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Pancreatic cancer, one of the most aggressive malignancies, has no effective treatment due to the lack of targets and drugs related to tumour metastasis. SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer. However, highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered. Here, we developed a novel SIRT6 allosteric inhibitor, compound 11e, with maximal inhibitory potency and an IC50 value of 0.98 ± 0.13 μmol/L. Moreover, compound 11e exhibited significant selectivity against other histone deacetylases (HADC1‒11 and SIRT1‒3) at concentrations up to 100 μmol/L. The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses. Importantly, we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis. To our knowledge, this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer. It not only provides a promising lead compound for subsequent inhibitor development targeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.

Objectives: To elucidate the characteristics of a colistin-resistant and hypervirulent Klebsiella quasipneumoniae subsp. similipneumoniae strain (KP8) using whole genome sequencing and various phenotypic assays. Methods: Antimicrobial susceptibility testing was performed using broth microdilution. Whole genome sequencing and comparative genomics were utilised to elucidate genomic characteristics. Phenotypic assays to evaluate virulence factors included measurements of mucosal viscosity, biofilm production, siderophore production, infection of A549 cells, serum-killing assays, and Galleria mellonella infection models. Results: Whole-genome sequencing revealed that the strain (KP8) belongs to sequence type 367 (ST367) and capsular type 1 (KL1), and it harbours several virulence genes, including regulator of mucoid phenotype (rmpA/A2), salmochelin (iroBCDN) and aerobactin (iucABCDiutA). Antibiotic susceptibility tests showed that KP8 was resistant to colistin. Genome analysis showed that the colistin resistance of KP8 might be related to amino acid insertions in pmrB (L215_D217, insL) and pagP (M1_S3, insV). Importantly, KP8 demonstrated comparable mucosal viscosity, biofilm production capacity, siderophore production levels to hvKP. Serum-killing experiments, A549 cell infection models, and G. mellonella infection models further indicated that KP8 displayed high virulence, akin to the hypervirulent strain NUTH-K2044. Notably, global genome analysis of the K. quasipneumoniae subsp. similipneumoniae strains highlighted that the ST367 lineage has a higher tendency to carry virulence-associated genes compared to other sequence types. The prevalence of virulence-associated factors concentrated within Chinese ST367 isolates reinforces this observation. Conclusion: These findings further enhance our understanding of the resistance and pathogenicity of ST367 K. quasipneumoniae subsp. similipneumoniae strain and also providing a broader perspective on the global epidemiological landscape.

Abstract Background Increasing evidence has indicated that long non-coding RNAs (lncRNAs) have been proven to regulate esophageal cancer progression. The lncRNA protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P1) has been shown to promote cancer stem cell properties; however, its mechanism of action remains unclear. In this study, we investigated the regulation of esophageal cancer stem cell properties by the interaction of PDIA3P1 with proteins. Methods The GEPIA2 and Gene Expression Omnibus databases were used to analyze gene expression. PDIA3P1 expression in human esophageal squamous cell carcinoma (ESCC) tissues and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Loss-of-function experiments were performed to determine the effects of PDIA3P1 on ESCC cell proliferation, migration, and invasion. The sphere formation assay, number of side population cells, and CD271 + /CD44 + cells were detected by flow cytometry to identify the cancer stem cell properties. RNA immunoprecipitation (RIP), RNA pull-down, co-immunoprecipitation (co-IP), dual luciferase reporter, and cleavage under targets and tagmentation (CUT&Tag) assays were performed to elucidate the underlying molecular mechanisms. Results PDIA3P1 expression was upregulated in ESCC cell lines and tissues. Functionally, higher PDIA3P1 expression promoted cell proliferation, invasion, and metastasis and inhibited apoptosis in esophageal cancer. Importantly, PDIA3P1 promoted cancer stem cell properties in ESCC. Mechanistically, PDIA3P1 interacted with and stabilized octamer-binding transcription factor 4 (OCT4) by eliminating its ubiquitination by the ubiquitinating enzyme WW domain-containing protein 2 (WWP2). Moreover, as a transcription factor, OCT4 bound to the PDIA3P1 promoter and promoted its transcription. Conclusions Our research revealed a novel mechanism by which a positive feedback loop exists between PDIA3P1 and OCT4. It also demonstrated that the PDIA3P1-WWP2-OCT4 loop is beneficial for promoting the cancer stem cell properties of ESCC. Owing to this regulatory relationship, the PDIA3P1-WWP2-OCT4-positive feedback loop might be used in the diagnosis and prognosis, as well as in the development of novel therapeutics for esophageal cancer.

Abstract Coagulation factor 2 thrombin receptor (F2R), a member of the G protein-coupled receptor family, plays an important role in regulating blood clotting through protein hydrolytic cleavage mediated receptor activation. However, the underlying biological mechanisms by which F2R affects the development of gastric adenocarcinoma are not fully understood. This study aimed to systematically analyze the role of F2R in gastric adenocarcinoma. Stomach adenocarcinoma (STAD)-related gene microarray data and corresponding clinicopathological information were downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differential expression genes (DEGs) associated with F2R were analyzed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), and protein–protein interaction (PPI) networks. F2R mRNA expression data were utilized to estimate stromal cell and immune cell scores in gastric cancer tissue samples, including stromal score, immune score, and ESTIMATE score, derived from single-sample enrichment studies. Analysis of TCGA and GEO databases revealed significantly higher F2R expression in STAD tissues compared to normal tissues. Patients with high F2R expression had shorter survival times than those with low F2R expression. F2R expression was significantly correlated with tumor (T) stage, node (N) stage, histological grade and pathological stage. Enrichment analysis of F2R-related genes showed that GO terms were mainly related to circulation-mediated human immune response, immunoglobulin, cell recognition and phagocytosis. KEGG analysis indicated associations to extracellular matrix (ECM) receptor interactions, neuroactive ligand-receptor interactions, the phosphoinositide-3-kinase-protein kinase B/Akt (PI3K-AKT) signaling pathway, the Wnt signaling pathway and the transforming growth factor-beta (TGF-β) signaling pathway. GSEA revealed connections to DNA replication, the Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway and oxidative phosphorylation. Drug sensitivity analysis demonstrated positive correlations between F2R and several drugs, including BEZ235, CGP-60474, Dasatinib, HG-6-64-1, Aazopanib, Rapamycin, Sunitinib and TGX221, while negative correlation with CP724714, FH535, GSK1904529A, JNK-9L, LY317615, pyrimidine, rTRAIL and Vinorelbine. Knocking down F2R in GC cell lines resulted in slowed proliferation, migration, and invasion. All statistical analyses were performed using R software (version 4.2.1) and GraphPad Prism 9.0. p

Background: The bone repair requires the bone scaffolds to meet various mechanical and biological requirements, which makes the design of bone scaffolds a challenging problem. Novel triply periodic minimal surface (TPMS)-based bone scaffolds were designed in this study to improve the mechanical and biological performances simultaneously.Methods: The novel bone scaffolds were designed by adding optimization-guided multi-functional pores to the original scaffolds, and finite element (FE) method was used to evaluate the performances of the novel scaffolds. In addition, the novel scaffolds were fabricated by additive manufacturing (AM) and mechanical experiments were performed to evaluate the performances.Results: The FE results demonstrated the improvement in performance: the elastic modulus reduced from 5.01 GPa (original scaffold) to 2.30 GPa (novel designed scaffold), resulting in lower stress shielding; the permeability increased from 8.58 × 10−9 m2 (original scaffold) to 5.14 × 10−8 m2 (novel designed scaffold), resulting in higher mass transport capacity.Conclusion: In summary, the novel TPMS scaffolds with multi-functional pores simultaneously improve the mechanical and biological performances, making them ideal candidates for bone repair. Furthermore, the novel scaffolds expanded the design domain of TPMS-based bone scaffolds, providing a promising new method for the design of high-performance bone scaffolds.

The performance and phase-separated microstructures of epoxy asphalt binders greatly depend on the concentration of epoxy resin or bitumen. In this paper, the effect of the epoxy resin (ER) concentration (10–90%) on the viscosity, thermo-mechanical properties, and phase-separated morphology of warm-mix epoxy asphalt binders (WEABs) was investigated using the Brookfield rotational viscometer, differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA) and laser scanning confocal microscopy (LSCM). Due to the high reactivity of epoxy resin, the viscosity of WEABs increases with time. Furthermore, the initial viscosity of WEABs decreases with the ER concentration. Depending on the ER concentration, the viscosity–time behavior of WEABs is divided into three stages: slow (10–40%), fast (50–80%), and extremely slow (90%). In the slow stage, the viscosity slightly increases with the ER concentration, while the fast stage shows an opposite trend. DSC and DMA results reveal that WEABs with 10–80% ER exhibit two glass transition temperatures (Tgs) for cured epoxy resin and bitumen. Moreover, the Tgs of epoxy resin and bitumen increase with the ER concentration. However, WEAB with 90 % ER has only one Tg. LSCM observation shows that phase separation occurs in all WEABs. For WEABs containing 10–40% ER, spherical epoxy particles act as the discontinuous phase and disperse in the continuous bitumen phase. However, in WEABs with 50–90% ER, phase inversion takes place. Contrarily, bitumen particles disperse in the continuous epoxy phase. The damping properties of WEABs with the continuous epoxy phases increase with the ER concentration, while the crosslinking density shows an opposite trend. The occurrence of phase inversion results in a sharp increase in the tensile strength of WEABs. For WEABs with the continuous epoxy phases, the elongation at break increases with the ER concentration. The toughness first increases and then decreases with the ER concentration. A maximum toughness value shows at 70% ER.

Waterborne polyurethane asphalt emulsion (WPUA) is an environmentally friendly bituminous material, whose performance is highly dependent on the phase structure of the continuous phase. In this paper, WPUAs in the vicinity of phase inversion were prepared using waterborne polyurethane (WPU) and asphalt emulsion. The chemical structures, thermal stability, dynamic mechanical properties, phase-separated morphology and mechanical performance of WPUAs were studied. Fourier-transform infrared (FTIR) spectra revealed that there are no –NCO bonds in either the pure WPU or WPUAs. Moreover, the preparation of WPUA is a physical process. The addition of WPU weakens the thermal stability of asphalt emulsion. WPU improves the storage modulus of asphalt emulsion at lower and higher temperatures. The glass transition temperatures of the WPUA films are higher than that of the pure WPU film. When the WPU concentration increases from 30 wt% to 40 wt%, phase inversion occurs; that is, the continuous phase shifts from asphalt to WPU. The WPUA films have lower tensile strength and toughness than the pure WPU film. However, the elongations at break of the WPUA films are higher than that of the pure WPU film. Both the tensile strength and toughness of the WPUA films increase with the WPU concentration. Due to the occurrence of phase inversion, the elongation at break, tensile strength and toughness of the WPUA film containing 30 wt% WPU are increased by 29%, 250% and 369%, respectively, compared to the film with 40 wt% WPU.

Abstract Cancer cells consistently utilize the unfolded protein response (UPR) to encounter the abnormal endoplasmic reticulum (ER) stress induced by the accumulation of misfolded proteins. Extreme activation of the UPR could also provoke maladaptive cell death. Previous reports have shown that NRF2 antioxidant signaling is activated by UPR and serves as noncanonical pathway to defense and reduce excessive ROS levels during ER stress. However, the mechanisms of regulating NRF2 signaling upon ER stress in glioblastoma have not been fully elucidated. Here we identify that SMURF1 protects against ER stress and facilitates glioblastoma cell survival by rewiring KEAP1-NRF2 pathway. We show that ER stress induces SMURF1 degradation. Knockdown of SMURF1 upregulates IRE1 and PERK signaling in the UPR pathway and prevents ER-associated protein degradation (ERAD) activity, leading to cell apoptosis. Importantly, SMURF1 overexpression activates NRF2 signaling to reduce ROS levels and alleviate UPR-mediated cell death. Mechanistically, SMURF1 interacts with and ubiquitinates KEAP1 for its degradation (NRF2 negative regulator), resulting in NRF2 nuclear import. Moreover, SMURF1 loss reduces glioblastoma cell proliferation and growth in subcutaneously implanted nude mice xenografts. Taken together, SMURF1 rewires KEAP1-NRF2 pathway to confer resistance to ER stress inducers and protect glioblastoma cell survival. ER stress and SMURF1 modulation may provide promising therapeutic targets for the treatment of glioblastoma.

Articular cartilage is critical for knee joint motion as a connective tissue to disperse loads and resist high-stress loadings. However, due to the lack of vascular, neural, and lymphatic tissues, the self-repair capacity of cartilage is fairly poor. Traditional clinical therapies including palliative and surgical treatments, have improved pain relief and defect filling, yet limitations such as immune rejection and fibrocartilage formation still exist. Therefore, it is a key concern to develop new approaches and materials for cartilage repair. Physically crosslinked polyvinyl alcohol (PVA) hydrogels possessing viscoelastic properties and excellent biocompatibility have become promising candidate materials for cartilage repair. Nevertheless, great improvements can still be made in terms of the mechanical, microstructural, and biological properties of the hydrogels. In this paper, we first summarize the basic properties and preparation methods of PVA hydrogels. Then, in the context of cartilage repair, an overview of recent advances in the improvement of the mechanical properties, structural design, and bioactivity of physically crosslinked PVA hydrogels is presented. Finally, we discuss the challenges and future trends in the development of PVA hydrogels for cartilage and osteochondral repair applications.

Abstract Background Macro-autophagy/Autophagy is an evolutionarily well-conserved recycling process to maintain the balance through precise spatiotemporal regulation. However, the regulatory mechanisms of biomolecular condensates by the key adaptor protein p62 via liquid-liquid phase separation (LLPS) remain obscure. Results In this study, we showed that E3 ligase Smurf1 enhanced Nrf2 activation and promoted autophagy by increasing p62 phase separation capability. Specifically, the Smurf1/p62 interaction improved the formation and material exchange of liquid droplets compared with p62 single puncta. Additionally, Smurf1 promoted the competitive binding of p62 with Keap1 to increase Nrf2 nuclear translocation in p62 Ser349 phosphorylation-dependent manner. Mechanistically, overexpressed Smurf1 increased the activation of mTORC1 (mechanistic target of rapamycin complex 1), in turn leading to p62 Ser349 phosphorylation. Nrf2 activation increased the mRNA levels of Smurf1, p62, and NBR1, further promoting the droplet liquidity to enhance oxidative stress response. Importantly, we showed that Smurf1 maintained cellular homeostasis by promoting cargo degradation through the p62/LC3 autophagic pathway. Conclusions These findings revealed the complex interconnected role among Smurf1, p62/Nrf2/NBR1, and p62/LC3 axis in determining Nrf2 activation and subsequent clearance of condensates through LLPS mechanism.

Among cancers, gastric cancer (GC) ranks third globally in morbidity and mortality, particularly in East Asia. Natriuretic peptide receptor A (NPRA), a receptor for guanylate cyclase, plays important roles in regulating water and sodium balance. Recent studies have suggested that NPRA is involved in tumorigenesis, but its role in GC development remains unclear. Herein, we showed that the expression level of NPRA was positively correlated with gastric tumor size and clinical stage. Patients with high NPRA expression had a lower five-year survival rate than those with low expression, and NPRA was identified as an independent predictor of GC prognosis. NPRA knockdown suppressed GC cell proliferation, migration and invasion. NPRA overexpression enhanced cell malignant behavior. Immunohistochemistry of collected tumor samples showed that tumors with high NPRA expression had higher peroxisome proliferator-activated receptor α (PPARα) levels. In vivo and in vitro studies showed that NPRA promotes fatty acid oxidation and tumor cell metastasis. Co-IP showed that NPRA binds to PPARα and prevents PPARα degradation. PPARα upregulation under NPRA protection activates arnitine palmitoyl transferase 1B (CPT1B) to promote fatty acid oxidation. In this study, new mechanisms by which NPRA promotes the development of GC and new regulatory mechanisms of PPARα were identified.

Abstract Hysteresis loss and relaxation loss are the two dominant heating mechanisms of magnetic nanoparticles (MNPs) in an alternating magnetic field (AMF). In magnetic induction hyperthermia, heating efficiency is one of the crucial factors. It is proposed that the MNPs with a dominant heating mechanism of relaxation loss will exhibit a higher heating efficiency. However, the relative experiments supporting the proposal is still absent due to the difficulty of obtaining the MNPs with the same components and similar morphology but different dominant heating mechanism. Here, the post-processing method of calcination is employed to change the cation distribution of the MNPs (Fe 3 O 4 and Zn 0.54 Co 0.46 Cr 0.6 Fe 1.4 O 4 ), so as to obtain the MNPs with similar morphology but different dominant heating mechanism. The magnetic heating experiments were conducted to examine the heating efficiency. The results suggest that the MNPs with relaxation loss have a higher heating efficiency under the investigated AMF.

Abstract Recurrent Neural Network, Long Short‐Term Memory, and Transformer have made great progress in predicting the trajectories of moving objects. Although the trajectory element with the surrounding scene features has been merged to improve performance, there still exist some problems to be solved. One is that the time series processing models will increase the inference time with the increase of the number of prediction sequences. Another problem is that the features cannot be extracted from the scene's image and point cloud in some situations. Therefore, an Obstacle‐Transformer is proposed to predict trajectory in a constant inference time. An ‘obstacle’ is designed by the surrounding trajectory rather than images or point clouds, making Obstacle‐Transformer more applicable in a wider range of scenarios. Experiments are conducted on ETH and UCY datasets to verify the performance of our model.

Zn0.6Mg0.4CrxFe2−xO4 (0 ≤ x ≤ 0.4) nanoparticles were synthesized using a hydrothermal technique. The obtained magnetic nanoparticles (MNPs) exhibited a spinel structure, where the lattice constant decreased with the Cr3+ ion content. The doping of Cr3+ ion (x = 0.1) increased the specific saturation magnetization to 46.4 emu/g but decreased to 20.0 emu/g with the further increase in the Cr3+ ion content to x = 0.4. The decrement in Curie temperature was ascribed to the weakened super-exchange interaction between the metal ions located at A-sites and B-sites, which arose from the doping of the Cr3+ ion. The T2-weighted images gradually darkened with the increase in Zn0.6Mg0.4Cr0.1Fe1.9O4 nanoparticles concentration, suggesting that the nanoparticles can enhance the image contrast. Zn0.6Mg0.4CrxFe2−xO4 (0 ≤ x ≤ 0.4) nanoparticles were able to heat the agar phantom to the hyperthermia temperature under the safe alternating magnetic field, which showed their potential in the magnetic induction hyperthermia.

Obesity and atherosclerosis are the most prevalent metabolic diseases. ApoE−/− and ob/ob mice are widely used as models to study the pathogenesis of these diseases. However, how gut microbes, gut bacteriophages, and metabolites change in these two disease models is unclear. Here, we used wild-type C57BL/6J (Wt) mice as normal controls to analyze the intestinal archaea, bacteria, bacteriophages, and microbial metabolites of ob/ob and ApoE−/− mice through metagenomics and metabolomics. Analysis of the intestinal archaea showed that the abundances of Methanobrevibacter and Halolamina were significantly increased and decreased, respectively, in the ob/ob group compared with those in the Wt and ApoE−/− groups (p < 0.05). Compared with those of the Wt group, the relative abundances of the bacterial genera Enterorhabdus, Alistipes, Bacteroides, Prevotella, Rikenella, Barnesiella, Porphyromonas, Riemerella, and Bifidobacterium were significantly decreased (p < 0.05) in the ob/ob mice, and the relative abundance of Akkermansia was significantly decreased in the ApoE−/− group. The relative abundances of A. muciniphila and L. murinus were significantly decreased and increased, respectively, in the ob/ob and ApoE−/− groups compared with those of the Wt group (p < 0.05). Lactobacillus_ prophage_ Lj965 and Lactobacillus _ prophage _ Lj771 were significantly more abundant in the ob/ob mice than in the Wt mice. Analysis of the aminoacyl-tRNA biosynthesis metabolic pathway revealed that the enriched compounds of phenylalanine, glutamine, glycine, serine, methionine, valine, alanine, lysine, isoleucine, leucine, threonine, tryptophan, and tyrosine were downregulated in the ApoE−/− mice compared with those of the ob/ob mice. Aminoacyl-tRNA synthetases are considered manifestations of metabolic diseases and are closely associated with obesity, atherosclerosis, and type 2 diabetes. These data offer new insight regarding possible causes of these diseases and provide a foundation for studying the regulation of various food nutrients in metabolic disease models.

The design of bionic bone scaffolds to mimic the behaviors of native bone tissue is crucial in clinical application, but such design is very challenging due to the complex behaviors of native bone tissues. In the present study, bionic bone scaffolds with the anisotropic mechanical properties similar to those of native bone tissues were successfully designed using a novel self-learning convolutional neural network (CNN) framework. The anisotropic mechanical property of bone was first calculated from the CT images of bone tissues. The CNN model constructed was trained and validated using the predictions from the heterogonous finite element (FE) models. The CNN model was then used to design the scaffold with the elasticity matrix matched to that of the replaced bone tissues. For the comparison, the bone scaffold was also designed using the conventional method. The results showed that the mechanical properties of scaffolds designed using the CNN model are closer to those of native bone tissues. In conclusion, the self-learning CNN framework can be used to design the anisotropic bone scaffolds and has a great potential in the clinical application.

Abstract Articular cartilage in knee joint can be anatomically divided into different regions: medial and lateral condyles of femur; patellar groove of femur; medial and lateral plateaus of tibia covered or uncovered by meniscus. The stress–strain curves of cartilage in uniaxially unconfined compression demonstrate strain rate dependency and exhibit distinct topographical variation among these seven regions. The femoral cartilage is stiffer than the tibial cartilage, and the cartilage in femoral groove is stiffest in the knee joint. Compared with the uncovered area, the area covered with meniscus shows the stiffer properties. To investigate the origin of differences in macroscopic mechanical properties, histological analysis of cartilage in seven regions are conducted. The differences are discussed in terms of the cartilage structure, composition content and distribution. Furthermore, the commonly used constitutive models for biological tissues, namely Fung, Ogden and Gent models, are employed to fit the experimental data, and Fung and Ogden models are found to be qualified in representing the stiffening effect of strain rate.

This study aimed to develop an in-situ field-repair approach, especially for aircraft composite structures, to enhance the interlaminar toughness of plain-woven composites (PWCs) by adding multi-walled carbon nanotubes (MWCNTs). MWCNTs were dispersed at each interface between prepreg layers by means of solvent spraying, with a density of 1.58 g/m2. Then, the layers were stacked with the predefined sequence and cured at 120 °C and 1 bar pressure, using a heat-repairing instrument. A standard double cantilever beam (DCB) test was used to investigate the interlaminar toughening effect that was due to the MWCNTs. For comparison, original samples were also prepared. The results indicated that the introduction of MWCNTs can favorably enhance the interlaminar toughness of PWCs in a field-repair approach and the Mode I fracture energy release rate, GIC, increased by 102.92%. Based on the finite element method (FEM) of continuum damage mechanics, the original samples and the MWCNTs toughening specimen under DCB Mode I fracture were modeled and analyzed. The simulation and the experiment were in good agreement. Finally, when the toughening mechanism of MWCNTs was explored with a scanning electron microscope (SEM), we found that a large amount of fiber-matrix (F-M) interface debonding and matrix cracking in mountain shape were the major modes of fracture, accompanied by a small amount of fiber breakage and matrix peeling for the MWCNTs-toughening specimens.

Street view imagery (SVI) provides efficient access to data that can be used to research spatial quality at the human scale. The previous reviews have mainly focused on specific health findings and neighbourhood environments. There has not been a comprehensive review of this topic. In this paper, we systematically review the literature on the application of SVI in the built environment, following a formal innovation–decision framework. The main findings are as follows: (I) SVI remains an effective tool for automated research assessments. This offers a new research avenue to expand the built environment-measurement methods to include perceptions in addition to physical features. (II) Currently, SVI is functional and valuable for quantifying the built environment, spatial sentiment perception, and spatial semantic speculation. (III) The significant dilemmas concerning the adoption of this technology are related to image acquisition, the image quality, spatial and temporal distribution, and accuracy. (IV) This research provides a rapid assessment and provides researchers with guidance for the adoption and implementation of SVI. Data integration and management, proper image service provider selection, and spatial metrics measurements are the critical success factors. A notable trend is the application of SVI towards a focus on the perceptions of the built environment, which provides a more refined and effective way to depict urban forms in terms of physical and social spaces.

The increasingly severe environmental pollution and the Earth’s ecological crisis make the concept of resilient cities (RCs) a hot topic in urban research. We ran a bibliometric analysis to analyze the research progress, areas, hotspots, and strategies pertaining to RCs. The core collection came from the Web of Science (WoS) database as the data source to explore 4462 literature works on RCs. The results revealed that development time series analysis is divided into three stages. Changes in the number of publications are linked to natural disasters, the ecological environment, and science policy. The top five issuing journals accounted for 24.15% of the total sample. Country cooperation mainly is concentrated in countries with good economic development trends, such as the United States, China, and the United Kingdom. There were 63 core authors. The most published research institution was the Chinese Academy of Sciences. The RC research hotspots included the definition of resilience and evolution, the study of resilience as an analytical framework for urban issues, and resilience assessment indicators. This paper shows that RCs should strengthen multi-country cooperation and interdisciplinary integration and should focus on comprehensive research on basic theories, evaluation systems, and action mechanisms to reference future research on RCs further.

This paper aims to investigate the relationship between local moisture concentration and mesoscale mechanical properties of epoxy adhesive under elevated temperature. Araldite® 2015 was chosen as the target adhesive due to its curing stability and possible validation with previously published literatures. The specimens were aged at 60 °C in deionised water and 5%wt NaCl solution, separately, with the water ingress evaluated by Fickian diffusion model. Nanoindentation was utilised to characterise the mesoscale modulus and hardness distribution along the water diffusion path. Then Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) were conducted to investigate the variation of functional groups and microstructure, respectively. The results show that mechanical properties degrade as ageing duration increases, with higher degradation observed in the edge region where higher moisture concentration exists. Besides, higher ageing temperature leads to larger decrease in mechanical properties of saturated specimens. An empirical relation between local mechanical properties and moisture concentration was established. Chemical and morphology performance of adhesives also exhibited variations when saturated. The obtained local moisture-mechanical relationship can then be used to improve the accuracy of numerical simulation on the environmental durability of structural adhesive in future work.

Indirect traumatic optic neuropathy (ITON) is an injury to the optic nerve due to head trauma and usually results in partial or complete loss of vision. In order to advance a mechanistic understanding of the injury to the optic nerve, we developed a head model with a biofidelic orbit. Head impacts were simulated under controlled conditions of impactor velocity. The locations of impact were varied to include frontal, lateral, and posterior parts of the head. Impact studies were conducted using two types of impactors that differed in their rigidity relative to the skull. The simulated results from both the impactors suggest that forehead impacts are those to which the optic nerve is most vulnerable. The mode and location of optic nerve injury is significantly different between the impacting conditions. Simulated results using a relatively rigid impactor (metal cylinder) suggest optic nerve injury initiates at the location of the intracranial end of the optic canal and spreads to the regions of the optic nerve in the vicinity of the optic canal. In this case, the deformation of the skull at the optic canal, resulting in deformation of the optic nerve, was the primary mode of injury. On the other hand, simulated results using a relatively compliant impactor (soccer ball) suggest that primary mode of injury comes from the brain tugging upon the optic nerve (from where it is affixed to the intracranial end of the optic canal) during coup countercoup motion of the brain. This study represents the first published effort to employ a biofidelic simulation of the full length of the optic nerve in which the orbit is integrated within the whole head.

Mesenchymal stem cells have cannabinoid (CB) receptors type 1 and type 2 and can alleviate a variety of neuropathic pains, including chronic constriction injury (CCI). A selective CB2 receptor agonist is AM1241. In the present study, it was found that mice with CCI displayed a longer duration of mechanical and thermal analgesia when intrathecally (i.t.) injected with AM1241-treated mesenchymal stem cells, compared to those injected with untreated mesenchymal stem cells or AM1241 alone. Moreover, CCI-induced upregulation of the phosphorylated extracellular signal-regulated kinase (ERK) 1/2 (p-ERK1/2) was inhibited following i.t. injection of AM1241-treated mesenchymal stem cells and this inhibition was noticeably higher compared to injection with untreated mesenchymal stem cells. The expression of transforming growth factor-β1 (TGF-β1) was also analyzed in the dorsal root ganglion (DRGs) and spinal cord of CCI mice. In untreated CCI mice, expression of TGF-β1 was increased, whereas pretreatment with AM1241-treated mesenchymal stem cells regulated the expression of TGF-β1 on 10 days and 19 days after surgery. In addition, i.t. injection of exogenous TGF-β1 slightly alleviated neuropathic pain whilst neutralization of TGF-β1 potently blocked the effect of AM1241-treated mesenchymal stem cells on thermal hyperalgesia and mechanical allodynia of CCI mice. In an in vitro experiment, AM1241 could enhance the release of TGF-β1 in the supernatant of BMSCs after lipopolysaccharide (LPS) simulation. Taken together, the findings of the current study show that i.t. administration of AM1241-treated mesenchymal stem cells has a positive effect on analgesia and that TGF-β1 and p-ERK1/2 may be the molecular signaling pathway involved in this process.

Efforts to develop an HIV-1 vaccine include those focusing on conserved structural elements as the target of broadly neutralizing monoclonal antibodies. MAb D5 binds to a highly conserved hydrophobic pocket on the gp41 N-heptad repeat (NHR) coiled coil and neutralizes through prevention of viral fusion and entry. Assessment of 17-mer and 36-mer NHR peptides presenting the D5 epitope in rodent immunogenicity studies showed that the longer peptide elicited higher titers of neutralizing antibodies, suggesting that neutralizing epitopes outside of the D5 pocket may exist. Although the magnitude and breadth of neutralization elicited by NHR-targeting antigens are lower than that observed for antibodies directed to other epitopes on the envelope glycoprotein complex, it has been shown that NHR-directed antibodies are potentiated in TZM-bl cells containing the FcγRI receptor. Herein, we report the design and evaluation of covalently stabilized trimeric 51-mer peptides encompassing the complete gp41 NHR. We demonstrate that these peptide trimers function as effective antiviral entry inhibitors and retain the ability to present the D5 epitope. We further demonstrate in rodent and nonhuman primate immunization studies that our 51-mer constructs elicit a broader repertoire of neutralizing antibody and improved cross-clade neutralization of primary HIV-1 isolates relative to 17-mer and 36-mer NHR peptides in A3R5 and FcγR1-enhanced TZM-bl assays. These results demonstrate that sensitive neutralization assays can be used for structural enhancement of moderately potent neutralizing epitopes. Finally, we present expanded trimeric peptide designs which include unique low-molecular-weight scaffolds that provide versatility in our immunogen presentation strategy. [ABSTRACT FROM AUTHOR]