CD8+ tissue-resident memory T cells are essential in bleomycin-induced pulmonary fibrosis.

Human tissue-resident memory T (TRM) cells play a crucial role in protecting the body from infections and cancers. Recent research observed increased numbers of TRM cells in the lung tissues of idiopathic pulmonary fibrosis patient. However, the functional consequences of TRM cells in pulmonary fibrosis remain unclear. Here, we found that the numbers of TRM cells, especially the CD8+ subset, were increased in the mouse lung with bleomycin-induced pulmonary fibrosis. Increasing or decreasing CD8+ TRM cells in mouse lungs accordingly altered the severity of fibrosis. In addition, adoptive transfer of CD8+ T cells containing a large number of CD8+ TRM cells from fibrotic lungs was sufficient to induce pulmonary fibrosis in control mice. Treatment with CCL18 to induced CD8+ TRM cell expansion and exacerbated fibrosis, while blocking CCR8 prevented CD8+ TRM recruitment and inhibited pulmonary fibrosis. In conclusion, CD8+ TRM cells are essential for bleomycin-induced pulmonary fibrosis, and targeting CCL18/CCR8/CD8+ TRM cells may be a potential therapeutic approach.

Causal association between peripheral immune cells and IgA nephropathy: a Mendelian randomization study.

Background: The relationship between peripheral immune cells and immunoglobulin A nephropathy (IgAN) is widely known; however, causal evidence of this link is lacking. Here, we aimed to determine the causal effect of peripheral immune cells, specifically total white blood cells, lymphocytes, monocytes, basophils, eosinophils, and neutrophils, as well as lymphocyte subset traits, on the IgAN risk using a Mendelian randomization (MR) analysis. Methods: The inverse-variance weighted (IVW) method was used for the primary analysis. We applied three complementary methods, including the weighted median, MR-Egger regression, and MR-PRESSO, to detect and correct for the effect of horizontal pleiotropy. Additionally, we performed a multivariable MR (MVMR) analysis, adjusting for the effects of C-reactive protein (CRP) levels. The roles of specific lymphocyte subtypes and their significance have garnered interest. Bidirectional two-sample MR analysis was performed to test the potential causal relationships between immune traits, including median fluorescence intensities (MFIs) and the relative cell count (AC), and IgAN. Results: The IVW-MR analysis suggested a potential causal relationship between lymphocyte counts and IgAN in Europe (OR per 1-SD increase: 1.43, 95% CI: 1.08-1.88, P = 0.0123). The risk effect of lymphocytes remained even after adjusting for CRP levels using the MVMR method (OR per 1-SD increase: 1.44, 95% CI: 1.05-1.96, P = 0.0210). The other sensitivity analyses showed a consistent trend. The largest GWAS published to date was used for peripheral blood immunophenotyping to explore the potential causal relationship between peripheral immune cell subsets and IgAN. Six AC-IgAN and 14 MFI-IgAN pairs that reached statistical significance (P < 0.05) were detected. Notably, CD3, expressed in eight subsets of T cells, consistently showed a positive correlation with IgAN. The bidirectional MR analysis did not reveal any evidence of reverse causality. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates. Conclusions: Genetically determined high lymphocyte counts were associated with IgAN, supporting that high lymphocyte counts is causal risk factor for IgAN.

DEC1 is involved in circadian rhythm disruption-exacerbated pulmonary fibrosis.

BACKGROUND: The alveolar epithelial type II cell (AT2) and its senescence play a pivotal role in alveolar damage and pulmonary fibrosis. Cell circadian rhythm is strongly associated with cell senescence. Differentiated embryonic chondrocyte expressed gene 1 (DEC1) is a very important circadian clock gene. However, the role of DEC1 in AT2 senescence and pulmonary fibrosis was still unclear. RESULTS: In this study, a circadian disruption model of light intervention was used. It was found that circadian disruption exacerbated pulmonary fibrosis in mice. To understand the underlying mechanism, DEC1 levels were investigated. Results showed that DEC1 levels increased in lung tissues of IPF patients and in bleomycin-induced mouse fibrotic lungs. In vitro study revealed that bleomycin and TGF-ß1 increased the expressions of DEC1, collagen-I, and fibronectin in AT2 cells. Inhibition of DEC1 mitigated bleomycin-induced fibrotic changes in vitro and in vivo. After that, cell senescence was observed in bleomycin-treated AT2 cells and mouse models, but these were prevented by DEC1 inhibition. At last, p21 was confirmed having circadian rhythm followed DEC1 in normal conditions. But bleomycin disrupted the circadian rhythm and increased DEC1 which promoted p21 expression, increased p21 mediated AT2 senescence and pulmonary fibrosis. CONCLUSIONS: Taken together, circadian clock protein DEC1 mediated pulmonary fibrosis via p21 and cell senescence in alveolar epithelial type II cells.

Distributed cyber attack detection and physical fault diagnosis for a class of interconnected large-scale systems.

In this paper we focus on the distributed cyber attack detection and physical fault diagnosis problem for a class of interconnected large-scale systems (ILSSs). In the proposed scheme, apart from node measurement, edge measurement is also used to construct distributed Kalman filter to estimate the state of each subsystem. The gain matrices of Kalman filter are determined by minimizing the covariance of estimation error in the attack-free and fault-free case, which reduces the false alarm rate of cyber attack detection and physical fault diagnosis. Based on this filter, a bank of adjacent residual generators is constructed to characterize the influence of cyber attack on the edge measurement, and the Chi-square test is used to detect whether the received edge measurements are attacked. At the same time, a local residual generator is constructed for each subsystem to characterize the influence of physical faults on it, and the residual signal is evaluated by variance and directional residual, so as to make distributed fault detection and isolation of each subsystem. It is worth noting that at each step, each subsystem first performs attack detection on the received edge measurements, and then estimates its own state using the attack-free edge measurements and node measurement, which further improves the accuracy of fault detection and isolation. In addition, a sufficient condition that ensuring the mean square exponential boundedness of the estimation error is given. Finally, the proposed scheme is verified by an illustrative example.

PM2.5 exposure-induced senescence-associated secretory phenotype in airway smooth muscle cells contributes to airway remodeling.

Fine particulate matter (PM2.5) has been linked to increased severity and incidence of airway diseases, especially chronic obstructive pulmonary disease (COPD) and asthma. Airway remodeling is an important event in both COPD and asthma, and airway smooth muscle cells (ASMCs) are key cells which directly involved in airway remodeling. However, it was unclear how PM2.5 affected ASMCs. This study investigates the effects of PM2.5 on airway smooth muscle and its mechanism. We first showed that inhaled particulate matter was distributed in the airway smooth muscle bundle, combined with increased airway smooth muscle bundle and collagen deposition in vivo. Then, we demonstrated that PM2.5 induced up-regulation of collagen-I and alpha-smooth muscle actin (α-SMA) expression in rat and human ASMCs in vitro. Next, we found PM2.5 led to rat and human ASMCs senescence and exhibited senescence-associated secretory phenotype (SASP) by autophagy-induced GATA4/TRAF6/NF-κB signaling, which contributed to collagen-I and α-SMA synthesis as well as airway smooth muscle remodeling. Together, our results provided evidence that SASP induced by PM2.5 in airway smooth muscle cells prompted airway remodeling.

BMAL1/p53 mediating bronchial epithelial cell autophagy contributes to PM2.5-aggravated asthma.

BACKGROUND: Fine particulate matter (PM2.5) is associated with increased incidence and severity of asthma. PM2.5 exposure disrupts airway epithelial cells, which elicits and sustains PM2.5-induced airway inflammation and remodeling. However, the mechanisms underlying development and exacerbation of PM2.5-induced asthma were still poorly understood. The aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) is a major circadian clock transcriptional activator that is also extensively expressed in peripheral tissues and plays a crucial role in organ and tissue metabolism. RESULTS: In this study, we found PM2.5 aggravated airway remodeling in mouse chronic asthma, and exacerbated asthma manifestation in mouse acute asthma. Next, low BMAL1 expression was found to be crucial for airway remodeling in PM2.5-challenged asthmatic mice. Subsequently, we confirmed that BMAL1 could bind and promote ubiquitination of p53, which can regulate p53 degradation and block its increase under normal conditions. However, PM2.5-induced BMAL1 inhibition resulted in up-regulation of p53 protein in bronchial epithelial cells, then increased-p53 promoted autophagy. Autophagy in bronchial epithelial cells mediated collagen-I synthesis as well as airway remodeling in asthma. CONCLUSIONS: Taken together, our results suggest that BMAL1/p53-mediated bronchial epithelial cell autophagy contributes to PM2.5-aggravated asthma. This study highlights the functional importance of BMAL1-dependent p53 regulation during asthma, and provides a novel mechanistic insight into the therapeutic mechanisms of BMAL1. Video Abstract.

Solid phase synthesis of oxidized sodium alginate-tobramycin conjugate and its application for infected wound healing.

Although sodium alginate possesses excellent biocompatibility, moisture retention and easy availability, it cannot be directly applied for infected wound treatment. Herein, a solid phase synthesis strategy was proposed to fabricate oxidized sodium alginate-tobramycin conjugate (OSA-TOB) for anti-infection dressing development. 13C nuclear magnetic resonance spectra indicated that the oxidization process does not change the ratio of ß-D-mannuronic acid (M) / α-L-guluronic acid (G) in OSA and the oxidization reaction shows no stereoselectivity. Elemental analysis disclosed that the graft ratio of tobramycin in OSA-TOB is 13.8 %. Antibacterial test indicated that OSA-TOB can effectively inhibit four prevalent pathogenic bacterial S.epidermidis, P. aeruginosa, S. aureus and E. coli via a different antibacterial mechanism compared to the original TOB. Hemolysis and cytotoxicity assays shown that OSA-TOB have superior hemocompatibility and cytocompatibility. Infected wound healing assay shown that the healing rate of OSA-TOB is the highest. Further analysis indicated that OSA-TOB can reduce the local inflammatory response, accelerate the form of epithelium and collagen deposition. In conclusions, OSA-TOB synthesized in solid phase can be potentially applied as a promising anti-infection wound dressing.

Blockade of phosphotyrosine pathways suggesting SH2 superbinder as a novel therapy for pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic disease with high mortality. Currently, pirfenidone and nintedanib are the only approved drugs for IPF by the U.S. Food and Drug Administration (FDA), but their efficacy is limited. The activation of multiple phosphotyrosine (pY) mediated signaling pathways underlying the pathological mechanism of IPF has been explored. A Src homology-2 (SH2) superbinder, which contains mutations of three amino acids (AAs) of natural SH2 domain has been shown to be able to block phosphotyrosine (pY) pathway. Therefore, we aimed to introduce SH2 superbinder into the treatment of IPF. Methods: We analyzed the database of IPF patients and examined pY levels in lung tissues from IPF patients. In primary lung fibroblasts obtained from IPF patient as well as bleomycin (BLM) treated mice, the cell proliferation, migration and differentiation associated with pY were investigated and the anti-fibrotic effect of SH2 superbinder was also tested. In vivo, we further verified the safety and effectiveness of SH2 superbinder in multiple BLM mice models. We also compared the anti-fibrotic effect and side-effect of SH2 superbinder and nintedanib in vivo. Results: The data showed that the cytokines and growth factors pathways which directly correlated to pY levels were significantly enriched in IPF. High pY levels were found to induce abnormal proliferation, migration and differentiation of lung fibroblasts. SH2 superbinder blocked pY-mediated signaling pathways and suppress pulmonary fibrosis by targeting high pY levels in fibroblasts. SH2 superbinder had better therapeutic effect and less side-effect compare to nintedanib in vivo. Conclusions: SH2 superbinder had significant anti-fibrotic effects both in vitro and in vivo, which could be used as a promising therapy for IPF.

Multi-agent based event-triggered distributed cooperative fault detection.

In this paper, we present a multi-agent based optimal event-triggered distributed cooperative fault detection scheme. First, for each agent, the event-triggered mechanism is used to determine whether the current measurements are transmitted to the corresponding neighbor agents, addressing the design of the cooperative estimator. Then, considering the effects of external bounded disturbances and additional faults as well as transmission errors caused by event triggering, a residual generator is proposed, which achieves the optimal tradeoff between robustness to external bounded disturbances and faults sensitivity. Meanwhile, by taking into account the effects of external disturbances and information loss caused by event triggering on the residual, a residual evaluator is designed to provide the corresponding time-varying threshold. Finally, an illustrative example is given to illustrate the effectiveness of the proposed scheme.

Pleural mesothelial cell migration into lung parenchyma by calpain contributes to idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia. It is unknown why fibrosis in IPF distributes in the peripheral or named sub-pleural area. Migration of pleural mesothelial cells (PMC) should contribute to sub-pleural fibrosis. Calpain is known to be involved in cell migration, but the role of calpain in PMC migration has not been investigated. In this study, we found that PMCs migrated into lung parenchyma in patients with IPF. Then using Wt1tm1(EGFP/Cre)Wtp /J knock-in mice, we observed PMC migration into lung parenchyma in bleomycin-induced pleural fibrosis models, and calpain inhibitor attenuated pulmonary fibrosis with prevention of PMC migration. In vitro studies revealed that bleomycin and transforming growth factor-ß1 increased calpain activity in PMCs, and activated calpain-mediated focal adhesion (FA) turnover as well as cell migration, cell proliferation, and collagen-I synthesis. Furthermore, we determined that calpain cleaved FA kinase in both C-terminal and N-terminal regions, which mediated FA turnover. Lastly, the data revealed that activated calpain was also involved in phosphorylation of cofilin-1, and p-cofilin-1 induced PMC migration. Taken together, this study provides evidence that calpain mediates PMC migration into lung parenchyma to promote sub-pleural fibrosis in IPF.

Irrelevant task suppresses the N170 of automatic attention allocation to fearful faces.

Recent researches have provided evidence that stimulus-driven attentional bias for threats can be modulated by top-down goals. However, it is highlight essential to indicate whether and to what extent the top-down goals can affect the early stage of attention processing and its early neural mechanism. In this study, we collected electroencephalographic data from 28 healthy volunteers with a modified spatial cueing task. The results revealed that in the irrelevant task, there was no significant difference between the reaction time (RT) of the fearful and neutral faces. In the relevant task, we found that RT of fearful faces was faster than that of neutral faces in the valid cue condition, whereas the RT of fearful faces was slower than that of neutral faces in the invalid cue condition. The N170 component in our study showed a similar result compared with RT. Specifically, we noted that in the relevant task, fearful faces in the cue position of the target evoked a larger N170 amplitude than neutral faces, whereas this effect was suppressed in the irrelevant task. These results suggest that the irrelevant task may inhibit the early attention allocation to the fearful faces. Furthermore, the top-down goals can modulate the early attentional bias for threatening facial expressions.

Splicing factor SRSF6 mediates pleural fibrosis.

Pleural fibrosis is defined as an excessive deposition of extracellular matrix that results in destruction of the normal pleural tissue architecture and compromised function. Tuberculous pleurisy, asbestos injury, and rheumatoid pleurisy are main causes of pleural fibrosis. Pleural mesothelial cells (PMCs) play a key role in pleural fibrosis. However, detailed mechanisms are poorly understood. Serine/arginine-rich protein SRSF6 belongs to a family of highly conserved RNA-binding splicing-factor proteins. Based on its known functions, SRSF6 should be expected to play a role in fibrotic diseases. However, the role of SRSF6 in pleural fibrosis remains unknown. In this study, SRSF6 protein was found to be increased in cells of tuberculous pleural effusions (TBPE) from patients, and decellularized TBPE, bleomycin, and TGF-ß1 were confirmed to increase SRSF6 levels in PMCs. In vitro, SRSF6 mediated PMC proliferation and synthesis of the main fibrotic protein COL1A2. In vivo, SRSF6 inhibition prevented mouse experimental pleural fibrosis. Finally, activated SMAD2/3, increased SOX4, and depressed miRNA-506-3p were associated with SRSF6 upregulation in PMCs. These observations support a model in which SRSF6 induces pleural fibrosis through a cluster pathway, including SRSF6/WNT5A and SRSF6/SMAD1/5/9 signaling. In conclusion, we propose inhibition of the splicing factor SRSF6 as a strategy for treatment of pleural fibrosis.

VEGF/Src signaling mediated pleural barrier damage and increased permeability contributes to subpleural pulmonary fibrosis.

The distribution of fibrosis in idiopathic pulmonary fibrosis (IPF) is subpleural with basal predominance. Alveolar epithelial cell was considered as the key cell in the initial phase of IPF. However, the idea of activation and damage of alveolar epithelial cells is very difficult to explain why fibrosis distributes in the subpleural area. In this study, human pleural mesothelial cell (PMC) line and primary rat PMC was used as in vitro model. Intraperitoneal injection of bleomycin was used for making a pulmonary fibrosis model. The integrity of cultured monolayer PMCs was determined by transepithelial electric resistance (TEER). Pleural permeability was estimated by measuring paracellular transport of fluorescein isothiocyanate (FITC)-conjugated dextran. Changes in lung tissue of patients with IPF were analyzed by Masson's and immunofluorescence staining. We found bleomycin induced PMCs damage and increased PMCs permeability; increased PMCs permeability aggravated bleomycin-induced subpleural inflammation and pulmonary fibrosis. Moreover, bleomycin was found to activate VEGF/Src signaling which increased PMCs permeability. In vivo, inhibition of VEGF/Src signaling prevented bleomycin-induced subpleural pulmonary fibrosis. At last, activation of VEGF/Src signaling was confirmed in subpleural area in patients with IPF. Taken together, our findings indicate that VEGF/Src signaling mediated pleural barrier damage and increased permeability which contributes to subpleural pulmonary fibrosis.

Three-month Follow-up Study of Survivors of Coronavirus Disease 2019 after Discharge.

BACKGROUND: Most patients including health care workers (HCWs) survived the coronavirus disease 2019 (COVID-19), however, knowledge about the sequelae of COVID-19 after discharge remains limited. METHODS: A prospectively observational 3-month follow-up study evaluated symptoms, dynamic changes of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) IgG and IgM, lung function, and high resolution computed tomography (HRCT) of survivors of COVID-19 after discharge at Wuhan Union Hospital, China. RESULTS: Seventy-six survivors (55 females) with a mean age of 41.3 ± 13.8 years were enrolled, and 65 (86%) were HCWs. A total of 69 (91%) patients had returned to their original work at 3-months after discharge. Most of the survivors had symptoms including fever, sputum production, fatigue, diarrhea, dyspnea, cough, chest tightness on exertion and palpitations in the three months after discharge. The serum troponin-I levels during the acute illness showed high correlation with the symptom of fatigue after hospital discharge (r = 0.782; P = 0.008) and lymphopenia was correlated with the symptoms of chest tightness and palpitations on exertion of patients after hospital discharge (r = -.285, P = 0.027; r = -.363, P = 0.004, respectively). The mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, total lung capacity and diffusion capacity were all normal (> 80% predicted) and lung HRCTs returned to normal in most of the patients (82%), however, 42% of survivors had mild pulmonary function abnormalities at 3-months after discharge. SARS-CoV-2 IgG turned negative in 11% (6 of 57 patients), 8% (4 of 52 patients) and 13% (7 of 55 patients), and SARS-CoV-2 IgM turned negative in 72% (41 of 57 patients), 85% (44 of 52 patients) and 87% (48 of 55 patients) at 1-month, 2-months and 3-months after discharge, respectively. CONCLUSION: Infection by SARS-CoV-2 caused some mild impairments of survivors within the first three months of their discharge and the duration of SARS-CoV-2 antibody was limited, which indicates the necessity of long-term follow-up of survivors of COVID-19.

Bleomycin induced apical-basal polarity loss in alveolar epithelial cell contributes to experimental pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrosing interstitial lung disease with limited therapeutic options and a median survival of 3 years after diagnosis. Dysregulated epithelial regeneration is key event involved in initiating and sustaining IPF. The type II alveolar epithelial cells (AECIIs) play a crucial role for epithelial regeneration and stabilisation of alveoli. Loss of cell apical-basal polarity contributes to fibrosis. AECII has apical-basal polarity, but it is poorly understood whether AECII apical-basal polarity loss is involved in fibrosis. Bleomycin is a traditional inducer of pulmonary fibrosis. Here firstly we observed that bleomycin induced apical-basal polarity loss in cultured AECIIs. Next, cell polarity proteins lethal (2) giant larvae 1 (Lgl1), PAR-3A, aPKC and PAR-6B were investigated. We found bleomycin induced increases of Lgl1 protein and decreases of PAR-3A protein, and bleomycin-induced PAR-3A depression was mediated by increased-Lgl1. Then Lgl1 siRNA was transfected into AECIIs. Lgl1 siRNA prevented apical-basal polarity loss in bleomycin-treated AECIIs. At last, Lgl1-conditional knockout mice were applied in making animal models. Bleomycin induced pulmonary fibrosis, but this was attenuated in Lgl1-conditional knockout mice. Together, these data indicated that bleomycin mediated AECII apical-basal polarity loss which contributed to experimental pulmonary fibrosis. Inhibition of Lgl1 should be a potential therapeutic strategy for the disease.

Crosstalk between pleural mesothelial cell and lung fibroblast contributes to pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive and fibrosing interstitial pneumonia of unknown cause. The main feature of IPF is a heterogeneous appearance with areas of sub-pleural fibrosis. However, the mechanism of sub-pleural fibrosis was poorly understood. In this study, our in vivo study revealed that pleural mesothelial cells (PMCs) migrated into lung parenchyma and localized alongside lung fibroblasts in sub-pleural area in mouse pulmonary fibrosis. Our in vitro study displayed that cultured-PMCs-medium induced lung fibroblasts transforming into myofibroblast, cultured-fibroblasts-medium promoted mesothelial-mesenchymal transition of PMCs. Furthermore, these changes in lung fibroblasts and PMCs were prevented by blocking TGF-ß1/Smad2/3 signaling with SB431542. TGF-ß1 neutralized antibody attenuated bleomycin-induced pulmonary fibrosis. Similar to TGF-ß1/Smad2/3 signaling, wnt/ß-catenin signaling was also activated in the process of PMCs crosstalk with lung fibroblasts. Moreover, inhibition of CD147 attenuated cultured-PMCs-medium induced collagen-I synthesis in lung fibroblasts. Blocking CD147 signaling also prevented bleomycin-induced pulmonary fibrosis. Our data indicated that crosstalk between PMC and lung fibroblast contributed to sub-pleural pulmonary fibrosis. TGF-ß1, Wnt/ß-catenin and CD147 signaling was involved in the underling mechanism.

Nosocomial outbreak of COVID-19 pneumonia in Wuhan, China.

BACKGROUND: The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infected over 3300 healthcare workers in early 2020 in China. Little information is known about nosocomial infections of healthcare workers in the initial period. We analysed data from healthcare workers with nosocomial infections in Wuhan Union Hospital (Wuhan, China) and their family members. METHODS: We collected and analysed data on exposure history, illness timelines and epidemiological characteristics from 25 healthcare workers with laboratory-confirmed coronavirus disease 2019 (COVID-19) and two healthcare workers in whom COVID-19 was highly suspected, as well as 10 of their family members with COVID-19, between 5 January and 12 February 2020. The demographics and clinical features of the 35 laboratory-confirmed cases were investigated and viral RNA of 12 cases was sequenced and analysed. RESULTS: Nine clusters were found among the patients. All patients showed mild to moderate clinical manifestation and recovered without deterioration. The mean period of incubation was 4.5 days, the mean±sd clinical onset serial interval (COSI) was 5.2±3.2 days, and the median virus shedding time was 18.5 days. Complete genomic sequences of 12 different coronavirus strains demonstrated that the viral structure, with small irrelevant mutations, was stable in the transmission chains and showed remarkable traits of infectious traceability. CONCLUSIONS: SARS-CoV-2 can be rapidly transmitted from person to person, regardless of whether they have symptoms, in both hospital settings and social activities, based on the short period of incubation and COSI. The public health service should take practical measures to curb the spread, including isolation of cases, tracing close contacts, and containment of severe epidemic areas. Besides this, healthcare workers should be alert during the epidemic and self-quarantine if self-suspected of infection.

Evaluation of miR-34b/c polymorphisms to the risk of ischemic stroke.

OBJECTIVES: Polymorphisms in microRNA genes are related to the risk of ischemic stroke, but the association between miR-34b/c polymorphisms and the risk of ischemic stroke has not been reported. METHODS: MiR-34b/c rs2187473 and rs4938723 polymorphisms were genotyped by Snapshot assay among 495 controls and 492 ischemic stroke patients. Expression levels of miR-34b and miR-34c were quantified by real-time PCR. Transcriptional activity of miR-34b/c promoter was measured by luciferase reporter assay. RESULTS: Rs4938723 was associated with an increased risk of ischemic stroke in our study (CC versus TT: OR = 2.34, 95% CI = 1.47-3.72, P = 0.001; C versus T: OR = 1.37, 95% CI = 1.12-1.68, P = 0.002; CC versus TT + TC: OR = 2.12, 95% CI = 1.37-3.29, P = 0.001). The expression levels of miR-34b and miR-34c were significantly downregulated in cases by contrast with controls (P < 0.05). Further analysis demonstrated that the expression levels of miR-34b and miR-34c were also downregulated in the individuals carrying rs4938723 CC genotype by contrast with that carrying TT + TC genotypes (P < 0.05). The result of luciferase reporter assay showed that rs4938723C allele decreased the transcriptional activity of miR-34b/c promoter compared with rs4938723 T allele. CONCLUSION: Our study showed a positive relation between the miR-34b/c rs4938723 polymorphism and the risk of ischemic stroke, which indicated that rs4938723 may be used for ischemic stroke prediction or therapy in the future.

Endorectal power Doppler/grayscale ultrasound-guided biopsies vs. multiparametric MRI/ultrasound fusion-guided biopsies in males with high risk of prostate cancer: A prospective cohort study.

Multiparametric MRI fusion with transrectal ultrasound (mpMRI/TRUS)-guided biopsy has the sensitivity of mpMRI with the practicality of TRUS, but males with no cancerous lesion(s) detected on mpMRI have a considerable remaining risk of cancer. Endorectal power Doppler ultrasound improves the sensitivity of grayscale ultrasound-guided biopsies. The objective of the present study was to evaluate the beneficial effect of endorectal power Doppler/grayscale ultrasound-guided biopsy over that of mpMRI/TRUS-guided biopsy for decision-making regarding prostatectomy in males with a high risk of prostate cancer. Data regarding endorectal power Doppler/grayscale ultrasound-guided biopsies and mpMRI/TRUS-guided biopsies of 1,094 males with elevated specific prostate antigen, were included. Radical prostatectomy was performed in males aged <70 years with Gleason scores ≥3+4 in any one of the biopsy reports. The histopathological data of the surgical specimen of 776 males were included in the analysis. Compared to the histopathology of the surgical specimen, endorectal power Doppler/grayscale ultrasound-guided biopsies had a lower sensitivity (0.930 vs. 1.000; P<0.0001) but mpMRI/TRUS-guided biopsies had the same sensitivity (0.990 vs. 1.000; P=0.02). The accuracy of mpMRI/TRUS-guided biopsies was higher than that of endorectal power Doppler/grayscale ultrasound-guided biopsies (0.944 vs. 0.783). On mpMRI, lesions of 105 subjects (10%) with a Likert scale score of <3 were identified. Among them, 14 subjects (2%) had Gleason scores of ≥3+4 as determined by endorectal power Doppler/grayscale ultrasound-guided biopsies. In addition, 20 (2%) false-positive lesions compared to the histopathological analysis of the surgical specimen were identified from mpMRI/TRUS-guided biopsies. In conclusion, mpMRI/TRUS-guided biopsy was indicated to have a moderate performance and endorectal power Doppler/grayscale ultrasound-guided biopsy had a scant performance for decision-making regarding prostatectomy.

Correlation between coronary stenosis and Toll-like receptors 2 and 4 levels in Chinese Zhuang patients with coronary heart disease.

The present study attempted to determine the correlation of the degree of coronary artery stenosis and Tolllike receptor 2/4 (TLR2/4) levels in Chinese Zhuang patients with coronary heart disease (CHD). A total of 466 Chinese patients from the Zhuang Ethnic population diagnosed with CHD at the Department of Cardiology the Affiliated Hospital of Youjiang Medical University between January 2016 and August 2017, together with 102 control patients, were recruited for the present study. The patients with CHD were divided into three groups depending on the number of diseased arteries. The patients with CHD were also classified according to their Gensini scores. Blood liver and renal function parameters, as well as blood sugar and lipid levels were measured. ELISA was used for TLR2/4 measurements. There were no significant differences with gender, age and body mass index between the CHD and control groups. The levels of TLR2/4 in the peripheral blood of the control and CHD groups were 2.34±0.85/5.08±2.41 and 5.22±3.16/9.33±4.92 ng/ml, respectively, and the differences were significant (P<0.001). Analysis of the three subgroups of vessel disease indicated that the expression of TLR2/4 was progressively higher with the increase in the number of affected vessels (P<0.01). There were also significant differences between the mild, moderate and severe stenosis groups (P<0.01). A positive linear correlation between TLR2/4 and the Gensini coronary artery score was identified (r=0.508 and 0.346, respectively; P<0.0001). In conclusion, the present study determined a positive correlation between the degree of coronary artery stenosis and the expression level of TLR2/4 in the serum of Chinese Zhuang patients with CHD. Serum TLR2/4 may be used to predict the severity of CHD.