Publications by authors named "Ting Gong"

206 Publications

Conversion of stem cells from apical papilla into endothelial cells by small molecules and growth factors.

Stem Cell Res Ther 2021 May 3;12(1):266. Epub 2021 May 3.

Restorative Dental Sciences, Faculty of Dentistry, The University of Hong Kong, Hong Kong Special Administrative Region, China.

Objectives: Recently, a new strategy has been developed to directly reprogram one cell type towards another targeted cell type using small molecule compounds. Human fibroblasts have been chemically reprogrammed into neuronal cells, Schwann cells and cardiomyocyte-like cells by different small molecule combinations. This study aimed to explore whether stem cells from apical papilla (SCAP) could be reprogrammed into endothelial cells (ECs) using the same strategy.

Materials And Methods: The expression level of endothelial-specific genes and proteins after chemical induction of SCAP was assessed by RT-PCR, western blotting, flow cytometry and immunofluorescence. The in vitro functions of SCAP-derived chemical-induced endothelial cells (SCAP-ECs) were evaluated by tube-like structure formation assay, acetylated low-density lipoprotein (ac-LDL) uptake and NO secretion detection. The proliferation and the migration ability of SCAP-ECs were evaluated by CCK-8 and Transwell assay. LPS stimulation was used to mimic the inflammatory environment in demonstrating the ability of SCAP-ECs to express adhesion molecules. The in vivo Matrigel plug angiogenesis assay was performed to assess the function of SCAP-ECs in generating vascular structures using the immune-deficient mouse model.

Results: SCAP-ECs expressed upregulated endothelial-specific genes and proteins; displayed endothelial transcriptional networks; exhibited the ability to form functional tubular-like structures, uptake ac-LDL and secrete NO in vitro; and contributed to generate blood vessels in vivo. The SCAP-ECs could also express adhesion molecules in the pro-inflammatory environment and have a similar migration and proliferation ability as HUVECs.

Conclusions: Our study demonstrates that the set of small molecules and growth factors could significantly promote endothelial transdifferentiation of SCAP, which provides a promising candidate cell source for vascular engineering and treatment of ischemic diseases.
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http://dx.doi.org/10.1186/s13287-021-02350-5DOI Listing
May 2021

A protein-fragment complementation assay reveals that celastrol and gambogic acid suppress ERα mutants in breast cancer.

Biochem Pharmacol 2021 Apr 26:114583. Epub 2021 Apr 26.

Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address:

Somatic gain-of-function mutations within estrogen receptor alpha (ERα) are highly associated with hormone therapy resistance in breast cancer. However, current understanding of abnormal activity of ERα mutants and its relevant targeted intervention is still very limited. Herein, we developed a new, real-time, and reliably Gaussia luciferase-based protein-fragment complementation assay (GLPCA) for ERα mutants. We found that, compared with ER WT, ERα mutants (Y537S/N and D538G) exhibit high ligand-independent activity, suggesting the gain-of-function phenotype of these ERα mutants. Notably, Y537S, the most common ERα mutant type, has the highest intrinsic activation. We then collected and screened a natural product library for potential ERα antagonists via GLPCA and identified celastrol and gambogic acid as new antagonists of the ERα Y537S mutant. Moreover, interactions between these two compounds and the ERα Y537S mutant were confirmed by molecular docking and cellular thermal shift assay. Importantly, we further demonstrated that celastrol and gambogic acid exhibit synergistic antiproliferative and pro-apoptotic effects when combined with an approved CDK4/6 inhibitor abemaciclib in breast cancer cells expressing ERα Y537S. In summary, GLPCA provides a powerful platform for exploring innovative functional biology and drug discovery of antagonists targeting ERα mutants.
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http://dx.doi.org/10.1016/j.bcp.2021.114583DOI Listing
April 2021

Building protein networks in synthetic systems from the bottom-up.

Biotechnol Adv 2021 Apr 12;49:107753. Epub 2021 Apr 12.

Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, United States of America. Electronic address:

The recent development of synthetic biology has expanded the capability to design and construct protein networks outside of living cells from the bottom-up. The new capability has enabled us to assemble protein networks for the basic study of cellular pathways, expression of proteins outside cells, and building tissue materials. Furthermore, the integration of natural and synthetic protein networks has enabled new functions of synthetic or artificial cells. Here, we review the underlying technologies for assembling protein networks in liposomes, water-in-oil droplets, and biomaterials from the bottom-up. We cover the recent applications of protein networks in biological transduction pathways, energy self-supplying systems, cellular environmental sensors, and cell-free protein scaffolds. We also review new technologies for assembling protein networks, including multiprotein purification methods, high-throughput assay screen platforms, and controllable fusion of liposomes. Finally, we present existing challenges towards building protein networks that rival the complexity and dynamic response akin to natural systems. This review addresses the gap in our understanding of synthetic and natural protein networks. It presents a vision towards developing smart and resilient protein networks for various biomedical applications.
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http://dx.doi.org/10.1016/j.biotechadv.2021.107753DOI Listing
April 2021

Measurement of the permanent electric dipole moment of ultracold ground state RbCs molecules by microwave coherent spectroscopy.

Opt Express 2021 Jan;29(2):1558-1565

We demonstrate measurement of the permanent electric dipole moment (EDM) of RbCs molecules in the absolute vibrational ground state by microwave (MW) coherent spectroscopy. The rotational states of the considered molecules, which are formed from short-range photoassociation of mixed cold atoms, are nondegenerated under external electric field. To measure the EDM based on electric-field-induced shifts of the sublevels of XΣ(v = 0, J = 1) rotational state, we utilized a MW coherent spectroscopy, which has a higher resolution than depletion spectroscopy and one-photon MW spectroscopy and can also eliminate the influence from Stark shift of the excited state existing in both spectroscopies above. In order to acquire accurate electric intensity, electromagnetic induced transparency spectroscopy of Rb Rydberg atoms is used to implement the calibration. The permanent EDM of RbCs molecules is finally determined to be 1.266(15) D, which agrees with the theoretical calculations and is comparable with the value of its isotopic molecule.
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http://dx.doi.org/10.1364/OE.411249DOI Listing
January 2021

Microwave-assisted coherent control of ultracold polar molecules in a ladder-type configuration of rotational states.

Phys Chem Chem Phys 2021 Feb;23(7):4271-4276

Shanxi University, State Key Laboratory of Quantum Optics and Quantum Optics Devices, Institute of Laser Spectroscopy, Wucheng Rd 92, 030006 Taiyuan, China. and Shanxi University, Collaborative Innovation Center of Extreme Optics, Wucheng Rd 92, 030006 Taiyuan, China.

We demonstrate microwave-assisted coherent control of ultracold 85Rb133Cs molecules in a ladder-type configuration of rotational states. Specifically, we use a probe and a control MW field to address the transitions between the J = 1 → 2 and J = 2 → 3 rotational states of the X1Σ+(v = 0) vibrational level, respectively, and use the control field to modify the response of the probe MW transition by coherently reducing the population of the intermediate J = 2 state. We observe that an increased Rabi frequency of the control field leads to broadening of the probe spectrum splitting and a shift of the central frequency. We apply Akaike's information criterion (AIC) to conclude that the observed coherent spectral response appears across the crossover regime between electromagnetically induced transparency and Aulter-Townes splitting. Our work is a significant development in microwave-assisted quantum control of ultracold polar molecules with multilevel configuration.
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http://dx.doi.org/10.1039/d1cp00202cDOI Listing
February 2021

Longitudinal Expression of Testicular from Prepuberty to Sexual Maturity in Congjiang Xiang Pigs.

Animals (Basel) 2021 Feb 8;11(2). Epub 2021 Feb 8.

College of Animal Science, Guizhou University, Guiyang 550025, China.

Testicular expression of taste receptor type 1 subunit 3 (T1R3), a sweet/umami taste receptor, has been implicated in spermatogenesis and steroidogenesis in mice. We explored the role of testicular T1R3 in porcine postnatal development using the Congjiang Xiang pig, a rare Chinese miniature pig breed. Based on testicular weights, morphology, and testosterone levels, four key developmental stages were identified in the pig at postnatal days 15-180 (prepuberty: 30 day; early puberty: 60 day; late puberty: 90 day; sexual maturity: 120 day). During development, testicular T1R3 exhibited stage-dependent and cell-specific expression patterns. In particular, T1R3 levels increased significantly from prepuberty to puberty ( < 0.05), and expression remained high until sexual maturity ( < 0.05), similar to results for phospholipase Cβ2 (PLCβ2). The strong expressions of T1R3/PLCβ2 were observed at the cytoplasm of elongating/elongated spermatids and Leydig cells. In the eight-stage cycle of the seminiferous epithelium in pigs, T1R3/PLCβ2 levels were higher in the spermatogenic epithelium at stages II-VI than at the other stages, and the strong expressions were detected in elongating/elongated spermatids and residual bodies. The message RNA (mRNA) levels of taste receptor type 1 subunit 1 (T1R1) in the testis showed a similar trend to levels of T1R3. These data indicate a possible role of T1R3 in the regulation of spermatid differentiation and Leydig cell function.
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http://dx.doi.org/10.3390/ani11020437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916009PMC
February 2021

Radiative lifetime measurement of ultracold cesium Rydberg states by a simplified optical pumping method.

Appl Opt 2021 Jan;60(2):276-280

We demonstrate one simplified all-optical method to measure the radiative lifetime of ultracold cesium (Cs) Rydberg atoms. This method is based on photodetection of one ground state atomic absorption in a ladder-type electromagnetic induced transparency (EIT), which contains one ground state, one intermediate state, and one Rydberg state. In the presence and absence of optical pumping between the Rydberg state and the intermediate state, the absorption difference with varying delay time can reconstruct the population evolution of target Rydberg atoms. By using this method, the radiative lifetimes of 50 and 50 of Cs atoms are measured to be 53(9)µ and 42(9)µ, respectively, which are consistent with theoretical calculations. The agreements show the reliability of our presented method, which can provide a route for researching light-matter interaction behavior without the need to quantify absorption characteristic.
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http://dx.doi.org/10.1364/AO.411240DOI Listing
January 2021

Salidroside Inhibits Reactive Astrogliosis and Glial Scar Formation in Late Cerebral Ischemia via the Akt/GSK-3β Pathway.

Neurochem Res 2021 Apr 3;46(4):755-769. Epub 2021 Jan 3.

China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People's Republic of China.

Cerebral ischemia leads to reactive astrogliosis and glial scar formation. Glial scarring can impede functional restoration during the recovery phase of stroke. Salidroside has been shown to have neuroprotective effects after ischemic stroke, but its impact on long-term neurological recovery, especially whether it regulates reactive astrogliosis and glial scar formation, is unclear. In this study, male adult C57/BL6 mice were subjected to transient cerebral ischemia injury followed by intravenous salidroside treatment. Primary astrocytes were treated with lipopolysaccharide (LPS) or conditioned medium from cultured primary neurons subjected to oxygen-glucose deprivation (CM-OGD). Salidroside significantly improved long-term functional outcomes following ischemic stroke in the rotarod and corner tests. It also reduced brain glial scar volume and decreased expression of the glial scar marker, glial fibrillary acidic protein (GFAP) and inhibited astrocyte proliferation. In primary astrocyte cultures, salidroside protected astrocytes from CM-OGD injury-induced reactive astroglial proliferation, increasing the percentage of cells in G0/G1 phase and reducing the S populations. The inhibitory effect of salidroside on the cell cycle was related to downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4) mRNA expression and increased p27Kip1 mRNA expression. Similar results were found in the LPS-stimulated injury model in astroglial cultures. Western blot analysis demonstrated that salidroside attenuated the CM-OGD-induced upregulation of phosphorylated Akt and glycogen synthase kinase 3β (GSK-3β). Taken together, these results suggested that salidroside can inhibit reactive astrocyte proliferation, ameliorate glial scar formation and improve long-term recovery, probably through its effects on the Akt/GSK-3β pathway.
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http://dx.doi.org/10.1007/s11064-020-03207-8DOI Listing
April 2021

Tensile Behavior of High-Strength, Strain-Hardening Cement-Based Composites (HS-SHCC) Reinforced with Continuous Textile Made of Ultra-High-Molecular-Weight Polyethylene.

Materials (Basel) 2020 Dec 10;13(24). Epub 2020 Dec 10.

Institute of Construction Materials, Technische Universität Dresden, 01062 Dresden, Germany.

The paper at hand presents an investigation of the tensile behavior of high-strength, strain-hardening cement-based composites (HS-SHCC), reinforced with a single layer of continuous, two-dimensional textile made of ultra-high molecular weight polyethylene (UHMWPE). Uniaxial tension tests were performed on the bare UHMWPE textiles, on plain HS-SHCC, and on the hybrid fiber-reinforced composites. The bond properties between the textile yarns and the surrounding composite were investigated in single-yarn pullout experiments. In order to assess the influence of bond strength between the yarn and HS-SHCC on the tensile behavior of the composites with hybrid fiber reinforcement, the textile samples were analyzed both with, and without, an additional coating of epoxy resin and sand. Compared to the composites reinforced with carbon yarns in previous studies by the authors, the high elongation capacity of the UHMWPE textile established the higher strain capacity of the hybrid fiber-reinforced composites, and showed superior energy absorption capacity up to failure. The UHMWPE textile limited the average crack width in comparison with that of plain HS-SHCC, but led to slightly larger crack widths when compared to equivalent composites reinforced with carbon textile, the reason for which was traced back to the lower Young's modulus and the higher elongation capacity of the polymer textile.
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http://dx.doi.org/10.3390/ma13245628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763599PMC
December 2020

microRNA-219-5p targets NEK6 to inhibit hepatocellular carcinoma progression.

Am J Transl Res 2020 15;12(11):7528-7541. Epub 2020 Nov 15.

Department of Anesthesiology, Shenzhen Hospital of Southern Medical University Shenzhen 518100, China.

MicroRNA-219-5p (miR-219-5p) is a key post-transcriptional regulator of gene expression that is known to regulate cancer progression, but its role in the context of hepatocellular carcinoma (HCC) remains to be fully elucidated. Herein, it was found that this miRNA functions as a tumor suppressor. Specifically, significant decreases in miR-219-5p expression were detected in HCC cells and patient serum samples relative to that found in the serum of 15 healthy people, and it was concluded that miR-219-5p overexpression was sufficient to impair HCC cell proliferation and and migration . At the mechanistic level, it was found that miR-219-5p was able to suppress the expression of NEK6 (never in mitosis gene a-related kinase 6), thereby resulting in dysregulated β-catenin/c-Myc-regulated gene expression. When NEK6 was overexpressed in HCC cells, this was sufficient to reverse the inhibitory impact of miR-219-5p on HCC cell proliferation both and and metastasis . Bioinformatics analyses were also conducted, and both miR-219-5p and Nek6 were linked to disease progression in HCC patients with advanced disease. More importantly, the serum specimen data showed that reduced perioperative plasma miR-219-5p correlated significantly with increased risk of early recurrence after curative hepatectomy, whereas it was opposed to NEK6. Together, these findings highlight miR-219-5p as a potentially valuable diagnostic biomarker that can potentially be leveraged to improve clinical outcomes in HCC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724362PMC
November 2020

A comment on "Serological survey of SARS-CoV-2 for experimental, domestic, companion and wild animals excludes intermediate hosts of 35 different species of animals".

Transbound Emerg Dis 2020 Nov 3. Epub 2020 Nov 3.

Scientific Research Center, Guilin Medical University, Guilin, 541199, China.

In May 2020, Deng et al. (2020) published their article in Transboundary and Emerging Diseases providing evidence that no SARS-CoV-2-specific antibodies were detected in 1,914 samples which excluded the possibility of 35 animal species as intermediate host for SARS-CoV-2. In order to ensure the stability of SARS-CoV-2-specific antibodies in storaged serum samples, we strongly suggest that standard serum banks should be established.
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http://dx.doi.org/10.1111/tbed.13910DOI Listing
November 2020

Reproducibility of volume and asymmetry measurements of hippocampus, amygdala, and entorhinal cortex on traveling volunteers: a multisite MP2RAGE prospective study.

Acta Radiol 2020 Oct 29:284185120963919. Epub 2020 Oct 29.

Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing, PR China.

Background: Multisite studies can considerably increase the pool of normally aging individuals with neurodegenerative disorders and thereby expedite the associated research. Understanding the reproducibility of the parameters of related brain structures-including the hippocampus, amygdala, and entorhinal cortex-in multisite studies is crucial in determining the impact of healthy aging or neurodegenerative diseases.

Purpose: To estimate the reproducibility of the fascinating structures by automatic (FreeSurfer) and manual segmentation methods in a well-controlled multisite dataset.

Material And Methods: Three traveling individuals were scanned at 10 sites, which were equipped with the same equipment (3T Prisma Siemens). They used the same scan protocol (two inversion-contrast magnetization-prepared rapid gradient echo sequences) and operators. Validity coefficients (intraclass correlations coefficient [ICC]) and spatial overlap measures (Dice Similarity Coefficient [DSC]) were used to estimate the reproducibility of multisite data.

Results: ICC and DSC values varied substantially among structures and segmentation methods, and values of manual tracing were relatively higher than the automated method. ICC and DSC values of structural parameters were greater than 0.80 and 0.60 across sites, as determined by manual tracing. Low reproducibility was observed in the amygdala parameters by automatic segmentation method (ICC = 0.349-0.529, DSC = 0.380-0.873). However, ICC and DSC scores of the hippocampus were higher than 0.60 and 0.65 by two segmentation methods.

Conclusion: This study suggests that a well-controlled multisite study could provide a reliable MRI dataset. Manual tracing of volume assessments is recommended for low reproducibility structures that require high levels of precision in multisite studies.
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http://dx.doi.org/10.1177/0284185120963919DOI Listing
October 2020

Scaffolds with controlled release of pro-mineralization exosomes to promote craniofacial bone healing without cell transplantation.

Acta Biomater 2020 12 13;118:215-232. Epub 2020 Oct 13.

Department of Biologic and Materials Science, School of Dentistry, University of Michigan, Ann Arbor, USA; Macromolecular Science and Engineering Center, College of Engineering, University of Michigan, Ann Arbor, USA; Department of Biomedical Engineering, College of Engineering and Medical School, University of Michigan, Ann Arbor, USA; Department of Materials Science and Engineering, College of Engineering, University of Michigan, Ann Arbor, USA. Electronic address:

Biomimetic bone regeneration methods which demonstrate both clinical and manufacturing feasibility, as alternatives to autogenic or allogenic bone grafting, remain a challenge to the field of tissue engineering. Here, we report the pro-osteogenic capacity of exosomes derived from human dental pulp stem cells (hDPSCs) to facilitate bone marrow stromal cell (BMSC) differentiation and mineralization. To support their delivery, we engineered a biodegradable polymer delivery platform to improve the encapsulation and the controlled release of exosomes on a tunable time scale from poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) triblock copolymer microspheres. Our delivery platform integrates within three-dimensional tissue engineering scaffolds to enable a straightforward surgical insertion into a mouse calvarial defect. We demonstrate the osteogenic potential of these functional constructs in vitro and in vivo. Controlled release of osteogenic hDPSC-derived exosomes facilitates osteogenic differentiation of BMSCs, leading to mineralization to a degree which is comparable to exogenous administration of the same exosomes in human and mouse BMSCs. By recruiting endogenous cells to the defects and facilitating their differentiation, the controlled release of osteogenic exosomes from a tissue engineering scaffold demonstrates accelerated bone healing in vivo at 8 weeks. Exosomes recapitulate the advantageous properties of mesenchymal stem/progenitor cells, without manufacturing or immunogenic concerns associated with transplantation of exogenous cells. This biomaterial platform enables exosome-mediated bone regeneration in an efficacious and clinically relevant way.
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http://dx.doi.org/10.1016/j.actbio.2020.09.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796555PMC
December 2020

Evidence for anaphase pulling forces during C. elegans meiosis.

J Cell Biol 2020 12;219(12)

Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA.

Anaphase chromosome movement is thought to be mediated by pulling forces generated by end-on attachment of microtubules to the outer face of kinetochores. However, it has been suggested that during C. elegans female meiosis, anaphase is mediated by a kinetochore-independent pushing mechanism with microtubules only attached to the inner face of segregating chromosomes. We found that the kinetochore proteins KNL-1 and KNL-3 are required for preanaphase chromosome stretching, suggesting a role in pulling forces. In the absence of KNL-1,3, pairs of homologous chromosomes did not separate and did not move toward a spindle pole. Instead, each homolog pair moved together with the same spindle pole during anaphase B spindle elongation. Two masses of chromatin thus ended up at opposite spindle poles, giving the appearance of successful anaphase.
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http://dx.doi.org/10.1083/jcb.202005179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577052PMC
December 2020

Deep learning-based method for reducing residual motion effects in diffusion parameter estimation.

Magn Reson Med 2021 04 15;85(4):2278-2293. Epub 2020 Oct 15.

Center for Brain Imaging Science and Technology, Key Laboratory for Biomedical Engineering of Ministry of Education, College of Biomedical Engineering and Instrumental Science, Zhejiang University, Hangzhou, China.

Purpose: Conventional motion-correction techniques for diffusion MRI can introduce motion-level-dependent bias in derived metrics. To address this challenge, a deep learning-based technique was developed to minimize such residual motion effects.

Methods: The data-rejection approach was adopted in which motion-corrupted data are discarded before model-fitting. A deep learning-based parameter estimation algorithm, using a hierarchical convolutional neural network (H-CNN), was combined with motion assessment and corrupted volume rejection. The method was designed to overcome the limitations of existing methods of this kind that produce parameter estimations whose quality depends strongly on a proportion of the data discarded. Evaluation experiments were conducted for the estimation of diffusion kurtosis and diffusion-tensor-derived measures at both the individual and group levels. The performance was compared with the robust approach of iteratively reweighted linear least squares (IRLLS) after motion correction with and without outlier replacement.

Results: Compared with IRLLS, the H-CNN-based technique is minimally sensitive to motion effects. It was tested at severe motion levels when 70% to 90% of the data are rejected and when random motion is present. The technique had a stable performance independent of the numbers and schemes of data rejection. A further test on a data set from children with attention-deficit hyperactivity disorder shows the technique can potentially ameliorate spurious group-level difference caused by head motion.

Conclusion: This method shows great potential for reducing residual motion effects in motion-corrupted diffusion-weighted-imaging data, bringing benefits that include reduced bias in derived metrics in individual scans and reduced motion-level-dependent bias in population studies employing diffusion MRI.
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http://dx.doi.org/10.1002/mrm.28544DOI Listing
April 2021

Comment on article "Seroprevalence of Herpes simplex virus types 1 and 2 in Indian and Filipino migrant populations in Qatar: a cross-sectional survey".

East Mediterr Health J 2020 08 25;26(8):886-887. Epub 2020 Aug 25.

Scientific Research Center, Guilin Medical University, Guilin, China.

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http://dx.doi.org/10.26719/2020.26.8.886DOI Listing
August 2020

Germline DNMT3A mutation in familial acute myeloid leukaemia.

Epigenetics 2021 May 28;16(5):567-576. Epub 2020 Aug 28.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Acute myeloid leukaemia (AML) is a heterogeneous myeloid malignancy characterized by recurrent clonal events, including mutations in epigenetically relevant genes such as , and . Next-generation sequencing analysis of a mother and son pair who both developed adult-onset diploid AML identified a novel germline missense mutation p.P709S. The p.P709S protein-altering variant resides in the highly conserved catalytic DNMT3A methyltransferase domain. Functional studies demonstrate that the p.P709S variant confers dominant negative effects when interacting with wildtype . LINE-1 pyrosequencing and reduced representation bisulphite sequencing (RBBS) analysis demonstrated global DNA hypomethylation in germline samples, not present in the leukaemic samples. Somatic acquisition of p.R172K mutations, in concert with additional acquired clonal DNMT3A events in both patients at the time of AML diagnosis, confirms the important pathogenic interaction of epigenetically active genes, and implies a strong selection and regulation of methylation in leukaemogenesis. Improved characterization of germline mutations may enable us to better predict malignant clonal evolution, improving our ability to provide customized treatment or future preventative strategies.
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http://dx.doi.org/10.1080/15592294.2020.1809871DOI Listing
May 2021

Monoclonal Antibodies Specific to the Extracellular Domain of Histidine Kinase YycG of Inhibit Biofilm Formation.

Front Microbiol 2020 7;11:1839. Epub 2020 Aug 7.

Key Laboratory of Medical Molecular Virology of MOE and MOH, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

is frequently associated with biofilm-related infections. Biofilms drastically reduce the efficacy of conventional antibiotics and the host immune system. In biofilm formation, a major role is played by the YycG/YycF two-component system, and previous findings have indicated that inhibitors targeting the cytoplasmic HATPase_c domain of YycG kinase in exhibit bactericidal and biofilm-killing activities. Therefore, we hypothesized that monoclonal antibodies (mAbs) against YycG extracellular (YycG) domain would block the signal transduction and influence the biofilm formation of . In this study, we screened out two YycG-specific mAbs showing the highest affinity for the target, mAbs 2F3 and 1H1. These mAbs inhibited biofilm formation in a dose-dependent manner, and at a concentration of 160 μg/mL, mAbs 2F3 and 1H1 caused 78.3 and 93.1% biofilm reduction, respectively, relative to normal mouse IgG control. When co-cultivated with YycG mAbs, cells showed diminished initial-adherence capacity, and the antibody treatment further led to a marked decrease in the synthesis of polysaccharide intercellular adhesin and in the transcriptional level of genes encoding proteins involved in biofilm formation. Lastly, we determined that the epitopes recognized by the two YycG mAbs are located within aa 59-70 of the YycG domain. It indicates that the YycG domain may be a potential candidate as a vaccine for the prevention of biofilm infections.
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http://dx.doi.org/10.3389/fmicb.2020.01839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426370PMC
August 2020

Postnatal differentiation and regional histological variations in the ductus epididymidis of the Congjiang Xiang pig.

Tissue Cell 2020 Dec 18;67:101411. Epub 2020 Jul 18.

Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, Guizhou University, No. 515 Jiaxiu South Road, Guiyang, 550025, PR China; College of Animal Science, Guizhou University, No. 515 Jiaxiu South Road, Guiyang, 550025, PR China.

The Congjiang Xiang pig is a rare Chinese miniature breed whose epididymal histologic features through the postnatal development are poorly understood. To clarify the histomorphological differences between each region of epididymis during postnatal development, 24 male Congjiang Xiang pigs aged from neonatal (15 d), peri-puberty (30 d), puberty (60 d) to adult (180 d) stages, were examined. Postnatal differentiation of the different regions (I-V) of the epididymis started from birth and continued until maturity that showed regional variations. Developmental progression was disto-proximal. At the neonatal stage, Wolffian duct differentiation starts in the distal region, then ascends to the middle region which forms regions V, IV and III, respectively. A simple lined cuboidal in the epidydimal epithelial, which gradually differentiated into a pseudostratified columnar with stereocilia from neonatal to post-pubertal. After puberty cell rearrangement occurred in the epithelium, differentiation accelerated, and spermatozoon seen in the lumen, especially the lumen of region II. In region III, both halo and apical cells were frequently observed. At the post-pubertal stage, clear cells were frequently observed in Region IV-V, and the epididymal duct was markedly increased in size and fully packed with spermatozoa. The information presented in this study will be helpful for future evaluations of Congjiang Xiang pig fertility. After puberty cell rearrangement occurred in the epithelium, differentiation accelerated, and spermatozoon seen in the lumen, especially the lumen of region II. In region III, both halo and apical cells were frequently observed. At the post-pubertal stage, clear cells were frequently observed in Region IV-V, and the epididymal duct was markedly increased in size and fully packed with spermatozoa. The information presented in this study will be helpful for future evaluations of Congjiang Xiang pig fertility.
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http://dx.doi.org/10.1016/j.tice.2020.101411DOI Listing
December 2020

A deep learning-based method for improving reliability of multicenter diffusion kurtosis imaging with varied acquisition protocols.

Magn Reson Imaging 2020 11 18;73:31-44. Epub 2020 Aug 18.

Center for Brain Imaging Science and Technology, Key Laboratory for Biomedical Engineering of Ministry of Education, College of Biomedical Engineering and Instrumental Science, Zhejiang University, Hangzhou, Zhejiang, China; Department of Imaging Sciences, University of Rochester, Rochester, NY, USA. Electronic address:

Multicenter magnetic resonance imaging is gaining more popularity in large-sample projects. Since both varying hardware and software across different centers cause unavoidable data heterogeneity across centers, its impact on reliability in study outcomes has also drawn much attention recently. One fundamental issue arises in how to derive model parameters reliably from image data of varying quality. This issue is even more challenging for advanced diffusion methods such as diffusion kurtosis imaging (DKI). Recently, deep learning-based methods have been demonstrated with their potential for robust and efficient computation of diffusion-derived measures. Inspired by these approaches, the current study specifically designed a framework based on a three-dimensional hierarchical convolutional neural network, to jointly reconstruct and harmonize DKI measures from multicenter acquisition to reformulate these to a state-of-the-art hardware using data from traveling subjects. The results from the harmonized data acquired with different protocols show that: 1) the inter-scanner variation of DKI measures within white matter was reduced by 51.5% in mean kurtosis, 65.9% in axial kurtosis, 53.7% in radial kurtosis, and 61.5% in kurtosis fractional anisotropy, respectively; 2) data reliability of each single scanner was enhanced and brought to the level of the reference scanner; and 3) the harmonization network was able to reconstruct reliable DKI values from high data variability. Overall the results demonstrate the feasibility of the proposed deep learning-based method for DKI harmonization and help to simplify the protocol setup procedure for multicenter scanners with different hardware and software configurations.
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http://dx.doi.org/10.1016/j.mri.2020.08.001DOI Listing
November 2020

A preclinical randomized controlled study of ischemia treated with Ginkgo biloba extracts: Are complex components beneficial for treating acute stroke?

Curr Res Transl Med 2020 11 16;68(4):197-203. Epub 2020 Aug 16.

China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, PR China. Electronic address:

The rigorous design of preclinical experimental studies of candidate neuroprotectants for the treatment of acute ischemic stroke is crucial for the success of subsequent randomized clinical trials. The efficacy of Ginkgo biloba extracts (GBEs) in complex mixtures for the treatment of acute ischemic stroke remains unclear. In this preclinical randomized controlled trail (pRCT), the effects of a novel (n)GBE containing pinitol versus traditional (t)GBE without pinitol were evaluated on the mouse models of acute transient and permanent stroke, separately. The sample size, an important aspect of study design, was calculated based on our experimental data. Mice with ischemia that were induced by transient middle cerebral artery occlusion (tMCAO) or permanent distal middle cerebral artery occlusion (pdMCAO), were treated with vehicle, nGBE, tGBE, or pinitol alone by tail-vein injection. Our results showed that nGBE significantly reduced infarct size in mice with tMCAO compared with vehicle-treated control mice. Both nGBE and tGBE significantly reduced infarct size in mice with pdMCAO compared with the vehicle-treated controls. None of the three treatments rescued weight loss or prevented the neurological deficits in either the tMCAO- or pdMCAO-model mice. These findings suggest that nGBE, which includes all of the components of tGBE and pinitol, is neuroprotective in two ischemic stroke models. Additional studies of complex GBE mixtures for stroke treatment compared to single component medications are undergoing evaluation.
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http://dx.doi.org/10.1016/j.retram.2020.07.002DOI Listing
November 2020

Copper Kills Persister Cells.

Antibiotics (Basel) 2020 Aug 12;9(8). Epub 2020 Aug 12.

Department of Chemical Engineering, Pennsylvania State University, University Park, PA 16802, USA.

Due to their reduced metabolism, persister cells can survive most antimicrobial treatments, which usually rely on corrupting active biochemical pathways. Therefore, molecules that kill bacterial persisters should function in a metabolism-independent manner. Some anti-persister compounds have been found previously, such as the DNA-crosslinkers mitomycin C and cisplatin, but more effective and lower cost alternatives are needed. Copper alloys have been used since ancient times due to their antimicrobial properties, and they are still used in agriculture to control plant bacterial diseases. By stopping transcription with rifampicin and by treating with ampicillin to remove non-persister cells, we created a population that consists solely of persister cells. Using this population of persister cells, we demonstrate that cupric compounds kill persister cells. Hence, copper ions may be used in controlling the spread of important bacterial strains that withstand treatment with conventional antimicrobials by forming persister cells.
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http://dx.doi.org/10.3390/antibiotics9080506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459663PMC
August 2020

Palmitic acid-modified bovine serum albumin nanoparticles target scavenger receptor-A on activated macrophages to treat rheumatoid arthritis.

Biomaterials 2020 11 4;258:120296. Epub 2020 Aug 4.

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

Palmitic acid-modified bovine serum albumin (PAB) was synthetized and found to own remarkable scavenger receptor-A (SR-A) targeting ability in vitro and in vivo, through which activated macrophages took up PAB nanoparticles (PAB NPs) 9.10 times more than bovine serum albumin nanoparticles (BSA NPs) and PAB NPs could delivery anti-inflammatory drugs celastrol (CLT) to inflamed tissues more effectively than BSA NPs. Compared with chondroitin sulfate modified BSA NPs targeting activated macrophages via CD44, PAB NPs show a more prominent targeting effect whether in vivo or in vitro. And PAB also demonstrated excellent biosafety compared to maleylated BSA, a known SR-A ligand that was lethal in our study. Furthermore, in adjuvant-induced arthritis rats, CLT-PAB NPs significantly improved disease pathology at a lower CLT dose with high safety, compared with CLT-BSA NPs. In addition, compared with the existing ligands with SR-A targeting due to strong electronegativity, the enhanced electronegativity and introduced PA are both important for the SR-A targeting effect of PAB. Therefore, PAB provides a novel direction for the treatment of rheumatoid arthritis and design of new ligands of SR-A.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120296DOI Listing
November 2020

Comparison of three in-situ gels composed of different oil types.

Int J Pharm 2020 Sep 30;587:119707. Epub 2020 Jul 30.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China.

A phospholipid-based phase separation in-situ gel (PPSG) system, which consists of phospholipids, medium chain oil (triglyceride) and ethanol as basic ingredients, has been previously developed in our lab. In addition, glycerol monooleate (monoglyceride) and glycerol dioleate (diglyceride) were also reported to be able to form liquid crystal gels. Monoglyceride, diglyceride and triglyceride have different degrees of hydroxyl substitution in glycerol and therefore different amphiphilic properties, which may cause different properties of gels composed of them. In this experiment, glycerol monooleate (GMO), glycerol dioleate (GDO) and glycerol trioleate (GTO) were selected to prepare three kinds of PPSGs. We systematically studied their in-vitro and in-vivo physicochemical properties and investigated their drug release behavior with octreotide (OCT) as the model drug. The results showed that PPSG composed of GTO (GTO-gel) had a different microstructure, a slower solvent diffusion speed and the less irritation to skin. In addition, the drug release result showed that the GTO-gel group had a lower initial release rate and a more stable release profile. All results above indicated that GTO-gel had a greater potential as a drug delivery system.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119707DOI Listing
September 2020

High-level soluble expression of human Cu,Zn superoxide dismutase with high activity in Escherichia coli.

World J Microbiol Biotechnol 2020 Jul 8;36(7):106. Epub 2020 Jul 8.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biosynthesis of Natural Products, CAMS Key Laboratory of Enzyme and Catalysis of Natural Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.

As the most important member of antioxidant defense system, human Cu,Zn superoxide dismutase (hCu,Zn-SOD) protects cells against the free radicals produced by aerobic metabolism. hCu,Zn-SOD has been widely used in food, cosmetic and medicine industry due to its health benefits and therapeutic potentials. However, a more extensive application of hCu,Zn-SOD is limited by the challenge of expensive and low production of high-activity hCu,Zn-SOD in large scale. In this study, the codon-optimized hCu,Zn-SOD gene was synthesized, cloned into pET-28a( +) and transformed into Escherichia coli BL21(DE3). After induction with IPTG or lactose, hCu,Zn-SOD was highly expressed as soluble form in LB medium with 800 μM Cu and 20 μM Zn at 25 °C. The recombinant hCu,Zn-SOD was efficiently purified by nickel affinity chromatography. Through optimization of fed-batch fermentation conditions, 342 mg purified hCu,Zn-SOD was obtained from 1 L cultures fermented in a 3-L bioreactor. Furthermore, the recombinant hCu,Zn-SOD retained the enzymatic specific activity of 46,541 U/mg. This study has opened up an effective avenue for industrial production of hCu,Zn-SOD through microbial fermentation in the future.
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http://dx.doi.org/10.1007/s11274-020-02883-6DOI Listing
July 2020

Orthogonal tuning of gene expression noise using CRISPR-Cas.

Nucleic Acids Res 2020 07;48(13):7606

Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, USA.

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http://dx.doi.org/10.1093/nar/gkaa537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367205PMC
July 2020

Controlled release of odontogenic exosomes from a biodegradable vehicle mediates dentinogenesis as a novel biomimetic pulp capping therapy.

J Control Release 2020 08 10;324:679-694. Epub 2020 Jun 10.

Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, United States of America; Macromolecular Science and Engineering Center, College of Engineering, University of Michigan, United States of America; Department of Biomedical Engineering, School of Medicine and College of Engineering, University of Michigan, United States of America; Department of Materials Science and Engineering, College of Engineering, University of Michigan, United States of America. Electronic address:

Mineralized enamel and dentin provide protection to the dental pulp, which is vital tissue rich with cells, vasculature, and nerves in the inner tooth. Dental caries left untreated threaten exposure of the dental pulp, providing facile access for bacteria to cause severe infection both in the pulp and systemically. Dental materials which stimulate the formation of a protective dentin bridge after insult are necessary to seal the pulp chamber in an effort to maintain natural dentition and prevent pulpal infection. Dental materials to date including calcium hydroxide paste, mineral trioxide aggregate, and glass ionomer resin, are used with mixed results. Herein we exploited the cell-cell communicative properties of exosomes, extracellular vesicles derived from both mineralizing primary human dental pulp stem cells (hDPSCs) and an immortalized murine odontoblast cell line (MDPC-23), to catalyze the formation of a reactionary dentin bridge by recruiting endogenous stem cells of the dental pulp, through an easy-to-handle delivery vehicle which allows for their therapeutic controlled delivery at the pulp interface. Exosomes derived from both hDPSCs and MDPCs upregulated odontogenic gene expression and increased mineralization in vitro. We designed an amphiphilic synthetic polymeric vehicle from a triblock copolymer which encapsulates exosomes by polymeric self-assembly and maintains their biologic integrity throughout release up to 8-12 weeks. The controlled release of odontogenic exosomes resulted in a reparative dentin bridge formation, superior to glass-ionomer cement alone in vivo, in a rat molar pulpotomy model after six weeks. We have developed a platform for the encapsulation and controlled, tunable release of cell-derived exosomes, which maintains their advantageous physiologic properties reflective of the donor cells. This platform is used to modulate downstream recipient cells towards a designed dentinogenic trajectory in vitro and in vivo. Additionally, we have demonstrated the utility of an immortalized cell line to produce a high yield of exosomes with cross-species efficacy.
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http://dx.doi.org/10.1016/j.jconrel.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429296PMC
August 2020

Orthogonal tuning of gene expression noise using CRISPR-Cas.

Nucleic Acids Res 2020 07;48(13):e76

Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, USA.

The control of gene expression noise is important for improving drug treatment and the performance of synthetic biological systems. Previous work has tuned gene expression noise by changing the rate of transcription initiation, mRNA degradation, and mRNA translation. However, these methods are invasive: they require changes to the target genetic components. Here, we create an orthogonal system based on CRISPR-dCas9 to tune gene expression noise. Specifically, we modulate the gene expression noise of a reporter gene in Escherichia coli by incorporating CRISPR activation and repression (CRISPRar) simultaneously in a single cell. The CRISPRar uses a single dCas9 that recognizes two different single guide RNAs (sgRNA). We build a library of sgRNA variants with different expression activation and repression strengths. We find that expression noise and mean of a reporter gene can be tuned independently by CRISPRar. Our results suggest that the expression noise is tuned by the competition between two sgRNAs that modulate the binding of RNA polymerase to promoters. The CRISPRar may change how we tune expression noise at the genomic level. Our work has broad impacts on the study of gene functions, phenotypical heterogeneity, and genetic circuit control.
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http://dx.doi.org/10.1093/nar/gkaa451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367181PMC
July 2020

Microwave coherent control of ultracold ground-state molecules formed by short-range photoassociation.

Phys Chem Chem Phys 2020 Jun 1;22(23):13002-13007. Epub 2020 Jun 1.

Shanxi University, State Key Laboratory of Quantum Optics and Quantum Optics Devices, Institute of Laser Spectroscopy, Wucheng Rd. 92, 030006 Taiyuan, China.

We report the observation of microwave coherent control of rotational states of ultracold RbCs molecules formed in their vibronic ground state by short-range photoassociation. Molecules are formed in the single rotational state X(v = 0, J = 1) by exciting pairs of atoms to the short-range state (2)Π(v = 11, J = 0), followed by spontaneous decay. We use depletion spectroscopy to record the dynamic evolution of the population distribution and observe clear Rabi oscillations while irradiating on a microwave transition between coupled neighbouring rotational levels. A density-matrix formalism that accounts for longitudinal and transverse decay times reproduces both the dynamic evolution during the coherent process and the equilibrium population. The coherent control reported here is valuable both for investigating coherent quantum effects and for applications of cold polar molecules produced by continuous short-range photoassociation.
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http://dx.doi.org/10.1039/d0cp01191fDOI Listing
June 2020