Lattice Strain and Mott-Schottky Effect of the Charge-Asymmetry Pd1Fe Single-Atom Alloy Catalyst for Semi-Hydrogenation of Alkynes with High Efficiency.

The ideal interface design between the metal and substrate is crucial in determining the overall performance of the alkyne semihydrogenation reaction. Single-atom alloys (SAAs) with isolated dispersed active centers are ideal media for the study of reaction effects. Herein, a charge-asymmetry "armor" SAA (named Pd1Fe SAA@PC), which consists of a Pd1Fe alloy core and a semiconducting P-doped C (PC) shell, is rationally designed as an ideal catalyst for the selective hydrogenation of alkynes with high efficiency. Multiple spectroscopic analyses and density functional theory calculations have demonstrated that Pd1Fe SAA@PC is dual-regulated by lattice tensile and Schottky effects, which govern the selectivity and activity of hydrogenation, respectively. (1) The PC shell layer applied an external traction force causing a 1.2% tensile strain inside the Pd1Fe alloy to increase the reaction selectivity. (2) P doping into the C-shell layer realized a transition from a p-type semiconductor to an n-type semiconductor, thereby forming a unique Schottky junction for advancing alkyne semihydrogenation activity. The dual regulation of lattice strain and the Schottky effect ensures the excellent performance of Pd1Fe SAA@PC in the semihydrogenation reaction of phenylethylene, achieving a conversion rate of 99.9% and a selectivity of 98.9% at 4 min. These well-defined interface modulation strategies offer a practical approach for the rational design and performance optimization of semihydrogenation catalysts.

BINOL-Based Chiral Macrocycles and Cages.

Chirality, a fundamental principle in chemistry, biology, and medicine, is prevalent in nature and in organisms. Chiral molecules, such as DNA, RNA, and proteins, are crucial in biomolecular synthesis, as well as in the development of functional materials. Among these, 1,1'-binaphthyl-2,2'-diol (BINOL) stands out for its stable chiral configuration, versatile functionality, and commercial availability. BINOL is widely employed in asymmetric catalysis and chiral materials. This review mainly focuses on recent research over the past five years concerning the use of BINOL derivatives for constructing chiral macrocycles and cages. Their contributions to chiral luminescence, enantiomeric separation, transmembrane transport, and asymmetric catalysis were examined.

Ancient mitochondrial genome depicts sheep maternal dispersal and migration in Eastern Asia.

Sheep have been one of the most important groups of animals since ancient times. However, the knowledge of their migration routes and genetic relationships is still poorly understood. To investigate sheep maternal migration histories alongside Eurasian communications routes, in this study, we obtain mitochondrial genomes (mitogenomes) from 17 sheep remains in 6 Chinese sites and 1 Uzbekistan site dated 4429-3100 years before present (BP). By obtaining the mitogenomes from the sheep (4429-3556 BP) found in the Tongtian Cave site in Xinjiang, Altai region of northwest China, our results support the emergence of haplogroup C sheep in Xinjiang as early as 4429-3556 BP. The combined phylogenetic analyses with extant ancient and modern sheep mitogenomes suggest that the Uzbekistan-Altai region may have been a migration hub for early sheep in eastern Asia. At least two migration events have taken place for sheep crossing Eurasia to China, one passing by Uzbekistan and Northwest China to the middle and lower reaches of the Yellow River at approximately 4000 BP and another following the Altai region to middle Inner Mongolia from 4429 BP to 2500 BP. Overall, this study provides further evidence for early sheep utilization and migration patterns in Eastern Asia.

Association analysis of mitochondrial genome polymorphisms with backfat thickness in pigs.

Mitochondrial DNA (mtDNA) variations and associated effects on economic traits have been widely reported in farm animals, as these genetic polymorphisms can affect the efficiency of energy production and cell metabolism. In studies related to metabolism, the deposition of fat was highly correlated with mitochondria. However, the effect of mtDNA polymorphisms on porcine backfat thickness (BFT) remained unclear. In this study, 243 pigs were collected to analyse the relationship between BFT and mtDNA polymorphisms. There were considerable differences in BFT, ranging from 5 mm to 18 mm. MtDNA D-loop sequencing discovered 48 polymorphic sites. Association analysis revealed that 30 variations were associated with BFT (P < 0.05). The polymorphism m.794A > G showed the maximum difference in BFT between A and G carriers, which differed at ∼2.5 mm (P < 0.001). The 48 polymorphic sites generated 22 haplotypes (H1-H22), which clustered into 4 haplogroups (HG1-HG4). HG1 had a lower BFT value than other three haplogroups (P < 0.01), whereas H4 in HG1 exhibited the lowest BFT of all haplotypes analyzed (P < 0.01). The results of this study highlight an association between mtDNA polymorphisms and BFT, and suggest the potential application of mtDNA in pig molecular breeding practices.

Enhancing Photocatalytic-Transfer Semi-Hydrogenation of Alkynes Over Pd/C3 N4 Through Dual Regulation of Nitrogen Defects and the Mott-Schottky Effect.

The selective hydrogenation of alkynes is an important reaction; however, the catalytic activity and selectivity in this reaction are generally conflicting. In this study, ultrafine Pd nanoparticles (NPs) loaded on a graphite-like C3 N4 structure with nitrogen defects (Pd/DCN) are synthesized. The resulting Pd/DCN exhibits excellent photocatalytic performance in the transfer hydrogenation of alkynes with ammonia borane. The reaction rate and selectivity of Pd/DCN are superior to those of Pd/BCN (bulk C3 N4 without nitrogen defects) under visible-light irradiation. The characterization results and density functional theory calculations show that the Mott-Schottky effect in Pd/DCN can change the electronic density of the Pd NPs, and thus enhances the hydrogenation selectivity toward phenylacetylene. After 1 h, the hydrogenation selectivity of Pd/DCN reaches 95%, surpassing that of Pd/BCN (83%). Meanwhile, nitrogen defects in the supports improve the visible-light response and accelerate the transfer and separation of photogenerated charges to enhance the catalytic activity of Pd/DCN. Therefore, Pd/DCN exhibits higher efficiency under visible light, with a turnover frequency (TOF) of 2002 min-1 . This TOF is five times that of Pd/DCN under dark conditions and 1.5 times that of Pd/BCN. This study provides new insights into the rational design of high-performance photocatalytic transfer hydrogenation catalysts.

A Retrospective Study to Evaluate the Role of Dynamic Fracture Mobility in the Conservative Treatment of Osteoporotic Vertebral Compression Fractures.

OBJECTIVE: To investigate whether dynamic fracture mobility could affect the outcome of conservative treatment in patients with acute osteoporotic vertebral compression fracture (OVCF). METHODS: A total of 158 patients who underwent conservative treatment in our hospital for painful OVCFs were included in this study and their data were retrospectively analyzed. According to the degree of pain relief, patients were divided into an excellent efficacy group and a poor efficacy group. Factors that may affect the outcome of conservative treatment were recorded for each patient. Variables with a statistical difference between the 2 groups were entered into multivariate logistic regression analysis to identify the factors influencing the outcome of conservative treatment. Receiver operating characteristic curve analysis was also performed. RESULTS: The result showed that dynamic fracture mobility, overweight, age, and bone mineral density (BMD) (all P < 0.001) were independent factors influencing the outcome of conservative treatment. Receiver operating characteristic curve analysis showed that the cutoff values for age and BMD that predicted treatment effect were 72.5 years and -3.30, respectively. CONCLUSIONS: This study confirmed that dynamic fracture mobility could be used as an independent factor predicting the outcome of conservative treatment in patients with acute OVCFs. It was also shown that overweight, age, and BMD were other independent factors influencing the outcome of conservative treatment. A comprehensive evaluation of these related factors can guide the doctor to take appropriate treatment for a unique acute OCVF.

The Value of Dynamic Fracture Mobility in Determining the Optimum Operation Choice for Acute Osteoporotic Vertebral Compression Fracture.

Purpose: This retrospective study aimed to verify whether the use of a balloon in balloon kyphoplasty (BKP) could offer a higher degree of vertebral height restoration and deformity correction than percutaneous vertebroplasty (PVP) after adjustment for preoperative dynamic fracture mobility. We expect that this research will help surgeons to determine the optimum operation choice (PVP or BKP) for treating osteoporotic vertebral compression fractures (OVCFs). Patients and Methods: We evaluated retrospectively 262 patients who were treated by PVP or BKP for acute, single-level OVCF at our institution from July 2015 to July 2019. According to the presence or absence of dynamic fracture mobility, the patients were divided into two groups: mobile group and fixed group. We compared the changes in the vertebral height and kyphotic angle for PVP and BKP, respectively, within each group. Results: In the mobile group, the anterior vertebral height restoration (BKP group, 8.73±5.27%; PVP group, 2.96±1.59%), middle vertebral height restoration (BKP group, 7.58±5.18%; PVP group, 2.74±1.24%) and kyphotic angle correction (BKP group, 4.41±4.46°; PVP group, 1.38±1.60°) due to percutaneous vertebral augmentation technique itself were more obvious in BKP group compared with PVP group (P < 0.05). The BKP group has lower incidence of bone cement leakage (BKP group, 10.17%; PVP group, 25.53%, P < 0.05). In the fixed group, differences from comparison of changes were not statistically significant between PVP and BKP (P > 0.05). Conclusion: The use of a balloon in BKP could offer greater kyphosis correction, higher vertebral body height restoration, and lower cement leakage rate than PVP if a fractured vertebral body existed dynamic mobility. However, all these advantages of BKP over PVP are not obvious and could be overrated for a fixed fracture exhibited no mobility. BKP is recommended for a fractured vertebral body with dynamic mobility. PVP is suggested for a fixed fractured vertebral body with no mobility as it produces similar capability of vertebral height restoration, kyphosis correction, and cement leakage as BKP.

A Retrospective Study to Evaluate the Effect of Dynamic Fracture Mobility on Cement Leakage in Percutaneous Vertebroplasty and Percutaneous Kyphoplasty in 286 Patients with Osteoporotic Vertebral Compression Fractures.

BACKGROUND Cement leakage is the most common complication following percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fractures (OVCFs). Dynamic fracture mobility was determined by comparing preoperative standing lateral radiographs with intraoperative prone lateral radiographs. This retrospective study from a single center aimed to evaluate the effect of dynamic fracture mobility on cement leakage in PVP and PKP in 286 patients with OVCFs. MATERIAL AND METHODS Records of patients who underwent PVP or PKP in our department between January 2016 and December 2019 were retrospectively analyzed, showing that 156 patients received PVP and 130 patients received PKP. Variables that were significantly related to presence of cement leakage in the univariate analysis were subsequently included in a multivariate logistic regression analysis for determining the independent risk factors for cement leakage. RESULTS The univariate analysis showed that dynamic fracture mobility (P<0.001), operative approach (P=0.026), peripheral vertebrae wall damage (P<0.001), intravertebral cleft (P<0.001), and cement volume injected (P<0.001) were correlated with cement leakage. Factors that showed differences by univariate analysis underwent multivariate logistic regression analysis, showing that peripheral vertebrae wall damage (OR=11.774,95% CI 4.384-31.619, P=0.000), dynamic fracture mobility (OR=5.884, 95% CI 2.295-15.087, P=0.000), operative approach (OR=3.143, 95% CI 1.136-8.698, P=0.027), and cement volume injected (OR=1.486, 95% CI 1.119-1.973, P=0.006) were independent risk factors for postoperative cement leakage. CONCLUSIONS This retrospective study showed that dynamic fracture mobility, peripheral vertebrae wall damage, operative approach, and cement volume injected were risk factors for cement leak following PVP and PKP.

Flexion Tibial Plateau Fractures: 3-dimensional CT Simulation-based Subclassification by Injury Pattern.

OBJECTIVE: To identify different injury patterns of flexion tibial plateau fractures (FTPFs) with 3D CT simulation technology. The association between these hypothesized injury patterns and concomitant injuries was also investigated. METHODS: The tibial plateau fracture cases of 297 patients consecutively treated at our trauma center from August 2016 to December 2018 were reviewed retrospectively. A total of 108 patients with FTPFs were enrolled. 3D CT simulation technology was used to reconstruct the position of the knee joint at the time of tibial plateau fracture. The 3D segments for the tibia and femur were created separately, the tibial 3D segment was aligned with the articular surface of the femoral condyle, and then the corresponding injury patterns were deduced. The magnitudes of translation and rotation incurred after the segments were repositioned were calculated by Mimics software. The associations between the hypothesized injury patterns and concomitant injuries were compared. RESULTS: FTPFs were classified into two groups according to the fracture region: unicondylar FTPFs (type I) and bicondylar FTPFs (type II). According to the injury patterns simulated in this study, these two types of FTPFs were further subclassified into five subgroups. Type I FTPFs were categorized into two subtypes based on the degree of rotation in the coronal plane (varus < 0°; valgus > 0°): pure flexion-varus fractures (type IA, -10.23° ± 2.11°, 3.7%, 4/108) and pure flexion-valgus fractures (type IB, 11.54° ± 2.63°, 26.9%, 29/108). Type II FTPFs were divided into three subgroups based on the degree of rotation in the axial plane (internal rotation >10°; flexion-neutral -10° to 10°; external rotation <-10°): flexion-neutral fractures (type IIA, 2.01° ± 3.43°, 13.0%, 14/108), flexion-internal rotation fractures (type IIB, 23.66° ± 6.17°, 35.2%, 38/108) and flexion-external rotation fractures (type IIC, -16.23° ± 4.27°, 21.3%, 23/108). The incidence of posterolateral quadrant collapse fractures among type IIB fractures was significantly increased relative to that of type IIC fractures (P < 0.001). The incidence of posterolateral quadrant split fractures, anterolateral quadrant fractures and proximal fibular fractures among type IIC fractures was significantly higher than that among type IIB fractures (P < 0.001). The number of these concomitant injuries significantly differed between type IIB and type IIC fractures (P < 0.001). CONCLUSION: 3D CT simulation-based subclassification according to the pattern of injury can help surgeons better understand FTPFs and select an appropriate treatment strategy.

Different patterns of tibial plateau fractures associated with hyperextension injuries of the knee with or without varus/valgus component.

ABSTRACT: This study aims to introduce a morphological classification of hyperextension tibial plateau fractures based on CT scans and to reveal the correlation between the anterior compression and posterior tension fractures.From January 2015 to January 2019, 37 patients with hyperextension tibial plateau fractures were studied retrospectively. Based on this classification, the fractures were divided into 2 groups: group A had anterolateral or anteromedial compression fractures while group B had both. Three observers classified the fractures and recorded the morphology and incidences of posterior plateau fractures and proximal fibular fractures.All 37 fractures were allocated to group A (n = 15; 40%) and B (n = 22; 60%). Of the posterior tibial plateau fractures, 10 (27%) fractures were defined as partial and 27 (73%) as total. Of the 37 fractures, 18 (49%) proximal fibular avulsion fractures were observed. There was a significant difference between groups A and B regarding the incidence of total posterior tibial plateau fractures (P < .05). However, there was no significant difference between the incidence of proximal fibular avulsion fractures in the 2 groups or the combined and non-combined type fractures in group B (P > .05).Hyperextension tibial plateau fractures with a decreased posterior slope angle always involve both the anteromedial and anterolateral plateaus. This CT-based classification may improve the understanding of fracture features and is helpful for planning treatment.

Expression and Purification of a PEDV-Neutralizing Antibody and Its Functional Verification.

Porcine epidemic diarrhea virus (PEDV) is a highly infectious and pathogenic virus causing high morbidity and mortality, especially in newborn piglets. There remain problems with contemporary PEDV vaccines, in part because of the rapid variation of PEDV, poor conferred immunity, and numerous side effects. The ability to produce PEDV-neutralizing antibodies suggests that we may be able to increase the success rate of PEDV prevention in piglets using these antibodies. In this study, we produced an anti-PEDV S protein monoclonal antibody (anti-PEDV mAb-2) that neutralized PEDV-CV777 (a G1 strain), PEDV-SDSX16 and PEDV-Aj1102 (two G2 strains). In vivo challenge experiments demonstrated that anti-PEDV mAb-2 inhibited the PEDV infection in piglets. We also produced three HEK293 cell lines that expressed anti-PEDV mAb-2. Overall, our study showed that anti-PEDV mAb-2 produced from hybridoma supernatants effectively inhibited PEDV infection in piglets, and the recombinant HEK293 cell lines expressed anti-PEDV mAb-2 genes.

Injury pattern simulation and mapping of complex tibial plateau fractures that involve the posterior plateau with three-dimensional computed tomography.

BACKGROUND: Tibial plateau fractures involving the posterior plateau (TPFIPs) are complex intra-articular fractures that are difficult to stabilize. Understanding the characteristics of these fractures together with the injury pattern is beneficial for surgeons to choose an optimal treatment strategy. However, the complicated morphology and injury patterns of TPFIPs are poorly characterized. The purpose of this retrospective study was to investigate the injury patterns and fracture characteristics of complex TPFs by applying three-dimensional (3D) simulation and fracture mapping methods. METHODS: In total, 171 TPFIPs were retrospectively reviewed, and the injury pattern was simulated and analyzed by applying a 3D method with Mimics software, which allowed matching of the fractured articular surfaces of the tibial plateau to the femoral condyle surface. The major articular fracture lines were mapped and then superimposed on a template. The tibial motion angle after fracture injury pattern simulation and the major fracture line angle were quantitatively analyzed, while the injury patterns and fracture characteristics were qualitatively analyzed. RESULTS: Four main injury patterns with distinctive fracture characteristics were observed in this study. In total, 72 TPFs exhibited extension as the pattern of injury with a split posterolateral fragment, and 61 fractures exhibited the flexion-internal rotation injury pattern; compression was the main feature of posterolateral fractures. Furthermore, 21 fractures exhibited the flexion-external rotation injury pattern, with a small posteromedial fragment, and 17 fractures exhibited the flexion-neutral injury pattern, with both parts of the posterior plateau fracture and anterior dislocation being observable. The major articular fracture line angles were significantly different between the four main injury patterns (85.92°, 46.79°, 148.26°, and 16.21°, median values, P<0.05). Two injury patterns, namely, flexion-internal rotation and flexion-external rotation, exhibited rotation in the axial plane (24.13°±8.33°, -15.13°±5.14°, P<0.05). CONCLUSIONS: In this study, a method involving a simulated injury pattern was developed and combined with evaluations of fracture characteristics, including two-dimensional (2D) and 3D analyses, to comprehensively describe both the morphologies and injury patterns of TPFIPs.

Analysis of medial tibial plateau fracture injury patterns using quantitative 3D measurements.

BACKGROUND: The Wahlquist system classifies tibial medial plateau fractures into three types based on the sagittal fracture line location, with type C at highest risk of complications. However, the injury mechanism of tibial medial plateau fractures, especially tibial rotation movement, remains unclear. The purpose of the present study was to determine the injury patterns of medial tibial plateau fractures using 3D model simulation and quantitative 3D measurements. METHODS: Seventy-eight consecutive AO/OTA type 41-B tibial plateau fractures were retrospectively analyzed using CT-based 3D models and quantitative 3D measurements. The knee posture at the moment of fracture occurrence was simulated, and various knee angles in the sagittal, coronal, and axial planes were measured to evaluate the mechanism of medial tibial plateau fracture. The mean valgus-varus, hyperextension-flexion, and internal-external rotation angles were determined, and the chi-square test was used for comparisons of categorical varus and valgus force data to determine the main force direction in Wahlquist type C fractures. RESULTS: Angle measurements in the coronal planes showed that 28 (35.9%) medial tibial plateau fractures resulted from a varus injury pattern, while 50 fractures (64.1%) resulted from a valgus pattern. Valgus force produced significantly more Wahlquist type C fractures (37 of 50 fractures) than varus force (2 of 28 fractures) (p < 0.05). There was no significant difference in the cases of patients with type C fractures between the tibial internal and external rotation injury patterns(P > 0.05). CONCLUSIONS: Valgus force was the cause of 64.1% of the medial tibia plateau fractures in the present cohort. Furthermore, valgus force produced more Wahlquist type C fractures than varus force. The present findings will help orthopedists understand the injury mechanism of the Wahlquist classification system, and will facilitate the identification of the common features of medial tibial plateau fractures induced by specific injury patterns.

Serum soluble VSIG4 as a surrogate marker for the diagnosis of lymphoma-associated hemophagocytic lymphohistiocytosis.

Lymphoma-associated haemophagocytic lymphohistiocytosis (L-HLH) is characterized by excessively activated macrophages and cytotoxic T lymphocytes, but few reliable markers for activated macrophages are available clinically. This study, designed to discover novel biomarkers for the diagnosis of lymphoma patients with L-HLH, was initiated between 2016 and 2018. Fifty-seven adult lymphoma patients were enrolled - 39 without HLH and 18 with HLH. The differential serum protein expression profile was first screened between lymphoma patients with and without L-HLH by a quantitative mass spectrometric approach. Soluble V-set and immunoglobulin domain-containing 4 (sVSIG4), specifically expressed by macrophages, was significantly upregulated in the L-HLH group. Subsequently, sVSIG4 concentration was confirmed by enzyme-linked immunosorbent assay to be significantly increased in lymphoma patients with L-HLH. When it was exploited for the diagnosis of lymphoma patients with L-HLH, the area under a receiver operating characteristic curve was 0·98 with an optimal cut-off point of 2195 pg/ml and the corresponding sensitivity and specificity were 94·44% and 94·87% respectively. In addition, the one-year overall survival was significantly worse in patients with a sVSIG4 concentration above 2195 pg/ml compared with those below 2195 pg/ml (5·3% vs. 72·2%, P < 0·0001). sVSIG4 may be a surrogate marker of activated macrophages for the diagnosis of lymphoma patients with L-HLH.

[Exploration of the Role of Tumor Suppressor Genes Foxo1 and PTEN in the Tumorigenesis of Mouse Natural Killer-Cell Lymphoma].

OBJECTIVE: To explore whether tumor suppressor gene Foxo1 and PTEN play a critical role in the tumorigenesis of mouse natural killer-cell lymphoma. METHODS: NKp46-iCre mice were crossed with mice carrying floxed Foxo1 alleles (Foxo1fl/fl) as well as floxed PTEN alleles (PTENfl/fl) to generate mice in which Foxo1 and PTEN in NK cells were knock-out, referred as Foxo1△NKPTEN△NK. The growth and development of the mice and tumor formation were observed. The flow cytometry was used to detect the percentages of NK cells in main lymphatic organs. B16F10 metanoma model of tumor metastasis was utilized to investigate NK cell-mediated tumor surveillance in vivo after NK cells special deletion of Foxol and PTEN. RESULTS: The mouse model with NK cell-special Foxo1 and PTEN double knockout was established. Compared with control group (Foxo1fl/flPTENfl/fl mice), Foxo1△NKPTEN△NK mice were born alive and appeared to be healthy over a period of 46 weeks. No spontaneous tumor formation was observed at this stage. There were no significant differences in NK cell percentages of gated lymphocytes from various organs including blood, bone marrow, peripheral lymph node and spleen between Foxo1△NKPTEN△NK mice and Foxo1fl/flPTENfl/fl mice [PB: 4.76%±0.46% vs 4.17%±0.64% (P＞0.05, n=8); BM: 1.13%±0.23% vs 1.31%±0.10% (P＞0.05, n=8) ; LN: 0.50%±0.10% vs 0.85%±0.20% (P＞0.05, n=8); SP: 4.41%±0.65% vs 3.50%±0.24% (P＞0.05, n=8)]. B16F10 melanoma metastasis model of tumor was established, No differences in median survival time were observed in the 2 types of mice (P＞0.05, n=13). CONCLUSION: The simultaneous deletion of the Foxo1 and PTEN genes may not plays significant role in the tumorigenesis of mouse natural killer-cell lymphoma and NK cell-mediated tumor surveillance in vivo.

Layer-by-Layer Heparinization of the Cell Surface by Using Heparin-Binding Peptide Functionalized Human Serum Albumin.

Layer-by-layer heparinization of therapeutic cells prior to transplantation is an effective way to inhibit the instant blood-mediated inflammatory reactions (IBMIRs), which are the major cause of early cell graft loss during post-transplantation. Here, a conjugate of heparin-binding peptide (HBP) and human serum albumin (HSA), HBP-HSA, was synthesized by using heterobifunctional crosslinker. After the first heparin layer was coated on human umbilical vein endothelial cells (HUVECs) by means of the HBP-polyethylene glycol-phospholipid conjugate, HBP-HSA and heparin were then applied to the cell surface sequentially to form multiple layers. The immobilization and retention of heparin were analyzed by confocal microscopy and flow cytometry, respectively, and the cytotoxity of HBP-HSA was further evaluated by cell viability assay. Results indicated that heparin was successfully introduced to the cell surface in a layer-by-layer way and retained for at least 24 h, while the cytotoxity of HBP-HSA was negligible at the working concentration. Accordingly, this conjugate provides a promising method for co-immobilization of heparin and HSA to the cell surface under physiological conditions with improved biocompatibility.

Molecular modeling of exquisitely selective c-Met inhibitors through 3D-QSAR and molecular dynamics simulations.

c-Met has been considered as an attractive target for developing antitumor agents. The highly selective c-Met inhibitors provide invaluable opportunities for the combination with other therapies safely to achieve the optimal efficacy. In this work, a series of triazolopyrazine c-Met inhibitors with exquisitely selectivity were investigated using a combination of molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular dynamics simulation. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models were developed to reveal the structural determinants for c-Met inhibition. Both models were validated to have high reliability and predictability, and contour map analysis suggested feature requirements for different substituents on the scaffold. It is worth noting that an important hydrogen bond rich region was identified in the unique narrow channel, which is distinct from other kinases. Molecular dynamics simulations and binding free energy calculations provided further support that suitable groups in this hydrogen bond rich region made great contributions to the binding of ligands. Moreover, hydrogen bonds with residues of the narrow channel were also indicated to be essential to improve the activity and selectivity. This study will facilitate the discovery and optimization of novel c-Met inhibitors with higher activity and selectivity.