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For small aspherical molds, it is difficult for the existing polishing method to take into account the correction of the surface error and the control of the uniformity of the surface roughness (SR) distribution, because the polishing tool is always larger than the small mold. Therefore, we used viscoelastic polyester fiber cloth to wrap the small steel ball as a polishing tool to adapt to the surface shape change of the aspherical mold, and designed a semi-flexible small polishing disc tool with microstructure, which can better adapt to the curvature change of aspherical surface and obtain better SR Ra. At the same time, a combined polishing method of constant speed and variable speed for screw feed was proposed to improve the uniformity of SR distribution in the paper. Then, a series of theoretical analysis and experimental verification were carried out in this paper to predict the tool influence function (TIF) of the two polishing tools and the effectiveness of the combined polishing method. In the experiment, a TIF bandwidth of about 0.46 mm was obtained with a small spherical polishing tool, which favors the surface shape correction of the small aspherical mold. The experiment of uniform removal with a small polishing disc tool was carried out to quickly reduce the Ra. Finally, the surface quality of the aspherical mold was effectively improved, combined with the constant speed and variable speed polishing modes of screw feed of the small spherical polishing tool and the smoothing effect of the small polishing disc tool. The peak valley (PV) of two small aspherical molds with an optical effective diameter less than 13 mm converged from 0.3572 μm and 0.2075 μm to 0.1282 μm and 0.071 μm, respectively. At the same time, the SR dispersion coefficient was reduced from 27.9% and 41.6% to 14.2% and 12.7%, respectively. The study provides a good solution for the surface quality control of small aspherical molds.

As a kind of reactive oxygen species, peroxynitrite is related to various diseases closely such as cancer and neurodegenerative diseases. Constructing probes with highly specific ability and a wide linear detection range for peroxynitrite detection is crucial for understanding the pathogenesis of related diseases and optimizing treatments. In this work, we developed a novel luminescent ratiometric fluorescence nanoprobe (PC-CDs) based on carbon dots and phycocyanin. PC-CDs are constructed by amidation reaction between carbon dots and phycocyanin. The nanoprobe we obtained has a good ability of distinguishing peroxynitrite from other reactive oxygen species and interfering substances. Moreover, the linear range of the nanoprobe is 0.5-100 μM and the limit of detection is 0.5 μM when detecting peroxynitrite. In the spiked recovery experiments under phosphate buffered saline (PBS) environment, our nanoprobe has a good recovery performance and the recovery is 99% - 104%, which will be beneficial to the further development of peroxynitrite testing and the research progress of related diseases. Finally, we discuss the quenching mechanism of peroxynitrite for nanoprobe, and found that there is the combination of dynamic and static quenching in the quenching process., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Orthopedic hybrid implants combining both titanium (Ti) and magnesium (Mg) have gained wide attraction nowadays. However, it still remains a huge challenge in the fabrication of Mg-Ti composites because of the different temperatures of Ti melting point and pure Mg volatilization point. In this study, we successfully fabricated a new Mg-Ti composite with bi-continuous interpenetrating phase architecture by infiltrating Mg melt into Ti scaffolds, which were prepared by 3D printing and subsequent acid treatment. We attempted to understand the 7-day degradation process of the Mg-Ti composite and examine the different Mg 2+ concentration composite impacts on the MC3T3-E1 cells, including toxicity, morphology, apoptosis, and osteogenic activity. CCK-8 results indicated cytotoxicity and absence of the Mg-Ti composite during 7-day degradation. Moreover, the composite significantly improved the morphology, reduced the apoptosis rate, and enhanced the osteogenic activity of MC3T3-E1 cells. The favorable impacts might be attributed to the appropriate Mg 2+ concentration of the extracts. The results on varying Mg 2+ concentration tests indicated that Mg 2+ showed no cell adverse effect under 10-mM concentration. The 8-mM group exhibited the best cell morphology, minimum apoptosis rate, and maximum osteogenic activity. This work may open a new perspective on the development and biomedical applications for Mg-Ti composites., Competing Interests: The reviewer CY declared a shared affiliation, with no collaboration, with the authors DR, HJ, ZL, and ZZ to the handling editor at the time of the review., (Copyright © 2022 Yang, Huang, Zhan, Ren, Ji, Liu, Wang, Zhang and Zhang.)

Polyploid breeding is an effective approach to improve plant biomass and quality. Both fast growth and dwarf types of in vitro or ex vitro plants are produced after polyploidization. However, little is known regarding the dwarf type mechanism in polyploids grown in vitro . In this study, the morphological and cytological characteristics were measured in tetraploid and diploid hybrid sweetgum ( Liquidambar styraciflua × L. formosana ) with the same genetic background. RNA sequencing (RNA-Seq) was used to analyse shoot and root variations between tetraploid and diploid plants; important metabolites were validated. The results showed that the shoot and root lengths were significantly shorter in tetraploids than in diploids after 25 d of culture. Most tetraploid root cells were wider and more irregular, and the length of the meristematic zone was shorter, while tetraploid cells were significantly larger than diploid cells. Differentially expressed genes (DEGs) were significantly enriched in the plant growth and organ elongation pathways, such as plant hormone biosynthesis and signal transduction, sugar and starch metabolism, and cell cycles. Hormone biosynthesis and signal transduction genes, such as YUCCA , TAA1 , GH3 , SAUR , CPS , KO , KAO , GA20ox , GA3ox , BAS1 and CYCD3 , which help to regulate organ elongation, were generally downregulated. The auxin, gibberellin, and brassinolide (BL) contents in roots and stems were significantly lower in tetraploids than in diploids, which may greatly contribute to slow growth in the roots and stems of tetraploid regenerated plants. Exogenous gibberellic acid (GA 3 ) and indole-3-acetic acid (IAA), which induced plant cell elongation, could significantly promote growth in the stems and roots of tetraploids. In summary, comparative transcriptomics and metabolite analysis showed that the slow growth of regenerated tetraploid hybrid sweetgum was strongly related to auxin and gibberellin deficiency. Our findings provide insights into the molecular mechanisms that underlie dwarfism in allopolyploid hybrid sweetgum., Competing Interests: DZ and ZP are employed by Guangxi Bagui Forest and Flowers Seedlings Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Zhang, Zhang, Zhan, Pang, Zhao and Zhang.)

In this paper, we investigate the mathematical models of discrete memristors based on Caputo fractional difference and G-L fractional difference. Specifically, the integer-order discrete memristor is a special model of those two cases. The " ∞ "-type hysteresis loop curves are observed when input is the bipolar periodic signal. Meanwhile, numerical analysis results show that the area of hysteresis decreases with the increase of frequency of input signal and the decrease of derivative order. Moreover, the memory effect, characteristics and physical realization of the discrete memristors are discussed, and a discrete memristor with short memory effects is designed. Furthermore, discrete memristive systems are designed by introducing the fractional-order discrete memristor and integer-order discrete memristor to the Sine map. Chaos is found in the systems, and complexity of the systems is controlled by the parameter of the memristor. Finally, FPGA digital circuit implementation is carried out for the integer-order and fractional-order discrete memristor and discrete memristive systems, which shows the potential application value of the discrete memristor in the engineering application field.

Background: The aim of this study was to investigate the immunogenicity and safety of the enterovirus 71 vaccine (EV71 vaccine) administered alone or simultaneously., Methods: A multi-center, open-label, randomized controlled trial was performed involving 1080 healthy infants aged 6 months or 8 months from Shandong, Shanxi, Shaanxi, and Hunan provinces. These infants were divided into four simultaneous administration groups and EV71 vaccine separate administration group. Blood samples were collected from the infants before the first vaccination and after the completion of the vaccination. This trial was registered in the Clinical Trials Registry (NCT03519568)., Results: A total of 895 were included in the per-protocol analysis. The seroconversion rates of antibodies against EV71 in four simultaneous administration groups (98.44% (189/192), 94.57% (122/129), 99.47% (187/188) and 98.45% (190/193)) were non-inferior to EV71 vaccine separate administration group (97.93% [189/193]) respectively. Fever was the most common adverse event, the pairwise comparison tests showed no difference in the incidence rate of solicited, systemic or local adverse events. Three serious adverse events related to the vaccination were reported., Conclusions: The evidence of immunogenicity and safety supports that the EV71 vaccine administered simultaneously with vaccines need to be administered during the same period of time recommended in China.

Continuous air pollution (CAP) incidents last even longer and generate greater health hazards relative to conventional air pollution episodes. However, few studies have focused on the spatiotemporal distribution characteristics and driving factors of CAP in China. Drawing on the daily reported ground monitoring data on the ambient air quality in 2019 in China, this paper identifies the spatiotemporal distribution characteristics of CAP across 337 Chinese cities above the prefecture level using descriptive statistics and spatial statistical analysis methods, and further examines the spatial heterogeneity effects of both socioeconomic factors and natural factors on CAP with a Multiscale Geographically Weighted Regression (MGWR) model. The results show that the average proportion of CAP days in 2019 reached 11.50% of the whole year across Chinese cities, a figure equaling to about 65 days, while the average frequency, the maximum amount of days and the average amount of days of CAP were 8.02 times, 7.85 days and 4.20 days, respectively. Furthermore, there was a distinct spatiotemporal distribution disparity in CAP in China. Spatially, the areas with high proportions of CAP days were concentrated in the North China Plain and the Southwestern Xinjiang Autonomous Region in terms of the spatial pattern, while the proportion of CAP days showed a monthly W-shaped change in terms of the temporal pattern. In addition, the types of regions containing major pollutants during the CAP period could be divided into four types, including "Composite pollution", "O 3 + NO 2 pollution", "PM 10 + PM 2.5 pollution" and "O 3 + PM 2.5 pollution", while the region type "PM 10 + PM 2.5 pollution" covered the highest number of cities. The MGWR model, characterized by multiple spatial scale impacts among the driving factors, outperformed the traditional OLS and GWR model, and both socioeconomic factors and natural factors were found to have a spatial non-stationary relationship with CAP in China. Our findings provide new policy insights for understanding the spatiotemporal distribution characteristics of CAP in urban China and can help the Chinese government make prevention and control measures of CAP incidents.

Gastric cancer (GC) is one of the most common malignant tumors with a high mortality rate worldwide and lacks effective methods for prognosis prediction. Postoperative adjuvant chemotherapy is the first-line treatment for advanced gastric cancer, but only a subgroup of patients benefits from it. Here, we used 833 formalin-fixed, paraffin-embedded resected tumor samples from patients with TNM stage II/III GC and established a proteomic subtyping workflow using 100 deep-learned features. Two proteomic subtypes (S-I and S-II) with overall survival differences were identified. S-I has a better survival rate and is sensitive to chemotherapy. Patients in the S-I who received adjuvant chemotherapy had a significant improvement in the 5-year overall survival rate compared with patients who received surgery alone (65.3% vs 52.6%; log-rank P = 0.014), but no improvement was observed in the S-II (54% vs 51%; log-rank P = 0.96). These results were verified in an independent validation set. Furthermore, we also evaluated the superiority and scalability of the deep learning-based workflow in cancer molecular subtyping, exhibiting its great utility and potential in prognosis prediction and therapeutic decision-making., Competing Interests: Author DZ was employed by Beijing Pineal Diagnostics Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Xia, Wang, Bai, Zhan and Shu.)

GATA transcription factors have been demonstrated to play key regulatory roles in plant growth, development, and hormonal response. However, the knowledge concerning the evolution of GATA genes in Eucalyptus urophylla and their trans-regulatory interaction is indistinct. Phylogenetic analysis and study of conserved motifs, exon structures, and expression patterns resolved the evolutionary relationships of these GATA proteins. Phylogenetic analysis showed that EgrGATAs are broadly distributed in four subfamilies. Cis -element analysis of promoters revealed that EgrGATA genes respond to light and are influenced by multiple hormones and abiotic stresses. Transcriptome analysis revealed distinct temporal and spatial expression patterns of EgrGATA genes in various tissues of E. urophylla S.T.Blake, which was confirmed by real-time quantitative PCR (RT-qPCR). Further research revealed that EurGNC and EurCGA1 were localized in the nucleus, and EurGNC directly binds to the cis -element of the EurGUN5 promoter, implying its potential roles in the regulation of chlorophyll synthesis. This comprehensive study provides new insights into the evolution of GATA s and could help to improve the photosynthetic assimilation and vegetative growth of E. urophylla at the genetic level.

Recently, recommender systems are applied to provide personalized recomendation for healthcare wearables. However, due to the sparsity problem, traditional recommendation algorithms are difficult to achieve desired performance. Considering that consumers often buy and rate other types of items on E-commerce platforms, we can leverage significant information in the auxiliary domains to improve the recommendation performance of healthcare wearables, which can be regarded as cross-domain recommendation. However, traditional cross-domain recommendation model cannot fully represent user's characteristics and fail to consider the leaks of original auxiliary domain ratings during the information transfer process. To overcome the two shortcomings, this paper proposes a Privacy-Preserving Cross-Domain Healthcare Wearables Recommendation algorithm (PPCDHWRec). Firstly, user's characteristics are divided into domain-dependent features and domain-independent features, which complement each other and fully depict the user's characteristics. Secondly, inspired by the latent factor model, we factorize the original rating information of each auxiliary domain by Funk-SVD and Orthogonal Nonnegative Matrix Tri-Factorization (ONMTF) model, to obtain user's domain-dependent and domain-independent features, respectively. Finally, the Factorization Machine algorithm is used to fuse the obtained user's features with the target domain information to provide the recommendation results. By hiding the item latent factors obtained in the factorization process, PPCDHWRec ensures that the original information cannot be inferred from the transferred user hidden vector. Hence, PPCDHWRec is a privacy-preserving recommendation model. Experiments on two groups of auxiliary domains, having high and low correlations with target domain, show the effectiveness of PPCDHWRec.

Background: There are limited sensitive evaluation methods to distinguish people's symptoms of peripheral fatigue and central fatigue simultaneously. The purpose of this study is to identify and evaluate them after acute exercise with a simple and practical scale., Methods: The initial scale was built through a literature review, experts and athlete population survey, and a small sample pre-survey. Randomly selected 1,506 students were evaluated with the initial scale after exercise. Subjective fatigue self-assessments (SFSA) were completed at the same time., Results: The Acute Exercise-Induced Fatigue Scale (AEIFS) was determined after performing a factor analysis. In the exploratory factor analysis, the cumulative variance contribution rate was 65.464%. The factor loadings of the total 8 questions were 0.661-0.816. In the confirmatory factor analysis, χ 2 /df = 2.529, GFI = 0.985, AGFI = 0.967, NFI = 0.982, IFI = 0.989, CFI = 0.989, and RMSEA = 0.048. The Cronbach's alpha coefficient for the scale was 0.872, and it was 0.833 for peripheral fatigue and 0.818 for central fatigue. The intra-class correlation coefficient for the scale was 0.536, and the intra-class correlation coefficients for peripheral fatigue and central fatigue were 0.421 and 0.548, respectively. The correlation coefficient between the total score of the AEIFS and the SFSA score was 0.592 ( p < 0.01)., Conclusion: Our results demonstrate that the AEIFS can distinguish peripheral fatigue and central fatigue and can also reflect their correlation. This scale can be a useful evaluation tool not only for measuring fatigue after acute exercise but also for guiding reasonable exercise, choosing objective testing indicators, and preventing sports injuries resulting from acute exercise-induced fatigue., Competing Interests: YW was employed by Beijing Peirong Biotech Co., Ltd. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lu, Yuan, Chen, Wang, Liu, Wu, Zhan, Zhao, Pei and Xie.)

Background: Myocardial injury induced by sepsis is the most common cause of death. Topiroxostat has been found to have organ protective effects, but its role in septic shock-related cardiomyocyte damage is still unclear and needs further study., Material and Methods: An endotoxemic shock model in rats was constructed. After topiroxostat treatment, hemodynamic parameters, myocardial injury marker enzymes, oxidative stress, myocardial injury, and apoptosis were measured by polyphysiograph, enzyme-linked immunosorbent assay, hematoxylin and eosin staining, TUNEL staining, and western blot. During in vitro experiments, the effect of topiroxostat on cell vitality, oxidative stress, inflammatory factors, apoptosis-related markers, phosphorylated-p65 (p-p65) and p65 expressions were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot., Results: Topiroxostat improved myocardial dysfunction and superoxide dismutase activity while suppressing levels of creatine kinase, lactate dehydrogenase and malondialdehyde in serum of endotoxemic shock rats. Additionally, topiroxostat augmented dry-wet weight ratios of the hearts in rats. Meanwhile, topiroxostat was proved to alleviate interstitial edema and apoptosis in myocardial tissues of endotoxemic shock rats. During in vitro experiments, topiroxostat pretreatment elevated lipopolysaccharide (LPS)-induced H9c2 cell vitality, and alleviated oxidative stress and inflammation. Moreover, topiroxostat pretreatment downregulated apoptosis-related markers, p-p65, and p-p65/p65 levels in LPS-induced H9c2 cells., Conclusions: Topiroxostat attenuated LPS-induced myocardial injury via repressing apoptosis and oxidative stress., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This paper constructs the ZSG-SBM model, comprehensive fairness allocation model, and balance allocation model from the perspectives of efficiency, fairness, and balance. Making use of the actual input-output data of China's provincial economic system in 2019, and the above three models to study the reasonable scheme of China's provincial carbon emission quota allocation in 2019. The results show that ZSG efficiency allocation can significantly improve the carbon emission efficiency of inefficient provinces, and the carbon emissions of inefficient provinces after allocation reach the efficiency frontier. The carbon emission quota of 16 provinces which located in the central and western regions of China with underdeveloped economy and relatively low carbon emission efficiency need to be decreased, while the eastern coastal provinces with more developed economy and high carbon emission efficiency in China should increase their carbon emission quota. On the one hand, comprehensive fairness allocation reduces the carbon emission reduction target constraints of economically underdeveloped provinces; on the other hand, it strengthens the carbon emission reduction target constraints of low-carbon technology backward provinces. As a result, the carbon emission quota of economically developed provinces and provinces with high carbon intensity per unit GDP is reduced in this method. The result of balancing efficiency and fairness lies between ZSG efficiency allocation and comprehensive fairness allocation. In order to alleviate the huge pressure on the emission reduction of provinces with low actual carbon emission efficiency under the ZSG efficiency allocation mode, the Chinese government can gradually increase the weight of ZSG efficiency allocation results, and finally adopt a complete ZSG efficiency allocation scheme in the carbon peak year to realize the transformation of low-carbon economy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

1,3-Dipolar cycloaddition of nonstabilized azomethine ylides derived from α-C-H functionalization of tetrahydroisoquinoline for regio- and diastereoselective synthesis of spirooxindole-pyrrolidines is developed. A three-component reaction of readily available cyclic amine, aryl aldehydes, and olefinic oxindoles provides a pot, atom and step economy (PASE) approach for making spiro-heterocyclic compounds with biological interest., Competing Interests: Conflicts of interest There are no conflicts to declare.

As one of the widespread phenols in nature, gallic acid (GA) has attracted a subject of attention due to its extensive biological properties. It is very important and significant to develop a sensitive and selective gallic acid sensor. In recent years, owing to their reversible covalent binding with Lewis bases and polyols, boronic acid compounds have been widely reported as fluorescence sensors for the identification of carbohydrates, ions and hydrogen peroxide, etc. However, boronic acid sensors for specific recognition of gallic acid have not been reported. Herein, a novel water-soluble boronic acid sensor with double recognition sites is reported. When the concentration of gallic acid added was 1.1 × 10 -4  M, the fluorescence intensity of sensor 9b decreased by 80%, followed by pyrogallic acid and dopamine. However, the fluorescence of the sensor 9b combined with other analytes such as ATP, sialic acid, and uridine was basically unchanged, indicating that the sensor 9b had no ability to recognize these analytes. Also, sensor 9b has a fast response time to gallic acid at room temperature, and has a high binding constant (12355.9 ± 156.89 M -1 ) and low LOD (7.30 × 10 -7  M). Moreover, gallic acid content of real samples was also determined, and the results showed that this method has a higher recovery rate. Therefore, sensor 9b can be used as a potential tool for detecting biologically significant gallic acid in actual samples such as food, medicine, and environmental analysis samples., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

DNA walkers have been recognized as a type of powerful signal amplification tool for biosensors, but how to adopt a proper strategy to increase their amplification efficiency is still highly desirable. Herein we design a dual-catalytic hairpin assembly (CHA)-mediated strategy for the high-efficient formation of a tripedal Mg 2+ -dependent DNAzyme (MNAzyme)-DNA walker, and thus develop a novel proteinase-free dual-mode biosensing method for the kanamycin (Kana) antibiotic assay. The first CHA is initiated by a target-biorecognition reaction, which can produce the DNA walker and also induce the target recycling. The second CHA is initiated by a special base sequence designed as a one-half substrate of the MNAzyme. Upon the first CHA-triggered DNA walking at a magnetic bead (MB) track, this "pseudo-target" sequence can be released to induce another CHA-cycle for the formation of the same DNA walker. Meanwhile, the other one-half substrate strand exposed on the MB surface will trigger the quantitative hybridization chain reaction (HCR)-assembly of a G-quadruplex DNAzyme (G-DNAzyme)-enriched double-stranded DNA polymer. So the enzymatic reaction of G-DNAzymes enabled the convenient colorimetric and photoelectrochemical dual-mode signal transduction of the method. Due to the dual-CHA facilitation to the tripedal and three-dimensional DNA walking and synergetic signal amplification of HCR, this method exhibits very low detection limits of 9.4 and 0.55 fg mL -1 , respectively. In combination with its wide linear range, automated manipulation, and excellent selectivity, repeatability and reliability, the proposed method is expected to be used for the convenient semiquantitative screening and accurate determination of possible antibiotic residues in complicated matrices., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Streptococcus suis serotype 2 (SS2), an emerging zoonotic pathogen, may induce severe infections and symptoms manifested as septicemia, meningitis and even death both in human and pigs. The aim of this article was to develop a new methodology as real-time recombinase polymerase amplification (RT-RPA) assay targeting cps2J gene for the detection of SS2 (or SS1/2). The sensitivity and reproducibility of RT-RPA results were evaluated and compared with a real-time quantitative PCR (RT-qPCR). The established RT-RPA reaction could be completed in 20 minutes with distinguishable specificity against the predominant S. suis infection serotypes of 3, 4, 5, 7, 9, 14, and 31. Lower detection limit for RT-RPA was 10 2 genomic DNA copies per reaction. The specimen performance of RT-RPA was tested in nasopharyngeal swab samples with the sensitivity and specificity as 97.5% and 100%, respectively. Thus, this RT-RPA method is a rapid and potential molecular diagnostic tool for SS2 detection., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To improve the awareness of Birt-Hogg-Dubé syndrome. Methods: We performed a retrospective analysis with two families of Birt-Hogg-Dubé syndrome (BHD syndrome) diagnosed in Department of Respiratory and Critical Care Medicine, Shenzhen People's Hospital from 2020 to 2021. Clinical manifestations, imaging features, diagnosis and gene detection results were summarized. Relative literatures were reviewed in Wanfang Database and PubMed from 2015 to 2021 by using the search terms of "BHD syndrome" "Birt-Hogg-Dubé" "Birt-Hogg-Dubé syndrome", respectively. Results: The probands of both families were female, aged 37 and 34 years respectively. The onset manifestation was pulmonary bullae combined with pneumothorax. Chest computed tomography (CT) imaging showed multiple pulmonary cysts in both lobes, and no skin lesions or renal tumors were found in either case. History of pneumothorax was present in Family 1 while absent in Family 2. The FLCN gene of the two probands and their relatives showed the same mutation site. Totally 12 Chinese literatures and 394 English literatures were retrieved, among which 96 reported lung involvement only. A total of 10 literatures about Chinese population were screened out from the English literatures, and 115 patients, 31 males and 84 females, were included. The incidence of spontaneous pneumothorax was 66.95% (77/115), while a family history of pneumothorax was 88.31%(68/77). The onset age of spontaneous pneumothorax was between 30 and 44 years. The most common mutation site of FLCN was c.1285dup. Conclusions: BHD syndrome in Asian population may only have lung involvement. Patients with pneumothorax and pulmonary cystic lesions should be inquired of the family history. We speculate that there are many underdiagnosed cases in clinical practice.

Background: This study aimed to determine the effect and mechanism of Celastrol inhibiting the proliferation and decreasing the drug resistance of cisplatin-resistant gastric cancer cells., Objective: The objective of this study was to explore the effect and mechanism of Celastrol on proliferation and drug resistance of human gastric cancer cisplatin-resistant cells SGC7901/DDP., Methods: The thiazole blue (MTT) method was used to detect the sensitivity of human gastric cancer cisplatinresistant cells SGC7901/DPP to cisplatin and Celastrol to determine the Drug Resistance Index (DRI). According to the half Inhibitory Concentration (IC50) value, the action of the concentration of the following experimental drugs was set to reduce the cytotoxicity. Annexin V-FITC/PI double staining method was used to detect the apoptosis of SGC7901/DDP cells induced by Celastrol. Western Blot was used to examine the expression levels of P-glycoprotein (P-gp), Multidrug Resistance Associated Protein 1 (MRP1), Breast Cancer Resistance Associated Protein (Breast Cancer Resistance)-relative protein (BCRP), and mechanistic Target of Rapamycin (mTOR) pathway-related proteins. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA expression levels of P-gp, MRP1, and BCRP., Results: (1) Compared with the control group (we set the untreated group as the control group), the proliferation of the SGC7901/DPP cells was significantly inhibited after treating with 0.1-6.4μmol/L Celastrol in a time- and concentration-dependent manner (P<0.05). The Drug Resistance Index (DRI) of the SGC7901/DPP cells to DDP was 5.64. (2) Compared with the control group, Celastrol could significantly inhibit the proliferation and induce the apoptosis of the SGC7901/DPP cells (P<0.05). (3) The mRNA and protein expression levels of P-gp, MRP1, and BCRP in the SGC7901/DPP cells were significantly higher than those in the SGC7901 cells. However, after treating with Celastrol, the expression levels of P-gp, MRP1, and BCRP in the SGC7901/DPP cells were significantly reduced (P<0.05). (4) Compared with the control group, the Celastrol treatment also reduced the expression of the mTOR signaling pathway-related proteins, suggesting that the mTOR signaling pathway may be involved in the process of Celastrol inhibiting the proliferation of the SGC7901/DDP cells and reducing their drug resistance. (5) Significantly, the combination of Celastrol and DDP reduced the expression of P-gp, MRP1, and BCRP in the SGC7901/DPP cells., Conclusion: Celastrol can inhibit the proliferation of the SGC7901/DDP cells, induce their apoptosis, and reduce the expression of drug resistance genes, probably by inhibiting the expression of the proteins related to the mTOR signaling pathway., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Hainan Province is in a tropical area of China and previously experienced serious P. falciparum and P. vivax malaria epidemics. After nearly 70 consecutive years of malaria prevention and control, malaria in Hainan has gradually been eliminated. To achieve the elimination of malaria, Hainan enacted six stages: investigative research and pilot prevention and control, large-scale antimalaria measures, adjustment of strategies for prevention and control, joint prevention and control measures, global funding of routine malaria control, and malaria elimination. Different strategies for malaria control were adopted at different stages. Malaria was most prevalent in the mountainous areas of central and southern Hainan, which contain a high-risk population (the forest goers) and two highly effective malaria vectors (An. dirus and An. minimus). Forest goers have been a high-risk population for malaria in Hainan since their identification in the 1990s. This paper summarizes malaria monitoring in forest goers and the response of forest goers to malaria control and elimination, distilling specific malaria control and elimination measures via case studies in Hainan Province. Two case studies in the malaria control stage demonstrated different measures for outbreaks and sporadic cases in forest goers. In view of the malaria outbreak in Sanya during the elimination stage, three-layered strategies (TLSs) were implemented to control outbreaks and improve control measures. Moreover, this paper also illustrates specific management measures to prevent malaria retransmission from sporadic imported malaria cases during the elimination phase. Hainan finally eliminated malaria in 2020. However, the risk of malaria retransmission is still high due to the prevalence of effective malaria vectors in Hainan, and forest goers are still a high-risk population for malaria retransmission., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Abstract: Few studies have reported an increase in vitamin B12 (VitB12) levels after bariatric surgery. This study reports the phenomenon and adverse reactions of serum VitB12 elevation 1 month after surgery and explores the possible etiologies.Retrospective analysis was performed on VitB12 data for 112 patients from January 2018 to October 2019. Then, 87 patients were included between November 2019 and August 2020. They were divided into 2 groups according to the level of VitB12 after surgery, and the demographic and clinical data were analyzed. Then, LASSO regression model analysis and multiple logistic regression analysis were performed to explore the risk factors for VitB12 elevation after surgery.Retrospective data showed that the VitB12 level was significantly increased 1 month after surgery. Comparison of data between the 2 groups found that more patients also had diabetes in the nonelevated group. The postoperative folic acid and VitB12 levels of the elevated group were significantly higher than those of the nonelevated group. More patients had concurrent constipation in the elevated group than in the nonelevated group. Two meaningful variables in LASSO regression analysis were incorporated into the multivariate logistic regression analysis, and constipation was found to be an independent risk factor for the increase in VitB12 after surgery. Of the 199 patients in this study, 111 patients had elevated VitB12 levels after surgery. Among them, 7 patients had peripheral nerve symptoms.Constipation is an independent risk factor for increased VitB12 levels after surgery. High levels of VitB12 may cause some peripheral nerve symptoms. Therefore, it is necessary to pay attention to patients with postoperative constipation, monitor their VitB12 level as soon as possible, and take measures to improve constipation to avoid some adverse reactions caused by elevated VitB12 levels., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disease that is caused by mutations in arginine vasopressin receptor 2 (AVPR2) or aquaporin 2 ( AQP2 ). Functional analysis of the mutated receptor is necessary to verify the impact of the mutation on receptor function and suggest some possible therapeutic strategies for specific functional defects. Methods: Family history and clinical information were collected. Whole-exome sequencing and sanger sequencing were performed to determine the potential genetic cause of diabetes insipidus. The identified variant was classified according to the American College of Medical Genetics (ACMG) criteria. Bioinformatic analysis was performed to predict the function of the identified variation. Moreover, wild-type and mutated AVPR2 vectors were constructed and transfection to HEK-293T cells. Immunofluorescence experiments were performed to investigate the expression and localization of the mutated protein and cAMP parameter assays were used to measure its activity in response to AVP. Results: The heights of the adult members affected with polyuria and polydipsia were normal, but all affected children had growth retardation. Next-generation sequencing identified a novel mutation in AVPR2 gene (c.530T > A) in this family. Bioinformatic analysis indicated that the mutation in AVPR2 changed the hydropathic characteristic of the protein and was probably deleterious. Although immunofluorescence showed that the mutated AVPR2 was normally expressed in the cell surface, the intracellular cAMP concentration stimulated by AVP was significantly lower in cells transfected with mutated AVPR2 than cells transfected with wild-type AVPR2. Based on the ACMG criteria, the novel c.530T > A variant of the AVPR2 gene was likely pathogenic and the affected family members were diagnosed as CNDI. After the confirmation of the diagnosis, the proband was treated with compound amiloride hydrochloride and rhGH, the symptoms of polyuria, polydipsia and growth retardation were all improved. Conclusion: These findings suggested that the novel mutation in AVPR2 (c.530T > A) was a true disease-causing variant with mild effects, which could be classified as a type III mutant receptor. Moreover, investigations of the function of growth hormone axis could be important for the pediatric CNDI patients with extreme short stature, and rhGH treatment might improve the final adult heights in these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guo, Wu, Li, Huang, Zhan, Zhang and Luo.)

A pseudo-five-component reaction involving double decarboxylative 1,3-dipolar cycloaddition of azomethine ylides with olefinic oxindoles for the diastereoselective synthesis of bispiro[oxindole-pyrrolidine]s is developed. The major diastereomers are unique butterfly shaped compounds with a plane of symmetry. Recyclable zeolite HY acid catalyst is used to promote the reaction, and only CO 2 and H 2 O are generated as byproducts.

Natural killer (NK) cells and T cells are key effectors of antitumor immune responses and major targets of checkpoint inhibitors. In multiple cancer types, we find that the expression of Wnt signaling potentiator R-spondin genes (e.g., RSPO3) is associated with favorable prognosis and positively correlates with gene signatures of both NK cells and T cells. Although endothelial cells and cancer-associated fibroblasts comprise the R-spondin 3-producing cells, NK cells and T cells correspondingly express the R-spondin 3 receptor LGR6 within the tumor microenvironment (TME). Exogenous expression or intratumor injection of R-spondin 3 in tumors enhanced the infiltration and function of cytotoxic effector cells, which led to tumor regression. NK cells and CD8+ T cells independently and cooperatively contributed to R-spondin 3-induced control of distinct tumor types. The effect of R-spondin 3 was mediated in part through upregulation of MYC and ribosomal biogenesis. Importantly, R-spondin 3 expression enhanced tumor sensitivity to anti-PD-1 therapy, thereby highlighting new therapeutic avenues., Significance: Our study identifies novel targets in enhancing antitumor immunity and sensitizing immune checkpoint inhibition, which provides a rationale for developing new immunotherapies against cancers. It also offers mechanistic insights on Wnt signaling-mediated modulation of anticancer immunity in the TME and implications for a putative R-spondin-LGR6 axis in regulating NK-cell biology. This article is highlighted in the In This Issue feature, p. 2945., (©2021 American Association for Cancer Research.)

Objective: To explore the molecular mechanisms underlying meniscus degeneration., Methods: We performed anterior cruciate ligament resection in the Hainan Wuzhishan pig to establish a meniscus degeneration model. We applied gene chip technology to detect differentially expressed genes (DEG) in the degenerative meniscus tissues. We applied Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, core gene network, and relevant MicroRNA analyses to identify regulatory networks relevant to meniscus degeneration. We detected 893 differentially expressed genes, mainly involved in hormone production, apoptosis, and inflammation., Results: We found that MUC13 , inflammatory mediator regulation of TRP channels, MDFI , and miR-335-5p may play a key role in the degenerative meniscus tissue., Conclusion: We found that meniscus degeneration involves several molecular mechanisms and provide molecular targets for future research into the disease., Competing Interests: None., (AJTR Copyright © 2021.)

Objectives: To study the effect of high-fat diet for maternal Sprague-Dawley rats at different stages on glucose and lipid metabolism in offspring and related mechanisms., Methods: According to the diet before pregnancy and during pregnancy and lactation, maternal rats were randomly divided into four groups ( n =9 each): CC (control diet before pregnancy and during pregnancy and lactation), HC (high-fat diet before pregnancy and control diet during pregnancy and lactation), CH (control diet before pregnancy and high-fat diet during pregnancy and lactation), and HH (high-fat diet before pregnancy and during pregnancy and lactation), and all offspring rats were given control diet after weaning. The body weight of maternal rats was recorded before and during pregnancy. Male offspring rats were selected from each group at the juvenile stage (3-week old) and the adult stage (12-week old) to measure the levels of fasting blood glucose (FBG) and fasting insulin (FINS) and the levels of triglyceride (TG) and total cholesterol (TC) in the liver. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was calculated, and the area under the curve (AUC) was calculated for glucose tolerance test (GTT) and insulin tolerance test (ITT). Lipid deposition in the liver was observed, and the mRNA and protein expression levels of the key genes in glucose and lipid metabolism ( IR , IRS , and AKT ), FASN , SREBP1c , and PPARα in the liver were also measured., Results: Compared with the control diet groups (CC and CH groups), the groups with high-fat diet before pregnancy (HC and HH groups) had a significant increase in body weight ( P <0.001). Compared with the CC group, the HC, CH, and HH groups had a significantly greater increase in body weight ( P <0.001). Compared with the CC group, the HC, CH, and HH groups had significant increases in body weight, the levels of TG and TC in the liver, and the mRNA and protein expression levels of FASN , SREBP1c , and PPARα in the offspring rats at week 3 after birth ( P <0.05), as well as a significant increase in lipid deposition in the liver, with the most significant increase of the parameters in the HH group. Compared with the CC group, the HH group had significant increases in the levels of FBG and FINS, HOMA-IR index, GTT-AUC, ITT-AUC, and the protein expression level of p-IRS in the liver and significant reductions in the mRNA and protein expression levels of IR and IRS in the liver in the offspring rats at week 3 after birth ( P <0.05). Compared with the CC group, the HC, CH, and HH groups had significant increases in body weight, the levels of FBG and FINS, HOMA-IR index, GTT-AUC, ITT-AUC, the levels of TG and TC in the liver, protein expression level of p-IRS in the liver, and the mRNA and protein expression levels of FASN , SREBP1c , and PPARα in the offspring rats at week 12 after birth ( P <0.05), as well as a significant increase in lipid deposition in the liver, with the most increase of the parameters in the HH group. Compared with the CC group, the HC, CH, and HH groups had significant reductions in the mRNA expression levels of IR , IRS , and AKT and the protein expression levels of IR, IRS, and p-AKT in the offspring rats at week 12 after birth ( P <0.05). There were no significant differences in the levels of glucose and lipid metabolism between the HC and CH groups at various stages ( P >0.05)., Conclusions: High-fat diet for rats at different stages before and after pregnancy has different effects on glucose and lipid metabolism of offspring rats, and high-fat diet before pregnancy and during pregnancy and lactation has the greatest effect. The effect of high-fat diet on glucose and lipid metabolism of offspring rats is considered associated with the changes in the expression of genes involved in glucose and lipid metabolism.

If hydrogen can be stored and carried safely at a high density, hydrogen-fuel cells offer effective solutions for vehicles. The stable chemisorption of atomic hydrogen on single layer graphene (SLG) seems a perfect solution in this regard, with a theoretical maximum storage capacity of 7.7 wt %. However, generating hydrogenated graphene from H 2 requires extreme temperatures and pressures. Alternatively, hydrogen adatoms can easily be produced under mild conditions by the electroreduction of protons in solid/liquid systems. Graphene is electrochemically inert for this reaction, but H-chemisorption on SLG can be carried out under mild conditions via a novel Pt-electrocatalyzed "spillover-surface diffusion-chemisorption" mechanism, as we demonstrate using dynamic electrochemistry and isotopic Raman spectroscopy. The apparent surface diffusion coefficient (∼10 -5 cm 2 s -1 ), capacity (∼6.6 wt %, ∼85.7% surface coverage), and stability of hydrogen adatoms on SLG at room temperature and atmospheric pressure are significant, and they are perfectly suited for applications involving stored hydrogen atoms on graphene.

Heterozygous isocitrate dehydrogenase (IDH) R132H mutation (IDH1 R132H/WT ) is an early event during gliomagenesis. Clinically, patients with glioma carrying mutant IDH1 respond better to antitumor therapies. However, the mechanism by which IDH1 mutations contribute to gliomagenesis and therapeutic response remains elusive. Here we report that senescence is involved in the improved therapeutic responses of mutant IDH1 glioma cells. Knocking-in IDH1 R132H/WT in glioma cells significantly enhanced gliomas cell senescence in response to temozolomide and radiation via a DNA-damage mediated mechanism. We further asked if senescence plays a role in IDH1 R132H/WT -induced gliomagenesis. Together with ATRX knockout and p53/RB loss, IDH1 R132H/WT transformed nonneoplastic human astroglial cells to form tumors in mouse brains. In-depth characterization revealed that a subset of these precancerous cells underwent senescence-like phenotypic changes, including flat and enlarged-cell morphology, increased senescence marker expression, decreased cell proliferation, and cell-cycle arrest at the G 2 -M phase. Mechanistic studies indicated that the combination of glioma driver genes (p53/RB/IDH1/ATRX) dramatically increased DNA damage and activated DNAdamage response (DDR) pathways ATR/ATR and Chk1/Chk2 in senescent cells. To determine how senescent cells drive tumor formation, we investigated non-cell-autonomous mechanisms such as senescence-associated secretory phenotype (SASP), a panel of proinflammatory and tissue-remodeling factors implicated in a tumor-permissive microenvironment. We found that astroglial cells carrying p53/RB/ATRX loss and IDH1 R132H/WT upregulated key factors in SASP via an epigenetic-mediated mechanism. Our work suggests that drugs that specifically eliminate senescent cells could help kill precancerous cells and senescent tumor cells following antitumor therapies. IMPLICATIONS: The mechanisms by which IDH1 mutations contribute to gliomagenesis and therapeutic responses remain incompletely characterized; this work reveals senescence as a novel mechanism of IDH-mutant-mediated biological impact and describes new therapeutic opportunities concerning IDH1-mutant gliomas., (©2021 American Association for Cancer Research.)

Users of social networks have a variety of social statuses and roles. For example, the users of Weibo include celebrities, government officials, and social organizations. At the same time, these users may be senior managers, middle managers, or workers in companies. Previous studies on this topic have mainly focused on using the categorical, textual and topological data of a social network to predict users' social statuses and roles. However, this cannot fully reflect the overall characteristics of users' social statuses and roles in a social network. In this paper, we consider what social network structures reflect users' social statuses and roles since social networks are designed to connect people. Taking an Enron email dataset as an example, we analyzed a preprocessing mechanism used for social network datasets that can extract users' dynamic behavior features. We further designed a novel social network representation learning algorithm in order to infer users' social statuses and roles in social networks through the use of an attention and gate mechanism on users' neighbors. The extensive experimental results gained from four publicly available datasets indicate that our solution achieves an average accuracy improvement of 2% compared with GraphSAGE-Mean, which is the best applicable inductive representation learning method.

The giant muscle protein titin plays important roles in heart function. Mutations in titin have emerged as a major cause of familial cardiomyopathy. Missense mutations have been identified in cardiomyopathy patients; however, it is challenging to distinguish disease-causing mutations from benign ones. Given the importance of titin mechanics in heart function, it is critically important to elucidate the mechano-phenotypes of cardiomyopathy-causing mutations found in the elastic I-band part of cardiac titin. Using single-molecule atomic force microscopy (AFM) and equilibrium chemical denaturation, we investigated the mechanical and thermodynamic effects of two missense mutations, R57C-I94 and S22P-I84, found in the elastic I-band part of cardiac titin that were predicted to be likely causing cardiomyopathy by bioinformatics analysis. Our AFM results showed that mutation R57C had a significant destabilization effect on the I94 module. R57C reduced the mechanical unfolding force of I94 by ∼30-40 pN, accelerated the unfolding kinetics, and decelerated the folding. These effects collectively increased the unfolding propensity of I94, likely resulting in altered titin elasticity. In comparison, S22P led to only modest destabilization of I84, with a decrease in unfolding force by ∼10 pN. It is unlikely that such a modest destabilization would lead to a change in titin elasticity. These results will serve as the first step toward elucidating mechano-phenotypes of cardiomyopathy-causing mutations in the elastic I-band.

Neutrophil-derived microvesicles (NDMVs) are liberated by neutrophils upon cell activation by molecules. Once activated, neutrophils are primarily involved in acute inflammation; however, the microvesicles they produce are largely anti-inflammatory. NDMVs have been shown to protect cartilage during inflammatory arthritis. They exert these effects by inhibiting or affecting the function of target cells, including macrophages. NDMVs have the potential to act as disease-modifying agents, especially for inflammatory diseases. This protocol describes a method using differential centrifugation to separate neutrophils from whole human blood. Subsequently, neutrophils are identified by cytospin and Wright's staining, and then the NDMVs are isolated using differential centrifugation., Competing Interests: Competing interestsThe authors declare no conflict of interest., (Copyright © 2021 The Authors; exclusive licensee Bio-protocol LLC.)

Tumor-associated microglia/macrophages (TAMs) are the main innate immune effector cells in malignant gliomas and have both pro- and anti-tumor functions. The plasticity of TAMs is partially dictated by oncogenic mutations in tumor cells. Heterozygous IDH1 mutation is a cancer driver gene prevalent in grade II/III gliomas, and IDH1 mutant gliomas have relatively favorable clinical outcomes. It is largely unknown how IDH mutation alters TAM phenotypes to influence glioma growth. Here we established clinically relevant isogenic glioma models carrying monoallelic IDH1 R132H mutation (IDH1 R132H/WT ) and found that IDH1 R132H/WT significantly downregulated immune response-related pathways in glioma cells, indicating an immunomodulation role of mutant IDH1. Co-culturing IDH1 R132H/WT glioma cells with human macrophages promoted anti-tumor phenotypes of macrophages and increased macrophage migration and phagocytic capacity. In orthotopic xenografts, IDH1 R132H/WT decreased tumor growth and prolonged animal survival, accompanied by increased TAM recruitment and upregulated phagocytosis markers, suggesting the induction of anti-tumor TAM functions. Using human cytokine arrays that query 36 proteins, we identified significant downregulation of ICAM-1/CD54 in IDH1 R132H/WT gliomas, which was further confirmed by ELISA and immunoblotting analyses. ICAM1 gain-of-function studies revealed that ICAM1 downregulation in IDH1 R132H/WT cells played a mechanistic role to mediate the immunomodulation function of IDH1 R132H/WT . ICAM-1 silencing in IDH1 wild-type glioma cells decreased tumor growth and increased the anti-tumor function of TAMs. Together, our studies support a new TAM-mediated phagocytic function within IDH1 mutant gliomas, and improved understanding of this process may uncover novel approaches to targeting IDH1 wild type gliomas., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: In the short-term after bariatric surgery, the incidence of gout flare was increased. Patients with hyperuricemia are among the high-risk group of postoperative gout attacks. The drastic fluctuation of uric acid is a risk factor for gout flare. This study aimed to explore factors that influenced the magnitudes of serum uric acid (sUA) fluctuation post-surgery in patients with hyperuricemia., Materials and Methods: One hundred and sixty-five patients with preoperative hyperuricemia undergoing bariatric surgery were reviewed. Pre- and postoperative parameters were collected at baseline and each follow-up point. Univariable and multiple linear regression analyses were performed to explore independent factors that influenced the magnitudes of sUA change., Results: The sUA significantly declined from 489.4 ± 93.7 to 372.6 ± 101.4 μmmol/L in 1 day after surgery, then increased to 531.6 ± 175.5 μmmol/L at 1-month follow-up, and then dropped to 415.2 ± 105.6 and 396.5 ± 114.2 μmmol/L at 3-month and 6-month follow-up, respectively. Preoperative estimated glomerular filtration rate (eGFR), glycated hemoglobin (HbA1c), magnesium (Mg), sex, and the change of zinc concentration during the first month are significantly related to magnitudes of sUA fluctuation in the short-term post-surgery period. Multiple linear regression analyses showed preoperative eGFR and HbA1c independently influenced the magnitudes of sUA change at 1 day after surgery; sex, the change of zinc concentration, and HbA1c at 1-month follow-up independently influenced the magnitudes of sUA change at 1-month follow-up., Conclusion: Preoperative eGFR, HbA1c, sex, and the change of zinc concentration postoperative are independent factors affecting the magnitude of the fluctuation. Large-scale studies are warranted to support these findings., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Glioblastoma (GBM, WHO grade IV glioma) is the most common and lethal malignant brain tumor in adults with a dismal prognosis. The extracellular matrix (ECM) supports GBM progression by promoting tumor cell proliferation, migration, and immune escape. Uridine diphosphate (UDP)-glucose 6-dehydrogenase (UGDH) is the rate-limiting enzyme that catalyzes the biosynthesis of glycosaminoglycans that are the principal component of the CNS ECM. We investigated how targeting UGDH in GBM influences the GBM immune microenvironment, including tumor-associated microglia/macrophages (TAMs) and T cells. TAMs are the main immune effector cells in GBM and can directly target tumor cells if properly activated. In co-cultures of GBM cells and human primary macrophages, UGDH knockdown in GBM cells promoted macrophage phagocytosis and M1-like polarization. In orthotropic human GBM xenografts and syngeneic mouse glioma models, targeting UGDH decreased ECM deposition, increased TAM phagocytosis marker expression, reduced M2-like TAMs and inhibited tumor growth. UGDH knockdown in GBM cells also promoted cytotoxic T cell infiltration and activation in orthotopic syngeneic mouse glioma models. The potent and in-human-use small molecule GAG synthesis inhibitor 4-methylumbelliferone (4-MU) was found to inhibit GBM cell proliferation and migration in vitro , mimic the macrophage and T-cell responses to UGDH knockdown in vitro and in vivo and inhibit growth of orthotopic murine GBM. Our study shows that UGDH supports GBM growth through multiple mechanisms and supports the development of ECM-based therapeutic strategies to simultaneously target tumor cells and their microenvironment., (© 2021 Chongqing Medical University. Production and hosting by Elsevier B.V.)

Background: We have recently showed that atorvastatin (ATO) combined with low dose of dexamethasone (DEX) was more efficacious in treating patients with chronic subdural haematoma (CSDH) than ATO monotherapy. This study was designed to investigate the underlying mechanisms of the improved efficacy of this combined therapy., Methods: Mass spectrometry was performed to quantitatively detect drugs in haematoma fluids and serum samples from CSDH patients and also in cultured macrophages after treatment with either ATO alone or in combination with DEX. The differentiation and apoptosis of macrophages were evaluated using flow cytometry. The expression of cytokines, chemokines and angiogenesis-related proteins was evaluated using proteome profile arrays, immunoblots and ELISA, respectively., Results: ATO was detected in haematoma fluids and serum samples, whose levels were increased significantly in samples collected from patients treated with both ATO and DEX. ATO was also increased in cultured macrophages treated with ATO and DEX. The numbers of M1-polarized macrophages were higher than the M2 phenotype in the haematoma fluids of patients. Cultured macrophages treated with ATO and DEX had reduced numbers of M1-polarized macrophages, increased numbers of M2-polarized macrophages as compared to monotherapies, and decreased rate of apoptosis induced by high-dose DEX. DEX enhanced the anti-inflammatory and anti-angiogenic activity of ATO by suppressing VEGFA and other inflammatory angiogenic factors. Consistent with the finding, patients responded well to the drug treatments had lower serum levels of VEGFA., Conclusions: We have shown for the first time that ATO given orally was detected in CSDH haematoma fluids. DEX enhances the anti-inflammatory and anti-angiogenic effects of ATO, primarily by increasing the presence of ATO in haematoma and macrophages and by regulating the functions of macrophages., (© 2021. The Author(s).)

Background: Schizophrenia (SCZ) is a severe mental illness with high heritability. This study aimed to explore the correlation between MAD1L1, TSNARE polymorphisms and SCZ susceptibility., Methods: A total of 493 SCZ patients and 493 healthy controls were included. The genotypes of MAD1L1 and TSNARE polymorphisms were identified by Agena MassARRAY platform. Odds ratio (OR) and 95% confidence intervals (CIs) were tested via logistic regression analysis in multiple genetic models and different subgroups., Results: We observed that AG genotype of rs1107592, AG genotype of rs4976976, and CA genotype of rs67756423 decreased the susceptibility to SCZ (p < 0.05). Age stratification analysis showed that the TC genotype of rs12666575, AG genotype of rs1107592, and AG genotype of rs4976976 decreased the risk of SCZ individuals older than 36 years (p < 0.05). In addition, the AG and AA genotype of rs4976976, the CA genotype of rs67756423 were associated with a lower risk of SCZ in males (p < 0.05). In females, the TT genotype of rs12666575 in recessive model, the AG and AA-AG genotype of rs1107592 in heterozygote and dominant model, could reduce the susceptibility to SCZ (p < 0.05). However, no significant association was found after Bonferroni correction., Conclusions: Our results suggest that MAD1L1 and TSNARE genetic polymorphisms exert a protective role in the risk of SCZ. These findings provide evidence that MAD1L1 and TSNARE may serve as potential biomarkers of SCZ. However, a replication experiment in a cohort with large sample size are required to confirm our findings. Trial registration Not applicable., (© 2021. The Author(s).)

With the aggravation of global aging, the rapid rise in the obesity rate, and the increasing number of patients with intervertebral disc degeneration (IDD), the principles and mechanism of this disease remain unclear. This study explored the molecular mechanism of IDD treatment through interactions of the lncRNA-miRNA-mRNA-signaling pathways and the effects on the proliferation and apoptosis of human nucleus pulposus cells (HNPCs) cultured in vitro. Our study revealed that lncRNA JPX is expressed at low levels in HNPCs under normoxic conditions. Luciferase and RNA pull-down assays were used to verify that lncRNA JPX directly bound to miR-18a-5p and influenced HNPC proliferation and apoptosis. Subsequently, a luciferase assay confirmed the direct binding of miR-18a-5p to HIF-1α and demonstrated a negative correlation between miR-18a-5p and HIF-1α. In addition, the HIF-1α antagonist reversed the inhibition of the Hippo-YAP pathway by the miR-18a-5p inhibitor. In conclusion, overexpression of lncRNA JPX upregulated HIF-1α by inhibiting the expression of miR-18a-5p, thereby inhibiting the Hippo-YAP pathway. By inhibiting this pathway, JPX overexpression promoted the proliferation of HNPCs and decreased their apoptosis. Therefore, the lncRNA JPX is a potential new target., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) is still a pandemic, with a high mortality rate in severe/critical cases. Therapies based on the Shenghuang Granule have proved helpful in viral infection and septic shock., Hypothesis/purpose: The objective of the current study was to compare the efficacy and safety of the traditional Chinese medicine, Shenhuang Granule, with standard care in hospitalized patients with severe/critical COVID-19., Study Design and Methods: This was an open-label, multicenter, randomized, controlled clinical trial. At 4 medical centers, a total of 111 severe/critical patients were randomly assigned to receive Shenhuang Granule (SHG group) twice a day for 14 days, in addition to standard care, or to receive standard care alone (Control group). The maximal follow up time was 75 days. The clinical endpoint was clinical improvement and mortality., Results: 54 patients were assigned to the control group and 57 to the SHG group. The overall mortality was 75.9% (41/54) in the control group, and 38.6% (22/57) in the SHG group (p < 0.01 vs. control). The post hoc analysis showed that in the severe category, the mortality of the control group vs. the SHG group was 58.8% (10/17) vs. 5.3% (1/19) (p < 0.01); while in the critical category, it was 83.8% (31/37) vs. 55.3% (21/38) (p < 0.05). In the severe category, the mortality of patients who eventually received an invasive ventilator in the control vs. the SHG group was 58.8% (10/17) vs. 0 (0/19) (p < 0.01). Administration of SHG was associated with increased lymphocytes and decreased adverse events., Conclusion: Shenhuang Granule is a promising integrative therapy for severe and critical COVID-19., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

While precision medicine driven by genome sequencing has revolutionized cancer care, such as lung cancer, its impact on gastric cancer (GC) has been minimal. GC patients are routinely treated with chemotherapy, but only a fraction of them receive the clinical benefit. There is an urgent need to develop biomarkers or algorithms to select chemo-sensitive patients or apply targeted therapy. Here, we carried out retrospective analyses of 1,020 formalin-fixed, paraffin-embedded GC surgical resection samples from 5 hospitals and developed a mass spectrometry-based workflow for proteomic subtyping of GC. We identified two proteomic subtypes: the chemo-sensitive group (CSG) and the chemo-insensitive group (CIG) in the discovery set. The 5-year overall survival of CSG was significantly improved in patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (64.2% vs. 49.6%; Cox P-value=0.002), whereas no such improvement was observed in CIG (50.0% vs. 58.6%; Cox P-value=0.495). We validated these results in an independent validation set. Further, differential proteome analysis uncovered 9 FDA-approved drugs that may be applicable for targeted therapy of GC. A prospective study is warranted to test these findings for future GC patient care., (© 2021. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Tea is an important global beverage crop and is largely clonally propagated. Despite previous studies on the species, its genetic and evolutionary history deserves further research. Here, we present a haplotype-resolved assembly of an Oolong tea cultivar, Tieguanyin. Analysis of allele-specific expression suggests a potential mechanism in response to mutation load during long-term clonal propagation. Population genomic analysis using 190 Camellia accessions uncovered independent evolutionary histories and parallel domestication in two widely cultivated varieties, var. sinensis and var. assamica. It also revealed extensive intra- and interspecific introgressions contributing to genetic diversity in modern cultivars. Strong signatures of selection were associated with biosynthetic and metabolic pathways that contribute to flavor characteristics as well as genes likely involved in the Green Revolution in the tea industry. Our results offer genetic and molecular insights into the evolutionary history of Camellia sinensis and provide genomic resources to further facilitate gene editing to enhance desirable traits in tea crops., (© 2021. The Author(s).)

In a cluster-randomized trial (CRT), the number of participants enrolled often varies across clusters. This variation should be considered during both trial design and data analysis to ensure statistical performance goals are achieved. Most methodological literature on the CRT design has assumed equal cluster sizes. This scoping review focuses on methodology for unequal cluster size CRTs. EMBASE, Medline, Google Scholar, MathSciNet and Web of Science databases were searched to identify English-language articles reporting on methodology for unequal cluster size CRTs published until March 2021. We extracted data on the focus of the paper (power calculation, Type I error etc.), the type of CRT, the type and the range of parameter values investigated (number of clusters, mean cluster size, cluster size coefficient of variation, intra-cluster correlation coefficient, etc.), and the main conclusions. Seventy-nine of 5032 identified papers met the inclusion criteria. Papers primarily focused on the parallel-arm CRT (p-CRT, n = 60, 76%) and the stepped-wedge CRT (n = 14, 18%). Roughly 75% of the papers addressed trial design issues (sample size/power calculation) while 25% focused on analysis considerations (Type I error, bias, etc.). The ranges of parameter values explored varied substantially across different studies. Methods for accounting for unequal cluster sizes in the p-CRT have been investigated extensively for Gaussian and binary outcomes. Synthesizing the findings of these works is difficult as the magnitude of impact of the unequal cluster sizes varies substantially across the combinations and ranges of input parameters. Limited investigations have been done for other combinations of a CRT design by outcome type, particularly methodology involving binary outcomes-the most commonly used type of primary outcome in trials. The paucity of methodological papers outside of the p-CRT with Gaussian or binary outcomes highlights the need for further methodological development to fill the gaps., Competing Interests: The author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The myelodysplastic syndromes (MDS) represent a group of clonal disorders characterized by ineffective hematopoiesis, resulting in peripheral cytopenias and frequent transformation to acute myeloid leukemia (AML). We and others have demonstrated that MDS arises in, and is propagated by malignant stem cells (MDS-SCs), that arise due to the sequential acquisition of genetic and epigenetic alterations in normal hematopoietic stem cells (HSCs). This review focuses on recent advancements in the cellular and molecular characterization of MDS-SCs, as well as their role in mediating MDS clinical outcomes. In addition to discussing the cell surface proteins aberrantly upregulated on MDS-SCs that have allowed the identification and prospective isolation of MDS-SCs, we will discuss the recurrent cytogenetic abnormalities and genetic mutations present in MDS-SCs and their roles in initiating disease, including recent studies demonstrating patterns of clonal evolution and disease progression from pre-malignant HSCs to MDS-SCs. We also will discuss the pathways that have been described as drivers or promoters of disease, including hyperactivated innate immune signaling, and how the identification of these alterations in MDS-SC have led to investigations of novel therapeutic strategies to treat MDS. It is important to note that despite our increasing understanding of the pathogenesis of MDS, the molecular mechanisms that drive responses to therapy remain poorly understood, especially the mechanisms that underlie and distinguish hematologic improvement from reductions in blast burden. Ultimately, such distinctions will be required in order to determine the shared and/or unique molecular mechanisms that drive ineffective hematopoiesis, MDS-SC maintenance, and leukemic transformation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhan and Park.)

Neutrophil-derived microvesicles (NDMVs) have the potential to exert anti-inflammatory effects. Our study aimed to explore the effects of NDMVs on proinflammatory cytokines expressed by tumor necrosis factor α (TNFα)-stimulated fibroblast-like synoviocytes (FLS). FLS were isolated from the synovium of knee osteoarthritis (OA) patients undergoing surgery. NDMVs, isolated from TNFα-stimulated healthy neutrophils, were characterized by electron microscopy and nanoparticle tracking analysis. MTT and scratch wound healing assays were used to measure FLS viability and migration after treatment with NDMVs, while internalization of fluorescently labeled NDMVs was appraised by flow cytometry and confocal microscopy. Levels of proinflammatory cytokines in supernatants were quantified by the Bio-Plex system. Incubation of FLS with NDMVs at a vesicle/cell ratio of 100 resulted in a time-dependent uptake, with 35% of synoviocytes containing microvesicles over a 6-24 h time period, with no significant change in cell viability. TNFα stimulated the cytokine expression in FLS, and NDMVs down-regulated TNFα-induced expression of IL-5, IL-6, IL-8, MCP-1, IFNγ and MIP-1β. However, this down-regulation was selective, as NDMVs had no significant effects on TNFα-stimulated expression of IL-2 or IL-4. NDMVs were internalized by FLS to inhibit TNFα-stimulated broad-spectrum proinflammatory cytokine secretion. NDMVs, therefore, may exhibit an anti-inflammatory role in the regulation of the FLS function.

Cell line development (CLD) by random integration (RI) can be labor intensive, inconsistent, and unpredictable due to uncontrolled gene integration after transfection. Unlike RI, targeted integration (TI) based CLD introduces the antibody-expressing cassette to a predetermined site by recombinase-mediated cassette exchange (RMCE). The key to success for the development of a TI host for therapeutic antibody production is to identify a transcriptionally active hotspot that enables highly efficient RMCE and antibody expression with good stability. In this study, a genome wide search for hotspots in the Chinese hamster ovary (CHO)-K1-M genome by either RI or PiggyBac (PB) transposase-based integration has been described. Two CHO-K1-M derived TI host cells were established with the Cre/Lox RMCE system and are described here. Both TI hosts contain a GFP-expressing landing pad flanked by two incompatible LoxP recombination sites (L3 and 2L). In addition, a third incompatible LoxP site (LoxFAS) is inserted in the GFP landing pad to enable an innovative two-plasmid based RMCE strategy, in which two separate vectors can be targeted to a single locus simultaneously. Cell lines generated by the TI system exhibit comparable or higher productivity, better stability and fewer sequence variant (SV) occurrences than the RI cell lines., (© 2021 American Institute of Chemical Engineers.)

In this cross-sectional study, we explored the relationship between loneliness and problematic mobile phone use among Chinese adolescents during the COVID-19 pandemic, considering the effects of escape motivation and self-control. We recruited 1034 adolescents (mean age 15.76 ± 1.20 years) from China. The results showed that loneliness was positively associated with escape motivation and adolescent problematic mobile phone use. Furthermore, when controlling for gender, escape motivation mediated the relationship between loneliness and problematic mobile phone use, and self-control moderated the relationship between escape motivation and problematic mobile phone use. Specifically, as self-control increased, escape motivation was less likely to induce problematic mobile phone use. Thus, loneliness and escape motivation may be factors that increase the risk of problematic mobile phone use, and self-control should be considered in prevention and intervention strategies aimed at attenuating adolescent problematic mobile phone use., (Copyright © 2021. Published by Elsevier Ltd.)

Due to their ultra-thin morphology, larger specific surface area and more exposed active sites, two-dimensional (2D) metal-organic framework (MOF) nanosheets can break the limitations of three-dimensional (3D) MOFs in sensitivity, response speed and the limit of detection for sensing applications. In this work, fluorescent NH2-MIL-53(Al) nanosheets were developed as a fluoride detection sensor compared with the 3D bulk counterpart. The morphological and structural characteristics of the obtained products were systematically characterized, and the favourable chemical and fluorescence stability of the NH2-MIL-53(Al) nanosheets were explored. The fluorescent NH2-MIL-53(Al) nanosheets showed high sensitivity, fast response speed (as short as 10 seconds), low limit of detection (15.2 ppb), and wide linear detection range (5-250 μM), and all performances were better than those of their bulk counterpart. In addition, the sensing mechanism was investigated to be based on the transformation of the NH2-MIL-53(Al) framework that induced the release of fluorescent ligands, resulting in an exceptionally enhanced fluorescence. This work highlights the advantages of 2D MOF nanosheets in fluorescence sensing applications.

Intervertebral disc degeneration and resulting low back pain arises from the programmed apoptosis of nucleus pulposus cells (NPCs). Recent studies show that hypoxia-inducible factor-1α plays a vital role in the etiology and pathogenesis of disc degeneration. However, the underlying mechanism of HIF-1α in NPCs is unclear. The present study identified 994 significant differentially expressed miRNAs by analyzing microarray data downloaded from the Gene Expression Omnibus database. MicroRNA(miR)-32-5p expression was 2.81-fold upregulated in NPCs compared with that of the healthy control tissues (P<0.05). A total of 331 significant differentially expressed mRNAs were identified, and PTEN was downregulated in NPCs of non-degenerative disc tissues from young patients. miR-32-5p was predicted to target the PTEN 3'-untranslated region (UTR). To confirm these results, in-vitro experiments investigating the molecular function of miR-32-5p and PTEN were performed. Furthermore, hypoxia induced miR-32-5p and PTEN expression. HIF-1α inhibited NPC proliferation and promoted cell apoptosis by regulating miR-32-5p and PTEN. miR-32-5p promoted NPC proliferation and decreased cell apoptosis. Next, it was verified whether miR-32-5p targeted the PTEN 3'-UTR using dual-luciferase reporter assays. Finally, it was observed that PI3K/AKT/mTOR signaling pathway was upregulated by a miR-32-5p mimic, which improved cell proliferation and decreased apoptosis. Importantly, PTEN was downregulated in these experiments; and inhibition of miR-32-5p had the opposite effect. Overall, these results demonstrate that HIF-1α regulates cell proliferation and apoptosis by controlling the miR-32-5p/PTEN/PI3K/AKT/mTOR axis in NPCs., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Zhan et al.)

Background: In a cross-sectional stepped-wedge cluster randomized trial comparing usual care to a new intervention, treatment allocation and time are correlated by design because participants enrolled early in the trial predominantly receive usual care while those enrolled late in the trial predominantly receive the new intervention. Current guidelines recommend adjustment for time effects when analyzing stepped-wedge cluster randomized trials to remove the confounding bias induced by this correlation. However, adjustment for time effects impacts study power. Within the Frequentist framework, adopting a sample size calculation that includes time effects would ensure the trial having adequate power regardless of the magnitude of the effect of time on the outcome. But if in fact time effects were negligible, this would overestimate the required sample size and could lead to the trial being deemed infeasible due to cost or unavailability of the required numbers of clusters or participants. In this study, we explore the use of prior information on time effects to potentially reduce the required sample size of the trial., Methods: We applied a Bayesian approach to incorporate the prior information on the time effects into cluster-level statistical models (for continuous, binary, or count outcomes) for the stepped-wedge cluster randomized trial. We conducted simulations to illustrate how the bias in the intervention effect estimate and the trial power vary as a function of the prior precision and the mis-specification of the prior means of the time effects in an example scenario., Results: When a nearly flat prior for the time effects was used, the power or sample size calculated using the Bayesian approach matched the result obtained using the Frequentist approach with time effects included. When a highly precise prior for the time effects (with accurately specified prior means) was used, the Bayesian result matched the Frequentist result obtained with time effects excluded. When the prior means of the time effects were nearly correctly specified, including this information improved the efficiency of the trial with little bias introduced into the intervention effect estimate. When the prior means of the time effects were greatly mis-specified and a precise prior was used, this bias was substantial., Conclusion: Including prior information on time effects using a Bayesian approach may substantially reduce the required sample size. When the prior can be justified, results from applying this approach could support the conduct of a trial, which would be deemed infeasible if based on the larger sample size obtained using a Frequentist calculation. Caution is warranted as biased intervention effect estimates may arise when the prior distribution for the time effects is concentrated far from their true values.