Publications by authors named "Qin Wang"

1,939 Publications

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Active sites of peptides Asp-Asp-Asp-Tyr and Asp-Tyr-Asp-Asp protect against cellular oxidative stress.

Food Chem 2021 Jul 19;366:130626. Epub 2021 Jul 19.

College of Light Industry and Food, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong 510225, China; Guangdong Provincial Key Laboratory of Lingnan Specialty Food Science and Technology, Guangzhou, Guangdong, China. Electronic address:

The protective effects of the peptides Asp-Asp-Asp-Tyr (DDDY) and Asp-Tyr-Asp-Asp (DYDD) against AAPH-induced HepG2 cells are unclear. Our objective was to investigate the active sites of these peptides and their cellular antioxidant mechanism. DDDY and DYDD show a direct free radical scavenging effect in reducing ROS levels and maintained cellular antioxidant enzymes at normal levels. The quantum chemistry analysis of the electronic properties of antioxidant activity showed that DYDD has a greater energy in the highest occupied molecular orbital than DDDY, and O-H and N-H were identified as the active antioxidant sites in DYDD and DDDY, respectively, indicating that the inconsistent arrangement of amino acids affects the distribution of the highest occupied orbital energy as well as the active sites; thus, influences the antioxidant activity of peptides. It provide valuable insights into the antioxidant active sites of peptides.
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http://dx.doi.org/10.1016/j.foodchem.2021.130626DOI Listing
July 2021

Synthesis and Biological Evaluation of Falcarinol-Type Analogues as Potential Calcium Channel Blockers.

J Nat Prod 2021 Jul 28. Epub 2021 Jul 28.

Department of Medicinal Chemistry, School of Pharmacy, Southwest Medical University, Luzhou 646000, People's Republic of China.

A series of enantiomers of falcarinol analogues () were synthesized using a chiral 1,1'-binaphth-2-ol (BINOL)-based catalytic system. The neuroprotective effects of falcarinol () and its analogues () on PC12 cells injured by sodium azide (NaN) were investigated. The structure-function relationships and possible mechanism were studied. Pretreatment of PC12 cells with falcarinol analogues ()- and ()- for 1 h following addition of NaN and culture in a CO incubator for 24 h resulted in significant elevation of cell viability, as determined by a CCK-8 assay and Hoechst staining, with reduction of LDH release and MDA content, increase of SOD activity, and decrease of ROS stress, when compared with the activity of natural falcarinol (). These observations indicated that the falcarinol analogues ()- and ()- can protect PC12 cells against NaN-induced apoptosis via increasing resistance to oxidative stress. For the first time, falcarinol () and its analogue ()- were found to have potential L-type calcium channel-blocking activity, as recorded using a manual patch clamp technique on HEK-293 cells stably expressing Cav1.2 (α1C/β2a/α2δ1). These findings suggest that the mechanism of the L-type calcium channel-blocking activity of falcarinol () and its analogue ()- might be involved in neuroprotection by falcarinol-type analogues by inhibiting calcium overload in the upstream of the signaling pathway.
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http://dx.doi.org/10.1021/acs.jnatprod.1c00136DOI Listing
July 2021

Single live birth derived from conjoined oocytes using laser-cutting technique: a case report.

Zygote 2021 Jul 27:1-4. Epub 2021 Jul 27.

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.

The finding of conjoined oocytes is a rare occurrence that accounts for only 0.3% of all human retrieved oocytes. This phenomenon is quite different from that of a traditional single oocyte emanating from one follicle, and may result in dizygotic twins and mosaicism. Given the insufficient evidence on how to approach conjoined oocytes, their fate is variable among different in vitro fertilization (IVF) centres. In this observational report, we propose a new protocol for the use of these conjoined oocytes using intracytoplasmic sperm injection (ICSI), laser-cutting technique and next-generation sequencing (NGS). The first case report demonstrates that conjoined oocytes can penetrate their shared zona pellucida (ZP) at Day 6. The second case is that of a 25-year-old female patient who underwent a successful embryo transfer cycle after removal of one oocyte in which a pair of conjoined human oocytes underwent ICSI, laser-cutting separation and NGS testing. The patient achieved pregnancy and gave birth to single healthy female originally derived from conjoined oocytes. This case provided a means through which normal pregnancy may be achieved from conjoined oocytes using laser-cutting separation techniques. The protocol described may be especially beneficial to patients with a limited number of oocytes.
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http://dx.doi.org/10.1017/S0967199421000526DOI Listing
July 2021

[Risk assessment of excess mortality attribute to PM_(2.5) exposure in 5 cities in China in 2018].

Wei Sheng Yan Jiu 2021 Jul;50(4):593-599

National Institute of Environmental Health, China CDC, Beijing 100021, China, China CDC Key Laboratory of Environment and Population Health, Beijing 100021, China.

Objective: To assess the risk of excess mortality caused by exposure to PM_(2.5) in 5 cities in China.

Methods: Surveillance data on daily concentration of PM_(2.5), meteorology and death-causes were collected from 2015 to 2018 in Harbin, Xi& apos; an, Nanjing, Chengdu and Guangzhou cities. Generalized additive model(GAM) was used to analyze acute exposure-response coefficients of PM_(2.5) exposure on the mortality. Using daily 24-hour average concentration of PM_(2.5) in 2018 to estimate the exposure levels of the population, with PM_(2.5) 24-hour average concentration limit of the ambient air quality standard(GB 3095-2012) for reference concentration(75 μg/m~3), and applicating the health risk assessment model, the excess deaths attribute to PM_(2.5) exposure in the 5 cities in 2018 was estimated.

Results: Attribute to PM_(2.5) exposure, the excess cases of death caused by circulatory system diseases in Harbin and Guangzhou were 35 and 92, the excess cases caused by respiratory diseases in Xi& apos; an was 70, the excess cases of caused by non-accident in Nanjing was 69, and the excess cases caused by non-accidental, respiratory and circulatory diseases in Chengdu were 588, 210 and 134 in 2018.

Conclusion: PM_(2.5) exposure could increase the excess mortality risk, which varies among different cities.
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http://dx.doi.org/10.19813/j.cnki.weishengyanjiu.2021.04.010DOI Listing
July 2021

Constructing Precise Coordination of Nickel Active Sites on Hierarchical Porous Carbon Framework for Superior Oxygen Reduction.

Small 2021 Jul 23:e2102125. Epub 2021 Jul 23.

College of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, P. R. China.

Single-atom catalysts (SACs) with specific coordination environment are expected to be efficient electrocatalysts for oxygen reduction reaction (ORR). Herein, NiN C coordination site is constructed through encapsulating Ni into the cavity of ZIF-8 as a self-sacrificing precursor and anchoring it on 3D N-doped carbon frameworks. The NiN C catalyst shows excellent ORR activity and stability, with a high half-wave potential (0.938 V vs RHE), which is currently the best performances in Ni-based SACs. The remarkable performance with high ORR activity in alkaline solution is attributed to the single-atom nickel active sites with faster electron transport and suitable electronic structure. Moreover, the power density of zinc-air battery assembled by NiN C as cathode is 47.1% higher than that of the commercial Pt/C. This work not only provides a facile method to prepare extremely active Ni-based SACs, but also studies the intrinsic mechanism toward the oxygen reduction reaction under alkaline condition.
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http://dx.doi.org/10.1002/smll.202102125DOI Listing
July 2021

Circulating miRNAs in Serum as Biomarkers for Early Diagnosis of Non-small Cell Lung Cancer.

Front Genet 2021 9;12:673926. Epub 2021 Jul 9.

Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

Background: Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers. This study aimed to discover the potential miRNA biomarkers for early detection of NSCLC.

Methods: Total circulating miRNAs were extracted from six patients and six volunteers and run on the miRNA chip. The differentially expressed miRNAs acquired by data mining were intersected with chip results, and qRT-PCR were carried out. Then the differentially miRNAs were validated by using a validation cohort (120 participants). ROC curves were established to evaluate the diagnostic efficacy of the differentially circulating miRNAs. The target genes of the differential miRNAs were identified using the miRTarBase database, and follow-up GO and KEGG enrichment analysis were conducted.

Results: We identified 577 miRNA which screened according to the criteria (fold change > 2 and value < 0.05). Among them, seven circulating miRNAs passed additional filtering based on data mining. These miRNAs were further validated in the training and validation cohort. miR-492, miR-590-3p, and miR-631 were differentially expressed in the patients' serum, and the area under the ROC curve (AUC) values of these miRNAs were 0.789, 0.792, and 0.711, respectively. When using them as a combination to discriminate healthy volunteers from patients, the AUC reached 0.828 (95% CI, 0.750-0.905, = 0.000) with a sensitivity of 86.7% and specificity of 71.7%. The follow-up enrichment analysis showed that target genes of three miRNA were associated with tumorigenesis and progression, such as cell cycle and P53 signaling pathway.

Conclusions: The combination of miR-492, miR-590-3p, and miR-631 can be utilized to distinguish healthy individuals and early-stage NSCLC patients.

Impact: The combination of miR-492, miR-590-3p, and miR-631 might be a promising serum biomarker in patients for the early diagnosis of NSCLC.
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http://dx.doi.org/10.3389/fgene.2021.673926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299278PMC
July 2021

Ameliorative effect of allicin on vascular calcification via inhibiting endoplasmic reticulum stress.

Vascular 2021 Jul 23:17085381211035291. Epub 2021 Jul 23.

Geriatric Department, The Third Hospital of Hangzhou, Hangzhou, China.

Objectives: Vascular calcification (VC) is an independent predictor for cardiovascular events and mortality. However, there are currently no effective methods to reverse or prevent it. The present study aimed to determine the ameliorative effect of allicin on VC.

Methods: VC model of rats was induced by high-dose vitamin D, which was valued by Alizarin Red staining, calcium contents, and alkaline phosphatase in the aorta. Systolic blood pressure, pulse pressure, and pulse wave velocity were measured to determine aortic stiffness. Protein levels were detected by Western blot.

Results: Allicin treatment rescued aortic VC and stiffness. The increased protein levels of RUNX2 and BMP2, two markers of osteoblastic phenotype of vascular smooth muscle cells, in the calcified aorta were attenuated by allicin, whereas the decreased levels of calponin and SM22α induced by calcification were improved. Allicin treatment significantly attenuated the increased protein levels of GRP78, GRP94, and CHOP, which are key markers of endoplasmic reticulum stress, in the calcified aorta. The activation of PERK/eIF2α/ATF4 cascades was also prevented by allicin.

Conclusions: Allicin could ameliorate aortic VC and stiffness. The ameliorative effect of allicin on VC might be mediated by inhibiting PERK/eIF2α/ATF4 cascades. Our results might provide a new proof for VC treatment.
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http://dx.doi.org/10.1177/17085381211035291DOI Listing
July 2021

Skin-inspired gelatin-based flexible bio-electronic hydrogel for wound healing promotion and motion sensing.

Biomaterials 2021 Jul 15;276:121026. Epub 2021 Jul 15.

BMI Center for Biomass Materials and Nanointerfaces, School of Biomass Science and Engineering, Sichuan University, Chengdu, Sichuan, 610065, China; John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA, 02115, United States; State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, Sichuan, 610065, China. Electronic address:

Next generation tissue-engineered skin scaffolds promise to provide sensory restoration through electrical stimulation in addition to effectively rebuilding and repairing skin. The integration of real-time monitoring of the injury motion activities can fundamentally improve the therapeutic efficacy by providing detailed data to guide the clinical practice. Herein, a mechanically-flexible, electroactive, and self-healable hydrogels (MESGel) was engineered for the combinational function of electrically-stimulated accelerated wound healing and motion sensing. MESGel shows outstanding biocompatibility and multifunctional therapeutic properties including flexibility, self-healing characteristics, biodegradability, and bioelectroactivity. Moreover, MESGel shows its potential of being a novel flexible electronic skin sensor to record the injury motion activities. Comprehensive in vitro and in vivo experiments prove that MESGel can facilitate effective electrical stimulation, actively promoting proliferation in Chinese hamster lung epithelial cells and therefore can accelerate favorable epithelial biology during skin wound healing, demonstrating an effective therapeutic strategy for a full-thickness skin defect model and leading to new-type flexible bioelectronics.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121026DOI Listing
July 2021

Discovery of Potent Selective Nonzinc Binding Autotaxin Inhibitor BIO-32546.

ACS Med Chem Lett 2021 Jul 14;12(7):1124-1129. Epub 2021 Jun 14.

Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.

Autotaxin (ATX) is a lysophospholipase D that is the main enzyme responsible for generating LPA in body fluids. Although ATX was isolated from a conditioned medium of melanoma cells, later it was discovered to play a critical role in vascular and neuronal development. ATX has also been implicated in primary brain tumor, fibrosis, and rheumatoid arthritis, as well as neurological diseases such as multiple sclerosis, Alzheimer's disease, and neuropathic pain. As ATX and LPA levels are increased upon neuronal injury, a selective ATX inhibitor could provide a new approach to treat neuropathic pain. Herein we describe the discovery of a novel series of nonzinc binding reversible ATX inhibitors, particularly a potent, selective, orally bioavailable, brain-penetrable tool compound BIO-32546, as well as its synthesis, X-ray cocrystal structure, pharmacokinetics, and in vivo efficacy.
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http://dx.doi.org/10.1021/acsmedchemlett.1c00211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274069PMC
July 2021

Quantitative proteomic analysis of the effects of melatonin treatment for mice suffered from small intestinal damage induced by γ-ray radiation.

Int J Radiat Biol 2021 Jul 29:1-11. Epub 2021 Jul 29.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China.

Purpose: Intestinal damage induced by radiation exposure is a major clinic concern of radiotherapy for patients with abdominal or pelvic tumor. Melatonin (-acetyl-5-methoxytryptamine) is likely be an ideal radioprotector to protect individuals from radiation exposure. The study aimed to define the role of melatonin in small intestinal damage caused by abdominal irradiation (ABI).

Materials And Methods: 30-day survival rate and pathological histology of the intestines from melatonin-treated mice after 13 Gy ABI exposure was first detected. Next, quantitative proteomics analysis of the small intestines tissue was examined and GO term and KEGG pathways analysis were performed.

Results: Melatonin treatment before ABI exposure significantly increased 30-day survival rate to 83% and ameliorated damage to the intestinal epithelial cells. Melatonin significantly altered the proteins profile of the small intestines following irradiation. For the irradiated mice treated with melatonin in comparison with the irradiated mice, the enriched GO terms were mainly involved in defense response to other organism (BP, GO: 0098542), response to other organism (BP, GO: 0051707), anion transmembrane transporter activity (MF, GO: 0008509), and secondary active transmembrane transporter activity (MF, GO: 0015291). In the process of antioxidant activity (MF, GO: 0016209), melatonin treatment prior to radiation exhibited high protein levels of Sod3 and Gpx3. The markedly KEGG pathways for melatonin treatment prior to radiation mainly included protein digestion and absorption (ko 04974) and mineral absorption (ko 04978). p53 signaling pathway and DNA repair pathways were enriched in melatonin treated mice. The amount of radiation-induced DNA damage and the cell apoptosis of the small intestines was decreased in the melatonin-treated mice.

Conclusions: Melatonin may protect small intestines from radiation damage through increasing DNA repair and decreasing cell apoptosis of the small intestines. Our data provided perspective for the study of melatonin in mitigating ABI-caused intestinal damage.
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http://dx.doi.org/10.1080/09553002.2021.1956006DOI Listing
July 2021

Complete hydatidiform mole in a 52-year-old postmenopausal woman: A case report and literature review.

Authors:
Qin Wang Hui Dong

Case Rep Womens Health 2021 Jul 19;31:e00338. Epub 2021 Jun 19.

Department of Pathology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, PR China.

Benign gestational trophoblastic disease generally occurs in women of reproductive age and is extremely rare in postmenopausal women. Here, the authors describe a case of complete hydatidiform mole in a 52-year-old postmenopausal woman with a history of lower abdominal bloating and vaginal bleeding. The paper summarizes the clinical manifestations, physiopathology, diagnosis, and treatment options for gestational trophoblastic disease in postmenopausal women. This study highlights that gestational trophoblastic disease can occur in postmenopausal women and that it is important to include it in the differential diagnosis of postmenopausal bleeding, to prevent delay in treatment.
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http://dx.doi.org/10.1016/j.crwh.2021.e00338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255813PMC
July 2021

High GP73 Expression Correlates with Poor Response to Neoadjuvant Chemotherapy and Survival in Gastric Cancer: A Tissue Microarray Study.

Pathol Oncol Res 2021 30;27:603838. Epub 2021 Mar 30.

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

Golgi protein 73 (GP73) is a type II Golgi transmembrane protein which is overexpressed in several cancers, however, its role in gastric cancer is still unclear. The aim of this study is to investigate if high GP73 expression is associated with pathological tumor response to neoadjuvant chemotherapy and prognosis for patients with gastric cancer. A total of 348 patients with gastric cancer, who had undergone surgery between 1999 and 2011 were retrospectively reviewed, GP73 expression was examined in tumor tissues using tissue microarray and the correlations between its expression and pathological response to neoadjuvant chemotherapy as well as patients prognosis were analyzed. We found that GP73 expression was not associated with clinicopathologic features including tumor size, differentiation and TNM stage. High expression of GP73 was associated with less pathological tumor response to neoadjuvant chemotherapy and poor survival in gastric cancer, multivariate analysis showed GP73 expression was an independent predictive factor for pathological response to neoadjuvant chemotherapy and for prognosis in patients with gastric cancer. Our results suggest that GP73 expression correlates with the effect of neoadjuvant chemotherapy and is a promising biomarker to identify patients with poor prognosis.
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http://dx.doi.org/10.3389/pore.2021.603838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262201PMC
March 2021

Association between Tfh and PGA in children with Henoch-Schönlein purpura.

Open Med (Wars) 2021 2;16(1):986-991. Epub 2021 Jul 2.

Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou 215025, China.

Objective: The aim of this study was to investigate the roles of follicular helper CD4 T cells (Tfh) and serum anti-α-1,4-d-polygalacturonic acid (PGA) antibody in the pathogenesis of Henoch-Schönlein purpura (HSP).

Methods: ELISA was performed to determine serum PGA-IgA and PGA-IgG. Flow cytometry was utilized to determine the peripheral CD4 CXCR5 and CD4 CXCR5 ICOS Tfh cells. Real-time PCR was conducted to determine the expression of Bcl-6 gene. Then the change of Tfh cells was analyzed, together with the association with the anti-PGA antibody as well as the roles in the pathogenesis of HSP.

Results: Compared with the cases with acute respiratory infection and elective surgery, the proportion of CD4 CXCR5 and CD4 CXCR5 ICOS Tfh cells in the HSP group showed significant elevation ( < 0.001). A significant correlation was noticed between PGA-IgA and CD4 CXCR5 Tfh cells ( = 0.380 and = 0.042) and CD4 CXCR5 ICOS Tfh cells ( = 0.906 and < 0.001). The expression of Bcl-6 in the HSP group showed no statistical difference compared with that in the acute respiratory infection and the surgery control ( < 0.05).

Conclusion: Increased activity of Tfh cells, which is closely related to mucosal immunity, may be a major contributor in the elevation of PGA-IgA, and Tfh cells and PGA-IgA are closely related to the occurrence of HSP.
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http://dx.doi.org/10.1515/med-2021-0318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254571PMC
July 2021

SIRT6 Promotes Osteogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells Through Antagonizing DNMT1.

Front Cell Dev Biol 2021 22;9:648627. Epub 2021 Jun 22.

Laboratory of Regenerative Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China.

Background: Adipose-derived stem cells (ADSCs) are increasingly used in regenerative medicine because of their potential to differentiate into multiple cell types, including osteogenic lineages. Sirtuin protein 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that plays important roles in cell differentiation. NOTCH signaling has also been reported to involve in osteogenic differentiation. However, the function of SIRT6 in osteogenic differentiation of ADSCs and its relation to the NOTCH signaling pathways are yet to be explored.

Methods: The study with human ADSCs (hADSCs) and experiments with nude mice have been performed. Alkaline phosphatase (ALP) assays and ALP staining were used to detect osteogenic activity. Alizarin Red staining was performed to detect calcium deposition induced by osteogenic differentiation of ADSCs. Western blot, RT-qPCR, luciferase reporter assay, and co-immunoprecipitation assay were applied to explore the relationship between of SIRT6, DNA methyltransferases (DNMTs) and NOTCHs.

Results: SIRT6 promoted ALP activity, enhanced mineralization and upregulated expression of osteogenic-related genes of hADSCs and . Further mechanistic studies showed that SIRT6 deacetylated DNMT1, leading to its unstability at protein level. The decreased expression of DNMT1 prevented the abnormal DNA methylation of NOTCH1 and NOTCH2, resulting in the upregulation of their transcription. SIRT6 overexpression partially suppressed the abnormal DNA methylation of NOTCH1 and NOTCH2 by antagonizing DNMT1, leading to an increased capacity of ADSCs for their osteogenic differentiation.

Conclusion: This study demonstrates that SIRT6 physical interacts with the DNMT1 protein, deacetylating and destabilizing DNMT1 protein, leading to the activation of NOTCH1 and NOTCH2, Which in turn promotes the osteogenic differentiation of ADSCs.
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http://dx.doi.org/10.3389/fcell.2021.648627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258422PMC
June 2021

Simultaneous determination of the PhIP-proline adduct and related precursors by UPLC-MS/MS for confirmation of direct elimination of PhIP by proline.

Food Chem 2021 Jun 26;365:130484. Epub 2021 Jun 26.

State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; International Joint Laboratory on Food Safety, Jiangnan University, Wuxi 214122, China. Electronic address:

The effect and elimination pathway of proline on reducing PhIP and the effect of processing temperature, duration, and proline addition on the PhIP-proline adduct and its precursors were investigated. The results have demonstrated that PhIP and proline could condense to produce the adduct by direct heating, which could also be detected in the PhIP-producing model system and in beef patties with proline. The analytical method was optimized and has a good limit of detection (0.006-73 ng/mL), limit of quantification (0.021-245 ng/mL), recovery rate (about 80%-120%), and precision (below 15%). A high dose of proline (5.0%, w/w) promoted the formation of the adduct and reduction of PhIP; long heating duration and high temperature were not conducive to the formation of the adduct in beef patties. With increased addition of proline, creatine and creatinine decreased in a dose-dependent manner; phenylalanine and glucose did not show the same trend.
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http://dx.doi.org/10.1016/j.foodchem.2021.130484DOI Listing
June 2021

The OX40/OX40L Axis Regulates T Follicular Helper Cell Differentiation: Implications for Autoimmune Diseases.

Front Immunol 2021 21;12:670637. Epub 2021 Jun 21.

School of Biology & Basic Medical Sciences, Medical College of Soochow University, Suzhou, China.

T Follicular helper (Tfh) cells, a unique subset of CD4 T cells, play an essential role in B cell development and the formation of germinal centers (GCs). Tfh differentiation depends on various factors including cytokines, transcription factors and multiple costimulatory molecules. Given that OX40 signaling is critical for costimulating T cell activation and function, its roles in regulating Tfh cells have attracted widespread attention. Recent data have shown that OX40/OX40L signaling can not only promote Tfh cell differentiation and maintain cell survival, but also enhance the helper function of Tfh for B cells. Moreover, upregulated OX40 signaling is related to abnormal Tfh activity that causes autoimmune diseases. This review describes the roles of OX40/OX40L in Tfh biology, including the mechanisms by which OX40 signaling regulates Tfh cell differentiation and functions, and their close relationship with autoimmune diseases.
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http://dx.doi.org/10.3389/fimmu.2021.670637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256170PMC
June 2021

Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women.

Nat Commun 2021 07 7;12(1):4198. Epub 2021 Jul 7.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants.
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http://dx.doi.org/10.1038/s41467-021-24327-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263739PMC
July 2021

A novel circular RNA, circPUS7 promotes cadmium-induced transformation of human bronchial epithelial cells by regulating Kirsten rat sarcoma viral oncogene homolog expression via sponging miR-770.

Metallomics 2021 Jul;13(7)

Department of Occupational and Environmental Health, Key Laboratory of Environment and Health, Ministry of Education, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.

Cadmium is a human carcinogen, which induces cancers by mechanisms that are not fully understood. Induction of oxidative stress, apoptosis resistance, genotoxic effects, and epigenetic modulations have been indicated to regulate cadmium-induced carcinogenesis. Circular RNAs are epigenetic regulators that have been recognized to play essential roles in carcinogenesis. Yet, the involvement of circular RNAs in cadmium carcinogenesis remains unclear. In this study, a novel circular RNA, circPUS7, was identified and described for the first time. CircPUS7 was significantly upregulated at week 12, 16, and 20 during the cadmium-induced transformation of human bronchial epithelial BEAS-2B cells. Knockdown of circPUS7 in cadmium-transformed BEAS-2B (T-BEAS-2B) cells significantly attenuated transformation markers including cell proliferation, migration, invasion, and anchorage-independent growth. Moreover, circPUS7 promoted malignant phenotypes by competitively binding with miR-770. Overexpression of miR-770 significantly inhibited the transformation properties of T-BEAS-2B cells while inhibition of miR-770 potently reversed the inhibitory effects of circPUS7 knockdown in proliferation, migration, invasion, and anchorage-independent growth of the T-BEAS-2B cells. Kirsten rat sarcoma viral oncogene homolog (KRAS), which was increased synchronically with circPUS7 during cadmium-induced cell transformation, was regulated by circPUS7 through sponging miR-770. In summary, our findings demonstrate that circPUS7 promotes cadmium-induced cell transformation through sponging miR-770 to regulate KRAS expression, providing a new perspective with the involvement of circular RNAs to further understand the mechanisms of cadmium carcinogenesis.
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http://dx.doi.org/10.1093/mtomcs/mfab043DOI Listing
July 2021

Assessing Liver Function by T1 Maps on Gd-EOB-DTPA-Enhanced MRI for up to 50 Min in Rat Models of Liver Fibrosis: A Longer Hepatobiliary Time Period may Help.

Chin Med Sci J 2021 Jun;36(2):110-119

Department of Radiology,Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.

Objectives To investigate whether a longer time period of gadolinium ethoxybenzyl diethylenetriaminepen-taacetic acid (Gd-EOB-DTPA)-enhanced T1 mapping scanning, as well as dynamic contrast-enhanced (DCE) and multiple hepatobiliary phase magnetic resonance imaging (MRI) have the potential to provide information about liver function in rats with liver fibrosis. Methods Forty rats were divided into the carbon tetrachloride-induced hepatic injury groups [carbon tetrachloride for four (=14), eight (=8), or twelve (=8) weeks] and the control group (=10). Gd-EOB-DTPA-enhanced MRI was performed including T1-mapping (delayed to 50 min), DCE, and multiple hepatobiliary phases. Indocyanine green retention rate at 15 min (ICG-R15) was determined. Parameters such as T1 reduction rate (ΔT1), elimination half-life of ΔT1 (T), relative enhancement (RE), time to maximum RE (T), and perfusion parameters were calculated. correlation analysis was used for correlation analysis between ICG-R15 and each MRI indices. Results ΔT1 at 30, 40, and 50 min showed significant positive correlations with ICG-R15 ( =0.784, 0.653, 0.757, =0.007, 0.041, 0.030). T showed a significant positive correlation with ICG-R15 (=0.685, =0.029). Tshowed a significant positive correlation with ICG-R15 (=0.532, =0.019). Conclusions ΔT1 in the late hepatobiliary phase and T exhibited moderate correlations with liver function. The longer time period of Gd-EOB-DTPA-enhanced T1 mapping scanning, as well as DCE and multiple hepatobiliary phases, may be of some value for estimating liver function in rats with liver fibrosis.
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http://dx.doi.org/10.24920/003794DOI Listing
June 2021

Predictive Score of Risk Associated with Progression of Patients with COVID-19 Pneumonia in Wuhan, China: the ALA Score.

Arab J Sci Eng 2021 Jun 28:1-9. Epub 2021 Jun 28.

Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150081 China.

The Coronavirus Disease 2019 (COVID-19) had become a Public Health Emergency of International Concern with more than 90 million confirmed cases worldwide. Therefore, this study aims to establish a predictive score model of progression to severe type in patients with COVID-19. This is a retrospective cohort study of 151 patients with COVID-19 diagnosed by nucleic acid test or specific serum antibodies from February 13, 2020, to March 14, 2020, hospitalized in a COVID-19-designed hospital in Wuhan, China. Of the 151 patients with average age of 63 years, 64 patients were male (42.4%), and 29 patients (19.2%) were classified as severe group. Multivariate analysis showed that age > 65 years (odds ratio [OR] = 9.72, 95%CI: 2.92-32.31,  < 0.001), lymphocyte count ≤ 1.1 × 10/L (OR = 3.42, 95%CI: 1.24-9.41,  = 0.017) and AST > 35 U/L (OR = 3.19, 95%CI: 1.11-9.19,  = 0.032) were independent risk factors for the disease severity. The area under curve (AUC) of receiver operating characteristic curve of the probabilities of the composite continuous variable (age + lymphocyte + AST) is 0.796. Finally, a predictive score model called ALA was established, and its AUC was 0.83 (95%CI: 0.75-0.92). Using a cutoff value of 9.5 points, the positive and negative predictive values were 54.1% (38-70.1%) and 92.1% (87.2-97.1%), respectively. The ALA score model can quickly identify severe patients with COVID-19, so as to help clinicians to better choose accurate management strategy.
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http://dx.doi.org/10.1007/s13369-021-05808-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237254PMC
June 2021

Changes in T Lymphocyte Subsets in Different Tumors Before and After Radiotherapy: A Meta-analysis.

Front Immunol 2021 16;12:648652. Epub 2021 Jun 16.

Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

Purpose: Radiation therapy (RT) induces an immune response, but the relationship of this response with tumor type is not fully understood. This meta-analysis further elucidated this relationship by analyzing the changes in T lymphocyte subsets in different tumors before and after radiotherapy.

Methods: We searched English-language electronic databases including PubMed, EMBASE, and the Cochrane Library to collect studies on the changes in peripheral blood CD3+ T lymphocytes, CD4+ T lymphocytes, and CD8+ T lymphocytes before and after radiotherapy in tumor patients from January 2015 to April 2021. The quality of the included literature was evaluated using the NOS scale provided by the Cochrane Collaboration, and statistical software RevMan 5.4 was used to analyze the included literature. P<0.05 was considered to indicate statistical significance.

Results: A total of 19 studies in 16 articles involving 877 tumor patients were included. All data were collected within 1 month before or after radiotherapy. Meta-analysis showed that numbers of CD3+ T lymphocytes (SMD: -0.40; 95% CI [-0.75, -0.04]; p = 0.03) and CD4+ T lymphocytes (SMD: -0.43; 95% CI: [-0.85, -0.02]; p = 0.04) were significantly reduced after radiotherapy compared with before treatment, but there was no statistically significant difference for CD8+ T lymphocytes (SMD: 0.33; 95% CI: [-0.88, 0.74]; p = 0.12). Subgroup analysis showed that peripheral blood T lymphocytes decreased in head and neck cancer. However, in prostate cancer and breast cancer, there was no significant change in peripheral blood. 1 month after radiotherapy, it has a potential proliferation and activation effect on lymphocytes in esophageal cancer and lung cancer. The results showed that CD8+T lymphocytes increased in peripheral blood after SBRT. Radiotherapy alone reduced CD3+ T lymphocyte numbers.

Conclusions: Within 1 month of radiotherapy, patients have obvious immunological changes, which can cause apoptosis and reduction of T lymphocytes, and affect the balance of peripheral blood immune cells. The degree of immune response induced by radiotherapy differed between tumor types.
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http://dx.doi.org/10.3389/fimmu.2021.648652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242248PMC
June 2021

The combined toxicity of ultra-small SiO nanoparticles and bisphenol A (BPA) in the development of zebrafish.

Comp Biochem Physiol C Toxicol Pharmacol 2021 Jul 1;248:109125. Epub 2021 Jul 1.

Institute of Nanochemistry and Nanobiology, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China. Electronic address:

The complex combined effects of nanoparticles and environmental pollutants in the aqueous environment will inevitably affect aquatic ecosystem and human life. Bisphenol A (BPA) is listed as a typical kind of endocrine disruptors, there is little research about the joint toxicity of co-exposure of SiO nanoparticles (NPs) and BPA. In this study, fluorescent ultra-small SiO NPs (US-FMSNs) around 6.3 nm were synthesized and investigated for their combined effects with BPA on zebrafish during the early developmental stages within 4-168 h post fertilization (hpf). The results showed that US-FMSNs could accumulate in the chorion, abdomen and intestine in zebrafish. In addition, the different concentration (0.1, 1, 10 μg/mL) of BPA and US-FMSNs (200 μg/mL) demonstrated strong impact on multiple toxic endpoints at four periods (72, 96, 120, 168 hpf). We found US-FMSNs had no significant toxic effect on zebrafish, while BPA (10 μg/mL) showed a degree of developmental toxicity. Compared with single BPA (10 μg/mL) exposure, combined exposure enhanced the developmental toxicity of zebrafish, including increased mortality, decreased hatching rate and body length, and decreased activity of total superoxide dismutase (T-SOD) and increased malondialdehyde (MDA) levels. Our results indicated that US-FMSNs and BPA induced oxidative stress, and the effect of the co-exposure was less than that of single exposure (10 μg/mL). This study hereby provides a basis for the potential ecological and health risks of SiO NPs and BPA exposure.
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http://dx.doi.org/10.1016/j.cbpc.2021.109125DOI Listing
July 2021

Amino Acid Profiling with Chemometric Analysis as a Feasible Tool for the Discrimination of Marine-Derived Peptide Powders.

Foods 2021 Jun 4;10(6). Epub 2021 Jun 4.

College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China.

Marine-derived peptide powders have suffered from adulteration via the substitution of lower-price peptides or the addition of adulterants in the market. This study aims to establish an effective approach for the discrimination and detection of adulterants for four representative categories of marine-derived peptide powders, namely, oyster peptides, sea cucumber peptides, Antarctic krill peptides, and fish skin peptides, based on amino acid profiling alongside chemometric analysis. The principal component analysis and orthogonal partial least squares discriminant analysis results indicate that four categories of marine-derived peptides could be distinctly classified into four clusters and aggregated with the respective raw materials. Taurine, glycine, lysine, and protein contents were the major discriminants. A reliable classification model was constructed and validated by the prediction dataset, mixture sample dataset, and unclassified sample dataset with accuracy values of 100%, 100%, and 100%, respectively.
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http://dx.doi.org/10.3390/foods10061294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229220PMC
June 2021

Enhancement of Patchoulol Production in Multiple Engineering Strategies.

J Agric Food Chem 2021 Jul 1;69(27):7572-7580. Epub 2021 Jul 1.

The Key Laboratory of Industrial Biotechnology of Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, People's Republic of China.

As a natural sesquiterpene compound with numerous biological activities, patchoulol has extensive applications in the cosmetic industry and potential usage in pharmaceuticals. Although several patchoulol-producing microbial strains have been constructed, the low productivity still hampers large-scale fermentation. possesses the ease of genetic manipulation and simple nutritional requirements and does not comprise competing pathways for the farnesyl diphosphate (FPP) precursor, showing its potential for patchoulol biosynthesis. Here, combinatorial strategies were applied to produce patchoulol in . The initial strain was constructed, and it produced 14 mg/L patchoulol after fermentation optimization. Patchoulol synthase (PTS) was engineered by semirational design, resulting in improved substrate binding affinity and a patchoulol titer of 40.3 mg/L; the patchoulol titer reached 66.2 mg/L after fusing of PTS with FPP synthase. To further improve the patchoulol production, the genome of an efficient chassis strain was engineered by deleting the competitive routes for acetate, lactate, ethanol, and succinate synthesis and cumulatively enhancing the expression of efflux transporters, which improved patchoulol production to 338.6 mg/L. When tested in a bioreactor, the patchoulol titer and productivity were further improved to 970.1 mg/L and 199 mg/L/d, respectively, and were among the highest levels reported using mineral salt medium.
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http://dx.doi.org/10.1021/acs.jafc.1c02399DOI Listing
July 2021

Smad3 gene C-terminal phosphorylation site mutation exacerbates CCl-induced hepatic fibrogenesis by promoting pSmad2L/C-mediated signaling transduction.

Naunyn Schmiedebergs Arch Pharmacol 2021 Aug 30;394(8):1779-1786. Epub 2021 Jun 30.

Department of Pharmacology, Key Laboratory of Anti-Inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China.

Current researches have confirmed that Smads, mediators of TGF-β signaling, are strictly controlled by domain-specific site phosphorylation in the process of hepatic disease. Usually, Smad3 phospho-isoform pSmad3L and pSmad3C are reversible and antagonistic; pSmad2L/C could act together with pSmad3L by stimulating PAI-1 expression and ECM synthesis to transmit fibrogenic signals. Our recent study found that pSmad3C mutation is supposed to perform a vigorous role on the early phase of liver injury and abates salvianolic acid B's anti-hepatic fibrotic-carcinogenesis. However, whether pSmad3C mutation expedites pSmad2L/C-mediated signaling transduction during hepatic fibrogenesis remains vague. Presently, Smad3 gene C-terminal phosphorylation site mutation heterozygote (pSmad3C) mice were constructed to probe if and how pSmad3C retards CCl-induced hepatic fibrogenesis by inhibiting pSmad2L/C-mediated signaling transduction. Twelve 6-week-old pSmad3C C57BL/6J mice were intraperitoneally injection with CCl for 6 weeks to induce liver fibrogenesis. Results showed that pSmad3C mutation aggravates the relative liver weight, biochemical parameters, collagenous fibers and fibrotic septa formation, contributes to fibrogenesis in HT-CCl mice. Furthermore, fibrotic-related proteins TGF-β, pSmad2C, pSmad2L, and PAI-1 were also increased in CCl-induced pSmad3C mice. These results suggest that pSmad3C mutation exacerbates hepatic fibrogenesis which relates to intensifying pSmad2L/C-mediated signaling transduction.
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http://dx.doi.org/10.1007/s00210-021-02114-1DOI Listing
August 2021

Solvent assistance induced surface N-modification of PtCu aerogels and their enhanced electrocatalytic properties.

Chem Commun (Camb) 2021 Jul;57(58):7140-7143

College of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot 010021, P. R. China.

A facile method involving the nitrogen modification of PtCu aerogel surfaces with N-methyl pyrrolidone as the sole nitrogen source is reported. The half wave potential (E1/2) of the PtCu aerogels was 0.932 V and the electrochemical active surface area (ECSA) was 102.04 m2 g-1 for the oxygen reduction reaction (ORR), and the mass activity (MA) for the methanol electrooxidation reaction (MOR) was measured to be 4.08 A mg-1, values better than those of a commercial Pt/C catalyst and other reported Pt-based catalysts.
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http://dx.doi.org/10.1039/d1cc02038bDOI Listing
July 2021

Cyclin-dependent kinase 15 upregulation is correlated with poor prognosis for patients with breast cancer.

J Int Med Res 2021 Jun;49(6):300060521999552

Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.

Objective: To investigate the clinical significance of cyclin-dependent kinase (CDK) 15 in breast cancer.

Methods: This prospective observational study enrolled 154 patients with breast cancer. Tumor tissues and paired paracancerous normal tissues were collected. Additionally, 85 samples of benign breast lesions were obtained from patients with mammary gland hyperplasia. Patient characteristics were recorded, and CDK15, human epidermal growth factor receptor (HER)2, estrogen receptor, progesterone receptor, and Ki67 immunohistochemical expression were determined.

Results: The rate of strong CDK15 expression was 63.6% (98/154) in breast cancer tissues, which was remarkably higher than that in benign breast lesions (34.1%, 29/85). Similarly, the ratio of strong CDK15 expression was markedly higher in tumor tissues (63.6%, 98/15) than in paracancerous normal tissues (27.3%, 42/154). Pearson's analysis showed that the CDK15 expression score was positively correlated with HER2 and Ki67. Patients with high CDK15 expression showed markedly higher ratios of TNM stage III to IV, lymph node metastasis, and increased tumor diameters but a significantly lower rate of ductal carcinoma in situ. The median survival time of these patients was significantly shorter. Kaplan-Meier curve analysis showed that low CDK15 expression predicted longer survival times.

Conclusion: Upregulated CDK15 predicted poor clinical outcomes in breast cancer.
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http://dx.doi.org/10.1177/0300060521999552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236788PMC
June 2021

An association between PM and pediatric respiratory outpatient visits in four Chinese cities.

Chemosphere 2021 Oct 18;280:130843. Epub 2021 May 18.

China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, China. Electronic address:

Background: The effects of exposure to particulate matter with aerodynamic diameter less than 2.5 μm (PM) on children's respiratory system were investigated in numerous epidemiological literatures. However, studies on the association between PM and pediatric outpatient visits for respiratory diseases, especially considering the multicenter studies were limited in China.

Objectives: To study the association between the short-term exposure to PM and the number of children's outpatient visits for respiratory diseases in four Chinese cities as well as the pooled health effects.

Methods: Data of pediatric outpatient visits for respiratory diseases (RD, ICD: J00-J99) from representative hospitals in Shijiazhuang (SJZ), Xi'an (XA), Nanjing (NJ) and Guangzhou (GZ) in China from 2015 to 2018 were collected and the air quality data for the same period were collected from environmental protection departments. Generalized additive model (GAM) with quasi-Poisson regression was conducted to analyze the effects of PM on the number of pediatric outpatient visits in each city. Single-day lag model (lag0 to lag7) and moving average lag model (lag01 and lag07) were used to examine the lag effects and cumulative effects. Random-effects meta-analysis was used to pool the estimated risks of four cities. The interactions between PM and temperature were also explored.

Results: The average daily/total outpatient visits for RD, in SJZ, XA, NJ and GZ from 2015 to 2018 were 854.2/1,245,384, 2353.9/3,439,025, 1267.2/1,851,438 and 1399.5/2,044,740 respectively. The percentages of acute upper respiratory infections (URD, ICD: J00-J06) and other acute lower respiratory infections (LRD, ICD: J20-J22) in RD were 33%, 13% (SJZ), 43%, 32% (XA), 26%, 21% (NJ) and 54%, 26% (GZ). The largest pooled estimates of single-day lag effects for RD, URD, and LRD were at lag0, lag0 and lag1. Every 10 μg/m increase in PM concentration was associated with a 0.46% (95%CI: 0.21%-0.70%), 0.50% (95%CI: 0.19%-0.81%) and 0.42% (95%CI: 0.06%-0.79%) increased number of outpatient visits significantly. While max cumulative effects which were all at lag 07 were 1.10% (95%CI: 0.46%-1.74%), 0.96% (95%CI: 0.20%-1.73%) and 1.06% (95%CI: 0.12%-2.00%). Less polluted cities (GZ and NJ) showed greater city-specific excess risks, but the excess risks significantly decreased after adjusting for NO in two-pollutant models. Generally, PM showed larger health hazards on lower temperature days.

Conclusions: Our study showed that exposure to the ambient PM was associated with the increase of the number of outpatient visits with pediatric respiratory diseases in four Chinese cities. The health effects of PM may not be independent of other air pollutants and could be modified by temperature.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130843DOI Listing
October 2021

The Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation.

Nat Commun 2021 06 22;12(1):3845. Epub 2021 Jun 22.

Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Atr is a serine/threonine kinase, known to sense single-stranded DNA breaks and activate the DNA damage checkpoint by phosphorylating Chek1, which inhibits Cdc25, causing cell cycle arrest. This pathway has not been implicated in neuroregeneration. We show that in Drosophila sensory neurons removing Atr or Chek1, or overexpressing Cdc25 promotes regeneration, whereas Atr or Chek1 overexpression, or Cdc25 knockdown impedes regeneration. Inhibiting the Atr-associated checkpoint complex in neurons promotes regeneration and improves synapse/behavioral recovery after CNS injury. Independent of DNA damage, Atr responds to the mechanical stimulus elicited during regeneration, via the mechanosensitive ion channel Piezo and its downstream NO signaling. Sensory neuron-specific knockout of Atr in adult mice, or pharmacological inhibition of Atr-Chek1 in mammalian neurons in vitro and in flies in vivo enhances regeneration. Our findings reveal the Piezo-Atr-Chek1-Cdc25 axis as an evolutionarily conserved inhibitory mechanism for regeneration, and identify potential therapeutic targets for treating nervous system trauma.
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http://dx.doi.org/10.1038/s41467-021-24131-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219705PMC
June 2021
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