bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effectiveness of supervised exercise, home-based exercise, or walk advice strategies on walking performance and muscle endurance in patients with intermittent claudication (SUNFIT trial): a randomized clinical trial
Authors: Sandberg Anna , Bäck Maria , Cider Åsa , Jivegård Lennart , Sigvant Birgitta , Wittboldt Susanna , Nordanstig Joakim 
Published: August 2022

Abstract

Aims
Supervised exercise is a guideline-recommended treatment in intermittent claudication (IC). Hospital-based supervised exercise programmes (SEPs) are underutilized, while home-based structured exercise programmes (HSEPs) have attracted interest. The results from HSEP in IC are inconsistent and may confer no benefit over walk advice (WA) and be less effective than SEP. The aim of the study was to compare the effectiveness of best medical treatment, including Nordic pole WA alone, or WA + SEP or WA + HSEP for patients with IC.

Methods and results
This three-armed, multicentre randomized clinical trial enrolled patients with IC; all patients received best medical treatment including walking poles and the advice of regular Nordic pole walking (WA). For HSEP and SEP, additional exercise programmes were provided. The primarily investigated hypothesis was a non-inferiority analysis of SEP vs. HSEP regarding the 6-min walk test (6MWT) maximum distance, with a pre-defined non-inferiority margin of 50 m. Supporting outcomes included muscle endurance tests and the walking impairment questionnaire. Outcomes were assessed at baseline, 3, 6, and 12 months by a blinded evaluator. Altogether 166 patients (mean age 72 years; 59% males) were randomized. In HSEP and SEP, 24 and 26% patients, respectively, were fully exercise adherent. All three groups improved pain-free walking distance over time, but there were no significant intergroup differences. The intergroup 6MWT difference between SEP and HSEP from 0 to 12 months was –11.6 m, 95% confidence interval: –36.4 to 13.0 m (i.e. within the pre-specified non-inferiority margin).

Conclusion
The HSEP was non-inferior to SEP in patients with IC. There were no significant differences observed between the three groups at 1 year.

Registration
ClinicialTrials.gov: NCT02341716.
Selective disruption of Drp1-independent mitophagy and mitolysosome trafficking by an Alzheimer’s disease relevant tau modification in a novelCaenorhabditis elegansmodel
Authors: Guha Sanjib , Cheng Anson , Carroll Trae , King Dennisha , Koren Shon A , Swords Sierra , Nehrke Keith , Johnson Gail V W 
Published: August 2022

AbstractAccumulation of inappropriately phosphorylated tau into neurofibrillary tangles is a defining feature of Alzheimer’s disease, with Tau pT231 being an early harbinger of tau pathology. Previously, we demonstrated that expressing a single genomic copy of human phosphomimetic mutant tau (T231E) in Caenorhabditis elegans drove age-dependent neurodegeneration. A critical finding was that T231E, unlike wild-type tau, completely and selectively suppressed oxidative stress-induced mitophagy. Here, we used dynamic imaging approaches to analyze T231E-associated changes in mitochondria and mitolysosome morphology, abundance, trafficking, and stress-induced mitophagy as a function of mitochondrial fission mediator dynamin-related protein 1, which has been demonstrated to interact with hyper phosphorylated tau and contribute to Alzheimer’s disease pathogenesis, as well as Pink1, a well-recognized mediator of mitochondrial quality control that works together with Parkin to support stress-induced mitophagy. T231E impacted both mitophagy and mitolysosome neurite trafficking with exquisite selectivity, sparing macroautophagy as well as lysosome and autolysosome trafficking. Both oxidative-stress-induced mitophagy and the ability of T231E to suppress it were independent of drp-1, but at least partially dependent on pink-1. Organelle trafficking was more complicated, with drp-1 and pink-1 mutants exerting independent effects, but generally supported the idea that the mitophagy phenotype is of greater physiologic impact in T231E. Collectively, our results refine the mechanistic pathway through which T231E causes neurodegeneration, demonstrating pathologic selectivity for mutations that mimic tauopathy-associated post-translational modifications, physiologic selectivity for organelles that contain damaged mitochondria, and molecular selectivity for dynamin-related protein 1-independent, Pink1-dependent, perhaps adaptive, and mitophagy.
Hippocampal DNA Methylation, Epigenetic Age, and Spatial Memory Performance in Young and Old Rats
Authors: Chiavellini Priscila , Lehmann Marianne , Canatelli Mallat Martina , Zoller Joseph A , Herenu Claudia B , Morel Gustavo R , Horvath Steve , Goya Rodolfo G 
Published: August 2022

AbstractIn humans and rats, aging is associated with a progressive deterioration of spatial learning and memory. These functional alterations are correlated with morphological and molecular changes in the hippocampus. Here, we assessed age-related changes in DNA methylation (DNAm) landscape in the rat hippocampus and the correlation of spatial memory with hippocampal DNAm age in 2.6- and 26.6-month-old rats. Spatial memory performance was assessed with the Barnes maze test. To evaluate learning ability and spatial memory retention, we assessed the time spent by animals in goal sector 1 (GS1) and 3 (GS3) when the escape box was removed. The rat pan-tissue clock was applied to DNAm data from hippocampal tissue. An enrichment pathway analysis revealed that neuron fate commitment, brain development, and central nervous system development were processes whose underlying genes were enriched in hypermethylated CpGs in the old rats. In the old rat hippocampi, the methylation levels of CpG proximal to transcription factors associated with genes Pax5, Lbx1, Nr2f2, Hnf1b, Zic1, Zic4, Hoxd9; Hoxd10, Gli3, Gsx1 and Lmx1b, and Nipbl showed a significant regression with spatial memory performance. Regression analysis of different memory performance indices with hippocampal DNAm age was significant. These results suggest that age-related hypermethylation of transcription factors related to certain gene families, such as Zic and Gli, may play a causal role in the decline in spatial memory in old rats. Hippocampal DNAm age seems to be a reliable index of spatial memory performance in young and old rats.
Bacterial DNAemia in Older Participants and Nonagenarian Offspring and Association With Redox Biomarkers: Results From MARK-AGE Study
Authors: Giacconi Robertina , D’Aquila Patrizia , Malavolta Marco , Piacenza Francesco , Bürkle Alexander , Villanueva María Moreno , Dollé Martijn E T , Jansen Eugène , Grune Tilman , Gonos Efstathios S , Franceschi Claudio , Capri Miriam , Gradinaru Daniela , Grubeck-Loebenstein Beatrix , Sikora Ewa , Stuetz Wolfgang , Weber Daniela , Toussaint Olivier , Debacq-Chainiaux Florence , Hervonen Antti , Hurme Mikko , Slagboom P Eline , Schön Christiane , Bernhardt Jürgen , Breusing Nicolle , Duncan Talbot , Passarino Giuseppe , Bellizzi Dina , Provinciali Mauro 
Published: August 2022

Abstract
Aging and age-related diseases have been linked to microbial dysbiosis with changes in blood bacterial DNA concentration. This condition may promote chronic low-grade inflammation, which can be further aggravated by antioxidant nutrient deficiency. Low plasma carotenoids are associated with an increased risk of inflammation and cellular damage and predict mortality. However, no evidence is yet available on the relationship between antioxidants and the blood bacterial DNA (BB-DNA). Therefore, this study aimed to compare BB-DNA from (a) GO (nonagenarian offspring), (b) age-matched controls (Randomly recruited Age-Stratified Individuals from the General population [RASIG]), and (c) spouses of GO (SGO) recruited in the MARK-AGE project, as well as to investigate the association between BB-DNA, behavior habits, Charlson Comorbidity Index (CCI), leucocyte subsets, and the circulating levels of some antioxidants and oxidative stress markers. BB-DNA was higher in RASIG than GO and SGO, whereas GO and SGO participants showed similar values. BB-DNA increased in smokers and males with CCI ≥ 2 compared with those with CCI ≤ 1 within RASIG. Moreover, BB-DNA was positively associated with lymphocyte, neutrophil, and monocyte counts, but not with self-reported dietary habits. Higher quartiles of BB-DNA were associated with low lutein and zeaxanthin and elevated malondialdehyde plasma concentrations in RASIG. BB-DNA was also positively correlated with nitric oxide levels. Herein, we provide evidence of a reduced BB-DNA in individuals from long-living families and their spouses, suggesting a decreased microbial dysbiosis and bacterial systemic translocation. BB-DNA was also associated with smoking, CCI, leukocyte subsets, and some redox biomarkers in older participants.
Comparative Effectiveness of Ustekinumab and Anti-TNF Agent as First-Line Biological Therapy in Luminal Crohn’s Disease: A Retrospective Study From 2 Referral Centers
Authors: Rivière Pauline , Kanters Caitlyn , Pellet Gauthier , Ni Alexander , Hupé Marianne , Aboulhamid Nesrine , Poullenot Florian , Bitton Alain , Zerbib Frank , Lakatos Peter L , Afif Waqqas , Laharie David , Bessissow Talat 
Published: August 2022

Abstract

Background
Real-life data on the efficacy of ustekinumab as first-line therapy for the treatment of luminal Crohn’s disease (CD) compared with anti-tumor necrosis factor (anti-TNF) agents are lacking. We compared the clinical response rates at 3 months in 2 cohorts of biologic-naïve patients treated by ustekinumab and anti-TNF agents.

Methods
Biologic-naïve patients starting either ustekinumab or an anti-TNF agent for luminal CD between 2016 and 2019 in 2 tertiary centers were retrospectively included. The primary endpoint was clinical response at 3 months, defined as a Harvey-Bradshaw Index &lt;4 or a 3-point drop in the score without steroids, need for CD-related surgery, or treatment discontinuation owing to failure or intolerance. Patients treated with ustekinumab were matched to patients receiving anti-TNF agents by a propensity score algorithm.

Results
We included 156 patients starting anti-TNF agents (95 adalimumab and 61 infliximab) and 50 ustekinumab. After matching, clinical response rates at 3 months were 64% and 86% in the ustekinumab and anti-TNF groups, respectively (P = .01). At 12 months, in multivariate analysis adjusted for disease duration, location, concomitant immunosuppressant and steroids, and symptoms, clinical remission was independently associated with the biological therapy received (odds ratio, 2.6 for anti-TNF agent vs ustekinumab; P = .02). With a median follow-up duration of 40 (interquartile range, 23-52) months, no difference was observed in terms of time to drug withdrawal (P = .29) or safety.

Conclusions
This retrospective real-world data suggest that an anti-TNF agent as a first-line biological therapy is associated with higher rates of response at 3 months than ustekinumab in patients with CD.
Overlapping Schwarz methods with GenEO coarse spaces for indefinite and nonself-adjoint problems
Authors: Bootland Niall , Dolean Victorita , Graham Ivan G , Ma Chupeng , Scheichl Robert 
Published: August 2022

Abstract
Generalized eigenvalue problems on the overlap(GenEO) is a method for computing an operator-dependent spectral coarse space to be combined with local solves on subdomains to form a robust parallel domain decomposition preconditioner for elliptic PDEs. It has previously been proved, in the self-adjoint and positive-definite case, that this method, when used as a preconditioner for conjugate gradients, yields iteration numbers that are completely independent of the heterogeneity of the coefficient field of the partial differential operator. We extend this theory to the case of convection–diffusion–reaction problems, which may be nonself-adjoint and indefinite, and whose discretizations are solved with preconditioned GMRES. The GenEO coarse space is defined here using a generalized eigenvalue problem based on a self-adjoint and positive-definite subproblem. We prove estimates on GMRES iteration counts that are independent of the variation of the coefficient of the diffusion term in the operator and depend only very mildly on variations of the other coefficients. These are proved under the assumption that the subdomain diameter is sufficiently small and the eigenvalue tolerance for building the coarse space is sufficiently large. While the iteration number estimates do grow as the nonself-adjointness and indefiniteness of the operator increases, practical tests indicate the deterioration is much milder. Thus, we obtain an iterative solver that is efficient in parallel and very effective for a wide range of convection–diffusion–reaction problems.
The International Criminal Court as a Law Laboratory
Authors: Christensen Mikkel Jarle , Orina Nabil M 
Published: August 2022

Abstract
This article investigates the International Criminal Court (ICC) as a law laboratory. Inspired by perspectives from the sociology of law, the article analyses how professional agents battled for control over the general direction and specific legal terminology of the Court, especially in its early life. Working also to distance the Court from what was perceived as excessive judicial creativity of the ad hoc international criminal tribunals for the former Yugoslavia and Rwanda, these agents created the conditions for a distinct laboratory of law in which new legal concepts and doctrines could be created. The article analyses in particular one new doctrine, the control theory based on Article 25(3) of the ICC Statute, as emblematic of battles to define the direction of the ICC as a law laboratory.
Mediators of Racial Disparities in Heart Dose Among Whole Breast Radiotherapy Patients
Authors: Chapman Christina Hunter , Jagsi Reshma , Griffith Kent A , Moran Jean M , Vicini Frank , Walker Eleanor , Dominello Michael , Abu-Isa Eyad , Hayman James , Laucis Anna M , Mietzel Melissa , Pierce Lori 
Published: August 2022

AbstractBackgroundRacial disparities in survival of patients with cancer motivate research to quantify treatment disparities and evaluate multilevel determinants. Previous research has not evaluated cardiac radiation dose in large cohorts of breast cancer patients by race nor examined potential causes or implications of dose disparities.MethodsWe used a statewide consortium database to consecutively sample 8750 women who received whole breast radiotherapy between 2012 and 2018. We generated laterality- and fractionation-specific models of mean heart dose. We generated patient- and facility-level models to estimate race-specific cardiac doses. We incorporated our data into models to estimate disparities in ischemic cardiac event development and death. All statistical tests were 2-sided.ResultsBlack and Asian race independently predicted higher mean heart dose for most laterality-fractionation groups, with disparities of up to 0.42 Gy for Black women and 0.32 Gy for Asian women (left-sided disease and conventional fractionation: 2.13 Gy for Black women vs 1.71 Gy for White women, P &lt; .001, 2-sided; left-sided disease and accelerated fractionation: 1.59 Gy for Asian women vs 1.27 Gy for White women, P = .002). Patient clustering within facilities explained 22%-30% of the variability in heart dose. The cardiac dose disparities translated to estimated excesses of up to 2.6 cardiac events and 1.3 deaths per 1000 Black women and 0.7 cardiac events and 0.3 deaths per 1000 Asian women vs White women.ConclusionsDepending on laterality and fractionation, Asian women and Black women experience higher cardiac doses than White women. This may translate into excess radiation-associated ischemic cardiac events and deaths. Solutions include addressing inequities in baseline cardiac risk factors and facility-level availability and use of radiation technologies.
Searching for stellar flares from low-mass stars using ASKAP and TESS
Authors: Rigney Jeremy , Ramsay Gavin , Carley Eoin P , Doyle J Gerry , Gallagher Peter T , Wang Yuanming , Pritchard Joshua , Murphy Tara , Lenc Emil , Kaplan David L 
Published: August 2022

ABSTRACT
Solar radio emission at low frequencies (&lt;1 GHz) can provide valuable information on processes driving flares and coronal mass ejections (CMEs). Radio emission has been detected from active M dwarf stars, suggestive of much higher levels of activity than previously thought. Observations of active M dwarfs at low frequencies can provide information on the emission mechanism for high energy flares and possible stellar CMEs. Here, we conducted two observations with the Australian Square Kilometre Array Pathfinder Telescope totalling 26 h and scheduled to overlap with the Transiting Exoplanet Survey Satellite Sector 36 field, utilizing the wide fields of view of both telescopes to search for multiple M dwarfs. We detected variable radio emission in Stokes I centred at 888 MHz from four known active M dwarfs. Two of these sources were also detected with Stokes V circular polarization. When examining the detected radio emission characteristics, we were not able to distinguish between the models for either electron cyclotron maser or gyrosynchrotron emission. These detections add to the growing number of M dwarfs observed with variable low-frequency emission.
Double-lens scintillometry: the variable scintillation of pulsar B1508 + 55
Authors: Sprenger Tim , Main Robert , Wucknitz Olaf , Mall Geetam , Wu Jason 
Published: August 2022

ABSTRACT
We report on observations of PSR B1508 + 55’s scintillation at the Effelsberg 100-m telescope spanning from early 2020 to early 2022. In the autumn of 2020, close to the time the pulsar was predicted to cross echoes in its pulse profile, a sudden transition in the scintillation arcs from peculiar stripe-like features to parabolic arclets was observed. To infer a geometric model of the scattering, we measure the effects of the annual velocity curve of Earth, of the relative movement of the line of sight, and of the projection of points on a second scattering screen and develop novel methods to do so. The latter phenomenon was discovered by this study and strongly indicates a two-screen scattering geometry. We derive an analytical two-screen model and demonstrate in a Markov chain Monte Carlo analysis as well as simulations that it can be successfully applied to explain the observations by interpreting the transition as a change of relative amplitudes of images as well as a shift in the orientation of anisotropy. The collection of methods, we demonstrate here is transferable to other pulsars with the potential to strongly improve constraints on scattering models.
HAlign 3: Fast Multiple Alignment of Ultra-Large Numbers of Similar DNA/RNA Sequences
Authors: Tang Furong , Chao Jiannan , Wei Yanming , Yang Fenglong , Zhai Yixiao , Xu Lei , Zou Quan 
Published: August 2022

Abstract
HAlign is a cross-platform program that performs multiple sequence alignments based on the center star strategy. Here we present two major updates of HAlign 3, which helped improve the time efficiency and the alignment quality, and made HAlign 3 a specialized program to process ultra-large numbers of similar DNA/RNA sequences, such as closely related viral or prokaryotic genomes. HAlign 3 can be easily installed via the Anaconda and Java release package on macOS, Linux, Windows subsystem for Linux, and Windows systems, and the source code is available on GitHub (https://github.com/malabz/HAlign-3).
Single-cell transcriptomes and runx2b−/− mutants reveal the genetic signatures of intermuscular bone formation in zebrafish
Authors: Nie Chun-Hong , Wan Shi-Ming , Chen Yu-Long , Huysseune Ann , Wu Ya-Ming , Zhou Jia-Jia , Hilsdorf Alexandre Wagner Silva , Wang Wei-Min , Witten Paul Eckhard , Lin Qiang , Gao Ze-Xia 
Published: August 2022

Abstract
Intermuscular bones (IBs) are mineralized spicules, present in the myosepta of many, but not all, teleost species. IBs are often small and sharp, and they consequently limit how the fish can be processed; the IBs may cause injury or trauma if lodged in consumers’ throats or mouths, and therefore affect the appeal of the fish to many consumers. The development of IBs in teleosts is still not fully understood and the molecular basis of IB development remains to be established. Here, the characteristics of IB tissue are evaluated based on single-cell transcriptomics in wild-type zebrafish. The analysis defined 18 distinct cell types. Differentiation trajectories showed that IBs are derived from tendons and that a core tendon-osteoblast cell lineage is related to IB formation. In particular, the functions of 10 candidate genes were evaluated via CRISPR-Cas9 mutants. Among those, runx2b−/− mutants completely lost IBs, while swimming performance, growth and bone mineral density were not significantly different from runx2b+/+ zebrafish. Comparative single-cell RNA sequencing (scRNA-seq) analysis in runx2b−/− and runx2b+/+ zebrafish revealed the role of osteoblasts in IB formation. In addition, differentially expressed genes were enriched in the transforming growth factor β/bone morphogenetic protein (TGF-β/BMP) pathway after runx2b deletion. This study provides evidence for the crucial role of runx2b regulation in IB formation. Genetic breeding can target runx2b regulation and generate strains of commercial fish species without IBs, which can improve the safe consumption and economic value of many farmed fish species.
Loss-of-function of SAWTOOTH 1 affects leaf dorsiventrality genes to promote leafy heads in lettuce
Authors: An Guanghui , Yu Changchun , Yan Chenghuan , Wang Menglu , Zhang Weiyi , Jia Yue , Shi Chunmei , Larkin Robert M , Chen Jiongjiong , Lavelle Dean , Michelmore Richard W , Kuang Hanhui 
Published: August 2022

Abstract
The mechanisms underlying leafy heads in vegetables are poorly understood. Here, we cloned a quantitative trait locus (QTL) controlling leafy heads in lettuce (Lactuca sativa). The QTL encodes a transcription factor, SAWTOOTH 1 (LsSAW1), which has a BEL1-like homeodomain and is a homolog of Arabidopsis thaliana. A 1-bp deletion in Lssaw1 contributes to the development of leafy heads. Laser-capture microdissection and RNA-sequencing showed that LsSAW1 regulates leaf dorsiventrality and loss-of-function of Lssaw1 downregulates the expression of many adaxial genes but upregulates abaxial genes. LsSAW1 binds to the promoter region of the adaxial gene ASYMMETRIC LEAVES 1 (LsAS1) to upregulate its expression. Overexpression of LsAS1 compromised the effects of Lssaw1 on heading. LsSAW1 also binds to the promoter region of the abaxial gene YABBY 1 (LsYAB1), but downregulates its expression. Overexpression of LsYAB1 led to bending leaves in LsSAW1 genotypes. LsSAW1 directly interacts with KNOTTED 1 (LsKN1), which is necessary for leafy heads in lettuce. RNA-seq data showed that LsSAW1 and LsKN1 exert antagonistic effects on the expression of thousands of genes. LsSAW1 compromises the ability of LsKN1 to repress LsAS1. Our results suggest that downregulation or loss-of-function of adaxial genes and upregulation of abaxial genes allow for the development of leafy heads.