PDE12 disrupts mitochondrial oxidative phosphorylation and mediates mitochondrial dysfunction to induce oral mucosal epithelial barrier damage in oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a chronic oral mucosal disease. The pathological changes of OSF include epithelial damage and subepithelial matrix fibrosis. This study aimed to reveal the epithelial injury mechanism of OSF. A histopathological method was used to analyze oral mucosal tissue from OSF patients and OSF rats. The expression of PDE12 in the oral epithelium was analyzed by immunohistochemistry. The epithelial-mesenchymal transition (EMT) and tight junction proteins in arecoline-treated HOKs were explored by western blotting. Epithelial leakage was assessed by transepithelial electrical resistance and lucifer yellow permeability. The expression of PDE12 and the mitochondrial morphology, mitochondrial permeability transition pore opening, mitochondrial membrane potential, and mitochondrial reactive oxygen species (mtROS) were evaluated in arecoline-induced HOKs. Oxidative phosphorylation (OXPHOS) complexes and ATP content were also explored in HOKs. The results showed significant overexpression of PDE12 in oral mucosal tissue from OSF patients and rats. PDE12 was also overexpressed and aggregated in mitochondria in arecoline-induced HOKs, resulting in dysfunction of OXPHOS and impaired mitochondrial function. An EMT, disruption of tight junctions with epithelial leakage, and extracellular matrix remodeling were also observed. PDE12 overexpression induced by PDE12 plasmid transfection enhanced the mtROS level and interfered with occludin protein localization in HOKs. Interestingly, knockdown of PDE12 clearly ameliorated arecoline-induced mitochondrial dysfunction and epithelial barrier dysfunction in HOKs. Therefore, we concluded that overexpression of PDE12 impaired mitochondrial OXPHOS and mitochondrial function and subsequently impaired epithelial barrier function, ultimately leading to OSF. We suggest that PDE12 may be a new potential target against OSF.

Redox Electrolytes-Assisting Aqueous Zn-Based Batteries by Pseudocapacitive Multiple Perovskite Fluorides Cathode and Charge Storage Mechanisms.

Aqueous Zn-based batteries (AZBs) have attracted intensive attention. However, to explore advanced cathode materials with in-depth elucidation of their charge storage mechanisms, improve energy storage capacity, and construct novel cell systems remain a great challenge. Herein, a new pseudocapacitive multiple perovskite fluorides (ABF3 ) cathode is designed, represented by KMF-(IV, V, and VI; M = NiCoMnZn/-Mg/-MgFe), and constructed Zn//KMF-(IV, V, and VI) AZBs and their flexible devices. Ex situ tests have revealed a typical bulk phase conversion mechanism of KMF-VI electrode for charge storage in alkaline media dominated by redox-active Ni/Co/Mn species, with transformation of ABF3 nanocrystals into amorphous metal oxide/(oxy)hydroxide nanosheets. By employing single or bipolar redox electrolyte strategies of 20 mm [Fe(CN)6 ]3- or/and 10 mm SO3 2- /Cu[(NH3 )4 ]2+ acting on KMF-(IV, V, and VI) cathode and Zn anode, the AZBs show an improved energy storage owing to additional capacity contribution of redox electrolytes. The as-designed Zn//polyvinyl alcohol (PVA)-KOH-K3 [Fe(CN)6 ]//KMF-(IV, V, and VI) redox gel electrolytes-assisting flexible AZBs (RGE-FAZBs) exhibit remarkable performance under different bending angles because of slight dissolution corrosion of zinc anode compared with liquid electrolytes. Overall, the work demonstrates the novel idea of conversion-type multiple ABF3 cathode for redox electrolytes-assisting AZBs (RE-AZBs) and their flexible systems, showing great significance on electrochemical energy storage.

Theoretical Study on the Formation and Decomposition Mechanisms of Coelenterazine Dioxetanone.

Bioluminescence has been drawing broad attention due to its high signal-to-noise ratio and high bioluminescence quantum yields, which has been widely applied in the fields of biomedicine, bioanalysis, and so on. Among numerous bioluminescent substrates, coelenterazine is famous for its wide distribution. However, the oxygenation reaction mechanism of coelenterazine is far from being completely understood. In this paper, the formation and decomposition mechanisms of coelenterazine dioxetanone were investigated via density functional theory (DFT) and time-dependent (TD) DFT approaches. The results showed that the oxygenation reaction first occurred along the triplet-state potential energy surface (PES), after the intersystem crossing (ISC), second jumped to the diradical-state PES, and ultimately formed coelenterazine dioxetanone. For the decomposition mechanism of dioxetanone, the computational results showed that the chemiexcitation of neutral dioxetanone was more efficient than that of other dioxetanone species. Moreover, the diradical properties and the degree of ionic character are modified by the counter ions.

Differentiating single cervical cells by mitochondrial fluorescence imaging and deep learning-based label-free light scattering with multi-modal static cytometry.

Cervical cancer is a high-risk disease that threatens women's health globally. In this study, we developed the multi-modal static cytometry that adopted different features to classify the typical human cervical epithelial cells (H8) and cervical cancer cells (HeLa). With the light-sheet static cytometry, we obtain brightfield (BF) images, fluorescence (FL) images and two-dimensional (2D) light scattering (LS) patterns of single cervical cells. Three feature extraction methods are used to extract multi-modal features based on different data characteristics. Analysis and classification of morphological and textural features demonstrate the potential of intracellular mitochondria in cervical cancer cell classification. The deep learning method is used to automatically extract deep features of label-free LS patterns, and an accuracy of 76.16% for the classification of the above two kinds of cervical cells is obtained, which is higher than the other two single modes (BF and FL). Our multi-modal static cytometry uses a variety of feature extraction and analysis methods to provide the mitochondria as promising internal biomarkers for cervical cancer diagnosis, and to show the promise of label-free, automatic classification of early cervical cancer with deep learning-based 2D light scattering.

Non-invasive discrimination of multiple myeloma using label-free serum surface-enhanced Raman scattering spectroscopy in combination with multivariate analysis.

We report non-invasive discrimination of multiple myeloma (MM) using label-free serum surface-enhanced Raman scattering (SERS) spectroscopy in combination with multivariate analysis. Colloidal silver nano-particles (AgNPs) were used as the SERS substrate. High quality serum SERS spectra were obtained from 53 MM patients and 44 healthy controls (HCs). The SERS spectral differences demonstrated variation of relative concentrations of biomolecules in the serum of MM patients in comparison to HCs. Multivariate analysis methods, including principal component analysis (PCA), linear discriminant analysis (LDA), and support vector machine (SVM), were used to build discrimination models for MM. Leave-one-out cross-validation (LOOCV) was used to evaluate the performances of the models, in terms of accuracy, sensitivity, specificity, and area under the receiver operating characteristic curves (AUC). Using the SVM model, the accuracy for discrimination of MM was achieved as 78.4%, and the corresponding sensitivity, specificity, and AUC values were 0.830, 0.727, and 0.840, respectively. The results show that the serum SERS in combination with multivariate analysis could be a fast, non-invasive, and cost-effective technique for discrimination of MM.

Diagnosis and staging of diffuse large B-cell lymphoma using label-free surface-enhanced Raman spectroscopy.

Non-invasive diagnosis and staging of diffuse large B-cell lymphoma (DLBCL) were achieved using label-free surface-enhanced Raman spectroscopy (SERS). SERS spectra were measured for serum samples of DLBCL patients at different progressive stages and healthy controls (HCs), using colloidal silver nano-particles (AgNPs) as the substrate. Differences in the spectral intensities of Raman peaks were observed between the DLBCL and HC groups, and a close correlation between the spectral intensities of Raman peaks with the progressive stages of the cancer was obtained, demonstrating the possibility of diagnosis and staging of the disease using the serum SERS spectra. Multivariate analysis methods, including principal component analysis (PCA), linear discriminant analysis (LDA), support vector machine (SVM) classifier, and k-nearest neighbors (kNN) classifier, were used to build the diagnosis and staging models for DLBCL. Leave-one-out cross-validation was used to evaluate the performances of the models. The kNN model achieved the best performances for both diagnosis and staging of DLBCL: for the diagnosis analysis, the accuracy, sensitivity, and specificity were 87.3%, 0.921, and 0.809, respectively; for the staging analysis between the early (Stage I & II) and the late (Stage III & IV) stages, the accuracy was 90.6%, and the sensitivity values for the early and the late stages were 0.947 and 0.800, respectively. The label-free serum SERS in combination with multivariate analysis could serve as a potential technique for non-invasive diagnosis and staging of DLBCL.

Effect and safety of acupotomy in treatment of knee osteoarthritis: a systematic review and Meta-analysis.

OBJECTIVE: To evaluate the clinical efficacy and safety of acupotomy in treatment of knee osteoarthritis (OA). METHODS: Extensive literature searches were carried out in PubMed, EMBASE, Cochrane Library (Issue 5, 2017), Chinese Biomedical Literature Database, China National Knowledge Infrastructure Database, China Science and Technology Journal Database and Wanfang Database. All databases were retrieved from their inception until May 31, 2017. Randomized controlled trials incorporating acupotomy versus intra-articular sodium hyaluronate for knee osteoarthritis were included. According to Cochrane Reviews' Handbook (5.2), two reviewers screened each article and extracted data independently and were blinded to the findings of each reviewer. Meta-analysis was performed by the Cochrane Collaboration's RevMan 5.3 software. RESULTS: We identified 12 studies involving 1150 patients aged between 40 and 78 years old. The pooled analysis indicated that acupotomy showed a significant improvement for short-term effect [cure rate: odds ratio (OR) = 2.04, 95% confidence interval (CI) (1.46, 2.85), P < 0.01; total effective rate: OR = 2.25, 95% CI (1.55, 3.28), P < 0.01; pain score: standard mean difference (SMD) = －1.02; 95% CI (－1.72, －0.31); P = 0.005; Western Ontario and McMaster Universities Questionnaire (WOMAC) score: SMD = －0.74; 95% CI (－1.11, －0.37); P < 0.01]; and also for long-term effect [total effective rate: OR = 2.99, 95%CI (1.88, 4.76), Z = 4.64, P < 0.01; pain score: SMD = －1.68; 95% CI (－2.14, －1.22); P < 0.001; WOMAC score: SMD = －0.91; 95% CI (－1.40, －0.41); P < 0.001]. In addition, there was no obvious difference between acupotomy group and control group in adverse events [OR = 2.13, 95%CI (0.14, 32.28), P = 0.58]. CONCLUSION: Acupotomy is a safe and effective treatment for KOA. However, due to the methodological deficiency of the included studies, well-designed randomized controlled trials are required to further confirm the findings.

Association of Depression/Anxiety Symptoms with Neck Pain: A Systematic Review and Meta-Analysis of Literature in China.

Background: Due to its high morbidity and prevalence, the potential relationships of depression/anxiety symptoms in neck pain (NP) are not well demonstrated. Objectives: This study aimed to conduct a comprehensive estimation of controlled trials of psychological problems and to test hypotheses concerning whether NP was statistically relative to anxiety/depression symptoms. Methods: Chinese literature databases such as the China National Knowledge Infrastructure (CNKI), VIP Information (VIP), Chinese Biomedicine (CBM), and Wanfang Data (WANFANG) were scientifically searched for reports published until February 5, 2018. Controlled trials incorporating NP patients with anxiety/depression versus healthy people were contained. Two researchers screened each article and extracted data, respectively, and blinded to the findings of each other. Meta-analysis was conducted by the Cochrane Collaboration's RevMan 5.3 and Stata 14.0 (Stata Corp LP, USA) software. Results: We identified 13 eligible studies involving 2339 patients and 3290 healthy people. Compared with healthy control participants, the findings indicated that depression/anxiety symptoms were more common or severe in NP patients (respectively, SMD = 0.89; 95% CI = (0.58, 1.20); P < 0.01 and SMD = 0.92; 95% CI = (0.65, 1.20); and P < 0.01), results from the pooled data demonstrated no statistical significance between depression/anxiety symptoms and gender in NP patients (resp., SMD = 0.16; 95% CI = (-0.18, 0.51); P=0.35 and SMD = -0.08; 95% CI = (-0.42, 0.27); and P=0.67), and the combined data of the incidence of depression or anxiety symptoms revealed significant difference between NP patients and healthy persons (resp., RR = 4.81; 95% CI = (3.30, 7.01); P < 0.01 and RR = 3.29; 95% CI = (2.16, 5.00); and P < 0.01). In addition, we did not find articles that met the inclusion criteria, which compared NP patients with other physical illnesses in terms of anxiety/depression symptoms. Conclusions: This meta-analysis suggests that anxiety/depression symptoms are associated with high morbidity in NP patients. We consider these reports support the viewpoint that nonspecific mechanisms mediate mental disturbances in NP. This study may have clinical value for NP, offering an underlying target for the prevention and treatment of anxiety/depression.