bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimation of Buffer Capacity of Model Systems and Natural Waters by Experimental and Calculation Methods
Authors: Kochergina O. , Onina S.
Published: December 2020

The aim of this work is to teach students to determine the stability of small lakes in relation to acidification processes by calculating the buffer capacity of water. A decrease in the pH of natural waters is caused by the influx of acid-forming oxides of sulfur and nitrogen into the atmosphere and water bodies. An increase in the acidity of water bodies has extremely negative consequences, contributes to the leaching of heavy metals, changes the ionic composition of water, and reduces the ability of natural water bodies to heal themselves. Low salinity waters of small lakes in the northern regions are especially vulnerable to acidification processes. The indicators of acid-neutralizing ability, the content of hydrocarbons, the value of the buffer capacity of natural waters are used as criteria for the stability of natural waters. To calculate the buffer capacity, the following indicators of the chemical composition of waters were used in this work: hydrogen index (pH), the content of organic (Corg) and mineral (Cmin) forms of carbon. Concentrations of conjugated forms of components of natural acid-base systems are calculated based on the concept of acid-base equilibrium in solutions of carbonic acid and humic acids.
Kelayakan Penggunaan Protokol WebSocket untuk Presensi Perkuliahan Jurusan Teknik Elektro Politeknik Negeri Sriwijaya Berteknologi Quick Response Code
Authors: Sukoco Nesa , Suroso Suroso , Ziad Ibnu
Published: December 2020

Perkembangan teknologi khususnya di bidang telekomunikasi memberikan perspektif baru untuk menjadikan proses presensi yang sebelumnya dilakukan manual dengan media kertas kini beralih ke penggunaan IT berupa web server sebagai admin dan aplikasi mobile berbasis android dengan teknologi Quick Response code (QR) sebagai client. Proses presensi mahasiswa membutuhkan koneksi yang real time. Salah satu protokol yang mendukung komunikasi real time adalah WebSocket. Protokol WebSocket tersebut digunakan dan dilakukan pengujian berdasarkan skenario yang telah ditentukan. Hasil pengujian menunjukkan bahwa semakin banyaknya request yang dikirim maka akan berpengaruh terhadap nilai Round Trip Time (RTT) dan request yang mampu dilayani oleh sistem.
Implementasi Metode Electre Dalam Menentukan Klasifikasi Hotel
Authors: Asrul Billy Eden William , Zuhriyah Sitti
Published: December 2020

Lembaga sertifikasi usaha sebagai badan yang berwenang menentukan klasifikasi hotel berdasarkan kelas hotel, bersinergi dengan dinas pariwisata, perhimpunan hotel dan restoran dalam proses audit, pembinaan dan pengawasan. pelaksanaan sertifikasi usaha pariwisata di kota makassar  masih perlu ditingkatkan secara efektivitas dan efisiensi, murah, mudah dan cepat. untuk mengatasi masalah tersebut dibuat sebuah sistem pendukung keputusan klasifikasi hotel, sistem ini mengimplementasikan metode Electre dalam mengolah data sehingga mempercepat proses klasifikasi status hotel,  memudahkan auditor dalam melakukan proses audit, membantu pelaksanaan pengawasan secara periodik. Metode ELECTRE memberikan keputusan multikriteria dengan konsep outranking perbandingan berpasangan dari alternatif-alternatif berdasarkan kriteria yang sesuai. Hasil uji akurasi dari sistem sebesar 85,71% dengan data uji sebanyak 15 data.
FACTORES QUE INFLUYEN EN LA CREATIVIDAD DE UNA PERSONA PARA IDENTIFICAR OPORTUNIDADES DE NEGOCIO EN EL CANTÓN DE GUARANDA, PROVINCIA DE BOLÍVAR EN EL AÑO 2020.
Authors:   Universidad Estatal de Bolívar, Viscarra Armijos Charles Paúl , Camacho Arellano Wilter Rodolfo ,   Universidad Estatal de Bolívar
Published: December 2020

La presente investigación tiene como finalidad determinar las circunstancias por las que las personas se inclinan a iniciar un negocio propio como también entender la importancia que tiene los factores de la creatividad que es la motivación, conocimiento amplio, personalidad y la experiencia que tiene al momento de emprender un negocio nuevo dentro del mercado siendo é sta la clave del éxito de muchos. El emprendimiento es un campo vasto que involucra diferentes temas de suma importancia como financiación del emprendimiento para comenzar a desarrollar la idea, características del emprendedor que son fundamentales para desenvolverse en el entorno, empresas de familia que son las que llegan a promover nuevas ideas, reconocimiento de oportunidades, aprendizaje y emprendimiento social, entre otros. Hoy en día es imposible ignorar la creatividad al instante de involucrarse en este círculo comercial, por lo cual en gran parte los emprendedores han tomado como punto de partida establecer diferentes ideas para luego escoger la mejor decisión puesto que en muchos casos existe fracaso de negocios por lanzarse de manera empírica sin contar con un conocimiento adecuado o falta de motivación que nace en nuestro interior. Como resultado se obtuvo que los emprendedores de Guaranda iniciaron negocios para adquirir recursos económicos extras para su hogar,
Faktor Faktor Yang Mempengaruhi Investasi Asing Langsung di Indonesia
Authors: Wage Sunarto
Published: December 2020

This study analyzes and analyzes the factors that influence investors to make investments. Many factors influence investors to make direct investments. Researchers are motivated to study and analyze the factors that influence the decision of multinational companies to make direct investments in Indonesia. Based on previous theory and research, there are some of the biggest determinants of investment, labor, infrastructure, trade openness, exchange rates, trade, interest rates, and economic growth. The theoretical basis used in this study of foreign investment is; (1) classical investment theory, (2) Keynesian investment theory, (3) comparative advantage theory, (4) product cycle theory developed, (4) modern monopolistic advantage theory, (5) leader following theory, (6) investment theory cross, (7) financial factor theory, (8) and eclectic theory. The object of research was carried out in Indonesia. To answer the research problem, the data used from 1997 to 2017 in Indonesia are sourced from the 2018 ASEAN Statistics Yearbook and answer using multiple regression with SPSS 25. Based on the research results, market size affects foreign direct investment in Indonesia while the workforce, infrastructure trade openness, exchange rates, ethnicity, and economic growth do not affect direct investment in Indonesia.
The Role of Eryptosis in the Pathogenesis of Renal Anemia: Insights From Basic Research and Mathematical Modeling
Authors: Dias Gabriela Ferreira , Grobe Nadja , Rogg Sabrina , Jörg David J. , Pecoits-Filho Roberto , Moreno-Amaral Andréa Novais , Kotanko Peter
Published: December 2020

Red blood cells (RBC) are the most abundant cells in the blood. Despite powerful defense systems against chemical and mechanical stressors, their life span is limited to about 120 days in healthy humans and further shortened in patients with kidney failure. Changes in the cell membrane potential and cation permeability trigger a cascade of events that lead to exposure of phosphatidylserine on the outer leaflet of the RBC membrane. The translocation of phosphatidylserine is an important step in a process that eventually results in eryptosis, the programmed death of an RBC. The regulation of eryptosis is complex and involves several cellular pathways, such as the regulation of non-selective cation channels. Increased cytosolic calcium concentration results in scramblase and floppase activation, exposing phosphatidylserine on the cell surface, leading to early clearance of RBCs from the circulation by phagocytic cells. While eryptosis is physiologically meaningful to recycle iron and other RBC constituents in healthy subjects, it is augmented under pathological conditions, such as kidney failure. In chronic kidney disease (CKD) patients, the number of eryptotic RBC is significantly increased, resulting in a shortened RBC life span that further compounds renal anemia. In CKD patients, uremic toxins, oxidative stress, hypoxemia, and inflammation contribute to the increased eryptosis rate. Eryptosis may have an impact on renal anemia, and depending on the degree of shortened RBC life span, the administration of erythropoiesis-stimulating agents is often insufficient to attain desired hemoglobin target levels. The goal of this review is to indicate the importance of eryptosis as a process closely related to life span reduction, aggravating renal anemia.
The Involvement of the hsa_circ_0088494-miR-876-3p-CTNNB1/CCND1 Axis in Carcinogenesis and Progression of Papillary Thyroid Carcinoma
Authors: Lou Weiyang , Ding Bisha , Wang Jiannan , Xu Yongfang
Published: December 2020

Recently, growing studies have demonstrated that circular RNAs (circRNAs) function as critical players in multiple human tumors, including papillary thyroid carcinoma (PTC). However, the expression and underlying potential mechanism of circRNAs in PTC are still not fully elucidated. In this study, 14 candidate differentially expressed circRNAs (DECs) between normal thyroid tissues and benign thyroid tissues or PTC were first screened using the GSE93522 dataset by the GEO2R online tool. Then, the structural loop graphs of these 14 circRNAs were obtained through the CSCD database. After performing miRNA co-prediction by combination of CSCD and CRI databases, a potential circRNA-miRNA sub-network, consisting of 9 circRNAs and 21 miRNAs, was successfully constructed. Subsequently, the expression and prognostic values of these miRNAs were further determined by starBase, and two miRNAs, namely, miR-605-5p and miR-876-3p, were identified as key miRNAs in PTC. Then, their downstream target genes were predicted by the miRNet database. CTNNB1 and CCND1 were found to be two most potential targets of miR-876-3p by combination of multiple in silico analyses, including protein–protein interaction (PPI), hub gene screening, correlation analysis, and expression analysis. Conclusively, we established a key hsa_circ_0088494-miR-876-3p-CTNNB1/CCND1 axis linked to carcinogenesis and progression of PTC, which may provide promising therapeutic targets in treating PTC in the future.
Modulation of TCR Signaling by Tyrosine Phosphatases: From Autoimmunity to Immunotherapy
Authors: Castro-Sanchez Patricia , Teagle Alexandra R. , Prade Sonja , Zamoyska Rose
Published: December 2020

Early TCR signaling is dependent on rapid phosphorylation and dephosphorylation of multiple signaling and adaptor proteins, leading to T cell activation. This process is tightly regulated by an intricate web of interactions between kinases and phosphatases. A number of tyrosine phosphatases have been shown to modulate T cell responses and thus alter T cell fate by negatively regulating early TCR signaling. Mutations in some of these enzymes are associated with enhanced predisposition to autoimmunity in humans, and mouse models deficient in orthologous genes often show T cell hyper-activation. Therefore, phosphatases are emerging as potential targets in situations where it is desirable to enhance T cell responses, such as immune responses to tumors. In this review, we summarize the current knowledge about tyrosine phosphatases that regulate early TCR signaling and discuss their involvement in autoimmunity and their potential as targets for tumor immunotherapy.
Extracellular Vesicles Are Key Regulators of Tumor Neovasculature
Authors: Kuriyama Naoya , Yoshioka Yusuke , Kikuchi Shinsuke , Azuma Nobuyoshi , Ochiya Takahiro
Published: December 2020

Tumor progression involves a series of biologically important steps in which the crosstalk between cancer cells and the surrounding environment is an important issue. Angiogenesis is a key tumorigenic phenomenon for cancer progression. Tumor-related extracellular vesicles (EVs) modulate the tumor microenvironment (TME) through cell-to-cell communication. Tumor cells in a hypoxic TME release more EVs than cells in a normoxic environment due to uncontrollable tumor proliferation. Tumor-derived EVs in the TME influence endothelial cells (ECs), which then play multiple roles, contributing to tumor angiogenesis, loss of the endothelial vascular barrier by binding to ECs, and subsequent endothelial-to-mesenchymal transition. In contrast, they also indirectly induce tumor angiogenesis through the phenotype switching of various cells into cancer-associated fibroblasts, the activation of tumor-associated ECs and platelets, and remodeling of the extracellular matrix. Here, we review current knowledge regarding the involvement of EVs in tumor vascular-related cancer progression.
A Mini Review of the Preparation and Photocatalytic Properties of Two-Dimensional Materials
Authors: Hao Shuhua , Zhao Xinpei , Cheng Qiyang , Xing Yupeng , Ma Wenxuan , Wang Xiaoke , Zhao Gang , Xu Xijin
Published: December 2020

The successful preparation and application of graphene shows that it is feasible for the materials with a thickness of a single atom or few atomic layers to exist stably in nature. These materials can exhibit unusual physical and chemical properties due to their special dimension effects. At present, researchers have made great achievements in the preparation, characterization, modification, and theoretical research of 2D materials. Because the structure of 2D materials is often similar, it has a certain degree of qualitative versatility. Besides, 2D materials often carry good catalytic performance on account of their more active sites and adjustable harmonic electronic structure. In this review, taking 2D materials as examples [graphene, boron nitride (h-BN), transition metal sulfide and so on], we review the crystal structure and preparation methods of these materials in recent years, focus on their photocatalyst properties (carbon dioxide reduction and hydrogen production), and discuss their applications and development prospects in the future.
Reliable Comparison of Pnicogen, Chalcogen, and Halogen Bonds in Complexes of 6-OXF2-Fulvene (X = As, Sb, Se, Te, Be, I) With Three Electron Donors
Authors: Liu Na , Li Qingzhong , McDowell Sean A. C.
Published: December 2020

The pnicogen, chalcogen, and halogen bonds between 6-OXF2-fulvene (X = As, Sb, Se, Te, Br, and I) and three nitrogen-containing bases (FCN, HCN, and NH3) are compared. For each nitrogen base, the halogen bond is strongest, followed by the pnicogen bond, and the chalcogen bond is weakest. For each type of bond, the binding increases in the FCN < HCN < NH3pattern. Both FCN and HCN engage in a bond with comparable strengths and the interaction energies of most bonds are < −6 kcal/mol. However, the strongest base NH3forms a much more stable complex, particularly for the halogen bond with the interaction energy going up to −18 kcal/mol. For the same type of interaction, its strength increases as the mass of the central X atom increases. These bonds are different in strength, but all of them are dominated by the electrostatic interaction, with the polarization contribution important for the stronger interaction. The presence of these bonds changes the geometries of 6-OXF2-fulvene, particularly for the halogen bond formed by NH3, where the F-X-F arrangement is almost vertical to the fulvene ring.
Potential of Fourier Transform Mass Spectrometry (Orbitrap and Ion Cyclotron Resonance) for Speciation of the Selenium Metabolome in Selenium-Rich Yeast
Authors: Bierla Katarzyna , Chiappetta Giovanni , Vinh Joëlle , Lobinski Ryszard , Szpunar Joanna
Published: December 2020

The evolution of the field of element speciation, from the targeted analysis for specific element species toward a global exploratory analysis for the entirety of metal- or metalloid-related compounds present in a biological system (metallomics), requires instrumental techniques with increasing selectivity and sensitivity. The selectivity of hyphenated techniques, combining chromatography, and capillary electrophoresis with element-specific detection (usually inductively coupled plasma mass spectrometry, ICP MS), is often insufficient to discriminate all the species of a given element in a sample. The necessary degree of specificity can be attained by ultrahigh-resolution (R >100,000 in the m/z < 1,000 range for a 1 s scan) mass spectrometry based on the Fourier transformation of an image current of the ions moving in an Orbitrap or an ion cyclotron resonance (ICR) cell. The latest developments, allowing the separate detection of two ions differing by a mass of one electron (0.5 mDa) and the measurement of their masses with a sub-ppm accuracy, make it possible to produce comprehensive lists of the element species present in a biological sample. Moreover, the increasing capacities of multistage fragmentation often allow their de novo identification. This perspective paper critically discusses the potential state-of-the-art of implementation, and challenges in front of FT (Orbitrap and ICR) MS for a large-scale speciation analysis using, as example, the case of the metabolism of selenium by yeast.
Efficient Amplification in Soai's Asymmetric Autocatalysis by a Transient Stereodynamic Catalyst
Authors: Trapp Oliver
Published: December 2020

Mechanisms leading to a molecular evolution and the formation of homochirality in nature are interconnected and a key to the underlying principles that led to the emergence of life. So far proposed mechanisms leading to a non-linear reaction behavior are based mainly on the formation of homochiral and heterochiral dimers. Since homochiral and heterochiral dimers are diastereomers of each other, the minor enantiomer is shifted out of equilibrium with the major enantiomer by dimer formation and thus a reaction or catalysis can be dominated by the remaining molecules of the major enantiomer. In this article a mechanism is shown that leads to homochirality by the formation of a highly catalytically active transient intermediate in a stereodynamically controlled reaction. This is demonstrated by Soai's asymmetric autocatalysis, in which aldehydes are transformed into the corresponding alcohols by addition of dialkylzinc reagents. The mechanism of chirogenesis proposed here shows that an apparently inefficient reaction is the best prerequisite for a selection mechanism. In addition, stereodynamic control offers the advantage that the minor diastereomeric intermediate can be interconverted into the major diastereomer and thus be stereoeconomically efficient. This is supported by computer simulation of reaction kinetics.
Interplay Between KSHV and the Host DNA Damage Response
Authors: Ohsaki Eriko , Ueda Keiji
Published: December 2020

Interactions between viruses and cellular factors are essential for viral replication or host defense. The DNA damage response (DDR) orchestrates a molecular network of cellular mechanisms that integrates cell cycle regulation and DNA repair or apoptosis. Numerous studies have revealed that the DDR is activated by virus infection, aberrant DNA structures generated by viral DNA replication, or the integration of retroviruses. Although the DDR is an essential function for maintaining the genomic integrity of cells, viruses may utilize this mechanism to build a convenient environment for themselves, and the resulting perturbation of the DDR has been shown to increase the risk of tumorigenesis. There have been many studies investigating the roles of the DDR in oncogenic viruses such as Epstein-Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), human T-cell leukemia virus type 1 (HTLV-1), and Kaposi’s sarcoma-associated herpesvirus (KSHV). This review summarizes current knowledge on the roles of DDR in the KSHV lifecycle.
The Role of MSC Therapy in Attenuating the Damaging Effects of the Cytokine Storm Induced by COVID-19 on the Heart and Cardiovascular System
Authors: Ellison-Hughes Georgina M. , Colley Liam , O'Brien Katie A. , Roberts Kirsty A. , Agbaedeng Thomas A. , Ross Mark D.
Published: December 2020

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has led to 47 m infected cases and 1. 2 m (2.6%) deaths. A hallmark of more severe cases of SARS-CoV-2 in patients with acute respiratory distress syndrome (ARDS) appears to be a virally-induced over-activation or unregulated response of the immune system, termed a “cytokine storm,” featuring elevated levels of pro-inflammatory cytokines such as IL-2, IL-6, IL-7, IL-22, CXCL10, and TNFα. Whilst the lungs are the primary site of infection for SARS-CoV-2, in more severe cases its effects can be detected in multiple organ systems. Indeed, many COVID-19 positive patients develop cardiovascular complications, such as myocardial injury, myocarditis, cardiac arrhythmia, and thromboembolism, which are associated with higher mortality. Drug and cell therapies targeting immunosuppression have been suggested to help combat the cytokine storm. In particular, mesenchymal stromal cells (MSCs), owing to their powerful immunomodulatory ability, have shown promise in early clinical studies to avoid, prevent or attenuate the cytokine storm. In this review, we will discuss the mechanistic underpinnings of the cytokine storm on the cardiovascular system, and how MSCs potentially attenuate the damage caused by the cytokine storm induced by COVID-19. We will also address how MSC transplantation could alleviate the long-term complications seen in some COVID-19 patients, such as improving tissue repair and regeneration.
Applications of 3D Paleontological Data at the Florida Museum of Natural History
Authors: Ziegler Michael J. , Perez Victor J. , Pirlo Jeanette , Narducci Rachel E. , Moran Sean M. , Selba Molly C. , Hastings Alexander K. , Vargas-Vergara Claudia , Antonenko Pavlo D. , MacFadden Bruce J.
Published: December 2020

The past decade has seen an exponential increase of innovative applications of 3D technology in the geosciences. Here, we present a case study from the Florida Museum of Natural History applied to the multidisciplinary field of paleontology. We have deployed 3D scanning and printing techniques for the purposes of scientific research, formal education, and informal outreach. Depending on the application of the 3D file, different techniques are utilized to create high-fidelity models of physical fossil specimens or geologic field sites. These techniques include X-ray CT scans, surface scans, and photogrammetry, all of which produce 3D models that vary in resolution and scale. Novel paleontological research applied non-destructive CT scanning to explore the internal anatomy of fossil museum specimens, additionally, 3D models are being used to create K–12 curricula aligned with national and state-specific education standards that are implemented in formal classroom settings. Many of these lessons are part of the NSF-funded iDigFossils project, which aims to evaluate students’ motivation and interest towards science, technology, engineering, and mathematics after participating in integrated 3D printing and paleontology lessons. Specifically, lessons on dinosaur trackways, horse evolution, and the Great American Biotic Interchange teach geologic concepts such as deep time, taphonomy, plate tectonics, and evolutionary trends. The same 3D models developed for these K–12 lessons have been used during Florida Museum’s outreach events to engage broad audiences with hands-on exhibits and activities. All 3D files are stored on open-access, online repositories, providing accessibility to fossil specimens and field sites. The application of 3D technology for the study of fossils and paleontology will continue to expand the impact of scientific discoveries for basic research as well as for broader impacts on society.
Cardiac Regeneration and Tumor Growth—What Do They Have in Common?
Authors: Dicks Severin , Jürgensen Lonny , Leuschner Florian , Hassel David , Andrieux Geoffroy , Boerries Melanie
Published: December 2020

Acute myocardial infarction is a leading cause of death. Unlike most adult mammals, zebrafish have the capability to almost fully regenerate their hearts after injury. In contrast, ischemic damage in adult human and mouse hearts usually results in scar tissue. mRNA-Sequencing (Seq) and miRNA-Seq analyses of heart regeneration in zebrafish over time showed that the process can be divided into three phases: the first phase represents dedifferentiation and proliferation of cells, the second phase is characterized by migration, and in the third phase cell signals indicate heart development and differentiation. The first two phases seem to share major similarities with tumor development and growth. To gain more insight into these similarities between cardiac regeneration and tumor development and growth, we used patient matched tumor normal (“healthy”) RNA-Seq data for several tumor entities from The Cancer Genome Atlas (TCGA). Subsequently, RNA data were processed using the same pipeline for both the zebrafish samples and tumor datasets. Functional analysis showed that multiple Gene Ontology terms (GO terms) are involved in both early stage cardiac regeneration and tumor development/growth across multiple tumor entities. These GO terms are mostly associated with cell cycle processes. Further analysis showed that orthologous genes are the same key players that regulated these changes in both diseases. We also observed that GO terms associated with heart development in the third late phase of cardiac regeneration are downregulated in the tumor entities. Taken together, our analysis illustrates similarities between cardiac remodeling and tumor progression.
Identification of Candidate Circular RNAs Underlying Intramuscular Fat Content in the Donkey
Authors: Li Bojiang , Feng Chunyu , Zhu Shiyu , Zhang Junpeng , Irwin David M. , Zhang Xiaoying , Wang Zhe , Zhang Shuyi
Published: December 2020

Intramuscular fat (IMF) content is a crucial indicator of meat quality. Circular RNAs (circRNAs) are a large class of endogenous RNAs that are involved in many physiological processes. However, the expression and function of circRNA in IMF in the donkey remains unresolved. Here we performed an expression profiling of circRNAs in the donkey longissimus dorsi muscle and identified 12,727 candidate circRNAs. Among these, 70% were derived from the exons of protein genes. Furthermore, a total of 127 differentially expressed (DE) circRNAs were identified in high (H) and low (L) IMF content groups, including 63 upregulated and 64 downregulated circRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the host genes of the DE circRNAs showed that the host genes were enriched in lipid metabolism related GO terms (e.g., fatty acid beta-oxidation using acyl-CoA dehydrogenase and MLL3/4 complex), and signaling pathways (e.g., TGF-beta and lysine degradation signaling pathway). Further analyses indicated that 127 DE circRNAs were predicted to potentially interact with miRNAs, leading to the construction of circRNA-miRNA regulatory network. Multiple circRNAs can potentially function as sponges of miRNAs that regulate the differentiation of adipocytes. Our results provide valuable expression profile information for circRNA in the donkey and new insight into the regulatory mechanisms of circRNAs in the regulation of IMF content.
Novel SOX10 Mutations in Waardenburg Syndrome: Functional Characterization and Genotype-Phenotype Analysis
Authors: Thongpradit Supranee , Jinawath Natini , Javed Asif , Jensen Laran T. , Chunsuwan Issarapa , Rojnueangnit Kitiwan , Tim-Aroon Thipwimol , Lertsukprasert Krisna , Shiao Meng-Shin , Sirachainan Nongnuch , Wattanasirichaigoon Duangrurdee
Published: December 2020

Waardenburg syndrome (WS) is a prevalent hearing loss syndrome, concomitant with focal skin pigmentation abnormalities, blue iris, and other abnormalities of neural crest-derived cells, including Hirschsprung’s disease. WS is clinically and genetically heterogeneous and it is classified into four major types WS type I, II, III, and IV (WS1, WS2, WS3, and WS4). WS1 and WS3 have the presence of dystopia canthorum, while WS3 also has upper limb anomalies. WS2 and WS4 do not have the dystopia canthorum, but the presence of Hirschsprung’s disease indicates WS4. There is a more severe subtype of WS4 with peripheral nerve and/or central nervous system involvement, namely peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung’s disease or PCW/PCWH. We characterized the genetic defects underlying WS2, WS4, and the WS4-PCW/PCWH) using Sanger and whole-exome sequencing and cytogenomic microarray in seven patients from six unrelated families, including two with WS2 and five with WS4. We also performed multiple functional studies and analyzed genotype–phenotype correlations. The cohort included a relatively high frequency (80%) of individuals with neurological variants of WS4. Six novel SOX10 mutations were identified, including c.89C > A (p.Ser30∗), c.207_8 delCG (p.Cys71Hisfs∗62), c.479T > C (p.Leu160Pro), c.1379 delA (p.Tyr460Leufs∗42), c.425G > C (p.Trp142Ser), and a 20-nucleotide insertion, c.1155_1174dupGCCCCACTATGGCTCAGCCT (p.Phe392Cysfs∗117). All pathogenic variants were de novo. The results of reporter assays, western blotting, immunofluorescence, and molecular modeling supported the deleterious effects of the identified mutations and their correlations with phenotypic severity. The prediction of genotype–phenotype correlation and functional pathology, and dominant negative effect vs. haploinsufficiency in SOX10-related WS were influenced not only by site (first two vs. last coding exons) and type of mutation (missense vs. truncation/frameshift), but also by the protein expression level, molecular weight, and amino acid content of the altered protein. This in vitro analysis of SOX10 mutations thus provides a deeper understanding of the mechanisms resulting in specific WS subtypes and allows better prediction of the phenotypic manifestations, though it may not be always applicable to in vivo findings without further investigations.
Identification of Potential Long Non-coding RNA Expression Quantitative Trait Methylations in Lung Adenocarcinoma and Lung Squamous Carcinoma
Authors: Wu Xiaohong , Gao Yue , Bu Jianlong , Deng Lin , Zhang Pinyi , Chi Meng , Jiang Lihua , Shi Xiaoding , Ning Shangwei , Wang Guonian
Published: December 2020

There are associations between DNA methylation and the expression of long non-coding RNA (lncRNA), also known as lncRNA expression quantitative trait methylations (lnc-eQTMs). Lnc-eQTMs may induce a wide range of carcinogenesis pathways. However, lnc-eQTMs have not been globally identified and studied, and their roles in lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) are largely unknown. In the present study, we identified some differential methylation sites located in genes of long intergenic non-coding RNAs (lincRNAs) and other types of lncRNAs in LUAD and LUSC. An integrated pipeline was established to construct two global cancer-specific regulatory networks of lnc-eQTMs in LUAD and LUSC. The associations between eQTMs showed common and specific features between LUAD and LUSC. Some lnc-eQTMs were also related with survival in LUAD- and LUSC-specific regulatory networks. Lnc-eQTMs were associated with cancer-related functions, such as lung epithelium development and vasculogenesis by functional analysis. Drug repurposing analysis revealed that these lnc-eQTMs may mediate the effects of some anesthesia-related drugs in LUAD and LUSC. In summary, the present study elucidates the roles of lnc-eQTMs in LUAD and LUSC, which could improve our understanding of lung cancer pathogenesis and facilitate treatment.
LPI-SKF: Predicting lncRNA-Protein Interactions Using Similarity Kernel Fusions
Authors: Zhou Yuan-Ke , Hu Jie , Shen Zi-Ang , Zhang Wen-Ya , Du Pu-Feng
Published: December 2020

Long non-coding RNAs (lncRNAs) play an important role in serval biological activities, including transcription, splicing, translation, and some other cellular regulation processes. lncRNAs perform their biological functions by interacting with various proteins. The studies on lncRNA-protein interactions are of great value to the understanding of lncRNA functional mechanisms. In this paper, we proposed a novel model to predict potential lncRNA-protein interactions using the SKF (similarity kernel fusion) and LapRLS (Laplacian regularized least squares) algorithms. We named this method the LPI-SKF. Various similarities of both lncRNAs and proteins were integrated into the LPI-SKF. LPI-SKF can be applied in predicting potential interactions involving novel proteins or lncRNAs. We obtained an AUROC (area under receiver operating curve) of 0.909 in a 5-fold cross-validation, which outperforms other state-of-the-art methods. A total of 19 out of the top 20 ranked interaction predictions were verified by existing data, which implied that the LPI-SKF had great potential in discovering unknown lncRNA-protein interactions accurately. All data and codes of this work can be downloaded from a GitHub repository (https://github.com/zyk2118216069/LPI-SKF).
Neutrophil Inflammatory Response Is Downregulated by Uptake of Superparamagnetic Iron Oxide Nanoparticle Therapeutics
Authors: Garcia Gustavo , Kim Min-Ho , Morikis Vasilios Aris , Simon Scott I.
Published: December 2020

Superparamagnetic iron oxide nanoparticles (SPION) are employed as diagnostics and therapeutics following intravenous delivery for the treatment of iron deficiency anemia (IDA) in adult patients with chronic kidney failure. Neutrophils are the first defense against blood borne foreign insult and recruit to vascular sites of inflammation via a sequential process that is characterized by adhesive capture, rolling, and shear resistant arrest. A primary chemotactic agonist presented on the glycocalyx of inflamed endothelium is IL-8, which upon binding to its cognate membrane receptor (CXCR1/2) activates a suite of responses in neutrophils. An early response is degranulation with accompanying upregulation of β2-integrin (CD11/CD18) and shedding of L-selectin (CD62L) receptors, which exert differential effects on the efficiency of endothelial recruitment. Feraheme is an FDA approved SPION treatment for IDA, but its effect on the innate immune response of neutrophils during inflammation has not been reported. Here, we studied the immunomodulatory effects of Feraheme on neutrophils freshly isolated from healthy human subjects and stimulated in suspension or on inflammatory mimetic substrates with IL-8. Cells treated with Feraheme exhibited reduced sensitivity to stimulation with IL-8, indicated by reduced upregulation of membrane CD11b/CD18 receptors, high affinity (HA) CD18, and shedding of CD62L. Feraheme also inhibited N-formyl-Met-Leu-Phe (fMLP) induced reactive oxygen species production. Neutrophil rolling, arrest, and migration was assessed in vascular mimetic microfluidic channels coated with E-selectin and ICAM-1 to simulate inflamed endothelium. Neutrophils exposed to Feraheme rolled faster on E-selectin and arrested less frequently on ICAM-1, in a manner dependent upon SPION concentration. Subsequent neutrophil shape change, and migration were also significantly inhibited in the presence of Feraheme. Lastly, Feraheme accelerated clearance of cytosolic calcium flux following IL-8 stimulation. We conclude that uptake of Feraheme by neutrophils inhibits chemotactic activation and downregulates normal rolling to arrest under shear flow. The mechanism involves increased calcium clearance following chemotactic activation, which may diminish the efficiency of recruitment from the circulation at vascular sites of inflammation.
Bixin Attenuates Experimental Autoimmune Encephalomyelitis by Suppressing TXNIP/NLRP3 Inflammasome Activity and Activating NRF2 Signaling
Authors: Yu Ye , Wu Dong-Ming , Li Jing , Deng Shi-Hua , Liu Teng , Zhang Ting , He Miao , Zhao Yang-Yang , Xu Ying
Published: December 2020

Multiple sclerosis (MS), an autoimmune and degenerative disease, is characterized by demyelination and chronic neuroinflammation. Bixin is a carotenoid isolated from the seeds of Bixa orellana that exhibits various potent pharmacological activities, including antioxidant, anti-inflammatory, and anti-tumor properties. However, the effects of bixin on MS have not yet been examined. To evaluate the effects and underlying molecular mechanisms of bixin on MS, experimental autoimmune encephalomyelitis (EAE) was established in C57BL/6 mice, which were treated via intragastric administration of bixin solutions. To evaluate the molecular mechanisms of bixin, quantitative reverse-transcription PCR, western blot, immunohistochemistry, flow cytometry, and enzyme-linked immunosorbent assay analyses were performed. We found that bixin significantly improved the symptoms and pathology in EAE mice, reduced the release of inflammatory cytokines TNF-α, IL-6, IL-8, IL-17, and IFN-γ, and increased the expression of the anti-inflammatory cytokine IL-10. And bixin reduced the proportion of Th1 and Th17 cells in the spleen and CNS, and suppressed microglia aggregation, and TXNIP/NLRP3 inflammasome activity by scavenging excessive reactive oxygen species (ROS) in EAE mice. Furthermore, bixin inhibited inflammation and oxidative stress via activating nuclear factor erythroid 2-related factor 2 (NRF2), and its downstream genes in EAE mice, meanwhile, these effects were suppressed upon treatment with an NRF2 inhibitor, ML385. Bixin prevented neuroinflammation and demyelination in EAE mice primarily by scavenging ROS through activation of the NRF2 signaling pathway. Taken together, our results indicate that bixin is a promising therapeutic candidate for treatment of MS.
Biologically Active TNIIIA2 Region in Tenascin-C Molecule: A Major Contributor to Elicit Aggressive Malignant Phenotypes From Tumors/Tumor Stroma
Authors: Iyoda Takuya , Fujita Motomichi , Fukai Fumio
Published: December 2020

Tenascin (TN)-C is highly expressed specifically in the lesions of inflammation-related diseases, including tumors. The expression level of TN-C in tumors and the tumor stroma is positively correlated with poor prognosis. However, no drugs targeting TN-C are currently clinically available, partly because the role of TN-C in tumor progression remains controversial. TN-C harbors an alternative splicing site in its fibronectin type III repeat domain, and its splicing variants including the type III-A2 domain are frequently detected in malignant tumors. We previously identified a biologically active region termed TNIIIA2 in the fibronectin type III-A2 domain of TN-C molecule and showed that this region is involved in promoting firm and persistent cell adhesion to fibronectin. In the past decade, through the exposure of various cell lines to peptides containing the TNIIIA2 region, we have published reports demonstrating the ability of the TNIIIA2 region to modulate distinct cellular activities, including survival/growth, migration, and invasion. Recently, we reported that the signals derived from TNIIIA2-mediated β1 integrin activation might play a crucial role for inducing malignant behavior of glioblastoma (GBM). GBM cells exposed to the TNIIIA2 region showed not only exacerbation of PDGF-dependent proliferation, but also acceleration of disseminative migration. On the other hand, we also found that the pro-inflammatory phenotypic changes were promoted when macrophages are stimulated with TNIIIA2 region in relatively low concentration and resulting MMP-9 upregulation is needed to release of the TNIIIA2 region from TN-C molecule. With the contribution of TNIIIA2-stimulated macrophages, the positive feedback spiral loop, which consists of the expression of TN-C, PDGF, and β1 integrin, and TNIIIA2 release, seemed to be activated in GBM with aggressive malignancy. Actually, the growth of transplanted GBM grafts in mice was significantly suppressedviathe attenuation of β1 integrin activation. In this review, we thus introduce that the TNIIIA2 region has a significant impact on malignant progression of tumors by regulating cell adhesion. Importantly, it has been demonstrated that the TNIIIA2 region exerts unique biological functions through the extremely strong activation of β1-integrins and their long-lasting duration. These findings prompt us to develop new therapeutic agents targeting the TNIIIA2 region.
A Systematic Review and Meta-Analysis of Health Utility Estimates in Chronic Spontaneous Urticaria
Authors: Yuan Yan , Xiao Yi , Chen Xiang , Li Jie , Shen Minxue
Published: December 2020

Background:Chronic spontaneous urticaria (CSU) is a common recurrent skin disease that adversely affect patient's quality of life condition to treat. Economic evaluations of health care often include patient preferences for health outcomes using utilities.

Objectives:The study aimed to determine pooled estimates of utility-based quality of life in patients with CSU.

Methods:We conducted a systematic review, meta-analysis, and meta-regression of peer-reviewed articles and conference papers that published from database inception to 31 April 2019 that reported utility estimates in patients with CSU. Scores reported with the EQ-5D, SF-6D, SF-12, and SF-36 instruments were converted to utilities using published mapping algorithms. Meta-analysis was used to calculate the pooled and meta-regression was used to examine the effects of possible factors.

Results:The pooled utility estimate for CSU was 0.68 [95% confidence interval (CI): 0.67–0.70]. The pooled utility estimate that converted from SF-36 or SF-12 was 0.66 (95% CI: 0.58–0.74), 0.72 (95% CI: 0.70–0.74) for EQ-5D, and 0.65 (95% CI: 0.63–0.67) for SF-6D, respectively. According to the meta-regression, higher proportion of female patients was significantly associated lower utility estimates (p= 0.013).

Conclusions:The study provides evidence-based utility estimates to inform health-related burden analysis of CSU and reference for the follow-up cost-effectiveness evaluation of chronic spontaneous urticaria intervention. These results highlight differences in common utility-based instruments and need to be cognizant of the specific instruments used when comparing the results of outcome studies.
D-dimer, Troponin, and Urea Level at Presentation With COVID-19 can Predict ICU Admission: A Single Centered Study
Authors: Hachim Mahmood Y. , Hachim Ibrahim Y. , Naeem Kashif Bin , Hannawi Haifa , Salmi Issa Al , Hannawi Suad
Published: December 2020

Background: Identifying clinical-features or a scoring-system to predict a benefit from hospital admission for patients with COVID-19 can be of great value for the decision-makers in the health sector. We aimed to identify differences in patients' demographic, clinical, laboratory, and radiological findings of COVID-19 positive cases to develop and validate a diagnostic-model predicting who will develop severe-form and who will need critical-care in the future.

Methods: In this observational retrospective study, COVID-19 positive cases (total 417) diagnosed in Al Kuwait Hospital, Dubai, UAE were recruited, and their prognosis in terms of admission to the hospital and the need for intensive care was reviewed until their tests turned negative. Patients were classified according to their clinical state into mild, moderate, severe, and critical. We retrieved all the baseline clinical data, laboratory, and radiological results and used them to identify parameters that can predict admission to the intensive care unit (ICU).

Results: Patients with ICU admission showed a distinct clinical, demographic as well as laboratory features when compared to patients who did not need ICU admission. This includes the elder age group, male gender, and presence of comorbidities like diabetes and history of hypertension. ROC and Precision-Recall curves showed that among all variables, D dimers (>1.5 mg/dl), Urea (>6.5 mmol/L), and Troponin (>13.5 ng/ml) could positively predict the admission to ICU in patients with COVID-19. On the other hand, decreased Lymphocyte count and albumin can predict admission to ICU in patients with COVID-19 with acceptable sensitivity (59.32, 95% CI [49.89–68.27]) and specificity (79.31, 95% CI [72.53–85.07]).

Conclusion: Using these three predictors with their cut of values can identify patients who are at risk of developing critical COVID-19 and might need aggressive intervention earlier in the course of the disease.
A Novel Ourmia-Like Mycovirus Confers Hypovirulence-Associated Traits on Fusarium oxysporum
Authors: Zhao Ying , Zhang Yuanyan , Wan Xinru , She Yuanyuan , Li Min , Xi Huijun , Xie Jiatao , Wen Caiyi
Published: December 2020

Fusarium wilt caused byFusarium oxysporumf. sp.momordicae(FoM) is an important fungal disease that affects the production of bitter gourd. Hypovirulence-associated mycoviruses have great potential and application prospects for controlling the fungal disease. In this study, a novel ourmia-like virus, namedFusarium oxysporumourmia-like virus 1 (FoOuLV1), was isolated fromFoMstrain HuN8. The viral genomic RNA is 2,712 nucleotides (nt) in length and contains an open reading frame (ORF) encoding a putative RNA-dependent RNA polymerase (RdRp) using either standard or mitochondrial codes. In strain HuN8, there was also a FoOuLV1-associated RNA segment with 1,173 nt in length with no sequence homology. Phylogenetic analysis showed that FoOuLV1 is a member of the genusMagoulivirusof the familyBotourmiaviridae. FoOuLV1 was found to be associated with hypovirulence inFoM. Moreover, FoOuLV1 and its hypovirulence trait can be transmitted horizontally to otherFoMstrains and also to other formae speciale strains ofF. oxysporum. In addition, FoOuLV1 showed significant biological control effect against the bitter gourd Fusarium wilt. To our knowledge, this study reveals the first description of a hypovirulence-associated ourmia-like mycovirus, which has the potential to the biological control of Fusarium wilt.
Dietary Inulin Supplementation Modulates Short-Chain Fatty Acid Levels and Cecum Microbiota Composition and Function in Chickens Infected With Salmonella
Authors: Song Jiao , Li Qinghe , Everaert Nadia , Liu Ranran , Zheng Maiqing , Zhao Guiping , Wen Jie
Published: December 2020

The current study investigated the effects of inulin on the gut microbiota, microbiome functions, and short-chain fatty acids (SCFAs) levels in specific pathogen-free (SPF) chickens infected with Salmonella enteritidis (SE). SPF Arbor Acres chickens (n = 240, 1-day-old) were divided into four groups: a control group (CON) fed a basal diet without inulin supplementation or SE infection, and three groups fed a basal diet supplemented with inulin 0, 0.5, and 1% (SE, 0.5%InSE, 1%InSE, respectively) up to 28-days-old, followed by SE challenge at 28 days of age. Cecal SCFA contents and microbiome composition and function were analyzed at 1-day post-infection. The results showed that SE infection significantly decreased cecal butyrate concentrations compared with the CON group (p < 0.05), while inulin supplementation reversed these changes compared with the SE group (p < 0.05). Inulin supplementation at 1% significantly increased the abundances of Lactobacillus and Streptococcus, and significantly decreased the abundances of Subdoligranulum and Sellimonas compared with the SE group (p < 0.05). The functional profiles of microbial communities based on metagenomic sequencing analysis showed that SE infection significantly increased the abundances of pathways related to carbohydrate metabolism, amino acid metabolism, energy metabolism, metabolism of cofactors and vitamins, and glycan biosynthesis and metabolism (p < 0.05), and significantly decreased the abundances of pathways related to nucleotide metabolism, translation, and replication and repair compared with the CON group (p < 0.05), and these effects were reversed by inulin supplementation (0.5 and 1%) (p < 0.05). In conclusion, inulin modulated the dysbiosis induced by SE infection via affecting SCFA metabolism and microbial functional profiles.