Spatiotemporal estimation of the PM2.5 concentration and human health risks combining the three-dimensional landscape pattern index and machine learning methods to optimize land use regression modeling in Shaanxi, China.

PM2.5 pollution endangers human health and urban sustainable development. Land use regression (LUR) is one of the most important methods to reveal the temporal and spatial heterogeneity of PM2.5, and the introduction of characteristic variables of geographical factors and the improvement of model construction methods are important research directions for its optimization. However, the complex non-linear correlation between PM2.5 and influencing indicators is always unrecognized by the traditional regression model. The two-dimensional landscape pattern index is difficult to reflect the real information of the surface, and the research accuracy cannot meet the requirements. As such, a novel integrated three-dimensional landscape pattern index (TDLPI) and machine learning extreme gradient boosting (XGBOOST) improved LUR model (LTX) are developed to estimate the spatiotemporal heterogeneity in the fine particle concentration in Shaanxi, China, and health risks of exposure and inhalation of PM2.5 were explored. The LTX model performed well with R2 = 0.88, RMSE of 8.73 µg/m3 and MAE of 5.85 µg/m3. Our findings suggest that integrated three-dimensional landscape pattern information and XGBOOST approaches can accurately estimate annual and seasonal variations of PM2.5 pollution The Guanzhong Plain and northern Shaanxi always feature high PM2.5 values, which exhibit similar distribution trends to those of the observed PM2.5 pollution. This study demonstrated the outstanding performance of the LTX model, which outperforms most models in past researches. On the whole, LTX approach is reliable and can improve the accuracy of pollutant concentration prediction. The health risks of human exposure to fine particles are relatively high in winter. Central part is a high health risk area, while northern area is low. Our study provides a new method for atmospheric pollutants assessing, which is important for LUR model optimization, high-precision PM2.5 pollution prediction and landscape pattern planning. These results can also contribute to human health exposure risks and future epidemiological studies of air pollution.

Estimating PM2.5 concentration using the machine learning GA-SVM method to improve the land use regression model in Shaanxi, China.

With rapid economic growth, urbanization and industrialization, fine particulate matter with aerodynamic diameters ≤ 2.5 µm (PM2.5) has become a major pollutant and shows adverse effects on both human health and the atmospheric environment. Many studies on estimating PM2.5 concentrations have been performed using statistical regression models and satellite remote sensing. However, the accuracy of PM2.5 concentration estimates is limited by traditional regression models; machine learning methods have high predictive power, but fewer studies have been performed on the complementary advantages of different approaches. This study estimates PM2.5 concentrations from satellite remote sensing-derived aerosol optical depth (AOD) products, meteorological data, terrain data and other predictors in 2015 in Shaanxi, China, using a combined genetic algorithm-support vector machine (GA-SVM) method, after which the spatial clustering pattern was explored at the season and year levels. The results indicated that temperature (r = -0.684), precipitation (r = -0.602) and normalized difference vegetation index (NDVI) (r = -0.523) were significantly negatively correlated with the PM2.5 concentration, while AOD (r = 0.337) was significantly positively correlated with the PM2.5 concentration. Compared to conventional land use regression (LUR) and SVM models and previous related studies, the GA-SVM method demonstrated a significantly better prediction accuracy of PM2.5 concentration, with a higher 10-fold cross-validation coefficient of determination (R2) of 0.84 and lower root mean square error (RMSE) and mean absolute error (MAE) of 12.1 µg/m3 and 10.07 µg/m3, respectively. Y-scrambling test shows that the models have no chance correlation. The central and southern parts of Shaanxi have high PM2.5 concentrations, which are mainly due to the pollutant emissions and meteorological and topographical conditions in those areas. There was a positive spatial agglomeration characteristic of regional PM2.5 pollution, and the spatial spillover effect of PM2.5 pollution for seasonal and annual variations does exist. In general, the GA-SVM method is robust and accurately estimates PM2.5 concentrations via a novel modeling framework application and high-quality spatiotemporal information. It also has great significance for the exploration of PM2.5 pollution estimation and high-precision mapping methods, especially early warning in high-risk areas. Finally, the prevention and control of atmospheric pollution should take pollution control measures from major cities and surrounding cities, and focus on the joint pollution control measures for plain cities.

L-Carnitine inhibits the senescence-associated secretory phenotype of aging adipose tissue by JNK/p53 pathway.

Senescence-associated secretory phenotype (SASP) plays a role in aging adipose tissue dysfunction by directly promoting chronic inflammation. The JNK/p53 pathway was reported as a potential mechanism that mediates SASP. In this study, we investigated the effects of L-carnitine, an inhibitor of the JNK/p53 pathway in adipose tissue SASP and dysfunction. Young and aging rat were given L-carnitine by gavage. Next, we detected the senescence, cytokines expression, chronic inflammation and insulin resistance of adipose tissue. Additionally, JNK/p53 pathway was estimated. Our results show a significant increase expression of SASP components in the adipose tissue of aging rats compared to young rats. Further, we found that infiltration of immune cells and the expression of pro-inflammatory cytokines were enhanced in aging adipose tissue while insulin signaling activity was reduced in aging adipose tissue. Interestingly, L-carnitine markedly reduced the expression of SASP factors. L-Carnitine could significantly reduce chronic inflammation, improving insulin resistance. Further, L-carnitine inhibited SASP by inhibiting JNK/p53 pathway. L-Carnitine inhibited SASP by JNK/p53 pathway and attenuated adipose tissue dysfunction of aging.

Functional analysis of human cytomegalovirus UL/b' region using SCID-hu mouse model.

Human cytomegalovirus (HCMV) attenuated strains, Towne, and AD169, differ from prototypic pathogenic strains, such as Toledo, in that they are missing a ∼15-kb segment in the UL/b' region. In contrast to the attenuated strains, Toledo can replicate in human tissue implants in SCID (SCID-hu) mice. Thus, this model provides a unique in vivo system to study the mechanism of viral pathogenesis. Twenty-two ORFs have been annotated in the UL/b' region, including tissue-tropic genes encoded in a pentameric gH/gl complex. To differentiate the role of the pentameric gH/gl complex versus the functions of other ORFs in the 15-kb region in supporting viral growth in vivo, a series of recombinant viral strains were constructed and their ability to replicate in SCID-hu mice was tested. The mutations in the Towne and AD169 strains were repaired to restore their pentameric gH/gl complex and it was found that these changes did not rescue their inability to replicate in the SCID-hu mice. Subsequently four deletion viruses (D1, D2, D3, and D4) in the 15-kb region from the Toledo strain were created. It was demonstrated that D2 and D3 were able to grow in SCID-hu mice, while D1 and D4 were not viable. Interestingly, co-infection of the implant with the D1 and D4 viruses could compensate their respective growth defect in vivo. The results demonstrated that rescuing viral epithelial tropism is not sufficient to revert the attenuation phenotype of AD169 or Towne, and pathogenic genes are located in the segments missing in D1 and D4 viruses. J. Med. Virol. 88:1417-1426, 2016. © 2016 Wiley Periodicals, Inc.

Evaluation of immunity to varicella zoster virus with a novel double antigen sandwich enzyme-linked immunosorbent assay.

Varicella is a highly contagious disease caused by primary infection of Varicella zoster virus (VZV). Varicella can be severe or even lethal in susceptible adults, immunocompromised patients and neonates. Determination of the status of immunity to VZV is recommended for these high-risk populations. Furthermore, measurement of population immunity to VZV can help in developing proper varicella vaccination programmes. VZV glycoprotein E (gE) is an antigen that has been demonstrated to be a highly accurate indicator of VZV-specific immunity. In this study, recombinant gE (rgE) was used to establish a double antigen sandwich enzyme-linked immunosorbent assay (ELISA). The established sandwich ELISA showed high specificity and sensitivity in the detection of human sera, and it could detect VZV-specific antibodies at a concentration of 11.25 m IU/mL with a detection linearity interval of 11.25 to 360 m IU/mL (R 2 = 0.9985). The double gE antigen sandwich ELISA showed a sensitivity of 95.08 % and specificity of 100 % compared to the fluorescent-antibody-to-membrane-antigen (FAMA) test, and it showed a sensitivity of 100 % and a specificity of 94.74 % compared to a commercial neutralizing antibody detection kit. Thus, the established double antigen sandwich ELISA can be used as a sensitive and specific quantitative method to evaluate immunity to VZV.

A monoclonal antibody-based VZV glycoprotein E quantitative assay and its application on antigen quantitation in VZV vaccine.

Varicella-zoster virus (VZV) is a highly infectious agent that causes varicella and herpes zoster (HZ), which may be associated with severe neuralgia. Vaccination is the most effective way to reduce the burden of the diseases. VZV glycoprotein E (gE) is the major and most immunogenic membrane protein that plays important roles in vaccine efficacy. A quantitative assay for gE content is desirable for the VZV vaccine process monitoring and product analysis. In this study, 70 monoclonal antibodies (mAbs) were obtained after immunizing mice with purified recombinant gE (rgE). The collection of mAbs was well-characterized, and a pair of high-affinity neutralization antibodies (capture mAb 4A2 and detection mAb 4H10) was selected to establish a specific and sensitive sandwich enzyme-linked immunosorbent assay (ELISA) to quantify the native and recombinant gE. The detection limit of this assay was found to be 1.95 ng/mL. Furthermore, a reasonably good correlation between the gE content (as measured by the mAb-based quantitative ELISA) and the virus titer (as measured by the "gold standard" plaque assay) was observed when both assays were performed for tracking the kinetics of virus growth during cell culture. A total of 16 batches of lyophilized VZV vaccine were tested using the newly developed quantitative ELISA and classical plaque assay, demonstrating reasonably good correlation between gE content and virus titer. Therefore, this mAb-based gE quantitative assay serves as a rapid, stable, and sensitive method for monitoring viral antigen content, one additional quantitative method for VZV vaccine process and product characterization. This quantitative ELISA may also serve as a complementary method for virus titering.

ORF7 of varicella-zoster virus is a neurotropic factor.

Varicella-zoster virus (VZV) is the causative agent of chickenpox and herpes zoster (shingles). After the primary infection, the virus remains latent in sensory ganglia and reactivates upon weakening of the cellular immune system due to various conditions, erupting from sensory neurons and infecting the corresponding skin tissue. The current varicella vaccine is highly attenuated in the skin and yet retains its neurovirulence and may reactivate and damage sensory neurons. The factors involved in neuronal invasion and establishment of latency are still elusive. Previously, we constructed a library of whole-gene deletion mutants carrying a bacterial artificial chromosome sequence and a luciferase marker in order to perform a comprehensive VZV genome functional analysis. Here, screening of dispensable gene deletion mutants in differentiated neuronal cells led to the identification of ORF7 as the first known, likely a main, VZV neurotropic factor. ORF7 is a virion component localized to the Golgi compartment in infected cells, whose deletion causes loss of polykaryon formation in epithelial cell culture. Interestingly, ORF7 deletion completely abolishes viral spread in human nervous tissue ex vivo and in an in vivo mouse model. This finding adds to our previous report that ORF7 is also a skin-tropic factor. The results of our investigation will not only lead to a better understanding of VZV neurotropism but could also contribute to the development of a neuroattenuated vaccine candidate against shingles or a vector for delivery of other antigens.

Value of echocardiography in evaluating efficacy of radiofrequency catheter ablation in patients with atrial fibrillation.

OBJECTIVE: To analyze the cardiac structure and function of patients with recurrent atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA) with echocardiography and to predict the factors affecting recurrence. METHODS: In this retrospective study, 87 patients who received RFCA for AF in the Weihai Municipal Hospital from June 2018 to December 2019 were enrolled. According to the recovery of postoperative sinus rhythm (SR), patients with recovered SR were assigned to the research group (Res group, n=60), while those with AF recurrence were included in the control group (Con group, n=27). The transthoracic echocardiography was adopted to measure the changes of left atrium-related parameters of patients before RFCA and at 6 months after surgery, and the transesophageal three-dimensional echocardiography was adopted for measuring the changes of left atrial appendage (LAA)-related parameters. In addition, multivariate logistic regression was performed to analyze the factors influencing postoperative recurrence of AF. RESULTS: After 6-month follow up, SR was restored in 60 cases and AF recurred in 27 cases. After surgery, the left atrial anteroposterior diameter (LAAPD), left atrial left and right diameter (LALRD), left atrial up and down diameter (LAUDD), maximum volume of left atrium (LAVmax), minimum volume of left atrium (LAVmin), opening diameter of LAA (LAAOD), maximum volume of LAA (LAAVmax), and minimum volume of LAA (LAAV min) of the Res group decreased, and were lower than those of the Con group. In addition, the left atrial ejection fraction (LAEF), vessel function index and dilatation index of the Res group increased significantly postoperatively, and were higher than those of the Con group. The Res group also showed significantly higher LAA area change percentage [LAAAC (%)] and LAA emptying velocity (LAAEV) than the Con group. Moreover, age, history of hypertension, LAVmax and LAAAC (%) were identified to be the independent risk factors for postoperative recurrence of AF. CONCLUSION: Patients with increased left atrial diameter and volume, large LAAOD, and small ejection fraction are more susceptible to AF recurrence, and LAAOD is a predictor of postoperative recurrence of AF.

Bivalent rotavirus VP4∗ stimulates protective antibodies against common genotypes of human rotaviruses.

Non-replicating rotavirus vaccines are an alternative strategy to improve the efficacy and safety of rotavirus vaccines. The spike protein VP4, which could be enzymatically cleaved into VP8∗ and VP5∗, is an ideal target for the development of recombinant rotavirus vaccine. In our previous studies, we demonstrated that the truncated VP4 (aa26-476, VP4∗) could be a more viable vaccine candidate compared to VP8∗ and VP5∗. Here, to develop a human rotavirus vaccine, the VP4∗ proteins of P[4], P[6], and P[8] genotype rotaviruses were expressed. All VP4∗ proteins can stimulate high levels of neutralizing antibodies in both guinea pigs and rabbits when formulated in aluminum adjuvant. Furthermore, bivalent VP4∗-based vaccine (P[8] + P[6]-VP4∗) can stimulate high levels of neutralizing antibodies against various genotypes of rotavirus with no significant difference as compared to the trivalent vaccines. Therefore, bivalent VP4∗ has the potential to be a viable rotavirus vaccine candidate for further development.

Development of a skin- and neuro-attenuated live vaccine for varicella.

Varicella caused by the primary infection of varicella-zoster virus (VZV) exerts a considerable disease burden globally. Current varicella vaccines consisting of the live-attenuated vOka strain of VZV are generally safe and effective. However, vOka retains full neurovirulence and can establish latency and reactivate to cause herpes zoster in vaccine recipients, raising safety concerns. Here, we rationally design a live-attenuated varicella vaccine candidate, v7D. This virus replicates like wild-type virus in MRC-5 fibroblasts and human PBMCs, the carrier for VZV dissemination, but is severely impaired for infection of human skin and neuronal cells. Meanwhile, v7D shows immunogenicity comparable to vOka both in vitro and in multiple small animal species. Finally, v7D is proven well-tolerated and immunogenic in nonhuman primates. Our preclinical data suggest that v7D is a promising candidate as a safer live varicella vaccine with reduced risk of vaccine-related complications, and could inform the design of other herpes virus vaccines.

RNA Interference inhibits hepatitis B virus of different genotypes in vitro and in vivo.

BACKGROUND: Hepatitis B virus (HBV) infection increases the risk of liver disease and hepatocellular carcinoma. Small interfering RNA (siRNA) can be a potential new tool for HBV therapy. Given the high heterogeneity of HBV strains and the sensitivity towards sequences changes of siRNA, finding a potent siRNA inhibitor against the conservative site on the HBV genome is essential to ensure a therapeutic application. RESULTS: Forty short hairpin RNA (shRNA) expression plasmids were constructed to target conserved regions among nine HBV genotypes. HBV 1.3-fold genome plasmids carrying various genotypes were co-transfected with shRNA plasmids into either Huh7 cells or mice. The levels of various viral markers were examined to assess the anti-HBV efficacy of siRNA. Four (B245, B376, B1581 and B1789) were found with the ability to potently inhibit HBV RNA, DNA, surface antigen (HBsAg), e antigen (HBeAg) and core antigen (HBcAg) expression in HBV genotypes A, B, C, D and I (a newly identified genotype) in Huh7 cells and in mice. No unusual cytotoxicity or off-target effects were noted. CONCLUSIONS: Such siRNA suggests an alternate way of inhibiting various HBV genotypes in vitro and in vivo, promising advances in the treatment of HBV.

Role of the CHADS2 Score in the Evaluation of Carotid Atherosclerosis in Patients with Atrial Fibrillation Undergoing Carotid Artery Ultrasonography.

OBJECTIVE: This study investigated the characteristics of carotid atherosclerosis in patients with atrial fibrillation (AF) and determined the feasibility and significance of the CHADS2 score in predicting the degree of carotid atherosclerosis. METHODS: Consecutive patients (n = 109) with nonvalvular AF were registered and classified into two groups, the paroxysmal AF group (n = 59) and persistent AF group (n = 50). Fifty healthy patients, matched by sex and age, were considered the control group. All patients were examined using carotid ultrasound and velocity vector imaging (VVI). RESULTS: Compared with the control group, the mean intimal-medial thickness in the paroxysmal AF group (0.56 ± 0.11 versus 0.61 ± 0.10, respectively, P < 0.05) and the persistent AF group (0.56 ± 0.11 versus 0.64 ± 0.13, respectively, P < 0.001) was significantly increased. The plaque index (PI) in the persistent AF group was significantly higher than that observed in the paroxysmal AF group (1.05 ± 1.33 versus 1.42 ± 1.47, respectively, P < 0.001). Regarding the VVI indices, those reflecting the long-axis longitudinal motion function of carotid arteries were significantly decreased in both AF groups. Compared with the control group, a significantly lower total longitudinal displacement (tLoD) index was observed in the persistent AF group (0.73 ± 0.66 versus 0.31 ± 0.23, respectively, P < 0·0001) and the paroxysmal AF group (0.73 ± 0.66 versus 0.34 ± 0.17, P < 0·0001). The CHADS2 score was related to indicators reflecting the structure and function of the carotid artery. CONCLUSIONS: Carotid arterial structure and function were significantly altered in patients with AF. The degree of carotid atherosclerosis depended on the duration of AF. The CHADS2 score may be useful as a predictor of the extent of carotid atherosclerosis in patients with AF.

Outer nuclear membrane fusion of adjacent nuclei in varicella-zoster virus-induced syncytia.

Syncytia formation has been considered important for cell-to-cell spread and pathogenesis of many viruses. As a syncytium forms, individual nuclei often congregate together, allowing close contact of nuclear membranes and possibly fusion to occur. However, there is currently no reported evidence of nuclear membrane fusion between adjacent nuclei in wild-type virus-induced syncytia. Varicella-zoster virus (VZV) is one typical syncytia-inducing virus that causes chickenpox and shingles in humans. Here, we report, for the first time, an interesting observation of apparent fusion of the outer nuclear membranes from juxtaposed nuclei that comprise VZV syncytia both in ARPE-19 human epithelial cells in vitro and in human skin xenografts in the SCID-hu mouse model in vivo. This work reveals a novel aspect of VZV-related cytopathic effect in the context of multinucleated syncytia. Additionally, the information provided by this study could be helpful for future studies on interactions of viruses with host cell nuclei.

Modulation of host CD59 expression by varicella-zoster virus in human xenografts in vivo.

Varicella-zoster virus (VZV) is the causative agent of both chickenpox (varicella) and shingles (zoster). VZV survives host defenses, even with an intact immune system, and disseminates in the host before causing disease. To date, several diverse immunomodulatory strategies used by VZV to undermine host immunity have been identified; however, few studies have addressed the complement evasion strategies used by this virus. Here, we show that expression of CD59, which is a key member of host regulators of complement activation (RCA), is significantly upregulated in response to VZV infection in human T cells and dorsal root ganglia (DRG) but not in human skin xenografts in SCID-hu mice in vivo. This is the first report demonstrating that VZV infection upregulates host CD59 expression in a tissue-specific manner in vivo, which may aid VZV in complement evasion and pathogenesis.

Serological Evaluation of Immunity to the Varicella-Zoster Virus Based on a Novel Competitive Enzyme-Linked Immunosorbent Assay.

Varicella-zoster virus (VZV) is a highly contagious agent of varicella and herpes zoster. Varicella can be lethal to immunocompromised patients, babies, HIV patients and other adults with impaired immunity. Serological evaluation of immunity to VZV will help determine which individuals are susceptible and evaluate vaccine effectiveness. A collection of 110 monoclonal antibodies (mAbs) were obtained by immunization of mice with membrane proteins or cell-free virus. The mAbs were well characterized, and a competitive sandwich ELISA (capture mAb: 8H6; labelling mAb: 1B11) was established to determine neutralizing antibodies in human serum with reference to the FAMA test. A total of 920 human sera were evaluated. The competitive sandwich ELISA showed a sensitivity of 95.6%, specificity of 99.77% and coincidence of 97.61% compared with the fluorescent-antibody-to-membrane-antigen (FAMA) test. The capture mAb 8H6 was characterized as a specific mAb for VZV ORF9, a membrane-associated tegument protein that interacts with glycoprotein E (gE), glycoprotein B (gB) and glycoprotein C (gC). The labelling mAb 1B11 was characterized as a complement-dependent neutralizing mAb specific for the immune-dominant epitope located on gE, not on other VZV glycoproteins. The established competitive sandwich ELISA could be used as a rapid and high-throughput method for evaluating immunity to VZV.