Algorithm for optimized mRNA design improves stability and immunogenicity.

Messenger RNA (mRNA) vaccines are being used to combat the spread of COVID-19 (refs. 1-3), but they still exhibit critical limitations caused by mRNA instability and degradation, which are major obstacles for the storage, distribution and efficacy of the vaccine products4. Increasing secondary structure lengthens mRNA half-life, which, together with optimal codons, improves protein expression5. Therefore, a principled mRNA design algorithm must optimize both structural stability and codon usage. However, owing to synonymous codons, the mRNA design space is prohibitively large-for example, there are around 2.4 × 10632 candidate mRNA sequences for the SARS-CoV-2 spike protein. This poses insurmountable computational challenges. Here we provide a simple and unexpected solution using the classical concept of lattice parsing in computational linguistics, where finding the optimal mRNA sequence is analogous to identifying the most likely sentence among similar-sounding alternatives6. Our algorithm LinearDesign finds an optimal mRNA design for the spike protein in just 11 minutes, and can concurrently optimize stability and codon usage. LinearDesign substantially improves mRNA half-life and protein expression, and profoundly increases antibody titre by up to 128 times in mice compared to the codon-optimization benchmark on mRNA vaccines for COVID-19 and varicella-zoster virus. This result reveals the great potential of principled mRNA design and enables the exploration of previously unreachable but highly stable and efficient designs. Our work is a timely tool for vaccines and other mRNA-based medicines encoding therapeutic proteins such as monoclonal antibodies and anti-cancer drugs7,8.

Extracellular vesicles from Zika virus-infected cells display viral E protein that binds ZIKV-neutralizing antibodies to prevent infection enhancement.

Mosquito-borne flaviviruses including Zika virus (ZIKV) represent a public health problem in some parts of the world. Although ZIKV infection is predominantly asymptomatic or associated with mild symptoms, it can lead to neurological complications. ZIKV infection can also cause antibody-dependent enhancement (ADE) of infection with similar viruses, warranting further studies of virion assembly and the function of envelope (E) protein-specific antibodies. Although extracellular vesicles (EVs) from flavivirus-infected cells have been reported to transmit infection, this interpretation is challenged by difficulties in separating EVs from flavivirions due to their similar biochemical composition and biophysical properties. In the present study, a rigorous EV-virion separation method combining sequential ultracentrifugation and affinity capture was developed to study EVs from ZIKV-infected cells. We find that these EVs do not transmit infection, but EVs display abundant E proteins which have an antigenic landscape similar to that of virions carrying E. ZIKV E-coated EVs attenuate antibody-dependent enhancement mediated by ZIKV E-specific and DENV-cross-reactive antibodies in both cell culture and mouse models. We thus report an alternative route for Flavivirus E protein secretion. These results suggest that modulation of E protein release via virions and EVs may present a new approach to regulating flavivirus-host interactions.

Broad-spectrum Delta-BA.2 tandem-fused heterodimer mRNA vaccine delivered by lipopolyplex.

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, continues to mutate and generates new variants with increasingly severe immune escape, urging the upgrade of COVID-19 vaccines. Here, based on a similar dimeric RBD design as our previous ZF2001 vaccine, we developed a novel broad-spectrum COVID-19 mRNA vaccine, SWIM516, with chimeric Delta-BA.2 RBD dimer delivered by lipopolyplex (LPP). Unlike the popular lipid nanoparticle (LNP), this LPP-delivered mRNA expresses only in the injection site, which avoids potential toxicity to the liver. We demonstrated the broad-spectrum humoral and cellular immunogenicity of this vaccine to Delta and Omicron sub-variants in naïve mice and as booster shots. When challenged with Delta or Omicron live virus, vaccinated human angiotensin-converting enzyme (hACE2) transgenic mice and rhesus macaques were both protected, displaying significantly reduced viral loads and markedly relieved pathological damages. We believe the SWIM516 vaccine qualifies as a candidate for the next-generation broad-spectrum COVID-19 vaccine.

Pattern of heterogeneity in normal brain ageing: screening for mild cognitive impairment and its risk of progression with a radiomics model.

PURPOSE: This study aimed to develop a normal brain ageing model based on magnetic resonance imaging and radiomics, therefore identifying radscore, an imaging indicator representing white matter heterogeneity and exploring the significance of radscore in detecting people's cognitive changes. METHODS: Three hundred sixty cognitively normal (CN) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and 105 CN subjects from the Parkinson's Progression Markers Initiative database were used to develop the model. In ADNI, 230 mild cognitive impairment (MCI) subjects were matched with 230 CN old-aged subjects to evaluate their heterogeneity difference. One hundred four MCI subjects with 48 months of follow-up were divided into low and high heterogeneity groups. Kaplan-Meier survival curve analysis was used to observe the importance of heterogeneity results for predicting MCI progression. RESULTS: The area under the receiver operating characteristic curve of the model in the training, internal test and external test sets was 0.7503, 0.7512 and 0.7514, respectively. There was a significantly positive correlation between age and radscore of CN subjects (r = 0.501; P < .001). The radscore of MCI subjects was significantly higher than that of matched CN subjects (P < .001). The median radscore ratios of MCI to CN from four age groups (66-70y, 71-75y, 76-80y and 81-85y) were 1.611, 1.760, 1.340 and 1.266, respectively. The probability to progression of low and high heterogeneity groups had a significant difference (P = .002). CONCLUSION: When radscore is significantly higher than that of normal ageing, it is necessary to alert the possibility of cognitive impairment and deterioration.

Is coronary artery calcium an independent risk factor for white matter hyperintensity?

BACKGROUND: Cardiovascular diseases have been considered the primary cause of disability and death worldwide. Coronary artery calcium (CAC) is an important indicator of the severity of coronary atherosclerosis. This study is aimed to investigate the relationship between CAC and white matter hyperintensity (WMH) in the context of diagnostic utility. METHODS: A retrospective analysis was conducted on 342 patients with a diagnosis of WMH on magnetic resonance images (MRI) who also underwent chest computed tomography (CT) scans. WMH volumes were automatically measured using a lesion prediction algorithm. Subjects were divided into four groups based on the CAC score obtained from chest CT scans. A multilevel mixed-effects linear regression model considering conventional vascular risk factors assessed the association between total WMH volume and CAC score. RESULTS: Overall, participants with coronary artery calcium (CAC score > 0) had larger WMH volumes than those without calcium (CAC score = 0), and WMH volumes were statistically different between the four CAC score groups, with increasing CAC scores, the volume of WMH significantly increased. In the linear regression model 1 of the high CAC score group, for every 1% increase in CAC score, the WMH volume increases by 2.96%. After including other covariates in model 2 and model 3, the ß coefficient in the high CAC group remains higher than in the low and medium CAC score groups. CONCLUSION: In elderly adults, the presence and severity of CAC is related to an increase in WMH volume. Our findings suggest an association between two different vascular bed diseases in addition to traditional vascular risk factors, possibly indicating a comorbid mechanism.

Relationship between self-reported sleep duration during week-/work-days and metabolic syndrome from NHANES 2013 to 2016.

PURPOSE: This research aimed at determining the relationship between self-reported sleep duration during week-/work-days and metabolic syndrome (MetS) from NHANES 2013 to 2016. METHODS: This study analyzed data from 11,181 people aged 16 or older who took part in the NHANES (National Health and Nutrition Examination Surveys) from 2013 to 2016. A standard questionnaire was used to define self-reported sleep duration, and MetS was defined on the basis of the NCEP (National Cholesterol Education Program)/ATP III revised diagnostic criteria. Logistic regression and restricted cubic splines (RCS) models were used to assess the relationship between self-reported sleep duration and MetS. RESULTS: The overall prevalence of MetS in the study cohort was 26.1%, with 24.8% for males and 27.3% for females. After adjusting for potential confounding factors, MetS was significantly associated with self-reported short sleep duration (odds ratio = 1.16, 95% confidence interval = 1.03-1.31, P = 0.013) but not with long sleep duration (P = 0.117). RCS regression revealed that self-reported sleep duration was nonlinearly related to MetS (P for nonlinearity = 0.0026). The risk of MetS decreased with increased sleep duration for durations of less than 7 h/day, while there was no association for longer sleep durations. CONCLUSION: These results suggest that self-reported short sleep duration is a risk factor for MetS, while long sleep duration is not.

Nomogram for predicting cancer-specific survival in undifferentiated pleomorphic sarcoma: A Surveillance, Epidemiology, and End Results -based study.

INTRODUCTION: The purpose of this study was to construct and validate a nomogram for predicting cancer-specific survival (CSS) in undifferentiated pleomorphic sarcoma (UPS) patients at 3, 5, and 8 years after the diagnosis. METHODS: Data for UPS patients were extracted from the SEER (Surveillance, Epidemiology, and End Results) database. The patients were randomly divided into a training cohort (70%) and a validation cohort (30%). The backward stepwise Cox regression model was used to select independent prognostic factors. All of the factors were integrated into the nomogram to predict the CSS rates in UPS patients at 3, 5, and 8 years after the diagnosis. The nomogram' s performance was then validated using multiple indicators, including the area under the time-dependent receiver operating characteristic curve (AUC), consistency index (C-index), calibration curve, decision-curve analysis (DCA), integrated discrimination improvement (IDI), and net reclassification improvement (NRI). RESULTS: This study included 2,009 UPS patients. Ten prognostic factors were identified after analysis of the Cox regression model in the training cohort, which were year of diagnosis, age, race, primary site, histological grade, T, N, M stage, surgery status, and insurance status. The nomogram was then constructed and validated internally and externally. The relatively high C-indexes and AUC values indicated that the nomogram has good discrimination ability. The calibration curves revealed that the nomogram was well calibrated. NRI and IDI values were both improved, indicating that our nomogram was superior to the AJCC (American Joint Committee on Cancer) system. DCA curves demonstrated that the nomogram was clinically useful. CONCLUSIONS: The first nomogram for predicting the prognosis of UPS patients has been constructed and validated. Its usability and performance showed that the nomogram can be applied to clinical practice. However, further external validation is still needed.

Competitive Risk Analysis of Prognosis in Patients With Cecum Cancer: A Population-Based Study.

BACKGROUND: The presence of competing risks means that the results obtained using the classic Cox proportional-hazards model for the factors affecting the prognosis of patients diagnosed with cecum cancer (CC) may be biased. OBJECTIVE: The purpose of this study was to establish a competitive risk model for patients diagnosed with CC to evaluate the relevant factors affecting the prognosis of patients, and to compare the results with the classical COX proportional risk model. METHODS: We extracted data on patients diagnosed with CC registered between 2004 and 2016 in the Surveillance, Epidemiology, and End Results (SEER) database. The univariate analysis utilized the cumulative incidence function and Gray's test, while a multivariate analysis was performed using the Fine-Gray, cause-specific (CS), and Cox proportional-hazards models. RESULTS: The 54463 eligible patients diagnosed with CC included 24387 who died: 12087 from CC and 12300 from other causes. The multivariate Fine-Gray analysis indicated that significant factors affecting the prognosis of patients diagnosed with CC include: age, race, AJCC stage, differentiation grade, tumor size, surgery, radiotherapy, chemotherapy and regional lymph nodes metastasis. Due to the presence of competitive risk events, COX model results could not provide accurate estimates of effects and false-negative results occurred. In addition, COX model misestimated the direction of association between regional lymph node metastasis and cumulative risk of death in patients diagnosed with CC. Competitive risk models tend to be more advantageous when analyzing clinical survival data with multiple endpoints. CONCLUSIONS: The present study can help clinicians to make better clinical decisions and provide patients diagnosed with CC with better support.

Relationship Between Body Mass Index and Kidney Stones Based on Dose-Response Analyses Using Restricted Cubic Splines Applied to NHANES 2011-2016 Data.

OBJECTIVE: The objective of the study was to estimate the dose-response relationship between body mass index (BMI) and the self-reported prevalence of kidney stones based on a restricted cubic spline (RCS) method. METHODS: This cross-sectional study analyzed 13,223 adults aged ≥20 years who had participated in the National Health and Nutrition Examination Survey performed during 2011-2016. Kidney stones were identified using a standard questionnaire, and physical examinations were used to determine BMI. Logistic regression was used to assess the relationship between BMI and the prevalence of kidney stones, with the dose-response relationship explored using RCSs. RESULTS: The overall prevalence of kidney stones was 9.7%: 10.6% in males and 8.9% in females. After adjusting for potential confounders, compared with those with a BMI in quartile 1, the odds ratios of kidney stones among those with BMIs in quartiles 2, 3, and 4 were 1.45, 1.60, and 2.00, respectively (95% confidence interval = 1.21-1.75, 1.33-1.92, and 1.67-2.39; all P < .001). Multivariate RCS regression revealed that BMI was related to kidney stones in a nonlinear manner (P for nonlinearity <0.001). There was a significant positive relationship, with the curves being steeper when BMI was <28 kg/m2. CONCLUSION: This analysis of National Health and Nutrition Examination Survey data has demonstrated that BMI is significantly associated with the prevalence of kidney stones.

Double-stranded RNA deaminase ADAR1 promotes the Zika virus replication by inhibiting the activation of protein kinase PKR.

Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged as a threat to global health. The family of adenosine deaminases acting on dsRNA (ADARs) are human host factors important for the genetic diversity and evolution of ZIKV. Here, we further investigated the role of ADAR1 in ZIKV replication by utilizing CRISPR/Cas9-based gene editing and RNAi-based gene knockdown techniques. Both ADAR1 knockout and knockdown significantly reduced ZIKV RNA synthesis, protein levels, and viral titers in several human cell lines. Trans-complementation with the full-length ADAR1 form p150 or the shorter form p110 lacking the Zα domain restored viral replication levels suppressed by the ADAR1 knockout. Moreover, we observed that the nuclear p110 form was redistributed to the cytoplasm in response to ZIKV infection. ADAR1 was not involved in viral entry but promoted viral protein translation by impairing ZIKV-induced activation of protein kinase regulated by dsRNA (PKR). Of note, the RNA-editing activity of ADAR1 was not required to promote ZIKV replication. We also found that the proviral role of ADAR1 was partially mediated through its ability to suppress IFN production and PKR activation. Our work identifies ADAR1 as a proviral factor involved in ZIKV replication, suggesting that ADAR1 could be a potential antiviral target.

Association between physical activity and kidney stones based on dose-response analyses using restricted cubic splines.

BACKGROUND: This study aimed to determine whether there is a dose-response relationship between physical activity and the self-reported prevalence of kidney stone, based on a restricted cubic splines (RCS) method. METHODS: This study analyzed 8931 adults aged ≥20 years who had participated in the National Health and Nutrition Examination Survey (NHANES) during 2013-16. Kidney stones and physical activity were defined using a standard questionnaire, and metabolic equivalents (MET) were used to quantify the physical activity level. Logistic regression was used to assess the association between physical activity and the risk of kidney stones, and the dose-response relationship was explored using RCS. RESULTS: Kidney stones were present in 10.3% of the analyzed individuals: 11.5% of males and 9.2% of females. After adjusting for potential confounders, compared with the first quartile (Q1) of MET, the odds ratios (ORs) of kidney stones for those with Q2, Q3 and Q4 of MET were 0.72 [95% confidence interval (CI)=0.59-0.87], 0.77 (95% CI = 0.63-0.93) and 0.63 (95% CI = 0.51-0.78), respectively (all P < 0.01). The RCS regression showed that physical activity was related to kidney stones in a non-linear manner (P for non-linearity = 0.0100). The prevalence of kidney stones decreasing as physical activity increased, reaching a plateau for physical activity at approximately 2480 MET-min week-1 (OR = 0.75, 95% CI = 0.63-0.91). CONCLUSIONS: Physical activity is inversely associated with the prevalence of kidney stones, and the dose-response relationship has a plateau, after which the prevalence of kidney stones does not change with the increase of physical activity.

Nomograms for predicting the survival rate for cervical cancer patients who undergo radiation therapy: a SEER analysis.

Aim: To integrate multiple independent risk factors to establish prognostic nomograms for better predicting overall survival and disease-specific survival in patients with cervical cancer receiving radiation therapy. Materials & methods: Cox analysis used to construct nomograms. The C-index, time-dependent receiver operating characteristic and calibration plots were used to evaluate the performance. The discrimination abilities were compared using the decision curve analysis, net reclassification improvement and integrated discrimination improvement. Results: After randomization, 2869 and 1230 cervical cancer patients were included in the training and validation sets, respectively. Nomograms that incorporated all of the significant independent factors for predicting the 3- and 5-year overall survival and disease-specific survival in the training cohort were established. Conclusion: Compared with the International Federation of Gynecology and Obstetrics staging system, the proposed nomograms exhibit superior prognostic discrimination and survival prediction.

Development and validation of a nomogram containing the prognostic determinants of chondrosarcoma based on the Surveillance, Epidemiology, and End Results database.

BACKGROUND: We aimed to develop and validate a reliable nomogram for predicting the disease-specific survival (DSS) of chondrosarcoma patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried from 2004 to 2015 to identify cases of histologically confirmed chondrosarcoma. Multivariate Cox regression analysis was performed to identify independent prognostic factors and construct a nomogram for predicting the 3- and 5-year DSS rates. Predictive values were compared between the new model and the American Joint Committee on Cancer (AJCC) staging system using concordance indexes (C-indexes), calibration plots, integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision curve analysis (DCA). RESULTS: Multivariate Cox regression identified 1180 patients, who were used to establish a nomogram based on a new model containing the predictive variables of age, socioeconomic status, tumor size, surgery status, chemotherapy status, and AJCC staging. In the nomogram, age at diagnosis is the factor with the highest risk, followed by AJCC stage IV and tumor size > 100 mm. Both the C-index and the calibration plots demonstrated the good performance of the nomogram. Moreover, both NRI and IDI were improved compared to the AJCC staging system, and also DCA demonstrated that the nomogram is clinically useful. CONCLUSION: We have developed a reliable nomogram for determining the prognosis and treatment outcomes of chondrosarcoma patients that is superior to the traditional AJCC staging system.

Visualizing the Essential Role of Complete Virion Assembly Machinery in Efficient Hepatitis C Virus Cell-to-Cell Transmission by a Viral Infection-Activated Split-Intein-Mediated Reporter System.

Hepatitis C virus (HCV) infects 2 to 3% of the world population and is a leading cause of liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma. Many aspects of HCV study, ranging from molecular virology and antiviral drug development to drug resistance profiling, were supported by straightforward assays of HCV replication and infection. Among these assays, the HCV-dependent fluorescence relocalization (HDFR) system allowed live-cell visualization of infection without modifying the viral genome, but this strategy required careful recognition of the fluorescence relocalization pattern for its high fluorescence background in the cytoplasm. In this study, to achieve background-free visualization of HCV infection, a viral infection-activated split-intein-mediated reporter system (VISI) was devised. Uninfected Huh7.5.1-VISI cells show no background signal, while HCV infection specifically illuminates the nuclei of infected Huh7.5.1-VISI cells with either green fluorescent protein (GFP) or mCherry. Combining VISI-GFP and VISI-mCherry systems, we revisited HCV cell-to-cell transmission with clear-cut distinction of donor and recipient cells in a live-cell manner. Independently of virion assembly, exosomes have been reported to transfer HCV subgenomic RNA to initiate replication in uninfected cells, which suggested an assembly-free pathway. However, our data demonstrated that HCV structural genes and the p7 gene were essential for not only cell-free infectivity but also cell-to-cell transmission. Additionally, depletion of apolipoprotein E (ApoE) from donor cells but not from recipient cells significantly reduced HCV cell-to-cell transmission efficiency. In summary, we developed a background-free cell-based reporter system for convenient live-cell visualization of HCV infection, and our data indicate that complete HCV virion assembly machinery is essential for both cell-free and cell-to-cell transmission. IMPORTANCE: Hepatitis C virus (HCV) infects hepatocytes via two pathways: cell-free infection and cell-to-cell transmission. Structural modules of the HCV genome are required for production of infectious cell-free virions; however, the role of specific genes within the structural module in cell-to-cell transmission is not clearly defined. Our data demonstrate that deletion of core, E1E2, and p7 genes individually results in no HCV cell-to-cell transmission and that ApoE knockdown from donor cells causes less-efficient cell-to-cell transmission. Thus, this work indicates that the complete HCV assembly machinery is required for HCV cell-to-cell transmission. At last, this work presents an optimized viral infection-activated split-intein-mediated reporter system for easy live-cell monitoring of HCV infection.

Chemokine receptor antagonist block inflammation and therapy Japanese encephalitis virus infection in mouse model.

Japanese encephalitis (JE) is a viral encephalitis disease caused by infection with the Japanese encephalitis virus (JEV). The virus can cross the blood-brain barrier and cause death or long-term sequela in infected humans or animals. In this study, we first investigated the distribution of JEV infection in brain and further analyzed the dynamic change in inflammation related genes, chemokines, as well as pathological characteristics. Results demonstrated that CCR2 and CCR5 antagonist could significantly inhibit the inflammation. The mice treated with CCR2 and CCR5 antagonists had a higher survival rate between 60% and 70%, respectively. In summary, our study thoroughly illustrated the characteristics of the dynamic change in inflammation related genes and chemokines induced by JEV infection. We further indicated that CCR5 and CCR2 are potential targets for treatment of JE.

Protective effects of Scutellaria baicalensis Georgi extract on D-galactose induced aging rats.

Scutellaria baicalensis Georgi (SBG), a traditional Chinese herb, has attracted considerable attention for its wide range of pharmacological activities. This study aimed to investigate the intervention effects of SBG ethanol extract on aging rats induced by D-galactose (D-gal) and to explore potential mechanisms by serum and liver metabolic profiles. The aging rats were induced by the D-gal (100 mg/kg) for 10 weeks continuously with subcutaneous injection, while the control rats received physiological saline. Two other groups of rats were administered with 100 mg/kg/day and 200 mg/kg/day of SBG by oral route following D-gal injections. The abilities of spatial and learning memory were evaluated by open-field test and Morris water maze test. Then, some biochemical indexes related to cognitive ability and aging were measured. Histopathological feature in hippocampal region was observed by Hematoxylin and eosin (HE) staining. The changes of metabolic profiles were evaluated using proton nuclear magnetic resonance (1H NMR) spectroscopy coupled with multivariate data analysis. Results showed that SBG could significantly improve the learning and memory functions, reducing oxidative damage and histological abnormalities of hippocampus neurons. In addition, significant differences in the metabolic profiles were observed both in serum and liver between the model group and the control group. After the treatment using SBG, the levels of these metabolites are significantly changed back to their similar levels in the control group. These metabolic changes are related to the disturbance in amino acid metabolism, glycometabolism and choline metabolism. Hence, SBG may have the potential to improve neurodegeneration and provide brain protection. Graphical abstract A 1H NMR-based metabonomic study was conducted to provide a global view of metabolites related to D-gal induced aging rats and assess the holistic efficacy of Scutellaria baicalensis Georgi.

Neglected but Important Role of Apolipoprotein E Exchange in Hepatitis C Virus Infection.

Hepatitis C virus (HCV) is a major cause of chronic liver disease, infecting approximately 170 million people worldwide. HCV assembly is tightly associated with the lipoprotein pathway. Exchangeable apolipoprotein E (apoE) is incorporated on infectious HCV virions and is important for infectious HCV virion morphogenesis and entry. Moreover, the virion apoE level is positively correlated with its ability to escape E2 antibody neutralization. However, the role of apoE exchange in the HCV life cycle is unclear. In this study, the relationship between apoE expression and cell permissiveness to HCV infection was assessed by infecting apoE knockdown and derived apoE rescue cell lines with HCV. Exchange of apoE between lipoproteins and HCV lipoviral particles (LVPs) was evaluated by immunoprecipitation, infectivity testing, and viral genome quantification. Cell and heparin column binding assays were applied to determine the attachment efficiency of LVPs with different levels of incorporated apoE. The results showed that cell permissiveness for HCV infection was determined by exogenous apoE-associated lipoproteins. Furthermore, apoE exchange did occur between HCV LVPs and lipoproteins, which was important to maintain a high apoE level on LVPs. Lipid-free apoE was capable of enhancing HCV infectivity for apoE knockdown cells but not apoE rescue cells. A higher apoE level on LVPs conferred more efficient LVP attachment to both the cell surface and heparin beads. This study revealed that exogenous apoE-incorporating lipoproteins from uninfected hepatocytes safeguarded the apoE level of LVPs for more efficient attachment during HCV infection. IMPORTANCE: In this study, a neglected but important role of apoE exchange in HCV LVP infectivity after virus assembly and release was identified. The data indicated that apoE expression level in uninfected cells is important for high permissiveness to HCV infection. Secreted apoE-associated lipoprotein specifically enhances infection of HCV LVPs. apoE exchange between HCV LVP and lipoproteins is important to maintain an adequate apoE level on LVPs for their efficient attachment to cell surface. These data defined for the first time an extracellular role of exchangeable apoE in HCV infection and suggested that exchangeable apolipoproteins reach a natural equilibrium between HCV LVPs and lipoprotein particles, which provides a new perspective to the understanding of the heterogeneity of HCV LVPs in composition.

[Advances in the study of the rat model of aging induced by D-galactose]

D-galactose (D-gal)-induced aging model is widely used in the study of the pharmacodynamics of antiaging drugs. The model has a shorter life-span, disorders in learning and memory, reduced immune function and other aging characteristics. Regular and quantitative injection of D-gal solution to rats can produce symptoms of natural aging models that are used in screening of antiaging drugs, and their pharmacological activities. This paper provides a summary of the mechanism of rat model induced with D-gal solution. The methods of building and evaluation of the aging models are provided. The theoretical basis is included to facilitate the subsequent research and experiment in the mechanism study of aging and antiaging medicines.

Longitudinal Study on Pre- and Post-Operation CT Imaging for Predicting Pedicle Screw Loosening in Patients with Lumbar Degenerative Disease.

Purpose: We conducted a longitudinal study to examine the predictive role of risk factors in the occurrence of pedicle screw loosening, assessed through pre- and post-operative computed tomography (CT) scans. Methods: A total of 103 patients with degenerative lumbar disease who had undergone L4/5 pedicle screw fixation (involving 412 screws) were included in this study. They were subsequently categorized into two groups-the "loosening group" and the "non-loosening group". The axial and sagittal angles of the screw trajectory in pre- and post-operative CT images were measured, and the deviation angles were computed. Additionally, measurements were taken of the Hounsfield unit (HU) within the screw entry point area, the pedicle, and the vertebral body in preoperative CT images. Logistic regression analysis was employed to ascertain the risk factors influencing the occurrence of screw loosening. Results: Elderly patients who experienced screw loosening tended to have bilateral screw issues at the L5 level (p < 0.005). The HU of the pedicle (p < 0.001), age (p < 0.001), and the axial deviation angle (p = 0.014) were identified as independent factors predicting screw loosening. Additionally, when HU of the pedicle < 126.5 or age ≥ 53.5 years, the axial deviation angle was found to be smaller in the group experiencing screw loosening (p = 0.018 and p = 0.019). Conclusion: Loosening of screws positioned at L5 was found to be more prevalent in elderly patients, particularly exhibiting a bilateral occurrence. Independent predictors of this phenomenon included a low HU value in the pedicle, advanced age in patients, and a substantial axial deviation angle. In the case of elderly patients with a low HU value in the pedicle, a reduced axial surgical deflection was necessitated to prevent the occurrence of screw loosening.

Kimura Disease: A Detailed Analysis of Clinical and Radiological Manifestations in a Retrospective Case Series.

Background: Kimura disease (KD) is a rare chronic inflammatory disease that affects mainly young Asian men and is characterized by painless subcutaneous masses, lymphadenopathy, and elevated serum IgE levels. Despite its benign nature, KD poses a diagnostic and therapeutic challenge due to its rarity and clinical variability. Objective: This study aimed to provide a comprehensive analysis of the clinical and radiological features of KD in a retrospective case series, to assess treatment outcomes, and to discuss the implications for diagnosis and management. Methods: We retrospectively analyzed four histologically confirmed cases of KD admitted to Zhejiang Provincial People's Hospital from January 2018 to October 2023. Clinical and radiological data were retrospectively analyzed, and imaging findings were analyzed by two neuroradiologists to determine lesion characteristics and contrast enhancement patterns. Results: Our findings showed that the patients were predominantly male, with a mean age of 43 years and an age range of 13-71 years. All patients presented with painless subcutaneous masses and three of them had peripheral blood eosinophilia and elevated serum IgE levels. Radiographically, the lesions were predominantly ill-defined with heterogeneous enhancement, accompanied by subcutaneous fat atrophy. Complete surgical excision and oral corticosteroids were effective treatments, and no recurrence was noted during follow-up. Conclusion: KD should be considered in the differential diagnosis of painless subcutaneous masses in the head and neck region, especially in the presence of eosinophilia and elevated IgE levels. Our findings contribute to the understanding of KD's clinical and radiological spectrum and highlight the need for long-term follow-up due to the risk of recurrence.