Resistin Enhances VCAM-1 Expression and Monocyte Adhesion in Human Osteoarthritis Synovial Fibroblasts by Inhibiting MiR-381 Expression through the PKC, p38, and JNK Signaling Pathways

The development of osteoarthritis (OA) is characterized by synovial inflammation and the upregulation of vascular cell adhesion molecule type 1 (VCAM-1) in human osteoarthritis synovial fibroblasts (OASFs). This increase in VCAM-1 expression promotes monocyte adhesion to OASFs. The adipokine resistin is known to promote the release of inflammatory cytokines during OA progression. In this study, we identified significantly higher levels of resistin and CD68 (a monocyte surface marker) expression in human OA tissue compared with in healthy control tissue. We also found that resistin enhances VCAM-1 expression in human OASFs and facilitates the adhesion of monocytes to OASFs. These effects were attenuated by inhibitors of PKCα, p38, and JNK; their respective siRNAs; and by a microRNA-381 (miR-381) mimic. In our anterior cruciate ligament transection (ACLT) rat model of OA, the inhibition of resistin activity prevented ACLT-induced damage to the OA rat cartilage and pathological changes in resistin and monocyte expression. We also found that resistin affects VCAM-1 expression and monocyte adhesion in human OASFs by inhibiting miR-381 synthesis via the PKCα, p38, and JNK signaling pathways. Our clarification of the crucial role played by resistin in the pathogenesis of OA may lead to more effective therapy that reduces OA inflammation.

Characterizing gene tree conflict in plastome-inferred phylogenies

Evolutionary relationships among plants have been inferred primarily using chloroplast data. To date, no study has comprehensively examined the plastome for gene tree conflict. Using a broad sampling of angiosperm plastomes, we characterize gene tree conflict among plastid genes at various time scales and explore correlates to conflict (e.g., evolutionary rate, gene length, molecule type). We uncover notable gene tree conflict against a backdrop of largely uninformative genes. We find alignment length and tree length are strong predictors of concordance, and that nucleotides outperform amino acids. Of the most commonly used markers, matK, greatly outperforms rbcL; however, the rarely used gene rpoC2 is the top-performing gene in every analysis. We find that rpoC2 reconstructs angiosperm phylogeny as well as the entire concatenated set of protein-coding chloroplast genes. Our results suggest that longer genes are superior for phylogeny reconstruction. The alleviation of some conflict through the use of nucleotides suggests that stochastic and systematic error is likely the root of most of the observed conflict, but further research on biological conflict within plastome is warranted given documented cases of heteroplasmic recombination. We suggest that researchers should filter genes for topological concordance when performing downstream comparative analyses on phylogenetic data, even when using chloroplast genomes.

Characterizing gene tree conflict in plastome-inferred phylogenies

ABSTRACTPremise of the studyEvolutionary relationships among plants have been inferred primarily using chloroplast data. To date, no study has comprehensively examined the plastome for gene tree conflict.MethodsUsing a broad sampling of angiosperm plastomes, we characterized gene tree conflict among plastid genes at various time scales and explore correlates to conflict (e.g., evolutionary rate, gene length, molecule type).Key resultsWe uncover notable gene tree conflict against a backdrop of largely uninformative genes. We find gene length is the strongest correlate to concordance, and that nucleotides outperform amino acids. Of the most commonly used markers, matK greatly outperforms rbcL; however, the rarely used gene rpoC2 is the top-performing gene in every analysis. We find that rpoC2 reconstructs angiosperm phylogeny as well as the entire concatenated set of protein-coding chloroplast genes.ConclusionsOur results suggest that longer genes are superior for phylogeny reconstruction. The alleviation of some conflict through the use of nucleotides suggests that systematic error is likely the root of most of the observed conflict, but further research on biological conflict within plastome is warranted given the documented cases of heteroplasmic recombination. We suggest rpoC2 as a useful marker for reconstructing angiosperm phylogeny, reducing the effort and expense of assembling and analyzing entire plastomes.

SOLUBLE ADHESION MOLECULES IN CHILDREN WITH HEMOLYTIC UREMIC SYNDROME

Atypical hemolytic uremic syndrom (aHUS) is a rare severe life-threatening form of thrombotic microangiopathy. aHUS is thought to be primarily mediated by dysfunctional complement regulation, due to mutations or genetic rearrangement of the complement components, or regulatory factors, as well as autoantibody production to the complement factors. These alterations promote uncontrolled complement activation by the alternative pathway on the surface of endothelial cells, followed by endothelial dysfunction, microthrombosis and organ damage, especially, renal pathology. Many studies showed that the biomarkers of endothelial activation/dysfunction including intercellular adhesion molecule type 1 (ICAM-1) and vascular cell adhesion molecule type 1 (VCAM-1) were associated with severe disease and could predict complications and clinical outcomes in different disorders. Increase of these biomarkers was observed in aHUS as well. Until recently, aHUS resulted in unfavorable outcomes, with high death rates in acute phase, and up to 2/3 patients progressed to the end-stage renal failure. Understanding the role of complement dysregulation in aHUS pathogenesis has led to major changes in therapeutic approaches. Eculizumab (a humanized anti-C5 monoclonal antibody) inhibits the terminal complement pathway. This drug has revolutionized treatment and improved prognosis in aHUS. Those patients who received eculizumab have shown sharp decreae in the C3 levels. However, the questions concerning duration of targeted therapy inremission still remains unclear.The aim of the present study was to evaluate serum С3, sICAM-1, sVCAM-1 levels in the children with aHUS remission supported by eculizumab maintenance treatment, or without it. Serum C3, sICAM-1 and sVCAM-1 levels were determined in 25 children with aHUS (14 treated with eculizumab and 15, without eculizumab). A control group included 17 children with a history of typical HUS. Serum levels of C3, sICAM-1 and sVCAM-1 were within normal age ranges in all the groups. The children treated with eculizumab showed decreased C3 levels (99±20 mg/l vs 112±15 mg/l, and 123±40 mg/l, respectively), and increased sICAM-1 levels (483±103 ng/ ml vs 343±50 ng/ml and 401±91 ng/ml, respectively) compared to other groups (p < 0.05). No differences in sVCAM-1 levels were revealed in the groups. Hence, no signs of subclinical complement activation or endothelial disfunction were revealed in the group free of eculizumab therapy. Normal C3, sICAM-1 and sVCAM-1 levels in blood indicate that normal endothelial state could be restored in aHUS, and this condition is maintained after discontinuation of the targeted therapy. Our results suggest that C3, sICAM-1 and sVCAM-1 monitoring may be useful for further management of these patients and for prediction of relapses.

Diagnostic and prognostic value of assessment of soluble adhesion molecules sICAM-1 and sVCAM-1 in septic patients

The review is devoted to the assessment of use of cell adhesion molecules including intercellular adhesion molecule type 1 (ICAM-1) and vascular cell adhesion molecule type 1 (VCAM-1) as additional laboratory markers for severity assessment and as predictors of outcome in septic patients. One of the very important pathogenetic components of this state is known to be endothelium activation replaced by its dysfunction. The level of expression of these molecules on endothelial cell membrane affects leukocyte migration from the vessels to surrounding tissues. Besides, a number of cell adhesion molecules are expressed on immunocompetent cells that influences the development of immune response (both innate and acquired). The main characteristics of ICAM-1 and VCAM-1 are presented, including the possibility of soluble forms formation (sICAM-1, sVCAM-1) due to shedding of cell membrane induced by proteolytic enzymes. The results of literature analysis demonstrate that in sepsis the serum content of sICAM-1 and sVCAM-1 is significantly higher than in healthy subjects. In most cases their level is higher than in patients with other critical states (such as severe infectious inflammatory processes, myocardial infarction, stroke, burns, etc.) that according to some authors allows their using for differential diagnosis of sepsis and other critical states. There is no consensus on correlation with disease severity (sepsis, severe sepsis, septic shock), presence of multiple organ failure and its prediction, and lethal outcomes. Results inconsistency most probably can be explained by differences in study design. Nevertheless, continuing studies in this direction is considered perspective.

Are You Taking the Fastest Route to the RESTAURANT?

Most words in books and digital media are written in lowercase. The primacy of this format has been brought out by different experiments showing that common words are identified faster in lowercase (e.g., molecule) than in uppercase (MOLECULE). However, there are common words that are usually written in uppercase (street signs, billboards; e.g., STOP, PHARMACY). We conducted a lexical decision experiment to examine whether the usual letter-case configuration (uppercase vs. lowercase) of common words modulates word identification times. To this aim, we selected 78 molecule-type words and 78 PHARMACY-type words that were presented in lowercase or uppercase. For molecule-type words, the lowercase format elicited faster responses than the uppercase format, whereas this effect was absent for PHARMACY-type words. This pattern of results suggests that the usual letter configuration of common words plays an important role during visual word processing.