36 results on '"Su B"'
Search Results
2. Oligomerization and a distinct tRNA-binding loop are important regulators of human arginyl-transferase function
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Xin Lan, Wei Huang, Su Bin Kim, Dechen Fu, Thilini Abeywansha, Jiemin Lou, Udayakumaran Balamurugan, Yong Tae Kwon, Chang Hoon Ji, Derek J. Taylor, and Yi Zhang
- Subjects
Science - Abstract
Abstract The arginyl-transferase ATE1 is a tRNA-dependent enzyme that covalently attaches an arginine molecule to a protein substrate. Conserved from yeast to humans, ATE1 deficiency in mice correlates with defects in cardiovascular development and angiogenesis and results in embryonic lethality, while conditional knockouts exhibit reproductive, developmental, and neurological deficiencies. Despite the recent revelation of the tRNA binding mechanism and the catalytic cycle of yeast ATE1, the structure-function relationship of ATE1 in higher organisms is not well understood. In this study, we present the three-dimensional structure of human ATE1 in an apo-state and in complex with its tRNA cofactor and a peptide substrate. In contrast to its yeast counterpart, human ATE1 forms a symmetric homodimer, which dissociates upon binding of a substrate. Furthermore, human ATE1 includes a unique and extended loop that wraps around tRNAArg, creating extensive contacts with the T-arm of the tRNA cofactor. Substituting key residues identified in the substrate binding site of ATE1 abolishes enzymatic activity and results in the accumulation of ATE1 substrates in cells.
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- 2024
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3. Full integration of highly stretchable inorganic transistors and circuits within molecular-tailored elastic substrates on a large scale
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Seung-Han Kang, Jeong-Wan Jo, Jong Min Lee, Sanghee Moon, Seung Bum Shin, Su Bin Choi, Donghwan Byeon, Jaehyun Kim, Myung-Gil Kim, Yong-Hoon Kim, Jong-Woong Kim, and Sung Kyu Park
- Subjects
Science - Abstract
Abstract The emergence of high-form-factor electronics has led to a demand for high-density integration of inorganic thin-film devices and circuits with full stretchability. However, the intrinsic stiffness and brittleness of inorganic materials have impeded their utilization in free-form electronics. Here, we demonstrate highly integrated strain-insensitive stretchable metal-oxide transistors and circuitry (442 transistors/cm2) via a photolithography-based bottom-up approach, where transistors with fluidic liquid metal interconnection are embedded in large-area molecular-tailored heterogeneous elastic substrates (5 × 5 cm2). Amorphous indium-gallium-zinc-oxide transistor arrays (7 × 7), various logic gates, and ring-oscillator circuits exhibited strain-resilient properties with performance variation less than 20% when stretched up to 50% and 30% strain (10,000 cycles) for unit transistor and circuits, respectively. The transistors operate with an average mobility of 12.7 ( ± 1.7) cm2 V−1s−1, on/off current ratio of > 107, and the inverter, NAND, NOR circuits operate quite logically. Moreover, a ring oscillator comprising 14 cross-wired transistors validated the cascading of the multiple stages and device uniformity, indicating an oscillation frequency of ~70 kHz.
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- 2024
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4. Mid-old cells are a potential target for anti-aging interventions in the elderly
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Young Hwa Kim, Young-Kyoung Lee, Soon Sang Park, So Hyun Park, So Yeong Eom, Young-Sam Lee, Wonhee John Lee, Juhee Jang, Daeha Seo, Hee Young Kang, Jin Cheol Kim, Su Bin Lim, Gyesoon Yoon, Hong Seok Kim, Jang-Hee Kim, and Tae Jun Park
- Subjects
Science - Abstract
Abstract The biological process of aging is thought to result in part from accumulation of senescent cells in organs. However, the present study identified a subset of fibroblasts and smooth muscle cells which are the major constituents of organ stroma neither proliferative nor senescent in tissues of the elderly, which we termed “mid-old status” cells. Upregulation of pro-inflammatory genes (IL1B and SAA1) and downregulation of anti-inflammatory genes (SLIT2 and CXCL12) were detected in mid-old cells. In the stroma, SAA1 promotes development of the inflammatory microenvironment via upregulation of MMP9, which decreases the stability of epithelial cells present on the basement membrane, decreasing epithelial cell function. Remarkably, the microenvironmental change and the functional decline of mid-old cells could be reversed by a young cell-originated protein, SLIT2. Our data identify functional reversion of mid-old cells as a potential method to prevent or ameliorate aspects of aging-related tissue dysfunction.
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- 2023
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5. Ratiometric measurement of MAM Ca2+ dynamics using a modified CalfluxVTN
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Eunbyul Cho, Youngsik Woo, Yeongjun Suh, Bo Kyoung Suh, Soo Jeong Kim, Truong Thi My Nhung, Jin Yeong Yoo, Tran Diem Nghi, Su Been Lee, Dong Jin Mun, and Sang Ki Park
- Subjects
Science - Abstract
Abstract Mitochondria-associated ER membrane (MAM) is a structure where these calcium-regulating organelles form close physical contact sites for efficient Ca2+ crosstalk. Despite the central importance of MAM Ca2+ dynamics in diverse biological processes, directly and specifically measuring Ca2+ concentrations inside MAM is technically challenging. Here, we develop MAM-Calflux, a MAM-specific BRET-based Ca2+ indicator. The successful application of the bimolecular fluorescence complementation (BiFC) concept highlights Ca2+-responsive BRET signals in MAM. The BiFC strategy imparts dual functionality as a Ca2+ indicator and quantitative structural marker specific for MAM. As a ratiometric Ca2+ indicator, MAM-Calflux estimates steady-state MAM Ca2+ levels. Finally, it enables the visualization of uneven intracellular distribution of MAM Ca2+ and the elucidation of abnormally accumulated MAM Ca2+ from the neurons of Parkinson’s disease mouse model in both steady-state and stimulated conditions. Therefore, we propose that MAM-Calflux can be a versatile tool for ratiometrically measuring dynamic inter-organellar Ca2+ communication.
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- 2023
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6. The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system
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Chang Hoon Ji, Hee Yeon Kim, Min Ju Lee, Ah Jung Heo, Daniel Youngjae Park, Sungsu Lim, Seulgi Shin, Woo Seung Yang, Chang An Jung, Kun Young Kim, Eun Hye Jeong, Sun Ho Park, Su Bin Kim, Su Jin Lee, Jeong Eun Na, Ji In Kang, Hyung Min Chi, Hyun Tae Kim, Yun Kyung Kim, Bo Yeon Kim, and Yong Tae Kwon
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Science - Abstract
Targeted protein degradation is a promising approach for basic research and therapeutic applications. Here, the authors develop a targeted protein degradation platform called AUTOTAC to degrade oncoproteins and neurodegeneration-associated proteins via the p62-dependent autophagy-lysosome system.
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- 2022
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7. Author Correction: The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system
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Chang Hoon Ji, Hee Yeon Kim, Min Ju Lee, Ah Jung Heo, Daniel Youngjae Park, Sungsu Lim, Seulgi Shin, Srinivasrao Ganipisetti, Woo Seung Yang, Chang An Jung, Kun Young Kim, Eun Hye Jeong, Sun Ho Park, Su Bin Kim, Su Jin Lee, Jeong Eun Na, Ji In Kang, Hyung Min Chi, Hyun Tae Kim, Yun Kyung Kim, Bo Yeon Kim, and Yong Tae Kwon
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Science - Published
- 2022
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8. Highly efficient genome editing by CRISPR-Cpf1 using CRISPR RNA with a uridinylate-rich 3′-overhang
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Su Bin Moon, Jeong Mi Lee, Jeong Gu Kang, Nan-Ee Lee, Dae-In Ha, Do Yon Kim, Sun Hee Kim, Kwangsun Yoo, Daesik Kim, Jeong-Heon Ko, and Yong-Sam Kim
- Subjects
Science - Abstract
Cpf1 is a promising alternative to Cas9 though indel generation efficiency is target dependent. Here the authors show that the addition of a polyU 3′ overhang can improve the efficiency of low efficiency guide RNAs.
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- 2018
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9. An extracellular matrix-related prognostic and predictive indicator for early-stage non-small cell lung cancer
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Su Bin LIM, Swee Jin TAN, Wan-Teck LIM, and Chwee Teck LIM
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Science - Abstract
Prognosis and prediction of adjuvant chemotherapy response in non-small cell lung cancer can have significant clinical impact. Here, the authors show that differential expression of a 29 extracellular matrix gene indicator, EPPI, can predict patient outcome.
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- 2017
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10. Modifiable lifestyle factors and the risk of post-COVID-19 multisystem sequelae, hospitalization, and death.
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Wang Y, Su B, Alcalde-Herraiz M, Barclay NL, Tian Y, Li C, Wareham NJ, Paredes R, Xie J, and Prieto-Alhambra D
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- Humans, Male, Female, Middle Aged, Aged, Risk Factors, United Kingdom epidemiology, Adult, Smoking epidemiology, Smoking adverse effects, Exercise, Alcohol Drinking adverse effects, Alcohol Drinking epidemiology, Post-Acute COVID-19 Syndrome, Cohort Studies, Sedentary Behavior, COVID-19 mortality, COVID-19 epidemiology, COVID-19 prevention & control, Hospitalization statistics & numerical data, Life Style, SARS-CoV-2
- Abstract
Effective prevention strategies for post-COVID complications are crucial for patients, clinicians, and policy makers to mitigate their cumulative burden. This study evaluated the association of modifiable lifestyle factors (smoking, alcohol intake, BMI, physical activity, sedentary time, sleep duration, and dietary habits) with COVID-19 multisystem sequelae, death, and hospitalization in the UK Biobank cohort (n = 68,896). A favorable lifestyle (6-10 healthy factors; 46.4%) was associated with a 36% lower risk of multisystem sequelae (HR, 0.64; 95% CI, 0.58-0.69; ARR at 210 days, 7.08%; 95% CI, 5.98-8.09) compared to an unfavorable lifestyle (0-4 factors; 12.3%). Risk reductions spanned all 10 organ systems, including cardiovascular, coagulation, metabolic, gastrointestinal, kidney, mental health, musculoskeletal, respiratory disorders, and fatigue. This beneficial effect was largely attributable to direct lifestyle impacts independent of corresponding pre-infection comorbidities (71% for any sequelae). A favorable lifestyle was also related to the risk of post-COVID death (HR 0.59, 0.52-0.66) and hospitalization (HR 0.78, 0.73-0.84). These associations persisted across acute and post-acute infection phases, irrespective of hospitalization status, vaccination, or SARS-CoV-2 variant. These findings underscore the clinical and public health importance of adhering to a healthy lifestyle in mitigating long-term COVID-19 adverse impacts and enhancing future pandemic preparedness., (© 2024. The Author(s).)
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- 2024
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11. Exceptional figure of merit achieved in boron-dispersed GeTe-based thermoelectric composites.
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Jiang Y, Su B, Yu J, Han Z, Hu H, Zhuang HL, Li H, Dong J, Li JW, Wang C, Ge ZH, Feng J, Sun FH, and Li JF
- Abstract
GeTe is a promising p-type material with increasingly enhanced thermoelectric properties reported in recent years, demonstrating its superiority for mid-temperature applications. In this work, the thermoelectric performance of GeTe is improved by a facile composite approach. We find that incorporating a small amount of boron particles into the Bi-doped GeTe leads to significant enhancement in power factor and simultaneous reduction in thermal conductivity, through which the synergistic modulation of electrical and thermal transport properties is realized. The thermal mismatch between the boron particles and the matrix induces high-density dislocations that effectively scatter the mid-frequency phonons, accounting for a minimum lattice thermal conductivity of 0.43 Wm
-1 K-1 at 613 K. Furthermore, the presence of boron/GeTe interfaces modifies the interfacial potential barriers, resulting in increased Seebeck coefficient and hence enhanced power factor (25.4 μWcm-1 K-2 at 300 K). Consequently, we obtain a maximum figure of merit Zmax of 4.0 × 10-3 K-1 at 613 K in the GeTe-based composites, which is the record-high value in GeTe-based thermoelectric materials and also superior to most of thermoelectric systems for mid-temperature applications. This work provides an effective way to further enhance the performance of GeTe-based thermoelectrics., (© 2024. The Author(s).)- Published
- 2024
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12. Relationship between HLA genetic variations, COVID-19 vaccine antibody response, and risk of breakthrough outcomes.
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Xie J, Mothe B, Alcalde Herraiz M, Li C, Xu Y, Jödicke AM, Gao Y, Wang Y, Feng S, Wei J, Chen Z, Hong S, Wu Y, Su B, Zheng X, Cohet C, Ali R, Wareham N, and Alhambra DP
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- Humans, Antibody Formation genetics, Antibody Formation immunology, Male, Female, Genotype, Vaccination, Middle Aged, Adult, Genetic Variation, HLA-DQ beta-Chains genetics, HLA-DQ beta-Chains immunology, Breakthrough Infections, COVID-19 Vaccines immunology, COVID-19 Vaccines administration & dosage, COVID-19 immunology, COVID-19 prevention & control, COVID-19 genetics, COVID-19 virology, SARS-CoV-2 immunology, SARS-CoV-2 genetics, Antibodies, Viral immunology, Antibodies, Viral blood, Alleles, HLA Antigens genetics, HLA Antigens immunology, Polymorphism, Single Nucleotide
- Abstract
The rapid global distribution of COVID-19 vaccines, with over a billion doses administered, has been unprecedented. However, in comparison to most identified clinical determinants, the implications of individual genetic factors on antibody responses post-COVID-19 vaccination for breakthrough outcomes remain elusive. Here, we conducted a population-based study including 357,806 vaccinated participants with high-resolution HLA genotyping data, and a subset of 175,000 with antibody serology test results. We confirmed prior findings that single nucleotide polymorphisms associated with antibody response are predominantly located in the Major Histocompatibility Complex region, with the expansive HLA-DQB1*06 gene alleles linked to improved antibody responses. However, our results did not support the claim that this mutation alone can significantly reduce COVID-19 risk in the general population. In addition, we discovered and validated six HLA alleles (A*03:01, C*16:01, DQA1*01:02, DQA1*01:01, DRB3*01:01, and DPB1*10:01) that independently influence antibody responses and demonstrated a combined effect across HLA genes on the risk of breakthrough COVID-19 outcomes. Lastly, we estimated that COVID-19 vaccine-induced antibody positivity provides approximately 20% protection against infection and 50% protection against severity. These findings have immediate implications for functional studies on HLA molecules and can inform future personalised vaccination strategies., (© 2024. The Author(s).)
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- 2024
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13. FOXP3 + regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity.
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Liu X, Zhang W, Han Y, Cheng H, Liu Q, Ke S, Zhu F, Lu Y, Dai X, Wang C, Huang G, Su B, Zou Q, Li H, Zhao W, Xiao L, Lu L, Tong X, Pan F, Li H, and Li B
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- Humans, Feedback, Cytokines metabolism, Forkhead Transcription Factors metabolism, Membrane Proteins metabolism, RNA-Binding Proteins metabolism, STAT1 Transcription Factor genetics, STAT1 Transcription Factor metabolism, T-Lymphocytes, Regulatory, Neoplasms genetics, Neoplasms therapy
- Abstract
Targeting tumor-infiltrating regulatory T cells (Tregs) is an efficient way to evoke an anti-tumor immune response. However, how Tregs maintain their fragility and stability remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. On the contrary, the decreased IFITM3 expression in STAT1-deficient Tregs indicates that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of tumor-infiltrating Tregs in the tumor model. Overall, our study demonstrates that the perturbation of tumor-infiltrating Tregs through the IFNγ-IFITM3-STAT1 feedback loop is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy., (© 2024. The Author(s).)
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- 2024
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14. Wide-temperature-range thermoelectric n-type Mg 3 (Sb,Bi) 2 with high average and peak zT values.
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Li JW, Han Z, Yu J, Zhuang HL, Hu H, Su B, Li H, Jiang Y, Chen L, Liu W, Zheng Q, and Li JF
- Abstract
Mg
3 (Sb,Bi)2 is a promising thermoelectric material suited for electronic cooling, but there is still room to optimize its low-temperature performance. This work realizes >200% enhancement in room-temperature zT by incorporating metallic inclusions (Nb or Ta) into the Mg3 (Sb,Bi)2 -based matrix. The electrical conductivity is boosted in the range of 300-450 K, whereas the corresponding Seebeck coefficients remain unchanged, leading to an exceptionally high room-temperature power factor >30 μW cm-1 K-2 ; such an unusual effect originates mainly from the modified interfacial barriers. The reduced interfacial barriers are conducive to carrier transport at low and high temperatures. Furthermore, benefiting from the reduced lattice thermal conductivity, a record-high average zT > 1.5 and a maximum zT of 2.04 at 798 K are achieved, resulting in a high thermoelectric conversion efficiency of 15%. This work demonstrates an efficient nanocomposite strategy to enhance the wide-temperature-range thermoelectric performance of n-type Mg3 (Sb,Bi)2 , broadening their potential for practical applications., (© 2023. The Author(s).)- Published
- 2023
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15. Associations of modern initial antiretroviral therapy regimens with all-cause mortality in people living with HIV in resource-limited settings: a retrospective multicenter cohort study in China.
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Wu X, Wu G, Ma P, Wang R, Li L, Chen Y, Xu J, Li Y, Li Q, Yang Y, Wang L, Xin X, Qiao Y, Fu G, Huang X, Su B, Zhang T, Wang H, and Zou H
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- Humans, Cohort Studies, Lopinavir, Retrospective Studies, Benzoxazines, China epidemiology, Nevirapine, Acquired Immunodeficiency Syndrome
- Abstract
Despite the proven virological advantages, there remains some controversy regarding whether first-line integrase strand transfer inhibitors (INSTIs)-based antiretroviral therapy (ART) contributes to reducing mortality of people living with HIV (PLHIV) in clinical practice. Here we report a retrospective study comparing all-cause mortality among PLHIV in China who were on different initial ART regimens (nevirapine, efavirenz, dolutegravir, lopinavir, and others [including darunavir, raltegravie, elvitegravir and rilpivirine]) between 2017 and 2019. A total of 41,018 individuals were included across China, representing 21.3% of newly reported HIV/AIDS cases collectively in the country during this period. Only the differences in all-cause mortality of PLHIV between the efavirenz group and the nevirapine group, the dolutegravir group and the nevirapine group, and the lopinavir group and the nevirapine group, were observed in China. After stratifying the cause of mortality, we found that the differences in mortality between initial ART regimens were mainly observed in AIDS-related mortality., (© 2023. Springer Nature Limited.)
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- 2023
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16. Dual donor-acceptor covalent organic frameworks for hydrogen peroxide photosynthesis.
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Qin C, Wu X, Tang L, Chen X, Li M, Mou Y, Su B, Wang S, Feng C, Liu J, Yuan X, Zhao Y, and Wang H
- Abstract
Constructing photocatalytically active and stable covalent organic frameworks containing both oxidative and reductive reaction centers remain a challenge. In this study, benzotrithiophene-based covalent organic frameworks with spatially separated redox centers are rationally designed for the photocatalytic production of hydrogen peroxide from water and oxygen without sacrificial agents. The triazine-containing framework demonstrates high selectivity for H
2 O2 photogeneration, with a yield rate of 2111 μM h-1 (21.11 μmol h-1 and 1407 μmol g-1 h-1 ) and a solar-to-chemical conversion efficiency of 0.296%. Codirectional charge transfer and large energetic differences between linkages and linkers are verified in the double donor-acceptor structures of periodic frameworks. The active sites are mainly concentrated on the electron-acceptor fragments near the imine bond, which regulate the electron distribution of adjacent carbon atoms to optimally reduce the Gibbs free energy of O2 * and OOH* intermediates during the formation of H2 O2 ., (© 2023. Springer Nature Limited.)- Published
- 2023
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17. RUFY3 regulates endolysosomes perinuclear positioning, antigen presentation and migration in activated phagocytes.
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Char R, Liu Z, Jacqueline C, Davieau M, Delgado MG, Soufflet C, Fallet M, Chasson L, Chapuy R, Camosseto V, Strock E, Rua R, Almeida CR, Su B, Lennon-Duménil AM, Nal B, Roquilly A, Liang Y, Méresse S, Gatti E, and Pierre P
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- Animals, Mice, Endosomes metabolism, Lysosomes metabolism, Phagocytes, Antigen Presentation, Lipopolysaccharides metabolism
- Abstract
Endo-lysosomes transport along microtubules and clustering in the perinuclear area are two necessary steps for microbes to activate specialized phagocyte functions. We report that RUN and FYVE domain-containing protein 3 (RUFY3) exists as two alternative isoforms distinguishable by the presence of a C-terminal FYVE domain and by their affinity for phosphatidylinositol 3-phosphate on endosomal membranes. The FYVE domain-bearing isoform (iRUFY3) is preferentially expressed in primary immune cells and up-regulated upon activation by microbes and Interferons. iRUFY3 is necessary for ARL8b + /LAMP1+ endo-lysosomes positioning in the pericentriolar organelles cloud of LPS-activated macrophages. We show that iRUFY3 controls macrophages migration, MHC II presentation and responses to Interferon-γ, while being important for intracellular Salmonella replication. Specific inactivation of rufy3 in phagocytes leads to aggravated pathologies in mouse upon LPS injection or bacterial pneumonia. This study highlights the role of iRUFY3 in controlling endo-lysosomal dynamics, which contributes to phagocyte activation and immune response regulation., (© 2023. The Author(s).)
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- 2023
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18. Reconstruction of the tumor spatial microenvironment along the malignant-boundary-nonmalignant axis.
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Xun Z, Ding X, Zhang Y, Zhang B, Lai S, Zou D, Zheng J, Chen G, Su B, Han L, and Ye Y
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- Eosine Yellowish-(YS), Gene Expression Profiling, Hematoxylin, Tumor Microenvironment, Fibroblasts
- Abstract
Although advances in spatial transcriptomics (ST) enlarge to unveil spatial landscape of tissues, it remains challenging to delineate pathology-relevant and cellular localizations, and interactions exclusive to a spatial niche (e.g., tumor boundary). Here, we develop Cottrazm, integrating ST with hematoxylin and eosin histological image, and single-cell transcriptomics to delineate the tumor boundary connecting malignant and non-malignant cell spots in tumor tissues, deconvolute cell-type composition at spatial location, and reconstruct cell type-specific gene expression profiles at sub-spot level. We validate the performance of Cottrazm along the malignant-boundary-nonmalignant spatial axis. We identify specific macrophage and fibroblast subtypes localized around tumor boundary that interacted with tumor cells to generate a structural boundary, which limits T cell infiltration and promotes immune exclusion in tumor microenvironment. In this work, Cottrazm provides an integrated tool framework to dissect the tumor spatial microenvironment and facilitates the discovery of functional biological insights, thereby identifying therapeutic targets in oncologic ST datasets., (© 2023. The Author(s).)
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- 2023
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19. Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia.
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Charpignon ML, Vakulenko-Lagun B, Zheng B, Magdamo C, Su B, Evans K, Rodriguez S, Sokolov A, Boswell S, Sheu YH, Somai M, Middleton L, Hyman BT, Betensky RA, Finkelstein SN, Welsch RE, Tzoulaki I, Blacker D, Das S, and Albers MW
- Subjects
- Humans, Drug Repositioning, Network Pharmacology, Sulfonylurea Compounds, Hypoglycemic Agents pharmacology, Hypoglycemic Agents therapeutic use, Medical Records, Metformin pharmacology, Metformin therapeutic use, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 complications, Dementia drug therapy, Dementia etiology
- Abstract
Metformin, a diabetes drug with anti-aging cellular responses, has complex actions that may alter dementia onset. Mixed results are emerging from prior observational studies. To address this complexity, we deploy a causal inference approach accounting for the competing risk of death in emulated clinical trials using two distinct electronic health record systems. In intention-to-treat analyses, metformin use associates with lower hazard of all-cause mortality and lower cause-specific hazard of dementia onset, after accounting for prolonged survival, relative to sulfonylureas. In parallel systems pharmacology studies, the expression of two AD-related proteins, APOE and SPP1, was suppressed by pharmacologic concentrations of metformin in differentiated human neural cells, relative to a sulfonylurea. Together, our findings suggest that metformin might reduce the risk of dementia in diabetes patients through mechanisms beyond glycemic control, and that SPP1 is a candidate biomarker for metformin's action in the brain., (© 2022. The Author(s).)
- Published
- 2022
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20. Evolution of defect structures leading to high ZT in GeTe-based thermoelectric materials.
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Jiang Y, Dong J, Zhuang HL, Yu J, Su B, Li H, Pei J, Sun FH, Zhou M, Hu H, Li JW, Han Z, Zhang BP, Mori T, and Li JF
- Abstract
GeTe is a promising mid-temperature thermoelectric compound but inevitably contains excessive Ge vacancies hindering its performance maximization. This work reveals that significant enhancement in the dimensionless figure of merit (ZT) could be realized by defect structure engineering from point defects to line and plane defects of Ge vacancies. The evolved defects including dislocations and nanodomains enhance phonon scattering to reduce lattice thermal conductivity in GeTe. The accumulation of cationic vacancies toward the formation of dislocations and planar defects weakens the scattering against electronic carriers, securing the carrier mobility and power factor. This synergistic effect on electronic and thermal transport properties remarkably increases the quality factor. As a result, a maximum ZT > 2.3 at 648 K and a record-high average ZT (300-798 K) were obtained for Bi
0.07 Ge0.90 Te in lead-free GeTe-based compounds. This work demonstrates an important strategy for maximizing the thermoelectric performance of GeTe-based materials by engineering the defect structures, which could also be applied to other thermoelectric materials., (© 2022. The Author(s).)- Published
- 2022
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21. Single-cell and spatial analysis reveal interaction of FAP + fibroblasts and SPP1 + macrophages in colorectal cancer.
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Qi J, Sun H, Zhang Y, Wang Z, Xun Z, Li Z, Ding X, Bao R, Hong L, Jia W, Fang F, Liu H, Chen L, Zhong J, Zou D, Liu L, Han L, Ginhoux F, Liu Y, Ye Y, and Su B
- Subjects
- Fibroblasts pathology, Humans, Immunotherapy, Macrophages pathology, Osteopontin, Spatial Analysis, Tumor Microenvironment, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology
- Abstract
Colorectal cancer (CRC) is among the most common malignancies with limited treatments other than surgery. The tumor microenvironment (TME) profiling enables the discovery of potential therapeutic targets. Here, we profile 54,103 cells from tumor and adjacent tissues to characterize cellular composition and elucidate the potential origin and regulation of tumor-enriched cell types in CRC. We demonstrate that the tumor-specific FAP
+ fibroblasts and SPP1+ macrophages were positively correlated in 14 independent CRC cohorts containing 2550 samples and validate their close localization by immuno-fluorescent staining and spatial transcriptomics. This interaction might be regulated by chemerin, TGF-β, and interleukin-1, which would stimulate the formation of immune-excluded desmoplasic structure and limit the T cell infiltration. Furthermore, we find patients with high FAP or SPP1 expression achieved less therapeutic benefit from an anti-PD-L1 therapy cohort. Our results provide a potential therapeutic strategy by disrupting FAP+ fibroblasts and SPP1+ macrophages interaction to improve immunotherapy., (© 2022. The Author(s).)- Published
- 2022
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22. Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development.
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He J, Shangguan X, Zhou W, Cao Y, Zheng Q, Tu J, Hu G, Liang Z, Jiang C, Deng L, Wang S, Yang W, Zuo Y, Ma J, Cai R, Chen Y, Fan Q, Dong B, Xue W, Tan H, Qi Y, Gu J, Su B, Eugene Chin Y, Chen G, Wang Q, Wang T, and Cheng J
- Subjects
- ATPases Associated with Diverse Cellular Activities metabolism, Acetylation, Allografts, Animals, Cell Line, Tumor, Cell Survival genetics, Colonic Neoplasms immunology, Fructosediphosphates metabolism, GTP Phosphohydrolases metabolism, Glucose deficiency, Metabolomics, Metalloendopeptidases metabolism, Mice, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Mitochondria genetics, Mitochondria ultrastructure, Mitochondrial Dynamics genetics, Mitochondrial Proteins metabolism, Oxidative Phosphorylation, Sirtuin 3 antagonists & inhibitors, Sirtuin 3 genetics, Sumoylation, T-Lymphocytes immunology, AMP-Activated Protein Kinases metabolism, CD8-Positive T-Lymphocytes immunology, Cysteine Endopeptidases metabolism, Immunologic Memory genetics, Mitochondria metabolism, Sirtuin 3 metabolism, T-Lymphocytes metabolism
- Abstract
Metabolic programming and mitochondrial dynamics along with T cell differentiation affect T cell fate and memory development; however, how to control metabolic reprogramming and mitochondrial dynamics in T cell memory development is unclear. Here, we provide evidence that the SUMO protease SENP1 promotes T cell memory development via Sirt3 deSUMOylation. SENP1-Sirt3 signalling augments the deacetylase activity of Sirt3, promoting both OXPHOS and mitochondrial fusion. Mechanistically, SENP1 activates Sirt3 deacetylase activity in T cell mitochondria, leading to reduction of the acetylation of mitochondrial metalloprotease YME1L1. Consequently, deacetylation of YME1L1 suppresses its activity on OPA1 cleavage to facilitate mitochondrial fusion, which results in T cell survival and promotes T cell memory development. We also show that the glycolytic intermediate fructose-1,6-bisphosphate (FBP) as a negative regulator suppresses AMPK-mediated activation of the SENP1-Sirt3 axis and reduces memory development. Moreover, glucose limitation reduces FBP production and activates AMPK during T cell memory development. These data show that glucose limitation activates AMPK and the subsequent SENP1-Sirt3 signalling for T cell memory development., (© 2021. The Author(s).)
- Published
- 2021
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23. MEKK2 mediates aberrant ERK activation in neurofibromatosis type I.
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Bok S, Shin DY, Yallowitz AR, Eiseman M, Cung M, Xu R, Li N, Sun J, Williams AL, Scott JE, Su B, Shim JH, and Greenblatt MB
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- Animals, Disease Models, Animal, Enzyme Activation, Extracellular Matrix Proteins genetics, Female, Humans, MAP Kinase Kinase Kinase 2 antagonists & inhibitors, MAP Kinase Kinase Kinase 2 genetics, Male, Mice, Transgenic, Neurofibromatosis 1 drug therapy, Neurofibromin 1 genetics, Neurofibromin 1 metabolism, Osteoblasts metabolism, Phosphorylation, Protein Kinase Inhibitors pharmacology, Skull cytology, Extracellular Signal-Regulated MAP Kinases metabolism, Imidazoles pharmacology, MAP Kinase Kinase Kinase 2 metabolism, Neurofibromatosis 1 etiology, Pyridazines pharmacology
- Abstract
Neurofibromatosis type I (NF1) is characterized by prominent skeletal manifestations caused by NF1 loss. While inhibitors of the ERK activating kinases MEK1/2 are promising as a means to treat NF1, the broad blockade of the ERK pathway produced by this strategy is potentially associated with therapy limiting toxicities. Here, we have sought targets offering a more narrow inhibition of ERK activation downstream of NF1 loss in the skeleton, finding that MEKK2 is a novel component of a noncanonical ERK pathway in osteoblasts that mediates aberrant ERK activation after NF1 loss. Accordingly, despite mice with conditional deletion of Nf1 in mature osteoblasts (Nf1
fl/fl ;Dmp1-Cre) and Mekk2-/- each displaying skeletal defects, Nf1fl/fl ;Mekk2-/- ;Dmp1-Cre mice show an amelioration of NF1-associated phenotypes. We also provide proof-of-principle that FDA-approved inhibitors with activity against MEKK2 can ameliorate NF1 skeletal pathology. Thus, MEKK2 functions as a MAP3K in the ERK pathway in osteoblasts, offering a potential new therapeutic strategy for the treatment of NF1.- Published
- 2020
- Full Text
- View/download PDF
24. Chromatin accessibility landscape and regulatory network of high-altitude hypoxia adaptation.
- Author
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Xin J, Zhang H, He Y, Duren Z, Bai C, Chen L, Luo X, Yan DS, Zhang C, Zhu X, Yuan Q, Feng Z, Cui C, Qi X, Ouzhuluobu, Wong WH, Wang Y, and Su B
- Subjects
- Altitude, Altitude Sickness ethnology, Altitude Sickness genetics, Altitude Sickness metabolism, Basic Helix-Loop-Helix Transcription Factors genetics, Cell Hypoxia genetics, Cells, Cultured, Chromatin genetics, Chromatin Immunoprecipitation Sequencing, Disease Resistance genetics, Female, Gene Expression Regulation, Human Umbilical Vein Endothelial Cells, Humans, Hypoxia genetics, Hypoxia metabolism, Oxygen metabolism, Polymorphism, Single Nucleotide, Pregnancy, Primary Cell Culture, RNA-Seq, Regulatory Elements, Transcriptional genetics, Selection, Genetic, Tibet ethnology, Transcription Factors metabolism, Whole Genome Sequencing, Acclimatization genetics, Chromatin metabolism, Ethnicity genetics, Gene Regulatory Networks, Models, Genetic
- Abstract
High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1, the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1, elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation.
- Published
- 2020
- Full Text
- View/download PDF
25. Trio deep-sequencing does not reveal unexpected off-target and on-target mutations in Cas9-edited rhesus monkeys.
- Author
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Luo X, He Y, Zhang C, He X, Yan L, Li M, Hu T, Hu Y, Jiang J, Meng X, Ji W, Zhao X, Zheng P, Xu S, and Su B
- Subjects
- Animals, Humans, Whole Genome Sequencing, CRISPR-Cas Systems, Gene Editing methods, High-Throughput Nucleotide Sequencing methods, Macaca mulatta genetics, Mutation
- Abstract
CRISPR-Cas9 is a widely-used genome editing tool, but its off-target effect and on-target complex mutations remain a concern, especially in view of future clinical applications. Non-human primates (NHPs) share close genetic and physiological similarities with humans, making them an ideal preclinical model for developing Cas9-based therapies. However, to our knowledge no comprehensive in vivo off-target and on-target assessment has been conducted in NHPs. Here, we perform whole genome trio sequencing of Cas9-treated rhesus monkeys. We only find a small number of de novo mutations that can be explained by expected spontaneous mutations, and no unexpected off-target mutations (OTMs) were detected. Furthermore, the long-read sequencing data does not detect large structural variants in the target region.
- Published
- 2019
- Full Text
- View/download PDF
26. Long-read assembly of the Chinese rhesus macaque genome and identification of ape-specific structural variants.
- Author
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He Y, Luo X, Zhou B, Hu T, Meng X, Audano PA, Kronenberg ZN, Eichler EE, Jin J, Guo Y, Yang Y, Qi X, and Su B
- Subjects
- Animals, China, Evolution, Molecular, Hominidae classification, Humans, Macaca mulatta classification, Male, Molecular Sequence Annotation, Phenotype, Sequence Analysis, RNA, Species Specificity, Genome, Hominidae genetics, Macaca mulatta genetics
- Abstract
We present a high-quality de novo genome assembly (rheMacS) of the Chinese rhesus macaque (Macaca mulatta) using long-read sequencing and multiplatform scaffolding approaches. Compared to the current Indian rhesus macaque reference genome (rheMac8), rheMacS increases sequence contiguity 75-fold, closing 21,940 of the remaining assembly gaps (60.8 Mbp). We improve gene annotation by generating more than two million full-length transcripts from ten different tissues by long-read RNA sequencing. We sequence resolve 53,916 structural variants (96% novel) and identify 17,000 ape-specific structural variants (ASSVs) based on comparison to ape genomes. Many ASSVs map within ChIP-seq predicted enhancer regions where apes and macaque show diverged enhancer activity and gene expression. We further characterize a subset that may contribute to ape- or great-ape-specific phenotypic traits, including taillessness, brain volume expansion, improved manual dexterity, and large body size. The rheMacS genome assembly serves as an ideal reference for future biomedical and evolutionary studies.
- Published
- 2019
- Full Text
- View/download PDF
27. AAV-ie enables safe and efficient gene transfer to inner ear cells.
- Author
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Tan F, Chu C, Qi J, Li W, You D, Li K, Chen X, Zhao W, Cheng C, Liu X, Qiao Y, Su B, He S, Zhong C, Li H, Chai R, and Zhong G
- Subjects
- Animals, Cells, Cultured, Female, Gene Transfer Techniques, Genetic Vectors genetics, Male, Mice, Mice, Inbred C57BL, Basic Helix-Loop-Helix Transcription Factors genetics, Dependovirus genetics, Genetic Therapy methods, Hair Cells, Auditory, Inner cytology, Hearing Loss genetics, Hearing Loss therapy
- Abstract
Hearing loss is the most common sensory disorder. While gene therapy has emerged as a promising treatment of inherited diseases like hearing loss, it is dependent on the identification of gene delivery vectors. Adeno-associated virus (AAV) vector-mediated gene therapy has been approved in the US for treating a rare inherited eye disease but no safe and efficient vectors have been identified that can target the diverse types of inner ear cells. Here, we identify an AAV variant, AAV-inner ear (AAV-ie), for gene delivery in mouse inner ear. Our results show that AAV-ie transduces the cochlear supporting cells (SCs) with high efficiency, representing a vast improvement over conventional AAV serotypes. Furthermore, after AAV-ie-mediated transfer of the Atoh1 gene, we find that many SCs trans-differentiated into new HCs. Our results suggest that AAV-ie is a useful tool for the cochlear gene therapy and for investigating the mechanism of HC regeneration.
- Published
- 2019
- Full Text
- View/download PDF
28. Tens of thousands additional deaths annually in cities of China between 1.5 °C and 2.0 °C warming.
- Author
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Wang Y, Wang A, Zhai J, Tao H, Jiang T, Su B, Yang J, Wang G, Liu Q, Gao C, Kundzewicz ZW, Zhan M, Feng Z, and Fischer T
- Subjects
- Acclimatization, Adolescent, Adult, Aged, China epidemiology, Cities epidemiology, Female, Humans, Male, Middle Aged, Socioeconomic Factors, Urban Population statistics & numerical data, Young Adult, Global Warming, Hot Temperature adverse effects, Mortality trends, Urban Population trends
- Abstract
The increase in surface air temperature in China has been faster than the global rate, and more high temperature spells are expected to occur in future. Here we assess the annual heat-related mortality in densely populated cities of China at 1.5 °C and 2.0 °C global warming. For this, the urban population is projected under five SSPs, and 31 GCM runs as well as temperature-mortality relation curves are applied. The annual heat-related mortality is projected to increase from 32.1 per million inhabitants annually in 1986-2005 to 48.8-67.1 per million for the 1.5 °C warming and to 59.2-81.3 per million for the 2.0 °C warming, taking improved adaptation capacity into account. Without improved adaptation capacity, heat-related mortality will increase even stronger. If all 831 million urban inhabitants in China are considered, the additional warming from 1.5 °C to 2 °C will lead to more than 27.9 thousand additional heat-related deaths, annually.
- Published
- 2019
- Full Text
- View/download PDF
29. Inhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours.
- Author
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Wu ZR, Yan L, Liu YT, Cao L, Guo YH, Zhang Y, Yao H, Cai L, Shang HB, Rui WW, Yang G, Zhang XB, Tang H, Wang Y, Huang JY, Wei YX, Zhao WG, Su B, and Wu ZB
- Subjects
- Animals, Cabergoline pharmacology, Carcinogenesis, Carrier Proteins, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation drug effects, Disease Progression, Down-Regulation, Female, HEK293 Cells, Heterografts, Humans, Mechanistic Target of Rapamycin Complex 2 metabolism, Mice, Phosphorylation drug effects, Pituitary Neoplasms drug therapy, RNA, Long Noncoding genetics, Ribosomal Protein S6 Kinases, 70-kDa metabolism, Up-Regulation, Adaptor Proteins, Signal Transducing metabolism, Mechanistic Target of Rapamycin Complex 1 drug effects, Phosphoproteins metabolism, Pituitary Neoplasms metabolism, RNA, Long Noncoding antagonists & inhibitors, RNA, Long Noncoding metabolism
- Abstract
Aberrant expression of long noncoding RNA H19 has been associated with tumour progression, but the underlying molecular tumourigenesis mechanisms remain largely unknown. Here, we report that H19 expression is frequently downregulated in human primary pituitary adenomas and is negatively correlated with tumour progression. Consistently, upregulation of H19 expression inhibits pituitary tumour cell proliferation in vitro and tumour growth in vivo. Importantly, we uncover a function of H19, which controls cell/tumour growth through inhibiting function of mTORC1 but not mTORC2. Mechanistically, we show that H19 could block mTORC1-mediated 4E-BP1 phosphorylation without affecting S6K1 activation. At the molecular level, H19 interacted with 4E-BP1 at the TOS motif and competitively inhibited 4E-BP1 binding to Raptor. Finally, we demonstrate that H19 is more effective than cabergoline treatment in the suppression of pituitary tumours. Together, our study uncovered the role of H19-mTOR-4E-BP1 axis in pituitary tumour growth regulation that may be a potential therapeutic target for human pituitary tumours.
- Published
- 2018
- Full Text
- View/download PDF
30. SENP3 maintains the stability and function of regulatory T cells via BACH2 deSUMOylation.
- Author
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Yu X, Lao Y, Teng XL, Li S, Zhou Y, Wang F, Guo X, Deng S, Chang Y, Wu X, Liu Z, Chen L, Lu LM, Cheng J, Li B, Su B, Jiang J, Li HB, Huang C, Yi J, and Zou Q
- Subjects
- Active Transport, Cell Nucleus, Animals, Antineoplastic Agents metabolism, Autoimmunity immunology, Bone Marrow Cells, CD4-Positive T-Lymphocytes, Cell Differentiation immunology, Cell Line, Tumor, Cell Nucleus immunology, Cysteine Endopeptidases, Female, Gene Deletion, Gene Expression Profiling, Gene Expression Regulation, HEK293 Cells, Homeostasis immunology, Humans, Lymphocyte Activation immunology, Melanoma, Experimental immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptide Hydrolases genetics, Reactive Oxygen Species, T-Lymphocytes, Regulatory pathology, Basic-Leucine Zipper Transcription Factors metabolism, Immune Tolerance immunology, Peptide Hydrolases metabolism, Sumoylation immunology, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism
- Abstract
Regulatory T (Treg) cells are essential for maintaining immune homeostasis and tolerance, but the mechanisms regulating the stability and function of Treg cells have not been fully elucidated. Here we show SUMO-specific protease 3 (SENP3) is a pivotal regulator of Treg cells that functions by controlling the SUMOylation and nuclear localization of BACH2. Treg cell-specific deletion of Senp3 results in T cell activation, autoimmune symptoms and enhanced antitumor T cell responses. SENP3-mediated BACH2 deSUMOylation prevents the nuclear export of BACH2, thereby repressing the genes associated with CD4
+ T effector cell differentiation and stabilizing Treg cell-specific gene signatures. Notably, SENP3 accumulation triggered by reactive oxygen species (ROS) is involved in Treg cell-mediated tumor immunosuppression. Our results not only establish the role of SENP3 in the maintenance of Treg cell stability and function via BACH2 deSUMOylation but also clarify the function of SENP3 in the regulation of ROS-induced immune tolerance.- Published
- 2018
- Full Text
- View/download PDF
31. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer.
- Author
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Fang T, Lv H, Lv G, Li T, Wang C, Han Q, Yu L, Su B, Guo L, Huang S, Cao D, Tang L, Tang S, Wu M, Yang W, and Wang H
- Subjects
- Animals, Cancer-Associated Fibroblasts pathology, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular secondary, Cell Communication, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Exosomes chemistry, Humans, Integrin beta1 genetics, Integrin beta1 metabolism, Interleukin-6 genetics, Interleukin-6 metabolism, Interleukin-8 genetics, Interleukin-8 metabolism, Liver Neoplasms genetics, Liver Neoplasms pathology, Lung Neoplasms genetics, Lung Neoplasms secondary, Male, Mice, Mice, Nude, MicroRNAs metabolism, N-Acetyllactosamine Synthase metabolism, Neoplasm Invasiveness, Neoplasm Transplantation, Neoplastic Cells, Circulating metabolism, Neoplastic Cells, Circulating pathology, Signal Transduction, Cancer-Associated Fibroblasts metabolism, Carcinoma, Hepatocellular metabolism, Exosomes metabolism, Gene Expression Regulation, Neoplastic, Liver Neoplasms metabolism, Lung Neoplasms metabolism, MicroRNAs genetics, N-Acetyllactosamine Synthase genetics
- Abstract
The communication between tumor-derived elements and stroma in the metastatic niche has a critical role in facilitating cancer metastasis. Yet, the mechanisms tumor cells use to control metastatic niche formation are not fully understood. Here we report that in the lung metastatic niche, high-metastatic hepatocellular carcinoma (HCC) cells exhibit a greater capacity to convert normal fibroblasts to cancer-associated fibroblasts (CAFs) than low-metastatic HCC cells. We show high-metastatic HCC cells secrete exosomal miR-1247-3p that directly targets B4GALT3, leading to activation of β1-integrin-NF-κB signaling in fibroblasts. Activated CAFs further promote cancer progression by secreting pro-inflammatory cytokines, including IL-6 and IL-8. Clinical data show high serum exosomal miR-1247-3p levels correlate with lung metastasis in HCC patients. These results demonstrate intercellular crosstalk between tumor cells and fibroblasts is mediated by tumor-derived exosomes that control lung metastasis of HCC, providing potential targets for prevention and treatment of cancer metastasis.
- Published
- 2018
- Full Text
- View/download PDF
32. Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex.
- Author
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Fisher OS, Deng H, Liu D, Zhang Y, Wei R, Deng Y, Zhang F, Louvi A, Turk BE, Boggon TJ, and Su B
- Subjects
- Animals, Animals, Newborn, Blood Vessels metabolism, Capillary Permeability genetics, Crystallization, Hemangioma, Cavernous, Central Nervous System genetics, MAP Kinase Kinase Kinase 3 metabolism, Mice, Mice, Knockout, Microfilament Proteins metabolism, Signal Transduction, rho GTP-Binding Proteins metabolism, rho-Associated Kinases metabolism, Blood Vessels embryology, Cerebrovascular Circulation genetics, Intracranial Hemorrhages genetics, MAP Kinase Kinase Kinase 3 genetics, Microfilament Proteins genetics, Neovascularization, Physiologic genetics
- Abstract
Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 Å cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho-ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease.
- Published
- 2015
- Full Text
- View/download PDF
33. NF-κB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis.
- Author
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Yan S, Xu Z, Lou F, Zhang L, Ke F, Bai J, Liu Z, Liu J, Wang H, Zhu H, Sun Y, Cai W, Gao Y, Su B, Li Q, Yang X, Yu J, Lai Y, Yu XZ, Zheng Y, Shen N, Chin YE, and Wang H
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Epidermis immunology, Epidermis metabolism, Female, Gene Expression Regulation, Humans, Hyperplasia genetics, Hyperplasia immunology, Male, Mice, Mice, Transgenic, Middle Aged, NF-kappa B metabolism, Phosphoprotein Phosphatases metabolism, Psoriasis immunology, Reverse Transcriptase Polymerase Chain Reaction, Young Adult, Cytokines immunology, Epidermis pathology, Keratinocytes metabolism, MicroRNAs genetics, NF-kappa B immunology, Phosphoprotein Phosphatases genetics, Psoriasis genetics, RNA, Messenger metabolism
- Abstract
NF-κB is constitutively activated in psoriatic epidermis. However, how activated NF-κB promotes keratinocyte hyperproliferation in psoriasis is largely unknown. Here we report that the NF-κB activation triggered by inflammatory cytokines induces the transcription of microRNA (miRNA) miR-31, one of the most dynamic miRNAs identified in the skin of psoriatic patients and mouse models. The genetic deficiency of miR-31 in keratinocytes inhibits their hyperproliferation, decreases acanthosis and reduces the disease severity in psoriasis mouse models. Furthermore, protein phosphatase 6 (ppp6c), a negative regulator that restricts the G1 to S phase progression, is diminished in human psoriatic epidermis and is directly targeted by miR-31. The inhibition of ppp6c is functionally important for miR-31-mediated biological effects. Moreover, NF-κB activation inhibits ppp6c expression directly through the induction of miR-31, and enhances keratinocyte proliferation. Thus, our data identify NF-κB-induced miR-31 and its target, ppp6c, as critical factors for the hyperproliferation of epidermis in psoriasis.
- Published
- 2015
- Full Text
- View/download PDF
34. Positioning and joining of organic single-crystalline wires.
- Author
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Wu Y, Feng J, Jiang X, Zhang Z, Wang X, Su B, and Jiang L
- Abstract
Organic single-crystal, one-dimensional materials can effectively carry charges and/or excitons due to their highly ordered molecule packing, minimized defects and eliminated grain boundaries. Controlling the alignment/position of organic single-crystal one-dimensional architectures would allow on-demand photon/electron transport, which is a prerequisite in waveguides and other optoelectronic applications. Here we report a guided physical vapour transport technique to control the growth, alignment and positioning of organic single-crystal wires with the guidance of pillar-structured substrates. Submicrometre-wide, hundreds of micrometres long, highly aligned, organic single-crystal wire arrays are generated. Furthermore, these organic single-crystal wires can be joined within controlled angles by varying the pillar geometries. Owing to the controllable growth of organic single-crystal one-dimensional architectures, we can present proof-of-principle demonstrations utilizing joined wires to allow optical waveguide through small radii of curvature (internal angles of ~90-120°). Our methodology may open a route to control the growth of organic single-crystal one-dimensional materials with potential applications in optoelectronics.
- Published
- 2015
- Full Text
- View/download PDF
35. Silver-catalysed direct amination of unactivated C-H bonds of functionalized molecules.
- Author
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Yang M, Su B, Wang Y, Chen K, Jiang X, Zhang YF, Zhang XS, Chen G, Cheng Y, Cao Z, Guo QY, Wang L, and Shi ZJ
- Abstract
Carbon-nitrogen bond formation from inert C-H bonds is an ideal organic transformation and a highly desirable method for the synthesis of N-containing molecules due to its high efficiency and atom economy. In this report, we develop a general reaction to achieve an unprecedented selective intramolecular amination of unactivated C-H bond in the absence of complex directing groups. Functionalized heterocyclic products are built up from readily available linear amines through simple and reliable silver catalysis, representing a new silver-based C-H functionalization. This method displays preference for primary sp(3) C-H bonds and exhibits distinct chemo- and regioselectivity compared to existing methods of direct amination (Hofmann-Löffler-Freytag reaction and nitrene insertion). The study highlights the manipulation of unfunctionalized groups in organic molecules to furnish complex structural units in the natural and bioactive molecules.
- Published
- 2014
- Full Text
- View/download PDF
36. Analysis of mitochondrial genome diversity identifies new and ancient maternal lineages in Cambodian aborigines.
- Author
-
Zhang X, Qi X, Yang Z, Serey B, Sovannary T, Bunnath L, Seang Aun H, Samnom H, Zhang H, Lin Q, van Oven M, Shi H, and Su B
- Subjects
- Asian People history, Bayes Theorem, Cambodia, Female, Genetic Variation, Haplotypes, History, Ancient, Human Migration, Humans, Inheritance Patterns, Male, Phylogeny, Phylogeography, Asian People genetics, DNA, Mitochondrial genetics, DNA, Mitochondrial history, Founder Effect, Genealogy and Heraldry, Genome, Mitochondrial
- Abstract
Cambodia harbours a variety of aboriginal (and presumably ancient) populations that have largely been ignored in studies of genetic diversity. Here we investigate the matrilineal gene pool of 1,054 Cambodians from 14 geographic populations. Using mitochondrial whole-genome sequencing, we identify eight new mitochondrial DNA haplogroups, all of which are either newly defined basal haplogroups or basal sub-branches. Most of the new basal haplogroups have very old coalescence ages, ranging from ~55,000 to ~68,000 years, suggesting that present-day Cambodian aborigines still carry ancient genetic polymorphisms in their maternal lineages, and most of the common Cambodian haplogroups probably originated locally before expanding to the surrounding areas during prehistory. Moreover, we observe a relatively close relationship between Cambodians and populations from the Indian subcontinent, supporting the earliest costal route of migration of modern humans from Africa into mainland Southeast Asia by way of the Indian subcontinent some 60,000 years ago.
- Published
- 2013
- Full Text
- View/download PDF
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