Publications by authors named "Zhen Tan"

205 Publications

A ligation-driven CRISPR-Cas biosensing platform for non-nucleic acid target detections.

Chem Commun (Camb) 2021 Jul 28;57(57):7051-7054. Epub 2021 Jun 28.

State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, Hunan University, Changsha 410082, P. R. China.

Herein, we describe a CRISPR-Cas12a sensing platform activated by a DNA ligation reaction for the sensitive detection of non-nucleic acid targets, including NAD, ATP and polynucleotide kinase (PNK). In this design, the DNA ligation reaction triggered by these biomolecules generates DNA duplexes, which can activate the nuclease activity of Cas12a to produce amplified fluorescence signals. As a result, this work provides an alternative strategy to expand the applicability of the CRISPR-Cas system into the detection of non-nucleic acid biomolecules.
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http://dx.doi.org/10.1039/d1cc02578cDOI Listing
July 2021

Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma.

Cell Mol Life Sci 2021 Jul 15;78(14):5505-5526. Epub 2021 Jun 15.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death due to its late diagnosis that removes the opportunity for surgery and metabolic plasticity that leads to resistance to chemotherapy. Metabolic reprogramming related to glucose, lipid, and amino acid metabolism in PDAC not only enables the cancer to thrive and survive under hypovascular, nutrient-poor and hypoxic microenvironments, but also confers chemoresistance, which contributes to the poor prognosis of PDAC. In this review, we systematically elucidate the mechanism of chemotherapy resistance and the relationship of metabolic programming features with resistance to anticancer drugs in PDAC. Targeting the critical enzymes and/or transporters involved in glucose, lipid, and amino acid metabolism may be a promising approach to overcome chemoresistance in PDAC. Consequently, regulating metabolism could be used as a strategy against PDAC and could improve the prognosis of PDAC.
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http://dx.doi.org/10.1007/s00018-021-03866-yDOI Listing
July 2021

Fecal microbial composition and functional diversity of Wuzhishan pigs at different growth stages.

AMB Express 2021 Jun 12;11(1):88. Epub 2021 Jun 12.

State Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China.

The mammalian gut microbiome participates in almost all life processes in the host. In addition to diet, the breed is the main factor affecting changes in the swine gut microbiota. The composition of the gut microbiota changes significantly during different growth stages. Research on developmental changes in the gut microbiota of indigenous Chinese pig breeds is limited. In this study, the fecal microbiota of Wuzhishan pigs (a Chinese indigenous miniature pig) at different growth stages was investigated using high-throughput 16S rRNA sequencing. Firmicutes and Bacteroidetes were the two dominant phyla, accounting for more than 80% of all sequences. With increasing age, the fecal microbial diversity increased, and the proportion of Firmicutes increased, whereas the proportion of Bacteroidetes decreased. A total of 49 biomarkers with statistical differences were detected in the four growth stages. The different microbiota among groups enhanced the ability to degrade fiber, carbohydrates, and other substances during the growth stages. The endocrine system was different in multiple growth stage paired comparisons, which was attributed to the different body statuses in the growth stages. This study revealed developmental changes in the structure and function of gut microbes in local pigs.
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http://dx.doi.org/10.1186/s13568-021-01249-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197691PMC
June 2021

Expanding mutational spectrum of HRAS by a patient with Schimmelpenning-Feuerstein-Mims syndrome.

J Dermatol 2021 Jun 9. Epub 2021 Jun 9.

Department of Pediatric Hematology-Oncology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

As one of the epidermal nevus syndromes, Schimmelpenning-Feuerstein-Mims (SFM) is characterized by craniofacial nevus sebaceous (NS) and extracutaneous abnormalities (e.g., brain, eyes, and bone). Here, we report a case of a 4-year-old boy who presented with significant skin abnormalities (NS in the scalp, extensive epidermal nevus along Blaschko's lines), ocular abnormalities (strabismus), central nervous system abnormalities (seizure and mental retardation), lymphatic dysplasia (chylous pleural and pericardial effusion), cardiac abnormalities (patent foramen ovale), urogenital system abnormalities (cryptorchidism, hypospadias), and a tumor predisposition (embryonal rhabdomyosarcoma). DNA samples from NS, rhabdomyosarcoma, and peripheral blood leukocytes were analyzed by next-generation sequencing. A novel mutation in the HRAS gene (c.38G>T; p.Gly13Val) was detected in a mosaic state in NS, rhabdomyosarcoma, and peripheral blood leukocytes, with different ratio of heterozygous mutation (HRAS c.38G>T) of 39.90% (9412/23 588 reads), 73.03% (205 562/281 468 reads), and 14.16% (15 837/111 842 reads), respectively. By predicting the impact of the mutation on the biological function of protein, we found that the novel HRAS mutation (c.38G>T; p.Gly13Val) had the highest damaging scores among other HRAS mutations reported so far. This is the first reported SFM syndrome patient with novel mosaic HRAS mutation, which may help to expand the mutational spectrum of HRAS and better understand the role of HRAS in the disease.
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http://dx.doi.org/10.1111/1346-8138.15922DOI Listing
June 2021

[Role of m A Reader YTHDC2 in Differentiation of Human Bone Marrow Mesenchymal Stem Cells].

Sichuan Da Xue Xue Bao Yi Xue Ban 2021 May;52(3):402-408

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Dental Implant, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.

Objective: To study the regulatory effect of YTH domain-containing protein 2 (YTHDC2), a member of N -methyladenosine (m A) readers, on the osteogenic or adipogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs).

Methods: 2 expression was knocked down by small interfering RNA (siRNA) . Osteogenic differentiation and adipogenic differentiation of hBMSCs were induced after 2 knockdown in order to study the changes in the differentiation phenotype of hBMSCs. Alkaline phosphatase staining (ALP staining) and alizarin red S staining were performed to examine osteogenic activity and calcium-nodular formation. Nile red staining was performed to examine lipid-droplet formation. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to assess the expression of osteogenesis and adipogenesis-related genes. RNA-sequencing was performed to identify the transcriptome changes after 2 knockdown and to explore the potential regulatory mechanism by which YTHDC2 regulated the diferentiation of hBMSCs.

Results: In this study, we found that siRNA-induced 2 knockdown resulted in increased ALP activity and calcium-nodular formation of hBMSCs during osteogenic differentiation, and significantly upregulated the expression of osteogenesis-related genes. In addition, the lipid-droplet formation capacity of hBMSCs was decreased during adipogenic differentiation. The expression of adipogenesis-related genes was significantly down-regulated. Gene-set enrichmen analysis of RNA-seq data showed that YTHDC2 was significantly correlated with ribosome function and mRNA-translation-related signaling pathways.

Conclusion: The findings indicate that knockdown can promote the osteogenic differentiation of hBMSCs and inhibit the adipogenic differentiation. knockdown may cause changes in ribosome function.
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http://dx.doi.org/10.12182/20210560204DOI Listing
May 2021

Novel Fe-Based Amorphous Composite Coating with a Unique Interfacial Layer Improving Thermal Barrier Application.

ACS Appl Mater Interfaces 2021 May 4;13(19):23057-23066. Epub 2021 May 4.

School of Materials Science and Engineering, Beijing Institute of Technology, Beijing 100081, China.

To improve thermal barrier applications in advanced vehicle engines, a novel Fe-based amorphous composite coating was designed by introducing ceramic oxides and was prepared by atmospheric plasma spraying (APS). The microstructure and related properties of the as-deposited coating were investigated in detail. The composite coating comprises a well-formed FeCrNbBSi amorphous metallic matrix and dispersed yttria-stabilized zirconia (YSZ) splats. A unique Si-oxide interfacial layer with a thickness of several nanometers and an amorphous structure forms between the metallic matrix and ceramic phase, which is attributed to a combination of multiple effects. The composite coating displays extremely low thermal conductivity from 2.28 W/mK at 100 °C to 3.36 W/mK at 600 °C and can increase the surface temperature of the piston crown by 18.93 °C, which implies a significant means of enhancing the power efficiency. The improved thermal barrier ability of the composite coating is revealed as the crucial effect of the Si-oxide interfacial layer, which induces an increased interfacial thermal resistance. The fracture toughness of the composite coating remains at 3.40 MPa·m, comparable to that of the monolithic amorphous coating, 3.74 MPa·m, which is closely related to the formation of a Si-oxide layer and its nanoscale thickness. Therefore, the Fe-based amorphous composite coating developed here demonstrates great potential as an innovative metal-based thermal barrier coating for application in vehicle engines and provides specific inspiration for future works exploring the interfacial engineering of coating.
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http://dx.doi.org/10.1021/acsami.0c22868DOI Listing
May 2021

Exploring the Allosteric Territory of Protein Function.

J Phys Chem B 2021 04 12;125(15):3763-3780. Epub 2021 Apr 12.

Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01, Matrix, 138671, Singapore.

While the pervasiveness of allostery in proteins is commonly accepted, we further show the generic nature of allosteric mechanisms by analyzing here transmembrane ion-channel viroporin 3a and RNA-dependent RNA polymerase (RdRp) from SARS-CoV-2 along with metabolic enzymes isocitrate dehydrogenase 1 (IDH1) and fumarate hydratase (FH) implicated in cancers. Using the previously developed structure-based statistical mechanical model of allostery (SBSMMA), we share our experience in analyzing the allosteric signaling, predicting latent allosteric sites, inducing and tuning targeted allosteric response, and exploring the allosteric effects of mutations. This, yet incomplete list of phenomenology, forms a complex and unique allosteric territory of protein function, which should be thoroughly explored. We propose a generic computational framework, which not only allows one to obtain a comprehensive allosteric control over proteins but also provides an opportunity to approach the fragment-based design of allosteric effectors and drug candidates. The advantages of allosteric drugs over traditional orthosteric compounds, complemented by the emerging role of the allosteric effects of mutations in the expansion of the cancer mutational landscape and in the increased mutability of viral proteins, leave no choice besides further extensive studies of allosteric mechanisms and their biomedical implications.
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http://dx.doi.org/10.1021/acs.jpcb.1c00540DOI Listing
April 2021

Amino Acid Conjugates of Aminothiazole and Aminopyridine as Potential Anticancer Agents: Synthesis, Molecular Docking and in vitro Evaluation.

Drug Des Devel Ther 2021 1;15:1459-1476. Epub 2021 Apr 1.

State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, People's Republic of China.

Purpose: The development of resistance to available anticancer drugs is increasingly becoming a major challenge and new chemical entities could be unveiled to compensate this therapeutic failure. The current study demonstrated the synthesis of 2-aminothiazole [() and ()] and 2-aminopyridine [() and ()] derivatives that can target multiple cellular networks implicated in cancer development.

Methods: Biological assays were performed to investigate the antioxidant and anticancer potential of synthesized compounds. Redox imbalance and oxidative stress are hallmarks of cancer, therefore, synthesized compounds were preliminarily screened for their antioxidant activity using DPPH assay, and further five derivatives , , , , and , with significant antioxidant potential, were selected for investigation of in vitro anticancer potential. The cytotoxic activities were evaluated against the parent (A2780) and cisplatin-resistant (A2780CISR) ovarian cancer cell lines. Further, Molecular docking studies of active compounds were performed to determine binding affinities.

Results: Results revealed that , , and displayed promising inhibition in cisplatin-resistant cell lines in comparison to parent cells in terms of both resistance factor (RF) and IC values. Moreover, proved to be most active compound in both parent and resistant cell lines with IC values 15.57 µM and 11.52 µM respectively. Our docking studies demonstrated that compounds , , and exhibited significant binding affinity with multiple protein targets of the signaling cascade.

Conclusion: Anticancer activities of compounds , , and in cisplatin-resistant cell lines suggested that these ligands may contribute as lead compounds for the development of new anticancer drugs.
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http://dx.doi.org/10.2147/DDDT.S297013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021256PMC
April 2021

Three new unsaturated fatty acids from marine-derived fungus sp. SCAU150.

Nat Prod Res 2021 Mar 25:1-7. Epub 2021 Mar 25.

Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, Hainan Normal University, Haikou, Hainan, China.

Four unsaturated fatty acid derivatives including three new pantheric acids (), together with three known polyketides (), were isolated from a culture broth of the marine-derived fungus sp. SCAU150. Their complete structures were determined by NMR and HRESIMS data analyses. The antifungal activity of the isolated compounds above was evaluated and was found to show moderated activity toward the phytopathogenic fungus bio-80814 with an inhibition zone diameter of 6 mm under 5 µg/disc.
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http://dx.doi.org/10.1080/14786419.2021.1903002DOI Listing
March 2021

Lithium and Copper Induce the Osteogenesis-Angiogenesis Coupling of Bone Marrow Mesenchymal Stem Cells via Crosstalk between Canonical Wnt and HIF-1 Signaling Pathways.

Stem Cells Int 2021 6;2021:6662164. Epub 2021 Mar 6.

Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China.

The combination of osteogenesis and angiogenesis dual-delivery trace element-carrying bioactive scaffolds and stem cells is a promising method for bone regeneration and repair. Canonical Wnt and HIF-1 signaling pathways are vital for BMSCs' osteogenic differentiation and secretion of osteogenic factors, respectively. Simultaneously, lithium (Li) and copper (Cu) can activate the canonical Wnt and HIF-1 signaling pathway, respectively. Moreover, emerging evidence has shown that the canonical Wnt and HIF signaling pathways are related to coupling osteogenesis and angiogenesis. However, it is still unclear whether the lithium- and copper-doped bioactive scaffold can induce the coupling of the osteogenesis and angiogenesis in BMSCs and the underlying mechanism. So, we fabricated a lithium- (Li-) and copper- (Cu-) doped organic/inorganic (Li 2.5-Cu 1.0-HA/Col) scaffold to evaluate the coupling osteogenesis and angiogenesis effects of lithium and copper on BMSCs and further explore its mechanism. We investigated that the sustained release of lithium and copper from the Li 2.5-Cu 1.0-HA/Col scaffold could couple the osteogenesis- and angiogenesis-related factor secretion in BMSCs seeding on it. Moreover, our results showed that 500 M Li could activate the canonical Wnt signaling pathway and rescue the XAV-939 inhibition on it. In addition, we demonstrated that the 25 M Cu was similar to 1% oxygen environment in terms of the effectiveness of activating the HIF-1 signaling pathway. More importantly, the combination stimuli of Li and Cu could couple the osteogenesis and angiogenesis process and further upregulate the osteogenesis- and angiogenesis-related gene expression via crosstalk between the canonical Wnt and HIF-1 signaling pathway. In conclusion, this study revealed that lithium and copper could crosstalk between the canonical Wnt and HIF-1 signaling pathways to couple the osteogenesis and angiogenesis in BMSCs when they are sustainably released from the Li-Cu-HA/Col scaffold.
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http://dx.doi.org/10.1155/2021/6662164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962875PMC
March 2021

Finding an easy way to harmonize: a review of advances in clinical research and combination strategies of EZH2 inhibitors.

Clin Epigenetics 2021 Mar 24;13(1):62. Epub 2021 Mar 24.

Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China.

Enhancer of zeste homolog 2 inhibitors (EZH2i) have garnered increased attention owing to their anticancer activity by targeting EZH2, a well-known cancer-promoting factor. However, some lymphomas are resistant to EZH2i, and EZH2i treatment alone is ineffective in case of EZH2-overexpressing solid tumors. The anti-cancer efficacy of EZH2i may be improved through safe and effective combinations of these drugs with other treatment modalities. Preclinical evidence indicates that combining EZH2i with other therapies, such as immunotherapy, chemotherapy, targeted therapy, and endocrine therapy, has complementary or synergistic antitumor effects. Therefore, elucidating the underlying mechanisms of the individual constituents of the combination therapies is fundamental for their clinical application. In this review, we have summarized notable clinical trials and preclinical studies using EZH2i, their progress, and combinations of EZH2i with different therapeutic modalities, aiming to provide new insights for tumor treatment.
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http://dx.doi.org/10.1186/s13148-021-01045-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992945PMC
March 2021

The High-Sensitivity C-Reactive Protein to Prealbumin Ratio Predicts Adverse Cardiovascular Events after ST-Elevation Myocardial Infarction.

Heart Surg Forum 2021 02 16;24(1):E153-E157. Epub 2021 Feb 16.

Cardiovascular Center, Suining Central Hospital, Suining, China.

Background: This study evaluated the association of the high-sensitivity C-reactive protein to prealbumin ratio (CPR) with adverse cardiovascular events after ST-elevation myocardial infarction (STEMI) in patients undergoing primary percutaneous coronary intervention (PCI).

Methods: The study included 682 patients who presented with STEMI and were treated with primary PCI. Patients were divided into 2 groups: high CPR (CPR ≥0.02) and low CPR (CPR <0.02). The primary endpoint of the study was the occurrence of major adverse cardiovascular events (MACE), defined as cardiovascular mortality or admission due to recurrent AMI or heart failure. Multivariate Cox regression models were used to assess the prognostic value of CPR on MACE in patients with STEMI.

Results: During a median follow-up of 18 months, the accumulated incidence rate of MACE was significantly higher in the high-CPR group than in the low-CPR group (38.7% versus 12.0%, P < .01). Multivariate analysis revealed that CPR was an independent predictor for increased risk of MACE (hazard ratio = 3.27, 95% confidence interval [CI] 2.14 to 4.49, P < .01). Receiver operating characteristic (ROC) curve analysis showed that the area under the ROC curve for predicting the diagnosis of MACE was higher for CPR (0.82, 95% CI 0.77 to 0.87) than hs-CRP (0.70, 95% CI 0.65 to 0.75).

Conclusion: CPR was independently associated with MACE and can be used for risk stratification in patients with STEMI.
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http://dx.doi.org/10.1532/hsf.3307DOI Listing
February 2021

Carveol a Naturally-Derived Potent and Emerging Nrf2 Activator Protects Against Acetaminophen-Induced Hepatotoxicity.

Front Pharmacol 2020 28;11:621538. Epub 2021 Jan 28.

State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, China.

Acetaminophen (N-acetyl p-aminophenol or APAP) is used worldwide for its antipyretic and anti-inflammatory potential. However, APAP overdose sometimes causes severe liver damage. In this study, we elucidated the protective effects of carveol in liver injury, using molecular and approaches. Male BALB/c mice were divided into two experimental cohorts, to identify the best dose and to further assess the role of carveol in the nuclear factor E2-related factor; nuclear factor erythroid 2; p45-related factor 2 (Nrf2) pathway. The results demonstrated that carveol significantly modulated the detrimental effects of APAP by boosting endogenous antioxidant mechanisms, such as nuclear translocation of Nrf2 gene, a master regulator of the downstream antioxidant machinery. Furthermore, an inhibitor of Nrf2, called all-trans retinoic acid (ATRA), was used, which exaggerated APAP toxicity, in addition to abrogating the protective effects of carveol; this effect was accompanied by overexpression of inflammatory mediators and liver = 2ltoxicity biomarkers. To further support our notion, we performed virtual docking of carveol with Nrf2-keap1 target, and the resultant drug-protein interactions validated the findings. Together, our findings suggest that carveol could activate the endogenous master antioxidant Nrf2, which further regulates the expression of downstream antioxidants, eventually ameliorating the APAP-induced inflammation and oxidative stress.
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http://dx.doi.org/10.3389/fphar.2020.621538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883019PMC
January 2021

Three-dimensional chromatin ensemble reconstruction via stochastic embedding.

Structure 2021 Jun 9;29(6):622-634.e3. Epub 2021 Feb 9.

Bioinformatics Institute (BII), Agency for Science, Technology and Research (A(∗)STAR), 30 Biopolis Street, #07-01, Matrix, Singapore 138671, Singapore; Department of Biological Sciences (DBS), National University of Singapore (NUS), 8 Medical Drive, Singapore 117597, Singapore. Electronic address:

We propose a comprehensive method for reconstructing the whole-genome chromatin ensemble from the Hi-C data. The procedure starts from Markov state modeling (MSM), delineating the structural hierarchy of chromatin organization with partitioning and effective interactions archetypal for corresponding levels of hierarchy. The stochastic embedding procedure introduced in this work provides the 3D ensemble reconstruction, using effective interactions obtained by the MSM as the input. As a result, we obtain the structural ensemble of a genome, allowing one to model the functional and the cell-type variability in the chromatin structure. The whole-genome reconstructions performed on the human B lymphoblastoid (GM12878) and lung fibroblast (IMR90) Hi-C data unravel distinctions in their morphologies and in the spatial arrangement of intermingling chromosomal territories, paving the way to studies of chromatin dynamics, developmental changes, and conformational transitions taking place in normal cells and during potential pathological developments.
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http://dx.doi.org/10.1016/j.str.2021.01.008DOI Listing
June 2021

Circular RNA in pancreatic cancer: a novel avenue for the roles of diagnosis and treatment.

Theranostics 2021 1;11(6):2755-2769. Epub 2021 Jan 1.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.

Pancreatic cancer (PC), an important cause of cancer-related deaths worldwide, is one of the most malignant cancers characterized by a dismal prognosis. Circular RNAs (circRNAs), a class of endogenous ncRNAs with unique covalently closed loops, have attracted great attention in regard to various diseases, especially cancers. Compelling studies have suggested that circRNAs are aberrantly expressed in different cancer tissues and cell types, including PC. More specifically, circRNAs can modify the proliferation, progression, tumorigenesis and chemosensitivity of PC, and some circRNAs could serve as biomarkers for diagnosis and prognosis. Herein, we summarize what is currently known to be related to the biogenesis, functions and potential roles of human circRNAs in PC and their application prospects for PC clinical treatments.
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http://dx.doi.org/10.7150/thno.56174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806488PMC
January 2021

The value of a metabolic reprogramming-related gene signature for pancreatic adenocarcinoma prognosis prediction.

Aging (Albany NY) 2020 11 20;12(23):24228-24241. Epub 2020 Nov 20.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. Extensive enhancement of glycolysis and reprogramming of lipid metabolism are both associated with the development and progression of PDAC. Previous studies have suggested that various gene signatures could convey prognostic information about PDAC. However, the use of these signatures has some limitations, perhaps because of a lack of knowledge regarding the genetic and energy supply backgrounds of PDAC. Therefore, we conducted multi-mRNA analysis based on metabolic reprogramming to identify novel signatures for accurate prognosis prediction in PDAC patients. In this study, a three-gene signature comprising MET, ENO3 and CD36 was established to predict the overall survival of PDAC patients. The three-gene signature could divide patients into high- and low-risk groups by disparities in overall survival verified by log-rank test in two independent validation cohorts and could differentiate tumors from normal tissues with excellent accuracy in four Gene Expression Omnibus (GEO) cohorts. We also found a positive correlation between the risk score of the gene signature and inherited germline mutations in PDAC predisposition genes. A glycolysis and lipid metabolism-based gene nomogram and corresponding calibration curves showed significant performance for survival prediction in the TCGA-PDAC dataset. The high-risk designation was closely connected with oncological signatures and multiple aggressiveness-related pathways, as determined by gene set enrichment analysis (GSEA). In summary, our study developed a three-gene signature and established a prognostic nomogram that objectively predicted overall survival in PDAC. The findings could provide a reference for the prediction of overall survival and could aid in individualized management for PDAC patients.
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http://dx.doi.org/10.18632/aging.104134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762467PMC
November 2020

Boosting Knowledge Base Automatically via Few-Shot Relation Classification.

Front Neurorobot 2020 27;14:584192. Epub 2020 Oct 27.

Science and Technology on Information Systems Engineering Laboratory, National University of Defense Technology, Changsha, China.

Relation classification (RC) aims at extracting structural information, i.e., triplets of two entities with a relation, from free texts, which is pivotal for automatic knowledge base construction. In this paper, we investigate a fully automatic method to train a RC model which facilitates to boost the knowledge base. Traditional RC models cannot extract new relations unseen during training since they define RC as a multiclass classification problem. The recent development of few-shot learning (FSL) provides a feasible way to accommodate to fresh relation types with a handful of examples. However, it requires a moderately large amount of training data to learn a promising few-shot RC model, which consumes expensive human labor. This issue recalls a kind of weak supervision methods, dubbed distant supervision (DS), which can generate the training data automatically. To this end, we propose to investigate the task of . As DS naturally brings in mislabeled training instances, to alleviate the negative impact, we incorporate various multiple instance learning methods into the classic prototypical networks, which can achieve sentence-level noise reduction. In experiments, we evaluate our proposed model under the standard -way -shot setting of few-shot learning. The experiment results show that our proposal achieves better performance.
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http://dx.doi.org/10.3389/fnbot.2020.584192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652790PMC
October 2020

Integrating CRISPR-Cas12a with a DNA circuit as a generic sensing platform for amplified detection of microRNA.

Chem Sci 2020 Jul 19;11(28):7362-7368. Epub 2020 Jun 19.

State Key Laboratory of Chemo/Biosensing and Chemometrics , College of Chemistry and Chemical Engineering , Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology , Hunan University , Changsha 410082 , P. R. China . Email:

CRISPR-based diagnostics (CRISPR-Dx) has shown great promise in molecular diagnostics, but its utility in the sensing of microRNA (miRNA) biomarkers is limited by sensitivity, cost and robustness. Here, we describe a CRISPR-Dx method for the sensitive and cost-effective detection of miRNAs by rationally integrating CRISPR-Cas12a with DNA circuits. In this work, a modular catalytic hairpin assembly (CHA) circuit is designed to convert and amplify each target into multiple programmable DNA duplexes, which serve as triggers to initiate the -cleavage activity of CRISPR-Cas12a for further signal amplification. Such rational integration provides a generic assay for the effectively amplified detection of miRNA biomarkers. By simply tuning the variable regions in the CHA modules, this assay achieves sub-femtomolar sensitivity for different miRNA biomarkers, which improves the detection limit of CRISPR-Dx in the analysis of miRNA by 3-4 orders of magnitude. With the usage of the proposed assay, the sensitive assessment of miR-21 levels in different cancer cell lines and clinical serum samples has been achieved, providing a generic method for the sensitive detection of miRNA biomarkers in molecular diagnosis.
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http://dx.doi.org/10.1039/d0sc03084hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553042PMC
July 2020

Bufalin exerts antitumor effects in neuroblastoma via the induction of reactive oxygen species‑mediated apoptosis by targeting the electron transport chain.

Int J Mol Med 2020 Dec 6;46(6):2137-2149. Epub 2020 Oct 6.

Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China.

The prognosis of high‑risk neuroblastoma remains poor. Clinical first‑line drugs for treating neuroblastoma have been developed over the previous half‑century; however, progress in the identification of new drugs with high efficiency is required. Bufalin, one of the major components of extracts obtained from the venom of the Chinese toad Bufo gargarizans, which is used to treat heart failure in Asian Pacific countries, has been reported to be a potential drug against multiple types of tumor; however, the detailed mechanisms underlying its antitumor activities remain unclear, largely due to lack of knowledge regarding its targets. In the present study, bufalin was revealed to exhibit potent antitumor effects against neuroblastoma, both in vitro and in vivo, using cell proliferation, colony formation, Transwell migration and flow cytometry assays, as well as a nude mouse subcutaneous xenograft model. Moreover, a chemically modified bufalin probe was designed to identify the potential targets of bufalin in neuroblastoma via chemical proteomics. With this strategy, it was revealed that the electron transport chain (ETC) on the inner membrane of mitochondria may contain potential targets for bufalin, and that bufalin‑induced mitochondrial‑dependent apoptosis may be caused by disruption of the ETC. Collectively, the present study suggests that bufalin may a promising drug for chemotherapy against neuroblastoma, and provides a foundation for further studies into the antitumor mechanisms of bufalin.
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http://dx.doi.org/10.3892/ijmm.2020.4745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595673PMC
December 2020

A Potent Antioxidant Endogenous Neurohormone Melatonin, Rescued MCAO by Attenuating Oxidative Stress-Associated Neuroinflammation.

Front Pharmacol 2020 21;11:1220. Epub 2020 Aug 21.

State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, China.

Ischemic stroke is an acute neurological syndrome either due to permanent or temporary obstruction of blood. Such obstruction immediately triggers abrupt pathological cascading processes, which collectively lead to neuronal cell death. Oxidative stress and neuroinflammation in ischemic stroke are critical regulating events that ultimately lead to neuronal death. Complicated interplay exists between the two processes which occur through several stages. Most often, oxidative stress precedes the inflammatory mechanisms and includes several interconnected cascades that underlie the ischemic stroke pathology. In continuation of the previously published data, here, we further ruled out the protective role of melatonin in focal cerebral ischemic injury model. Administration of 5 mg/kg dose of melatonin 30 min prior to ischemia reduced brain infarction associated with sequentially rescued neuronal apoptosis. Furthermore, melatonin attenuated neuroinflammatory markers and reactive oxygen species (ROS), induced by ischemic stroke, halting the key players of mitogen stress family (p38/JNK). Besides, melatonin modulated the endogenously produced antioxidant enzyme, thioredoxin (Trx) pathway. These broader therapeutic efficacies of melatonin suggest that melatonin could be further investigated for its diverse therapeutic actions with multiple targets in recovering, preventing and halting the detrimental outcomes of MCAO, such as elevated oxidative stress, neuroinflammation, and neurodegeneration.
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http://dx.doi.org/10.3389/fphar.2020.01220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472569PMC
August 2020

Sex Differences in Intestinal Microbial Composition and Function of Hainan Special Wild Boar.

Animals (Basel) 2020 Sep 2;10(9). Epub 2020 Sep 2.

College of Animal Science and Technology, Hainan University, Haikou 570228, China.

The gut microbiome plays an important role in the health and disease status of the host. Research on the effect of sex on animal intestinal microorganisms is still limited; and the effect of castration on the gut microbiome of male pigs has not been fully investigated. In this study, 30 Hainan special wild boars at the same growth stage were divided into three groups (10 entire males, 10 females, and 10 castrated males). High-throughput 16S rRNA sequencing was used to investigate the fecal microbiota of the Hainan special wild boar. Firmicutes, Bacteroidetes, Actinobacteria, Spirochaetes, and Proteobacteria were the five dominant phyla found in the specimens. The relative abundance of Bacteroidetes was higher in the microbiota of female pigs than in male pigs, while Firmicutes was on the contrary. The percentage of and was higher in males than females. The microbial diversity of females was significantly higher compared to males; castration increased the intestinal microbial diversity of males. Functional prediction showed that male fecal microorganisms were rich in membrane transport and carbohydrate metabolism; energy metabolism, glycan biosynthesis, and metabolism of cofactors and vitamins were rich in the female group; the fecal microorganisms of castrated males had higher membrane transport abundance.
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http://dx.doi.org/10.3390/ani10091553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552319PMC
September 2020

Evaluation of resorption and osseointegration of autogenous bone ring grafting in vertical  bone defect with simultaneous  implant placement in dogs.

J Oral Implantol 2020 Aug 31. Epub 2020 Aug 31.

Southwest Medical Universtiy College of stomatology 2, Jiangyang South Road CHINA Luzhou Sichuan 646000 Sichuan University;Southwest Medical Universtiy.

The aim of this research was to evaluate the resorption and osseointegration of an autogenous bone ring, which was grafted in a local vertical alveolar defect with simultaneous implant placement. Six Beagle dogs were enrolled in the study; their four nonadjacent mandibular premolars were extracted, and the buccal plate was removed to create bone defects in two of the four sites. Three months after extraction, Straumann implants (Ø 3.3 mm, length of 8 mm) were placed in the bone defect sites with simultaneous autogenous bone ring grafting and in the conventional extraction sites. After a 3-month healing period and a 3-month loading period, the animals were euthanized. The harvested samples were analyzed using micro-CT scanning and histological analysis. From the micro-CT measurements, the average vertical bone resorption of the bone ring was 0.23±0.03 mm, which was not significantly different from that around the conventional implant, 0.24±0.12 mm (P > 0.05). The ratio of the bone volume to the total volume of the bone ring group was 91.11±0.02, which was higher than that of the control group, 88.38±2.34 (P < 0.05). From the hard tissue section, the bone rings developed fine osseointegration with the implants and the base alveolar bone. The results suggest autogenous bone ring grafting with simultaneous implant placement can survive in a local vertical bone defect with little bone resorption and good osseointegration in dogs with strict management. A bone ring graft must be compared with guided bone generation (GBR), and a larger and longer observation must be confirmed in clinical patients.
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http://dx.doi.org/10.1563/aaid-joi-D-19-00199DOI Listing
August 2020

New Incision and Flap Designs in Autogenous Bone Ring Grafting with Simultaneous Implant Placement and an Evaluation of the Effect of First-Stage Wound Dehiscence in Dogs.

Int J Oral Maxillofac Implants 2020 Jul/Aug;35(4):721-730

Purpose: The aim of this study was to explore the effect of preventing first-stage wound dehiscence with new types of incision and flap design and to evaluate the effect of wound dehiscence on the bone resorption of the autogenous bone ring graft.

Materials And Methods: In six beagle dogs, the second and fourth premolars on the bilateral mandible were extracted. After 3 months, on the left extraction sites, conventional alveolar crest incisions were made and the full-thickness flaps were elevated. However, on the right sites, the incisions were made at the mucogingival junction, the split-thickness flaps were elevated toward the lingual side, and the periosteum was elevated toward the buccal side. Then, Straumann implants (. 3.3, length 8 mm) were placed with simultaneous autogenous bone ring grafting. Next, the wounds on the left side were closed with periosteal releasing on buccal flaps conventionally, but the semi-thickness flaps on the right side were sutured with the elevated periosteum. After 3 months, the animals were euthanized, and the harvested samples were analyzed using microcomputed tomography and histology.

Results: The incidence rate of wound dehiscence in the new incision group was 16.7%, which was significantly lower than that in the conventional incision group (75%). There was hardly any vertical bone loss of the bone ring in the samples without wound dehiscence, but in wound dehiscence samples, severe bone loss, 2.47 ± 0.17 mm, was found on the buccal side of the bone ring, which was significantly higher than that on the lingual, mesial, and distal sides, 1.37 ± 0.14 mm, 1.00 ± 0.15 mm, and 1.03 ± 0.05 mm, respectively.

Conclusion: The use of a mucogingival junction incision and split-thickness flap design can effectively prevent first-stage wound dehiscence in autogenous bone ring grafting, which plays a key role in bone resorption of the graft.
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http://dx.doi.org/10.11607/jomi.8010DOI Listing
August 2020

Potent Natural Antioxidant Carveol Attenuates MCAO-Stress Induced Oxidative, Neurodegeneration by Regulating the Nrf-2 Pathway.

Front Neurosci 2020 26;14:659. Epub 2020 Jun 26.

State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, China.

Ischemic stroke is a severe neurological disorder with a high prevalence rate in developed countries. It is characterized by permanent or transient cerebral ischemia and it activates syndrome of pathological events such as membrane depolarization, glutamate excitotoxicity, and intracellular calcium buildup. Carveol is widely employed as anti-inflammatory and antioxidant in traditional Chinese medicine. In the present study, the neuroprotective effects of post-treated carveol were demonstrated against transient middle cerebral artery occlusion (MCAO) induced focal ischemic cerebral injury. Male Sprague Dawley (SD) rats were subjected to two different experimental protocols to determine the dose and effects of carveol, and to demonstrate the underlying role of the nuclear factor E2-related factor (Nrf2) pathway. Our results showed that MCAO induced marked neuronal injury in the ipsilateral cortex and striatum associated with higher inflammatory cytokines expression, along with apoptotic markers such as caspase-3 and the phosphorylated -Jun -terminal kinase (JNK). Furthermore, MCAO induced a marked increase in oxidative stress as evidenced by high lipid peroxidase (LPO) content accompanied by the depressed antioxidant system. Carveol significantly reversed the oxidative stress and downregulated inflammatory cascades by enhancing endogenous antioxidant mechanisms including the Nrf2 gene, which critically regulates the expression of several downstream antioxidants. Further, to determine the possible involvement of Nrf2 in carveol mediated neuroprotection, we antagonized Nrf2 by all- retinoic acid (ATRA), and such treatment abrogated the protective effects of carveol accompanied with exaggerated neuronal toxicity as demonstrated by higher infarction area. The target effects of carveol were further supported by molecular docking analysis of drug-protein interactions. Together, our findings suggest that carveol could activate endogenous master anti-oxidant Nrf2, which further regulates the expression of downstream antioxidants, eventually ameliorating MCAO-induced neuroinflammation and neurodegeneration.
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http://dx.doi.org/10.3389/fnins.2020.00659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344277PMC
June 2020

Machine Learning Models of Groundwater Arsenic Spatial Distribution in Bangladesh: Influence of Holocene Sediment Depositional History.

Environ Sci Technol 2020 08 23;54(15):9454-9463. Epub 2020 Jul 23.

Guangdong Provincial Key Laboratory of Soil and Groundwater Pollution Control, School of Environmental Science and Engineering, Southern University of Science and Technology, Shenzhen 518055, China.

Recent advances in machine learning methods offer the opportunity to improve risk assessment and to decipher factors influencing the spatial variability of groundwater arsenic ([As]). A systematic comparison reveals that boosted regression trees (BRT) and random forest (RF) outperform logistic regression. The probability of [As] exceeding 5 μg/L (approximate median value of Bangladesh [As]), 10 μg/L (WHO provisional guideline value), and 50 μg/L (Bangladesh drinking water standard) is modeled by BRT and RF methods for Bangladesh and its four subregions demarcated by major rivers. Of the 109 geo-environmental and hydrochemical predictor variables, phosphorus and iron emerge as the most important across spatial scales, consistent with known As mobilization mechanisms. Well depth is significant only when hydrochemical parameters are not considered, consistent with prior studies. A peak of probability of [As] exceedance at ∼30 m depth is evident in the partial dependence plots (PDPs) for spatial-parameter-only models but not in the equivalent all-parameter models, suggesting that sediment depositional history explains interdependent spatial patterns of groundwater As-P-Fe in Holocene aquifers. The South region exhibits a decrease of probability of [As] exceedance below 150 m depth in PDPs for spatial-parameter-only and all-parameter models, supporting that the deeper Pleistocene aquifer is a low-As water resource.
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http://dx.doi.org/10.1021/acs.est.0c03617DOI Listing
August 2020

Correlation between gingival phenotype in the aesthetic zone and craniofacial profile-a CBCT-based study.

Clin Oral Investig 2021 Mar 9;25(3):1363-1374. Epub 2020 Jul 9.

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

Objectives: To investigate the correlation between gingival phenotype and craniofacial profile and to evaluate the morphology of periodontal supporting tissues in the maxillary and mandibular anterior zones.

Materials And Methods: A total of 66 patients with 264 central incisors in good periodontal health were included in this cross-sectional study. CBCT images were used to assess gingiva and alveolar bone thickness of the maxillary and mandibular incisors at four vertical levels. Cephalometric analysis was used to assess the sagittal profile of the craniofacial structures. Gingival thickness was compared in patients with different craniofacial profiles based on ANB value. Linear regression coefficients adjusted by age and gender were used to evaluate the correlation between gingival thickness and the cephalometric parameters.

Results: Individuals with a smaller ANB value (ANB< 2) presented with thinner supporting tissue and a keratinized gingiva width in the anterior zone. Labial gingival thickness on the mandibular incisors at the cementoenamel junction (G1) and at the alveolar bone crest (G2) was positively related to cephalometric measures, indicating a maxillae-mandibular sagittal relationship (ANB value, Wits appraisal, A-NPog value).

Conclusions: A moderate correlation was found between mandibular gingival thickness and the sagittal craniofacial profile. Patients with a concave craniofacial profile had a smaller keratinized gingiva width and gingival thickness in the aesthetic zone.

Clinical Relevance: Knowledge of these features on supporting tissue and their correlations with craniofacial morphology will help clinicians to develop a reasonable treatment plan and make decisions to achieve the best aesthetic outcome.
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http://dx.doi.org/10.1007/s00784-020-03444-9DOI Listing
March 2021

Melatonin Act as an Antidepressant via Attenuation of Neuroinflammation by Targeting Sirt1/Nrf2/HO-1 Signaling.

Front Mol Neurosci 2020 12;13:96. Epub 2020 Jun 12.

State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.

Physical or psychological stress can cause an immunologic imbalance that disturbs the central nervous system followed by neuroinflammation. The association between inflammation and depression has been widely studied in recent years, though the molecular mechanism is still largely unknown. Thus, targeting the signaling pathways that link stress to neuroinflammation might be a useful strategy against depression. The current study investigated the protective effect of melatonin against lipopolysaccharide (LPS)-induced neuroinflammation and depression. Our results showed that LPS treatment significantly induced depressive-like behavior in mice. Moreover, LPS-treatment enhanced oxidative stress, pro-inflammatory cytokines including TNFα, IL-6, and IL-1β, NF-κB phosphorylation, and glial cell activation markers including GFAP and Iba-1 in the brain of mice. Melatonin treatment significantly abolished the effect of LPS, as indicated by improved depressive-like behaviors, reduced cytokines level, reduced oxidative stress, and normalized LPS-altered Sirt1, Nrf2, and HO-1 expression. However, the melatonin protective effects were reduced after luzindole administration. Collectively, it is concluded that melatonin receptor-dependently protects against LPS-induced depressive-like behaviors via counteracting LPS-induced neuroinflammation.
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http://dx.doi.org/10.3389/fnmol.2020.00096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304371PMC
June 2020

Maternal exposure to environmental endocrine disruptors during pregnancy is associated with pediatric germ cell tumors.

Nagoya J Med Sci 2020 May;82(2):323-333

Department of Pediatric Hematology/Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.

Environmental endocrine disruptors (EEDs) are natural or synthetic chemical compounds that interfere with normal endocrine function in both wildlife and humans. Previous studies have indicated that EEDs may contribute to oncogenesis. This study explores the relationship between EEDs and pediatric germ cell tumors (GCTs). A case-control study was conducted in 84 pediatric patients from 2014 to 2017, including 42 subjects with immature teratoma, yolk sac tumor, or germinoma, and 42 controls who experienced pneumonia or trauma. Serum PFASs, including PFBS, PFHpA, PFHxS, PFOA, PFOS, PFNA, PFDA, PFUA, PFOSA, and PFDoA, were measured in each subject, and their history of possible EED exposure was reviewed. Six of the 10 measured PFASs were significantly increased in the GCT group relative to the control group. With respect to lifestyle history, only PFHxS levels were statistically significantly associated with GCTs as determined by logistic regression analysis. The odds ratio for a 1 ng/L increase in PFHxS was 19.47 (95% CI: 4.20-90.26). Furthermore, in the GCT and control groups, both parental consumption of barbecued foods and hair dye use among parents were significantly correlated with elevated serum PFHxS levels (ρ = 0.383, 0.325 in the patient group and ρ = 0.370, 0.339 in the control group; < 0.05). Our study confirmed that children with GCTs from our institute had relatively high serum levels of PFASs relative to those of tumor-free pediatric patients. Serum PFHxS levels were independently associated with germ cell tumor occurrence.
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http://dx.doi.org/10.18999/nagjms.82.2.315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276419PMC
May 2020

Insights into the Role of Magnesium Ions in Affecting Osteogenic Differentiation of Mesenchymal Stem Cells.

Biol Trace Elem Res 2021 Feb 24;199(2):559-567. Epub 2020 May 24.

National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen, 518036, People's Republic of China.

Bone marrow mesenchymal stem cells (MSCs) are multipotent stem cells with the ability to differentiate into bone-producing cells, which is essential for bone formation. Magnesium biomedical materials, such as biodegradable matters with osteoinductive properties, play a vital role in the osteogenic differentiation of MSCs. International and Chinese studies have shown that magnesium ions, which are produced by biodegradation, mainly achieve this effect by regulating the expression of genes and proteins associated with osteogenesis, activating multiple signal pathways, elevating autophagic activities, and adjusting the pH in the microenvironment. It is of great significance to study the regulatory mechanisms and identify the optimal conditions that how magnesium ions promote osteogenic differentiation of MSCs. In this study, we summarized the regulatory mechanisms noted above.
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http://dx.doi.org/10.1007/s12011-020-02183-yDOI Listing
February 2021

AlloSigMA 2: paving the way to designing allosteric effectors and to exploring allosteric effects of mutations.

Nucleic Acids Res 2020 07;48(W1):W116-W124

Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01, Matrix, 138671, Singapore.

The AlloSigMA 2 server provides an interactive platform for exploring the allosteric signaling caused by ligand binding and/or mutations, for analyzing the allosteric effects of mutations and for detecting potential cancer drivers and pathogenic nsSNPs. It can also be used for searching latent allosteric sites and for computationally designing allosteric effectors for these sites with required agonist/antagonist activity. The server is based on the implementation of the Structure-Based Statistical Mechanical Model of Allostery (SBSMMA), which allows one to evaluate the allosteric free energy as a result of the perturbation at per-residue resolution. The Allosteric Signaling Map (ASM) providing a comprehensive residue-by-residue allosteric control over the protein activity can be obtained for any structure of interest. The Allosteric Probing Map (APM), in turn, allows one to perform the fragment-based-like computational design experiment aimed at finding leads for potential allosteric effectors. The server can be instrumental in elucidating of allosteric mechanisms and actions of allosteric mutations, and in the efforts on design of new elements of allosteric control. The server is freely available at: http://allosigma.bii.a-star.edu.sg.
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http://dx.doi.org/10.1093/nar/gkaa338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319554PMC
July 2020