The receptor‐binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike (S) protein plays a central role in mediating the first step of virus infection to cause disease: virus ...binding to angiotensin‐converting enzyme 2 (ACE2) receptors on human host cells. Therefore, S/RBD is an ideal target for blocking and neutralization therapies to prevent and treat coronavirus disease 2019 (COVID‐19). Using a target‐based selection approach, we developed oligonucleotide aptamers containing a conserved sequence motif that specifically targets S/RBD. Synthetic aptamers had high binding affinity for S/RBD‐coated virus mimics (KD≈7 nM) and also blocked interaction of S/RBD with ACE2 receptors (IC50≈5 nM). Importantly, aptamers were able to neutralize S protein‐expressing viral particles and prevent host cell infection, suggesting a promising COVID‐19 therapy strategy.
Synthetic ssDNA aptamers containing a conserved sequence motif that specifically targets the receptor‐binding domain (RBD) of the SARS‐CoV‐2 spike have the capacity to neutralize the virus and prevent host cell infection in vitro, suggesting a new therapeutic approach to treat COVID‐19.
Cleavage of transfer (t)RNA and ribosomal (r)RNA are critical and conserved steps of translational control for cells to overcome varied environmental stresses. However, enzymes that are responsible ...for this event have not been fully identified in high eukaryotes. Here, we report a mammalian tRNA/rRNA-targeting endoribonuclease: SLFN13, a member of the Schlafen family. Structural study reveals a unique pseudo-dimeric U-pillow-shaped architecture of the SLFN13 N'-domain that may clamp base-paired RNAs. SLFN13 is able to digest tRNAs and rRNAs in vitro, and the endonucleolytic cleavage dissevers 11 nucleotides from the 3'-terminus of tRNA at the acceptor stem. The cytoplasmically localised SLFN13 inhibits protein synthesis in 293T cells. Moreover, SLFN13 restricts HIV replication in a nucleolytic activity-dependent manner. According to these observations, we term SLFN13 RNase S13. Our study provides insights into the modulation of translational machinery in high eukaryotes, and sheds light on the functional mechanisms of the Schlafen family.
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy with a complex tumor ecosystem. How the interplay between tumor cells, EBV, and the microenvironment contributes to ...NPC progression and immune evasion remains unclear. Here we performed single-cell RNA sequencing on ~104,000 cells from 19 EBV
NPCs and 7 nonmalignant nasopharyngeal biopsies, simultaneously profiling the transcriptomes of malignant cells, EBV, stromal and immune cells. Overall, we identified global upregulation of interferon responses in the multicellular ecosystem of NPC. Notably, an epithelial-immune dual feature of malignant cells was discovered and associated with poor prognosis. Functional experiments revealed that tumor cells with this dual feature exhibited a higher capacity for tumorigenesis. Further characterization of the cellular components of the tumor microenvironment (TME) and their interactions with tumor cells revealed that the dual feature of tumor cells was positively correlated with the expression of co-inhibitory receptors on CD8
tumor-infiltrating T cells. In addition, tumor cells with the dual feature were found to repress IFN-γ production by T cells, demonstrating their capacity for immune suppression. Our results provide new insights into the multicellular ecosystem of NPC and offer important clinical implications.
Background
Previous studies had explored the diagnostic or prognostic value of NRP‐1/CD304 in blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), and B‐cell acute ...lymphoblastic leukemia (B‐ALL), whereas the expression and application value of NRP‐1/CD304 in other common hematological diseases have not been reported.
Methods
Bone marrow samples from 297 newly diagnosed patients with various hematological diseases were collected to detect the expression of NRP‐1/CD304 by flow cytometry (FCM). The diagnostic efficacy of NRP‐1/ CD304‐positive diseases was analyzed by receiver operating characteristic (ROC) curve, and the area under the ROC curve (AUC) was compared.
Results
In the research cohort, the total positive rate of NRP‐1/CD304 was 14.81% (44/297), mainly distributed in BPDCN (100%, 6/6), B‐ALL (48.61%, 35/72), and AML (4.48%, 3/67), with statistically significant differences (p < 0.01). Other diseases, such as T‐cell acute lymphoblastic leukemia (T‐ALL), B‐cell non‐Hodgkin lymphoma (B‐NHL), T/NK‐cell lymphoma and plasma cell neoplasms, did not express NRP‐1/CD304. The AUC of NRP‐1/CD304 was 0.936 (95% CI 0.898–0.973), 0.723 (95% CI 0.646–0.801), and 0.435 (95% CI 0.435) in BPDCN, B‐ALL and AML, respectively. Besides, CD304 was commonly expressed in B‐ALL with BCR‐ABL1 gene rearrangement (p = 0.000), and CD304 expression was positively correlated with CD34 co‐expression (p = 0.009) and CD10 co‐expression (p = 0.007).
Conclusions
NRP‐1/CD304 is only expressed in BPDCN, B‐ALL and AML, but not in other common hematological diseases. This indicates that NRP‐1/CD304 has no obvious diagnostic and follow‐up study value in hematological diseases other than BPDCN, B‐ALL, and AML.
The study was to evaluate the diagnostic efficacy of NRP‐1/CD304 in hematological diseases. We found that NRP‐1/CD304 was only expressed in BPDCN, B‐ALL and AML, but not in other common hematological diseases. This indicates that NRP‐1/CD304 has no obvious diagnostic and follow‐up study value in hematological diseases other than BPDCN, B‐ALL and AML.
Hydrogels as flexible sensor have attracted significant attention due to its conductivity, stretchability and flexibility. However, it is still a great challenge to prepare hydrogels that ...simultaneously possess high strength, anti-fatigue, self-adhesion, and anti-freezing. Herein, a multifunctional dual-network hydrogel was prepared by in situ polymerization of acrylic monomer in chitosan chains, and coordinated with aluminum chloride and glycerol. Based on chain entanglement, hydrogen bonding and coordination interactions, this dual-network hydrogel exhibited excellent mechanical properties, good fatigue resistance, and excellent adhesion performance. It can be used as a strain sensor for its stable conductivity and high sensitivity, which could monitor both large human motions and subtle motions. Due to the presence of glycerol, the hydrogel showed outstanding freezing resistance and still kept flexible and conductive even at low temperatures (−20 °C). This hydrogel can be applied as a flexible wearable sensor for monitoring human motion in extreme low-temperature condition.
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As one of only a handful of countries that have achieved both Millennium Development Goals (MDGs) 4 and 5, China has substantially lowered maternal mortality in the past two decades. Little is known, ...however, about the levels and trends of maternal mortality at the county level in China.
Using a national registration system of maternal mortality at the county level, we estimated the maternal mortality ratios for 2852 counties in China between 1996 and 2015. We used a state-of-the-art Bayesian small-area estimation hierarchical model with latent Gaussian layers to account for space and time correlations among neighbouring counties. Estimates at the county level were then scaled to be consistent with country-level estimates of maternal mortality for China, which were separately estimated from multiple data sources. We also assessed maternal mortality ratios among ethnic minorities in China and computed Gini coefficients of inequality of maternal mortality ratios at the country and provincial levels.
China as a country has experienced fast decline in maternal mortality ratios, from 108·7 per 100 000 livebirths in 1996 to 21·8 per 100 000 livebirths in 2015, with an annualised rate of decline of 8·5% per year, which is much faster than the target pace in MDG 5. However, we found substantial heterogeneity in levels and trends at the county level. In 1996, the range of maternal mortality ratios by county was 16·8 per 100 000 livebirths in Shantou, Guangdong, to 3510·3 per 100 000 livebirths in Zanda County, Tibet. Almost all counties showed remarkable decline in maternal mortality ratios in the two decades regardless of those in 1996. The annualised rate of decline across counties from 1996 to 2015 ranges from 4·4% to 12·9%, and 2838 (99·5%) of the 2852 counties had achieved the MDG 5 pace of decline. Decline accelerated between 2005 and 2015 compared with between 1996 and 2005. In 2015, the lowest county-level maternal mortality ratio was 3·4 per 100 000 livebirths in Nanhu District, Zhejiang Province. The highest was still in Zanda County, Tibet, but the fall to 830·5 per 100 000 livebirths was only 76·3%. 26 ethnic groups had population majorities in at least one county in China, and all had achieved declines in maternal mortality ratios in line with the pace of MDG 5. Intercounty Gini coefficients for maternal mortality ratio have declined at the national level in China, indicating improved equality, whereas trends in inequality at the provincial level varied.
In the past two decades, maternal mortality ratios have reduced rapidly and universally across China at the county level. Fast improvement in maternal mortality ratios is possible even in less economically developed places with resource constraints. This finding has important implications for improving maternal mortality ratios in developing countries in the Sustainable Development Goal era.
National Health and Family Planning Commission of the People's Republic of China, China Medical Board, WHO, University of Washington Center for Demography and Economics of Aging, Bill & Melinda Gates Foundation.
Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) present unique molecular signatures, but the tumorigenesis of EBVaGCs and the role EBV plays during this process remain poorly ...understood.
We applied whole-exome sequencing, EBV genome sequencing, and whole-genome bisulfite sequencing to multiple samples (n = 123) derived from the same patients (n = 25), which covered saliva samples and different histological stages from morphologically normal epithelial tissues to dysplasia and EBVaGCs. We compared the genomic landscape between EBVaGCs and their precursor lesions and traced the clonal evolution for each patient. We also analyzed genome sequences of EBV from samples of different histological types. Finally, the key molecular events promoting the tumor evolution were demonstrated by MTT, IC50, and colony formation assay in vitro experiments and in vivo xenograft experiments.
Our analysis revealed increasing mutational burden and EBV load from normal tissues and low-grade dysplasia (LD) to high-grade dysplasia (HD) and EBVaGCs, and oncogenic amplifications occurred late in EBVaGCs. Interestingly, within each patient, EBVaGCs and HDs were monoclonal and harbored single-strain-originated EBV, but saliva or normal tissues/LDs had different EBV strains from that in EBVaGCs. Compared with precursor lesions, tumor cells showed incremental methylation in promotor regions, whereas EBV presented consistent hypermethylation. Dominant alterations targeting the PI3K-Akt and Wnt pathways were found in EBV-infected cells. The combinational inhibition of these two pathways in EBV-positive tumor cells confirmed their synergistic function.
We portrayed the (epi) genomic evolution process of EBVaGCs, revealed the extensive genomic diversity of EBV between tumors and normal tissue sites, and demonstrated the synergistic activation of the PI3K and Wnt pathways in EBVaGCs, offering a new potential treatment strategy for this disease.
The metabolic effect of fructose in sugar-sweetened beverages (SSB) has been linked to de novo lipogenesis and uric acid (UA) production.
This study investigated the biological effects of SSB ...consumption on serum lipid profiles and retinol-binding protein 4 (RBP4) among Taiwanese adolescents.
We evaluated the anthropometric parameters and biochemical outcomes of 200 representative adolescents (98 boys and 102 girls) who were randomly selected from a large-scale cross-sectional study. Data were analyzed using multiple regression models adjusted for covariates.
Increased SSB consumption was associated with increased waist and hip circumferences, body mass index (BMI) values and serum UA, triglyceride (TG) and RBP4 levels. Adolescents who consumed >500 ml/day of beverages half-to-heavily sweetened with high-fructose corn syrup (HFCS) exhibited TG and RBP4 levels 22.7 mg/dl and 13.92 ng/ml higher than non-drinkers, respectively. HFCS drinkers with hyperuricemia had higher TG levels than HFCS drinkers with normal UA levels (98.6 vs. 81.6 mg/dl). The intake of HFCS-rich SSBs and high value of BMI (≥24) interactively reinforced RBP4 levels among overweight/obese adolescents. Circulating RBP4 levels were significantly correlated with weight-related outcomes and TG and UA concentration among HFCS drinkers (r = 0.253 to 0.404), but not among non-drinkers.
High-quantity HFCS-rich beverage consumption is associated with higher TG and RBP4 levels. Hyperuricemia is likely to intensify the influence of HFCS-rich SSB intake on elevated TG levels, and in overweight and obese adolescents, high BMI may modify the action of fructose on higher circulating levels of RBP4.
BACKGROUND Shixiang plaster is a traditional Chinese medicine has been used to treat chronic ulcers, including diabetic ulcers. Aminoguanidine is a hydrazine derivative that inhibits the formation of ...advanced glycosylation end products (AGEs). This study aimed to investigate the effects of shixiang plaster and aminoguanidine on wound healing in the streptozotocin-induced rat model of diabetes and the molecular mechanisms involved. MATERIAL AND METHODS Sprague-Dawley rats treated with intraperitoneal streptozotocin and given surgical wounds were divided into the untreated chronic ulcer group (n=10), the aminoguanidine group (n=10), the shixiang plaster group (n=10), and the control group with sham surgery (n=10). Granulation tissue samples underwent light microscopy to evaluate angiogenesis and immunohistochemistry to identify AGE, vascular endothelial growth factor (VEGF), and CD34 expression. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot measured mRNA and protein expression of receptor for advanced glycation end products (RAGE), vascular cell adhesion molecule-1 (VCAM-1), nuclear factor kappa B (NF-kappaB) and endothelial nitric oxide synthase (eNOS). RESULTS The shixiang plaster group showed a significant increase in angiogenesis in ulcer granulation tissue, significantly reduced expression of AGEs and increased expression of VEGF and CD34 expression in granulation tissue compared with the untreated chronic ulcer group (p<0.05). The shixiang plaster group showed significantly down-regulated expression of RAGE and VCAM-1 compared with the untreated chronic ulcer group (p<0.05). Shixiang plaster promoted angiogenesis by activating the NF-kappaB p65 associated pathway and eNOS activation. CONCLUSIONS Shixiang plaster promoted healing in a rat model of diabetic ulcer through the RAGE/NF-kappaB and VEGF/VCAM-1/eNOS signaling pathways.
Purpose
The aim of the study is to explore interhemispheric homotopic functional connectivity alterations in systemic lupus erythematosus (SLE) patients with and without neuropsychiatric lupus (NPSLE ...and non-NPSLE, respectively) and their potential correlations with clinical characteristics and neuropsychological performance.
Methods
Based on resting-state functional MRI (rs-fMRI) data collected from SLE patients and matched healthy controls (HCs), the voxel-mirrored homotopic connectivity (VMHC) analysis was conducted to measure functional homotopy. Subsequently, correlations between altered functional homotopy and clinical/neuropsychological data were analyzed.
Results
Compared with the HC group, both NPSLE and non-NPSLE groups showed attenuated homotopic connectivity in middle temporal gyrus (MTG), cuneus (CUN), middle occipital gyrus (MOG), angular gyrus (ANG), and postcentral gyrus (PoCG). NPSLE patients also exhibited decreased homotopic connectivity in inferior parietal gyrus (IPG) and middle frontal gyrus (MFG). Compared with non-NPSLE patients, NPSLE patients showed weaker interhemispheric homotopic functional connectivity in MOG. Decreased homotopic functional connectivity in PoCG, IPG, and MOG were associated with the anxiety state of SLE patients.
Conclusions
Our findings revealed attenuated functional homotopy in both NPSLE and non-NPSLE groups compared to the HC group, which appeared to be more severe in patients with comorbid neuropsychiatric lupus. Interhemispheric homotopy dysconnectivity may participate in the neuropathology of anxiety symptoms in SLE.
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