bluuebunny/crossref_metadata_2025_split huggingface dataset:
Everchanging range: how the changing environment has influenced the genetic diversity and differentiation of an iconic North American palm species
Authors: Klimova Anastasia , Landis Jacob 
Published: February 2025

Abstract

Background and Aims
Understanding spatial patterns of neutral and adaptive genetic variation and linking them to future climate change have become crucial in assessing the genetic vulnerability of species and developing conservation strategies. Using a combination of genomic approaches, this study aimed to explain the demographic history of Washingtonia palms, predict the adaptive potential in Washingtonia palm populations on the Baja California Peninsula (BCP) and southern California, and determine the geographical areas where climate change will have the most drastic effects.

Methods
We used over 5000 single nucleotide polymorphisms from 155 individuals across 18 populations spanning the entire distribution range of Washingtonia palms on the BCP and southern California. We examined past and current genetic diversity distribution patterns and identified outliers using genetic differentiation and genotype–environment association methods. Genetic vulnerability was predicted, and species distribution modelling was utilized for the geographical regions that will be at risk under future climate scenarios.

Key Results
Demographic modelling supported a bottleneck related to the Wisconsin glaciation, which was stronger and longer in northern Washingtonia populations. Genomic diversity presented a strong relationship to geography and provided evidence for range expansions from several refugia. Gradient Forest Analysis revealed that the genetic variation was shaped primarily by variables related to latitude and temperature during the coldest quarter, indicating adaptation to local thermal environments. We found limited adaptive potential and high levels of genetic vulnerability in lowland southern and central populations. Accordingly, species distribution modelling found that the southern distribution range will be affected by climate change, particularly under a high-emissions scenario.

Conclusions
Our findings include a history of population bottleneck related to postglacial range expansion, population divergence with limited gene flow, and probable future changes in distribution under changing conditions. Under long-term climate change, southern and central lowland populations of Washingtonia will experience harsher climate conditions and strong genomic offset.
Speeding up interval estimation for R2-based mediation effect of high-dimensional mediators via cross-fitting
Authors: Xu Zhichao , Li Chunlin , Chi Sunyi , Yang Tianzhong , Wei Peng 
Published: February 2025

Abstract
Mediation analysis is a useful tool in investigating how molecular phenotypes such as gene expression mediate the effect of exposure on health outcomes. However, commonly used mean-based total mediation effect measures may suffer from cancellation of component-wise mediation effects in opposite directions in the presence of high-dimensional omics mediators. To overcome this limitation, we recently proposed a variance-based R-squared total mediation effect measure that relies on the computationally intensive nonparametric bootstrap for confidence interval estimation. In the work described herein, we formulated a more efficient two-stage, cross-fitted estimation procedure for the R2 measure. To avoid potential bias, we performed iterative Sure Independence Screening (iSIS) in two subsamples to exclude the non-mediators, followed by ordinary least squares regressions for the variance estimation. We then constructed confidence intervals based on the newly derived closed-form asymptotic distribution of the R2 measure. Extensive simulation studies demonstrated that this proposed procedure is much more computationally efficient than the resampling-based method, with comparable coverage probability. Furthermore, when applied to the Framingham Heart Study, the proposed method replicated the established finding of gene expression mediating age-related variation in systolic blood pressure and identified the role of gene expression profiles in the relationship between sex and high-density lipoprotein cholesterol level. The proposed estimation procedure is implemented in R package CFR2M.
Co-occurrence of CT-based radiological sarcopenia and frailty are related to impaired survival in surgical oncology
Authors: Weerink Linda B M , van Leeuwen Barbara L , Kwee Thomas C , Lamoth Claudine J C , van Munster Barbara C , de Bock Geertruida H 
Published: February 2025

Abstract

Objectives
The objective of this study was to investigate the association of radiological sarcopenia and frailty with postoperative outcomes in adult patients undergoing oncological surgery.

Methods
Data were derived from the PICNIC study, consisting of two consecutive series of patients undergoing surgical cancer treatment. Radiological sarcopenia was assessed based on CT imaging. The presence of low muscle mass and/or low muscle density was determined based on lowest quartile gender specific cut-off values. Frailty was defined by a score of ≥4 on the Groningen frailty index. Postoperative overall survival was analysed with Kaplan-Meier curves and Logrank testing. Multivariable Cox regression analyses adjusted for age and gender were performed to calculate adjusted hazard ratios (HR).

Results
A total of 372 patients were included. Median age was 69 (28-86) years, 77 patients (23.5%) were frail and radiological sarcopenia was present in 134 patients (41.0%). Combined radiological sarcopenia and frailty was present in 35 patients (10.7%). One-year (65.6% versus 87.0%) and three-year survival (31.4% versus 66.8%) were significantly worse in patients with combined radiological sarcopenia and frailty. The combined presence of radiological sarcopenia and frailty was associated with significantly decreased overall survival (HRadjusted: 2.06, 95% CI: 1.39-3.05, P &lt; .001).

Conclusion
Co-occurrence of radiological sarcopenia and frailty is strongly related to impaired survival in surgical cancer patients.

Advances in knowledge
The combined presence of radiological sarcopenia and frailty is associated with decreased postoperative survival, strongly exceeding the effects of both risk factors separately. The use of radiological sarcopenia in addition to frailty screening can further optimize preoperative risk stratification.
Modulating nociception networks: the impact of low-intensity focused ultrasound on thalamocortical connectivity
Authors: Mishra Arabinda , Yang Pai-Feng , Manuel Thomas J , Newton Allen T , Phipps M Anthony , Luo Huiwen , Sigona Michelle K , Dockum Allison Q , Reed Jamie L , Gore John C , Grissom William A , Caskey Charles F , Chen Li Min 
Published: February 2025

Abstract
Pain engages multiple brain networks, with the thalamus serving as a critical subcortical hub. This study aims to explore the effects of low-intensity transcranial focused ultrasound (FUS) induced suppression on the organization of thalamocortical nociceptive networks. We employed MR-guided focused ultrasound (MRgFUS), a potential non-invasive therapy, with real-time ultrasound beam localization feedback and fMRI monitoring. We first functionally identified the focused ultrasound target at the thalamic ventroposterior lateral nucleus by mapping the whole brain blood oxygenation level-dependent responses to nociceptive heat stimulation of the hand using fMRI in each individual macaque monkey under light anesthesia. The blood oxygenation level-dependent fMRI signals from the heat-responsive thalamic ventroposterior lateral nucleus were analyzed to derive thalamocortical effective functional connectivity network using the psychophysical interaction method. Nineteen cortical regions across sensorimotor, cognitive, associative, and limbic networks exhibited strong effective functional connectivity to the thalamic ventroposterior lateral during heat nociceptive processing. Focused ultrasound-induced suppression of heat activity in the thalamic VPL altered nociceptive responses in most of the nineteen regions. Data-driven hierarchical clustering analyses of blood oxygenation level-dependent time courses across all thalamocortical ROI pairs identified two effective functional connectivity subnetworks. The concurrent suppression of thalamic heat response with focused ultrasound reorganized these subnetworks and modified thalamocortical connection strength. Our findings suggest that the thalamic ventroposterior lateral nucleus has extensive and causal connections to a wide array of cortical areas during nociceptive processing. The combination of MRgFUS with fMRI enables precise dissection and modulation of nociceptive networks in the brain, a capability that no other device-based neuromodulation methods have achieved. This presents a promising non-invasive tool for modulating pain networks with profound clinical relevance. The robust modulation of nociceptive effective functional connectivity networks by focused ultrasound strongly supports the thalamic ventroposterior lateral as a viable target for pain management strategies.
Photoinduced synthesis of ultrafine Pt nanoparticles loaded on the surface of MOFs-modified carbon materials for efficient catalytic reduction reactions
Authors: Xian Liang , Tian Xiaoxia , Liu Zhaomin , Liu Shuxin , Zhao Jiuzhou 
Published: February 2025

Abstract
In this paper, ultrafine platinum nanoparticles (Pt/Co-N-C) were prepared by irradiating the mixture of Co-N-C and K2[PtCl4] with near-ultraviolet (UV) light at a wavelength of 395 nm and visible light at 450 and 550 nm without adding any reducing and stabilizing agents using MOFs-modified carbon materials (Co-N-C) as the carrier. The composition and morphology of the Pt/Co-N-C catalysts were investigated using characterization tools such as X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and high-resolution transmission electron microscopy (HR-TEM), etc. The results showed that the Pt nanoparticles were well dispersed on the surface of the Co-N-C, with average particle sizes of about 2.39, 2.86, and 3.53 nm, respectively. In the catalytic 4-NP reduction experiments, the catalyst (Pt/Co-N-C-1) prepared under near-ultraviolet light (395 nm) irradiation showed the highest catalytic activity with a rate constant k=0.64 min-1. After five cycles, the conversion rate was still maintained at about 90%, which was highly reusable. It was demonstrated that 395 nm near-ultraviolet light was more favorable for the modulation of the distribution of the species during the hydrolysis and reduction of platinum in this reaction to form smaller-sized platinum nanocrystals, which was conducive to the catalyst to exhibit higher activity.
Clinical relevance of Thiopurine methyl transferase genotype testing for azathioprine in dermatology
Authors: Ramassamy Sivaranjini , Chandrashekar Laxmisha , Mathaiyan Jayanthi , Rajappa Medha , Devanathan Reka , Selvarathinam Sujeevan , Goud Alladi Charanraj 
Published: February 2025

Abstract

Background
Polymorphisms in thiopurine methyltransferase (TPMT) are a predominant cause of azathiopurine-induced leukopenia in the Western countries. The exact role of these polymorphisms in Indian population with dermatological disorders is uncertain.

Methods
We included consecutive patients on Azathioprine who were initiated for dermatological disorders from south India. Three TPMT polymorphisms (c.238 G &gt; C, c.460 G &gt; A, and c.719A &gt; G) were assessed. A comparison of the proportion of adverse events to azathioprine, especially myelosuppression, was performed between those with wild-type genotype and those with TPMT polymorphisms.

Results
Of the 123 patients (61 males, mean age 46 years), 65% had autoimmune blistering disorder. Adverse event to azathioprine was noted in 25 (20.3%), of which 16 (13%) had myelosuppression, four (3.2%) each had hepatotoxicity and gastrointestinal intolerance. TPMT polymorphisms were detected amongst 13 (10.7%), of which five had experienced adverse events. The polymorphisms could explain 25% (4 out of 16) of the cases of leucopenia. The odds of developing leukopenia in TPMT polymorphism was not significant (3.63, 95% CI 0.96-13.60, p=0.055).

Conclusion
The tested TPMT polymorphisms could not predict the adverse events, particularly the haematological toxicity of azathioprine in dermatological use among the south Indian population.
KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation
Authors: Bouys Lucas , Vaduva Patricia , Jouinot Anne , Violon Florian , Vaczlavik Anna , Barat Maxime , Charchar Helaine , Chasseloup Fanny , Kamilaris Crystal , Espiard Stéphanie , Haissaguerre Magalie , Raverot Gérald , Kroiss Matthias , Berthon Annabel , Perlemoine Karine , Tauveron Igor , Guignat Laurence , Libé Rossella , Groussin Lionel , Assié Guillaume , Pasmant Eric , Reincke Martin , Borson-Chazot Françoise , Ferrière Amandine , Vantyghem Marie-Christine , Stratakis Constantine A , Kamenický Peter , Fragoso Maria Candida Barisson Villares , Chansavang Albain , Ragazzon Bruno , Bertherat Jérôme 
Published: February 2025

Abstract

Objective
ARMC5 is the most prevalent gene predisposing to primary bilateral macronodular adrenal hyperplasia (PBMAH), but germline KDM1A variants have been identified in the rare PBMAH associated with food-dependent Cushing's syndrome (FDCS). The purpose of this work was to assess the frequency of KDM1A variants in a large series of PBMAH patients.

Design
A total of 301 consecutive PBMAH index cases from 8 international endocrinology departments were included. Clinical, biological, and imaging data were collected retrospectively.

Results
Ten (3.3%) patients carried a germline KDM1A pathogenic or likely pathogenic variant, 60 (19.9%) carried a germline ARMC5 alteration, and 231 (76.8%) had no identified genetic predisposition. Food-dependent Cushing's syndrome was present in all patients with KDM1A variants and absent in the 2 other groups. KDM1A patients had a higher 24-h urinary free cortisol (3.0-fold upper limit of normal vs 1.36 for ARMC5 patients and 0.66 for wild-type patients, respectively, P = .0001). In accordance with FDCS pathophysiology, patients with KDM1A variants had a lower morning fasting plasma cortisol (192 nmol/L vs 407 and 428, respectively, P = .0003) and a higher midnight plasma cortisol (487 nmol/L vs 297 and 171.96, respectively, P = .0004). Morning/midnight plasma cortisol ratio below 0.65 holds 100% sensitivity and specificity for the detection of FDCS. All patients with KDM1A variants were women, vs 65% of ARMC5 patients and 67% of wild-type patients (P = .0337).

Conclusions
KDM1A germline pathogenic variants are rare in PBMAH and account for &lt;5% of index cases. KDM1A seems constantly associated with FDCS, which can be evoked in front of a morning/midnight plasma cortisol ratio below 0.65.
Reference equations for peak oxygen uptake for treadmill cardiopulmonary exercise tests based on the NHANES lean body mass equations, a FRIEND registry study
Authors: Santana Everton J , Kim Daniel Seung , Christle Jeffrey W , Cauwenberghs Nicholas , Celestin Bettia E , Tso Jason V , Wheeler Matthew T , Ashley Euan A , Peterman James E , Gardner Christopher , Arena Ross , Harber Matthew , Kaminsky Leonard A , Kuznetsova Tatiana , Myers Jonathan N , Haddad Francois 
Published: February 2025

Abstract

Aims
Cardiorespiratory fitness (CRF), measured by peak oxygen uptake (VO2peak), is a strong predictor of mortality. Despite its widespread clinical use, current reference equations for VO2peak show distorted calibration in obese individuals. Using data from the Fitness Registry and the Importance of Exercise National Database (FRIEND), we sought to develop novel reference equations for VO2peak better calibrated for overweight/obese individuals - in both males and females, by considering body composition metrics.

Methods
Graded treadmill tests from 6,836 apparently healthy individuals were considered in data analysis. We used the National Health and Nutrition Examination Survey equations to estimate lean body mass (eLBM) and body fat percentage (eBF). Multivariable regression was used to determine sex-specific equations for predicting VO2peak considering age terms, eLBM and eBF.

Results
The resultant equations were expressed as VO2peak (male) = 2633.4 + 48.7✕eLBM (kg) - 63.6✕eBF (%) - 0.23✕Age2 (R2=0.44) and VO2peak (female) = 1174.9 + 49.4✕eLBM (kg) - 21.7✕eBF (%) - 0.158✕Age2 (R2=0.53). These equations were well-calibrated in subgroups based on sex, age and body mass index (BMI), in contrast to the Wasserman equation. In addition, residuals for the percent-predicted VO2peak (ppVO2) were stable over the predicted VO2peak range, with low CRF defined as &lt; 70% ppVO2 and average CRF defined between 85-115%.

Conclusions
The derived VO2peak reference equations provided physiologically explainable and were well-calibrated across the spectrum of age, sex and BMI. These equations will yield more accurate VO2peak evaluation, particularly in obese individuals.
Depletion of mitochondrial CypD in endothelial and smooth muscle cells attenuates vascular dysfunction and hypertension
Authors: Dikalova Anna , Ao Mingfang , Lantier Louise , Gutor Sergey , Dikalov Sergey 
Published: February 2025

Abstract
Hypertension is a major risk factor of cardiovascular disease affecting nearly half of adult population, but only 25% patients have their blood pressure under control. Hypertension is associated with mitochondrial dysfunction; however, its molecular mechanisms and causative role are still elusive. Understanding these mechanisms is important to develop new therapies. Cyclophilin D (CypD) promotes mitochondrial swelling and dysfunction. The objective of this study is to test if CypD depletion attenuates vascular dysfunction and hypertension. To test this hypothesis, we used endothelial-specific and smooth muscle-specific CypD knockout mice in angiotensin II model of vascular dysfunction and hypertension. Our results show that depletion of endothelial CypD prevents angiotensin II-induced impairment of endothelial-dependent vasorelaxation, preserves endothelial nitric oxide and mitochondrial respiration, reduces hypertension, vascular oxidative stress and vascular metabolic glycolytic-switch compared with wild-type littermates. Depletion of smooth muscle CypD slightly reduces angiotensin II-induced hypertension, partially attenuates reduction in vascular nitric oxide and vasorelaxation, abolishes vascular superoxide overproduction, diminishes angiotensin II-induced vascular glycolysis, hypertrophy and fibrosis. Our data showed an intriguing “metabolic” and “redox” crosstalk between endothelial and smooth muscle cells. Depletion of endothelial CypD reduces not only angiotensin II-induced endothelial glycolysis but also attenuates smooth muscle cell glycolytic switch. Interestingly, depletion of smooth muscle CypD was also not limited to the effect on smooth muscle glycolysis, but it also reduced endothelial cell glycolysis. Vascular oxidative stress was inhibited both in EcCypDKO and SmcCypDKO mice, therefore, cell-specific CypD depletion had a “global” antioxidant effect on the entire vasculature. Our results support a novel function of mitochondrial CypD in regulation of superoxide production and metabolism of vascular smooth muscle and endothelial cells which affect endothelial barrier and smooth muscle vascular functions. We suggest that blocking vascular CypD reduces vascular oxidative stress, improves vascular metabolism and vascular function which may be beneficial in cardiovascular disease.
Loneliness as a risk factor for time to care home entry for older adults receiving community care
Authors: Rickman Sam , Fernandez Jose-Luis , Malley Juliette 
Published: February 2025

Abstract

Background and Objectives
International efforts to contain long-term care costs have prioritised personal care. However, reductions in services aimed at addressing loneliness or promoting social participation may affect demand for long-term care facilities. Research on the impact of loneliness on entry to residential or nursing care is based on survey data, which under-represents those with highest needs. Administrative records include such individuals and, unlike surveys, contain continuous data on service receipt, enabling accurate modelling of time to care home entry.

Research Design and Methods
We use administrative data for 1,101 individuals receiving care in a London local authority. We extract loneliness from free text notes using a large language model and model its impact on care home entry five years after assessment, controlling for needs and demographics. We use logistic regression and a competing risks survival model to measure time until care home entry.

Results
The odds ratio for care home entry associated with loneliness is 1.45 with logistic regression (95% CI 1.04 – 2.01). The hazard ratio is 1.32 (95% CI 1.01 – 1.72) with a cause-specific model, and 1.39 (95% CI 1.08 - 1.79) using the Fine & Gray method. Among those most likely to enter a care home, the median time to entry is 9 months (95% CI 228 - 328 days) earlier for those who are lonely.

Discussion and Implications
The hazard ratio of loneliness on care home entry is around the magnitude associated with gender, ethnicity or living alone. However, loneliness is modifiable. Reductions to services for social participation, such as day centres, are likely to cause an increase in loneliness. We demonstrate that for those with the highest needs, loneliness is a significant risk factor for time until care home entry. Policymakers seeking to delay care home entry should consider the impact of services for loneliness.
Pilot Randomized Controlled Trial of the Feasibility of a Mobile App-Delivered Mindfulness-Based Intervention for Caregiver Stress
Authors: Plys Evan , Seward Morgan , Allen Elizabeth M , Tatar Raquel G , Huberty Jennifer , Vranceanu Ana-Maria 
Published: February 2025

Abstract

Background and Objectives
We tested feasibility and preliminary benefits of a free mobile app-delivered mindfulness-based intervention for stress among dementia caregivers (i.e., Healthy Minds Program for Caregivers [HMP-C]).

Research Design and Methods
Single-blind Stage 1b pilot randomized controlled trial compared 12 weeks of HMP-C (n = 47) with a dose-matched education podcast control (n = 48; Wellness App [WA]). T-tests examined between-group differences.

Results
Feasibility benchmarks were met for acceptability (90% eligible enrolled), demand (95% completed post-tests), and data collection (100% measures complete). Treatment satisfaction was sufficient for HMP-C. Adherence was lower than benchmarks (&gt;52.5 minutes weekly) for HMP-C (57%) and WA (59%). Mechanistic targets of mindfulness (p &lt; .001; d = -1.21) and positive aspects of caregiving (p &lt; .001; d = -0.92) showed large pre-post improvements in the HMP-C group. Mechanistic validity was established through significant correlations between change in stress and change in mindfulness (r =-.40, p =.006) and positive aspects of caregiving (r =-.49, p =.001). Pre-post improvements in HMP-C were not statistically significantly compared with WA for stress (p = .097; d = -0.35), depression (p = .110; d = -0.34), or anxiety (p = .237; d = -0.25).

Discussion and Implications
The current study demonstrated feasibility and mechanistic target engagement and validity for HMP-C. As expected in an underpowered feasibility trial, clinical outcomes did not improve more than control, but trends favored HMP-C. Together, findings demonstrate that a fully powered Stage 2 trial is warranted to test the efficacy of HMP-C compared with WA.