Removal of Hsf4 leads to cataract development in mice through down-regulation of γS-crystallin and Bfsp expression

<p>Abstract</p> <p>Background</p> <p>Heat-shock transcription factor 4 (HSF4) mutations are associated with autosomal dominant lamellar cataract and Marner cataract. Disruptions of the <it>Hsf4 </it>gene cause lens defects in mice, indicating a requirement for HSF4 in fiber cell differentiation during lens development. However, neither the relationship between HSF4 and crystallins nor the detailed mechanism of maintenance of lens transparency by HSF4 is fully understood.</p> <p>Results</p> <p>In an attempt to determine how the underlying biomedical and physiological mechanisms resulting from loss of HSF4 contribute to cataract formation, we generated an <it>Hsf4 </it>knockout mouse model. We showed that the <it>Hsf4 </it>knockout mouse (<it>Hsf4</it>^-/-) partially mimics the human cataract caused by HSF4 mutations. Q-PCR analysis revealed down-regulation of several cataract-relevant genes, including <it>γS-crystallin (Crygs) </it>and lens-specific beaded filament proteins 1 and 2 (<it>Bfsp1 </it>and <it>Bfsp2</it>), in the lens of the <it>Hsf4</it>^-/-mouse. Transcription activity analysis using the dual-luciferase system suggested that these cataract-relevant genes are the direct downstream targets of HSF4. The effect of HSF4 on <it>γS-crystallin </it>is exemplified by the cataractogenesis seen in the <it>Hsf4</it>^-/-,<it>rncat </it>intercross. The 2D electrophoretic analysis of whole-lens lysates revealed a different expression pattern in 8-week-old <it>Hsf4</it>^-/-mice compared with their wild-type counterparts, including the loss of some αA-crystallin modifications and reduced expression of γ-crystallin proteins.</p> <p>Conclusion</p> <p>Our results indicate that HSF4 is sufficiently important to lens development and disruption of the <it>Hsf4 </it>gene leads to cataracts via at least three pathways: 1) down-regulation of <it>γ-crystallin</it>, particularly <it>γS-crystallin</it>; 2) decreased lens beaded filament expression; and 3) loss of post-translational modification of αA-crystallin.</p

Multiobjective Optimization of the Performance and Emissions of a Large Low-Speed Dual-Fuel Marine Engine Based on MNLR-MOPSO

With increasingly strict emission regulations and growing environmental concerns, it is urgent to improve engine performance and reduce emissions. In this paper, multivariate nonlinear regression (MNLR) combined with multiobjective particle swarm optimization (MOPSO) was implemented to optimize the performance and emissions of a large low-speed two-stroke dual-fuel marine engine. First, a simulation model of a dual-fuel engine was established using AVL-BOOST software. Next, a single-factor scanning value method was applied to control a range of variables, including intake pressure, intake temperature, and natural gas mass fraction. Then, a nonlinear regression model was established using the statistical multivariate nonlinear regression equation. Finally, the multiobjective optimization algorithm implementing MOPSO was used to solve the trade-off between performance and emissions. It was found that when the intake pressure was 3.607 bar, the intake temperature was 297.15 K and the natural gas mass fraction was 0.962. The engine power increased by 0.34%, the brake specific fuel consumption (BSFC) reduced by 0.21%, and the NOx emissions reduced by 39.56%. The results show that the combination of multiple nonlinear regression and intelligent optimization algorithm is an effective method to optimize engine parameter settings

Preparation of supported carbon molecular sieve membrane from novolac phenol-formaldehyde resin

An asymmetric carbon membrane was prepared by coating alcohol solution of novolac phenol-formaldehyde resin containing a little hexamine on a porous resin support from the same material. After drying in air for two days at room temperature, the coated support was heated at 150 degrees C for I h in air (heating rate: 0.5 degrees C/min) and then carbonized at 800 degrees C (heating rate: 0.5 degrees C/min) in Ar atmosphere. The support and the membrane layer were carbonized simultaneously. The coating-pyrolysis cycle only needed one time. SEM photographs showed the carbon membrane had an asymmetric structure formed by a dense skin layer with a thickness of around 35 mu m and a porous substrate. Pure gases of different molecular size (H-2, CO2, O-2, N-2 and CH4) were used to test the carbon membrane permeance property. The membrane has a good selectivity for H-2/N-2 and H-2/CH4 with H-2 permeance of 4.05 x 10(-6) cm(3) cm(-2) s(-1) cmHg(-1). The permeance is independent of pressure. The results indicate that the gases transport through the membrane according to molecular sieve mechanism. (c) 2007 Elsevier B.V. All rights reserved

A Framework for Assessing the Interference from NGSO Satellite Systems to a Radio Astronomy System

As the number of non-geostationary orbit (NGSO) satellites continues to grow, interference with other communication systems, including radio astronomy systems (RASs), is becoming increasingly critical. In this study, an interference simulation framework was developed to analyse the potential impact of NGSO systems on RAS in accordance with the relevant International Telecommunication Union (ITU) regulations and recommendations. In addition to the simulation of interference generated by individual NGSO satellite systems, the framework also supports the analysis of aggregate interference from multiple NGSO satellite systems. By inputting satellite system parameters, including constellation configuration, user distribution and beam scheduling strategy, the framework is able to obtain interference probability distributions for a typical RAS ground station at different latitudes and observation directions. The simulation results provide a reference for the analysis of interference from NGSO satellite systems to RASs, and can also be used to guide the development of strategies to mitigate harmful interference to RASs

Effects of Continuous LPS Induction on Oxidative Stress and Liver Injury in Weaned Piglets

Due to imperfections in their immune and digestive systems, weaned piglets are susceptible to invasions of the external environment and diseases, especially bacterial infections, which lead to slow growth, tissue damage, and even the death of piglets. Here, a model of weaned piglets induced by Escherichia coli lipopolysaccharide (LPS) was established to explore the effects of continuous low-dose LPS induction on the mechanism of liver injury. A total of forty-eight healthy 28-day-old weaned piglets (weight = 6.65 ± 1.19 kg) were randomly divided into two groups: the CON group and LPS group. During the experimental period of thirteen days, the LPS group was injected intraperitoneally with LPS (100 μg/kg) once per day, and the CON group was treated with the same volume of 0.9% NaCl solution. On the 1st, 5th, 9th, and 13th days, the serum and liver of the piglets were collected for the determination of serum biochemical indexes, an antioxidant capacity evaluation, and histopathological examinations. In addition, the mRNA expression levels of the TLR4 pathway and inflammatory cytokines were detected. The results showed that the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in the serum increased after LPS induction. The activities of total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px) in the serum and liver homogenate of the LPS group were lower than those of the CON group, while the malondialdehyde (MDA) content in the serum and the activities of catalase (CAT) and superoxide dismutase (SOD) in the liver of the LPS group were higher than those in the CON group. At the same time, morphological impairment of the livers occurred, including hepatocyte caryolysis, hepatocyte vacuolization, karyopycnosis, and inflammatory cell infiltration, and the mRNA expression levels of TLR4, MyD88, NF-κB, TNF-α, IL-6, and IL-10 were upregulated in the livers after LPS induction. The above results were more obvious on the 1st and 5th days of LPS induction, while the trend during the later period was not significant. It was concluded that the oxidative stress and liver injury occurred at the early stage of LPS induction, while the liver damage weakened at the later stage. The weaned piglets probably gradually developed tolerance to the endotoxin after the continuous low-dose induction of LPS

Suppression of Th17 cell differentiation by misshapen/NIK-related kinase MINK1

T helper type 17 cells (Th17 cells) are major contributors to many autoimmune diseases. In this study, we demonstrate that the germinal center kinase family member MINK1 (misshapen/NIK-related kinase 1) negatively regulates Th17 cell differentiation. The suppressive effect of MINK1 on induction of Th17 cells is mediated by the inhibition of SMAD2 activation through direct phosphorylation of SMAD2 at the T324 residue. The importance of MINK1 to Th17 cell differentiation was strengthened in the animal model of experimental autoimmune encephalomyelitis (EAE). Moreover, we show that the reactive oxygen species (ROS) scavenger N-acetyl cysteine boosts Th17 cell differentiation in a MINK1-dependent manner and exacerbates the severity of EAE. Thus, we have not only established MINK1 as a critical regulator of Th17 cell differentiation, but also clarified that accumulation of ROS may limit the generation of Th17 cells. The contribution of MINK1 to ROS-regulated Th17 cell differentiation may suggest an important mechanism for the development of autoimmune diseases influenced by antioxidant dietary supplements