Publications by authors named "Mingjie Zhang"

306 Publications

Liquid-Liquid Phase Separation in Biology: Specific Stoichiometric Molecular Interactions vs Promiscuous Interactions Mediated by Disordered Sequences.

Biochemistry 2021 Jul 22. Epub 2021 Jul 22.

School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.

Extensive studies in the past few years have shown that nonmembrane bound organelles are likely assembled via liquid-liquid phase separation (LLPS), a process that is driven by multivalent protein-protein and/or protein-nucleic acid interactions. Both stoichiometric molecular interactions and intrinsically disordered region (IDR)-driven interactions can promote the assembly of membraneless organelles, and the field is currently dominated by IDR-driven biological condensate formation. Here we discuss recent studies that demonstrate the importance of specific biomolecular interactions for functions of diverse physiological condensates. We suggest that phase separation based on combinations of specific interactions and promiscuous IDR-driven interactions is likely a general feature of biological condensation under physiological conditions.
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http://dx.doi.org/10.1021/acs.biochem.1c00376DOI Listing
July 2021

Optical characterization of GeAsS glass for an on-chip supercontinuum.

Appl Opt 2021 Jun;60(18):5451-5455

An on-chip supercontinuum (SC) source spanning from 900 nm to 2000 nm has been experimentally presented and analyzed based on a (GeAsS) planar waveguide at telecommunication wavelength. The nonlinear response parameter () of the GeAsS waveguide is estimated to be ∼12// at the pump wavelength using resonant grating waveguide (RGW) nonlinear refractive index (=2×10/), which is measured by the z-scan technique. The dispersion of the waveguide is carefully engineered based on the refractive index of the GeAsS film where the film structure is confirmed by a Raman spectrum exhibiting consistency with the corresponding glass. The results suggest that the GeAsS glass is expected to be an ideal platform for on-chip devices.
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http://dx.doi.org/10.1364/AO.426456DOI Listing
June 2021

Clustering acetylcholine receptors in neuromuscular junction by phase-separated Rapsn condensates.

Neuron 2021 06;109(12):1907-1909

School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China. Electronic address:

In this issue of Neuron, Xing et al. (2021) demonstrate that the multidomain scaffold protein Rapsn can form dense molecular condensates in vitro and in vivo via phase separation. The formation of Rapsn condensates is essential for clustering acetylcholine receptors on muscle membranes and for forming neuromuscular junctions.
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http://dx.doi.org/10.1016/j.neuron.2021.05.024DOI Listing
June 2021

Comprehensive Design of the High-Sulfur-Loading Li-S Battery Based on MXene Nanosheets.

Nanomicro Lett 2020 May 20;12(1):112. Epub 2020 May 20.

State Key Laboratory of Chem/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, People's Republic of China.

The lithium-sulfur battery is the subject of much recent attention due to the high theoretical energy density, but practical applications are challenged by fast decay owing to polysulfide shuttle and electrode architecture degradation. A comprehensive study of the sulfur host microstructure design and the cell architecture construction based on the MXene phase (TiCT nanosheets) is performed, aiming at realize stable cycling performance of Li-S battery with high sulfur areal loading. The interwoven [email protected] composite formed by self-assembly of MXene and Ktejen black, not only provides superior conductivity and maintains the electrode integrality bearing the volume expansion/shrinkage when used as the sulfur host, but also functions as an interlayer on separator to further retard the polysulfide cross-diffusion that possibly escaped from the cathode. The [email protected] interlayer is only 0.28 mg cm in areal loading and 3 μm in thickness, which accounts a little contribution to the thick sulfur electrode; thus, the impacts on the energy density is minimal. By coupling the robust [email protected] cathode and the effective [email protected] modified separator, a stable Li-S battery with high sulfur areal loading (5.6 mg cm) and high areal capacity (6.4 mAh cm) at relatively lean electrolyte is achieved.
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http://dx.doi.org/10.1007/s40820-020-00449-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770945PMC
May 2020

Elevated Arterial-Central Venous Carbon Dioxide Partial Pressure Difference Indicates Poor Prognosis in the Early Postoperative Period of Open Heart Surgery in Infants with Congenital Heart Disease.

Pediatr Cardiol 2021 Jun 9. Epub 2021 Jun 9.

Cardiac Intensive Care Unit, Department of Cardiovascular and Thoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.

Background: Elevated arterial-central venous carbon dioxide partial pressure difference (AVCO) may be an important marker to predict tissue and organ hypoperfusion in adults. We analyzed the hemodynamic data of infants with congenital heart disease who underwent corrective repair with cardiopulmonary bypass (CPB) to identify whether AVCO has clinical significance in early postoperative tissue hypoperfusion, occurrence of complications, and clinical outcomes.

Methods: Infants with clinical conditions of hypoperfusion, without volume responsiveness and with ineffective initial treatment, within 3 h of cardiac surgery were enrolled in this study. A pulse contour cardiac output catheter was used to monitor the cardiac index (CI). Eight measurements of arterial blood gas and central venous blood gas were taken within 42 h after surgery. Clinical data of all patients were recorded.

Results: A total of 69 children were enrolled in this study. Arteriovenous oxygen difference, AVCO, lactic acid level, and vasoactive inotropic score in the hypoperfusion group (oxygen supply/oxygen consumption ratio [DO/VO] of ≤ 2) were significantly higher than those in the non-hypoperfusion group (DO/VO > 2), while the CI in the hypoperfusion group was significantly lower than that in the non-hypoperfusion group. The cutoff value of AVCO to predict DO/VO ≤ 2 was 12.3 within 42 h of surgery with area under the curve of 0.84. High AVCO is more likely to be associated with some complications and prolonged mechanical ventilation and length of stay in the intensive care unit.

Conclusion: Elevated AVCO within 42 h of CPB in infants is associated with tissue and organ hypoperfusion and incidence of complications. Persistent or repeated increase in AVCO indicates poor prognosis.
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http://dx.doi.org/10.1007/s00246-021-02646-6DOI Listing
June 2021

Presynaptic bouton compartmentalization and postsynaptic density-mediated glutamate receptor clustering via phase separation.

Neuropharmacology 2021 08 26;193:108622. Epub 2021 May 26.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China. Electronic address:

Neuronal synapses encompass three compartments: presynaptic axon terminal, synaptic cleft, and postsynaptic dendrite. Each compartment contains densely packed molecular machineries that are involved in synaptic transmission. In recent years, emerging evidence indicates that the assembly of these membraneless substructures or assemblies that are not enclosed by membranes are driven by liquid-liquid phase separation. We review here recent studies that suggest the phase separation-mediated organization of these synaptic compartments. We discuss how synaptic function may be linked to its organization as biomolecular condensates. We conclude with a discussion of areas of future interest in the field for better understanding of the structural architecture of neuronal synapses and its contribution to synaptic functions.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108622DOI Listing
August 2021

Clinicopathological significance of SOX4 and epithelial-mesenchymal transition markers in patients with laryngeal squamous cell carcinoma.

Auris Nasus Larynx 2021 May 14. Epub 2021 May 14.

Department of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, Guangdong 510632, China; Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, China. Electronic address:

Objective: Sex-determining region-Y-related high-mobility-group box 4 (SOX4) is associated with the metastasis and prognosis of many cancer types. However, studies on the role of SOX4 in laryngeal squamous cell carcinoma (LSCC) are few, and hence the mechanism is unclear. Epithelial-mesenchymal transition (EMT) allows neoplastic cells to gain the plasticity and motility required for tumor progression and metastasis. This study aimed to analyze the relationship between SOX4 and EMT, and their relationship with clinicopathological factors and related prognosis.

Methods: Immunohistochemical staining was used to detect the positive expression of SOX4 protein, EMT-related transcription factor protein, and related marker protein in 127 LSCC tissue samples. At the same time, data on various parameters of clinical pathology and postoperative survival were collected.

Results: The positive expression rate of SOX4 and Slug in LSCC was related to pathological differentiation, Lymph node metastasis (LNM), and pathological TNM of a tumor. The expression rates of ZEB1, E-cadherin, N-cadherin, and β-catenin in LSCC correlated with LNM and pTNM. The expression of SOX4, combined expression of SOX4 and ZEB1, and LNM were independent prognostic factors for the total survival time of patients with LSCC.

Conclusions: In summary, SOX4 was vital in the LSCC EMT process, which might be mediated by transcription factor ZEB1. SOX4 and ZEB1 might serve as potential biomarkers of metastasis and prognosis, as well as promising therapeutic targets of LSCC.
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http://dx.doi.org/10.1016/j.anl.2021.04.013DOI Listing
May 2021

CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation.

Nat Neurosci 2021 Jun 29;24(6):777-785. Epub 2021 Apr 29.

Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Transient information input to the brain leads to persistent changes in synaptic circuits, contributing to the formation of memory engrams. Pre- and postsynaptic structures undergo coordinated functional and structural changes during this process, but how such changes are achieved by their component molecules remains largely unknown. We found that activated CaMKII, a central player of synaptic plasticity, undergoes liquid-liquid phase separation with the NMDA-type glutamate receptor subunit GluN2B. Due to CaMKII autophosphorylation, the condensate stably persists even after Ca is removed. The selective binding of activated CaMKII with GluN2B cosegregates AMPA receptors and the synaptic adhesion molecule neuroligin into a phase-in-phase assembly. In this way, Ca-induced liquid-liquid phase separation of CaMKII has the potential to act as an activity-dependent mechanism to crosslink postsynaptic proteins, which may serve as a platform for synaptic reorganization associated with synaptic plasticity.
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http://dx.doi.org/10.1038/s41593-021-00843-3DOI Listing
June 2021

Non-alcoholic fatty liver disease is a risk factor for occurrence of hepatocellular carcinoma after sustained virologic response in chronic hepatitis C patients: A prospective four-years follow-up study.

Metabol Open 2021 Jun 26;10:100090. Epub 2021 Mar 26.

Department of Liver Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.

Background And Aim: The incidence of hepatocellular carcinoma (HCC) decreases significantly in chronic hepatitis C (CHC) patients with sustained virologic response (SVR) after pegylated-interferon plus ribavirin (PR) or direct-acting antiviral (DAAs) therapy. We follow-up a single cohort of CHC patients to identify risk factors associated with HCC development post-SVR.

Method: CHC patients with SVR in Beijing/Hong Kong were followed up at 12-24 weekly intervals with surveillance for HCC by ultrasonography and alpha-fetoprotein (AFP). Multivariate Cox proportional hazards regression analysis was used to explore factors associated with HCC occurrence.

Results: Between October 2015 and May 2017, SVR was observed in 519 and 817 CHC patients after DAAs and PR therapy respectively. After a median post -SVR follow-up of 48 months, HCC developed in 54 (4.4%) SVR subjects. By adjusted Cox analysis, older age (≥55 years) [HR 2.4, 95% CI (1.3-4.3)], non-alcoholic fatty liver diseases [HR 2.4, 95%CI (1.3-4.2), higher AFP level (≥20 ng/ml) [HR 3.4, 95%CI (2.0-5.8)], higher liver stiffness measurement (≥14.6 kPa) [HR 4.2, 95%CI (2.3-7.6)], diabetes mellitus [HR 4.2, 95%CI (2.4-7.4)] at pre-treatment were associated with HCC occurrence. HCC patients in the DAAs induced SVR group had a higher prevalence of NAFLD as compared with those in the PR induced SVR group, 62% (18/29) vs 28% (7/25), p = 0.026. A nomogram formulated with the above six independent variables had a Concordance-Index of 0.835 (95% CI 0.783-0.866).

Conclusion: Underlying NAFLD is associated with increased incidence of HCC in chronic HCV patients post-SVR, particularly in those treated with DAA.
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http://dx.doi.org/10.1016/j.metop.2021.100090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050772PMC
June 2021

Identification of HOXA1 as a Novel Biomarker in Prognosis of Head and Neck Squamous Cell Carcinoma.

Front Mol Biosci 2020 8;7:602068. Epub 2021 Mar 8.

Department of Otolaryngology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China.

Hox genes, a highly conserved homolog in most animals, play vital functions in cell development and organ formation. In recent years, researchers have discovered that it can act as a tumor regulator, and its members can participate in tumorigenesis by regulating receptor signaling, cell differentiation, apoptosis, migration, EMT, and angiogenesis. Hox genes and which major members play a vital role in the progress of head and neck squamous cell carcinoma (HNSCC) is still unclear. After analyzing the expression differences and prognostic value of all Hox genes through the TCGA-HNSC database, we use histochemistry stains in 52 pairs of HNSCC slices to verify the expression level of the key member-HOXA1. In correlation analysis, we found that high HOXA1 expression is related to poor pathological grade ( = 0.0077), advanced T stage ( = 0.021) and perineural invasion (PNI) ( = 0.0019). Furthermore, we used Cox univariate and multivariate regression analysis to confirm the independent predictive power of HOXA1 expression. To explore the underlying mechanisms behind HOXA1, we ran GSVA and GSEA and found fourteen mutual signaling pathways, including neuroprotein secretion and transport, tumor-associated signaling pathways, cell adhere junction and metabolic reprogramming. Finally, we found that the high expression of HOXA1 is significantly related to the decrease of CD8+ T cell infiltration and the decline of DNA methylation level. Our findings demonstrated that HOXA1, as a notable member of the HOX family, maybe an independent prognostic indicator in HNSCC.
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http://dx.doi.org/10.3389/fmolb.2020.602068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982851PMC
March 2021

Clinicopathological significance of SOX4 and epithelial-mesenchymal transition markers in patients with laryngeal squamous cell carcinoma.

Medicine (Baltimore) 2021 Mar;100(12):e25028

Department Of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, Guangdong.

Background And Aim: Sex-determining region-Y-related high-mobility-group box 4 (SOX4) is associated with the metastasis and prognosis of many cancer types. However, studies on the role of SOX4 in laryngeal squamous cell carcinoma (LSCC) are few, and hence the mechanism is unclear. Epithelial-mesenchymal transition (EMT) allows neoplastic cells to gain the plasticity and motility required for tumor progression and metastasis. This study aimed to analyze the relationship between SOX4 and EMT, and their relationship with clinicopathological factors and related prognosis.

Methods: Immunohistochemical staining was used to detect the positive expression of SOX4 protein, EMT-related transcription factor protein, and related marker protein in 127 LSCC tissue samples. At the same time, data on various parameters of clinical pathology and postoperative survival were collected.

Results: The positive expression rate of SOX4 and Slug in LSCC was related to pathological differentiation, lymphatic invasion, and pathological tumor node metastasis (TNM) of a tumor. The expression rates of ZEB1, Twist, E-cadherin, N-cadherin, and β-catenin in LSCC correlated with lymphatic invasion and pathological tumor node metastasis. The expression of SOX4, combined expression of SOX4 and ZEB1, and lymphatic invasion were independent prognostic factors for the total survival time of patients with LSCC.

Conclusions: In summary, SOX4 was vital in the LSCC EMT process, which might be mediated by transcription factor ZEB1. SOX4 and ZEB1 might serve as potential biomarkers of metastasis and prognosis, as well as promising therapeutic targets of LSCC.
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http://dx.doi.org/10.1097/MD.0000000000025028DOI Listing
March 2021

Paxbp1 controls a key checkpoint for cell growth and survival during early activation of quiescent muscle satellite cells.

Proc Natl Acad Sci U S A 2021 Mar;118(13)

State Key Laboratory of Molecular Neuroscience, Division of Life Science, Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong, China;

Adult mouse muscle satellite cells (MuSCs) are quiescent in uninjured muscles. Upon muscle injury, MuSCs exit quiescence, reenter the cell cycle to proliferate and self-renew, and then differentiate and fuse to drive muscle regeneration. However, it remains poorly understood how MuSCs transition from quiescence to the cycling state. Here, we report that Pax3 and Pax7 binding protein 1 (Paxbp1) controls a key checkpoint during this critical transition. Deletion of in adult MuSCs prevented them from reentering the cell cycle upon injury, resulting in a total regeneration failure. Mechanistically, we found an abnormal elevation of reactive oxygen species (ROS) in -null MuSCs, which induced p53 activation and impaired mTORC1 signaling, leading to defective cell growth, apoptosis, and failure in S-phase reentry. Deliberate ROS reduction partially rescued the cell-cycle reentry defect in mutant MuSCs. Our study reveals that Paxbp1 regulates a late cell-growth checkpoint essential for quiescent MuSCs to reenter the cell cycle upon activation.
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http://dx.doi.org/10.1073/pnas.2021093118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020634PMC
March 2021

A new 2D Cu-MOF constructed from carboxylate ligands containing C-Hπ interactions as a recyclable responsive luminescent sensor for VOCs.

Dalton Trans 2021 Mar 17;50(12):4124-4128. Epub 2021 Mar 17.

Department of Chemistry, School of Sciences, Tianjin University, Tianjin 30035, P. R. China.

A new type of 2D metal-organic framework (MOF), namely Cu-MOF, was constructed from Cu(NO)·3HO and the novel ligand 1,4-bis(4-naphthoic acid)benzene. The C-Hπ interactions in the Cu-MOF effectively reduced aggregation-caused quenching (ACQ) due to restrictions in intramolecular motion (RIM), increased fluorescence, and controlled crystal packing properties, resulting in low dimensional parallelogram channels and a responsive "turn-on" fluorescence. The activated Cu-MOF exhibited excellent chemical sensing properties to various volatile organic compounds (VOCs) and showed excellent recyclability.
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http://dx.doi.org/10.1039/d0dt04363jDOI Listing
March 2021

Multiple neurological manifestations in a patient with systemic lupus erythematosus and anti-NXP2-positive myositis: A case report.

Medicine (Baltimore) 2021 Mar;100(10):e25063

Department of Neurology, The General Hospital of Western Theater Command, Jinniu District, Chengdu, Sichuan Province, People's Republic of China.

Rationale: Systemic lupus erythematosus (SLE) is a complex autoimmune inflammatory disease that frequently affects various organs. Neuropsychiatric manifestations in SLE patients, known as neuropsychiatric SLE, are clinically common. However, the principal manifestation of cranial neuropathy in patients with SLE and comorbidities is relatively rare.

Patient Concerns: In this report, we describe a 51-year-old Chinese woman who was admitted with a chief complaint of chronic-onset facial paresthesia, dysphagia, and choking cough when drinking water, accompanied by slurred speech, salivation, and limb weakness. The blood autoantibody test results showed that many SLE-associated antibodies were positive. Meanwhile, anti-nuclear matrix protein 2 (NXP2) antibody was strongly positive in the idiopathic inflammatory myopathy (IIM) spectrum test from the serum. Muscle biopsy indicated inflammatory infiltration of the muscle fiber stroma.

Diagnoses: Taking into account the clinical manifestations and laboratory tests of the present case, the diagnosis of SLE and probable IIM was established.

Interventions: Corticosteroids and additional gamma globulin were administered and the clinical symptoms were relieved during the treatment process.

Outcomes: Unfortunately, the patient experienced sudden cardiac and respiratory arrest. Multiple system dysfunctions exacerbated disease progression, but in the present case, we speculated that myocardial damage resulting from SLE could explain why she suddenly died.

Lessons: To our knowledge, multiple neurological manifestations in patients with SLE and anti-NXP2-positive myositis are rare. Note that SLE is still a life-threatening disease that causes multiple system dysfunctions, which requires increasing attention.
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http://dx.doi.org/10.1097/MD.0000000000025063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969320PMC
March 2021

Effects of repairing ventricular septal defects with right vertical infra-axillary mini-incision on lung function and postoperative analgosedation.

Exp Ther Med 2021 Apr 29;21(4):302. Epub 2021 Jan 29.

Department of Cardiac Intensive Care Unit, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China.

The present study aimed to assess the effects of repairing ventricular septal defects (VSDs) with right vertical infra-axillary mini-incision (RVAI). A total of 116 patients with VSDs were prospectively enrolled and underwent cardiac surgery between June 2017 and December 2018 at the cardiac intensive care unit of Shanghai Children's Medical Center (Shanghai, China). Of these, 58 patients underwent the RVAI procedure and 58 patients matched 1:1 underwent the standard median sternotomy incision (MSI) procedure and were designated as the control group. The demographic data and clinical outcomes intra- and postoperatively were compared. A bedside lung ultrasound was performed to evaluate the degree of lung injury and the number of B-lines was quantified and compared between the two groups. The sedation and analgesia levels were also assessed after the operation. No significant difference was identified between the two groups regarding the overall cardiopulmonary bypass or aortic cross-clamp time. All patients were extubated within 8 h. The RVAI group had shorter incision lengths (median, 4.6 cm) and less drainage (median, 15 ml) than the MSI group. Furthermore, compared to the MSI group, the RVAI group had a significantly higher number of B-lines in the right lung regions immediately after surgery and at 12 h postsurgery (24.1 and 5.2%, respectively) but eventually exhibited no differences at 24 and 36 h postsurgery; by contrast, there were no differences in the left lung regions. The bedside bispectral index score and the Face, Legs, Activity, Cry, Consolability scale score exhibited no significant differences after the operation. In conclusion, the RVAI procedure appears to be a safe alternative for repairing VSDs in addition to satisfactory cosmetic results and the incision does not interfere with postoperative analgosedation.
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http://dx.doi.org/10.3892/etm.2021.9733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885067PMC
April 2021

Premonitory symptoms in migraine from China: A multi-clinic study of 4821 patients.

Cephalalgia 2021 Aug 25;41(9):991-1003. Epub 2021 Feb 25.

Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, China.

Objective: To observe the prevalence and characteristics of premonitory symptoms in Chinese migraineurs and explore their associations with migraine-related factors.

Method: Migraineurs who visited a tertiary headache clinic and one of nine neurology clinics between May 2014 and November 2019 were studied.

Result: Among the 4821 patients meeting the migraine criteria (International Classification of Headache Disorders, 3rd edition), 1038 (21.5%) patients experienced at least one premonitory symptom. The most common premonitory symptoms were neck stiffness, dizziness, yawning and drowsiness. The logistic regression analysis demonstrated that aura, photophobia, aggravation by routine physical activity, triggers, family history, depression, coffee consumption and physical exercise were associated with an increased probability of experiencing premonitory symptoms ( ≤ 0.001). The premonitory symptoms of migraine with and without aura differ in prevalence and most common symptoms. The cluster analysis revealed pairwise clustering of the following premonitory symptoms: Photophobia/phonophobia, concentration change/dysesthesia, loquacity/overactivity, yawning/drowsiness, fatigue/dizziness, and mood change/irritability. The correlation analysis of triggers and premonitory symptoms revealed that temperature change, environment change, sleep disorder, activity and stress were related to multiple premonitory symptoms, and that food, light, menstruation, alcohol and odor were related to special premonitory symptoms ( ≤ 0.001).

Conclusion: The prevalence of premonitory symptoms among migraineurs in China is 21.5%. Some factors influence the probability of experiencing premonitory symptoms. Paired premonitory symptoms in the clustering analysis may share similar origins. Certain triggers associated with multiple premonitory symptoms may induce brain dysfunction; however, other triggers that overlap with corresponding special premonitory symptoms may be premonitory symptoms or a form of premonitory symptom.
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http://dx.doi.org/10.1177/0333102421997850DOI Listing
August 2021

TRPV1 activation inhibits phenotypic switching and oxidative stress in vascular smooth muscle cells by upregulating PPARα.

Biochem Biophys Res Commun 2021 03 4;545:157-163. Epub 2021 Feb 4.

Department of Neurology, Army Medical University Daping Hospital, 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, PR China. Electronic address:

The proliferation and migration of vascular smooth muscle cells (VSMCs) is one of main reasons of vascular remodeling and is the pathogenesis of atherosclerosis and other vascular diseases. Transient receptor potential vanilloid 1 (TRPV1) is the specific receptor of capsaicin. TRPV1 has been previously reported to inhibit proliferation, migration and phenotypic switching, but the regulatory mechanisms and relevant signalling pathways are not clear. The aim of this study was to investigate the effects of capsaicin-activated TRPV1 on VSMC phenotypic switching. In this study, oxidized low density lipoprotein (ox-LDL) was used to induce the proliferation and migration of VSMCs. Our data showed that the VSMC proliferation induced by ox-LDL was dependent on the concentration of ox-LDL. Nevertheless, the data showed that capsaicin activated TRPV1 significantly decreased ox-LDL-induced superoxide anion generation. Phenotypic switching of VSMCs was inhibited by the activation of TRPV1. Furthermore, capsaicin decreased ox-LDL-induced superoxide anion generation by activating peroxisome proliferator activated receptor α (PPARα). TRPV1 inhibited VSMC phenotypic switching via upregulated expression of PPARα. It may be considered a useful target for the treatment of vascular remodeling.
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http://dx.doi.org/10.1016/j.bbrc.2021.01.072DOI Listing
March 2021

Overproduced CPSF4 Promotes Cell Proliferation and Invasion via PI3K-AKT Signaling Pathway in Oral Squamous Cell Carcinoma.

J Oral Maxillofac Surg 2021 05 5;79(5):1177.e1-1177.e14. Epub 2021 Jan 5.

Professor, Department of Orthodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China. Electronic address:

Purpose: Invasion and metastasis are major challenges in the treatment of oral cancer. We hypothesize that cleavage and polyadenylation specific factor 4 (CPSF4), a key mediator of cell growth and metastasis in several types of cancers, contributes to oral squamous cell carcinoma (OSCC) pathogenesis.

Materials And Methods: The expression and production of CPSF4 in OSCC cell lines and tumor tissues were assessed by RT-PCR and western blot, respectively. The relationships between CPSF4 production and OSCC clinicopathological features were analyzed using immunohistochemistry. The effects of CPSF4 on viability, proliferation, migration, invasion, cell cycle distribution, and apoptosis of OSCC cells were measured by MTS assay, colony formation assay, wound-healing, transwell invasion assay, flow cytometry, and cell apoptosis assay, respectively. Western blot analysis was used to assess alteration of PI3K-AKT pathway member levels in cell lines transfected with CPSF4 siRNA. Mice xenograft models were used to determine the effect of CPSF4 on OSCC tumor growth in vivo.

Results: CPSF4 was highly expressed in OSCC cell lines and tumor tissues compared with adjacent normal oral tissues. High CPSF4 expression was strongly correlated with vascular invasion (P = .004), distant metastasis (P = .001), and TNM stages (P = .001). Moreover, reduction of CPSF4 levels contributed to the inhibition of cell viability, proliferation, invasion and migration, and the induction of apoptosis in OSCC cell lines. Reduction of CPSF4 levels results in OSCC cell cycle arrest in G1 phase by targeting c-Myc. CPSF4 contributed to proliferation inhibition via PI3K-AKT signaling pathway. Reduction of CPSF4 levels inhibits OSCC tumor growth in vivo.

Conclusions: Our results suggest that CPSF4 supports OSCC invasion and metastasis and may be a promising therapeutic target for OSCC.
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http://dx.doi.org/10.1016/j.joms.2020.12.047DOI Listing
May 2021

Liquid-Liquid Phase Separation in Physiology and Pathophysiology of the Nervous System.

J Neurosci 2021 02 20;41(5):834-844. Epub 2021 Jan 20.

Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.

Molecules within cells are segregated into functional domains to form various organelles. While some of those organelles are delimited by lipid membranes demarcating their constituents, others lack a membrane enclosure. Recently, liquid-liquid phase separation (LLPS) revolutionized our view of how segregation of macromolecules can produce membraneless organelles. While the concept of LLPS has been well studied in the areas of soft matter physics and polymer chemistry, its significance has only recently been recognized in the field of biology. It occurs typically between macromolecules that have multivalent interactions. Interestingly, these features are present in many molecules that exert key functions within neurons. In this review, we cover recent topics of LLPS in different contexts of neuronal physiology and pathology.
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http://dx.doi.org/10.1523/JNEUROSCI.1656-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880275PMC
February 2021

Teaching NeuroImages: Magnetic Susceptibility-Weighted Imaging Mapped the Migratory Route of a Paragonimus in Brain.

Authors:
Ke Yu Mingjie Zhang

Neurology 2021 05 13;96(18):e2351-e2352. Epub 2021 Jan 13.

From the Department of Neurology, The General Hospital of Western Theater Command, Chengdu, China.

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http://dx.doi.org/10.1212/WNL.0000000000011492DOI Listing
May 2021

Structural basis of GABARAP-mediated GABA receptor trafficking and functions on GABAergic synaptic transmission.

Nat Commun 2021 01 12;12(1):297. Epub 2021 Jan 12.

MOE Key Laboratory for Membraneless Organelles & Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, P.R. China.

GABA receptors (GABARs) are the primary fast inhibitory ion channels in the central nervous system. Dysfunction of trafficking and localization of GABARs to cell membranes is clinically associated with severe psychiatric disorders in humans. The GABARAP protein is known to support the stability of GABARs in synapses, but the underlying molecular mechanisms remain to be elucidated. Here, we show that GABARAP/GABARAPL1 directly binds to a previously unappreciated region in the γ2 subunit of GABAR. We demonstrate that GABARAP functions to stabilize GABARs via promoting its trafficking pathway instead of blocking receptor endocytosis. The GABARAPL1-γ2-GABAR crystal structure reveals the mechanisms underlying the complex formation. We provide evidence showing that phosphorylation of γ2-GABAR differentially modulate the receptor's binding to GABARAP and the clathrin adaptor protein AP2. Finally, we demonstrate that GABAergic synaptic currents are reduced upon specific blockage of the GABARAP-GABAR complex formation. Collectively, our results reveal that GABARAP/GABARAPL1, but not other members of the Atg8 family proteins, specifically regulates synaptic localization of GABARs via modulating the trafficking of the receptor.
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http://dx.doi.org/10.1038/s41467-020-20624-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803741PMC
January 2021

[Identification of pathogenic variant in a Chinese pedigree affected with non-syndromic cleft lip and palate].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021 Jan;38(1):52-55

People's Hospital of Henan University, People's Hospital of Zhenzhou University, Insitute of Medical Genetics, Hennan Provincial Pelple's Hospital, Henan 450003, China. [email protected] 126.com.

Objective: To explore the genetic basis for a Chinese pedigree affected with non-syndromic cleft lip and cleft palate (NSCLP).

Methods: With informed consent obtained, members of the pedigree were subjected to clinical examination and history taking to exclude syndromic cleft lip and palate. One affected member was subjected to whole-exome sequencing and bioinformatics analysis. Candidate variant was verified by Sanger sequencing and co-segregation analysis of her family members and 100 unrelated healthy individuals.

Results: Whole-exome sequencing and co-segregation analysis showed that all affected members of this pedigree have carried a heterozygous missense c.253A>G (p.Cys85Arg) variant in exon 4 of the IRF6 gene, which has co-segregated with the phenotype and was not found among the 100 unrelated healthy individuals.

Conclusion: The missense c.253A>G variant in exon 4 of the IRF6 gene probably underlay the NSCLP in this pedigree.
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http://dx.doi.org/10.3760/cma.j.cn511374-20200308-00144DOI Listing
January 2021

Mesophasic Assembly of Inhibitory Postsynaptic Density.

Neurosci Bull 2021 01 23;37(1):141-143. Epub 2020 Dec 23.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.

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http://dx.doi.org/10.1007/s12264-020-00623-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811965PMC
January 2021

Medical Image-Based Hemodynamic Analyses in a Study of the Pulmonary Artery in Children With Pulmonary Hypertension Related to Congenital Heart Disease.

Front Pediatr 2020 2;8:521936. Epub 2020 Dec 2.

Department of Thoracic and Cardiovascular Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Pulmonary hypertension related to congenital heart disease (PH-CHD) is a devastating disease caused by hemodynamic disorders. Previous hemodynamic research in PH-CHD mainly focused on wall shear stress (WSS). However, energy loss (EL) is a vital parameter in evaluation of hemodynamic status. We investigated if EL of the pulmonary artery (PA) is a potential biomechanical marker for comprehensive assessment of PH-CHD. Ten PH-CHD patients and 10 age-matched controls were enrolled. Subject-specific 3-D PA models were reconstructed based on computed tomography. Transient flow, WSS, and EL in the PA were calculated using non-invasive computational fluid dynamics. The relationship between body surface area (BSA)-normalized EL ( ) and PA morphology and PA flow were analyzed. Morphologic analysis indicated that the BSA-normalized main PA (MPA) diameter (D), MPA/aorta diameter ratio (D/D), and MPA/(left PA + right PA) [D/D] diameter ratio were significantly larger in PH-CHD patients. Hemodynamic results showed that the velocity of the PA branches was higher in PH-CHD patients, in whom PA flow rate usually increased. WSS in the MPA was lower and was higher in PH-CHD patients. was positively correlated with D, D/D, and D/D ratios and the flow rate in the PA. was a sensitive index for the diagnosis of PH-CHD. is a potential biomechanical marker for PH-CHD assessment. This hemodynamic parameter may lead to new directions for revealing the potential pathophysiologic mechanism of PH-CHD.
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http://dx.doi.org/10.3389/fped.2020.521936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738347PMC
December 2020

Calmodulin binds to Drosophila TRP with an unexpected mode.

Structure 2021 04 15;29(4):330-344.e4. Epub 2020 Dec 15.

Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China; Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen 518055, China; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Electronic address:

Drosophila TRP is a calcium-permeable cation channel essential for fly visual signal transduction. During phototransduction, Ca mediates both positive and negative feedback regulation on TRP channel activity, possibly via binding to calmodulin (CaM). However, the molecular mechanism underlying Ca modulated CaM/TRP interaction is poorly understood. Here, we discover an unexpected, Ca-dependent binding mode between CaM and TRP. The TRP tail contains two CaM binding sites (CBS1 and CBS2) separated by an ∼70-residue linker. CBS1 binds to the CaM N-lobe and CBS2 recognizes the CaM C-lobe. Structural studies reveal the lobe-specific binding of CaM to CBS1&2. Mutations introduced in both CBS1 and CBS2 eliminated CaM binding in full-length TRP, but surprisingly had no effect on the response to light under physiological conditions, suggesting alternative mechanisms governing Ca-mediated feedback on the channel activity. Finally, we discover that TRPC4, the closest mammalian paralog of Drosophila TRP, adopts a similar CaM binding mode.
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http://dx.doi.org/10.1016/j.str.2020.11.016DOI Listing
April 2021

Identification of Novel Fragments Binding to the PDZ1-2 Domain of PSD-95.

ChemMedChem 2021 Mar 30;16(6):949-954. Epub 2020 Dec 30.

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.

Inhibition of PSD-95 has emerged as a promising strategy for the treatment of ischemic stroke, as shown with peptide-based compounds that target the PDZ domains of PSD-95. In contrast, developing potent and drug-like small molecules against the PSD-95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD-95 PDZ1-2 domain and use fragment screening to investigate if this protein is prone to binding small molecules. We screened 2500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR), including an inhibition counter-test, and found four promising fragments. Three ligand efficient fragments were shown by H, N HSQC NMR to bind in the small hydrophobic P pockets of PDZ1-2, and one of them underwent structure-activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1-2 of PSD-95 and disclose novel fragments that can serve as starting points for optimization towards small-molecule PDZ domain inhibitors.
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http://dx.doi.org/10.1002/cmdc.202000865DOI Listing
March 2021

CaMKIIα-driven, phosphatase-checked postsynaptic plasticity via phase separation.

Cell Res 2021 01 24;31(1):37-51. Epub 2020 Nov 24.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.

Ca/calmodulin-dependent kinase IIα (CaMKIIα) is essential for synaptic plasticity and learning by decoding synaptic Ca oscillations. Despite decades of extensive research, new mechanisms underlying CaMKIIα's function in synapses are still being discovered. Here, we discover that Shank3 is a specific binding partner for autoinhibited CaMKIIα. We demonstrate that Shank3 and GluN2B, via combined actions of Ca and phosphatases, reciprocally bind to CaMKIIα. Under basal condition, CaMKIIα is recruited to the Shank3 subcompartment of postsynaptic density (PSD) via phase separation. Rise of Ca concentration induces GluN2B-mediated recruitment of active CaMKIIα and formation of the CaMKIIα/GluN2B/PSD-95 condensates, which are autonomously dispersed upon Ca removal. Protein phosphatases control the Ca-dependent shuttling of CaMKIIα between the two PSD subcompartments and PSD condensate formation. Activation of CaMKIIα further enlarges the PSD assembly and induces structural LTP. Thus, Ca-induced and phosphatase-checked shuttling of CaMKIIα between distinct PSD nano-domains can regulate phase separation-mediated PSD assembly and synaptic plasticity.
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http://dx.doi.org/10.1038/s41422-020-00439-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852677PMC
January 2021

Micro-Nanostructure of Coal and Adsorption-Diffusion Characteristics of Methane.

J Nanosci Nanotechnol 2021 Jan;21(1):422-430

School of Civil Engineering, Qingdao University of Technology, Qingdao, 266520, China.

The adsorption and diffusion characteristics of coal are important parameters for coalbed methane (CBM) extraction and mine gas control. However, the adsorption test can only obtain the apparent adsorption amount, and it cannot obtain the actual adsorption amount, which leads to a large error during the calculation of the coal diffusion coefficient. Taking the anthracite coal in the Jiulishan Mine as the research object, the micro-nanostructure and instantaneous apparent methane adsorption isotherms of the primary structure coal and tectonic coal were determined by low-temperature CO₂ adsorption, mercury intrusion and methane diffusion kinetics tests, and the instantaneous apparent adsorption isotherms of methane were corrected to the instantaneous actual adsorption isotherm by the Langmuir model. The results demonstrate that the micro-nanopore, Density Function Theory (DFT) pore volume and specific surface area values below 1-2 nm in tectonic coal are larger than those in the primary structure coal, which is the fundamental reason why the ultimate adsorption capacity of tectonic coal is larger than that of the primary structure coal. The apparent adsorption amounts of the tectonic coal and the primary structure coal reach the maximum at 8 MPa and 10 MPa, respectively. Thereafter, the instantaneous isotherms of the apparent adsorption amount decrease with increasing of gas pressure. However, the instantaneous isotherms of the actual adsorption amount tend to be stable. The diffusion coefficient undergoes a rapid decay with time under low gas pressure, and undergoes a slow decay with under the high gas pressure.
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http://dx.doi.org/10.1166/jnn.2021.18733DOI Listing
January 2021

Vesicle Tethering on the Surface of Phase-Separated Active Zone Condensates.

Mol Cell 2021 01 16;81(1):13-24.e7. Epub 2020 Nov 16.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Center of Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Electronic address:

Tethering of synaptic vesicles (SVs) to the active zone determines synaptic strength, although the molecular basis governing SV tethering is elusive. Here, we discover that small unilamellar vesicles (SUVs) and SVs from rat brains coat on the surface of condensed liquid droplets formed by active zone proteins RIM, RIM-BP, and ELKS via phase separation. Remarkably, SUV-coated RIM/RIM-BP condensates are encapsulated by synapsin/SUV condensates, forming two distinct SUV pools reminiscent of the reserve and tethered SV pools that exist in presynaptic boutons. The SUV-coated RIM/RIM-BP condensates can further cluster Ca channels anchored on membranes. Thus, we reconstitute a presynaptic bouton-like structure mimicking the SV-tethered active zone with its one side attached to the presynaptic membrane and the other side connected to the synapsin-clustered SV condensates. The distinct interaction modes between membraneless protein condensates and membrane-based organelles revealed here have general implications in cellular processes, including vesicular formation and trafficking, organelle biogenesis, and autophagy.
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http://dx.doi.org/10.1016/j.molcel.2020.10.029DOI Listing
January 2021
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