bluuebunny/crossref_metadata_2025_split huggingface dataset:
Remodelling of plasma lipoproteins by icosapent ethyl -supplementation and its impact on cardiovascular disease risk markers in normolipidemic individuals
Authors: Äikäs Lauri , Kovanen Petri T. , Lorey Martina , Laaksonen Reijo , Holopainen Minna , Ruhanen Hanna , Käkelä Reijo , Jauhiainen Matti , Hermansson Martin , Öörni Katariina 
Published: November 2024

ABSTRACTBACKGROUND AND AIMSIcosapent ethyl (IPE), an ethyl ester of eicosapentaenoic acid (EPA), can reduce cardiovascular disease (CVD). We examined the effect of IPE-supplementation on lipoprotein subclasses, lipidomes and atherogenic properties.METHODSNormolipidemic volunteers received daily 3.9g of IPE for 28 days. Using three independent metabolomic platforms, the fatty acid and lipoprotein profiles in plasma, and lipidomes of isolated VLDL, LDL and HDL, were determined. Aggregation propensity of LDL and the proteoglycan-binding of apoB-containing plasma lipoproteins, and the cholesterol efflux– inducing capacity of HDL were determined.RESULTSIPE-supplementation increased plasma EPA concentrations by 4-fold with consequent reductions in saturated, monounsaturated, and n-6 polyunsaturated fatty acids. This resulted in reduction of multiple clinical risk markers, including triglyceride-, remnant cholesterol-, and apoB-levels, and 10-year CVD risk score. IPE induced uniform alterations across all lipoprotein classes. However, intrinsic interindividual differences in lipoprotein lipidomes outweighed IPE-induced changes. IPE did not alter LDL aggregation propensity or HDL-mediated cholesterol efflux but reduced the affinity of apoB-lipoproteins for proteoglycans. This correlated with decreased apoB-particle concentration and cholesterol content, alongside changes in specific lipid species in LDL, notably phosphatidylcholine 38:3 previously associated with CVD.CONCLUSIONSIPE-supplementation rapidly increases circulating EPA, which integrates equally into all lipoprotein classes. Reduced proteoglycan binding of apoB-lipoproteins likely contributes to the known IPE-induced reduction in CVD risk. Features associated with increased lipoprotein proteoglycan-binding included characteristics of metabolic syndrome, and specific lipid species. The data underscore persistence of distinct interindividual lipoprotein signatures despite extensive IPE-induced remodelling, highlighting the need for personalised approaches in ASCVD-treatment.STRUCTURED GRAPHICAL ABSTRACTGraphical Abstract:The figure summarizes the study design and the main findings of this study. CVD, cardiovascular disease; EPA, eicosapentaenoic acid; FA fatty acid; IPE, icosapent ethyl; LDL, low-density lipoprotein; NMR, nuclear magnetic resonance (spectroscopy). Figure created withBioRender.com.
A Double Machine Learning Approach for the Evaluation of COVID-19 Vaccine Effectiveness under the Test-Negative Design: Analysis of Québec Administrative Data
Authors: Jiang Cong , Talbot Denis , Carazo Sara , Schnitzer Mireille E 
Published: December 2024

AbstractThe test-negative design (TND), which is routinely used for monitoring seasonal flu vaccine effectiveness (VE), has recently become integral to COVID-19 vaccine surveillance, notably in Québec, Canada. Some studies have addressed the identifiability and estimation of causal parameters under the TND, but efficiency bounds for nonparametric estimators of the target parameter under the unconfoundedness assumption have not yet been investigated. Motivated by the goal of improving adjustment for measured confounders when estimating COVID-19 VE among community-dwelling people aged ≥ 60 years in Québec, we propose a one-step doubly robust and locally efficient estimator called TNDDR (TND doubly robust), which utilizes cross-fitting (sample splitting) and can incorporate machine learning techniques to estimate the nuisance functions and thus improve control for measured confounders. We derive the efficient influence function (EIF) for the marginal expectation of the outcome under a vaccination intervention, explore the von Mises expansion, and establish the conditions for−consistency, asymptotic normality and double robustness of TNDDR. The proposed estimator is supported by both theoretical and empirical justifications.
Longitudinal interaction between muscle impairments and gait pathology in growing children with Duchenne muscular dystrophy
Authors: Vandekerckhove Ines , Molenberghs Geert , Van den Hauwe Marleen , Goemans Nathalie , De Waele Liesbeth , Van Campenhout Anja , De Groote Friedl , Desloovere Kaat 
Published: December 2024

AbstractAimThe aim of this longitudinal observational cohort study was to investigate the longitudinal interaction between progressive muscle impairments and progressive gait pathology in growing boys with Duchenne muscular dystrophy (DMD).MethodsThirty-one boys with DMD (aged 4y7mo-16y5mo), were repeatedly measured between 2015 and 2022, resulting in a total dataset of 152 observations. Fixed dynamometry, goniometry and 3D gait analysis were used to asses lower limb muscle weakness, passive range of motion and gait. Joint random-effects models between gait and muscle impairment outcomes were fitted. The correlation between the random intercepts (ra) and random slopes (rb) indicated the degree to which respectively the starting levels and progression rates over time of two outcomes were related in boys with DMD.ResultsSpecific muscle impairments were related to specific gait features, in terms of starting levels (ra=0.470-0.757; p<0.029) and progression rates (rb=0.547-0.812; p<0.024).InterpretationThe findings improved insights into how specific muscle impairments may contribute to specific gait features in DMD. This could enhance clinical decision making, advance rehabilitation, orthotic and orthopedic interventions, and reveal sensitive outcome measures to prove the efficacy of novel treatments in clinical trials.What this paper addsObjective quantification of the relationships between muscle impairments and gait featuresRelationships between starting levels of specific muscle impairments and specific gait featuresRelationships between progression rates of specific muscle impairments and specific gait featuresImproved insights into how muscle impairments may contribute to gait features
Parkinson’s Disease affects the contextual control, but not the expression, of a rapid visuomotor response that initiates visually-guided reaching: Evidence for multiple, interacting motor pathways and implications for motor symptoms in Parkinson’s Disease
Authors: Gilchrist Madeline , Kozak Rebecca A. , Prenger Margaret , Anello Mimma , Hedger Kathryne Van , MacDonald Penny A , Corneil Brian D 
Published: December 2024

AbstractDespite significant deficits in voluntary motor control, patients with Parkinson’s disease (PD) can generate reflexive or stimulus-driven movements. How are such spared capabilities realized? Here, we recorded upper limb muscle activity in patients with PD and age-matched healthy controls (HCs) as they reached either toward or away from a visual stimulus. The task promoted express visuomotor responses (EVRs), which are brief bursts of muscle recruitment time-locked (<100 ms) to stimulus presentation that are thought to originate from the midbrain superior colliculus. Across two experiments, we observed a remarkable sparing of the latency and magnitude of EVRs in patients with PD, but a decreased ability for patients with PD to contextually modulate the EVR depending on trial instruction. EVR Magnitudes were strikingly strongly correlated with PD Reaction times and Error rates, despite compromised levels of electromyographic (EMG) recruitment in subsequent phases of muscle activity, which predicted lower Peak velocities. Our results are consistent with a differential influence of PD on parallel-but-interacting subcortical and cortical pathways that converge onto brainstem and spinal circuits during reaching. This differential influence is discriminable even within a single trial in the selective sparing of stimulus-aligned but not movement-aligned muscle recruitment, and has implications for our understanding of the motor and cognitive deficits seen in PD.
Recombinant production of spider silk protein in Physcomitrella photobioreactors
Authors: Ramezaniaghdam Maryam , Bohlender Lennard L. , Parsons Juliana , Hoernstein Sebastian N. W. , Decker Eva L. , Reski Ralf 
Published: December 2024

AbstractSpider dragline silk stands out as a remarkable biomaterial, representing one of nature’s toughest fibres. Its strength rivals that of many synthetic fibres used commercially, rendering it applicable across various industrial and medical domains. However, its widespread utilisation requires cost-effective mass production. Biotechnology presents a promising avenue for achieving this goal, particularly through the production of recombinant dragline silk proteins in transgenic plant systems. This study aimed to assess the feasibility of producing one key protein component of dragline silk, MaSp1, from the western black widow spider,Latrodectus hesperus, (LhMaSp1) in the moss Physcomitrella (Physcomitrium patens). Here, we present the successful recombinant production of spider silk protein containing both the N- and C-terminal domains (NTD and CTD) of LhMaSp1 protein in moss cells. NTD and CTD are necessary domains for protein assembly in spider silk. The production of recombinant LhMaSp1 protein in Physcomitrella was performed in shake flasks and in five-litre photobioreactors and the correct synthesis of LhMaSp1 was provenviamass spectrometry.Key messageWe report the first successful plant-produced recombinant spider silk key protein component containing both the N- and the C-terminal domain.
Dynamic heterogeneity in anE. colistress response regulon mediates gene activation and antimicrobial peptide tolerance
Authors: Blassick Caroline M. , Lugagne Jean-Baptiste , Dunlop Mary J. 
Published: December 2024

AbstractThe bacterial stress response is an intricately regulated system that plays a critical role in cellular resistance to drug treatment. The complexity of this response is further complicated by cell-to-cell heterogeneity in the expression of bacterial stress response genes. These genes are often organized into networks comprising one or more transcriptional regulators that control expression of a suite of downstream genes. While the expression heterogeneity of many of these upstream regulators has been characterized, the way in which this variability affects the larger downstream stress response remains hard to predict, prompting two key questions. First, how does heterogeneity and expression noise in stress response regulators propagate to the diverse downstream genes in their regulons. Second, when expression levels vary, how do multiple downstream genes act together to protect cells from stress. To address these questions, we focus on the transcription factor PhoP, a critical virulence regulator which coordinates pathogenicity in several gram-negative species. We use optogenetic stimulation to precisely control PhoP expression levels and examine how variations in PhoP affect the downstream activation of genes in the PhoP regulon. We find that these downstream genes exhibit differences both in mean expression level and sensitivity to increasing levels of PhoP. These response functions can also vary between individual cells, increasing heterogeneity in the population. We tie these variations to cell survival when bacteria are exposed to a clinically-relevant antimicrobial peptide, showing that high expression of the PhoP-regulon genepmrDprovides a protective effect against Polymyxin B. Overall, we demonstrate that even subtle heterogeneity in expression of a stress response regulator can have clear consequences for enabling bacteria to survive stress.
Trigger Point Injections for Post-Mastectomy Pain Syndrome: A Protocol for a Randomized Double-Blind Clinical Trial (NCT04267315)
Authors: Leite Victor Figueiredo , de Andrade Rodrigo Guimarães , de Brito Christina May Moran 
Published: December 2024

AbstractINTRODUCTIONPost-Mastectomy Pain Syndrome (PMPS) refers to a condition of chronic pain persisting for more than three months after a breast surgical procedure. It affects 11 to 70% of individuals with breast cancer. The pain has a mixed etiology, often with the frequent presence of associated myofascial pain. Trigger Point Injection (TPI) is a well-established procedure in the treatment of myofascial pain in the general population. However, there are no controlled studies evaluating the efficacy of TPI in the treatment of PMPS.OBJECTIVETo evaluate the efficacy of TPI in individuals with PMPS when combined with interdisciplinary rehabilitation and pharmacological treatment.METHODSThis is the protocol for a double-blind, placebo-controlled clinical trial. Both groups will receive routine care by a Physiatrist and Rehabilitation Team blinded to the allocation. The active group will receive Trigger Point Injections with 1% lidocaine at each identified trigger point once a week for up to three consecutive weeks. The control group will receive subcutaneous infiltrations of saline at the same points and frequency. This protocol was registered at theClinicalTrials.govwebsite (NCT04267315).STATISTICAL ANALYSISAnalysis of Covariance (ANCOVA) for between-group differences at baseline, one month, and three months for pain, central sensitization, and functionality (n=120). A significance level of alpha=5% and statistical power of 80% will be employed.
Developmental DNA Methylation in the Parasitoid WaspNasonia vitripennis
Authors: Thomas CL , Mallon EB 
Published: November 2024

AbstractDNA methylation is a crucial epigenetic mark the development of many insect species, being essential for fertility and the progression of development in a range of organisms. However, the mechanisms underpinning the role of DNA methylation in insect development remains elusive. Furthermore, the patterns of methylation in different species can be varied. Here we aim to profile methylation across metamorphosis in the insect DNA methylation modelNasonia vitripennisfor the first time. We find DNA methylation is at the highest in the embryo, and at the lowest in the larva. We find that the gene expression levels ofNvTetandNvDnmtenzymes compliment the observed methylation patterns. Performing differential methylation analysis we find enriched GO terms for developmentally specific processes and find sites with differential methylation are share homology with developmentally linked transcription factors. Additionally, we identify sites uniquely methylated in each developmental stage, many of which also share homology with developmentally linked transcription factors. In all, we find that methylation is variable in its global methylation levels and site specific methylation throughoutNasonia vitripennisdevelopment, but find no obvious link with gene expression.
The comparative analysis of lineage-pair traits
Authors: Anderson Sean A. S. , Kaushik Sachin , Matute Daniel R. 
Published: November 2024

AbstractA powerful but poorly understood analysis in ecology and evolutionary biology is the comparative study of lineage-pair traits. “Lineage-pair traits” are characters like ‘diet niche overlap’ and ‘strength of reproductive isolation’ that are defined for pairs of lineages instead of individual taxa. Comparative tests for causal relationships among such variables have led to groundbreaking insights in several classic studies, but the statistical validity of these analyses has been unclear due to the complex dependency structure of the data. Specifically, lineage-pair datasets contain non-independent observations, but studies to-date have relied on untested workarounds for data dependency rather than direct models of linear-pair covariance, and the statistical consequences of non-independence have not been thoroughly explored. Here we consider how evolutionary relatedness among taxa translates into non-independence among taxonomic pairs. We develop models by which phylogenetic signal in an underlying character generates covariance among pairs in a lineage-pair trait. We incorporate the resulting lineage-pair covariance matrix into a modified version of phylogenetic generalized least squares and a new beta regression model suitable for bounded response variables. Both models outperform previous approaches in simulation tests. We re-analyze two empirical datasets and find dramatic improvements in model fit and, in the case of avian hybridization data, an even stronger relationship between pair age and RI than revealed by standard linear regression. We present a new tool, the R packagephylopairs, to allow empiricists from a variety of biological fields to test relationships among pairwise-defined variables in a manner that is statistical robust and more straightforward to implement.
Intragenomic variants of a putative effector drive early-stage infection in a broad host-range rust fungus
Authors: Degnan Rebecca M. , Sawyer Anne , Gardiner Donald M. , Luo Zhenyan , Frampton Rebekah , Schwessinger Benjamin , Mitter Neena , Carroll Bernard J. , Smith Grant R. , McTaggart Alistair R. , Shuey Louise S. 
Published: November 2024

AbstractRust fungi are pathogens that impact plants of environmental, agricultural, cultural, and economic importance. Their mechanisms of pathogenicity are not well-understood but are likely governed by effectors, secreted proteins that manipulate host cellular processes to facilitate infection and suppress immune responses. We sought to understand how three effector candidates (EFC1, EFC2, andEFC3) expressed in the first stages ofAustropuccinia psidii(myrtle rust) infection influence pathogenicity. We experimentally tested gene function through application of double-stranded RNA (dsRNA) and characterised the genomic landscape of putative effectors expressed during infection to assess whether putative effectors are needed for infection, and whether they are under selection pressure. One of the three screened candidates,EFC1, met our criteria of an effector in that it was predicted to be secreted, and was needed to cause but not maintain infection. We identified that this effector belongs to a gene family of intragenomic variants in tandem repeats flanked by transposable elements. Single nucleotide polymorphisms among these variants have signatures of non-neutral selection. This effector has predicted structural homology to a glycosaminoglycan-binding domain and may have a role in pectin or chitin-binding. We hypothesise that intragenomic variability in this family of effector genes facilitates host-range versatility in theA. psidii-Myrtaceae pathosystem.
Identification of disease-specific extracellular vesicle-associated plasma protein biomarkers for Duchenne Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy
Authors: Bayazit Mustafa Bilal , Henderson Don , Nguyen Kim Truc , Reátegui Eduardo , Tawil Rabi , Flanigan Kevin M. , Harper Scott Q. , Saad Nizar Y. 
Published: November 2024

AbstractObjectiveReliable, circulating biomarkers for Duchenne, Becker and facioscapulohumeral muscular dystrophies (DBMD and FSHD) remain unvalidated. Here, we investigated the plasma extracellular vesicle (EV) proteome to identify disease-specific biomarkers that could accelerate therapy approvals.MethodsWe extracted EVs from the plasma of DBMD and FSHD patients and healthy controls using size-exclusion chromatography, conducted mass spectrometry on the extracted EV proteins, and performed comparative analysis to identify disease-specific biomarkers. We correlated the levels of these biomarkers with clinical outcome measures and confounding factors.ResultsThe muscle-associated proteins PYGM, MYOM3, FLNC, MYH2 and TTN were exclusively present in DBMD EVs. PYGM, MYOM3, and TTN negatively correlated with age. PYGM and MYOM3 levels were elevated in patients without cardiomyopathy, and PYGM levels were specifically elevated in ambulatory DMD patients. On the other hand, female FSHD patients displayed significantly higher MBL2 and lower GPLD1 levels. However, male FSHD patients exhibited higher C9 and lower C4BPB levels. Additionally, desmosome proteins JUP and DSP were uniquely found in FSHD males. MBL2 positively correlated with age and C4BPB negatively correlated with FSHD severity in male patients.InterpretationOur findings underscore the sensitivity of analyzing circulating EV content to identify disease-specific protein biomarkers for DBMD and FSHD. Our results also emphasize the potential of EV-based biomarker discovery as a promising approach to monitor disease progression as well as effectiveness of therapies in muscular dystrophy, potentially contributing to their approval. Further research with larger cohorts is needed to validate these biomarkers and explore their clinical implications.
Influence of Environmental Exposures on T Follicular Helper Cell Function and Implications on Immunity: a comparison of Bangladeshi and American Children
Authors: Van Fossen Dana , Cho Hyunjae , Wagar Lisa , Ma Jennie Z. , Haque Rashidul , Davis Mark , Petri William A. 
Published: December 2024

ABSTRACTT follicular helper (Tfh) cells are crucial for B cell activation and subsequent antibody production. This functionality is influenced by surface markers such as CD40L, a costimulatory factor which promotes B cell activation, and CD57 which is a well-known marker of senescence. This study examined age-specific differences in Tfh cell function in Bangladeshi and American children. At age two, Bangladeshi children displayed impaired CD40L upregulation and significant CD57 downregulation upon stimulation. These patterns, not observed in American children of the same age, suggested an exhaustion-like phenotype potentially driven by environmental factors. Predictors of Tfh cell response to stimulation were analyzed using Random Forest and Generalized Estimating Equations (GEE) models. Exclusive breastfeeding duration, antibiotic treatments, diarrheal episodes, and malnutrition were identified as variables that significantly impacted the Tfh response to stimuli. To assess Tfh cell ability to promote antibody responses, we correlated Tfh functionality with antibody concentration post-vaccination and in response to infection with Cryptosporidium, an endemic apicomplexan parasite. Increased CD40L expression upon stimulation correlated positively with anti-Poliovirus type 2/3 neutralizing antibody and anti-Cp17 (a Cryptos-poridium sporozoite antigen) IgA concentrations. In contrast, increased CD57 expression was significantly correlated with decreased anti-Cp17 IgA. This indicates that an activation-supportive phenotype (CD40L+) may be more effective in promoting immunity than a senescent phenotype (CD57+). Together, these findings suggest that early-life environmental exposures may program Tfh cell functionality, impacting immune response potential in settings with high pathogen exposure.IMPORTANCET follicular helper (Tfh) cells are upstream mediators that shape the humoral immune response to specific antigens. The generation of an effective memory response to infection is vital to prevent subsequent reinfections. However, in areas with high burdens of exposure to infections, such as the urban community from Bangladesh studied here, children are consistently exposed to inflammatory pathogens. Specific environmental exposures significantly influenced Tfh cell activation and senescence phenotypes. Additionally, Tfh cell responses correlated with antibody concentrations following vaccination or infection, indicating that environmental factors may play a critical role in shaping effective immunity in early childhood.