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"Zhang, Zhiling"
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Challenges and developments in universal vaccine design against SARS-CoV-2 variants
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had become a global concern because of its unexpectedly high pathogenicity and transmissibility. SARS-CoV-2 variants that reduce the immune protection elicited from previous vaccination or natural infection raise challenges in controlling the spread of the pandemic. The development of universal vaccines against these variants seems to be a practical solution to alleviate the physical and economic effects caused by this disease, but it is hard to achieve. In this review, we describe the high mutation rate of RNA viruses and dynamic molecular structures of SARS-CoV-2 variants in several major neutralizing epitopes, trying to answer the question of why universal vaccines are difficult to design. Understanding the biological basis of immune evasion is crucial for combating these obstacles. We then summarize several advancements worthy of further study, including heterologous prime-boost regimens, construction of chimeric immunogens, design of protein nanoparticle antigens, and utilization of conserved neutralizing epitopes. The fact that some immunogens can induce cross-reactive immune responses against heterologous coronaviruses provides hints for universal vaccine development. We hope this review can provide inspiration to current universal vaccine studies.
Journal Article
Validation of Reference Genes in Solenopsis invicta in Different Developmental Stages, Castes and Tissues
To accurately assess gene expression levels, it is essential to normalize real-time quantitative PCR (RT-qPCR) data with suitable internal reference genes. For the red imported fire ant, Solenopsis invicta, reliable reference genes to assess the transcript expression levels of the target genes have not been previously investigated. In this study, we examined the expression levels of five candidate reference genes (rpl18, ef1-beta, act, GAPDH, and tbp) in different developmental stages, castes and tissues of S. invicta. To evaluate the suitability of these genes as endogenous controls, three software-based approaches (geNorm, BestKeeper and NormFinder) and one web-based comprehensive tool (RefFinder) were used to analyze and rank the tested genes. Furthermore, the optimal number of reference gene(s) was determined by the pairwise variation value. Our data showed that two of the five candidate genes, rpl18 and ef1-beta, were the most suitable reference genes because they have the most stable expression among different developmental stages, castes and tissues in S. invicta. Although widely used as reference gene in other species, in S. invicta the act gene has high variation in expression and was consequently excluded as a reliable reference gene. The two validated reference genes, rpl18 and ef1-beta, can be widely used for quantification of target gene expression with RT-qPCR technology in S. invicta.
Journal Article
Engineering of a genome-reduced strain Bacillus amyloliquefaciens for enhancing surfactin production
Background
Genome reduction and metabolic engineering have emerged as intensive research hotspots for constructing the promising functional chassis and various microbial cell factories. Surfactin, a lipopeptide-type biosurfactant with broad spectrum antibiotic activity, has wide application prospects in anticancer therapy, biocontrol and bioremediation.
Bacillus amyloliquefaciens
LL3, previously isolated by our lab, contains an intact
srfA
operon in the genome for surfactin biosynthesis.
Results
In this study, a genome-reduced strain GR167 lacking ~ 4.18% of the
B. amyloliquefaciens
LL3 genome was constructed by deleting some unnecessary genomic regions. Compared with the strain NK-1 (LL3 derivative, Δ
upp
ΔpMC1), GR167 exhibited faster growth rate, higher transformation efficiency, increased intracellular reducing power level and higher heterologous protein expression capacity. Furthermore, the chassis strain GR167 was engineered for enhanced surfactin production. Firstly, the iturin and fengycin biosynthetic gene clusters were deleted from GR167 to generate GR167ID. Subsequently, two promoters PR
suc
and PR
tpxi
from LL3 were obtained by RNA-seq and promoter strength characterization, and then they were individually substituted for the native
srfA
promoter in GR167ID to generate GR167IDS and GR167IDT. The best mutant GR167IDS showed a 678-fold improvement in the transcriptional level of the
srfA
operon relative to GR167ID, and it produced 311.35 mg/L surfactin, with a 10.4-fold increase relative to GR167.
Conclusions
The genome-reduced strain GR167 was advantageous over the parental strain in several industrially relevant physiological traits assessed and it was highlighted as a chassis strain for further genetic modification. In future studies, further reduction of the LL3 genome can be expected to create high-performance chassis for synthetic biology applications.
Journal Article
Mitochondria-Targeted Antioxidant Mito-Tempo Protects Against Aldosterone-Induced Renal Injury In Vivo
Background/Aims: Growing evidence suggests mitochondrial dysfunction (MtD) and the Nlrp3 inflammasome play critical roles in chronic kidney disease (CKD) progression. We previously reported that Aldosterone (Aldo)-induced renal injury in vitro is directly caused by mitochondrial reactive oxygen species (mtROS)-mediated activation of the Nlrp3 inflammasome. Here we aimed to determine whether a mitochondria-targeted antioxidant (Mito-Tempo) could prevent Aldo-induced kidney damage in vivo. Methods: C57BL/6J mice were treated with Aldo and/or Mito-Tempo (or ethanol as a control) for 4 weeks. Renal injury was evaluated by Periodic Acid-Schiff reagent or Masson’s trichrome staining and electron microscopy. ROS were measured by DCFDA fluorescence and ELISA. MtD was determined by real-time PCR and electron microscopy. Activation of the Nlrp3 inflammasome and endoplasmic reticulum stress (ERS) was detected via western blot. Results: Compared with control mice, Aldo-infused mice showed impaired renal function, increased mtROS production and MtD, Nlrp3 inflammasome activation, and elevated ERS. We showed administration of Mito-Tempo significantly improved renal function and MtD, and reduced Nlrp3 inflammasome activation and ERS in vivo. Conclusion: Mitochondria-targeted antioxidants may attenuate Aldo-infused renal injury by inhibiting MtD, the Nlrp3 inflammasome, and ERS in vivo. Therefore, targeting mtROS might be an effective strategy for preventing CKD.
Journal Article
ZHX3 promotes the progression of urothelial carcinoma of the bladder via repressing of RGS2 and is a novel substrate of TRIM21
Clinically, patients with urothelial carcinoma of the bladder (UCB) with tumor metastasis are incurable. To find new therapeutic strategies, the mechanisms underlying UCB invasion and metastasis should be further investigated. In this study, zinc finger and homeobox 3 (ZHX3) was first screened as a critical oncogenic factor associated with poor prognosis in a UCB dataset from The Cancer Genome Atlas (TCGA). These results were also confirmed in a large cohort of clinical UCB clinical samples. Next, we found that ZHX3 could promote the migration and invasion capacities of UCB cells both in vitro and in vivo. Mechanistically, coimmunoprecipitation (coIP) and mass spectrometry (MS) analysis indicated that ZHX3 was a target of tripartite motif 21 (TRIM21), which mediates its ubiquitination, and subsequent degradation. Notably, RNA‐seq analysis showed that ZHX3 repressed the expression of regulator of G protein signaling 2 (RGS2). Generally, our results suggest that ZHX3 plays an oncogenic role in UCB pathogenesis and might serve as a novel therapeutic target for UCB.
ZHX3 promotes UCB cell invasive and metastatic capacities. ZHX3 could activate RhoA by repressing RGS2. TRIM21 promotes ZHX3 ubiquitination and degradation in UCB cells.
Journal Article
Automatic parking trajectory planning in narrow spaces based on Hybrid A and NMPC
The rapid acceleration of urbanization and the surge in car ownership necessitate efficient automatic parking solutions in constricted spaces to address the escalating urban parking issue. To optimize space utilization, enhance traffic efficiency, and mitigate accident risks, a method is proposed for smooth, comfortable, and adaptable automatic parking trajectory planning. This study initially employs a hybrid A* algorithm to generate a preliminary path, then fits the velocity and acceleration based on a cubic polynomial. The kinematic constraints of the vehicle and obstacle avoidance constraints are then meticulously defined, and a coupled nonlinear model predictive control (NMPC) method is employed to optimize the trajectory. Compared to the hybrid A* algorithm, the optimized trajectory demonstrates superior space utilization and improved smoothness. The experimental results indicate that the proposed method performs effectively in automated parking tasks in confined spaces, suggesting promising applications and broad prospects for future.
Journal Article
A machine learning model for predicting severe mycoplasma pneumoniae pneumonia in school-aged children
Objective
To develop an interpretable machine learning (ML) model for predicting severe
Mycoplasma pneumoniae
pneumonia (SMPP) in order to provide reliable factors for predicting the clinical type of the disease.
Methods
We collected clinical data from 483 school-aged children with
M. pneumoniae
pneumonia (MPP) who were hospitalized at the Children's Hospital of Soochow University between September 2021 and June 2024. Difference analysis and univariate logistic regression were employed to identify predictors for training features in ML. Eight ML algorithms were used to build models based on the selected features, and their effectiveness was validated. The area under the curve (AUC), accuracy, five-fold cross-validation, and decision curve analysis (DCA) were utilized to evaluate model performance. Finally, the best-performing ML model was selected, and the Shapley Additive Explanations (SHAP) method was applied to rank the importance of clinical features and interpret the final model.
Results
After feature selection, 30 variables remained. We constructed eight ML models and assessed their effectiveness, finding that the CatBoost model exhibited the best predictive performance, with an AUC of 0.934 and an accuracy of 0.9175. DCA was used to compare the clinical benefits of the models, revealing that the CatBoost model provided greater net benefits than the other ML models within the threshold probability range of 34% to 75%. Additionally, we applied the SHAP method to interpret the CatBoost model, and the SHAP diagram was used to visually show the influence of predictor variables on the outcome. The results identified the top six risk factors as the number of days with fever, D-dimer, platelet count (PLT), C-reactive protein (CRP), lactate dehydrogenase (LDH), and the neutrophil-to-lymphocyte ratio (NLR).
Conclusions
The interpretable CatBoost model can help physicians accurately identify school-aged children with SMPP. This early identification facilitates better treatment options and timely prevention of complications. Furthermore, the SHAP algorithm enhances the model's transparency and increases its trustworthiness in practical applications.
Journal Article
Cntnap4 partial deficiency exacerbates α-synuclein pathology through astrocyte–microglia C3-C3aR pathway
Parkinson’s disease (PD) is the most common progressive neurodegenerative movement disorder, which is characterized by dopaminergic (DA) neuron death and the aggregation of neurotoxic α-synuclein.
Cntnap4
, a risk gene of autism, has been implicated to participate in PD pathogenesis. Here we showed
Cntnap4
lacking exacerbates α-synuclein pathology, nigrostriatal DA neuron degeneration and motor impairment, induced by injection of adeno-associated viral vector (AAV)-mediated human α-synuclein overexpression (AAV-
h
α-Syn). This scenario was further validated in A53T α-synuclein transgenic mice injected with AAV-Cntnap4 shRNA. Mechanistically, α-synuclein derived from damaged DA neuron stimulates astrocytes to release complement C3, activating microglial C3a receptor (C3aR), which in turn triggers microglia to secrete complement C1q and pro-inflammatory cytokines. Thus, the astrocyte–microglia crosstalk further drives DA neuron death and motor dysfunction in PD. Furthermore, we showed that in vivo depletion of microglia and microglial targeted delivery of a novel C3aR antagonist (SB290157) rescue the aggravated α-synuclein pathology resulting from
Cntnap4
lacking. Together, our results indicate that Cntnap4 plays a key role in α-synuclein pathogenesis by regulating glial crosstalk and may be a potential target for PD treatment.
Journal Article
Perirenal fat thickness may be a significant predictor of prognosis and postoperative renal function in renal cancer surgery patients
Renal cell carcinoma accounts for a significant number of kidney malignancy-related fatalities globally. Perirenal Fat Thickness (PRFT) may indicate a state of nutritional excess in patients, which is potentially directly linked to both the incidence and prognosis of kidney cancer. This study investigated the association between perirenal fat thickness (PRFT) and overall survival (OS), as well as the predictive value of PRFT for postoperative estimated glomerular filtration rate (eGFR) in patients with renal cell carcinoma (RCC). A retrospective cohort of 1647 RCC patients from 2014 to 2021 was analyzed, divided into radical nephrectomy (RN) and partial nephrectomy (PN) groups. Preoperative measurements included visceral fat area, PRFT, and subcutaneous fat area. Kaplan-Meier curves compared OS between high and low PRFT groups, while Cox regression analyses identified prognostic factors for OS, and linear regression analyses assessed predictors of postoperative eGFR. PRFT significantly influenced OS in RN patients in univariate analysis (HR: 0.32; 95% CI: 0.19–0.52;
P
< 0.001), but not in PN patients. After adjusting for covariates such as age, sex, sarcomatoid features, necrosis, T stage, Fuhrman grade, smoking status, subcutaneous adipose tissue, and BMI, PRFT remained an independent risk factor for OS (HR: 0.56; 95% CI: 0.33–0.96;
P
< 0.001). Kaplan-Meier analysis showed that higher PRFT was associated with improved OS in RN patients. Univariate linear regression revealed that high PRFT correlated with reduced postoperative eGFR in both RN (β = -0.2,
P
= 0.002) and PN (β = -0.34,
P
< 0.001) groups; however, this correlation was not significant after multivariate adjustment. In conclusion, Low PRFT is independently associated with higher mortality in RCC patients undergoing RN. High PRFT is associated with reduced postoperative eGFR in initial analyses, but this association was not significant in multivariate analysis.
Journal Article