Structure Mechanism Research Articles

The Plasmodium falciparum NCR1 transporter is an antimalarial target that exports cholesterol from the parasite's plasma membrane.

Malaria, a devastating parasitic infection, is the leading cause of death in many developing countries. Unfortunately, the most deadliest causative agent of malaria, Plasmodium falciparum, has developed resistance to nearly all currently available antimalarial drugs. The P. falciparum Niemann-Pick type C1-related (PfNCR1) transporter has been identified as a druggable target, but its structure and detailed molecular mechanism are not yet available. Here, we present three structures of PfNCR1 with and without the functional inhibitor MMV009108 at resolutions between 2.98 and 3.81 Å using single-particle cryo-electron microscopy (cryo-EM), suggesting that PfNCR1 binds cholesterol and forms a cholesterol transport tunnel to modulate the composition of the parasite plasma membrane. Cholesterol efflux assays show that PfNCR1 is an exporter capable of extruding cholesterol from the membrane. Additionally, the inhibition mechanism of MMV009108 appears to be due to a direct blockage of PfNCR1, preventing this transporter from shuttling cholesterol.

Ionic control of small GTPase HRas using calmodulin.

HRas is a small GTPase that plays physiologically important roles in various intracellular signal transduction processes, such as cell growth and proliferation. The structure and action mechanisms of HRas have been well-characterized, leading to widespread its use as a molecular switch in bionanomachines. calmodulin, a calcium ion-binding protein, acts as an ion-binding molecular switch and activates the target enzymes. We previously demonstrated that the fusion protein of HRas (M13-HRas) with the calmodulin target peptide M13 at the N-terminus of HRas exhibits reversible regulation of GTPase activity and the interaction between M13-HRas and the downstream signaling factor Raf by calcium ions with calmodulin. In this study, we prepared two new HRas fusion proteins with the M13 peptide at the C-terminus (HRas-M13) and both termini (M13-HRas-M13) of HRas and analyzed the calcium-dependent regulation of HRas function. M13-HRas-M13 more efficiently controlled GTPase, interaction with Raf, and the HRas regulator GEF by calcium ions with calmodulin.

Structural mechanism of CB1R binding to peripheral and biased inverse agonists

The cannabinoid receptor 1 (CB1R) regulates synaptic transmission in the central nervous system, but also has important roles in the peripheral organs controlling cellular metabolism. While earlier generations of brain penetrant CB1R antagonists advanced to the clinic for their effective treatment of obesity, such molecules were ultimately shown to exhibit negative effects on central reward pathways that thwarted their further therapeutic development. The peripherally restricted CB1R inverse agonists MRI-1867 and MRI-1891 represent a new generation of compounds that retain the metabolic benefits of CB1R inhibitors while sparing the negative psychiatric effects. To understand the mechanism of binding and inhibition of CB1R by peripherally restricted antagonists, we developed a nanobody/fusion protein strategy for high-resolution cryo-EM structure determination of the GPCR inactive state, and used this method to determine structures of CB1R bound to either MRI-1867 or MRI-1891. These structures reveal how these compounds retain high affinity and specificity for CB1R’s hydrophobic orthosteric site despite incorporating polar functionalities that lead to peripheral restriction. Further, the structure of the MRI-1891 complex along with accompanying molecular dynamics simulations shows how differential engagement with transmembrane helices and the proximal N-terminus can propagate through the receptor to contribute to biased inhibition of β-arrestin signaling.

Programmable Self‐assembly from Two‐dimensional Nanosheets to Spiral, Twisted and Branched Nanostructures

Self‐assembly of nanomaterials into hierarchical structure is of great interest to fabricate functional materials. However, programmable design of the assembled structures remains a great challenge. Herein, we reported a programmable self‐assembly strategy to customize the assembled structure. The self‐assembly strategy is designed to orderly transform the two‐dimensional (2D) Ca ions assembled F127 nanosheets (Ca‐F127 NSs) into spiral nanosheet structures (S‐Ca‐F127 NSs), branched nanosheet structures (B‐Ca‐F127 NSs), branched‐spiral nanosheet structures (B‐S‐Ca‐F127 NSs), and twisted‐branched structures (T‐Ca‐F127 NBs). Wide‐angle X‐ray scattering (WAXS) and X‐ray absorption spectroscopy (XAS) indicate that these different structures maintain the same orthorhombic phase and Ca‐O octahedral coordination structure. Selected area electron diffraction (SAED) in the double‐tilt liquid nitrogen cooling holder identifies the Eshelby twist in the twisted structures, demonstrating the spiral structure are formed by screw dislocation growth. Cryo‐electron microscopy (cryo‐EM) proves the oriented epitaxial growth in the B‐Ca‐F127 NSs. Furthermore, the formation mechanisms of spiral structure and branched structure can be recombined to form complex hierarchical structures. The epitaxial growth along screw dislocation can lead to the formation of B‐S‐Ca‐F127 NSs, while the twisted epitaxial growth in the screw dislocation can lead to the formation of T‐Ca F127 NBs.

Synergy of tensile strength and ductility in a novel additively manufactured Al-Mg-Mn-Er-Zr alloy with a trilevel equiaxed heterogeneous structure

ABSTRACT This study investigates a novel Al-Mg-Mn-Er-Zr alloy with high strength and elongation. The uneven distribution of L12-Al3Er and Al3(Er, Zr) phases in the molten pool structure results in a trilevel equiaxed heterogeneous structure in the alloy. The as-printed alloy exhibits various forms of Al3(Er, Zr) phases and Er-containing primary phases (such as Al3(Zr, Er)5), demonstrating an excellent combination of strength (ultimate tensile strength of 531 MPa, yield strength of 455 MPa) and elongation (fracture elongation of 27%). The strengthening mechanism and strain distribution behaviour of the heterogeneous structure are explored to understand the alloy's elongation and strength mechanism. The large equiaxed grains concentrated in the centre of the molten pool contribute to high elongation, while heterogeneous deformation-induced (HDI) strengthening caused by heterogeneous grains increases the strength. The ultrafine grains at the molten pool boundaries ensure that strength remains at a high level, achieving a good balance of strength and elongation.

Dynamic Evolution of the Power Structure and Contracting State Status in the Regional Trade Agreement Network and Its Trade Feedback Effects

ABSTRACT Against the backdrop of the serious setback in WTO multilateral negotiations, countries around the world have signed a large number of regional trade agreements (RTAs) to further reduce trade barriers and promote trade liberalization. These RTAs have formed a complex network of crisscrossing and mutually reinforcing dependencies that reshape the trade effects of individual RTAs. This paper uses the complex network analysis method to discuss the construction and development issues of RTAs among countries around the world and reveals the historical changes in the power structure of the economic and trade rules network and the dynamic evolution of the network status of core countries in international trade since 1995. Based on this, the feedback mechanism of the overall structure of the network and the node country status on the trade effect of RTAs is explored and tested. The analysis results show the following: (1) The global RTA network follows a power law distribution, the unbalanced characteristics of bipolarization in international economic and trade rules are very significant, and the gap in national network status is enormous. European countries are almost always in the center of the network, and China’s network status has not improved significantly. (2) The network shows obvious competitive and balancing relationships, and the pattern of international economic and trade rules has a trend toward short-term multi-polarization. (3) The test results of the trade effect feedback mechanism of the network show that the redundancy relationship of the overall network and the concentration of power structure have a negative influence on the trade effect of RTAs, while the bridging cluster function and transitivity of the overall network have a positive feedback effect on the trade effect of RTAs. The core position and control of a single country in the network form a positive feedback and high return on the trade effect of RTAs.

Seismic Performance Research on a Graded-Yielding Metal Brace with Self-Centering Functions

With the aim of achieving a graded-protection braced frame structure and minimizing the excessive residual deformation of traditional metal dampers under intense seismic action, a graded-yield-type metal self-centering brace (SC-GYMB) is proposed. The brace is composed of X-shaped and U-shaped steel plates with different yield point displacements, which jointly dissipate energy. Additionally, it employs a composite disc spring as a self-centering element to provide restoring force for the brace. The brace’s basic structure and working mechanism are described, and the theoretical model for its restoring force is derived. The ABAQUS finite element software (ABAQUS 2021) is utilized to investigate the hysteretic performance of the SC-GYMB under low-cycle reciprocating load, while thoroughly discussing the influence of various model parameters on its key mechanical behavior. The results demonstrate a strong agreement between the theoretical restoring force model and the numerical simulation results. The hysteretic curves of the braces exhibit a distinct “flag” characteristic, indicating excellent energy dissipation capacity and self-centering performance. Moreover, these curves display a hierarchical yield behavior that satisfies the seismic performance requirements for different intensity earthquakes. The deformation mechanism of X-shaped steel sheets transitions from bending deformation during the initial loading stage to tensile deformation in the subsequent loading stage. Increasing the initial pre-compression force of the combined disc spring enhances the restoration performance of the brace. Augmenting the thickness of X-shaped or U-shaped steel sheets modifies the displacement and load at both the first and second yield points, thereby enhancing energy dissipation capacity and bearing capacity of the brace; however, it also leads to increased residual deformation.

Insight into the Structure and Formation Mechanism of Esmolol Hydrochloride Polymorphs Based on Experiments and Molecular Simulations

Insight into the Structure and Formation Mechanism of Esmolol Hydrochloride Polymorphs Based on Experiments and Molecular Simulations

Neurological Recovery Following Surgical Intervention in Patients with Traumatic Spinal Cord Injury at the University Teaching Hospital in Zambia

Introduction Traumatic spinal cord injuries cause long-term disability and functional impairment. Timely and proper surgical treatment improves neurological recovery and functional outcomes. However, in low-resource setting countries, surgical intervention is usually delayed raising concerns about the recovery of patients. Hence, this study investigated the neurological improvement of patients undergoing surgery for traumatic spinal cord injuries at the University Teaching Hospital in Lusaka, Zambia. Methods This was a retrospective study that included all eligible patients with traumatic spinal cord injury managed surgically at the University Teaching Hospital between 2018 and 2022. The study assessed neurological improvement by comparing the American Spinal Injury Association’s neurological grading before surgery to that at discharge. Data was analysed using Stata 17, and the level of significance was set at 5%. Results Out of the 96 patients in the study, 45.8% showed neurological improvement of at least one grade after surgery. Patients with thoracic injuries showed lower improvement rates (25.0%) than those with cervical (55.0%) or lumbar injuries (65.0%), while those with incomplete injuries showed higher improvement rates (78.7%) (p <0.05). Thoracic injuries were associated with reduced neurological improvement (AOR 0.21; 95% CI: 0.04 – 0.95, p = 0.043), while incomplete injuries were associated with higher neurological improvement (AOR 18.58; 95% CI: 6.11 – 56.51, p < 0.001). Conclusion Neurological improvement was poor for thoracic injuries and complete injuries, highlighting the necessity for further investigation into the specific structural features and mechanisms of injury that contribute to poor neurological improvement in thoracic injuries and the identification of effective recovery approaches for these patients.

Structural mechanisms of PIP2 activation and SEA0400 inhibition in human cardiac sodium-calcium exchanger NCX1.

Na+/Ca2+ exchangers (NCXs) transport Ca2+ across the plasma membrane in exchange for Na+ and play a vital role in maintaining cellular Ca2+ homeostasis. Our previous structural study of human cardiac NCX1 (HsNCX1) reveals the overall architecture of the eukaryotic exchanger and the formation of the inactivation assembly by the intracellular regulatory domain that underlies the cytosolic Na+-dependent inactivation and Ca2+ activation of NCX1. Here we present the cryo-EM structures of HsNCX1 in complex with a physiological activator phosphatidylinositol 4,5-bisphosphate (PIP2), or pharmacological inhibitor SEA0400 that enhances the inactivation of the exchanger. We demonstrate that PIP2 binding stimulates NCX1 activity by inducing a conformational change at the interface between the TM and cytosolic domains that destabilizes the inactivation assembly. In contrast, SEA0400 binding in the TM domain of NCX1 stabilizes the exchanger in an inward-facing conformation that facilitates the formation of the inactivation assembly, thereby promoting the Na+-dependent inactivation of NCX1. Thus, this study reveals the structural basis of PIP2 activation and SEA0400 inhibition of NCX1 and provides some mechanistic understandings of cellular regulation and pharmacology of NCX family proteins.

Research on the Mechanism of Load Transfer Structures in the Construction Process of “Internal Support—Large Block” Prefabricated Subway Stations

In the context of rising global temperatures, countries around the world are increasingly tailoring their own “carbon neutrality” plans. China has also formulated its “dual-carbon” goals, and the construction industry is gradually transitioning towards prefabrication to reduce carbon emissions. This paper uses the Sha Pu Station of Shenzhen’s Metro Line 12 as a case study by which to explore the effects and mechanisms of the load transfer structure during the assembly process of prefabricated subway stations. A three-dimensional finite element model considering soil–structure interaction was established using MIDAS GTS NX finite element software, 2018 version. The internal forces, stresses, and deformations of the station structure were compared under two scenarios—with and without the load transfer structure—using a control variable method. The research results indicate that the load transfer structure effectively reduces shear forces, bending moments, and stresses in the station structure; limits lateral displacements during the assembly process; and effectively concentrates the maximum stresses during construction at the location of the load transfer structure, thereby preventing stress concentration phenomena and enhancing the overall stability of the station structure. This study elucidates the role and effectiveness of the load transfer structure during the assembly of prefabricated components in subway stations, providing a reference for the construction of similar prefabricated metro stations.

Partially precise instrument measurements-aided deep learning for industrial quality prediction

Material composition is a kind of important quality index in the process industry. Even though instruments for online measuring these compositions have been widely applied, the precision of material composition measurements is suspicious due to corrosion, scaling and other factors. Laboratory values are more convinced, while these instruments are largely idle in real applications. Nevertheless, despite suspicious precision, partially precise trends exist in these measurements, which are also useful for indicating the variation in quality. This means that a wealth of information directly related to quality variables can provide positive guidance for quality prediction. Enlightened by the requirement of information utilization, a long short-term memory network with embedded trend consistency criteria (TCC-LSTM) is proposed for industrial quality prediction through extremely efficient utilization of partially precise quality instrument data. Specifically, based on the property that the trends of the measured values for quality variable are similar to that of the corresponding laboratory values over time, six trend consistency criteria are designed to evaluate the reliability of instrument data, so as to determine the contribution weights of these data in deep learning-based quality prediction. Moreover, in the neural network structure, the space-wise and time-wise attention mechanisms are designed for capturing important variables and time information. Extensive experiments on an actual alumina digestion process demonstrate the efficiency of TCC-LSTM, whose correlation coefficient is averagely improved by 0.2247 and mean absolute error is as low as 0.008079.

Nanomaterial‐Mediated Modulation of TRPV1 Ion Channels for Biomedical Applications

AbstractTransient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cation channel involved in various physiological processes such as pain perception, thermoregulation, and inflammatory responses. Nanomaterials have emerged as precise tools to modulate TRPV1 activity, offering high spatiotemporal resolution and specificity. These nanomaterials act as transducers, responding to internal or external stimuli such as pH, light, electric, and magnetic fields to deliver modulatory agents like agonists, antagonists, heat, reactive species, and mechanical forces to TRPV1 channels. This strategy enables non‐invasive and targeted therapeutic interventions for diseases associated with TRPV1 dysfunction. In this review, recent advances are highlighted in nanomaterial‐mediated TRPV1 modulation and its biomedical applications. The TRPV1 structure and activation mechanisms, the integration of nanomaterials for effective TRPV1 modulation, and the required material properties are covered. Moreover, biomedical applications are discussed, including neurostimulation, neurological disorder therapies, cancer therapies, metabolic disease treatments, and cardiovascular disease interventions. Future research directions and challenges in this field are also proposed.

Type A monoamine oxidase; its unique role in mood, behavior and neurodegeneration.

Monoamine oxidase catalyzes oxidative deamination of monoamine transmitters and plays a critical role in the pathogenesis of neuropsychiatric diseases. Monoamine oxidase is classified into type A and B (MAO-A, MAO-B) according to the substrate specificity and sensitivity to inhibitors. The isoenzymes are different proteins coded by different genes localized on the X-chromosome, but they have identical intron-exon organization, similar protein structure and enzymatic mechanism and are considered to be derived from the same ancestral gene. The isoform-specific transcription organization regulates expression and function of MAO-A in response to cellular signaling pathways and environmental factors. MAO-A shows distinct properties and functions: isoform-specified polymorphisms, localization in catecholamine neurons, expression during early embryonic stage, regulation of brain architecture development and mediation of death and survival of neuronal cells. MAO-A is more flexible to genetic and environmental changes than MAO-B. Defective MAO-A expression impairs embryonic brain development and causes adult abnormal mood and behavior, as shown by human male cases with MAO-A deletion. This paper presents the regulation of brain MAO-A expression epigenetically by interaction between genetic and environmental factors. Association of aberrant MAO-A expression and activity with aggression, asocial behaviors, depressive disorders, and neurodegenerative diseases is discussed. Novel therapeutic strategy for psychiatric diseases by intervention to the regulation of MAO-A expression and activity is proposed.

Polyglot entrainment for higher dimensional neuronal models

The entrainment of biological oscillators is a classic problem in the field of dynamical systems and synchronization. This paper explores a novel type of entrainment mechanism referred to as polyglot entrainment [Khan et al., “The emergence of polyglot entrainment responses to periodic inputs in vicinities of Hopf bifurcations in slow–fast systems,” Chaos 32, 063137 (2022)] (multiple disconnected 1:1 regions for a range of forcing amplitude) for higher dimensional nonlinear systems. Polyglot entrainment has been recently explored only in two-dimensional slow–fast models in the vicinity of Hopf bifurcations (HBs). Heading toward generality, in this research, we investigate the phenomenon of polyglot entrainment in higher-dimensional conductance-based models including the four-dimensional Hodgkin-Huxley model and its reduced three-dimensional version. We utilize dynamical systems tools to uncover the mechanism of entrainment and geometric structure of the null surfaces to explore the conditions for the existence of polyglot entrainment in these models. In light of our findings, in the vicinity of HB, when an unforced system acts as a damped oscillator and the fixed point is located near a cubic-like manifold, polyglot entrainment is observed.

Investigation on the progressive collapse resistance and failure mechanism of truss string structure with alternate cables

Investigation on the progressive collapse resistance and failure mechanism of truss string structure with alternate cables

A fluorescent probe for selective detection of Pd2+ combined with fluorescent composite membranes and bioimaging

Palladium, as a transition metal of the platinum group elements, plays an indispensable role in chemical, pharmaceutical, and industrial production. However, its potential toxicity can pose risks to our health and the environment. In this work, a novel parallel alkyne-amine naphthalene ring fluorescent probe LNA based on Pd2+ coordination has been developed. The basic structure and detection mechanism of the probe have been confirmed by nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), and liquid chromatography-mass spectrometry (LC-MS). The probe LNA has a fluorescence-off response to the Pd2+ with high sensitivity (as fast as 60 s) and excellent selectivity (with a detection limit as low as 0.12 μM). Due to the outstanding fluorescence properties of LNA and the low cytotoxicity of its ligand complexes, it has been successfully applied to carboxymethyl cellulose-based fluorescent composite membranes as well as Pd2+ imaging of living cells.

Connecting the X-Ray/UV Variability of Fairall 9 with NICER: A Possible Warm Corona

The Seyfert 1 active galactic nucleus Fairall 9 was targeted by NICER, Swift, and ground-based observatories for a ∼1000 day long reverberation mapping campaign. The following analysis of NICER spectra taken at a 2 day cadence provides new insights into the structure and heating mechanisms of the central black hole environment. Observations of Fairall 9 with NICER and Swift revealed a strong relationship between the flux of the UV continuum and the X-ray soft excess, indicating the presence of a “warm” Comptonized corona that likely lies in the upper layers of the innermost accretion flow, serving as a second reprocessor between the “hot” X-ray corona and the accretion disk. The X-ray emission from the hot corona lacks sufficient energy and variability to power slow changes in the UV light curve on timescales of 30 days or longer, suggesting an intrinsic disk-driven variability process in the UV and soft X-rays. Fast variability in the UV on timescales shorter than 30 days can be explained through X-ray reprocessing, and the observed weak X-ray/UV correlation suggests that the corona changes dynamically throughout the campaign.

Insights into the structure and polymerization mechanisms of CO molecules under pressure

High pressure technique can greatly enrich the chemistry research by innovating the traditional research paradigm. Recently, tremendous attentions have been paid to the high-pressure behavior of low-Z molecules, such as CO, CO2, N2, O2 and mixtures. These molecules tend to polymerize into extended solids at the pressure of 1−100 GPa, but the structures and polymerization mechanisms are still poorly understood. Herein, as a research model, high pressure polymerization process of carbon monoxide (CO) is studied in detail both experimentally and theoretically. The in-situ Raman spectra and angle- resolved X-ray diffraction experiments prove the successful synthesis of p-CO and its amorphous structure. The theoretical simulations reveal that two CO molecules dimerize into the ethylenedione (OCCO) diradical with spin-polarized singlet state firstly, then the OCCO diradical induces the subsequent chain elongation, ring closure and chain crosslinking reactions, leading to formation of the amorphous 3D network. The multiple basic units, hybrid coordination of C/O atoms and complex connecting styles in p-CO are revealed. Based on the polymerization mechanisms, the fundamental principles governing the character (amorphous or crystalline) of extended solids under high pressure are elucidated. Due to the small dipole moment and the head-to-tail disorder of CO molecules, it is reasonable to speculate that crystalline p-CO may exist under more rigorous conditions than 110 GPa and 2000 K, at which the isoelectronic nitrogen (N2) molecules polymerize into a single-bonded cubic form of nitrogen. Our study provides a profound insight into the polymerization mechanism and structures of low-Z CO molecules under compression, contributes to the diversified chemical researches and has a generally scientific implications for the interior dynamics of planets.

Slag rim structure and phase formation mechanism in molds during the continuous casting of high-Mn high-Al steel

The slag–steel reaction between low basicity mold flux and high-Mn and high-Al steel results in changes to the composition and properties of the mold flux, forming a slag rim at the meniscus of the mold during continuous casting. In this study, the slag rim was divided into five layers comprising the glass, columnar crystals, fine crystals, coarse crystals, and sinter layers from mold to molten steel based on their morphological features. Compared to the original slag, the Al2O3 content in the slag rim significantly increased and the SiO2 content decreased, thereby increasing the Al2O3/SiO2 mass ratio from 0.05 to 5.52. Phases with high melting points, such as Na2O·CaO·2Al2O3 and LiAlO2, were identified in the slag rim. According to crystallization process calculations using FactSage, these phases were the primary causes of slag rim formation. Thus, new slags with a low O/F mass ratio were subsequently designed to mitigate the generation and growth of Na2O·CaO·2Al2O3. These new compositions reduced the melting point and viscosity, thereby ensuring sufficient fluidity in slags with a high Al2O3/SiO2 mass ratio.