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Gold nanoparticles (AuNPs) are prospective tools for nano-based medicine that can directly target cellular biological processes to influence cell fate and function. Studies have revealed the essential role of AuNPs in metabolic remodeling for macrophage polarization. Nevertheless, as a hallmark of cancer cells, metabolic changes in tumor cells in response to AuNPs have not yet been reported. In the present study, polymer- and folate-conjugated AuNPs with satisfactory biocompatibility and tumor-targeting activity were synthesized to investigate their underlying roles in tumor metabolism. Tumor cells were significantly suppressed by AuNPs in vitro and in vivo, with little cytotoxicity in non-tumor cells. Subcellular localization showed that AuNPs localized in the mitochondria of tumor cells and impaired their structure and function, leading to excessive oxidative stress and mitochondrial apoptosis. Metabolic stress, with decreased glycolysis and insufficient nutrients, was also caused by AuNPs exposure in tumor cells. Mechanistically, the key enzymes (GLUT1 and HK2) for glycolysis modulation were remarkably reduced by AuNPs in a c-Myc-dependent manner. The present study demonstrated a new mechanism for AuNPs in the inhibition of tumor growth, that is, via directly targeting glycolysis and depriving energy. These findings provide new strategies for the design of nano-based medicines and anti-glycolytic therapeutics to inhibit the development of malignant tumors. STATEMENT OF SIGNIFICANCE: Gold nanoparticles (AuNPs) have acquired ever-increasing interest for applications in cancer treatment and diagnosis due to their high biosafety and facile surface modification. Recent studies have shown that AuNPs can work as active agents to directly target the cellular processes and harbor antitumor properties, while the underlying mechanisms remain largely unknown. From the present findings, the stabilized AuNPs showed direct inhibition effects on tumor growth by glycolysis inhibition and energy deprivation. These results provide new insights of AuNPs for tumor treatments, which will further contribute to the development of promising nano-based medicines and anti-glycolytic therapies.

PD-1 blockade has been recommended as first-line therapy for nonresectable or metastatic mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). However, the safety and efficacy of neoadjuvant PD-1 blockade immunotherapy for locally advanced dMMR/MSI-H CRC remain unclear.From June 2020 to June 2022, 11 locally advanced dMMR/MSI-H CRC patients treated at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) were enrolled. All patients received 6 sintilimab (Innovent, LTD) injections (200 mg/injection, every 3 weeks) before radical laparoscopic resection. The patient clinical and pathological data were analyzed retrospectively.dMMR was confirmed by immunohistochemistry for all patients. However, polymerase chain reaction (PCR) or next-generation sequencing confirmed MSI-H for only 90.9% (10/11) of the patients, while 1 patient had microsatellite stable (MSS) disease. After 6 injections of neoadjuvant anti-PD-1 therapy, 90.9% (10/11) of the patients (those confirmed to have dMMR and MSI-H disease) achieved pathological complete response (pCR). The other patient, who achieved major pathological response with residual tumor1%, had dMMR but MSS disease. No grade 3 or above immunotherapy-related adverse events occurred [Common Terminology Criteria for Adverse Events ; version 5.0]. Overall, 72.7% (8/11) of the patients had grade 1-2 immunotherapy-related adverse events . No operational mortality or complications occurred within 30 days after surgery.Single-agent neoadjuvant PD-1 antibody immunotherapy was safe and effective in locally advanced dMMR/MSI-H CRC. Dual confirmation of MMR and MSI status by immunohistochemistry and next-generation sequencing or PCR is necessary for dMMR/MSI-H CRC patients before immunotherapy. The immunotherapy regimen used in this study deserves further validation in phase II and III clinical studies.

Aims Increasing evidence implicates the microbiome as a susceptibility factor for ischaemic stroke (IS). Interpretation of this evidence is difficult, for the composition of the microbiome is influenced by various factors and might affect differently in IS subtypes. We aim to determine if the specific gut microbiome is causally associated with IS subtypes and suggest potential approaches for stroke prevention. Methods and results We conducted a two-sample Mendelian randomization (MR) analysis to test the causal relationship between gut microbiome and IS subtypes. For exposure data, we extracted genetic variants associated with 194 bacterial traits from MiBioGen consortium (n = 18 340). For outcomes, we selected three IS subtypes including cardioembolic stroke (CES, n = 410 484), small vessel stroke (SVS, n = 198 048), and large artery stroke (LAS, n = 198 048). Additionally, we performed a sequence of sensitivity analyses to validate preliminary MR results. There were four, three, and four bacteria showing an increased risk for LAS, SVS, and CES, respectively, and there were five, six, and five bacteria leading a decreasing risk for LAS, SVS, and CES, respectively. Amongst these, the genus_Intestinimonas showed negative associations with LAS [odds ratio (OR) = 0.77, 95% confidence interval (CI) (0.61–0.98)] and SVS (0.85, 0.73–0.98). The genus_LachnospiraceaeNK4A136group was genetically associated with decreased risk of both SVS (0.81, 0.66–0.99) and CES (0.75, 0.60–0.94). Conclusion The study revealed the causal effect of the abundance of specific bacterial features on the risk of IS subtypes. Notably, genus_Intestinimonas and genus_LachnospiraceaeNK4A136group displayed significant protection against more than one IS subtype, further suggesting potential applications of targeted probiotics in IS prevention.

Background: Cytochrome P450 (CYP) 46A1 enzyme is a neuro-specific metabolic enzyme that converts cholesterol to 24-hydroxycholesterol. Inhibition of CYP46A1 activity is of great significance to improve neurodegenerative disorder. Objective: The present study aimed to investigate the inhibitory effect of wolfberry dicaffeoylspermidine derivatives on CYP46A1. Methods: The inhibitory effect of six wolfberry dicaffeoylspermidine derivatives on CYP46A1 activity was investigated using cholesterol as a substrate in vitro. Molecular docking was used to simulate the interactions between wolfberry dicaffeoylspermidine derivatives and CYP46A1. Results: Of these spermidines, lycibarbarspermidines D (1) and A (2) showed highly-selective and strong inhibitory effects on CYP46A1 but not on other human CYP isoforms. Both 1 and 2 exhibit mixed partial competitive inhibition of CYP46A1, with Ki values of 106 nM and 258 nM, respectively. Notably, 1 and 2 had excellent orientations within the active cavity of CYP46A1, and both formed three water-hydrogen bonds with W732 and W765, located near the heme of CYP46A1. Conclusion: Compounds 1 and 2 showed a highly-selective and nanomolar affinity for CYP46A1 in vitro. These findings suggested that compounds 1 and 2 could be used as potent inhibitors of CYP46A1 in vitro.

An efficient biocatalytic reduction of difluoromethylene group-containing ketones with commercial ketoreductase K234 was reported to access chiral difluoromethylene-containing secondary alcohols with excellent yields and high enantioselectivity.

A novel copper-catalyzed three-component reaction of monofluoroalkylation agents, alkenes (alkynes) and TMSCN has been developed, allowing the facile synthesis of various cyanomonofluoroalkyl compounds in generally moderate to good yields.

Background: In Parkinson’s disease (PD), excessive iron deposition in the substantia nigra may exacerbate α-synuclein aggregation, facilitating the degeneration of dopaminergic neurons and their neural projection. Objective: To investigate the interaction effect between nigral iron deposition and PD status on brain networks. Methods: Eighty-five PD patients and 140 normal controls (NC) were included. Network function and nigral iron were measured using multi-modality magnetic resonance imaging. According to the median of nigral magnetic susceptibility of NC (0.095 ppm), PD and NC were respectively divided into high and low nigral iron group. The main and interaction effects were investigated by mixed effect analysis. Results: The main effect of disease was observed in basal ganglia network (BGN) and visual network (VN). The interaction effect between nigral iron and PD status was observed in left inferior frontal gyrus and left insular lobe in BGN, as well as right middle occipital gyrus, right superior temporal gyrus, and bilateral cuneus in VN. Furthermore, multiple mediation analysis revealed that the functional connectivity of interaction effect clusters in BGN and medial VN partially mediated the relationship between nigral iron and Unified Parkinson’s Disease Rating Scale II score. Conclusion: Our study demonstrates an interaction of nigral iron deposition and PD status on brain networks, that is, nigral iron deposition is associated with the change of brain network configuration exclusively when in PD. We identified a potential causal mediation pathway for iron to affect disease severity that was mediated by both BGN dysfunction and VN hyperfunction in PD.

In 2007, in order to meet the development needs of socialist modernization, the Academic Degrees Committee of the State Council and the Ministry of Education approved the establishment of Master of Translation and Interpreting (MTI) in China to cultivate advanced translators with professional interpretation and translation capabilities. Today, more than 200 colleges and universities have set up this major, which has cultivated a large number of translation talents for the society. This paper takes the recent five years of Guangxi University of Science and Technology's English translation master's degree thesis as the research object, and conducts analysis from the aspects of topic selection, theory, and case analysis. The research found that these papers have problems such as too simple topic selection, insufficient Chinese-English translation, insufficient integration of theory and practice, and insufficient case analysis. In order to solve the above-mentioned series of problems, corresponding measures can be taken from the three aspects of tutors, schools and students to improve the writing quality of students' dissertations.

In order to conduct a special study on the financing efficiency of a certain industry, the authors propose a method for calculating the financing efficiency of energy enterprises based on the Internet of Things. Combining the DEA method with the Bootstrap method, taking the IoT data of 30 SME boards and 30 energy companies listed on the ChiNext listed in 2010 as a research sample, and using R language and Deap2.1 software, the financing efficiency from 2011 to 2015 is calculated. Experimental results show that from 2011 to 2015, only 28.3% of the enterprises reached the effective state of technical efficiency on average, and the financing efficiency of energy enterprises was generally inefficient. The pure technical efficiency value of the whole enterprise decreases year by year, and its technical efficiency value lower than its scale efficiency is the main reason that its technical efficiency is generally not high.

In higher education teaching work, college students not only need to master the professional knowledge and professional skills they learn during their school study but also need to improve their self-education and self-cultivation and constantly improve their comprehensive ability of learning. At present, there are differences and relationships between the education of college students in civic and mental normal education, and how to play the role of the integration of the two educations has become a problem that needs to be considered in the current work of college students’ training. The integration between civic education and mental normal education can make up for the shortcomings of monolithic civic education and mental normal education work and also optimize the teaching methods between them from a certain perspective to achieve the development goals of complementing each other and not being independent of each other, so that students can understand more learning methods and contents that promote the normal development of their own minds and minds. In response to the problem that mind-normal education cannot be automatically integrated into the teaching of university thought and political science courses, in the context of artificial intelligence, this paper proposes a multi-channel-based mind-normal and ideological and political information fusion model. The model has two channels, BERT+CNN and BERT and BiLSTM-Attention; firstly, the pretraining model BERT is used to obtain the word vector representation of the fused text context; then, the CNN network of channel one is used to enhance the ability of local feature extraction of the text, and the BiLSTM-Attention model of channel two enhances the ability of long sequence text processing and is key. Finally, the fused features of channel 1 and channel 2 are classified using a softmax excitation function. To verify the effectiveness of the proposed model, experiments are conducted on public datasets to demonstrate the effectiveness of the proposed method.

Surface-enhanced Raman scattering spectroscopy (SERS) is a highly-sensitive technology to detect trace target analytes. Herein, a series of flexible SERS substrate for the detection of malachite green (MG) bactericide were developed via in situ photochemical synthesis of silver nanoparticles (AgNPs) based on two dimentional (2D) nanocellulose film without additional reducing agent. For the first time, silver nanocubes (AgNCs) with sharp edges and corners, which are conductive to the formation of hot spots, were successfully prepared and uniformly loaded on the nanocellulose film by controlling the reaction conditions. The obtained composite SERS substrate showed high sensitivity to Rhodamine 6G (R6G) and MG with limit of detection (LOD) of 4.7 × 10

The genetic bases of halophytes for salinity tolerance are crucial for genetically breeding salt-tolerant crops. All natural Nitrariaceae species that exclusively occur in arid environments are highly tolerant to salt stress, but the underlying genomic bases to this adaptation remain unknown. Here we present a high-quality, chromosome-level genome sequence of Nitraria sibirica, with an assembled size of 456.66 Mb and 23,365 annotated genes. Phylogenomic analyses confirmed N. sibirica as the sister to all other sampled representatives from other families in Sapindales, and no lineage-specific whole-genome duplication was found except the gamma triplication event. Still, we found that the genes involved in K+ retention, energy supply, and Fe absorption expanded greatly in N. sibirica. Deep transcriptome analyses showed that leaf photosynthesis and cuticular wax formation in roots were enhanced under salt treatments. Furthermore, many transcription factors involved in salt tolerance changed their expressions significantly and displayed tissue- and concentration-dependent signalling in response to salt stress. Additionally, we found vacuolar Na+ compartmentalization is an ongoing process under salt treatment, while Na+ exclusion tends to function at high salt concentrations. These genomic and transcriptomic changes conferred salt tolerance in N. sibirica and pave the way for the future breeding of salt-tolerant crops.

Background Neoadjuvant therapy followed by radical surgery is recommended for locally advanced rectal cancer (LARC). But radiotherapy can cause potential adverse effects. The therapeutic outcomes, postoperative survival and relapse rates between neoadjuvant chemotherapy (N-CT) and neoadjuvant chemoradiotherapy (N-CRT) patients have rarely been studied. Methods From February 2012 to April 2015, patients with LARC who underwent N-CT or N-CRT followed by radical surgery at our center were included. Pathologic response, surgical outcomes, postoperative complications and survival outcomes (including overall survival [OS], disease-free survival [DFS], cancer-specific survival [CSS] and locoregional recurrence-free survival [LRFS]) were analyzed and compared. Concurrently, the Surveillance, Epidemiology, and End Results Program (SEER) database was used to compare OS in an external source. Results A total of 256 patients were input into the propensity score-matching (PSM) analysis, and 104 pairs remained after PSM. After PSM, the baseline data were well matched and there was a significantly lower tumor regression grade (TRG) (P P = 0.009) (especially anastomotic fistula, P = 0.003) and a longer median hospital stay (P = 0.049) in the N-CRT group than in the N-CT group. No significant difference was observed in OS (P = 0.737), DFS (P = 0.580), CSS (P = 0.920) or LRFS (P = 0.086) between the N-CRT group and the N-CT group. In the SEER database, patients who received N-CT had similar OS in both TNM II (P = 0.315) and TNM III stages (P = 0.090) as those who received N-CRT. Conclusion N-CT conferred similar survival benefits but caused fewer complications than N-CRT. Thus, it could be an alternative treatment of LARC.

Purpose Material extrusion technology is considered to be an effective way to realize the accurate and integrated manufacturing of high-performance metal diamond tools with complex structures. The present work aims to report the G4 binder that can be used to create metal composite filament loading high concentrations of large diamond particles through comparative experiments. Design/methodology/approach The quality of filaments was evaluated by surface topography observation and porosity measurement. And the printability of filaments was further studied by the tensile test, rheological test, shear analysis and printing test. Findings The results show that the G4 binder exhibits the best capacity for loading diamonds among G1–G4. The L4 filament created with G4 has no defects such as pores, cracks and patterns on the surface and section, and has the lowest porosity, which is about 1/3 of the L1. Therefore, the diamond-containing composite filament based on G4 binder exhibits the best quality. On the other hand, the results of the tensile test of L5–L8 filaments reveal that as the diamond content increases from 10% to 30%, the tensile strength of the filament decreases by 29.52%, and the retention force coefficient decreases by 15.74%. This can be attributed to the formation of inefficient bonding areas of the clustered diamond particles inside the composite filament, which also leads to a weakening of the shear strength. Despite this, the results of the printing test show that the diamond-containing composite filament based on the G4 binder has reliable printability. Originality/value Therefore, the G4 binder is considered to solve the most critical first challenge in the development of diamond-containing filament.

Objective. Our previous research showed that TCR+CD4-CD8-double-negative (DN) T cells protect renal epithelial cells from cisplatin-induced acute kidney injury (AKI). Therefore, this study is aimed at investigating the mechanism underlying the effect of DN T cells against Cis-induced AKI. Methods. HK-2 cells cultured alone or with DN T cells were treated with or without Cis. After treatment, the cell viability and death were analyzed by a CCK-8 kit and flow cytometric assay with Annexin V/PI staining, respectively. The expressions of inflammatory factors in HK-2 and DN T cells were analyzed using qPCR. The expression levels of nephrotoxicity-associated biomarkers (KIM, calbindin, and TIMP-1), Bcl-2, and angiotensin AT2 receptor (AT2R) were determined by Western blot and qPCR. Results. The administration of cisplatin significantly decreased the cell viability and AT2R expression, and increased cell death, inflammatory factors, and nephrotoxicity-associated biomarkers of HK-2 cells, while these effects were partly attenuated when cocultured with DN T cells. IL-10 expression was significantly increased in DN T cells after coculture, and cisplatin treatment aggravated this elevation. IL-10 supplementation exhibited a similar effect to coculture, whereas anti-IL-10 antibody reversed the effect of coculture on cisplatin-treated HK-2 cells. Finally, PD123319, an AT2R antagonist, also reversed the effect of IL-10 and coculture on the cell viability, death, and the expression of KIM, calbindin, TIMP-1, and Bcl-2 of cisplatin-treated HK-2 cells. Conclusions. DN T cells protected HK-2 cells from cisplatin-induced injury through IL-10/AT2R axis, which may act as a potential target for the treatment of cisplatin-induced AKI.

Diabetic foot ulcers and other chronic wounds with impaired healing can be treated with bioengineered skin or with growth factors. However, most patients do not benefit from these treatments. Here we report the development and preclinical therapeutic performance of a strain-programmed patch that rapidly and robustly adheres to diabetic wounds, and promotes wound closure and re-epithelialization. The patch consists of a dried adhesive layer of crosslinked polymer networks bound to a pre-stretched hydrophilic elastomer backing, and implements a hydration-based shape-memory mechanism to mechanically contract diabetic wounds in a programmable manner on the basis of analytical and finite-element modelling. In mouse and human skin, and in mini-pigs and humanized mice, the patch enhanced the healing of diabetic wounds by promoting faster re-epithelialization and angiogenesis, and the enrichment of fibroblast populations with a pro-regenerative phenotype. Strain-programmed patches might also be effective for the treatment of other forms of acute and chronic wounds.

l-homoarginine (hARG) is involved in nitric oxide biosynthesis, but its role and concentration in preeclampsia (PE) have not been fully revealed. The purpose of this study was to develop and validate a feasible clinical assay to quantify serum hARG, arginine (ARG), asymmetric (ADMA) and symmetric dimethylarginines (SDMA) levels by LC–MS/MS and investigate their differences at different stages of pregnancy with or without preeclampsia. Serum samples were collected from 84 pregnant women without complications (controls), 84 with mild preeclampsia (MPE), and 81 with severe preeclampsia (SPE) at various gestation stages (before the 20th week, during the 20th–28th week or after the 28th week of gestation). No significant difference in ARG levels was observed between PE and controls at any stage (P > 0.05). The serum hARG levels and hARG/ADMA ratios of MPE before the 20th week were higher than those of controls (P P P P

Smart artificial viruses have been successfully developed by co-assembly of de novo designed peptides with DNA, which achieved stimuli-responsibility and efficient gene transfection in cancer cells. The peptides were designed to incorporate several functional segments, including a hydrophobic aromatic segment to drive self-assembly, two or more cysteines to regulate the assemblage shape and stabilize the assembled nanostructures via forming disulfide bonds, several lysines to facilitate co-assembly with DNA and binding to cell membranes, and an enzyme-cleavable segment to introduce cancer sensitivity. The rationally designed peptides self-assembled into stable nanospheres with a uniform diameter of 10 nm, which worked as capsid-like subunits to further interact with DNA to produce hierarchical virus-mimicking structures by encapsulating DNA in the interior. Such artificial viruses can effectively protect DNA from nuclease digestion and achieve efficient genome release by enzyme-triggered structure disassembly, which ensured a high level of gene transfection in tumor cells. The system emulates very well the structural and functional properties of natural viruses from the aspects of capsid formation, genome package and gene transfection, which is highly promising for application as efficient gene vectors.