The majority of CAKUT-associated CNVs overlap at least one miRNA gene, thus affecting the cellular levels of the corresponding miRNA. We aimed to investigate the potency of restitution of ...CNV-affected miRNA levels to remediate the dysregulated expression of target genes involved in kidney physiology and development in vitro.
Heterozygous MIR484 knockout HEK293 and homozygous MIR185 knockout HEK293 cell lines were used as models depicting the deletion of the frequently affected miRNA genes by CAKUT-associated CNVs. After treatment with the corresponding miRNA mimics, the levels of the target genes have been compared to the non-targeting control treatment. For both investigated miRNAs, MDM2 and PKD1 were evaluated as common targets, while additional 3 genes were investigated as targets of each individual miRNA (NOTCH3, FIS1 and APAF1 as hsa-miR-484 targets and RHOA, ATF6 and CDC42 as hsa-miR-185-5p targets).
Restitution of the corresponding miRNA levels in both knockout cell lines has induced a change in the mRNA levels of certain candidate target genes, thus confirming the potential to alleviate the CNV effect on miRNA expression. Intriguingly, HEK293 WT treatment with investigated miRNA mimics has triggered a more pronounced effect, thus suggesting the importance of miRNA interplay in different genomic contexts.
Dysregulation of multiple mRNA targets mediated by CNV-affected miRNAs could represent the underlying mechanism behind the unresolved CAKUT occurrence and phenotypic variability observed in CAKUT patients. Characterizing miRNAs located in CNVs and their potential to become molecular targets could eventually help in understanding and improving the management of CAKUT.
Rare copy number variants (CNVs) are among the most common genomic disorders underlying CAKUT. miRNAs located in rare CNVs represent well-founded functional variants for human CAKUT research. The ...study aimed to identify and functionally interpret miRNAs most frequently affected by rare CNVs in CAKUT and to estimate the overall burden of rare CNVs on miRNA genes in CAKUT. The additional aim of this study was to experimentally confirm the effect of a rare CNV in CAKUT on candidate miRNA's expression and the subsequent change in mRNA levels of selected target genes. A database of CAKUT-associated rare CNV regions, created by literature mining, was used for mapping of the miRNA precursors. miRNAs and miRNA families, most frequently affected by rare CAKUT-associated CNVs, have been subjected to bioinformatic analysis. CNV burden analysis was performed to identify chromosomes with over/underrepresentation of miRNA genes in rare CNVs associated with CAKUT. A functional study was performed on HEK293 MIR484
KO and HEK293 WT cell lines, followed by the analysis of relative miRNA and mRNA target gene levels. 80% of CAKUT patients with underlying rare CNV had at least one miRNA gene overlapping the identified CNV. Network analysis of the most frequently affected miRNAs has revealed the dominant regulation of the two miRNAs, hsa-miR-484 and hsa-miR-185-5p. Additionally, miR-548 family members have shown substantial enrichment in rare CNVs in CAKUT. An over/underrepresentation of miRNA genes in rare CNVs associated with CAKUT was observed in multiple chromosomes, such as chr16, chr20, and chr21. A significant 0.37 fold downregulation of hsa-miR-484, followed by a notable upregulation of MDM2 and APAF1 and downregulation of NOTCH3 was detected in HEK293 MIR484
KO compared to HEK293 WT cell lines, supporting the study hypothesis. miRNA genes are frequently affected by rare CNVs in CAKUT patients. Understanding the potential of CNV-affected miRNAs to participate in CAKUT as genetic drivers represent a crucial implication for the development of novel therapeutic approaches.
Congenital anomalies of the kidney and urinary tract (CAKUT) represent structural and functional urinary system malformations and take place as one of the most common congenital malformations with an ...incidence of 1:500. Ureteral obstruction-induced hydronephrosis is associated with renal fibrosis and chronic kidney diseases in the pediatric CAKUT. We aimed to construct interaction network of previously bioinformatically associated miRNAs with CAKUT differentially expressed genes in order to prioritize those associated with fibrotic process and to experimentally validate the expression of selected miRNAs in CAKUT patients compared to control group. We constructed interaction network of hsa-miR-101-3p, hsa-miR-101-5p and hsa-miR-29c-3p that showed significant association with fibrosis. The top enriched molecular pathway was extracellular matrix-receptor interaction (adjusted p = .0000263). We experimentally confirmed expression of three miRNAs (hsa-miR-29c-3p, hsa-miR-101-3p and hsa-miR-101-5p) in obstructed ureters (ureteropelvic junction obstruction and primary obstructive megaureter) and vesicoureteral reflux. The hsa-miR-29c-3p was shown to have lower expression in both patient groups compared to controls. Relative levels of hsa-miR-101-5p and hsa-miR-101-3p showed significant positive correlations in both groups of patients. Statistically significant correlation was observed between hsa-miR-101 (-3p and -5p) and hsa-miR-29c-3p only in the obstructed group. The significant downregulation of anti-fibrotic hsa-miR-29c-3p in obstructive CAKUT could explain activation of genes involved in fibrotic processes. As miRNAs are promising candidates in therapeutic approaches our results need further measurement of fibrotic markers or assessment of extent of fibrosis and functional evaluation of hsa-miR-29c.
Introduction. The COVID-19 pandemic caused by the SARS-CoV-2 virus has led to significant public health problems, severe complications, and functional impairment in persons who have recovered from ...this disease. Case report. A 60-years-old male deconditioned patient was transferred from Corona 4 Center to the Center for Physical Medicine and Rehabilitation of the University Clinical Center in Kragujevac for a post-COVID rehabilitation due to pronounced muscle weakness and inability to walk. After functional testing, an individual rehabilitation plan was created and a kinesitherapy program was adjusted daily based on the patient's respiratory status. After the kinesitherapy program, Respivol was used-a volumetric medical device for breathing exercises in patients with respiratory difficulties. At the time of admission, the patient could not move independently, could not move from the lying to the sitting position on his own, and could not maintain balance in the sitting position. Hypotrophy caused by prolonged inactivity of the muscles of the whole body dominated the clinical picture. A six-week rehabilitation treatment performed on the patient showed a significant improvement in functionality (FIM test), muscle strength (manual muscle test), daily life activity (Barthel index), as well as a reduction of anxiety (GAD-7 scale). Conclusion. The goal of the rehabilitation program is to restore the patient's state of functionality before the initiation of COVID-19 treatment, so that they can perform their regular professional activities and achieve complete independence in performing activities of daily living (ADL).
Polycystic ovary syndrome (PCOS) represents the most common endocrinopathy among childbearing-age women, with oxidative stress (OS) underlying its etiopathogenesis. Metformin (MET) represents a ...frequently used agent in PCOS. However, weak results encourage alternative treatments. We aimed to investigate isolated and synergistic effects of Standardized Aronia melanocarpa extract (SEA) and MET for alleviating reproductive and metabolic PCOS abnormalities. PCOS induction was followed by 28-day treatment with MET, SAE, or MET + SEA. Bodyweight (BW), cyclicity, histological, and ultrasonographical ovarian analyses were performed. Hormonal, glycemic, and lipid profiles were accessed, as well as systemic and ovarian oxidative status; BW, cyclicity, ovarian histomorphology, ovarian volume, testosterone and progesterone levels, as well as LDL, triglycerides, and total cholesterol levels were aggravated after PCOS-induction and improved after MET, SEA, and MET + SEA treatment. MET + SEA had the greatest impact on glycoregulation. Alterations in OS parameters (TBARS, O2−, H2O2, catalase, superoxide dismutase, and reduced glutathione) could be responsible for observed differences; (4) Conclusions: Our findings confirmed that SAE alone or along with MET was capable of ameliorating reproductive and metabolic disturbances in the PCOS rat model, with the restoration of OS parameters. SAE alone did not alter the protective effects of MET in PCOS.
Non-alcoholic fatty liver disease (NAFLD) can progress to more severe stages, such as steatohepatitis and fibrosis. Thermoneutral housing together with high-fat diet promoted NAFLD progression in ...C57BL/6J mice. Due to possible differences in steatohepatitis development between different C57BL/6 substrains, we examined how thermoneutrality affects NAFLD progression in C57BL/6N mice.
Male mice were fed standard or high-fat diet for 24 weeks and housed under standard (22°C) or thermoneutral (30°C) conditions.
High-fat feeding promoted weight gain and hepatic steatosis, but the effect of thermoneutral environment was not evident. Liver expression of inflammatory markers was increased, with a modest and inconsistent effect of thermoneutral housing; however, histological scores of inflammation and fibrosis were generally low (<1.0), regardless of ambient temperature. In standard diet-fed mice, thermoneutrality increased weight gain, adiposity, and hepatic steatosis, accompanied by elevated
lipogenesis and changes in liver metabolome characterized by complex decreases in phospholipids and metabolites involved in urea cycle and oxidative stress defense.
Thermoneutrality appears to promote NAFLD-associated phenotypes depending on the C57BL/6 substrain and/or the amount of dietary fat.
Due to the development of resistance to previously effective therapies, there is a constant need for novel treatment modalities for metastatic melanoma. Nischarin (NISCH) is a druggable scaffolding ...protein reported as a tumor suppressor and a positive prognostic marker in breast and ovarian cancers through regulation of cancer cell survival, motility and invasion. The aim of this study was to examine the expression and potential role of nischarin in melanoma. We found that nischarin expression was decreased in melanoma tissues compared to the uninvolved skin, and this was attributed to the presence of microdeletions and hyper-methylation of the
NISCH
promoter in the tumor tissue. In addition to the previously reported cytoplasmic and membranous localization, we observed nischarin in the nuclei in melanoma patients’ tissues.
NISCH
expression in primary melanoma had favorable prognostic value for female patients, but, unexpectedly, high
NISCH
expression predicted worse prognosis for males. Gene set enrichment analysis suggested significant sex-related disparities in predicted association of
NISCH
with several signaling pathways, as well as with different tumor immune infiltrate composition in male and female patients. Taken together, our results imply that nischarin may have a role in melanoma progression, but that fine-tuning of the pathways it regulates is sex-dependent.
Key messages
Nischarin is a tumor suppressor whose role has not been investigated in melanoma.
Nischarin expression was downregulated in melanoma tissue compared to the normal skin.
Nischarin had the opposite prognostic value in male and female melanoma patients.
Nischarin association with signaling pathways differed in females and males. Our findings challenge the current view of nischarin as a universal tumor suppressor.
Background: Doppler ultrasound examination of blood vessels has a significant role in planning and identifying parameters that affect the functioning and maturation of arteriovenous fistula (AVF). ...Our goal was to determine the predictive parameters of Doppler ultrasound, measured at different time distances, which affect the maturation of AVF for hemodialysis. Materials and Methods: The research was a retrospective cohort study. The criteria for selecting patients in our study was the existence of information on ultrasound examinations of the lumen of blood vessels before the creation of AVF, as well as lumens of fistula conduits and blood flow measurements, at time intervals of 6–8 weeks and 2–4 months, after the creation of AVF, which we recorded in 105 patients. The respondents were divided into two groups: a group of patients with immature, and mature fistulas. Basic demographic data, clinical characteristics of the responders and laboratory parameters were analyzed. Results: By comparing clinical and laboratory parameters between the group of subjects with and without AVF maturation, a statistically significant difference was determined between the lumen of the proximal radial vein (p = 0.008) and the lumen of the distal radial vein (p = 0.001). The diameter of the fistulous veins (p = 0.037), and the blood flow through the AVF 6–8 weeks (p = 0.001) and 2–4 months (p = 0.001) after its creation were statistically significantly higher in subjects with mature fistulas. By univariate regression analysis, brachial vein (p = 0.04), proximal (p = 0.011) and distal radial artery (p = 0.001), fistula vein, after 6–8 weeks (p = 0.002), blood flow through AVF 6–8 weeks (p = 0.001) and 2–4 months (p = 0.001) after AVF creation, are statistically significant parameters. Predictive parameters of AVF maturation are AVF blood flow after 6–8 weeks (p = 0.010) and AVF blood flow after 2–4 months (p = 0.001). Conclusion: Our research confirmed that greater the blood flow through AVF, at time intervals of 6–8 weeks and 2–4 months after creation, the better the maturation.
On generalized highly potential words Ago, Kristina; Bašić, Bojan; Hačko, Stefan ...
Theoretical computer science,
01/2021, Letnik:
849
Journal Article
Recenzirano
The number of palindromic factors of a given finite word is bounded above by its length increased by 1. The difference between this upper bound and the actual number of palindromic factors of a given ...word is called the palindromic defect (or only defect) of a given word (by definition, the defect is always nonnegative). Though the definition of defect fundamentally relies on finiteness of a given word, it can be naturally extended to infinite words. There are many results in the literature about words of defect 0, but there are significantly less results about infinite words of finite positive defect. In this article we construct a new family of infinite words whose defect is finite, and in many cases positive (with fully characterized cases when the defect is 0). All the words from our family have the set of factors closed under reversal, and each of them is either periodic (which is a less interesting case, and explicitly characterized), or recurrent but not uniformly recurrent. The fact that they are not uniformly recurrent (unless they are periodic) is of a particular significance since: first, there are some results and examples here and there featuring uniformly recurrent words of finite defect, while next to nothing is known about aperiodic words that are not uniformly recurrent; second, it is known that any uniformly recurrent word of finite defect is a morphic image of some word of zero defect, which suggests that uniformly recurrent words are in a way pretty “tame,” and that those that are not uniformly recurrent are an unexplored territory that deserves a closer look.
Chronic kidney disease leads to significant functional limitations and severe disability, which requires the application of an appropriate physical rehabilitation strategy that helps patients achieve ...social well-being and significant health benefits. Data sources MEDLINE, PubMed, Google Scholar and Web of Science were electronically searched, by using search terms: physical exercise, hemodialysis, barriers, risks of exercise, expected benefits. The contraindications for exercise are recent myocardial infarction, uncontrolled arrhythmia and hypertension, unstable angina pectoris, unregulated diabetes mellitus, the presence of neurological and muscular dysfunctions, malignancies, and pregnancy. The implementation of the physical exercise program for hemodialysis patients confirmed all the expected benefits: improvement of cardiovascular functions, stabilization of blood pressure, increased muscle strength, improvement of nutritional status and quality of dialysis, reduction of negative emotions, anxiety and depression, as well as social interaction of patients and their families. Despite the fact that a large number of studies have proven the beneficial effects of exercise during hemodialysis, a physical rehabilitation program as a standard form of treatment has not yet been introduced. Although there is no doubt that the effects of physical activity on the survival and the quality of life of patients on hemodialysis are positive, rehabilitation program still falls under the routine practice program in a small number of dialysis centers. One of the biggest obstacles to the implementation of the physical therapy program in hemodialysis patients is the lack of a clearly defined program that defines all the needs of dialysis patients.DOI: 10.52547/ijkd.7570
