bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age at onset mediates genetic impact on disease severity in facioscapulohumeral muscular dystrophy
Authors: Zheng Fuze , Lin Yawen , Qiu Liangliang , Zheng Ying , Zeng Minghui , Lin Xiaodan , He Qifang , Lin Yuhua , Chen Long , Lin Xin , Chen Xinyue , Lin Lin , Wang Lili , He Junjie , Lin Feng , Yang Kang , Wang Ning , Lin Minting , Lian Sheng , Wang Zhiqiang 
Published: December 2024

Abstract
Facioscapulohumeral muscular dystrophy type 1 (FSHD1) patients exhibit marked variability in both age at onset (AAO) and disease severity. Early onset FSHD1 patients are at an increased risk of severe weakness, and early onset has been tentatively linked to the length of D4Z4 repeat units (RUs) and methylation levels. The present study explored potential relationships among genetic characteristics, AAO and disease severity in FSHD1.
This retrospective and observational cohort study was conducted at the Fujian Neuromedical Centre (FNMC) in China. Genetically confirmed participants with FSHD1 recruited from 2001 to 2023 underwent distal D4Z4 methylation assessment. Disease severity was assessed by FSHD clinical score, age-corrected clinical severity score (ACSS) and onset age of lower extremity involvement. Mediation analyses were used to explore relationships among genetic characteristics, AAO and disease severity. Finally, machine learning was employed to explore AAO prediction in FSHD1.
A total of 874 participants (including 804 symptomatic patients and 70 asymptomatic carriers) were included. Multivariate Cox regression analyses indicated that male gender, low DUZ4 RUs, low CpG6 methylation levels, non-mosaic mutation and de novo mutation were independently associated with early onset in FSHD1. Early onset patients (AAO &lt; 10 years) had both a significantly higher proportion and an earlier median onset age of lower extremity involvement compared to the typical adolescent onset (10 ≤ AAO &lt; 20 years), typical adult onset (20 ≤ AAO &lt; 30 years) and late onset (AAO ≥ 30 years) subgroups. AAO was negatively correlated with both clinical score and ACSS. We found that AAO exerted mediation effects, accounting for 12.2% of the total effect of D4Z4 RUs and CpG6 methylation levels on ACSS and 38.6% of the total effect of D4Z4 RUs and CpG6 methylation levels on onset age of lower extremity involvement. A random forest model that incorporated variables including gender, age at examination, inheritance pattern, mosaic mutation, D4Z4 RUs and D4Z4 methylation levels (at CpG3, CpG6 and CpG10 loci) performed well for AAO prediction. The predicted AAO (pAAO) was negatively correlated with ACSS (Spearman’s ρ = −0.692).
Our study revealed independent contributions from D4Z4 RUs, D4Z4 methylation levels, mosaic mutation and inheritance pattern on AAO variation in FSHD1. AAO mediates effects of D4Z4 RUs and methylation levels on disease severity. The pAAO values from our random forest model informatively reflect disease severity, offering insights that can support efficacious patient management.
Distinctive clinical features in biopsy-proven nerve large-arteriole vasculitis and microvasculitis
Authors: Soontrapa Pannathat , Pinto Marcus V , Shouman Kamal , Mandrekar Jay , Engelstad JaNean K , Aragon Pinto Catarina , Taylor Sean , Mauermann Michelle L , Berini Sarah E , Bosch E Peter , Rubin Devon I , Koster Matthew J , Weyand Cornelia M , Warrington Kenneth J , Klein Christopher J , Dyck Peter J , Dyck P James B 
Published: December 2024

Abstract
Vasculitic neuropathy is caused by inflammatory destruction of nerve blood vessels resulting in nerve ischaemia. Nerve vasculitis can be divided into two categories based on vessel size: large-arteriole vasculitis (≥75 µm) and microvasculitis (&lt;75 µm). Herein, we characterize the clinical features of nerve large-arteriole vasculitis in comparison to nerve microvasculitis.
This is a retrospective cohort study of patients evaluated and biopsied at Mayo sites between 2001 and 2020. We collected clinical and histopathological data from patients whose nerve biopsies were either diagnostic or highly suggestive of nerve vasculitis.
Two hundred and seventy-eight cases were identified: 125 cases of large-arteriole vasculitis and 153 cases of microvasculitis. Nerve large-arteriole vasculitis presented with a more acute (50.4% versus 26.8%) versus chronic onset (33.6% versus 57.5%) than nerve microvasculitis (P = 0.0001). Nerve microvasculitis had longer mean time to diagnosis (10.5 versus 4.3 months; P &lt; 0.0001) and longer time to plateau (8.9 versus 3.5 months; P &lt; 0.0001). Nerve large-arteriole vasculitis typically presented as distal asymmetric polyneuropathy (48.0%), whereas nerve microvasculitis typically presented as radiculoplexus neuropathy/polyradiculoneuropathy (more proximal involvement of shoulder and thigh) (43.8%) (P &lt; 0.0001). Systemic autoimmune disease was more common in nerve large-arteriole vasculitis (70.4% versus 22.9%, odds ratio, 8.0; 95% confidence interval, 4.7–13.7; P &lt; 0.0001). Nerve microvasculitis was significantly related to non-systemic vasculitis (71% versus 23%, odds ratio, 7.9; 95% confidence interval, 4.6–13.6; P &lt; 0.0001). Nerve microvasculitis had more autonomic involvement (24.2% versus 7.2%, odds ratio, 4.1; 95% confidence interval, 1.9–8.9; P = 0.0002).
Nerve large-arteriole vasculitis and nerve microvasculitis have different but overlapping clinical features. Nerve large-arteriole vasculitis usually presents with acute onset, distal asymmetric polyneuropathy, associated with other autoimmune diseases and systemic involvement. In contrast, nerve microvasculitis usually presents with a subacute/chronic onset, as radiculoplexus neuropathy/polyradiculopathy (distal and proximal pattern) with autonomic involvement, and is more often a form of non-systemic vasculitis.
Single-pulse transcranial magnetic stimulation of the dorsolateral prefrontal cortex does not directly affect muscle sympathetic nerve activity in humans
Authors: McCarthy Brendan , Sesa-Ashton Gianni , Rim Donggyu , Henderson Luke A , Macefield Vaughan G 
Published: December 2024

Abstract
Transcranial magnetic stimulation (TMS) is applied both in research settings and clinically, notably in treating depression through the dorsolateral prefrontal cortex (dlPFC). We have recently shown that transcranial alternating current stimulation of the dlPFC partially entrains muscle sympathetic nerve activity (MSNA) to the stimulus. We, therefore, aimed to further explore the sympathetic properties of the dlPFC, hypothesizing that single-pulse TMS could generate de novo MSNA bursts. Microneurography was performed on the right common peroneal nerve in 12 participants. TMS pulses were then delivered to the ipsilateral dlPFC at resting motor threshold (MT) of the first dorsal interosseous muscle and at powers 20 below, 10 below, 10% above, and 20% above MT. The MT and 10% above MT intensities were also used to stimulate the right motor cortex and shoulder. Comparisons between stimulus intensities at the same site and between sites at the same intensities revealed no differences in MSNA burst frequency, burst incidence, or single MSNA spikes. Most stimulus trains, however, showed reduced burst frequency and incidence from baseline, regardless of site. This suggests that the TMS itself was evoking arousal-based sympathoinhibition, independent of dlPFC influences. It seems the dlPFC is capable of modulating MSNA but cannot directly generate bursts.
The Current and Future State of Vaccines for Lyme Disease
Authors: Plotkin Stanley A , Shapiro Eugene D 
Published: December 2024

Abstract
Lyme disease is caused by Borrelia species that are transmitted by Ixodes ticks prevalent in parts of the United States and Europe. A Lyme vaccine containing the outer surface protein A (OspA) antigens from the single Borrelia species most prevalent in the United States was marketed in the 1990s, but was withdrawn because of unproven concerns about safety, which led to insufficient sales. Since then, the incidence of Lyme disease has increased in the United States owing to the geographical spread of infected ticks. Lyme disease due to multiple different species of Borrelia is also widely prevalent in many European countries. New Lyme vaccines, using OspA antigens from multiple species of American and European Borrelia, are in advanced clinical development, and one such vaccine is in phase 3 trials. When licensed, new vaccines are likely to have an impact in preventing Lyme disease, although the need for periodic boosters remains to be defined.
Symbolic value and embeddedness of an industrial megaproject: Tesla’s Gigafactory Berlin-Brandenburg
Authors: Roessler Max , Prenzel Paula , Schiller Daniel 
Published: December 2024

Abstract
Large-scale industrial settlements, such as the establishment of multinational enterprise (MNE) subsidiaries, are megaprojects that face additional challenges when embedding the subsidiary in the region. Part of these challenges may be due to contrasting symbolic values of the industrial project, which can facilitate or hinder embeddedness. This study considers the relevance of symbolic value for the embeddedness of an industrial megaproject through the case of Tesla’s Gigafactory Berlin-Brandenburg. Based on 23 interviews, we examine differences in the symbolic representation of the project among stakeholder groups and show that symbolic value can have supportive or divisive effects on the settlement process and embeddedness.
Small Remnants versus Large Triglyceride-Rich Lipoproteins in Risk of Atherosclerotic Cardiovascular Disease
Authors: Wadström Benjamin N , Wulff Anders B , Pedersen Kasper M , Nordestgaard Børge G 
Published: December 2024

Abstract

Background
Small remnants may penetrate the arterial intima more efficiently compared to large triglyceride-rich lipoproteins (TGRL). We tested the hypothesis that the importance of remnant cholesterol for the risk of atherosclerotic cardiovascular disease (ASCVD) may depend on the size of the remnants and TGRL carrying cholesterol.

Methods
The cholesterol content of small remnants and large TGRL were measured in 25 572 individuals from the Copenhagen General Population Study (2003–2015) and in 222 721 individuals from the UK Biobank (2006–2010) using nuclear magnetic resonance spectroscopy. In the Copenhagen cohort during up to 15 years of follow-up and in the UK Biobank cohort during up to 16 years of follow-up, the numbers of individuals diagnosed with ASCVD (=myocardial infarction, ischemic stroke, and peripheral artery disease) in national health registries were 3869 and 11 424, respectively.

Results
Compared to individuals with low cholesterol content in both small remnants and large TGRL (cutpoints were median cholesterol content), multivariable-adjusted hazard ratios for risk of ASCVD were 1.21 (95% confidence interval: 1.07–1.37) for individuals with high cholesterol content in small remnants only and 0.94 (0.83–1.07) for individuals with high cholesterol content in large TGRL only; the multivariable-adjusted hazard ratio for risk of ASCVD per 10 percentile-units higher cholesterol content in small remnants vs that in large TGRL was 1.04 (1.01–1.07). In the UK Biobank cohort, corresponding hazard ratios were 1.11 (1.03–1.20), 1.01 (0.93–1.09), and 1.05 (1.04–1.07), respectively.

Conclusion
The importance of remnant cholesterol for the risk of ASCVD may depend on the size of the TGRL and remnants carrying cholesterol.
HMB/Arg/Gln may improve short-term outcomes after esophagectomy in patients with thoracic esophageal cancer
Authors: Takebayashi Katsushi , Kaida Sachiko , Otake Reiko , Fukuo Asuka , Miyake Toru , Kojima Masatsugu , Tani Soichiro , Maehira Hiromitsu , Mori Haruki , Ishikawa Hajime , Tani Masaji 
Published: December 2024

Abstract

Background
The wound healing effects of a specialized amino acid supplement containing calcium beta-hydroxy-beta-methylbutyrate, L-arginine, and L-glutamine (HMB/Arg/Gln) have been reported. This study aimed to investigate the effectiveness of HMB/Arg/Gln in the perioperative management of patients with thoracic esophageal cancer.

Methods
This retrospective cohort study included 131 patients who underwent esophagectomy for thoracic esophageal cancer between January 2016 and November 2023. Postoperative infectious complications (PICs) were compared between patients who received HMB/Arg/Gln for 7 days before surgery (n = 95) and those who did not (control group, n = 36).

Results
Among the 111 male and 20 female patients (median age 68 years, range 38–84 years), stage I disease was found in 37 patients, stage II in 26, stage III in 61, and stage IVa in 7. Of the 131 patients, 36 (27.5%) had PICs, with PICs occurring in 20 (21%) of the HMB/Arg/Gln group and 16 (44.4%) of the control group. The PIC rate was significantly lower in the HMB/Arg/Gln than in the control group (p = 0.007). Propensity score matching analysis showed lower rates of anastomotic leakage (5.5% vs. 22.2%; p = 0.04) and Clavien–Dindo grade III or higher PICs (5.5% vs. 27.8%; p = 0.011) in the HMB/Arg/Gln than in the control group. The healing time for anastomotic leakage was shorter in the HMB/Arg/Gln (18 days, range 7–25 days) than in the control group (25 days, range 21–56 days) (p = 0.033).

Conclusions
HMB/Arg/Gln supplementation was associated with reduced risk of anastomotic leakage and PIC severity following esophagectomy.
3D computed tomography integration guiding permanent Aveir AR leadless pacemaker implantation: a case report
Authors: Magdy Mohamed , Botros Maichel , Mostafa Mohammed , Gharbi Maro , Alnooryani Arif 
Published: December 2024

Abstract

Background
The use of single-chamber, right ventricular (RV) leadless pacemakers (LPs) has been well established, the introduction of a right atrial LPs has opened the door for dual-chamber leadless pacing. Cardiac computed tomography (CT) segmentation integration might provide proper visual guide during the procedure.

Case summary
A 58-year-old male patient was brought to the emergency department with dizziness and complete heart block. The patient underwent single-chamber permanent LP implantation. During the upgrade to a dual-chamber LP, 3D CT image fusion with fluoroscopy was utilized to accurately identify the ideal and safe implantation site for the device.

Discussion
Integrating CT image guidance with fluoroscopy could enhance procedure safety, success rates, and reduces fluoroscopy time.
Influence of age and sex on the diagnostic yield of inherited cardiac conditions in sudden arrhythmic death syndrome decedents
Authors: Gray Belinda , Behr Elijah R , Papatheodorou Efstathios , Bakalakos Athanasios , Raju Hariharan , Wijeyeratne Yanushi D , Finocchiaro Gherardo , Malhotra Aneil , Whiffin Nicola , Ware James S , Esteban Maria Tome , Sheppard Mary N , Sharma Sanjay , Papadakis Michael 
Published: December 2024

Abstract

Aims
Sudden arrhythmic death syndrome (SADS) refers to a sudden death, which remains unexplained despite comprehensive post-mortem examination and a toxicological screen. We aimed to investigate the impact of age and sex on the overall diagnostic yield and underlying aetiology in decedents with SADS using a combined approach of familial evaluation (FE) and molecular autopsy (MA).

Methods and results
Consecutive referrals to a single centre for FE only, MA only or both, following a SADS death were included. First-degree family members underwent comprehensive FE and decedents with post-mortem DNA were sequenced with a 36 cardiac gene panel for MA. A Bayesian framework for analysis was performed to identify associations. Among 760 SADS decedents (66% male; mean age 31 ± 12 years) the overall diagnostic yield for an inherited cardiac condition was 37% (32–42%) and 9% (6–12%) for FE and MA cohorts. In a subset where both FE and MA were performed the diagnostic yield was 45% (38–61%). The relative risk of an FE diagnosis of long QT syndrome (LQTS) or Catecholaminergic polymorphic ventricular tachycardia (CPVT) vs. remaining unexplained declined by 5.6% [RR 0.94 (0.91–0.98)] and by 11% [RR 0.89 (0.81–0.97)], for each year increase in age. Females were more likely to have a diagnosis by both FE [40% (34–45%) vs. 36% (31–41%)] and MA [15% (10–21%) vs. 6% (3–8%)]. Females [8.1% (4.1–13.4%)], were more likely to be diagnosed with LQTS than males [1.2% (0.2–2.7%)] in the MA cohort.

Conclusion
After a SADS death, the diagnostic yield of comprehensive FE, MA, or both in an expert setting can be up to 45% with a combined approach. Females had higher diagnostic yield than males, most notable with LQTS. CPVT and LQTS diagnoses declined with increasing age. These data highlight the relative utility of FE and MA depending on age and sex for determining underlying diagnoses following SADS deaths.
Did organs precede organisms in the origin of life?
Authors: Baquero Fernando , Bever Gabriel S , de Lorenzo Victor , Fernández-Lanza Val , Briones Carlos 
Published: December 2024

Abstract
Evolutionary processes acting on populations of organized molecules preceded the origin of living organisms. These prebiotic entities were independently and repeatedly produced [i.e. (re)-produced] by the assembly of their components, following an iterative process giving rise to nearly but not fully identical replicas, allowing for a prebiotic form of Darwinian evolution. Natural selection favored the more persistent assemblies, some possibly modifying their own internal structure, or even their environment, thereby acquiring function. We refer to these assemblies as proto-organs. In association with other assemblies (e.g. in a coacervate or encapsulated within a vesicle), such proto-organs could evolve and acquire a role within the collective when their coexistence favored the selection of the ensemble. Along millions of years, an extraordinarily small number of successful combinations of those proto-organs co-occurring in spatially individualizing compartments might have co-evolved forming a proto-metabolic and proto-genetic informative network, eventually leading to the selfreplication of a very few. Thus, interactions between encapsulated proto-organs would have had a much higher probability of evolving into proto-organisms than interactions among simpler molecules. Multimolecular forms evolve functions; thus, functional organs would have preceded organisms.
Effect of copper and nickel exposure on ribosomal DNA variation in Daphnia pulex mutation accumulation lines
Authors: Elguweidi Abir , Cristescu Melania E , Crease Teresa J 
Published: December 2024

Abstract
The release of heavy metals from industrial, agricultural, and mining activities poses significant risks to aquatic ecosystems by degrading water quality and generating reactive oxygen species that can damage DNA in aquatic organisms. Daphnia is a widespread keystone species in freshwater ecosystems that is routinely exposed to a range of anthropogenic and natural stressors. With a fully sequenced genome, a well-understood life history and ecology, and an extensive library of responses to toxicity, Daphnia serves as an ideal model organism for studying the impact of environmental stressors on genomic stability. Ribosomal DNA (rDNA) encodes ribosomal RNA (rRNA), which is essential for protein synthesis, and the spacers that separate the rRNA genes contain regulatory elements. However, the effects of heavy metals on this region of the genome are not well documented. We used short-read whole-genome sequences to analyze copy number and sequence variation in Daphnia pulex mutation accumulation lines exposed to nickel and copper, both individually and in combination, at concentrations that mimic levels often found at contaminated sites. We found no significant direct effect of chronic exposure to either metal on rDNA copy number or sequence variation. However, the results suggest that nickel and copper exposure may indirectly influence rDNA by altering recombination rates. We also emphasize the importance of interval length between generational samples for accurately assessing the frequency and magnitude of rDNA copy number changes. In addition, we observed differential expansion of rDNA haplotypes, suggesting that they may be clustered within the rDNA array.
Investigating the Impact of Whole-Genome Duplication on Transposable Element Evolution in Teleost Fishes
Authors: Mallik Rittika , Wcisel Dustin J , Near Thomas J , Yoder Jeffrey A , Dornburg Alex 
Published: December 2024

Abstract
Transposable elements (TEs) can make up more than 50% of any given vertebrate's genome, with substantial variability in TE composition among lineages. TE variation is often linked to changes in gene regulation, genome size, and speciation. However, the role that genome duplication events have played in generating abrupt shifts in the composition of the mobilome over macroevolutionary timescales remains unclear. We investigated the degree to which the teleost genome duplication (TGD) shaped the diversification trajectory of the teleost mobilome. We integrate a new high coverage genome of Polypterus bichir with data from over 100 publicly available actinopterygian genomes to assess the macroevolutionary implications of genome duplication events on TE evolution in teleosts. Our results provide no evidence for a substantial shift in mobilome composition following the TGD event. Instead, the diversity of the teleost mobilome appears to have been shaped by a history of lineage-specific shifts in composition that are not correlated with commonly evoked drivers of diversification such as body size, water column usage, or latitude. Collectively, these results provide additional evidence for an emerging perspective that TGD did not catalyze bursts of diversification and innovation in the actinopterygian mobilome.
Two shikimate dehydrogenases play an essential role in the biosynthesis of galloylated catechins in tea plants
Authors: Wang Liubin , Wang Yongxin , Wang Yueqi , Wu Liyun , He Mengdi , Mao Zhuozhuo , Liu Guanhua , Wei Kang , Wang Liyuan 
Published: December 2024

Abstract
Tea (Camellia sinensis) is widely cultivated throughout the world for its unique flavor and health benefits. Galloylated catechins in tea plants serve as important secondary metabolites that play a pivotal role in tea taste determination and pharmacological effects. However, the genetic basis of galloylated-catechins traits remains elusive. We identified a stable and major-effect quantitative trait locus (QTL) associated with galloylated catechins index (GCI), designated qGCI6.2. Within the QTL’s confidence interval, two shikimate dehydrogenases (CsSDH4, CsSDH3) were identified. These enzymes catalyze gallic acid (GA) production from 3-dehydroquinate dehydratase, thereby contributing to galloylated catechins accumulation. RT-qPCR analysis revealed that CsSDH4 and CsSDH3 expression levels and GA and galloylated catechins contents were positively correlated. Furthermore, overexpressing CsSDH4 and CsSDH3 in transgenic tomato plants markedly increased GA and galloylated catechin contents. RNA-seq analysis of transgenic tomato indicated that CsSDH4 and CsSDH3 primarily regulate genes related to shikimic acid and flavonoid pathways, and jointly promote galloylated catechins synthesis. Our findings have further elucidated the galloylated catechins synthesis pathway and provided a theoretical basis for cultivation of tea cultivars with high galloylated catechin contents.