Gamma-carboxylation, catalyzed by gamma-glutamyl carboxylase (GGCX), is a critical post-translational modification essential for the biological activity of vitamin K-dependent proteins (VKDPs). Mutations in GGCX, depending on their specific location, result in vitamin K-dependent coagulation factor deficiency type 1 (VKCFD1), which encompasses a broad spectrum of clinical manifestations ranging from mild to severe, including bleeding disorders, osteoporosis, and vascular calcification. The limited knowledge of GGCX's structure and functional regions hinders our understanding of the consequences of GGCX mutations and the treatment for VKCFD1. This study aimed to identify key functional regions of GGCX and their interactions with VKDPs to better elucidate the molecular mechanisms underlying these diverse clinical symptoms. Using AlphaFold 3 and molecular dynamics simulations, we developed a complex binding model of GGCX, FIX, and reduced vitamin K, which revealed critical regions and residues involved in their interaction. Site-directed mutagenesis and cell-based assays further validated the model, confirming that multisite and regional cooperative binding of FIX to GGCX plays a key role in modulating gamma-carboxylation efficiency. Additionally, novel residues (I296, M303, M401, M402) were identified as essential for GGCX's dual enzymatic activities: carboxylation and vitamin K epoxidation. We further demonstrated that the spatial proximity of these active sites supports that GGCX's carboxylation and vitamin K epoxidation centers are interconnected, ensuring the efficient coupling of these processes. Our GGCX-FIX binding and carboxylation model aligns with known pathogenic GGCX mutations, providing valuable insights into the molecular basis of coagulation disorders caused by GGCX mutants.
To grasp the hydraulic performance and abrasion characteristics of a particular model pump before manufacture, this paper firstly numerically calculates the three-dimensional viscous steady incompressible flow of a solid-liquid two-phase flow centrifugal pump with specific speed n s =93 based on the Mixture model and obtains the influences of the three typical particle attributes (particle diameter, solid-phase concentration, and solid-phase density) on the hydraulic performance of the calculation model pump. Subsequently, numerical prediction of the abrasion of major overflow parts due to particle collision impacts was carried out based on the DPM model. The results show that the solid-phase concentration has the most significant effect on the hydraulic performance of solid-liquid two-phase flow pumps, and the diameter of solid-phase particles has the most minor effect. With the increase of particle diameter and solid-phase concentration, head and efficiency are gradually reduced. In contrast, with the increase of solid-phase density, head and efficiency show a trend of increasing and then decreasing. The most severe decrease in hydraulic performance occurs at a C v of 30%, where the head decreases to 20.19m, and the efficiency decreases to 66.90%. With the increase of the three typical solid-phase properties, the abrasion in the overflow inner wall surface of the solid-liquid two-phase flow centrifugal pump shows different degrees of deterioration, and the maximum degree of wear of about 0.0010kg/m 2 s.
Centrifugal pumps are widely used in the metallurgy, coal, and building sectors.In order to study the hydraulic characteristics of a closed impeller centrifugal pump during its shutdown in the so-called power frequency and frequency conversion modes, experiments were carried to determine the characteristic evolution of parameters such as speed, inlet and outlet pressure, head, flow rate and shaft power.A quasi-steady-state method was also used to further investigate these transient behaviors.The results show that, compared to the power frequency input, the performance parameter curves for the frequency conversion input are less volatile and smoother.The characteristic time is longer and the response to shutdown is slower.The quasi-steady-state theoretical head-flow curves match the experimental head-flow curves more closely at low flow rates when the frequency conversion input is considered.Moreover, in this case, the similarity law predicts the hydraulic performance more accurately.
Staphylococcus aureus (S. aureus), commonly known as “superbugs”, is a highly pathogenic bacterium that poses a serious threat to human health. There is an urgent need to replace traditional antibiotics with novel drugs to combat S. aureus. Sortase A (SrtA) is a crucial transpeptidase involved in the adhesion process of S. aureus. The reduction in virulence and prevention of S. aureus infections have made it a significant target for antimicrobial drugs. In this study, we combined virtual screening with experimental validation to identify potential drug candidates from a drug library. Three hits, referred to as Naldemedine, Telmisartan, and Azilsartan, were identified based on docking binding energy and the ratio of occupied functional sites of SrtA. The stability analysis manifests that Naldemedine and Telmisartan have a higher binding affinity to the hydrophobic pockets. Specifically, Telmisartan forms stable hydrogen bonds with SrtA, resulting in the highest binding energy. Our experiments prove that the efficiency of adhesion and invasion by S. aureus can be decreased without significantly affecting bacterial growth. Our work identifies Telmisartan as the most promising candidate for inhibiting SrtA, which can help combat S. aureus infection.
This bioinformatics report attempts to explore the cross-talk genes, transcription factors (TFs), and pathways related to myocardial ischemia-reperfusion injury (MIRI) as well as the gut microbiome.The datasets GSE61592 (three MIRI and three sham samples) and GSE160516 (twelve MIRI and four sham samples) were selected in the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) identification (p < 0.05 and |log FC (fold change)| ≥1) together with functional annotation (p < 0.05) was implemented. The Cytoscape platform established the protein-protein interaction (PPI) network. Genes associated with gut microbiome disorder were extracted based on the DisGeNET database, and those associated with MIRI were overlapped. The Recursive Feature Elimination (RFE) algorithm was adopted for selecting features, and cross-talk genes were predicted by the Support Vector Machine (SVM) models. A network encompassing cross-talk genes along with the TFs was thereby established.The MIRI datasets comprised 138 shared DEGs, with 101 showing up-regulation whereas 37 showing down-regulation. Notably, the PPI interwork for MIRI contained 2517 edges along with 1818 nodes. By using RFE and SVM methods, six feature genes with the highest prediction were identified: B2m, VCAM-1, PDIA4, Ptgds, Mlxipl, and ACADS. Among these genes, B2m and PDIA4 were most highly expressed in MIRI and the gut microbiome disorder.B2m and PDIA4 were identified to be significantly correlated with candidate cross-talk genes of MIRI with gut microbiome disorder, implying a similarity between MIRI and Gut microbiome disorder (GMD). These genes can serve as an experimental research basis for future studies.
Abstract To study the effect of the width-to-narrow ratio on the forward and reverse flow characteristics of the Tesla valve, five different models of the Tesla valve with different width-to-narrow ratios are established in this paper. The numerical calculations of forward and reverse flow under different working conditions are carried out by the CFD method in the laminar flow regime, and the reliability of the numerical calculation method is verified by comparing it with the experimental results. The results show that: in forward flow, the main flow-through channel is not related to the width-to-narrow ratio, the flow rate of the straight channel increases with the increase of the width-to-narrow ratio, and the static pressure in the diversion section is in the shape of “∞”; while in reverse flow, the main flow-through channel is weakly related to the width-to-narrow ratio, the flow rate of the arc channel is not increased with the increase of the width-to-narrow ratio, and the static pressure in the diversion section is in the shape of “bench”. As the width-to-narrow ratio decreases, the pressure drop during forward and reverse flow becomes more significant.
To investigate the influence of the flow channel’s width-to-narrow ratio on the Tesla valve’s flow characteristics, this paper establishes five Tesla valve models with different width-to-narrow ratios. Employing the laminar flow model, CFD methods were used to numerically simulate both the forward and reverse flows through the Tesla valve across a spectrum of width-to-narrow ratios, ranging from 0.2 to 1. The results reveal the flow trends in the straight or arc channels show opposite variation patterns when flowing in forward and reverse directions. The flow rate passing through straight channel is more sensitive to the response of a small width-to-narrow ratio. Irrespective of the flow direction, as the width-to-narrow ratio increases, the fluid flow within the valve demonstrates increasingly pronounced stratification. The pressure curve of the diversion section assumes an “∞” shape in forward flow, whereas in reverse flow, it assumes a “flat plate” shape.
Tesla valves are widely used in the field of fluid control. To study the hydraulic performance of straight-through Tesla valves in forward and reverse flow, 16 straight-through Tesla valves with diverse blade parameters were designed in this paper, and hydraulic loss tests were carried out in forward and reverse flow under different working conditions. The results show that the hydraulic loss increases with the increasing working flow rate in forward and reverse flow; at the identical flow rate, the reverse loss is higher than the forward loss. Both the hydraulic loss through the valve and the unidirectional conductivity of the valve increase with increasing blade length, pitch, and number of blades, but too long of a length results in weakened unidirectional conductivity. The hydraulic loss increases with the increase of blade angle, and the unidirectional conductivity decreases with the increase of blade angle. When the blades are arranged in perfect symmetry, the hydraulic loss through the valve is maximum, and the valve has the best unidirectional conductivity.
Left- and right-handed chiral molecule inducers have been frequently used to guide the formation of chiral nanomaterials with binary chiral shapes. However, the transition of chiral nanomaterials from discrete to continuously tunable chiral shapes is imperative but challenging and will contribute to a deep understanding of the fundamental relations between chiral nanostructures and their chemical properties. This study shows that chiral polyaniline nanohelices (PANI NHs) with similar aspect ratios (∼5.0) but continuously tunable screw pitches (293 to ∞ nm) and tilt angles (33° to 0°) can be fabricated by adjusting the enantiomer excess of
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