Abstract
Background
The duration of humoral and T and B cell response after the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear.
Methods
We performed a ...cross-sectional study to assess the virus-specific antibody and memory T and B cell responses in coronavirus disease 2019 (COVID-19) patients up to 343 days after infection. Neutralizing antibodies and antibodies against the receptor-binding domain, spike, and nucleoprotein of SARS-CoV-2 were measured. Virus-specific memory T and B cell responses were analyzed.
Results
We enrolled 59 patients with COVID-19, including 38 moderate, 16 mild, and 5 asymptomatic patients; 31 (52.5%) were men and 28 (47.5%) were women. The median age was 41 years (interquartile range, 30–55). The median day from symptom onset to enrollment was 317 days (range 257 to 343 days). We found that approximately 90% of patients still have detectable immunoglobulin (Ig)G antibodies against spike and nucleocapsid proteins and neutralizing antibodies against pseudovirus, whereas ~60% of patients had detectable IgG antibodies against receptor-binding domain and surrogate virus-neutralizing antibodies. The SARS-CoV-2-specific IgG+ memory B cell and interferon-γ-secreting T cell responses were detectable in more than 70% of patients.
Conclusions
Severe acute respiratory syndrome coronavirus 2-specific immune memory response persists in most patients approximately 1 year after infection, which provides a promising sign for prevention from reinfection and vaccination strategy.
SARS-CoV-2-specific antibody and memory T and B cell responses were detectable in most patients approximately 1 year after infection, indicating that durable immunity against secondary COVID-19 disease is possible in most individuals.
Zinc oxide nanoparticles (ZnO-NPs) are increasingly used in sunscreens, food additives, pigments, rubber manufacture, and electronic materials. Several studies have shown that ZnO-NPs inhibit cell ...growth and induce apoptosis by the production of oxidative stress in a variety of human cancer cells. However, the anti-cancer property and molecular mechanism of ZnO-NPs in human gingival squamous cell carcinoma (GSCC) are not fully understood. In this study, we found that ZnO-NPs induced growth inhibition of GSCC (Ca9-22 and OECM-1 cells), but no damage in human normal keratinocytes (HaCaT cells) and gingival fibroblasts (HGF-1 cells). ZnO-NPs caused apoptotic cell death of GSCC in a concentration-dependent manner by the quantitative assessment of oligonucleosomal DNA fragmentation. Flow cytometric analysis of cell cycle progression revealed that sub-G1 phase accumulation was dramatically induced by ZnO-NPs. In addition, ZnO-NPs increased the intracellular reactive oxygen species and specifically superoxide levels, and also decreased the mitochondrial membrane potential. ZnO-NPs further activated apoptotic cell death via the caspase cascades. Importantly, anti-oxidant and caspase inhibitor clearly prevented ZnO-NP-induced cell death, indicating the fact that superoxide-induced mitochondrial dysfunction is associated with the ZnO-NP-mediated caspase-dependent apoptosis in human GSCC. Moreover, ZnO-NPs significantly inhibited the phosphorylation of ribosomal protein S6 kinase (p70S6K kinase). In a corollary in vivo study, our results demonstrated that ZnO-NPs possessed an anti-cancer effect in a zebrafish xenograft model. Collectively, these results suggest that ZnO-NPs induce apoptosis through the mitochondrial oxidative damage and p70S6K signaling pathway in human GSCC. The present study may provide an experimental basis for ZnO-NPs to be considered as a promising novel anti‑tumor agent for the treatment of gingival cancer.
Obesity increases the risk of developing cardiovascular disease and other metabolic diseases. We intended to compare three different anthropometric indicators of obesity, in predicting the incidence ...of cardiovascular events in Chinese type 2 diabetes. Beijing Community Diabetes Study was a prospective multi-center study conducted in Beijing community health centers. Type 2 diabetes patients from fourteen community health centers were enrolled at baseline. The primary endpoint was cardiovascular events. The upper quartile of neck circumference (NC) was set as greater NC. A total of 3299 diabetes patients were enrolled. In which, 941 (28.52%) had cardiovascular disease at baseline. Logistic analysis showed that central obesity (waist circumference (WC) above 90 cm in men and 85 cm in women) and greater NC were all related to baseline cardiovascular disease (adjusted OR = 1.49, and 1.55). After 10-year follow-up, 340 (10.31%) had cardiovascular events. Compared with patients without cardiovascular events, those having cardiovascular events had higher BMI, larger WC and NC. Cox regression analysis showed that greater WC and NC were all associated with the occurrence of cardiovascular events (adjusted HR = 1.41, and 1.38). A higher NC and WC might increase the risk of cardiovascular events by about 40% in type 2 diabetes patients in Beijing communities.
Revealing the single-cell immune ecosystems in true versus de novo hepatocellular carcinoma (HCC) recurrences could help the optimal development of immunotherapies.
We performed 5'and VDJ single-cell ...RNA-sequencing on 34 samples from 20 recurrent HCC patients. Bulk RNA-sequencing, flow cytometry, multiplexed immunofluorescence, and in vitro functional analyses were performed on samples from two validation cohorts.
Analyses of mutational profiles and evolutionary trajectories in paired primary and recurrent HCC samples using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The tumour immune microenvironment (TIME) of truly recurrent HCCs was characterised by an increased abundance in KLRB1
CD8
T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8
T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed elevated GDF15 expression on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited antitumour immunity in truly recurrent lesions. In contrast, myeloid cells' cross talk with T cells-mediated T cell exhaustion and immunosuppression in the TIME of
recurrent HCCs. Consistent with these findings, a phase 2 trial of neoadjuvant anti-PD-1 immunotherapy showed more responses in de novo recurrent HCC patients.
True and de novo HCC recurrences occur early, have distinct TIME and may require different immunotherapy strategies. Our study provides a source for genomic diagnosis and immune profiling for guiding immunotherapy based on the type of HCC recurrence and the specific TIME.
Abstract Cellular uptake of nanoparticles for stem cell labeling/tracking is considered as the most promising method. Recently mesoporous silica nanoparticles (MSNs) are emerging as an idea agent for ...efficient stem cell labeling. The objective of this study was to evaluate the effect of surface charge on the highly efficient cellular uptake and in vitro cytotoxicity of MSNs in human mesenchymal stem cells (hMSCs). The surface charge was varied by the degree of surface modification with N -trimethoxysilylpropyl- N , N , N -trimethylammonium chloride and the uptake of MSNs was detected by flow cytometry. 3T3-L1 cells were also used to compare the uptake behavior of MSNs between cell types. A clear correlation of positive surface charge and the number of fluorescence-labeled cells was mainly observed in 3T3-L1 cells. In both cells, uptake of unmodified MSNs was inhibited by phenylarsine oxide (PAO) and cytochalasin D (Cyt D) suggesting a clathrin- and an actin-dependent endocytosis were involved. With strongly positive-charged MSNs, the inhibitory effects were observed in 3T3-L1 cells but not in hMSCs. Without regard to the surface charge, uptake of MSNs into both cells did not affect their viability, proliferation, and differentiation. Our results show that MSNs uptake by hMSCs can be regulated by a threshold of positive surface charge but also imply that the modulation of surface charge on MSNs uptake is specific to cell type.
The brown planthopper, Nilaparvata lugens, the most destructive pest of rice, is a typical monophagous herbivore that feeds exclusively on rice sap, which migrates over long distances. Outbreaks of ...it have re-occurred approximately every three years in Asia. It has also been used as a model system for ecological studies and for developing effective pest management. To better understand how a monophagous sap-sucking arthropod herbivore has adapted to its exclusive host selection and to provide insights to improve pest control, we analyzed the genomes of the brown planthopper and its two endosymbionts.
We describe the 1.14 gigabase planthopper draft genome and the genomes of two microbial endosymbionts that permit the planthopper to forage exclusively on rice fields. Only 40.8% of the 27,571 identified Nilaparvata protein coding genes have detectable shared homology with the proteomes of the other 14 arthropods included in this study, reflecting large-scale gene losses including in evolutionarily conserved gene families and biochemical pathways. These unique genomic features are functionally associated with the animal's exclusive plant host selection. Genes missing from the insect in conserved biochemical pathways that are essential for its survival on the nutritionally imbalanced sap diet are present in the genomes of its microbial endosymbionts, which have evolved to complement the mutualistic nutritional needs of the host.
Our study reveals a series of complex adaptations of the brown planthopper involving a variety of biological processes, that result in its highly destructive impact on the exclusive host rice. All these findings highlight potential directions for effective pest control of the planthopper.
A superparamagnetic iron oxide (SPIO) nanoparticle is emerging as an ideal probe for noninvasive cell tracking. However, its low intracellular labeling efficiency has limited the potential usage and ...has evoked great interest in developing new labeling strategies. We have developed fluorescein isothiocyanate (FITC)-incorporated silica-coated core−shell SPIO nanoparticles, SPIO@SiO2(FITC), with diameters of 50 nm, as a bifunctionally magnetic vector that can efficiently label human mesenchymal stem cells (hMSCs), via clathrin- and actin-dependent endocytosis with subsequent intracellular localization in late endosomes/lysosomes. The uptake process displays a time- and dose-dependent behavior. In our system, SPIO@SiO2(FITC) nanoparticles induce sufficient cell MRI contrast at an incubation dosage as low as 0.5 μg of iron/mL of culture medium with 1.2 × 105 hMSCs, and the in vitro detection threshold of cell number is about 1 × 104 cells. Furthermore, 1.2 × 105 labeled cells can also be MRI-detected in a subcutaneous model in vivo. Labeled hMSCs are unaffected in their viability, proliferation, and differentiation capacities into adipocytes and osteocytes which can still be readily MRI detected. This is the first report that hMSCs can be efficiently labeled with MRI contrast nanoparticles and can be monitored in vitro and in vivo with a clinical 1.5-T MRI imager under low incubation concentration of iron oxide, short incubation time, and low detection cell numbers at the same time.
Reverse engineering Computer-Aided Design (CAD) models based on the original geometry is a valuable and challenging research problem that has numerous applications across various tasks. However, ...previous approaches have often relied on excessive manual interaction, leading to limitations in reconstruction speed. To mitigate this issue, in this study, we approach the reconstruction of a CAD model by sequentially constructing geometric primitives (such as vertices, edges, loops, and faces) and performing Boolean operations on the generated CAD modules. We address the complex reconstruction problem in four main steps. Firstly, we use a plane to cut the input mesh model and attain a loop cutting line, ensuring accurate normals. Secondly, the cutting line is automatically fitted to edges using primitive information and connected to form a primitive loop. This eliminates the need for time-consuming manual selection of each endpoint and significantly accelerates the reconstruction process. Subsequently, we construct the loop of primitives as a chunked CAD model through a series of CAD procedural operations, including extruding, lofting, revolving, and sweeping. Our approach incorporates an automatic height detection mechanism to minimize errors that may arise from manual designation of the extrusion height. Finally, by merging Boolean operations, these CAD models are assembled together to closely approximate the target geometry. We conduct a comprehensive evaluation of our algorithm using a diverse range of CAD models from both the Thingi10K dataset and real-world scans. The results validate that our method consistently delivers accurate, efficient, and robust reconstruction outcomes while minimizing the need for manual interactions. Furthermore, our approach demonstrates superior performance compared to competing methods, especially when applied to intricate geometries.
•We develop a systematic CAD reconstruction pipeline for reverse engineering CAD modeling, which ensures faithful CAD reconstruction with high precision and significantly reduces the reliance on manual or interactive operations.•We introduce an algorithm for automatically determining the height of the extruding body, effectively reducing errors that may occur during its construction.•We develop an efficient algorithm that rapidly fits the cutting line of a model to a primitive loop. This approach significantly reduces the time required compared to manual construction methods.
The pathways for Romidepsin-induced apoptosis and cell cycle arrest in HCC cells.
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The aim of the study is to demonstrate the effect of Romidepsin in hepatocellular carcinoma (HCC) by ...inducing G2/M phase arrest via Erk/cdc25C/cdc2/cyclinB pathway and apoptosis through JNK/c-Jun/caspase3 pathway in vitro and in vivo. Human HCC cell lines were cultured with Romidepsin and DMSO (negative control) and 5-fluorouracil (positive control). Then the cells’ viability and apoptosis were determined by cell proliferation assay and flow cytometry. Protein concentrations and expression changes were measured by Western blot. Subsequently, Huh7 cells were subcutaneously inoculated into the nude mice, which were employed to further probe the tumor-suppressive effect of Romidepsin in vivo. Romidepsin treatment led to a time- and dose-dependent induction of cell cycle arrest in the G2/M phase and apoptosis. G2/M phase arrest inhibited the proliferation of HCC cells by alterations in p21/cdc25C/cdc2/cyclinB proteins. Increased concentrations of Erk and JNK phosphorylations were observed in a dose-dependent manner in the Romidepsin group, but p38 phosphorylation was not affected. G2/M phase arrest and the apoptosis of HCC cells induced by Romidepsin were mediated by the activation of Erk/MAPK pathways and JNK/MAPK pathways. The tumor size was significantly larger in the negative control group compared to Romidepsin group and no significant loss in body weight was observed in the Romidepsin group. Our findings offer proof-of-concept for use of Romidepsin as a novel class of chemotherapy in the treatment of HCC.
Increasing evidence has demonstrated that vitamin D deficiency is associated with prostate cancer progression, but its mechanism remains unclear. This study investigated effects of vitamin D ...deficiency on growth and metastasis of prostate cancer. Nude mice and Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed with vitamin D-deficient (VDD) diets. Prostate cancer growth was aggravated in VDD diet-fed nude mice and TRAMP mice. Invasion and metastasis of prostate cancer were exacerbated in VDD diet-fed TRAMP mice. In vitro experiments showed that calcitriol, an active vitamin D3, inhibited migration and invasion in transforming growth factor (TGF)-β1 -stimulated and -unstimulated PC-3 and DU145 cells. Mechanistically, calcitriol inhibited epithelial-mesenchymal transition (EMT) in TGF-β1 -stimulated and -unstimulated DU145 cells. Unexpectedly, calcitriol did not inhibit Smad2/3 phosphorylation in TGF-β1-stimulated DU145 cells. Instead, calcitriol downregulated expression of proliferation-, metastasis- and EMT-related genes, includes Cyclin D1, MMP7, and Zeb1, by inhibiting interaction between TCF4 and β-catenin. In addition, calcitriol promoted interaction between cytoplasmic VDR and β-catenin, reduced β-catenin phosphorylation and elevated β-catenin/E-cadherin adherens junction complex formation. We provide novel evidence that vitamin D deficiency aggravates growth and metastasis of prostate cancer possibly through promoting EMT in two β-catenin-related mechanisms.
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