Publications by authors named "Chen Wu"

665 Publications

circ_0000467 promotes the proliferation, metastasis, and angiogenesis in colorectal cancer cells through regulating KLF12 expression by sponging miR-4766-5p.

Open Med (Wars) 2021 24;16(1):1415-1427. Epub 2021 Sep 24.

Department of Gastroenterology and General Surgery, Sichuan Mianyang 404 Hospital, No. 56, Yuejin Street, Fucheng District, 621000, Mianyang, Sichuan, China.

Background: Circular RNAs have been identified as crucial players in the initiation and progression of cancers, including colorectal cancer (CRC). The Has_circ_0000467 (circ_0000467) expression has been found to be upregulated in CRC, but its function and mechanism remain unclear.

Methods: The expression levels of circ_0000467, microRNA-4766-5p (miR-4766-5p), and Krueppel-like factor 12 (KLF12) were examined using reverse transcription-quantitative polymerase chain reaction. Cell proliferation was analyzed by cell counting kit-8 assay and colony formation assay. The apoptosis was measured by flow cytometry. Transwell migration and invasion assays were applied to evaluate cell metastatic ability. Angiogenesis was detected using tube formation assay. All protein expressions were quantified by western blot assay. Dual-luciferase reporter assay was used to analyze intergenic binding. Xenograft models were constructed for the experiment of circ_0000467 .

Results: The expression of circ_0000467 was upregulated in CRC tissues and cells. Knockdown of circ_0000467 repressed cell proliferation, metastasis, and angiogenesis, but it induced apoptosis in CRC cells. circ_0000467 targeted miR-4766-5p and inhibited the expression of miR-4766-5p. Silencing of circ_0000467 inhibited CRC progression by upregulating miR-4766-5p. miR-4766-5p suppressed the expression of target gene KLF12 and KLF12 overexpression reversed the effects of miR-4766-5p on CRC cell behaviors. circ_0000467 positively regulated the expression of KLF12 by targeting miR-4766-5p. circ_0000467 downregulation reduced CRC tumorigenesis by regulating miR-4766-5p and KLF12.

Conclusion: circ_0000467 acted as an oncogene in CRC through regulating KLF12 expression by sponging miR-4766-5p. Therefore, circ_0000467 can be used as an effective target in CRC diagnosis and therapy.
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http://dx.doi.org/10.1515/med-2021-0358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464181PMC
September 2021

CstF64-induced shortening of the BID 3'UTR promotes esophageal squamous cell carcinoma progression by disrupting ceRNA crosstalk with ZFP36L2.

Cancer Res 2021 Oct 4. Epub 2021 Oct 4.

Carcinogenesisi department, CICAMS.

The majority of human genes have multiple polyadenylation sites, which are differentially utilized through the process of alternative polyadenylation (APA). Dysregulation of APA contributes to numerous diseases, including cancer. However, specific genes subject to APA that impact oncogenesis have not been well characterized, and many cancer APA landscapes remain underexplored. Here we used Dynamic Analyses of APA from RNA-seq (DaPars) to define both the 3'UTR APA profile in esophageal squamous cell carcinoma (ESCC) and to identify 3'UTR shortening events that may drive tumor progression. In four distinct squamous cell carcinoma datasets, BID 3'UTRs were recurrently shortened and BID mRNA levels were significantly upregulated. Moreover, system correlation analysis revealed that CstF64 is a candidate upstream regulator of BID 3'UTR length. Mechanistically, a shortened BID 3'UTR promoted proliferation of ESCC cells by disrupting competing endogenous RNA (ceRNA) crosstalk, resulting in downregulation of the tumor suppressor gene ZFP36L2. These in vitro and in vivo results were supported by human patient data whereby 3'UTR shortening of BID and low expression of ZFP36L2 are prognostic factors of survival in ESCC. Collectively, these findings demonstrate that a key ceRNA network is disrupted through APA and promotes ESCC tumor progression.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1201DOI Listing
October 2021

Neural basis for regulation of vasopressin secretion by anticipated disturbances in osmolality.

Elife 2021 Sep 29;10. Epub 2021 Sep 29.

Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States.

Water balance, tracked by extracellular osmolality, is regulated by feedback and feedforward mechanisms. Feedback regulation is reactive, occurring as deviations in osmolality are . Feedforward or presystemic regulation is proactive, occurring when disturbances in osmolality are . Vasopressin (AVP) is a key hormone regulating water balance and is released during hyperosmolality to limit renal water excretion. AVP neurons are under feedback and feedforward regulation. Not only do they respond to disturbances in blood osmolality, but they are also rapidly suppressed and stimulated, respectively, by drinking and eating, which will ultimately decrease and increase osmolality. Here, we demonstrate that AVP neuron activity is regulated by multiple anatomically- and functionally-distinct neural circuits. Notably, presystemic regulation during drinking and eating are mediated by non-overlapping circuits that involve the lamina terminalis and hypothalamic arcuate nucleus, respectively. These findings reveal neural mechanisms that support differential regulation of AVP release by diverse behavioral and physiological stimuli.
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http://dx.doi.org/10.7554/eLife.66609DOI Listing
September 2021

Progressive Collapse Safety Evaluation of Truss Structures Considering Material Plasticity.

Materials (Basel) 2021 Sep 7;14(18). Epub 2021 Sep 7.

Xiamen Jiahe Construction Co., Ltd., Xiamen 361022, China.

Theoretical or numerical progressive collapse analysis is necessary for important civil structures in case of unforeseen accidents. However, currently, most analytical research is carried out under the assumption of material elasticity for problem simplification, leading to the deviation of analysis results from actual situations. On this account, a progressive collapse analysis procedure for truss structures is proposed, based on the assumption of elastoplastic materials. A plastic importance coefficient was defined to express the importance of truss members in the entire system. The plastic deformations of members were involved in the construction of local and global stiffness matrices. The conceptual removal of a member was adopted, and the impact of the member loss on the truss system was quantified by bearing capacity coefficients, which were subsequently used to calculate the plastic importance coefficients. The member failure occurred when its bearing capacity arrived at the ultimate value, instead of the elastic limit. The extra bearing capacity was embodied by additional virtual loads. The progressive collapse analysis was performed by iterations until the truss became a geometrically unstable system. After that, the critical progressive collapse path inside the truss system was found according to the failure sequence of the members. Lastly, the proposed method was verified against both analytical and experimental truss structures. The critical progressive collapse path of the experimental truss was found by the failure sequence of damaged members. The experimental observation agreed well with the corresponding analytical scenario, proving the method feasibility.
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http://dx.doi.org/10.3390/ma14185135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469360PMC
September 2021

LncRNA TUG1 attenuates ischaemia-reperfusion-induced apoptosis of renal tubular epithelial cells by sponging miR-144-3p via targeting Nrf2.

J Cell Mol Med 2021 Oct 21;25(20):9767-9783. Epub 2021 Sep 21.

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

Renal ischaemia/reperfusion (I/R) injury may induce kidney damage and dysfunction, in which oxidative stress and apoptosis play important roles. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are reported to be closely related to renal I/R, but the specific molecular mechanism is still unclear. The purpose of this research was to explore the regulatory effect of lncRNA TUG1 on oxidative stress and apoptosis in renal I/R injury. This research revealed that in renal I/R injury and hypoxia/reperfusion (H/R) injury in vitro, the expression level of lncRNA TUG1 was upregulated, and oxidative stress levels and apoptosis levels were negatively correlated with the expression level of lncRNA TUG1. Using bioinformatics databases such as TargetScan and microRNA.org, microRNA-144-3p (miR-144-3p) was predicted to be involved in the association between lncRNA TUG1 and Nrf2. This study confirmed that the level of miR-144-3p was significantly reduced following renal I/R injury and H/R injury in vitro, and miR-144-3p was determined to target Nrf2 and inhibit its expression. In addition, lncRNA TUG1 can reduce the inhibitory effect of miR-144-3p on Nrf2 by sponging miR-144-3p. In summary, our research shows that lncRNA TUG1 regulates oxidative stress and apoptosis during renal I/R injury through the miR-144-3p/Nrf2 axis, which may be a new treatment target for renal I/R injury.
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http://dx.doi.org/10.1111/jcmm.16924DOI Listing
October 2021

Serum branched-chain amino acids modifies the associations between air pollutants and insulin resistance.

Ecotoxicol Environ Saf 2021 Dec 16;225:112780. Epub 2021 Sep 16.

State Key Joint Laboratory of Environmental Simulation and Pollution Control, International Joint Laboratory for Regional Pollution Control (IJRC), Ministry of Education, College of Environmental Sciences and Engineering, Beijing 100871, China. Electronic address:

Growing evidence supports that air pollution exposure has become a risk factor of type II diabetes mellitus through the induction of insulin resistance (IR), but the presented findings did not provide a consistent relationship between air pollution exposure and IR in the temporal scale and the magnitude. Reported associated with IR and air pollution exposure, branched-chain amino acids (BCAAs) in blood might modify the association between air pollution exposure and IR. We took advantage of an existing panel study on elderly people who were healthy or with pre-diabetes. Amino acids were analyzed from the serum samples using a UPLC-QQQ-MS, and the homeostasis model assessment of insulin resistance (HOMA-IR) values were calculated to represent the levels of IR in each visit. Exposures to PM, NO, SO, CO, O, and black carbon (BC) were estimated using data from a monitoring station. Linear mixed-effects models were applied to estimate the associations between the air pollution and HOMA-IR, as well as the modifying effects of BCAAs. We found significantly higher concentrations of BCAAs in the pre-diabetic subjects than healthy ones. The concentrations of BCAAs were all significantly associated with HOMA-IR. For subjects with high-level BCAAs, HOMA-IR was positively associated with an IQR increase in PM, NO, BC, and CO at lag day 2 and in PM, SO, NO, BC, and CO at lag day 7. While for subjects with low-level BCAAs, there was no significant association observed at any lag day except for CO at lag day 5. The study provided evidence that circulating BCAAs may modify the relationship between air pollution exposure and the level of insulin resistance in humans.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112780DOI Listing
December 2021

Spatiotemporal analysis and the characteristics of the case transmission network of 2019 novel coronavirus disease (COVID-19) in Zhejiang Province, China.

PLoS One 2021 17;16(9):e0257587. Epub 2021 Sep 17.

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

Background: Zhejiang Province is one of the five provinces in China that had the highest incidence of novel coronavirus disease (COVID-19). Zhejiang, ranked fourth highest in COVID-19 incidence, is located in the Yangtze River Delta region of southeast China. This study was undertaken to identify the space-time characteristics of COVID-19 in Zhejiang.

Methods: Data on COVID-19 cases in Zhejiang Province from January to July 2020 were obtained from this network system. Individual information on cases and deaths was imported, and surveillance information, including demographic characteristics and geographic and temporal distributions, was computed by the system. The Knox test was used to identify possible space-time interactions to test whether cases that are close in distance were also close in time. Network analysis was performed to determine the relationship among the cases in a transmission community and to try to identify the key nodes.

Results: In total, 1475 COVID-19 cases and 1 fatal case were reported from January to July 2020 in Zhejiang Province, China. Most of the cases occurred before February 15th, which accounted for 90.10%. The imported cases increased and became the main risk in Zhejiang Province after February 2020. The risk areas showed strong heterogeneity according to the Knox test. The areas at short distances within 1 kilometer and at brief periods within 5 days presented relatively high risk. The numbers of subcommunities for the four clusters were 12, 9, 6 and 4. There was obvious heterogeneity in the modularity of subcommunities. The maximum values of the node centrality for the four clusters were 2.9474, 4.3706, 4.1080 and 2.7500.

Conclusions: COVID-19 was brought under control over a short period in Zhejiang Province. Imported infections from outside of mainland China then became a new challenge. The effects of spatiotemporal interaction exhibited interval heterogeneity. The characteristics of transmission showed short range and short term risks. The importance to the cluster of each case was detected, and the key patients were identified. It is suggested that we should focus on key patients in complex conditions and in situations with limited control resources.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257587PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448332PMC
September 2021

Exosomal miR-21 from tubular cells contributes to renal fibrosis by activating fibroblasts via targeting PTEN in obstructed kidneys.

Theranostics 2021 2;11(18):8660-8673. Epub 2021 Aug 2.

Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.

Ureteral obstruction-induced hydronephrosis is associated with renal fibrosis and progressive chronic kidney disease (CKD). Exosome-mediated cell-cell communication has been suggested to be involved in various diseases, including renal fibrosis. However, little is known regarding how exosomes regulate renal fibrosis in obstructed kidneys. We first examined the secretion of exosomes in UUO (unilateral ureteral obstruction) mouse kidneys and TGF-β1-stimulated tubular epithelial cells (NRK-52E). Exosomes from NRK-52E cells were subsequently harvested and incubated with fibroblasts (NRK-49F) or injected into UUO mice via the tail vein. We next constructed Rab27a knockout mice to further confirm the role of exosome-mediated epithelial-fibroblast communication relevant to renal fibrosis in UUO mice. High-throughput miRNA sequencing was performed to detect the miRNA profiles of TGFβ1-Exos. The roles of candidate miRNAs, their target genes and relevant pathways were predicted and assessed and by setting specific miRNA mimic, miRNA inhibitor, siRNA or miRNA LNA groups. Increased renal fibrosis was associated with prolonged UUO days, and the secretion of exosomes was markedly increased in UUO kidneys and TGF-β1-stimulated NRK-52E cells. Purified exosomes from TGF-β1-stimulated NRK-52E cells could activate fibroblasts and aggravate renal fibrosis and . In addition, the inhibition of exosome secretion by Rab27a knockout or GW4869 treatment abolished fibroblast activation and ameliorated renal fibrosis. Exosomal miR-21 was significantly increased in TGFβ1-Exos compared with Ctrl-Exos, and PTEN is a certain target of miR-21. The promotion or inhibition of epithelial exosomal miR-21 correspondingly accelerated or abolished fibroblast activation , and renal fibrosis after UUO was alleviated by miR-21-deficient exosomes through the PTEN/Akt pathway. Our findings reveal that exosomal miR-21 from tubular epithelial cells may accelerate the development of renal fibrosis by activating fibroblasts via the miR-21/PTEN/Akt pathway in obstructed kidneys.
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http://dx.doi.org/10.7150/thno.62820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419054PMC
August 2021

The positive effects of inoculation using arbuscular mycorrhizal fungi and/or dark septate endophytes on the purification efficiency of CuO-nanoparticles-polluted wastewater in constructed wetland.

J Hazard Mater 2021 08 25;416:126095. Epub 2021 May 25.

School of Civil Engineering and Architecture, Wuhan University of Technology, Wuhan 430070, Hubei, China. Electronic address:

The extent to which, and mechanisms by which, arbuscular mycorrhizal fungi (AMF) and dark septate endophytes (DSE) purify wetlands polluted by metallic nanoparticles (metallic NPs) are not well understood. In this study, micro-vertical flow constructed wetlands (MVFCWs) with the Phragmites australis (reeds)-AMF/DSE symbiont were used to treat CuO nanoparticles (CuO-NPs)-polluted wastewater. The results showed that (1) the removal efficiencies of chemical oxygen demand (COD), total nitrogen (TN), and CuO-NPs in three inoculated groups significantly exceeded those in the control check (CK) groups by 28.94-98.72%, 16.63-47.66%, and 0.53-19.12%, respectively; (2) inoculation with AMF and/or DSE significantly promoted the growth, nutrient content, and photosynthesis of reeds, increased the osmoregulation substance content and antioxidant enzyme activities, and decreased the malondialdehyde and reactive oxygen species contents of reeds under CuO-NPs stress; (3) higher Cu accumulation and smaller transport coefficients were found in the inoculated groups than in the CK group; (4) inoculation with AMF and/or DSE changed the subcellular structure distribution and chemical form of Cu in reeds. We therefore conclude that inoculation with AMF and/or DSE in MVFCWs improves the purification of CuO-NPs-polluted wastewater, and the MVFCW-reeds-AMF/DSE associations exhibit great potential for application in remediation of metallic-NPs-polluted wastewater.
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http://dx.doi.org/10.1016/j.jhazmat.2021.126095DOI Listing
August 2021

Dissecting esophageal squamous-cell carcinoma ecosystem by single-cell transcriptomic analysis.

Nat Commun 2021 09 6;12(1):5291. Epub 2021 Sep 6.

Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Esophageal squamous-cell carcinoma (ESCC), one of the most prevalent and lethal malignant disease, has a complex but unknown tumor ecosystem. Here, we investigate the composition of ESCC tumors based on 208,659 single-cell transcriptomes derived from 60 individuals. We identify 8 common expression programs from malignant epithelial cells and discover 42 cell types, including 26 immune cell and 16 nonimmune stromal cell subtypes in the tumor microenvironment (TME), and analyse the interactions between cancer cells and other cells and the interactions among different cell types in the TME. Moreover, we link the cancer cell transcriptomes to the somatic mutations and identify several markers significantly associated with patients' survival, which may be relevant to precision care of ESCC patients. These results reveal the immunosuppressive status in the ESCC TME and further our understanding of ESCC.
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http://dx.doi.org/10.1038/s41467-021-25539-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421382PMC
September 2021

The efficacy and safety of Anyu Peibo Capsule in the treatment of patients with major depressive disorder in China: study protocol for a randomized placebo-controlled trial.

Trials 2021 Sep 3;22(1):585. Epub 2021 Sep 3.

Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wan Ping Nan Road, Shanghai, 200030, People's Republic of China.

Background: Major depressive disorder is the second leading cause of years lost to disability worldwide. Anyu Peibo Capsule has been shown to be effective and safe in phase II trials.

Methods: This clinical study is a multi-center, randomized, double-blinded, placebo-controlled, parallel-group, phase III trial of Anyu Peibo Capsule in China. The aim is to test whether the administration of Anyu Peibo Capsule compared to placebo improves clinical outcomes in adults (aged 18 to 65 years) with MDD. Patients will receive an 8-week treatment of Anyu Peibo Capsule 1.6 g per day or placebo. The primary outcome will be the change from baseline in the total score for the Montgomery-Asberg Depression Rating Scale at the end of the 8-week treatment.

Discussion: The trial aims to provide pivotal evidence for the efficacy and safety of Anyu Peibo Capsule in patients with major depressive disorder.

Trial Registration: ClinicalTrials.gov NCT04210973 . Registered on December 26, 2019.
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http://dx.doi.org/10.1186/s13063-021-05550-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414707PMC
September 2021

Proinflammatory lipid signals trigger the health effects of air pollution in individuals with prediabetes.

Environ Pollut 2021 Aug 24;290:118008. Epub 2021 Aug 24.

BIC-ESAT and SKL-ESPC, College of Environmental Sciences and Engineering, Peking University, Beijing, China. Electronic address:

Individuals with metabolic disorders exhibit enhanced susceptibility to the cardiovascular health effects of particulate air pollution, but the underlying mechanisms are not yet understood. We aim to assess whether changes in proinflammatory lipid signals are associated with fine particulate matter (PM) exposure in individuals with and without prediabetes. A longitudinal panel study was conducted in Beijing, China, and included 120 participants followed up over 589 clinical visits from August 2013 to February 2015. We measured 12 lipids derived from arachidonic acid pathways in blood samples of the participants via targeted lipidomic analyses. Ambient PM concentrations were continuously monitored at a station for associations with the lipids. Among the 120 participants, 110 (mean [SD] age at recruitment, 56.5 [4.2] years; 31 prediabetics) who visited the clinic at least twice over the follow-up period were assigned exposure values of the outdoor residential PM concentrations during the 1-14 days preceding each clinical visit. With an interquartile range increase in the 1-day-lag PM exposure (64.0 μg/m), the prediabetic group had consistently greater increases in the concentration of arachidonate metabolites derived from the cytochrome P450 (CYP450) pathway (5,6-DHET, 15.8% [95% CI, 3.5-29.7%]; 8,9-DHET, 9.7% [95% CI, 0.6-19.6%]; 11,12-DHET, 8.3% [95% CI, 1.9-15.1%]; 14,15-DHET, 7.4% [95% CI, 0.9-14.4%]; and 20-HETE, 8.9% [95% CI, 1.0-17.5%]), compared with the healthy group. Among CYP450-derived lipids, 14,15-DHET and 20-HETE significantly mediated 8% and 8% of the PM-associated increase in white blood cells, 10% and 13% of that in neutrophils, and 20% and 23% of that in monocytes, respectively, in the prediabetic group. In conclusion, proinflammatory lipid signals from CYP450 pathways triggered the health effects of particulate air pollution in individuals with prediabetes, suggesting that targeting lipid metabolism has therapeutic potential to attenuate or prevent the cardiovascular effects of air pollution in susceptible populations.
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http://dx.doi.org/10.1016/j.envpol.2021.118008DOI Listing
August 2021

Comparative study of gut microbiota from captive and confiscated-rescued wild pangolins.

J Genet Genomics 2021 Sep 5;48(9):825-835. Epub 2021 Aug 5.

State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming 650091, China. Electronic address:

Pangolins are among the most critically endangered animals due to widespread poaching and worldwide trafficking. Captive breeding is considered to be one way to protect them and increase the sizes of their populations. However, comparative studies of captive and wild pangolins in the context of gut microbiota are rare. Here, the gut microbiome of captive and confiscated-rescued wild pangolins is compared, and the effects of different periods of captivity and captivity with and without antibiotic treatment are considered. We show that different diets and periods of captivity, as well as the application of antibiotic therapy, can alter gut community composition and abundance in pangolins. Compared to wild pangolins, captive pangolins have an increased capacity for chitin and cellulose/hemicellulose degradation, fatty acid metabolism, and short-chain fatty acid synthesis, but a reduced ability to metabolize exogenous substances. In addition to increasing the ability of the gut microbiota to metabolize nutrients in captivity, captive breeding imposes some risks for survival by resulting in a greater abundance of antibiotic resistance genes and virulence factors in captive pangolins than in wild pangolins. Our study is important for the development of guidelines for pangolin conservation, including health assessment, disease prevention, and rehabilitation of wild pangolin populations.
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http://dx.doi.org/10.1016/j.jgg.2021.07.009DOI Listing
September 2021

VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance.

Signal Transduct Target Ther 2021 Aug 30;6(1):322. Epub 2021 Aug 30.

Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Radiotherapy remains the mainstay for treatment of various types of human cancer; however, the clinical efficacy is often limited by radioresistance, in which the underlying mechanism is largely unknown. Here, using esophageal squamous cell carcinoma (ESCC) as a model, we demonstrate that guanine nucleotide exchange factor 2 (VAV2), which is overexpressed in most human cancers, plays an important role in primary and secondary radioresistance. We have discovered for the first time that VAV2 is required for the Ku70/Ku80 complex formation and participates in non-homologous end joining repair of DNA damages caused by ionizing radiation. We show that VAV2 overexpression substantially upregulates signal transducer and activator of transcription 1 (STAT1) and the STAT1 inhibitor Fludarabine can significantly promote the sensitivity of radioresistant patient-derived ESCC xenografts in vivo in mice to radiotherapy. These results shed new light on the mechanism of cancer radioresistance, which may be important for improving clinical radiotherapy.
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http://dx.doi.org/10.1038/s41392-021-00735-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405816PMC
August 2021

A body map of somatic mutagenesis in morphologically normal human tissues.

Nature 2021 09 25;597(7876):398-403. Epub 2021 Aug 25.

Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China.

Somatic mutations that accumulate in normal tissues are associated with ageing and disease. Here we performed a comprehensive genomic analysis of 1,737 morphologically normal tissue biopsies of 9 organs from 5 donors. We found that somatic mutation accumulations and clonal expansions were widespread, although to variable extents, in morphologically normal human tissues. Somatic copy number alterations were rarely detected, except for in tissues from the oesophagus and cardia. Endogenous mutational processes with the SBS1 and SBS5 mutational signatures are ubiquitous among normal tissues, although they exhibit different relative activities. Exogenous mutational processes operate in multiple tissues from the same donor. We reconstructed the spatial somatic clonal architecture with sub-millimetre resolution. In the oesophagus and cardia, macroscopic somatic clones that expanded to hundreds of micrometres were frequently seen, whereas in tissues such as the colon, rectum and duodenum, somatic clones were microscopic in size and evolved independently, possibly restricted by local tissue microstructures. Our study depicts a body map of somatic mutations and clonal expansions from the same individual.
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http://dx.doi.org/10.1038/s41586-021-03836-1DOI Listing
September 2021

m6A Methyltransferase 3 Promotes the Proliferation and Migration of Gastric Cancer Cells through the m6A Modification of YAP1.

J Oncol 2021 4;2021:8875424. Epub 2021 Aug 4.

Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, Jiangsu Province, China.

Gastric cancer is the most common gastrointestinal tumor with an increasing incidence. Furthermore, advanced gastric cancer is more common, but the mechanism underlying the proliferation and metastasis of gastric cancer has not been thoroughly explored. N6-methyladenosine (m6A) methyltransferase 3 (METTL3) may be involved in the proliferation and metastasis of gastric cancer. Therefore, Yes-associated protein 1 (YAP1) in the Hippo pathway was selected as the target, and the relationship between METTL3 and the proliferation and metastasis of gastric cancer was proved through a series of experiments. This research showed that the expression of m6A and METTL3 was upregulated in human gastric cancer tissues and gastric cancer cell lines. After lentiviral transfection, silencing in AGS (human gastric adenocarcinoma cell line AGS) and MKN-45 (human gastric cancer cell line MKN-45) gastric cancer cell lines directly inhibited the proliferation, aggressiveness, and migration of gastric cancer cells. Mechanically, the inhibition of the YAP1-TEAD signaling pathway by peptide 17 reduces m6A methylation and the total mRNA level of YAP1. It also eliminates the promoting effect of on the proliferation and migration of gastric cancer cells. In turn, the overexpression of eliminates the inhibitory effect of silencing on the proliferation, migration, and invasion of gastric cancer cells. This article proved that m6A methyltransferase METTL3 promoted the proliferation and migration of gastric cancer cells through the m6A modification of YAP1.
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http://dx.doi.org/10.1155/2021/8875424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357513PMC
August 2021

A neuropathological cell model derived from Niemann-Pick disease type C patient-specific iPSCs shows disruption of the p62/SQSTM1-KEAP1-NRF2 Axis and impaired formation of neuronal networks.

Mol Genet Metab Rep 2021 Sep 24;28:100784. Epub 2021 Jul 24.

Advanced Clinical Research Center, Southern Tohoku Research Institute for Neuroscience, 255 Furusawa, Asao-ku, Kawasaki 215-0026, Japan.

Niemann-Pick disease type C (NPC) is a rare neurodegenerative disorder caused by a recessive mutation in the or gene, in which patients exhibit lysosomal accumulation of unesterified cholesterol and glycolipids. Most of the research on NPC has been done in patient-derived skin fibroblasts or mouse models. Therefore, we developed NPC patient neurons derived from induced pluripotent stem cells (iPSCs) to investigate the neuropathological cause of the disease. Although an accumulation of cholesterol and glycolipids, which is characteristic of NPC, was observed in both undifferentiated iPSCs and derived neural stem cells (NSCs), we could not observed the abnormalities in differentiation potential and autophagic activity in such immature cells. However, definite neuropathological features were detected in mature neuronal cells generated from NPC patient-derived iPSCs. Abnormal accumulation of cholesterol and other lipids identified by lipid droplets and number of enlarged lysosomes was more prominent in mature neuronal cells rather than in iPSCs and/or NSCs. Thin-sectioning electron microscopic analysis also demonstrated numerous typical membranous cytoplasmic bodies in mature neuronal cells. Furthermore, TUJ1-positive neurite density was significantly reduced in NPC patient-derived neuronal cells. In addition, disruption of the p62/SQSTM1-KEAP1-NRF2 axis occurred in neurons differentiated from NPC patient-derived iPSCs. These data indicate the impairment of neuronal network formation associated with neurodegeneration in mature neuronal cells derived from patients with NPC.
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http://dx.doi.org/10.1016/j.ymgmr.2021.100784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327345PMC
September 2021

Near-infrared light triggered activation of pro-drug combination cancer therapy and induction of immunogenic cell death.

Int J Pharm 2021 Sep 4;607:120972. Epub 2021 Aug 4.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849 USA. Electronic address:

Disulfiram copper complex [Cu(DDC)] nanoparticles have been explored as promising anticancer agents but with concerns of toxic side effects. To improve tumor specificity and enhance anticancer efficacy, we developed a novel [copper sulfide nanoparticle (CuS NP) + disulfiram prodrug (DQ) micelle + near-infrared (NIR) laser] (CDL) combination therapy. DQ, a reactive oxygen species (ROS)-responsive prodrug, can be selectively activated at the tumor site with elevated ROS to release DDC and form Cu(DDC)in situ. The CuS NP + NIR laser treatment can effectively increase the intra-tumor ROS levels and efficiently activate the DQ prodrug. The CDL therapy kills cancer cells through multiple mechanisms, including ROS amplification cascade and Cu(DDC) chemotherapy. NIR light-triggered tumor-specific "nontoxic-to-toxic" transition can significantly improve the specificity of anticancer effects and reduce systemic toxicity. Also, CDL therapy can effectively induce immunogenic cell death (ICD) and has the potential of eliciting antitumor immunity.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120972DOI Listing
September 2021

[The Diagnostic Value of Peripheral Blood Cell Parameters for Early Recognition of Myelodysplastic Syndrome].

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2021 Aug;29(4):1231-1235

Department of Hematology ,The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China E-mail:

Objective: To evaluate the diagnostic value of peripheral blood cell parameters for early recognition of myelodysplastic syndrome (MDS) patients.

Methods: The clinical and laboratory data of 86 patients with MDS and 72 patients with non-malignant clonal anemia treated in first diagnosed in the Second Hospital of Hebei Medical University from January 1, 2015 to December 31, 2017 was retrospectively analyzed. The peripheral blood cell parameters of the patients in two groups were analyzed, generated the receiver operator characteristic curve (ROC curve) from the statistically significant parameters, the binary logistic model was build to calculate and compare the area under the ROC curve (AUC) combined with multiple indicators and individual indicators, sensitivity, specificity, positive and negative likelihood ratio, and diagnostic accuracy, the diagnostic efficacy of the patients was analyzed.

Results: Compared with patients in the non-malignant clonal anemia group ,white blood cell count (WBC), neutrophil percentage (NE%), eosinophil percentage (E%), eosinophil absolute value (E#), platelet count (PLT), platelet specific volume (PCT%) in the MDS patients were significantly reduced; while percentage of lymphocytes (LY%), basophilic percentage (B%), and the width of platelet distribution (PDW) significantly increased. The several ROC curves with the above indicators were established, which showed that AUC%=0.718 (P=0.040); AUC=0.674 (P=0.044); AUC=0.650 (P=0.044) were >0.5. After established a binary logistic regression model, the AUC obtained by combining the three indicators of LY%, PDW and B% was 0.777 (P=0.037), which was significantly higher than the AUC of any indicator alone. When the sensitivity was 77.91% and the specificity was 61.11%, the corresponding threshold value was 0.47, the positive likelihood ratio was 2.00, the negative likelihood ratio was 0.36, and the case ratio of correct classification was 54.40%.

Conclusion: PDW, B% and LY% in peripheral blood cell parameters have certain diagnostic value for early recognition of MDS.
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http://dx.doi.org/10.19746/j.cnki.issn.1009-2137.2021.04.032DOI Listing
August 2021

Parathyroid hormone promotes the osteogenesis of lipopolysaccharide-induced human bone marrow mesenchymal stem cells through the JNK MAPK pathway.

Biosci Rep 2021 Aug;41(8)

Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.

Periodontitis is a series of inflammatory processes caused by bacterial infection. Parathyroid hormone (PTH) plays a critical role in bone remodeling. The present study aimed to investigate the influences of PTH on human bone marrow mesenchymal stem cells (HBMSCs) pretreated with lipopolysaccharide (LPS). The proliferative ability was measured using cell counting kit-8 (CCK-8) and flow cytometry. The optimal concentrations of PTH and LPS were determined using alkaline phosphatase (ALP) activity assay, ALP staining, and Alizarin Red staining. Osteogenic differentiation was further assessed by quantitative reverse-transcription polymerase chain reaction (RT-qPCR), Western blot analysis, and immunofluorescence staining. PTH had no effects on the proliferation of HBMSCs. Also, 100 ng/ml LPS significantly inhibited HBMSC osteogenesis, while 10-9 mol/l PTH was considered as the optimal concentration to reverse the adverse effects. Mechanistically, c-Jun N-terminal kinase (JNK) phosphorylation was activated by PTH in LPS-induced HBMSCs. SP600125, a selective inhibitor targeting JNK mitogen-activated protein kinase (MAPK) signaling, weakened the effects of PTH. Taken together, the findings revealed the role and mechanism of PTH and JNK pathway in promoting the osteogenic differentiation of LPS-induced HBMSCs, which offered an alternative for treating periodontal diseases.
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http://dx.doi.org/10.1042/BSR20210420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380916PMC
August 2021

Efficient adsorptive removal of short-chain perfluoroalkyl acids using reed straw-derived biochar (RESCA).

Sci Total Environ 2021 Dec 20;798:149191. Epub 2021 Jul 20.

Department of Chemistry and Environmental Science, New Jersey Institute of Technology, Newark, NJ 07102, United States. Electronic address:

Drinking water and groundwater treatment of perfluoroalkyl acids (PFAAs) heavily relies on adsorption-based approaches using carbonaceous materials, such as granular activated carbon (GAC). Application of GAC is restricted by its inefficiency to remove short-chain PFAAs that have prevalently emerged as substitutes and/or metabolites of long-chain polyfluoroalkyl and perfluoroalkyl substances (PFAS). Here, we synthesized reed straw-derived biochar (RESCA) exhibiting exceptional removal efficiencies (>92%) toward short-chain PFAAs at environment-relevant concentrations (e.g., 1 μg/L). Pseudo-second-order kinetic constants of RESCA were 1.13 and 1.23 L/(mg h) for perfluorobutanoic acid (PFBA) and perfluorobutanesulfonic acid (PFBS), respectively, over six times greater than GAC. SEM imaging and BET analysis revealed the combination of highly hydrophobic surface and scattered distribution of mesopores (2-10 nm in diameter) was associated with the rapid adsorption of short-chain PFAAs. RESCA-packed filters demonstrated effective removal of the mixture of three short-chain and three long-chain PFAAs in the influent with the flow rate up to 45 mL/min. In contrast, GAC-packed filters were significantly less efficient in the removal of short-chain PFAAs, which were also negatively affected by the increase of the flow rate. Efficacy of RESCA-packed filters was also validated in four PFAA-spiked groundwater samples from different sites. Dissolved organic matter (DOC) of >8 mg/L can negatively affect the removal of short-chain PFAAs by RESCA. Feasibility of scaling up the RESCA adsorption system was investigated using breakthrough simulation. Overall, RESCA represents a green adsorbent alternative for the feasible and scalable treatment of a wide spectrum of PFAAs of different chain lengths and functional moieties.
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http://dx.doi.org/10.1016/j.scitotenv.2021.149191DOI Listing
December 2021

Enhancement of edeine production in Brevibacillus brevis X23 via in situ promoter engineering.

Microb Biotechnol 2021 Jul 26. Epub 2021 Jul 26.

College of Plant Protection, Hunan Agricultural University, Changsha, 410128, China.

Edeines, a group of cationic antimicrobial peptides produced by the soil bacterium Brevibacillus, have broad biological effects, such as antimicrobial, anticancer and immunosuppressive activities. However, the yield of edeines in wild-type (WT) Brevibacillus is extremely low, and chemical synthesis of edeines is a time-consuming process. Genetic engineering has proven to be an effective approach to produce antibiotics with high yield. In this study, the edeine biosynthetic gene cluster (ede BGC), which is involved in edeine production, was identified and characterized in Brevibacillus brevis X23. To improve edeine production in B. brevis X23, the ede BGC promoter was replaced with six different promoters, P , P , P , P , P or P , through double-crossover homologous recombination. The new promoters significantly increased the expression of the ede BGC as well as edeine production by 2.9 ± 0.4 to 20.5 ± 1.2-fold and 3.6 ± 0.1to 8.7 ± 0.7-fold respectively. The highest yield of edeines (83.6 mg l ) was obtained in B. brevis X23 with the P promoter. This study provides a practical approach for producing high yields of edeines in B. brevis.
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http://dx.doi.org/10.1111/1751-7915.13825DOI Listing
July 2021

New progress in elucidating the relationship between cancer therapy and cardiovascular toxicity.

Biosci Trends 2021 Sep 23;15(4):211-218. Epub 2021 Jul 23.

Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Onco-cardiology is an emerging field linking cancer with cardiovascular injury. Understanding the mechanism of cardiac injury helps improve the quality of life of cancer survivors. A series of studies on adverse reactions to cancer or oncological treatments has indicated that adverse cardiovascular events related to cancer treatments may occur over a longer period of survival, and even years after therapy has concluded. Current cancer therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, have been found to have latent cardiovascular toxicity. These toxic effects are often progressive and irreversible and ultimately lead to cardiovascular events such as heart failure, hypertension, coronary heart diseases, arrhythmia, and thromboembolism. Therefore, more emphasis should be placed on revealing the mechanism of cancer treatment-related cardiovascular toxicity. This would help to guide prevention, diagnosis, and treatment of CVDs in cancer survivors.
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http://dx.doi.org/10.5582/bst.2021.01278DOI Listing
September 2021

Distal leaf removal made balanced source-sink vines, delayed ripening, and increased flavonol composition in Cabernet Sauvignon grapes and wines in the semi-arid Xinjiang.

Food Chem 2022 Jan 15;366:130582. Epub 2021 Jul 15.

Center for Viticulture and Enology, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; Key Laboratory of Viticulture and Enology, Ministry of Agriculture and Rural Affairs, Beijing 100083, China. Electronic address:

Leaf removal applied in the upper canopy of modified vertical shooting positioning trellis system has been proposed as an effective strategy to mitigate the adverse effects of global warming on grape and wine quality. In this study, we removed the upper leaves of Cabernet Sauvignon canopy in a semi-arid climate for three consecutive years (2018-2020). About one-third of the whole canopy leaves were removed at the beginning of véraison (LR1) and post-véraison (LR2). All leaf removal treatments included two schemes: (i) leaf removal in the same vines in all vintages to investigate the carry-over effects (1-LR1 and 1-LR2); (ii) leaf removal in different vines in each vintage as repeated experiments among vintages (2-LR1 and 2-LR2). Results showed that leaf removal treatments significantly decreased total soluble solids accumulation in grapes without affecting titratable acidity and pH. LR1 treatments could delay ripening to 6.6 days on average, which was 2.6 days longer than LR2 treatments. LR treatments did not affect the yield but decreased soluble sugar content in canes. Leaves net assimilation rate showed no compensation for the loss of leaves. For phenolic composition, LR treatments increased flavonol concentration in both wines and grapes while had inconsistent effects on anthocyanins and flavanols over three seasons. Principal component analysis (PCA) showed that different LR treatment stages (LR1s vs LR2s) and whether LR in the same vines over consecutive years (1-LRs vs 2-LRs) had limited effects on phenolic profiles. In conclusion, LR in consecutive years at the upper canopy of grapevines was a practical strategy to face global warming in Xinjiang.
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http://dx.doi.org/10.1016/j.foodchem.2021.130582DOI Listing
January 2022

Reopening International Borders without Quarantine: Contact Tracing Integrated Policy against COVID-19.

Int J Environ Res Public Health 2021 07 14;18(14). Epub 2021 Jul 14.

Department of Land Surveying and Geo-Informatics, Hong Kong Polytechnic University, Hong Kong, China.

With the COVID-19 vaccination widely implemented in most countries, propelled by the need to revive the tourism economy, there is a growing prospect for relieving the social distancing regulation and reopening borders in tourism-oriented countries and regions. This need incentivizes stakeholders to develop border control strategies that fully evaluate health risks if mandatory quarantines are lifted. In this study, we have employed a computational approach to investigate the contact tracing integrated policy in different border-reopening scenarios in Hong Kong, China. Explicitly, by reconstructing the COVID-19 transmission from historical data, specific scenarios with joint effects of digital contact tracing and other concurrent measures (i.e., controlling arrival population and community nonpharmacological interventions) are applied to forecast the future development of the pandemic. Built on a modified SEIR epidemic model with a 30% vaccination coverage, the results suggest that scenarios with digital contact tracing and quick isolation intervention can reduce the infectious population by 92.11% compared to those without contact tracing. By further restricting the inbound population with a 10,000 daily quota and applying moderate-to-strong community nonpharmacological interventions (NPIs), the average daily confirmed cases in the forecast period of 60 days can be well controlled at around 9 per day (95% CI: 7-12). Two main policy recommendations are drawn from the study. First, digital contact tracing would be an effective countermeasure for reducing local virus spread, especially when it is applied along with a moderate level of vaccination coverage. Second, implementing a daily quota on inbound travelers and restrictive community NPIs would further keep the local infection under control. This study offers scientific evidence and prospective guidance for developing and instituting plans to lift mandatory border control policies in preparing for the global economic recovery.
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http://dx.doi.org/10.3390/ijerph18147494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303901PMC
July 2021

A chromosome-scale assembly of the bilberry genome identifies a complex locus controlling berry anthocyanin composition.

Mol Ecol Resour 2021 Jul 14. Epub 2021 Jul 14.

Genomics Aotearoa, Dunedin, New Zealand.

Bilberry (Vaccinium myrtillus L.) belongs to the Vaccinium genus, which includes blueberries (Vaccinium spp.) and cranberry (V. macrocarpon). Unlike its cultivated relatives, bilberry remains largely undomesticated, with berry harvesting almost entirely from the wild. As such, it represents an ideal target for genomic analysis, providing comparisons with the domesticated Vaccinium species. Bilberry is prized for its taste and health properties and has provided essential nutrition for Northern European indigenous populations. It contains high concentrations of phytonutrients, with perhaps the most important being the purple colored anthocyanins, found in both skin and flesh. Here, we present the first bilberry genome assembly, comprising 12 pseudochromosomes assembled using Oxford Nanopore (ONT) and Hi-C Technologies. The pseudochromosomes represent 96.6% complete BUSCO genes with an assessed LAI score of 16.3, showing a high conservation of synteny against the blueberry genome. Kmer analysis showed an unusual third peak, indicating the sequenced samples may have been from two individuals. The alternate alleles were purged so that the final assembly represents only one haplotype. A total of 36,404 genes were annotated after nearly 48% of the assembly was masked to remove repeats. To illustrate the genome quality, we describe the complex MYBA locus, and identify the key regulating MYB genes that determine anthocyanin production. The new bilberry genome builds on the genomic resources and knowledge of Vaccinium species, to help understand the genetics underpinning some of the quality attributes that breeding programs aspire to improve. The high conservation of synteny between bilberry and blueberry genomes means that comparative genome mapping can be applied to transfer knowledge about marker-trait association between these two species, as the loci involved in key characters are orthologous.
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http://dx.doi.org/10.1111/1755-0998.13467DOI Listing
July 2021

Genetically engineered microbial remediation of soils co-contaminated by heavy metals and polycyclic aromatic hydrocarbons: Advances and ecological risk assessment.

J Environ Manage 2021 Oct 6;296:113185. Epub 2021 Jul 6.

College of Environment Science and Resources, Xiangtan University, Xiangtan, 411105, PR China; Hunan Engineering Laboratory for High Efficiency Purification Technology and Its Application on Complex Heavy Metal Wastewater Treatment, Xiangtan, 411105, PR China.

Soils contaminated with heavy metals (HMs) and polycyclic aromatic hydrocarbons (PAHs) have been becoming a worldwide concerned environmental problem because of threatening public healthy via food chain exposure. Thus soils polluted by HMs and PAHs need to be remediated urgently. Physical and chemical remediation methods usually have some disadvantages, e.g., cost-expensiveness and incomplete removal, easily causing secondary pollution, which are hence not environmental-friendly. Conventional microbial approaches are mostly used to treat a single contaminant in soils and lack high efficiency and specificity for combined contaminants. Genetically engineered microorganisms (GEMs) have emerged as a desired requirement of higher bioremediation efficiency for soils polluted with HMs and PAHs and environmental sustainability, which can provide a more eco-friendly and cost-effective strategy in comparison with some conventional techniques. This review comments the recent advances about successful bioremediation techniques and approaches for soil contaminated with HMs and/or PAHs by GEMs, and discusses some challenges in the simultaneous removal of HMs and PAHs from soil by designing multi-functional genetic engineering microorganisms (MFGEMs), such as improvement of higher efficiency, strict environmental conditions, and possible ecological risks. Also, the modern biotechnological techniques and approaches in improving the ability of microbial enzymes to effectively degrade combined contaminants at a faster rate are introduced, such as reasonable gene editing, metabolic pathway modification, and protoplast fusion. Although MFGEMs are more potent than the native microbes and can quickly adapt to combined contaminants in soils, the ecological risk of MFGEMs needs to be evaluated under a regulatory, safety, or costs benefit-driving system in a way of stratified regulation. Nevertheless, the innovation of genetic engineering to produce MFGEMs should be inspired for the welfare of successful bioremediation for soils contaminated with HMs and PAHs but it must be supervised by the public, authorities, and laws.
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http://dx.doi.org/10.1016/j.jenvman.2021.113185DOI Listing
October 2021

Unsupervised Change Detection in Multitemporal VHR Images Based on Deep Kernel PCA Convolutional Mapping Network.

IEEE Trans Cybern 2021 Jul 8;PP. Epub 2021 Jul 8.

With the development of Earth observation technology, a very-high-resolution (VHR) image has become an important data source of change detection (CD). These days, deep learning (DL) methods have achieved conspicuous performance in the CD of VHR images. Nonetheless, most of the existing CD models based on DL require annotated training samples. In this article, a novel unsupervised model, called kernel principal component analysis (KPCA) convolution, is proposed for extracting representative features from multitemporal VHR images. Based on the KPCA convolution, an unsupervised deep siamese KPCA convolutional mapping network (KPCA-MNet) is designed for binary and multiclass CD. In the KPCA-MNet, the high-level spatial-spectral feature maps are extracted by a deep siamese network consisting of weight-shared KPCA convolutional layers. Then, the change information in the feature difference map is mapped into a 2-D polar domain. Finally, the CD results are generated by threshold segmentation and clustering algorithms. All procedures of KPCA-MNet do not require labeled data. The theoretical analysis and experimental results in two binary CD datasets and one multiclass CD datasets demonstrate the validity, robustness, and potential of the proposed method.
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http://dx.doi.org/10.1109/TCYB.2021.3086884DOI Listing
July 2021

Aryl Fluoride Activation Through Palladium-Magnesium Bimetallic Cooperation: A Mechanistic and Computational Study.

ACS Catal 2020 Jul 22;10(14):7934-7944. Epub 2020 Jun 22.

Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.

Herein is described a mechanistic study of a palladium-catalyzed cross-coupling of aryl Grignard reagents to fluoroarenes that proceeds via a low-energy heterobimetallic oxidative addition pathway. Traditional oxidative additions of aryl chlorides to Pd complexes are known to be orders of magnitude faster than with aryl fluorides, and many palladium catalysts do not activate aryl fluorides at all. The experimental and computational studies outlined herein, however, support the view that at elevated Grignard : ArX ratios (i.e. 2.5 : 1) a Pd-Mg heterobimetallic mechanism predominates, leading to a remarkable decrease in the energy required for Ar-F bond activation. The heterobimetallic transition state for C-X bond cleavage is proposed to involve simultaneous Pd backbonding to the arene and Lewis acid activation of the halide by Mg to create a low-energy transition state for oxidative addition. The insights gained from this computational study led to the development of a phosphine ligand that was shown to be similarly competent for Ar-F bond activation.
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http://dx.doi.org/10.1021/acscatal.0c01301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248268PMC
July 2020

DNMT1-mediated methylation of BEX1 regulates stemness and tumorigenicity in liver cancer.

J Hepatol 2021 Jul 1. Epub 2021 Jul 1.

Department of Colorectal Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou 310006, China. Electronic address:

Background & Aims: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) both exhibit notable cancer stem cell (CSC) features. Moreover, the development of both diseases is closely associated with the presence of CSCs. We investigated the role of brain-expressed X-linked protein 1 (BEX1) in regulating the CSC properties of HB and a subtype of HCC with high CSC features (CSC-HCC).

Methods: Stemness scores were analyzed in 5 murine HCC models. A subpopulation of BEX1-positive cells and BEX1-negative cells were sorted from HCC cell lines, and subjected to transcriptome analysis. The expression and function of BEX1 was examined via western blotting, sphere formation assays, and xenograft tumor models.

Results: We identified BEX1 as a novel CSC marker that was required for the self-renewal of liver CSCs. Furthermore, zebularine, a potent DNMT1 inhibitor, can induce the reactivation of BEX1 by removing epigenetic inhibition. Notably, BEX1 was highly expressed in patients with HB and CSC-HCC, but not in patients with non-CSC HCC. Moreover, DNMT1-mediated methylation of the BEX1 promoter resulted in differential BEX1 expression patterns in patients with HB, CSC-HCC, and non-CSC-HCC. Mechanistically, BEX1 interacted with RUNX3 to block its inhibition of β-catenin transcription, which led to the activation of Wnt/β-catenin signaling, and stemness maintenance in both HB and CSC-HCC. In contrast, downregulated BEX1 expression released RUNX3 and inhibited the activation of Wnt/β-catenin signaling in non-CSC-HCC.

Conclusion: BEX1, under the regulation of DNMT1, is necessary for the self-renewal and maintenance of liver CSCs through activation of Wnt/β-catenin signaling, rendering BEX1 a potentially valuable therapeutic target in both HB and CSC-HCC.

Lay Summary: Cancer stem cells (CSCs) contribute to a high rate of cancer recurrence, as well as resistance to conventional therapies. However, the regulatory mechanisms underlying their self-renewal remains elusive. Herein, we have reported that BEX1 plays a key role in regulating CSC properties in different types of liver cancer. Targeting BEX1-mediated Wnt/β-catenin signaling may help to address the high rate of recurrence, and heterogeneity of liver cancer.
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http://dx.doi.org/10.1016/j.jhep.2021.06.025DOI Listing
July 2021
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