@article{10754, abstract = {Targeting dysregulated Ca2+ signaling in cancer cells is an emerging chemotherapy approach. We previously reported that store-operated Ca2+ entry (SOCE) blockers, such as RP4010, are promising antitumor drugs for esophageal cancer. As a tyrosine kinase inhibitor (TKI), afatinib received FDA approval to be used in targeted therapy for patients with EGFR mutation-positive cancers. While preclinical studies and clinical trials have shown that afatinib has benefits for esophageal cancer patients, it is not known whether a combination of afatinib and RP4010 could achieve better anticancer effects. Since TKI can alter intracellular Ca2+ dynamics through EGFR/phospholipase C-γ pathway, in this study, we evaluated the inhibitory effect of afatinib and RP4010 on intracellular Ca2+ oscillations in KYSE-150, a human esophageal squamous cell carcinoma cell line, using both experimental and mathematical simulations. Our mathematical simulation of Ca2+ oscillations could fit well with experimental data responding to afatinib or RP4010, both separately or in combination. Guided by simulation, we were able to identify a proper ratio of afatinib and RP4010 for combined treatment, and such a combination presented synergistic anticancer-effect evidence by experimental measurement of intracellular Ca2+ and cell proliferation. This intracellular Ca2+ dynamic-based mathematical simulation approach could be useful for a rapid and cost-effective evaluation of combined targeting therapy drugs.}, author = {Chang, Yan and Funk, Marah and Roy, Souvik and Stephenson, Elizabeth R and Choi, Sangyong and Kojouharov, Hristo V. and Chen, Benito and Pan, Zui}, issn = {14220067}, journal = {International Journal of Molecular Sciences}, number = {3}, publisher = {MDPI}, title = {{Developing a mathematical model of intracellular Calcium dynamics for evaluating combined anticancer effects of afatinib and RP4010 in esophageal cancer}}, doi = {10.3390/ijms23031763}, volume = {23}, year = {2022}, } @article{9906, abstract = {Endometriosis is a common gynecological disorder characterized by ectopic growth of endometrium outside the uterus and is associated with chronic pain and infertility. We investigated the role of the long intergenic noncoding RNA 01133 (LINC01133) in endometriosis, an lncRNA that has been implicated in several types of cancer. We found that LINC01133 is upregulated in ectopic endometriotic lesions. As expression appeared higher in the epithelial endometrial layer, we performed a siRNA knockdown of LINC01133 in an endometriosis epithelial cell line. Phenotypic assays indicated that LINC01133 may promote proliferation and suppress cellular migration, and affect the cytoskeleton and morphology of the cells. Gene ontology analysis of differentially expressed genes indicated that cell proliferation and migration pathways were affected in line with the observed phenotype. We validated upregulation of p21 and downregulation of Cyclin A at the protein level, which together with the quantification of the DNA content using fluorescence-activated cell sorting (FACS) analysis indicated that the observed effects on cellular proliferation may be due to changes in cell cycle. Further, we found testis-specific protein kinase 1 (TESK1) kinase upregulation corresponding with phosphorylation and inactivation of actin severing protein Cofilin, which could explain changes in the cytoskeleton and cellular migration. These results indicate that endometriosis is associated with LINC01133 upregulation, which may affect pathogenesis via the cellular proliferation and migration pathways.}, author = {Yotova, Iveta and Hudson, Quanah J. and Pauler, Florian and Proestling, Katharina and Haslinger, Isabella and Kuessel, Lorenz and Perricos, Alexandra and Husslein, Heinrich and Wenzl, René}, issn = {14220067}, journal = {International Journal of Molecular Sciences}, number = {16}, publisher = {MDPI}, title = {{LINC01133 inhibits invasion and promotes proliferation in an endometriosis epithelial cell line}}, doi = {10.3390/ijms22168385}, volume = {22}, year = {2021}, } @article{9907, abstract = {DivIVA is a protein initially identified as a spatial regulator of cell division in the model organism Bacillus subtilis, but its homologues are present in many other Gram-positive bacteria, including Clostridia species. Besides its role as topological regulator of the Min system during bacterial cell division, DivIVA is involved in chromosome segregation during sporulation, genetic competence, and cell wall synthesis. DivIVA localizes to regions of high membrane curvature, such as the cell poles and cell division site, where it recruits distinct binding partners. Previously, it was suggested that negative curvature sensing is the main mechanism by which DivIVA binds to these specific regions. Here, we show that Clostridioides difficile DivIVA binds preferably to membranes containing negatively charged phospholipids, especially cardiolipin. Strikingly, we observed that upon binding, DivIVA modifies the lipid distribution and induces changes to lipid bilayers containing cardiolipin. Our observations indicate that DivIVA might play a more complex and so far unknown active role during the formation of the cell division septal membrane. }, author = {Labajová, Naďa and Baranova, Natalia S. and Jurásek, Miroslav and Vácha, Robert and Loose, Martin and Barák, Imrich}, issn = {14220067}, journal = {International Journal of Molecular Sciences}, number = {15}, publisher = {MDPI}, title = {{Cardiolipin-containing lipid membranes attract the bacterial cell division protein diviva}}, doi = {10.3390/ijms22158350}, volume = {22}, year = {2021}, } @article{7488, abstract = {Characteristic or classic phenotype of Cornelia de Lange syndrome (CdLS) is associated with a recognisable facial pattern. However, the heterogeneity in causal genes and the presence of overlapping syndromes have made it increasingly difficult to diagnose only by clinical features. DeepGestalt technology, and its app Face2Gene, is having a growing impact on the diagnosis and management of genetic diseases by analysing the features of affected individuals. Here, we performed a phenotypic study on a cohort of 49 individuals harbouring causative variants in known CdLS genes in order to evaluate Face2Gene utility and sensitivity in the clinical diagnosis of CdLS. Based on the profile images of patients, a diagnosis of CdLS was within the top five predicted syndromes for 97.9% of our cases and even listed as first prediction for 83.7%. The age of patients did not seem to affect the prediction accuracy, whereas our results indicate a correlation between the clinical score and affected genes. Furthermore, each gene presents a different pattern recognition that may be used to develop new neural networks with the goal of separating different genetic subtypes in CdLS. Overall, we conclude that computer-assisted image analysis based on deep learning could support the clinical diagnosis of CdLS.}, author = {Latorre-Pellicer, Ana and Ascaso, Ángela and Trujillano, Laura and Gil-Salvador, Marta and Arnedo, Maria and Lucia-Campos, Cristina and Antoñanzas-Pérez, Rebeca and Marcos-Alcalde, Iñigo and Parenti, Ilaria and Bueno-Lozano, Gloria and Musio, Antonio and Puisac, Beatriz and Kaiser, Frank J. and Ramos, Feliciano J. and Gómez-Puertas, Paulino and Pié, Juan}, issn = {14220067}, journal = {International Journal of Molecular Sciences}, number = {3}, publisher = {MDPI}, title = {{Evaluating Face2Gene as a tool to identify Cornelia de Lange syndrome by facial phenotypes}}, doi = {10.3390/ijms21031042}, volume = {21}, year = {2020}, } @article{8532, abstract = {The molecular anatomy of synapses defines their characteristics in transmission and plasticity. Precise measurements of the number and distribution of synaptic proteins are important for our understanding of synapse heterogeneity within and between brain regions. Freeze–fracture replica immunogold electron microscopy enables us to analyze them quantitatively on a two-dimensional membrane surface. Here, we introduce Darea software, which utilizes deep learning for analysis of replica images and demonstrate its usefulness for quick measurements of the pre- and postsynaptic areas, density and distribution of gold particles at synapses in a reproducible manner. We used Darea for comparing glutamate receptor and calcium channel distributions between hippocampal CA3-CA1 spine synapses on apical and basal dendrites, which differ in signaling pathways involved in synaptic plasticity. We found that apical synapses express a higher density of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and a stronger increase of AMPA receptors with synaptic size, while basal synapses show a larger increase in N-methyl-D-aspartate (NMDA) receptors with size. Interestingly, AMPA and NMDA receptors are segregated within postsynaptic sites and negatively correlated in density among both apical and basal synapses. In the presynaptic sites, Cav2.1 voltage-gated calcium channels show similar densities in apical and basal synapses with distributions consistent with an exclusion zone model of calcium channel-release site topography.}, author = {Kleindienst, David and Montanaro-Punzengruber, Jacqueline-Claire and Bhandari, Pradeep and Case, Matthew J and Fukazawa, Yugo and Shigemoto, Ryuichi}, issn = {14220067}, journal = {International Journal of Molecular Sciences}, number = {18}, publisher = {MDPI}, title = {{Deep learning-assisted high-throughput analysis of freeze-fracture replica images applied to glutamate receptors and calcium channels at hippocampal synapses}}, doi = {10.3390/ijms21186737}, volume = {21}, year = {2020}, } @article{8283, abstract = {Drought and salt stress are the main environmental cues affecting the survival, development, distribution, and yield of crops worldwide. MYB transcription factors play a crucial role in plants’ biological processes, but the function of pineapple MYB genes is still obscure. In this study, one of the pineapple MYB transcription factors, AcoMYB4, was isolated and characterized. The results showed that AcoMYB4 is localized in the cell nucleus, and its expression is induced by low temperature, drought, salt stress, and hormonal stimulation, especially by abscisic acid (ABA). Overexpression of AcoMYB4 in rice and Arabidopsis enhanced plant sensitivity to osmotic stress; it led to an increase in the number stomata on leaf surfaces and lower germination rate under salt and drought stress. Furthermore, in AcoMYB4 OE lines, the membrane oxidation index, free proline, and soluble sugar contents were decreased. In contrast, electrolyte leakage and malondialdehyde (MDA) content increased significantly due to membrane injury, indicating higher sensitivity to drought and salinity stresses. Besides the above, both the expression level and activities of several antioxidant enzymes were decreased, indicating lower antioxidant activity in AcoMYB4 transgenic plants. Moreover, under osmotic stress, overexpression of AcoMYB4 inhibited ABA biosynthesis through a decrease in the transcription of genes responsible for ABA synthesis (ABA1 and ABA2) and ABA signal transduction factor ABI5. These results suggest that AcoMYB4 negatively regulates osmotic stress by attenuating cellular ABA biosynthesis and signal transduction pathways. }, author = {Chen, Huihuang and Lai, Linyi and Li, Lanxin and Liu, Liping and Jakada, Bello Hassan and Huang, Youmei and He, Qing and Chai, Mengnan and Niu, Xiaoping and Qin, Yuan}, issn = {14220067}, journal = {International Journal of Molecular Sciences}, number = {16}, publisher = {MDPI}, title = {{AcoMYB4, an Ananas comosus L. MYB transcription factor, functions in osmotic stress through negative regulation of ABA signaling}}, doi = {10.3390/ijms21165727}, volume = {21}, year = {2020}, }