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Not only are teeth essential for mastication, but also missing teeth are considered a social handicap due to speech and aesthetic problems, with a resulting high impact on emotional well-being. Several treatment procedures are currently available for tooth replacement with mostly inert prosthetic materials and implants. Natural tooth substitution based on copying the developmental process of tooth formation is particularly challenging and creates a rapidly developing area of molecular dentistry. In any approach, functional interactions among the tooth, the surrounding bone, and the periodontium must be established. Therefore, recent research in craniofacial genetics searches for mechanisms responsible for correct cell and tissue interactions, not only within a specific structure, but also in the context of supporting structures. A tooth crown that is not functionally anchored to roots and bone is useless. This review aims to summarize the developmental and tissue homeostatic aspects of the tooth-bone interface, from the initial patterning toward tooth eruption and lifelong interactions between the tooth and its surrounding alveolar bone.

The paper presents the development of an advanced extraction and fast analytical LC MS/MS method for simultaneous analyses of reduced and oxidized glutathione (GSH and GSSG, respectively) in different animal tissues. The simultaneous determination of GSH and GSSG is crucial because the amount and ratio of both GSH and GSSG may be altered in response to oxidative stress, an important mechanism of toxicity. The method uses the derivatization of free thiol groups in GSH. Its performance was demonstrated for less explored tissues (lung, brain, and liver) in mouse. The combined extraction and analytical method has very low variability and good reproducibility, maximum coefficients of variance for within-run and between-run analyses under 8 %, and low limits of quantification; for GSH and GSSG, these were 0.2 nM (0.06 ng/mL) and 10 nM (6 ng/mL), respectively. The performance of the method was further demonstrated in a model experiment addressing changes in GSH and GSSG concentrations in lung of mice exposed to CdO nanoparticles during acute 72 h and chronic 13-week exposures. Inhalation exposure led to increased GSH concentrations in lung. GSSG levels were in general not affected; nonsignificant suppression occurred only after the longer 13-week period of exposure. The developed method for the sensitive detection of both GSH and GSSG in very low tissue mass enables these parameters to be studied in cases where only a little sample is available, i.e. in small organisms or in small amounts of tissue.

Cadmium nanoparticles can represent a risk in both industrial and environmental settings, but there is little knowledge on the impacts of their inhalation, especially concerning longer-term exposures. In this study, mice were exposed to cadmium oxide (CdO) nanoparticles in whole body inhalation chambers for 4 to 72 h in acute and 1 to 13 weeks (24 h/day, 7 days/week) in chronic exposure to investigate the dynamics of nanoparticle uptake and effects. In the acute experiment, mice were exposed to 2.95 × 10 6 particles/cm 3 (31.7 μg CdO/m 3 ). The same concentration and a lower one (1.18 × 10 6 particles/cm 3 , 12.7 μg CdO/m 3 ) were used for the chronic exposure. Transmission electron microscopy documented distribution of nanoparticles into all studied organs. Major portion of nanoparticles was retained in the lung, but longer exposure led to a greater relative redistribution into secondary organs, namely the kidney, and also the liver and spleen. Accumulation of Cd in the lung and liver occurred already after 24 h and in the brain, kidney, and spleen after 72 h of exposure, and a further increase of Cd levels was observed throughout the chronic exposure. There were significant differences in both Cd accumulation and effects between the two exposure doses. Lung weight in the higher exposure group increased up to 2-fold compared to the control. Histological analyses showed dose-dependent alterations in lung and liver morphology and damage to their tissue. Modulation of oxidative stress parameters including glutathione levels and increased lipid peroxidation occurred mainly after the greater chronic exposure. The results emphasize risk of longer-term inhalation of cadmium nanoparticles, since adverse effects occurring after shorter exposures gradually progressed with a longer exposure duration.

Recently, it has been proven that manganese from inhaled particles of manganese compounds can accumulate in the internal organs of laboratory animals. Nevertheless, there were only a few researches dealing with changes in body morphology induced by inhalation of these particles, even though results of some studies indicate existence of such changes. The aim of our research was to assess the effect of inhaled manganese oxides nanoparticles on weight of internal organs. For this purpose a long-term inhalation experiment on laboratory mice was performed, during which the mice were exposed to MnO.Mn2O3 nanoparticles in concentration 2 × 106 particles cm3 for 17 weeks, 24 hours a day, 7 days a week. Manganese oxides nanoparticles were synthesized continuously via aerosol route in a hot wall tube flow reactor using thermal decomposition of metal organic precursor manganese(II)acetylacetonate in the flow tube reactor at temperature 750 °C in the presence of 30 vol% of oxygen. It was proven that inhaled nanoparticles can influence the weight of internal organs of mice. Moreover, it was discovered that the resulting change in weight of selected organs is disproportional. The mice from the experimental group had statistically significantly lighter kidneys, liver and spleen and heavier pancreas compared to the mice from the control group.

Carbamate pesticides generally possess low toxicity for warm-blooded vertebrates, but developmental data are scarce. We have therefore evaluated embryotoxicity of choline esterase inhibitor bendiocarbamate in the chick embryo. The pesticide was dissolved in 5% acetone in distilled water and a volume of 200 μl was administered over the embryo through membrana papyracea on embryonic days 2, 3, 4, 5, and 10. Sampling was performed on embryonic day 10, while the embryos treated on embryonic day 10 were sampled on embryonic day 17. The toxicity of bendiocarbamate was fairly low, and LD 50 decreased with advancing development from 1 mg/ embryo on embryonic day 2 to 29 mg on embryonic day 5. Malformations in surviving embryos were observed rarely (< 3 %) and occurred in both control and experimental groups. There was a mild but statistically significant dose-dependent reduction in body weight, most pronounced in the treatment on embryonic days 5 and 10, but the maximum difference from controls was below 15 %. A small but not significant increase in the number of positive cells was observed in the eye, limb buds, and the central nervous system of embryos treated on embryonic days 3 and 4 and examined after supravital wholemount staining with Lysotracker Red for apoptosis. In agreement with previously published studies in other vertebrate animals, we conclude that bendiocarbamate does not possess significant toxicity in the avian embryo.

Mammalian teeth develop during embryogenesis as epithelio-mesenchymal organs. The primary enamel knot is considered as a signaling center in tooth morphogenesis. After tooth bell formation, this epithelial structure undergoes apoptosis. Activation of caspase 3 represents a crucial step in the intracellular death machinery. Procaspase 3 and caspase 3 molecules were localized in the primary enamel knot of the field vole using immunohistochemistry. Different fixation procedures in cryopreserved and paraffin-embedded tissues and detection systems based on peroxidase and alkaline phosphatase mediated color reactions were applied. Apoptosis was detected using morphological criteria and the TUNEL assay. Procaspase 3 was found in both the epithelial and mesenchymal part of the tooth germ. Active caspase 3 was localized particularly in the primary enamel knot, its distribution correlated with dental apoptosis and showed a similar pattern in the field vole as in the mouse.

Along with the recent progress in the development of advanced synthetic methods, the chemical community has witnessed an increasing interest in promising carbon-rich materials. Among them, helicenes are unique 3D aromatic systems that are inherently chiral and attractive for asymmetric catalysis, chiral recognition and material science. However, there have been only limited attempts at synthesizing long helicenes, which represent challenging targets. Here, we report on an organometallic approach to the derivatives of undecacyclic helicene, which is based on intramolecular [2 + 2 + 2] cycloisomerization of aromatic hexaynes under metal catalysis closing 6 new cycles of a helicene backbone in a single operation. The preparation of nonracemic compounds relied on racemate resolution or diastereoselective synthesis supported by quantum chemical (density functional theory) calculations. The fully aromatic [11] helicene was studied in detail including the measurement and theoretical calculation of its racemization barrier and its organization on the InSb (001) surface by STM. This research provides a strategy for the synthesis of long helical aromatics that inherently comprise 2 possible channels for charge transport: Along a π-conjugated pathway and across an intramolecularly π-π stacked aromatic scaffold.

Not only are teeth essential for mastication, but also missing teeth are considered a social handicap due to speech and aesthetic problems, with a resulting high impact on emotional well-being. Several treatment procedures are currently available for tooth replacement with mostly inert prosthetic materials and implants. Natural tooth substitution based on copying the developmental process of tooth formation is particularly challenging and creates a rapidly developing area of molecular dentistry. In any approach, functional interactions among the tooth, the surrounding bone, and the periodontium must be established. Therefore, recent research in craniofacial genetics searches for mechanisms responsible for correct cell and tissue interactions, not only within a specific structure, but also in the context of supporting structures. A tooth crown that is not functionally anchored to roots and bone is useless. This review aims to summarize the developmental and tissue homeostatic aspects of the tooth-bone interface, from the initial patterning toward tooth eruption and lifelong interactions between the tooth and its surrounding alveolar bone. [PUBLICATION ABSTRACT]

Over half of cutaneous melanoma tumors have BRAFV600E/K mutations. Acquired resistance to BRAF inhibitors (BRAFi) remains a major hurdle in attaining durable therapeutic responses. In this study we demonstrate that ~50–60% of melanoma cell lines with vemurafenib resistance acquired in vitro show activation of RhoA family GTPases. In BRAFi-resistant melanoma cell lines and tumors, activation of RhoA is correlated with decreased expression of melanocyte lineage genes. Using a machine learning approach, we built gene expression-based models to predict drug sensitivity for 265 common anticancer compounds. We then projected these signatures onto the collection of TCGA cutaneous melanoma and found that poorly differentiated tumors were predicted to have increased sensitivity to multiple Rho kinase (ROCK) inhibitors. Two transcriptional effectors downstream of Rho, MRTF and YAP1, are activated in the RhoHigh BRAFi-resistant cell lines, and resistant cells are more sensitive to inhibition of these transcriptional mechanisms. Taken together, these results support the concept of targeting Rho-regulated gene transcription pathways as a promising therapeutic approach to restore sensitivity to BRAFi-resistant tumors or as a combination therapy to prevent the onset of drug resistance.