bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivo Evaluation of Fibrous Collagen Dura Substitutes
Authors: Liu Wenbo , Wang Xin , Su Jinlei , Jiang Qingsong , Wang Jing , Xu Yang , Zheng Yudong , Zhong Zhihui , Lin Hai
Published: February 2021

Dura substitutes are applied in duraplasty to repair lost or damaged dura. Collagen-based dura substitutes are mainstream products in both the US and Chinese markets. In this study, dura substitute devices with potential dura regeneration ability are evaluated. The dura substitutes are composed of fibrous type I collagen that were purified from bovine tendon. Physical and chemical characterization demonstrated that the tested dura substitute has desirable porous scaffolding structures and is composed of highly purified type I collagen. The collagen dura substitutes were further investigated in vivo with a rabbit model for 6 months to evaluate their safety and performance to repair and regenerate dura. No inflammation or infection was observed during the course of in vivo study. The integration of the collagen dura substitutes with surrounding tissue was normal as compared to native tissue. The macroscopic and microscopic histological assessments of the sampled animal tissue showed that the damaged dura were regenerated. The collagen dura substitutes were resorbed between 3 and 6 months along with newly regenerated dura. Both tissue adhesion and dura repair was the worst in blank control group as compared to those in the collagen dura substitutes. Taken together, regenerative collagen dura substitutes demonstrated with suitable physicochemical properties. The in vivo evaluation in a rabbit model further demonstrated the safety and performance of such substitutes for dura repair and regeneration.
Impact of Early Conventional Treatment on Adult Bone and Joints in a Murine Model of X-Linked Hypophosphatemia
Authors: Cauliez Axelle , Zhukouskaya Volha V. , Hilliquin Stéphane , Sadoine Jérémy , Slimani Lotfi , Miceli-Richard Corinne , Briot Karine , Linglart Agnès , Chaussain Catherine , Bardet Claire
Published: February 2021

X-linked hypophosphatemia (XLH) is the most common form of genetic rickets. Mainly diagnosed during childhood because of growth retardation and deformities of the lower limbs, the disease affects adults with early enthesopathies and joint structural damage that significantly alter patient quality of life. The conventional treatment, based on phosphorus supplementation and active vitamin D analogs, is commonly administered from early childhood to the end of growth; unfortunately, it does not allow complete recovery from skeletal damage. Despite adequate treatment during childhood, bone and joint complications occur in adults and become a dominant feature in the natural history of the disease. Our previous data showed that the Hyp mouse is a relevant model of XLH for studying early enthesophytes and joint structural damage. Here, we studied the effect of conventional treatment on the development of bone and joint alterations in this mouse model during growth and young adulthood. Mice were supplemented with oral phosphorus and calcitriol injections, following two timelines: (i) from weaning to 3 months of age and (ii) from 2 to 3 months to evaluate the effects of treatment on the development of early enthesophytes and joint alterations, and on changes in bone and joint deformities already present, respectively. We showed that early conventional treatment improved bone microarchitecture, and partially prevented bone and joint complications, but with no noticeable improvement in enthesophytes. In contrast, later administration had limited efficacy in ameliorating bone and joint alterations. Despite the improvement in bone microarchitecture, the conventional treatment, early or late, had no effect on osteoid accumulation. Our data underline the usefulness of the Hyp murine model for preclinical studies on skeletal and extraskeletal lesions. Although the early conventional treatment is important for the improvement of bone microarchitecture, the persistence of osteomalacia implies seeking new therapeutic strategies, in particular anti-FGF23 approach, in order to optimize the treatment of XLH.
THBS1/CD47 Modulates the Interaction of γ-Catenin With E-Cadherin and Participates in Epithelial–Mesenchymal Transformation in Lipid Nephrotoxicity
Authors: Gao Li , Yang Ting-ting , Zhang Jun-sheng , Liu Hong-xia , Cai Dong-cheng , Wang Lin-tao , Wang Jing , Li Xin-wei , Gao Kun , Zhang Su-ya , Cao Yu-jia , Ji Xiao-xia , Yang Miao-miao , Han Biao , Wang Sheng , He Lu , Nie Xiao-yan , Liu Dan-mei , Meng Gang , He Chao-yong
Published: February 2021

Hyperlipidemia, an important risk factor for cardiovascular and end-stage renal diseases, often aggravates renal injury and compromises kidney function. Here, histological analysis of human kidney samples revealed that high lipid levels induced the development of renal fibrosis. To elucidate the mechanism underlying lipid nephrotoxicity, we used two types of mouse models (Apoe−/− and C57BL/6 mice fed a 45 and 60% high-fat diet, respectively). Histological analysis of kidney tissues revealed high-lipid-induced renal fibrosis and inflammation; this was confirmed by examining fibrotic and inflammatory marker expression using Western blotting and real-time polymerase chain reaction. Oxidized low-density lipoprotein (OX-LDL) significantly induced the fibrotic response in HK-2 tubular epithelial cells. RNA-sequencing and Gene Ontology analysis of differentially expressed mRNAs in OX-LDL-treated HK-2 tubular epithelial cells and real-time PCR validation in Apoe−/− mice showed that the expression of thrombospondin-1 (THBS1) in the high-fat group was significantly higher than that of the other top known genes, along with significant overexpression of its receptor CD47. THBS1 knockdown cells verified its relation to OX-LDL-induced fibrosis and inflammation. Liquid chromatography tandem mass spectrometry and STRING functional protein association network analyses predicted that THBS1/CD47 modulated the interaction between γ-catenin and E-cadherin and was involved in epithelial–mesenchymal transition, which was supported by immunoprecipitation and immunohistochemistry. CD47 downregulation following transfection with small-hairpin RNA in OX-LDL-treated tubular epithelial cells and treatment with anti-CD47 antibody restored the expression of E-cadherin and attenuated renal injury, fibrosis, and inflammatory response in OX-LDL-treated cells and in type 2 diabetes mellitus. These findings indicate that CD47 may serve as a potential therapeutic target in long-term lipid-induced kidney injury.
Circular RNA POSTN Promotes Myocardial Infarction-Induced Myocardial Injury and Cardiac Remodeling by Regulating miR-96-5p/BNIP3 Axis
Authors: Cheng Nan , Wang Ming-Yan , Wu Yuan-Bin , Cui Hui-Min , Wei Shi-Xiong , Liu Bing , Wang Rong
Published: February 2021

Myocardial infarction (MI) is the most prevalent cardiac disease with high mortality, leading to severe heart injury. Circular RNAs (circRNAs) are a new type of regulatory RNAs and participate in multiple pathological cardiac progressions. However, the role of circRNAs Postn (circPostn) in MI modulation remains unclear. Here, we aimed to explore the effect of circPostn on MI-induced myocardial injury and cardiac remodeling. We identified that the expression of circPostn was elevated in the plasma of MI patients, MI mouse model, and hypoxia and reoxygenation (H/R)-treated human cardiomyocytes. The depletion of circPostn significantly attenuated MI-related myocardium injury and reduced the infarct size in MI mouse model. The circPostn knockdown obviously enhanced left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) and inhibited left ventricular anterior wall thickness at diastole (LVAWd) and left ventricular posterior wall thickness at diastole (LVPWd). The depletion of circPostn was able to decrease MI-induced expression of collagen 1α1 and collagen 3α1 in the ventricular tissues of mice. The protein expression of collagen and α-smooth muscle actin (SMA) was up-regulated in MI mice and was inhibited by circPostn knockdown. Meanwhile, the expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was repressed by circPostn depletion in the ventricular tissues of MI mice. Besides, the circPostn depletion attenuated cardiomyocyte apoptosis in mice. Mechanically, circPostn served as a miR-96-5p sponge and miR-96-5p-targeted BNIP3 in human cardiomyocytes, in which circPostn up-regulated BNIP3 expression by targeting miR-96-5p. circPostn promoted H/R-induced cardiomyocyte injury by modulating miR-96-5p/BNIP3 axis. Thus, we conclude that circPostn contributes to MI-induced myocardial injury and cardiac remodeling by regulating miR-96-5p/BNIP3 axis. Our finding provides new insight into the mechanism by which circPostn regulates MI-related cardiac dysfunction. circPostn, miR-96-5p, and BNIP3 are potential targets for the treatment of MI-caused heart injury.
Targeted Reducing of Tauopathy Alleviates Epileptic Seizures and Spatial Memory Impairment in an Optogenetically Inducible Mouse Model of Epilepsy
Authors: Gao Yang , Zheng Jie , Jiang Tao , Pi Guilin , Sun Fei , Xiong Rui , Wang Weijin , Wu Dongqin , Li Shihong , Lei Huiyang , Yu Huiling , Zhou Qiuzhi , Yang Ying , Zhang Huaqiu , Wang Jian-Zhi
Published: February 2021

Intracellular deposition of hyperphosphorylated tau has been reported in the brain of epilepsy patients, but its contribution to epileptic seizures and the association with spatial cognitive functions remain unclear. Here, we found that repeated optogenetic stimulation of the excitatory neurons in ventral hippocampal CA1 subset could induce a controllable epileptic seizure in mice. Simultaneously, the mice showed spatial learning and memory deficits with a prominently elevated total tau and phospho-tau levels in the brain. Importantly, selective facilitating tau degradation by using a novel designed proteolysis-targeting chimera named C4 could effectively ameliorate the epileptic seizures with remarkable restoration of neuronal firing activities and improvement of spatial learning and memory functions. These results confirm that abnormal tau accumulation plays a pivotal role in the epileptic seizures and the epilepsy-associated spatial memory impairments, which provides new molecular target for the therapeutics.
Analysis of Differentially Expressed Genes in Endothelial Cells Following Tumor Cell Adhesion, and the Role of PRKAA2 and miR-124-3p
Authors: Pan Yan , Abdureyim Marhaba , Yao Qing , Li Xuejun
Published: February 2021

Tumor cell adhesion to the endothelium is one pattern of tumor–endothelium interaction and a key step during tumor metastasis. Endothelium integrity is an important barrier to prevent tumor invasion and metastasis. Changes in endothelial cells (ECs) due to tumor cell adhesion provide important signaling mechanisms for the angiogenesis and metastasis of tumor cells. However, the changes happened in endothelial cells when tumor–endothelium interactions are still unclear. In this study, we used Affymetrix Gene Chip Human Transcriptome Array 2.0. and quantitative real-time PCR (qPCR) to clarify the detailed gene alteration in endothelial cells adhered by prostate tumor cells PC-3M. A total of 504 differentially expressed mRNAs and 444 lncRNAs were obtained through chip data analysis. Gene Ontology (GO) function analysis showed that differentially expressed genes (DEGs) mainly mediated gland development and DNA replication at the biological level; at the cell component level, they were mainly involved in the mitochondrial inner membrane; and at the molecular function level, DEGs were mainly enriched in ATPase activity and catalytic activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway analysis showed that the DEGs mainly regulated pathways in cancer, cell cycle, pyrimidine metabolism, and the mTOR signaling pathway. Then, we constructed a protein–protein interaction functional network and mRNA–lncRNA interaction network using Cytoscape v3.7.2. to identify core genes, mRNAs, and lncRNAs. The miRNAs targeted by the core mRNA PRKAA2 were predicted using databases (miRDB, RNA22, and Targetscan). The qPCR results showed that miR-124-3p, the predicted target miRNA of PRKAA2, was significantly downregulated in endothelial cells adhered by PC-3M. With a dual luciferase reporter assay, the binding of miR-124-3p with PRKAA2 3’UTR was confirmed. Additionally, by using the knockdown lentiviral vectors of miR-124-3p to downregulate the miR-124-3p expression level in endothelial cells, we found that the expression level of PRKAA2 increased accordingly. Taken together, the adhesion of tumor cells had a significant effect on mRNAs and lncRNAs in the endothelial cells, in which PRKAA2 is a notable changed molecule and miR-124-3p could regulate its expression and function in endothelial cells.
Genotype-Phenotype Analysis and Mutation Spectrum in a Cohort of Chinese Patients With Congenital Nystagmus
Authors: Wang Xiao-Fang , Chen Hui , Huang Peng-Juan , Feng Zhuo-Kun , Hua Zi-Qi , Feng Xiang , Han Fang , Xu Xiao-Tao , Shen Ren-Juan , Li Yang , Jin Zi-Bing , Yu Huan-Yun
Published: February 2021

Purpose: Congenital nystagmus (CN) is a genetically and clinically heterogeneous ocular disorder that manifests as involuntary, periodic oscillations of the eyes. To date, only FRMD7 and GPR143 have been reported to be responsible for causing CN. Here, we aimed to identify the disease-causing mutations and describe the clinical features in the affected members in our study.

Methods: All the subjects underwent a detailed ophthalmic examination. Direct sequencing of all coding exons and splice site regions in FRMD7 and GPR143 and a mutation assessment were performed in each patient.

Results: We found 14 mutations in 14/37 (37.8%) probands, including nine mutations in the FRMD7 gene and five mutations in the GPR143 gene, seven of which are novel, including c.284G>A(R95K), c.964C>T(P322S), c.284+10T>G, c.901T>C (Y301H), and c.2014_2023delTCACCCATGG(S672Pfs*12) in FRMD7, and c.250+1G>C, and c.485G>A (W162*) in GPR143. The mutation detection rate was 87.5% (7/8) of familial vs. 24.1% (7/29) of sporadic cases. Ten mutations in 24 (41.7%) non-syndromic subjects and 4 mutations in 13(30.8%) syndromic subjects were detected. A total of 77.8% (7/9) of mutations in FRMD7 were concentrated within the FERM and FA domains, while all mutations in GPR143 were located in exons 1, 2, 4 and 6. We observed that visual acuity tended to be worse in the GPR143 group than in the FRMD7 group, and no obvious difference in other clinical manifestations was found through comparisons in different groups of patients.

Conclusions: This study identified 14 mutations (seven novel and seven known) in eight familial and 29 sporadic patients with congenital nystagmus, expanding the mutational spectrum and validating FRMD7 and GPR143 as mutation hotspots. These findings also revealed a significant difference in the screening rate between different groups of participants, providing new insights for the strategy of genetic screening and early clinical diagnosis of CN.
Hydrogen Sulfide Plays an Important Role in Diabetic Cardiomyopathy
Authors: Zhao Shizhen , Li Xiaotian , Li Xinping , Wei Xiaoyun , Wang Honggang
Published: February 2021

Diabetic cardiomyopathy is an important complication of diabetes mellitus and the main cause of diabetes death. Diabetic cardiomyopathy is related with many factors, such as hyperglycemia, lipid accumulation, oxidative stress, myocarditis, and apoptosis. Hydrogen sulfide (H2S) is a newly discovered signal molecule, which plays an important role in many physiological and pathological processes. Recent studies have shown that H2S is involved in improving diabetic cardiomyopathy, but its mechanism has not been fully elucidated. This review summarizes the research on the roles and mechanisms of H2S in diabetic cardiomyopathy in recent years to provide the basis for in-depth research in the future.
Tendon Stem/Progenitor Cell Subpopulations and Their Implications in Tendon Biology
Authors: Huang Zizhan , Yin Zi , Xu Jialu , Fei Yang , Heng Boon Chin , Jiang Xuesheng , Chen Weishan , Shen Weiliang
Published: February 2021

Tendon harbors a cell population that possesses stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity, commonly referred to as tendon stem/progenitor cells (TSPCs). Various techniques have been employed to study how TSPCs are implicated in tendon development, homeostasis and healing. Recent advances in single-cell analysis have enabled much progress in identifying and characterizing distinct subpopulations of TSPCs, which provides a more comprehensive view of TSPCs function in tendon biology. Understanding the mechanisms of physiological and pathological processes regulated by TSPCs, especially a particular subpopulation, would greatly benefit treatment of diseased tendons. Here, we summarize the current scientific literature on the various subpopulations of TSPCs, and discuss how TSPCs can contribute to tissue homeostasis and pathogenesis, as well as examine the key modulatory signaling pathways that determine stem/progenitor cell state. A better understanding of the roles that TSPCs play in tendon biology may facilitate the development of novel treatment strategies for tendon diseases.
Contributions of Embryonic HSC-Independent Hematopoiesis to Organogenesis and the Adult Hematopoietic System
Authors: Neo Wen Hao , Lie-A-Ling Michael , Fadlullah Muhammad Zaki Hidayatullah , Lacaud Georges
Published: February 2021

During ontogeny, the establishment of the hematopoietic system takes place in several phases, separated both in time and location. The process is initiated extra-embryonically in the yolk sac (YS) and concludes in the main arteries of the embryo with the formation of hematopoietic stem cells (HSC). Initially, it was thought that HSC-independent hematopoietic YS cells were transient, and only required to bridge the gap to HSC activity. However, in recent years it has become clear that these cells also contribute to embryonic organogenesis, including the emergence of HSCs. Furthermore, some of these early HSC-independent YS cells persist into adulthood as distinct hematopoietic populations. These previously unrecognized abilities of embryonic HSC-independent hematopoietic cells constitute a new field of interest. Here, we aim to provide a succinct overview of the current knowledge regarding the contribution of YS-derived hematopoietic cells to the development of the embryo and the adult hematopoietic system.
Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions
Authors: Wang Junwen , Xiao Xueshan , Li Shiqiang , Wang Panfeng , Sun Wenmin , Zhang Qingjiong
Published: February 2021

RP1 truncation variants, including frameshift, nonsense, and splicing, are a common cause of retinitis pigmentosa (RP). RP1 is a unique gene where truncations cause either autosomal dominant RP (adRP) or autosomal recessive RP (arRP) depending on the location of the variants. This study aims to clarify the boundaries between adRP and arRP caused by RP1 truncation variants based on a systemic analysis of 165 RP1 variants from our in-house exome-sequencing data of 7,092 individuals as well as a thorough review of 185 RP1 variants from published literature. In our cohort, potential pathogenic variants were detected in 16 families, including 11 new and five previously described families. Of the 16, seven families with adRP had heterozygous truncations in the middle portion, while nine families with either arRP (eight) or macular degeneration had biallelic variants in the N- and C-terminals, involving 10 known and seven novel variants. In the literature, 147 truncations in RP1 were reported to be responsible for either arRP (85) or adRP (58) or both (four). An overall evaluation of RP1 causative variants suggested three separate regions, i.e., the N-terminal from c.1 (p.1) to c.1837 (p.613), the middle portion from c.1981 (p.661) to c.2749 (p.917), and the C-terminal from c.2816 (p.939) to c.6471 (p.2157), where truncations in the middle portion were associated with adRP, while those in the N- and C-terminals were responsible for arRP. Heterozygous truncations alone in the N- and C- terminals were unlikely pathogenic. However, conflict reports with reverse situation were present for 13 variants, suggesting a complicated pathogenicity awaiting to be further elucidated. In addition, pathogenicity for homozygous truncations around c.5797 and thereafter might also need to be further clarified, so as for missense variants and for truncations located in the two gaps. Our data not only confirmed and refined the boundaries between dominant and recessive RP1 truncations but also revealed unsolved questions valuable for further investigation. These findings remind us that great care is needed in interpreting the results of RP1 variants in clinical gene testing as well as similar features may also be present in some other genes.
Caldesmon: Biochemical and Clinical Implications in Cancer
Authors: Yao Yi-Bo , Xiao Chang-Fang , Lu Jin-Gen , Wang Chen
Published: February 2021

Caldesmon, an actin-binding protein, can inhibit myosin binding to actin and regulate smooth muscle contraction and relaxation. However, caldesmon has recently attracted attention due to its importance in cancer. The upregulation of caldesmon in several solid cancer tissues has been reported. Caldesmon, as well as its two isoforms, is considered as a biomarker for cancer and a potent suppressor of cancer cell invasion by regulating podosome/invadopodium formation. Therefore, caldesmon may be a promising therapeutic target for diseases such as cancer. Here, we review new studies on the gene transcription, isoform structure, expression, and phosphorylation regulation of caldesmon and discuss its clinical implications in cancer.
Tissue Mechanics in Haired Murine Skin: Potential Implications for Skin Aging
Authors: Harn Hans I-Chen , Chen Chih-Chiang , Wang Sheng-Pei , Lei Mingxing , Chuong Cheng-Ming
Published: February 2021

During aging, the skin undergoes changes in architecture and composition. Skin aging phenotypes occur due to accumulated changes in the genome/epigenome, cytokine/cell adhesion, cell distribution/extracellular matrix (ECM), etc. Here we review data suggesting that tissue mechanics also plays a role in skin aging. While mouse and human skin share some similarities, their skin architectures differ in some respects. However, we use recent research in haired murine skin because of the available experimental data. Skin suffers from changes in both its appendages and inter-appendage regions. The elderly exhibit wrinkles and loose dermis and are more likely to suffer from wounds and superficial abrasions with poor healing. They also have a reduction in the number of skin appendages. While telogen is prolonged in aging murine skin, hair follicle stem cells can be rejuvenated to enter anagen if transplanted to a young skin environment. We highlight recent single-cell analyses performed on epidermis and aging human skin which identified new basal cell subpopulations that shift in response to wounding. This may be due to alterations of basement membrane stiffness which would change tissue mechanics in aging skin, leading to altered homeostatic dynamics. We propose that the extracellular matrix (ECM) may play a key role as a chemo-mechanical integrator of the multi-layered senescence-associated signaling pathways, dictating the tissue mechanical landscape of niche microenvironments in aging phenotypes. We show examples where failed chemo-mechanical signaling leads to deteriorating homeostasis during skin aging and suggest potential therapeutic strategies to guide future research to delay the aging processes.
Chromatin and Epigenetic Rearrangements in Embryonic Stem Cell Fate Transitions
Authors: Sun Li , Fu Xiuling , Ma Gang , Hutchins Andrew P.
Published: February 2021

A major event in embryonic development is the rearrangement of epigenetic information as the somatic genome is reprogrammed for a new round of organismal development. Epigenetic data are held in chemical modifications on DNA and histones, and there are dramatic and dynamic changes in these marks during embryogenesis. However, the mechanisms behind this intricate process and how it is regulating and responding to embryonic development remain unclear. As embryos develop from totipotency to pluripotency, they pass through several distinct stages that can be captured permanently or transientlyin vitro. Pluripotent naïve cells resemble the early epiblast, primed cells resemble the late epiblast, and blastomere-like cells have been isolated, although fully totipotent cells remain elusive. Experiments using thesein vitromodel systems have led to insights into chromatin changes in embryonic development, which has informed exploration of pre-implantation embryos. Intriguingly, human and mouse cells rely on different signaling and epigenetic pathways, and it remains a mystery why this variation exists. In this review, we will summarize the chromatin rearrangements in early embryonic development, drawing from genomic data fromin vitrocell lines, and human and mouse embryos.
A Biomimetic Biphasic Scaffold Consisting of Decellularized Cartilage and Decalcified Bone Matrixes for Osteochondral Defect Repair
Authors: Cao Runfeng , Zhan Anqi , Ci Zheng , Wang Cheng , She Yunlang , Xu Yong , Xiao Kaiyan , Xia Huitang , Shen Li , Meng Depeng , Chen Chang
Published: February 2021

It is challenging to develop a biphasic scaffold with biomimetic compositional, structural, and functional properties to achieve concomitant repair of both superficial cartilage and subchondral bone in osteochondral defects (OCDs). This study developed a biomimsubchondraletic biphasic scaffold for OCD repair via an iterative layered lyophilization technique that controlled the composition, substrate stiffness, and pore size in each phase of the scaffold. The biphasic scaffold consisted of a superficial decellularized cartilage matrix (DCM) and underlying decalcified bone matrix (DBM) with distinct but seamlessly integrated phases that mimicked the composition and structure of osteochondral tissue, in which the DCM phase had relative low stiffness and small pores (approximately 134 μm) and the DBM phase had relative higher stiffness and larger pores (approximately 336 μm). In vitro results indicated that the biphasic scaffold was biocompatible for bone morrow stem cells (BMSCs) adhesion and proliferation, and the superficial DCM phase promoted chondrogenic differentiation of BMSCs, as indicated by the up-regulation of cartilage-specific gene expression (ACAN, Collagen II, and SOX9) and sGAG secretion; whereas the DBM phase was inducive for osteogenic differentiation of BMSCs, as indicated by the up-regulation of bone-specific gene expression (Collagen I, OCN, and RUNX2) and ALP deposition. Furthermore, compared with the untreated control group, the biphasic scaffold significantly enhanced concomitant repair of superficial cartilage and underlying subchondral bone in a rabbit OCD model, as evidenced by the ICRS macroscopic and O’Driscoll histological assessments. Our results demonstrate that the biomimetic biphasic scaffold has a good osteochondral repair effect.
Identification of a Potentially Functional microRNA–mRNA Regulatory Network in Lung Adenocarcinoma Using a Bioinformatics Analysis
Authors: Wang Xiao-Jun , Gao Jing , Wang Zhuo , Yu Qin
Published: February 2021

Background

Lung adenocarcinoma (LUAD) is a common lung cancer with a high mortality, for which microRNAs (miRNAs) play a vital role in its regulation. Multiple messenger RNAs (mRNAs) may be regulated by miRNAs, involved in LUAD tumorigenesis and progression. However, the miRNA–mRNA regulatory network involved in LUAD has not been fully elucidated.

Methods

Differentially expressed miRNAs and mRNA were derived from the Cancer Genome Atlas (TCGA) dataset in tissue samples and from our microarray data in plasma (GSE151963). Then, common differentially expressed (Co-DE) miRNAs were obtained through intersected analyses between the above two datasets. An overlap was applied to confirm the Co-DEmRNAs identified both in targeted mRNAs and DEmRNAs in TCGA. A miRNA–mRNA regulatory network was constructed using Cytoscape. The top five miRNA were identified as hub miRNA by degrees in the network. The functions and signaling pathways associated with the hub miRNA-targeted genes were revealed through Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The key mRNAs in the protein–protein interaction (PPI) network were identified using the STRING database and CytoHubba. Survival analyses were performed using Gene Expression Profiling Interactive Analysis (GEPIA).

Results

The miRNA–mRNA regulatory network consists of 19 Co-DEmiRNAs and 760 Co-DEmRNAs. The five miRNAs (miR-539-5p, miR-656-3p, miR-2110, let-7b-5p, and miR-92b-3p) in the network were identified as hub miRNAs by degrees (>100). The 677 Co-DEmRNAs were targeted mRNAs from the five hub miRNAs, showing the roles in the functional analyses of the GO analysis and KEGG pathways (inclusion criteria: 836 and 48, respectively). The PPI network and Cytoscape analyses revealed that the top ten key mRNAs were NOTCH1, MMP2, IGF1, KDR, SPP1, FLT1, HGF, TEK, ANGPT1, and PDGFB. SPP1 and HGF emerged as hub genes through survival analysis. A high SPP1 expression indicated a poor survival, whereas HGF positively associated with survival outcomes in LUAD.

Conclusion

This study investigated a miRNA–mRNA regulatory network associated with LUAD, exploring the hub miRNAs and potential functions of mRNA in the network. These findings contribute to identify new prognostic markers and therapeutic targets for LUAD patients in clinical settings.
The Interplay Between Tumor Suppressor p53 and Hypoxia Signaling Pathways in Cancer
Authors: Zhang Cen , Liu Juan , Wang Jianming , Zhang Tianliang , Xu Dandan , Hu Wenwei , Feng Zhaohui
Published: February 2021

Hypoxia is a hallmark of solid tumors and plays a critical role in different steps of tumor progression, including proliferation, survival, angiogenesis, metastasis, metabolic reprogramming, and stemness of cancer cells. Activation of the hypoxia-inducible factor (HIF) signaling plays a critical role in regulating hypoxic responses in tumors. As a key tumor suppressor and transcription factor, p53 responds to a wide variety of stress signals, including hypoxia, and selectively transcribes its target genes to regulate various cellular responses to exert its function in tumor suppression. Studies have demonstrated a close but complex interplay between hypoxia and p53 signaling pathways. The p53 levels and activities can be regulated by the hypoxia and HIF signaling differently depending on the cell/tissue type and the severity and duration of hypoxia. On the other hand, p53 regulates the hypoxia and HIF signaling at multiple levels. Many tumor-associated mutant p53 proteins display gain-of-function (GOF) oncogenic activities to promote cancer progression. Emerging evidence has also shown that GOF mutant p53 can promote cancer progression through its interplay with the hypoxia and HIF signaling pathway. In this review, we summarize our current understanding of the interplay between the hypoxia and p53 signaling pathways, its impact upon cancer progression, and its potential application in cancer therapy.
Azole Resistance in Aspergillus fumigatus: A Five-Year Follow Up Experience in a Tertiary Hospital With a Special Focus on Cystic Fibrosis
Authors: Guegan Hélène , Prat Emilie , Robert-Gangneux Florence , Gangneux Jean-Pierre
Published: February 2021

Azole-resistant Aspergillus fumigatus (ARAf) has emerged worldwide during the last decades. Drug pressure after long term treatments of chronically infected patients and the propagation of environmental clones selected under the pressure of imidazoles fungicides used in agriculture and farming both account for this emergence. The objectives of this study were to determine the rate of azole resistance in Aspergillus fumigatus during a 5-year period, taking into account (i) differences between underlying diseases of the patients treated, (ii) cross-resistance between azoles, and (iii) focusing on the 5-year evolution of our center’s cystic fibrosis cohort. Overall, the rates of voriconazole (VRC)-resistant and itraconazole (ITC)-resistant A. fumigatus isolates were 4.1% (38/927) and 14.5% (95/656), respectively, corresponding to 21/426 (4.9%) and 44/308 (14.3%) patients, respectively. Regarding cross-resistance, among VRC-R isolates tested for ITC, nearly all were R (20/21;95%), compared to only 27% (20/74) of VRC-R among ITC-R isolates. The level of azole resistance remained somewhat stable over years but greatly varied according to the azole drug, patient origin, and clinical setting. Whereas azole resistance during invasive aspergillosis was very scarce, patients with cystic fibrosis were infected with multiple strains and presented the highest rate of resistance: 5% (27/539) isolates were VRC-R and 17.9% (78/436) were ITC-R. These results underline that the interpretation of the azole resistance level in Aspergilllus fumigatus in a routine setting may consider the huge variability depending on the azole drug, the clinical setting, the patient background and the type of infection.
Subgroup Invariant Perturbation for Unbiased Pre-Trained Model Prediction
Authors: Majumdar Puspita , Chhabra Saheb , Singh Richa , Vatsa Mayank
Published: February 2021

Modern deep learning systems have achieved unparalleled success and several applications have significantly benefited due to these technological advancements. However, these systems have also shown vulnerabilities with strong implications on the fairness and trustability of such systems. Among these vulnerabilities, bias has been an Achilles’ heel problem. Many applications such as face recognition and language translation have shown high levels of bias in the systems towards particular demographic sub-groups. Unbalanced representation of these sub-groups in the training data is one of the primary reasons of biased behavior. To address this important challenge, we propose a two-fold contribution: a bias estimation metric termed as Precise Subgroup Equivalence to jointly measure the bias in model prediction and the overall model performance. Secondly, we propose a novel bias mitigation algorithm which is inspired from adversarial perturbation and uses the PSE metric. The mitigation algorithm learns a single uniform perturbation termed as Subgroup Invariant Perturbation which is added to the input dataset to generate a transformed dataset. The transformed dataset, when given as input to the pre-trained model reduces the bias in model prediction. Multiple experiments performed on four publicly available face datasets showcase the effectiveness of the proposed algorithm for race and gender prediction.
Hydroclimate of the Andes Part II: Hydroclimate Variability and Sub-Continental Patterns
Authors: Arias Paola A. , Garreaud René , Poveda Germán , Espinoza Jhan Carlo , Molina-Carpio Jorge , Masiokas Mariano , Viale Maximiliano , Scaff Lucia , van Oevelen Peter J.
Published: February 2021

This paper provides an updated review of the most relevant scientific literature related to the hydroclimate of the Andes. The Andes, the longest cordillera in the world, faces major challenges regarding climate variability and climate change, which impose several threats to sustainable development, including water supply and the sustainability of ecosystem services. This review focuses on hydroclimate variability of the Andes at a sub-continental scale. The annual water cycle and long-term water balance along the Andes are addressed first, followed by the examination of the effects of orography on convective and frontal precipitation through the study of precipitation gradients in the tropical, subtropical and extratropical Andes. In addition, a review is presented of the current scientific literature on the climate variability in the Andes at different timescales. Finally, open research questions are presented in the last section of this article.
How Can Climate Models Be Used in Paleoelevation Reconstructions?
Authors: Botsyun Svetlana , Ehlers Todd A.
Published: February 2021

Paleoelevation reconstructions derived from proxy data such as stable oxygen isotope records in terrestrial archives have been determined for Cenozoic mountain ranges around the world. Recent studies have highlighted that a variety of paleoclimate processes can contribute to the isotopic composition of a measured precipitation (δ18Op) signal used in elevation reconstructions. These processes can include: regional, global, and topographic variations in paleotemperature; environmental conditions of an air mass before orographic ascent; evapotranspiration; water vapor recycling; and changes in the vapor source. In some cases, these processes can overprint the elevation signal sought in proxy data and preclude robust elevation reconstructions. Recent advances in isotope tracking climate models allow us to estimate paleoclimate changes during orogen development and associated changes in paleo δ18Op due to both climate and topographic changes. These models account for adiabatic and non-adiabatic temperature changes, relative humidity variations, changing continental evapotranspiration, vapor recycling, vapor source changes, etc. Modeling strategies using high-resolution isotopes-enabled General Circulation Models (iGCMs) together with time-specific boundary conditions and variable topography provide a powerful tool for enhancing elevation reconstructions from δ18Op proxy data. In this review, we discuss the principles, benefits and caveats of using iGCMs for interpreting isotopic records from natural archives for paleoelevation reconstructions. We also highlight future challenges for the application of iGCMs to paleoaltimetry proxy data that open up new avenues for research on tectonic-climate interactions.
The Role of Lipoxidation in the Pathogenesis of Diabetic Retinopathy
Authors: Augustine Josy , Troendle Evan P. , Barabas Peter , McAleese Corey A. , Friedel Thomas , Stitt Alan W. , Curtis Tim M.
Published: February 2021

Lipids can undergo modification as a result of interaction with reactive oxygen species (ROS). For example, lipid peroxidation results in the production of a wide variety of highly reactive aldehyde species which can drive a range of disease-relevant responses in cells and tissues. Such lipid aldehydes react with nucleophilic groups on macromolecules including phospholipids, nucleic acids, and proteins which, in turn, leads to the formation of reversible or irreversible adducts known as advanced lipoxidation end products (ALEs). In the setting of diabetes, lipid peroxidation and ALE formation has been implicated in the pathogenesis of macro- and microvascular complications. As the most common diabetic complication, retinopathy is one of the leading causes of vision loss and blindness worldwide. Herein, we discuss diabetic retinopathy (DR) as a disease entity and review the current knowledge and experimental data supporting a role for lipid peroxidation and ALE formation in the onset and development of this condition. Potential therapeutic approaches to prevent lipid peroxidation and lipoxidation reactions in the diabetic retina are also considered, including the use of antioxidants, lipid aldehyde scavenging agents and pharmacological and gene therapy approaches for boosting endogenous aldehyde detoxification systems. It is concluded that further research in this area could lead to new strategies to halt the progression of DR before irreversible retinal damage and sight-threatening complications occur.
Vitamin A and Its Multi-Effects on Pancreas: Recent Advances and Prospects
Authors: Zhou Yunting , Wang Huiying , Zhou Junming , Qiu Shanhu , Cai Tingting , Li Huiqin , Shen Ziyang , Hu Yun , Ding Bo , Luo Menghui , Huang Rong , Yan Rengna , Xu Wei , He Cong , Zhang Yumin , Li Fengfei , Sun Zilin , Ma Jianhua
Published: February 2021

Vitamin A (VA), which is stored in several forms in most tissues, is required to maintain metabolite homeostasis and other processes, including the visual cycle, energy balance, epithelial cell integrity, and infection resistance. In recent years, VA molecules, also known as retinoids, have been extensively explored and used in the treatment of skin disorders and immune-related tumors. To date, several observational and interventional studies have explored the relationship between VA status and the pathogenesis of diabetes. In particular, VA micronutrients have been shown to regulate pancreatic development, β-cell function, pancreatic innate immune responses, and pancreatic stellate cells phenotypes through multiple mechanisms. However, there are still many problems to be proven or resolved. In this review, we summarize and discuss recent and available evidence on VA biological metabolism in the pancreas. Analysis of the effects of VA on metabolism in the pancreas will contribute to our understanding of the supportive physiological roles of VA in pancreas protection.
Potential Deployment of Reversible Solid-Oxide Cell Systems to Valorise Organic Waste, Balance the Power Grid and Produce Renewable Methane: A Case Study in the Southern Italian Peninsula
Authors: Carbone Claudio , Gracceva Francesco , Pierro Nicola , Motola Vincenzo , Zong Yi , You Shi , Pérez-Fortes Mar , Wang Ligang , Agostini Alessandro
Published: February 2021

The large market penetration of non-dispatchable renewable power sources (vRES), i.e., wind and photovoltaic, may be hampered by an increasing need for large scale energy storage capacity and the challenges of balancing the power grid. Novel technologies integrating waste gasification with reversible Solid-Oxide Cell systems have been proposed to provide flexible grid balancing services. The rSOC system operated in electrolysis mode uses excess power from vRES to generate hydrogen (H2), which is combined with syngas derived from waste gasification to produce methane (CH4). The rSOC system can also be operated in fuel cell mode by oxidising syngas to produce electricity. This paper presents a well-defined case study which aimed to estimate the potential deployment of a novel rSOC technology in a future power system dominated by intermittent renewables. The hourly power grid residual loads (i.e., the difference between load and vRES power generation) and the availability of low-grade organic waste and residues are quantified and matched for the southern Italian peninsula in 2030. The results show that the theoretical grid flexibility needs approximately 10 TW h of overproduction and 5 TW h of underproduction in 2030 to ensure the complete disposal of the municipal organic waste generated in 2030 (6.7 Mt) and that production of renewable CH4 will need to be 1.4–2.4 Mt, pointing to an intriguing perspective for the deployment of rSOC systems at a large scale. The multifunctionality of the system proposed is an added value that can make it a convenient and efficient piece of the puzzle of technologies required in a climate-neutral and circular economy. The results and methods here presented are intended to form the basis for estimations of future potential deployment and economic and environmental assessments of competing technologies.
An Automated Method for Mapping Giant Kelp Canopy Dynamics from UAV
Authors: Cavanaugh Katherine C. , Cavanaugh Kyle C. , Bell Tom W. , Hockridge Evan G.
Published: February 2021

Satellite and aerial imagery have been used extensively for mapping the abundance and distribution of giant kelp (Macrocystis pyrifera) in southern California. There is now great potential for using unoccupied aerial vehicles (UAVs) to map kelp canopy at very high resolutions. However, tides and currents have been shown to affect the amount of floating kelp canopy on the water surface, and the impacts of these processes on remotely sensed kelp estimates in this region have not been fully quantified. UAVs were used to map fine-scale changes in canopy area due to tidal height and current speed at kelp forests off the coast of Palos Verdes, CA and Santa Barbara, CA. An automated method for detecting kelp canopy was developed that was 67% accurate using red-green-blue (RGB) UAV imagery and 93% accurate using multispectral UAV imagery across a range of weather, ocean, and illumination conditions. Increases in tidal height of 1 m reduced the amount of floating kelp canopy by 15% in Santa Barbara and by over 30% in Palos Verdes. The effect of current speed on visible kelp canopy was inconclusive, but there was a trend towards lower canopy area with increased current speed. Therefore, while tidal height and current speed can introduce significant variability to estimates of kelp abundance, the magnitude of this variability is site specific. Still, UAVs are a valuable tool for mapping of kelp canopy and can provide greater spatial resolution and temporal coverage than is possible from many satellite sensors. This data can provide insight into the patterns and drivers of high frequency fluctuations in kelp abundance.
Regional Differences of Manufacturing Green Development Efficiency Considering Undesirable Outputs in the Yangtze River Economic Belt Based on Super-SBM and WSR System Methodology
Authors: Li Gen , Zhou Ying , Liu Fan , Wang Tao
Published: February 2021

To explore the evolution mechanism of manufacturing green development efficiency is of great significance to realize green transformation of manufacturing industry in the Yangtze River Economic Belt. This paper fully considers the resource inputs and undesirable outputs in the production process and applies WSR methodology to construct the index system of influencing factors. Based on the panel data of 11 provinces and cities in the Yangtze River Economic Belt from 1998 to 2017, the super-SBM model is used to calculate the manufacturing green development efficiency. Then, the regional differences of manufacturing green development efficiency in the Yangtze River Economic Belt are deeply analyzed. Finally, Tobit model is applied to analyze the influencing factors of the manufacturing green development efficiency. And it turns out, during the statistics period, manufacturing green development efficiency in the Yangtze River Economic Belt is “U” shaped distribution, the mean value of each province over the years is 0.812, which is at the medium development level; the manufacturing green development efficiency in the Yangtze River Economic Belt is on the rise, and the low scale efficiency is the main reason that restricts the manufacturing green development efficiency in the Yangtze River Economic Belt. All the influencing factors have different effects on the manufacturing green development efficiency in different regions. Therefore, this paper puts forward corresponding policy suggestions from the three dimensions of Wuli, Shili and Renli.