bluuebunny/crossref_metadata_2025_split huggingface dataset:
Signaling Downstream of Focal Adhesions Regulates Stiffness-Dependent Differences in the TGF-β1-Mediated Myofibroblast Differentiation of Corneal Keratocytes
Authors: Maruri Daniel P. , Iyer Krithika S. , Schmidtke David W. , Petroll W. Matthew , Varner Victor D. 
Published: May 2022

Following injury and refractive surgery, corneal wound healing can initiate a protracted fibrotic response that interferes with ocular function. This fibrosis is related, in part, to the myofibroblast differentiation of corneal keratocytes in response to transforming growth factor beta 1 (TGF-β1). Previous studies have shown that changes in the mechanical properties of the extracellular matrix (ECM) can regulate this process, but the mechanotransductive pathways that govern stiffness-dependent changes in keratocyte differentiation remain unclear. Here, we used a polyacrylamide (PA) gel system to investigate how mechanosensing via focal adhesions (FAs) regulates the stiffness-dependent myofibroblast differentiation of primary corneal keratocytes treated with TGF-β1. Soft (1 kPa) and stiff (10 kPa) PA substrata were fabricated on glass coverslips, plated with corneal keratocytes, and cultured in defined serum free media with or without exogenous TGF-β1. In some experiments, an inhibitor of focal adhesion kinase (FAK) activation was also added to the media. Cells were fixed and stained for F-actin, as well as markers for myofibroblast differentiation (α-SMA), actomyosin contractility phosphorylated myosin light chain (pMLC), focal adhesions (vinculin), or Smad activity (pSmad3). We also used traction force microscopy (TFM) to quantify cellular traction stresses. Treatment with TGF-β1 elicited stiffness-dependent differences in the number, size, and subcellular distribution of FAs, but not in the nuclear localization of pSmad3. On stiff substrata, cells exhibited large FAs distributed throughout the entire cell body, while on soft gels, the FAs were smaller, fewer in number, and localized primarily to the distal tips of thin cellular extensions. Larger and increased numbers of FAs correlated with elevated traction stresses, increased levels of α-SMA immunofluorescence, and more prominent and broadly distributed pMLC staining. Inhibition of FAK disrupted stiffness-dependent differences in keratocyte contractility, FA patterning, and myofibroblast differentiation in the presence of TGF-β1. Taken together, these data suggest that signaling downstream of FAs has important implications for the stiffness-dependent myofibroblast differentiation of corneal keratocytes.
Tricuspid Annular Abnormalities in Isolated Left Ventricular Non-compaction—Insights From the Three-dimensional Speckle-Tracking Echocardiographic MAGYAR-Path Study
Authors: Nemes Attila , Rácz Gergely , Kormányos Árpád 
Published: May 2022

IntroductionProminent trabecular left ventricular (LV) meshwork and deep intertrabecular LV recesses are featuring LV non-compaction (LVNC). The aim of this study was to evaluate tricuspid annular (TA) morphological and functional abnormalities by three-dimensional speckle-tracking echocardiography (3DSTE) in patients with LVNC without right ventricular (RV) involvement.Materials and MethodsThis study consisted of 21 patients with isolated LVNC, from which 6 cases were excluded due to inferior image quality. The remaining patient group consisted of 15 subjects with a mean age of 52.1 ± 11.4 years (9 males). LVNC was defined according to the Jenni's criteria. Their results were compared to 21 age- and gender-matched healthy controls (mean age: 52.4 ± 3.9 years, 14 males). Complete routine 2-dimensional Doppler echocardiographic examination was performed in all the patients with isolated LVNC and healthy controls. End-systolic and end-diastolic TA dimensions were assessed on selected planes derived from full-volume 3D echocardiographic datasets during 3DSTE.ResultsPatients with isolated LVNC showed significantly dilated end-systolic and end-diastolic TA diameter and area, which were accompanied with preserved TA functional properties and associated with right atrial (RA) volumes. TA plane systolic excursion (TAPSE) showed mild correlations with TA fractional area change (TAFAC) and TA fractional shortening (TAFS). No correlations could be demonstrated between TAPSE and TA morphological features. Extent of LVNC did not correlate with any echocardiographic parameters.ConclusionTA is dilated with preserved sphincter-like function in patients with isolated LVNC. Longitudinal (TAPSE) and sphincter-like (TAFAC and TAFS) TA movements correlate with each other. TA dilation is associated with an increased RA volumes respecting cardiac cycle.
Ablation of Outflow Tract Arrhythmias in Patients With and Without Structural Heart Disease—A Comparative Analysis
Authors: Schleberger Ruben , Riess Jan , Brauer Anika , Pinnschmidt Hans O. , Rottner Laura , Moser Fabian , Moser Julia , Kany Shinwan , My Ilaria , Lemoine Marc D. , Reissmann Bruno , Meyer Christian , Metzner Andreas , Ouyang Feifan , Kirchhof Paulus , Rillig Andreas 
Published: May 2022

IntroductionCatheter ablation of ventricular arrhythmias emerging from the ventricular outflow tracts and adjacent structures is very effective and considered almost curative in patients without structural heart disease (SHD). Outcomes of patients with SHD undergoing ablation of outflow tract arrhythmias are not known.MethodsConsecutive patients (2019–2021) undergoing catheter ablation of ventricular arrhythmias in a single high-volume center were retrospectively analyzed. Patients with ablation of outflow tract arrhythmias were identified and divided in individuals with and without SHD. Procedural parameters and acute outcome were compared.ResultsWe identified 215 patients with outflow tract arrhythmias (35.3% female, mean age 58.3 ± 16.0 years). Of those, 93 (43.3%) had SHD. Patients with SHD and outflow tract arrhythmias were older (65.0 ± 12.8 vs. 53.3 ± 16.3 years; p &lt; 0.001), more often male (82.8 vs. 50.0%; p &lt; 0.001) and had more comorbidities than patients without SHD (arterial hypertension: 62.4 vs. 34.4%, p &lt; 0.001; diabetes: 22.6 vs. 8.2%, p = 0.005; chronic lung disease: 20.4 vs. 7.4%, p = 0.007). Outflow tract arrhythmias in patients with SHD had their origin more often in the left ventricle (68.8 vs. 53.3%, p = 0.025). The acute success rate was similar in both patient groups (93.4 vs. 94.2%, p = 0.781). Patients with SHD were discharged later {median length of hospital stay with SHD 5 [6 (interquartile range)] days, without SHD 2 [4] days, p &lt; 0.001}. Periprocedural complications were numerically more frequent in patients with SHD [with SHD 12 (12.9%), without SHD 8 (6.6%), p = 0.154].ConclusionOutflow tract arrhythmia ablation has a high success rate irrespective of the presence of SHD. Longer hospital stay and potentially a higher risk of periprocedural complications should be considered when discussing this treatment option with patients.
Radiomics Analysis of Computed Tomography for Prediction of Thyroid Capsule Invasion in Papillary Thyroid Carcinoma: A Multi-Classifier and Two-Center Study
Authors: Wu Xinxin , Yu Pengyi , Jia Chuanliang , Mao Ning , Che Kaili , Li Guan , Zhang Haicheng , Mou Yakui , Song Xicheng 
Published: May 2022

ObjectiveTo investigate the application of computed tomography (CT)-based radiomics model for prediction of thyroid capsule invasion (TCI) in papillary thyroid carcinoma (PTC).MethodsThis retrospective study recruited 412 consecutive PTC patients from two independent institutions and randomly assigned to training (n=265), internal test (n=114) and external test (n=33) cohorts. Radiomics features were extracted from non-contrast (NC) and artery phase (AP) CT scans. We also calculated delta radiomics features, which are defined as the absolute differences between the extracted radiomics features. One-way analysis of variance and least absolute shrinkage and selection operator were used to select optimal radiomics features. Then, six supervised machine learning radiomics models (k-nearest neighbor, logistic regression, decision tree, linear support vector machine [L-SVM], Gaussian-SVM, and polynomial-SVM) were constructed. Univariate was used to select clinicoradiological risk factors. Combined models including optimal radiomics features and clinicoradiological risk factors were constructed by these six classifiers. The prediction performance was evaluated using the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA).ResultsIn the internal test cohort, the best combined model (L-SVM, AUC=0.820 [95% CI 0.758–0.888]) performed better than the best radiomics model (L-SVM, AUC = 0.733 [95% CI 0.654–0.812]) and the clinical model (AUC = 0.709 [95% CI 0.649–0.783]). Combined-L-SVM model combines 23 radiomics features and 1 clinicoradiological risk factor (CT-reported TCI). In the external test cohort, the AUC was 0.776 (0.625–0.904) in the combined-L-SVM model, showing that the model is stable. DCA demonstrated that the combined model was clinically useful.ConclusionsOur combined model based on machine learning incorporated with CT radiomics features and the clinicoradiological risk factor shows good predictive ability for TCI in PTC.
Repetitive Elements, Sequence Turnover and Cyto-Nuclear Gene Transfer in Gymnosperm Mitogenomes
Authors: Liu Hui , Zhao Wei , Zhang Ren-Gang , Mao Jian-Feng , Wang Xiao-Ru 
Published: May 2022

Among the three genomes in plant cells, the mitochondrial genome (mitogenome) is the least studied due to complex recombination and intergenomic transfer. In gymnosperms only ∼20 mitogenomes have been released thus far, which hinders a systematic investigation into the tempo and mode of mitochondrial DNA evolution in seed plants. Here, we report the complete mitogenome sequence of Platycladus orientalis (Cupressaceae). This mitogenome is assembled as two circular-mapping chromosomes with a size of ∼2.6 Mb and which contains 32 protein-coding genes, three rRNA and seven tRNA genes, and 1,068 RNA editing sites. Repetitive sequences, including dispersed repeats, transposable elements (TEs), and tandem repeats, made up 23% of the genome. Comparative analyses with 17 other mitogenomes representing the five gymnosperm lineages revealed a 30-fold difference in genome size, 80-fold in repetitive content, and 230-fold in substitution rate. We found dispersed repeats are highly associated with mitogenome expansion (r = 0.99), and most of them were accumulated during recent duplication events. Syntenic blocks and shared sequences between mitogenomes decay rapidly with divergence time (r = 0.53), with the exceptions of Ginkgo and Cycads which retained conserved genome structure over long evolutionary time. Our phylogenetic analysis supports a sister group relationship of Cupressophytes and Gnetophytes; both groups are unique in that they lost 8–12 protein-coding genes, of which 4–7 intact genes are likely transferred to nucleus. These two clades also show accelerated and highly variable substitution rates relative to other gymnosperms. Our study highlights the dynamic and enigmatic evolution of gymnosperm mitogenomes.
A RE-AIM Framework Analysis of DNA-Based Population Screening: Using Implementation Science to Translate Research Into Practice in a Healthcare System
Authors: Jones Laney K. , Strande Natasha T. , Calvo Evan M. , Chen Jingheng , Rodriguez Gabriela , McCormick Cara Z. , Hallquist Miranda L. G. , Savatt Juliann M. , Rocha Heather , Williams Marc S. , Sturm Amy C. , Buchanan Adam H. , Glasgow Russell E. , Martin Christa L. , Rahm Alanna Kulchak 
Published: May 2022

Introduction: DNA-based population screening has been proposed as a public health solution to identify individuals at risk for serious health conditions who otherwise may not present for medical care. The clinical utility and public health impact of DNA-based population screening is a subject of active investigation. Geisinger, an integrated healthcare delivery system, was one of the first healthcare systems to implement DNA screening programs (MyCode Community Health Initiative (MyCode) and clinical DNA screening pilot) that leverage exome data to identify individuals at risk for developing conditions with potential clinical actionability. Here, we demonstrate the use of an implementation science framework, RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance), to conduct a post-hoc evaluation and report outcomes from these two programs to inform the potential impact of DNA-based population screening.Methods: Reach and Effectiveness outcomes were determined from the MyCode research program, while Adoption and Implementation outcomes were measured using the clinical DNA screening pilot. Reach was defined as the number of patients who were offered and consented to participate in MyCode. Effectiveness of DNA screening was measured by reviewing MyCode program publications and synthesizing findings from themes. Adoption was measured by the total number of DNA screening tests ordered by clinicians at the clinical pilot sites. Implementation was assessed by interviewing a subset of clinical pilot clinicians about the deployment of and recommended adaptations to the pilot that could inform future program dissemination.Results:Reach: As of August 2020, 68% (215,078/316,612) of individuals approached to participate in the MyCode program consented. Effectiveness: Published evidence reported from MyCode demonstrates that DNA screening identifies at-risk individuals more comprehensively than clinical ascertainment based on phenotypes or personal/family history. Adoption: From July 2018 to June 2021, a total of 1,026 clinical DNA screening tests were ordered by 60 clinicians across the three pilot clinic sites. Implementation: Interviews with 14 clinicians practicing at the pilot clinic sites revealed motivation to provide patients with DNA screening results and yielded future implementation strategies.Conclusion: The RE-AIM framework offers a pragmatic solution to organize, analyze, and report outcomes across differently resourced and designed precision health programs that include genomic sequencing and return of clinically actionable genomic information.
Presence of Circulatory Autoantibodies Against ROS-Modified Histone H1 Protein in Lymphoma Patients
Authors: Binsaleh Naif K. , Eltayeb Reem , Qanash Husam , Aziz Mohammad Azhar , Albaradie Raid , Khan Mohd Wajid Ali 
Published: May 2022

Lymphoma is a chronic inflammatory disease in which the immune system is highly affected. Increased oxidative stress is one of the common conditions of cancer and affects macromolecules. Histone modifications affect the chromatin structure and functions. In this study, histone H1 (His-H1) protein was modified by reactive oxygen species (ROS), and structural and chemical changes were studied. Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients were selected, and oxidative stress markers, inflammatory cytokines, and serum autoantibodies were analyzed using biochemical and immunological assays. Furthermore, the formation of antigen-antibody immune complexes was assessed by the Langmuir plot. ROS-modified His-H1 (ROS-His-H1) showed substantial structural perturbation in protein (UV-hyperchromicity and increased intrinsic fluorescence) compared to the native His-H1 protein. A possible explanation for the changes is suggested by the exposure of the aromatic chromophore to the solvent. In-depth structural analysis by circular dichroism (CD) exhibited major changes in α-helix (−21.43%) and turns (+33%), reflecting changes in the secondary structure of histone H1 protein after ROS exposure. ELISA and competitive ELISA findings revealed high recognitions of serum autoantibodies to ROS-His-H1 from NHL, followed by HL subjects. Healthy controls showed negligible binding. Non-modified His-H1 did not show any binding with serum samples from either cohort. High apparent association constants (ACCs) were calculated for ROS-His-H1 using purified IgGs from NHL (1.46 × 10–6 M) compared to HL (1.33 × 10–6 M) patients. Non-modified His-H1 exhibited a hundred times less ACC for NHL (2.38 × 10–8 M) and HL (2.46 × 10–8 M) patients. Thus, ROS modifications of histone H1 cause structural changes and expose cryptic neo-epitopes on the protein against which autoantibodies were generated. These perturbations might affect the histone DNA interaction dynamics and potentially be correlated with gene dysregulation. These subtle molecular changes with an immune imbalance might further aggravate the disease.
Associations Between Serum Fatty Acids and Immunological Markers in Children Developing Islet Autoimmunity—The TRIGR Nested Case–Control Study
Authors: Niinistö Sari , Miettinen Maija E. , Cuthbertson David , Honkanen Jarno , Hakola Leena , Autio Reija , Erlund Iris , Arohonka Petra , Vuorela Arja , Härkönen Taina , Hyöty Heikki , Krischer Jeffrey P. , Vaarala Outi , Knip Mikael , Virtanen Suvi M. ,   TRIGR Investigators
Published: May 2022

AimsAltered immune functions as well as fatty acid intake and status have been associated with the development of type 1 diabetes. We aimed to study the relationship between fatty acids and immunological markers in young children with increased genetic risk for type 1 diabetes in order to define putative mechanisms related to development of islet autoimmunity.MethodsSerum samples for fatty acid and immunological marker measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children born between 2002 and 2007 in 15 countries. Case children (n = 95) were defined as having repeated positivity for at least two out of four diabetes-associated autoantibodies. For each case child, control children were selected matched for country and date of birth (n = 173). Serum fatty acids and immunological markers were measured from cord serum and at the age of 6 and 12 months. Spearman correlation coefficients were calculated between fatty acids and immunological markers.ResultsCorrelations between circulating fatty acids and immunological markers were different in case children who developed islet autoimmunity than in control children already at birth continuing across the first year of life. In case children, saturated fatty acids (SFAs) showed stronger correlations with immunological markers, while in controls, polyunsaturated fatty acids (PUFAs) showed stronger correlations.ConclusionsIn cases, SFAs were associated with several immunological markers (CXCL10, IL-6, IL-9, IL-17, and CM-CSF) previously linked to the type 1 diabetes disease process. Findings indicate that fatty acids could have immunomodulatory potential in the early phase of the disease development, although causality between fatty acids and the immunological pathways remains to be explored.Trial registry numberNCT00179777
A Roadmap for Investigating Preclinical Autoimmunity Using Patient-Oriented and Epidemiologic Study Designs: Example of Rheumatoid Arthritis
Authors: Kowalski Emily N. , Qian Grace , Vanni Kathleen M.M. , Sparks Jeffrey A. 
Published: May 2022

Background &amp; AimsRheumatoid arthritis (RA) is a prototypic autoimmune disease causing inflammatory polyarthritis that affects nearly 1% of the population. RA can lead to joint destruction and disability along with increased morbidity and mortality. Similar to other autoimmune diseases, RA has distinct preclinical phases corresponding to genetic risk, lifestyle risk factors, autoantibody development, and non-specific symptoms prior to clinical diagnosis. This narrative review will detail observational studies for RA risk and clinical trials for RA prevention as a roadmap to investigating preclinical autoimmunity that could be applied to other diseases.MethodsIn this narrative review, we summarized previous and ongoing research studies investigating RA risk and prevention, categorizing them related to their design and preclinical phases.ResultsWe detailed the following types of studies investigating RA risk and prevention: retrospective population-based and administrative datasets; prospective studies (case-control and cohort; some enrolling based on genetics, first-degree relative status, elevated biomarkers, or early symptoms/arthritis); and randomized clinical trials. These correspond to all preclinical RA phases (genetic, lifestyle, autoimmunity, early signs/symptoms). Previous and ongoing randomized controlled trials have enrolled individuals at very elevated risk for RA based on biomarkers, symptoms, imaging abnormalities, or early signs/symptoms.ConclusionWe detailed the rich variety of study designs that is necessary to investigate distinct preclinical phases of an autoimmune disease such as RA. However, further progress is needed to fully elucidate the pathogenesis of RA that may ultimately lead to prevention or delay of disease onset.
Twin Growth Discordance and Risk of Postpartum Hemorrhage: A Retrospective Cohort Study
Authors: Cao Xiuhong , Luo Ye , Zhou Shuangqiong , Zhao Qingsong , Qin Xuewei , Liu Zhiqiang , Xu Zhendong 
Published: May 2022

BackgroundIn recent years, the incidence of postpartum hemorrhage has increased globally. Multiple pregnancies and cesarean sections are well-known risk factors for postpartum hemorrhage. No studies have evaluated the associations between fetal growth anomalies and postpartum hemorrhage in women with twin pregnancies undergoing cesarean section. This study aimed to identify the relationship between fetal growth anomalies and postpartum hemorrhage in women with twin pregnancies undergoing cesarean section.MethodsThis retrospective single-center study included 3,180 women with twin pregnancies at a tertiary hospital between August 2013 and July 2020. Singleton reference charts were used to assess fetal growth restriction at birth. Discordant growth was defined as an intertwin birth weight difference of ≥20%. Logistic regression analyses were used to evaluate the association between fetal growth anomalies and postpartum hemorrhage. Additionally, sensitivity analysis of abnormal placenta and stratification by twin chorionicity were conducted.ResultsThe overall incidence of postpartum hemorrhage was 4.3%. Twin growth discordance, especially with fetal growth restriction, was associated with an increased risk of postpartum hemorrhage (adjusted odds ratio [AOR] = 1.62, 95% confidence interval [CI], 1.05–2.51, P = 0.031; AOR = 1.71; 95% CI, 1.08–2.70, P = 0.022; AOR = 1.98, 95% CI, 1.21–3.25, P = 0.006, respectively). After stratification, this relationship persisted in dichorionic twins (OR = 1.71, 95% CI, 1.04–2.82, P = 0.036; OR = 1.90, 95% CI, 1.13–3.21, P = 0.016; OR = 2.48, 95% CI, 1.41–4.38, P = 0.002, respectively). However, no significant association was observed in monochorionic twin pregnancies.ConclusionGrowth discordance, especially complicated by fetal growth restriction, was associated with an increased risk of postpartum hemorrhage in women with twin pregnancies undergoing cesarean section, and was more evident in patients with dichorionic twins.