The functions and potential roles of extracellular vesicle noncoding RNAs in gynecological malignancies

Extracellular vesicles (EVs) are small membranous vesicles secreted by multiple kinds of cells and are widely present in human body fluids. EVs containing various constituents can transfer functional molecules from donor cells to recipient cells, thereby mediating intercellular communication. Noncoding RNAs (ncRNAs) are a type of RNA transcript with limited protein-coding capacity, that have been confirmed to be enriched in EVs in recent years. EV ncRNAs have become a hot topic because of their crucial regulating effect in disease progression, especially in cancer development. In this review, we summarized the biological functions of EV ncRNAs in the occurrence and progression of gynecological malignancies. In addition, we reviewed their potential applications in the diagnosis and treatment of gynecological malignancies.

Circular RNAs in osteoporosis: expression, functions and roles

Osteoporosis, which is caused by an imbalance in osteoblasts and osteoclasts, is a global age-related metabolic disease. Osteoblasts induce osteocyte and bone matrix formation, while osteoclasts play an important role in bone resorption. Maintaining a balance between osteoblast formation and osteoclastic absorption is crucial for bone remodeling. Circular RNAs (circRNAs), which are characterized by closed-loop structures, are a class of novel endogenous transcripts with limited protein-coding abilities. Accumulating evidence indicates that circRNAs play important roles in various bone diseases, such as osteosarcoma, osteoarthritis, osteonecrosis, and osteoporosis. Recent studies have shown that circRNAs regulate osteoblast and osteoclast differentiation and may be potential biomarkers for osteoporosis. In the current review, we summarize the expression, function, and working mechanisms of circRNAs involved in osteoblasts, osteoclast differentiation, and osteoporosis.

Functional interplay between long non-coding RNAs and the Wnt signaling cascade in osteosarcoma

Osteosarcoma is a common and highly malignant bone tumor among children, adolescents and young adults. However, the underlying molecular mechanisms remain largely unexplored. LncRNAs are transcripts with no or limited protein-coding capacity in human genomes, and have been demonstrated to play crucial functions in initiation, progression, therapeutic resistance, recurrence and metastasis of tumor. Considerable studies revealed a dysregulated lncRNA expression pattern in osteosarcoma, which may act as oncogenes or suppressors to regulate osteosarcoma progression. Wnt signaling pathway is an important cascade in tumorigenesis by modulation of pleiotropic biological functions including cell proliferation, apoptosis, differentiation, stemness, genetic stability and chemoresistance. Hyperactivation or deficiency of key effectors in Wnt cascade is a common event in many osteosarcoma patients. Recently, increasing evidences have suggested that lncRNAs could interplay with component of Wnt pathway, and thereby contribute to osteosarcoma onset, progression and dissemination. In this review, we briefly summarize Wnt signaling-related lncRNAs in osteosarcoma progression, aiming to gain insights into their underlying crosstalk as well as clinical application in osteosarcoma therapeutic modalities.

A site-and-branch-heterogeneous model on an expanded dataset favor mitochondria as sister to known Alphaproteobacteria

Determining the phylogenetic origin of mitochondria is key to understanding the ancestral mitochondrial symbiosis and its role in eukaryogenesis. However, the precise evolutionary relationship between mitochondria and their closest bacterial relatives remains hotly debated. The reasons include pervasive phylogenetic artefacts, as well as limited protein and taxon sampling. Here, we developed a new model of protein evolution that accommodates both across-site and across-branch compositional heterogeneity. We applied this site-and-branch-heterogeneous model (MAM60 + GFmix) to a considerably expanded dataset that comprises 108 mitochondrial proteins of alphaproteobacterial origin, and novel metagenome-assembled genomes from microbial mats, microbialites, and sediments. The MAM60 + GFmix model fits the data much better and agrees with analyses of compositionally homogenized datasets with conventional site-heterogenous models. The consilience of evidence thus suggests that mitochondria is sister to the Alphaproteobacteria to the exclusion of MarineProteo1 and Magnetococcia. We also show that the ancestral presence of a crista-developing MICOS complex (a Mitofilin domain-containing Mic60) supports this relationship.

MO613EFFECT OF 12 WEEK TRAINIG ON PHYSICAL ACTIVITY ON PATIENT ON A LOW PROTEIN DIET

Background and Aims Symptoms such as fatigue, muscle weakness and impaired nutritional status are common in CKD and lead to decreased exercise tolerance. The aim of the study was to study the effect of 12-week training on physical activity in patients with pre-dialysis stages of CKD on a low-protein diet. Method The study included 119 patients with CKD C3 and C4 stages. Clinical data included anthropometric data: body mass index (BMI), mid-thigh circumference and mid-shoulder circumference, laboratory data: urea, creatinine, electrolytes, albumin, total protein, hemoglobin. All patients underwent instrumental research methods: ECG, EchoCG, cardiopulmonary stress test. The patients included in the study were offered three dietary options - with a low protein content (0.6 g / kg / day;) and a limited protein content (0.6-0.8 g / kg / day;), and low protein diet with keto analogs (1 tab / 5 kg body weight / day). The physical exercise program was designed for independent home use and included cardiovascular exercises (primarily walking, morning exercises) and strength training exercises with dumbbells 1 and 3 kg. The training frequency was at least 3 times a week and had a duration of at least 20–30 minutes. The patients kept exercise diaries, which were reviewed by the doctor at each subsequent visit. The training exercise was adjusted depending on the self-perception of the patients; if necessary, the training time was increased to 60 minutes. Results The 1 group 24% of patients received a diet with a low protein content, the second group consisted of 40% of patients, the third group consisted of 37% of patients receiving a diet with a limited protein content. The male to female ratio, mean glomerular filtration rate, daily proteinuria and BMI did not differ significantly between groups. In the dynamics of 12 weeks of training, an increase in the mid-thigh and upper arm circumference was recorded. The study of physical activity of patients with different types of diet showed that in patients of the 1st group, even with a low nutritional status in the dynamics of 12 weeks of training, there was an improvement in such physical indicators as the circumference of the mid-thigh and upper arm, and also a slight improvement in the BMD. When comparing the groups of patients who received and did not receive ketoanologs (groups 2 and 3, respectively), physical training for 12 weeks instilled a significant improvement in indicators such as mid-arm circumference and maximum oxygen consumption(peak VO2). However, in the group receiving keto analogs, there was a significantly greater improvement in maximum oxygen consumption (peak VO2). Conclusion Regular dosed exercise has a positive effect on physical fitness in CKD patients on a low-protein diet. Correction of nutrition with keto analogs improves the cardiorespiratory status of patients.

Suboptimal proteome allocation during changing environments constrains bacterial response and growth recovery

To sustain growth in fluctuating environments microbial organisms must respond appropriately. The response generally requires the synthesis of novel proteins, but this synthesis can be impeded due to the depletion of biosynthetic precursors when growth conditions vary. Microbes must thus devise effective response strategies to manage depleting precursors. To better understand these strategies, we here investigate the active response of Escherichia coli to changes in nutrient conditions, connecting transient gene-expression behavior to growth phenotypes. By synthetically modifying the gene expression during changing growth conditions, we show how the competition by genes for the limited protein synthesis capacity constrains the cellular response. Despite this constraint, cells substantially express genes that are not required, severely slowing down the response. These findings highlight that cells do not optimize growth and recovery in every encountered environment but rather exhibit hardwired response strategies that may have evolved to promote growth and fitness in their native environment and include the regulation of multiple genes. The constraint and the suboptimality of the cellular response uncovered in this study provides a conceptual framework relevant for many research applications, from the prediction of evolution and adaptation to the improvement of gene circuits in biotechnology.

The Role of the Proteasome in Platelet Function

Platelets are megakaryocyte-derived acellular fragments prepped to maintain primary hemostasis and thrombosis by preserving vascular integrity. Although they lack nuclei, platelets harbor functional genomic mediators that bolster platelet activity in a signal-specific manner by performing limited de novo protein synthesis. Furthermore, despite their limited protein synthesis, platelets are equipped with multiple protein degradation mechanisms, such as the proteasome. In nucleated cells, the functions of the proteasome are well established and primarily include proteostasis among a myriad of other signaling processes. However, the role of proteasome-mediated protein degradation in platelets remains elusive. In this review article, we recapitulate the developing literature on the functions of the proteasome in platelets, discussing its emerging regulatory role in platelet viability and function and highlighting how its functional coupling with the transcription factor NF-κB constitutes a novel potential therapeutic target in atherothrombotic diseases.

Pervasive cooperative mutational effects on multiple catalytic enzyme traits emerge via long-range conformational dynamics

Multidimensional fitness landscapes provide insights into the molecular basis of laboratory and natural evolution. To date, such efforts usually focus on limited protein families and a single enzyme trait, with little concern about the relationship between protein epistasis and conformational dynamics. Here, we report a multiparametric fitness landscape for a cytochrome P450 monooxygenase that was engineered for the regio- and stereoselective hydroxylation of a steroid. We develop a computational program to automatically quantify non-additive effects among all possible mutational pathways, finding pervasive cooperative signs and magnitude epistasis on multiple catalytic traits. By using quantum mechanics and molecular dynamics simulations, we show that these effects are modulated by long-range interactions in loops, helices and β-strands that gate the substrate access channel allowing for optimal catalysis. Our work highlights the importance of conformational dynamics on epistasis in an enzyme involved in secondary metabolism and offers insights for engineering P450s.