender dynamics.

Findings
We identify five macro-level environmental factors that influence female labour participation, leadership positions and entrepreneurship. These factors are mediated by career motivation, corporate culture and men’s attitudes towards gender equality. Distinguishing between first-loop gendering, which focuses on problem-solving for improved gender equality, and second-loop gendering, which examines the underlying assumptions of social norms, values and beliefs, offers insights into the challenges Japan faces in achieving female leadership and equality. Second-loop gendering may help explain the paradoxical state of Japan’s women professionals, characterized by slow progress in gender equality despite significant political and financial resources. Our analysis reveals complex, multi-level interactions and influences within this socially constructed phenomenon.

Originality/value
This viewpoint paper provides a critical analysis of gender studies in the Japanese context, offering potential avenues for IB explorations. The insights extend to future IB studies, international comparisons of gender equality and the management of gender diversity in multinational corporations (MNCs).