Publications by authors named "Lipeng Chen"

53 Publications

Methyltransferase-like protein 11A promotes migration of cervical cancer cells via up-regulating ELK3.

Pharmacol Res 2021 Aug 25;172:105814. Epub 2021 Aug 25.

Department of Gynaecology, The First Affiliated Hospital of Jinan University, Guangzhou, China. Electronic address:

Cervical cancer is one of the common malignancies in women, which is characterized with high invasion and metastatic tendency in its advanced stage. Increasing evidence indicates that methyltransferase-like (METTL) gene family is involved in the progression of various cancers. However, the functional role of methyltransferase-like gene family in cervical cancer remains unclear. In the present study, we found that METTL11A, a member of the methyltransferase-like gene family, was significantly over-expressed in cervical carcinoma by analyzing TCGA database. This finding was further validated in clinical tissue samples. Moreover, ectopic expression of METTL11A in cervical cancer cell lines promoted cell proliferation and migration both in vitro and in vivo. Differential gene expression analysis in the transcriptomic sequencing data indicated that ELK3 was down-regulated in METTL11A-silenced cervical cancer cells, which was further verified at both protein and mRNA levels. Functional experiments identified that METTL11A promoted migration of cervical cancer cells in an ELK3-dependent manner. This study will promote understanding the mechanism of cervical cancer progression and the functional role of methyltransferase-like gene families in cancers.
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http://dx.doi.org/10.1016/j.phrs.2021.105814DOI Listing
August 2021

Victimization and depressive symptoms among Chinese adolescents: A moderated mediation model.

J Affect Disord 2021 Nov 20;294:375-381. Epub 2021 Jul 20.

School of Humanities and Social Sciences, University of Science and Technology of China, No. 96 Jinzhai Road, Baohe District, Hefei 230022, PR China. Electronic address:

Background: Victimization as an inducing factor of depressive symptoms has been confirmed in previous studies. However, little is known about how and when it induces depressive symptoms in adolescents.

Methods: In total, 1174 Chinese adolescents were recruited to complete the Juvenile Victimization Questionnaire, Security Questionnaire, Positive Psychological Capital Questionnaire, and the Chinese version of the Center for Epidemiologic Studies Depression Scale.

Results: After controlling for gender and school type, the sense of security partially mediated the association between victimization and depressive symptoms. Moreover, direct association and the mediating effect of the sense of security were moderated by psychological capital. The moderating effect occurred in the second half of the mediating effect.

Limitations: Causal conclusions cannot be drawn based on cross-sectional research design. All measures were based on participant self-report.

Conclusions: The mediating model constructed in this study emphasized the important influence of stress, emotion, and psychological diathesis on adolescent depressive symptoms.
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http://dx.doi.org/10.1016/j.jad.2021.07.022DOI Listing
November 2021

Plasma Levels of Heat Shock Protein 90 Alpha Associated With Colorectal Cancer Development.

Front Mol Biosci 2021 8;8:684836. Epub 2021 Jul 8.

Department of Research, Guangxi Medical University Cancer Hospital, Nanning, China.

The role of plasma heat shock protein 90 alpha (HSP90α) in colorectal cancer patients remains unclear. This study aimed to evaluate the relationship between HSP90α and the occurrence and development of colorectal cancer through diagnosis and prognosis value. 635 colorectal cancer patients and 295 healthy controls were recruited. The HSP90α was measured by using the ELISA kit in all objects and the immune cells and common biomarkers as CEA, AFP, CA125, CA153 and CA199 were measured in all colorectal cancer patients. The relationship between plasma HSP90α with clinical features, common tumor markers and immune cells were also conducted. The survival analysis endpoint was progression-free survival (PFS). The levels of plasma HSP90α were significantly higher in colorectal cancer patients compared to healthy controls [51.4 (ng/ml) vs. 43.7 (ng/ml), < 0.001]. In additional, the levels of plasma HSP90α were associated with gender and disease progress as stage, lymphatic and distant metastasis. Furthermore, plasma HSP90α was closed correlation with CEA, CA125, CA199 and percentage of B cells. However, the initial expression level of plasma HSP90α failed to show a prognostic value for progression-free survival in colorectal cancer. The plasma Hsp90α was remarkable higher in colorectal cancer and correlated with common tumor biomarkers and immune cells. Plasma Hsp90α levels were associated with disease progress but a poor diagnosis performance and also failed to show a prognostic value in colorectal cancer.
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http://dx.doi.org/10.3389/fmolb.2021.684836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295900PMC
July 2021

Fully Quantum Modeling of Exciton Diffusion in Mesoscale Light Harvesting Systems.

Materials (Basel) 2021 Jun 14;14(12). Epub 2021 Jun 14.

School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore.

It has long been a challenge to accurately and efficiently simulate exciton-phonon dynamics in mesoscale photosynthetic systems with a fully quantum mechanical treatment due to extensive computational resources required. In this work, we tackle this seemingly intractable problem by combining the Dirac-Frenkel time-dependent variational method with Davydov trial states and implementing the algorithm in graphic processing units. The phonons are treated on the same footing as the exciton. Tested with toy models, which are nanoarrays of the B850 pigments from the light harvesting 2 complexes of purple bacteria, the methodology is adopted to describe exciton diffusion in huge systems containing more than 1600 molecules. The superradiance enhancement factor extracted from the simulations indicates an exciton delocalization over two to three pigments, in agreement with measurements of fluorescence quantum yield and lifetime in B850 systems. With fractal analysis of the exciton dynamics, it is found that exciton transfer in B850 nanoarrays exhibits a superdiffusion component for about 500 fs. Treating the B850 ring as an aggregate and modeling the inter-ring exciton transfer as incoherent hopping, we also apply the method of classical master equations to estimate exciton diffusion properties in one-dimensional (1D) and two-dimensional (2D) B850 nanoarrays using derived analytical expressions of time-dependent excitation probabilities. For both coherent and incoherent propagation, faster energy transfer is uncovered in 2D nanoarrays than 1D chains, owing to availability of more numerous propagating channels in the 2D arrangement.
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http://dx.doi.org/10.3390/ma14123291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232211PMC
June 2021

Simulation of Time- and Frequency-Resolved Four-Wave-Mixing Signals at Finite Temperatures: A Thermo-Field Dynamics Approach.

J Chem Theory Comput 2021 Jul 9;17(7):4359-4373. Epub 2021 Jun 9.

School of Science, Hangzhou Dianzi University, Hangzhou 310018, China.

We propose a new approach to simulate four-wave-mixing signals of molecular systems at finite temperatures by combining the multiconfigurational Ehrenfest method with the thermo-field dynamics theory. In our approach, the four-time correlation functions at finite temperatures are mapped onto those at zero temperature in an enlarged Hilbert space with twice the vibrational degrees of freedom. As an illustration, we have simulated three multidimensional spectroscopic signals, time- and frequency-resolved fluorescence spectra, transient-absorption pump-probe spectra, and electronic two-dimensional (2D) spectra at finite temperatures, for a conical intersection-mediated singlet fission model of a rubrene crystal. It is shown that a detailed dynamical picture of the singlet fission process can be extracted from the three spectroscopic signals. An increasing temperature leads to lower intensities of the signals and broadened vibrational peaks, which can be attributed to faster singlet-triplet population transfer and stronger bath-induced electronic dephasing at higher temperatures.
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http://dx.doi.org/10.1021/acs.jctc.1c00259DOI Listing
July 2021

Prognostic Role of the Ubiquitin Proteasome System in Clear Cell Renal Cell Carcinoma: A Bioinformatic Perspective.

J Cancer 2021 13;12(14):4134-4147. Epub 2021 May 13.

Department of Urology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, 250012, China.

Clear cell renal cell carcinoma (ccRCC) is a common malignant tumor of the urinary system. The ubiquitin proteasome system (UPS) plays an important role in the generation, metabolism and survival of tumor. We are aimed to make a comprehensive exploration of the UPS's role in ccRCC with bioinformatic tools, which may contribute to the understanding of UPS in ccRCC, and give insight for further research. The UPS-related genes (UPSs) were collected by an integrative approach. The expression and clinical data were downloaded from TCGA database. R soft was used to perform the differentially expressed UPSs analysis, functional enrichment analysis. We also estimated prognostic value of each UPS with the help of GEPIA database. Two predicting models were constructed with the differentially expressed UPSs and prognosis-related genes, respectively. The correlations of risk score with clinical characteristics were also evaluated. Data of GSE29609 cohort were obtained from GEO database to validate the prognostic models. We finally identified 91 differentially expressed UPSs, 48 prognosis related genes among them, and constructed a prognostic model with 18 UPSs successfully, the AUC was 0.760. With the help of GEPIA, we found 391 prognosis-related UPSs, accounting for 57.84% of all UPSs. Another prognostic model was constructed with 28 prognosis-related genes of them, and with a better AUC of 0.825. Additionally, our models can also stratify patients into high and low risk groups accurately in GSE29609 cohort. Similar prognostic values of our models were observed in the validated GSE29609 cohort. UPS is dysregulated in ccRCC. UPS related genes have significant prognostic value in ccRCC. Models constructed with UPSs are effective and applicable. An abnormal ubiquitin proteasome system should play an important role in ccRCC and be worthy of further study.
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http://dx.doi.org/10.7150/jca.53760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176417PMC
May 2021

KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1.

Mol Cancer 2021 05 18;20(1):77. Epub 2021 May 18.

Key Laboratory for Experimental Teratology of Ministry of Education, Department of Medical Genetics, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.

Background: KDM6A, a histone demethylase, is frequently mutated in bladder cancer (BCa). However, the role and detailed molecular mechanism of KDM6A involved in bladder cancer progression remains unknown.

Methods: Tissue specimens were used to determine the expression levels and prognostic values of KDM6A and ARHGDIB. The MTT, colony formation, wound healing and Transwell migration and invasion assays were employed to detect the BCa cell proliferation, migration and invasion, respectively. Chemotaxis of macrophages was used to evaluate the ability of KDM6A to recruit macrophages. A subcutaneous tumour model and tail vein tumour injection in nude mice were used to assess the role of KDM6A in vivo. RNA sequencing, qPCR, Western blot, ChIP and phalloidin staining assay were performed to investigate the molecular functions of KDM6A. Dual-luciferase reporter assay was used to determine the effects of KDM6A and FOXA1 on the promoters of the ARHGDIB and KDM6A.

Results: We showed that the KDM6A inhibited the motility and invasiveness of the BCa cells. Mechanistically, KDM6A promotes the transcription of ARHGDIB by demethylating histone H3 lysine di/trimethylation (H3K27me2/3) and consequently leads to inhibition of Rac1. EZH2, which catalyses the methylation of H3K27, functions to silence ARHGDIB expression, and an EZH2 inhibitor can neutralize the metastatic effect caused by KDM6A deficiency. Furthermore, we demonstrated that FOXA1 directly binds to the KDM6A promoter and thus transactivates KDM6A, leading to diminished metastatic potential.

Conclusion: Our findings establish the critical role of the FOXA1-KDM6A-ARHGDIB axis in restraining the malignancy of BCa and identify KDM6A and EZH2 as potential therapeutic targets in the management of BCa.
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http://dx.doi.org/10.1186/s12943-021-01369-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130406PMC
May 2021

Hierarchical Equations-of-Motion Method for Momentum System-Bath Coupling.

J Phys Chem B 2021 May 30;125(18):4863-4873. Epub 2021 Apr 30.

Max Planck Institute for the Physics of Complex Systems, D-01187 Dresden, Germany.

For a broad class of quantum models of practical interest, we demonstrate that the Hamiltonian of the system nonlinearly coupled to a harmonic bath through the system and bath coordinates can be equivalently mapped into the Hamiltonian of the system bilinearly coupled to the bath through the system and bath momenta. We show that the Hamiltonian with bilinear system-bath momentum coupling can be treated by the hierarchical equations-of-motion (HEOM) method and present the corresponding proof-of-principle simulations. The developed methodology creates the opportunity to scrutinize a new family of nonlinear quantum systems by the numerically accurate HEOM method.
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http://dx.doi.org/10.1021/acs.jpcb.1c02431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279550PMC
May 2021

Ab Initio Surface-Hopping Simulation of Femtosecond Transient-Absorption Pump-Probe Signals of Nonadiabatic Excited-State Dynamics Using the Doorway-Window Representation.

J Chem Theory Comput 2021 Apr 23;17(4):2394-2408. Epub 2021 Mar 23.

Department of Chemistry, Technical University of Munich, D-85747 Garching, Germany.

An ab initio theoretical framework for the simulation of femtosecond time-resolved transient absorption (TA) pump-probe (PP) spectra with quasi-classical trajectories is presented. The simulations are based on the classical approximation to the doorway-window (DW) representation of third-order four-wave-mixing signals. The DW formula accounts for the finite duration and spectral shape of the pump and probe pulses. In the classical DW formalism, classical trajectories are stochastically sampled from a positive definite doorway distribution, and the signals are evaluated by averaging over a positive definite window distribution. Nonadiabatic excited-state dynamics is described by a stochastic surface-hopping algorithm. The method has been implemented for the pyrazine molecule with the second-order algebraic-diagrammatic construction (ADC(2)) ab initio electronic-structure method. The methodology is illustrated by ab initio simulations of the ground-state bleach, stimulated emission, and excited-state absorption contributions to the TA PP spectrum of gas-phase pyrazine.
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http://dx.doi.org/10.1021/acs.jctc.1c00109DOI Listing
April 2021

Metformin ameliorates bladder dysfunction in a rat model of partial bladder outlet obstruction.

Am J Physiol Renal Physiol 2021 05 1;320(5):F838-F858. Epub 2021 Mar 1.

Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Alteration of bladder morphology and function was the most important consequence of bladder outlet obstruction (BOO). Using a rat model of partial BOO (pBOO), we found that rats treated with metformin showed lower baseline pressures with a reduced inflammatory reaction in the early phase (2 wk) after pBOO. The NLR family pyrin domain containing 3 inflammasome pathway was inhibited in pBOO rat bladders with treatment of metformin in the early phase. Metformin reduced the activity of NLR family pyrin domain containing 3 in primary urothelial cells. In the chronic phase (9 wk after pBOO), metformin treatment ameliorated bladder fibrosis and improved the reduced compliance. Treatment with metformin suppressed the activation of Smad3 and compensated the diminished autophagy in 9-wk pBOO rat bladders. Autophagy was inhibited with upregulation of profibrotic proteins in primary fibroblasts from chronic pBOO bladders, which could be restored by administration of metformin. The antifibrotic effects of metformin on fibroblasts were diminished after silencing of AMP-activated protein kinase or light chain 3B. In summary, this study elucidates that oral administration of metformin relieves inflammation in the bladder during the early phase of pBOO. Long-term oral administration of metformin can prevent functional and histological changes in the pBOO rat bladder. The current study suggests that metformin might be used to prevent the development of bladder dysfunction secondary to BOO. The present study in a rat model showed that oral administration of metformin alleviated inflammation following partial bladder outlet obstruction in the early phase and ameliorated bladder fibrosis as well as bladder dysfunction by long-term treatment. Our study indicated that metformin is a potential drug to inhibit bladder remodeling and alleviate bladder dysfunction. Clinical trials are needed to validate the effect of metformin on the bladder dysfunction and bladder fibrosis in the future.
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http://dx.doi.org/10.1152/ajprenal.00625.2020DOI Listing
May 2021

Efficient simulation of time- and frequency-resolved four-wave-mixing signals with a multiconfigurational Ehrenfest approach.

J Chem Phys 2021 Feb;154(5):054105

Division of Materials Science, Nanyang Technological University, Singapore 639798, Singapore.

We have extended the multiconfigurational Ehrenfest approach to the simulation of four-wave-mixing signals of systems involving multiple electronic and vibrational degrees of freedom. As an illustration, we calculate signals of three widely used spectroscopic techniques, time- and frequency-resolved fluorescence spectroscopy, transient absorption spectroscopy, and two-dimensional (2D) electronic spectroscopy, for a two-electronic-state, twenty-four vibrational-mode conical intersection model. It has been shown that all these three spectroscopic signals characterize fast population transfer from the higher excited electronic state to the lower excited electronic state. While the time- and frequency-resolved spectrum maps the wave packet propagation exclusively on the electronically excited states, the transient absorption and 2D electronic spectra reflect the wave packet dynamics on both electronically excited states and the electronic ground state. Combining trajectory-guided Gaussian basis functions and the nonlinear response function formalism, the present approach provides a promising general technique for the applications of various Gaussian basis methods to the calculations of four-wave-mixing spectra of polyatomic molecules.
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http://dx.doi.org/10.1063/5.0038824DOI Listing
February 2021

Single-cell transcriptomes of mouse bladder urothelium uncover novel cell type markers and urothelial differentiation characteristics.

Cell Prolif 2021 Apr 3;54(4):e13007. Epub 2021 Feb 3.

Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Objectives: Much of the information to date in terms of subtypes and function of bladder urothelial cells were derived from anatomical location or by the expression of a small number of marker genes. To have a comprehensive map of the cellular anatomy of bladder urothelial cells, we performed single-cell RNA sequencing to thoroughly characterize mouse bladder urothelium.

Materials And Methods: A total of 18,917 single cells from mouse bladder urothelium were analysed by unbiased single-cell RNA sequencing. The expression of the novel cell marker was confirmed by immunofluorescence using urinary tract infection models.

Results: Unsupervised clustering analysis identified 8 transcriptionally distinct cell subpopulations from mouse bladder urothelial cells. We discovered a novel type of bladder urothelial cells marked by Plxna4 that may be involved with host response and wound healing. We also found a group of basal-like cells labelled by ASPM that could be the progenitor cells of adult bladder urothelium. ASPM urothelial cells are significantly increased after injury by UPEC. In addition, specific transcription factors were found to be associated with urothelial cell differentiation. At the last, a number of interstitial cystitis/bladder pain syndrome-regulating genes were found differentially expressed among different urothelial cell subpopulations.

Conclusions: Our study provides a comprehensive characterization of bladder urothelial cells, which is fundamental to understanding the biology of bladder urothelium and associated bladder disease.
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http://dx.doi.org/10.1111/cpr.13007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016651PMC
April 2021

CUL4B promotes aggressive phenotypes of renal cell carcinoma via upregulating c-Met expression.

Int J Biochem Cell Biol 2021 01 20;130:105887. Epub 2020 Nov 20.

Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address:

Cullin 4B (CUL4B), encoding a scaffold protein in Cullin RING ubiquitin-ligase complexes (CRL4B), is overexpressed and serves as an oncogene in various solid tumors. However, the roles and the underlying mechanisms of CUL4B in renal cell carcinoma (RCC) are still unknown. In this study, we demonstrated that CUL4B was significantly upregulated in RCC cells and clinical specimens, and its overexpression was correlated with poor survival of RCC patients. Knockdown of CUL4B resulted in the inhibition of proliferation, migration and invasion of RCC cells. Furthermore, we found that the expression of CUL4B is positively correlated with c-Met expression in RCC cells and tissues. Konckdown of c-Met or treatment with c-Met inhibitor, SU11274, could block the increase in cell proliferation, migration and invasion induced by CUL4B-overexpression. We also showed that CUL4B overexpression significantly accelerated xenograft tumor growth, and administration of SU11274 could also abrogate the accelerated tumor growth induced by CUL4B overexpression in vivo. These findings shed light on the contribution of CUL4B to tumorigenesis in RCC via activating c-Met signaling and its therapeutic implications in RCC patients.
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http://dx.doi.org/10.1016/j.biocel.2020.105887DOI Listing
January 2021

Temperature effects on singlet fission dynamics mediated by a conical intersection.

J Chem Phys 2020 Nov;153(19):194106

School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore.

Finite-temperature dynamics of singlet fission in crystalline rubrene is investigated by utilizing the Dirac-Frenkel time-dependent variational method in combination with multiple Davydov D trial states. To probe temperature effects on the singlet fission process mediated by a conical intersection, the variational method is extended to include number state propagation with thermally averaged Boltzmann distribution as initialization. This allows us to simulate two-dimensional electronic spectroscopic signals of two-mode and three-mode models of crystalline rubrene in the temperature range from 0 K to 300 K. It is demonstrated that an elevated temperature facilitates excitonic population transfer and accelerates the singlet fission process. In addition, increasing temperature leads to dramatic changes in two-dimensional spectra, thanks to temperature-dependent electronic dephasing and to an increased number of system eigenstates amenable to spectroscopic probing.
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http://dx.doi.org/10.1063/5.0031435DOI Listing
November 2020

Ultrafast dynamics in rubrene and its spectroscopic manifestation.

J Chem Phys 2020 Nov;153(17):174105

School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore.

A multimode Brownian oscillator model is employed to investigate absorption line shapes of rubrene in solutions and thin films. Excellent agreement has been obtained between simulated and measured absorption spectra. Furthermore, using the parameters obtained from the fitting absorption spectra of rubrene, the dynamics of singlet fission is explored by the Dirac-Frenkel time-dependent variation with multiple Davydov trial states. By comparing the absorption spectra between a conical intersection model and the multimode Brownian oscillator model, the optimal system-bath coupling parameter of η = 0.2 is determined, and ensuing population dynamics of the S1 state is found to concur with a previously proposed coherent singlet fission mechanism. We further simulate the two-dimensional spectra to reveal the wavepacket dynamics on both excited state and ground state potential energy surfaces. It is demonstrated that the wavepacket motion of tuning modes plays a significant role in the evolution of two-dimensional spectra.
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http://dx.doi.org/10.1063/5.0023887DOI Listing
November 2020

Multi-faceted spectroscopic mapping of ultrafast nonadiabatic dynamics near conical intersections: A computational study.

J Chem Phys 2020 Nov;153(17):174111

School of Science, Hangzhou Dianzi University, Hangzhou 310018, China.

We studied spectroscopic signatures of the nonadiabatic dynamics at conical intersections formed by the lowest excited singlet states in pyrazine. We considered two ab initio models of conical intersections in the excited states of pyrazine developed by Sala et al. [Phys. Chem. Chem. Phys. 16, 15957 (2014)]: a two-state (B and B), five-mode model and a three-state (B, B, and A), nine-mode model. We simulated the signals of three widely used techniques: time- and frequency-resolved fluorescence spectroscopy, transient absorption pump-probe spectroscopy, and electronic two-dimensional spectroscopy. The signals were calculated through third-order response functions, which, in turn, were evaluated with the numerically accurate multiple Davydov ansatz. We establish spectroscopic signatures of the optically dark A state and demonstrate that the key features of the photoinduced dynamics, such as electronic/nuclear populations, electronic/nuclear coherences, and electronic/nuclear energy transfer processes, are imprinted in the spectroscopic signals. We show that a fairly complete picture of the nonadiabatic dynamics at conical intersections can be obtained when several spectroscopic techniques are combined. Provided that the time resolution is sufficient, time- and frequency-resolved fluorescence may provide the best visualization of the nonadiabatic dynamics near conical intersections.
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http://dx.doi.org/10.1063/5.0024148DOI Listing
November 2020

Identification of a distinct luminal subgroup diagnosing and stratifying early stage prostate cancer by tissue-based single-cell RNA sequencing.

Mol Cancer 2020 10 8;19(1):147. Epub 2020 Oct 8.

Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.

Background: The highly intra-tumoral heterogeneity and complex cell origination of prostate cancer greatly limits the utility of traditional bulk RNA sequencing in finding better biomarker for disease diagnosis and stratification. Tissue specimens based single-cell RNA sequencing holds great promise for identification of novel biomarkers. However, this technique has yet been used in the study of prostate cancer heterogeneity.

Methods: Cell types and the corresponding marker genes were identified by single-cell RNA sequencing. Malignant states of different clusters were evaluated by copy number variation analysis and differentially expressed genes of pseudo-bulks sequencing. Diagnosis and stratification of prostate cancer was estimated by receiver operating characteristic curves of marker genes. Expression characteristics of marker genes were verified by immunostaining.

Results: Fifteen cell groups including three luminal clusters with different expression profiles were identified in prostate cancer tissues. The luminal cluster with the highest copy number variation level and marker genes enriched in prostate cancer-related metabolic processes was considered the malignant cluster. This cluster contained a distinct subgroup with high expression level of prostate cancer biomarkers and a strong distinguishing ability of normal and cancerous prostates across different pathology grading. In addition, we identified another marker gene, Hepsin (HPN), with a 0.930 area under the curve score distinguishing normal tissue from prostate cancer lesion. This finding was further validated by immunostaining of HPN in prostate cancer tissue array.

Conclusion: Our findings provide a valuable resource for interpreting tumor heterogeneity in prostate cancer, and a novel candidate marker for prostate cancer management.
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http://dx.doi.org/10.1186/s12943-020-01264-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545561PMC
October 2020

Effects of high pulse intensity and chirp in two-dimensional electronic spectroscopy of an atomic vapor.

Opt Express 2020 Aug;28(18):25806-25829

The effects of high pulse intensity and chirp on two-dimensional electronic spectroscopy signals are experimentally investigated in the highly non-perturbative regime using atomic rubidium vapor as clean model system. Data analysis is performed based on higher-order Feynman diagrams and non-perturbative numerical simulations of the system response. It is shown that higher-order contributions may lead to a fundamental change of the static appearance and beating-maps of the 2D spectra and that chirped pulses enhance or suppress distinct higher-order pathways. We further give an estimate of the threshold intensity beyond which the high-intensity effects become visible for the system under consideration.
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http://dx.doi.org/10.1364/OE.396108DOI Listing
August 2020

Wogonin Induces Apoptosis and Reverses Sunitinib Resistance of Renal Cell Carcinoma Cells Inhibiting CDK4-RB Pathway.

Front Pharmacol 2020 24;11:1152. Epub 2020 Jul 24.

Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Wogonin, an active component derived from Scutellaria baicalensis, has shown anti-tumor activities in several malignancies. However, the roles of wogonin in RCC cells remain elusive. Here, we explored the effects of wogonin on RCC cells and the underlying mechanisms. We found that wogonin showed significant cytotoxic effects against RCC cell lines 786-O and OS-RC-2, with much lower cytotoxic effects on human normal embryonic kidney cell line HEK-293 cells. Wogonin treatment dramatically inhibited the proliferation, migration, and invasion of RCC cells. We further showed that by inhibiting CDK4-RB pathway, wogonin transcriptionally down-regulated CDC6, disturbed DNA replication, induced DNA damage and apoptosis in RCC cells. Moreover, we found that the levels of p-RB, CDK4, and Cyclin D1 were up-regulated in sunitinib resistant 786-O, OS-RC-2, and TK-10 cells, and inhibition of CDK4 by palbociclib or wogonin effectively reversed the sunitinib resistance, indicating that the hyperactivation of CDK4-RB pathway may at least partially contribute to the resistance of RCC to sunitinib. Together, our findings demonstrate that wogonin could induce apoptosis and reverse sunitinib resistance of RCC cells inhibiting CDK4-RB pathway, thus suggesting a potential therapeutic implication in the future management of RCC patients.
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http://dx.doi.org/10.3389/fphar.2020.01152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394056PMC
July 2020

Profiles of Immune Infiltration in Bladder Cancer and its Clinical Significance: an Integrative Genomic Analysis.

Int J Med Sci 2020 5;17(6):762-772. Epub 2020 Mar 5.

Department of Urology, Qilu Hospital of Shandong University, Jinan, P.R. China.

Tumor-infiltrating immune cells are closely related to the prognosis of bladder cancer. Analysis of tumor infiltrating immune cells is usually based on immunohistochemical analysis. Since many immune cell marker proteins are not specific for different immune cells, which may induce misleading or incomplete. CIBERSORT is an algorithm to estimate specific cell types in a mixed cell population using gene expression data. In this study, the CIBERSORT algorithm was used to identify the immune cell infiltration signatures. The gene expression profiles, mutation data, and clinical data were collected from The Cancer Genome Atlas (TCGA) database. Unsupervised consensus clustering was used to acquire the immune cell infiltration subtypes of bladder cancer based on the fractions of 22 immune cell types. Four immune cell clusters with different immune infiltrate and mutation characteristics were identified. In addition, this stratification has a prognostic relevance, with cluster 2 having the best outcome, cluster 1 the worst. These clusters showed distinct mRNA expression patterns. The characteristic genes in subtype cluster 1 were mainly involved in cell division, those in subtype cluster 2 were mainly related in antigen processing and presentation, those in subtype cluster 3 were mainly involved in epidermal cell differentiation, and those in subtype cluster 4 were mainly related in the humoral immune response. These differences may affect the development of the bladder cancer, the sensitivity to treatment as well as the prognosis. Through further validation, this study may contribute to the development of personalized therapy and precision medical treatments.
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http://dx.doi.org/10.7150/ijms.42151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085262PMC
December 2020

The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer.

Oncogene 2020 04 3;39(17):3588-3603. Epub 2020 Mar 3.

The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.

CUL4B, which acts as a scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complexes, participates in a variety of biological processes. Previous studies have shown that CUL4B is often overexpressed and exhibits oncogenic activities in a variety of solid tumors. However, the roles and the underlying mechanisms of CUL4B in bladder cancer (BC) were poorly understood. Here, we showed that CUL4B levels were overexpressed and positively correlated with the malignancy of BC, and CUL4B could confer BC cells increased motility, invasiveness, stemness, and chemoresistance. The PIK3CA/AKT pathway was identified as a critical downstream mediator of CUL4B-driven oncogenicity in BC cells. Furthermore, we demonstrated that CRL4B epigenetically repressed the transcription of miR-372/373, via catalyzing monoubiquitination of H2AK119 at the gene cluster encoding miR-372/373, leading to upregulation of PIK3CA and activation of AKT. Our findings thus establish a critical role for the CUL4B-miR-372/373-PIK3CA/AKT axis in the pathogenesis of BC and have important prognostic and therapeutic implications in BC.
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http://dx.doi.org/10.1038/s41388-020-1236-1DOI Listing
April 2020

Identification of gene expression profiles and immune cell infiltration signatures between low and high tumor mutation burden groups in bladder cancer.

Int J Med Sci 2020 1;17(1):89-96. Epub 2020 Jan 1.

Department of Urology, Qilu Hospital of Shandong University, Jinan, China.

Bladder cancer is one of the most commonly diagnosed tumors and is results from the accumulation of somatic mutations in the DNA. Tumor mutation burden (TMB) has been associated with cancer immunotherapeutic response. In this study, we attempted to explore the correlation between TMB and cancer prognosis. Identify the different expressed genes and immune cell infiltration signatures between low and high TMB group. Mutation data, gene expression profiles and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Patients were divided into high and low TMB groups, allowing differentially expressed genes (DEGs) to be identified. Functional enrichment and protein-protein interaction (PPI) network analysis were used to identify the functions of the DEGs. And immune cell infiltration signatures were evaluated by CIBERSORT algorithm. These results shown that high TMB was significantly associated with prognosis. We obtained a list of TMB related genes which may influence the infiltrations of immune cells. We also found a higher proportion of CD8 T cells, CD4 T cells and NK cells in the high TMB group. Our data suggest that higher TMB tends to promote the infiltrations of T cells and NK cells and patients with higher TMB may achieve a more favorable prognosis in bladder cancer.
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http://dx.doi.org/10.7150/ijms.39056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945555PMC
October 2020

Redox-responsive nanoparticles from disulfide bond-linked poly-(N-ε-carbobenzyloxy-l-lysine)-grafted hyaluronan copolymers as theranostic nanoparticles for tumor-targeted MRI and chemotherapy.

Int J Biol Macromol 2020 Apr 8;148:483-492. Epub 2020 Jan 8.

Department of Radiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510180, China; Department of Radiology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510640, China. Electronic address:

Redox-responsive theranostic nanoparticles based on poly-(N-ε-carbobenzyloxy-l-lysine) (PZLL) grafted hyaluronan (HA) (HA-g-SS-PZLL) copolymers were constructed for hepatocellular carcinoma diagnosis and therapy. These hyaluronan derivatives formed nanoparticles via a self-assembly process in aqueous solution at low concentration. Theranostic nanoparticles were obtained after loading hydrophobic doxorubicin (DOX) and superparamagnetic iron oxide (SPIO) into the core of the nanoparticles via a dialysis method. Theranostic nanoparticles exhibited redox triggered DOX release behavior, and faster DOX released from theranostic nanoparticles was detected under a reducing environment compared with slow DOX release under a normal physiological environment. Confocal laser scanning microscopy (CLSM), flow cytometry and Prussian blue staining against HepG2 cells demonstrated that HA-g-SS-PZLL theranostic nanoparticles were capable of delivering DOX and SPIO into the cells. The analysis of the anticancer effect revealed that the HA-g-SS-PZLL theranostic nanoparticles shown higher cytotoxicity against HepG2 cells than DOX-loaded HA-g-PZLL nanoparticles. In vitro T magnetic resonance imaging (MRI) results exhibited that theranostic nanoparticles showed a good contrast enhancement effect, and the r relaxivity value was approximately 231 Fe mM s. Finally, the theranostic nanoparticles acted as nanoprobes for HepG2 tumor-bearing BALB/c mice for in vivo MRI. Therefore, HA-g-SS-PZLL copolymers have great potential as theranostic nanoparticles for tumor-targeted diagnosis and treatment.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.01.071DOI Listing
April 2020

Cigarette smoke induces the pyroptosis of urothelial cells through ROS/NLRP3/caspase-1 signaling pathway.

Neurourol Urodyn 2020 02 6;39(2):613-624. Epub 2020 Jan 6.

Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong, China.

Aims: Cell death and inflammation are involved in the development of bladder dysfunction. Pyroptosis is programmed cell death, causing cytotoxic effects and local inflammation. As one of the biggest health threats in the world, smoking is also closely related to urinary system diseases. The aims of this study were to investigate the role of NLRP3 inflammasome-mediated pyroptosis in the bladder after cigarette smoke exposure.

Methods: The expression of NLRP3 inflammasome and the activity of caspase-1 in bladder tissue was investigated after cigarette smoke exposure. In vitro, bladder urothelial cells were stimulated by cigarette smoke extract and then the activity of caspase-1 and the expression of NLRP3 inflammasome were measured. The role of oxidative stress was also assessed.

Results: The activity of caspase-1 in bladder tissue increased by 50% after cigarette smoke exposure. Cigarette smoke caused oxidative stress injury and the activation of NLRP3 inflammasome. In addition, reactive oxygen species (ROS) inhibitor N-acetyl-cysteine alleviated the pyroptosis of urothelial cells.

Conclusions: Cigarette smoke-induced pyroptosis of bladder tissue by activating ROS/NLRP3/caspase-1 signaling pathway. Inhibition of bladder urothelial cell pyroptosis may be a new approach to alleviate bladder damage caused by smoking.
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http://dx.doi.org/10.1002/nau.24271DOI Listing
February 2020

Dynamics of a one-dimensional Holstein polaron: The multiconfigurational Ehrenfest method.

J Chem Phys 2019 Dec;151(24):244116

School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom.

We have extended the multiconfigurational Ehrenfest (MCE) approach to investigate the dynamics of a one-dimensional Holstein molecular crystal model. It has been shown that the extended MCE approach yields results in perfect agreement with benchmark calculations by the hierarchy equations of motion method. The accuracies of the MCE approach in describing the dynamical properties of the Holstein polaron over a wide range of exciton transfer integrals and exciton-phonon couplings are carefully examined by a detailed comparison with the fully variational multiple Davydov D ansatz. It is found that while the MCE approach and the multi-D ansatz produce almost exactly the same results for a small transfer integral, the results obtained by the multi-D ansatz start to deviate from those by the MCE approach at longer times for a large transfer integral. A large number of coherent state basis functions are required to characterize the delocalized features of the phonon wavefunction in the case of large transfer integral, which becomes computationally too demanding for the multi-D ansatz. The MCE approach, on the other hand, uses hundreds to thousands of trajectory guided basis functions and converges very well, thus providing an effective tool for accurate and efficient simulations of polaron dynamics.
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http://dx.doi.org/10.1063/1.5132341DOI Listing
December 2019

Comparative Plastome Analysis of Root- and Stem-Feeding Parasites of Santalales Untangle the Footprints of Feeding Mode and Lifestyle Transitions.

Genome Biol Evol 2020 01;12(1):3663-3676

BGI-Shenzhen, Shenzhen, China.

In plants, parasitism triggers the reductive evolution of plastid genomes (plastomes). To disentangle the molecular evolutionary associations between feeding on other plants below- or aboveground and general transitions from facultative to obligate parasitism, we analyzed 34 complete plastomes of autotrophic, root- and stem-feeding hemiparasitic, and holoparasitic Santalales. We observed inexplicable losses of housekeeping genes and tRNAs in hemiparasites and dramatic genomic reconfiguration in holoparasitic Balanophoraceae, whose plastomes have exceptionally low GC contents. Genomic changes are related primarily to the evolution of hemi- or holoparasitism, whereas the transition from a root- to a stem-feeding mode plays no major role. In contrast, the rate of molecular evolution accelerates in a stepwise manner from autotrophs to root- and then stem-feeding parasites. Already the ancestral transition to root-parasitism coincides with a relaxation of selection in plastomes. Another significant selectional shift in plastid genes occurs as stem-feeders evolve, suggesting that this derived form coincides with trophic specialization despite the retention of photosynthetic capacity. Parasitic Santalales fill a gap in our understanding of parasitism-associated plastome degeneration. We reveal that lifestyle-genome associations unfold interdependently over trophic specialization and feeding mode transitions, where holoparasitic Balanophoraceae provide a system for exploring the functional realms of plastomes.
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http://dx.doi.org/10.1093/gbe/evz271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953812PMC
January 2020

Cannabinoid receptor 2 activation decreases severity of cyclophosphamide-induced cystitis via regulating autophagy.

Neurourol Urodyn 2020 01 14;39(1):158-169. Epub 2019 Nov 14.

Department of Urology, Qilu Hospital of Shandong University, Jinan, China.

Purpose: Cannabinoids have been shown to exert analgesic and anti-inflammatory effects, and the effects of cannabinoids are mediated primarily by cannabinoid receptors 1 and 2 (CB1 and CB2). The objective of this study was to determine efficacy and mechanism of CB2 activation on cyclophosphamide (CYP)-induced cystitis in vivo.

Methods: Cystitis was induced by intraperitoneal (IP) injection of CYP in female C57BL/6J mice. Mice were pretreated with CB2 agonist JWH-133 (1 mg/kg, intraperitoneally), CB2 antagonist AM-630 (1 mg/kg, intraperitoneally) or autophagy inhibitor 3-methyladenine (3-MA) (50 mM, intraperitoneally) before IP injection of CYP. Peripheral nociception and spontaneous voiding were investigated in these mice. Bladders were collected, weighed, and processed for real-time polymerase chain reaction, immunoblotting analysis, histological and immunohistochemical analysis.

Results: Twenty-four hours after IP injection of CYP, the bladder of CYP-treated mice showed histological evidence of inflammation. The expression of CB2 in bladder was significantly increased in CYP-treated mice. Mechanical sensitivity was significantly increased in CYP-treated mice and CB2 agonist JWH-133 attenuated this effect (P < .05). The number of urine spots was significantly increased after CYP treatment and it was decreased in JWH-133 treated mice (P < .05). Activating CB2 with JWH-133 significantly alleviated bladder tissue inflammatory responses and oxidative stress induced by CYP. Activation of CB2 by JWH-133 increased the expression of LC3-II/LC3-I ratio, and decreased the expression of SQSTM1/p62 in the bladder of cystitis mice, whereas AM-630 induced inverse effects. Further study indicated that JWH-133 could promote autophagy and blocking autophagy by 3-MA dismissed the effort of CB2 in alleviating bladder tissue inflammatory responses and oxidative stress injury. Furthermore, treatment with 3-MA decreased the expression of p-AMPK and induced the phosphorylation of mTOR in the presence of JWH-133 stimulation in cystitis model.

Conclusions: Activation of CB2 decreased severity of CYP-induced cystitis and ameliorated bladder inflammation. CB2 activation is protective in cystitis through the activation of autophagy and AMPK-mTOR pathway may be involved in the initiation of autophagy.
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http://dx.doi.org/10.1002/nau.24205DOI Listing
January 2020

Monitoring of singlet fission via two-dimensional photon-echo and transient-absorption spectroscopy: Simulations by multiple Davydov trial states.

J Chem Phys 2019 Sep;151(11):114102

Division of Materials Science, Nanyang Technological University, Singapore 639798, Singapore.

Employing the Dirac-Frenkel time dependent variational method, the nonlinear spectra monitoring the singlet fission process mediated by a conical intersection (CI) of the two lowest excited electronic states are investigated for different optical dephasings. The simulated two-dimensional spectra at different population times follow ultrafast population transfer through the CI and exhibit spectral features related to the tuning mode. The anticorrelated oscillations of cross peaks located at symmetric positions with respect to the main diagonal are clearly identified after the stimulated-emission contribution quenches. The simulated transient absorption signals show a fast decay of the first excited singlet state and exhibit multiple peaks revealing the tuning mode. These findings could be regarded as signatures of the CI in the singlet fission process.
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http://dx.doi.org/10.1063/1.5109251DOI Listing
September 2019

Mapping of Wave Packet Dynamics at Conical Intersections by Time- and Frequency-Resolved Fluorescence Spectroscopy: A Computational Study.

J Phys Chem Lett 2019 Oct 19;10(19):5873-5880. Epub 2019 Sep 19.

Department of Chemistry , Technische Universität München , D-85747 Garching , Germany.

Monitoring of wave packet dynamics at conical intersections by time- and frequency-resolved fluorescence spectroscopy has been investigated theoretically for a three-state two-mode model of a conical intersection coupled to a dissipative environment. The ideal and the actually measurable time- and frequency-gated fluorescence spectra are accurately and efficiently simulated by combining the hierarchy equations-of-motion method for dissipative quantum dynamics with the methodology of the equation-of-motion phase-matching approach for the calculation of spectroscopic signals. It is shown that time- and frequency-resolved fluorescence spectra reveal essential aspects of the wave packet dynamics at conical intersections and the effects of environment-induced dissipation. The results of the present work indicate that fluorescence up-conversion spectroscopy with femtosecond time resolution is an efficient tool for the characterization of ultrafast dynamics at conical intersections.
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http://dx.doi.org/10.1021/acs.jpclett.9b02208DOI Listing
October 2019

Orientational relaxation of a quantum linear rotor in a dissipative environment: Simulations with the hierarchical equations-of-motion method.

J Chem Phys 2019 Jul;151(3):034101

Department of Chemistry, Technische Universität München, D-85747, Garching, Germany.

We study the effect of a dissipative environment on the orientational relaxation of a three-dimensional quantum linear rotor. We provide a derivation of the Hamiltonian of a linear rotor coupled to a harmonic bath from first principles, confirming earlier conjectures. The dynamics generated by this Hamiltonian is investigated by the hierarchical equations-of-motion method assuming a Drude spectral density of the bath. We perform numerically accurate simulations and analyze the behavior of orientational correlation functions and the rotational structures of infrared absorption and Raman scattering spectra. We explore the features of orientational correlation functions and their spectra for a wide range of system-bath couplings, bath memory times, and temperatures. We discuss the signatures of the orientational relaxation in the underdamped regime, the strongly damped regime, and the librational regime. We show that the behavior of orientational correlation functions and their spectra can conveniently be analyzed in terms of three characteristic times, which are explicitly expressed in terms of the parameters of the Hamiltonian.
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http://dx.doi.org/10.1063/1.5105375DOI Listing
July 2019
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