microRNAs (miRNAs) are short non-coding RNAs (ncRNAs) that act as post-transcriptional regulators of coding gene expression. Long non-coding RNAs (lncRNAs) have been recently reported to interact ...with miRNAs. The sponge-like function of lncRNAs introduces an extra layer of complexity in the miRNA interactome. DIANA-LncBase v1 provided a database of experimentally supported and in silico predicted miRNA Recognition Elements (MREs) on lncRNAs. The second version of LncBase (www.microrna.gr/LncBase) presents an extensive collection of miRNA:lncRNA interactions. The significantly enhanced database includes more than 70 000 low and high-throughput, (in)direct miRNA:lncRNA experimentally supported interactions, derived from manually curated publications and the analysis of 153 AGO CLIP-Seq libraries. The new experimental module presents a 14-fold increase compared to the previous release. LncBase v2 hosts in silico predicted miRNA targets on lncRNAs, identified with the DIANA-microT algorithm. The relevant module provides millions of predicted miRNA binding sites, accompanied with detailed metadata and MRE conservation metrics. LncBase v2 caters information regarding cell type specific miRNA:lncRNA regulation and enables users to easily identify interactions in 66 different cell types, spanning 36 tissues for human and mouse. Database entries are also supported by accurate lncRNA expression information, derived from the analysis of more than 6 billion RNA-Seq reads.
MHD free convection of a liquid metal is studied in a closed vertical annulus in which the upper and bottom walls are adiabatic while the cylindrical walls are kept at different temperatures. The ...flow is driven by two mechanisms; the temperature difference between the two cylindrical walls and the volumetric heating. A constant horizontal magnetic field is also imposed resisting the fluid motion. The laminar and turbulent regimes of the flow are assessed by performing three-dimensional direct numerical simulations. The results show that in the absence of the magnetic field, turbulent flow is developed in most of the cases, while as the magnetic field increases the flow becomes laminar. The highest temperature is found in the upper-central part of the annular cavity when the fluid is heated volumetrically, resulting in the creation of two convection currents as the hot fluid ascends in the central part and descends close to both colder walls. The Hartmann and Roberts layers developing near the walls normal and parallel to the magnetic field, respectively, are found to be responsible for the loss of axisymmetry of the present flow.
OBJECTIVE:Vascular endothelium dysfunction represents target organ damage in patients with arterial hypertension. The integrity of endothelial glycocalyx (EG) plays a vital role in vascular ...permeability, inflammation and elasticity and finally to cardiovascular disease. Sideview Darkfield imaging allows for non-invasive automated estimation of EG dimensions based on the erythrocyte column distribution. Increased HDL cholesterol (HDL-C) offers protection against cardiovascular disease. We aimed to investigate any differences regarding EG dimensions in hypertensive patients with extremely increased and decreased HDL-C levels.
DESIGN AND METHOD:One hundred-eighty four (184) patients with arterial hypertension under treatment (mean age 61 + 13 years, 88 males) were divided regarding HDL-C quartiles in two groups. Eighty nine patients (48%) were under treatment with statins. In group A, HDL-C was >71 mg/dl (upper HDL-C quartile, n = 53, mean age 63 + 12 years, 8 males). In group B, HDL-C was < 71 mg/dl (three lower HDL-C quartiles, n = 131, mean age 60 + 13 years, 80 males). Increased perfusion boundary region (PBR) of the sublingual arterial microvessels (ranged from 5–25 micrometers) using Sideview Darkfield imaging (Microscan, Glycocheck) was measured as a non-invasive accurate index of reduced EG thickness.
RESULTS:No significant differences were found within groups regarding age, LDL-C levels, systolic blood pressure and pulse pressure. EG dimensions were significantly different between Group A and B regarding arterial microvessels ranged 5–9 mm (PBR 5–9 was 1.18 + 0.1 vs. 1.22 + 0.1 mm, p < 0.05). A significant negative correlation was found between HDL-C and PBR 5–9 in the whole population (r = −0.11, p < 0.05). In a multiple linear regression analysis model, using age, smoking habit, LDL-levels as independent variables, we found that this association between HDL-C and PBR 5–9 was independent (Beta = −0.24, p < 0.05).
CONCLUSIONS:We found that endothelial function, represented by EG levels, seems to be protected in hypertensive patients with extremely increased HDL-C levels. Future studies in several groups of low or high risk hypertensive patients are needed in order to evaluate the possible role of EG as a novel marker in essential hypertension.
MicroRNAs (miRNAs) are small endogenous RNA molecules that regulate gene expression through mRNA degradation and/or translation repression, affecting many biological processes. DIANA-microT web ...server (http://www.microrna.gr/webServer) is dedicated to miRNA target prediction/functional analysis, and it is being widely used from the scientific community, since its initial launch in 2009. DIANA-microT v5.0, the new version of the microT server, has been significantly enhanced with an improved target prediction algorithm, DIANA-microT-CDS. It has been updated to incorporate miRBase version 18 and Ensembl version 69. The in silico-predicted miRNA-gene interactions in Homo sapiens, Mus musculus, Drosophila melanogaster and Caenorhabditis elegans exceed 11 million in total. The web server was completely redesigned, to host a series of sophisticated workflows, which can be used directly from the on-line web interface, enabling users without the necessary bioinformatics infrastructure to perform advanced multi-step functional miRNA analyses. For instance, one available pipeline performs miRNA target prediction using different thresholds and meta-analysis statistics, followed by pathway enrichment analysis. DIANA-microT web server v5.0 also supports a complete integration with the Taverna Workflow Management System (WMS), using the in-house developed DIANA-Taverna Plug-in. This plug-in provides ready-to-use modules for miRNA target prediction and functional analysis, which can be used to form advanced high-throughput analysis pipelines.
Stromal tumor infiltrating lymphocytes (TILs) density is an outcome predictor in triple-negative breast cancer (TNBC). Herein we asked whether TILs are related to coding mutation load and to the ...chemical class of the resulting mutated amino acids, i.e., charged, polar, and hydrophobic mutations.
We examined paraffin tumors from TNBC patients who had been treated with adjuvant chemotherapy mostly within clinical trials (training cohort, N = 133; validation, N = 190) for phenotype concordance; TILs density; mutation load and types.
Concordance of TNBC phenotypes was 42.1% upon local / central, and 72% upon central / central pathology assessment. TILs were not associated with mutation load, type and class of mutated amino acids. Polar and charged mutation patterns differed between TP53 and PIK3CA (p<0.001). Hydrophobic mutations predicted for early relapse in patients with high nodal burden and <50% TILs tumors (training: HR 3.03, 95%CI 1.11-8.29, p = 0.031; validation: HR 2.90, 95%CI 0.97-8.70, p = 0.057), especially if compared to patients with >50% TILs tumors (training p = 0.003; validation p = 0.015).
TILs density is unrelated to mutation load in TNBC, which may be regarded as an unstable phenotype. If further validated, hydrophobic mutations along with TILs density may help identifying TNBC patients in higher risk for relapse.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dietary intervention is an enticing approach in the fight against cognitive impairment. Nutritional supplements and dietetic counseling are relatively easy and benign interventions, but research has ...not yet yielded irrefutable evidence as to their clinical utility. Heterogeneity in the results of available clinical studies, as well as methodological and practical issues, does not allow replication and generalization of findings. The paper at hand reviews only randomized clinical trials of single nutrients, multi-nutrient formulations and dietary counseling in mild cognitive impairment and dementia of the Alzheimer's type focusing on both cognitive and functional outcomes. Thus far, folate, vitamin E, Ω-3 fatty acids, and certain multi-nutrient formulations have shown some preliminary promising results; larger, well-designed trials are needed to confirm these findings before nutritional elements can be incorporated in recommended clinical guidelines.
Dietary intervention is an enticing approach in the fight against cognitive impairment. Nutritional supplements and dietetic counseling are relatively easy and benign interventions, but research has ...not yet yielded irrefutable evidence as to their clinical utility. Heterogeneity in the results of available clinical studies, as well as methodological and practical issues, does not allow replication and generalization of findings. The paper at hand reviews only randomized clinical trials of single nutrients, multi-nutrient formulations and dietary counseling in mild cognitive impairment and dementia of the Alzheimer's type focusing on both cognitive and functional outcomes. Thus far, folate, vitamin E, Ω-3 fatty acids, and certain multi-nutrient formulations have shown some preliminary promising results; larger, well-designed trials are needed to confirm these findings before nutritional elements can be incorporated in recommended clinical guidelines.
In alcohol-associated hepatitis (AH), inflammation and neutrophil counts correlate with poor clinical outcomes. Here, we investigated how neutrophils contribute to liver damage in AH.
We isolated ...blood neutrophils from individuals with AH to examine neutrophil extracellular traps (NETs) and performed RNA sequencing to explore their unique characteristics.
We observed a significant increase in NET production in AH. We also observed a unique low-density neutrophil (LDN) population in individuals with AH and alcohol-fed mice that was not present in healthy controls. Transcriptome analysis of peripheral LDNs and high-density neutrophils (HDNs) from individuals with AH revealed that LDNs exhibit a functionally exhausted phenotype, while HDNs are activated. Indeed, AH HDNs exhibited increased resting reactive oxygen species (ROS) production and produced more ROS upon lipopolysaccharide stimulation than control HDNs, whereas AH LDNs failed to respond to lipopolysaccharide. We show that LDNs are generated from HDNs after alcohol-induced NET release in vitro, and this LDN subset has decreased functionality, including reduced phagocytic capacity. Moreover, LDNs showed reduced homing capacity and clearance by macrophage efferocytosis; therefore, dysfunctional neutrophils could remain in the circulation and liver. Depletion of both HDNs and LDNs in vivo prevented alcohol-induced NET production and liver damage in mice. Granulocyte-colony stimulating factor treatment also ameliorated alcohol-induced liver injury in mice.
Neutrophils contribute to liver damage through increased NET formation which increases defective LDNs in AH. Alcohol induces phenotypic changes in neutrophils; HDNs are activated whereas LDNs are defective. Our findings provide mechanistic insights that could guide the development of therapeutic interventions for AH.
In this study we discovered heterogeneity of neutrophils in alcohol-associated hepatitis, including high-density and low-density neutrophils that show hyper-activated or exhausted transcriptomic profiles, respectively. We found that alcohol induces neutrophil extracellular trap (NET) formation, which contributes to liver damage. NET release by high-density neutrophils resulted in low-density neutrophils that reside in the liver and escape clean-up by macrophages. Our findings help to understand the opposing neutrophil phenotypes observed in individuals with alcohol-associated hepatitis and provide mechanistic insights that could guide therapeutic strategies targeting neutrophils.
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•Alcohol directly induces neutrophil extracellular trap formation in neutrophils.•Alcohol-induced neutrophil extracellular trap production increases low-density neutrophils in AH.•Low-density neutrophils in AH have a defective phenotype and exhibit reduced homing and clearance.•High-density neutrophils in AH have an activated phenotype.
The auditory filter shape of delphinid odontocetes was previously considered to be typically mammalian constant-quality in which filter bandwidths increase proportionally with frequency. Recent ...studies with porpoises demonstrate constant-bandwidth portions of the auditory filter. The critical ratios for a bottlenose dolphin were measured between 40 and 120 kHz by behaviorally determining the subject's ability to detect pure tones in the presence of white noise. Critical ratios as a function of frequency were constant, indicating the auditory filter acts as a constant-bandwidth system in this frequency range. Re-analysis of past studies supports these findings, and suggests the delphinid auditory system is best characterized as a constant-Q system below 40 kHz and a constant-bandwidth-like system between 40 kHz and 120 kHz before returning to a constant Q pattern at the highest frequencies.
microRNA-22 (miR-22) is an oncogenic miRNA whose up-regulation promotes epithelial-mesenchymal transition (EMT), tumor invasion, and metastasis in hormone-responsive breast cancer. Here we show that ...miR-22 plays a key role in triple negative breast cancer (TNBC) by promoting EMT and aggressiveness in 2D and 3D cell models and a mouse xenograft model of human TNBC, respectively. Furthermore, we report that miR-22 inhibition using an LNA-modified antimiR-22 compound is effective in reducing EMT both in vitro and in vivo. Importantly, pharmacologic inhibition of miR-22 suppressed metastatic spread and markedly prolonged survival in mouse xenograft models of metastatic TNBC highlighting the potential of miR-22 silencing as a new therapeutic strategy for the treatment of TNBC.
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