bluuebunny/crossref_metadata_2025_split huggingface dataset:
m6A modification suppresses ocular melanoma through modulating HINT2 mRNA translation
Authors: Jia Ruobing , Chai Peiwei , Wang Shanzheng , Sun Baofa , Xu Yangfan , Yang Ying , Ge Shengfang , Jia Renbing , Yang Yun-Gui , Fan Xianqun 
Published: November 2019

AbstractBackgroundDynamic N6-methyladenosine (m6A) RNA modification generated and erased by N6-methyltransferases and demethylases regulates gene expression, alternative splicing and cell fate. Ocular melanoma, comprising uveal melanoma (UM) and conjunctival melanoma (CM), is the most common primary eye tumor in adults and the 2nd most common melanoma. However, the functional role of m6A modification in ocular melanoma remains unclear.Methodsm6A assays and survival analysis were used to explore decreased global m6A levels, indicating a late stage of ocular melanoma and a poor prognosis. Multiomic analysis of miCLIP-seq, RNA-seq and Label-free MS data revealed that m6A RNA modification posttranscriptionally promoted HINT2 expression. RNA immunoprecipitation (RIP)-qPCR and dual luciferase assays revealed thatHINT2mRNA specifically interacted with YTHDF1. Furthermore, polysome profiling analysis indicated a greater amount ofHINT2mRNA in the translation pool in ocular melanoma cells with higher m6A methylation.ResultsHere, we show that RNA methylation significantly inhibits the progression of UM and CM. Ocular melanoma samples showed decreased m6A levels, indicating a poor prognosis. Changes in global m6A modification were highly associated with tumor progression in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of methylatedHINT2mRNA, a tumor suppressor in ocular melanoma.ConclusionsOur work uncovers a critical function for m6A methylation in ocular melanoma and provides additional insight into the understanding of m6A modification.
Analysis of miRNA signatures in CSF identifies upregulation of miR-21 and miR-146a/b in patients with multiple sclerosis and active lesions
Authors: Muñoz-San Martín María , Reverter Gemma , Robles-Cedeño Rene , Buxò Maria , Ortega Francisco José , Gómez Imma , Tomàs-Roig Jordi , Celarain Naiara , Villar Luisa María , Perkal Hector , Fernández-Real José Manuel , Quintana Ester , Ramió-Torrentà Lluís 
Published: November 2019

Abstract
Background
MicroRNAs (miRNAs) have been reported as deregulated in active brain lesions derived from patients with multiple sclerosis (MS). In there, these post-transcriptional regulators may elicit very important effects but proper identification of miRNA candidates as potential biomarkers and/or therapeutic targets is scarcely available.

Objective
The aim of the study was to detect the presence of a set of candidate miRNAs in cell-free cerebrospinal fluid (CSF) and to determine their association with gadolinium-enhancing (Gd+) lesions in order to assess their value as biomarkers of MS activity.

Methods
Assessment of 28 miRNA candidates in cell-free CSF collected from 46 patients with MS (26 Gd+ and 20 Gd− patients) was performed by TaqMan assays and qPCR. Variations in their relative abundance were analyzed by the Mann-Whitney U test and further evaluated by receiver operating characteristic (ROC) analysis. Signaling pathways and biological functions of miRNAs were analyzed using bioinformatic tools (miRTarBase, Enrichr, REVIGO, and Cytoscape softwares).

Results
Seven out of 28 miRNA candidates were detected in at least 75% of CSF samples. Consistent increase of miR-21 and miR-146a/b was found in Gd+ MS patients. This increase was in parallel to the number of Gd+ lesions and neurofilament light chain (NF-L) levels. Gene Ontology enrichment analysis revealed that the target genes of these miRNAs are involved in biological processes of key relevance such as apoptosis, cell migration and proliferation, and in cytokine-mediated signaling pathways.

Conclusion
Levels of miR-21 and miR-146a/b in cell-free CSF may represent valuable biomarkers to identify patients with active MS lesions.
Cytokine and immune cell profiling in the cerebrospinal fluid of patients with neuro-inflammatory diseases
Authors: Lepennetier Gildas , Hracsko Zsuzsanna , Unger Marina , Van Griensven Martijn , Grummel Verena , Krumbholz Markus , Berthele Achim , Hemmer Bernhard , Kowarik Markus C. 
Published: November 2019

Abstract
Background
Cytokines play multiple roles during neuro-inflammatory processes and several cytokines have been studied in the context of specific diseases. This study provides a comprehensive picture of cerebrospinal fluid (CSF) changes during neuro-inflammation by analyzing multiple cytokines in combination with immune cell subsets and standard CSF parameters.

Methods
Using multiplex assays, we simultaneously measured 36 cytokines (CCL1–3, CCL7, CCL8, CCL11, CCL13, CCL19, CCL20, CCL22–27, CXCL1, CXCL2, CXCL5, CXCL6, CXCL8, CXCL9, CXCL11–13, CXCL16, CX3CL1, IL2, IL4, IL6, IL10, IL16, GM-CSF, IFNγ, MIF, TNFα, and MIB1β) in the CSF and serum of 75 subjects. Diagnoses included clinically isolated syndrome and relapsing-remitting multiple sclerosis (MS, n = 18), secondary progressive MS (n = 8), neuro-syphilis (n = 6), Lyme neuro-borreliosis (n = 13), bacterial and viral meningitis (n = 20), and patients with non-inflammatory neurological diseases (NIND, n = 10). Cytokine concentrations were correlated with CSF standard parameters and CSF immune cell subsets (CD4 and CD8 T cells, B cells, plasmablasts, monocytes, and NK cells) quantified by flow cytometry.

Results
We observed increased levels of multiple cytokines (26/36) in patients with neuro-inflammatory diseases when compared to NIND that consistently correlated with CSF cell count and QAlbumin. Most CSF cytokine concentrations correlated with each other, but correlations between CSF and serum values were scarce (3/36). Within the CSF compartment, CXCL13 showed a strong association with B cells when analyzing all patients, as well as patients with an intact blood-brain barrier (BBB). NK cells positively correlated with CSF concentrations of multiple cytokines (22/36) when analyzing all patients. These correlations were maintained when looking at patients with a disrupted BBB but not detectable in patients with an intact BBB.

Conclusions
Under conditions of neuro-inflammation, multiple CSF cytokines are regulated in parallel and most likely produced locally. A combined increase of CSF CXCL13 levels and B cells occurs under conditions of an intact BBB. Under conditions of a disrupted BBB, CSF NK cells show significantly increased values and seem to have a major contribution to overall inflammatory processes, reflected by a strong correlation with multiple cytokines. Future studies are necessary to address the exact kinetics of these cytokines during neuro-inflammation and their relation to specific diseases phenotypes.
Improving bimanual interaction with a prosthesis using semi-autonomous control
Authors: Volkmar Robin , Dosen Strahinja , Gonzalez-Vargas Jose , Baum Marcus , Markovic Marko 
Published: November 2019

Abstract
Background
The loss of a hand is a traumatic experience that substantially compromises an individual’s capability to interact with his environment. The myoelectric prostheses are state-of-the-art (SoA) functional replacements for the lost limbs. Their overall mechanical design and dexterity have improved over the last few decades, but the users have not been able to fully exploit these advances because of the lack of effective and intuitive control. Bimanual tasks are particularly challenging for an amputee since prosthesis control needs to be coordinated with the movement of the sound limb. So far, the bimanual activities have been often neglected by the prosthetic research community.

Methods
We present a novel method to prosthesis control, which uses a semi-autonomous approach in order to simplify bimanual interactions. The approach supplements the commercial SoA two-channel myoelectric control with two additional sensors. Two inertial measurement units were attached to the prosthesis and the sound hand to detect the movement of both limbs. Once a bimanual interaction is detected, the system mimics the coordination strategies of able-bodied subjects to automatically adjust the prosthesis wrist rotation (pronation, supination) and grip type (lateral, palmar) to assist the sound hand during a bimanual task. The system has been evaluated in eight able-bodied subjects performing functional uni- and bi-manual tasks using the novel method and SoA two-channel myocontrol. The outcome measures were time to accomplish the task, semi-autonomous system misclassification rate, subjective rating of intuitiveness, and perceived workload (NASA TLX).

Results
The results demonstrated that the novel control interface substantially outperformed the SoA myoelectric control. While using the semi-autonomous control the time to accomplish the task and the perceived workload decreased for 25 and 27%, respectively, while the subjects rated the system as more intuitive then SoA myocontrol.

Conclusions
The novel system uses minimal additional hardware (two inertial sensors) and simple processing and it is therefore convenient for practical implementation. By using the proposed control scheme, the prosthesis assists the user’s sound hand in performing bimanual interactions while decreasing cognitive burden.
Effect of blood contamination of cerebrospinal fluid on amino acids, biogenic amines, pterins and vitamins
Authors: Batllori Marta , Casado Mercedes , Sierra Cristina , Salgado Maria del Carmen , Marti-Sanchez Laura , Maynou Joan , Fernandez Guerau , Garcia-Cazorla Angels , Ormazabal Aida , Molero-Luis Marta , Artuch Rafael 
Published: November 2019

Abstract
Background
Cerebrospinal fluid (CSF) metabolomic investigations are a powerful tool for studying neurometabolic diseases. We aimed to assess the effect of CSF contamination with blood on the concentrations of selected biomarkers.

Methods
CSF samples were spiked in duplicate with increasing volumes of whole blood under two conditions: (A) pooled CSF spiked with fresh whole blood and frozen to cause red blood cell (RBC) lysis; (B) pooled CSF spiked with fresh blood and centrifuged (the supernatant with no RBCs was frozen until the moment of analysis). CSF concentrations of amino acids, biogenic amines, pterins, and vitamins were analysed by HPLC coupled with tandem mass spectrometry, electrochemical and fluorescence detection.

Results
Aspartate, glutamate, taurine, ornithine, glycine, citrulline, pyridoxal 5´-phosphate, 5-methyltetrahydrofolate, and thiamine showed higher values when RBCs were lysed when compared with those of CSF with no RBC, while arginine, 5-hydroxyindoleacetic and homovanillic acids showed lower values. When RBCs were removed from CSF, only some amino acids, thiamine and pyridoxal 5´-phosphate showed moderately higher values when compared with the non-spiked CSF sample.

Conclusions
CSF-targeted metabolomic analysis is feasible even when substantial RBC contamination of CSF has occurred since CSF centrifugation to remove RBC prior to freezing eliminated most of the interferences observed.
Early detection of subclinical left ventricular dysfunction after breast cancer radiation therapy using speckle-tracking echocardiography: association between cardiac exposure and longitudinal strain reduction (BACCARAT study)
Authors: Walker Valentin , Lairez Olivier , Fondard Olivier , Pathak Atul , Pinel Baptiste , Chevelle Christian , Franck Denis , Jimenez Gaëlle , Camilleri Jérémy , Panh Loïc , Broggio David , Derreumaux Sylvie , Bernier Marie-Odile , Laurier Dominique , Ferrières Jean , Jacob Sophie 
Published: November 2019

Abstract
Background
Breast cancer (BC) radiotherapy (RT) can induce cardiotoxicity, with adverse events often observed many years after BC RT. Subclinical left ventricular (LV) dysfunction can be detected early after BC RT with global longitudinal strain (GLS) measurement based on 2D speckle-tracking echocardiography. This 6-month follow-up analysis from the BACCARAT prospective study aimed to investigate the association between cardiac radiation doses and subclinical LV dysfunction based on GLS reduction.

Methods
The patient study group consisted of 79 BC patients (64 left-sided BC, 15 right-sided BC) treated with RT without chemotherapy. Echocardiographic parameters, including GLS, were measured before RT and 6 months post-RT. The association between subclinical LV dysfunction, defined as GLS reduction > 10%, and radiation doses to whole heart and the LV were performed based on logistic regressions. Non-radiation factors associated with subclinical LV dysfunction including age, BMI, hypertension, hypercholesterolemia and endocrine therapy were considered for multivariate analyses.

Results
A mean decrease of 6% in GLS was observed (− 15.1% ± 3.2% at 6 months vs. − 16.1% ± 2.7% before RT, p = 0.01). For left-sided patients, mean heart and LV doses were 3.1 ± 1.3 Gy and 6.7 ± 3.4 Gy respectively. For right-sided patients, mean heart dose was 0.7 ± 0.5 Gy and median LV dose was 0.1 Gy. Associations between GLS reduction > 10% (37 patients) and mean doses to the heart and the LV as well as the V20 were observed in univariate analysis (Odds Ratio = 1.37[1.01–1.86], p = 0.04 for Dmean Heart; OR = 1.14 [1.01–1.28], p = 0.03 for Dmean LV; OR = 1.08 [1.01–1.14], p = 0.02 for LV V20). In multivariate analysis, these associations did not remain significant after adjustment for non-radiation factors. Further exploratory analysis allowed identifying a subgroup of patients (LV V20 > 15%) for whom a significant association with subclinical LV dysfunction was found (adjusted OR = 3.97 [1.01–15.70], p = 0.048).

Conclusions
This analysis indicated that subclinical LV dysfunction defined as a GLS decrease > 10% is associated with cardiac doses, but adjustment for non-radiation factors such as endocrine therapy lead to no longer statistically significant relationships. However, LV dosimetry may be promising to identify high-risk subpopulations. Larger and longer follow-up studies are required to further investigate these associations.

Trial registration
ClinicalTrials.gov: NCT02605512, Registered 6 November 2015 - Retrospectively registered
Biomechanical analysis of a novel height-adjustable nano-hydroxyapatite/polyamide-66 vertebral body: a finite element study
Authors: Chen Guanghui , Xin Baoquan , Yin Mengchen , Fan Tianqi , Wang Jing , Wang Ting , Bai Guangjian , Xiao Jianru , Liu Tielong 
Published: November 2019

Abstract
Background
To compare the biomechanical properties of a novel height-adjustable nano-hydroxyapatite/polyamide-66 vertebral body (HAVB) with the titanium mesh cage (TMC) and artificial vertebral body (AVB), and evaluate its biomechanical efficacy in spinal stability reconstruction.

Methods
A 3D nonliner FE model of the intact L1-sacrum was established and validated. Three FE models which instrumented HAVB, TMC, and AVB were constructed for surgical simulation. A pure moment of 7.5 Nm and a 400-N preload were applied to the three FE models in 3D motion. The peak von Mises stress upon each prosthesis and the interfaced endplate was recorded for analysis. In addition, the overall and intersegmental range of motion (ROM) of each model was investigated to assess the efficacy of each model in spinal stability reconstruction.

Results
AVB had the greatest stress concentration compared with TMC and HAVB in all motions (25.6–101.8 times of HAVB, 0.8–8.1 times of TMC). The peak stress on HAVB was 3.1–10.3% of TMC and 1.6–3.9% of AVB. The maximum stress values on L2 caudal and L4 cranial endplates are different between the three FE models: 0.9–1.9, 1.3–12.1, and 31.3–117.9 times of the intact model on L2 caudal endplates and 0.9–3.5, 7.2–31.5, and 10.3–56.4 times of the intact model on L4 cranial endplates in HAVB, TMC, and AVB, respectively, while the overall and segmental ROM reduction was similar between the three models, with AVB providing a relatively higher ROM reduction in all loading conditions (88.1–84.7% of intact model for overall ROM and 69.5–82.1% for L1/2, 87.0–91.7% for L2/4, and 71.1–87.2% for L4/5, respectively).

Conclusions
HAVB had similar biomechanical efficacy in spinal stability reconstruction as compared with TMC and AVB. The material used and the anatomic design of HAVB can help avoid stress concentration and the stress shielding effect, thus greatly reducing the implant-associated complications. HAVB exhibited some advantageous biomechanical properties over TMC and AVB and may prove to be a potentially viable option for spinal stability reconstruction. Further in vivo and vitro studies are still required to validate our findings and conclusions.
Obesity in achondroplasia patients: from evidence to medical monitoring
Authors: Saint-Laurent Celine , Garde-Etayo Laura , Gouze Elvire 
Published: November 2019

AbstractAchondroplasia is a rare genetic disease representing the most common form of short-limb dwarfism. It is characterized by bone growth abnormalities that are well characterized and by a strong predisposition to abdominal obesity for which causes are unknown. Despite having aroused interest at the end of the 20 h century, there are still only very little data available on this aspect of the pathology. Today, interest is rising again, and some studies are now proposing mechanistic hypotheses and guidance for patient management. These data confirm that obesity is a major health problem in achondroplasia necessitating an early yet complex clinical management. Anticipatory care should be directed at identifying children who are at high risk to develop obesity and intervening to prevent the metabolic complications in adults. In this review, we are regrouping available data characterizing obesity in achondroplasia and we are identifying the current tools used to monitor obesity in these patients.
What drives mortality among HIV patients in a conflict setting? A prospective cohort study in the Central African Republic
Authors: Crellen Thomas , Ssonko Charles , Piening Turid , Simaleko Marcel Mbeko , Geiger Karen , Siddiqui M. Ruby 
Published: November 2019

Abstract
Background
Provision of antiretroviral therapy (ART) in conflict settings is rarely attempted and little is known about the expected patterns of mortality. The Central African Republic (CAR) continues to have a low coverage of ART despite an estimated 110,000 people living with HIV and 5000 AIDS-related deaths in 2018. We present results from a cohort in Zemio, Haut-Mboumou prefecture. This region had the highest prevalence of HIV nationally (14.8% in a 2010 survey), and was subject to repeated attacks by armed groups on civilians during the observed period.

Methods
Conflict from armed groups can impact cohort mortality rates i) directly if HIV patients are victims of armed conflict, or ii) indirectly if population displacement or fear of movement reduces access to ART. Using monthly counts of civilian deaths, injuries and abductions, we estimated the impact of the conflict on patient mortality. We also determined patient-level risk factors for mortality and how the risk of mortality varies with time spent in the cohort. Model-fitting was performed in a Bayesian framework, using logistic regression with terms accounting for temporal autocorrelation.

Results
Patients were recruited and observed in the HIV treatment program from October 2011 to May 2017. Overall 1631 patients were enrolled and 1628 were included in the analysis giving 48,430 person-months at risk and 145 deaths. The crude survival rate after 12 months was 0.92 (95% CI 0.90, 0.93). Our model showed that patient mortality did not increase during periods of heightened conflict; the odds ratios (OR) 95% credible interval (CrI) for i) civilian fatalities and injuries, and ii) civilian abductions on patient mortality both spanned unity. The risk of mortality for individual patients was highest in the second month after entering the cohort, and declined seven-fold over the first 12 months. Male sex was associated with a higher mortality (odds ratio 1.70 [95% CrI 1.20, 2.33]) along with the severity of opportunistic infections (OIs) at baseline (OR 2.52; 95% CrI 2.01, 3.23 for stage 2 OIs compared with stage 1).

Conclusions
Our results show that chronic conflict did not appear to adversely affect rates of mortality in this cohort, and that mortality was driven predominantly by patient-specific risk factors. The risk of mortality and recovery of CD4 T-cell counts observed in this conflict setting are comparable to those in stable resource poor settings, suggesting that conflict should not be a barrier in access to ART.
Evaluating nanopore sequencing data processing pipelines for structural variation identification
Authors: Zhou Anbo , Lin Timothy , Xing Jinchuan 
Published: November 2019

Abstract
Background
Structural variations (SVs) account for about 1% of the differences among human genomes and play a significant role in phenotypic variation and disease susceptibility. The emerging nanopore sequencing technology can generate long sequence reads and can potentially provide accurate SV identification. However, the tools for aligning long-read data and detecting SVs have not been thoroughly evaluated.

Results
Using four nanopore datasets, including both empirical and simulated reads, we evaluate four alignment tools and three SV detection tools. We also evaluate the impact of sequencing depth on SV detection. Finally, we develop a machine learning approach to integrate call sets from multiple pipelines. Overall SV callers’ performance varies depending on the SV types. For an initial data assessment, we recommend using aligner minimap2 in combination with SV caller Sniffles because of their speed and relatively balanced performance. For detailed analysis, we recommend incorporating information from multiple call sets to improve the SV call performance.

Conclusions
We present a workflow for evaluating aligners and SV callers for nanopore sequencing data and approaches for integrating multiple call sets. Our results indicate that additional optimizations are needed to improve SV detection accuracy and sensitivity, and an integrated call set can provide enhanced performance. The nanopore technology is improving, and the sequencing community is likely to grow accordingly. In turn, better benchmark call sets will be available to more accurately assess the performance of available tools and facilitate further tool development.
Evaluation of commonly used analysis strategies for epigenome- and transcriptome-wide association studies through replication of large-scale population studies
Authors:   BIOS consortium, van Rooij Jeroen , Mandaviya Pooja R. , Claringbould Annique , Felix Janine F. , van Dongen Jenny , Jansen Rick , Franke Lude , ’t Hoen Peter A. C. , Heijmans Bas , van Meurs Joyce B. J. 
Published: November 2019

Abstract
Background
A large number of analysis strategies are available for DNA methylation (DNAm) array and RNA-seq datasets, but it is unclear which strategies are best to use. We compare commonly used strategies and report how they influence results in large cohort studies.

Results
We tested the associations of DNAm and RNA expression with age, BMI, and smoking in four different cohorts (n = ~ 2900). By comparing strategies against the base model on the number and percentage of replicated CpGs for DNAm analyses or genes for RNA-seq analyses in a leave-one-out cohort replication approach, we find the choice of the normalization method and statistical test does not strongly influence the results for DNAm array data. However, adjusting for cell counts or hidden confounders substantially decreases the number of replicated CpGs for age and increases the number of replicated CpGs for BMI and smoking. For RNA-seq data, the choice of the normalization method, gene expression inclusion threshold, and statistical test does not strongly influence the results. Including five principal components or excluding correction of technical covariates or cell counts decreases the number of replicated genes.

Conclusions
Results were not influenced by the normalization method or statistical test. However, the correction method for cell counts, technical covariates, principal components, and/or hidden confounders does influence the results.