Publications by authors named "Jiansheng Wu"

139 Publications

The association between hyperuricemia and left atrial enlargement in healthy adults.

Ann Transl Med 2021 Jul;9(14):1176

Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Background: Although hyperuricemia (HU) has been reported to be related to atrial fibrillation (AF), the relationship between HU and left atrial (LA) enlargement is unclear. The aim of this study was to investigate the interaction between HU and LA enlargement in healthy adults in China.

Methods: This study retrospectively surveyed 5,392 people (3,336 males and 2,056 females) who underwent health checks. Basic data were obtained from all participants, including baseline characteristics and general health status through laboratory tests, echocardiography, and interviews. Multinomial logistic regression was used to analyze the experimental data and determine the association between HU and LA enlargement. In addition, the relationship between HU and LA enlargement in different gender groups was analyzed.

Results: The prevalence of HU in this study was 20.3%. Compared with the normal LA group, the prevalence of HU in the LA enlargement group was significantly higher [31.5% 18.1%; P<0.001; odds ratio (OR) =2.09, 95% confidence interval (CI): 1.78-2.45]. After adjustment for confounding variables, the interrelation of HU on LA enlargement was found to be independent in the total participants (OR =1.25, 95% CI: 1.04-1.51; P=0.017), especially in women (OR =1.73; 95% CI: 1.10-2.74; P=0.019) but not in men (P=0.195).

Conclusions: HU is independently associated with LA enlargement in healthy adults, especially in women.
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http://dx.doi.org/10.21037/atm-21-3402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350625PMC
July 2021

Targeting HER2 Exon 20 Insertion-Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib.

Cancer Res 2021 Aug 11. Epub 2021 Aug 11.

Perlmutter Cancer Center, New York University Langone Medical Center

No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of pre-clinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50 / WT EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, while HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1) synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion-mutant lung adenocarcinoma patients.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1526DOI Listing
August 2021

Urban road greenbelt configuration: The perspective of PM removal and air quality regulation.

Environ Int 2021 Jul 24;157:106786. Epub 2021 Jul 24.

Key Laboratory for Urban Habitat Environmental Science and Technology, School of Urban Planning and Design, Peking University, Shenzhen 518055, PR China. Electronic address:

The establishment of the road green belt (RGB) is an effective means to reduce particle matter (PM) emissions from road traffic. This study tested the ability of 23 common tree species in Shenzhen to reduce PM concentrations using field investigations and wind tunnel tests. The association between leaf microstructure and individual reduction ability was also analyzed. Finally, the impact of three RGB configurations (i.e., arbor, shrub, arbor + shrub) on road PM dispersion and deposition was simulated using the ENVI-met three-dimensional aerodynamic model, based on which an optimal RGB configuration was proposed. There were three key findings of the tests. First, the wind speed was the main factor affecting the PM concentration (54.2%), followed by vehicle flow (27.7%), temperature (14.2%), and time factor (7.6%). Second, the range of dry deposition velocity (V) was 0.04-6.4 m/s, and the dominant dust-retaining plant species were the evergreen trees, Ficus microcarpa and Ficus altissima, and the evergreen shrubs, Codiaeum variegatum and Fagraea ceilanica. A higher proportion of grooves or larger stomata would increase the probability that the blade would capture PM. Third, the shrub RGB demonstrated the best performance in terms of pollutant dispersion; its PM concentration at the respiratory height (RH, 1.5 m) on the pedestrian crossing was 15-20% lower than the other RGB configurations. In terms of pollutant deposition, the arbor + shrub composite RGB was two-fold better than the other RGB configurations. Moreover, it was more advantageous to plant shrub RGBs in street canyons to achieve a balance between the lowest concentration and the largest deposition of PM pollutants. The findings of this study will facilitate the RGB configurations with good dust retention ability.
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http://dx.doi.org/10.1016/j.envint.2021.106786DOI Listing
July 2021

Electrical contacts to few-layer MoS with phase-engineering and metal intercalation for tuning the contact performance.

J Chem Phys 2021 May;154(18):184705

College of Physics Science and Technology, Hebei University, Baoding 071002, China.

Due to Fermi-level pinning in metal-two-dimensional MoS junctions, improving the performance of MoS-based electrical devices is still under extensive study. The device performance of few-layer MoS depends strongly on the number of layers. In this work, via density-functional theory calculations, a comprehensive understanding from the atomistic view was reached for the interlayer interaction between metal and few-layer MoS with phase-engineering and intercalation doping, which are helpful for improving the contact performance. These two methods are probed to tune the performance of few-layer MoS-based field-effect transistors, and both of them can tune the Schottky barrier height. Phase-engineering, which means that the MoS layer in contact with metal is converted to the T phase, can transform the Schottky barrier from n- to p-type. Intercalation doping, which takes advantage of annealing and results in metal atom interaction in between MoS layers, makes the MoS layers become quasi-freestanding and converts the indirect bandgap into direct bandgap. Our atomistic insights help improve the performance of few-layer MoS-based electronic devices.
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http://dx.doi.org/10.1063/5.0046338DOI Listing
May 2021

Spatiotemporal effects of urban sprawl on habitat quality in the Pearl River Delta from 1990 to 2018.

Sci Rep 2021 Jul 7;11(1):13981. Epub 2021 Jul 7.

Key Laboratory for Urban Habitat Environmental Science and Technology, School of Urban Planning and Design, Peking University, Shenzhen, 518055, People's Republic of China.

Since the implementation of the Chinese economic reforms. The habitat quality of coastal has gradually deteriorated with economic development, but the concept of "ecological construction" has slowed the negative trend. For quantitative analysis of the correlation between the Pearl River Delta urban expansion and changes in habitat quality under the influence of the policy, we first analyzed the habitat quality change based on the InVEST model and then measured the impact of construction land expansion on the habitat quality through habitat quality change index (HQCI) and contribution index (CI) indicators. Finally, the correlation between urbanization level and habitat quality was evaluated using geographically weighted regression (GWR) and the Self-organizing feature mapping neural network (SOFM). The results indicated that: (1) during the study period from 2000 to 2020, habitat quality declined due to urban sprawl, indicating a deterioration of ecological structure and function, and the decrease was most significant from 2000 to 2010. (2) The urbanization index had a negative effect on the habitat quality, but the negative effect have improved after 2000, reflecting the positive effect of policies such as "ecological civilization construction" (3) The implementation degree of ecological civilization varies greatly among cities in the study area: Shenzhen, Dongguan, Foshan, and Zhongshan have the best level of green development. These results reflect the positive role of policies in the prevention of damage to habitat quality caused by economic development and provide a reference for the formulation of sustainable urban development policies with spatial differences.
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http://dx.doi.org/10.1038/s41598-021-92916-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263729PMC
July 2021

Exploring common factors influencing PM and O concentrations in the Pearl River Delta: Tradeoffs and synergies.

Environ Pollut 2021 Sep 20;285:117138. Epub 2021 Apr 20.

School of GeoSciences, The University of Edinburgh, Edinburgh, EH9 3FF, UK.

Particulate matter with an aerodynamic equivalent dimeter less than 2.5 μm (PM) and ozone (O) are major air pollutants, with coupled and complex relationships. The control of both PM and O pollution requires the identification of their common influencing factors, which has rarely been attempted. In this study, land use regression (LUR) models based on the least absolute shrinkage and selection operator were developed to estimate PM and O concentrations in China's Pearl River Delta region during 2019. The common factors in the tradeoffs between the two air pollutants and their synergistic effects were analyzed. The model inputs included spatial coordinates, remote sensing observations, meteorological conditions, population density, road density, land cover, and landscape metrics. The LUR models performed well, capturing 54-89% and 42-83% of the variations in annual and seasonal PM and O concentrations, respectively, as shown by the 10-fold cross validation. The overlap of variables between the PM and O models indicated that longitude, aerosol optical depth, O column number density, tropospheric NO column number density, relative humidity, sunshine duration, population density, the percentage cover of forest, grass, impervious surfaces, and bare land, and perimeter-area fractal dimension had opposing effects on PM and O. The tropospheric formaldehyde column number density, wind speed, road density, and area-weighted mean fractal dimension index had complementary effects on PM and O concentrations. This study has improved our understanding of the tradeoff and synergistic factors involved in PM and O pollution, and the results can be used to develop joint control policies for both pollutants.
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http://dx.doi.org/10.1016/j.envpol.2021.117138DOI Listing
September 2021

Climatic modification effects on the association between PM1 and lung cancer incidence in China.

BMC Public Health 2021 05 7;21(1):880. Epub 2021 May 7.

Department of Atmospheric and Oceanic Science, Earth System Science Interdisciplinary Center, University of Maryland, College Park, MD, USA.

Background: Nationwide studies that examine climatic modification effects on the association between air pollution and health outcome are limited in developing countries. Moreover, few studies focus on PM1 pollution despite its greater health effect.

Objectives: This study aims to determine the modification effects of climatic factors on the associations between PM1 and the incidence rates of lung cancer for males and females in China.

Methods: We conducted a nationwide analysis in 345 Chinese counties (districts) from 2014 to 2015. Mean air temperature and relative humidity over the study period were used as the proxies of climatic conditions. In terms of the multivariable linear regression model, we examined climatic modification effects in the stratified and combined datasets according to the three-category and binary divisions of climatic factors. Moreover, we performed three sensitivity analyses to test the robustness of climatic modification effects.

Results: We found a stronger association between PM1 and the incidence rate of male lung cancer in counties with high levels of air temperature or relative humidity. If there is a 10 μg/m shift in PM1, then the change in male incidence rate relative to its mean was higher by 4.39% (95% CI: 2.19, 6.58%) and 8.37% (95% CI: 5.18, 11.56%) in the middle and high temperature groups than in the low temperature group, respectively. The findings of climatic modification effects were robust in the three sensitivity analyses. No significant modification effect was discovered for female incidence rate.

Conclusions: Male residents in high temperature or humidity counties suffer from a larger effect of PM1 on the incidence rate of lung cancer in China. Future research on air pollution-related health impact assessment should consider the differential air pollution effects across different climatic conditions.
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http://dx.doi.org/10.1186/s12889-021-10912-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106137PMC
May 2021

Presence of Metabolic Syndrome and Thyroid Nodules in Subjects with Colorectal Polyps.

Authors:
Yue Yu Jiansheng Wu

Med Sci Monit 2021 Feb 1;27:e927935. Epub 2021 Feb 1.

Department of Clinical Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China (mainland).

BACKGROUND Thyroid nodules (TNs) and metabolic syndrome (MS) have been individually associated with colorectal polyps. However, the potential joint relationship between them in relation to colorectal polyps has not been fully evaluated. This study aimed to validate the association of TNs/MS and colorectal polyps/adenomas and to determine the risk of colonic polyps in patients with TNs/MS. MATERIAL AND METHODS A retrospective study was conducted on patients undergoing routine health checks in the First Affiliated Hospital of Wenzhou Medical University from July 2014 to August 2017. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for colorectal polyps/adenomas after adjusting for confounding factors. Then patients were divided into 4 groups according to whether they had TNs or MS. Relative excess risks of interaction, attributable proportion, and synergy index were used to determine the additive interaction of TNs and MS on colorectal polyps/adenomas. RESULTS A total of 4514 eligible patients were included in this study. TNs and MS were confirmed to be independent risk factors for colorectal polyps/adenomas. Compared with the group of TNs(-)/MS(-), the odds ratios of TNs(+)/MS(+) in colorectal polyps (odds ratio [OR]: 3.031, 95% confidence interval [CI]: 2.262-4.062, P<0.05) or adenomas (OR: 2.894, 95% CI: 2.099-3.990, P<0.05) were significantly increased, and there was an interactive additive effect between TNs and MS. CONCLUSIONS TNs and MS have an associative and superimposing effect on the increased occurrence of colorectal adenomas. Colonoscopy screening should be advocated for patients with both of these diseases.
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http://dx.doi.org/10.12659/MSM.927935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863561PMC
February 2021

Classification of Mild Cognitive Impairment with Multimodal Data using both Labeled and Unlabeled Samples.

IEEE/ACM Trans Comput Biol Bioinform 2021 Jan 20;PP. Epub 2021 Jan 20.

Mild Cognitive Impairment (MCI) is a preclinical stage of Alzheimer's Disease (AD) and is clinical heterogeneity. The classification of MCI is crucial for the early diagnosis and treatment of AD. In this study, we investigated the potential of using both labeled and unlabeled samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to classify MCI through the multimodal co-training method. We utilized both structural magnetic resonance imaging (sMRI) data and genotype data of 364 MCI samples including 228 labeled and 136 unlabeled MCI samples from the ADNI-1 cohort. First, the selected quantitative trait (QT) features from sMRI data and SNP features from genotype data were used to build two initial classifiers on 228 labeled MCI samples. Then, the co-training method was implemented to obtain new labeled samples from 136 unlabeled MCI samples. Finally, the random forest algorithm was used to obtain a combined classifier to classify MCI patients in the independent ADNI-2 dataset. The experimental results showed that our proposed framework obtains an accuracy of 85.50% and an AUC of 0.825 for MCI classification, respectively, which showed that the combined utilization of sMRI and SNP data through the co-training method could significantly improve the performances of MCI classification.
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http://dx.doi.org/10.1109/TCBB.2021.3053061DOI Listing
January 2021

Do socioeconomic factors modify the effects of PM1 and SO2 on lung cancer incidence in China?

Sci Total Environ 2021 Feb 28;756:143998. Epub 2020 Nov 28.

Department of Urban Planning and Design, The University of Hong Kong, Hong Kong, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen 518057, PR China. Electronic address:

Background: It remains uncertain whether socioeconomic factors modify the effect of air pollution on human health. Moreover, studies investigating socioeconomic modifying roles on the effect of PM1 are quite limited, especially in developing countries.

Objectives: The present study aims to investigate socioeconomic modification effects on the associations of the incidence rate of male lung cancer with ambient PM1 and SO2 in China.

Methods: We conducted a nationwide analysis in 345 Chinese counties (districts) between 2014 and 2015. In terms of multivariable linear regression models, we examined the modification effects of urban-rural division, education level and proportion of construction workers in the stratified and combined datasets according to the tertile and binary divisions of the three factors. Moreover, we performed three sensitivity analyses to test the robustness of socioeconomic modification effects.

Results: We found a larger effect of PM1 on the incidence rate of male lung cancer in urban areas than in rural areas. The association between PM1 (or SO2) and the incidence rate of male lung cancer was stronger in counties with low education levels than in those with high education levels. The findings of the significant modification effects of urban-rural division and education level were robust in the three sensitivity analyses. No significant modification effect was observed for the proportion of construction workers.

Conclusions: Male residents in urban areas have a high risk of lung cancer incidence associated with ambient PM1. Male residents with low education levels suffer from larger effects of PM1 and SO2 on the incidence rate of lung cancer. Area- and population-specific strategies should be developed to reduce the urban-rural and educational disparities in air pollution effects, which thereby alleviates air pollution-associated health disparities in China.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143998DOI Listing
February 2021

The Preoperative Enhanced Degree of Contrast-enhanced CT Images: A Potential Independent Predictor in Gastric Adenocarcinoma Patients After Radical Gastrectomy.

Cancer Manag Res 2020 23;12:11989-11999. Epub 2020 Nov 23.

Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325006, People's Republic of China.

Aim: To discover the value of contrast-enhanced CT parameters in predicting the prognosis of gastric adenocarcinoma (GAC) patients after radical gastrectomy.

Methods: The patients with a clinical diagnosis of GAC were retrospectively enrolled. Two radiologists drew the regions of interest (ROIs) in CT images and measured the CT attenuate value (CAV) in each phase and the corrected CAV (cCAV) in each contrast-enhanced phase. Patients were divided into two groups (high/low-enhancement) according to receiver operating characteristic (ROC) curve. Kaplan-Meier curve and Cox proportional hazards regression analysis were performed to evaluate correlation between prognosis and variables. Subgroup analysis was used to further analyze the prognostic value of variables.

Results: In total 435 patients were included. According to ROC curve, the cCAV in delayed phase (DP-cCAV) with maximum AUC and Youden index was chosen. A total of 312 patients (71.7%) entered DP-cCAV group and remaining 123 (28.3%) patients were in DP-cCAV group. According to univariate (high vs low, HR=2.120, <0.001) and multivariate (high vs low, HR=1.623, <0.001) Cox regression analysis, the low-enhancement state was considered as an independent protective factor. Subgroup analysis was based on age, maximum diameter of tumor, differentiation, vascular invasion status, and TNM staging. In most subgroups, the overall survival (OS) of DP-cCAV group was overwhelmingly satisfactory (all HR >1, expect TNM stage I, IV and differentiated type subgroups).

Conclusion: The prognostic effectiveness of CT parameters as biomarkers for OS in GAC patients treated with radical gastrectomy has potential value.
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http://dx.doi.org/10.2147/CMAR.S271879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695603PMC
November 2020

Modifiers versus Channels: Creating Shape-Selective Catalysis of Metal Nanoparticles/Porous Nanomaterials.

Angew Chem Int Ed Engl 2021 Jan 10;60(2):976-982. Epub 2020 Nov 10.

Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Nanjing Tech University (Nanjing Tech), 30 South Puzhu Road, Nanjing, 211816, China.

Shape-selective catalysis plays a key role in chemical synthesis. Porous nanomaterials with uniform pore structures are ideal supports for metal nanoparticles (MNPs) to generate efficient shape-selective catalysis. However, many commercial irregular porous nanomaterials face the challenge to realize satisfactory shape selectivity due to the lack of molecular sieving structures. Herein, we report a concept of creating shape selectivity in MNPs/porous nanomaterials through intentionally poisoning certain MNPs using suitable modifiers. The remaining MNPs within the substrates can cooperate with the channels to generate selectivity. Such a strategy not only applies to regular porous nanomaterials (such as MOFs, zeolites) but also extended to irregular porous nanomaterials (such as active carbon, P25). Potentially, the matching among different MNPs, corresponding modifiers, and porous nanomaterials makes our strategy promising in selective catalytic systems.
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http://dx.doi.org/10.1002/anie.202011866DOI Listing
January 2021

Will polycentric cities cause more CO emissions? A case study of 232 Chinese cities.

J Environ Sci (China) 2020 Oct 24;96:33-43. Epub 2020 May 24.

Key Laboratory for Urban Habitat Environmental Science and Technology, School of Urban Planning and Design, Peking University, Shenzhen 518055, China.

From 2000 to 2010 China experienced rapid economic development and urbanization. Many cities in economically developed areas have developed from a single-center status to polycentricity. In this study, we used exploratory spatial data analysis (ESDA) to identify the population centers, which identified 232 cities in China as having urban centers. COMP was used to represent urban agglomeration, and POLYD (representing how far is the city's sub-centers to the main center), POLYC (representing the number of a city's centers), and POLYP (representing the population distributed between the main center and the sub-centers) were used to indicate urban polycentricity. Night light data were used to determine the CO emissions from various cities in China. A mixed model was used to study the impact of urban aggregation and polycentric data on the CO emission efficiency in 2000 and 2010. The study found that cities with higher compactness were distributed in coastal areas, and the cities with higher multicentricity were distributed in the Yangtze River Delta and Shandong Province. The more compact the city was, the less conducive it was to improving CO emission efficiency. Polycentric development of the city was conducive to improving the CO emission efficiency, but the number of urban centers had no significant relationship with the CO emission efficiency. Our research showed that the compactness and multicentricity of the city had an impact on the CO emission efficiency and provided some planning suggestions for the low carbon development of the city.
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http://dx.doi.org/10.1016/j.jes.2020.04.025DOI Listing
October 2020

Coupling mobile phone data with machine learning: How misclassification errors in ambient PM2.5 exposure estimates are produced?

Sci Total Environ 2020 Nov 18;745:141034. Epub 2020 Jul 18.

Department of Urban Planning and Design, The University of Hong Kong, Hong Kong, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen 518057, PR China. Electronic address:

Background: Most studies relying on time-activity diary or traditional air pollution modelling approach are insufficient to suggest the impacts of ignoring individual mobility and air pollution variations on misclassification errors in exposure estimates. Moreover, very few studies have examined whether such impacts differ across socioeconomic groups.

Objectives: We aim to examine how ignoring individual mobility and PM2.5 variations produces misclassification errors in ambient PM2.5 exposure estimates.

Methods: We developed a geo-informed backward propagation neural network model to estimate hourly PM2.5 concentrations in terms of remote sensing and geospatial big data. Combining the estimated PM2.5 concentrations and individual trajectories derived from 755,468 mobile phone users on a weekday in Shenzhen, China, we estimated four types of individual total PM2.5 exposures during weekdays at multi-temporal scales. The estimate ignoring individual mobility, PM2.5 variations or both was compared with the hypothetical error-free estimate using paired sample t-test. We then quantified the exposure misclassification error using Pearson correlation analysis. Moreover, we examined whether the misclassification error differs across different socioeconomic groups. Taking findings of ignoring individual mobility as an example, we further investigated whether such findings are robust to the different selections of time.

Results: We found that the estimate ignoring PM2.5 variations, individual mobility or both was statistically different from the hypothetical error-free estimate. Ignoring both factors produced the largest exposure misclassification error. The misclassification error was larger in the estimate ignoring PM2.5 variations than that ignoring individual mobility. People with high economic status suffered from a larger exposure misclassification error. The findings were robust to the different selections of time.

Conclusions: Ignoring individual mobility, PM2.5 variations or both leads to misclassification errors in ambient PM2.5 exposure estimates. A larger misclassification error occurs in the estimate neglecting PM2.5 variations than that ignoring individual mobility, which is seldom reported before.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141034DOI Listing
November 2020

Who are more exposed to PM2.5 pollution: A mobile phone data approach.

Environ Int 2020 10 20;143:105821. Epub 2020 Jul 20.

Department of Urban Planning and Design, The University of Hong Kong, Hong Kong, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen 518057, PR China. Electronic address:

Background: Few studies have examined exposure disparity to ambient air pollution outside North America and Europe. Moreover, very few studies have investigated exposure disparity in terms of individual-level data or at multi-temporal scales.

Objectives: This work aims to examine the associations between individual- and neighbourhood-level economic statuses and individual exposure to PM2.5 across multi-temporal scales.

Methods: The study population included 742,220 mobile phone users on a weekday in Shenzhen, China. A geo-informed backward propagation neural network model was developed to estimate hourly PM2.5 concentrations by the use of remote sensing and geospatial big data, which were then combined with individual trajectories to estimate individual total exposure during weekdays at multi-temporal scales. Coupling the estimated PM2.5 exposure with housing price, we examined the associations between individual- and neighbourhood-level economic statuses and individual exposure using linear regression and two-level hierarchical linear models. Furthermore, we performed five sensitivity analyses to test the robustness of the two-level effects.

Results: We found positive associations between individual- and neighbourhood-level economic statuses and individual PM2.5 exposure at a daytime, daily, weekly, monthly, seasonal or annual scale. Findings on the effects of the two-level economic statuses were generally robust in the five sensitivity analyses. In particular, despite the insignificant effects observed in three of newly selected time periods in the sensitivity analysis, individual- and neighbourhood-level economic statuses were still positively associated with individual total exposure during each of other newly selected periods (including three other seasons).

Conclusions: There are statistically positive associations of individual PM2.5 exposure with individual- and neighbourhood-level economic statuses. That is, people living in areas with higher residential property prices are more exposed to PM2.5 pollution. Findings emphasize the need for public health intervention and urban planning initiatives targeting socio-economic disparity in ambient air pollution exposure, thus alleviating health disparities across socioeconomic groups.
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http://dx.doi.org/10.1016/j.envint.2020.105821DOI Listing
October 2020

An in situ decorated cathode with LiF and [email protected] for performance enhanced Li-S batteries.

Chem Commun (Camb) 2020 Jun;56(47):6444-6447

Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, P. R. China.

A simple but effective in situ decorated cathode is presented for Li-S batteries, utilizing the irreversible discharge products between a cathode additive (carbon fluoride) and Li. The in situ formed LiF and F doped carbon can be functional and beneficial to the battery performance, not only suppressing the "shuttle effect", but also facilitating the electron and ion transportation and accelerating the reaction kinetics.
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http://dx.doi.org/10.1039/d0cc01462aDOI Listing
June 2020

The spatial non-stationary effect of urban landscape pattern on urban waterlogging: a case study of Shenzhen City.

Sci Rep 2020 04 30;10(1):7369. Epub 2020 Apr 30.

Key Laboratory for Urban Habitat Environmental Science and Technology, School of Urban Planning and Design, Peking University, Shenzhen, 518055, PR China.

The problem of urban waterlogging has consistently affected areas of southern China, and has generated widespread concerns among the public and professionals. The geographically weighted regression model (GWR) is widely used to reflect the spatial non-stationarity of parameters in different locations, with the relationship between variables able to change with spatial position. In this research, Shenzhen City, which has a serious waterlogging problem, was used as a case study. Several key results were obtained. (1) The spatial autocorrelation of flood spot density in Shenzhen was significant at the 5% level, but because the Z value was not large it was not very obvious. (2) The degree of impact on flood disasters from large to small was: Built up_ DIVISION > SHDI > Built up_ COHESION > CONTAG > Built up_ LPI. (3) The degree of waterlogging disasters in higher altitude regions was less affected by the landscape pattern. The results of this study highlight the important role of the landscape pattern on waterlogging disasters and also indicate the different impacts of different regional landscape patterns on waterlogging disasters, which provides useful information for planning the landscape pattern and controlling waterlogging.
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http://dx.doi.org/10.1038/s41598-020-64113-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193673PMC
April 2020

Transitional MOFs: Exposing Metal Sites with Porosity for Enhancing Catalytic Reaction Performance.

ACS Appl Mater Interfaces 2020 May 14;12(21):23968-23975. Epub 2020 May 14.

Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, P. R. China.

The exploration of transitional metal-organic frameworks (MOFs) is important because of their unique properties and promising applications. Hence, finding a suitable strategy to design transitional MOFs with different states has become a key issue. Herein, we develop a modulator-induced strategy for fabricating transitional MOFs with carboxylic ligands by building esterification reaction. The exposed metal sites, mesoporous systems, morphologies, crystallinities, and components of transitional MOFs can be finely controlled when different modulators are employed. Notably, the Pt/solid-transitional MOF catalyst with more mesopores enhances conversion in the hydrogenation reaction of -hexene, and the flower-like-transitional MOF catalyst with more Lewis acid sites exhibits better performance in the cycloaddition reaction. Therefore, the modulator-induced strategy may provide significant inspiration for preparing various transitional MOFs by building suitable chemical reactions.
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http://dx.doi.org/10.1021/acsami.0c04606DOI Listing
May 2020

CoO nanoparticles embedded in nitrogen-doped graphitic carbon fibers as a free-standing electrode for promotion of lithium ion storage with capacitive contribution.

Chem Commun (Camb) 2020 May 22;56(43):5767-5770. Epub 2020 Apr 22.

Key Laboratory of Flexible Electronics (KLOFE), Institute of Advanced Materials (IAM), Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing, 211816, China.

Here, we wrap CoO nanoparticles with nitrogen-doped graphitic carbon nanofibers ([email protected]) as a self-standing electrode for lithium-ion batteries. In this structure, graphitic carbon acts as a composite framework that enhances conductivity, accommodates volume expansion and increases contact with the electrolyte. Meanwhile, the porosity of [email protected] not only facilitates rapid electron transfer, but also exposes more active sites for lithium storage.
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http://dx.doi.org/10.1039/d0cc00947dDOI Listing
May 2020

Contrast-Enhanced CT Parameters of Gastric Adenocarcinoma: Can Radiomic Features Be Surrogate Biomarkers for HER2 Over-Expression Status?

Cancer Manag Res 2020 18;12:1211-1219. Epub 2020 Feb 18.

Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325002, People's Republic of China.

Objective: The aim of this study was to determine the role of contrast-enhanced computed tomography (CE-CT) parameters in predicting the expression status of HER2 in gastric adenocarcinoma (GAC) patients before radical gastrectomy.

Materials And Methods: A total of 460 GAC patients who underwent non-contrast CT (NC-CT) and CE-CT examinations before radical resection were enrolled in this retrospective study. The radiologists reviewed their CT scans and recorded parameters, including CT attenuate value (CAV) and corrected CAV (cCAV). The pathologist identified the postoperative HER2 expression status, and HER2 expression status was evaluated by immunohistochemical staining (IHC). The association between CE-CT parameters and HER2 expression status was analyzed.

Results: Among the 460 patients, 84 patients had HER2 over-expression status, at a prevalence of 18.3%. The CAVs were significantly different between the 2 different HER2 expression groups in the non-contrast and arterial phases (non-contrast phase: p = 0.005; arterial phase: p < 0.001). Besides, there was a significant difference in the cCAVs between the 2 groups in the arterial phase (arterial phase: p = 0.003). Univariate and multivariate logistic regression analyses identified that the maximum diameter of tumor, differentiation degree, CAV in non-contrast, arterial, and portal phases, and cCAV in the arterial phase were predictive factors of HER2 expression status.

Conclusion: Our analyses showed that the CE-CT parameters were significantly different between different HER2 expression groups. CE-CT parameters could serve as simple, objective predictive factors of HER2 expression status of GAC patients.
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http://dx.doi.org/10.2147/CMAR.S230138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035892PMC
February 2020

Ambient PM2.5 and Annual Lung Cancer Incidence: A Nationwide Study in 295 Chinese Counties.

Int J Environ Res Public Health 2020 02 25;17(5). Epub 2020 Feb 25.

Key Laboratory for Urban Habitat Environmental Science and Technology, Shenzhen Graduate School, Peking University, Shenzhen 518055, China.

Most studies have examined PM2.5 effects on lung cancer mortalities, while few nationwide studies have been conducted in developing countries to estimate the effects of PM2.5 on lung cancer incidences. To fill this gap, this work aims to examine the effects of PM2.5 exposure on annual incidence rates of lung cancer for males and females in China. We performed a nationwide analysis in 295 counties (districts) from 2006 to 2014. Two regression models were employed to analyse data controlling for time, location and socioeconomic characteristics. We also examined whether the estimates of PM2.5 effects are sensitive to the adjustment of health and behaviour covariates, and the issue of the changing cancer registries each year. We further investigated the modification effects of region, temperature and precipitation. Generally, we found significantly positive associations between PM2.5 and incidence rates of lung cancer for males and females. If concurrent PM2.5 changes by 10 g/m, then the incidence rate relative to its baseline significantly changes by 4.20% (95% CI: 2.73%, 5.88%) and 2.48% (95% CI: 1.24%, 4.14%) for males and females, respectively. The effects of exposure to PM2.5 were still significant when further controlling for health and behaviour factors or using 5 year consecutive data from 91 counties. We found the evidence of long-term lag effects of PM2.5. We also found that temperature appeared to positively modify the effects of PM2.5 on the incidence rates of lung cancer for males. In conclusion, there were significantly adverse effects of PM2.5 on the incidence rates of lung cancer for both males and females in China. The estimated effect sizes might be considerably lower than those reported in developed countries. There were long-term lag effects of PM2.5 on lung cancer incidence in China.
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http://dx.doi.org/10.3390/ijerph17051481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084498PMC
February 2020

The Therapeutic Effect of Melatonin on GC by Inducing Cell Apoptosis and Autophagy Induced by Endoplasmic Reticulum Stress.

Onco Targets Ther 2019 26;12:10187-10198. Epub 2019 Nov 26.

Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China.

Background: Gastric cancer (GC) is the main malignancy affecting a large population worldwide. Lack of effective enough treatment is one of the leading factors contributing to the high mortality rate. Melatonin, a naturally occurring compound, has been proven to exert cytotoxic and antiproliferative effects on human gastric cancers. Nevertheless, the mechanisms of anti-gastric cancer of melatonin remain elucidated. It is believed that endoplasmic reticulum (ER) stress and its resultant unfolded protein response (UPR) are connected to the survival, progression, and chemoresistance of various tumor cells via multiple cellular procedures, such as autophagy. In this study, the effects of melatonin on human gastric cancer cell lines AGS and SGC-7901 was assessed to reveal the interaction between melatonin, endoplasmic reticulum stress, and autophagy in gastric cancer.

Methods: CCK-8, the wound healing analysis, colony formation assay, immunofluorescence analysis, Western blotting, flow cytometry, and animal models were used in the current study.

Results: The data demonstrated that melatonin could inhibit GC growth, proliferation, and invasion both in vivo and in vitro. Apoptosis and autophagy induced in a concentration-dependent manner is response to melatonin-induced ER stress. Melatonin induced the expression of apoptotic and autophagy-related proteins, which was markedly attenuated by the ER stress inhibitor 4-PBA and autophagy inhibitor 3-MA. In addition, we used the specific IRE1 inhibitor STF 083010, finding that inhibiting IRE1 could considerably relieve ER stress-induced autophagy activity, as revealed by the reduction of LC3-II and Beclin-1.

Conclusion: This study confirmed that melatonin-induced inhibition of GC cell proliferation is mediated by the activation of the IRE/JNK/Beclin1 signaling.
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http://dx.doi.org/10.2147/OTT.S226140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884966PMC
November 2019

Mapping the cumulative impacts of long-term mining disturbance and progressive rehabilitation on ecosystem services.

Sci Total Environ 2020 May 8;717:137214. Epub 2020 Feb 8.

Key Laboratory for Urban Habitat Environmental Science and Technology, School of Urban Planning and Design, Peking University, Shenzhen 518055, China; Key Laboratory for Earth Surface Processes, Ministry of Education, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China.

Open-cut coal mining can seriously disturb and reshape natural landscapes which results in a range of impacts on local ecosystems and the services they provide. To address the negative impacts of disturbance, progressive rehabilitation is commonly advocated. However, there is little research focusing on how these impacts affect ecosystem services within mine sites and changes over time. The aim of this study was to assess the cumulative impacts of mining disturbance and rehabilitation on ecosystem services through mapping and quantifying changes at multiple spatial and temporal scales. Four ecosystem services including carbon sequestration, air quality regulation, soil conservation and water yield were assessed in 1989, 1997, 2005 and 2013. Disturbance and rehabilitation was mapped using LandTrendr algorithm with Landsat. We mapped spatial patterns and pixel values for each ecosystem service with corresponding model and the landscape changes were analyzed with landscape metrics. In addition, we assessed synergies and trade-offs using Spearman's correlation coefficient for different landscape classes and scales. The results showed that carbon sequestration, air quality regulation and water yield services were both positively and negatively affected by vegetation cover changes due to mined land disturbance and rehabilitation, while soil conservation service were mainly influenced by topographic changes. There were strong interactions between carbon sequestration, air quality regulation and water yield, which were steady among different spatial scales and landscape types. Soil conservation correlations were weak and changed substantially due to differences of spatial scales and landscape types. Although there are limitations associated with data accessibility, this study provides a new research method for mapping impacts of mining on ecosystem services, which offer spatially explicit information for decision-makers and environmental regulators to carry out feasible policies, balancing mining development with ecosystem services provision.
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http://dx.doi.org/10.1016/j.scitotenv.2020.137214DOI Listing
May 2020

Can policy maintain habitat connectivity under landscape fragmentation? A case study of Shenzhen, China.

Sci Total Environ 2020 May 22;715:136829. Epub 2020 Jan 22.

Key Laboratory for Urban Habitat Environmental Science and Technology, School of Urban Planning and Design, Peking University, Shenzhen 518055, China; Laboratory of Earth Surface Processes of Ministry, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China.

The acceleration of urbanization has aggravated the fragmentation of ecological patches and increased the uncertainty risk of habitat connectivity. In the context of landscape fragmentation, government need to establish sound policies that effectively protect the stepping-stones of habitat connection and realize urban ecological integration. In this study, a circuit theory model was used to identify the potential ecological corridors in the city and corresponding stepping-stone groups, with two important stepping-stone groups selected as our areas of focus. By establishing the potential linkages between stepping-stone nodes, we constructed stepping-stone networks within the potential ecological corridors and formulated four scenarios to analyze the robustness of the stepping-stone networks under different policies. The results show that there are 46 important habitats and 22 potential ecological corridors in Shenzhen, including 22 stepping-stone networks. The most important stepping-stone network in the central Shenzhen area connects 7 important habitats and contains 110 stepping-stone nodes. The most important stepping-stone network in the northeast area of Shenzhen connects 5 important habitats and contains 130 stepping-stone nodes. Comparing the robustness and form of the stepping-stone networks under the four policy scenarios, we found that the centrality of stepping-stones is of great significance for maintaining the connectivity of important habitats. For instance, there are five stepping-stone networks in Shenzhen that have not been successfully protected by existing ecological protection policies because their highly central nodes are vulnerable to threats. This study analyzed the maintenance of habitat connectivity under different ecological protection policies in the process of urbanization and discussed the significance of highly central stepping-stone nodes in maintaining habitat connectivity. With this effort, a new perspective on habitat connectivity protection under landscape fragmentation is provided, producing a reference for the formulation of urban ecological protection policy.
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http://dx.doi.org/10.1016/j.scitotenv.2020.136829DOI Listing
May 2020

Homologous G Protein-Coupled Receptors Boost the Modeling and Interpretation of Bioactivities of Ligand Molecules.

J Chem Inf Model 2020 03 18;60(3):1865-1875. Epub 2020 Feb 18.

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.

G protein-coupled receptors (GPCRs) are one of the most important drug targets, accounting for ∼34% of drugs on the market. For drug discovery, accurate modeling and explanation of bioactivities of ligands is critical for the screening and optimization of hit compounds. Homologous GPCRs are more likely to interact with chemically similar ligands, and they tend to share common binding modes with ligand molecules. The inclusion of homologous GPCRs in learning bioactivities of ligands potentially enhances the accuracy and interpretability of models due to utilizing increased training sample size and the existence of common ligand substructures that control bioactivities. Accurate modeling and interpretation of bioactivities of ligands by combining homologous GPCRs can be formulated as multitask learning with joint feature learning problem and naturally matched with the group lasso learning algorithm. Thus, we proposed a multitask regression learning with group lasso (MTR-GL) implemented by -norm regularization to model bioactivities of ligand molecules and then tested the algorithm on a series of thirty-five representative GPCRs datasets that cover nine subfamilies of human GPCRs. The results show that MTR-GL is overall superior to single-task learning methods and classic multitask learning with joint feature learning methods. Moreover, MTR-GL achieves better performance than state-of-the-art deep multitask learning based methods of predicting ligand bioactivities on most datasets (31/35), where MTR-GL obtained an average improvement of 38% on correlation coefficient () and 29% on root-mean-square error over the DeepNeuralNet-QSAR predictors.
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http://dx.doi.org/10.1021/acs.jcim.9b01000DOI Listing
March 2020

Is tailored therapy based on antibiotic susceptibility effective ? a multicenter, open-label, randomized trial.

Front Med 2020 Feb 3;14(1):43-50. Epub 2020 Jan 3.

The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.

An effective eradication therapy of Helicobacter pylori (H. pylori) should be used for the first time. In this study, we assessed whether tailored therapy based on antibiotic susceptibility testing is more effective than traditional therapy. We also evaluated the factors that cause treatment failure in high-resistance areas. For this multicenter trial, we recruited 467 H. pylori-positive patients. The patients were randomly assigned to receive tailored triple therapy (TATT), tailored bismuth-containing quadruple therapy (TABQT), or traditional bismuth-containing quadruple therapy (TRBQT). For the TATT and TABQT groups, antibiotic selection proceeded via susceptibility testing using an agar-dilution test. The patients in the TRBQT group were given amoxicillin, clarithromycin, esomeprazole, and bismuth. Successful eradication was defined as a negative C-urea breath test at least eight weeks after the treatment ended. Susceptibility testing was conducted using an agar-dilution test. The eradication rate was examined via intention-to-treat (ITT) and per-protocol (PP) analyses. The clarithromycin, levofloxacin, and metronidazole resistance rates were 26.12%, 28.69%, and 96.79%, respectively. Resistance against amoxicillin and furazolidone was rare. The eradication rates for TATT, TRBQT, and TABQT were 67.32%, 63.69%, and 85.99% in the ITT analysis (P 0.001) and 74.64%, 68.49%, and 91.22% in the PP analysis (P 0.001), respectively. The efficacy of TABQT was affected by clarithromycin resistance, and bismuth exerted a direct influence on TATT failure. TABQT was the most efficacious regimen for use in high-resistance regions, especially among clarithromycin-susceptible patients.
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http://dx.doi.org/10.1007/s11684-019-0706-8DOI Listing
February 2020

Metal-Organic Frameworks as Metal Ion Precursors for the Synthesis of Nanocomposites for Lithium-Ion Batteries.

Angew Chem Int Ed Engl 2020 Mar 28;59(12):4763-4769. Epub 2020 Feb 28.

Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Nanjing Tech University (NanjingTech), Nanjing, 211800, China.

Metal-organic frameworks (MOFs) are promising materials with fascinating properties. Their widespread applications are sometimes hindered by the intrinsic instability of frameworks. However, this instability of MOFs can also be exploited for useful purposes. Herein, we report the use of MOFs as metal ion precursors for constructing functional nanocomposites by utilizing the instability of MOFs. The heterogeneous growth process of nanostructures on substrates involves the release of metal ions, nucleation on substrates, and formation of a covering structure. Specifically, the synthesized CoS with carbon nanotubes as substrates display enhanced performance in a lithium-ion battery. Such strategy not only presents a new way for exploiting the instability of MOFs but also supplies a prospect for designing versatile functional nanocomposites.
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http://dx.doi.org/10.1002/anie.201915279DOI Listing
March 2020

SnSe Nanoparticles Chemically Embedded in a Carbon Shell for High-Rate Sodium-Ion Storage.

ACS Appl Mater Interfaces 2020 Jan 6;12(2):2346-2353. Epub 2020 Jan 6.

Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM) , Nanjing Tech University , Nanjing 211816 , China.

The development of advanced anode materials is crucial to enhance the performance of sodium-ion batteries (SIBs). In this study, SnSe nanoparticles chemically embedded in a carbon shell ([email protected]) were fabricated from Sn-organic frameworks and evaluated as an anode material for SIBs. The structural characterization demonstrated that there existed C-Sn chemical bonds between the SnSe nanoparticles and carbon shell, which could strongly anchor SnSe nanoparticles to the carbon shell. Such a structure can not only facilitate charge transfer but also ensure the structural stability of the [email protected] electrode. In addition, the carbon shell also helped in the dispersion of SnSe nanoparticles, thus offering more redox-active sites for Na storage. The as-prepared [email protected] nanocomposite could deliver good cycling stability and a superior rate capability of 324 mA h g at 2 A g for SIBs.
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http://dx.doi.org/10.1021/acsami.9b16659DOI Listing
January 2020

Deubiquitinase inhibitor degrasyn suppresses metastasis by targeting USP5-WT1-E-cadherin signalling pathway in pancreatic ductal adenocarcinoma.

J Cell Mol Med 2020 01 17;24(2):1370-1382. Epub 2019 Dec 17.

Laboratory of Internal Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.

Wilm's tumour-1 (WT1) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and enhances metastasis. Deubiquitination stabilizes target proteins, and inhibiting deubiquitination facilitates the degradation of target proteins. However, whether inhibiting deubiquitination of WT1 facilitates its degradation and presents anti-cancer ability in PDAC is unknown. Here, we found that deubiquitinase inhibitor degrasyn rapidly induced the degradation of endogenous and exogenous WT1 through enhancing ubiquitination of WT1 followed by the up-regulation of E-cadherin. Knockdown of WT1 by short hairpin RNAs (shRNAs) inhibited metastasis and overexpression of WT1 partially prevented degrasyn-induced anti-metastasis activity, suggesting that degrasyn presents anti-metastasis activity partially through degrading WT1 protein. We further identified that USP5 deubiquitinated WT1 and stabilized its expression. The higher expressions of USP5 and WT1 are associated with tumour metastasis. More importantly, degrasyn inhibited the activity of USP5 and overexpression of USP5 partially prevented degrasyn-induced degradation of WT1 protein, suggesting that degrasyn degraded WT1 protein through inhibiting the activity of USP5. Finally, degrasyn reduced the tumorigenicity in a xenograft mouse model and reduced the metastasis in vivo. Our results indicate that degrasyn presents strong anti-cancer activity through USP5-WT1-E-cadherin signalling in PDAC. Therefore, degrasyn holds promise as cancer therapeutic agent in PDAC with high expressions of USP5 and WT1.
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http://dx.doi.org/10.1111/jcmm.14813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991651PMC
January 2020

Dissecting the molecular basis of high viscosity of monospecific and bispecific IgG antibodies.

MAbs 2020 Jan-Dec;12(1):1692764

Antibody Engineering, Genentech Inc., South San Francisco, CA, USA.

Some antibodies exhibit elevated viscosity at high concentrations, making them poorly suited for therapeutic applications requiring administration by injection such as subcutaneous or ocular delivery. Here we studied an anti-IL-13/IL-17 bispecific IgG antibody, which has anomalously high viscosity compared to its parent monospecific antibodies. The viscosity of the bispecific IgG in solution was decreased by only ~30% in the presence of NaCl, suggesting electrostatic interactions are insufficient to fully explain the drivers of viscosity. Intriguingly, addition of arginine-HCl reduced the viscosity of the bispecific IgG by ~50% to its parent IgG level. These data suggest that beyond electrostatics, additional types of interactions such as cation-π and/or π-π may contribute to high viscosity more significantly than previously understood. Molecular dynamics simulations of antibody fragments in the mixed solution of free arginine and explicit water were conducted to identify hotspots involved in self-interactions. Exposed surface aromatic amino acids displayed an increased number of contacts with arginine. Mutagenesis of the majority of aromatic residues pinpointed by molecular dynamics simulations effectively decreased the solution's viscosity when tested experimentally. This mutational method to reduce the viscosity of a bispecific antibody was extended to a monospecific anti-GCGR IgG antibody with elevated viscosity. In all cases, point mutants were readily identified that both reduced viscosity and retained antigen-binding affinity. These studies demonstrate a new approach to mitigate high viscosity of some antibodies by mutagenesis of surface-exposed aromatic residues on complementarity-determining regions that may facilitate some clinical applications.
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http://dx.doi.org/10.1080/19420862.2019.1692764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927759PMC
January 2021
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