Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic-Ischemic Brain Damage in Neonatal Rats.

c-Jun N-terminal kinase (JNK) plays a key role in the regulation of neuronal apoptosis. Previous studies have revealed that forkhead transcription factor (FOXO3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the JNK/FOXO3a pathway is involved in neuronal apoptosis in the developing rat brain after hypoxia-ischemia (HI). In this study, we generated an HI model using postnatal day 7 rats. Fluorescence immunolabeling and Western blot assays were used to detect the distribution and expression of total and phosphorylated JNK and FOXO3a and the pro-apoptotic proteins Bim and CC3. We found that JNK phosphorylation was accompanied by FOXO3a dephosphorylation, which induced FOXO3a translocation into the nucleus, resulting in the upregulation of levels of Bim and CC3 proteins. Furthermore, we found that JNK inhibition by AS601245, a specific JNK inhibitor, significantly increased FOXO3a phosphorylation, which attenuated FOXO3a translocation into the nucleus after HI. Moreover, JNK inhibition downregulated levels of Bim and CC3 proteins, attenuated neuronal apoptosis and reduced brain infarct volume in the developing rat brain. Our findings suggest that the JNK/FOXO3a/Bim pathway is involved in neuronal apoptosis in the developing rat brain after HI. Agents targeting JNK may offer promise for rescuing neurons from HI-induced damage

Semiparametric Normal Transformation Models for Spatially Correlated Survival Data

There is an emerging interest in modeling spatially correlated survival data in biomedical and epidemiological studies. In this paper, we propose a new class of semiparametric normal transformation models for right censored spatially correlated survival data. This class of models assumes that survival outcomes marginally follow a Cox proportional hazard model with unspecified baseline hazard, and their joint distribution is obtained by transforming survival outcomes to normal random variables, whose joint distribution is assumed to be multivariate normal with a spatial correlation structure. A key feature of the class of semiparametric normal transformation models is that it provides a rich class of spatial survival models where regression coefficients have population average interpretation and the spatial dependence of survival times is conveniently modeled using the transformed variables by flexible normal random fields. We study the relationship of the spatial correlation structure of the transformed normal variables and the dependence measures of the original survival times. Direct nonparametric maximum likelihood estimation in such models is practically prohibited due to the high dimensional intractable integration of the likelihood function and the infinite dimensional nuisance baseline hazard parameter. We hence develop a class of spatial semiparametric estimating equations, which conveniently estimate the population-level regression coefficients and the dependence parameters simultaneously. We study the asymptotic properties of the proposed estimators, and show that they are consistent and asymptotically normal. The proposed method is illustrated with an analysis of data from the East Boston Ashma Study and its performance is evaluated using simulations

Regulation of autophagy by the nuclear factor κB signaling pathway in the hippocampus of rats with sepsis

BACKGROUND: Sepsis with brain dysfunction has contributed to an increase risk of morbidity and mortality. In its pathophysiology, both autophagy and nuclear factor κB (NF-κB) have been suggested to play important roles. Based on the fact that crosstalk between autophagy and NF-κB, two stress-response signaling pathways, has been detected in other pathophysiological processes, this study was undertaken to explore the process of autophagy in the hippocampus of septic rats and the role NF-κB plays in the regulation of autophagy during the process. METHODS: Cecal ligation and puncture (CLP) or a sham operation was conducted on male Wistar rats. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of the NF-κB signaling pathway, or a vehicle control, was used to treat with the rats 2 h before the CLP operation. Hematoxylin-eosin staining and biological signal recording was used to measure the morphological and physiological signs of hippocampal dysfunction. An electron microscope was used to observe autophagosome formation and lysosome activation in the hippocampus after CLP. Western blotting and immune histochemistry were used to detect the hippocampus levels of NF-κB and essential proteins involved in formation of the autophagosome (microtubule-associated protein light chain 3 (LC3), Beclin1, Lamp-1, and Rab7). RESULTS: Compared with sham-operated rats, the CLP rats showed decreasing mean arterial pressure (MAP), increasing heart rate (HR), and pathological histological changes. CLP rats exhibited not only increased vacuolization through electron micrographs but also increased LC3-II, decreased Beclin1, LAMP-1, and Rab7 through the immunofluorescence and Western blot. However, PDTC + CLP rats revealed that inhibition of the NF-κB signal axis by PDTC increased the levels of LC3-II, Beclin1, LAMP-1, and Rab7 and improved physiological function including blood pressure and heart rate. CONCLUSIONS: The autophagy process during the hippocampus of CLP rats might be blocked by the activation of NF-κB signaling pathway. Inhibition of NF-κB signaling pathway could enhance the completion of autophagy with a neuroprotective function in septic brains

Shrinkage deformation of different shape of foamed concrete specimen

In construction field, the most important element is concrete. Majority of construction in Malaysia use the concrete and the improvement of concrete technology is very important. Example of concrete technology improvement is foamed concrete. Foamed concrete is additional of foaming agent in the concrete mixture to control the concrete density and the foamed concrete do not used the course aggregate. The foaming agent used to trap the air to reduce the concrete density. The strength of foamed concrete is lower than normal concrete and it is suitable to be used at the uncritical structure in the construction. The foamed agent also expose to crack effected by drying shrinkage. Some of the factors causes the drying shrinkage are investigated. Two factors of drying shrinkage investigated in this study are different density of foamed concrete and different shapes of concrete specimens. Prism sized 100mm x 100mm x 500mm, cylinder sized 150mm 0 x 300mm and 150mm cube for 1200 kg/m3 and 1600 kg/m3 density were produced throughout this experiment. The uses of prism and cylinder specimens are because it is normal shape of concrete structure with different surface expose to environmental for shrinkage observation. The cube was used for compressive strength test to prove the targeted density. The result of compressive strength test shows the increments of concrete density produced high strength of concrete. On the other hand, the increments of concrete density reduce the shrinkage value as well as the reduction of surface exposes to the environmental

Testing the Correlation for Clustered Categorical and Censored Discrete Time‐to‐Event Data When Covariates Are Measured without/with Errors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92373/1/1541-0420.00004.pd

Constructing Long Short-Term Memory based Deep Recurrent Neural Networks for Large Vocabulary Speech Recognition

Long short-term memory (LSTM) based acoustic modeling methods have recently been shown to give state-of-the-art performance on some speech recognition tasks. To achieve a further performance improvement, in this research, deep extensions on LSTM are investigated considering that deep hierarchical model has turned out to be more efficient than a shallow one. Motivated by previous research on constructing deep recurrent neural networks (RNNs), alternative deep LSTM architectures are proposed and empirically evaluated on a large vocabulary conversational telephone speech recognition task. Meanwhile, regarding to multi-GPU devices, the training process for LSTM networks is introduced and discussed. Experimental results demonstrate that the deep LSTM networks benefit from the depth and yield the state-of-the-art performance on this task.Comment: submitted to ICASSP 2015 which does not perform blind review

Heart rate variability and DNA methylation levels are altered after short-term metal fume exposure among occupational welders: a repeated-measures panel study

Background: In occupational settings, boilermakers are exposed to high levels of metallic fine particulate matter (PM2.5) generated during the welding process. The effect of welding PM2.5 on heart rate variability (HRV) has been described, but the relationship between PM2.5, DNA methylation, and HRV is not known. Methods: In this repeated-measures panel study, we recorded resting HRV and measured DNA methylation levels in transposable elements Alu and long interspersed nuclear element-1 (LINE-1) in peripheral blood leukocytes under ambient conditions (pre-shift) and right after a welding task (post-shift) among 66 welders. We also monitored personal PM2.5 level in the ambient environment and during the welding procedure. Results: The concentration of welding PM2.5 was significantly higher than background levels in the union hall (0.43 mg/m3 vs. 0.11 mg/m3, p < 0.0001). The natural log of transformed power in the high frequency range (ln HF) had a significantly negative association with PM2.5 exposure (β = -0.76, p = 0.035). pNN10 and pNN20 also had a negative association with PM2.5 exposure (β = -0.16%, p = 0.006 and β = -0.13%, p = 0.030, respectively). PM2.5 was positively associated with LINE-1 methylation [β = 0.79%, 5-methylcytosince (%mC), p = 0.013]; adjusted for covariates. LINE-1 methylation did not show an independent association with HRV. Conclusions: Acute decline of HRV was observed following exposure to welding PM2.5 and evidence for an epigenetic response of transposable elements to short-term exposure to high-level metal-rich particulates was reported. Electronic supplementary material The online version of this article (doi:10.1186/1471-2458-14-1279) contains supplementary material, which is available to authorized users

Characterisation of fresh extruded rice with added soybean protein isolate

Incorporating proteins into gluten-free foods can often improve their nutritional value. Plant-based proteins are often used as a good source of protein due to their easy absorption in the body and low environmental impact. The utilization of Soy Protein Isolate (SPI) in an extruded food product aimed to examine the impact of SPI on the physicochemical characteristics of Fresh Extruded Rice (FER) in this study. We used rheological techniques and thermal analysis to determine the suitability of the extrusion process and the loss of heating mass. The microstructure, textural properties, sensory evaluation and rice taste analyser scores of FER were determined. A new gluten-free food product was produced and its quality was improved by the addition of SPI. When the content of SPI was 3%, the microstructure and texture properties showed that the FER had medium hardness, good elasticity and cohesion, which was better than paddy rice in food quality analysis. In the extrusion process, SPI has the potential to enhance not only the rheological, thermogravimetric, microstructure, and texture properties of FER, but also serve as a dietary supplement to elevate the sensory experience of FER

Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity.

The endoplasmic reticulum (ER) is the main site of protein and lipid synthesis, membrane biogenesis, xenobiotic detoxification and cellular calcium storage, and perturbation of ER homeostasis leads to stress and the activation of the unfolded protein response. Chronic activation of ER stress has been shown to have an important role in the development of insulin resistance and diabetes in obesity. However, the mechanisms that lead to chronic ER stress in a metabolic context in general, and in obesity in particular, are not understood. Here we comparatively examined the proteomic and lipidomic landscape of hepatic ER purified from lean and obese mice to explore the mechanisms of chronic ER stress in obesity. We found suppression of protein but stimulation of lipid synthesis in the obese ER without significant alterations in chaperone content. Alterations in ER fatty acid and lipid composition result in the inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA) activity and ER stress. Correcting the obesity-induced alteration of ER phospholipid composition or hepatic Serca overexpression in vivo both reduced chronic ER stress and improved glucose homeostasis. Hence, we established that abnormal lipid and calcium metabolism are important contributors to hepatic ER stress in obesity