bluuebunny/crossref_metadata_2025_split huggingface dataset:
iRGvalid: A Robust in silico Method for Optimal Reference Gene Validation
Authors: Zhu Zhongxu , Gregg Keqin , Zhou Wenli 
Published: August 2021

BackgroundAppropriate reference genes are critical to accurately quantifying relative gene expression in research and clinical applications. Numerous efforts have been made to select the most stable reference gene(s), but a consensus has yet to be achieved. In this report, we propose an in silico reference gene validation method, iRGvalid, that can be used as a universal tool to validate the reference genes recommended from different resources so as to identify the best ones without a need for any wet lab validation tests.MethodsiRGvalid takes advantage of high throughput gene expression data and is built on a double-normalization strategy. First, the expression level of each individual gene is normalized against the total gene expression level of each sample, followed by a target gene normalization to the candidate reference gene(s). Linear regression analysis is then performed between the pre- and post- normalized target gene across the whole sample set to evaluate the stability of the reference gene(s), which is positively associated with the Pearson correlation coefficient, Rt. The higher the Rt value, the more stable the reference gene. We applied iRGvalid to 14 candidate reference genes to validate and identify the most stable reference genes in four cancer types: lung adenocarcinoma, breast cancer, colon adenocarcinoma, and nasopharyngeal cancer. The stability of the reference gene is evaluated both individually and in groups of all possible combinations.ResultsHighly stable reference genes resulted in high Rt values regardless of the target gene used. The highest stability was achieved with a specific combination of 3 to 6 reference genes. A few genes were among the best reference genes across the cancer types studied here.ConclusioniRGvalid provides an easy and robust method to validate and identify the most stable reference gene or genes from a pool of candidate reference genes. The inclusivity of large expression data sets as well as the direct comparison of candidate reference genes makes it possible to identify reference genes with universal quality. This method can be used in any other gene expression studies when large cohorts of expression data are available.
Clinical and Genetic Analysis of Costa Rican Patients With Parkinson's Disease
Authors: Torrealba-Acosta Gabriel , Yu Eric , Lobo-Prada Tanya , Ruíz-Martínez Javier , Gorostidi-Pagola Ana , Gan-Or Ziv , Carazo-Céspedes Kenneth , Trempe Jean-François , Mata Ignacio F. , Fornaguera-Trías Jaime 
Published: August 2021

Background: Most research in genomics of Parkinson's disease (PD) has been done in subjects of European ancestry, leading to sampling bias and leaving Latin American populations underrepresented. We sought to clinically characterize PD patients of Costa Rican origin and to sequence familial PD and atypical parkinsonism-associated genes in cases and controls.Methods: We enrolled 118 PD patients with 97 unrelated controls. Collected information included demographics, exposure to risk and protective factors, and motor and cognitive assessments. We sequenced coding and untranslated regions in familial PD and atypical parkinsonism-associated genes including GBA, SNCA, VPS35, LRRK2, GCH1, PRKN, PINK1, DJ-1, VPS13C, and ATP13A2.Results: Mean age of PD probands was 62.12 ± 13.51 years; 57.6% were male. The frequency of risk and protective factors averaged ~45%. Physical activity significantly correlated with better motor performance despite years of disease. Increased years of education were significantly associated with better cognitive function, whereas hallucinations, falls, mood disorders, and coffee consumption correlated with worse cognitive performance. We did not identify an association between tested genes and PD or any damaging homozygous or compound heterozygous variants. Rare variants in LRRK2 were nominally associated with PD; six were located between amino acids p.1620 and 1623 in the C-terminal-of-ROC (COR) domain of Lrrk2. Non-synonymous GBA variants (p.T369M, p.N370S, and p.L444P) were identified in three healthy individuals. One PD patient carried a pathogenic GCH1 variant, p.K224R.Discussion: This is the first study that describes sociodemographics, risk factors, clinical presentation, and genetics of Costa Rican patients with PD, adding information to genomics research in a Latino population.
Subacute Cognitive Impairment in Individuals With Mild and Moderate COVID-19: A Case Series
Authors: Matos Aline de Moura Brasil , Dahy Flavia Esper , de Moura João Victor Luisi , Marcusso Rosa Maria Nascimento , Gomes Andre Borges Ferreira , Carvalho Fernanda Martins Maia , Fernandes Gustavo Bruniera Peres , Felix Alvina Clara , Smid Jerusa , Vidal Jose Ernesto , Frota Norberto Anizio Ferreira , Casseb Jorge , Easton Ava , Solomon Tom , Witkin Steven S. , Malta Romano Camila , de Oliveira Augusto César Penalva ,   NeuroCovBR Study Group
Published: August 2021

Background: Previous reported neurologic sequelae associated with SARS-CoV-2 infection have mainly been confined to hospital-based patients in which viral detection was restricted to nasal/throat swabs or to IgM/IgG peripheral blood serology. Here we describe seven cases from Brazil of outpatients with previous mild or moderate COVID-19 who developed subacute cognitive disturbances.Methods: From June 1 to August 15, 2020, seven individuals 18 to 60 years old, with confirmed mild/moderate COVID-19 and findings consistent with encephalopathy who were observed &gt;7 days after respiratory symptom initiation, were screened for cognitive dysfunction. Paired sera and CSF were tested for SARS-CoV-2 (IgA, IgG ELISA, and RT-PCR). Serum and intrathecal antibody dynamics were evaluated with oligoclonal bands and IgG index. Cognitive dysfunction was assessed by the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Clock Drawing Test (CDT).Results: All but one of our patients were female, and the mean age was 42.6 years. Neurologic symptoms were first reported a median of 16 days (IQR 15–33) after initial COVID-19 symptoms. All patients had headache and altered behavior. Cognitive dysfunction was observed mainly in phonemic verbal fluency (MoCA) with a median of six words/min (IQR 5.25–10.75) and altered visuospatial construction with a median of four points (IQR 4–9) (CDT). CSF pleocytosis was not detected, and only one patient was positive for SARS-CoConclusions: A subacute cognitive syndrome suggestive of SARS-CoV-2-initiated damage to cortico-subcortical associative pathways that could not be attributed solely to inflammation and hypoxia was present in seven individuals with mild/moderate COVID-19.
Melodic Intonation Therapy for Post-stroke Non-fluent Aphasia: Systematic Review and Meta-Analysis
Authors: Haro-Martínez Ana , Pérez-Araujo Carmen M. , Sanchez-Caro Juan M. , Fuentes Blanca , Díez-Tejedor Exuperio 
Published: August 2021

Introduction: Melodic intonation therapy (MIT) is one of the most studied speech and language therapy (SLT) approaches for patients with non-fluent aphasia, although the methodological quality of the studies has been rated as low in previous reviews. The aim of this study is to update current evidence on the possible efficacy of MIT for the treatment of non-fluent post-stroke aphasia.Methods: A systematic review and meta-analysis. We selected randomized clinical trials (RCT) that included adult patients over 18 years of age with non-fluent post-stroke aphasia, whose intervention was MIT vs. no therapy or other therapy. We excluded non-RCT studies, mixed populations including patients with aphasia of non-stroke etiology, studies with no availability of post-stroke aphasia-specific data, and incomplete studies. Three sections of communicative ability were analyzed as outcomes: functional communication, expressive language (naming and repetition), and comprehension.Results: We identified a total of four eligible RCTs involving 94 patients. Despite the heterogeneity in the psychometric tests employed among the trials, a significant effect of MIT on functional communication (evaluated by the Communication Activity Log) was found (SMD 1.47; 95% CI 0.39–2.56). In addition, a positive effect of MIT on expressive language (repetition) was found (SMD 0.45; 95% CI 0.01–0.90). No significant effects on comprehension measurements were found, despite a lack of significant statistical heterogeneity.Conclusion: This systematic review and meta-analysis shows a significant effect of MIT on improving functional communication and on repetition tasks. Future larger RCT specifically addressing those outcomes should provide the definite evidence on the efficacy of MIT on post-stroke aphasia recovery.Systematic Review Registration:PROSPERO-URL https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020144604.
The Application of Fat-Free Mass Index for Survival Prediction in Cancer Patients With Normal and High Body Mass Index
Authors: Zhang Xi , Zhang Qi , Feng Li-jin , Zhang Kang-Ping , Tang Meng , Song Meng-meng , Ruan Guo-tian , Zhang Xiao-wei , Li Wei , Zhou Fu-xiang , Cong Ming-Hua , Shi Han-Ping 
Published: August 2021

Background: Fat-free mass (FFM) depletion can be masked by a stable body weight or weight gain in the presence of a normal or high body mass index (BMI). This study investigated the prognostic value of low fat-free mass index (FFMI) in cancer patients with normal or high BMI.Methods: This multicenter retrospective cohort study included 1,602 cancer patients with normal/high BMI. The association of FFMI with patients' overall survival (OS) was analyzed by the Kaplan-Meier method and a Cox model.Results: In this analysis, there were 974 (60.8%) females and 628 (39.2%) males. Low FFMI was associated with worse OS when compared with those patients with normal FFMI. After multivariate adjustment, low FFMI was demonstrated to be an independent unfavorable prognostic factor (HR: 1.69; 95% CI: 1.28, 2.23; P &lt; 0.001) in cancer patients with normal/high BMI. For specific tumor type, low FFMI was found to be associated with worse prognosis in patients with lung cancer, breast cancer and upper gastrointestinal cancer. In subgroup analysis, the association of low FFMI with worse survival was significantly modified by weight loss (P for interaction = 0.012), and those patients with concurrent low FFMI and weight loss showed the worst prognosis (HR: 3.53; 95% CI: 2.04, 6.11; P &lt; 0.001).Conclusion: Low FFMI was associated with worse prognosis in cancer patients with normal/high BMI. This study highlights the usefulness of FFMI for prognostic estimation in these patients.
Significance of DMBT1 in Papillary Thyroid Carcinoma Concurrent With Hashimoto’s Thyroiditis
Authors: Gan Xiao-xiong , Li Ya-yi , Li Si-jin , Mo Shi-sen , Feng Jian-hua , Shen Fei , Cai Wen-song , Lai Ye-qian , Xu Bo 
Published: August 2021

BackgroundPapillary thyroid carcinoma (PTC) concurrent with Hashimoto’s thyroiditis (HT) was associated with a better clinical prognosis. This study aimed to investigate a potential mRNA gene that affects the development of PTC, which helps PTC concurrent with HT patients have a better prognosis.Material/MethodsPTC data were obtained from The Cancer Genome Atlas (TCGA) database. And the validation data of tissue specimens were collected from Guangzhou First People’s Hospital. The thyroid tissue sections were hybridized with deleted in malignant brain tumor 1 (DMBT1) probes by situ hybridization. Survival rates were analyzed using Kaplan-Meier curves, and the log-rank test was used to compare group survival rates. Prognosis clinicopathological factors were analyzed by Cox regression. Gene Ontology (GO) and Kyoto Gene and Genomic Encyclopedia (KEGG) pathway enrichment analyses were performed using single-sample gene set enrichment analysis (ssGSEA). Finally, the correlation of deletion in DMBT1 expression with overall immune status, tumor purity, and human leukocyte antigen (HLA) gene expression profile was analyzed.ResultsHT was significantly associated with sex, tumor foci, extrathyroidal extension (ETE), residual tumor, and tumor stage (T stage). Moreover, PTC concurrent with HT had a lower risk of recurrence versus non-HT groups. A total of 136 differentially expressed mRNAs (DEMs) were identified between HT and non-HT groups. Among them, the expression level of DMBT1 in HT groups was statistically higher than that in non-HT groups. A significant association with ETE and recurrence was revealed in the high expression and the low expression of DMBT1. Furthermore, DMBT1 was an independent predictor of survival. The overall immune activity of high expression of DMBT1 was higher than that of the low-expression group.ConclusionsThe PTC patients with HT had better behavior features and prognosis than those with simple PTC. DMBT1 in PTC-HT patients was a potential possible factor that inhibits tumors. High expression of DMBT1 may improve PTC prognosis by immune-related pathways.
Puerarin Inhibits Ferroptosis and Inflammation of Lung Injury Caused by Sepsis in LPS Induced Lung Epithelial Cells
Authors: Xu Baiye , Wang Haidao , Chen Zhen 
Published: August 2021

Background: Ferroptosis is a new type of programmed cell death, which plays an important role in lung injury caused by sepsis. Studies have reported that Puerarin (Pue) can treat lung injury caused by sepsis in children, but whether it plays a role by regulating iron death has not been reported.Methods: LPS induced human alveolar epithelial cell A549 to form a model of lung injury caused by sepsis. MTT detected the effect of Pue on A549 cell viability and the effect of Pue on LPS-induced A549 cell viability. The effects of Pue on LPS-induced inflammatory cytokines TNF-α, IL-8, IL-1β in A549 cells were determined by ELISA assay. The expression level of MDA was detected by TBARS colorimetric quantitative detection kit. GSH kit was used to detect the expression of GSH in cells. The iron kit detected the total iron level and the expression level of ferric divalent ions in the cells. DCFH-DA fluorescent probe was used to detect ROS levels. Western blot was used to detect the expression of ferroptosis-related proteins in cells.Results: Pue alleviated LPS-induced injury and inflammatory response in A549 cells, and Pue reduced the expression of ROS, MDA and GSH in LPS-induced A549 cells. In addition, Pue reduced total iron levels and ferrous ion levels in LPS-induced A549 cells, and decreased the expression of iron ferroptosis-related proteins.Conclusion: Puerarin inhibited ferroptosis and inflammation of lung injury caused by sepsis in children in LPS induced lung epithelial cells.
Crotoxin Inhibits Endothelial Cell Functions in Two- and Three-dimensional Tumor Microenvironment
Authors: Kato Ellen Emi , Pimenta Luciana Araújo , Almeida Maíra Estanislau Soares de , Zambelli Vanessa Olzon , Santos Marinilce Fagundes dos , Sampaio Sandra Coccuzzo 
Published: August 2021

Antitumor property of Crotoxin (CTX), the major toxin from Crotalus durissus terrificus snake venom, has been demonstrated in experimental animal models and clinical trials. However, the direct action of this toxin on the significant events involved in neovascularization, which are essential for tumor growth and survival, has not been confirmed. This study investigated the effects of CTX on the key parameters of neovascularization in two- and three-dimensional culture models. Murine endothelial cell lines derived from thymus hemangioma (t.End.1) were treated at different concentrations of CTX (6.25–200 nM). Endothelial cell proliferation, cell adhesion, and actin cytoskeletal dynamics on laminin (10 µg/ml), type I collagen (10 µg/ml), and fibronectin (3 µg/ml) were evaluated along with the endothelial cell migration and formation of capillary-like tubes in 3D Matrigel. CTX concentration of 50 nM inhibited tube formation on 3D Matrigel and impaired cell adhesion, proliferation, and migration under both culture medium and tumor-conditioned medium. These actions were not accountable for the loss of cell viability. Inhibition of cell adhesion to different extracellular matrix components was related to the reduction of αv and α2 integrin distribution and cytoskeletal actin polymerization (F-actin), accompanied by inhibition of focal adhesion kinase (FAK), Rac1 (GTPase) signaling proteins, and actin-related protein 2/3 (Arp 2/3) complex. This study proved that CTX inhibits the major events involved in angiogenesis, particularly against tumor stimuli, highlighting the importance of the anti-angiogenic action of CTX in inhibition of tumor progression.
Muscle in Variable Gravity: “I Do Not Know Where I Am, But I Know What to Do”
Authors: Monti Elena , Waldvogel Janice , Ritzmann Ramona , Freyler Kathrin , Albracht Kirsten , Helm Michael , De Cesare Niccolò , Pavan Piero , Reggiani Carlo , Gollhofer Albert , Narici Marco Vincenzo 
Published: August 2021

Purpose: Fascicle and sarcomere lengths are important predictors of muscle mechanical performance. However, their regulation during stretch-shortening cycle (SSC) activities in usual and challenging conditions is poorly understood. In this study, we aimed to investigate muscle fascicle and sarcomere behavior during drop jumps (a common SSC activity) in conditions of variable gravity.Methods: Fifteen volunteers performed repeated drop jumps in 1 g, hypo-gravity (0 to 1 g), and hyper-gravity (1 to 2 g) during a parabolic flight. Gastrocnemius medialis (GM) electromyographic activity and fascicle length (Lf) were measured at drop-off, ground contact (GC), minimum ankle joint angle (MAJ), and push-off. GM sarcomere number was estimated by dividing Lf, measured by ultrasound at rest, by published data on GM sarcomere length, and measured in vivo at the same joint angle. Changes in sarcomere length were estimated by dividing GM Lf in each jump phase by sarcomere number calculated individually. The sarcomere force-generating capacity in each jump phase was estimated from the sarcomere length-tension relationship previously reported in the literature.Results: The results showed that, regardless of the gravity level, GM sarcomeres operated in the ascending portion of their length-tension relationship in all the jump phases. Interestingly, although in hypo-gravity and hyper-gravity during the braking phase (GC-MAJ) GM fascicles and sarcomeres experienced a stretch (as opposed to the quasi-isometric behavior in 1 g), at MAJ they reached similar lengths as in 1 g, allowing sarcomeres to develop about the 70% of their maximum force.Conclusion: The observed fascicle behavior during drop jumping seems useful for anchoring the tendon, enabling storage of elastic energy and its release in the subsequent push-off phase for effectively re-bouncing in all gravity levels, suggesting that an innate neuromuscular wisdom enables to perform SSC movements also in challenging conditions.
Biopsychosocial Functions of Human Walking and Adherence to Behaviourally Demanding Belief Systems: A Narrative Review
Authors: O’Mara Shane 
Published: August 2021

Human walking is a socially embedded and shaped biological adaptation: it frees our hands, makes our minds mobile, and is deeply health promoting. Yet, today, physical inactivity is an unsolved, major public health problem. However, globally, tens of millions of people annually undertake ancient, significant and enduring traditions of physiologically and psychologically arduous walks (pilgrimages) of days-to-weeks extent. Pilgrim walking is a significant human activity requiring weighty commitments of time, action and belief, as well as community support. Paradoxically, human walking is most studied on treadmills, not ‘in the wild’, while mechanistically vital, treadmill studies of walking cannot, in principle, address why humans walk extraordinary distances together to demonstrate their adherence to a behaviourally demanding belief system.Pilgrim walkers provide a rich ‘living laboratory’ bridging humanistic inquiries, to progressive theoretical and empirical investigations of human walking arising from a behaviourally demanding belief system. Pilgrims vary demographically and undertake arduous journeys on precisely mapped routes of tracked, titrated doses and durations on terrain of varying difficulty, allowing investigations from molecular to cultural levels of analysis. Using the reciprocal perspectives of ‘inside→out’ (where processes within brain and body initiate, support and entrain movement) and ‘outside→in’ (where processes in the world beyond brain and body drive activitywithinbrain and body), we examine how pilgrim walking might shape personal, social and transcendental processes, revealing potential mechanisms supporting the body and brain in motion, to how pilgrim walking might offer policy solutions for physical inactivity.
A Structural Equation Model of Health-Related Quality of Life in Chinese Patients With Rheumatoid Arthritis
Authors: Shen Biyu , Chen Haoyang , Yang Dongliang , Yolanda Ogbolu , Yuan Changrong , Du Aihua , Xu Rong , Geng Yaqin , Chen Xin , Li Huiling , Xu Guang-Yin 
Published: August 2021

Background: The aim of this study was to examine how body image, Disease Activity Score in 28 joints, the feeling of being anxious, depression, fatigue, quality of sleep, and pain influence the quality of life (QoL) in patients with rheumatoid arthritis (RA).Methods: A multicenter cross-sectional survey with convenience sampling was conducted from March 2019 and December 2019, 603 patients with RA from five hospitals were evaluated using the Body Image Disturbance Questionnaire, Disease Activity Score in 28 joints, Hospital Anxiety and Depression Scale, Fatigue Severity Scale, Pittsburgh Sleep Quality Index, Short Form 36 Health Survey, and Global Pain Scale. The relationship between quality of life and other variables was evaluated by using the structural equation model (SEM).Results: A total of 580 patients were recruited. SEM fitted the data very well with a root mean square error of approximation (RMSEA) of 0.072. Comparative fit index of 0.966, and Tucker-Lewis index of 0.936. The symptoms and the normalized factor load of six variables showed that the normalized factor load of pain was 0.99.Conclusions: The QoL model was used to fit an SEM to systematically verify and analyze the population disease data, biological factors, and the direct and indirect effects of the symptom group on the QoL, and the interactions between the symptoms. Therefore, the diagnosis, treatment and rehabilitation of RA is a long-term, dynamic, and complex practical process. Patients' personal symptoms, needs, and experiences also vary greatly. Comprehensive assessment of patients' symptoms, needs, and experiences, as well as the role of social support cannot be ignored, which can help to meet patients' nursing needs, improve their mood and pain-based symptom management, and ultimately improve patients' QoL.