bluuebunny/crossref_metadata_2025 huggingface dataset:
Cigarette Smoking Is Related to Endothelial Dysfunction of Resistance, but Not Conduit Arteries in the General Population—Results From the Gutenberg Health Study
Authors: Hahad Omar , Arnold Natalie , Prochaska Jürgen H. , Panova-Noeva Marina , Schulz Andreas , Lackner Karl J. , Pfeiffer Norbert , Schmidtmann Irene , Michal Matthias , Beutel Manfred , Wild Philipp S. , Keaney John F. , Daiber Andreas , Münzel Thomas
Published: May 2021

Aims: Cigarette smoking is one of the most complex and least understood cardiovascular risk factors. Importantly, differences in the tobacco-related pathophysiology of endothelial dysfunction, an early event in atherogenesis, between circulatory beds remain elusive. Therefore, this study evaluated how smoking impacts endothelial function of conduit and resistance arteries in a large population-based cohort.

Methods and results: 15,010 participants (aged 35–74 years) of the Gutenberg Health Study were examined at baseline from 2007 to 2012. Smoking status, pack-years of smoking, and years since quitting smoking were assessed by a computer-assisted interview. Endothelial function of conduit and resistance arteries was determined by flow-mediated dilation (FMD) of the brachial artery, reactive hyperemia index (RHI) using peripheral arterial tonometry, as well as by reflection index (RI) derived from digital photoplethysmography, respectively. Among all subjects, 45.8% had never smoked, 34.7% were former smokers, and 19.4% were current smokers. Mean cumulative smoking exposure was 22.1 ± 18.1 pack-years in current smokers and mean years since quitting was 18.9 ± 12.7 in former smokers. In multivariable linear regression models adjusted for typical confounders, smoking status, pack-years of smoking, and years since quitting smoking were independently associated with RHI and RI, while no association was found for FMD. Overall, no clear dose-dependent associations were observed between variables, whereby higher exposure tended to be associated with pronounced resistance artery endothelial dysfunction.

Conclusions: Cigarette smoking is associated with altered endothelial function of resistance, but not conduit arteries. The present results suggest that smoking-induced endothelial dysfunction in different circulatory beds may exhibit a differential picture.
Working in Inclusive or Non-Inclusive Contexts: Relations Between Collaborative Variables and Special Education Teachers’ Burnout
Authors: Squillaci Myriam , Hofmann Verena
Published: May 2021

Over the last two decades, the nature of teachers' work has undergone significant structural changes due to political, social, organizational, technological, and philosophical factors. With the development of inclusive policies, the roles and functions of special education teachers (SETs) have evolved over the years. Inclusive work in general classrooms is often seen as a source of stress for SETs as they may have less autonomy at work, and more complex collaboration than their peers working in special classes. This stress can lead to a burnout syndrome, which is characterized by emotional exhaustion, depersonalization and a lack of personal accomplishment. Less is known about the effects of teaching contexts on the SETs’ health. Therefore, this study aimed to compare the perceived health of a sample of SETs in Switzerland (N = 306) working in inclusive contexts (n = 79) with those working in non-inclusive contexts (n = 227). The sample filled out a self-reported questionnaire measuring personal variables, burnout at work with the Maslach Burnout Inventory, and collaborative variables with the School Quality Survey. Research results show three main findings. 1. Differences in perceived health at work are not significant between the two subgroups. 2. The two subsamples are not exhausted or depersonalized, but present a reduced personal achievement. 3. The collaboration-related variables exert different effects on the three burnout dimensions.
Nuclear Magnetic Resonance Derived Biomarkers for Evaluating Cardiometabolic Risk in Youth and Young Adults Across the Spectrum of Glucose Tolerance
Authors: Chung Stephanie T. , Matta Samantha T. , Meyers Abby G. , Cravalho Celeste K. , Villalobos-Perez Alfredo , Dawson Joshua M. , Sharma Vandhna R. , Sampson Maureen L. , Otvos James D. , Magge Sheela N.
Published: May 2021

Youth with obesity have an increased risk for cardiometabolic disease, but identifying those at highest risk remains a challenge. Four biomarkers that might serve this purpose are “by products” of clinical NMR LipoProfile® lipid testing: LPIR (Lipoprotein Insulin Resistance Index), GlycA (inflammation marker), BCAA (total branched-chain amino acids), and glycine. All are strongly related to insulin resistance and type 2 diabetes (T2DM) in adults (glycine inversely) and are independent of biological and methodological variations in insulin assays. However, their clinical utility in youth is unclear. We compared fasting levels of these biomarkers in 186 youth (42 lean normal glucose tolerant (NGT), 88 obese NGT, 23 with prediabetes (PreDM), and 33 with T2DM. All four biomarkers were associated with obesity and glycemia in youth. LPIR and GlycA were highest in youth with PreDM and T2DM, whereas glycine was lowest in youth with T2DM. While all four were correlated with HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), LPIR had the strongest correlation (LPIR: r = 0.6; GlycA: r = 0.4, glycine: r = −0.4, BCAA: r = 0.2, all P < 0.01). All four markers correlated with HbA1c (LPIR, GlycA, BCAA: r ≥ 0.3 and glycine: r = −0.3, all P < 0.001). In multi-variable regression models, LPIR, GlycA, and glycine were independently associated with HOMA-IR (Adjusted R2 = 0.473, P < 0.001) and LPIR, glycine, and BCAA were independently associated with HbA1c (Adjusted R2 = 0.33, P < 0.001). An LPIR index of >44 was associated with elevated blood pressure, BMI, and dyslipidemia. Plasma NMR-derived markers were related to adverse markers of cardiometabolic risk in youth. LPIR, either alone or in combination with GlycA, should be explored as a non-insulin dependent predictive tool for development of insulin resistance and diabetes in youth.

Clinical Trial Registration

Clinicaltrials.gov, identifier NCT:02960659
Sex-Bias in Irritable Bowel Syndrome: Linking Steroids to the Gut-Brain Axis
Authors: So Sik Yu , Savidge Tor C.
Published: May 2021

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that is more common in females. Despite its high global incidence, the disease mechanism is still unclear and therapeutic options remain limited. The sexual dimorphism in IBS incidence suggests that sex steroids play a role in disease onset and symptoms severity. This review considers sex steroids and their involvement in IBS symptoms and the underlying disease mechanisms. Estrogens and androgens play important regulatory roles in IBS symptomology, including visceral sensitivity, gut motility and psychological conditions, possibly through modulating the gut-brain axis. Steroids are regulators of hypothalamic-pituitary-adrenal activity and autonomic nervous system function. They also modulate gut microbiota and enteric nervous systems, impacting serotonin and mast cell signaling. Sex steroids also facilitate bidirectional cross-talk between the microbiota and host following bacterial transformation and recycling of steroids by the intestine. The sex-specific interplay between sex steroids and the host provides neuroendocrinology insight into the pathophysiology, epigenetics and treatment of IBS patients.
DNA Methylation, Deamination, and Translesion Synthesis Combine to Generate Footprint Mutations in Cancer Driver Genes in B-Cell Derived Lymphomas and Other Cancers
Authors: Rogozin Igor B. , Roche-Lima Abiel , Tyryshkin Kathrin , Carrasquillo-Carrión Kelvin , Lada Artem G. , Poliakov Lennard Y. , Schwartz Elena , Saura Andreu , Yurchenko Vyacheslav , Cooper David N. , Panchenko Anna R. , Pavlov Youri I.
Published: May 2021

Cancer genomes harbor numerous genomic alterations and many cancers accumulate thousands of nucleotide sequence variations. A prominent fraction of these mutations arises as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases followed by the replication/repair of edited sites by DNA polymerases (pol), as deduced from the analysis of the DNA sequence context of mutations in different tumor tissues. We have used the weight matrix (sequence profile) approach to analyze mutagenesis due to Activation Induced Deaminase (AID) and two error-prone DNA polymerases. Control experiments using shuffled weight matrices and somatic mutations in immunoglobulin genes confirmed the power of this method. Analysis of somatic mutations in various cancers suggested that AID and DNA polymerases η and θ contribute to mutagenesis in contexts that almost universally correlate with the context of mutations in A:T and G:C sites during the affinity maturation of immunoglobulin genes. Previously, we demonstrated that AID contributes to mutagenesis in (de)methylated genomic DNA in various cancers. Our current analysis of methylation data from malignant lymphomas suggests that driver genes are subject to different (de)methylation processes than non-driver genes and, in addition to AID, the activity of pols η and θ contributes to the establishment of methylation-dependent mutation profiles. This may reflect the functional importance of interplay between mutagenesis in cancer and (de)methylation processes in different groups of genes. The resulting changes in CpG methylation levels and chromatin modifications are likely to cause changes in the expression levels of driver genes that may affect cancer initiation and/or progression.
A Profound Membrane Reorganization Defines Susceptibility of Plasmodium falciparum Infected Red Blood Cells to Lysis by Granulysin and Perforin
Authors: Hernández-Castañeda Maria Andrea , Lavergne Marilyne , Casanova Pierina , Nydegger Bryan , Merten Carla , Subramanian Bibin Yesodha , Matthey Patricia , Lannes Nils , Mantel Pierre-Yves , Walch Michael
Published: May 2021

Malaria remains one of the most serious health problems in developing countries. The causative agent of malaria,Plasmodiumspp., have a complex life cycle involving multiple developmental stages as well as different morphological, biochemical and metabolic requirements. We recently found that γδ T cells control parasite growth using pore-forming proteins to deliver their cytotoxic proteases, the granzymes, into blood residing parasites. Here, we follow up on the molecular mechanisms of parasite growth inhibition by human pore-forming proteins. We confirm thatPlasmodium falciparuminfection efficiently depletes the red blood cells of cholesterol, which renders the parasite surrounding membranes susceptible to lysis by prokaryotic membrane disrupting proteins, such as lymphocytic granulysin or the human cathelicidin LL-37. Interestingly, not the cholesterol depletion but rather the simultaneous exposure of phosphatidylserine, a negatively charged phospholipid, triggers resistance of late stage parasitized red blood cells towards the eukaryotic pore forming protein perforin. Overall, by revealing the molecular events we establish here a pathogen-host interaction that involves host cell membrane remodeling that defines the susceptibility towards cytolytic molecules.
The Expression of Chemokines Is Downregulated in a Pre-Clinical Model of TTR V30M Amyloidosis
Authors: Moreira João , Costelha Susete , Saraiva Margarida , Saraiva Maria João
Published: May 2021

Inflammation is a hallmark of several neurodegenerative disorders including hereditary amyloidogenic transthyretin amyloidosis (ATTRv). ATTRv is an autosomal dominant neurodegenerative disorder with extracellular deposition of mutant transthyretin (TTR) aggregates and fibrils, particularly in nerves and ganglia of the peripheral nervous system. Nerve biopsies from ATTRv patients show increased cytokine production, but interestingly no immune inflammatory cellular infiltrate is observed around TTR aggregates. Here we show that as compared to Wild Type (WT) animals, the expression of several chemokines is highly downregulated in the peripheral nervous system of a mouse model of the disease. Interestingly, we found that stimulation of mouse Schwann cells (SCs) with WT TTR results in the secretion of several chemokines, a process that is mediated by toll-like receptor 4 (TLR4). In contrast, the secretion of all tested chemokines is compromised upon stimulation of SCs with mutant TTR (V30M), suggesting that V30M TTR fails to activate TLR4 signaling. Altogether, our data shed light into a previously unappreciated mechanism linking TTR activation of SCs and possibly underlying the lack of inflammatory response observed in the peripheral nervous system of ATTRv patients.
Development of ESAT-6 Based Immunosensor for the Detection of Mycobacterium tuberculosis
Authors: Omar Rishabh Anand , Verma Nishith , Arora Pankaj Kumar
Published: May 2021

Early secreted antigenic target of 6 kDa (ESAT-6) has recently been identified as a biomarker for the rapid diagnosis of tuberculosis. We propose a stable and reusable immunosensor for the early diagnosis of tuberculosis based on the detection and quantification of ESAT-6 via cyclic voltammetry (CV). The immunosensor was synthesized by polymerizing aniline dispersed with the reduced graphene oxide (rGO) and Ni nanoparticles, followed by surface modification of the electroconductive polyaniline (PANI) film with anti-ESAT-6 antibody. Physicochemical characterization of the prepared materials was performed by several analytical techniques, including FE-SEM, EDX, XRD, FT-IR, Raman, TGA, TPR, and BET surface area analysis. The antibody-modified Ni-rGO-PANI electrode exhibited an approximately linear response (R2 = 0.988) towards ESAT-6 during CV measurements over the potential range of -1 to +1 V. The lower detection limit for ESAT-6 was approximately 1.0 ng mL-1. The novelty of this study includes the development of the reusable Ni-rGO-PANI-based electrochemical immunosensor for the early diagnosis of tuberculosis. Furthermore, this study successfully demonstrates that electro-conductive PANI may be used as a polymeric substrate for Ni nanoparticles and rGO.
A Sensitive Whole Blood Assay Detects Antigen-Stimulated Cytokine Release From CD4+ T Cells and Facilitates Immunomonitoring in a Phase 2 Clinical Trial of Nexvax2 in Coeliac Disease
Authors: Hardy Melinda Y. , Goel Gautam , Russell Amy K. , Chen Yi Mei Swee Lin G. , Brown Gregor J. E. , Wang Suyue , Szymczak Evan , Zhang Ruan , Goldstein Kaela E. , Neff Kristin M. , Williams Leslie J. , Truitt Kenneth E. , Dzuris John L. , Tye-Din Jason A. , Anderson Robert P.
Published: May 2021

Improved blood tests assessing the functional status of rare gluten-specific CD4+ T cells are needed to effectively monitor experimental therapies for coeliac disease (CD). Our aim was to develop a simple, but highly sensitive cytokine release assay (CRA) for gluten-specific CD4+ T cells that did not require patients to undergo a prior gluten challenge, and would be practical in large, multi-centre clinical trials. We developed an enhanced CRA and used it in a phase 2 clinical trial (“RESET CeD”) of Nexvax2, a peptide-based immunotherapy for CD. Two participants with treated CD were assessed in a pilot study prior to and six days after a 3-day gluten challenge. Dye-dilution proliferation in peripheral blood mononuclear cells (PBMC) was assessed, and IL-2, IFN-γ and IL-10 were measured by multiplex electrochemiluminescence immunoassay (ECL) after 24-hour gluten-peptide stimulation of whole blood or matched PBMC. Subsequently, gluten-specific CD4+ T cells in blood were assessed in a subgroup of the RESET CeD Study participants who received Nexvax2 (maintenance dose 900 μg, n = 12) or placebo (n = 9). The pilot study showed that gluten peptides induced IL-2, IFN-γ and IL-10 release from PBMCs attributable to CD4+ T cells, but the PBMC CRA was substantially less sensitive than whole blood CRA. Only modest gluten peptide-stimulated IL-2 release could be detected without prior gluten challenge using PBMC. In contrast, whole blood CRA enabled detection of IL-2 and IFN-γ before and after gluten challenge. IL-2 and IFN-γ release in whole blood required more than 6 hours incubation. Delay in whole blood incubation of more than three hours from collection substantially reduced antigen-stimulated IL-2 and IFN-γ secretion. Nexvax2, but not placebo treatment in the RESET CeD Study was associated with significant reductions in gluten peptide-stimulated whole blood IL-2 and IFN-γ release, and CD4+ T cell proliferation. We conclude that using fresh whole blood instead of PBMC substantially enhances cytokine secretion stimulated by gluten peptides, and enables assessment of rare gluten-specific CD4+ T cells without requiring CD patients to undertake a gluten challenge. Whole blood assessment coupled with ultra-sensitive cytokine detection shows promise in the monitoring of rare antigen-specific T cells in clinical studies.
A Clinical Perspective on the Dietary Therapies for Pediatric Eosinophilic Esophagitis: The Gap Between Research and Daily Practice
Authors: De Vlieger Liselot , Smolders Lieselot , Nuyttens Lisa , Verelst Sophie , Breynaert Christine , Vanuytsel Tim , Hoffman Ilse , Bullens Dominique MA
Published: May 2021

Pediatric eosinophilic esophagitis (ped-EoE) is an immune-mediated pathology affecting 34 per 100.000 children. It is characterized by an esophageal inflammation caused by an immune response towards food antigens that come into contact with the esophageal lining. Depending on the age of the child, symptoms can vary from abdominal pain, vomiting and failure to thrive to dysphagia and food impaction. The diagnosis of this chronic disease is based on the symptoms of esophageal dysfunction combined with an infiltration of more than 15 eosinophils per high-power field and the exclusion of secondary causes. The treatment modalities include the 3Ds: Drugs, allergen avoidance by Diet and/or esophageal Dilation. In this review we focused on the efficacy of dietary approaches in ped-EoE, which currently include the elemental diet (amino acid-based diet), the empiric elimination diet and the allergy test-directed elimination diet. Although several reviews have summarized these dietary approaches, a lack of consistency between and within the elimination diets hampers its clinical use and differences in subsequent reintroduction phases present a barrier for dietary advice in daily clinical practice. We therefore conducted an analysis driven from a clinician’s perspective on these dietary therapies in the management of ped-EoE, whereby we examined whether these variations within dietary approaches, yet considered to be similar, could result in significant differences in dietary counseling.
Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets
Authors: Al-Jaberi Fatima A. H. , Kongsbak-Wismann Martin , Aguayo-Orozco Alejandro , Krogh Nicolai , Buus Terkild B. , Lopez Daniel V. , Rode Anna K. O. , Gravesen Eva , Olgaard Klaus , Brunak Søren , Woetmann Anders , Ødum Niels , Bonefeld Charlotte M. , Geisler Carsten
Published: May 2021

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH)2D3 signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)2D3 and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH)2D3-induced gene regulation was reduced by ~ 50% indicating that the expression level of wild-type VDR determines 1,25(OH)2D3 responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH)2D3-induced translocation of the VDR to the nucleus and 1,25(OH)2D3-induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.
Investigating the Impact of Cerium Oxide Nanoparticles Upon the Ecologically Significant Marine Cyanobacterium Prochlorococcus
Authors: Dedman Craig J. , Rizk Marwa M. I. , Christie-Oleza Joseph A. , Davies Gemma-Louise
Published: May 2021

Cerium oxide nanoparticles (nCeO2) are used at an ever-increasing rate, however, their impact within the aquatic environment remains uncertain. Here, we expose the ecologically significant marine cyanobacterium Prochlorococcus sp. MED4 to nCeO2 at a wide range of concentrations (1 μg L–1 to 100 mg L–1) under simulated natural and nutrient rich growth conditions. Flow cytometric analysis of cyanobacterial populations displays the potential of nCeO2 (100 μg L–1) to significantly reduce Prochlorococcus cell density in the short-term (72 h) by up to 68.8% under environmentally relevant conditions. However, following longer exposure (240 h) cyanobacterial populations are observed to recover under simulated natural conditions. In contrast, cell-dense cultures grown under optimal conditions appear more sensitive to exposure during extended incubation, likely as a result of increased rate of encounter between cyanobacteria and nanoparticles at high cell densities. Exposure to supra-environmental nCeO2 concentrations (i.e., 100 mg L–1) resulted in significant declines in cell density up to 95.7 and 82.7% in natural oligotrophic seawater and nutrient enriched media, respectively. Observed cell decline is associated with extensive aggregation behaviour of nCeO2 upon entry into natural seawater, as observed by dynamic light scattering (DLS), and hetero-aggregation with cyanobacteria, confirmed by fluorescent microscopy. Hence, the reduction of planktonic cells is believed to result from physical removal due to co-aggregation and co-sedimentation with nCeO2 rather than by a toxicological and cell death effect. The observed recovery of the cyanobacterial population under simulated natural conditions, and likely reduction in nCeO2 bioavailability as nanoparticles aggregate and undergo sedimentation in saline media, means that the likely environmental risk of nCeO2 in the marine environment appears low.
Phenotypic and Multi-Omics Characterization of Escherichia coli K-12 Adapted to Chlorhexidine Identifies the Role of MlaA and Other Cell Envelope Alterations Regulated by Stress Inducible Pathways in CHX Resistance
Authors: Gregorchuk Branden S. J. , Reimer Shelby L. , Green Kari A. C. , Cartwright Nicola H. , Beniac Daniel R. , Hiebert Shannon L. , Booth Timothy F. , Chong Patrick M. , Westmacott Garrett R. , Zhanel George G. , Bay Denice C.
Published: May 2021

Chlorhexidine (CHX) is an essential medicine used as a topical antiseptic in skin and oral healthcare treatments. The widespread use of CHX has increased concerns regarding the development of antiseptic resistance in Enterobacteria and its potential impact on cross-resistance to other antimicrobials. Similar to other cationic antiseptics, resistance to CHX is believed to be driven by three membrane-based mechanisms: lipid synthesis/transport, altered porin expression, and increased efflux pump activity; however, specific gene and protein alterations associated with CHX resistance remain unclear. Here, we adapted Escherichia coli K-12 BW25113 to increasing concentrations of CHX to determine what phenotypic, morphological, genomic, transcriptomic, and proteomic changes occurred. We found that CHX-adapted E. coli isolates possessed no cross-resistance to any other antimicrobials we tested. Scanning electron microscopy imaging revealed that CHX adaptation significantly altered mean cell widths and lengths. Proteomic analyses identified changes in the abundance of porin OmpF, lipid synthesis/transporter MlaA, and efflux pump MdfA. Proteomic and transcriptomic analyses identified that CHX adaptation altered E. coli transcripts and proteins controlling acid resistance (gadE, cdaR) and antimicrobial stress-inducible pathways Mar-Sox-Rob, stringent response systems. Whole genome sequencing analyses revealed that all CHX-resistant isolates had single nucleotide variants in the retrograde lipid transporter gene mlaA as well as the yghQ gene associated with lipid A transport and synthesis. CHX resistant phenotypes were reversible only when complemented with a functional copy of the mlaA gene. Our results highlight the importance of retrograde phospholipid transport and stress response systems in CHX resistance and the consequences of prolonged CHX exposure.
Low Expression of RILPL2 Predicts Poor Prognosis and Correlates With Immune Infiltration in Endometrial Carcinoma
Authors: Liu Jinhui , Xu Mengting , Wu Zhipeng , Yang Yan , Yuan Shuning , Liang Jianqiang , Zhu Hongjun
Published: May 2021

Increasing numbers of biomarkers have been identified in various cancers. However, biomarkers associated with endometrial carcinoma (EC) remain largely to be explored. In the current research, we downloaded the RNA-seq data and corresponding clinicopathological features from the Cancer Genome Atlas (TCGA) database. We conducted an expression analysis, which resulted in RILPL2 as a novel diagnostic biomarker in EC. The dysregulation of RILPL2 in EC was also validated in multiple datasets. The correlations between clinical features and RILPL2 expression were assessed by logistic regression analysis. Then, Kaplan-Meier analysis, univariate and multivariate Cox regression analysis were performed to estimate prognostic values of RILPL2 in the TCGA cohort, which revealed that increased level of RILPL2 was remarkably associated with better prognosis and could act as an independent prognostic biomarker in patients with EC. Moreover, correlation analysis of RILPL2 and tumor-infiltrating immune cells (TIICs) indicated that RILPL2 might play a critical role in regulating immune cell infiltration in EC and is related to immune response. Besides, high methylation level was a significant cause of low RILPL2 expression in EC. Subsequently, weighted gene co-expression network analysis (WGCNA) and enrichment analysis were conducted to explore the RILPL2-involved underlying oncogenic mechanisms, and the results indicated that RILPL2 mainly regulated cell cycle. In conclusion, our findings provided evidence that downregulation of RILPL2 in EC is an indicator of adverse prognosis and RILPL2 may act as a promising target for the therapeutics of EC.
Wastewater Remediation Technologies Using Macroscopic Graphene-Based Materials: A Perspective
Authors: Hirani Rajan Arjan Kalyan , Asif Abdul Hannan , Rafique Nasir , Shi Lei , Zhang Shu , Wu Hong , Sun Hongqi
Published: May 2021

Three-dimensional (3D) graphene-based macrostructures are being developed to combat the issues associated with two-dimensional (2D) graphene materials in practical applications. The 3D macrostructures (3DMs), for example, membranes, fibres, sponges, beads, and mats, can be formed by the self-assembly of 2D graphene-based precursors with exceptional surface area and unique chemistry. With rational design, the 3D macrostructures can then possess outstanding properties and exclusive structures. Thanks to various advantages, these macrostructures are competing in a variety of applications with promising performances unlike the traditional activated carbons, biochars and hydrochars, which have less flexibilities for modifications towards versatile applications. However, despite having such a wide range of applications, 3DMs remain applicable on laboratory scale due to the associated factors like cost and extensive research. This perspective provides an overview of available graphene-based macrostructures and their diverse synthesis protocols. In the synthesis, hydrothermal route, chemical vapor deposition (CVD), wet spinning, 3D printing, vacuum filtration, spray drying and emulsion methods are highlighted. In addition, the physio-chemical properties of these macrostructures are discussed with the relationship among the porosity, surface area and the bulk density. The perspective also highlights the versatile potentials of different 3DMs in wastewater remediation by adsorption, desalination, and catalytic oxidation, etc. Following the concluding remarks, future outlooks on commercial applications of 3DMs are also provided.
Topographic Quadrant Analysis of Peripapillary Superficial Microvasculature in Optic Disc Drusen
Authors: Yan Yan , Zhou Xiao , Chu Zhongdi , Stell Laurel , Shariati Mohammad Ali , Wang Ruikang K. , Liao Yaping Joyce
Published: May 2021

Background: Limited information is known about the topographic effect of optic disc drusen (ODD) on peripapillary retinal nerve fibers and microvasculature.

Objective: This study aims to understand the structural and functional impact of ODD in different quadrants of the optic disc.

Methods: We performed a retrospective case-control study of 22 ODD patients (34 eyes) and 26 controls (33 eyes) to compare optical coherence tomography (OCT) retinal nerve fiber layer (RNFL), OCT angiography (OCTA), and corresponding static perimetry mean deviation (MD) calculated using the modified Garway-Heath map in different quadrants of the optic disc. OCTA was analyzed using custom MATLAB script to measure six parameters in a peripapillary annulus with large vessel removal: vessel area density (VAD), vessel skeleton density (VSD), vessel perimeter index (VPI), vessel complexity index (VCI), flux, and vessel diameter index (VDI).

Results: Quadrant analysis revealed that OCTA VAD and VCI were significantly decreased in superior, nasal, and inferior but not temporal quadrant. RNFL, VSD, and VPI were significantly impacted only in the superior and nasal quadrants. Corresponding visual field MDs in all ODD eyes were not different in the four quadrants, although eyes with MD equal or worse than −5 dB (32%) had worst visual field corresponding to the superior quadrant of the optic disc (inferior arcuate visual field). Structure-structure comparison of OCT and OCTA showed high correlation of RNFL with multiple OCTA measurements in the superior, nasal, and inferior quadrants but not temporal quadrant. Structure-function analysis revealed significant correlation of VAD and VCI and visual field MD in every quadrant, but RNFL was only significantly correlated in the superior and inferior quadrants.

Conclusions: Peripapillary VAD and VCI are decreased in more quadrants than RNFL, supporting the clinical utility of performing OCTA in addition to OCT. Consistent with the most common locations of ODD, five OCT/OCTA measurements (VAD, VCI, RNFL, VSD, VPI) are decreased in the superior and nasal quadrants. OCT/OCTA measurements were significantly impacted in contrast to the relatively mild effect on corresponding visual field MD, consistent with the idea that a decrease in objective structural and vascular measurements occurs without parallel change in subjective visual function in ODD.
Insights on the Relationship Between Hippocampal Connectivity and Memory Performances at the Early Stage of Multiple Sclerosis
Authors: Boscheron Juliette , Ruet Aurélie , Deloire Mathilde , Charré-Morin Julie , Saubusse Aurore , Brochet Bruno , Tourdias Thomas , Koubiyr Ismail
Published: May 2021

While memory impairment in multiple sclerosis (MS) is known to be associated with hippocampal alterations, whether hippocampal networks could dynamically reorganize as a compensation mechanism is still a matter of debate. In this context, our aim was to identify the patterns of structural and functional connectivity between the hippocampus and the rest of the brain and their possible relevance to memory performances in early MS. Thirty-two patients with a first episode suggestive of MS together with 10 matched healthy controls were prospectively explored at baseline, 1 and 5 years follow up. They were scanned with MRI and underwent a neuropsychological battery of tests that included the Selective Reminding Test and the Brief Visual Memory Test Revised to assess verbal and visuo-spatial memory, respectively. Hippocampal volume was computed together with four graph theory metrics to study the structural and functional connectivity of both hippocampi with the rest of the brain. Associations between network parameters and memory performances were assessed using linear mixed-effects (LME) models. Considering cognitive abilities, verbal memory performances of patients decreased over time while visuo-spatial memory performances were maintained. In parallel, hippocampal volumes decreased significantly while structural and functional connectivity metrics were modified, with an increase in hippocampal connections over time. More precisely, these modifications were indicating a reinforcement of hippocampal short-distance connections. LME models revealed that the drop in verbal memory performances was associated with hippocampal volume loss, while the preservation of visuo-spatial memory performances was linked to decreased hippocampal functional shortest path length. In conclusion, we demonstrated a differential impairment in memory performances in the early stages of MS and an important interplay between hippocampal-related structural and functional networks and those performances. As the structural damage increases, functional reorganization seems to be able to maintain visuo-spatial memory performances with strengthened short-distance connections.
Thermal and Acidic Treatments of Gluten Epitopes Affect Their Recognition by HLA-DQ2 in silico
Authors: Gao Jihui , Du Haolan , Zhou Zekun , Liang Zhongxin , Liang Hongrui , Zhang PeiAo , Wei Xue , Liu Shujun , Fu Linglin , Wang Yanbo , Che Huilian , Xue Wentong , Xin Fengjiao , Yang Dong
Published: May 2021

Celiac disease (CD) is a prevalent disorder with autoimmune features. Dietary exposure of wheat gluten (including gliadins and glutenins) to the small intestine activates the gluten-reactive CD4+ T cells and controls the disease development. While the human leukocyte antigen (HLA) is the single most important genetic factor of this polygenic disorder, HLA-DQ2 recognition of gluten is the major biological step among patients with CD. Gluten epitopes are often rich in Pro and share similar primary sequences. Here, we simulated the solution structures changes of a variety of gluten epitopes under different pH and temperatures, to mimic the fermentation and baking/cooking processes. Based on the crystal structure of HLA-DQ2, binding of differently processed gluten epitopes to DQ2 was studied in silico. This study revealed that heating and pH change during the fermentation process impact the solution structure of gluten epitope. However, binding of differently treated gluten epitope peptide (GEP) to HLA-DQ2 mainly depended on its primary amino acid sequence, especially acidic amino acid residues that play a pivotal role in their recognition by HLA-DQ2.
FUT8-AS1 Inhibits the Malignancy of Melanoma Through Promoting miR-145-5p Biogenesis and Suppressing NRAS/MAPK Signaling
Authors: Chen Xiang-jun , Liu Sha , Han Dong-mei , Han De-zhi , Sun Wei-jing , Zhao Xiao-chun , Liang Jun-qing , Yu Li
Published: May 2021

Melanoma is the major lethal skin malignancy. However, the critical molecular drivers governing melanoma progression and prognosis are still not clear. By analyzing The Cancer Genome Atlas (TCGA) data, we identified FUT8-AS1 as a prognosis-related long non-coding RNA (lncRNA) in melanoma. We further confirmed that FUT8-AS1 is downregulated in melanoma. Reduced expression of FUT8-AS1 is correlated with aggressive clinical factors and inferior overall survival. Using in vitro functional assays, our findings demonstrated that ectopic expression of FUT8-AS1 represses melanoma cell proliferation, migration, and invasion. FUT8-AS1 silencing promotes melanoma cell proliferation, migration, and invasion. Furthermore, in vivo functional assays demonstrated that FUT8-AS1 represses melanoma growth and metastasis. Mechanistically, FUT8-AS1 was found to bind NF90, repress the interaction between NF90 and primary miR-145 (pri-miR-145), relieve the repressive roles of NF90 on mature miR-145-5p biogenesis, and thus promote miR-145-5p biogenesis and upregulate mature miR-145-5p level. The expression of FUT8-AS1 is positively correlated with miR-145-5p in melanoma tissues. Via upregulating miR-145-5p, FUT8-AS1 reduces the expression of NRAS, a target of miR-145-5. FUT8-AS1 further represses MAPK signaling via downregulating NRAS. Functional rescue assays demonstrated that inhibition of miR-145-5p reverses the tumor suppressive roles of FUT8-AS1 in melanoma. The oncogenic roles of FUT8-AS1 silencing are also blocked by MAPK signaling inhibitor MEK162. In conclusion, these findings demonstrate that FUT8-AS1 exerts tumor suppressive roles in melanoma via regulating NF90/miR-145-5p/NRAS/MAPK signaling axis. Targeting FUT8-AS1 and its downstream molecular signaling axis represent promising therapeutic strategies for melanoma.
Dysregulation of Transcription Factor Networks Unveils Different Pathways in Human Papillomavirus 16-Positive Squamous Cell Carcinoma and Adenocarcinoma of the Uterine Cervix
Authors: Bispo Saloe , Farias Ticiana D. J. , de Araujo-Souza Patricia Savio , Cintra Ricardo , Santos Hellen Geremias dos , Jorge Natasha Andressa Nogueira , Castro Mauro Antônio Alves , Wajnberg Gabriel , Scherer Nicole de Miranda , Genta Maria Luiza Nogueira Dias , Carvalho Jesus Paula , Villa Luisa Lina , Sichero Laura , Passetti Fabio
Published: May 2021

Squamous cell carcinoma (SCC) and adenocarcinoma (ADC) are the most common histological types of cervical cancer (CC). The worse prognosis of ADC cases highlights the need for better molecular characterization regarding differences between these CC types. RNA-Seq analysis of seven SCC and three ADC human papillomavirus 16-positive samples and the comparison with public data from non-tumoral human papillomavirus-negative cervical tissue samples revealed pathways exclusive to each histological type, such as the epithelial maintenance in SCC and the maturity-onset diabetes of the young (MODY) pathway in ADC. The transcriptional regulatory network analysis of cervical SCC samples unveiled a set of six transcription factor (TF) genes with the potential to positively regulate long non-coding RNA genes DSG1-AS1, CALML3-AS1, IGFL2-AS1, and TINCR. Additional analysis revealed a set of MODY TFs regulated in the sequence predicted to be repressed by miR-96-5p or miR-28-3p in ADC. These microRNAs were previously described to target LINC02381, which was predicted to be positively regulated by two MODY TFs upregulated in cervical ADC. Therefore, we hypothesize LINC02381 might act by decreasing the levels of miR-96-5p and miR-28-3p, promoting the MODY activation in cervical ADC. The novel TF networks here described should be explored for the development of more efficient diagnostic tools.
A Model Combining Skeletal Muscle Mass and a Hematological Biomarker to Predict Survival in Patients With Nasopharyngeal Carcinoma Undergoing Concurrent Chemoradiotherapy
Authors: Huang Han-Ying , Lin Fei , Chen Xiao-Yu , Wen Wen , Xie Shuang-Yan , Long Zhi-Qing , Guo Ling , Lin Huan-Xin
Published: May 2021

Background

Using the current tumor lymph node metastasis (TNM) staging system to make treatment decisions and predict survival in patients with nasopharyngeal carcinoma (NPC) lacks sufficient accuracy. Patients at the same stage often have different survival prognoses.

Methods

In the current study 802 NPC patients who underwent concurrent radiotherapy and chemotherapy from January 2010 to December 2014 at Sun Yat-sen University Cancer Center in China were retrospectively assessed. The optimal cut-off points for skeletal muscle index (SMI) and monocyte-to-lymphocyte ratio (MLR) were determined via receiver operating characteristic curves. SMI-MLR (S-M) grade and a nomogram were developed and used as clinical indicators in NPC patients. The consistency index (C-index) and a calibration curve were used to measure the accuracy and discriminative capacity of prediction.

Results

The predictive performance of S-M grade was better than that of TNM staging (C-index 0.639, range 0.578–0.701 vs. 0.605, range 0.545–0.665; p = 0.037). In multivariate analysis S-M grade, T stage, and N stage were independent prognostic factors. These three factors were then combined, yielding a nomogram with a C-index of 0.71 (range 0.64–0.77), indicating good predictive capacity.

Conclusion

We developed and validated a prognostic parameter, S-M grade, which increased prediction accuracy significantly and can be combined with TNM staging to predict survival in patients with NPC undergoing concurrent chemoradiotherapy.
Arterial Spin Labeling MRI for Predicting Microvascular Invasion of T1 Staging Renal Clear Cell Carcinoma Preoperatively
Authors: Zhang Han-Mei , Wen Da-Guang , Wang Yi , Bao Yi-Ge , Yuan Yuan , Chen Yun-Tian , Song Bin
Published: May 2021

Background

Microvascular invasion (MVI) is a valuable factor for T1 staging renal clear cell carcinoma (ccRCC) operation strategy decision, which is confirmed histopathologically post-operation. This study aimed to prospectively evaluate the performance of arterial spin labeling (ASL) MRI for predicting MVI of T1 staging ccRCC preoperatively.

Methods

16 volunteers and 39 consecutive patients were enrolled. MRI examinations consisted of ASL (three post label delays separately) of the kidney, followed by T1 and T2-weighted imaging. Two sessions of ASL were used to evaluate the reproducibility on volunteers. Renal blood flow of renal cortex, medulla, the entire and solid part of the tumor were measured on ASL images. Conventional imaging features were extracted. MVI and WHO/ISUP classification were evaluated histopathologically. A paired t‐test was used to compare the renal cortex and medulla between ASL 1 and ASL 2. The reproducibility was assessed using the intraclass correlation. Differences in mean perfusion between the entire and the solid parts of tumors with or without MVI were assessed separately using Student’s t test. The diagnostic performance was assessed. Logistic regression analysis was used to indicate the independent prediction index for MVI.

Results

The two sessions of ASL showed no significant difference between the mean cortex values of RBF. The cortical RBF measurements demonstrated good agreement. 12 ccRCCs presented with MVI histopathologically. Mean perfusion of the solid part of tumors with MVI were 536.4 ± 154.8 ml/min/100 g (PLD1), 2912.5 ± 939.3 ml/min/100 g (PLD2), 3280.3 ± 901.2 ml/min/100 g (PLD3). Mean perfusion of the solid part of tumors without MVI were 453.5 ± 87.2 ml/min/100 g (PLD1), 1043.6 ± 695.8 ml/min/100 g (PLD2), 1577.6 ± 1085.8 ml/min/100 g (PLD3). These two groups have significant difference at all the PLDs (p < 0.05). The RBF of PLD1 of the solid part of tumor perfusion showed well diagnostic performance for predicting MVI: sensitivity 75%, specificity 100%, positive predictive value 66.7%, and negative predictive value 95.7%. The maximum diameter of the tumor, ill-defined margin, and the solid part of tumor perfusion were the independent prediction index for MVI.

Conclusion

ASL MR imaging has good reproducibility for renal cortex, and good diagnostic performance for predicting MVI for ccRCC.
Intraoperative B-Mode Ultrasound Guided Surgery and the Extent of Glioblastoma Resection: A Randomized Controlled Trial
Authors: Incekara Fatih , Smits Marion , Dirven Linda , Bos Eelke M. , Balvers Rutger K. , Haitsma Iain K. , Schouten Joost W. , Vincent Arnaud J. P. E.
Published: May 2021

Background

Intraoperative MRI and 5-aminolaevulinic acid guided surgery are useful to maximize the extent of glioblastoma resection. Intraoperative ultrasound is used as a time-and cost-effective alternative, but its value has never been assessed in a trial. The goal of this randomized controlled trial was to assess the value of intraoperative B-mode ultrasound guided surgery on the extent of glioblastoma resection.

Materials and Methods

In this randomized controlled trial, patients of 18 years or older with a newly diagnosed presumed glioblastoma, deemed totally resectable, presenting at the Erasmus MC (Rotterdam, The Netherlands) were enrolled and randomized (1:1) into intraoperative B-mode ultrasound guided surgery or resection under standard neuronavigation. The primary outcome of this study was complete contrast-enhancing tumor resection, assessed quantitatively by a blinded neuroradiologist on pre- and post-operative MRI scans. This trial was registered with ClinicalTrials.gov (NCT03531333).

Results

We enrolled 50 patients between November 1, 2016 and October 30, 2019. Analysis was done in 23 of 25 (92%) patients in the intraoperative B-mode ultrasound group and 24 of 25 (96%) patients in the standard surgery group. Eight (35%) of 23 patients in the intraoperative B-mode ultrasound group and two (8%) of 24 patients in the standard surgery group underwent complete resection (p=0.036). Baseline characteristics, neurological outcome, functional performance, quality of life, complication rates, overall survival and progression-free survival did not differ between treatment groups (p>0.05).

Conclusions

Intraoperative B-mode ultrasound enables complete resection more often than standard surgery without harming patients and can be considered to maximize the extent of glioblastoma resection during surgery.
Immunophenotyping Reveals Longitudinal Changes in Circulating Immune Cells During Radium-223 Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer
Authors: Creemers Jeroen H. A. , van der Doelen Maarten J. , van Wilpe Sandra , Hermsen Rick , Duiveman-de Boer Tjitske , Somford Diederik M. , Janssen Marcel J. R. , Sedelaar J. P. Michiel , Mehra Niven , Textor Johannes , Westdorp Harm
Published: May 2021

Background

Radium-223 improves overall survival (OS) in men with bone metastatic castration-resistant prostate cancer (mCRPC). While the exact mechanism behind this survival benefit remains unclear, radium-induced immunological mechanisms might contribute to the OS advantage. We performed a comprehensive evaluation of the immunological changes in mCRPC patients by phenotyping the peripheral blood mononuclear cells (PBMCs) during radium-223 therapy.

Materials and Methods

In this prospective, single-arm, exploratory study, PBMCs of 30 mCRPC patients were collected before, during, and after treatment with radium-223. Lymphocyte and monocyte counts were analyzed to get insight into general immune cell trends. Next, we analyzed changes in T cell subsets, myeloid-derived suppressor cells (MDSCs), and immune checkpoint expression using linear regression models. Per subset, the 6-month change (% of baseline) was determined. Bootstrapped 95% confidence intervals were used to measure the degree of uncertainty of our findings.

Results

We observed a substantial decrease in absolute lymphocyte counts (-0.12 * 10^9 cells/L per injection, 95% CI: -0.143 - -0.102). Simultaneously, an increase was observed in the proportion of T cells that expressed costimulatory (ICOS) or inhibitory (TIM-3, PD-L1, and PD-1) checkpoint molecules. Moreover, the fraction of two immunosuppressive subsets – the regulatory T cells and the monocytic MDSCs – increased throughout treatment. These findings were not more pronounced in patients with an alkaline phosphatase response during therapy.

Conclusion

Immune cell subsets in patients with mCRPC changed during radium-223 therapy, which warrants further research into the possible immunological consequences of these changes.