Structure of human Niemann–Pick C1 protein Li, Xiaochun; Wang, Jiawei; Coutavas, Elias ...
Proceedings of the National Academy of Sciences - PNAS,
07/2016, Letnik:
113, Številka:
29
Journal Article
Recenzirano
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Niemann–Pick C1 protein (NPC1) is a late-endosomal membrane protein involved in trafficking of LDL-derived cholesterol, Niemann–Pick disease type C, and Ebola virus infection. NPC1 contains 13 ...transmembrane segments (TMs), five of which are thought to represent a “sterol-sensing domain” (SSD). Although present also in other key regulatory proteins of cholesterol biosynthesis, uptake, and signaling, the structure and mechanism of action of the SSD are unknown. Here we report a crystal structure of a large fragment of human NPC1 at 3.6 Å resolution, which reveals internal twofold pseudosymmetry along TM 2–13 and two structurally homologous domains that protrude 60 Å into the endosomal lumen. Strikingly, NPC1’s SSD forms a cavity that is accessible from both the luminal bilayer leaflet and the endosomal lumen; computational modeling suggests that this cavity is large enough to accommodate one cholesterol molecule. We propose a model for NPC1 function in cholesterol sensing and transport.
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•The intra- and inter-species leaf-root-soil N:P stoichiometry was analyzed.•Soil total N:P was far less than available N:P, showing high availability of soil N.•Leaf had high N and ...N:P but leaf and root N, P, and N:P were unrelated with soils.•P controlled N:P ratio, and roots dominated N and P allocation in leaves and roots.•A strong stoichiometric homeostasis and successful survival strategy were revealed.
Soil nutrient stoichiometry can influence the biodiversity, vegetation productivity, and biogeochemical cycles in terrestrial ecosystems. However, the soil nutrient status, distribution patterns, and driving factors on sand dunes in modern deserts were still unclear. The soil C, N, P, and K contents in 65 plots across two continuous linear sand dunes (220 m × 110 m) located in the Gurbantunggut Desert, a typical temperate desert in Central Asia, were investigated by the traditional statistical, geostatistical, and structural equation modeling (SEM) techniques. Results indicated that soil C, N, and P contents were low and presented remarkable interactions with each other. The order of soil nutrient deficiency in the sand dunes was C > N > P > K, in which soil C exhibited a higher accumulation rate than N and P based on allometric analysis. Soil C, N, P, and their ratios to K exhibited an obvious U-shaped curve opposite to the shape of the sand dune, had strong spatial dependence (structural variance ratios: 81.4–94.3%), and presented evidently longitudinal zonal distribution patterns along the sand dunes. Pearson's correlation analysis and canonical correspondence analysis demonstrated that the topographic (slope position, relative height, convexity, and curvature), vegetation (herbaceous richness, abundance, coverage and biomass, and deep-rooted small shrubbery), soil abiotic (pH, electronic conductivity, and soil water content), and soil biotic (i.e., biological soil crust) factors interacted with each other and were significantly correlated with most soil stoichiometric parameters. The SEM analysis further demonstrated that the topography was the most direct driving factor influencing soil C, N, and P and their ratios to K on sand dunes. The results revealed that sand dune fixation and lowering promoted the formation of a stable and sustainable soil–plant relationship in temperate deserts of Central Asia.
In this study, we aim to determine cellular mechanisms linking nutrient metabolism to the regulation of inflammation and insulin resistance. The nutrient sensors AMP-activated protein kinase (AMPK) ...and SIRT1 show striking similarities in nutrient sensing and regulation of metabolic pathways. We find that the expression, activity, and signaling of the major isoform α1AMPK in adipose tissue and macrophages are substantially down-regulated by inflammatory stimuli and in nutrient-rich conditions, such as exposure to lipopolysaccharide (LPS), free fatty acids (FFAs), and diet-induced obesity. Activating AMPK signaling in macrophages by 5-aminoimidazole-4-carboxamide-1-β4-ribofuranoside or constitutively active α1AMPK (CA-α1) significantly inhibits; although inhibiting α1AMPK by short hairpin RNA knock-down or dominant-negative α1AMPK (DN-α1) increases LPS- and FFA-induced tumor necrosis factor α expression. Chromatin immunoprecipitation and luciferase reporter assays show that activation of AMPK by CA-α1 in macrophages significantly inhibits LPS- or FFA-induced NF-κB signaling. More importantly, in a macrophage-adipocyte co-culture system, we find that inactivation of macrophage AMPK signaling inhibits adipocyte insulin signaling and glucose uptake. Activation of AMPK by CA-α1 increases the SIRT1 activator NAD+ content and SIRT1 expression in macrophages. Furthermore, α1AMPK activation mimics the effect of SIRT1 on deacetylating NF-κB, and the full capacity of AMPK to deacetylate NF-κB and inhibit its signaling requires SIRT1. In conclusion, AMPK negatively regulates lipid-induced inflammation, which acts through SIRT1, thereby contributing to the protection against obesity, inflammation, and insulin resistance. Our study defines a novel role for AMPK in bridging the signaling between nutrient metabolism and inflammation.
Electrocatalytic hydrogen evolution in alkaline and neutral media offers the possibility of adopting platinum‐free electrocatalysts for large‐scale electrochemical production of pure hydrogen fuel, ...but most state‐of‐the‐art electrocatalytic materials based on nonprecious transition metals operate at high overpotentials. Here, a monolithic nanoporous multielemental CuAlNiMoFe electrode with electroactive high‐entropy CuNiMoFe surface is reported to hold great promise as cost‐effective electrocatalyst for hydrogen evolution reaction (HER) in alkaline and neutral media. By virtue of a surface high‐entropy alloy composed of dissimilar Cu, Ni, Mo, and Fe metals offering bifunctional electrocatalytic sites with enhanced kinetics for water dissociation and adsorption/desorption of reactive hydrogen intermediates, and hierarchical nanoporous Cu scaffold facilitating electron transfer/mass transport, the nanoporous CuAlNiMoFe electrode exhibits superior nonacidic HER electrocatalysis. It only takes overpotentials as low as ≈240 and ≈183 mV to reach current densities of ≈1840 and ≈100 mA cm−2 in 1 m KOH and pH 7 buffer electrolytes, respectively; ≈46‐ and ≈14‐fold higher than those of ternary CuAlNi electrode with bimetallic Cu–Ni surface alloy. The outstanding electrocatalytic properties make nonprecious multielemental alloys attractive candidates as high‐performance nonacidic HER electrocatalytic electrodes in water electrolysis.
Nonprecious nanoporous multielemental alloy electrodes composed of electroactive surface high‐entropy CuNiMoFe alloy hold great promise as cost‐effective electrocatalysts for hydrogen evolution reaction (HER) in nonacidic media. Associated with hierarchical nanoporous architecture to facilitate electron transfer and offer abundant high‐entropy CuNiMoFe active sites, the nanoporous CuAlNiMoFe hybrid electrode exhibits remarkably enhanced HER activity and durability.
Adipose tissue macrophages (ATMs) undergo a phenotypic switch from alternatively activated antiinflammatory M2 macrophages in lean individuals to classically activated proinflammatory M1 macrophages ...in obese subjects. However, the molecular mechanism underlying this process remains unclear. In this study we aim to determine whether DNA methyltransferase 3b (DNMT3b) regulates macrophage polarization and inflammation. We found that the expression of DNMT3b was significantly induced in macrophages exposed to the saturated fatty acid stearate, was higher in ATMs isolated from obese mice, but was significantly lower in alternatively activated M2 vs classically activated M1 ATMs, suggesting a role for DNMT3b in regulation of macrophage polarization and inflammation in obesity. DNMT3b knockdown promoted macrophage polarization to alternatively activated M2 phenotype and suppressed macrophage inflammation, whereas overexpressing DNMT3b did the opposite. Importantly, in a macrophage-adipocyte coculture system, we found that DNMT3b knockdown significantly improved adipocyte insulin signaling. The promoter of peroxisome proliferator activated receptor (PPAR)γ1, a key transcriptional factor that regulates macrophage polarization, is enriched with CpG sites. Chromatin immunoprecipitation assays showed that DNMT3b bound to the methylation region at PPARγ1 promoter, which was further enhanced by stearate. Moreover, pyrosequencing analysis revealed that stearate increased DNA methylation at PPARγ1, which was prevented by DNMT3b deficiency. Therefore, our data demonstrate that DNMT3b plays an important role in regulating macrophage polarization through epigenetic mechanisms. In obesity, elevated saturated fatty acids enhance DNMT3b expression, leading to DNA methylation at the PPARγ1 promoter, which may contribute to deregulated adipose tissue macrophage polarization, inflammation, and insulin resistance.
Summary
When a lithium‐ion battery works under high current, its working temperature is easy to exceed the allowable working temperature, resulting in the decrease of battery life. This may cause the ...non‐uniformity of the internal working temperature of the battery and affect the working parameters of the battery. Therefore, an effective thermal management system is needed to enhance the thermal performance of the battery, improve the work efficiency, and extend the service life of the battery. In this study, we propose a new type of fork type mini‐channel cooling plate based on genetic optimization algorithm to reduce the working temperature of battery and obtain better thermal uniformity. First, the thermal performance of co‐current type cooling plates is experimentally and numerically studied. The heat transfer ability of cross flow cooling plates used to cool the Li‐ion Battery is evaluated by parametric method. Second, a multi‐objective genetic algorithm optimization is finally performed, considering the balance of the maximum value for temperature and pressure drop. Compared with the previous study, the reduction of temperature difference of this cooling plate can be up to 2°C. In contrast, the pressure drop penalty and thermal resistance of the optimized cooling plates can be reduced by 20% and 40%, respectively. Thirdly the thermal performance of a battery module with eight battery cells is also examined numerically. The maximum ∆T of the battery pack among cells is 4.83°C for V = 48 mL/s, which implies that the battery pack can work normally. This study indicates that batteries with the proposed new cooling plates have much better temperature uniformity.
To reduce the operating temperature of lithium battery and prolong the cycle life, we aim to propose a novel fork‐type mini‐channel network cooling plate, and the performance of cooling plate for the Li‐ion battery is experimentally and numerically studied. A multi‐objective genetic algorithm optimization is performed considering the balance of the maximum temperature and pressure drop. The results showed that the cooling plate kept the battery at a normal operating temperature.
A binocular full-color holographic three-dimensional near eye display system using a single spatial light modulator (SLM) is proposed. In the display system, the frequency spectrum shifting operation ...and color spectrum shifting operation are adopted to realize the frequency division multiplexing (FDM) and frequency superposition multiplexing (FSM) by manipulating the frequency spectrums of each color- and view-channel sub-holograms. The FDM combined with polarization multiplexing will be used to implement binocular display using a single SLM, and the FSM working with a bandpass filter for each view-channel will be used to achieve full-color display from single frame hologram. The optical analysis and experiments with 3D color objects confirm the feasibility of the proposed system in the practical application.
Aqueous aluminum batteries are promising post-lithium battery technologies for large-scale energy storage applications because of the raw materials abundance, low costs, safety and high theoretical ...capacity. However, their development is hindered by the unsatisfactory electrochemical behaviour of the Al metal electrode due to the presence of an oxide layer and hydrogen side reaction. To circumvent these issues, we report aluminum-copper alloy lamellar heterostructures as anode active materials. These alloys improve the Al-ion electrochemical reversibility (e.g., achieving dendrite-free Al deposition during stripping/plating cycles) by using periodic galvanic couplings of alternating anodic α-aluminum and cathodic intermetallic Al
Cu nanometric lamellas. In symmetric cell configuration with a low oxygen concentration (i.e., 0.13 mg L
) aqueous electrolyte solution, the lamella-nanostructured eutectic Al
Cu
alloy electrode allows Al stripping/plating for 2000 h with an overpotential lower than ±53 mV. When the Al
Cu
anode is tested in combination with an Al
MnO
cathode material, the aqueous full cell delivers specific energy of ~670 Wh kg
at 100 mA g
and an initial discharge capacity of ~400 mAh g
at 500 mA g
with a capacity retention of 83% after 400 cycles.
Background and Objectives
B(A) phenotype is usually formed by nucleotide mutations in the ABO*B.01 allele, with their products exhibiting glycosyltransferases (GTs) A and B overlapping functionality. ...We herein report a B(A) allele found in a Chinese family.
Materials and Methods
The entire ABO genes of the probands, including flanking regulatory regions, were sequenced through PacBio third‐generation long‐read single‐molecule real‐time sequencing. 3D molecular models of the wild‐type and mutant GTB were generated using the DynaMut web server. The effect of the mutation on the enzyme function was predicted by PROVEAN and PolyPhen2. The predictions of stability changes were performed using DynaMut and SNPeffect.
Results
Based on serological and sequencing features, we concluded the two probands as possible cases of the B(A) phenotype. Crystallization analysis showed that Thr266 substitution does not disrupt the hydrogen bonds. However, some changes in interatomic contacts, such as loss of ionic interactions and hydrophobic contacts, and addition of weak hydrogen bonds, may have affected protein stability to some extent. This mutation was predicted to have a benign effect on enzyme function and slightly reduce protein stability.
Conclusion
The probands had the same novel B(A) allele with a c.797T>C (p.Met266Thr) mutation on the ABO*B.01 backbone.
Although sorafenib (Sora) shows improved efficacy in clinical liver cancer therapy, its therapeutic efficacy is still greatly limited due to side effects as well as drug resistance. Thus new drug ...intervention strategies are imperative. Our research showed the combined application of Dihydroartemisinin (DHA) and Sora had a synergistic inhibitory effect on HepG2 and SW480 cells, and DHA enhanced Sora efficacy on xenograft tumor in nude mice. DHA and Sora significantly inhibited the cell energy metabolism by decreasing the ATP synthesis rate of oxidative phosphorylation and glycolysis rate, and induced ferroptosis by increasing the level of lipid reactive oxygen species (L-ROS), labile iron pool (LIP) as well as malondialdehyde (MDA) and decreasing the level of glutathione (GSH) in HepG2 cells. In addition, DHA and Sora significantly decreased the levels of SLC7A11 (xCT), GCLC, GPX4, and HO-1 protein in HepG2 cells. Importantly, the above-mentioned indicators changed more significantly after the combined application of DHA and Sora as compared with Sora. In conclusion, DHA and Sora had the same mechanism, and the combined application of them could have a synergistic anti-tumor effect by inducing ferroptosis and inhibiting energy metabolism in HepG2 cells.
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