Publications by authors named "Yang Zhou"

2,071 Publications

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Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy.

Nat Commun 2021 06 10;12(1):3530. Epub 2021 Jun 10.

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA.

Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.
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http://dx.doi.org/10.1038/s41467-021-23164-2DOI Listing
June 2021

CDC42EP3 is a key promoter involved in the development and progression of gastric cancer.

Carcinogenesis 2021 Jun 10. Epub 2021 Jun 10.

Department of gastrointestinal surgery, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China.

Gastric cancer (GC) is one of the most prevalent cancers and severely endangers human health. Due to the low rate of diagnosis, most patients with gastric cancer are diagnosed as advanced. CDC42 effector protein 3 (CDC42EP3) has been revealed to be involved in several types of human cancers' development and progression. However, the function of CDC42EP3 in GC is not yet clear. CDC42EP3 expression was detected by immunohistochemistry (IHC), qRT-PCR and Western blot assay in tumor tissues and cell lines of GC. CDC42EP3 knockdown cell models were constructed by lentivirus transfection. Cell proliferation was evaluated by the MTT assay. The wound-healing assay and the transwell assay were utilized to assess the cell migration. Also, the cell apoptosis and the cell cycle were evaluated by flow cytometry. Moreover, the mechanism was investigated by Human Apoptosis Antibody Array. The in vivo experiments were conducted to verify the effects of CDC42EP3 knockdown on the tumor growth of GC. The expression level of CDC42EP3 was up-regulated in tumor tissues. High CDC42EP3 expression was positively related to more advanced tumor grade. CDC42EP3 knockdown inhibited cell proliferation and migration, promoted cell apoptosis and suppressed the tumor growth. On the other hand, it was also found that the silencing of CDC42EP3 inhibited HSP27 and IGF-1sR expression as well as promoted Caspase3, p53, TNF-α, TNF-β, TRAILR-1 and TRAILR-2 expression. CDC42EP3 was revealed to work as a tumor promoter in the development and progression of GC, which could be a promising therapeutic target for the therapy of GC.
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http://dx.doi.org/10.1093/carcin/bgab048DOI Listing
June 2021

Excess Ion-Induced Efficiency Roll-Off in High-Efficiency Perovskite Light-Emitting Diodes.

ACS Appl Mater Interfaces 2021 Jun 10. Epub 2021 Jun 10.

Department of Electronic Engineering, The Chinese University of Hong Kong, New Territories, Hong Kong.

Applying extensively excess ammonium halides in forming perovskites is a widely used approach to achieve high-performance perovskite light-emitting diodes (PeLEDs). However, most of these PeLEDs suffer from severe external quantum efficiency (EQE) roll-off at high current densities, thereby restricting the realization of high-brightness PeLEDs and laser diodes. In this work, we explore the underlying mechanism of the EQE roll-off in high-efficiency formamidinium lead iodide (FAPbI)-based PeLEDs. By combining voltage-dependent electrical stress measurements and ex situ ion distribution analysis of PeLEDs, we found that the electric field-driven migration and local segregation of excess iodide ions, originated from nonstoichiometric precursors, trigger the EQE roll-off via promoting imbalanced charge injection. Based on this discovery, we introduced a simple wash-off treatment with chloroform to remove the excess iodides from the perovskite surface and demonstrated that the treatment is highly effective in suppressing the roll-off behavior. By combining the treatment and the use of an ultrathin poly(methyl methacrylate) (PMMA) interlayer, we achieved a high-brightness PeLED with an EQE of 19.6%, a critical current density of 1550 mA cm, and a radiance of 875 W sr m. The study reveals the double-edge sword effect of precursor nonstoichiometry and highlights the importance of managing excess ions in perovskite films.
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http://dx.doi.org/10.1021/acsami.1c05458DOI Listing
June 2021

Analysis of the epidemiological and clinical characteristics of 65 patients with scrub typhus on the east coast of China.

Ann Palliat Med 2021 May;10(5):5694-5705

Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China.

Background: The present study set out to investigate the epidemiological and clinical characteristics of 65 patients with tsutsugamushi disease.

Methods: The clinical data of 65 patients with tsutsugamushi disease, who were admitted to the Affiliated Hospital of Nantong University were retrospectively analyzed. The clinical symptoms, laboratory examination results, clinical treatment plans, treatments, and outcomes of the patients were analyzed.

Results: The 65 patients with tsutsugamushi disease, included 40 males (61.54%) and 25 females (38.46%). The patients were aged from 1 year and 7 months to 88 years old, and the peak age was 60-70 years old. Geographically, the patients were concentrated in Rugao and Tongzhou District. Infections were most common between October and December (categorized as "autumn type"), and peaked in November. Farmers had the highest infection rate of any occupation (66%). All patients had the symptom of fever, with the body temperature of 60 (92.31%) patients exceeding 38.5 °C, while 58 (89%) and 51 (78%) patients had characteristic eschar and skin rash, respectively. There were 56 (86.15%) patients with varying degrees of liver damage, 8 (12.31%) cases of elevated D-dimer, 3 (4.62%) cases of myocardial injury, 38 (58.46%) cases of superficial lymph node enlargement, 8 (12.31%) cases of splenomegaly, and 2 cases (3.08%) of bulbar conjunctival congestion. Of the 65 patients enrolled, the overall misdiagnosis rate of first medical contact was 64.62.

Conclusions: Tsutsugamushi disease, infection has obvious seasonality and a susceptible population, especially among farmers and the elderly.
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http://dx.doi.org/10.21037/apm-21-1100DOI Listing
May 2021

Mechanistic Insights into Rapid Generation of Nitroxyl from a Photocaged -Hydroxysulfonamide Incorporating the (6-Hydroxynaphthalen-2-yl)methyl Chromophore.

J Org Chem 2021 Jun 9. Epub 2021 Jun 9.

School of Science, Auckland University of Technology, Private Bag 92006, Auckland 1142, New Zealand.

HNO is a highly reactive molecule that shows promise in treating heart failure. Molecules that rapidly release HNO with precise spatial and temporal control are needed to investigate the biology of this signaling molecule. (Hydroxynaphthalen-2-yl)methyl-photocaged -hydroxysulfonamides are a new class of photoactive HNO generators. Recently, it was shown that a (6-hydroxynaphthalen-2-yl)methyl (6,2-HNM)-photocaged derivative of -hydroxysulfonamide incorporating the trifluoromethanesulfonamidoxy group () quantitatively generates HNO. Mechanistic studies have now been carried out on this system and reveal that the ground state protonation state plays a key role in whether concerted heterolytic C-O/N-S bond cleavage to release HNO occurs versus undesired O-N bond cleavage. -Deprotonation of can be achieved by adding an aqueous buffer or a carboxylate salt to an aprotic solvent. Evidence is presented for C-O/N-S bond heterolysis occurring directly from the singlet excited state of the -deprotonated parent molecule on the picosecond time scale, using femtosecond time-resolved transient absorption spectroscopy, to give a carbocation and NO. This is consistent with the observation of significant fluorescence quenching when HNO is generated. The carbocation intermediate reacts rapidly with nucleophiles including water, MeOH, or even (H)NO in the absence of a molecule that reacts rapidly with (H)NO to give an oxime.
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http://dx.doi.org/10.1021/acs.joc.1c00457DOI Listing
June 2021

The Protective Effects of Parathyroid Hormone (1-34) on Cartilage and Subchondral Bone Through Down-Regulating JAK2/STAT3 and WNT5A/ROR2 in a Collagenase-Induced Osteoarthritis Mouse Model.

Orthop Surg 2021 Jun 8. Epub 2021 Jun 8.

Department of Orthopedic Surgery, Hebei Medical University, Shijiazhuang, China.

Objective: To assess the effects of PTH (1-34) on bone and cartilage metabolism in a collagenase-induced mouse model of osteoarthritis (OA) and examine whether PTH (1-34) affects the expression of JAK2/STAT3 and WNT5A/ROR2 in this process.

Methods: Eighteen 12-week-old male C57Bl/6 mice were randomly assigned into three groups as follows: sham group (Group A), the collagenase + saline injection group (Group B), and the collagenase + PTH (1-34) treatment group (Group C). Collagenase was injected (intra-articular) into the knee joint of Group B and C. The PTH (1-34)-treatment was started at 6 weeks after the operation and lasted for 6 weeks. Cartilage pathology was evaluated by gross visual, histological, and immunohistochemical assessments. Subchondral bone was evaluated by microcomputed tomography (micro-CT) and immunohistochemical analyses.

Results: The OARSI macroscopic and microscopic scores of Group B were higher than those of Group A (P = 0.026; P = 0.002, respectively). Group C showed statistically significant differences in macroscopic and microscopic scores from Group B (P = 0.041; P = 0.008, respectively). The results showed that the Col-II and AGG expression levels in the cartilage tissue were significantly lower in Group B than Group A (P < 0.001; P = 0.008, respectively). The Col-II and AGG expression levels were significantly higher in Group C than Group B (P = 0.009; P = 0.014, respectively). MMP-13, ADAMTS-4, Caspase-3, P53, and Bax expression levels were significantly higher in Group B than the Group A (P < 0.001; P < 0.001; P = 0.04; P < 0.001; P = 0.005, respectively); however, the cartilage tissue in Group C showed significantly less ADAMTS-4, MMP-13, Caspase-3, P53, and Bax expression than Group B (P < 0.001, P < 0.001, P = 0.044; P = 0.002; P = 0.005, respectively). Over-expressed JAK2/STAT3 and WNT5A/ROR2 were observed in both cartilage and subchondral bone in this model; however, these changes were prevented by PTH (1-34) treatment. These parameters (bone mineral density, bone volume ratio, trabecular bone pattern factor, and structure model index) of micro-CT indicated subchondral bone loss and architecture changes in Group B, but improvements in these parameters in Group C.

Conclusions: PTH (1-34) exhibits protective effects on both cartilage and subchondral bone in a collagenase-induced OA mouse model, and it may be involved in down-regulating the expression of JAK2/STAT3 and WNT5A/ROR2.
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http://dx.doi.org/10.1111/os.13019DOI Listing
June 2021

Selective inhibition of PKCβ2 improves Caveolin-3/eNOS signaling and attenuates lipopolysaccharide-induced injury by inhibiting autophagy in H9C2 cardiomyocytes.

J Mol Histol 2021 Jun 8. Epub 2021 Jun 8.

Department of Anaesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.

Lipopolysaccharide (LPS)-induced autophagy is involved in sepsis-associated myocardial injury with increased PKCβ2 activation. We previously found hyperglycemia-induced PKCβ2 activation impaired the expression of caveolin-3 (Cav-3), the dominant isoform to form cardiomyocytes caveolae which modulate eNOS signaling to confer cardioprotection in diabetes. However, little is known about the roles of PKCβ2 in autophagy and Cav-3/eNOS signaling in cardiomyocytes during LPS exposure. We hypothesize LPS-induced PKCβ2 activation promotes autophagy and impairs Cav-3/eNOS signaling in LPS-treated cardiomyocytes. H9C2 cardiomyocytes were treated with LPS (10 µg/mL) in the presence or absence of PKCβ2 inhibitor CGP53353 (CGP, 1 µM) or autophagy inhibitor 3-methyladenine (3-MA, 10 µM). LPS stimulation induced cytotoxicity overtime in H9C2 cardiomyocytes, accompanied with excessive PKCβ2 activation. Selective inhibition of PKCβ2 with CGP significantly reduced LPS-induced cytotoxicity and autophagy (measured by LC-3II, Beclin-1, p62 and autophagic flux). In addition, CGP significantly attenuated LPS-induced oxidative injury, and improved Cav-3 expression and eNOS activation, similar effects were shown by the treatment of autophagy inhibitor 3-MA. LPS-induced myocardial injury is associated with excessive PKCβ2 activation, which contributes to elevated autophagy and impaired Cav-3/eNOS signaling. Selective inhibition of PKCβ2 improves Cav-3/eNOS signaling and attenuates LPS-induced injury through inhibiting autophagy in H9C2 cardiomyocytes.
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http://dx.doi.org/10.1007/s10735-021-09990-0DOI Listing
June 2021

Using the lamina nutrient foramen as the entry point for posterior cervical pedicle screw placement.

Clin Neurol Neurosurg 2021 May 25;207:106711. Epub 2021 May 25.

Medical Innovation Center, the First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China; Institute of Spine and Spinal Cord, Nanchang University, Nanchang 330006, PR China. Electronic address:

Study Design: A prospective study and technique description.

Objective: This study introduced a method for posterior cervical pedicle screw placement by using the bilateral posterior lamina nutrient foramens as the entry point.

Methods: Firstly, 30 dry C3-C7 vertebrae specimens were harvested for measurement. The lamina nutrient foramens were used as the entry points for posterior cervical pedicle screw placement and four linear and two angle parameters were obtained from a computed tomography scan(CT). Then, 60 patients who underwent C3-C7 pedicle screw fixation using this method were included, linear and angle parameters were obtained from a postoperative CT.

Results: The average incidences of lamina nutrient foramen on the C3-C7 specimens were 88.3%, 90.0%, 95.0%, 95.0%, and 96.7%, respectively. The distances from the entry point to the pedicle screw tip (OD), the pedicle transverse angles (α), and the pedicle sagittal angles (β) measure for the entry points from C3-C7 were 28.74 ± 3.45-30.15 ± 2.01 mm, 26.88 ± 6.89° to 32.72 ± 5.91°, and 12.48 ± 9.31° to 19.71 ± 8.45°, respectively, with no significant differences between the left and right sides. In the 60 patients who underwent surgery, the lengths of the pedicle screws (PL) were 28.34 ± 2.25-30.15 ± 2.31 mm, the pedicle transverse angles (α) were 26.89 ± 6.86° to 32.36 ± 5.65°, and the pedicle sagittal angles (β) were 12.49 ± 9.11° to 20.06 ± 8.91°. The new method had a 96.8% (454/469) success rate among these patients, with no screws penetrating the spinal canal or signs of vertebral artery injury.

Conclusion: Entry at the bilateral lamina nutrient foramen represents an alternative posterior cervical pedicle screw placement technique that is feasible and safe.
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http://dx.doi.org/10.1016/j.clineuro.2021.106711DOI Listing
May 2021

Sanguisorba parviflora (Maxim.) Takeda alleviates cyclophosphamide-induced leukopenia by regulating haematopoietic cell-specific protein 1-associated protein X-1 gene expression.

J Clin Pharm Ther 2021 Jun 8. Epub 2021 Jun 8.

School of Pharmacy, Mudanjiang Medical University, Mudanjiang, China.

What Is Known And Objective: We have previously shown that the saponins of Sanguisorba parviflora (Maxim.) Takeda (Sp. T) relieved cyclophosphamide-induced myelosuppression in leukopenic mice. Haematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) participated in the survival of neutrophils through the regulation of mitochondrial function. The aim of the present study was to comprehensively identify the role of HAX-1 in the mechanism of leukopenia alleviation by Sp. T.

Methods: HAX-1 gene and protein expression levels in peripheral blood neutrophils were examined using real-time quantitative reverse transcription-polymerase chain reaction, western blot and immunohistochemical assays. Neutrophil apoptosis was measured using flow cytometry. Mitochondrial function was determined via assessments of the reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm) integrity levels.

Results And Discussion: The HAX-1 gene expression level in the peripheral blood neutrophils was significantly lower in patients with leukopenia than in healthy donors. The saponins of Sp. T induced HAX-1 expression and promoted myeloid progenitor cell (mEB8-ER cell) viability. HAX-1 overexpression reduced the production of ROS and maintained ΔΨm integrity. Cyclophosphamide-induced mitochondrial dysfunction and apoptosis could be abrogated by treatment with Sp. T or metformin.

What Is New And Conclusion: Our data suggest a mechanism through which Sp. T protects against chemotherapy-induced leukopenia by regulating HAX-1 gene expression in a mitochondrial-dependent manner.
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http://dx.doi.org/10.1111/jcpt.13468DOI Listing
June 2021

Amphiphilic alginate-based fluorescent polymer nanoparticles: Fabrication and multifunctional applications.

Int J Biol Macromol 2021 Jun 4. Epub 2021 Jun 4.

Key Laboratory of Advanced Materials of Tropical Island Resources, Ministry of Education, School of Materials and Chemical Engineering, Hainan University, Hainan, Haikou 570228, China. Electronic address:

Alginate has been widely applied in various biological systems due to its great biocompatibility. Endowing it fluorescent imaging would make people to further understand its complex structure, process and mechanism. In this work, amphiphilic alginate conjugated with aggregation-induced emission (AIE) moiety fluorescent polymer was successfully fabricated through the Ugi one-pot condensation. The synthetic polymer particles were fully evaluated by various characterizations including H NMR, FTIR, fluorescent spectroscopies, and transmission electron microscopy (TEM). These amphiphilic alginate particles showed great multicolor fluorescence emission in both solid and solution states. The corresponding biological evaluation results confirmed that the fluorescent biopolymer showed excellent biocompatibility and desirable bioimaging property. Particularly, the leaf stomata were directly visualized using the amphiphilic AIE-active alginate biopolymer. Furthermore, the alginate-based polymer can also be employed as the drug carrier for hydrophobic curcumin. These results indicated that our synthetic AIE-active alginate particles might provide great potential for the further utilization of alginate in the understanding of various relative biological systems.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.05.211DOI Listing
June 2021

The thermal regime modifies the response of aquatic keystone species Daphnia to microplastics: Evidence from population fitness, accumulation, histopathological analysis and candidate gene expression.

Sci Total Environ 2021 Aug 17;783:147154. Epub 2021 Apr 17.

Jiangsu Key Laboratory for Biodiversity and Biotechnology, School of Biological Sciences, Nanjing Normal University, Nanjing 210023, China. Electronic address:

The water bodies are greatly influenced by chemical contamination and global increasing temperature. As an emerging pollutant, microplastics are widely distributed in the freshwater environment, raising concerns regarding their potential toxicity to organisms. Especially for zooplankton filter feeders, many of microplastics are in similar size as their food. Individually, both microplastics and temperature have profound effects on zooplankton populations and their function in ecosystems. However, the strength and direction of their interactive effects are still not clear. Here, we performed a comprehensive biotoxicity assessment providing empirical evidence that the temperature played a key role in shaping the sensitivity of the zooplankter, Daphnia magna, against microplastic toxicity. We found that exposure to microplastics generally caused negative effects on Daphnia individual fitness, such as increased lethality, declined fecundity and reduced population growth rate. This microplastic toxicity was more prominent at 30 °C than at 20 °C, and was rather minor at 15 °C. Moreover, the warming accelerated the ingestion of microplastics, and triggered abnormal ultrastructure of intestinal epithelial cells. In addition, the expression profiling of candidate genes revealed oxidative damage, fecundity impairment and energy retardation by microplastics were amplified with increasing temperature, which may contribute to the enhancement of microplastic toxicity under warming. Given that high temperature fluctuations are becoming more common and difficult to predict, the interactive effects of microplastics and climate warming on Daphnia population dynamics and biomass production may become increasingly aggravated in nature. Collectively, extrapolation for environmental risk assessment studies conducted under different temperature contexts may broaden our knowledge microplastic toxicity on aquatic organism fitness.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147154DOI Listing
August 2021

Inhibition of EZH2 primes the cardiac gene activation via removal of epigenetic repression during human direct cardiac reprogramming.

Stem Cell Res 2021 May 27;53:102365. Epub 2021 Apr 27.

Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35233, USA. Electronic address:

Cardiovascular disease, until now, is still the leading cause of death in the United States. Due to the limited regenerative capacity of adult hearts, the damage caused by heart injury cannot be reversed and eventually progress into heart failure. In need of cardiovascular disease treatment, many therapies aimed at either cell transplantation or cell regeneration have been proposed. Direct reprogramming of somatic cells into induced cardiomyocytes (iCMs) is considered to be a promising strategy for regenerative medicine. The induction of cardiomyocytes from non-myocytes can be achieved efficiently via ectopic expression of reprogramming factors both in vitro and in vivo in the mouse model, however, the generation of human induced cardiomyocyte-like cells (hiCMs) remains challenging. The inefficiency of hiCMs production called for the identification of the additional epigenetic memories in non-myocytes which might be damping the hiCM reprogramming. Here, we conducted an unbiased loss-of-function screening focusing on epigenetic regulators and identified enhancer of zeste homolog 2 (EZH2) as an important epigenetic barrier during hiCM reprogramming. We found that the removal of EZH2 via genetic knockdown or treatment of EZH2 selective degrader significantly increased the hiCM reprogramming efficiency and led to profound activation of cardiac genes and repression of collagen and extracellular matrix genes. Furthermore, EZH2 inhibitors targeting its catalytic activity also promotes hiCM reprogramming, suggesting that EZH2 may restrain cardiac conversion through H3K27me3-mediated gene repression. Indeed, genomic profiling of H3K27me3 revealed a subset of cardiac genes that remain repressed with high levels of H3K27me3 despite of the delivery of the reprogramming factors. Inhibition of EZH2, however, leads to reduced H3K27me3 occupancy and robust activation of these cardiac genes. Taken together, our data suggested that EZH2 inhibition facilitates the activation of cardiac genes in fibroblasts and eases the production of hiCMs.
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http://dx.doi.org/10.1016/j.scr.2021.102365DOI Listing
May 2021

Cell‑cell fusion as an important mechanism of tumor metastasis (Review).

Oncol Rep 2021 Jul 3;46(1). Epub 2021 Jun 3.

Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China.

Cell‑cell fusion is a dynamic biological phenomenon, which plays an important role in various physiological processes, such as tissue regeneration. Similarly, normal cells, particularly bone marrow‑derived cells (BMDCs), may attempt to fuse with cancer cells to rescue them. The rescue may fail, but the fused cells end up gaining the motility traits of BMDCs and become metastatic due to the resulting genomic instability. In fact, cell‑cell fusion was demonstrated to occur in cancer and was revealed to promote tumor metastasis. However, its existence and role may be underestimated, and has not been widely acknowledged. In the present review, the milestones in cell fusion research were highlighted, the evidence for cell‑cell fusion and in cancer was evaluated, and the current understanding of the molecular mechanisms by which cell‑cell fusion occurs was summarized, to emphasize their important role in tumor metastasis. The summary provided in the present review may promote further study into this process and result in novel discoveries of strategies for future treatment of tumor metastasis.
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http://dx.doi.org/10.3892/or.2021.8096DOI Listing
July 2021

Deep transfer learning based on magnetic resonance imaging can improve the diagnosis of lymph node metastasis in patients with rectal cancer.

Quant Imaging Med Surg 2021 Jun;11(6):2477-2485

College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, China.

Background: Lymph node (LN) metastasis is the main prognostic factor for local recurrence and overall survival of patients with rectal cancer. The accurate evaluation of LN status in rectal cancer patients is associated with improved treatment and prognosis. This study aimed to apply deep transfer learning to classify LN status in patients with rectal cancer to improve N staging accuracy.

Methods: The study included 129 patients with 325 rectal cancer screenshots of LN T2-weighted (T2W) images from April 2018 to March 2019. Deep learning was applied through a pre-trained model, Inception-v3, for recognition and detection of LN status. The results were compared to manual identification by experienced radiologists. Two radiologists reviewed images and independently identified their status using various criteria with or without short axial (SA) diameter measurements. The accuracy, positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve (AUC) were calculated.

Results: When the same radiologist performed the analysis, the AUC was not significantly different in the presence or absence of LN diameter measurements (P>0.05). In the deep transfer learning method, the PPV, NPV, sensitivity, and specificity were 95.2%, 95.3%, 95.3%, and 95.2%, respectively, and the AUC and accuracy were 0.994 and 95.7%, respectively. These results were all higher than that achieved with manual diagnosis by the radiologists.

Conclusions: The internal details of LNs should be used as the main criteria for positive diagnosis when using MRI. Deep transfer learning can improve the MRI diagnosis of positive LN metastasis in patients with rectal cancer.
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http://dx.doi.org/10.21037/qims-20-525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107313PMC
June 2021

Sanguisorba parviflora (Maxim) Takeda alleviates cyclophosphamide-induced leukopenia via regulating the hematopoietic cell-specific protein 1-associated protein X-1 gene.

J Clin Pharm Ther 2021 Jun 1. Epub 2021 Jun 1.

School of Pharmacy, Mudanjiang Medical University, Mudanjiang, China.

What Is Known And The Objective: Our previous studies have shown that saponins of Sanguisorba parviflora (Maxim) Takeda (Sp. T) relieved cyclophosphamide-induced myelosuppression in mice with leukopenia. The hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) participated in the survival of neutrophils through the regulation of mitochondrial function. This study aimed to comprehensively identify the role of HAX-1 in Sp. T to alleviate leukopenia.

Methods: HAX-1 expression was examined in the peripheral blood neutrophils using real-time polymerase chain reaction (PCR), Western blot analysis and immunohistochemical staining. Neutrophil apoptosis was measured by flow cytometry. Mitochondrial function was evaluated via reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm) integrity.

Results And Discussion: Our study indicated that the expression of the HAX-1 gene was significantly decreased in the peripheral blood neutrophils of leukopenia patients compared with healthy donors. The saponins of Sp. T induced HAX-1 expression and promoted myeloid progenitor cell (mEB8-ER cell) viability, while overexpression of HAX-1 reduced the production of reactive oxygen species (ROS) and maintained the integrity of the mitochondrial membrane potential. Cyclophosphamide-induced mitochondrial dysfunction and apoptosis could be abrogated by treatment with Sp. T or the addition of metformin.

What Is New And Our Conclusion: Our data support a mechanism where Sp. T protects against chemotherapy-induced leukopenia by regulating HAX-1 gene expression in a mitochondrial-dependent manner.
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http://dx.doi.org/10.1111/jcpt.13450DOI Listing
June 2021

Mechanical Properties and Toxicity Risks of Lead-Zinc Sulfide Tailing-Based Construction Materials.

Materials (Basel) 2021 May 29;14(11). Epub 2021 May 29.

College of Environmental Science and Engineering, Zhongkai University of Agriculture and Engineering, Guangzhou 510408, China.

The leaching residue of the lead-zinc sulfide tailing (LRT) is the only residue generated from the tailing leaching recovery process; it is a typical hazardous material for its high heavy-metal contents and high acidity. Due to the large output of LRT, and because its main components are Ca, Si, and Al, the preparation of building construction materials with LRT was studied. The results showed that when the LRT addition is less than 47%, with the ordinary Portland cement (OPC) and fly ash (FA) added and the curing conditions appropriate, the strength values of the tested specimens meet the M15 Class of the autoclaved lime sand brick standard (GB/T 16753-1997). The carbonization coefficient and drying shrinkage of the specimen were 0.79 and smaller than 0.42, respectively. As the SEM, TG, and XRD analysis have shown, the LRT can chemically react with additives to form stable minerals. The heavy metal contents that were leached out well met the limits in GB5085.3-2007. Based on the high addition of the LRT, the good strength and lower heavy metals were leached out of the prepared test specimen, and the tailing could be reused completely with the leaching recovery and the LRT reuse process. LRT can be used to replace OPC, allowing more sustainable concrete production and improved ecological properties of LRT.
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http://dx.doi.org/10.3390/ma14112940DOI Listing
May 2021

Construction and Characterization of an Multi-Gene Deletion Strain and Evaluation of Its Potential as a Live-Attenuated Vaccine in Grass Carp.

Vaccines (Basel) 2021 May 3;9(5). Epub 2021 May 3.

College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.

is an important pathogen that causes motile septicemia (MAS) in the aquaculture industry. Aerolysin, hemolysin, serine protease and enterotoxins are considered to be the major virulence factors of . In this study, we constructed a five-gene (A, , , and ) deletion mutant strain (named five-gene deletion strain, AHFGDS) to observe the biological characteristics and detect its potential as a live-attenuated vaccine candidate. AHFGDS displayed highly attenuated and showed increased susceptibility to fish blood and skin mucus killing, while the wild-type strain ZYAH72 was highly virulent. In zebrafish (), AHFGDS showed a 240-fold higher 50% lethal dose (LD50) than that of the wild-type strain. Immunization with AHFGDS by intracelomic injection or immersion routes both provided grass carp () significant protection against the challenge of the strain ZYAH72 or J-1 and protected the fish organs from serious injury. Further agglutinating antibody titer test supported that AHFGDS could elicit a host-adaptive immune response. These results suggested the potential of AHFGDS to serve as a live-attenuated vaccine to control infection in aquaculture.
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http://dx.doi.org/10.3390/vaccines9050451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147641PMC
May 2021

Purification, Structural Characterization and Immunomodulatory Effects of Polysaccharides from Lour. on RAW 264.7 Macrophages.

Molecules 2021 May 2;26(9). Epub 2021 May 2.

School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.

Lour. () is a folk medicine that has been used for more than 1300 years. However, study of the polysaccharides of is seriously neglected. The objectives of this study are to explore the structural characteristics of polysaccharides from (AVPs) and their effects on immune cells. In this study, the acidic polysaccharides (AVPG-1 and AVPG-2) were isolated from AVPs and purified via anion exchange and gel filtration chromatography. The structural characteristics of the polysaccharides were characterized by methylation, HPSEC-MALLS-RID, HPLC, FT-IR, SEM, GC-MS and NMR techniques. AVPG-1 with a molecular weight of 514 kDa had the backbone of → 4)-α-d-Glc-(1 → 3,4)-β-d-Glc-(1 → 4)-α-d-Glc-(1 →. AVPG-2 with a higher molecular weight (14800 kDa) comprised a backbone of → 4)-α-d-Glc-(1 → 3,6)-β-d-Gal-(1 → 4)-α-d-Glc-(1 →. RAW 264.7 cells were used to investigate the potential effect of AVPG-1 and AVPG-2 on macrophages, and lipopolysaccharide (LPS) was used as a positive control. The results from bioassays showed that AVPG-2 exhibited stronger immunomodulatory activity than AVPG-1. AVPG-2 significantly induced nitric oxide (NO) production as well as the release of interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α), and upregulated phagocytic capacities of RAW 264.7 cells. Real-time PCR analysis revealed that AVPG-2 was able to turn the polarization of macrophages to the M1 direction. These results suggested that AVPs could be explored as potential immunomodulatory agents of the functional foods or complementary medicine.
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http://dx.doi.org/10.3390/molecules26092672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125432PMC
May 2021

The role of Methanomassiliicoccales in trimethylamine metabolism in the rumen of dairy cows.

Animal 2021 May 28;15(7):100259. Epub 2021 May 28.

Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing 210095, China; National Experimental Teaching Demonstration Center of Animal Science, Nanjing Agricultural University, Nanjing 210095, China.

A considerable amount of trimethylamine (TMA) is likely generated in the rumen; however, its metabolism is still unclear. This study aimed to investigate the role of Methanomassiliicoccales (Mmc) in TMA metabolism in the rumen of dairy cows. Three experiments, two rumen in vitro fermentation trials and one dairy cow in vivo trial, were conducted. Four groups were set in Experiment 1: control, nitroglycerin (NG, a methanogen inhibitor), TMA (7.2 mmol/L), and TMA + NG. The methanogenic activity was completely inhibited in the NG group, and no methane production was observed in the NG and TMA + NG groups. The TMA content hardly reduced in the TMA + NG group (6.9 mmol/L) following a 2 d-incubation; in contrast, it demonstrated a significant reduction by 47.2% in the TMA group. Methanogen 16S rRNA gene sequencing and real-time PCR showed that the relative abundance of Mmc increased in the TMA group (P = 0.005). The increase was mainly attributed to two species-level taxa, Group 9 sp. ISO4-G1 and Group 10 sp. Four groups were set in Experiment 2: control, NG, choline (choline chloride, 7.2 mmol/L), and choline + NG. Choline was completely degraded in 24 h, and the TMA content reached the peak point (7.3 mmol/L) in the fermentation culture. The TMA content remained relatively stable in the choline + NG group following the peak point. However, it started to decrease after 24 h in the choline group, corresponding to the rapid increase in methane production and the abundance of Mmc. Eight mid-lactating, rumen-fistulated Holstein cows were randomly assigned to the control (n = 4) or choline (n = 4) group in Experiment 3: In the choline group, cows were gradually supplemented with 100-250 g/(cow·d) of choline chloride over 4 weeks. Compared to the control group, TMA accumulated in the rumen fluid, and the abundance of Mmc 16S rRNA gene and choline-degrading bacterial cutC gene increased in the rumen content in the choline group (P < 0.050). The trimethylamine N-oxide content in the plasma and milk of the dairy cows was approximately 10 times higher in the choline group than that in the control at the end of the experiment. These findings revealed that Mmc played an important role in the elimination of TMA in the rumen. The accumulation of TMA in the rumen would lead to a large amount of TMA absorbed into the blood stream of the dairy cows.
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http://dx.doi.org/10.1016/j.animal.2021.100259DOI Listing
May 2021

Rockwood Grade-III Acromioclavicular Joint Separation: A Cost-Effectiveness Analysis of Treatment Options.

JB JS Open Access 2021 Apr-Jun;6(2). Epub 2021 May 4.

Department of Orthopaedic Surgery, Henry Ford Hospital, Detroit, Michigan.

Background: The treatment of Rockwood Grade-III acromioclavicular (AC) joint separation has been widely disputed since the introduction of the classification system. The present literature does not reach consensus on whether operative or nonoperative management is more advantageous, nor does it effectively distinguish between operative measures. We hypothesized that nonoperative treatment of Rockwood Grade-III AC joint separation would be more cost-effective when compared with surgical options.

Methods: We created a decision-tree model outlining the treatment of Rockwood Grade-III separations using nonoperative management or hook-plate, suture-button, or allograft fixation. After nonoperative intervention, the possible outcomes predicted by the model were uneventful healing, delayed operative management, a second round of sling use and physical therapy, or no reduction and no action; and after operative intervention, the possible outcomes were uneventful healing, loss of reduction and revision, and depending on the implant, loss of reduction and no action, or removal of the implant. A systematic review was conducted, and probabilities of each model state were averaged. A cost-effectiveness analysis was conducted both through rollback analysis yielding net monetary benefit and through incremental cost-effectiveness ratios (ICERs). Thresholds of $50,000/quality-adjusted life-year (QALY) and $100,000/QALY were used for ICER analysis. Furthermore, a sensitivity analysis was utilized to determine whether differential probabilities could impact the model.

Results: Forty-five papers were selected from a potential 768 papers identified through our literature review. Nonoperative treatment was used as our reference case and showed dominance over all 3 of the operative measures at both the $50,000 and $100,000 ICER thresholds. Nonoperative treatment also showed the greatest net monetary benefit. Nonoperative management yielded the lowest total cost ($6,060) and greatest utility (0.95 QALY). Sensitivity analysis showed that allograft fixation became the favored technique at a willingness-to-pay threshold of $50,000 if the rate of failure of nonoperative treatment rose to 14.6%. Similarly, at the $100,000 threshold, allograft became dominant if the probability of failure of nonoperative treatment rose to 22.8%.

Conclusions: The cost-effectiveness of nonoperative treatment is fueled by its notably lower costs and overall high rates of success in Grade-III separations. It is important to note that, in our analysis, the societal cost (measured in lost productivity) of nonoperative treatment neared that of surgical treatment, but the cost from the health-care system perspective was minimal. Physicians should bear in mind the sensitivity of these conclusions and should consider cost-effectiveness analyses in their decision-making guidelines.

Level Of Evidence: Economic and Decision Analysis Level IV. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.OA.20.00171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154465PMC
May 2021

Salidroside Inhibits CCl-Induced Liver Fibrosis in Mice by Reducing Activation and Migration of HSC Induced by Liver Sinusoidal Endothelial Cell-Derived Exosomal SphK1.

Front Pharmacol 2021 13;12:677810. Epub 2021 May 13.

Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Sphingosine kinase 1 (SphK1)/Sphingosine-1-phosphate (S1P)/S1PRs signaling pathway is known to involve the advancement of liver fibrosis. Exosomal SphK1 promotes hepatic stellate cells (HSC) migration. Salidroside (Sal) inhibits liver fibrosis, but its mechanism is yet to be elucidated. This study was to explore the influences of Sal on the SphK/S1P/S1PRs signaling pathway in liver fibrosis induced by carbon tetrachloride (CCl) , and investigated the mechanism of Sal affecting the migration and activation of HSC triggered by exosomal SphK1 . Our data showed that Sal reduced the activities of alanine transaminase (ALT), aspartate aminotransferase (AST) in serum, and hydroxyproline (Hyp) content in the liver tissue. Sal subdued the expression of α-smooth muscle actin (α-SMA), fibronectin (FN) and type I collagen (Col I) of the liver. Sal also reduced mitochondria-induced hepatocyte apoptosis and to inhibit JNK activation. Furthermore, Sal remarkably eradicated the influence of SphK1, SphK2, S1P, and S1PRs triggered by CCl, whether stimulating or hindering. Compared with serum-derived exosomes from model group mice, serum-derived exosomes from Sal group mice expressed lower SphK1 and reduced JS 1 (mouse HSC cell line) migration. In addition, Sal was also observed to subdue Col I expression, AKT activation, and LX-2 migration induced by exosomal SphK1 from SK-HEP-1 (a kind of liver sinusoidal endothelial cells (LSEC) cell line). In conclusion, Sal could effectively alleviate liver injury, hepatocyte apoptosis, and liver fibrosis , providing supports that the protective effects of Sal might be realized by suppressing JNK activation and modulating the SphK/S1P/S1PRs axis. , it was observed that Sal might alleviate LX-2 migration and activation induced by exosomal SphK1 by inhibiting the AKT activation.
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http://dx.doi.org/10.3389/fphar.2021.677810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155673PMC
May 2021

Phelligridin D from Inonotus obliquus attenuates oxidative stress and accumulation of ECM in mesangial cells under high glucose via activating Nrf2.

J Nat Med 2021 May 29. Epub 2021 May 29.

School of Pharmacy and Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.

Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes mellitus and becomes the financial burden and health problem. Pathogenesis of DN has revealed that high glucose has resulted in the oxidative stress and accumulation of extracellular matrix (ECM). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor regulating the expression of anti-oxidant enzymes. Therefore, activating Nrf2 gives a promising approach for the treatment of DN. In the discovery of bioactive phytochemicals targeting DN, we have identified phelligridin D from Inonotus obliquus and explored its protective effects against oxidative stress and accumulation of ECM using mesangial cells under high glucose and potential mechanisms. In addition to inhibiting the self-limited proliferation of mesangial cells cultured in high glucose, phelligridin D can attenuate oxidative stress through reducing reactive oxygen species (ROS) and malondialdehyde (MDA) as well as elevating the activity of superoxide dismutase (SOD) and catalase (CAT). Meanwhile, the major components of ECM including collagen IV, fibronectin and laminin were decreased by phelligridin D via inhibiting the secretion of transforming growth factor-β (TGF-β) and downstream connective tissue growth factor (CTGF). Further investigations have revealed phelligridin D activated Nrf2 in mesangial cells under high glucose, which was involved in its protective effects. These findings can provide evidences for the discovery of novel therapy targeting DN and application of I. obliquus in practice.
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http://dx.doi.org/10.1007/s11418-021-01534-wDOI Listing
May 2021

18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging in atrial fibrillation: a pilot prospective study.

Eur Heart J Cardiovasc Imaging 2021 May 29. Epub 2021 May 29.

Department of Nuclear Medicine, Beijing Chaoyang Hospital, Capital Medical University, 8th Gongtinanlu Rd, Chaoyang District, Beijing 100020, China.

Aims: This prospective study explored relevant factors and clinical significance of atrial 18F-fluorodeoxyglucose (FDG) uptake in patients with atrial fibrillation (AF).

Methods And Results: One hundred AF patients underwent baseline FDG imaging prior to radiofrequency catheter ablation (RFCA). Of those, 30 subjects underwent additional FDG imaging at 3 months post-RFCA. Voltage mapping of the left atrium was analysed as a voltage score. Patients who received RFCA were followed for 26 months (17-31 months) to assess recurrence. At baseline FDG imaging, 74% of patients with persistent AF (PsAF) and 24% of patients with paroxysmal AF showed increased atrial FDG uptake. The prevalence was higher in the right atrium (49%) than in the left atrium (15%, P < 0.001) or left atrial appendage (21%, P < 0.001). Multivariate analysis demonstrated that PsAF and elevated B-type natriuretic peptide (BNP) were related to enhanced right atrial (RA) activity, and increased epicardial adipose tissue (EAT) activity was predictive of left atrial (LA) activity. LA activity was inversely associated with voltage score, while increased FDG uptake in the right atrium was predictive of successful AF termination by RFCA. Atrial FDG activities decreased significantly post-RFCA, but none of the FDG parameters were predictive of AF recurrence.

Conclusions: Enhanced RA activity was associated with elevated BNP level, whereas LA activity was related to the increased activity of EAT and inversely correlated with LA fibrosis. Increased RA activity was predictive of successful AF termination by RFCA in PsAF patients.
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http://dx.doi.org/10.1093/ehjci/jeab088DOI Listing
May 2021

Interfacial self-assembled behavior of pH/light-responsive host-guest alginate-based supra-amphiphiles for controlling emulsifying property.

Carbohydr Polym 2021 Aug 27;266:118121. Epub 2021 Apr 27.

Key Laboratory of Advanced Materials of Tropical Island Resources, Ministry of Education, College of Chemical Engineering and Technology, Hainan University, 58 Renmin Road, Haikou 570228, Hainan Province, China. Electronic address:

Soft emulsifiers with relatively suitable structural controllability are necessarily required for the preparation of multifunctional Pickering emulsions. Herein, a β-cyclodextrin-grafted alginate/azobenzene-functionalized dodecyl (Alg-β-CD/AzoC. 12) polymeric supra-amphiphile was designed based on the host-guest interfacial self-assembly. As compared with Alg-β-CD amphiphilic polymers, the interfacial tension of Alg-β-CD/AzoC12 supra-amphiphilic assemblies reduced from 29.57 mN/m to 0.18 mN/m, indicating the great amphiphilicity derived from Alg-β-CD/AzoC12 supra-amphiphilic assemblies. With the increase of pH, the interfacial microstructures transformed from flocculated structures, spherical structures into deformed structures. Especially, the spherical microstructures with the highest interfacial viscoelasticity and thickness demonstrated the highest emulsifying efficiency due to the steric hindrance mechanism. Moreover, the interfacial elastic modulus of adsorbed layers exhibited ~4 times of that upon the ultraviolet illumination. These results disclosed that the interfacial microstructures could be readily regulated by the tunable amphiphilicity of Alg-β-CD/AzoC12 assemblies, which would be useful for the applications of Pickering emulsions in numerous fields.
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http://dx.doi.org/10.1016/j.carbpol.2021.118121DOI Listing
August 2021

Inverse-designed semiconductor nanocatalysts for targeted CO reduction in water.

Nanoscale 2021 Jun 26;13(22):10024-10034. Epub 2021 May 26.

Pollard Institute, School of Electronic and Electrical Engineering, University of Leeds, Leeds LS2 9JT, UK.

The most commonly used photocatalyst for CO reduction is TiO. However, this semiconductor material is far from being ideally suited for this purpose, owing to its inefficient energy harvesting (it absorbs in the UV), low reduction rates (it exhibits short carrier lifetimes), and lack of selectivity with respect to competing reactions (such as the nearly isoenergetic and kinetically more favourable water reduction). In this work we compile a wish-list of properties for the ideal photocatalyst (including high reaction selectivity, availability of multiple redox equivalents at one time, large contact area for CO adsorption with independently tunable band gap, and availability of electrons and holes at different locations on the surface for the two redox reactions to take place), and, using the principles of inverse design, we engineer a semiconductor nanostructure that not only meets all the necessary fundamental criteria to act as a catalyst for CO reduction, but also exhibits all the wish-list properties, as confirmed by our state-of-the-art atomistic semi-empirical pseudopotential modelling. The result is a potentially game-changing material.
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http://dx.doi.org/10.1039/d1nr01550hDOI Listing
June 2021

Acid rain leaching behavior of Zn-contaminated soils solidified/stabilized using cement-soda residue.

Chemosphere 2021 May 17;281:130916. Epub 2021 May 17.

School of Resource and Environmental Engineering, Hefei University of Technology, Hefei, 230009, China.

Cement-soda residue (CSR) has been proven to be an effective binder for treating heavy metal-contaminated soils, and the durability is its most important characteristic. In this study, the effects of acid rain (AR) on the leaching behavior of CSR-solidified/stabilized, zinc-contaminated soils were investigated using flexible-wall soil column leaching tests. After leaching, some parameters were determined such as the unconfined compressive strength (UCS) and permeability coefficient of the samples, the concentrations of Zn and Ca in the filtrate. The test results showed that after AR leaching, the UCS of the solidified soil samples decreased and the permeability coefficient increased, while the zinc concentration in the filtrate always met the third grade of the applicable standard, the Chinese National Environmental Quality Standards (<1 mg⋅L). To reveal the binding mechanism, scanning electron microscopy (SEM) and mercury intrusion testing (MIP) were used to observe the microscopic characteristics of the soil samples. At the micro scale, the MIP and SEM results confirmed that the hydration products in the soil samples-hydrated calcium silicate, calcium hydroxide, and calcium zincate hydrate-partially dissolved during AR leaching, resulting in the loss of their internal structure. Consequently, the high alkalinity of the soda residue contributed to H neutralization in the AR leaching agent, indicating that soda residue can not only solidify heavy metal zinc ions effectively but can also buffer the erosive effect of AR on soil.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130916DOI Listing
May 2021

The protein corona hampers the transcytosis of transferrin-modified nanoparticles through blood-brain barrier and attenuates their targeting ability to brain tumor.

Biomaterials 2021 Jul 18;274:120888. Epub 2021 May 18.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China. Electronic address:

The modification of targeting ligands on nanoparticles (NPs) is anticipated to enhance the delivery of therapeutics to diseased tissues. However, once exposed to the blood stream, NPs can immediately adsorb proteins to form the "protein corona," which may greatly hinder the targeting ligand from binding to its receptor. For brain-targeting delivery, nanotherapeutics must traverse the blood-brain barrier (BBB) to enter the brain parenchyma and then target the diseased cells. However, it remains elusive whether, apart from receptor recognition, the protein corona can affect other processes involved in BBB transcytosis, such as endocytosis, intracellular trafficking, and exocytosis. Furthermore, the targeting ability of NPs toward diseased cells after transcytosis remains unclear. Herein, transferrin (Tf), a brain-targeting ligand, was coupled to NPs to evaluate BBB transcytosis and brain tumor targeting ability. Different impacts of the in vitro and in vivo protein corona on receptor targeting, lysosomal escape, and BBB transcytosis were found. The in vitro protein corona abolished the Tf-mediated effects of the abovementioned processes, whereas the in vivo protein corona attenuated these effects. After crossing the BBB, Tf retained its targeting specificity towards brain tumor cells. Together, these results revealed that several bound apolipoproteins, especially apolipoprotein A-I, may help NPs traverse the BBB, thereby providing novel insights into the development of brain-targeted delivery.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120888DOI Listing
July 2021

A novel classification method of lymph node metastasis in colorectal cancer.

Bioengineered 2021 Dec;12(1):2007-2021

College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, Heilongjiang Province, China.

Colorectal cancer lymph node metastasis, which is highly associated with the patient's cancer recurrence and survival rate, has been the focus of many therapeutic strategies that are highly associated with the patient's cancer recurrence and survival rate. The popular methods for classification of lymph node metastasis by neural networks, however, show limitations as the available low-level features are inadequate for classification, and the radiologists are unable to quickly review the images. Identifying lymph node metastasis in colorectal cancer is a key factor in the treatment of patients with colorectal cancer. In the present work, an automatic classification method based on deep transfer learning was proposed. Specifically, the method resolved the problem of repetition of low-level features and combined these features with high-level features into a new feature map for classification; and a merged layer which merges all transmitted features from previous layers into a map of the first full connection layer. With a dataset collected from Harbin Medical University Cancer Hospital, the experiment involved a sample of 3,364 patients. Among these samples, 1,646 were positive, and 1,718 were negative. The experiment results showed the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 0.8732, 0.8746, 0.8746 and 0.8728, respectively, and the accuracy and AUC were 0.8358 and 0.8569, respectively. These demonstrated that our method significantly outperformed the previous classification methods for colorectal cancer lymph node metastasis without increasing the depth and width of the model.
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http://dx.doi.org/10.1080/21655979.2021.1930333DOI Listing
December 2021

Airway epithelial integrin β4-deficiency exacerbates lipopolysaccharide-induced acute lung injury.

J Cell Physiol 2021 May 21. Epub 2021 May 21.

Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.

Airway epithelial cells, the first barrier of the respiratory tract, play an indispensable role in innate immunity. Integrin β4 (ITGB4) is a structural adhesion molecule that is involved in the pathological progression of acute inflammatory diseases and is downregulated in asthmatic patients. Research has shown that endothelial ITGB4 has proinflammatory properties in acute lung injury (ALI). However, the role of epithelial ITGB4 in a murine ALI model is still unknown. This study investigated the role of ITGB4 in lipopolysaccharide (LPS)-induced ALI. We found that ITGB4 in the airway epithelium had remarkably increased after the introduction of LPS in vivo and in vitro. Then, we constructed airway epithelial cell-specific ITGB4 knockout (ITGB4 ) mice to study its role in ALI. At a time point of 12 h after the tracheal injection of LPS, ITGB4 mice showed increased macrophages (mainly M1-type macrophages) and neutrophil infiltration into the lungs; inflammation-related proteins including interleukin (IL)-6, tumor necrosis factor, and IL-17A were significantly elevated compared to their levels in ITGB4 mice. Furthermore, we investigated the role of ITGB4 in the anti-inflammatory response. Intriguingly, in the ITGB4  + LPS group, we found significantly reduced expression of anti-inflammatory factors, including IL-10 messenger RNA (mRNA) and ARG-1 mRNA. We also observed that monocyte chemotactic protein (MCP-1) increased significantly both in vivo and in vitro. Airway epithelium activates macrophages, most likely driven by MCP-1, which we confirmed in the coculture of epithelia and macrophages. These phenomena indicate that ITGB4 in airway epithelial cells plays an important role in the process of inflammation and activation of macrophages in ALI. Overall, these data demonstrated a novel link between airway epithelial ITGB4 and the inflammatory response in LPS-induced ALI.
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http://dx.doi.org/10.1002/jcp.30422DOI Listing
May 2021

Association of Prenatal, Early Postnatal, or Current Exposure to Secondhand Smoke With Attention-Deficit/Hyperactivity Disorder Symptoms in Children.

JAMA Netw Open 2021 May 3;4(5):e2110931. Epub 2021 May 3.

Guangdong Provincial Engineering Technology Research Center of Environmental Pollution and Health Risk Assessment, Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou, China.

Importance: Few studies have investigated the association between the exposure window (prenatal, early postnatal, and current period) of secondhand smoke (SHS) and attention-deficit/hyperactivity disorder (ADHD) symptoms and subtypes in children.

Objective: To evaluate the associations of prenatal, early postnatal, or current SHS exposure with ADHD symptoms and subtypes among school-aged children.

Design, Setting, And Participants: In this cross-sectional study, 48 612 children aged 6 to 18 years from elementary and middle schools in Liaoning province, China, between April 2012 and January 2013 were eligible for participation. Data on SHS exposure and ADHD symptoms and subtypes for each child were collected via questionnaires administered to parents or guardians by school teachers. Data were analyzed from September 14 to December 2, 2020.

Main Outcomes And Measures: The ADHD symptoms and subtypes (inattention, hyperactivity-impulsivity, and combined) were measured based on a validated tool developed from the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). Generalized linear mixed models were evaluated to estimate the association of SHS exposure with ADHD symptoms and subtypes.

Results: A total of 45 562 participants completed the questionnaires and were included in this study (22 905 girls [50.3%]; mean [SD] age, 11.0 [2.6] years; 2170 [4.8%] with ADHD symptoms). Compared with their unexposed counterparts, children who were ever exposed (odds ratio [OR], 1.50; 95% CI, 1.36-1.66) or always exposed to SHS (OR, 2.88; 95% CI, 2.55-3.25) from pregnancy to childhood had higher odds of having ADHD symptoms and subtypes (ORs ranged from 1.46 [95% CI, 1.31-1.62] to 2.94 [95% CI, 2.09-4.13]). Compared with their unexposed counterparts, children with SHS exposure had higher odds of having ADHD symptoms when exposed in the prenatal period (OR, 2.28; 95% CI, 2.07-2.51), early postnatal period (OR, 1.47; 95% CI, 1.29-1.68), or current period (OR, 1.20; 95% CI, 1.09-1.31). Compared with their unexposed counterparts, children whose fathers smoked 10 or more cigarettes/d on both weekdays and weekends had higher odds of having ADHD symptoms and subtypes (ORs ranged from 1.48 [95% CI, 1.28-1.70] to 2.25 [95% CI, 1.29-3.93]).

Conclusions And Relevance: Being exposed to SHS from pregnancy to childhood was associated with higher odds of having ADHD symptoms and subtypes among school-aged children, and the associations were somewhat stronger for SHS exposure during prenatal and early postnatal periods. Our findings highlight the important public health implications of reducing SHS exposure, which may decrease the health and economic burdens of individuals with ADHD.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.10931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138689PMC
May 2021