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Cholesterol is an essential component of mammalian cell membranes, constituting up to 50% of plasma membrane lipids. By contrast, it accounts for only 5% of lipids in the endoplasmic reticulum (ER) 1 . The ER enzyme sterol O -acyltransferase 1 (also named acyl-coenzyme A:cholesterol acyltransferase, ACAT1) transfers a long-chain fatty acid to cholesterol to form cholesteryl esters that coalesce into cytosolic lipid droplets. Under conditions of cholesterol overload, ACAT1 maintains the low cholesterol concentration of the ER and thereby has an essential role in cholesterol homeostasis 2 , 3 . ACAT1 has also been implicated in Alzheimer’s disease 4 , atherosclerosis 5 and cancers 6 . Here we report a cryo-electron microscopy structure of human ACAT1 in complex with nevanimibe 7 , an inhibitor that is in clinical trials for the treatment of congenital adrenal hyperplasia. The ACAT1 holoenzyme is a tetramer that consists of two homodimers. Each monomer contains nine transmembrane helices (TMs), six of which (TM4–TM9) form a cavity that accommodates nevanimibe and an endogenous acyl-coenzyme A. This cavity also contains a histidine that has previously been identified as essential for catalytic activity 8 . Our structural data and biochemical analyses provide a physical model to explain the process of cholesterol esterification, as well as details of the interaction between nevanimibe and ACAT1, which may help to accelerate the development of ACAT1 inhibitors to treat related diseases. The structure of human ACAT1 in complex with the inhibitor nevanimibe is resolved by cryo-electron microscopy.

Lightweight materials are of paramount importance to reduce energy consumption and emissions in today’s society. For materials to qualify for widespread use in lightweight structural assembly, they must be weldable or joinable, which has been a long-standing issue for high strength aluminum alloys, such as 7075 (AA7075) due to their hot crack susceptibility during fusion welding. Here, we show that AA7075 can be safely arc welded without hot cracks by introducing nanoparticle-enabled phase control during welding. Joints welded with an AA7075 filler rod containing TiC nanoparticles not only exhibit fine globular grains and a modified secondary phase, both which intrinsically eliminate the materials hot crack susceptibility, but moreover show exceptional tensile strength in both as-welded and post-weld heat-treated conditions. This rather simple twist to the filler material of a fusion weld could be generally applied to a wide range of hot crack susceptible materials. In contrast to steels, fusion welding high strength aluminum alloys such as AA7075 is notoriously difficult. Here, the authors add nanoparticles to a weld filler rod to successfully weld AA7075 without hot cracks or loss of strength at the weld.

Effective control of melting and solidification behaviours of materials is significant for numerous applications. It has been a long-standing challenge to increase the melted zone (MZ) depth while shrinking the heat-affected zone (HAZ) size during local melting and solidification of materials. In this paper, nanoparticle-induced unusual melting and solidification behaviours of metals are reported that effectively solve this long-time dilemma. By introduction of Al 2 O 3 nanoparticles, the MZ depth of Ni is increased by 68%, while the corresponding HAZ size is decreased by 67% in laser melting at a pulse energy of 0.18 mJ. The addition of SiC nanoparticles shows similar results. The discovery of the unusual melting and solidification of materials that contain nanoparticles will not only have impacts on existing melting and solidification manufacturing processes, such as laser welding and additive manufacturing, but also on other applications such as pharmaceutical processing and energy storage. A material with a deep melted zone (MZ) but small heat-affected zone (HAZ) is ideal for manufacturing, but improving one zone comes at the expense of the other. Here, the authors resolve this contradiction in metals by adding nanoparticles, which change the metals’ properties in such a way that both expands MZ and minimizes HAZ.

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)P 2 ), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P 2 , another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P 2 and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P 2 , PtdIns(4,5)P 2 , or ML-SA1 and PtdIns(3,5)P 2 , revealing a unique lipid-binding site. PtdIns(3,5)P 2 and PtdIns(4,5)P 2 bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P 2 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. Transient receptor potential mucolipin 1 (TRPML1) is a lysosomal channel which maintains the low pH and calcium levels for lysosomal function. Here authors use structural biology and electrophysiology to show how lipids bind and allosterically activate TRPML1.

The Hedgehog (HH) signaling pathway is important in development, and excessive HH signaling is associated with cancer. Signaling occurs through the G protein–coupled receptor Smoothened. The pathway is repressed by the membrane receptor Patched-1 (PTCH1), and this inhibition is relieved when PTCH1 binds the secreted protein HH. Two recent papers have described structures of HH bound to PTCH1, but surprisingly, each described a different binding epitope on HH. Qi et al. present a cryo–electron microscopy structure that explains this apparent contradiction by showing that a single HH protein uses both of these interfaces to engage two PTCH1 receptors (see the Perspective by Sommer and Lemmon). Functional assays suggest that both interfaces must be bound for efficient signaling. Science , this issue p. eaas8843 ; see also p. 26 The cryo–electron microscopy structure of a key complex involved in regulating a pathway important in development and cancer is elucidated. Aberrant Hedgehog (HH) signaling leads to various types of cancer and birth defects. N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH complex structure visualized a palmitate-mediated binding site on HH, which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH co-receptors. Our 3.5-angstrom resolution cryo–electron microscopy structure of native Sonic Hedgehog (SHH-N) in complex with PTCH1 at a physiological calcium concentration reconciles these disparate findings and demonstrates that one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupt the individual interfaces illustrate that simultaneous engagement of both interfaces is required for efficient signaling in cells.

The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal from the tumour suppressor Patched-1 (PTCH1) to the glioma-associated-oncogene (GLI) transcription factors, which activates the Hedgehog signalling pathway 1 , 2 . It has remained unknown how PTCH1 modulates SMO, how SMO is stimulated to form a complex with heterotrimeric G proteins and whether G-protein coupling contributes to the activation of GLI proteins 3 . Here we show that 24,25-epoxycholesterol, which we identify as an endogenous ligand of PTCH1, can stimulate Hedgehog signalling in cells and can trigger G-protein signalling via human SMO in vitro. We present a cryo-electron microscopy structure of human SMO bound to 24( S ),25-epoxycholesterol and coupled to a heterotrimeric G i protein. The structure reveals a ligand-binding site for 24( S ),25-epoxycholesterol in the 7-transmembrane region, as well as a G i -coupled activation mechanism of human SMO. Notably, the G i protein presents a different arrangement from that of class-A GPCR–G i complexes. Our work provides molecular insights into Hedgehog signal transduction and the activation of a class-F GPCR. Cryo-electron microscopy structure of the human Smoothened protein bound to 24( S ),25-epoxycholesterol and a heterotrimeric G i protein provides insights into the activation of a Frizzled-class G-protein-coupled receptor and Hedgehog signal transduction.

Metasomatic alteration of fluorapatite has been reported in several iron-oxide apatite (IOA) deposits, but its effect on elemental and isotopic variations has not been well understood. In this study, we present integrated elemental, U-Pb, Sr, and O isotopic microanalytical data on fresh and altered domains in fluorapatite from the Taocun IOA deposit, Eastern China, to evaluate the timing and nature of the metasomatism and its effects on the ore-forming event. Orebodies of the Taocun deposit are spatially associated with a subvolcanic, intermediate intrusion, which displays zonal alteration patterns with albite in the center and increasing actinolite, chlorite, epidote, and carbonate toward the margin. Both disseminated and vein-type ores are present in the Taocun deposit, and fluorapatite commonly occurs with magnetite and actinolite in most ores. Fluorapatite grains from the both types of ores have been variably metasomatized through a coupled dissolution-reprecipitation mechanism. Many trace elements, including Na, Cl, S, Si, Mg, Sr, U, Th, and (REEs+Y), were variably leached from the fluorapatite grains during this process and the Sr and O isotopic signatures of the grains were also modified. The altered fluorapatite grains/domains have in situ 87Sr/86Sr ratios (0.70829-0.70971) slightly higher than those of the fresh fluorapatite (0.70777-0.70868), and δ18O values (-3.0 to +3.4 ppm) variably lower than the primary domains (+5.3 to +7.5 ppm). The Sr and O isotopes of the primary fluorapatite are consistent with or slightly higher than those of the ore-hosting intrusion, implying that the early-stage, ore-forming fluids were magmatic in origin but underwent weak interaction with the country rocks. U-Pb dating of the fresh and altered domains of the fluorapatite yielded indistinguishable ages of ∼131 Ma, which are the same as the age of the ore-hosting intrusion. In combination with fluid inclusion data, we propose that the metasomatism of fluorapatite was induced by hydrothermal fluids at a late stage of the ore-forming event. The shifts to higher 87Sr/86Sr ratios and lower δ18O values in the altered fluorapatite indicate that the alteration was induced by fluids with more radioactive Sr and lighter O isotope signatures. The metasomatic fluids were likely dominated by meteoric waters that were mixed with the earlier magmatic fluids and interacted with sedimentary rocks. Our study highlights that elemental and isotopic compositions of fluorapatite can be significantly modified by hydrothermal fluids during ore-forming events. Thus, instead of traditional bulk-rock analysis, in situ microanalysis is important to provide accurate constraints on the magmatic and/or hydrothermal evolution of complex ore-forming systems.

This paper established an open general equilibrium model to study the effect of the change of rural–urban migrants’ remittances rate on agricultural pollution. We found that the increase of migrants’ remittances rate would not influence the output of agricultural pollution factor production sector or the agricultural pollution in the capital specific case; and in the mobile capital case, the increase in the rural–urban migrants’ remittances rate will decrease the output of the agricultural pollution factor production sector and then decrease the agricultural pollution. In addition, we investigated the numerical characteristics of the effects of the change in the rural–urban migrants’ remittances rate on the relevant variables, and we also found that the increase in the migrants’ remittances rate would increase the national income and improve the level of gross national welfare under certain conditions, no matter in the capital specific case or in the mobile capital case.

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.