Numerical Investigations on ultimate Strength of a double hull VLCC under combined loads and initial imperfections

Nonlinear finite element analyses are performed to determine the ultimate strength of a double hull VLCC under pure vertical, horizontal and biaxial bending. A parametric finite element model is developed and the influence of nonlinear material behavior, mesh size and model length on the hull girder ultimate strength is demonstrated exemplarily for hogging and sagging conditions. An appropriate parameter configuration with respect to numerical efforts and accuracy is used to perform static implicit analyses for horizontal bending and biaxial load cases. Convergence is reached by using the full Newton-Raphson scheme - an incremental iterative solution approach. The results are validated against the well-established Smith method. Due to welding, initial deflections and residual stresses are produced. For the proposed finite element model initial deflections of plating and stiffeners have been considered. Furthermore, the influence of welding residual stresses on the ultimate hull girder strength is demonstrated for the different load cases. Nonlinear finite element analyses are also performed to determine the residual strength of the damaged double hull VLCC under combined loads. Different symmetric grounding damages are implemented by removing structural components of the model. Expectedly, the results show that the ultimate strength of the structure decreases as the damage extent increases

MicroRNAs are stored in human MII oocyte and their expression profile changes in reproductive aging

Maternal RNAs are synthesized by the oocyte during its growth; some of them are utilized for oocyte-specific processes and metabolism, others are stored and used during early development before embryonic genome activation. The appropriate expression of complex sets of genes is needed for oocyte maturation and early embryo development. In spite of the basic role of noncoding RNAs in the regulation of gene expression, few studies have analyzed their role in human oocytes. In this study, we identified the microRNAs (miRNAs) expressed in human metaphase II stage oocytes, and found that some of them are able to control pluripotency, chromatin remodeling, and early embryo development. We demonstrated that 12 miRNAs are differentially expressed in women of advanced reproductive age and, by bioinformatics analysis, we identified their mRNA targets, expressed in human oocytes and involved in the regulation of pathways altered in reproductive aging. Finally, we found the upregulation of miR-29a-3p, miR-203a-3p, and miR-494-3p, evolutionarily conserved miRNAs, also in aged mouse oocytes, and demonstrated that their overexpression is antithetically correlated with the downregulation of DNA methyltransferase 3A (Dnmt3a), DNA methyltransferase 3B (Dnmt3b), phosphatase and tensin homolog (Pten), and mitochondrial transcription factor A (Tfam). We propose that oocyte miRNAs perform an important regulatory function in human female germ cells, and their altered regulation could explain the changes occurring in oocyte aging

Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells

The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modulating insulin signaling in triple negative breast cancer (TNBC) cells. We generated murine 4T1 TNBC cells deleted from the endogenous insulin receptor (INSR) gene and expressing comparable levels of either human IR-A or IR-B. We then measured IR isoform-specific in vitro and in vivo biological effects and transcriptome in response to insulin. Overall, the IR-A was more potent than the IR-B in mediating cell migration, invasion, and in vivo tumor growth. Transcriptome analysis showed that approximately 89% of insulin-stimulated transcripts depended solely on the expression of the specific isoform. Notably, in cells overexpressing IR-A, insulin strongly induced genes involved in tumor progression and immune evasion including chemokines and genes related to innate immunity. Conversely, in IR-B overexpressing cells, insulin predominantly induced the expression of genes primarily involved in the regulation of metabolic pathways and, to a lesser extent, tumor growth and angiogenesis

Non-Coding RNAs in Endometrial Physiopathology

The Human Genome Project led to the discovery that about 80% of our DNA is transcribed in RNA molecules. Only 2% of the human genome is translated into proteins, the rest mostly produces molecules called non-coding RNAs, which are a heterogeneous class of RNAs involved in different steps of gene regulation. They have been classified, according to their length, into small non-coding RNAs and long non-coding RNAs, or to their function, into housekeeping non-coding RNAs and regulatory non-coding RNAs. Their involvement has been widely demonstrated in all cellular processes, as well as their dysregulation in human pathologies. In this review, we discuss the function of non-coding RNAs in endometrial physiology, analysing their involvement in embryo implantation. Moreover, we explore their role in endometrial pathologies such as endometrial cancer, endometriosis and chronic endometritis

26. The Role of Macrophages In Mediating Radiation-induced Fibrosis

Purpose: Radiation-induced fibrosis (RIF) remains a clinically challenging problem in cancer patients without effective treatment or prevention. To elucidate the mechanisms of RIF, we investigated the role of macrophages as mediators of fibrosis, and the reciprocal signaling that occurs between macrophages and fibroblasts. Methods: Bone marrow-derived macrophages and dermal fibroblasts were isolated from C57BL/6 mice. Cells were co-cultured in a three-dimensional collagen gel system and subjected to radiation. Gel contracture was measured over time. Flow cytometry was utilized to analyze macrophage polarization towards inflammatory and anti-inflammatory phenotypes using cell surface markers such as CD38 and CD206, respectively. Macrophages from both radiated and non-radiated co-cultures were subjected to RNA sequencing to investigate radiation induced phenotypic and functional changes. Results: Co-culturing fibroblasts and macrophages led to pronounced collagen gel contraction compared to fibroblasts alone, highlighting the essential role of macrophages. In addition, radiated macrophages had a significantly increased effect on gel contracture compared to non-radiated controls indicating a changed phenotype promoting contraction. Since macrophage involvement was found to be critical for radiation-induced functional alteration in collagen gels, we investigated macrophage phenotypes in response to radiation. Flow cytometry analysis revealed that radiation-induced alternate activation (M2) of macrophages, as shown by increased CD206 expression. Similarly, RNA sequencing data showed increased expression of interferon response genes such as Ifi206 and chemokines including c-c motif chemokine ligand 7 (ccl7) suggesting a distinct inflammatory response to radiation. Furthermore, we analyzed the impact of radiation on macrophage plasticity. Interestingly, when macrophages were polarized to M2 phenotype and then radiated, their potential to repolarize to M1 was lost, as opposed to non-radiated macrophages suggesting potential loss of macrophage plasticity during radiation. Conclusion: Our study highlights the crucial role of macrophages in early RIF and their potential as a therapeutic target to mitigate the negative side effects of radiation therapy. We observed that radiation exposure induces an M2 phenotype, upregulates interferon response genes in macrophages, and impairs plasticity. These findings suggest that radiation may contribute to the pro-fibrotic environment by activating macrophages in a physiologically distinct manner. Our study offers insights into the underlying mechanisms of RIF and the role of macrophages in this process

Transcriptome Analysis of Human Endogenous Retroviruses at Locus-Specific Resolution in Non-Small Cell Lung Cancer

Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer deaths worldwide. Among its subtypes, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the most common, accounting for more than 85% of lung cancer diagnoses. Despite the incredible efforts and recent advances in lung cancer treatments, patients affected by this condition still have a poor prognosis. Therefore, novel diagnostic biomarkers are needed. Recently, a class of transposable elements called human endogenous retroviruses (HERVs) has been found to be implicated in cancer development and later employed as novel biomarkers for several tumor types. In this study, we first ever characterized the expression of HERVs at genomic locus-specific resolution in both LUAD and LUSC cohorts available in The Cancer Genome Atlas (TCGA). Precisely, (i) we profiled the expression of HERVs in TCGA-LUAD and TCGA-LUSC cohorts; (ii) we identified the dysregulated HERVs in both lung cancer subtypes; (iii) we evaluated the impact of the dysregulated HERVs on signaling pathways using neural network-based predictions; and (iv) we assessed their association with overall survival (OS) and relapse-free survival (RFS). In conclusion, we believe this study may help elucidate another layer of dysregulation that occurs in lung cancer involving HERVs, paving the way for identifying novel lung cancer biomarkers