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"She, Ji"
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Study on Shear–Softening Constitutive Law of Rock–Concrete Interface
To study fracture properties and establish a shear–softening constitutive law for rock–concrete interfaces, direct tension, three-point bending, and single shear push-out tests were conducted on composite rock–concrete specimens with different degrees of interface roughness. The relationships between tensile strength (ft), average shear strength (τav), initial fracture toughness (Kini 1C), mode I fracture energy (GIf) and interfacial roughness were determined based on experimental results. A shear–softening constitutive law for rock–concrete interface was developed by measuring strain variations on rock surfaces under loading stages during single shear push-out tests and defined based on shear strength (τmax) and mode II fracture energy (GIIf). For practical applications, the relationships between τmax and ft and between GIf and GIIf were determined by statistically fitting the experimental data in such a way that shear–softening constitutive law could be conveniently determined simply by measuring ft and GIf parameters of rock–concrete interface. Also, numerical simulations were carried out to investigate crack propagation in rock–concrete interfaces under mixed mode I–II fractures. Predicted load versus crack mouth opening displacement (CMOD) curves agreed well with experimental findings and verified the shear–softening constitutive law for rock–concrete interfaces obtained in this study.
Journal Article
Structure and function of human XPR1 in phosphate export
Xenotropic and polytropic retrovirus receptor 1 (XPR1) functions as a phosphate exporter and is pivotal in maintaining human phosphate homeostasis. It has been identified as a causative gene for primary familial brain calcification. Here we present the cryogenic electron microscopy (cryo-EM) structure of human XPR1 (HsXPR1). HsXPR1 exhibits a dimeric structure in which only TM1 directly constitutes the dimer interface of the transmembrane domain. Each HsXPR1 subunit can be divided spatially into a core domain and a scaffold domain. The core domain of HsXPR1 forms a pore-like structure, along which two phosphate-binding sites enriched with positively charged residues are identified. Mutations of key residues at either site substantially diminish the transport activity of HsXPR1. Phosphate binding at the central site may trigger a conformational change at TM9, leading to the opening of the extracellular gate. In addition, our structural analysis reveals a new conformational state of HsXPR1 in which the cytoplasmic SPX domains form a V-shaped structure. Altogether, our results elucidate the overall architecture of HsXPR1 and shed light on XPR1-mediated phosphate export.
XPR1, a phosphate exporter, plays a vital role in maintaining phosphate homeostasis in humans. Here, the authors offer structural and functional insights into its dimeric architecture and the mechanisms of phosphate recognition and efflux.
Journal Article
Application of interpretable machine learning algorithms to predict distant metastasis in osteosarcoma
Background Osteosarcoma is well‐established as the most common bone cancer in children and adolescents. Patients with localized disease have different prognoses and management than those with metastasis at the time of diagnosis. The purpose of this study was to explore potential risk factors for metastatic disease. Methods The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify patients diagnosed with osteosarcoma between 2004 and 2015. We developed prediction models for distant metastasis using six machine learning (ML) techniques, including logistic regression (LR), support vector machine (SVM), Gaussian Naive Bayes (GaussianNB), Extreme Gradient Boosting (XGBoost), random forest (RF), and k‐nearest neighbor algorithm (kNN). The adaptive synthetic (ADASYN) technique was used to deal with imbalanced data. The Shapley Additive Explanation (SHAP) analysis generated visualized explanations for each patient. Finally, the average precision (AP), sensitivity, specificity, accuracy, F1 score, precision‐recall curves, calibration plots, and decision curve analysis (DCA) were conducted to evaluate the models' effectiveness. Results The six machine learning algorithms achieved AP of 0.661–0.781 for predicting distant metastasis. The RF model yielded the best performance with an accuracy of 71.8 percent and an AP of 0.781 and was highly dependent on tumor size, primary surgery, and age. SHAP analysis provided model‐independent interpretation, highlighting significant clinical factors associated with the risk of metastasis in osteosarcoma patients. Conclusions An accurate machine learning‐based prediction model was established for metastasis in osteosarcoma patients to help clinicians during clinical decision‐making. We developed a machine learning‐based model to predict the explore potential risk factors for metastatic disease in osteosarcoma patients according to the tumor features and the treatment duration in this study. As a result, the Random Forest model outperformed all other models in training and validation sets. To improve the interpretability of our machine learning model, we reported the SHAP values and a list of highly influential features.
Journal Article
Structures of the calcium-activated, non-selective cation channel TRPM4
TRPM4 is a calcium-activated, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P
2
) -modulated, non-selective cation channel that belongs to the family of melastatin-related transient receptor potential (TRPM) channels. Here we present the electron cryo-microscopy structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain and inhibits channel activity. TRPM4 has an exceptionally wide filter but is only permeable to monovalent cations; filter residue Gln973 is essential in defining monovalent selectivity. The S1–S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca
2+
- and PtdIns(4,5)P
2
-binding sites. These structures provide an essential starting point for elucidating the complex gating mechanisms of TRPM4 and reveal the molecular architecture of the TRPM family.
Electron cryo-microscopy structures of mouse TRPM4, a calcium-activated, non-selective cation channel, in the apo and ATP-bound states.
Scoping out TRPM channels
Melastatin-related transient receptor potential (TRPM) ion channels are the largest group of the TRP superfamily and, as such, are widespread throughout the body with diverse physiological roles including heat and taste sensation and regulating ion homeostasis. For example, TRPM4 is a Ca
2+
-activated non-selective channel expressed in many of the central organs including the brain and heart, and is involved in the cardiac rhythm, breath pacemaking and insulin secretion. In this issue of
Nature
, two groups report the structure of TRPM4 by electron cryo-microscopy. Wei Lü and colleagues solved the structure of human TRPM4, which shows an umbrella-like structure, bound to Ca(ɪɪ) and decavanadate. Youxing Jiang and colleagues report the structure of mouse TRPM4 with and without ATP, which inhibits channel activity. These studies provide the first structural insights into the TRPM family.
Journal Article
Structural basis of vitamin C recognition and transport by mammalian SVCT1 transporter
Vitamin C (L-ascorbic acid) is an essential nutrient for human health, and its deficiency has long been known to cause scurvy. Sodium-dependent vitamin C transporters (SVCTs) are responsible for vitamin C uptake and tissue distribution in mammals. Here, we present cryogenic electron microscopy structures of mouse SVCT1 in both the apo and substrate-bound states. Mouse SVCT1 forms a homodimer with each protomer containing a core domain and a gate domain. The tightly packed extracellular interfaces between the core domain and gate domain stabilize the protein in an inward-open conformation for both the apo and substrate-bound structures. Vitamin C binds at the core domain of each subunit, and two potential sodium ions are identified near the binding site. The coordination of sodium ions by vitamin C explains their coupling transport. SVCTs probably deliver substrate through an elevator mechanism in combination with local structural arrangements. Altogether, our results reveal the molecular mechanism by which SVCTs recognize vitamin C and lay a foundation for further mechanistic studies on SVCT substrate transport.
Sodium-dependent vitamin C transporters are responsible for vitamin C uptake and tissue distribution in mammals. Here, authors present cryo-EM structures of mouse SVCT1 in both the apo and substrate-bound states, revealing the structural basis of substrate recognition and transport.
Journal Article
Structural mechanisms of phospholipid activation of the human TPC2 channel
Mammalian two-pore channels (TPCs) regulate the physiological functions of the endolysosome. Here we present cryo-EM structures of human TPC2 (HsTPC2), a phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2)-activated, Na+ selective channel, in the ligand-bound and apo states. The apo structure captures the closed conformation, while the ligand-bound form features the channel in both open and closed conformations. Combined with functional analysis, these structures provide insights into the mechanism of PI(3,5)P2-regulated gating of TPC2, which is distinct from that of TPC1. Specifically, the endolysosome-specific PI(3,5)P2 binds at the first 6-TM and activates the channel – independently of the membrane potential – by inducing a structural change at the pore-lining inner helix (IS6), which forms a continuous helix in the open state but breaks into two segments at Gly317 in the closed state. Additionally, structural comparison to the voltage-dependent TPC1 structure allowed us to identify Ile551 as being responsible for the loss of voltage dependence in TPC2.
Journal Article
Structure of mammalian endolysosomal TRPML1 channel in nanodiscs
The structure of mouse transient receptor potential mucolipin 1 (TRPML1), a cation channel located within endosomal and lysosomal membranes, is resolved using single-particle electron cryo-microscopy.
Closing in on ion channels
Numerous ion channels sit in the membranes of intracellular organelles and are responsible for maintaining concentration gradients and ionic signalling. The transient receptor potential mucolipin (TRPML) channels are Ca(
II
)-releasing channels that are crucial to endolysosomal function. While TRPML channels regulate physiological processes including membrane trafficking and exocytosis, mutations of TRPML1 cause the lysosomal storage disorder mucolipidosis type IV. Three papers in this issue of
Nature
report the structure of TRPML channels by cryo-electron microscopy. Seok-Yong Lee and colleagues report the structure of TRPML3, while studies from teams led by Xiaochun Li and Youxing Jiang present the structure of TRPML1. Together, these studies reveal the open and closed states of the TRPML family, indicating the regulatory mechanisms of these channels. As with most TRP channels, TRPML can be gated by specific lipids, and these studies provide insights into substrate binding and channel activation.
Transient receptor potential mucolipin 1 (TRPML1) is a cation channel located within endosomal and lysosomal membranes. Ubiquitously expressed in mammalian cells
1
,
2
, its loss-of-function mutations are the direct cause of type IV mucolipidosis, an autosomal recessive lysosomal storage disease
3
,
4
,
5
,
6
. Here we present the single-particle electron cryo-microscopy structure of the mouse TRPML1 channel embedded in nanodiscs. Combined with mutagenesis analysis, the TRPML1 structure reveals that phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P
2
) binds to the N terminus of the channel—distal from the pore—and the helix–turn–helix extension between segments S2 and S3 probably couples ligand binding to pore opening. The tightly packed selectivity filter contains multiple ion-binding sites, and the conserved acidic residues form the luminal Ca
2+
-blocking site that confers luminal pH and Ca
2+
modulation on channel conductance. A luminal linker domain forms a fenestrated canopy atop the channel, providing several luminal ion passages to the pore and creating a negative electrostatic trap, with a preference for divalent cations, at the luminal entrance. The structure also reveals two equally distributed S4–S5 linker conformations in the closed channel, suggesting an S4–S5 linker-mediated PtdInsP
2
gating mechanism among TRPML channels
7
,
8
.
Journal Article
Chitin-Induced Dimerization Activates a Plant Immune Receptor
Pattern recognition receptors confer plant resistance to pathogen infection by recognizing the conserved pathogen-associated molecular patterns. The cell surface receptor chitin elicitor receptor kinase 1 of Arabidopsis (AtCERK1) directly binds chitin through its lysine motif (LysM)-containing ectodomain (AtCERK1-ECD) to activate immune responses. The crystal structure that we solved of an AtCERK1-ECD complexed with a chitin pentamer reveals that their interaction is primarily mediated by a LysAA and three chitin residues. By acting as a bivalent ligand, a chitin octamer induces AtCERK1-ECD dimerization that is inhibited by shorter chitin oligomers. A mutation attenuating chitin-induced AtCERK1-ECD dimerization or formation of nonproductive AtCERK1 dimer by overexpression of AtCERK1-ECD compromises AtCERK1-mediated signaling in plant cells. Together, our data support the notion that chitin-induced AtCERK1 dimerization is critical for its activation.
Journal Article