bluuebunny/crossref_metadata_2025 huggingface dataset:
Obatoclax, a Pan-BCL-2 Inhibitor, Downregulates Survivin to Induce Apoptosis in Human Colorectal Carcinoma Cells Via Suppressing WNT/β-catenin Signaling
Authors: Or Chi-Hung R. , Huang Chiao-Wen , Chang Ching-Chin , Lai You-Chen , Chen Yi-Ju , Chang Chia-Che
Published: March 2020

Colorectal cancer (CRC) is a highly prevailing cancer and the fourth leading cause of cancer mortality worldwide. Aberrant expression of antiapoptotic BCL-2 family proteins is closely linked to neoplastic progression and chemoresistance. Obatoclax is a clinically developed drug, which binds antiapoptotic BCL-2, BCL-xL, and MCL-1 for inhibition to elicit apoptosis. Survivin is an antiapoptotic protein, whose upregulation correlates with pathogenesis, therapeutic resistance, and poor prognosis in CRC. Herein, we provide the first evidence delineating the functional linkage between Obatoclax and survivin in the context of human CRC cells. In detail, Obatoclax was found to markedly downregulate survivin. This downregulation was mainly achieved via transcriptional repression, as Obatoclax lowered the levels of both survivin mRNA and promoter activity, while blocking proteasomal degradation failed to prevent survivin from downregulation by Obatoclax. Notably, ectopic survivin expression curtailed Obatoclax-induced apoptosis and cytotoxicity, confirming an essential role of survivin downregulation in Obatoclax-elicited anti-CRC effect. Moreover, Obatoclax was found to repress hyperactive WNT/β-catenin signaling activity commonly present in human CRC cells, and, markedly, ectopic expression of dominant-active β-catenin mutant rescued the levels of survivin along with elevated cell viability. We further revealed that, depending on the cell context, Obatoclax suppresses WNT/β-catenin signaling in HCT 116 cells likely via inducing β-catenin destabilization, or by downregulating LEF1 in DLD-1 cells. Collectively, we for the first time define survivin downregulation as a novel, pro-apoptotic mechanism of Obatoclax as a consequence of Obatocalx acting as an antagonist to WNT/β-catenin signaling.
A Systematic Test of Receptor Binding Kinetics for Ligands in Tumor Necrosis Factor Superfamily by Computational Simulations
Authors: Su Zhaoqian , Wu Yinghao
Published: March 2020

Ligands in the tumor necrosis factor (TNF) superfamily are one major class of cytokines that bind to their corresponding receptors in the tumor necrosis factor receptor (TNFR) superfamily and initiate multiple intracellular signaling pathways during inflammation, tissue homeostasis, and cell differentiation. Mutations in the genes that encode TNF ligands or TNFR receptors result in a large variety of diseases. The development of therapeutic treatment for these diseases can be greatly benefitted from the knowledge on binding properties of these ligand–receptor interactions. In order to complement the limitations in the current experimental methods that measure the binding constants of TNF/TNFR interactions, we developed a new simulation strategy to computationally estimate the association and dissociation between a ligand and its receptor. We systematically tested this strategy to a comprehensive dataset that contained structures of diverse complexes between TNF ligands and their corresponding receptors in the TNFR superfamily. We demonstrated that the binding stabilities inferred from our simulation results were compatible with existing experimental data. We further compared the binding kinetics of different TNF/TNFR systems, and explored their potential functional implication. We suggest that the transient binding between ligands and cell surface receptors leads into a dynamic nature of cross-membrane signal transduction, whereas the slow but strong binding of these ligands to the soluble decoy receptors is naturally designed to fulfill their functions as inhibitors of signal activation. Therefore, our computational approach serves as a useful addition to current experimental techniques for the quantitatively comparison of interactions across different members in the TNF and TNFR superfamily. It also provides a mechanistic understanding to the functions of TNF-associated cell signaling pathways.
Comparative Root Transcriptomics Provide Insights into Drought Adaptation Strategies in Chickpea (Cicer arietinum L.)
Authors: Bhaskarla Vijay , Zinta Gaurav , Ford Rebecca , Jain Mukesh , Varshney Rajeev K. , Mantri Nitin
Published: March 2020

Drought adversely affects crop production across the globe. The root system immensely contributes to water management and the adaptability of plants to drought stress. In this study, drought-induced phenotypic and transcriptomic responses of two contrasting chickpea (Cicer arietinum L.) genotypes were compared at the vegetative, reproductive transition, and reproductive stages. At the vegetative stage, drought-tolerant genotype maintained higher root biomass, length, and surface area under drought stress as compared to sensitive genotype. However, at the reproductive stage, root length and surface area of tolerant genotype was lower but displayed higher root diameter than sensitive genotype. The shoot biomass of tolerant genotype was overall higher than the sensitive genotype under drought stress. RNA-seq analysis identified genotype- and developmental-stage specific differentially expressed genes (DEGs) in response to drought stress. At the vegetative stage, a total of 2161 and 1873 DEGs, and at reproductive stage 4109 and 3772 DEGs, were identified in the tolerant and sensitive genotypes, respectively. Gene ontology (GO) analysis revealed enrichment of biological categories related to cellular process, metabolic process, response to stimulus, response to abiotic stress, and response to hormones. Interestingly, the expression of stress-responsive transcription factors, kinases, ROS signaling and scavenging, transporters, root nodulation, and oxylipin biosynthesis genes were robustly upregulated in the tolerant genotype, possibly contributing to drought adaptation. Furthermore, activation/repression of hormone signaling and biosynthesis genes was observed. Overall, this study sheds new insights on drought tolerance mechanisms operating in roots with broader implications for chickpea improvement.
UL36 Encoded by Marek’s Disease Virus Exhibits Linkage-Specific Deubiquitinase Activity
Authors: Lin Junyan , Ai Yongxing , Zhou Hongda , Lv Yan , Wang Menghan , Xu Jiacui , Yu Cong , Zhang Huanmin , Wang Mengyun
Published: March 2020

(1) Background: Deubiquitinase (DUB) regulates various important cellular processes via reversing the protein ubiquitination. The N-terminal fragment of a giant tegument protein, UL36, encoded by the Marek’s disease (MD) virus (MDV), encompasses a putative DUB (UL36-DUB) and shares no homology with any known DUBs. The N-terminus 75 kDa fragment of UL36 exists in MD T lymphoma cells at a high level and participates in MDV pathogenicity. (2) Methods: To characterize deubiquitinating activity and substrate specificity of UL36-DUB, the UL36 N-terminal fragments, UL36(323), UL36(480), and mutants were prepared using the Bac-to-Bac system. The deubiquitinating activity and substrate specificity of these recombinant UL36-DUBs were analyzed using various ubiquitin (Ub) or ubiquitin-like (UbL) substrates and activity-based deubiquitinating enzyme probes. (3) Results: The results indicated that wild type UL36-DUBs show a different hydrolysis ability against varied types of ubiquitin chains. These wild type UL36-DUBs presented the highest activity to K11, K48, and K63 linkage Ub chains, weak activity to K6, K29, and K33 Ub chains, and no activity to K27 linkage Ub chain. UL36 has higher cleavage efficiency for K48 and K63 poly-ubiquitin than linear ubiquitin chain (M1-Ub4), but no activity on various ubiquitin-like modifiers. The mutation of C98 and H234 residues eliminated the deubiquitinating activity of UL36-DUB. D232A mutation impacted, but did not eliminated UL36(480) activity. The Ub-Br probe can bind to wild type UL36-DUB and mutants UL36(480)H234A and UL36(480)D232A, but not C98 mutants. These in vitro results suggested that the C98 and H234 are essential catalytic residues of UL36-DUB. UL36-DUB exhibited a strict substrate specificity. Inhibition assay revealed that UL36-DUB exhibits resistance to the Roche protease inhibitor cocktail and serine protease inhibitor, but not to the Solarbio protease inhibitor cocktail. (4) Conclusions: UL36-DUB exhibited a strict substrate preference, and the protocol developed in the current study for obtaining active UL36-DUB protein should promote the high-throughput screening of UL36 inhibitors and the study on the function of MDV-encoded UL36.
Using Serum Amino Acids to Predict Traumatic Brain Injury: A Systematic Approach to Utilize Multiple Biomarkers
Authors: Hajiaghamemar Marzieh , Kilbaugh Todd , Arbogast Kristy B. , Master Christina L. , Margulies Susan S.
Published: March 2020

Traumatic brain injury (TBI) can cause biochemical and metabolomic alterations in the brain tissue and serum. These alterations can be used for diagnosis and prognosis of TBI. Here, the serum concentrations of seventeen amino acids (AA) were studied for their potential utility as biomarkers of TBI. Twenty-five female, 4-week-old piglets received diffuse (n = 13) or focal (n = 12) TBI. Blood samples were obtained both pre-injury and at either 24-h or 4-days post-TBI. To find a robust panel of biomarkers, the results of focal and diffuse TBIs were combined and multivariate logistic regression analysis, coupled with the best subset selection technique and repeated k-fold cross-validation method, was used to perform a thorough search of all possible subsets of AAs. The combination of serum glycine, taurine, and ornithine was optimal for TBI diagnosis, with 80% sensitivity and 86% overall prediction rate, and showed excellent TBI diagnostic performance, with 100% sensitivity and 78% overall prediction rate, on a separate validation dataset including four uninjured and five injured animals. We found that combinations of biomarkers outperformed any single biomarker. We propose this 3-AA serum biomarker panel to diagnose mild-to-moderate focal/diffuse TBI. The systematic approaches implemented herein can be used for combining parameters from various TBI assessments to develop/evaluate optimal multi-factorial diagnostic/prognostic TBI metrics.
Integrated Transcriptomic and Un-Targeted Metabolomics Analysis Reveals Mulberry Fruit (Morus atropurpurea) in Response to Sclerotiniose Pathogen Ciboria shiraiana Infection
Authors: Bao Lijun , Gao Hongpeng , Zheng Zelin , Zhao Xiaoxiao , Zhang Minjuan , Jiao Feng , Su Chao , Qian Yonghua
Published: March 2020

Mulberry sclerotiniose caused by Ciboria shiraiana is a devastating disease of mulberry (Morus alba L.) fruit in Northwest China. At present, no disease-resistant varieties are used in production, as the molecular mechanisms of this disease are not well understood. In this study, to explore new prevention methods and provide direction for molecular breeding, transcriptomic sequencing and un-targeted metabolomics were performed on healthy (CK), early-stage diseased (HB1), and middle-stage diseased (HB2) mulberry fruits. Functional annotation, gene ontology, a Kyoto encyclopedia of genes and genomes (KEGG) analysis, and a Mapman analysis of the differentially expressed genes revealed differential regulation of genes related to plant hormone signal transduction, transcription factors, and phenylpropanoid biosynthesis. A correspondence between the transcript pattern and metabolite profile was observed in the phenylpropanoid biosynthesis pathway. It should be noted that the log2 ratio of eugenol (isoeugenol) in HB1 and HB2 are 85 times and 23 times higher than CK, respectively. Our study shows that phenylpropanoid biosynthesis may play an essential role in response to sclerotiniose pathogen infection and eugenol(isoeugenol) enrichment in mulberry fruit, which may provide a novel method for mulberry sclerotiniose control.
Reperfusion Arrhythmias Increase after Superior Cervical Ganglionectomy Due to Conduction Disorders and Changes in Repolarization
Authors: Prado Natalia Jorgelina , Muñoz Estela Maris , Farias Altamirano Luz Estefanía , Aguiar Francisco , Ponce Zumino Amira Zulma , Sánchez Francisco Javier , Miatello Roberto Miguel , Pueyo Esther , Diez Emiliano Raúl
Published: March 2020

Pharmacological concentrations of melatonin reduce reperfusion arrhythmias, but less is known about the antiarrhythmic protection of the physiological circadian rhythm of melatonin. Bilateral surgical removal of the superior cervical ganglia irreversibly suppresses melatonin rhythmicity. This study aimed to analyze the cardiac electrophysiological effects of the loss of melatonin circadian oscillation and the role played by myocardial melatonin membrane receptors, SERCA2A, TNFα, nitrotyrosine, TGFβ, KATP channels, and connexin 43. Three weeks after bilateral removal of the superior cervical ganglia or sham surgery, the hearts were isolated and submitted to ten minutes of regional ischemia followed by ten minutes of reperfusion. Arrhythmias, mainly ventricular tachycardia, increased during reperfusion in the ganglionectomy group. These hearts also suffered an epicardial electrical activation delay that increased during ischemia, action potential alternants, triggered activity, and dispersion of action potential duration. Hearts from ganglionectomized rats showed a reduction of the cardioprotective MT2 receptors, the MT1 receptors, and SERCA2A. Markers of nitroxidative stress (nitrotyrosine), inflammation (TNFα), and fibrosis (TGFβ and vimentin) did not change between groups. Connexin 43 lateralization and the pore-forming subunit (Kir6.1) of KATP channels increased in the experimental group. We conclude that the loss of the circadian rhythm of melatonin predisposes the heart to suffer cardiac arrhythmias, mainly ventricular tachycardia, due to conduction disorders and changes in repolarization.
Inhibitory Plasticity: From Molecules to Computation and Beyond
Authors: Gandolfi Daniela , Bigiani Albertino , Porro Carlo Adolfo , Mapelli Jonathan
Published: March 2020

Synaptic plasticity is the cellular and molecular counterpart of learning and memory and, since its first discovery, the analysis of the mechanisms underlying long-term changes of synaptic strength has been almost exclusively focused on excitatory connections. Conversely, inhibition was considered as a fixed controller of circuit excitability. Only recently, inhibitory networks were shown to be finely regulated by a wide number of mechanisms residing in their synaptic connections. Here, we review recent findings on the forms of inhibitory plasticity (IP) that have been discovered and characterized in different brain areas. In particular, we focus our attention on the molecular pathways involved in the induction and expression mechanisms leading to changes in synaptic efficacy, and we discuss, from the computational perspective, how IP can contribute to the emergence of functional properties of brain circuits.
Restoration of Neurological Function Following Peripheral Nerve Trauma
Authors: Kuffler Damien P. , Foy Christian
Published: March 2020

Following peripheral nerve trauma that damages a length of the nerve, recovery of function is generally limited. This is because no material tested for bridging nerve gaps promotes good axon regeneration across the gap under conditions associated with common nerve traumas. While many materials have been tested, sensory nerve grafts remain the clinical “gold standard” technique. This is despite the significant limitations in the conditions under which they restore function. Thus, they induce reliable and good recovery only for patients < 25 years old, when gaps are <2 cm in length, and when repairs are performed <2–3 months post trauma. Repairs performed when these values are larger result in a precipitous decrease in neurological recovery. Further, when patients have more than one parameter larger than these values, there is normally no functional recovery. Clinically, there has been little progress in developing new techniques that increase the level of functional recovery following peripheral nerve injury. This paper examines the efficacies and limitations of sensory nerve grafts and various other techniques used to induce functional neurological recovery, and how these might be improved to induce more extensive functional recovery. It also discusses preliminary data from the clinical application of a novel technique that restores neurological function across long nerve gaps, when repairs are performed at long times post-trauma, and in older patients, even under all three of these conditions. Thus, it appears that function can be restored under conditions where sensory nerve grafts are not effective.
Bisphenol S Impaired Human Granulosa Cell Steroidogenesis in Vitro
Authors: Amar Sarah , Binet Aurélien , Téteau Ophélie , Desmarchais Alice , Papillier Pascal , Lacroix Marlène Z. , Maillard Virginie , Guérif Fabrice , Elis Sebastien
Published: March 2020

Bisphenol S (BPS) is a structural analog of the endocrine disruptor bisphenol A (BPA); it is the main BPA replacement in the plastics industry. Previous studies have shown that BPA and BPS exhibit similar effects on reproduction in fish and rodent species. BPS reportedly alters steroidogenesis in bovine granulosa cells. Luteinised granulosa cells collected from 59 women who were undergoing an in vitro fertilization procedure were cultured for 48 h in the presence or absence of BPS (10 nM, 100 nM, 1 µM, 10 µM or 50 µM). BPS exposure was investigated by assessing follicular fluids from these 59 women for their BPS content. Culture medium, cells, total messenger RNA (mRNA) and total protein extracted from the luteinised granulosa cells were examined for oestradiol and progesterone secretion, cellular proliferation, viability, gene expression, steroidogenic enzyme expression and cell signaling. BPS was measured in follicular fluids using mass spectrometry. Exposure of granulosa cells to 10 or 50 µM BPS for 48 h induced a 16% (p = 0.0059) and 64% (p < 0.0001) decrease, respectively, in progesterone secretion; 50 µM BPS decreased oestradiol secretion by 46% (p < 0.0001). Ten µM BPS also tended to reduce CYP11A1 protein expression by 37% (p = 0.0947) without affecting HSD3B1 and CYP19A1 expression. Fifty µM BPS increased ERRγ expression. Environmental levels of BPS (nanomolar range) did not induce changes in steroidogenesis in human granulosa cells. The effects of BPS were observed after only 48 h of BPS exposure. These acute effects might be similar to chronic effects of physiological BPS levels.
A Brief Review of Nutraceutical Ingredients in Gastrointestinal Disorders: Evidence and Suggestions
Authors: Gao Xiang , Liu Jingwen , Li Li , Liu Wei , Sun Meiyan
Published: March 2020

The dietary effect on gut health has long been recognized through the empirical practice of soothing gastric discomfort with certain types of food, and recently the correlation between specific diets with lower incidences of several gastrointestinal diseases has been revealed. Ingredients from those considered beneficial foods have been isolated and studied, and some of them have already been put into the supplement market. In this review, we focus on latest studies of these food-derived ingredients for their proposed preventive and therapeutic roles in gastrointestinal disorders, with the attempt of drawing evidence-based suggestions on consuming these products.
Interaction of the Coffee Diterpenes Cafestol and 16-O-Methyl-Cafestol Palmitates with Serum Albumins
Authors: Berti Federico , Navarini Luciano , Guercia Elena , Oreški Ana , Gasparini Alessandra , Scoltock Jeremy , Forzato Cristina
Published: March 2020

The main coffee diterpenes cafestol, kahweol, and 16-O-methylcafestol, present in the bean lipid fraction, are mostly esterified with fatty acids. They are believed to induce dyslipidaemia and hypercholesterolemia when taken with certain types of coffee brews. The study of their binding to serum albumins could help explain their interactions with biologically active xenobiotics. We investigated the interactions occurring between cafestol and 16-O-methylcafestol palmitates with Bovine Serum Albumin (BSA), Human Serum Albumin (HSA), and Fatty Free Human Serum Albumin (ffHSA) by means of circular dichroism and fluorimetry. Circular Dichroism (CD) revealed a slight change (up to 3%) in the secondary structure of fatty-free human albumin in the presence of the diterpene esters, suggesting that the aliphatic chain of the palmitate partly occupies one of the fatty acid sites of the protein. A warfarin displacement experiment was performed to identify the binding site, which is probably close but not coincident with Sudlow site I, as the affinity for warfarin is enhanced. Fluorescence quenching titrations revealed a complex behaviour, with Stern–Volmer constants in the order of 103–104 Lmol−1. A model of the HSA-warfarin-cafestol palmitate complex was obtained by docking, and the most favourable solution was found with the terpene palmitate chain inside the FA4 fatty acid site and the cafestol moiety fronting warfarin at the interface with site I.
A Meta-Analysis of Multiple Whole Blood Gene Expression Data Unveils a Diagnostic Host-Response Transcript Signature for Respiratory Syncytial Virus
Authors: Barral-Arca Ruth , Gómez-Carballa Alberto , Cebey-López Miriam , Bello Xabier , Martinón-Torres Federico , Salas Antonio
Published: March 2020

Respiratory syncytial virus (RSV) is one of the major causes of acute lower respiratory tract infection worldwide. The absence of a commercial vaccine and the limited success of current therapeutic strategies against RSV make further research necessary. We used a multi-cohort analysis approach to investigate host transcriptomic biomarkers and shed further light on the molecular mechanism underlying RSV-host interactions. We meta-analyzed seven transcriptome microarray studies from the public Gene Expression Omnibus (GEO) repository containing a total of 922 samples, including RSV, healthy controls, coronaviruses, enteroviruses, influenzas, rhinoviruses, and coinfections, from both adult and pediatric patients. We identified > 1500 genes differentially expressed when comparing the transcriptomes of RSV-infected patients against healthy controls. Functional enrichment analysis showed several pathways significantly altered, including immunologic response mediated by RSV infection, pattern recognition receptors, cell cycle, and olfactory signaling. In addition, we identified a minimal 17-transcript host signature specific for RSV infection by comparing transcriptomic profiles against other respiratory viruses. These multi-genic signatures might help to investigate future drug targets against RSV infection.
Anti-Ageing Effect of Physalis alkekengi Ethyl Acetate Layer on a d-galactose-Induced Mouse Model through the Reduction of Cellular Senescence and Oxidative Stress
Authors: Sun Kaiyue , Sun Yingting , Li Heyang , Han Dongyao , Bai Yuting , Zhao Rong , Guo Zijiao
Published: March 2020

We aimed to study the effects of an ethyl acetate fraction of Physalis alkekengi (PAE) on d-galactose (d-gal)-induced senescence and the underlying mechanism. Firstly, analysis of the phytochemical composition revealed total flavonoids, total phenolics, total saponins, rutin, and luteolin contents of 71.72 ± 2.99 mg rutin equivalents/g, 40.19 ± 0.47 mg gallic acid equivalents/g, 128.13 ± 1.04 mg oleanolic acid equivalents/g, 1.67 ± 0.07 mg/g and 1.61 ± 0.01 mg/g, respectively. The mice were treated with d-gal for six weeks, and from the fifth week, the mice were administered with PAE by gavage once a day for five weeks. We found significant d-gal-induced ageing-related changes, such as learning and memory impairment in novel object recognition and Y-maze, fatigue in weight-loaded forced swimming, reduced thymus coefficient, and histopathological injury of the liver, spleen, and hippocampus. The PAE effectively protected from such changes. Further evaluation showed that PAE decreased the senescence-associated β-galactosidase of the liver, spleen, and hippocampus, as well as the oxidative stress of the liver, plasma, and brain. The abundance of flavonoids, phenols, and saponins in PAE may have contributed to the above results. Overall, this study showed the potential application of PAE for the prevention or treatment of ageing-associated disorders.
In Vivo Allergen-Activated Eosinophils Promote Collagen I and Fibronectin Gene Expression in Airway Smooth Muscle Cells via TGF-β1 Signaling Pathway in Asthma
Authors: Janulaityte Ieva , Januskevicius Andrius , Kalinauskaite-Zukauske Virginija , Bajoriuniene Ieva , Malakauskas Kestutis
Published: March 2020

Eosinophils infiltration and releasing TGF-β1 in the airways has been implicated in the pathogenesis of asthma, especially during acute episodes provoked by an allergen. TGF-β1 is a major mediator involved in pro-inflammatory responses and fibrotic tissue remodeling in asthma. We aimed to evaluate the effect of in vivo allergen-activated eosinophils on the expression of COL1A1 and FN in ASM cells in asthma. A total of 12 allergic asthma patients and 11 healthy subjects were examined. All study subjects underwent bronchial challenge with D. pteronyssinus allergen. Eosinophils from peripheral blood were isolated before and 24 h after the bronchial allergen challenge using high-density centrifugation and magnetic separation. Individual co-cultures of blood eosinophils and immortalized human ASM cells were prepared. The TGF-β1 concentration in culture supernatants was analyzed using ELISA. Gene expression was analyzed using qRT-PCR. Eosinophils integrins were suppressed with linear RGDS peptide before co-culture with ASM cells. Results: The expression of TGF-β1 in asthmatic eosinophils significantly increased over non-activated asthmatic eosinophils after allergen challenge, p < 0.001. The TGF-β1 concentration in culture supernatants was significantly higher in samples with allergen-activated asthmatic eosinophils compared to baseline, p < 0.05. The effect of allergen-activated asthmatic eosinophils on the expression of TGF-β1, COL1A1, and FN in ASM cells was more significant compared to non-activated eosinophils, p < 0.05, however, no difference was found on WNT-5A expression. The incubation of allergen-activated asthmatic eosinophils with RGDS peptide was more effective compared to non-activated eosinophils as the gene expression in ASM cells was downregulated equally to the same level as healthy eosinophils.
Changes in the Intestinal Microbiota Are Seen Following Treatment with Infliximab in Children with Crohn’s Disease
Authors: Kowalska-Duplaga Kinga , Kapusta Przemysław , Gosiewski Tomasz , Sroka-Oleksiak Agnieszka , Ludwig-Słomczyńska Agnieszka H. , Wołkow Paweł P. , Fyderek Krzysztof
Published: March 2020

The aim of the study was to determine the impact of biological treatment with tumor necrosis factor α antibodies (anti-TNF-α) on the intestinal microbiome of children with severe Crohn’s disease (CD) and to evaluate the differences in the intestinal microbiome between patients treated with biological therapy and healthy children. Microbiota composition was analyzed by 16S next-generation sequencing (NGS) and microbial profiles were compared between studied groups. Fifty-four samples (from 18 patients before and after anti-TNF-α induction therapy and 18 healthy children) were used in the sequencing analysis. Shannon’s diversity index (p = 0.003, adj. p = 0.010) and observed operational taxonomic units (OTUs) (p = 0.007, adj. p = 0.015) were different between controls and patients with prior therapy for CD. Statistically significant dissimilarities between beta diversity metrics, indicating distinct community composition across groups, were observed in patients with CD before and after therapy. We did not observe any differences between controls and patients with CD after therapy. Core microbiome analysis at species level showed that 32 species were present only in patients with CD but not in controls. The results show that biological treatment is associated with changes in the intestinal microbiome of patients with CD: these changes result in an intestinal microbiome pattern similar to that seen in healthy children. Long-term observation is necessary to determine whether treatment can lead to full restoration of a healthy-like microbiome.
Accuracy of Digital and Conventional Full-Arch Impressions in Patients: An Update
Authors: Schmidt Alexander , Klussmann Leona , Wöstmann Bernd , Schlenz Maximiliane Amelie
Published: March 2020

The aim of this clinical study was to update the available data in the literature regarding the transfer accuracy (trueness/precision) of four current intraoral scanners (IOS) equipped with the latest software versions and to compare these data with conventional impressions (CVI). A metallic reference aid served as a reference dataset. Four digital impressions (Trios3Cart, Trios3Pod, Trios4Pod, and Primescan) and one CVI were investigated in five patients. Scan data were analyzed using three-dimensional analysis software and conventional models using a coordinate measurement machine. The transfer accuracy between the reference aid and the impression methods were compared. Differences with p < 0.05 were considered to be statistically significant. Overall, mean ± standard deviation (SD) transfer accuracy ranged from 24.6 ± 17.7 µm (CVI) to 204.5 ± 182.1 µm (Trios3Pod). The Primescan yielded the lowest deviation for digital impressions (33.8 ± 31.5 µm), followed by Trios4Pod (65.2 ± 52.9 µm), Trios3Cart (84.7 ± 120.3 µm), and Trios3Pod. Within the limitations of this study, current IOS equipped with the latest software versions demonstrated less deviation for short-span distances compared with the conventional impression technique. However, for long-span distances, the conventional impression technique provided the lowest deviation. Overall, currently available IOS systems demonstrated improvement regarding transfer accuracy of full-arch scans in patients.
Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival
Authors: Ito Takamichi , Kaku-Ito Yumiko , Murata Maho , Furue Kazuhisa , Shen Che-Hung , Oda Yoshinao , Furue Masutaka
Published: March 2020

Acral melanoma, a distinct form of cutaneous melanoma originating in the glabrous skin of the palms, soles, and nail beds, has a different genetic background from other subtypes of cutaneous melanoma. The roles of oncogenic BRAF mutations of acral melanoma in pathogenesis and patient outcomes have not been fully elucidated. We retrieved a total of 112 patients with primary acral melanoma and checked their BRAF V600E status using immunohistochemical staining of VE1 antibody. Among these cases, 21 acral melanoma samples (18.8%) showed positive BRAF V600E staining, and of those, 11 samples (9.8%) showed a heterogeneous staining pattern, with a mixture of VE1-positive and VE1-negative cells. BRAF V600E positivity was significantly associated with thicker melanoma (p = 0.0015). There was no significant difference in clinicopathological factors between homogeneous and heterogeneous VE1-positive acral melanoma. Both patients with BRAF V600E-positive acral melanoma and those with heterogeneous BRAF V600E had significantly shorter melanoma-specific survival than those with BRAF V600E-negative melanoma in Kaplan–Meier analysis (p = 0.0283 and p = 0.0065, respectively). These findings provide novel insights into the pathobiology of acral melanoma.
Post-Concussion Syndrome and Sleep Apnea: A Retrospective Study
Authors: Santos Alexandra , Walsh Hannah , Anssari Neda , Ferreira Ivone , Tartaglia Maria
Published: March 2020

Background: Concussion symptoms typically resolve within 7–10 days, but 10–25% of patients do not fully recover. They can develop post-concussion syndrome (PCS), which includes sleep abnormalities such as obstructive sleep apnea. It is unclear how specific sleep problems manifest in PCS and how it relates to cognition and symptomology. Methods: A retrospective chart review was conducted on PCS patients seen at the University Health Network (UHN) Concussion Clinic and sent for sleep study. Neuropsychology tests, concussion features, PCS symptoms, and demographics were abstracted from clinical charts. Sleep measures were abstracted from the overnight sleep study. Data were analyzed using chi-squared tests and linear regression. Results: Fifty-one patients completed the sleep study; 78% of these were diagnosed with sleep apnea. Patients with sleep apnea reported significantly more memory symptoms. A trend existed for higher total symptom number. Age was significantly different between the two groups. Women and men were equally at risk of being diagnosed with sleep apnea. Conclusions: Sleep apnea is common in PCS patients complaining of non-restorative sleep and/or waking up with headaches. Sleep apnea was associated with more memory symptoms. PCS patients are at higher risk for sleep apnea and sleep study should be considered if complaining of non-restorative sleep and/or waking up with headaches, regardless of sex and other known risk factors.
Sarcoscore: A Novel Approach for Assessing Sarcopenia and Functional Disability in Older Adults
Authors: Osuka Yosuke , Kim Hunkyung , Kawai Hisashi , Taniguchi Yu , Yokoyama Yuri , Seino Satoshi , Obuchi Shuichi , Kitamura Akihiko , Shinkai Shoji
Published: March 2020

Sarcopenia is associated with instrumental activities of daily living (IADL) and basic activities of daily living (BADL) disabilities. We developed an index for assessing sarcopenia degree (sarcoscore) and compared it to the Asian Working Group for Sarcopenia (AWGS) criteria. Principal component analyses of walking speed, handgrip strength, and skeletal muscle index were performed to develop a sarcoscore using 3088 Japanese population-based cross-sectional data. During the nine-year follow-up, 278 of 2571 and 88 of 2341 participants developed IADL and BADL disabilities, respectively. Adjusted Cox proportional hazards regression models showed that the sarcoscore criteria, defined as proportional to the sarcopenia prevalence diagnosed by the AWGS criteria, had higher hazard ratios (HRs) and 95% confidence interval (CI) for disability onset than the AWGS criteria (IADL disability: 2.19 (1.64–2.93) vs. 1.79 (1.32–2.43), BADL disability: 4.28 (2.63–6.96) vs. 3.22 (1.97–5.27)). The adjusted HRs for IADL and BADL disabilities were reduced by 4% and 8% per point increase in the sarcoscore, respectively. The sarcoscore assessed the degree of sarcopenia and had a satisfactory performance for predicting functional disabilities in older Japanese adults, suggesting its usefulness as a complementary composite marker for clinical diagnosis.
Changes in Serum Creatinine Levels and Natural Evolution of Acute Kidney Injury with Conservative Management of Hemodynamically Significant Patent Ductus Arteriosus in Extremely Preterm Infants at 23–26 Weeks of Gestation
Authors: Seo Eun , Sung Se , Ahn So , Chang Yun , Park Won
Published: March 2020

Changes in kidney function in extremely preterm infants (EPT) with conservatively managed hemodynamically significant (HS) patent ductus arteriosus (PDA) are not known well. We aimed to present the postnatal course in serum creatinine levels (sCr), prevalence of acute kidney injury (AKI), then relevance between AKI and adverse outcomes in EPT with conservatively managed HS PDA. By review of medical records, we analyzed the postnatal course of sCr and prevalence of stage 3 AKI defined by the modified Kidney Disease Improving Global Outcome (KDIGO) in EPT at gestational age of 23 to 26 weeks with conservatively treated HS PDA. We investigated if the presence and/or prolonged duration of stage 3 AKI elevated the risk of adverse outcomes. The results showed that, neither factor was associated with adverse outcomes. While the average PDA closure date was at postnatal day (P) 41 and 53, sCr peaked at P 10 and 14 and the cumulative prevalence of stage 3 AKI was 57% and 72% in the EPT of 25–26 and 23–24 weeks’ gestation, respectively. The high prevalence of stage 3 AKI without adverse outcomes in EPT with conservatively managed HS PDA suggests that it might reflect renal immaturity rather than pathologic conditions.
A Multimodal Eye Assessment in Psoriatic Arthritis Patients sine-Psoriasis: Evidence for a Potential Association with Systemic Inflammation
Authors: Chimenti Maria Sole , Triggianese Paola , Salandri Giorgia , Conigliaro Paola , Canofari Claudia , Caso Francesco , Costa Luisa , Nucci Carlo , Aiello Francesco , Cesareo Massimo , Perricone Roberto
Published: March 2020

Background: Ocular involvement in Psoriatic Arthritis (PsA) patients is mainly associated with uveitis but there remains a paucity of data on dry eye and retinal abnormalities. We aimed to analyze dry eye and subclinical retinal abnormalities in a cohort of PsA patients sine-psoriasis (PsO). Methods: PsA patients sine-PsO were enrolled. Best-corrected-visual-acuity, ocular-surface-disease-index (OSDI), Schirmer test, tear film breakup-time, standard-automated-perimetry (SAP, mean deviation—MD, pattern standard deviation—PSD), fundus-perimetry (FP), and spectral-domain-optical-coherence-tomography (SD-OCT) were performed. Results: A total of 80 eyes from 40 PsA patients with moderate-severe disease activity, and 70 eyes from 35 healthy control (HC) were evaluated. Higher dry eye prevalence occurred in PsA than HC (p < 0.0001). ESR was positively related with OSDI (p < 0.001) and negatively related with Schirmer (p = 0.007). In PsA, SAP registered higher MD (p < 0.0001) and higher PSD (p = 0.005) in comparison with HC. PSD resulted positively correlated with ESR (p = 0.04) and CRP (p = 0.01), while MD showed a negative correlation with CRP (p = 0.01). Both FP mean differential sensitivity and mean defect were lower in PsA then HC (p < 0.0001). In PsA, FP differential sensitivity was directly related with cumulative steroids (p = 0.02). Conclusions: In PsA patients sine-PsO, dry eye and subclinical abnormalities in visual functions occurred being potentially related to systemic inflammation.
Numerical Simulation of the Posterior Malleolus Fracture with the Finite Element Method
Authors: Ampla Rafailia , Vasiliadis Angelo V. , Katakalos Konstantinos
Published: March 2020

The high demand for biodegradable implants in bone fracture fixations has dramatically increased the use of polymers for biomedical applications as well. However, the replacement of stainless steel and titanium screws by biodegradable materials represents one of the most critical aspects of biomechanics. In this study, the mechanical behavior of polycaprolactone (PCL) in tension and compression is examined. Driven by the advanced technology of computational mechanics, the fixation of the posterior malleolus fracture has been designed and analyzed. The core idea depicts the static analysis of screws made of PCL fixed in the ankle joint. The focus of the study is on this bio-absorbable, polymer-based material performance under constant compression. Parametric analysis is employed for the optimization of the PCL scaffold. Future studies will focus on the experimental verification of the numerical analysis results.
Effect of Laminin Derived Peptides IKVAV and LRE Tethered to Hyaluronic Acid on hiPSC Derived Neural Stem Cell Morphology, Attachment and Neurite Extension
Authors: Perera T. Hiran , Lu Xi , Smith Callahan Laura A
Published: March 2020

Low neural tissue extracellular matrix (ECM) content has led to the understudy of its effects on neural cells and tissue. Hyaluronic acid (HA) and laminin are major neural ECM components, but direct comparisons of their cellular effects could not be located in the literature. The current study uses human-induced pluripotent stem-cell-derived neural stem cells to assess the effects of HA, laminin, and HA with laminin-derived peptides IKVAV and LRE on cellular morphology, attachment, neurite extension and ECM remodeling. Increased attachment was observed on HA with and without IKVAV and LRE compared to laminin. Cellular morphology and neurite extension were similar on all surfaces. Using a direct binding inhibitor of Cav2.2 voltage gated calcium channel activity, a known binding partner of LRE, reduced attachment on HA with and without IKVAV and LRE and altered cellular morphology on surfaces with laminin or IKVAV and LRE. HA with IKVAV and LRE reduced the fluorescent intensity of fibronectin staining, but did not alter the localization of ECM remodeling enzymes matrix metalloprotease 2 and 9 staining compared to HA. Overall, the data indicate HA, IKVAV and LRE have complementary effects on human-induced pluripotent stem-cell-derived neural stem cell behavior.
Synthesis and Electrochemical Properties of Bi2MoO6/Carbon Anode for Lithium-Ion Battery Application
Authors: Zhang Tingting , Olsson Emilia , Choolaei Mohammadmehdi , Stolojan Vlad , Feng Chuanqi , Wu Huimin , Wang Shiquan , Cai Qiong
Published: March 2020

High capacity electrode materials are the key for high energy density Li-ion batteries (LIB) to meet the requirement of the increased driving range of electric vehicles. Here we report the synthesis of a novel anode material, Bi2MoO6/palm-carbon composite, via a simple hydrothermal method. The composite shows higher reversible capacity and better cycling performance, compared to pure Bi2MoO6. In 0–3 V, a potential window of 100 mA/g current density, the LIB cells based on Bi2MoO6/palm-carbon composite show retention reversible capacity of 664 mAh·g−1 after 200 cycles. Electrochemical testing and ab initio density functional theory calculations are used to study the fundamental mechanism of Li ion incorporation into the materials. These studies confirm that Li ions incorporate into Bi2MoO6 via insertion to the interstitial sites in the MoO6-layer, and the presence of palm-carbon improves the electronic conductivity, and thus enhanced the performance of the composite materials.
Developing Conductive Highly Ordered Zinc Oxide Nanorods by Acetylacetonate-Assisted Growth
Authors: A Karim Siti Shafura , Takamura Yuzuru , Tue Phan Trong , Tung Nguyen Thanh , Kazmi Jamal , Dee Chang Fu , Yeop Majlis Burhanuddin , Mohamed Mohd Ambri
Published: March 2020

Highly ordered vertically grown zinc oxide nanorods (ZnO NRs) were synthesized on ZnO-coated SiO2/Si substrate using zinc acetylacetonate hydrate as a precursor via a simple hydrothermal method at 85 °C. We used 0.05 M of ZnO solution to facilitate the growth of ZnO NRs and the immersion time was varied from 0.5 to 4 h. The atomic force microscopy revealed the surface roughness of ZnO seed layer used to grow the ZnO NRs. The morphology of vertically grown ZnO NRs was observed by field emission scanning electron microscopy. X-ray diffraction examination and transmission electron microscopy confirmed that the structure of highly ordered ZnO NRs was crystalline with a strong (002) peak corresponded to ZnO hexagonal wurtzite structure. The growth of highly ordered ZnO NRs was favorable due to the continuous supply of Zn2+ ions and chelating agents properties obtained from the acetylacetonate-derived precursor during the synthesis. Two-point probe current–voltage measurement and UV–vis spectroscopy of the ZnO NRs indicated a resistivity and optical bandgap value of 0.44 Ω.cm and 3.35 eV, respectively. The photoluminescence spectrum showed a broad peak centered at 623 nm in the visible region corresponded to the oxygen vacancies from the ZnO NRs. This study demonstrates that acetylacetonate-derived precursors can be used for the production of ZnO NRs-based devices with a potential application in biosensors.
Modification Tests to Optimize Highway Construction in Crown of Slate Random Embankments with Compaction Quality Control
Authors: Teijón-López-Zuazo Evelio , Vega-Zamanillo Ángel , Calzada-Pérez Miguel Ángel , Ramos-Pereira Luis Damián
Published: March 2020

The compaction control of random fills has developed very little due to the limitations of particle sizes, with methods usually using a simple procedural control. In order to develop new quality control procedures for random slate filling, the necessary field work and laboratory tests were carried out. New test procedures for wheel-tracking or settlement tests have been successfully investigated. A total of 4500 in situ measurements of density and 580 topographic settlements, 960 wheel-tracking trolley tests and more than 130 slab rolling tests have been determined. An analysis of variance (ANOVA) has been carried out, obtaining correlations between tests in order to replace the deductibles. The variables that were used to analyze variance were the average lot density, the average settlement between last and first roller pass, the average wheel impression after test carriage, the first vertical modulus of the plate bearing test (PLT), the second vertical modulus of the PLT and the relation between second and first modulus of the PLT. The research proposes a new procedure for the quality control of the compaction of the randomized slate filling used in the crown area.
Alkali Activation of Copper and Nickel Slag Composite Cementitious Materials
Authors: Zhang Tingting , Zhi Shiwei , Li Tong , Zhou Ziyu , Li Min , Han Junnan , Li Wenchen , Zhang Dan , Guo Lijie , Wu Zhenlin
Published: March 2020

Alkali-activated copper and nickel slag cementitious materials (ACNCMs) are composite cementitious materials with CNS (copper and nickel slag) as the main materials and GGBFS (ground-granulated blast-furnace slag) as a mineral admixture. In this paper, the activity indexes of CNS with different grinding times were studied using CNS to replace a portion of cement. NaOH, Na2SO4, and Na2SiO3 activators were used to study the alkaline solution of the CNS glass phase. The effects of the fineness of CNS and the type of activator on the hydration of ACNCMs were investigated via physical/mechanical grinding and chemical activation. The hydration products of ACNCMs were analyzed via XRD, SEM, FT-IR, TG, and MIP. The results of the study revealed that the activity indexes of CNS ground with different grinding times (10, 30 and 50 min) were 0.662, 0.689, and 0.703, respectively. When Na2SiO3 was used as the activator, the glass phase dissolved the most Si4+, Al3+, and Ca2+, and the respective concentrations in the solution were found to be 2419, 39.55, and 3.38 mg/L. Additionally, the hydration products of ACNCMs were found to have a 28-day compressive strength of up to 84 MPa.
Shear Behavior of Concrete Beams Reinforced with a New Type of Glass Fiber Reinforced Polymer Reinforcement: Experimental Study
Authors: Bywalski Czesław , Drzazga Michał , Kaźmierowski Maciej , Kamiński Mieczysław
Published: March 2020

The article presents experimental tests of a new type of composite bar that has been used as shear reinforcement for concrete beams. In the case of shearing concrete beams reinforced with steel stirrups, according to the theory of plasticity, the plastic deformation of stirrups and stress redistribution in stirrups cut by a diagonal crack are permitted. Tensile composite reinforcement is characterized by linear-elastic behavior throughout the entire strength range. The most popular type of shear reinforcement is closed frame stirrups, and this type of Fiber Reinforced Polymer (FRP) shear reinforcement was the subject of research by other authors. In the case of FRP stirrups, rupture occurs rapidly without the shear reinforcement being able to redistribute stress. An attempt was made to introduce a quasi-plastic character into the mechanisms transferring shear by appropriately shaping the shear reinforcement. Experimental material tests covered the determination of the strength and deformability of straight Glass Fiber Reinforced Polymer (GFRP) bars and GFRP headed bars. Experimental studies of shear reinforced beams with GFRP stirrups and GFRP headed bars were carried out. This allowed a direct comparison of the shear behavior of beams reinforced with standard GFRP stirrups and a new type of shear reinforcement: GFRP headed bars. Experimental studies demonstrated that GFRP headed bars could be used as shear reinforcement in concrete beams. Unlike GFRP stirrups, these bars allow stress redistribution in bars cut by a diagonal crack.