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Rapid growth of single-cell transcriptomic data provides unprecedented opportunities for close scrutinizing of dynamical cellular processes. Through investigating epithelial-to-mesenchymal transition (EMT), we develop an integrative tool that combines unsupervised learning of single-cell transcriptomic data and multiscale mathematical modeling to analyze transitions during cell fate decision. Our approach allows identification of individual cells making transition between all cell states, and inference of genes that drive transitions. Multiscale extractions of single-cell scale outputs naturally reveal intermediate cell states (ICS) and ICS-regulated transition trajectories, producing emergent population-scale models to be explored for design principles. Pirtobrutinib BTK inhibitor Testing on the newly designed single-cell gene regulatory network model and applying to twelve published single-cell EMT datasets in cancer and embryogenesis, we uncover the roles of ICS on adaptation, noise attenuation, and transition efficiency in EMT, and reveal their trade-off relations. Overall, our unsupervised learning method is applicable to general single-cell transcriptomic datasets, and our integrative approach at single-cell resolution may be adopted for other cell fate transition systems beyond EMT.Preexisting/pregestational diabetes enhances the risk of birth defects. Several factors have been involved during the implantation process, such as cytokines (granulocyte-macrophage-colony-stimulating factor [GM-CSF]). The objective was to evaluate the effects of two levels of diabetes on the redox status of preimplantation embryos during the implantation process to comprehend how both are involved in embryo and fetal viability against maternal diabetes. Female Sprague-Dawley rats received streptozotocin at birth (mild diabetes [MD]) or at adulthood (severe diabetes [SD]) to obtain two experimental diabetes intensities. After confirming the diabetic status, the nondiabetic and diabetic groups were mated around day 110 of life. At gestational day (GD) 21, fetuses were assessed for viability and malformations and ovaries for embryo loss before implantation. Other pregnant nondiabetic and diabetic rats were sacrificed at GD2-4 for maternal and preimplantation embryo oxidative stress markers, maternal serum insulin, uterine fluid GM-CSF, and preimplantation embryo morphological analysis. MD and SD caused abnormal redox levels, lower GM-CSF and insulin levels during the preimplantation period, and embryonic loss before implantation. SD caused lower fetal viability and higher fetal malformation percentages at GD21. The SD dam-derived preimplantation embryos presented lower glutathione levels and higher thiobarbituric acid reactive substances concentration at GD3 and an increased frequency of abnormal preimplantation embryos at GD4. In conclusion, preexisting diabetes leads to complications in the implantation process. Furthermore, maternal oxidative stress and other metabolic changes alter the redox state and morphological structure of preimplantation embryos, contributing to damaged growth and development in late pregnancy.Perihematomal edema (PHE) occurs within hours after intracerebral hemorrhage (ICH), leading to secondary injury manifested by impaired blood-brain barrier (BBB) integrity and destruction of adjacent tissue. To dissect the mechanisms underlying PHE formation, we profiled human and mouse perihematomal tissues and identified natural killer (NK) cells as the predominant immune cell subset that outnumbers other infiltrating immune cell types during early stages of ICH. Unbiased clustering of single-cell transcriptional profiles revealed two major NK cell subsets that respectively possess high cytotoxicity or robust chemokine production features in the brain after ICH, distinguishing them from NK cells of the periphery. NK cells exacerbate BBB disruption and brain edema after ICH via cytotoxicity toward cerebral endothelial cells and recruitment of neutrophils that augment focal inflammation. Thus, brain-bound NK cells acquire new features that contribute to PHE formation and neurological deterioration following ICH.The APOBEC3 family of antiviral DNA cytosine deaminases is implicated as the second largest source of mutation in cancer. This mutational process may be a causal driver or inconsequential passenger to the overall tumor phenotype. We show that human APOBEC3A expression in murine colon and liver tissues increases tumorigenesis. All other APOBEC3 family members, including APOBEC3B, fail to promote liver tumor formation. Tumor DNA sequences from APOBEC3A-expressing animals display hallmark APOBEC signature mutations in TCA/T motifs. Bioinformatic comparisons of the observed APOBEC3A mutation signature in murine tumors, previously reported APOBEC3A and APOBEC3B mutation signatures in yeast, and reanalyzed APOBEC mutation signatures in human tumor datasets support cause-and-effect relationships for APOBEC3A-catalyzed deamination and mutagenesis in driving multiple human cancers.

microRNAs serve as important regulators of the pathogenesis of cardiac hypertrophy. Among them, miR-183 is well documented as a novel tumor suppressor in previous studies, whereas it exhibits a downregulated expression in cardiac hypertrophy recently. The present study was aimed to examine the effect of miR-183 on cardiomyocytes hypertrophy.

Angiotensin II (Ang II) was used for establishment of cardiac hypertrophy model in vitro. Neonatal rat ventricular cardiomyocytes (NRVMs) transfected with miR-183 mimic or negative control were further utilized for the phenotype analysis. Moreover, the bioinformatics analysis and luciferase reporter assays were used for exploring the potential target of miR-183 in cardiomyocytes.

We observed a significant decreased expression of miR-183 in hypertrophic cardiomyocytes. Overexpression of miR-183 significantly attenuated the cardiomyocytes size morphologically and pro-hypertrophic genes expression. Moreover, we demonstrated that TIAM1 was a direct target gene of miR-183 verified by bioinformatics analysis and luciferase reporter assays, which showed a decreased mRNA and protein expression in the cardiomyocytes transfected with miR-183 upon Ang II stimulation. Additionally, the downregulated TIAM1 expression was required for the attenuated effect of miR-183 on cardiomyocytes hypertrophy.

Taken together, these evidences indicated that miR-183 acted as a cardio-protective regulator for the development of cardiomyocytes hypertrophy via directly regulation of TIAM1.

Taken together, these evidences indicated that miR-183 acted as a cardio-protective regulator for the development of cardiomyocytes hypertrophy via directly regulation of TIAM1.