Mechanisms of chromium(VI)-induced carcinogenesis: The involvement of reactive oxygen species and signal transduction pathway.

Although Cr(VI)-containing compounds have been widely recognized as carcinogens for over 100 years, the mechanisms of their actions are not fully understood. The overall objective of this study is to investigate the role of reactive oxygen species (ROS) in Cr(VI)-induced carcinogenesis, focusing on tumor suppressor protein p53 and regulatory signal transduction pathways. In the present study, the role of ROS in p53 activation was investigated and the following conclusions were obtained: (a) Cr(VI) is able to activate p53 protein; (b) ROS, especially ·OH radical, are responsible for the p53 activation induced by Cr(VI). In addition, we presented a mechanism of cellular ROS generation induced by Cr(VI). After entering the cell, Cr(VI) can be reduced to Cr(V). During the reduction process, molecular oxygen is reduced to O2 ·− radical, which generates H2O2 via dismutation. Cr(V) reacts with H2O2 to generate ·OH radicals via a Fenton-like reaction. For the molecular mechanism of p53 activation induced by Cr(VI), post-translational modifications, including Ser 15 phosphorylation, Lys 382 acetylation, and mdm2 dissociation were found to play a crucial role. Erk, but not p38 kinase, is responsible for the phosphorylation of Ser 15 induced by Cr(VI). The present study also investigated the interaction of NF-κB and p53 protein in Cr(VI)-induced apoptosis. NF-κB activation is capable of diminishing Cr(VI)-induced p53 activation, and protecting cells from apoptosis. These studies on Ras overexpressed cells presented a new scheme for ROS generation from Cr(VI)-induced cells different from the one described above. O2·− radical, which is produced by overexpressed Ras protein, reacts with Cr(VI) to generate Cr(V). The Cr(V) further reacts with H2O2, which is produced by O 2·− radical dismutation, to produce ·OH radical. These results implicate Cr(VI) and O2·− radical into the signal transduction pathways mediated by Ras protein. Since Ras signaling pathway is important in regulating cell proliferation, the involvements of Cr(VI) in Ras signal transduction pathway may be one of the mechanisms for Cr(VI)-induced carcinogenesis. This study provides a molecular basis for the understanding of the mechanisms of Cr(VI)-induced cellular responses, and contributes to a better understanding for the carcinogenic process induced by this metal. These new findings also have the impact on other carcinogens and chemical particles that have a ROS generation machinery similar to Cr(VI)

Temperature and composition insensitivity of thermoelectric properties of high-entropy half-heusler compounds

Composition modification by doping and solid solution is a well-studied strategy in thermoelectric (TE) materials to optimize their properties. Recently, the concept of entropy stabilization has offered the possibility of forming random solid solutions that have properties that go beyond the rule of mixture. In this study, we prepared a series of high-entropy half-Heusler solid solutions (HEHHs) with varying valence electron counts (VEC), (Ti0.33Zr0.33Hf0.33)1-x(V0.33Nb0.33Ta0.33)xCoSb (x = 0.5 to 0.75). Compared to their medium- and low-entropy counterparts, the TE properties of HEHHs are less sensitive to temperature and composition variation (charge carrier concentration efficiency of ∼10 %). An ultra-low lattice thermal conductivity for half-Heusler of 1.19 W·m−1·K−1 was achieved.Peer reviewe

Neuronally released vasoactive intestinal polypeptide alters atrial electrophysiological properties and may promote atrial fibrillation

BACKGROUND: Vagal hyperactivity promotes atrial fibrillation (AF), which has been almost exclusively attributed to acetylcholine. Vasoactive intestinal polypeptide (VIP) and acetylcholine are neurotransmitters co-released during vagal stimulation. Exogenous VIP has been shown to promote AF by shortening action potential duration (APD), increasing APD spatial heterogeneity, and causing intra-atrial conduction block. OBJECTIVE: The purpose of this study was to investigate the effects of neuronally released VIP on atrial electrophysiologic properties during vagal stimulation. METHODS: We used a specific VIP antagonist (H9935) to uncover the effects of endogenous VIP released during vagal stimulation in canine hearts. RESULTS: H9935 significantly attenuated (1) the vagally induced shortening of atrial effective refractory period and widening of atrial vulnerability window during stimulation of cervical vagosympathetic trunks (VCNS) and (2) vagal effects on APD during stimulation through fat-pad ganglion plexus (VGPS). Atropine completely abolished these vagal effects during VCNS and VGPS. In contrast, VGPS-induced slowing of local conduction velocity was completely abolished by either VIP antagonist or atropine. In pacing-induced AF during VGPS, maximal dominant frequencies and their spatial gradients were reduced significantly by H9935 and, more pronouncedly, by atropine. Furthermore, VIP release in the atria during vagal stimulation was inhibited by atropine, which may account for the concealment of VIP effects with muscarinic blockade. CONCLUSION: Neuronally released VIP contributes to vagal effects on atrial electrophysiologic properties and affects the pathophysiology of vagally induced AF. Neuronal release of VIP in the atria is inhibited by muscarinic blockade, a novel mechanism by which VIP effects are concealed by atropine during vagal stimulation

The Modified Shields Classification and 12 Families with Defined DSPP Mutations

Mutations in Dentin Sialophosphoprotein (DSPP) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II (DGI-II), and dentinogenesis imperfecta type-III (DGI-III). DSPP mutations fall into two groups: a 5′-group that affects protein targeting and a 3′-group that shifts translation into the −1 reading frame. Using whole-exome sequence (WES) analyses and Single Molecule Real-Time (SMRT) sequencing, we identified disease-causing DSPP mutations in 12 families. Three of the mutations are novel: c.53T>C/p.(Val18Ala); c.3461delG/p.(Ser1154Metfs*160); and c.3700delA/p.(Ser1234Alafs*80). We propose genetic analysis start with WES analysis of proband DNA to identify mutations in COL1A1 and COL1A2 causing dominant forms of osteogenesis imperfecta, 5′-DSPP mutations, and 3′-DSPP frameshifts near the margins of the DSPP repeat region, and SMRT sequencing when the disease-causing mutation is not identified. After reviewing the literature and incorporating new information showing distinct differences in the cell pathology observed between knockin mice with 5′-Dspp or 3′-Dspp mutations, we propose a modified Shields Classification based upon the causative mutation rather than phenotypic severity such that patients identified with 5′-DSPP defects be diagnosed as DGI-III, while those with 3′-DSPP defects be diagnosed as DGI-II

Traffic fuel consumption evaluation of the on-ramp with acceleration lane based on cellular automata

Based on Nagel–Schreckenberg (NaSch) traffic flow model, a novel fuel consumption model of on-ramp with acceleration lane under open boundary condition is proposed. Phase diagram is determined by analysis of spatial–temporal patterns. The phase diagram is divided into free flow on the main upstream and the on-ramp; free flow on the main upstream and low-speed motion on the on-ramp; low-speed motion on the main upstream and free flow on the on-ramp; low-speed motion on the main upstream, and global congestion on the on-ramp. The difference in the appearance of phase diagram is found to be related to the length of acceleration lane. The longer of acceleration lane, the more prone to low-speed motion on the main upstream. The numerical computations for fuel consumption in the injected probability of the main road, the injected probability of the on-ramp, and the length of acceleration lane are carried out. Fuel consumption is explained by the traffic flow, average velocity, and lane-change frequency of the accelerated lane. The injected probability of the main road and the on-ramp has a great impact on fuel consumption in free flow. The highest fuel consumption occurs during low-speed motion, whereas the lowest fuel consumption is observed during global congestion. Moreover, the results indicate that fuel consumption on the main road increases potentially by curtailing the length of acceleration lane in low-speed motion of the main road

LPE-Unet: An Improved UNet Network Based on Perceptual Enhancement

In Computed Tomography (CT) images of the coronary arteries, the segmentation of calcified plaques is extremely important for the examination, diagnosis, and treatment of coronary heart disease. However, one characteristic of the lesion is that it has a small size, which brings two difficulties. One is the class imbalance when computing loss function and the other is that small-scale targets are prone to losing details in the continuous downsampling process, and the blurred boundary makes the segmentation accuracy less satisfactory. Therefore, the segmentation of calcified plaques is a very challenging task. To address the above problems, in this paper, we design a framework named LPE-UNet, which adopts an encoder–decoder structure similar to UNet. The framework includes two powerful modules named the low-rank perception enhancement module and the noise filtering module. The low-rank perception enhancement module extracts multi-scale context features by increasing the receptive field size to aid target detection and then uses an attention mechanism to filter out redundant features. The noise filtering module suppresses noise interference in shallow features to high-level features in the process of multi-scale feature fusion. It computes a pixel-wise weight map of low-level features and filters out useless and harmful information. To alleviate the problem of class imbalance caused by small-sized lesions, we use a weighted cross-entropy loss function and Dice loss to perform mixed supervised training on the network. The proposed method was evaluated on the calcified plaque segmentation dataset, achieving a high F1 score of 0.941, IoU of 0.895, and Dice of 0.944. This result verifies the effectiveness and superiority of our approach for accurately segmenting calcified plaques. As there is currently no authoritative publicly available calcified plaque segmentation dataset, we have constructed a new dataset for coronary artery calcified plaque segmentation (Calcified Plaque Segmentation Dataset, CPS Dataset)