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Isoorientin (Iso), a natural bioactive flavonoid, possesses significant anti-tumor and anti-oxidant activities. Benzo[a]pyrene (BaP) is a food processing injurant with carcinogenicity, teratogenicity, and genotoxicity. Our preliminary study demonstrates that Iso attenuated the pyroptotic hepatocyte damage induced by BaP, however, the molecular mechanism remains unknown. The present study showed that Iso reduced the increase caused by BaP in the overflow of LDH, NO, and the electrical conductivity and the protein expressions of GSDMD-N, IL-18, and IL-1β, further showing that Iso could reduced the pyroptotic damage in HL-7702 cells induced by BaP. Caspase-1 inhibitor (Z-VAD-FMK) inhibited the characteristic pyroptosis protein expressions of Caspase-1, GSDMD-N, IL-18, and IL-1β, showing that the classic pyroptosis pathway depending on Caspase-1 was caused by BaP in HL-7702 cells. Consistent with the effects of the NLRP3 inhibitor (MCC950), NF-κB inhibitor (PDTC), ROS, and mtROS inhibitor (NAC and Mito-TEMPO), Iso weakened the stimulatory effects of BaP on the levels of ROS, the nuclear localization of NF-κB, and the activation of NLRP3 inflammasome and the characteristic indices of pyroptosis, demonstrating that Iso could alleviate the BaP-induced pyroptotic hepatocytes injury through inhibiting the ROS/NF-κB/NLRP3/Caspase-1 signaling pathway, which provides a new perspective and strategy to prevent liver injury induced by BaP.

Perovskite solar cells (PSCs) have attracted increasing attentions for their outstanding efficiency and simple fabrication process. However, the commonly used typical titanium dioxide (TiO2) electron transport layer (ETL) requires a high-temperature treatment to crystallize. In this work, the low-temperature (150 °C) atomic layer deposition (ALD) processed TiO2 ETL, and the SnO2/PCBM double interfacial modifier have been adopted to fabricate the high performance PSCs of ITO/ALD-TiO2/SnO2/PC61BM/MA0.7FA0.3PbI(3-x)Cl(x)/Spiro-OMeTAD/Ag. The measurement results show that the PSCs with ALD-TiO2 ETL obtain the higher champion PCE of 19.45% than that of PSC with solution-TiO2 ETLs (PCE = 18.64%), along with the obviously enhanced FF and VOC, as well as the better light stability and repeatability. And the transient photocurrent and photovoltage results demonstrate that the performance improvement origins from the enhanced charge transport and suppressed charge recombination. Therefore, the low-temperature ALD-TiO2 ETL with suitable modification is a promising strategy to fabricate efficient PSCs and flexible devices.

To analyze the effects of hydrogen charge concentration (HCC) and injection angle (IA) on the lean combustion in a gasoline Wankel engine, the present work implemented a numerical simulation model coupling with the kinetic mechanisms and validated with the experimental data. Results found that with the increase in HCC, the penetration of hydrogen injection is enlarged and the area of the high-speed jet flow is expanded. The jet-flow area for IAs of 45° or 135° is larger than that of 90°. Changing IA could obtain the hydrogen distribution at different regions of the rotor chamber and IA of 90° acquires the smallest hydrogen-rich region. Increasing IA brings about the reduced flame speed substantially; the flame area for IAs of 45° and 90° expands with the increment of HCC whereas the contrary pattern is witnessed at the IA of 135°. Smaller IA leads to the major burning occurring untimely, which resulting in less work delivery of the engine. The hydrogen consumption for IAs of 45° and 90° increases as HCC is ascendant while that for IA of 135° is just the reverse. Variations in the mixture distribution and turbulence are the intrinsic mechanism of how the HCC and IA reflects the combustion progress. As hydrogen is injected with larger HCC and smaller IA, a relatively richer mixture and higher turbulent kinetic energy are distributed close in the spark ignition region. The peak combustion pressure reduces and its corresponding crank position delays with the widened IA at any HCC. Considering the fuel combustion and nitric oxide formation, as hydrogen volume fraction is 3% and IA is 45°, the engine could realize the optimized performance under the computational condition. An efficient combustion performance may be performed in engineering application if the hydrogen IA is in accordance with the rotor rotating direction at lower HCC.

Background Previous studies suggest that Huntingtin, the protein mutated in Huntington's disease (HD), is required for actin based changes in cell morphology, and undergoes stimulus induced targeting to plasma membranes where it interacts with phospholipids involved in cell signaling. The small GTPase Rac1 is a downstream target of growth factor stimulation and PI 3-kinase activity and is critical for actin dependent membrane remodeling. Objective To determine if Rac1 activity is impaired in HD or regulated by normal Huntingtin. Methods Analyses were performed in differentiated control and HD human stem cells and HD Q140/Q140 knock-in mice. Biochemical methods included SDS-PAGE, western blot, immunoprecipitation, affinity chromatography, and ELISA based Rac activity assays. Results Basal Rac1 activity increased following depletion of Huntingtin with Huntingtin specific siRNA in human primary fibroblasts and in human control neuron cultures. Human cells (fibroblasts, neural stem cells, and neurons) with the HD mutation failed to increase Rac1 activity in response to growth factors. Rac1 activity levels were elevated in striatum of 1.5-month-old HD Q140/Q140 mice and in primary embryonic cortical neurons from HD mice. Affinity chromatography analysis of striatal lysates showed that Huntingtin is in a complex with Rac1, p85α subunit of PI 3-kinase, and the actin bundling protein α-actinin and interacts preferentially with the GTP bound form of Rac1. The HD mutation reduced Huntingtin interaction with p85α. Conclusions These findings suggest that Huntingtin regulates Rac1 activity as part of a coordinated response to growth factor signaling and this function is impaired early in HD.

Neural stem/progenitor cell (NSPC) based therapy represents an attractive treatment for Alzheimer's disease (AD), the most common neurodegenerative disorder with no effective treatment to date. This can be achieved by stimulating endogenous NSPCs and/or administrating exogenously produced NSPCs. Successful repair requires the migration of NSPCs to the loci where neuronal loss occurs, differentiation and integration into neural networks. However, the progressive loss of neurons in the brain of AD patients suggests that the repair by endogenous NSPCs in the setting of AD may be defective. The production and deposition of amyloid-β1-42 (Aβ1-42) peptides is thought to be a central event in the pathogenesis of AD. Here we report that Aβ1-42 peptides inhibit the migration of in vitro cultured NSPCs by disturbing the ERK-MAPK signal pathway. We found that the migratory capacity of NSPCs was compromised upon treatment with oligomeric Aβ1-42; the inhibitory effect occurred in a dose-dependent manner. Our previous studies have shown that Aβ1-42 triggers the expression of GRK2 by unknown mechanism. Herein we found that the Aβ1-42 evoked upregulation of GRK2 expression was attenuated upon treatment with the ERK inhibitor SCH772984 at 2.5 μM, but not with inhibitors for p38 or JNK. We detected a dose-dependent increase in levels of phosphorylated ERK1/2 after incubation of cells with oligomeric Aβ1-42 peptides for 3 days. We observed that an increase in the phosphorylation of p38 and JNK coincided with reduced phosphorylation of ERK1/2 upon treatment with Aβ1-42 for 6 and/or 9 days. We hypothesize that the divergence of the activation of the MAPK family of pathways may contribute to the inhibition of NSPCs migration after the long-term incubation with Aβ1-42. Pretreatment with 1 μM MEK inhibitor U0126 reversed the effects of Aβ1-42 on GRK2 expression of and NSPC migration. Together, our results suggest that Aβ1-42 oligomers compromise the migratory capacity of NSPCs through the MEK-ERK pathway.

Benzo[a]pyrene (BaP), a carcinogen, leads to the severe liver injury. Isoorientin (ISO), a natural flavonoid, is known for its bioactivities, including anti-oxidation, anti-inflammation, and so on. However, there is no report on the effects of ISO on liver injury induced by BaP. The present study demonstrated that ISO treatment could relieve BaP-caused autophagic and pyroptotic injury in HL-7702 human hepatocyte and male BALB/c mice by down-regulating the numbers of autophagosomes, the mRNA expression of LC3 II and Beclin-1, and the levels of pyroptotic characteristic indices. Histopathology stained also confirmed that ISO could suppress the BaP-induced liver injury. Meanwhile, ISO was able to improve the liver function, and remarkably (p

Bifacial photovoltaic technology has been established as an effective strategy for increasing electric power generation while reducing the area-related costs of silicon solar cells. For third-generation solar cells of organolead halide perovskites, the monofacial power conversion efficiency (PCE) has exceeded 23%. Therefore, the development of efficient bifacial cells is expected, but the top transparent electrode is a crucial obstacle that must be overcome. In this work, ultrathin silver (Ag) film was selected as the top transparent electrode and, particularly, a tellurium oxide (TeO2) optical coupling layer was adopted to enhance the transmittance of the Ag film in the visible light region, which markedly increased the light absorption of devices. Compared with PSCs with a pure Ag electrode, the device with a TeO2 (40 nm)/Ag (11 nm) top electrode showed significantly enhanced bifacial short-circuit current-density and bifacial PCEs of 18.86% (illuminated from the ITO electrode) and 15.12% (illuminated from the Ag electrode). Consequently, in addition to its role as a transmittance enhancement layer, TeO2 acted as a back reflector when the device was illuminated from the ITO side. Furthermore, a previously proposed phenylethylammonium iodide treatment method was adopted to improve charge transport at the perovskite/fullerene interface. Remarkably, the device achieved champion bifacial PCEs of 20.96% (ITO side) and 17.36% (Ag side), a bifaciality factor of 82.82%, and a steady PCE output and good reproducibility. The large-area device (1 cm2) achieved bifacial PCEs of 12.42% (ITO side) and 10.55% (Ag side), with better performance predicted by simulations. Therefore, the TeO2/Ag films are promising transparent electrodes for fabricating cost-effective bifacial PSCs.

Dysfunction at synapses is thought to be an early change contributing to cognitive, psychiatric and motor disturbances in Huntington’s disease (HD). In neurons, mutant Huntingtin collects in aggregates and distributes to the same sites as wild-type Huntingtin including on membranes and in synapses. In this study, we investigated the biochemical integrity of synapses in HD mouse striatum. We performed subcellular fractionation of striatal tissue from 2 and 6-month old knock-in Q175/Q7 HD and Q7/Q7 mice. Compared to striata of Q7/Q7 mice, proteins including GLUT3, Na+/K+ ATPase, NMDAR 2b, PSD95, and VGLUT1 had altered distribution in Q175/Q7 HD striata of 6-month old mice but not 2-month old mice. These proteins are found on plasma membranes and pre- and postsynaptic membranes supporting hypotheses that functional changes at synapses contribute to cognitive and behavioral symptoms of HD. Lipidomic analysis of mouse fractions indicated that compared to those of wild-type, fractions 1 and 2 of 6 months Q175/Q7 HD had altered levels of two species of PIP2, a phospholipid involved in synaptic signaling, increased levels of cholesterol ester and decreased cardiolipin species. At 2 months, increased levels of species of acylcarnitine, phosphatidic acid and sphingomyelin were measured. EM analysis showed that the contents of fractions 1 and 2 of Q7/Q7 and Q175/Q7 HD striata had a mix of isolated synaptic vesicles, vesicle filled axon terminals singly or in clusters, and ER and endosome-like membranes. However, those of Q175/Q7 striata contained significantly fewer and larger clumps of particles compared to those of Q7/Q7. Human HD postmortem putamen showed differences from control putamen in subcellular distribution of two proteins (Calnexin and GLUT3). Our biochemical, lipidomic and EM analysis show that the presence of the HD mutation conferred age dependent disruption of localization of synaptic proteins and lipids important for synaptic function. Our data demonstrate concrete biochemical changes suggesting altered integrity of synaptic compartments in HD mice that may mirror changes in HD patients and presage cognitive and psychiatric changes that occur in premanifest HD.

Our group has previously reported that lack of adipose tissue (lipodystrophy) leads to glucose intolerance and impaired endothelial-dependent vasorelaxation (EDR) via reduced signaling of the adipokine, leptin in the endothelium. However, the identity of the adipose depot responsible for endothelial leptin signaling activation and the underlying mechanism remains ill-defined. Our new data indicate that the perivascular adipose tissue (PVAT) is an important source of leptin. Thus, we hypothesized that leptin specifically derived from PVAT restores EDR and glucose tolerance in a mouse model with global deficiency in adipose tissue (lipodystrophic, BSCL2 -/- ). Restoration of PVAT in BSCL2 -/- mice corrected systemic glycemic status (GTT AUC, BSCL2 -/- + PVAT 635.3 ± 31.28 vs sham 741.6 ± 45.87, p-/- + PVAT 224.9 ± 23.97 vs 109 ± 19, P-/- + PVAT 143.8 ± 22.29 vs sham 131.3 ± 11.54, P-/- mice showed a trend towards an increase in PFKFB3 mRNA expression compared to WT mice. Moreover, we found that overexpression of PFKFB3 in aortic rings and endothelial cells impaired EDR and increased the ROS generating enzyme, Nox1 expression, respectively. Collectively, our results showed the critical role of PVAT-driven leptin and endothelial leptin receptor signaling in regulating systemic glucose disposal as well as endothelial function via a mechanism that potentially regulates endothelial glycolysis and oxidative stress-mediated via PFKFB3/NOX1.

Coordinated actions of Rab and Rho are necessary for numerous essential cellular processes ranging from vesicle budding to whole cell movement. How Rab and Rho are choreographed is poorly understood. Here, we report a protein complex comprised of kalirin, a Rho guanine nucleotide exchange factor (GEF) activating Rac1, and RabGEF transport protein particle (TRAPP). Kalirin was identified in a mass spectrometry analysis of proteins precipitated by trappc4 and detected on membranous organelles containing trappc4. Acute knockdown of kalirin did not affect trappc4, but significantly reduced overall and membrane-bound levels of trappc9, which specifies TRAPP toward activating Rab11. Trappc9 deficiency led to elevated expression of kalirin in neurons. Co-localization of kalirin and Rab11 occurred at a low frequency in NRK cells under steady state and was enhanced upon expressing an inactive Rab11 mutant to prohibit the dissociation of Rab11 from the kalirin-TRAPP complex. The small RNA-mediated depletion of kalirin diminished activities in cellular membranes for activating Rab11 and resulted in a shift in size of Rab11 positive structures from small to larger ones and tubulation of recycling endosomes. Our study suggests that kalirin and TRAPP form a dual GEF complex to choreograph actions of Rab11 and Rac1 at recycling endosomes.

A new kind of flexible and stretchable strip-shaped thermochromic resistive heater (TRH) has been fabricated by incorporating an aligned carbon nanotube sheet and a thermochromic silicone elastomer. This strip-shaped TRH demonstrates rapid thermal response and high stability even under stretching at a speed of 2 mm s−1. The resulting TRH textiles woven from the strip-shaped TRHs are flexible, stretchable, and breathable, and they can stably work under various deformations such as twisting. The temperatures of TRH textiles during working can be visually evaluated from the designed patterns for both high efficiency and safety. The weaving structure in the TRH textile is available for local heating, which has been demonstrated for thermal therapy.

A novel polymer-based optoelectronic device is created to independently realize either photoelectric conversion or light emission. It is produced by coating photoactive materials on one side of an aligned carbon nanotube sheet electrode and polymer light-emitting materials on the other through an all-solution process. The power conversion efficiency exceeds 2% and the brightness reaches 1040 cd m−2 for photoelectric conversion and light emission, respectively. This study indicates a promising potential for the all-solution-based process for a wide variety of applications, including microelectronics, and smart and multi-function devices.

Benzo[a]pyrene (BaP, most toxic polycyclic aromatic hydrocarbon) is a global food-borne pollutant, and is associated with many diseases and gut microbiota disorders. The present study was designed to investigate the protective effects of isoorientin (ISO), a flavonoid compound in the human diet, on BaP-induced colonic damage and gut microbial disorders in mice. ISO was administered orally to mice at doses of 20 mg/kg body weight before BaP challenge (oral administration, 50 mg/kg body weight). The results revealed that ISO suppressed the BaP-induced reduction of body weight in mice, and it also prevented colonic damage, as evidenced by the increase in colon total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) activities, and the decrease in colon malonaldehyde (MDA) and hydrogen peroxide (H2O2) levels, compared to BaP-treated mice. Meanwhile, we used 16S rRNA gene sequencing to investigate the impact of BaP with or without ISO on the colon contents associated bacteria in mice. ISO could relieve the BaP-induced change in the abundance of gut microbiota, especially the genera of Feacalibaculum, Lactobacillus, Acinetobacter, Desulfovibrio and Alistipes. And ISO ameliorated BaP-induced microbiota metabolic disturbance, especially the metabolic pathways of LPS and sulphur compounds. In conclusion, our findings indicated that ISO could be of significant advantage in suppressing the colonic injury and the gut microbiota disorder induced by BaP.

Isoorientin (ISO) is a natural flavonoid, which is a 6-C-glucoside of luteolin, and has been demonstrated to possess multiple biological properties. In this study, the effects of ISO on the growth performance and gut microbiota of BALB/c mice were investigated. The results showed that ISO could promote food intake and body weight gain, increase the digestibility of crude proteins and utilization of the gross energy, and strengthen antioxidant capacity of mice. We also demonstrated it has no side effects on hepatic and renal functions. Moreover, ISO inhibited the growth of most bacteria in gut microbiota, especially the pathogenic genera of Alistipes, Helicobacter, and Oscillibacter, which could lead to inflammation. Metabolisms of epithelial cell signaling in Helicobacter pylori infection, lipopolysaccharide (LPS) biosynthesis, and LPS biosynthesis proteins in gut microbiota of the control group were more abundant than those in the ISO group, while lipid metabolism and vitamin B6 metabolism were enriched ...

Saline lacustrine source rocks in China provide the resource basis for many giant oil fields. Here, we report the first discovery of such source rocks in the piedmont area of the northern Tianshan Mountains in the southern Junggar Basin of NW China. These source rocks are Cretaceous and Paleogene in age. Organic geochemistry and trace-element data suggest that these mudstones were formed in a brackish–saline lacustrine environment, characterized by deep-water and reducing conditions, and in a warm and dry paleoclimate. Evidence for this environment includes mudstone Pr/Ph values of 0.4, and negative Ce and Eu anomalies. The total organic carbon (TOC) contents of these Cretaceous and Paleogene mudstones are typically >0.5%, with maximum values of 1.45% and 2.22%, respectively, signifying moderate to high organic matter abundance. Rock-Eval and kerogen analyses suggest that the organic matter was dominated by type II kerogen. The mudstones are generally thermally mature, suggesting favorable conditions for hydrocarbon (particularly oil) generation. Oil–source correlation confirms the oil generation of these two sets of source rocks, whose development are controlled mainly by reducing environments. These Cretaceous and Paleogene mudstones should therefore be a target for regional exploration in the southern Junggar Basin in addition to the known gas-producing Jurassic rocks. This oil-bearing potential is unique amongst the Early Cretaceous and Eocene–Oligocene central Asian petroliferous basins, as the eastern portion of this realm is considered to host predominantly Jurassic coal-based source rocks, giving rise to numerous large gas fields rather than oil resources.

Pneumonia is a leading cause of death in children and the elderly worldwide, accounting for 15% of all deaths of children under 5 years old. Streptococcus pneumoniae is a common and aggressive cause of pneumonia and can also contribute to meningitis and sepsis. Despite the widespread use of antibiotics, mortality rates for pneumonia remain unacceptably high in part due to the release of bacterial toxins. Pneumolysin (PLY), is a cholesterol-dependent toxin that is produced by Streptococcus and it is both necessary and sufficient for the development of the extensive pulmonary permeability edema that underlies acute lung injury (ALI). The mechanisms by which PLY disrupt the pulmonary endothelial barrier are not fully understood. Previously we found that reactive oxygen species (ROS) contribute to the barrier destructive effects of PLY and identified an unexpected but potent role of Hsp70 in suppressing ROS production. The ability of Hsp70 to influence PLY-induced barrier dysfunction is not yet described and the goal of the current study was to identify whether Hsp70 upregulation is an effective strategy to protect the lung microvascular endothelial barrier from G+ bacterial toxins. Overexpression of Hsp70 via adenovirus-mediated gene transfer attenuated PLY-stimulated increases in permeability in human lung microvascular endothelial cells (HLMVEC) with no evidence of cytotoxicity. To adopt a more translational approach, we employed a pharmacological approach using geranylgeranylacetone (GGA) to acutely upregulate endogenous Hsp70 expression. Following acute treatment (6h) with GGA, HLMVECs exposed to PLY displayed improved cell viability and enhanced endothelial barrier function as measured by both Electric Cell-substrate Impedance Sensing (ECIS) and transwell permeability assays compared to control treated cells. PLY promoted increased mitochondrial ROS, decreased mitochondrial oxygen consumption and increased caspase 3 cleavage and cell death, which were collectively improved in cells pre-treated with GGA. In mice, IP pre-treatment with GGA 24h prior to IT administration of PLY resulted in significantly less Evans Blue Dye extravasation compared to vehicle, indicating preserved endothelial barrier integrity and suggesting that the acute upregulation of Hsp70 may be an effective therapeutic approach in the treatment of lung injury associated with pneumonia.

Human huntingtin (Htt) contains 3144 amino acids and has an expanded polyglutamine region near the NH2-terminus in patients with Huntington’s disease. While numerous binding partners have been identified to NH2-terminal Htt, fewer proteins are known to interact with C-terminal domains of Htt. Here we report that kalirin, a Rac1 activator, is a binding partner to C-terminal Htt. Kalirin and Htt co-precipitated from mouse brain endosomes and co-localized at puncta in NRK and immortalized striatal cells and primary cortical neurons. We mapped the interaction domains to kalirin674-1272 and Htt2568-3144 and determined that the interaction between kalirin and Htt was independent of HAP1, a known interactor for Htt and kalirin. Kalirin precipitated with mutant Htt was more abundant than with wild-type Htt and had a reduced capacity to activate Rac1 when mutant Htt was present. Expression of Htt2568-3144 caused cytotoxicity, partially rescued by co-expressing kalirin674-1272 but not other regions of kalirin. Our study suggests that the interaction of kalirin with the C-terminal region of Htt influences the function of kalirin and modulates the cytotoxicity induced by C-terminal Htt.

The status of B10 cells in patients with rheumatoid arthritis (RA) has not been consistently reported. In this study, we observed the kinetic changes of the B10 cells in collagen-induced arthritis (CIA) mice and the influence of multiple cytokines on the B10 cells to investigate the potential mechanism underlying the changes of B10 cells.The kinetic changes of frequency and function of the CD19(+)CD1d(hi)CD5(+) cells in splenic cells were observed during the complete progress of CIA mice. The kinetic changes of cytokines IL-4, IL-6, IL-17A, IL-18, TNF-α, IFN-γ and TGF-β1 were also detected. Then influence of these cytokines on the status of B10 cells was investigated both in vitro and in vivo.The frequency and suppressive ability of the CD19(+)CD1d(hi)CD5(+) cells increased to its peak on the 14th day while gradually decreased subsequently. IFN-γ showed a similar tendency with the CD19(+)CD1d(hi)CD5(+) cells, whereas IL-6, IL-17A, IL-18, TNF-α, and TGF-β1 reached its peak on the 28-35th day. In addition, IFN-γ up-regulated while TGF-β1 down-regulated the frequency and function of the CD19(+)CD1d(hi)CD5(+) cells both in vitro and in vivo.The B10 cells in CIA mice could be regulated by IFN-γ and TGF-β1, suggesting that the status of B10 cells in RA may be influenced by the balance of pro-inflammatory and anti-inflammatory factors, and the impaired B10 cells could be recovered in vitro by adequate treatment before being used for a therapeutic method in clinical practice.

A fibre-shaped light emitting electrochemical cell that can be woven and integrated with textiles offers new opportunities for smart fabrics.

A fiber-shaped polymer light-emitting electrochemical cell (PLEC) was developed by sandwiching an electroluminescent polymer layer between two aligned carbon nanotube (CNT) sheet electrodes. Similar to a conventional planar PLEC, the electroluminescent polymer layer and two carbon nanotube electrodes are closely and stably contacted, so that the injected charges can be rapidly and efficiently transported. Due to their one-dimensional structure, the fiber-shaped PLEC demonstrates unique and promising advantages, e.g., the luminance is almost independent on the observation angle. In addition, the fiber-shaped PLEC is thin, lightweight and flexible, which bespeaks a promising future for various electronic textiles.

Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vasculature that involves the loss of endothelial function together with inappropriate smooth muscle cell growth, inflammation, and fibrosis. These changes underlie a progressive remodeling of blood vessels that alters flow and increases pulmonary blood pressure. Elevated pressures in the pulmonary artery imparts a chronic stress on the right ventricle which undergoes compensatory hypertrophy but eventually fails. How PAH develops remains incompletely understood and evidence for the altered production of reactive oxygen and nitrogen species (ROS, RNS respectively) in the pulmonary circulation has been well documented. There are many different types of ROS and RNS, multiple sources, and collective actions and interactions. This review summarizes past and current knowledge of the sources of ROS and RNS and how they may contribute to the loss of endothelial function and changes in smooth muscle proliferation in the pulmonary circulation.

An all-solid-state, lightweight, flexible, and wearable polymer solar cell (PSC) textile with reasonable photovoltaic performance has been developed. A metal textile electrode made from micrometer-sized metal wires is used as the cathode, and the surfaces of the metal wires are dip-coated with the photoactive layers. Two ultrathin, transparent, and aligned carbon nanotube sheets that exhibit remarkable electronic and mechanical properties were coated onto the modified metal textile at both sides as the anode to produce the desired PSC textile. Because of the designed sandwich structure, the PSC textile displays the same energy conversion efficiencies regardless of which side it is irradiated from. As expected, the PSC textiles are highly flexible, and their energy conversion efficiencies varied by less than 3% after bending for more than 200 cycles. The PSC textile shows an areal density (5.9 mg cm(-2)) that is lower than that of flexible film-based PSCs (31.3 mg cm(-2)).

Huntington disease (HD) is caused by polyglutamine expansion in the N terminus of huntingtin (htt). Analysis of human postmortem brain lysates by SDS-PAGE and Western blot reveals htt as full-length and fragmented. Here we used Blue Native PAGE (BNP) and Western blots to study native htt in human postmortem brain. Antisera against htt detected a single band broadly migrating at 575–850 kDa in control brain and at 650–885 kDa in heterozygous and Venezuelan homozygous HD brains. Anti-polyglutamine antisera detected full-length mutant htt in HD brain. There was little htt cleavage even if lysates were pretreated with trypsin, indicating a property of native htt to resist protease cleavage. A soluble mutant htt fragment of about 180 kDa was detected with anti-htt antibody Ab1 (htt-(1–17)) and increased when lysates were treated with denaturants (SDS, 8 m urea, DTT, or trypsin) before BNP. Wild-type htt was more resistant to denaturants. Based on migration of in vitro translated htt fragments, the 180-kDa segment terminated ≈htt 670–880 amino acids. If second dimension SDS-PAGE followed BNP, the 180-kDa mutant htt was absent, and 43–50 kDa htt fragments appeared. Brain lysates from two HD mouse models expressed native full-length htt; a mutant fragment formed if lysates were pretreated with 8 m urea + DTT. Native full-length mutant htt in embryonic HD140Q/140Q mouse primary neurons was intact during cell death and when cell lysates were exposed to denaturants before BNP. Thus, native mutant htt occurs in brain and primary neurons as a soluble full-length monomer.

Patients with Huntington's disease suffer severe neuronal loss and signs of oxidative damage in the brain. Previously we found that primary neurons from embryonic cortex of mice bearing the Huntington's disease mutation (140 glutamines inserted into exon 1 of huntingtin) showed higher levels of reactive oxygen species before cell death. Here, we treated mutant neurons with known neuroprotective agents and determined the effects on neuronal survival and levels of reactive oxygen species. Primary neurons were exposed to the neurotrophin, brain derived neurotrophic factor, the antioxidant N-acetyl-cysteine or a specific inhibitor of glycogen synthase kinase 3-β, SB216763. Each reagent increased the survival of the mutant neurons compared with untreated mutant neurons and also reduced the levels of reactive oxygen species to levels of wild-type neurons. These results suggest that reducing the levels of reactive oxygen species may be necessary to protect neurons with the Huntington's disease mutation from cell death.

By the combination of high-temperature organometallic synthesis and phase transfer through complete ligand-exchange with mixed phosphate, highly water-dispersible Fe3O4 nanoparticles with narrow size distribution are obtained, which show applicable response to magnetic field. IR and ξ-potential characterization of this system provides insights into ligand structures on particle surface.

The present work studies the effects of titanium carbide (TiC) particle additions on the microstructure and mechanical properties of hypereutectic high chromium cast iron containing about 20%Cr and 4.0%C by the optical microscopy (OM), the transmission electron microscopy (TEM), the X-ray diffraction (XRD) analysis, the digital image analysis system, impact tester, and hardness tester. The carbides of high chromium cast iron are refined gradually and the shape of the primary M7C3-type carbides became more isotropic with the increase of TiC particles. When the addition of TiC particles exceeds 1.0 wt.%, the change of microstructure is not obvious. The hardness of high chromium cast iron has a slight increase and impact toughness has a obvious increase with the increase of TiC additions. However, when the addition of TiC particles exceeds 1.0 wt.%, the impact toughness has no obvious change.

Heat shock protein 90 (Hsp90) is a molecular chaperone that orchestrates the folding and stability of proteins that regulate cellular signaling, proliferation and inflammation. We have previously shown that Hsp90 controls the production of reactive oxygen species by modulating the activity of Noxes1-3 and 5, but not Nox4. The goal of the current study was to define the regions on Nox5 that bind Hsp90 and determine how Hsp90 regulates enzyme activity. In isolated enzyme activity assays, we found that Hsp90 inhibitors selectively decrease superoxide, but not hydrogen peroxide, production. The addition of Hsp90 alone only modestly increases Nox5 enzyme activity but in combination with the co-chaperones, Hsp70, HOP, Hsp40, and p23 it robustly stimulated superoxide, but not hydrogen peroxide, production. Proximity ligation assays reveal that Nox5 and Hsp90 interact in intact cells. In cell lysates using a co-IP approach, Hsp90 binds to Nox5 but not Nox4, and the degree of binding can be influenced by calcium-dependent stimuli. Inhibition of Hsp90 induced the degradation of full length, catalytically inactive and a C-terminal fragment (aa398-719) of Nox5. In contrast, inhibition of Hsp90 did not affect the expression levels of N-terminal fragments (aa1-550) suggesting that Hsp90 binding maintains the stability of C-terminal regions. In Co-IP assays, Hsp90 was bound only to the C-terminal region of Nox5. Further refinement using deletion analysis revealed that the region between aa490-550 mediates Hsp90 binding. Converse mapping experiments show that the C-terminal region of Nox5 bound to the M domain of Hsp90 (aa310-529). In addition to Hsp90, Nox5 bound other components of the foldosome including co-chaperones Hsp70, HOP, p23 and Hsp40. Silencing of HOP, Hsp40 and p23 reduced Nox5-dependent superoxide. In contrast, increased expression of Hsp70 decreased Nox5 activity whereas a mutant of Hsp70 failed to do so. Inhibition of Hsp90 results in the loss of higher molecular weight complexes of Nox5 and decreased interaction between monomers. Collectively these results show that the C-terminal region of Nox5 binds to the M domain of Hsp90 and that the binding of Hsp90 and select co-chaperones facilitate oligomerization and the efficient production of superoxide.

A mutation in the huntingtin (Htt) gene produces mutant Htt and Huntington's disease (HD), a neurodegenerative disorder. HD patients have oxidative damage in the brain, but the causes are unclear. Compared with controls, we found brain levels of NADPH oxidase (NOX) activity, which produces reactive oxygen species (ROS), elevated in human HD postmortem cortex and striatum and highest in striatum of presymptomatic individuals. Synaptosome fractions from cortex and striatum of HD(140Q/140Q) mice had elevated NOX activity at 3 months of age and a further rise at 6 and 12 months compared with synaptosomes of age-matched wild-type (WT) mice. High NOX activity in primary cortical and striatal neurons of HD(140Q/140Q) mice correlated with more ROS and neurite swellings. These features and neuronal cell death were markedly reduced by treatment with NOX inhibitors such as diphenyleneiodonium (DPI), apocynin (APO) and VAS2870. The rise in ROS levels in mitochondria of HD(140Q/140Q) neurons followed the rise in NOX activity and inhibiting only mitochondrial ROS was not neuroprotective. Mutant Htt colocalized at plasma membrane lipid rafts with gp91-phox, a catalytic subunit for the NOX2 isoform. Assembly of NOX2 components at lipid rafts requires activation of Rac1 which was also elevated in HD(140Q/140Q) neurons. HD(140Q/140Q) mice bred to gp91-phox knock-out mice had lower NOX activity in the brain and in primary neurons, and neurons had normal ROS levels and significantly improved survival. These findings suggest that increased NOX2 activity at lipid rafts is an early and major source of oxidative stress and cell death in HD(140Q/140Q) neurons.

Huntingtin has an expanded polyglutamine tract in patients with Huntington's disease. Huntingtin localizes to intracellular and plasma membranes but the function of huntingtin at membranes is unknown. Previously we reported that exogenously expressed huntingtin bound pure phospholipids using protein-lipid overlays. Here we show that endogenous huntingtin from normal (Hdh(7Q/7Q)) mouse brain and mutant huntingtin from Huntington's disease (Hdh(140Q/140Q)) mouse brain bound to large unilamellar vesicles containing phosphoinositol (PI) PI 3,4-bisphosphate, PI 3,5-bisphosphate, and PI 3,4,5-triphosphate [PI(3,4,5)P3]. Huntingtin interactions with multivalent phospholipids were similar to those of dynamin. Mutant huntingtin associated more with phosphatidylethanolamine and PI(3,4,5)P3 than did wild-type huntingtin, and associated with other phospholipids not recognized by wild-type huntingtin. Wild-type and mutant huntingtin also bound to large unilamellar vesicles containing cardiolipin, a phospholipid specific to mitochondrial membranes. Maximal huntingtin-phospholipid association required inclusion of huntingtin amino acids 171-287. Endogenous huntingtin recruited to the plasma membrane in cells that incorporated exogenous PI 3,4-bisphosphate and PI(3,4,5)P3 or were stimulated by platelet-derived growth factor or insulin growth factor 1, which both activate PI 3-kinase. These data suggest that huntingtin interacts with membranes through specific phospholipid associations and that mutant huntingtin may disrupt membrane trafficking and signaling at membranes.

Huntingtin is ubiquitously expressed and enriched in the brain. Deletion of the huntingtin gene in mice is lethal during early embryonic development. The function of huntingtin is, however, not clear. Here, we report that huntingtin is important for the function of Rab11, a critical GTPase in regulating membrane traffic from recycling endosomes to the plasma membrane. In huntingtin-null embryonic stem cells, the levels of Rab11 on membranes and nucleotide exchange activity on Rab11 were significantly reduced compared with normal embryonic stem cells. In brain membranes, an antibody against huntingtin immunoprecipitated a nucleotide exchange activity on Rab11 and huntingtin was coprecipitated with Rab11 in the presence of guanosine diphosphate. These data suggest a role for huntingtin in a complex that activates Rab11.

Sphingomyelin- and cholesterol-enriched microdomains can be isolated as detergent-resistant membranes from total cell extracts (total-DRM). It is generally believed that this total-DRM represents microdomains of the plasma membrane. Here we describe the purification and detailed characterization of microdomains from Golgi membranes. These Golgi-derived detergent-insoluble complexes (GICs) have a low buoyant density and are highly enriched in lipids, containing 25% of total Golgi phospholipids including 67% of Golgi-derived sphingomyelin, and 43% of Golgi-derived cholesterol. In contrast to total-DRM, GICs contain only 10 major proteins, present in nearly stoichiometric amounts, including the α- and β-subunits of heterotrimeric G proteins, flotillin-1, caveolin, and subunits of the vacuolar ATPase. Morphological data show a brefeldin A-sensitive and temperature-sensitive localization to the Golgi complex. Strikingly, the stability of GICs does not depend on its membrane environment, because, after addition of brefeldin A to cells, GICs can be isolated from a fused Golgi-endoplasmic reticulum organelle. This indicates that GIC microdomains are not in a dynamic equilibrium with neighboring membrane proteins and lipids. After disruption of the microdomains by cholesterol extraction with cyclodextrin, a subcomplex of several GIC proteins including the B-subunit of the vacuolar ATPase, flotillin-1, caveolin, and p17 could still be isolated by immunoprecipitation. This indicates that several of the identified GIC proteins localize to the same microdomains and that the microdomain scaffold is not required for protein interactions between these GIC proteins but instead might modulate their affinity.