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Search results for: FHL2

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#33566725   2020/10/14 To Up

mutation alters immune system activation, inflammation, and risk of autoimmunity.

Defective alleles within the gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines-cytokine storm.
Carlo Sidore, Valeria Orrù, Eleonora Cocco, Maristella Steri, Jamie Rj Inshaw, Maristella Pitzalis, Antonella Mulas, Stuart McGurnaghan, Jessica Frau, Eleonora Porcu, Fabio Busonero, Mariano Dei, Sandra Lai, Gabriella Sole, Francesca Virdis, Valentina Serra, Fausto Poddie, Alessandro Delitala, Michele Marongiu, Francesca Deidda, Mauro Pala, Matteo Floris, Marco Masala, Suna Onengut-Gumuscu, Catherine C Robertson, Lidia Leoni, Annapaola Frongia, Maria Rossella Ricciardi, Margherita Chessa, Nazario Olla, Mario Lovicu, Annalisa Loizedda, Andrea Maschio, Luisa Mereu, Paola Ferrigno, Nicolo Curreli, Lenuta Balaci, Francesco Loi, Liana Ap Ferreli, Maria Grazia Pilia, Antonello Pani, Maria Giovanna Marrosu, Goncalo R Abecasis, Stephen S Rich, Helen Colhoun, John A Todd, David Schlessinger, Edoardo Fiorillo, Francesco Cucca, Magdalena Zoledziewska

2625 related Products with: mutation alters immune system activation, inflammation, and risk of autoimmunity.

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#33554560   2020/12/02 To Up

Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) represents the most frequent form of cardiomyopathy, leading to heart failure, cardiac arrhythmias and death. Accumulating evidence convincingly demonstrates the crucial role of genetic defects in the pathogenesis of DCM, and over 100 culprit genes have been implicated with DCM. However, DCM is of substantial genetic heterogeneity, and the genetic determinants underpinning DCM remain largely elusive.
Qi Qiao, Cui-Mei Zhao, Chen-Xi Yang, Jia-Ning Gu, Yu-Han Guo, Min Zhang, Ruo-Gu Li, Xing-Biao Qiu, Ying-Jia Xu, Yi-Qing Yang

1297 related Products with: Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy.

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#33509101   2021/01/28 To Up

Integrative transcriptomic, proteomic, and machine learning approach to identifying feature genes of atrial fibrillation using atrial samples from patients with valvular heart disease.

Atrial fibrillation (AF) is the most common arrhythmia with poorly understood mechanisms. We aimed to investigate the biological mechanism of AF and to discover feature genes by analyzing multi-omics data and by applying a machine learning approach.
Yaozhong Liu, Fan Bai, Zhenwei Tang, Na Liu, Qiming Liu

1767 related Products with: Integrative transcriptomic, proteomic, and machine learning approach to identifying feature genes of atrial fibrillation using atrial samples from patients with valvular heart disease.

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#33324790   2020/11/23 To Up

Identification of Potential Phosphorylation in the Cytoplasmic Domain of Epithelial Cell Adhesion Molecule.

The epithelial cell adhesion molecule (EpCAM) is a transmembrane cell adhesion glycoprotein, which primarily contributes to stemness, proliferation, and metastasis properties of tumor cells. Regulated intramembrane proteolysis by ADAM proteases and γ-secretase cleaves EpCAM into an ∼27 kDa soluble extracellular and an ∼4 kDa cytoplasmic domain (EpICD). After the EpICD fragment is released inside the cell, the formation of a nuclear signaling complex with the FHL2 molecule is critical for exerting its regulatory role. Trop-2, a homologous protein of EpCAM, undergoes phosphorylation in its cytoplasmic domain (Trop-IC). The phosphorylation of Trop-2 is reported to be crucial for its function. This led us to ask the fundamental question if EpCAM does undergo similar post-translational modification(PTM) like its homologous protein to carry out its diverse biological function. Here, we identify a putative phosphorylation site at Tyr297 located in the cytoplasmic domain of EpCAM. Molecular dynamic simulation (MDS) of 90 ns was carried out to understand the biological/functional relevance of the putative phosphorylation. It was observed that this phosphorylation stabilizes the α-helical structure of the EpICD. Though Tyr297 does not affect the γ-secretase mediated cleavage of EpCAM, it affects the binding of EpICD to FHL2. Docking analysis revealed that phosphorylation mediated structural stability of EpICD positively impacts its binding affinity with FHL2, which was further validated using 100 ns MDS. Phosphorylated EpICD forms higher numbers of hydrogen bonds, salt bridges, and other non-bonded interactions with FHL2, leading to enhanced interactions. This study reveals a potential PTM in the EpICD, providing the basis for future research in understanding the mechanism behind the diverse biological function of EpCAM.
Arijit Mal, Pranay Dey, Robert Michael Hayes, Justin V McCarthy, Arjun Ray, Abhijit De

1407 related Products with: Identification of Potential Phosphorylation in the Cytoplasmic Domain of Epithelial Cell Adhesion Molecule.

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#33322916   2020/12/16 To Up

PPARγ-p53-Mediated Vasculoregenerative Program to Reverse Pulmonary Hypertension.

In pulmonary arterial hypertension (PAH), endothelial dysfunction and obliterative vascular disease are associated with DNA damage and impaired signaling of BMPR2 (bone morphogenetic protein type 2 receptor) via two downstream transcription factors, PPARγ (peroxisome proliferator-activated receptor gamma), and p53.
Jan K Hennigs, Aiqin Cao, Caiyun G Li, Minyi Shi, Julia Mienert, Kazuya Miyagawa, Jakob Körbelin, David P Marciano, Pin-I Chen, Matthew Roughley, Matthew V Elliott, Rebecca L Harper, Matthew A Bill, James Chappell, Jan-Renier Moonen, Isabel Diebold, Lingli Wang, Michael P Snyder, Marlene Rabinovitch

1119 related Products with: PPARγ-p53-Mediated Vasculoregenerative Program to Reverse Pulmonary Hypertension.

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#33092075   2020/10/20 To Up

Four and a Half LIM Domains 2 (FHL2) Contribute to the Epithelial Ovarian Cancer Carcinogenesis.

Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic malignancies. To date, the etiology of this deadly disease remains elusive. FHL2, a member of the four and a half LIM domain family, has been shown to serve either as an oncoprotein or as a tumor suppressor in various cancers. Our previous study showed that FHL2 plays a critical role in the initiation and progression of ovarian granulosa cell tumor via regulating AKT1 transcription. However, direct and systematic evidence of FHL2 in the initiation and progression of EOC remains unclear. In the present study, immunohistochemical analysis from EOC patient tissues showed that positivity and intensity of FHL2 immunosignal were up-regulated in the EOC tissues compared with normal ovary tissues. Knockdown of FHL2 in SKOV-3 cell line reduced cell growth and cell viability, blocked cell cycle progression, and inhibited cell migration. Ectopic expression of FHL2 in IGROV-1 cells which have low endogenous FHL2, promoted cell growth, improved cell viability and enhanced cell migration. Additionally, knock down of FHL2 in the SKOV-3 cell line significantly inhibited anchorage-independent growth indicated by the soft agar assay. In comparison, overexpression of FHL2 in IGROV-1 cell improved the colonies growth in soft agar. Western blot data showed that knockdown of FHL2 downregulated AKT expression level, and upregulated apoptosis related proteins such as cleaved PARP, and cleaved-lamin A. Finally, by employing stable SKOV-3/FHL2 stable knock down cell line, our data clearly showed that knockdown of FHL2 inhibited EOC xenograft initiation in vivo. Taken together, our results showed that FHL2, via regulating cell proliferation, cell cycle, and adhesion, has a critical role in regulating EOC initiation and progression. These results indicate that FHL2 could be a potential target for the therapeutic drugs against EOC.
Chen Wang, Xiangmin Lv, Chunbo He, John S Davis, Cheng Wang, Guohua Hua

2119 related Products with: Four and a Half LIM Domains 2 (FHL2) Contribute to the Epithelial Ovarian Cancer Carcinogenesis.

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#33073486   2020/10/18 To Up

Characterization of the prognostic and oncologic values of ITGB superfamily members in pancreatic cancer.

Integrin β (ITGB) superfamily members have been reported to play important roles in multiple biological functions in various cancers. However, the prognostic and oncologic values of ITGB superfamily members have not been systematically investigated in pancreatic cancer (PC). In this study, the mRNA expression and biological functions of ITGB superfamily members in PC were evaluated by bioinformatic analysis. Our results demonstrated that ITGB1, ITGB4, ITGB5 and ITGB6 overexpressions were significantly associated with advanced AJCC stage and histologic grade, and worse prognosis in PC. A prognostic signature based on ITGB1, ITGB4, ITGB5 and ITGB6 showed a reliable predictive performance. Furthermore, one CpGs (cg20545410) in promoter region of ITGB1, four (cg18709893, cg15700850, cg20667796 and cg18326022) of ITGB4, two (cg10977398 and cg03518058) of ITGB5 and one (cg23008083) of ITGB6 were negatively associated with their corresponding mRNA expression, and positively associated with prognosis in PC. We also identified TFAP2A as the potential transcription factor for ITGB4, SP1 for ITGB1 and ITGB6, and FHL2 for ITGB5 and ITGB6. ITGB1, ITGB4, ITGB5 and ITGB6 overexpressions were all significantly involved in focal adhesion signalling pathway. ITGB1 and ITGB5 overexpressions also associated with up-regulation of TGF-β and WNT signalling pathway, whereas ITGB4 and ITGB6 overexpressions associated with up-regulation of Notch signalling pathway. Besides, ITGB1, ITGB5 and ITGB6 overexpressions significantly correlated with immunosuppression in PC. In summary, our study investigated the multilevel prognostic and biological values of ITGB superfamily members in PC.
Hongkai Zhuang, Zixuan Zhou, Zuyi Ma, Zhenchong Li, Chunsheng Liu, Shanzhou Huang, Chuanzhao Zhang, Baohua Hou

1310 related Products with: Characterization of the prognostic and oncologic values of ITGB superfamily members in pancreatic cancer.



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#33058779   2020/10/14 To Up

Mechanosensing through Direct Binding of Tensed F-Actin by LIM Domains.

Mechanical signals transmitted through the cytoplasmic actin cytoskeleton must be relayed to the nucleus to control gene expression. LIM domains are protein-protein interaction modules found in cytoskeletal proteins and transcriptional regulators. Here, we identify three LIM protein families (zyxin, paxillin, and FHL) whose members preferentially localize to the actin cytoskeleton in mechanically stimulated cells through their tandem LIM domains. A minimal actin-myosin reconstitution system reveals that representatives of all three families directly bind F-actin only in the presence of mechanical force. Point mutations at a site conserved in each LIM domain of these proteins disrupt tensed F-actin binding in vitro and cytoskeletal localization in cells, demonstrating a common, avidity-based mechanism. Finally, we find that binding to tensed F-actin in the cytoplasm excludes the cancer-associated transcriptional co-activator FHL2 from the nucleus in stiff microenvironments. This establishes direct force-activated F-actin binding as a mechanosensing mechanism by which cytoskeletal tension can govern nuclear localization.
Xiaoyu Sun, Donovan Y Z Phua, Lucas Axiotakis, Mark A Smith, Elizabeth Blankman, Rui Gong, Robert C Cail, Santiago Espinosa de Los Reyes, Mary C Beckerle, Clare M Waterman, Gregory M Alushin

2038 related Products with: Mechanosensing through Direct Binding of Tensed F-Actin by LIM Domains.

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#33055253   2020/12/09 To Up

Structural and Functional Characterization of Host FHL1 Protein Interaction with Hypervariable Domain of Chikungunya Virus nsP3 Protein.

Decades of insufficient control have resulted in unprecedented spread of chikungunya virus (CHIKV) around the globe, and millions have suffered from the highly debilitating disease. Nevertheless, the current understanding of CHIKV-host interactions and adaptability of the virus to replication in mosquitoes and mammalian hosts is still elusive. Our new study shows that four-and-a-half LIM domain protein (FHL1) is one of the host factors that interact with the hypervariable domain (HVD) of CHIKV nsP3. Unlike G3BPs, FHL1 is not a prerequisite of CHIKV replication, and many commonly used cell lines do not express FHL1. However, its expression has a detectable stimulatory effect(s) on CHIKV replication, and knockout (KO) cell lines demonstrate slower infection spread. Nuclear magnetic resonance (NMR)-based studies revealed that the binding site of FHL1 in CHIKV nsP3 HVD overlaps that of another proviral host factor, CD2AP. The structural data also demonstrated that FHL1-HVD interaction is mostly determined by the LIM1 domain of FHL1. However, it does not mirror binding of the entire protein, suggesting that other LIM domains are involved. In agreement with previously published data, our biological experiments showed that interactions of CHIKV HVD with CD2AP and FHL1 have additive effects on the efficiency of CHIKV replication. This study shows that CHIKV mutants with extensive modifications of FHL1- or both FHL1- and CD2AP-binding sites remain viable and develop spreading infection in multiple cell types. Our study also demonstrated that other members of the FHL family can bind to CHIKV HVD and thus may be involved in viral replication. Replication of chikungunya virus (CHIKV) is determined by a wide range of host factors. Previously, we have demonstrated that the hypervariable domain (HVD) of CHIKV nsP3 contains linear motifs that recruit defined families of host proteins into formation of functional viral replication complexes. Now, using NMR-based structural and biological approaches, we have characterized the binding site of the cellular FHL1 protein in CHIKV HVD and defined the biological significance of this interaction. In contrast to previously described binding of G3BP to CHIKV HVD, the FHL1-HVD interaction was found to not be a prerequisite of viral replication. However, the presence of FHL1 has a stimulatory effect on CHIKV infectivity and, subsequently, the infection spread. FHL1 and CD2AP proteins were found to have overlapping binding sites in CHIKV HVD and additive proviral functions. Elimination of the FHL1-binding site in the nsP3 HVD can be used for the development of stable, attenuated vaccine candidates.
Tetyana Lukash, Tatiana Agback, Francisco Dominguez, Nikita Shiliaev, Chetan Meshram, Elena I Frolova, Peter Agback, Ilya Frolov

2876 related Products with: Structural and Functional Characterization of Host FHL1 Protein Interaction with Hypervariable Domain of Chikungunya Virus nsP3 Protein.

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#32973877   2020/08/19 To Up

A Comparison of Forensic Age Prediction Models Using Data From Four DNA Methylation Technologies.

Individual age estimation can be applied to criminal, legal, and anthropological investigations. DNA methylation has been established as the biomarker of choice for age prediction, since it was observed that specific CpG positions in the genome show systematic changes during an individual's lifetime, with progressive increases or decreases in methylation levels. Subsequently, several forensic age prediction models have been reported, providing average age prediction error ranges of ±3-4 years, using a broad spectrum of technologies and underlying statistical analyses. DNA methylation assessment is not categorical but quantitative. Therefore, the detection platform used plays a pivotal role, since quantitative and semi-quantitative technologies could potentially result in differences in detected DNA methylation levels. In the present study, we analyzed as a shared sample pool, 84 blood-based DNA controls ranging from 18 to 99 years old using four different technologies: EpiTYPER, pyrosequencing, MiSeq, and SNaPshot. The DNA methylation levels detected for CpG sites from , , and with each system were compared. A restricted three CpG-site age prediction model was rebuilt for each system, as well as for a combination of technologies, based on previous training datasets, and age predictions were calculated accordingly for all the samples detected with the previous technologies. While the DNA methylation patterns and subsequent age predictions from EpiTYPER, pyrosequencing, and MiSeq systems are largely comparable for the CpG sites studied, SNaPshot gives bigger differences reflected in higher predictive errors. However, these differences can be reduced by applying a z-score data transformation.
A Freire-Aradas, E Pośpiech, A Aliferi, L Girón-Santamaría, A Mosquera-Miguel, A Pisarek, A Ambroa-Conde, C Phillips, M A Casares de Cal, A Gómez-Tato, M Spólnicka, A Woźniak, J Álvarez-Dios, D Ballard, D Syndercombe Court, W Branicki, Ángel Carracedo, M V Lareu

1703 related Products with: A Comparison of Forensic Age Prediction Models Using Data From Four DNA Methylation Technologies.

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