bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA methylation markers for cancer risk prediction of vulvar intraepithelial neoplasia
Authors: Thuijs Nikki B. , Berkhof Johannes , Özer Müjde , Duin Sylvia , van Splunter Annina P. , Snoek Barbara C. , Heideman Daniëlle A. M. , van Beurden Marc , Steenbergen Renske D. M. , Bleeker Maaike C. G. 
Published: January 2021

AbstractCurrent clinical and histological classifications are unable to determine the risk of vulvar squamous cell carcinoma (VSCC) in high‐grade vulvar intraepithelial neoplasia (VIN), making prognostic biomarkers highly needed. We studied host‐cell DNA methylation markers in high‐grade squamous intraepithelial lesion (HSIL) and differentiated VIN (dVIN) without VSCC, in HSIL and dVIN adjacent to VSCC and in human papillomavirus (HPV) positive and negative VSCC, relative to control vulvar tissues. A series of 192 formalin‐fixed paraffin‐embedded vulvar samples, including VSCC (n = 58), VIN adjacent to VSCC (n = 30), VIN without VSCC during follow‐up (n = 41) and normal vulvar tissues (n = 63), were tested for 12 DNA methylation markers with quantitative multiplex methylation‐specific PCR (qMSP). HPV status was determined by p16INK4A immunohistochemistry and high‐risk HPV PCR analysis. Logistic regression analyses were used to determine methylation patterns and methylation marker performance for VIN and VSCC detection. Methylation markers showed significantly higher methylation levels with increasing severity of disease. VIN adjacent to VSCC showed a similar methylation‐high pattern as VSCC, while VIN without VSCC displayed a heterogeneous methylation pattern. Vulvar carcinogenesis is associated with increased DNA methylation. Higher DNA methylation levels in VIN seem to reflect higher cancer risk, emphasizing the high potential of DNA methylation biomarkers in the diagnostic workup of VIN. As a next step, longitudinal studies are needed to verify the prognostic value of methylation biomarkers as a clinical tool for stratification of cancer risk in women with VIN.
International trade and economic growth: The role of institutional factors and ethnic diversity in sub‐Saharan Africa
Authors: Coulibaly Romaric Gninlgonakan 
Published: January 2021

AbstractThe aim of this article is to analyse the role of trade on sub‐Saharan countries growth considering the effect of governance and ethnic diversity. We start by the framework of the augmented Solow growth model in which we include a set of control variables like trade as openness measure. The estimated model uses Pooled Mean Group technique on a sample of 44 countries of sub‐Saharan Africa during 1980–2017. It emerges that trade has a positive and significant influence on per capita income in the sub‐Saharan zone. This positive effect can also be empowered by improving the level of governance and by ethnic fragmentation. This fact shows the importance of a good political governance and the mastering of trade policies to gain more from trade openness for these countries.
Systems Engineering the Conditions of the Possibility (Towards Systems Engineering v2.0)
Authors: Willett Keith D. 
Published: January 2021

ABSTRACTTraditional systems engineering's focus is on cause and effect. When we turn a wheel, pull a lever, or flip a switch we expect a certain outcome. This is a rules‐based approach where stimulus‐response is deterministic in a well‐defined, well‐bounded, finite, and predominantly static system. If anything deviates from the expected, simple systemic structures (logic gates) or simple rules (if‐then‐else) provide optional preplanned action. Human intervention provides the intelligence and action necessary for dynamic adjustment to a negative event (adversity, avoid loss) or detecting and dynamically adjusting to a positive event (opportunity, seek gain). The now and future discipline of systems engineering (systems engineering v2.0) has the tools to transcend cause‐effect and effectively embrace the nondeterministic, flexibly defined, blurred‐boundaries, highly combinatorial if not infinite, and adaptability. Systems engineers can design solutions to adapt to predictable and unpredictable change for the system to remain viable while encountering adversity (loss‐driven) and relevant when threatened by obsolescence (opportunity‐driven). In addition to cause and effect, systems engineering v2.0 is systems engineering the conditions of the possibility.This paper does not intend to provide answers, but provides a framework for discerning better questions and eliciting research in the many technical areas providing continual dynamic adaptation of complex socio‐technical systems of systems. Realizing systems engineering v2.0 will come from the hard work of many over years. We are already on the way with this being one more step toward formalizing a new discipline.
Toxicity evaluation of mesoporous silica particles Santa Barbara No. 15 amorphous in human umbilical vein endothelial cells: influence of particle morphology
Authors: Teng Wenqi , Yang Zhaogang , Wang Suiping , Xiong Di , Chen Yifei , Wu Zhimin 
Published: January 2021

AbstractMorphology plays a vital role in determining the biological effects of silica nanoparticles (NPs), but its influence on the toxicity of silica NPs in endothelial cells (ECs) is still inconclusive. We synthesized five kinds of Santa Barbara 15 amorphous (SBA‐15) particles with different shapes and added them to human umbilical vein endothelial cells (HUVEC). After 24 After incubation and treatment with 100 ml, more than 80% of the cells are still alive. The microgram/ml of SBA‐15 indicates that SBA‐15 has high biocompatibility. Fibrous SBA‐15 (5) leads to the highest Si element concentration in HUVEC. No NP reduces the release of NO, and NO is an important signaling molecule in the vascular system. Only the aggregated spherical SBA‐15 (3) will moderately reduce the endothelial nitric oxide synthase (eNOS) protein. Regarding transcription factors regulating eNOS, we found that all SBA‐15 types significantly increased Kruppel‐like factor 2 (KLF2) protein, irregular SBA‐15 (1), non‐aggregated spherical SBA‐15 (2) and aggregation The spherical SBA‐15 (3) greatly reduces KLF4 by more than 50%. Overall, our results indicate that SBA‐15 with different morphologies can be internalized into HUVEC and only cause moderate cytotoxicity. All silica NPs have the smallest effect on the NO‐eNOS pathway, but the irregular spherical SBA‐15 reduces the eNOS modifier KLF4. The rod‐shaped SBA‐15 (4) seems to have higher biocompatibility because they are internalized and have negligible adverse effects on HUVEC. These results provide new evidence for the toxic effects of different forms of silica nanoparticles on HUVEC.
Wnt16 Elicits a Protective Effect Against Fractures and Supports Bone Repair in Zebrafish
Authors: McGowan Lucy M , Kague Erika , Vorster Alistair , Newham Elis , Cross Stephen , Hammond Chrissy L 
Published: January 2021

ABSTRACTBone homeostasis is a dynamic, multicellular process that is required throughout life to maintain bone integrity, prevent fracture, and respond to skeletal damage. WNT16 has been linked to bone fragility and osteoporosis in human genome wide‐association studies, as well as the functional hematopoiesis of leukocytes in vivo. However, the mechanisms by which WNT16 promotes bone health and repair are not fully understood. In this study, CRISPR‐Cas9 was used to generate mutant zebrafish lacking Wnt16 (wnt16−/−) to study its effect on bone dynamically. The wnt16 mutants displayed variable tissue mineral density (TMD) and were susceptible to spontaneous fractures and the accumulation of bone calluses at an early age. Fractures were induced in the lepidotrichia of the caudal fins of wnt16−/− and WT zebrafish; this model was used to probe the mechanisms by which Wnt16 regulates skeletal and immune cell dynamics in vivo. In WT fins, wnt16 expression increased significantly during the early stages for bone repair. Mineralization of bone during fracture repair was significantly delayed in wnt16 mutants compared with WT zebrafish. Surprisingly, there was no evidence that the recruitment of innate immune cells to fractures or soft callus formation was altered in wnt16 mutants. However, osteoblast recruitment was significantly delayed in wnt16 mutants postfracture, coinciding with precocious activation of the canonical Wnt signaling pathway. In situ hybridization suggests that canonical Wnt‐responsive cells within fractures are osteoblast progenitors, and that osteoblast differentiation during bone repair is coordinated by the dynamic expression of runx2a and wnt16. This study highlights zebrafish as an emerging model for functionally validating osteoporosis–associated genes and investigating fracture repair dynamically in vivo. Using this model, it was found that Wnt16 protects against fracture and supports bone repair, likely by modulating canonical Wnt activity via runx2a to facilitate osteoblast differentiation and bone matrix deposition. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
Severity of Megakaryocyte-Driven Osteosclerosis in Mpig6b-Deficient Mice Is Sex-Linked
Authors: Stavnichuk Mariya , Tauer Josephine T , Nagy Zoltan , Mazharian Alexandra , Welman Mélanie , Lordkipanidzé Marie , Senis Yotis A , Komarova Svetlana V 
Published: January 2021

ABSTRACT
Patients with chronic myelofibrosis often suffer from osteosclerosis, which is associated with bone pain and may lead to bone marrow failure. The pathogenesis of myelofibrosis is linked to aberrant megakaryocyte development and function. Null and loss-of-function mutations in MPIG6B, which codes for the inhibitory heparan sulfate receptor G6b-B, result in severe macrothrombocytopenia, large megakaryocyte clusters, and focal primary myelofibrosis in mice and humans. We investigated the development of osteosclerosis in Mpig6b null (Mpig6b−/−) mice. Although male and female Mpig6b−/− mice presented with elevated bone marrow megakaryocyte number and macrothrombocytopenia, female Mpig6b−/− mice developed progressive splenomegaly starting at 8 weeks of age. Micro–computed tomography (μCT) of femurs showed that female Mpig6b−/− mice had increased cortical thickness and reduced bone marrow area starting at 8 weeks of age and developed occlusion of the medullary cavity by trabeculae by 16 weeks of age. In contrast, male Mpig6b−/− mice developed only a small number of trabeculae in the medullary cavity at the proximal diaphysis and demonstrated a temporary decrease in bone volume fraction and trabecular thickness at 16 weeks. Ovariectomy of 10-week-old female Mpig6b−/− mice prevented the development of medullary cavity osteosclerosis, whereas orchiectomy of male Mpig6b−/− mice did not exacerbate their disease. Importantly, ovariectomized female Mpig6b−/− mice also demonstrated improvement in spleen weight compared to sham-operated Mpig6b−/− mice, establishing estrogen as a contributing factor to the severity of the megakaryocyte-driven osteosclerosis. © 2021 American Society for Bone and Mineral Research (ASBMR).
miR‐101‐loaded exosomes secreted by bone marrow mesenchymal stem cells requires the FBXW7/HIF1α/FOXP3 axis, facilitating osteogenic differentiation
Authors: Li Yanhong , Wang Jing , Ma Yanchao , Du Wenjia , Feng Kai , Wang Shuanke 
Published: January 2021

AbstractExosomes derived from mesenchymal stem cells (MSCs) have emerged as significant mediators of intercellular communication, with studies highlighting their role in the transmission of biological signals between cells. Dominant microRNA (miRNA)‐mediated translational repression of messenger RNAs has been extensively investigated in regard to its influence in orchestrating osteogenic differentiation. In the current study, we sought to ascertain the contributory role of miRNA‐101 (miR‐101) encapsulated in the process of bone marrow mesenchymal stem cell (BMSC)‐derived exosomes in osteogenic differentiation. Exosomes were initially extracted from BMSCs at Days 0, 3, 12, and 21 of osteogenic differentiation by ultracentrifugation. Artificial modulation of miR‐101 and FBXW7 (silencing and overexpression) were performed in the BMSCs to identify its effects on osteogenic factors, alkaline phosphatase activity, and osteogenic differentiation. Mechanistic exploration was performed to evaluate the binding affinity between miR‐101 and FBXW7, the FBXW7‐mediated HIF1α ubiquitination, and the HIF1α enrichment in the FOXP3 promoter region. Exosomes from MSCs in the late stage of osteogenic differentiation exhibited enhanced osteogenic differentiation. Upregulated miR‐101 in MSC‐derived exosomes was detected during osteogenic differentiation, while diminished levels of FBXW7 expression was noted. Importantly, miR‐101 was found to specifically bind to the 3′‐untranslated region of FBXW7. Meanwhile, data was obtained indicating that FBXW7 could ubiquitinate and degrade HIF1α to repress its upregulation during osteogenic differentiation. HIF1α bound to the promoter region of FOXP3 to facilitate osteogenic differentiation. Ultimately, the findings of the current study demonstrate that BMSC‐derived exosomal miR‐101 augments osteogenic differentiation in MSCs by inhibiting FBXW7 to regulate the HIF1α/FOXP3 axis.
A novel strategy for engineering of a smart generation of immune ribonucleases against EGFR+ cells
Authors: Taghizadegan Nooshin , Firoozrai Mohsen , Nassiri Mohammadreza , Ariannejad Hamid 
Published: January 2021

AbstractThe overexpression of epidermal growth factor receptor (EGFR) could result in the development of solid tumors of prostate, breast, gastric, colorectal, ovarian, and head and neck, leading to carcinoma. Antibody therapies are ideal methods to overcome malignant diseases. However, immunoribonucleases are a new generation of antibodies in which an RNase binds to a specific antibody and shows a stronger ability to terminate cancer cells. In this study, we engineered Rana pipiens RNase to bind to the scFv of human antiepidermal growth factor receptor antibody. The molecular dynamic simulations confirmed protein stability and the ability of scFv−ranpirnase (rantoxin) to bind to epidermal growth factor receptor protein. Then, the rantoxin construct was synthesized in a pCDNA 3.1 Neo vector. CHO‐K1 cells were used as expression hosts and the construct was transfected. Cells were selected by antibiotic therapies using neomycin, 120 mg/ml, and the high‐yield colony was screened by real‐time polymerase chain reaction (PCR) methods. Then, the recombinant protein production was confirmed using the sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blot analyses. The molecular dynamic simulation (MDS) confirmed that the I467, S468, Q408, and H409 amino acids of EGFR bonded well to rantoxin. As revealed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS–PAGE) and western blot analyses, the rantoxin production and PCR analysis showed that the T3 colony can produce rantoxin messenger RNA fourfold higher than the GAPDH gene. The immunotoxin function was assessed in A431 cancer cells and EGFR‐negative HEK293 cells, and IC50 values were estimated to be 22.4 ± 3 and >620.4 ± 5 nM, respectively. The results indicated that the immunotoxins produced in this study had the potential for use as anticancer drugs.
Silencing of long noncoding RNA MYLK‐AS1 suppresses nephroblastoma via down‐regulation of CCNE1 through transcription factor TCF7L2
Authors: Zhu Shibo , Zhang Jingqi , Gao Xiaofeng , Tang Xiangliang , Cui Yanhong , Li Dian , Jia Wei 
Published: January 2021

AbstractNephroblastoma, a pediatric kidney cancer, caused by pluripotent embryonic renal precursors. Long noncoding RNAs (lncRNAs) are commonly abnormal expressed in many cancers. In the present study, we fousced on one newly discrovered lncRNA, MYLK Antisense RNA 1 (MYLK‐AS1), and its functional role in proliferation and cycle distribution of nephroblastoma cells. Micorarray‐based analysis revealed the highly expressed Cyclin E1 (CCNE1) and MYLK‐AS1 in nephroblastoma. After nephroblastoma tissue sample collection, RT‐qPCR confirmed the upregulated expression of MYLK‐AS1 and CCNE1 in nephroblastoma tissues and cells. Kaplan–Meier curve exhibited that patients with elevated CCNE1 had lower overall survival rate in follow‐up study. RNA binding protein immunoprecipitation, chromatin immunoprecipitation, and dual‐luciferase reporter gene assay were employed to determine the relationship among MYLK‐AS1, TCF7L2, and CCNE1, which validated that transcription factor 7‐like 2 (TCF7L2) could specifically bind to MYLK‐AS1 and TCF7L2 could positively promote CCNE1. After gain‐ and loss‐of function assays, the conclusion that silencing of MYLK‐AS1 could inhibit expression of CCNE1 through the transcription factor TCF7L2 to regulate the cell proliferation and cell cycle distribution of nephroblastoma cells was obtained. Subsequently, the subcutaneous tumor formation ability of nephroblastoma cell in nude mice was observed and the silencing of MYLK‐AS1 exerts suppressive role in the tumorigenic ability of nephroblastoma cells in vivo. Taken together, MYLK‐AS1 constitutes a promising biomarker for the early detection and treatment of nephroblastoma.
Vitamin C deficient reduces proliferation in a human periventricular tumor stem cell‐derived glioblastoma model
Authors: Jara Nery , Ramirez Eder , Ferrada Luciano , Salazar Katterine , Espinoza Francisca , González‐Chavarría Iván , Nualart Francisco 
Published: January 2021

AbstractGlioblastoma multiforme (GBM) is the most common and aggressive brain tumor with a median survival of 14.6 months. GBM is highly resistant to radio‐ and chemotherapy, and remains without a cure; hence, new treatment strategies are constantly sought. Vitamin C, an essential micronutrient and antioxidant, was initially described as an antitumor molecule; however, several studies have shown that it can promote tumor progression and angiogenesis. Thus, considering the high concentrations of vitamin C present in the brain, our aim was to study the effect of vitamin C deficiency on the progression of GBM using a GBM model generated by the stereotactic injection of human GBM cells (U87‐MG or HSVT‐C3 cells) in the subventricular zone of guinea pig brain. Initial characterization of U87‐MG and HSVT‐C3 cells showed that HSVT‐C3 are highly proliferative, overexpress p53, and are resistant to ferroptosis. To induce intraperiventricular tumors, animals received control or a vitamin C‐deficient diet for 3 weeks, after which histopathological and confocal microscopy analyses were performed. We demonstrated that the vitamin C‐deficient condition reduced the glomeruloid vasculature and microglia/macrophage infiltration in U87‐MG tumors. Furthermore, tumor size, proliferation, glomeruloid vasculature, microglia/macrophage infiltration, and invasion were reduced in C3 tumors carried by vitamin C‐deficient guinea pigs. In conclusion, the effect of the vitamin C deficiency was dependent on the tumor cell used for GBM induction. HSVT‐C3 cells, a cell line with stem cell features isolated from a human subventricular GBM, showed higher sensitivity to the deficient condition; however, vitamin C deficiency displayed an antitumor effect in both GBM models analyzed.
BKCa channel participates in insulin‐induced lipid deposition in adipocytes by increasing intracellular calcium
Authors: Ren Jie , Cheng Yuan , Wen Xinxin , Liu Ping , Zhao Feng , Xin Fang , Wang Meili , Huang Haixia , Wang Wei 
Published: January 2021

AbstractStoring energy in the form of triglyceride (TG) is one of the basic functions of adipose tissue. Large‐conductance calcium‐activated potassium channels (BKCa channels) are expressed in adipose tissue and adipocyte‐specific BKCa deficiency resists obesity in mice, but the role of BKCa channels in lipid deposition and the underlying mechanisms have not been elucidated. In the present study, we generated BKCa knockout (KO) rats and performed a transcriptome analysis of adipose tissue. We found that the phosphoinositide 3‐kinase (PI3K)–protein kinase B (Akt) signaling pathway, which is important for lipid deposition, exhibited the most notable reduction among various signaling pathways in BKCa KO rats compared to wild‐type rats. Insulin‐induced TG deposition, glucose uptake, and Akt (Ser473) phosphorylation were significantly reduced in cultured adipocytes differentiated from adipose‐derived stem cells of BKCa KO rats. Furthermore, we found that the insulin‐induced increase of intracellular calcium resulting from extracellular calcium influx was significantly impaired in BKCa KO adipocytes. Finally, insulin activated BKCa currents through PI3K, which was independent of Akt and intracellular calcium. The results of this study suggested that BKCa channels participate in the insulin signaling pathway and promote TG deposition by increasing extracellular calcium influx in adipocytes.
An unusual case of painless type A aortic dissection
Authors: Sonaglioni Andrea , Lombardo Michele , Rigamonti Elisabetta , Nicolosi Gian Luigi , Trevisan Roberta , Zompatori Maurizio , Anzà Claudio 
Published: January 2021

AbstractThe pathogenesis of acute aortic dissection (AAD) is not fully elucidated yet, but it was recently shown that inflammation contributes to the occurrence and development of both Stanford type A and type B AAD. We describe a rare case of a painless type A aortic dissection that occurred in an 85‐year‐old male, with moderate calcified aortic stenosis and a moderately dilated ascending aorta in 6‐month clinical and echocardiographic follow‐up. A chronic calculous cholecystitis with neutrophilic leukocytosis and severely increased C reactive protein was diagnosed in the last 3 months. In this patient, a chronic systemic inflammatory state might have contributed to generate the intimal entry tear in the aortic root. In particular, a neutrophil mobilization might have played a causative role in aortic rupture.
Urea nitrate–catalyzed C‐N and C‐S bond formation: A mechanochemical approach for 5‐chloro‐2‐arylbenzo[d]thiazole derivatives
Authors: Sethiya Ayushi , Sahiba Nusrat , Soni Jay , Agarwal Shikha 
Published: January 2021

AbstractA series of substituted 5‐chloro‐2‐arylbenzo[d]thiazoles were synthesized using 4‐chloro‐2‐aminothiophenol and aromatic aldehydes in the presence of urea nitrate as a catalyst using the mechanochemical grindstone technique. This protocol was effectively carried out under metal‐free conditions at room temperature, and the desired products were obtained in high to excellent yields in short reaction time (30–60 s). The structure of all the synthesized derivatives was confirmed by spectral characterization. The designed protocol has several benefits like eco‐friendly, solvent‐free, high yields, easy workup, and recyclability of catalyst. The catalyst was reusable at least four times without significant loss of activity. The good functional group tolerance with a series of derivatives has been demonstrated.