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Abstract Background Osteoarthritis (OA) is a degenerative osteoarticular disease, involving genetic predisposition. How the risk variants confer the risk of OA through their effects on proteins remains largely unknown. Therefore, we aimed to discover new and effective drug targets for OA and its subtypes. Methods A proteome-wide association study (PWAS) was performed based on OA and its subtypes genome-wide association studies (GWAS) summary datasets and the protein quantitative trait loci (pQTL) data. Subsequently, Mendelian randomization (MR) and colocalization analysis was conducted to estimate the associations between protein and OA risk. The replication analysis was performed in an independent dataset of human plasma pQTL data. Results The abundance of seven proteins was causally related to OA, two proteins to knee OA and six proteins to hip OA, respectively. We replicated 2 of these proteins using an independent pQTL dataset. With the further support of colocalization, and higher ECM1 level was causally associated with a higher risk of OA and hip OA. Higher PCSK1 level was causally associated with a lower risk of OA. And higher levels of ITIH1, EFEMP1, and ERLEC1 were associated with decreased risk of hip OA. Conclusion Our study provides new insights into the genetic component of protein abundance in OA and a promising therapeutic target for future drug development.

Abstract Helicobacter pylori (H. pylori), known for causing gastric inflammation, gastritis and gastric cancer, prompted our study to investigate the differential expression of cytokines in gastric tissues, which is crucial for understanding H. pylori infection and its potential progression to gastric cancer. Focusing on Il-1β, IL-6, IL-8, IL-12, IL-18, and TNF-α, we analysed gene and protein levels to differentiate between H. pylori-infected and non-infected gastritis. We utilised real-time quantitative polymerase chain reaction (RT-qPCR) for gene quantification, immunohistochemical staining, and ELISA for protein measurement. Gastric samples from patients with gastritis were divided into three groups: (1) non-gastritis (N-group) group, (2) gastritis without H. pylori infection (G-group), and (3) gastritis with H. pylori infection (GH-group), each consisting of 8 samples. Our findings revealed a statistically significant variation in cytokine expression. Generally, cytokine levels were higher in gastritis, but in H. pylori-infected gastritis, IL-1β, IL-6, and IL-8 levels were lower compared to H. pylori-independent gastritis, while IL-12, IL-18, and TNF-α levels were higher. This distinct cytokine expression pattern in H. pylori-infected gastritis underscores a unique inflammatory response, providing deeper insights into its pathogenesis.

PurposeTo develop a predictive model using machine learning for levothyroxine (L-T4) dose selection in patients with differentiated thyroid cancer (DTC) after resection and radioactive iodine (RAI) therapy and to prospectively validate the accuracy of the model in two institutions.MethodsA total of 266 DTC patients who received RAI therapy after thyroidectomy and achieved target thyroid stimulating hormone (TSH) level were included in this retrospective study. Sixteen clinical and biochemical characteristics that could potentially influence the L-T4 dose were collected; Significant features correlated with L-T4 dose were selected using machine learning random forest method, and a total of eight regression models were established to assess their performance in prediction of L-T4 dose after RAI therapy; The optimal model was validated through a two-center prospective study (n=263).ResultsSix significant clinical and biochemical features were selected, including body surface area (BSA), weight, hemoglobin (HB), height, body mass index (BMI), and age. Cross-validation showed that the support vector regression (SVR) model was with the highest accuracy (53.4%) for prediction of L-T4 dose among the established eight models. In the two-center prospective validation study, a total of 263 patients were included. The TSH targeting rate based on constructed SVR model were dramatically higher than that based on empirical administration (Rate 1 (first rate): 52.09% (137/263) vs 10.53% (28/266); Rate 2 (cumulative rate): 85.55% (225/263) vs 53.38% (142/266)). Furthermore, the model significantly shortens the time (days) to achieve target TSH level (62.61 ± 58.78 vs 115.50 ± 71.40).ConclusionsThe constructed SVR model can effectively predict the L-T4 dose for postoperative DTC after RAI therapy, thus shortening the time to achieve TSH target level and improving the quality of life for DTC patients.

This paper presents an experimental study on the compressive properties and creep behavior of Mg-Gd-Y-Zn-Mn-Nd alloy. A total of 42 specimens are prepared and tested, including 18 compression tests and 24 creep tests. The investigation aims to evaluate the influence of material orientation, temperature, and initial stress (for creep test only) on the compressive behavior of the Mg-Gd-Y-Zn-Mn-Nd alloy. First, the results of compression tests are analyzed, revealing insights into the anisotropic behavior, failure mode, yield strength, ultimate compressive strength, and failure strain of the Mg-Gd-Y-Zn-Mn-Nd alloy under compressive loading. Then, according to the experimental data from creep tests, where the steady creep rate, stress exponent and activation energy are calibrated. Furthermore, the creep mechanisms of the Mg-Gd-Y-Zn-Mn-Nd alloy under various material orientations are discussed. Additionally, the authors analyze and compare the Electron Backscatter Diffraction (EBSD) data of the Mg-Gd-Y-Zn-Mn-Nd alloy before and after undergoing compressive creep. Finally, based on the test results, a mathematical model is proposed to describe the development of compressive creep strain.

Abstract Background The consolidation tumor ratio (CTR) is a predictor of invasiveness in peripheral T1N0M0 lung adenocarcinoma. However, its association with spread through air spaces (STAS) remains largely unexplored. We aimed to explore the correlation between the CTR of primary tumors and STAS in peripheral T1N0M0 lung adenocarcinoma. Methods We collected data from patients who underwent surgery for malignant lung neoplasms between January and November 2022. Univariate and multivariate analyses following propensity-score matching with sex, age, BMI, were performed to identify the independent risk factors for STAS. The incidence of STAS was compared based on pulmonary nodule type. A smooth fitting curve between CTR and STAS was produced by the generalized additive model (GAM) and a multiple regression model was established using CTR and STAS to determine the dose-response relationship and calculate the odds ratio (OR) and 95% confidence interval (CI). Results 17 (14.5%) were diagnosed with STAS. The univariate analysis demonstrated that the history of the diabetes, size of solid components, spiculation, pleural indentation, pulmonary nodule type, consolidation/tumor ratio of the primary tumor were statistically significant between the STAS-positive and STAS-negative groups following propensity-score matching(p = 0.047, 0.049, 0.030, 0.006, 0.026, and

An innovative complex lidar system deployed on an airborne rotorcraft platform for remote sensing of atmospheric pollution is proposed and demonstrated. The system incorporates integrated-path differential absorption lidar (DIAL) and coherent-doppler lidar (CDL) techniques using a dual tunable TEA CO2 laser in the 9–11 μm band and a 1.55 μm fiber laser. By combining the principles of differential absorption detection and pulsed coherent detection, the system enables agile and remote sensing of atmospheric pollution. Extensive static tests validate the system’s real-time detection capabilities, including the measurement of concentration-path-length product (CL), front distance, and path wind speed of air pollution plumes over long distances exceeding 4 km. Flight experiments is conducted with the helicopter. Scanning of the pollutant concentration and the wind field is carried out in an approximately 1 km slant range over scanning angle ranges from 45° to 65°, with a radial resolution of 30 m and 10 s. The test results demonstrate the system’s ability to spatially map atmospheric pollution plumes and predict their motion and dispersion patterns, thereby ensuring the protection of public safety.

Abstract Purpose To establish a multivariate linear equation to predict the diameter (outer diameter) of the acetabular prosthesis used in total hip arthroplasty. Methods A cohort of 258 individuals who underwent THA at our medical facility were included in this study. The independent variables encompassed the patients' height, weight, foot length, gender, age, and surgical access. The dependent variable in this study was the diameter of the acetabular prosthesis utilized during the surgical procedure. The entire cohort dataset was randomly partitioned into a training cohort and a validation cohort, with a ratio of 7:3, employing the SPSS 26.0 software. Pearson correlation analysis was conducted to examine the relationships between the patients' height, weight, foot length, gender, age, surgical access, and the diameter of the acetabular prosthesis in the training cohort. Additionally, a multiple linear regression equation was developed using the independent variables from the training cohort and the diameter of the acetabular prosthesis as the dependent variable. This equation aimed to predict the diameter of the acetabular prosthesis based on the patients' characteristics. The accuracy of the equation was evaluated by substituting the data of the validation cohort into the multiple linear equation. The predicted acetabular prosthesis diameters were then compared with the actual diameters used in the operation. Results The correlation analysis conducted on the training cohort revealed that surgical access (r = 0.054) and age (r = −0.120) exhibited no significant correlation with the diameter of the acetabular prosthesis utilized during the intraoperative procedure. Conversely, height (r = 0.687), weight (r = 0.654), foot length (r = 0.687), and sex (r = 0.354) demonstrated a significant correlation with the diameter of the acetabular prosthesis used intraoperatively. Furthermore, a predictive equation, denoted as Y (acetabular prosthesis diameter in mm) = 20.592 + 0.548 × foot length (cm) + 0.083 × height (cm) + 0.077 × weight (kg), was derived. This equation accurately predicted the diameter within one size with an accuracy rate of 64.94% and within two sizes with an accuracy rate of 94.81%. Conclusion Anthropometric data can accurately predict the diameter of acetabular prosthesis during total hip arthroplasty.

Plasmopara viticola (Berk.et Curtis) Berl. Et de Toni is the pathogen that causes grape downy mildew, which is an airborne disease that severely affects grape yield and causes huge economic losses. The usage of effective control methods can reduce the damage to plants induced by grape downy mildew. Biocontrol has been widely used to control plant diseases due to its advantages of environmental friendliness and sustainability. However, to date, only a few comprehensive reviews on the biocontrol of grape downy mildew have been reported. In this review, we summarize the biological characteristics of P. viticola and its infection cycle, followed by a detailed overview of current biocontrol agents, including bacteria and fungi that could be used to control grape downy mildew, and their control effects. Furthermore, potential control mechanisms of biocontrol agents against grape downy mildew are discussed. Lastly, suggestions for future research on the biocontrol of grape downy mildew are provided. This review provides the basis for the application of grape downy mildew biocontrol.

Background: Observational evidence suggests that type 1 diabetes mellitus (T1DM) is associated with the risk of osteoporosis (OP). Nevertheless, it is not apparent whether these correlations indicate a causal relationship. To elucidate the causal relationship, a two-sample Mendelian randomization (MR) analysis was performed. Methods: T1DM data was obtained from the large genome-wide association study (GWAS), in which 6683 cases and 12,173 controls from 12 European cohorts were involved. Bone mineral density (BMD) samples at four sites were extracted from the GEnetic Factors for OSteoporosis (GEFOS) consortium, including forearm (FA) (n = 8,143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498), and heel (eBMD) (n = 426,824). The former three samples were from mixed populations and the last one was from European. Inverse variance weighting, MR-Egger, and weighted median tests were used to test the causal relationship between T1DM and OP. A series of sensitivity analyses were then conducted to verify the robustness of the results. Results: Twenty-three independent SNPs were associated with FN-BMD and LS-BMD, twenty-seven were associated with FA-BMD, and thirty-one were associated with eBMD. Inverse variance-weighted estimates indicated a causal effect of T1DM on FN-BMD (odds ratio (OR) =1.033, 95 % confidence interval (CI): 1.012–1.054, p = 0.002) and LS-BMD (OR = 1.032, 95 % CI: 1.005–1.060, p = 0.022) on OP risk. Other MR methods, including weighted median and MR-Egger, calculated consistent trends. While no significant causation was found between T1DM and the other sites (FA-BMD: OR = 1.008, 95 % CI: 0.975–1.043, p = 0.632; eBMD: OR = 0.993, 95 % CI: 0.985–1.001, p = 0.106). No significant heterogeneity (except for eBMD) or horizontal pleiotropy was found for instrumental variables, suggesting these results were reliable and robust. Conclusions: This study shows a causal relationship between T1DM and the risk of some sites of OP (FN-BMD, LS-BMD), allowing for continued research to discover the clinical and experimental mechanisms of T1DM and OP. It also contributes to the recommendation if patients with T1DM need targeted care to promote bone health and timely prevention of osteoporosis.

BackgroundImmunotherapy targeting factors related to immune imbalance has been widely employed for RA treatment. This study aimed to evaluate the efficacy and safety of low-dose interleukin (IL)-2 combined with tocilizumab (TCZ), a biologics targeting IL-6, in RA patients.MethodsFifty adults with active RA who met the criteria with complete clinical data were recruited, and divided into three groups: control group (n=15), IL-2 group (n=26), and IL-2+TCZ group (n=9). In addition to basic treatment, participants in the IL-2 group received IL-2 (0.5 MIU/day), while participants in the IL-2+TCZ group received IL-2 (0.5 MIU/day) along with one dose of TCZ (8 mg/kg, maximum dose: 800 mg). All subjects underwent condition assessment, laboratory indicators and safety indicators detection, and records before treatment and one week after treatment.ResultsCompared with the baseline, all three groups showed significant improvement in disease conditions, as evidenced by significantly reduced disease activity indicators. The low-dose IL-2 and combination treatment groups demonstrated a violent proliferation of Tregs, while the absolute number of Th1, Th2, and Th17 cells in the latter group showed a decreasing trend. The decrease in the Th17/Treg ratio was more pronounced in the IL-2+TCZ groups. No significant adverse reactions were observed in any of the patients.ConclusionExogenous low doses of IL-2 combined TCZ were found to be safe and effective in reducing effector T cells and appropriately increasing Treg levels in RA patients with high effector T cell levels. This approach helps regulate immune homeostasis and contributes to the prevention of disease deterioration.Clinical trial registrationhttps://www.chictr.org.cn/showprojEN.html?proj=13909, identifier ChiCTR-INR-16009546.

Abstract Background The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, has been found to have increased expression in the joints of patients with RA compared to healthy individuals. However, the causal relationship between the expression level of IL-17 or IL-17 receptor (IL-17R) and RA remained unknown. In this study, two-sample Mendelian randomization (MR) was used to investigate the causal relationship between IL-17 and RA. Methods Summary statistics for RA (14,361 RA cases and 43,923 healthy controls) and IL-17 (3,301 samples) were obtained from an available meta-analysis of published genome-wide association studies (GWAS). Relevant single nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. Then we used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality. MR and MVMR analyses progressed mainly using inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods, which were applied to the genetic instrumental variables (IVs) of IL-17A/IL-17 RA, IL-17C/IL-17 RC, and IL-17D/IL-17RD and RA. For assessing the robustness of the results, we also carried out a sensitivity analysis to assess heterogeneity and pleiotropy, such as MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO). Results Two-sample MR Analysis showed the causal relationship between IL-17A/IL-17RA and RA. The presence of genetically high IL-17A/IL-17RA may increase the risk of RA (IL-17A(OR = 1.095; 95% C.I., 0.990-1.210, p.adj = 0.013), IL-17RA(OR = 1.113, 95%CI = 1.006-1.231, p.adj = 0.006)). However, the results indicated that IL-17C/IL-17RC, and IL-17D/IL-17RD demonstrated no causal impact on RA (IL-17C(OR = 1.007, 95%CI = 0.890-1.139, p.adj = 0.152), IL-17RC(OR = 1.006, 95%CI = 0.904-1.119, p.adj = 0.152), IL-17D(OR = 0.979, 95%CI = 0.843-1.137, p.adj = 0.130), IL-17RD(OR = 0.983, 95%CI = 0.876-1.104, p.adj = 0.129)). Furthermore, MVMR analysis shown that IL-17RA(OR = 1.049, 95% CI: 0.997-1.102, p.adj = 0.014) was associated with increased risk of RA. Sensitivity analysis showed no heterogeneity and pleiotropy, suggesting that the above results were robust and reliable. Conclusion The MR analysis provides evidence that IL-17A/IL-17RA are risk factors for RA. This emphasizes the importance of intervention on IL-17A/IL-17RA in patients with RA. Developing drugs that limit IL-17A may reduce the risk of RA.

Abstract Rheumatoid arthritis (RA) is an autoimmune disease characterized by the accumulation of leukocytes and inflammatory mediators within the synovial tissue. Leukocyte counts are proposed to play a role in the pathogenesis of RA. However, the causality remains unclear. To investigate the causal relationship between various leukocytes and RA by implementing two-sample univariable Mendelian Randomization (MR) and multivariable MR. MR analysis was performed using respective genome-wide association study (GWAS) summary statistics for the exposure traits (eosinophil counts, neutrophil counts, lymphocyte counts, monocyte counts, basophil counts, and white blood cell counts) and outcome trait (RA). Summary statistics for leukocytes were extracted from the Blood Cell Consortium meta-analysis and INTERVAL studies. Public GWAS information for RA included 14,361 cases and 43,923 controls. Inverse variance weighted, weighted median, MR-Egger regression, MR pleiotropy residual sum and outlier, and multivariable MR analyses were performed in MR analysis. Univariable MR found elevated eosinophil counts (OR 1.580, 95% CI 1.389–2.681, p = 1.30 × 10–7) significantly increased the risk of RA. Multivariable MR further confirmed that eosinophil counts were a risk factor for RA. Increased eosinophils were associated with higher risk of RA. Further elucidations of the causality and mechanisms underlying are likely to identify feasible interventions to promote RA prevention.

Abstract Increasing evidence shows the African lineage Zika virus (ZIKV) displays a more severe neurovirulence compared to the Asian ZIKV. However, viral determinants and the underlying mechanisms of enhanced virulence phenotype remain largely unknown. Herein, we identify a panel of amino acid substitutions that are unique to the African lineage of ZIKVs compared to the Asian lineage by phylogenetic analysis and sequence alignment. We then utilize reverse genetic technology to generate recombinant ZIKVs incorporating these lineage-specific substitutions based on an infectious cDNA clone of Asian ZIKV. Through in vitro characterization, we discover a mutant virus with a lysine to arginine substitution at position 101 of capsid (C) protein (termed K101R) displays a larger plaque phenotype, and replicates more efficiently in various cell lines. Moreover, K101R replicates more efficiently in mouse brains and induces stronger inflammatory responses than the wild type (WT) virus in neonatal mice. Finally, a combined analysis reveals the K101R substitution promotes the production of mature C protein without affecting its binding to viral RNA. Our study identifies the role of K101R substitution in the C protein in contributing to the enhanced virulent phenotype of the African lineage ZIKV, which expands our understanding of the complexity of ZIKV proteins.

Abstract Background Rotator cuff-related shoulder pain (RCRSP) is the most common cause of shoulder disorders. In China, manipulation has been used extensively for the treatment of patients with RCRSP. However, high-quality clinical evidence to support the therapeutic effect of manipulation is still limited. Methods A multicenter, participant-, outcome assessor-, and data analyst-blinded, randomized, placebo-controlled trial will be conducted. A total of 280 participants with RCRSP will be recruited from three hospitals and randomly assigned to a five-step shoulder manipulation (FSM) group or a sham manipulation (SM) group. Each group will receive four weekly treatment sessions, with all participants performing exercises at home for 12 weeks. Assessments, namely the Constant–Murley score, visual analog scale, range of motion, and 36-Item Short Form Survey, will be made at baseline, 4, 12, 18, and 24 weeks. Adverse events during the study will also be recorded. Discussion This is a pragmatic clinical trial to evaluate the efficacy and safety of FSM in patients with RCRSP. The findings of this study will provide worthy clinical evidence for manual therapy for RCRSP. Trial registration China Registered Clinical Trial Registration Center ChiCTR2000037577. Registered on 29 August 2020.

IntroductionThe impact of stress on reproductive function is significant. Hypothalamic paraventricular nucleus (PVN) corticotrophin-releasing hormone (CRH) plays a major role in regulating the stress response. Understanding how the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis interact is crucial for comprehending how stress can lead to reproductive dysfunction. However, whether stress influences reproductive function via modulating PVN CRH or HPA sequelae is not fully elucidated.MethodsIn this study, we investigated the impact of chemogenetic activation of PVN CRH neurons on reproductive function. We chronically and selectively stimulated PVN CRH neurons in female CRH-Cre mice using excitatory designer receptor exclusively activated by designer drugs (DREADDs) viral constructs, which were bilaterally injected into the PVN. The agonist compound-21 (C21) was delivered through the drinking water. We determined the effects of DREADDs activation of PVN CRH neurons on the estrous cycles, LH pulse frequency in diestrus and metestrus and LH surge in proestrus mice. The effect of long-term C21 administration on basal corticosterone secretion and the response to acute restraint stress during metestrus was also examined. Additionally, computer simulations of a mathematical model were used to determine the effects of DREADDs activation of PVN CRH neurons, simulating chronic stress, on the physiological parameters examined experimentally.ResultsAs a result, and consistent with our mathematical model predictions, the length of the estrous cycle was extended, with an increase in the time spent in estrus and metestrus, and a decrease in proestrus and diestrus. Additionally, the frequency of LH pulses during metestrus was decreased, but unaffected during diestrus. The occurrence of the preovulatory LH surge during proestrus was disrupted. The basal level of corticosterone during metestrus was not affected, but the response to acute restraint stress was diminished after long-term C21 application.DiscussionThese data suggest that PVN CRH neurons play a functional role in disrupting ovarian cyclicity and the preovulatory LH surge, and that the activity of the GnRH pulse generator remains relatively robust during diestrus but not during metestrus under chronic stress exposure in accordance with our mathematical model predictions.

Abstract Virus spillover remains a major challenge to public health. A panel of SARS-CoV-2-related coronaviruses have been identified in pangolins, while the infectivity and pathogenicity of these pangolin-origin coronaviruses (pCoV) in humans remain largely unknown. Herein, we comprehensively characterized the infectivity and pathogenicity of a recent pCoV isolate (pCoV-GD01) in human cells and human tracheal epithelium organoids and established animal models in comparison with SARS-CoV-2. pCoV-GD01 showed similar infectivity to SARS-CoV-2 in human cells and organoids. Remarkably, intranasal inoculation of pCoV-GD01 caused severe lung pathological damage in hACE2 mice and could transmit among cocaged hamsters. Interestingly, in vitro neutralization assays and animal heterologous challenge experiments demonstrated that preexisting immunity induced by SARS-CoV-2 infection or vaccination was sufficient to provide at least partial cross-protection against pCoV-GD01 challenge. Our results provide direct evidence supporting pCoV-GD01 as a potential human pathogen and highlight the potential spillover risk.

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease of unexplained causes. Its pathological features include synovial tissue hyperplasia, inflammatory cell infiltration in joint cavity fluid, cartilage bone destruction, and joint deformation. C–C motif chemokine ligand 3 (CCL3) belongs to inflammatory cell chemokine. It is highly expressed in inflammatory immune cells. Increasingly, studies have shown that CCL3 can promote the migration of inflammatory factors to synovial tissue, the destruction of bone and joint, angiogenesis, and participate in the pathogenesis of RA. These symptoms indicate that the expression of CCL3 is highly correlated with RA disease. Therefore, this paper reviews the possible mechanism of CCL3 in the pathogenesis of RA, which may provide some new insights for the diagnosis and treatment of RA.

Abstract Biomimetic viral mineralization improves viral vaccine stability and immunogenicity using inorganic metals such as Ca, Al, or Fe. Mn is a metal found in high concentrations in mammalian tissues; however, under natural or laboratory conditions, Mn mineralization by medical viruses has yet to be established. Herein, a single IAV particle is successfully encapsulated with manganese phosphate (MnP) under specific conditions using the human influenza A virus (IAV). MnP‐mineralized IAVs (IAV@Mn) exhibited physiochemical and in vitro properties similar to Ca‐mineralized IAVs. In animal models, IAV@Mn shows limited replication in immune‐competent cells and a significant attenuation compared to naïve cells. Moreover, a single‐dose vaccination with IAV@Mn induced robust humoral and cellular immune responses and conferred significant protection against a wild‐type IAV challenge in mice. Thus, Mn mineralization in pathogenic viruses provides a rapid and universal strategy for generating an emergency vaccine in response to emerging viruses.

AIM: To illustrate clinicopathological features of orbital non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), and to compare the treatment outcome between postoperative radiotherapy (RT) and chemotherapy in a retrospective analysis nearly 20y. METHODS: A retrospective cohort study of 56 patients with orbital NRSTS were reviewed, 34 of whom received postoperative RT, and 22 received postoperative chemotherapy. The clinicopathological features, local recurrence, metastases, and survival data were recorded. Survival analysis was performed using the Kaplan-Meier method. RESULTS: During follow-up (111.8mo, ranged 8-233mo) for 56 patients, 19 patients of them developed local recurrence, and 7 patients developed distant metastases. Fifteen patients died during follow-up period. Overall survival rates considering the whole study group was 78.57% at 5y, and 72.16% at 10y after the initial diagnosis. Compared with chemotherapy, RT was associated with lower risk of local recurrence [hazard ratio for RT vs chemotherapy, 0.263, 95% confidence interval (CI), 0.095-0.728, P=0.0015]; with lower risk of distant metastasis (hazard ratio for RT vs chemotherapy, 0.073, 95%CI, 0.015-0.364, P=0.0014); and with lower risk of death from disease (hazard ratio for RT vs chemotherapy, 0.066, 95%CI, 0.022-0.200, P

Human RNA binding protein Musashi-1 binds various host transcripts as well as Zika virus RNA in neural progenitor cells. Here, Chen et al. characterise the interactions between Musashi-1 and its binding site using a combination of molecular and biophysical methods to shed light on its role in viral neurotropism.

CKRC3/TCU2 interacts with the NatB catalytic subunit to form a NatB complex, catalyzing the N-terminal acetylation of YUC proteins for their intracellular stability to maintain auxin homeostasis in plants.

Osteoporosis (OP) is a metabolic disease characterized by bone formation and resorption disturbances. Quanduzhong Capsule (QDZC) is a common treatment for OP in China; however, the effective components and metabolites of the drug after oral administration remain largely unknown. This study aims to identify the active components, analyze the metabolite changes, and investigate the underlying mechanism against OP. In the study, ovariectomy-induced rat OP model was established, then treated with QDZC. Alendronate sodium tablets (ASTs) were used as a reference drug. The chemical constituents of QDZC were analyzed by UPLC-QTOF-MS (ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry) and network pharmacology. The metabolomics was used to analyze differences in serum metabolites of rats in different groups [Sham, Model, Model + QDZC, and Model + AST] at 4, 8, and 12 weeks. Body weight and bone mineral density (BMD) were assessed. Enzyme-linked immunosorbent assay was used to determine serum levels of Akt, p-Akt, ERK, and p-ERK. Our data suggested 86 different chemicals from QDZC, including nine core compounds. QDZC significantly regulated 25 biomarkers linked to arachidonic acid metabolism and unsaturated fatty acid biosynthesis, and promoted serum expression of Akt, p-Akt, ERK, and p-ERK. QDZC might act by activating PI3K-Akt and MAPK signaling pathways. In addition, QDZC may use arachidonic acid derivatives to inhibit osteoclast generation and bone resorption and enhance calcitriol formation to improve calcium absorption and increase bone mass.

Over 700 bright millisecond-duration radio transients, known as fast radio bursts (FRBs), have been identified to date. Nevertheless, the origin of FRBs remains unknown. Two repeating FRBs (FRB 20121102A and FRB 20190520B) have been verified to be associated with persistent radio sources (PRSs), making them the best candidates to study the nature of FRBs. Monitoring the variability in PRSs is essential for understanding their physical nature. We conducted 22 observations of the PRSs linked to FRB 20121102A and FRB 20190520B using the Karl G. Jansky Very Large Array, to study their variability. We have observed significant flux variability for the PRSs of FRB 20121102A and FRB 20190520B, with a confidence level exceeding 99.99%, based on the observations covering the longest timescale recorded to date. The observed variability of the two PRSs exhibits no significant difference in amplitude across both short and long timescales. We found that the radio-derived star formation rates of the two FRB hosts are significantly higher than those measured by the optical H _α emissions, indicating that their host galaxies are highly obscured or most radio emissions are not from star formation processes. The observed timescale of PRS flux evolution constrained the magnetic field of FRB 20121102A with B _∥ ≳ 1 mG and FRB 20190520B with B _∥ ≳ 0.1 mG.

Sgr A* often shows bright, episodic flares observationally, but the mechanism of the flares' intermittent brightening is not very clear. Many people believe the flares may be formed by the nonthermal particles, which can be a consequence of the magnetic reconnection and shock waves. In this work, we use the larger magnetic loop in the presence of pseudo-Newtonian potential, which mimics general relativistic effects. The simulation results show that the reconnection of magnetic field lines passes through a current sheet, which bifurcates into two pairs of slow shocks. We also find the shock waves heat the plasma, especially when the plasma density is low. The shock wave heating effect by the magnetic reconnection is confirmed by the simulation results, and thus the process of instantaneous brightening of the flares on the accretion disk can be explained.

Abstract Background Recognition of viral invasion by innate antiviral immune system triggers activation of the type I interferon (IFN-I) and proinflammatory signaling pathways. Subsequently, IFN-I induction regulates expression of a group of genes known as IFN-I-stimulated genes (ISGs) to block viral infection. The tripartite motif containing 22 (TRIM22) is an ISG with strong antiviral functions. Results Here we have shown that the TRIM22 has been strongly upregulated both transcriptionally and translationally upon Zika virus (ZIKV) infection. ZIKV infection is associated with a wide range of clinical manifestations in human from mild to severe symptoms including abnormal fetal brain development. We found that the antiviral function of TRIM22 plays a crucial role in counterattacking ZIKV infection. Overexpression of TRIM22 protein inhibited ZIKV growth whereas deletion of TRIM22 in host cells increased ZIKV infectivity. Mechanistically, TRIM22, as a functional E3 ubiquitin ligase, promoted the ubiquitination and degradation of ZIKV nonstructural protein 1 (NS1) and nonstructural protein 3 (NS3). Further studies showed that the SPRY domain and Ring domain of TRIM22 played important roles in protein interaction and degradation, respectively. In addition, we found that TRIM22 also inhibited other flaviviruses infection including dengue virus (DENV) and yellow fever virus (YFV). Conclusion Thus, TRIM22 is an ISG with important role in host defense against flaviviruses through binding and degradation of the NS1 and NS3 proteins.

Abstract Background Phospholipase C-like 1 (PLCL1), a protein that lacks catalytic activity, has similar structures to the PLC family. The aim of this research was to find the function and underlying mechanisms of PLCL1 in fibroblast-like synoviocyte (FLS) of rheumatoid arthritis (RA). Methods In this study, we first analyzed the expression of PLCL1 in the synovial tissue of RA patients and K/BxN mice by immunohistochemical staining. Then silencing or overexpressing PLCL1 in FLS before stimulating by TNF-α. The levels of IL-6, IL-1β and CXCL8 in FLS and supernatants were detected by Western Blot (WB), Real-Time Quantitative PCR and Enzyme Linked Immunosorbent Assay. We used INF39 to specifically inhibit the activation of NLRP3 inflammasomes, and detected the expression of NLRP3, Cleaved Caspase-1, IL-6 and IL-1β in FLS by WB. Result When PLCL1 was silenced, the level of IL-6, IL-1β and CXCL8 were down-regulated. When PLCL1 was overexpressed, the level of IL-6, IL-1β and CXCL8 were unregulated. The previous results demonstrated that the mechanism of PLCL1 regulating inflammation in FLS was related to NLRP3 inflammasomes. INF39 could counteract the release of inflammatory cytokines caused by overexpression of PLCL1. Conclusion Result showed that the function of PLCL1 in RA FLS might be related to the NLRP3 inflammasomes. We finally confirmed our hypothesis with the NLRP3 inhibitor INF39. Our results suggested that PLCL1 might promote the inflammatory response of RA FLS by regulating the NLRP3 inflammasomes.

Metamaterials with low-frequency band gap have always been the focus of research. For this reason, many researchers have proposed many structural design schemes. In this paper, an innovative star-shaped hybrid metamaterial structure is proposed. Based on Bloch's theorem and finite element method, a dynamic model of the proposed structure is established, the band gap characteristics of the proposed structure are analyzed, and the generation mechanism of band gap is discussed with the mode shape of specific frequency. Then, the propagation characteristics of elastic wave in the proposed structure are analyzed by using the dispersion surface and group velocity images, and the attenuation region of vibration transmission in the finite periodic structure is consistent with the frequency range of band gap. Finally, the relationship between band gap and structure parameters is explored. The results show that the proposed structure has good band gap characteristics in the frequency range of 1000 Hz, the lowest frequency of band gap reaches 60.207 Hz, and the total band gap width accounts for 54.463%. This research opens up an ideological route for the design of low frequency metamaterial structures.

ObjectiveThis study aimed to explore the relationship between the plasma metabolites of adolescent obesity and hypertension and whether metabolite alterations had a mediating effort between adolescent obesity and hypertension.MethodsWe applied untargeted ultra-performance liquid chromatography–mass spectrometry (UPLC-MS) to detect the plasma metabolomic profiles of 105 adolescents. All participants were selected randomly based on a previous cross-sectional study. An orthogonal partial least squares- discriminant analysis (OPLS-DA), followed by univariate statistics and enrichment analysis, was used to identify differential metabolites. Using logistic regression for variable selection, an obesity-related metabolite score (OMS, OMS=∑k=1nβnmetabolite n) was constructed from the metabolites identified, and hypertension risk was estimated.ResultsIn our study, based on P< 0.05, variable importance in projection (VIP) > 1.0, and impact value > 0.1, we identified a total of 12 differential metabolites. Significantly altered metabolic pathways were the sphingolipid metabolism, purine metabolism, pyrimidine metabolism, phospholipid metabolism, steroid hormone biosynthesis, tryptophan, tyrosine, and phenylalanine biosynthesis. The logistic regression selection resulted in a four-metabolite score (thymidine, sphingomyelin (SM) d40:1, 4-hydroxyestradiol, and L-lysinamide), which was positively associated with hypertension risk (odds ratio: 7.79; 95% confidence interval: 2.13, 28.47; for the quintile 4 compared with quartile 1 of OMS) after multivariable adjustment.ConclusionsThe OMS constructed from four differential metabolites was used to predict the risk of hypertension in adolescents. These findings could provide sensitive biomarkers for the early recognition of hypertension in adolescents with obesity.

BackgroundThe study aims to explore the relationship between obesity and serum uric acid in adolescents by combining body mass index and waist height ratio.Methods475 adolescents in our study were classified as normal weight without central obesity (NW), normal weight but central obesity (NWCO), overweight or obesity without central obesity (OB) and overweight or obesity with central obesity (OBCO). Odds ratios (OR) and 95% confidence intervals (CI) for hyperuricemia were calculated using a logistic regression model. The dose-response association between obesity indicators and serum uric acid were explored by restricted cubic spline model.ResultsThe highest serum uric acid level and the OR for hyperuricemia were found in the OBCO group, regardless of sex. After controlling for waist height ratio, the risk of hyperuricemia increased with increasing body mass index in boys and girls. The restricted cubic spline model showed that boys had higher ORs for hyperuricemia at the 25th and 75th percentiles of body mass index than for waist height ratio and girls had a higher OR for hyperuricemia than waist height ratio at the 25th percentile of body mass index.ConclusionsHyperuricemia in adolescence was not only associated with the overweight or obesity in BMI, but with the combination of overweight or obesity in BMI and central obesity in WHtR. However, in boys and girls, the increased risk of hyperuricemia associated with elevated body mass index was significantly better than that of waist height ratio.

In this paper, novel two-dimensional single-phase three-ligament, four-ligament and six-ligament chiral structure models are proposed. The advantage is that it is easy to manufacture with few components, has good sound insulation and vibration damping performance, and is more practical. The dispersion information of the structure is calculated by combining Bloch's theorem and the finite element method. By varying the geometric parameters of the new structural single-cell and simulating the vibration transmission of the finite period structure to check the vibration suppression capability of the optimized structure. Three combined structures were constructed to compare their energy band properties with the base structure. The wave propagation characteristics within the combined structure are also analyzed by comprehensive means. It is shown that the optimized structure has a significantly lower bandgap down to below 1 kHz and a significantly wider bandgap width up to 3.6 kHz. The combined structure can open up a wider omnidirectional bandgap for multi-frequency and broadband vibration attenuation. The flexibility of the structure combination gives it a large potential for use, providing a new solution for broadband and multi-frequency vibration and noise reduction, while plane wave analysis provides theoretical support for structural optimization.

To achieve multi-frequency vibration suppression and wave propagation modulation, eight branching ligament structures for wind models are proposed. Using lattice theory, dynamical model and finite element release method, the structures are verified to have multi-frequency bandgaps. By attaching a solid disc at the center of the model, the bandgap coverage of the structure is improved and the bandgap frequency is reduced. The modal analysis shows that the vibration of branch ligaments and border ligaments has a suppression effect on elastic waves. The phase constant surface, phase velocity and wave propagation direction plots at specific frequencies are calculated to verify the directional and regional nature of wave propagation. And the good correspondence of group velocity and wave propagation finite element simulation results at specific frequencies. Finally, the calculated bandgap frequency range is compared with the vibration transfer function, and the two agree well. And the stress cloud diagram also shows that the optimized structure has an excellent vibration suppression capability. The innovatively designed structure has the combined advantages of light weight, ease of fabrication, wide frequency and low frequency vibration control, while the integrated in-plane wave analysis provides the theoretical basis for structural optimization.

Abstract Sugarcane is an established industrial crop providing sugar, ethanol and biomass‐derived electricity worldwide. Cane sugar content is an important breeding target, but its improvement remains very slow in many breeding programmes. Biotechnology strategies to improve sucrose accumulation made little progress at the crop level, mainly due to the limited understanding of its regulation. miRNAs regulate many metabolic processes in plants. However, their roles and target genes associated with sugarcane sucrose accumulation remain unknown. Here, we conducted high‐throughput sequencing of transcriptome, small RNAs and degradome of leaves and stem of two early‐maturing sugarcane genotypes with contrasting sucrose content from the early to late stages of sucrose accumulation stages, which provided more insights into miRNA‐associated gene regulation during sucrose accumulation. The stem sucrose content in both genotypes increased steadily with time during sucrose accumulation stage. Transcriptome analysis identified 18,722 differentially expressed genes (DEGs) between both genotypes during sucrose accumulation. The major DEGs identified were involved in starch and sucrose metabolism, and photosynthesis. miRNA sequencing identified 563 known and 281 novel miRNAs from both genotypes during sucrose accumulation. Of these, 311 miRNAs were differentially expressed. A combined transcriptome and miRNA data analysis revealed differentially expressed miRNA‐target mRNA pairs related to sugar metabolism, of which 46 targets were transcription factors (TFs). miR172, miR164, miR396 and miR169 appear to regulate AP2/ERF, NAC, GRF and bZIP TF members associated with sugar metabolism. This is the first report of sugarcane miRNAs associated with sugar accumulation.

Abstract Background Childhood obesity is more likely to increase the chance of many adult health problems. Numerous studies have shown obese children to be more prone to elevated blood pressure (BP) and hypertension. It is important to identify an obesity anthropometric index with good discriminatory power for them in pediatric population. Methods MEDLINE/PubMed, Web of Science, and Cochrane databases were retrieved comprehensively for eligible studies on childhood obesity and hypertension/elevated BP through June 2021. The systematic review and meta-analysis of studies used receiver operating characteristics (ROC) curves for evaluating the discriminatory power of body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR) in distinguishing children with elevated BP and hypertension. Results 21 cross-sectional studies involving 177,943 children and 3–19 years of age were included in our study. Meta-analysis showed that the pooled area under the reporting receiver-operating characteristic curves (AUC) and 95% confidence intervals (CIs) for BMI, WC, and WHtR to detect hypertension of boys were 0.68 (0.64, 0.72), 0.69 (0.64, 0.74), 0.67 (0.63, 0.71), for elevated BP, the pooled AUCs and 95% CIs were 0.67 (0.61, 0.73), 0.65 (0.58, 0.73), 0.65 (0.61, 0.71). The pooled AUCs and 95% CIs for BMI, WC and WHtR of predicting hypertension were 0.70 (0.66, 0.75), 0.69 (0.64, 0.75), 0.67 (0.63, 0.72) in girls, the pooled AUCs and 95% CIs of predicting elevated BP were 0.63 (0.61, 0.65), 0.62 (0.60, 0.65), 0.62 (0.60, 0.64) respectively. There was no anthropometric index was statistically superior in identifying hypertension and elevated BP, however, the accuracy of BMI predicting hypertension was significantly higher than elevated BP in girls (P

Abstract Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by synovial hyperplasia, inflammatory cell infiltration, and proliferation of inflammatory tissue (angiogranuloma). The destruction of joints and surrounding tissues eventually causes joint deformities and dysfunction or even loss. The S100 protein family is one of the biggest subtribes in the calcium-binding protein family and has more than 20 members. The overexpression of most S100 proteins in rheumatoid arthritis is closely related to its pathogenesis. This paper reviews the relationship between S100 proteins and the occurrence and development of rheumatoid arthritis. It will provide insights into the development of new clinical diagnostic markers and therapeutic targets for rheumatoid arthritis.

Summary: Background: Zika virus (ZIKV) is an emerging arbovirus of the genus flavivirus that is associated with congenital Zika syndrome (CZS) in newborns. A wide range of clinical symptoms including intellectual disability, speech delay, coordination or movement problems, and hearing and vision loss, have been well documented in children with CZS. However, whether ZIKV can invade the olfactory system and lead to post-viral olfactory dysfunction (PVOD) remains unknown. Methods: We investigated the susceptibility and biological responses of the olfactory system to ZIKV infection using mouse models and human olfactory organoids derived from patient olfactory mucosa. Findings: We demonstrate that neonatal mice infected with ZIKV suffer from transient olfactory dysfunction when they reach to puberty. Moreover, ZIKV mainly targets olfactory ensheathing cells (OECs) and exhibits broad cellular tropism colocalizing with small populations of mature/immature olfactory sensory neurons (mOSNs/iOSNs), sustentacular cells and horizontal basal cells in the olfactory mucosa (OM) of immunodeficient AG6 mice. ZIKV infection induces strong antiviral immune responses in both the olfactory mucosa and olfactory bulb tissues, resulting in the upregulation of proinflammatory cytokines/chemokines and genes related to the antiviral response. Histopathology and transcriptomic analysis showed typical tissue damage in the olfactory system. Finally, by using an air-liquid culture system, we showed that ZIKV mainly targets sustentacular cells and OECs and support robust ZIKV replication. Interpretation: Our results demonstrate that olfactory system represents as significant target for ZIKV infection, and that PVOD may be neglected in CZS patients. Funding: Stated in the acknowledgment.

Abstract Messenger RNA (mRNA) vaccine technology has shown its power in preventing the ongoing COVID-19 pandemic. Two mRNA vaccines targeting the full-length S protein of SARS-CoV-2 have been authorized for emergency use. Recently, we have developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor-binding domain (RBD) of SARS-CoV-2 (termed ARCoV), which confers complete protection in mouse model. Herein, we further characterized the protection efficacy of ARCoV in nonhuman primates and the long-term stability under normal refrigerator temperature. Intramuscular immunization of two doses of ARCoV elicited robust neutralizing antibodies as well as cellular response against SARS-CoV-2 in cynomolgus macaques. More importantly, ARCoV vaccination in macaques significantly protected animals from acute lung lesions caused by SARS-CoV-2, and viral replication in lungs and secretion in nasal swabs were completely cleared in all animals immunized with low or high doses of ARCoV. No evidence of antibody-dependent enhancement of infection was observed throughout the study. Finally, extensive stability assays showed that ARCoV can be stored at 2–8 °C for at least 6 months without decrease of immunogenicity. All these promising results strongly support the ongoing clinical trial.

ObjectiveTumor hypoxia is frequently observed in primary solid malignancies, but the hypoxic status of tumor cells floating in body cavity effusions is largely unknown, especially in patients. This study was to observe the hypoxia and proliferation status of cancer cells floating in effusions in mice and patients.MethodsThe distribution of hypoxia in cancer cells floating in ascites was first studied in nude mice. Hypoxia was detected by immunofluorescent visualization of pimonidazole and GLUT-1. For cancer patients, we retrospectively collected 21 ascites and 7 pleural effusion sample blocks of cancer patients, which were confirmed to contain tumor cells. Immunohistochemistry was performed to detect the expression of endogenous hypoxic markers HIF-1α and GLUT-1, proliferation index Ki-67. 18F-FDG PET/CT was performed to detect the glucose metabolism status of tumor cells in effusions.ResultsThe tumor cells collected from ascites were positive for pimonidazole and GLUT-1, which suggesting that the cancer cells floating in ascites were hypoxic. Patterns of tumor hypoxia in human patients are similar to those observed in animal. HIF-1α and GLUT-1 were expressed by tumor cells in nearly all 28 cytological cases. For Ki-67 index, ascites tumor cells had a relatively low expression level compared with their corresponding primary or its metastatic lesions. Tumor cells in effusions showed high 18F-FDG uptake indicated the enhanced activity of glucose metabolism.ConclusionTumor cells in body cavity effusions, as a unique subgroup of tumor, are in a state of hypoxia and low proliferation, which would be one of the driven causes of chemo-radiotherapy resistance. Novel therapeutic interventions are urgently needed to overcome tumor hypoxia.

ARCoV is a candidate mRNA vaccine encoding receptor-binding domain of SARS-CoV-2. Its safety, tolerability, and immunogenicity profile have been confirmed in the phase 1 clinical trial in China. A multi-regional phase 3 clinical trial is currently underway to test the efficacy of ARCoV (NCT04847102). Here, we tested the cross-neutralization against SARS-CoV-2 variants of concern (VOCs) of a panel of serum samples from participants in the phase 1 clinical trial of ARCoV by pesudo- and authentic SARS-CoV-2. Our data suggest the immunity induced by the ARCoV vaccine reduced but still has significant neutralization against the Alpha and Delta variants. Moreover, ARCoV maintained activity against the Beta variant, despite of its obvious reduction in neutralizing titers. Our findings further support the solid protective neutralization activity against VOCs induced by ARCoV vaccine.

BackgroundRegulatory T cells (Tregs) have been found to play crucial roles in immune tolerance. However, the status of Tregs in refractory rheumatoid arthritis (RA) is still unclear. Moreover, low-dose interleukin-2 (IL-2) has been reported to selectively promote the expansion of Tregs. This study investigated the status of CD4+ Tregs and low-dose IL-2 therapy in patients with refractory RA.MethodsThe absolute number of CD4+CD25+FOXP3+ Treg (CD4 Treg), CD4+IL17+ T (Th17), and other subsets in peripheral blood (PB) from 41 patients with refractory RA and 40 healthy donors was characterized by flow cytometry combined with an internal microsphere counting standard. Twenty-six patients with refractory RA were treated with daily subcutaneous injections of 0.5 million IU of human IL-2 for five consecutive days. Then, its effects on CD4 Treg and Th17 cells in PB were analyzed.ResultsA decrease in the absolute number of PB CD4 Tregs rather than the increase in the number of Th17 was found to contribute to an imbalance between Th17 and CD4 Tregs in these patients, suggesting an essential role of CD4 Tregs in sustained high disease activity. Low-dose IL-2 selectively increased the number of CD4 Tregs and rebalanced the ratio of Th17 and CD4 Tregs, leading to increased clinical symptom remission without the observed side effects.ConclusionsAn absolute decrease of PB CD4 Tregs in patients with refractory RA was associated with continuing disease activation but not the increase of Th17 cells. Low-dose IL-2, a potential therapeutic candidate, restored decreased CD4 Tregs and promoted the rapid remission of patients with refractory RA without overtreatment and the observed side effects.Clinical trial registrationhttp://www.chictr.org.cn/showproj.aspx?proj=13909, identifier ChiCTR-INR-16009546.

ABSTRACT The yellow fever (YF) live attenuated vaccine strain 17D (termed 17D) has been widely used for the prevention and control of YF disease. However, 17D retains significant neurovirulence and viscerotropism in mice, which is probably linked to the increased occurrences of serious adverse events following 17D vaccination. Thus, the development of an updated version of the YF vaccine with an improved safety profile is of high priority. Here, we generated a viable bicistronic YF virus (YFV) by incorporating the internal ribosome entry site (IRES) from Encephalomyocarditis virus into an infectious clone of YFV 17D. The resulting recombinant virus, 17D-IRES, exhibited similar replication efficiency to its parental virus (17D) in mammalian cell lines, while it was highly restricted in mosquito cells. Serial passage of 17D-IRES in BHK-21 cells showed good genetic stability. More importantly, in comparison with the parental 17D, 17D-IRES displayed significantly decreased mouse neurovirulence and viscerotropism in type I interferon (IFN)-signaling-deficient and immunocompetent mouse models. Interestingly, 17D-IRES showed enhanced sensitivity to type I IFN compared with 17D. Moreover, immunization with 17D-IRES provided solid protection for mice against a lethal challenge with YFV. These preclinical data support further development of 17D-IRES as an updated version for the approved YF vaccine. This IRES-based attenuation strategy could be also applied to the design of live attenuated vaccines against other mosquito-borne flaviviruses. IMPORTANCE Yellow fever (YF) continually spreads and causes epidemics around the world, posing a great threat to human health. The YF live attenuated vaccine 17D is considered the most efficient vaccine available and helps to successfully control disease epidemics. However, side effects may occur after vaccination, such as viscerotropic disease (YEL-AVD) and neurotropic adverse disease (YEL-AND). Thus, there is an urgent need for a safer YF vaccine. Here, an IRES strategy was employed, and a bicistronic YFV was successfully developed (named 17D-IRES). 17D-IRES showed effective replication and genetic stability in vitro and high attenuation in vivo. Importantly, 17D-IRES induced humoral and cellular immune responses and conferred full protection against lethal YFV challenge. Our study provides data suggesting that 17D-IRES, with its prominent advantages, could be a vaccine candidate against YF. Moreover, this IRES-based bicistronic technology platform represents a promising strategy for developing other live attenuated vaccines against emerging viruses.

Abstract N-terminal acetylation (NTA) is a highly abundant protein modification catalyzed by N-terminal acetyltransferases (NATs) in eukaryotes. However, the plant NATs and their biological functions have been poorly explored. Here we reveal that loss of function of CKRC3 and NBC-1, the auxiliary subunit (Naa25) and catalytic subunit (Naa20) of Arabidopsis NatB, respectively, led to defects in skotomorphogenesis and triple responses of ethylene. Proteome profiling and WB test revealed that the 1-amincyclopropane-1-carboxylate oxidase (ACO, catalyzing the last step of ethylene biosynthesis pathway) activity was significantly down-regulated in natb mutants, leading to reduced endogenous ethylene content. The defective phenotypes could be fully rescued by application of exogenous ethylene, but less by its precursor ACC. The present results reveal a previously unknown regulation mechanism at the co-translational protein level for ethylene homeostasis, in which the NatB-mediated NTA of ACOs render them an intracellular stability to maintain ethylene homeostasis for normal growth and responses.

Abstract SARS-CoV-2 infection causes a wide spectrum of clinical manifestations in humans, and olfactory dysfunction is one of the most predictive and common symptoms in COVID-19 patients. However, the underlying mechanism by which SARS-CoV-2 infection leads to olfactory disorders remains elusive. Herein, we demonstrate that intranasal inoculation with SARS-CoV-2 induces robust viral replication in the olfactory epithelium (OE), not the olfactory bulb (OB), resulting in transient olfactory dysfunction in humanized ACE2 (hACE2) mice. The sustentacular cells and Bowman’s gland cells in the OE were identified as the major target cells of SARS-CoV-2 before invasion into olfactory sensory neurons (OSNs). Remarkably, SARS-CoV-2 infection triggers massive cell death and immune cell infiltration and directly impairs the uniformity of the OE structure. Combined transcriptomic and quantitative proteomic analyses revealed the induction of antiviral and inflammatory responses, as well as the downregulation of olfactory receptor (OR) genes in the OE from the infected animals. Overall, our mouse model recapitulates olfactory dysfunction in COVID-19 patients and provides critical clues for understanding the physiological basis for extrapulmonary manifestations of COVID-19.

Auxin is one of the most important plant growth regulators of plant morphogenesis and response to environmental stimuli. Although the biosynthesis pathway of auxin has been elucidated, the mechanisms regulating auxin biosynthesis remain poorly understood. The transcription of auxin biosynthetic genes is precisely regulated by complex signaling pathways. When the genes are expressed, epigenetic modifications guide mRNA synthesis and therefore determine protein production. Recent studies have shown that different epigenetic factors affect the transcription of auxin biosynthetic genes. In this review, we focus our attention on the molecular mechanisms through which epigenetic modifications regulate auxin biosynthesis.

BackgroundRheumatoid arthritis is a highly heterogeneous autoimmune disease characterized by unpredictable disease flares and significant differences in therapeutic response to available treatments. One possible reason for poor efficacy is that it cannot be treated accurately due to no optimal stratification for RA patients.ObjectiveThis study aims to construct an RA classification model by m6A characters and further predict response to medication.MethodsTwenty m6A regulators were used to construct a random forest diagnosis model, and RNA-seq analysis was employed for external validation. The RNA modification patterns mediated by 20 m6A regulators were systematically evaluated in 1191 RA samples and explored different molecular clusters associated with other immune microenvironment characteristics and biological pathways. Then, we established an m6A score model to quantify the m6A modification patterns. The model was applied to patients at baseline to test the association between m6Ascore and infliximab responsiveness.ResultsThe m6A diagnosis model showed good discriminatory ability in distinguishing RA. Patients with RA were classified into three clusters with distinct molecular and cellular signatures. Cluster A displayed strongly activated inflammatory cells and pathways. Specific innate lymphocytes occupied cluster B. Cluster C was mainly enriched in prominent adaptive lymphocytes and NK-mediated cytotoxicity signatures with the highest m6A score. Patients with a low m6Ascore exhibited significantly infliximab therapeutic benefits compared with those with a high m6Ascore (p< 0.05).ConclusionOur study is the first to provide a comprehensive analysis of m6A modifications in RA, which provides an innovative patient stratification framework and potentially enables improved therapeutic decisions.

Differentiated thyroid cancer is the most frequently diagnosed endocrine tumor. While differentiated thyroid cancers often respond to initial treatment, little is known about the differences in circulating immune cells amongst patients who respond differently. A prospective study of 39 patients with differentiated thyroid cancer was conducted. Serum thyroglobulin levels and thyroid and immunological functions were tested before and after radioactive iodine treatment (RAIT). Efficacy assessments were performed 6 to 12 months after radioactive iodine treatment. Most patients showed an excellent response to radioactive iodine treatment. Before radioactive iodine treatment, the excellent response group had considerably fewer circulating CD4+ T cell subsets than the non-excellent response group. Both the excellent response and non-excellent response groups had considerably lower circulating CD4+ T lymphocyte subsets 30 days after radioactive iodine treatment, but those of the excellent response group were still lower than those of the non-excellent response group. All circulating CD4+ T cell subsets in the excellent response group rose by varying degrees by the 90th day, but only Treg cell amounts increased in the non-excellent response group. Interestingly, in the non-excellent response group, we noticed a steady drop in Th1 cells. However, the bulk of circulating CD4+ T cell subsets between the two groups did not differ appreciably by the 90th day. Finally, we discovered that CD4+ T cell subsets had strong predictive potential, and we thus developed high-predictive-performance models that deliver more dependable prognostic information. In conclusion, in individuals with differentiated thyroid cancer, there is great variation in circulating immune cells, resulting in distinct treatment outcomes. Low absolute CD4+ T cell counts is linked to improved clinical outcomes as well as stronger adaptive and resilience capacities.

Objective: Calcium-activated chloride channel 2 (CLCA2) is closely related to the invasion, metastasis, and prognosis of some common malignant tumors. The present study aimed to evaluate the role of CLCA2 in cervical squamous cell carcinoma (CESC) using bioinformatics analysis. Materials and methods: The mRNA sequencing data and the corresponding clinical data were obtained from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database respectively. Then univariate analysis of variance was used to analyze the differential mRNA expression of CLCA2 between normal, cervical Intraepithelial neoplasia (CIN), and CESC tissues and clinicopathological characteristics. The Gene Expression Profiling Interactive Analysis (GEPIA) was used to assess the association between CLCA2 and Disease-Free Survival (DFS), overall survival (OS). The Gene Set Enrichment Analysis (GSEA) was used to explore the associated signaling pathways. The Tumor Immune Estimation Resource (TIMER) was used to predict the potential biological roles of CLCA2 in tumor-immune of CESC. Results: CLCA2 expression was significantly decreased in CESC tissues compared with normal and CIN tissues (P 0.05). The survival analysis indicated that for DFS, CESC with high CLCA2 expression was associated with better prognoses compared with those with low expression levels (P

Abstract MicroRNAs (miRNAs) are dysregulated in many tumors and have been found to play crucial roles in cancer biology. Retinoblastoma is a rare tumor that develops rapidly from a malignant tumor of immature cells in the retina known as photoreceptor progenitors. Our study aimed to explore the role of miR‐146a in the pathology of retinoblastoma. Potential target gene of miR‐146a was predicted by Targetscan. Reverse transcription quantitative polymerase chain reaction (RT‐PCR) showed that miR‐146a was downregulated and ventral nerve tumor antigen 1 (Neuro ‐ oncological ventral antigen 1, NOVA1) was upregulated in retinoblastoma. Luciferase assay confirmed that miR‐146a directly target NOVA1. MiR‐146a knockdown and overexpression experiments were performed and found that miR‐146a could regulate the expression of NOVA1. The miR‐146a knockdown and overexpression experiments were conducted to investigate the biological function of miR‐146a. MiR‐146a was found inhibited the viability, proliferation and invasion of retinoblastoma cell by MTT, EdU, and transwell assays. Flow cytometry was performed for the apoptosis analysis and miR‐146a increased the apoptosis of retinoblastoma cell was found. Above phenomenon can be rescued by overexpression of NOVA1. In conclusion, these results suggest that miR‐146a acts as a tumor suppressor and can act as a potential therapeutic target for retinoblastoma in the future.

Abstract Introduction Osthole has a potential therapeutic application for anti-osteoporosis. The present study verified whether osthole downregulates osteoclastogenesis via targeting OPG. Methods In vivo, 12-month-old male mice were utilized to evaluate the effect of osthole on bone mass. In vitro, bone marrow stem cells (BMSCs) were isolated and extracted from 3-month-old OPG−/− mice and the littermates of OPG+/+ mice. Calvaria osteoblasts were extracted from 3-day-old C57BL/6J mice or 3-day-old OPG−/− mice and the littermates of OPG+/+ mice. Results Osthole significantly increased the gene and protein levels of OPG in primary BMSCs in a dose-dependent manner. The deletion of the OPG gene did not affect β-catenin expression. The deletion of the β-catenin gene inhibited OPG expression in BMSCs, indicating that osthole stimulates the expression of OPG via activation of β-catenin signaling. Conclusion Osthole attenuates osteoclast formation by stimulating the activation of β-catenin-OPG signaling and could be a potential drug for the senile osteoporosis.

Abstract The mosquito-borne Zika virus is an emerging pathogen from the Flavivirus genus for which there are no approved antivirals or vaccines. Using the clinically validated PDK-53 dengue virus vaccine strain as a backbone, we created a chimeric dengue/Zika virus, VacDZ, as a live attenuated vaccine candidate against Zika virus. VacDZ demonstrates key markers of attenuation: small plaque phenotype, temperature sensitivity, attenuation of neurovirulence in suckling mice, and attenuation of pathogenicity in interferon deficient adult AG129 mice. VacDZ may be administered as a traditional live virus vaccine, or as a DNA-launched vaccine that produces live VacDZ in vivo after delivery. Both vaccine formulations induce a protective immune response against Zika virus in AG129 mice, which includes neutralising antibodies and a strong Th1 response. This study demonstrates that VacDZ is a safe and effective vaccine candidate against Zika virus.