αV-Integrins Are Required for Mechanotransduction in MDCK Epithelial Cells

The properties of epithelial cells within tissues are regulated by their immediate microenvironment, which consists of neighboring cells and the extracellular matrix (ECM). Integrin heterodimers orchestrate dynamic assembly and disassembly of cell-ECM connections and thereby convey biochemical and mechanical information from the ECM into cells. However, the specific contributions and functional hierarchy between different integrin heterodimers in the regulation of focal adhesion dynamics in epithelial cells are incompletely understood. Here, we have studied the functions of RGD-binding αV-integrins in a Madin Darby Canine Kidney (MDCK) cell model and found that αV-integrins regulate the maturation of focal adhesions (FAs) and cell spreading. αV-integrin-deficient MDCK cells bound collagen I (Col I) substrate via α2β1-integrins but failed to efficiently recruit FA components such as talin, focal adhesion kinase (FAK), vinculin and integrin-linked kinase (ILK). The apparent inability to mature α2β1-integrin-mediated FAs and link them to cellular actin cytoskeleton led to disrupted mechanotransduction in αV-integrin deficient cells seeded onto Col I substrate

Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas

Background Uterine leiomyomas (ULs) are the most common gynecologic tumors and affect 3 of every 4 women by the age of 50 years. The majority of ULs are classified as conventional tumors, whereas 10% represent various histopathological subtypes with features that mimic malignancy. These subtypes include cellular and mitotically active ULs and ULs with bizarre nuclei. Uterine leiomyosarcoma (ULMS), the malignant counterpart of UL, is an aggressive cancer with poor overall survival. The early diagnosis and preoperative differentiation of ULMS from UL are often challenging because their symptoms and morphology resemble one another. Recent studies have shown frequent loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein (DAXX) expression in ULMS, and this is often associated with an alternative lengthening of telomeres (ALT) phenotype. Methods To investigate ATRX and DAXX expression and the presence of ALT in UL subtypes, immunohistochemical and telomere-specific fluorescence in situ hybridization analyses were performed. The study material consisted of 142 formalin-fixed, paraffin-embedded tissue samples representing various UL subtypes and 64 conventional ULs. Results A loss of ATRX or DAXX and/or ALT was detected in 6.3% of the histopathological UL subtype samples (9 of 142). Two patients whose ULs showed either ATRX loss or ALT were later diagnosed with a pulmonary smooth muscle tumor. Pulmonary tumors displayed molecular alterations found in the corresponding uterine tumors, which indicated metastasis to the lungs. All conventional ULs displayed normal ATRX, DAXX, and telomeres. Conclusions These results highlight the differences between conventional and histopathologically atypical ULs and indicate that some UL subtype tumors may harbor long-term malignant potential. Cancer 2018;124:4650-4656. (C) 2018 American Cancer Society.Peer reviewe

Physicochemical and biological characterization of silica-coated alumina particles

ObjectivesA tribochemical silica-coating (TSC) method has been developed to improve the adhesion of dental resin composites to various substrates. The method utilizes airborne-particle abrasion using particles having a silica surface and an alumina core. The impact of the TSC method has been extensively studied but less attention has been paid to the characterization of the silica-modified alumina particles. Due to the role of silicate ions in cell biology, e.g. osteoblast function and bone mineralization, silica-modified alumina particles could also be potentially used as a biomaterial in scaffolds of tissue regeneration. Thus, we carried out detailed physicochemical characterization of the silica-modified alumina particles.MethodsSilica-modified alumina particles (Rocatec, 3 M-ESPE) of an average particle size of 30 µm were studied for the phase composition, spectroscopic properties, surface morphology, dissolution, and the capability to modify the pH of an immersion solution. The control material was alumina without silica modification. Pre-osteoblastic MC3T3-E1 cells were used to assess cell viability in the presence of the particles. Cell viability was tested at 1, 3, 7 and 10 days of culture with various particle quantities. Multivariate ANOVA was used for statistical analyses.ResultsMinor quantities of silica enrichment was verified on the surface of alumina particles and the silica did not evenly cover the alumina surface. In the dissolution test, no change in the pH of the immersion solution was observed in the presence of the particles. Minor quantities of silicate ions were dissolved from the particles to the cell culture medium but no major differences were observed in the viability of pre-osteoblastic cells, whether the cells were cultured with silica-modified or plain alumina particles.SignificanceCharacterization of silica-modified alumina particles demonstrated differences in the particle surface structure compared to control alumina. Dissolution of silica layer in Tris buffer or SBF solution varied from that of cell culture medium: minor quantities of dissolved Si were observed in cell culture test medium. The cell viability test did not shown significant differences between control alumina and its silica-modified counterpart.</p

Structural and elemental characterization of glass and ceramic particles for bone surgery

AbstractObjectiveClinically used bioceramics have been characterized previously with different kinds of methods and comparison of results have proven to be difficult due to varieties of the material properties of interest. Therefore, in this study we compared clinically commonly used bioceramics of hydroxyapatite and carbonate apatite, two bioactive glasses 45S5 and S53P4, and alumina with respect of properties which according to the present knowledge are significant for bone biology.MethodsPhysicochemical properties of the materials were characterized by various methods. Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) was used to analyze the material vibrational features. X-ray Power Diffraction (XRD) was used to characterize the material crystal structure and scanning electron microscopy-energy-dispersive x-ray analysis (SEM-EDXA) was used to evaluate the morphology and size of the materials and to calculate their oxide content. The dissolution behavior of the materials, ion release and pH changes in Tris buffer in a continuous flow-through reaction for 24-hours were determined. The change of the surface of the bioactive glasses by interfacial reaction during the Tris immersion was examined and the thickness of the surface reaction layer of the materials was studied.ResultsSEM examination showed that the particle morphology of BG 45S5, BG S53P4 and alumina particle’s surface was smooth. The surface of HAP was porous, but also CAP showed some surface porosity. An increase in the pH of the immersion solution was observed especially for BG 45S5 and BG S53P4. HAP, CAP and alumina caused only a minor increase in pH. BGs 45S5 and S53P4 showed a rapid initial release of sodium and calcium ions, followed by the release of silicon species. Minor release of sodium ions was registered for HAP, CAP and alumina. Calcium ion release was low but constant over the experimental time while only a minor initial dissolution was measured for HAP.SignificanceThe in vitro study showed differences in the materials’ properties, which are considered to be important for biological suitability and in clinical applications, such as materials tomography, ion release and pH changes.</p

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studie

Standard of hygiene and immune adaptation in newborn infants

Peer reviewe

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: A multi-cohort analysis

Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life.We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries.The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect.Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: A multi-cohort analysis

Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life. We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries. The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect. Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity

Transgenerational Effects of Parental Larval Diet on Offspring Development Time, Adult Body Size and Pathogen Resistance in Drosophila melanogaster

Environmental conditions experienced by parents are increasingly recognized to affect offspring performance. We set out to investigate the effect of parental larval diet on offspring development time, adult body size and adult resistance to the bacterium Serratia marcescens in Drosophila melanogaster. Flies for the parental generation were raised on either poor or standard diet and then mated in the four possible sex-by-parental diet crosses. Females that were raised on poor food produced larger offspring than females that were raised on standard food. Furthermore, male progeny sired by fathers that were raised on poor food were larger than male progeny sired by males raised on standard food. Development times were shortest for offspring whose one parent (mother or the father) was raised on standard and the other parent on poor food and longest for offspring whose parents both were raised on poor food. No evidence for transgenerational effects of parental diet on offspring disease resistance was found. Although paternal effects have been previously demonstrated in D. melanogaster, no earlier studies have investigated male-mediated transgenerational effects of diet in this species. The results highlight the importance of not only considering the relative contribution each parental sex has on progeny performance but also the combined effects that the two sexes may have on offspring performance