Publications by authors named "Hao Yan"

879 Publications

Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation.

Biomed Pharmacother 2021 Oct 12;144:112297. Epub 2021 Oct 12.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, PR China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China. Electronic address:

High incidence of cutaneous toxicity ranging from 29.2% to 71.2% has been reported during clinical use of vandetanib, which is a multi-target kinase inhibitor indicated for the treatment of unresectable medullary thyroid carcinoma. The cutaneous toxicity of vandetanib has limited its clinical benefits, but the underlying mechanisms and protective strategies are not well studied. Hence, we firstly established an in vivo model by continuously administrating vandetanib at 55 mg/kg/day to C57BL/6 for 21 days and verified that vandetanib could induce skin rash in vivo, which was consistent with the clinical study. We further cultured HaCaT and NHEK cells, the immortalized or primary human keratinocyte line, and investigated vandetanib (0-10 μM, 0-24 h)-caused alteration in cellular survival and death processes. The western blot showed that the expression level of apoptotic-related protein, c-PARP, c-Caspase 3 and Bax were increased, while the anti-apoptotic protein Bcl2 and MCL1 level were decreased. Meanwhile, vandetanib downregulated mitochondrial membrane potential which in turn caused the release of Cytochrome C, excessive production of reactive oxygen species and DNA damage. Furthermore, we found that 5 μM bisdemethoxycurcumin partially rescued vandetanib-induced mitochondria pathway-dependent keratinocyte apoptosis via activation of autophagy in vivo and in vitro, thereby ameliorated cutaneous toxicity. Conclusively, our study revealed the mechanisms of vandetanib-induced apoptosis in keratinocytes during the occurrence of cutaneous toxicity, and suggested bisdemethoxycurcumin as a potential protective drug. This work provided a potentially promising therapeutic strategy for the treatment of vandetanib-induced cutaneous toxicity.
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http://dx.doi.org/10.1016/j.biopha.2021.112297DOI Listing
October 2021

Childhood urbanicity interacts with polygenic risk for depression to affect stress-related medial prefrontal function.

Transl Psychiatry 2021 Oct 12;11(1):522. Epub 2021 Oct 12.

Lieber Institute for Brain Development, Baltimore, MD, 21205, USA.

Urbanization is increasing globally, and is associated with stress and increased mental health risks, including for depression. However, it remains unclear, especially at the level of brain function, how urbanicity, social threat stressors, and psychiatric risk may be linked. Here, we aim to define the structural and functional MRI neural correlates of social stress, childhood urbanicity, and their putative mechanistic relevance to depressive illness risk, in terms of behavioral traits and genetics. We studied a sample of healthy adults with divergent urban and rural childhoods. We examined childhood urbanicity effects on brain structure as suggested by MRI, and its functional relevance to depression risk, through interactions between urbanicity and trait anxiety-depression, as well as between urbanicity and polygenic risk for depression, during stress-related medial prefrontal cortex (mPFC) engagement. Subjects with divergent rural and urban childhoods were similar in adult socioeconomic status and were genetically homogeneous. Urban childhood was associated with relatively reduced mPFC gray matter volumes as suggested by MRI. MPFC engagement under social status threat correlated with the higher trait anxiety-depression in subjects with urban childhoods, but not in their rural counterparts, implicating an exaggerated physiological response to the threat context with urbanicity, in association with behavioral risk for depression. Stress-associated mPFC engagement also interacted with polygenic risk for depression, significantly predicting a differential mPFC response in individuals with urban but not rural childhoods. Developmental urbanicity, therefore, appears to interact with genetic and behavioral risk for depression on the mPFC neural response to a threat context.
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http://dx.doi.org/10.1038/s41398-021-01650-xDOI Listing
October 2021

A C2H2-Type Zinc-Finger Protein from , MpZFP1, Enhances Salt Tolerance in Transgenic Arabidopsis.

Int J Mol Sci 2021 Oct 7;22(19). Epub 2021 Oct 7.

Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China.

C2H2 zinc finger proteins (ZFPs) play important roles in plant development and response to abiotic stresses, and have been studied extensively. However, there are few studies on ZFPs in mangroves and mangrove associates, which represent a unique plant community with robust stress tolerance. , which is highly induced by salt stress in the mangrove associate , was cloned and functionally characterized in this study. MpZFP1 protein contains two zinc finger domains with conserved QALGGH motifs and targets to the nucleus. The heterologous expression of in Arabidopsis increased the seeds' germination rate, seedling survival rate, and biomass accumulation under salt stress. The transgenic plants also increased the expression of stress-responsive genes, including and , and reduced the accumulation of reactive oxygen species (ROS). These results indicate that MpZFP1 is a positive regulator of plant responses to salt stress due to its activation of gene expression and efficient scavenging of ROS.
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http://dx.doi.org/10.3390/ijms221910832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509772PMC
October 2021

DNA Programmable Self-Assembly of Planar, Thin-Layered Chiral Nanoparticle Superstructures with Complex Two-Dimensional Patterns.

ACS Nano 2021 Oct 12. Epub 2021 Oct 12.

State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Donghua University, Shanghai 201620, People's Republic of China.

Planar, thin-layered chiral plasmonic superstructures with complex two-dimensional (2D) patterns, namely, double-layered binary stars (bi-stars) and pinwheels, were realized through DNA programmable 2D supramolecular self-assembly of gold nanorods (AuNRs). The chirality of the chiral superstructures was defined by a finite number of AuNR pairs as enantiomeric motifs, and their sizes (∼240 nm) were precisely defined by the underlying DNA template. These planar, thin-layered chiral nanoparticle superstructures exhibited prescribed shapes and sizes at the dried state on the substrate surface and are characteristic of giant anisotropy of chiroptical responses, with enhanced -factors from the axial incident excitation as compared to the in-plane excitation. This work will inspire possibilities for the construction of 2D chiral materials, for example, chiral metasurfaces, for the on-chip manipulation of chiral light-matter interactions programmable self-assembly of nanoparticles.
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http://dx.doi.org/10.1021/acsnano.1c06639DOI Listing
October 2021

Dynamical and noninvasive monitoring of curcumin effect on the changes in the viscoelasticity of human breast cancer cells: A novel model to assess cell apoptosis.

Talanta 2022 Jan 22;236:122899. Epub 2021 Sep 22.

Department of Immunology, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519041, PR China.

A real-time quartz crystal microbalance (QCM) cytosensor was first developed for dynamical and noninvasive monitoring of cell viscoelasticity for evaluation of apoptosis degree. In this work, human breast cancer cells MCF-7 and MDA-MB-231 were employed as cell model and respectively captured on the surface of QCM electrode modified with mercaptosuccinic acid and poly-l-lysine. Cell viscoelasticity was measured dynamically by real-time monitoring energy dissipation with QCM, and the dynamic diagram of the energy dissipation of MDA-MB-231 cells treated with curcumin was first obtained. The results displayed that the changes of energy dissipation in MDA-MB-231 cells and MCF-7 cells were 8.81 × 10 and 5.29 × 10, particularly due to the difference in cell viscoelasticity. Furthermore, curcumin was used to induce cell apoptosis and suppress energy dissipation of MDA-MB-231 cells. Combining apoptosis assay with QCM measurement, the results revealed good linear relationship between cell viscoelasticity inhibition and apoptosis rate with correlation coefficient R = 0.9908. The QCM cytosensor could rapidly, accurately, dynamically, and noninvasively monitor the changes of cell viscoelasticity for evaluation of apoptosis degree in MDA-MB-231 cells. The study established a new model for cell apoptosis assessment, facilitating understanding of the mechanisms of cell apoptosis on the aspect of mechanical properties.
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http://dx.doi.org/10.1016/j.talanta.2021.122899DOI Listing
January 2022

Cross-iteration multi-step optimization strategy for three-dimensional intensity position correction in phase diverse phase retrieval.

Opt Express 2021 Aug;29(18):29186-29201

Parameters mismatching between the real optical system and phase retrieval model undermines wavefront reconstruction accuracy. The three-dimensional intensity position is corrected in phase retrieval, which is traditionally separated from lateral position correction and axial position correction. In this paper, we propose a three-dimensional intensity position correction method for phase diverse phase retrieval with the cross-iteration nonlinear optimization strategy. The intensity position is optimized via the coarse optimization method at first, then the intensity position is cross-optimized in the iterative wavefront reconstruction process with the exact optimization method. The analytic gradients about the three-dimensional intensity position are derived. The cross-iteration optimization strategy avoids the interference between the incomplete position correction and wavefront reconstruction during the iterative process. The accuracy and robustness of the proposed method are verified both numerically and experimentally. The proposed method achieves robust and accurate intensity position correction and wavefront reconstruction, which is available for wavefront measurement and phase imaging.
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http://dx.doi.org/10.1364/OE.436172DOI Listing
August 2021

Two characterization methods of ripple errors for the large square aperture.

Appl Opt 2021 Oct;60(28):8706-8715

The specification and characterization of mid-spatial-frequency (MSF) ripples for the large-square-aperture optical elements, typically used in high-power laser systems, have received considerable critical attention. It is necessary to resort to a simple and robust way to characterize error surfaces for facilitating prediction of performance degradation and guiding the fabrication and tolerance settings. In this paper, we characterize residual periodic surface undulations called ripple errors for the large square aperture generated from modern subapertures and deterministic optical fabrication techniques through two methods, taking a step from qualitative judgment to quantitative analysis. The cross artifact reduction technology, instead of traditional windowed preprocessing, is introduced into power spectral density to suppress spectrum leakage while retaining the information about the part. An efficient algorithm to generate Legendre moments for two-dimensional Legendre polynomials is proposed to quantify ripple errors. This work contributes to understanding the optical degradation caused by MSF errors and associating the design and performance index with surface parametric description.
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http://dx.doi.org/10.1364/AO.433144DOI Listing
October 2021

Addition-Elimination Mechanism-Activated Nucleotide Transition Sequencing for RNA Dynamics Profiling.

Anal Chem 2021 Oct 6. Epub 2021 Oct 6.

Institute of Analytical Chemistry and Instrument for Life Science, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xianning West Road, Xi'an, Shaanxi 710049, China.

Dynamic information of intracellular transcripts is essential to understand their functional roles. Routine RNA-sequencing (RNA-seq) methods only measure RNA species at a steady state and do not provide RNA dynamic information. Here, we develop addition-elimination mechanism-activated nucleotide transition sequencing (AENT-seq) for transcriptome-wide profiling of RNA dynamics. In AENT-seq, nascent transcripts are metabolically labeled with 4-thiouridine (4sU). The total RNA is treated with NH·HO under aqueous conditions. NH·HO is demonstrated to convert 4sU to 4-hydrazino cytosine (C*) based on an addition-elimination chemistry. C* is regarded as cytosine (C) during the DNA extension process. This 4sU-to-C transition marks nascent transcripts, so it enables sequencing analysis of RNA dynamics. We apply our AENT-seq to investigate transcript dynamic information of several genes involved in cancer progression and metastasis. This method uses a simple chemical reaction in aqueous solutions and will be rapidly disseminated with extensive applications.
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http://dx.doi.org/10.1021/acs.analchem.1c03361DOI Listing
October 2021

Mechanism of subchronic vinyl chloride exposure combined with a high-fat diet on hepatic steatosis.

J Appl Toxicol 2021 Oct 3. Epub 2021 Oct 3.

Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, China.

Vinyl chloride (VC) is a common industrial organic chlorine and environmental pollutant. In recent years, the dietary structure of residents especially Chinese has gradually shifted to western dietary patterns. VC aggravates dietary fatty acid-induced hepatic steatosis, but its mechanism is still unclear. And if the risk factors for steatosis persist, more severe diseases such as fibrosis and cirrhosis will occur. Therefore, we studied the effects and mechanisms of VC (160 and 800 mg/m ) and its metabolite (chloroacetaldehyde, 2.25, 4.5, and 9 μM) on hepatic steatosis of high-fat diet (HFD)-fed mice and palmitic acid (PA, 100 μM) treated HepG2 cells. Liver and serum biochemical indicators and pathological staining of the liver showed that the hepatic steatosis of VC combined with HFD groups was more severe than that of single-exposure groups (HFD group, low-dose VC group, and high-dose VC group). Moreover, VC enhanced HFD-induced oxidative stress (OS) and endoplasmic reticulum stress (ERS) and further upregulated the expression of sterol regulatory element-binding protein 1 (SREBP-1) and FAS. Besides, antioxidants and ERS inhibitors reduced the steatosis of HepG2 cells induced by VC metabolites and PA. These results suggest that VC exposure can enhance the degree of hepatic steatosis in HFD-fed mice. VC combined with HFD led to OS and ERS and upregulated the expression of de novo lipogenesis-related proteins, which may be related to the occurrence of hepatic steatosis. And the increased expression of CYP2E1 induced by VC combined with HFD may be the cause of OS.
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http://dx.doi.org/10.1002/jat.4234DOI Listing
October 2021

Blocking hsa_circ_0074027 suppressed non-small cell lung cancer chemoresistance via the miR-379-5p/IGF1 axis.

Bioengineered 2021 Sep 30. Epub 2021 Sep 30.

Department of respiratory disease, the second people's hospital of Chengdu, No. 10, qingyun south street, Chengdu 610021, Sichuan, China.

Cancer cell chemoresistance is the primary reason behind cancer treatment failure. Previous reports suggest that circular RNA (circRNA) hsa_circ_0074027 (HC0074027) is a crucial modulator of non-small cell lung cancer (NSCLC) disease progression. Herein, we delineated the underlying mechanism of HC0074027-regulated chemoresistance in NSCLC. We employed quantitative real-time polymerase chain reaction (qRT-PCR) or Elisa in the detection of HC0074027, micoRNA-379-5p (miR-379-5p), and insuline-like growth factor I (IGF1) expressions. Cell survival was evaluated via the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Direct associations among HC0074027, miR-379-5p, and IGF1 were examined via dual-luciferase reporter (DLR) and RNA immunoprecipitation (RIP) assays. Lastly, HC0074027 was incorporated into nude mice to examine its biological activity . Based on our analysis, HC0074027 levels strongly correlated with NSCLC chemoresistance to docetaxel (DTX), cisplatin (DDP), and paclitaxel (PTX). Alternately, HC0074027 silencing enhanced chemosensitivity , HC0074027 downregulation suppressed tumor expansion and increased cancer cell sensitivity to chemotherapy. We also revealed that HC0074027 physically interacts with miR-379-5p to exert its biological function . Moreover, IGF1 is a functionally crucial target of miR-379-5p in modulating NSCLC chemoresistance . Finally, we demonstrated that HC0074027 can indirectly modulate IGF1 levels via sequestering miR-379-5p. We demonstrated that HC0074027 promotes NSCLC chemoresistance via sequestering miR-379-5p activity, and modulating IGF1 expression. Our work highlights the significance of HC0074027 in NSCLC chemoresistance and suggests HC0074027 to be an excellent candidate for targeted NSCLC therapy.
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http://dx.doi.org/10.1080/21655979.2021.1987053DOI Listing
September 2021

Graphene Quantum Dots Improved "Caterpillar"-like TiO for Highly Efficient Photocatalytic Hydrogen Production.

Materials (Basel) 2021 Sep 16;14(18). Epub 2021 Sep 16.

State Key Laboratory of Alternate Electrical Power System with Renewable Energy Sources, North China Electric Power University, Beijing 102206, China.

Photocatalytic water splitting for hydrogen production via heterojunction provides a convenient approach to solve the world crises of energy supply. Herein, graphene quantum dots modified TiO hybrids (TiO-GQDs) with a "caterpillar"-like structure exhibit stronger light absorption in the visible region and an enhanced hydrogen production capacity of about 3.5-fold compared to the pristine TiO caterpillar. These results inferred that the addition of GQDs drastically promotes the interfacial electron transfer from GQDs to TiO through C-O-Ti bonds via the bonding between oxygen vacancy sites in TiO and in-plane oxygen functional groups in GQDs. Using a "caterpillar"-like structure are expected to provide a new platform for the development of highly efficient solar-driven water splitting systems based on nanocomposite photocatalyst.
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http://dx.doi.org/10.3390/ma14185354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466931PMC
September 2021

YF/CoF co-doped 1D carbon nanofibers with dual functions of lithium polysulfudes adsorption and efficient catalytic activity as a cathode for high-performance Li-S batteries.

J Colloid Interface Sci 2021 Sep 20;607(Pt 2):922-932. Epub 2021 Sep 20.

State Key Laboratory of Separation Membranes and Membrane Processes/National Center for International Joint Research on Separation Membranes, Tiangong University, Tianjin 300387, China; School of Textile Science and Engineering, Tiangong University, Tianjin 300387, China. Electronic address:

Lithium-sulfur (Li-S) batteries have attracted extensive attention in the field of energy storage due to their high energy density and low cost. However, conundrums such as severe polarization, poor cyclic performance originating from shuttle effect of lithium polysulfides and sluggish sulfur redox kinetics are stumbling blocks for their practical application. Herein, a novel sulfur cathode integrating sulfur and polyvinylpyrrolidone(PVP)-derived N-doped porous carbon nanofibers (PCNFs) with embedded CoF and YF nanoparticles are designed and prepared though the electrostatic blowing technology and carbonization process. The unique flexible PCNFs with embedded polar CoF and YF nanoparticles not only offer enough voids for volume expansion to maintain the structural stability during the electrochemical process, but also promote the physical encapsulation and chemical entrapment of all sulfur species. Moreover, the uniform distribution of YF/CoF nanoparticles also can expose more binding active sites to lithium polysulfide and present more catalytic sites to the greatest extent. Therefore, the assembled cells with the prepared cathode exhibited stable performances with an outstanding initial capacity of 1055.2 mAh g and an extended cycling stability of 0.029% per cycle during the 300 cycles at 0.5C. Even at a high sulfur loading of 2.1 mg cm, The YF/CoF doped-PCNFs exhibited a high discharge specific capacity of 1038 mAh g, and the decay rate is also as low as 0.05% over 1000 cycles. This work shares a convenient and safe strategy for the synthesis of multi-dimension, dual-functional and stable superstructure electrode for advanced Li-S batteries.
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http://dx.doi.org/10.1016/j.jcis.2021.09.079DOI Listing
September 2021

Robust Silica-Bacterial Cellulose Composite Aerogel Fibers for Thermal Insulation Textile.

Gels 2021 Sep 17;7(3). Epub 2021 Sep 17.

School of Chemistry and Chemical Engineering, Inner Mongolia University of Science & Technology, Baotou 014010, China.

Aerogels are nanoporous materials with excellent properties, especially super thermal insulation. However, owing to their serious high brittleness, the macroscopic forms of aerogels are not sufficiently rich for the application in some fields, such as thermal insulation clothing fabric. Recently, freeze spinning and wet spinning have been attempted for the synthesis of aerogel fibers. In this study, robust fibrous silica-bacterial cellulose (BC) composite aerogels with high performance were synthesized in a novel way. Silica sol was diffused into a fiber-like matrix, which was obtained by cutting the BC hydrogel and followed by secondary shaping to form a composite wet gel fiber with a nanoscale interpenetrating network structure. The tensile strength of the resulting aerogel fibers reached up to 5.4 MPa because the quantity of BC nanofibers in the unit volume of the matrix was improved significantly by the secondary shaping process. In addition, the composite aerogel fibers had a high specific area (up to 606.9 m/g), low density (less than 0.164 g/cm), and outstanding hydrophobicity. Most notably, they exhibited excellent thermal insulation performance in high-temperature (210 °C) or low-temperature (-72 °C) environments. Moreover, the thermal stability of CAFs (decomposition temperature was about 330 °C) was higher than that of natural polymer fiber. A novel method was proposed herein to prepare aerogel fibers with excellent performance to meet the requirements of wearable applications.
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http://dx.doi.org/10.3390/gels7030145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482140PMC
September 2021

Adjunctive interleukin-2 for the treatment of drug-susceptible tuberculosis: a randomized control trial in China.

Infection 2021 Sep 25. Epub 2021 Sep 25.

Fuyang No.2 Hospital, Fuyang, China.

Purpose: Evaluation of the efficacy and safety of IL-2 in the treatment of drug-susceptible tuberculosis.

Methods: First, the cases of diagnosed drug-susceptible tuberculosis were randomized into two groups-the control group that received the background regimen of isoniazid, rifampin, pyrazinamide, and ethambutol, and the experimental group that received the background regimen plus IL-2. The efficacy and safety evaluations were performed throughout the therapy process as well as 12 months after the treatment completion.

Results: A total of 1151 patients underwent the randomization, among which 539 (96.2%) of the 560 in the experimental group achieved the sputum culture conversion to negative, compared to the 551 (93.2%) of the 591 in the control group, after 2 months of treatment, with significant difference observed between the groups (P = 0.025). Cavity closure after 2 months in the IL-2 (experimental) group was 60/211 (28.4%) compared to 46/248 (18.5%) in the control group, with a significant difference between the groups (P = 0.001). After treatment completion, the proportion of favorable outcomes was 559/560 (99.8%) in the experimental group and 587/591 (99.3%) in the control group, with no significant difference between the groups. Twelve months after treatment completion, relapse occurred in 15/560 (2.6%) in the IL-2 group and 19/591 (3.2%) in the control group, with no significant difference.

Conclusion: IL-2 may enhance culture conversion and the cavity closure rate in the early treatment phase, although the enhancement may not be significant after treatment completion.
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http://dx.doi.org/10.1007/s15010-021-01698-3DOI Listing
September 2021

Hyperbaric oxygen treatment on keloid tumor immune gene expression.

Chin Med J (Engl) 2021 Sep 13;134(18):2205-2213. Epub 2021 Sep 13.

Department of Plastic Surgery, Peking Union Medical College Hospital, Beijing 100730, China.

Background: Hyperbaric oxygen treatment (HBOT) has been demonstrated to influence the keloid recurrence rate after surgery and to relieve keloid symptoms and other pathological processes in keloids. To explore the mechanism of the effect of HBOT on keloids, tumor immune gene expression and immune cell infiltration were studied in this work.

Methods: From February 2021 to April 2021, HBOT was carried out on keloid patients four times before surgery. Keloid tissue samples were collected and divided into an HBOT group (keloid with HBOT before surgery [HK] group, n = 6) and a non-HBOT group (K group, n = 6). Tumor gene expression was analyzed with an Oncomine Immune Response Research Assay kit. Data were mined with R package. The differentially expressed genes between the groups were compared. Hub genes between the groups were determined and verified with Quantitative Real-time PCR. Immune cell infiltration was analyzed based on CIBERSORT deconvolution algorithm analysis of gene expression and verified with immunohistochemistry (IHC).

Results: Inflammatory cell infiltration was reduced in the HK group. There were 178 upregulated genes and 217 downregulated genes. Ten hub genes were identified, including Integrin Subunit Alpha M (ITGAM), interleukin (IL)-4, IL-6, IL-2, Protein Tyrosine Phosphatase Receptor Type C (PTPRC), CD86, transforming growth factor (TGF), CD80, CTLA4, and IL-10. CD80, ITGAM, IL-4, and PTPRC with significantly downregulated expression were identified. IL-10 and IL-2 were upregulated in the HK group but without a significant difference. Infiltration differences of CD8 lymphocyte T cells, CD4 lymphocyte T-activated memory cells, and dendritic resting cells were identified with gene CIBERSORT deconvolution algorithm analysis. Infiltration levels of CD4 lymphocyte T cell in the HK group were significantly higher than those of the K group in IHC verification.

Conclusion: HBOT affected tumor gene expression and immune cell infiltration in keloids. CD4 lymphocyte T cell, especially activated memory CD4+T, might be the key regulatory immune cell, and its related gene expression needs further study.
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http://dx.doi.org/10.1097/CM9.0000000000001780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478393PMC
September 2021

Significant but Spatiotemporal-Heterogeneous Health Risks Caused by Airborne Exposure to Multiple Toxic Trace Elements in China.

Environ Sci Technol 2021 10 19;55(19):12818-12830. Epub 2021 Sep 19.

School of Environment, Tsinghua University, Beijing 100084, China.

Airborne trace elements (TEs) pose a notable threat to human health due to their toxicity and carcinogenicity, whereas their exposures and associated health risks in China remain unclear. Here, we present the first nationwide assessment of spatiotemporal exposure to 11 TEs in China by coupling a bottom-up emission inventory with a modified CMAQ model capable of TE simulation. Associated health risks of 11 TEs are then evaluated using a set of risk assessment models. Our results show that the CMAQ model could reasonably reproduce the spatiotemporal variations of 11 TEs in China compared to observations. We find significant but spatiotemporal-heterogeneous cancer risks associated with high-level exposure of TEs in China. Gridded cell concentrations of hexavalent chromium, arsenic, and nickel in eastern and central China usually exceed China's air quality standard limits, resulting in significant cancer risks that affected over 85% of the entire population in China in 2015. National annual mean population-weighted concentrations of 11 TEs decrease by 9.8-35.6% from 2012 to 2015, largely attributed to emission reduction from coal combustion. Our study provides critical insights for policymakers to implement stricter measures to alleviate health burdens and benefit relevant epidemiological research on airborne TEs.
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http://dx.doi.org/10.1021/acs.est.1c01775DOI Listing
October 2021

Extrusion of chromatin loops by a composite loop extrusion factor.

Phys Rev E 2021 Aug;104(2-1):024414

Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, Connecticut 06511, USA.

Chromatin loop extrusion by structural maintenance of chromosome (SMC) complexes is thought to underlie intermediate-scale chromatin organization inside cells. Motivated by a number of experiments suggesting that nucleosomes may block loop extrusion by SMCs, such as cohesin and condensin complexes, we introduce and characterize theoretically a composite loop extrusion factor (composite LEF) model. In addition to an SMC complex that creates a chromatin loop by encircling two threads of DNA, this model includes a remodeling complex that relocates or removes nucleosomes as it progresses along the chromatin, and nucleosomes that block SMC translocation along the DNA. Loop extrusion is enabled by SMC motion along nucleosome-free DNA, created in the wake of the remodeling complex, while nucleosome rebinding behind the SMC acts as a ratchet, holding the SMC close to the remodeling complex. We show that, for a wide range of parameter values, this collection of factors constitutes a composite LEF that extrudes loops with a velocity, comparable to the velocity of remodeling complex translocation on chromatin in the absence of SMC, and much faster than loop extrusion by an isolated SMC that is blocked by nucleosomes.
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http://dx.doi.org/10.1103/PhysRevE.104.024414DOI Listing
August 2021

Optimization of photocatalytic degradation conditions and toxicity assessment of norfloxacin under visible light by new lamellar structure magnetic ZnO/g-CN.

Ecotoxicol Environ Saf 2021 Dec 6;225:112742. Epub 2021 Sep 6.

Department of Building, Civil and Environmental Engineering, Faculty of Engineering & Computer Sciences, Concordia University, Montreal, Quebec H3G1M8, Canada.

Degradation of norfloxacin (NFX) by zinc oxide (ZnO)/g-CN, a magnetic sheet ZnO with g-CN on its surface was studied. Through a new preparation system method, hydrothermal reaction provides a solid-layered magnetic ZnO material basis, and the simple thermal condensation method was used to transform the urea into g-CN on the magnetic sheet ZnO in a uniform and orderly manner to increase the stability and photocatalytic performance of the material. Compared with previous studies, the pore volume and photocatalytic performance of the material are improved, and became more stable. By studying the degradation effect of basic and photocatalytic materials prepared in different proportions, the kinetic constant of ZGF is 0.01446 (min). The response surface methodology (RSM) was used to study the optimization and effect of solution pH (4-12), photocatalyst concentration (0.2-1.8 g/L), and NFX concentration (3-15 mg/L) on the degradation rate of NFX during photocatalytic degradation. The R value of the RSM model was 0.9656. The NFX removal rate is higher than 90% when the amount of catalyst is 1.43 g/L, the solution pH is 7.12, and the NFX concentration is less than 8.61 mg/L. After 5 cycles, the degradation rate of magnetic materials decreased to 92.8% of the first time. The capture experiment showed that the photocatalytic machine Toxicities was mainly hole action. The TOC removal rate within 2 h was 30%, a special intermediate toxicity analysis method was adopted according to the characteristics of NFX's inhibitory effect on Escherichia coli community. The toxicity of degraded NFX solution disappeared, and the possibility of non-toxic harm of by-products was verified. LC-Q-TOF method was used to detect and analyze various intermediate products converted from NFX after photocatalytic degradation, and the photocatalytic degradation pathway of NFX was proposed.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112742DOI Listing
December 2021

Defining therapeutic targets for renal fibrosis: Exploiting the biology of pathogenesis.

Biomed Pharmacother 2021 Nov 3;143:112115. Epub 2021 Sep 3.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address:

Renal fibrosis is a failed wound-healing process of the kidney tissue after chronic, sustained injury, which is a common pathway and pathological marker of virtually every type of chronic kidney disease (CKD), regardless of cause. However, there is a lack of effective treatment specifically targeting against renal fibrosis per se to date. The main pathological feature of renal fibrosis is the massive activation and proliferation of renal fibroblasts and the excessive synthesis and secretion of extracellular matrix (ECM) deposited in the renal interstitium, leading to structural damage, impairment of renal function, and eventually end-stage renal disease. In this review, we summarize recent advancements regarding the participation and interaction of many types of kidney residents and infiltrated cells during renal fibrosis, attempt to comprehensively discuss the mechanism of renal fibrosis from the cellular level and conclude by highlighting novel therapeutic targets and approaches for development of new treatments for patients with renal fibrosis.
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http://dx.doi.org/10.1016/j.biopha.2021.112115DOI Listing
November 2021

Autophagic degradation of CCN2 (cellular communication network factor 2) causes cardiotoxicity of sunitinib.

Autophagy 2021 Aug 25:1-22. Epub 2021 Aug 25.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China.

Excessive macroautophagy/autophagy is one of the causes of cardiomyocyte death induced by cardiovascular diseases or cancer therapy, yet the underlying mechanism remains unknown. We and other groups previously reported that autophagy might contribute to cardiomyocyte death caused by sunitinib, a tumor angiogenesis inhibitor that is widely used in clinic, which may help to understand the mechanism of autophagy-induced cardiomyocyte death. Here, we found that sunitinib-induced autophagy leads to apoptosis of cardiomyocyte and cardiac dysfunction as the cardiomyocyte-specific heterozygous mice are resistant to sunitinib. Sunitinib-induced maladaptive autophagy selectively degrades the cardiomyocyte survival mediator CCN2 (cellular communication network factor 2) through the TOLLIP (toll interacting protein)-mediated endosome-related pathway and cardiomyocyte-specific knockdown of through adeno-associated virus serotype 9 (AAV9) mimics sunitinib-induced cardiac dysfunction , suggesting that the autophagic degradation of CCN2 is one of the causes of sunitinib-induced cardiotoxicity and death of cardiomyocytes. Remarkably, deletion of (high mobility group box 1) inhibited sunitinib-induced cardiomyocyte autophagy and apoptosis, and the HMGB1-specific inhibitor glycyrrhizic acid (GA) significantly mitigated sunitinib-induced autophagy, cardiomyocyte death and cardiotoxicity. Our study reveals a novel target protein of autophagic degradation in the regulation of cardiomyocyte death and highlights the pharmacological inhibitor of HMGB1 as an attractive approach for improving the safety of sunitinib-based cancer therapy.
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http://dx.doi.org/10.1080/15548627.2021.1965712DOI Listing
August 2021

Chloroplast Phylogenomic Analyses Resolve Multiple Origins of the Species (Poaceae: Triticeae) Independent Polyploidization Events.

Front Plant Sci 2021 6;12:682040. Epub 2021 Aug 6.

Triticeae Research Institute, Sichuan Agricultural University, Chengdu, China.

is a group of allohexaploid species that arose from two hybridization events followed by genome doubling of three ancestral diploid species with different genomes St, Y, and P in the Triticeae. Estimating the phylogenetic relationship in resolution of the maternal lineages has been difficult, owing to the extremely low rate of sequence divergence. Here, phylogenetic reconstructions based on the plastome sequences were used to explore the role of maternal progenitors in the establishment of polyploid species. The plastome sequences of 11 species were analyzed together with 12 tetraploid species (PP, StP, and StY) and 33 diploid taxa representing 20 basic genomes in the Triticeae. Phylogenomic analysis and genetic divergence patterns suggested that (1) is closely related to , , , , , and ; (2) both the StY genome tetraploids and the PP genome tetraploids served as the maternal donors during the speciation of species; (3) the different species derived their StY genome from different species. Multiple origins of species independent polyploidization events have occurred in the genus , resulting in a maternal haplotype polymorphism. This helps explain the rich diversity and wide adaptation of polyploid species in the genus .
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http://dx.doi.org/10.3389/fpls.2021.682040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377392PMC
August 2021

Atmospheric Vanadium Emission Inventory from Both Anthropogenic and Natural Sources in China.

Environ Sci Technol 2021 09 20;55(17):11568-11578. Epub 2021 Aug 20.

State Key Joint Laboratory of Environmental Simulation & Pollution Control, School of Environment, Beijing Normal University, Beijing 100875, China.

Vanadium is a strategically important metal in the world, although sustained exposure under high vanadium levels may lead to notable adverse impact on health. Here, we leverage a bottom-up approach to quantitatively evaluate vanadium emissions from both anthropogenic and natural sources during 1949-2017 in China for the first time. The results show that vanadium emissions increased by 86% from 1949 to 2005 to a historical peak value and then gradually decreased to 12.9 kt in 2017. With the effective implementation of air pollution control measures, vanadium emissions from anthropogenic sources decreased sharply after 2011. During 2011-2017, about half of vanadium emissions came from coal and oil combustion. In addition, industrial processes and natural sources also cannot be ignored, with the total contributions of more than 24%. The high levels of vanadium emissions were mainly distributed throughout the North China Plain and the eastern and coastal regions, especially in several urban agglomerations. Furthermore, the comprehensive evaluation by incorporating contrastive analysis, Monte Carlo approach, and GEOS-Chem simulation shows that vanadium emissions estimated in this study were reasonable and acceptable. The findings of our study provide not only a scientific foundation for investigating the health effects of vanadium but also useful information for formulating mitigation strategies.
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http://dx.doi.org/10.1021/acs.est.1c04766DOI Listing
September 2021

Sleep problems in children with autism spectrum disorder: a multicenter survey.

BMC Psychiatry 2021 08 16;21(1):406. Epub 2021 Aug 16.

Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Childhood Nutrition and Health, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.

Background: High prevalence of sleep problems have been reported in children with Autism Spectrum Disorder (ASD). This study aims to investigate the sleep conditions of ASD children in China, and explore the relationship between the common sleep problems and core symptoms and developmental levels.

Methods: Using a cross-sectional design, we included 2 to 7-year-old children from 13 cities in China: 1310 with ASD and 1158 with typically-developing (TD) children. The neurodevelopmental level was evaluated with the revised Children Neuropsychological and Behavior Scale (CNBS-R2016). ASD were diagnosed with DSM-5 and Child Autism Rating Scale (CARS). the Social Responsiveness Scale (SRS), the Autism Behavior Checklist (ABC) and the communication warning behavior sub-scale in CNBS-R2016 valued autism behaviors. The children' s sleep habits questionnaire (CSHQ) assessed sleep conditions.

Results: The prevalence of sleep disorders in ASD children was significantly higher than that in TD (67.4% vs. 51%, p < 0.01), and among them the four dimensions with the highest prevalence of sleep problems were bedtime resistance (25.6%), sleep anxiety (22.7%), sleep onset delay (17.9%) and daytime sleepiness (14.7%). ASD children with sleep onset delay or sleep anxiety had higher ABC, SRS scores and higher scores on communication warning behavior with sleep anxiety, with daytime sleepiness had higher ABC, SRS and CARS scores, and with bedtime resistance had higher SRS total scores. Differences in the neurodevelopmental level were not significant.

Conclusion: Children with ASD have a higher prevalence of sleep problems. Bedtime resistance, anxiety, sleep onset delay and daytime sleepiness may be related to the core symptoms, but not be related to the developmental level in ASD children. In the clinic, sleep assessment should be included in the routine of ASD visits, and during the intervention, sleep hygiene education is as important as the treatment of biological factors.

Trial Registration: The study was approved by the ethics committee of the Children's Hospital of Chongqing Medical University, Approval Number: (2018) IRB (STUDY) NO. 121, and registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2000031194 ).
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http://dx.doi.org/10.1186/s12888-021-03405-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365936PMC
August 2021

Simultaneous Detection of Ebola Virus and Pathogens Associated With Hemorrhagic Fever by an Oligonucleotide Microarray.

Front Microbiol 2021 30;12:713372. Epub 2021 Jul 30.

Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China.

Ebola virus infection causes severe hemorrhagic fever, and its mortality rates varied from 25 to 90% in the previous outbreaks. The highly infectious and lethal nature of this virus highlights the need for reliable and sensitive diagnostic methods to distinguish it from other diseases present with similar clinical symptoms. Based on multiplex polymerase chain reaction (PCR) and oligonucleotide microarray technology, a cost-effective, multipathogen and high-throughput method was developed for simultaneous detection of Ebola virus and other pathogens associated with hemorrhagic fever, including Marburg virus, Lassa fever virus, Junin virus, Machupo virus, Rift Valley fever virus, Crimean-Congo hemorrhagic fever virus, malaria parasite, hantavirus, severe fever with thrombocytopenia syndrome virus, dengue virus, yellow fever virus, Chikungunya virus, influenza A virus, and influenza B virus. This assay had an excellent specificity for target pathogens, without overlap signal between the probes. The limit of detection was approximately 10 pathogen copies/μl. A total of 60 positive nucleic acid samples for different pathogens were detected, a concordance of 100% was observed between microarray assay and real-time PCR analysis. Consequently, the described oligonucleotide microarray may be specific and sensitive assay for diagnosis and surveillance of infections caused by Ebola virus and other species of hemorrhagic fever pathogens.
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http://dx.doi.org/10.3389/fmicb.2021.713372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363200PMC
July 2021

EDIL3 deficiency ameliorates adverse cardiac remodeling by neutrophil extracellular traps (NET)-mediated macrophage polarization.

Cardiovasc Res 2021 Aug 10. Epub 2021 Aug 10.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China.

Aims: After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodeling after MI.

Methods And Results: Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3-/- mice showed improvement of post-MI adverse remodeling, as they exhibited lower mortality, better cardiac function, shorter scar length and smaller LV cavity. Accordingly, infarcted hearts of Edil3-/- mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin (α-SMA) myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk-MHC-IIlo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 (CXCR2) antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3-/- mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3-/- mice, contributed to Mertk-MHC-IIlo-int polarization via toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodeling, thus removed the differences of cardiac function between WT and Edil3-/- mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodeling during MI.

Conclusion: We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI.

Translational Perspective: We established EDIL3 as a critical regulator of neutrophil recruitment and macrophage polarization during post-MI cardiac remodeling. EDIL3 may be a candidate prognostic biomarker and drug target for cardiovascular diseases. The novel pathways and mechanisms revealed in this study has renewed our understanding of the role of leukocyte adhesion inhibitors in cardiovascular disease. Meanwhile, our study reaffirmed the indispensable role of inflammation in the healing process, thereby prompting the reevaluation of post-MI anti-inflammatory treatments.
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http://dx.doi.org/10.1093/cvr/cvab269DOI Listing
August 2021

Metabolic Syndrome and Psoriasis: Mechanisms and Future Directions.

Front Immunol 2021 23;12:711060. Epub 2021 Jul 23.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.

Psoriasis is an immune-mediated systemic disease with associated comorbidities, including metabolic syndrome (MetS) which contributes substantially to premature mortality in patients with psoriasis. However, the pathological mechanisms underlying this comorbidity are unclear. Studies have shown that the pathological parameters of psoriasis mediate the development of MetS. We reviewed the potential mechanisms which mediate the association between psoriasis and MetS, including endoplasmic reticulum stress, pro-inflammatory cytokine releases, excess production of reactive oxygen species, alterations in adipocytokine levels and gut microbiota dysbiosis. Here, we highlight important research questions regarding this association and offer insights into MetS research and treatment.
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http://dx.doi.org/10.3389/fimmu.2021.711060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343100PMC
July 2021

Incremental peritoneal dialysis in incident end-stage kidney disease patients.

Perit Dial Int 2021 Aug 9:8968608211036796. Epub 2021 Aug 9.

Division of Nephrology, University Health Network, Toronto, Ontario, Canada.

Background: This retrospective cohort study investigated the characteristics and outcomes of the end-stage kidney disease (ESKD) patients treated with incremental peritoneal dialysis (PD) at a large academic centre.

Methods: ESKD patients initiating PD with a dialysate volume ≤6 L/day were analysed.

Results: One hundred and seventy-five patients were included and were followed up for 352.6 patient-years. The baseline residual kidney function (RKF) was 8.3 ± 3.4 mL/min/1.73 m. The unadjusted 1- to 5-year patient survival rate was 89.6%, 80.4%, 65.4%, 62.7% and 48.8%, respectively, and the corresponding time on PD therapy rate was 95.1%, 89.1%, 89.1%, 82.4% and 77.6%. Greater initial PD dose (hazard ratio = 1.608, 95% confidence interval 1.089-2.375) was associated with death after adjusting for age, Charlson comorbidity index (CCI), haemodialysis prior to PD, assisted PD and baseline RKF, likely as a result of residual confounding. There was no association with PD discontinuation. The average peritonitis rate and hospitalisation rate were 0.122 and 0.645 episodes per patient-year, respectively. The dialysate volume increased from 4.5 (4.3-5.7) L/day to 8.0 (6.0-9.8) L/day at 5 years. Fifty-seven (32.6%) patients graduated to full-dose PD at a median time of 10.3 (6.2, 15.7) months. Male sex, greater body mass index and lower baseline serum albumin were risk factors for increasing PD dose to over 6 L/day within 1 year.

Conclusions: Incremental PD is a safe approach to initiate dialysis, and it offers satisfactory outcomes. Close monitoring, comprehensive evaluation of clinical responses and prompt adjustment of the prescription as needed play a crucial role in this patient-centred treatment.
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http://dx.doi.org/10.1177/08968608211036796DOI Listing
August 2021

[Risk Control of UPS Power Supply for Medical Equipment].

Zhongguo Yi Liao Qi Xie Za Zhi 2021 Jul;45(4):459-462

Medical Equipment Department, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 201204.

Objective: Putting forward that the risk of using UPS for medical matching is easy to be ignored by managers.

Methods: The method of UPS inspection was designed and used in hospital.

Results: The qualified rate of UPS for equipment matching was 66.7% and the problems were corrected. Based on the Internet of Things technology, the UPS monitoring technology was prospected.

Conclusions: It is effective to control the risk of UPS by recognizing the risk of using UPS and specifying the strategy.
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http://dx.doi.org/10.3969/j.issn.1671-7104.2021.04.024DOI Listing
July 2021

Common and Distinct Alterations of Cognitive Function and Brain Structure in Schizophrenia and Major Depressive Disorder: A Pilot Study.

Front Psychiatry 2021 20;12:705998. Epub 2021 Jul 20.

Institute of Mental Health, The Sixth Hospital, Peking University, Beijing, China.

Numerous studies indicate that schizophrenia (SCZ) and major depressive disorder (MDD) share pathophysiological characteristics. Investigating the neurobiological features of psychiatric-affective disorders may facilitate the diagnosis of psychiatric disorders. Hence, we aimed to explore whether patients with SCZ and patients with MDD had the similar or distinct cognitive impairments and GMV alterations to further understand their underlying pathophysiological mechanisms. We recruited a total of 52 MDD patients, 64 SCZ patients, and 65 healthy controls (HCs). The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery was used to assess cognitive functions. In addition, voxel-based morphometry (VBM) analysis was used to evaluate the gray matter volume (GMV) by using MRI scanning. One-way ANOVA and tests were used to find the differences among the MDD, SCZ, and HCs. Finally, we explored the correlation between structural alterations and cognitive functions. Compared with that of HCs, processing speed was impaired in both patients with SCZ and patients with MDD ( = 49.505, < 0.001). SCZ patients displayed impaired cognitive performance in all dimensions of cognitive functions compared with HCs ( < 0.001, except social cognition, = 0.043, Bonferroni corrected). Whole-brain VBM analysis showed that both SCZ and MDD groups had reductions of GMV in the medial superior frontal cortex (cluster-level FWE < 0.05). Patients with SCZ exhibited declining GMV in the anterior cingulate cortex and right middle frontal cortex (MFC) compared with HCs and MDD patients (cluster-level FWE < 0.05). The mean values of GMV in the right MFC had a positive correlation with the attention/vigilance function in patients with MDD ( = 0.014, partial. = 0.349, without Bonferroni correction). In total, our study found that MDD and SCZ groups had common cognitive impairments and brain structural alterations, but the SCZ group exhibited more severe impairment than the MDD group in both fields. The above findings may provide a potential support for recognizing the convergent and divergent brain neural pathophysiological mechanisms between MDD and SCZ.
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http://dx.doi.org/10.3389/fpsyt.2021.705998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329352PMC
July 2021
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