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A gold nanoparticle (AuNP) aggregation-induced colorimetric aptasensing method for quantitative detection of sulfadimethoxine (SDM) with a smartphone was developed. AuNPs were complexed with aptamers which protected AuNPs from aggregating in high-concentration salt solutions. In the presence of SDM, SDM bound with the aptamer on the surface of AuNPs with higher affinity, which competitively desorbed the aptamer from the AuNP surface and resulted in AuNPs aggregation, accompanied with a color change from red to purple-blue. The R, G and B values of images taken by a smartphone camera were analyzed with an app on the smartphone, and were utilized for quantitative analysis of SDM. Under the optimized conditions, the colorimetric aptasensing method using a smartphone showed high sensitivity for SDM, with the limit of detection of 0.023 ppm, lower than the allowed maximum SDM residue limit. This study provides a simple, fast, and easy to read method for on-site quantitative biochemical and cellular analysis.

The determination of pH values is essential in many chemical, medical, and environmental monitoring processes, which has been relying on conventional pH meters (glass electrodes) for quantitation and pH test strips for qualitative (or semi-quantitative) assessment. In this work, we demonstrate a smartphone-based pH determination technique, which performs digital image analysis of commercial test strips, particularly the determination of either the dominant wavelength (λd) or complementary wavelength (λc) of the color image. In conjunction with a 3D-printed optical accessory (with a surface light source and a macro lens), the quality of captured images have been warranted, and the quantitation accuracy of 0.05 pH units has been achieved. More importantly, the performance of this smartphone-based pH reading system (namely "Smart-pH-Reader") was validated using multiple real-world samples, as the results are consistent with those determined with a standard pH meter. The Smart-pH-Reader is envisioned to be a simple, portable, and accurate tool for pH determination in the fields of environmental monitoring, medical diagnosis, and beyond.

A new ferrous phyllosilicate, meifuite, has been discovered in the Yinachang Fe-Cu-REE (rare-earth element) deposit in China. The structural formula, calculated using averaged electron probe microanalysis (EPMA) results, is K0.72Na0.20(Fe5.56Mg0.31Mn0.13)Σ6.00(Si6.95Al1.04)Σ7.99O18.84(OH)4.84 Cl1.33, with an ideal formula of KFe6(AlSi7)O19(OH)4Cl2. The structure of meifuite has a $$ P\overline{1} $$ space group symmetry, with unit-cell parameters of a = 22.7773(13) A, b = 9.5553(5) A, c =14.3282(8) A, α = 99.258(4)°, β = 136.750(3)°, γ = 89.899(4)°, Z = 2, and V = 2077.9(2) A3. Meifuite has a strip-modulated 2:1 layer (T–O–T) structure similar to that of minnesotaite. About 1/8 of the tetrahedra in the T sheet are occupied by Al instead of Si, and the interlayer cavities are partially occupied by K and Na. Some of the OH sites in the octahedral sheet in the layer structure are fully or partially substituted by Cl, which is apparently the primary reason for the meifuite structure being more stable than stilpnomelane, the most common ferrous layer silicate mineral found at similar temperature and pressure conditions. An updated, more accurate structure model of minnesotaite is also provided for comparison with the meifuite structure. The mineral is named after Meifu Zhou in honor of his outstanding contributions to the field of economic geology.

Thermal performance of Al nanocomposites is of significance for broad applications. In this study, we successfully fabricated Al–TiC, Al–ZrB2, and Al–TiB2 nanocomposites via a novel in situ molten-salt-assisted method and systematically investigated their thermal properties, including thermal diffusivity, heat capacity, and thermal conductivity. Different contributions from electron and phonon have been semi-quantitatively decoupled for interfacial thermal transport in these Al-based nanocomposites. Then, the interfacial thermal conductance between aluminum and the electrically conductive TiC, ZrB2, and TiB2 nanoparticles was quantitatively studied and compared with existing models. An engineering model of the interfacial thermal conductance has been proposed and validated. It was confirmed that a higher interfacial separation energy and more effective interfacial bonding by better wettability can be conducive to a higher interfacial thermal transport.

Aluminum-matrix nanocomposites offer advantageous properties over conventional aluminum alloys. However, controlling the size and size distribution of ceramic nanoparticles during in situ synthesis at high temperatures has been a long-term challenge due to a lack of effective size-control mechanisms. Here, we successfully synthesized titanium diboride (TiB2) nanoparticles with an unprecedented narrow size distribution in molten aluminum. The average size of TiB2 nanoparticles was tunable from 22.1 to 171.4 nm by solely controlling the reaction temperature under a diluted reactant salt solution. To uncover the mechanism of particle size control, an interface diffusion-controlled model was developed. The dilution of reactant salt was crucial to achieve a steady reaction environment while confining the growth of the particles in a shallow region. The model suggests that the average size of as-synthesized nanoparticles is mostly controlled by reaction temperature and unaffected by the titanium salt concentration in a diluted solution due to a steady diffusion of titanium and boron. Temperature controls the diffusion of reactants and nucleation rate to dictate the average size of the as-synthesized nanoparticles.

Highlights The (SnO2-cPCN) ETL shows superior electron mobility of 3.3 × 10−3 cm2 V−1 s−1, which is about three times higher than that of pristine SnO2.The less wettable SnO2-cPCN leads to perovskite layers with reduced grain boundaries and enhanced qualities due to suppressed heterogeneous nucleation of perovskite.The PSCs based on SnO2-cPCN showed negligible J–V hysteresis and two champion PCE of 23.17% and 20.3% on devices with 0.1 and 1 cm2 active area, respectively. Supplementary Information The online version contains supplementary material available at 10.1007/s40820-021-00636-0., Efficient electron transport layers (ETLs) not only play a crucial role in promoting carrier separation and electron extraction in perovskite solar cells (PSCs) but also significantly affect the process of nucleation and growth of the perovskite layer. Herein, crystalline polymeric carbon nitrides (cPCN) are introduced to regulate the electronic properties of SnO2 nanocrystals, resulting in cPCN-composited SnO2 (SnO2-cPCN) ETLs with enhanced charge transport and perovskite layers with decreased grain boundaries. Firstly, SnO2-cPCN ETLs show three times higher electron mobility than pristine SnO2 while offering better energy level alignment with the perovskite layer. The SnO2-cPCN ETLs with decreased wettability endow the perovskite films with higher crystallinity by retarding the crystallization rate. In the end, the power conversion efficiency (PCE) of planar PSCs can be boosted to 23.17% with negligible hysteresis and a steady-state efficiency output of 21.98%, which is one of the highest PCEs for PSCs with modified SnO2 ETLs. SnO2-cPCN based devices also showed higher stability than pristine SnO2, maintaining 88% of the initial PCE after 2000 h of storage in the ambient environment (with controlled RH of 30% ± 5%) without encapsulation. Supplementary Information The online version contains supplementary material available at 10.1007/s40820-021-00636-0.

Pharmacological inhibition of vacuolar-type H+-ATPase (V-ATPase) by its specific inhibitor can abrogate tumor metastasis, prevent autophagy, and reduce cellular signaling responses. Bafilomycin A1, a member of macrolide antibiotics and an autophagy inhibitor, serves as a specific and potent V-ATPases inhibitor. Although there are many V-ATPase structures reported, the molecular basis of specific inhibitors on V-ATPase remains unknown. Here, we report the cryo-EM structure of bafilomycin A1 bound intact bovine V-ATPase at an overall resolution of 3.6-Å. The structure reveals six bafilomycin A1 molecules bound to the c-ring. One bafilomycin A1 molecule engages with two c subunits and disrupts the interactions between the c-ring and subunit a, thereby preventing proton translocation. Structural and sequence analyses demonstrate that the bafilomycin A1-binding residues are conserved in yeast and mammalian species and the 7’-hydroxyl group of bafilomycin A1 acts as a unique feature recognized by subunit c., Bafilomycin A1, a member of macrolide antibiotics and an autophagy inhibitor, serves as a specific and potent V-ATPases inhibitor. Here authors report the cryo-EM structure of bafilomycin A1-bound V-ATPase with six bafilomycin A1 molecules bound to the c-ring and reveal the molecular basis for Bafilomycin A1 inhibition of the V-ATPase.

As a sort of cathode material with appreciable theoretical capacity, sulfur has received a lot of attention for lithium–sulfur batteries. There is extensive research focused on cathode materials. H...

Ultra-long metal nanowires and their facile fabrication have been long sought after as they promise to offer substantial improvements of performance in numerous applications. However, ultra-long metal ultrafine/nanowires are beyond the capability of current manufacturing techniques, which impose limitations on their size and aspect ratio. Here we show that the limitations imposed by fluid instabilities with thermally drawn nanowires can be alleviated by adding tungsten carbide nanoparticles to the metal core to arrive at wire lengths more than 30 cm with diameters as low as 170 nm. The nanoparticles support thermal drawing in two ways, by increasing the viscosity of the metal and lowering the interfacial energy between the boron silicate and zinc phase. This mechanism of suppressing fluid instability by nanoparticles not only enables a scalable production of ultralong metal nanowires, but also serves for widespread applications in other fluid-related fields., Thermal drawing of glass-cladded metal nanowires is limited by fluid instabilities. Hwang et al. show how admixing tungsten carbide nanoparticles to the zinc core of a borosilicate-cladded wire leads to intact fibres over lengths significantly exceeding those of metals with high melting points.

The permeability of coal is an indispensable parameter for predicting the coalbed methane (CBM) and enhanced CBM (ECBM) production. Considering the low permeability characteristics of coal, the permeability is usually measured by the transient technique in the laboratory. Normally, it is assumed that the calculated permeability will not greatly vary if the pulse pressure applied in the experiment is small (less than 10% of pore pressure) and previous studies have not focused on the effect of the pulse pressure on the measurement permeability. However, for sorptive rock, such as coals and shales, the sorption effect may cause different measurement results under different pulse pressures. In this study, both nonadsorbing gas (helium) and adsorbing gas (carbon dioxide) were used to investigate the adsorption effect on the gas permeability of coal measurement with the pulse-decay technique. A series of experiments under different pore pressures and pulse pressures was performed, and the carbon dioxide permeability was calculated by both Cui et al.’s and Jones’ methods. The results show that the carbon dioxide permeability calculated by Jones’ method was underestimated because the adsorption effect was not considered. In addition, by comparing the helium and carbon dioxide permeabilities under different pulse pressures, we found that the carbon dioxide permeability of coal was more sensitive to the pulse pressure due to the adsorption effect. Thus, to obtain the accurate permeability of coal, the effect of adsorption should be considered when measuring the permeability of adsorptive media with adsorbing gas by the transient technique, and more effort is required to eliminate the effect of the pulse pressure on the measured permeability.

Smoothened (SMO), a class Frizzled G protein-coupled receptor (class F GPCR), transduces the Hedgehog signal across the cell membrane. Sterols can bind to its extracellular cysteine-rich domain (CRD) and to several sites in the seven transmembrane helices (7-TMs) of SMO. However, the mechanism by which sterols regulate SMO via multiple sites is unknown. Here we determined the structures of SMO–Gi complexes bound to the synthetic SMO agonist (SAG) and to 24(S),25-epoxycholesterol (24(S),25-EC). A novel sterol-binding site in the extracellular extension of TM6 was revealed to connect other sites in 7-TMs and CRD, forming an intramolecular sterol channel from the middle side of 7-TMs to CRD. Additional structures of two gain-of-function variants, SMOD384R and SMOG111C/I496C, showed that blocking the channel at its midpoints allows sterols to occupy the binding sites in 7-TMs, thereby activating SMO. These data indicate that sterol transport through the core of SMO is a major regulator of SMO-mediated signaling. Cryo-EM structural work shows sterols binding at four adjacent locations within the class F GPCR Smoothened (SMO), where the transmembrane core functions as a sterol tunnel in which occupancy activates SMO for downstream Hedgehog signaling.

Though geologic carbon storage (GCS) is widely recognized as a promising strategy to reduce emissions of greenhouse gas (GHG), the potential for mobilization of radioactive uranium (U) from U-bearing minerals in deep subsurface due to CO2 injection remains a concern. In this study, supercritical CO2 and brine flowing through a fracture surrounded by reservoir rock containing uranium is simulated so as to study the potential of uranium release as a result of CO2 injection and the impact of various factors on total uranium release rate. Mineral compositions of the reservoir rock are from previously published literature, which mimics typical sandstone mineral compositions. The reservoir rock is assumed to have 2 × 10−4 vol% UO2 in solid phase. Simulation results show that CO2 injection induces UO2 dissolution, and both CO2 and mobilized uranium are able to migrate in both the fracture and the rock matrix surrounding the fracture. However, the released uranium concentration is quite low in a 60-day simulation period. Mineral dissolution causes a very small porosity increase surrounding the fracture in the simulation period. Sensitivity analysis shows that an increase of UO2 specific surface area and UO2 content in reservoir rock causes a significant increase in released uranium concentration. In other words, total uranium release rate is positively correlated with the specific surface area of UO2 and UO2 content in reservoir rock because the increase of specific surface area and UO2 content increases the total area of UO2 in contact with HCO3− and O2, which raises total uranium release rate. In summary, uranium release in and surrounding the fracture is mainly controlled by uranium supply of the reservoir rock, and the risk of environmental contamination by CO2-induced uranium release is quite low in the scenario reported.

In situ leaching (ISL) is the main mining method for sandstone-type uranium deposits. The thermodynamic model can provide important information to real project decision making. However, systematic ...

Niemann-Pick C1 (NPC1), a lysosomal protein of 13 transmembrane helices (TMs) and three lumenal domains, exports low-density-lipoprotein (LDL)-derived cholesterol from lysosomes. TMs 3–7 of NPC1 comprise the Sterol-Sensing Domain (SSD). Previous studies suggest that mutation of the NPC1-SSD or the addition of the anti-fungal drug itraconazole abolishes NPC1 activity in cells. However, the itraconazole binding site and the mechanism of NPC1-mediated cholesterol transport remain unknown. Here, we report a cryo-EM structure of human NPC1 bound to itraconazole, which reveals how this binding site in the center of NPC1 blocks a putative lumenal tunnel linked to the SSD. Functional assays confirm that blocking this tunnel abolishes NPC1-mediated cholesterol egress. Intriguingly, the palmitate anchor of Hedgehog occupies a similar site in the homologous tunnel of Patched, suggesting a conserved mechanism for sterol transport in this family of proteins and establishing a central function of their SSDs., Niemann-Pick C1 (NPC1) exports low-density-lipoprotein (LDL)-derived cholesterol from lysosomes and comporses a Sterol-Sensing Domain (SSD). Here authors report a cryo-EM structure of human NPC1 bound to itraconazole which reveals how this binding site in the center of NPC1 blocks a putative lumenal tunnel linked to the SSD.

Chromium borides (CrBx) have been considered as promising strengthening phases for copper (Cu). However, traditional manufacturing methods such as powder metallurgy greatly restrict the sample size and part complexity. Here, we report that bulk Cu containing high volume percentages of uniformly distributed CrBx were fabricated by casting via in-situ reduction assisted by aluminum (Al). Two sets of precursors, i.e., borax-CuCr and KBF4-CrF3, were used and the respective reaction mechanisms were illustrated. In addition, the resultant in-situ particle morphologies and sizes from the precursors were studied. The use of KBF4-CrF3 generated smaller in-situ particles due to the less severe coalescence of particles. The microhardness of in-situ Cu/CrBx was significantly enhanced over pure Cu.

Metal-free photocatalysis has evoked broad research interest in green energy applications. Herein, two-dimensional (2D) carbon-doped BN (C-BN) nanosheets are vertically aligned on a conductive substrate by low-temperature plasma enhanced chemical vapor deposition (PE-CVD) and are demonstrated to be a photoelectrocatalytic device for water oxidation under sunlight irradiation. By virtue of this geometry, the unique 2D material presents advantages for the catalytic reaction. In addition, adjusting the carbon concentration can facilely control the structure and optoelectronic properties of the C-BN nanosheets to improve light harvesting in the solar spectrum. As a result, the photocurrent density exhibits a 60-fold enhancement over that of the C-BN films achieved by traditional deposition of C-BN powder. Experimental and theoretical studies of band structures are performed and the results are in agreement with each other. This 2D C-BN nanofilm based device could stimulate interest in advanced applications in many fields such as catalysis, sensors, transistors and others.

Zinc (Zn) matrix composite has been newly discovered categories of biodegradable materials. With a combination of chemical stability, thermal stability and biocompatibility, ceramic nanoparticles outperformed intermetallics of zinc alloys with inherent advantages of retaining a proper corrosion rate and an exceptional ductility. Compared with Zn alloys, Zn matrix nanocomposites showed an unprecedented strengthening without sacrifices of corrosion rate, which were introduced by intermetallics. In this work, in situ titanium diboride (TiB2) reinforced Zn nanocomposite was prepared via a few cost-effective and economical methods: flux-assisted synthesis (FAS), ultrasound-assisted nanoparticle homogenization and hot rolling. 3 vol.% of TiB2 nanoparticles were synthesized with an average size of 454nm, followed by molten salt assisted ultrasound homogenization and hot rolling. Hot-rolled (HR) Zn-TiB2 performed high strength and high ductility, mostly due to precipitation strengthening (Orowan strengthening). Yield stress (YS) and ultimate tensile stress (UTS) increased by 90% and 45%, respectively, while the elongation to failure retained 23%. The mechanical performance of Zn-TiB2 made it promise to serve as an innovative biodegradable material for load-bearing applications.

The cryo-EM structures of human NPC1L1 reveal a dimeric state mediating cholesterol and vitamin E uptake., Polytopic Niemann-Pick C1-like 1 (NPC1L1) plays a major role in intestinal absorption of biliary cholesterol, vitamin E (VE), and vitamin K (VK). The drug ezetimibe inhibits NPC1L1-mediated absorption of cholesterol, lowering of circulating levels of low-density lipoprotein cholesterol. Here, we report cryo–electron microscopy structures of human NPC1L1 (hNPC1L1) bound to either cholesterol or a lipid resembling VE. These findings, together with functional assays, reveal that the same intramolecular channel in hNPC1L1 mediates transport of VE and cholesterol. hNPC1L1 exists primarily as a homodimer; dimerization is mediated by aromatic residues within a region of transmembrane helix 2 that exhibits a horizonal orientation in the membrane. Mutation of tryptophan-347 lies in this region disrupts dimerization and the resultant monomeric NPC1L1 exhibits reduced efficiency of cholesterol uptake. These findings identify the oligomeric state of hNPC1L1 as a target for therapies that inhibit uptake of dietary cholesterol and reduce the incidence of cardiovascular disease.

Zinc (Zn) has been widely investigated as a biodegradable metal for orthopedic implants and vascular stents due to its ideal corrosion in vivo and biocompatibility. However, pure Zn lacks adequate mechanical properties for load-bearing applications. Alloying elements, such as iron (Fe), have been shown to improve the strength significantly, but at the cost of compromised ductility and corrosion rate. In this study, tungsten carbide (WC) nanoparticles were incorporated into the Zn-2Fe alloy system for strengthening, microstructure modification, and ductility enhancement. Thermally stable WC nanoparticles modified the intermetallic $$ \zeta $$ -FeZn13 interface morphology from faceted to non-faceted. Consequently, WC nanoparticles simultaneously enhance mechanical strength and ductility while maintaining a reasonable corrosion rate. Overall, this novel Zn-Fe-WC nanocomposite could be used as biodegradable material for biomedical applications where pure Zn is inadequate.

Thermal and chemical unfolding of lysozyme in the presence of the guanidine HCl denaturant is a model system to compare the conventional two-state model of protein unfolding with the multistate Zimm-Bragg theory. The two-state model is shown to be the noncooperative limit of the Zimm-Bragg theory. In particular, the Zimm-Bragg theory provides a molecular interpretation of the empirical linear extrapolation method (LEM) of the two-state model. Differential scanning calorimetry (DSC) experiments reported in the literature are analyzed with both methods. Lysozyme unfolding is associated with a large endothermic enthalpy that decreases significantly upon addition of guanidine HCl. In contrast, the Gibbs free energy of unfolding is small, negative, and independent of the guanidine HCl concentration, contradicting, in part, the conclusions of the LEM. The unfolding enthalpy is compensated by an even larger entropy term. The multistate Zimm-Bragg theory predicts a larger conformational enthalpy and a smaller Gibbs free energy than the two-state model. The Zimm-Bragg theory provides the protein cooperativity parameter, the average length of independently folding protein domains, and the Gibbs free energy of unfolding of individual amino acid residues. Guanidine HCl binding to lysozyme is exothermic and counteracts the endothermic unfolding enthalpy. The number of bound denaturant molecules is determined from the decrease in enthalpy and is extrapolated to the guanidine HCl-to-amino acid stoichiometry at complete lysozyme unfolding. Chemical unfolding isotherms measured with circular dichroism (CD) spectroscopy are analyzed with both models. The chemical Zimm-Bragg theory is a cooperative molecular model, yielding the guanidine HCl binding constant and the protein cooperativity parameter. It allows a quantitative comparison between thermal and chemical protein unfolding. The two reactions have almost identical changes in Gibbs free energy. However, thermal unfolding is significantly more cooperative than chemical unfolding. Finally, distinct differences are observed in thermal unfolding between DSC and CD spectroscopy.

While laser-printed metals do not tend to match the mechanical properties and thermal stability of conventionally-processed metals, incorporating and dispersing nanoparticles in them should enhance their performance. However, this remains difficult to do during laser additive manufacturing. Here, we show that aluminum reinforced by nanoparticles can be deposited layer-by-layer via laser melting of nanocomposite powders, which enhance the laser absorption by almost one order of magnitude compared to pure aluminum powders. The laser printed nanocomposite delivers a yield strength of up to 1000 MPa, plasticity over 10%, and Young’s modulus of approximately 200 GPa, offering one of the highest specific Young’s modulus and specific yield strengths among structural metals, as well as an improved specific strength and thermal stability up to 400 °C compared to other aluminum-based materials. The improved performance is attributed to a high density of well-dispersed nanoparticles, strong interfacial bonding between nanoparticles and Al matrix, and ultrafine grain sizes., Incorporating and dispersing dense nanoparticles into metals remains a challenge. Here, the authors use nanocomposite powders containing very dense nanoparticles to print an aluminium nanocomposite with one of the highest specific modulus and yield strength among all structural materials.

Conventional circulating activated sludge techniques (CASS) are time consuming (72 h) and energy intensive, all of which greatly limits their use. Although advanced oxidation techniques (e.g., photocatalysis, photoelectrocatalysis UV/•OH, and Electro-Fenton) can reduce the treatment time by several hours, the slow generation and fast coupling of electron and hole make the low degradation efficiency. In this work, an intact route using a two-step strategy is developed to eliminate organic dyes from wastewater in only a few minutes. The electron and hole exhibit “fast generation and slow coupling” by using the new technique via electrolytic discharge plasma (EDP) combined with a core-shell structure Au@SiO2 nanocatalyst for [Rhodamine (RhB)/Eosin yellowish (EY)] dyes degradation in wastewater. Results demonstrate that the synergy of EDP and Au@SiO2 nanocatalyst enhances degradation kinetics, and it is effective in degrading different concentrations of RhB and EY dyes in the range of 50–1.5 mg/L. Then, the Au@SiO2 nanocatalyst (over 99%) and carbon impurities are filtered by a porous nanocomposite ultrafiltration membrane. Favorable contributions of the two-step strategy are further ascertained based on chemical oxygen demand (COD) and relative removal efficiency. This two-step strategy provides an unprecedented rapid approach for industrial wastewater treatment.

In this brief review, a comprehensive collection of previous studies about geochemistry in geologic CO2 utilization and storage is presented and discussed to demonstrate the importance of CO2-rock and CO2-wellbore cement interactions in geologic CO2 utilization and storage scenarios. For CO2-rock interaction, CO2 injection reduces the pH of brine in CO2 storage reservoir, which triggers dissolution of silicate and oxide minerals in the reservoir. Dissolution of silicate and oxide minerals causes concentration increase of cations and anions, which induces secondary precipitation of silica, silicates and carbonates. For CO2-cement interaction, the interaction between CO2 and wellbore cement results in formation of a unique “sandwich” structure in cement (i.e., one carbonate precipitation zone in the middle and two dissolution zones on two sides). For both CO2-rock and CO2-cement interactions, pH plays a key role in the extent of mineral dissolution and precipitation, and the extent is dependent on pH buffering capacity of the CO2 storage reservoir. The potential of CO2-induced contaminant mobilization in deep CO2 storage reservoir and shallow aquifer is also discussed, and the chance for CO2 injection and CO2 leakage to cause severe shallow aquifer contamination is low. Cited as : Zhang, L., Wang, Y., Miao, X., Gan, M., Li, X. Geochemistry in geologic CO2 utilization and storage: A brief review. Advances in Geo-Energy Research, 2019, 3(3): 304-313, doi: 10.26804/ager.2019.03.08

3-β-hydroxysteroid-Δ8, Δ7-isomerase, known as Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy, oligodendrocyte formation. The mutation on EBP can cause Conradi-Hunermann syndrome, an inborn error. Interestingly, EBP binds an abundance of structurally diverse pharmacologically active compounds, causing drug resistance. Here, we report two crystal structures of human EBP, one in complex with the anti-breast cancer drug tamoxifen and the other in complex with the cholesterol biosynthesis inhibitor U18666A. EBP adopts an unreported fold involving five transmembrane-helices (TMs) that creates a membrane cavity presenting a pharmacological binding site that accommodates multiple different ligands. The compounds exploit their positively-charged amine group to mimic the carbocationic sterol intermediate. Mutagenesis studies on specific residues abolish the isomerase activity and decrease the multidrug binding capacity. This work reveals the catalytic mechanism of EBP-mediated isomerization in cholesterol biosynthesis and how this protein may act as a multi-drug binder., Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy and oligodendrocyte formation. Here, authors report two crystal structures of human EBP and identify a pharmacological binding site that accommodates multiple different ligands.

Nanoparticles can be added to metals to tune their properties for numerous applications. Recently extensive research has been conducted to measure the mechanical properties of nanoparticle reinforced metals. However, few theories exist to understand how nanoparticles interact with metals to affect their electrical performance, partly due to the difficulty in producing bulk metal samples, containing dispersed nanoparticles. In this work, copper and copper alloys (Cu, Cu-40 wt% Zn, and Cu-60 wt% Ag) containing dispersed tungsten carbide (WC) nanoparticles of more than 20 vol% were successfully fabricated via solidification processing. The experimental results show that copper and its alloys with an increasing volume fraction of nanoparticles, the electrical conductivity of the samples decays exponentially. Therefore, a theoretical model, compatible with the Nordheim's rule was established to predict the electrical behaviour of metals containing dispersed nanoparticles. This new model on the electrical behaviour of copper nanocomposites is experimentally validated by low-temperature resistivity measurements and electronic heat capacity measurements above Debye temperature.

This work presents the manufacturing and characterization of zinc-tungsten carbide (Zn-WC) nanocomposite as a potential biodegradable material. A highly homogeneous WC nanoparticle dispersion in a Zn matrix was achieved by molten salt assisted stir casting followed with hot rolling. The Vickers microhardness and ultimate tensile strength of zinc were enhanced more than 50% and 87%, respectively, with the incorporation of up to 4.4 vol. % WC nanoparticles. Additionally, Zn-WC nanocomposite retained high ductility (> 65%). However, the electrical and thermal conductivities were reduced by 12% and 21%, respectively. The significant enhancement in mechanical strength makes nanoparticle-reinforced zinc a promising candidate material for biodegradable metallic implants for a wide range of clinical applications, including orthopaedic and cardiovascular implants as well as bioresorbable electronics.

Summary Transient receptor potential mucolipin 1 (TRPML1) regulates lysosomal calcium signaling, lipid trafficking, and autophagy-related processes. This channel is regulated by phosphoinositides and the low pH environment of the lysosome, maintaining calcium levels essential for proper lysosomal function. Recently, several small molecules specifically targeting the TRPML family have been demonstrated to modulate channel activity. One of these, a synthetic antagonist ML-SI3, can prevent lysosomal calcium efflux and has been reported to block downstream TRPML1-mediated induction of autophagy. Here, we report a cryo–electron microscopy structure of human TRPML1 with ML-SI3 at 2.9-A resolution. ML-SI3 binds to the hydrophobic cavity created by S5, S6, and PH1, the same cavity where the synthetic agonist ML-SA1 binds. Electrophysiological characterizations show that ML-SI3 can compete with ML-SA1, blocking channel activation yet does not inhibit PI(3,5)P2-dependent activation of the channel. Consequently, this work provides molecular insight into how ML-SI3 and native lipids regulate TRPML1 activity.

The use of high strength, lightweight aluminum alloys in high-tech applications such as aerospace, as well as in the emerging field of electric vehicles, is an integral part of our society’s push towards high energy efficiency. However, solidification processing of such alloys, especially fusion welding and additive manufacturing, remains challenging due to solute segregations and, ultimately, solidification cracking. Recently the use of refractory nanoparticles in hot crack susceptible aluminum alloys showed great potential to mitigate cracking during solidification. This work investigates the solidification mechanisms for aluminum alloy (AA) 7075 treated with a low volume fraction nanoparticles. Using Differential Scanning Calorimetry (DSC), we showed a significant deviation in the solidification behavior of nano-treated alloys from their commercial counterparts and found evidence of the underlying mechanisms in the microstructure of the material.

Zinc (Zn) and Zn-based alloys have been extensively studied as innovative materials for bioresorbable stents (BRS) in the last decade due to their favorable biodegradability and biocompatibility. However, most Zn alloys lack the necessary combination of adequate strength, ductility and corrosion rate needed for such clinical applications. Additionally, due to the low melting temperature of Zn, Zn-based alloys are also thermally unstable and undergo microstructural changes over time at ambient and physiological temperatures, which negatively impacts the mechanical properties during storage, implantation, and service. In this study, tungsten carbide (WC) nanoparticles were successfully incorporated into Zn alloyed with 0.5 wt.% magnesium (Mg). The resulting Zn-0.5Mg-WC nanocomposite’s microstructure, mechanical properties, in vitro corrosion rate and aging behavior were evaluated. SEM and TEM microstructural analysis showed that Mg2Zn11 precipitates with a granular morphology formed at the Zn/WC nanoparticle interface. This microstructure resulted in a combination of enhanced strength and ductility, and the Zn-0.5Mg-WC nanocomposite was able to survive at least 10 million cycles of tensile loading. Due to the granular precipitate morphology, the loss of ductility caused by aging was not observed over a 90-day study. Furthermore, the Zn-0.5Mg-WC nanocomposite had an in vitro corrosion rate comparable to pure Zn, which is ideal for BRS applications. Stent prototypes were fabricated using this composition and were successfully deployed during bench testing without fracture. This study shows that the Zn-0.5Mg-WC nanocomposite is a promising material for BRS applications.

Copper–chromium alloys are a class of high-strength high-conductivity copper alloys. However, limited by the copper–chromium (Cu–Cr) phase diagram, the strength of copper–chromium (Cu–Cr) alloys by precipitation-hardening has reached a certain limit. Suitable nanoparticles incorporating into copper–chromium (Cu–Cr) alloys, i.e., nano-treating, are expected to modify the aging behavior and further improve their properties. In this study, copper–chromium (Cu–Cr) alloy containing tungsten (W) nanoparticles was cast. The aging behavior of the nano-treated Cu-Cr and Cu–Cr counterparts is assessed. Tungsten (W) nanoparticles accelerate the precipitation, leading to a significant reduction in the peak aging time. Besides, the microhardness of the nano-treated copper–chromium (Cu–Cr) is increased over Cu–Cr after 45-min aging. Cold rolling can further enhance the microhardness of the nano-treated copper–chromium (Cu–Cr). Moreover, the nano-treated sample exhibits a much improved thermal stability. Thus, nano-treating the copper–chromium (Cu–Cr) alloy by tungsten (W) nanoparticles is promising to break the limits of current copper–chromium (Cu–Cr) alloys.

Author(s): Lu, B; Olivera, E; Scharf, J; Chouchane, M; Fang, C; Ceja, M; Pangilinan, LE; Zheng, S; Dawson, A; Cheng, D; Bao, W; Arcelus, O; Franco, AA; Li, X; Tolbert, SH; Meng, YS | Abstract: Lithium metal has been an attractive candidate as a next-generation anode material. Despite its popularity, stability issues of lithium in the liquid electrolyte and the formation of lithium whiskers have kept it from practical use. Three-dimensional (3D) current collectors have been proposed as an effective method to mitigate whisker growth. Although extensive research has been done, the effects of three key parameters of the 3D current collectors, namely, the surface area, the tortuosity factor, and the surface chemistry, on the performance of lithium metal batteries remain elusive. Herein, we quantitatively studied the role of these three parameters by synthesizing four types of porous copper networks with different sizes of well-structured microchannels. X-ray microscale computed tomography (micro-CT) allowed us to assess the surface area, the pore size, and the tortuosity factor of the porous copper materials. A metallic Zn coating was also applied to study the influence of surface chemistry on the performance of the 3D current collectors. The effects of these parameters on the performance were studied in detail through scanning electron microscopy (SEM) and titration gas chromatography (TGC). Stochastic simulations further allowed us to interpret the role of the tortuosity factor in lithiation. The optimal range of the key parameters is thereby found for the porous coppers and their performance is predicted. Using these parameters to inform the design of porous copper anodes for Li deposition, Coulombic efficiencies (CEs) of up to 99.63% are achieved, thus paving the way for the design of effective 3D current collector systems.

Mg-MOF-74/Cu was synthesized by a one-step method and then using the product as a lithium-ion anode material. The flocculent Cu caused by the Jahn-Teller effect conspicuously improves the electrochemical performance of Mg-MOF-74 by enhancing the conductivity of electrode materials. The as-prepared materials exhibited superior rate performance (298.3 mAh g-1 at a current density of 2000 mA g-1) and remarkable cyclability (a specific capacity of 534.5 mAh g-1 is obtained after 300 cycles at 500 mA g-1, which remains at 89.1%). In addition, an electrochemical test of coating an anode material on a stainless steel sheet has also been carried out, and the performance is comparable to that of traditional coating on copper foil (a reversible capacity of 531.7 mAh g-1 is collected, which retains 88.7% of initial capacity). The superior performance, facile one-step synthesis, and low cost of Mg-MOF-74/Cu show promise for practical applications.

The design and testing of integrated colorimetric microarray immunochips (immuno-microarrays) are reported for the quantitation and direct visual determination of multiple illicit drugs (e.g., morphine, cocaine and amphetamine) in body fluids. Such an immuno-microarray platform utilizes a competitive immunoassay format, which is based on silver staining for quantitative detection and multicolor staining for direct visualization (i.e., qualitative identification) of analytes present in the sample. Under optimized conditions, the dynamic response ranges of 3.7–1000, 1.1–300 and 1.5–300 ng mL−1 were achieved for amphetamine, cocaine, and morphine, respectively, which are wider towards low concentrations than those of standard enzyme-linked immunosorbent assay (ELISA) tests. The limits of detection (LODs) for morphine, cocaine, and amphetamine were determined to be 1.5 ± 0.1, 1.1 ± 0.1 and 3.7 ± 0.2 ng mL−1, respectively in oral fluids, which meet government regulations for law enforcement. The obvious advantages of multiplexing, simultaneous visual recognition, and accurate quantitation make the on-site detection feasible, confirming that such a colorimetric immuno-microarray holds promise for practical applications.

The relative permeability of coal to gas and water is an essential parameter for characterizing coalbed methane (CBM) reservoirs and predicting coal seam gas production, particularly in numerical simulations. Although a variety of studies related to the relative permeability of coals have been conducted, the results hardly meet the needs of practical engineering applications. To track the dynamic development of relative permeability measurements in the laboratory, discover the deficiencies, and discuss further work in this field, this paper investigates the relative permeability measurement preparation work and laboratory methods and summarizes the development of techniques used to determine the water saturation during experimentation. The previously determined relative permeability curves are also assembled and classified according to coal rank and the absolute permeability. It is found that the general operations in the relative permeability measurement process are still not standardized. The techniques applied to determine the water saturation of coal in experiments have been refined to some extent, but no optimal technique has been recognized yet. New techniques, such as the incorporation of high-precision differential pressure gauges, can be used to determine the water production during relative permeability measurement. In addition, the existing relative permeability data are limited, and no study has focused on supercritical carbon dioxide-water and mixed gas (methane and carbon dioxide)-water relative permeability measurements. To meet the requirements of actual projects, further research on this topic must be conducted.

Aluminum alloy 7075 (Al 7075) with a T73 heat treatment is commonly used in aerospace applications due to exceptional specific strength properties. Challenges with manufacturing the material from the melt has previously limited the processing of Al 7075 via welding, casting, and additive manufacturing. Recent research has shown the capabilities of nanoparticle additives to control the solidification behavior of high-strength aluminum alloys, showcasing the first Al 7075 components processed via casting, welding, and AM. In this work, the properties of nanoparticle-enhanced aluminum 7075 are investigated on welded parts, overlays and through wire-based additive manufacturing. The hardness and tensile strength of the deposited materials were measured in the as-welded and T73 heat-treated conditions showing that the properties of Al 7075 T73 can be recovered in welded and layer-deposited parts. The work shows that Al 7075 now has the potential to be conventionally welded or additively manufactured from wire into high-strength, crack-free parts.

The vacuolar-type H+-ATPases (V-ATPase) hydrolyze ATP to pump protons across the plasma or intracellular membrane, secreting acids to the lumen or acidifying intracellular compartments. It has been implicated in tumor metastasis, renal tubular acidosis, and osteoporosis. Here, we report two cryo-EM structures of the intact V-ATPase from bovine brain with all the subunits including the subunit H, which is essential for ATPase activity. Two type-I transmembrane proteins, Ac45 and (pro)renin receptor, along with subunit c”, constitute the core of the c-ring. Three different conformations of A/B heterodimers suggest a mechanism for ATP hydrolysis that triggers a rotation of subunits DF, inducing spinning of subunit d with respect to the entire c-ring. Moreover, many lipid molecules have been observed in the Vo domain to mediate the interactions between subunit c, c”, (pro)renin receptor, and Ac45. These two structures reveal unique features of mammalian V-ATPase and suggest a mechanism of V1-Vo torque transmission., The vacuolar-type H+ -ATPases (V-ATPase) hydrolyze ATP to pump protons across the plasma or intracellular membrane. Here authors report two cryo-EM structures of the intact V-ATPase from bovine brain with all the subunits including the subunit H, which is essential for ATPase activity.

Two cryo-EM structures of IGF2R at different pH values imply the mechanism for its ligand release in endocytic compartments., Many cell surface receptors internalize their ligands and deliver them to endosomes, where the acidic pH causes the ligand to dissociate. The liberated receptor returns to the cell surface in a process called receptor cycling. The structural basis for pH-dependent ligand dissociation is not well understood. In some receptors, the ligand binding domain is composed of multiple repeated sequences. The insulin-like growth factor 2 receptor (IGF2R) contains 15 β strand–rich repeat domains. The overall structure and the mechanism by which IGF2R binds IGF2 and releases it are unknown. We used cryo-EM to determine the structures of the IGF2R at pH 7.4 with IGF2 bound and at pH 4.5 in the ligand-dissociated state. The results reveal different arrangements of the receptor in different pH environments mediated by changes in the interactions between the repeated sequences. These results have implications for our understanding of ligand release from receptors in endocytic compartments.

High-zinc Al–Zn–Mg–Cu alloys offer the highest strength among all aluminum alloys mostly due to high-volume precipitates after heat treatment. However, the high zinc content makes the alloys more sensitive to hot cracking and stress corrosion cracking during solidification and solid state processing. Recently, a revolutionary method, Nanotreating, becomes significant in metals processing by introducing ceramic nanoparticles into metals. It is an emerging method to modify the microstructures (both primary and secondary phases) during solidification, deformation and heat treatment. In this work, In situ TiC nanoparticles were added into Al–8.6Zn–2.8Mg–1.8Cu alloy to study the nanotreating effects. The grain size of the as-cast alloy has been reduced significantly from 272.3 μm to about 30.4 μm by 1 vol% TiC nanoparticles. The size of remaining large secondary phase after heat treatment were reduced significantly as well. Furthermore, the hardness was enhanced. Nanotreating is promising as an effective approach to modify the microstructure, relieve the manufacturing difficulty, and enhance the properties of the high-zinc Al–Zn–Mg–Cu alloys for widespread applications.

Incorporating structural parts into functional assemblies using a variety of techniques, such as bolting, riveting, brazing, and welding is important for today’s industry and society. When joining AA6061 by Tungsten Inert Gas welding, designers so far had to rely on filler materials, such as ER5356 and ER4043 to dilute the joints melting zone and therefore suppress AA6061’s intrinsic susceptibility to hot cracking. However, welding with dissimilar alloys as filler materials is always a tradeoff between enabling the material for fusion welding and accepting drawbacks of the diluted melting zone’s properties. In this work, a low volume fraction of titanium carbide particles were incorporated into AA6061 to fabricate filler rods. The fabricated AA6061-TiC filler material was further used to TIG weld AA6061 base material. The welds produced by using the nanotreated filler rods were free of cracks and showed exceptional mechanical properties in both as welded and post weld heat treatment condition. The new nanotreated AA6061 filler materials offer a great potential for widespread applications.

It is of significant interests to enhance the strength of Cu alloys while retaining their good electrical conductivity for broad applications. In situ incorporation of nano-phase into Cu alloys is a promising method for this objective. However, little success has been reported. In this study, we successfully fabricated in situ Cu–TiB2 nanocomposites by a molten salt processing and systematically studied their mechanical and electrical properties. During the processing, Al was used to react and introduce nano- and submicron-size TiB2 efficiently into the copper melt. Immiscible Fe was later added to recover the electrical conductivity through sequential solutionizing, hot rolling, and electrical conductivity-recovering. Detailed microstructure, phase, and electrical studies validate the feasibility of the proposed procedures to achieve high-strength and high-conductivity Cu(–Fe)-TiB2 nanocomposites. Cu-1 wt.% Fe-5 vol% TiB2 offers 554.3 MPa in ultimate tensile strength, 4.4% in ductility, and 62.4% IACS in electrical conductivity. The new method paves an effective way to synthesize and incorporate nano-phase into copper melt for high-performance Cu nanocomposites.

Copper (Cu) has high electrical conductivity and is widely used for many industrial applications. However, pure Cu is very soft and improving the mechanical properties of Cu comes at the great expense of electrical and thermal conductivity. In this work, high-performance Cu with superior mechanical properties and reasonable electrical/thermal conductivity was fabricated using a scalable two-step method. First, Cu micro-powders with uniformly dispersed tungsten carbide (WC) nanoparticles were created by a molten salt-assisted self-incorporation process. A bulk nanocomposite was then obtained by melting the powders under pressure. The as-solidified Cu with 40 vol% uniformly dispersed WC nanoparticles exhibits high hardness, a yield strength over 1000 MPa, a Young’s modulus of over 250 GPa, and reasonable electrical and thermal conductivity.

Transient receptor potential mucolipin 1 (TRPML1), a lysosomal channel, maintains the low pH and calcium levels for lysosomal function. Several small molecules modulate TRPML1 activity. ML-SA1, a synthetic agonist, binds to the pore region and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P2, another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P2 and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P2, PtdIns(4,5)P2, or ML-SA1 and PtdIns(3,5)P2, revealing a unique lipid-binding site. PtdIns(3,5)P2 and PtdIns(4,5)P2 bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P2 induces Y355 to form a π-cation interaction with R403, moving the S4–S5 linker, thus allosterically activating the channel. Our structures and electrophysiological characterizations reveal an allosteric site and provide molecular insight into how lipids regulate TRP channels.

Polymeric carbon nitride (PCN) films are synthesized for solar water splitting devices. Herein, five precursors and their mixtures are attempted, achieving PCN films in ca. 40 different morphologies. We find that sulfur (S) containing and non-S precursors must be mixed to grow PCN films on fluorine doped tin oxide (FTO) glasses. Through the investigations of the PCN films, S is found to only exist at the interfaces between the PCN and FTO films. In this case, S acts not only as the initialization for the growth of the PCN films but also as connections to assist charge migration for water splitting devices. As a result, the best performance ca. 100 μA/cm2 is achieved at 1.23 VRHE under AM 1.5 illumination in NaOH electrolyte solution without sacrificial agent. This result can be attributed to the reduced defects along the interfaces and the lessened charge recombination. This synthesis of PCN films with the improved chemical adhesion to the FTO layer envisages such organic material for the construction of ...

Apamin-sensitive small-conductance Ca2+-activated K+ (SK) current ( IKAS) is encoded by Ca2+-activated K+ channel subfamily N ( KCNN) genes. IKAS importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that IKAS inhibition contributes to drug-induced long QT syndrome (diLQTS), we screened for KCNN variants among patients with diLQTS, determined the properties of heterologously expressed wild-type (WT) and variant KCNN channels, and determined if the 5-HT3 receptor antagonist ondansetron blocks IKAS. We searched 2,306,335 records in the Indiana Network for Patient Care and found 11 patients with diLQTS who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-yr-old woman presenting with corrected QT interval prolongation at baseline (473 ms) and further corrected QT interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNE1 and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 variant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca2+ sensitivity, increasing IKAS density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of WT KCNN2 protein. Ondansetron at nanomolar concentrations inhibited WT and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced IKAS inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F503L KCNN2 variant increases Ca2+ sensitivity and IKAS density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent IKAS blocker. NEW & NOTEWORTHY We showed that ondansetron, a 5-HT3 receptor antagonist, blocks small-conductance Ca2+-activated K+ (SK) current. Ondansetron may be useful in controlling arrhythmias in which increased SK current is a likely contributor. However, its SK-blocking effects may also facilitate the development of drug-induced long QT syndrome.

Lightweight high-performance metallic powders have great potentials for applications in metal-based additive manufacturing. To enhance their mechanical performance and extend their potentials in addictive manufacturing, ceramic nanoparticles are now incorporated into metal matrix microparticles. However, successful incorporation of high volume percentage nanoparticles and related scalable processing methods have not been developed yet. Here we show an effective manufacturing approach to produce aluminum (Al) and magnesium (Mg) nanocomposite microparticles with densely-packed titanium diboride and titanium carbide nanoparticles. Through a flux-assisted solidification processing method, up to 30 vol% of the nanoparticles were efficiently self-incorporated and self-dispersed into Al and Mg microparticles.