Publications by authors named "Ke Shi"

283 Publications

Placenta-specific protein 1 promotes cell proliferation via the AKT/GSK-3β/cyclin D1 signaling pathway in gastric cancer.

IUBMB Life 2021 Jun 10. Epub 2021 Jun 10.

Division of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China.

Gastric cancer is a malignant tumor with a poor prognosis. Therefore, it is important to search for molecules that play a vital role in the development, diagnosis, and treatment of this disease. Placenta-specific 1 (PLAC1) is one of the cancer-testis antigens; it plays an important role in both placental development and tumorigenesis. However, the role of PLAC1 in gastric cancer has not been fully investigated, and its underlying mechanism needs further study. We first explored the expression and clinical relevance of PLAC1 in gastric cancer and performed gene set enrichment analysis of PLAC1-related genes using online databases. Subsequently, we studied the function and mechanism of PLAC1 in gastric cancer cells through in vitro experiments. Our results showed that PLAC1 is highly expressed in gastric cancer, is associated with poor prognosis, and can promote gastric cancer cell proliferation through the AKT/GSK-3β/cyclin D1 signaling pathway. Moreover, we discovered that AKTi attenuates the effect of PLAC1. Our study further revealed the role and mechanism of PLAC1 in gastric cancer and suggested that this antigen might be a useful molecular marker for gastric cancer diagnosis, prognosis, and treatment.
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http://dx.doi.org/10.1002/iub.2514DOI Listing
June 2021

Soluble Methane Monooxygenase Component Interactions Monitored by F NMR.

Biochemistry 2021 Jun 8. Epub 2021 Jun 8.

Soluble methane monooxygenase (sMMO) is a multicomponent metalloenzyme capable of catalyzing the fissure of the C-H bond of methane and the insertion of one atom of oxygen from O to yield methanol. Efficient multiple-turnover catalysis occurs only in the presence of all three sMMO protein components: hydroxylase (MMOH), reductase (MMOR), and regulatory protein (MMOB). The complex series of sMMO protein component interactions that regulate the formation and decay of sMMO reaction cycle intermediates is not fully understood. Here, the two tryptophan residues in MMOB and the single tryptophan residue in MMOR are converted to 5-fluorotryptophan (5FW) by expression in defined media containing 5-fluoroindole. In addition, the mechanistically significant N-terminal region of MMOB is F-labeled by reaction of the K15C variant with 3-bromo-1,1,1-trifluoroacetone (BTFA). The 5FW and BTFA modifications cause minimal structural perturbation, allowing detailed studies of the interactions with sMMOH using F NMR. Resonances from the 275 kDa complexes of sMMOH with 5FW-MMOB and BTFA-K15C-5FW-MMOB are readily detected at 5 μM labeled protein concentration. This approach shows directly that MMOR and MMOB competitively bind to sMMOH with similar values, independent of the oxidation state of the sMMOH diiron cluster. These findings suggest a new model for regulation in which the dynamic equilibration of MMOR and MMOB with sMMOH allows a transient formation of key reactive complexes that irreversibly pull the reaction cycle forward. The slow kinetics of exchange of the sMMOH:MMOB complex is proposed to prevent MMOR-mediated reductive quenching of the high-valent reaction cycle intermediate before it can react with methane.
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http://dx.doi.org/10.1021/acs.biochem.1c00293DOI Listing
June 2021

Neutrophil-lymphocyte ratio and the risk of hepatocellular carcinoma in patients with hepatitis B-caused cirrhosis.

Eur J Gastroenterol Hepatol 2021 May 31. Epub 2021 May 31.

Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University Department of Hepatology, Tianjin Second People's Hospital Department of Infection Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Aim: The neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic marker of hepatocellular carcinoma (HCC); however, the relationship between NLR and risk of HCC occurrence has yet to be systematically elucidated. We aimed to investigate the association between NLR and HCC risk in patients with hepatitis B-caused cirrhosis (HBC) undergoing antiviral therapy.

Methods: A total of 1599 patients with HBC receiving entecavir or tenofovir at three tertiary hospitals between June 2014 and November 2017 were included. Cox proportional hazards regression was used to identify the association between NLR and risk of HCC occurrence by adjusting for potential risk factors. The cumulative incidence of HCC was evaluated using Kaplan-Meier analysis.

Results: At study enrollment, the median NLR was 2.0 (interquartile range, 1.4-3.0). The 3-year cumulative probabilities of HCC were 4.8, 8.4, 13.2, and 18.0% across the NLR quartiles, respectively (P < 0.001). Compared with the lowest quartile, higher NLR correlated with an increased HCC occurrence [NLR 1.4-2.0: adjusted hazard ratio (aHR), 1.18 (95% confidence interval (CI), 1.11-1.25); NLR 2.0-3.0: aHR, 2.09 (95% CI, 1.19-3.66); NLR > 3.0: aHR, 2.80 (95% CI, 1.59-4.95); P for trend = 0.001] in the fully adjusted models. In the subgroup analysis, elevated NLR was associated with increased HCC risk, regardless of stratification criteria.

Conclusion: Elevated NLR is an independent risk factor for HCC occurrence in patients with HBC undergoing antiviral therapy.
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http://dx.doi.org/10.1097/MEG.0000000000002217DOI Listing
May 2021

Increased oxygenation is associated with myocardial inflammation and adverse regional remodeling after acute ST-segment elevation myocardial infarction.

Eur Radiol 2021 May 18. Epub 2021 May 18.

Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Objectives: To explore the relationships between oxygenation signal intensity (SI) with myocardial inflammation and regional left ventricular (LV) remodeling in reperfused acute ST-segment elevation myocardial infarction (STEMI) using oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR).

Methods: Thirty-three STEMI patients and 22 age- and sex-matched healthy volunteers underwent CMR. The protocol included cine function, OS imaging, precontrast T1 mapping, T2 mapping, and late gadolinium enhancement (LGE) imaging. A total of 880 LV segments were included for analysis based on the American Heart Association 16-segment model. For validation, 15 pigs (10 myocardial infarction (MI) model animals and 5 controls) received CMR and were sacrificed for immunohistochemical analysis.

Results: In the patient study, the acute oxygenation SI showed a stepwise rise among remote, salvaged, and infarcted segments compared with healthy myocardium. At convalescence, all oxygenation SI values besides those in infarcted segments with microvascular obstruction decreased to similar levels. Acute oxygenation SI was associated with early myocardial injury (T1: r = 0.38; T2: r = 0.41; all p < 0.05). Segments with higher acute oxygenation SI values exhibited thinner diastolic walls and decreased wall thickening during follow-up. Multivariable regression modeling indicated that acute oxygenation SI (β = 2.66; p < 0.05) independently predicted convalescent segment adverse remodeling (LV wall thinning). In the animal study, alterations in oxygenation SI were correlated with histological inflammatory infiltrates (r = 0.59; p < 0.001).

Conclusions: Myocardial oxygenation by OS-CMR could be used as a quantitative imaging biomarker to assess myocardial inflammation and predict convalescent segment adverse remodeling after STEMI.

Key Points: • Oxygenation signal intensity (SI) may be an imaging biomarker of inflammatory infiltration that could be used to assess the response to anti-inflammatory therapies in the future. • Oxygenation SI early after myocardial infarction (MI) was associated with left ventricular segment injury at acute phase and could predict regional functional recovery and adverse remodeling late after acute MI. • Oxygenation SI demonstrated a stepwise increase among remote, salvaged, and infarcted segments. Infarcted zones with microvascular obstruction demonstrated a higher oxygenation SI than those without. However, the former showed less pronounced changes over time.
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http://dx.doi.org/10.1007/s00330-021-08032-3DOI Listing
May 2021

Arylazopyrazole-Based Dendrimer Solar Thermal Fuels: Stable Visible Light Storage and Controllable Heat Release.

ACS Appl Mater Interfaces 2021 May 10;13(19):22655-22663. Epub 2021 May 10.

School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083, China.

Solar thermal fuels offer a closed cycle and a renewable energy storage strategy by harvesting photon energy within the chemical conformations of molecules and retrieving energy by an induced release of heat. However, the majority of reports are limited to the ultraviolet light storage, which potentially interferes with the surrounding environment and reduces the material lifetime. Here, we present a novel arylazopyrazole (AAP)-containing dendrimer that not only addresses the hindrance of visible light storage for solar thermal fuels but also exhibits outstanding performances of abundant energy conversion and stable storage, which are attributed to the substantial absorbance in visible wavelengths of -thiomethyl-substituted AAP groups and the stability of isomers, respectively. The energy density of the dendrimer fuel after efficiently harvesting blue light (405 nm) is as high as 0.14 MJ kg (67 kJ mol), and the storage half-life of the fabricated dendrimer film can reach up to 12.9 days. Moreover, the heat release of the dendrimer film can be triggered by different stimuli (light and heat). The dendrimer film displays a 6.5 °C temperature difference between isomers and isomers during green light irradiation. Our work provides a fascinating avenue to fabricate visible light storage solar thermal fuels and unlocks the possibility of developing natural sunlight storage in the future.
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http://dx.doi.org/10.1021/acsami.1c05163DOI Listing
May 2021

Altered interhemispheric functional homotopy and connectivity in temporal lobe epilepsy based on fMRI and multivariate pattern analysis.

Neuroradiology 2021 May 3. Epub 2021 May 3.

Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, Nanning, China.

Purpose: This study aimed to investigate how the functional homotopy and further functional connectivity (FC) of whole brain changed in temporal lobe epilepsy (TLE). We also evaluated which brain regions played a decisive role in classification by using functional magnetic resonance imaging (fMRI).

Methods: Patients with TLE and matched healthy controls were included to collect the fMRI data and perform the voxel-mirrored homotopic connectivity (VMHC) and FC analyses. The correlation between the changed functional homotopy and neuropsychology tests was examined. Based on VMHC, the weight of each region in the classification was obtained using multivariate pattern analysis (MVPA).

Results: The patients exhibited decreased functional coordination in the bilateral inferior temporal gyrus (ITG) and increased functional homotopy in the bilateral lingual gyrus compared with the control group in the VMHC analysis. Compared with healthy controls, the Montreal Cognitive Assessment score was lower, and the scores of Hamilton Anxiety (HAMA) and Hamilton Depression Scales were higher. The score of the HAMA Scale was positively correlated with the altered bilateral ITG. The FC analysis revealed increased connections between the right lingual gyrus and the left superior temporal gyrus/left insula. The MVPA showed that the accuracy, sensitivity, and specificity of classification were 68.49, 66.67 and 70.27%, respectively, and it confirmed that the temporal lobe, cerebellum, and parietal lobe provided significant contributions.

Conclusion: These findings demonstrated that the VMHC and FC changed in TLE, and the alterations were correlated with the anxiety state. The MVPA indicated that the abnormal VMHC was a crucial fMRI feature.
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http://dx.doi.org/10.1007/s00234-021-02706-xDOI Listing
May 2021

Structural Characterization of a Minimal Antibody against Human APOBEC3B.

Viruses 2021 04 12;13(4). Epub 2021 Apr 12.

Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.

APOBEC3B (A3B) is one of seven human APOBEC3 DNA cytosine deaminases that restrict viral infections as part of the overall innate immune response, but it also plays a major role in tumor evolution by mutating genomic DNA. Given the importance of A3B as a restriction factor of viral infections and as a driver of multiple human cancers, selective antibodies against A3B are highly desirable for its specific detection in various research and possibly diagnostic applications. Here, we describe a high-affinity minimal antibody, designated 5G7, obtained via a phage display screening against the C-terminal catalytic domain (ctd) of A3B. 5G7 also binds APOBEC3A that is highly homologous to A3Bctd but does not bind the catalytic domain of APOBEC3G, another Z1-type deaminase domain. The crystal structure of 5G7 shows a canonical arrangement of the heavy and light chain variable domains, with their complementarity-determining region (CDR) loops lining an antigen-binding cleft that accommodates a pair of α-helices. To understand the mechanism of A3Bctd recognition by 5G7, we used the crystal structures of A3Bctd and 5G7 as templates and computationally predicted the A3B-5G7 complex structure. Stable binding poses obtained by the simulation were further tested by site-directed mutagenesis and in vitro binding analyses. These studies mapped the epitope for 5G7 to a portion of C-terminal α6 helix of A3Bctd, with Arg374 playing an essential role. The same region of A3Bctd was used previously as a peptide antigen for generating a rabbit monoclonal antibody (mAb 5210-87-13), suggesting that this region is particularly immunogenic and that these antibodies from very different origins may share similar binding modes. Our studies provide a platform for the development of selective antibodies against A3B and other APOBEC3 family enzymes.
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http://dx.doi.org/10.3390/v13040663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070380PMC
April 2021

Uniaxial Tensile Behavior, Flexural Properties, Empirical Calculation and Microstructure of Multi-Scale Fiber Reinforced Cement-Based Material at Elevated Temperature.

Materials (Basel) 2021 Apr 7;14(8). Epub 2021 Apr 7.

School of Civil Engineering and Architecture, Zhengzhou University of Aeronautics, Zhengzhou 450046, China.

Fire is one of the most unfavorable conditions that cement-based composites can face during their service lives. The uniaxial tensile and flexural tensile properties of the steel-polyvinyl alcohol fiber-calcium carbonate whisker (CW) multi-scale fiber reinforced cement matrix composites (MSFRCs) under high temperatures are studied, including strength, deformation capacity, energy dissipation capacity, and its ability to be assessed through the empirical calculation method. The study showed that with the increase of the treatment temperature, the MSFRC residual bending strength, bending toughness, and tensile strength decreased overall, but the decline was slow at 600 °C. The peak flexural deflection and peak tensile strain of MSFRC first reduced and then increased with the increase of the temperature. As the temperature increased, the nominal stiffness of MSFRC bending and straight gradually reduced, and the rate of decline was faster than that of its strength. However, the uniaxial tensile properties were more sensitive to the temperature and degraded more rapidly. A quantitative relationship was established between MSFRC residual bending, tensile strength, and temperature. A comparison with existing research results shows that MSFRC has achieved an ideal effect of high temperature resistance. The multi-scale hybrid fiber system significantly alleviates the deterioration of cement-based composite's mechanical properties under high temperatures. With the help of an optical microscope and scanning electron microscope (SEM), the high temperature influence mechanism on the uniaxial tensile and flexural properties of MSFRC was revealed.
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http://dx.doi.org/10.3390/ma14081827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067801PMC
April 2021

A Cable-Driven Three-DOF Wrist Rehabilitation Exoskeleton With Improved Performance.

Front Neurorobot 2021 8;15:664062. Epub 2021 Apr 8.

School of Instrument Science and Engineering, Southeast University, Nanjing, China.

This paper developed a cable-driven three-degree-of-freedom (DOF) wrist rehabilitation exoskeleton actuated by the distributed active semi-active (DASA) system. Compared with the conventional cable-driven robots, the workspace of this robot is increased greatly by adding the rotating compensation mechanism and by optimizing the distribution of the cable attachment points. In the meanwhile, the efficiency of the cable tension is improved, and the parasitic force (the force acting on the joint along the limb) is reduced. Besides, in order to reduce the effects of compliant elements (e.g., cables or Bowden cables) between the actuators and output, and to improve the force bandwidth, we designed the DASA system composed of one geared DC motor and four magnetorheological (MR) clutches, which has low output inertia. A fast unbinding strategy is presented to ensure safety in abnormal conditions. A passive training algorithm and an assist-as-needed (AAN) algorithm were implemented to control the exoskeleton. Several experiments were conducted on both healthy and impaired subjects to test the performance and effectiveness of the proposed system for rehabilitation. The results show that the system can meet the needs of rehabilitation training for workspace and force-feedback, and provide efficient active and passive training.
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http://dx.doi.org/10.3389/fnbot.2021.664062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060699PMC
April 2021

Melatonin indirectly decreases gastric cancer cell proliferation and invasion via effects on cancer-associated fibroblasts.

Life Sci 2021 Jul 18;277:119497. Epub 2021 Apr 18.

Division of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, PR China. Electronic address:

Aims: Gastric cancer is a malignant tumor with a poor prognosis, and the interaction between tumor cells and cancer-associated fibroblasts (CAFs) further contributes to progression and treatment failure. Recent studies have revealed the potential value of melatonin in cancer therapy, but its role in gastric cancer and CAFs requires further exploration.

Main Methods: CAFs were isolated using the tissue block method. Cell Counting Kit-8 and cell cycle assays were used to determine the cell proliferation ability, while the cell metastatic capacity was detected by a wound healing assay and Transwell migration/invasion assay. Furthermore, the expression levels of proteins involved were examined using quantitative real-time PCR (qRT-PCR) and western blotting.

Key Findings: Melatonin not only inhibits cell proliferation and metastasis by reducing the production of reactive oxygen species (ROS) in gastric cancer cells but also inhibits CAFs-induced gastric cancer cell progression by reducing the production of metalloproteinase 2 (MMP2) and metalloproteinase 2 (MMP9) in CAFs. The direct and indirect inhibitory effects of melatonin on gastric cancer cells are involved in the NF-kB signaling pathways.

Significance: This study provides insights into the role of melatonin in the tumor microenvironment, further deepens available knowledge regarding the mechanism of action of melatonin in gastric cancer and suggests the potential value of melatonin in gastric cancer treatment.
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http://dx.doi.org/10.1016/j.lfs.2021.119497DOI Listing
July 2021

Exosomes and Their Role in Cancer Progression.

Front Oncol 2021 22;11:639159. Epub 2021 Mar 22.

Departments of Plastic and Reconstructive Surgery, The Third Xiangya Hospital, Central South University, Changsha, China.

Exosomes from extracellular vesicles can activate or inhibit various signaling pathways by transporting proteins, lipids, nucleic acids and other substances to recipient cells. In addition, exosomes are considered to be involved in the development and progression of tumors from different tissue sources in numerous ways, including remodeling of the tumor microenvironment, promoting angiogenesis, metastasis, and invasion, and regulating the immune escape of tumor cells. However, the precise molecular mechanisms by which exosomes participate in these different processes remains unclear. In this review, we describe the research progress of tumor cell-derived exosomes in cancer progression. We also discuss the prospects of the application of exosomes combined with nanoengineered chemotherapeutic drugs in the treatment of cancer.
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http://dx.doi.org/10.3389/fonc.2021.639159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020998PMC
March 2021

Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN.

bioRxiv 2021 Apr 4. Epub 2021 Apr 4.

High-fidelity replication of the large RNA genome of coronaviruses (CoVs) is mediated by a 3'-to-5' exoribonuclease (ExoN) in non-structural protein 14 (nsp14), which excises nucleotides including antiviral drugs mis-incorporated by the low-fidelity viral RNA-dependent RNA polymerase (RdRp) and has also been implicated in viral RNA recombination and resistance to innate immunity. Here we determined a 1.6-Å resolution crystal structure of SARS-CoV-2 ExoN in complex with its essential co-factor, nsp10. The structure shows a highly basic and concave surface flanking the active site, comprising several Lys residues of nsp14 and the N-terminal amino group of nsp10. Modeling suggests that this basic patch binds to the template strand of double-stranded RNA substrates to position the 3' end of the nascent strand in the ExoN active site, which is corroborated by mutational and computational analyses. Molecular dynamics simulations further show remarkable flexibility of multi-domain nsp14 and suggest that nsp10 stabilizes ExoN for substrate RNA-binding to support its exoribonuclease activity. Our high-resolution structure of the SARS-CoV-2 ExoN-nsp10 complex serves as a platform for future development of anti-coronaviral drugs or strategies to attenuate the viral virulence.
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http://dx.doi.org/10.1101/2021.04.02.438274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020977PMC
April 2021

The Insula Is a Hub for Functional Brain Network in Patients With Anti--Methyl-D-Aspartate Receptor Encephalitis.

Front Neurosci 2021 15;15:642390. Epub 2021 Mar 15.

Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.

Background: In recent years, imaging technologies have been rapidly evolving, with an emphasis on the characterization of brain structure changes and functional imaging in patients with autoimmune encephalitis. However, the neural basis of anti--methyl-D-aspartate receptor (NMDAR) encephalitis and its linked cognitive decline is unclear. Our research aimed to assess changes in the functional brain network in patients with anti-NMDAR encephalitis and whether these changes lead to cognitive impairment.

Methods: Twenty-one anti-NMDAR encephalitis patients and 22 age-, gender-, and education status-matched healthy controls were assessed using resting functional magnetic resonance imaging (fMRI) scanning and neuropsychological tests, including the Hamilton Depression Scale (HAMD), the Montreal Cognitive Assessment (MoCA), and the Hamilton Anxiety Scale (HAMA). A functional brain network was constructed using fMRI, and the topology of the network parameters was analyzed using graph theory. Next, we extracted the aberrant topological parameters of the functional network as seeds and compared causal connectivity with the whole brain. Lastly, we explored the correlation of aberrant topological structures with deficits in cognitive performance.

Results: Relative to healthy controls, anti-NMDAR encephalitis patients exhibited decreased MoCA scores and increased HAMA and HAMD scores ( < 0.05). The nodal clustering coefficient and nodal local efficiency of the left insula (Insula_L) were significantly decreased in anti-NMDAR encephalitis patients ( < 0.05 following Bonferroni correction). Moreover, anti-NMDAR encephalitis patients showed a weakened causal connectivity from the left insula to the left inferior parietal lobe (Parietal_Inf_L) compared to healthy controls. Conversely, the left superior parietal lobe (Parietal_sup_L) exhibited an enhanced causal connectivity to the left insula in anti-NMDAR encephalitis patients compared to controls. Unexpectedly, these alterations were not correlated with any neuropsychological test scores.

Conclusion: This research describes topological abnormalities in the functional brain network in anti-NMDAR encephalitis. These results will be conducive to understand the structure and function of the brain network of patients with anti-NMDAR encephalitis and further explore the neuropathophysiological mechanisms.
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http://dx.doi.org/10.3389/fnins.2021.642390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005702PMC
March 2021

Cryo-EM structure of the Rous sarcoma virus octameric cleaved synaptic complex intasome.

Commun Biol 2021 Mar 12;4(1):330. Epub 2021 Mar 12.

Department of Molecular Microbiology and Immunology, School of Medicine, Saint Louis University, St. Louis, MO, USA.

Despite conserved catalytic integration mechanisms, retroviral intasomes composed of integrase (IN) and viral DNA possess diverse structures with variable numbers of IN subunits. To investigate intasome assembly mechanisms, we employed the Rous sarcoma virus (RSV) IN dimer that assembles a precursor tetrameric structure in transit to the mature octameric intasome. We determined the structure of RSV octameric intasome stabilized by a HIV-1 IN strand transfer inhibitor using single particle cryo-electron microscopy. The structure revealed significant flexibility of the two non-catalytic distal IN dimers along with previously unrecognized movement of the conserved intasome core, suggesting ordered conformational transitions between intermediates that may be important to capture the target DNA. Single amino acid substitutions within the IN C-terminal domain affected intasome assembly and function in vitro and infectivity of pseudotyped RSV virions. Unexpectedly, 17 C-terminal amino acids of IN were dispensable for virus infection despite regulating the transition of the tetrameric intasome to the octameric form in vitro. We speculate that this region may regulate the binding of highly flexible distal IN dimers to the intasome core to form the octameric complex. Our studies reveal key steps in the assembly of RSV intasomes.
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http://dx.doi.org/10.1038/s42003-021-01855-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955051PMC
March 2021

Structural basis for recognition of distinct deaminated DNA lesions by endonuclease Q.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455;

Spontaneous deamination of DNA cytosine and adenine into uracil and hypoxanthine, respectively, causes C to T and A to G transition mutations if left unrepaired. Endonuclease Q (EndoQ) initiates the repair of these premutagenic DNA lesions in prokaryotes by cleaving the phosphodiester backbone 5' of either uracil or hypoxanthine bases or an apurinic/apyrimidinic (AP) lesion generated by the excision of these damaged bases. To understand how EndoQ achieves selectivity toward these structurally diverse substrates without cleaving undamaged DNA, we determined the crystal structures of EndoQ bound to DNA substrates containing uracil, hypoxanthine, or an AP lesion. The structures show that substrate engagement by EndoQ depends both on a highly distorted conformation of the DNA backbone, in which the target nucleotide is extruded out of the helix, and direct hydrogen bonds with the deaminated bases. A concerted swing motion of the zinc-binding and C-terminal helical domains of EndoQ toward its catalytic domain allows the enzyme to clamp down on a sharply bent DNA substrate, shaping a deep active-site pocket that accommodates the extruded deaminated base. Within this pocket, uracil and hypoxanthine bases interact with distinct sets of amino acid residues, with positioning mediated by an essential magnesium ion. The EndoQ-DNA complex structures reveal a unique mode of damaged DNA recognition and provide mechanistic insights into the initial step of DNA damage repair by the alternative excision repair pathway. Furthermore, we demonstrate that the unique activity of EndoQ is useful for studying DNA deamination and repair in mammalian systems.
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http://dx.doi.org/10.1073/pnas.2021120118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958190PMC
March 2021

Design of green coating material of combining rigid and flexible properties for the extraction of aminoglycosides residues.

J Chromatogr A 2021 Mar 18;1641:462006. Epub 2021 Feb 18.

Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, School of Pharmacy, China Pharmaceutical University, No.24, Tongjiaxiang, Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, No.24, Tongjiaxiang, Nanjing 210009, China. Electronic address:

Bio-based and low-cost hybrid polyvinyl alcohol (PVA) and gelatin (Gel) hydrophilic macromolecular complex coated microspheres were prepared based on one-pot process, characterized, and applied as novel sorbent materials for the purification of trace aminoglycosides from complex matrices. PVA acts as a "rigid" component in the hybrid complex to enhance its mechanical properties, while Gel's "flexible" role is to improve the swelling properties of the hybrid complex in water. It is shown that hybrid PVA/Gel-functionalized sorbents are more efficient than the respective PVA or Gel sorbents since the presence of Gel increases the material selectivity for aminoglycosides, which is due to the specific interactions occurring between the targets and amino acid residues in the hybrid materials. Under the optimum conditions, material preparation and pretreatment processes were entirely carried out in single water system without toxic organic solvent. The detection limit (LOD) of spectinomycin, kanamycin, streptomycin and dihydrostreptomycin in honey were 0.811, 0.303, 0.168, 0.045 μg⋅kg respectively. Linearity was obtained in the range of 20 to 2000 ug⋅kg, relative recovery yield up to 84.1-111.7% were obtained and matrix effect of all four aminoglycosides was within 100.8-107.6%. Intra-day and inter-day precision under four spiking levels (5, 200, 500 and 1000 ug⋅kg) were less than 10.9% (n=6) and 13.6% (n=3) respectively. In addition, the sorbents exhibited excellent reusability even after six recycles. This work demonstrates the potential of bio-based and low-cost hybrid polymer extraction platforms as promising bonded phase alternatives, in which eco-friendly and natural-based polymers can be used to improve the material selectivity and are conducive to the realization of "green chemistry".
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http://dx.doi.org/10.1016/j.chroma.2021.462006DOI Listing
March 2021

Accelerated bioremediation of a complexly contaminated river sediment through ZVI-electrode combined stimulation.

J Hazard Mater 2021 07 11;413:125392. Epub 2021 Feb 11.

State Key Laboratory of Urban Water Resource and Environment, School of Environment, Harbin Institute of Technology, Harbin 150090, China; School of Civil & Environmental Engineering, Harbin Institute of Technology (Shenzhen), Shenzhen 518055, China; Key Laboratory of Environmental Biotechnology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.

Complexly contaminated river sediment caused by reducible and oxidizable organic pollutants is a growing global concern due to the adverse influence on ecosystem safety and planetary health. How to strengthen indigenous microbial metabolic activity to enhance biodegradation and mineralization efficiency of refractory composite pollutants is critical but poorly understood in environmental biotechnology. Here, a synergetic biostimulation coupling electrode with zero-valent iron (ZVI) was investigated for the bioremediation of river sediments contaminated by 2,4,6-tribromophenol (TBP, reducible pollutant) and hydrocarbons (oxidizable pollutants). The bioremediation efficiency of ZVI based biostimulation coupling electrode against TBP debromination and hydrocarbons degradation were 1.1-3 times higher than the electrode used solely, which was attributed to the shape of distinctive microbial communities and the enrichment of potential dehalogenators (like Desulfovibrio, Desulfomicrobium etc.). The sediment microbial communities were significantly positively correlated with the enhanced degradation efficiencies of TBP and hydrocarbons (P < 0.05). Moreover, the coupled system predominately increased positive microbial interactions in the ecological networks. The possible mutual relationship between microbes i.e., Thiobacillus (iron-oxidizing bacteria) and Desulfovibrio (dehalogenator) as well as Pseudomonas (electroactive bacteria) and Clostridium (hydrocarbons degraders) were revealed. This study proposed a promising approach for efficient bioremediation of complexly contaminated river sediments.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125392DOI Listing
July 2021

Multi-scale Attention Convolutional Neural Network for time series classification.

Authors:
Wei Chen Ke Shi

Neural Netw 2021 Apr 6;136:126-140. Epub 2021 Jan 6.

School of Computer Science and Technology, Huazhong University of Science and Technology, China. Electronic address:

With the rapid increase of data availability, time series classification (TSC) has arisen in a wide range of fields and drawn great attention of researchers. Recently, hundreds of TSC approaches have been developed, which can be classified into two categories: traditional and deep learning based TSC methods. However, it remains challenging to improve accuracy and model generalization ability. Therefore, we investigate a novel end-to-end model based on deep learning named as Multi-scale Attention Convolutional Neural Network (MACNN) to solve the TSC problem. We first apply the multi-scale convolution to capture different scales of information along the time axis by generating different scales of feature maps. Then an attention mechanism is proposed to enhance useful feature maps and suppress less useful ones by learning the importance of each feature map automatically. MACNN addresses the limitation of single-scale convolution and equal weight feature maps. We conduct a comprehensive evaluation of 85 UCR standard datasets and the experimental results show that our proposed approach achieves the best performance and outperforms the other traditional and deep learning based methods by a large margin.
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http://dx.doi.org/10.1016/j.neunet.2021.01.001DOI Listing
April 2021

The first detection of , an emerging zoonotic sp., in erythrocytes.

Emerg Microbes Infect 2021 Dec;10(1):226-234

College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, People's Republic of China.

An emerging infectious disease caused by "" was reported in a 2015 survey of 477 hospital patients with a tick-bite history in China. However, the morphological characteristics and parasitic location of this pathogen are still unclear, and the pathogen has not been officially classified as a member of the genus . -positive blood samples were collected, blood cells separated, and DNA of whole blood cells, erythrocytes, and leukocytes extracted. Multiplex PCR detection assay was used to detect whole blood cell, erythrocytes and leukocytes, DNA samples, and PCR identification, nucleic acid sequencing, and phylogenetic analyses based on , 16S rRNA, and genes. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), Wright-Giemsa staining, chromogenic in situ hybridization (CISH), immunocytochemistry, and indirect immunofluorescence assay (IFA) were used to identify the location and morphological characteristics of . Multiple gene loci results demonstrated that erythrocyte DNA samples were -positive, while leukocyte DNA samples were -negative. Phylogenetic analysis showed that is in the same clade with the sequence reported previously. SEM and TEM showed one or more pathogens internally or on the outer surface of erythrocytes. Giemsa staining, CISH, immunocytochemistry, and IFA indicated that erythrocytes were -positive. This study is the first to identify the novel zoonotic tick-borne sp., "," in host erythrocytes. Based on our results, we suggest revision of Genus and formally name "" as sp. nov.
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http://dx.doi.org/10.1080/22221751.2021.1876532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894429PMC
December 2021

Noninvasive oxygenation assessment after acute myocardial infarction with breathing maneuvers-induced oxygenation-sensitive magnetic resonance imaging.

J Magn Reson Imaging 2021 Jul 12;54(1):284-289. Epub 2021 Jan 12.

Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.

The safety profiles when performing stress oxygenation-sensitive magnetic resonance imaging (OS-MRI) have raised concerns in clinical practice. Adenosine infusion can cause side effects such as chest pain, dyspnea, arrhythmia, and even cardiac death. The aim of this study was to investigate the feasibility of breathing maneuvers-induced OS-MRI in acute myocardial infarction (MI). This was a prospective study, which included 14 healthy rabbits and nine MI rabbit models. This study used 3 T MRI/modified Look-Locker inversion recovery sequence for native T mapping, balanced steady-state free precession sequence for OS imaging, and phase-sensitive inversion recovery sequence for late gadolinium enhancement. The changes in myocardial oxygenation (ΔSI) were assessed under two breathing maneuvers protocols in healthy rabbits: a series of extended breath-holding (BH), and a combined maneuver of hyperventilation followed by the extended BH (HVBH). Subsequently, OS-MRI with HVBH in acute MI rabbits was performed, and the ΔSI was compared with that of adenosine stress protocol. Student's t-test, Wilcoxon rank test, and Friedman test were used to compare ΔSI in different subgroups. Pearson and Spearman correlation was used to obtain the association of ΔSI between breathing maneuvers and adenosine stress. Bland-Altman analysis was used to assess the bias of ΔSI between HVBH and adenosine stress. In healthy rabbits, BH maneuvers from 30 to 50 s induced significant increase in SI compared with the baseline (all p < 0.05). By contrast, hyperventilation for 60 s followed by 10 s-BH (HVBH 10 s) exhibited a comparable ΔSI to that of stress test (p = 0.07). In acute MI rabbits, HVBH 10 s-induced ΔSIs among infarcted, salvaged, and the remote myocardial area were no less effectiveness than adenosine stress when performing OS-MRI (r = 0.84; p < 0.05). Combined breathing maneuvers with OS-MRI have the potential to be used as a nonpharmacological alternative for assessing myocardial oxygenation in patients with acute MI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.
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http://dx.doi.org/10.1002/jmri.27509DOI Listing
July 2021

Molecular underpinnings of ssDNA specificity by Rep HUH-endonucleases and implications for HUH-tag multiplexing and engineering.

Nucleic Acids Res 2021 01;49(2):1046-1064

Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Twin Cities, Minneapolis, MN 55455, USA.

Replication initiator proteins (Reps) from the HUH-endonuclease superfamily process specific single-stranded DNA (ssDNA) sequences to initiate rolling circle/hairpin replication in viruses, such as crop ravaging geminiviruses and human disease causing parvoviruses. In biotechnology contexts, Reps are the basis for HUH-tag bioconjugation and a critical adeno-associated virus genome integration tool. We solved the first co-crystal structures of Reps complexed to ssDNA, revealing a key motif for conferring sequence specificity and for anchoring a bent DNA architecture. In combination, we developed a deep sequencing cleavage assay, termed HUH-seq, to interrogate subtleties in Rep specificity and demonstrate how differences can be exploited for multiplexed HUH-tagging. Together, our insights allowed engineering of only four amino acids in a Rep chimera to predictably alter sequence specificity. These results have important implications for modulating viral infections, developing Rep-based genomic integration tools, and enabling massively parallel HUH-tag barcoding and bioconjugation applications.
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http://dx.doi.org/10.1093/nar/gkaa1248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826260PMC
January 2021

Mechanisms regulating DMTF1β/γ expression and their functional interplay with DMTF1α.

Int J Oncol 2021 01 10;58(1):20-32. Epub 2020 Nov 10.

Key Laboratory of Saline‑Alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, Harbin, Heilongjiang 150040, P.R. China.

The cyclin D binding myb‑like transcription factor 1 (DMTF1), a haplo‑insufficient tumor suppressor gene, has 3 alternatively spliced mRNA isoforms encoding DMTF1α, β and γ proteins. Previous studies have indicated a tumor suppressive role of DMTF1α and the oncogenic activity of DMTF1β, while the function of DMTF1γ remains largely undetermined. In the present study, the mechanisms regulating DMTF1 isoform expression were investigated and the functional interplay of DMTF1β and γ with DMTF1α was characterized. It was found that specific regions of DMTF1β and γ transcripts can impair their mRNA integrity or stability, and thus reduce protein expression levels. Additionally, DMTF1β and γ proteins exhibited a reduced stability compared to DMTF1α and all 3 DMTF1 isoforms were localized in the nuclei. Two basic residues, K52 and R53, in the DMTF1 isoforms determined their nuclear localization. Importantly, both DMTF1β and γ could associate with DMTF1α and antagonize its transactivation of the ARF promoter. Consistently, the ratios of both DMTF1β/α and γ/α were significantly associated with a poor prognoses of breast cancer patients, suggesting oncogenic roles of DMTF1β and γ isoforms in breast cancer development.
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http://dx.doi.org/10.3892/ijo.2020.5146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721083PMC
January 2021

The Development of a Novel Nanobody Therapeutic for SARS-CoV-2.

bioRxiv 2020 Nov 17. Epub 2020 Nov 17.

Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a novel series of single-domain antibodies (i.e., nanobody), Nanosota-1, from a camelid nanobody phage display library. Structural data showed that bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking out viral receptor ACE2. The lead drug possessing an Fc tag ( ) bound to SARS-CoV-2 RBD with a K of 15.7picomolar (∼3000 times more tightly than ACE2 did) and inhibited SARS-CoV-2 infection with an ND of 0.16microgram/milliliter (∼6000 times more potently than ACE2 did). Administered at a single dose, demonstrated preventive and therapeutic efficacy in hamsters subjected to SARS-CoV-2 infection. Unlike conventional antibody drugs, was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of c documented a greater than 10-day half-life efficacy and high tissue bioavailability. is a potentially effective and realistic solution to the COVID-19 pandemic.

Impact Statement: Potent and low-cost drugs block SARS-CoV-2 infections both and and act both preventively and therapeutically.
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http://dx.doi.org/10.1101/2020.11.17.386532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685322PMC
November 2020

Structural basis of superinfection exclusion by bacteriophage T4 Spackle.

Commun Biol 2020 11 19;3(1):691. Epub 2020 Nov 19.

Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 321 Church Street S.E., Minneapolis, MN, 55455, USA.

A bacterial cell infected with T4 phage rapidly establishes resistance against further infections by the same or closely related T-even-type bacteriophages - a phenomenon called superinfection exclusion. Here we show that one of the T4 early gene products and a periplasmic protein, Spackle, forms a stoichiometric complex with the lysozyme domain of T4 tail spike protein gp5 and potently inhibits its activity. Crystal structure of the Spackle-gp5 lysozyme complex shows that Spackle binds to a horseshoe-shaped basic patch surrounding the oligosaccharide-binding cleft and induces an allosteric conformational change of the active site. In contrast, Spackle does not appreciably inhibit the lysozyme activity of cytoplasmic T4 endolysin responsible for cell lysis to release progeny phage particles at the final step of the lytic cycle. Our work reveals a unique mode of inhibition for lysozymes, a widespread class of enzymes in biology, and provides a mechanistic understanding of the T4 bacteriophage superinfection exclusion.
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http://dx.doi.org/10.1038/s42003-020-01412-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677548PMC
November 2020

Adjuvant Fuzheng Huayu Capsule Reduces the Incidence of Hepatocellular Carcinoma in Patients with Hepatitis B-Caused Cirrhosis.

Evid Based Complement Alternat Med 2020 29;2020:8826091. Epub 2020 Oct 29.

Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China.

Aim: Fuzhenghuayu (FZHY) capsule can inhibit the progression of cirrhosis. This study explored whether FZHY can reduce the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis B-caused cirrhosis (HBC) undergoing antiviral therapy.

Methods: A retrospective review of 842 patients with HBC between 2011 and 2015 was performed, including 270 treated with FZHY combined with nucleos (t) ide analogues (NAs) and 572 with NAs alone. The incidence of HCC was compared between the FZHY ( = 259) and control ( = 259) groups using 1 : 1 propensity score (PS) matching. The incidence of HCC in patients with HBC with different Child-Turcotte-Pugh (CTP) classifications and Toronto HCC risk index (THRI) scores was analyzed using Kaplan-Meier curves.

Results: The 5-year cumulative incidence of HCC before and after PS matching was 151 (17.9%) and 86 (16.6%), respectively. In PS-matched samples, the multivariate Cox proportional-hazards model indicated that the FZHY group demonstrated a significantly lower risk for HCC than the control group (adjusted hazard ratio [aHR] = 0.32, 95% CI 0.19-0.53 < 0.001). The risk of HCC diminished with increased duration of FZHY use. The stratified analysis revealed that the FZHY group, regardless of CTP classification, benefited significantly from FZHY therapy. Patients in the medium- and high-THRI risk groups were the dominant population for FZHY.

Conclusions: FZHY combined with NAs was associated with a significantly lower risk of HCC than NAs alone in patients with HBC, which supports the integration of FZHY with antiviral treatment into clinical practice.
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http://dx.doi.org/10.1155/2020/8826091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644307PMC
October 2020

Photochromic Dendrimers for Photoswitched Solid-To-Liquid Transitions and Solar Thermal Fuels.

ACS Appl Mater Interfaces 2020 Nov 21;12(44):50135-50142. Epub 2020 Oct 21.

School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083, China.

Dendrimers are well-defined, highly branched macromolecules that have been widely applied in the fields of catalysis, sensing, and biomedicine. Here, we present a novel multifunctional photochromic dendrimer fabricated through grafting azobenzene units onto dendrimers, which not only enables controlled switching of adhesives and effective repair of coating scratches but also realizes high-performance solar energy storage and on-demand heat release. The switchable adhesives and healable coatings of azobenzene-containing dendrimers are attributed to the reversible solid-to-liquid transitions because trans-isomers and cis-isomers have different glass transition temperatures. The adhesion strengths increase significantly with the increase in dendrimer generations, wherein the adhesion strength of fifth-generation photochromic dendrimers (G5-Azo) can reach up to 1.62 MPa, five times higher than that of pristine azobenzenes. The solar energy storage and heat release of dendrimer solar thermal fuels, the isomers of which possess different chemical energies, can be also enhanced remarkably with the amplification of azobenzene groups on dendrimers. The storage energy density of G5-Azo can reach 59 W h kg, which is much higher than that of pristine azobenzenes (36 W h kg). The G5-Azo fuels exhibit a 5.2 °C temperature difference between cis-isomers and trans-isomers. These findings provide a new perspective and tremendously attractive avenue for the fabrication of photoswitchable adhesives and coatings and solar thermal fuels with dendrimer structures.
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http://dx.doi.org/10.1021/acsami.0c14160DOI Listing
November 2020

Selective N-Terminal BET Bromodomain Inhibitors by Targeting Non-Conserved Residues and Structured Water Displacement*.

Angew Chem Int Ed Engl 2021 01 18;60(3):1220-1226. Epub 2020 Nov 18.

Department of Chemistry, University of Minnesota-Twin Cities, 207 Pleasant St. SE, Minneapolis, MN, 55455, USA.

Bromodomain and extra-terminal (BET) family proteins, BRD2-4 and T, are important drug targets; however, the biological functions of each bromodomain remain ill-defined. Chemical probes that selectively inhibit a single BET bromodomain are lacking, although pan inhibitors of the first (D1), and second (D2), bromodomain are known. Here, we develop selective BET D1 inhibitors with preferred binding to BRD4 D1. In competitive inhibition assays, we show that our lead compound is 9-33 fold selective for BRD4 D1 over the other BET bromodomains. X-ray crystallography supports a role for the selectivity based on reorganization of a non-conserved lysine and displacement of an additional structured water in the BRD4 D1 binding site relative to our prior lead. Whereas pan-D1 inhibitors displace BRD4 from MYC enhancers, BRD4 D1 inhibition in MM.1S cells is insufficient for stopping Myc expression and may lead to its upregulation. Future analysis of BRD4 D1 gene regulation may shed light on differential BET bromodomain functions.
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http://dx.doi.org/10.1002/anie.202008625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855888PMC
January 2021

Circular RNA circ-NCOR2 accelerates papillary thyroid cancer progression by sponging miR-516a-5p to upregulate metastasis-associated protein 2 expression.

J Int Med Res 2020 Sep;48(9):300060520934659

Department of Nuclear Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Objective: Papillary thyroid cancer (PTC) is one of the most prevalent endocrine malignancies and the fifth most common cancer in women. Circular RNAs (circRNAs) have been shown to play vital functions in cancers, but few studies have focused on the functions and mechanism of dysregulated circRNAs in PTC.

Methods: Quantitative reverse transcription PCR was used to measure circ-NCOR2 levels in PTC tissues and cell lines. The functions of circ-NCOR2 in PTC were examined by analysis using the cell counting kit-8, clone forming, flow cytometry, and Transwell experiments. Bioinformatic analysis and dual luciferase reporter gene testing were used to identify the mechanisms of circ-NCOR2.

Results: Circ-NCOR2 overexpression was observed in PTC tissues and cells. Silenced or overexpressed expression of circ-NCOR2 strikingly attenuated or facilitated, respectively, the growth, migration, and invasion of PTC cells. Mechanistically, miR-615a-5p was identified as the target of circ-NCOR2. Moreover, circ-NCOR2 enhanced the expression of metastasis-associated protein 2 (MTA2) by sponging miR-615a-5p, thereby facilitating PTC cell progression.

Conclusions: Taken together, our findings reveal a novel circ-NCOR2/miR-615a-5p/MTA2 axis in PTC, which could become a potential therapeutic target for this disease.
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http://dx.doi.org/10.1177/0300060520934659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503031PMC
September 2020

Effects of Adjuvant Chinese Patent Medicine Therapy on Prevention of Variceal Rebleeding: A Retrospective Cohort Study.

Chin J Integr Med 2020 Sep 1. Epub 2020 Sep 1.

Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.

Objective: To assess whether adjuvant Chinese patent medicines (CPMs) to standard treatment could reduce recurrent bleeding after variceal bleeding in cirrhotic patients.

Methods: This study retrospectively collected 555 consecutive patients who recovered from variceal bleeding. A population-based cohort study was established depending on if adjuvant CPMs were administered to prevent rebleeding. A total of 139 patients who had taken ⩾28 cumulative defined daily doses (cDDDs) of CPMs were included in the CPMs cohort, and 416 patients who used <28 cDDDs of CPMs were enrolled in the non-CPMs cohort. On evaluation of rebleeding incidence, 1:2 propensity score matched was used to estimate for reducing bias. Patients were followed for at least 12 months. The end-point of this study was clinically significant esophagogastric variceal rebleeding.

Results: Following multivariate analysis, CPMs therapy was an independent factor for variceal rebleeding [adjusted hazard ratio (AHR)=0.657; 95% confidence interval=0.497-0.868; P=0.003]. After the 1:2 propensity score matching, a significant reduction (23.5%) in the incidence of variceal rebleeding in patients was observed, from 58.3% in the non-CPMs cohort to 44.6% in the CPMs cohort (modified log-rank test, P=0.002) within a year. The AHRs for rebleeding were 0.928, 0.553, and 0.105, for 28-90 cDDDs, 91-180 cDDDs, and >180 cDDDs of CPMs, respectively. The median rebleeding interval in the CPMs cohort was significantly larger compared with the non-CPMs cohort (113.5 vs. 93.0 days; P=0.008).

Conclusion: Adjuvant CPMs to standard therapy can significantly reduce the incidence of variceal rebleeding and delay the time to rebleeding.
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http://dx.doi.org/10.1007/s11655-020-3272-7DOI Listing
September 2020

Crystal structure of bacteriophage T4 Spackle as determined by native SAD phasing.

Acta Crystallogr D Struct Biol 2020 Sep 25;76(Pt 9):899-904. Epub 2020 Aug 25.

Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.

The crystal structure of a bacteriophage T4 early gene product, Spackle, was determined by native sulfur single-wavelength anomalous diffraction (SAD) phasing using synchrotron radiation and was refined to 1.52 Å resolution. The structure shows that Spackle consists of a bundle of five α-helices, forming a relatively flat disc-like overall shape. Although Spackle forms a dimer in the crystal, size-exclusion chromatography with multi-angle light scattering shows that it is monomeric in solution. Mass spectrometry confirms that purified mature Spackle lacks the amino-terminal signal peptide and contains an intramolecular disulfide bond, consistent with its proposed role in the periplasm of T4 phage-infected Escherichia coli cells. The surface electrostatic potential of Spackle shows a strikingly bipolar charge distribution, suggesting a possible mode of membrane association and inhibition of the tail lysozyme activity in T4 bacteriophage superinfection exclusion.
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http://dx.doi.org/10.1107/S2059798320010979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466748PMC
September 2020