TMC7 functions as a suppressor of Piezo2 in primary sensory neurons blunting peripheral mechanotransduction.

The transmembrane channel-like (TMC) protein family comprises eight members, with TMC1 and TMC2 being extensively studied. This study demonstrates substantial co-expression of TMC7 with the mechanosensitive channel Piezo2 in somatosensory neurons. Genetic deletion of TMC7 in primary sensory ganglia neurons in vivo enhances sensitivity in both physiological and pathological mechanosensory transduction. This deletion leads to an increase in proportion of rapidly adapting (RA) currents conducted by Piezo2 in dorsal root ganglion (DRG) neurons and accelerates RA deactivation kinetics. In HEK293 cells expressing both proteins, TMC7 significantly suppresses the current amplitudes of co-expressed Piezo2. Our findings reveal that TMC7 and Piezo2 exhibit physical interactions, and both proteins also physically interact with cytoskeletal ß-actin. We hypothesize that TMC7 functions as an inhibitory modulator of Piezo2 in DRG neurons, either through direct inhibition or by disrupting the transmission of mechanical forces from the cytoskeleton to the channel.

Nav1.8 in small dorsal root ganglion neurons contributes to vincristine-induced mechanical allodynia.

Vincristine-induced peripheral neuropathy (VIPN) is a common side effect of vincristine treatment, which is accompanied by pain and can be dose-limiting. The molecular mechanisms that underlie vincristine-induced pain are not well understood. We have established an animal model to investigate pathophysiological mechanisms of vincristine induced pain. Our previous studies have shown that the tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channel NaV1.6 in medium-diameter dorsal root ganglion (DRG) neurons contributes to the maintenance of vincristine-induced allodynia. In this study, we investigated the effects of vincristine administration on excitability in small-diameter DRG neurons and whether the tetrodotoxin-resistant (TTX-R) NaV1.8 channels contribute to mechanical allodynia. Current-clamp recordings demonstrated that small DRG neurons become hyper-excitable following vincristine treatment, with both reduced current threshold and increased firing frequency. Using voltage-clamp recordings in small DRG neurons we now show an increase in TTX-R current density and a -7.3 mV hyperpolarizing shift in V1/2 of activation of NaV1.8 channels in vincristine-treated animals, which likely contributes to the hyperexcitability that we observed in these neurons. Notably, vincristine treatment did not enhance excitability of small DRG neurons from NaV1.8 knockout mice, and the development of mechanical allodynia was delayed but not abrogated in these mice. Together, our data suggest that sodium channel NaV1.8 in small DRG neurons contributes to the development of vincristine-induced mechanical allodynia.

Impact of electronic cigarette usage on the onset of respiratory symptoms and COPD among Chinese adults.

The prevalence of dual usage and the relatively low cessation rate among e-cigarette (EC) users suggest that ECs have not demonstrated significant effectiveness as a smoking cessation tool. Furthermore, there has been a substantial increase in the prevalence of EC usage in recent years. Therefore, the objective of this study is to investigate the association between EC use and the incidence of respiratory symptoms and chronic obstructive pulmonary disease (COPD). A total of 10,326 participants aged between 20 and 55 years, without any respiratory diseases or COPD, were recruited for the study. These individuals attended employee physical examinations conducted at 16 public hospitals in Hebei province, China from 2015 to 2020. Logistic regression models were utilized to assess the association between EC use and the risk of respiratory symptoms and COPD using risk ratios along with their corresponding 95% confidence intervals. Restricted cubic spline functions were employed to investigate the dose-response non-linear relationship. The robustness of the logistic regression models was evaluated through subgroup analyses, and sensitivity analyses. During the 5-year follow-up period, a total of 1071 incident cases of respiratory symptoms and 146 incident cases of COPD were identified in this cohort study. After adjusting for relevant confounding factors, EC users demonstrated a respective increase in the risk of reporting respiratory symptoms and COPD by 28% and 8%. Furthermore, dual users who used both ECs and combustible cigarettes exhibited an elevated risk of incident respiratory symptoms and COPD by 41% and 18%, respectively, compared to those who had never used non-users of any cigarette products. The association between daily EC consumption and the development of respiratory symptoms, as well as COPD, demonstrated a significant J-shaped pattern. The potential adverse association between the consumption of ECs, particularly when used in combination with combustible cigarettes, and the development of respiratory symptoms and COPD necessitates careful consideration. Policymakers should approach ECs cautiously as a prospective smoking cessation tool.

Exploring Patients' Intentions for Usage of Video Telemedicine Follow-Up Services: Cross-Sectional Study.

Background: Data suggest that regarding completion rates and lower readmission rates, video telemedicine follow-up is as efficient as in-person consultations. However, evidence of patients' intention to adopt such service is lacking. The objective of this study was to determine the essential factors influencing Chinese patients' intention to adopt video telemedicine follow-up. Methods: The researchers extended the technology acceptance model (TAM) by incorporating trust, subjective norms (SNs), perceived risk (PR), and perceived disease threat (PDT). A survey was conducted with 793 Chinese patients, and the collected data were analyzed using the partial least-squares approach. Results: The study revealed that trust emerged as the strongest factor influencing patients' behavioral intention (BI) to use video telemedicine follow-up, followed by SNs, perceived ease of use (PEOU), and perceived usefulness (PU). PR and PDT had no significant influence on patients' intention to adopt video telemedicine follow-up. PEOU mediated the relationship between trust, SNs, and BI, and PU mediated the relationship between trust and BI. The study also found that gender, age, and usage experience moderated certain relationships in the model. Conclusions: Our findings support the use of the extended TAM in understanding individual's motivations for using video telemedicine follow-up in China. In addition, this study contributes to the existing literature on telemedicine promotion by identifying significant mediation mechanisms. These findings have practical implications for planning, creating, and implementing improved video telemedicine follow-up services.

Effect of cardiac function in patients with gastrointestinal cancer with or without acute kidney injury assessed using a non-invasive impedance cardiography: a case-control study.

OBJECTIVES: This study aimed to analyze the possible causes of changes in cardiac function and investigate the feasibility of clinical assessment of gastrointestinal cancer in patients with or without acute kidney injury (AKI) assessed using a non-invasive impedance cardiography (ICG, Bioz. Cardio Dynamics, USA) to identify independent risk factors. METHODS: Patients admitted to the Fourth Hospital of Hebei Medical University, China, between May 1, 2019, and February 15, 2022, were included in this study. A total of 51 patients with gastrointestinal cancer (31 men and 20 women, mean age 61.1 ± 10.9 years) with or without AKI were evaluated for ICG. A total of 19 patients underwent ultrasound cardiography (UCG) and ICG evaluations. RESULT: There was a significant positive correlation between cardiac output (CO), cardiac index (CI), stroke volume (SV), left cardiac work index (LCWI), and ejection fraction (EF) measured using UCG and ICG. The relationship was observed between COICG and COUCG (r = 0.707, P = 0.001), CIICG and CIUCG (r = 0.718, P = 0.001), SVICG and SVUCG (r = 0.837, P < 0.001), and LCWIICG and EFUCG (r = 0.540, P = 0.017). Cardiac function parameters measured using ICG were statistically different between patients with gastrointestinal cancer with or without AKI (P ≤ 0.05). Multivariate analysis revealed that AKI independently affects cardiac function in patients with gastrointestinal cancer. CONCLUSIONS: UCG and ICG methods are significantly associated with cardiac function in patients with or without AKI, and patients with gastrointestinal cancer with AKI are worse than those without AKI. AKI is an independent risk factor for cardiac function in patients with gastrointestinal cancer.

Protective effects of low-intensity pulsed ultrasound (LIPUS) against cerebral ischemic stroke in mice by promoting brain vascular remodeling via the inhibition of ROCK1/p-MLC2 signaling pathway.

Vascular remodeling is essential for patients with cerebral ischemic stroke (CIS). Our previous study proved that low-intensity pulsed ultrasound (LIPUS) could increase cortical hemodynamics. However, the effects and mechanisms of LIPUS on cerebral vascular remodeling after CIS are still unknown. In this study, we applied LIPUS to the mouse brain at 0.5 h after distal middle cerebral artery occlusion (dMCAO) and subsequently daily for a stimulation time of 30 min. Results showed that compared with the dMCAO group, LIPUS markedly increased cerebral blood flow (CBF), reduced brain swelling, and improved functional recovery at day 3 after CIS. LIPUS promoted leptomeningeal vasculature remodeling, enlarged vascular diameter, and increased the average vessel length and density at day 3 after CIS. Proteomic analysis highlighted that LIPUS mainly participated in the regulation of actin cytoskeleton pathway. Rho kinase 1 (ROCK1) was downregulated by LIPUS and participated in regulation of actin cytoskeleton. Subsequently, we verified that ROCK1 was mainly expressed in pericytes. Furthermore, we demonstrated that LIPUS inhibited ROCK1/p-MLC2 signaling pathway after CIS, which had positive effects on vascular remodeling and cerebral blood circulation. In conclusion, our preliminary study revealed the vascular remodeling effects and mechanism of LIPUS in CIS, provided evidence for potential clinical application of LIPUS.

MiR-217-5p inhibits smog (PM2.5)-induced inflammation and oxidative stress response of mouse lung tissues and macrophages through targeting STAT1.

OBJECTIVE: To explore the roles of macrophages' miR-217-5p in the process of PM2.5 induced acute lung injury. METHODS: GEO database and KEGG pathway enrichment analysis as well as GSEA were used to predicted the miRNA and associated target signals. And then mice and RAW246.7 macrophages treated with PM2.5 to imitate PM2.5 induced acute lung injury environment and then transfected with miR-217-5p NC or miR-217-5p mimic. The levels of inflammatory factors TNF-α and anti-inflammatory factor IL-10 of mice serum were tested by ELISA. And the pathological changes and ROS level of mouse lung tissues were stained by HE and DHE staining. The proteins expression of phosphorylated-STAT1, total-STAT1, TNF-α, IFN-γ as well as p47, gp91, NOX4 in mice or RAW264.7 cells were tested by western blot or immunofluorescence of RAW264.7 cell slides. RESULTS: The results of bioinformatics analysis indicated the miR-217 as well as STAT1 were involved PM2.5 associated lung injury. After exposure to PM2.5, the decreased levels of serum TNF-α but not IL-10, consistent with reduced macrophages' accumulation as well as decreased ROS levels in lung tissues in miR-217-5p mimic group vs miR-217-5p NC group mice, and moreover, the protein expression levels of phosphorylated--STAT1, total-STAT1, TNF-α, IFN-γ, p47, gp91 and NOX4 in mouse lung tissues and RTAW246.7 macrophages cells were all significantly reduced with miR-217-5p mimic administration. The above phenomena were reversed by specific STAT1-inhibitor HY-N8107. CONCLUSIONS: miR-217-5p suppressed the activated STAT1-signal induced inflammation and oxidative stress trigged by PM2.5 in macrophages and resulted in the decreased lung injure caused by PM2.5.

Establishment of two canine models of benign airway stenosis and the effect of mitomycin C on airway stenosis.

OBJECTIVES: Cuffed endotracheal intubation and stent implantation were employed to simulate two types of benign airway stenosis and further to analysis the different features between them from trachecscopic characteristics, gross anatomy to histopathological changes. In addition, our study explored the therapeutic effect of mitomycin C at different concentrations on granulation tissue caused by stent implantation in order to provide a new therapeutic strategy for clinical treatment of benign airway stenosis. METHODS: Twelve beagle dogs were randomly divided into four groups, with three dogs in each group. Group A: Three beagle dogs were intubated through oral trachea after general anesthesia and cuff pressure maintained at 200 mmHg for 24 h. Group B, Group C and Group D: endotracheal coated self-expanding metal stents were placed after general anesthesia under the guidance of bronchoscope. On the Day7 after stent implantation, Group B, as control group, was injected phosphate buffer solution of 1 ml into granulation tissue at the end of stent; Group C was injected mitomycin C of 1 ml at 0.4 mg/ml and Group D was injected mitomycin C of 1 ml at 0.8 mg/ml into granulation tissue at the end of metal airway stent respectively, the same method as Group B. Bronchoscopy was used to observe tracheal lumen on the seventh day, fourteenth day and twenty-first day after modeling and pathological changes were examined on twenty-first day. RESULTS: Two models of benign airway stenosis can be established by cuffed endotracheal intubation and stent implantation. There was tracheal rupture in the trachea cartiage ring in the cuffed endotracheal intubation group, but was't in stent implantation group. Histopathological characteristics were different between cuffed endotracheal intubation and stent implantation groups. In stent placement groups, we found that the stenosis degree of mitomycin C at 0.4 mg/ml was approximately 19%-32%, mitomycin C at 0.8 mg/ml was approximately 16%-21% and the control group was approximately 36%-47%. CONCLUSION: The two models of canine benign tracheal stenosis induced by cuffed endotracheal intubation and stent implantation are relatively simple, reliable and reproducible and have different characteristics. Mitomycin C could inhibit proliferation of granulation tissue and attenuate the degree of airway stenosis caused by stent implantation.

Effect of high-level fine particulate matter and its interaction with meteorological factors on AECOPD in Shijiazhuang, China.

Epidemiological evidence of the effect of high-level air pollution and its interaction with meteorological factors on the risk of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is limited. Daily data on AECOPD cases, air pollutants and meteorological factors were collected from 2015 to 2018 in Shijiazhuang. A distributed lag non-linear model (DLNM) was used to explore the lag and cumulative effect of PM2.5 on the risk of AECOPD. The effect of the interaction between PM2.5 and meteorological factors on AECOPD was estimated by a generalized additive model (GAM) and a stratification model. A total of 4766 patients with AECOPD were enrolled. After controlling for confounders, each 10 µg/m3 increase in PM2.5 led to a 5.8% increase in the risk of AECOPD on day lag 0. The cumulative effect of PM2.5 on AECOPD risk showed an increasing trend after 3 days. Similar results were observed in both smoking and non-smoking patients. There was an interaction between PM2.5 and meteorological factors, and the risk of AECOPD was higher in cold and lower humidity conditions than in other conditions. High-level PM2.5 exposure is positively associated with the risk of AECOPD onset, and the effect of PM2.5 can be modified by the temperature and relative humidity. Public health guidelines should pay close attention to AECOPD risk under the condition of high-level PM2.5 with low temperature or low humidity.

SET8, a novel regulator to ameliorate vascular calcification via activating PI3K/Akt mediated anti-apoptotic effects.

Previous studies have shown that the apoptosis of vascular smooth muscle cells (VSMCs) underlies the mechanism of pathological calcification in patients with chronic kidney disease (CKD). SET domain-containing protein 8 (SET8) is an efficient protein that modulates apoptosis in hepatocellular carcinoma cells, esophageal squamous cells, and neuronal cells by regulating pathological processes, such as cell cycle progression and transcription regulation. However, whether SET8 is involved in high phosphorus-induced vascular calcification by mediating apoptosis remains unclear. Here, we report that SET8 is located both in the nucleus and cytoplasm and is significantly downregulated in calcification models. SET8 deficiency promoted apoptosis of VSMCs, as indicated by the increased Bax/Bcl-2 and cleaved caspase-3/total caspase-3 ratios. Mechanistically, the PI3K/Akt pathway was mediated by SET8, and inhibition of the PI3K/Akt signaling pathway by administering LY294002 or transfecting the Akt phosphorylation-inactivated mutation plasmid increased apoptosis and calcification. Akt phosphorylation constitutively activated mutations can reduce the apoptosis and calcification of VSMCs. Furthermore, exogenous overexpression of SET8 reversed the effect of PI3K/Akt inhibition on VSMC apoptosis and calcification. In summary, our research suggests that SET8 overexpression ameliorates high phosphorus-induced calcification of VSMCs by activating PI3K/Akt mediated anti-apoptotic effects.

Ultrasonic thalamic stimulation modulates neural activity of thalamus and motor cortex in the mouse.

Objective.Previous studies have demonstrated that ultrasound thalamic stimulation (UTS) can treat disorders of consciousness. However, it is still unclear how UTS modulates neural activity in the thalamus and cortex.Approach.In this study, we performed UTS in mice and recorded the neural activities including spike and local field potential (LFP) of the thalamus and motor cortex (M1). We analyzed the firing rate of spikes and the power spectrum of LFPs and evaluated the coupling relationship between LFPs from the thalamus and M1 with Granger causality.Main results.Our results clearly indicate that UTS can directly induce neural activity in the thalamus and indirectly induce neural activity in the M1. We also found that there is a strong connection relationship of neural activity between thalamus and M1 under UTS.Significance.These results demonstrate that UTS can modulate the neural activity of the thalamus and M1 in mice. It has the potential to provide guidance for the ultrasound treatment of thalamus-related diseases.

MicroRNA-103a regulates the calcification of vascular smooth muscle cells by targeting runt-related transcription factor 2 in high phosphorus conditions.

Vascular calcification, such as atherosclerosis, is a serious complication of chronic kidney disease that is characterized by tunica media calcification, and has gained increasing attention from researchers. The commonly observed association between vascular calcification and osteoporosis suggests a link between bone and vascular disorders. As microRNAs (miRNAs) have a wide range of gene regulation functions, such as cell proliferation, apoptosis, stress and transdifferentiation, the current study aimed to determine whether miRNAs play a vital role in the calcification and osteoblastic differentiation of rat thoracic aorta vascular smooth muscle cells (VSMCs). Gene expression analysis was performed on seven miRNAs (miR-29a, -30b, -103a, -125b, -133a, -143 and -211) that maybe potentially involved in the differentiation of smooth muscle cells into osteoblastic cells. The results showed that the levels of miR-29a, -30b, -103a, -125b and -143 were markedly reduced in the VSMC calcification model, particularly miR-103a, whereas runt-related transcription factor 2 (RUNX2) expression was increased. Furthermore, it was found that the expression of RUNX2 was significantly decreased following the upregulation of miR-103a, and that the expression of RUNX2 was significantly increased by downregulating miR-103a in VSMCs. Therefore, it was concluded that miR-103a plays a notable role in the transdifferentiation of the VSMCs in high phosphorus-induced calcification by targeting the regulation of RUNX2, and may therefore constitute a new target for the diagnosis and treatment of vascular calcification.

The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to alkalinization-induced vascular calcification in vitro.

OBJECTIVE: In order to find new strategies for the prevention of vascular calcification in uremic individuals especially treated by dialysis and develop novel therapeutic targets in vascular calcification, we explore the role of KCa3.1 in alkalinization-induced VSMCs calcification in vitro. METHOD: Rat VSMCs calcification model was established by beta-glycerophosphate (ß-GP, 10 mM) induction. The pH of Dulbecco's modified Eagle's medium (DMEM) was adjusted every 24 h with 10 mM HCl or 10 mM NaHCO3 . The mineralization was measured by Alizarin Red staining and O-cresolphthalein complex one method. mRNA and protein expression were detected by RT-PCR and Western blot or immunofluorescence. Ca2+ influx was measured by Elisa. RESULT: The results indicated that alkalization induced an increase in Ca2+ influx to enhance VSMCs calcification. Furthermore, the increase of calcification was associated with the expression of KCa3.1 via advanced expression of osteoblastic differentiation markers alkaline phosphatase (ALP) and Runt-related transcription factor 2 (Runx2). Blocking KCa3.1 with TRAM-34 or shRNA vector can significantly lowered the effects of calcification in the activity of ALP and Runx2 expression. CONCLUSION: Together all, our studies suggested that alkalinization can promote vascular calcification by upregulating KCa3.1 channel and enhancing osteogenic/chondrogenic differentiation by upregulating Runx2. The specific inhibitor TRAM-34 and KCa3.1-shRNA ameliorated VSMCs calcification by downregulating KCa3.1.

Novel insights into the role of BRD4 in fine particulate matter induced airway hyperresponsiveness.

Epidemiological research has identified that exposure to fine particulate matter (PM2.5) can increase airway hyperresponsiveness (AHR) which is considered a typical characteristic of asthma. Although the effect of PM2.5 on AHR has been elucidated to a certain degree, its exact mechanism remains unclear. Bromodomain-containing protein 4 (BRD4) is recognized as a member of the bromodomain and extraterminal (BET) family, with the ability to maintain higher-order chromatin configuration and regulate gene expression programs. The primary objective of our study was to examine the role of BRD4 in AHR triggered by PM2.5, and to elucidate its possible molecular mechanism. A mouse model with AHR was established using a nose-only PM2.5 exposure system. We observed that PM2.5 enhanced AHR in the experimental group compared to the control group, and this alteration was accompanied by increased lung inflammation and BRD4 expression in bronchi-lung tissue. However, the BRD4 inhibitor (ZL0420) could alleviate the aforementioned alterations in the mouse model with PM2.5 exposure. To explore the exact molecular mechanism, we further examined the role of BRD4 in human airway smooth muscle cells (hASMCs) after exposure to PM2.5 DMSO extracts. We found that PM2.5 DMSO extracts, which promoted the contraction and migration of hASMCs, was accompanied by an increase in the levels of BRD4, kallikrein 14 (KLK14), bradykinin 2 receptor (B2R), matrix metalloproteinases2(MMP-2), matrix metalloproteinases9(MMP-9), vimentin and bradykinin (BK) secretion, while ZL0420 and BRD4 gene silencing could reverse this response. In summary, these results demonstrate that BRD4 is an important player in AHR triggered by PM2.5, and BRD4 inhibition can ameliorate AHR induced by PM2.5. In addition, PM2.5 DMSO extracts can promote the contraction and migration of hASMCs by increasing BRD4 expression.

Ghrelin ameliorates chronic obstructive pulmonary disease-associated infllammation and autophagy.

Chronic obstructive pulmonary disease (COPD) is a chronic and devastating condition characterized by poor airflow and breath. Smoking and other environmental factors-caused inflammations triggered excessive autophagy of normal lung epithelial cells, eventually leading to impaired lung functions. Previous studies showed that ghrelin exhibited beneficial effects on patients with COPD. However, the mechanisms underlying this impact remained largely unknown. In this study, in vitro and in vivo models of COPD-associated inflammation were established, and we found that inflammation and autophagy were abonormally activated through nuclear factor kappa b (NF-κB) and activator protein-1 (AP-1) signaling pathways. Interestingly, ghrelin could inhibit the excessive inflammation pathways and autophagy induced by particle matter and/or cigarette extract in bronchial epithelial cells. Furthermore, NF-κB and AP-1 signaling were both inhibited while lung functions were significantly improved. Taken together, identification of downstream signaling of ghrelin in inflammation provided a new avenue in the treatment of COPD.

Identification of a genome-wide serum microRNA expression profile as potential noninvasive biomarkers for chronic kidney disease using next-generation sequencing.

OBJECTIVE: To identify serum microRNAs (miRNAs) as potential non-invasive biomarkers for patients with chronic kidney disease (CKD). METHODS: We collected serum samples from healthy controls, CKD stage 1 (CKD1), and stage 5 (CKD5) patients with primary glomerulonephritis (GN), screened differentially expressed miRNAs (DEMs) using next-generation sequencing (NGS), and confirmed the sequencing data using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS: We identified 20 and 42 DEMs in the CKD1 and CKD5 patients compared with the controls, respectively, and 70 DEMs in the CKD5 compared with the CKD1 patients. The qRT-PCR results showed that miR-483-5p was up-regulated in the CKD1 and CKD5 patients compared with controls (fold change = 2.56 and 18.77, respectively). miR-363-3p was down-regulated in the CKD5 patients compared with the controls and CKD1 patients (fold change = 0.27 and 0.48, respectively). CONCLUSION: We identified a genome-wide serum miRNA expression profile in CKD patients, and serum miR-483-5p and miR-363-3p may act as potential diagnostic biomarkers for CKD.

Antagonism of interleukin 17 protects chronic obstructive pulmonary disease rat lungs from adverse effects of environmental PM2.5.

Severe air pollution has raised concerns about the adverse effects of particulate matters 2.5 µm in size (PM2.5) on human health. However, the mechanisms elucidating how PM2.5 affects lungs, especially in COPD, remain unclear. In this study, we examined the concentration changes of environmental PM2.5 from 2013 to 2019 in Shijiazhuang city. PM2.5 was collected to study its effects on a COPD lung. Inflammatory factors present in bronchoalveolar lavage fluid (BLF) were examined after exposure. An antagonist of IL-17 was used to reverse PM2.5-induced pathological and functional impairments in COPD rat lungs. Our results show that the degree of air pollution changed significantly (55.873, P < 0.001) during the study period in accordance with PM tendency. PM2.5 and PM10 was present in higher concentrations from December 2013 to January 2014 and December 2016 to January 2017, respectively. After COPD rats were exposed to PM2.5 for 2 or 4 weeks, all indicators of lung function (FEV0.3, FVC, FEV0.3/FVC, PEF, Rrs) decreased continuously and significantly. The levels of TGF-ß1, IL-6, IL-17, and IL-21 in BLF, as well as the expression of IL-17 in lung tissues, were significantly increased after exposure for 2 or 4 weeks. When an IL-17 antagonist was introduced following PM2.5 exposure, inflammatory factor levels in BLF and pathological scores of lung tissues decreased significantly. Moreover, lung functions were partially rescued. Collectively, our data demonstrate that IL-17 is a potential therapeutic target for COPD lungs after PM2.5 exposure.

LRRCA8A and ANO1 contribute to serum-induced VRAC in a Ca2+-dependent manners.

The volume-regulated anion channel (VRAC) plays a central role in maintaining cell volume in response to osmotic stress. Leucine-rich repeat-containing 8A (LRRC8A) was recently identified as an essential component of VRAC although other Cl- channels were also suggested to contribute to VRAC. VRAC is activated when a cell is challenged with a hypotonic environment or even in isotonic conditions challenged with different stimuli. It is not clear how VRAC is activated and whether activation of VRAC in hypotonic and isotonic conditions share the same mechanism. In this present study, we investigated relative contribution of LRRC8A and anoctamin 1(ANO1) to VRAC currents activated by fetal bovine serum (FBS) in isotonic condition, and studied the role of intracellular Ca2+ in this activation. We used CRISPR/Cas9 gene editing approach, electrophysiology, and pharmacology approaches to show that VRAC currents induced by FBS is mostly mediated by LRRC8A in HEK293 cells, but also with significant contribution from ANO1. FBS induces Ca2+ transients and these Ca2+ signals are required for the activation of VRAC by serum. These findings will help to further understand the mechanism in activation of VRAC.

Fine particulate matter increases airway hyperresponsiveness through kallikrein-bradykinin pathway.

Epidemiological studies have reported short-term fine particulate matter (PM2.5) exposure to increase incidence of asthma, related to the increase of airway hyperresponsiveness (AHR); however, the underlying mechanism remains unclear. Aim of this study was to elucidate the role of kallikrein in PM2.5-induced airway hyperresponsiveness and understand the underlying mechanism. Nose-only PM2.5 exposure system was used to generate a mouse model of airway hyperresponsiveness. Compared with the control group, PM2.5 exposure could significantly increase airway resistance, lung inflammation, kallikrein expression of bronchi-lung tissue and bradykinin (BK) secretion. However, these changes could be alleviated by kallikrein inhibitor. In addition，PM2.5 could increase the viability of human airway smooth muscle cells (hASMCs), accompanied by increased expression of kallikrein 14 (Klk14), bradykinin 2 receptor (B2R), bradykinin secretion and cytosol calcium level, while kallikrein 14 gene knockdown could significantly amelioratethe above response induced by PM2.5. Taken together, the data suggested kallikrein to play a key role in PM2.5-induced airway hyperresponsiveness, and that it could be a potential therapeutic target in asthma.

CT-Radiomic Approach to Predict G1/2 Nonfunctional Pancreatic Neuroendocrine Tumor.

RATIONALE AND OBJECTIVES: Tumor grading of nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) determines the choice of clinical treatment and management. The pathological grade of pancreatic neuroendocrine tumors is usually assessed on postoperative specimens. The goal of our study is to establish a tumor grade (G) prediction model for preoperative G1/2 NF-pNETs using radiomics for multislice spiral CT image analysis. MATERIALS AND METHODS: This retrospective study included a primary cohort of 59 patients and an independent validation cohort of 40 consecutive patients; their multislice spiral CT images were collected from October 2012 to October 2016 and October 2016 to June 2018, respectively. All 99 patients were diagnosed with clinicopathologically confirmed NF-pNETs. Most significant radiomic features were selected using the minimum redundancy and maximum relevance algorithm. Support vector machine classifier with a radial basis function-based predictive model was subsequently developed for clinical use. RESULTS: A total of 585 radiomics features were extracted from every phase for each patient. Six of these radiomics features were identified as most discriminant features for G1 and G2 tumors and used to construct the tumor grade prediction model. The prediction model resulted in the area under the curve values of 0.968 (95% CI: 0.900-0.991) and 0.876 (95% CI: 0.700-0.963) for the training cohort and validation cohort, respectively. Sensitivity and specificity were 96.4% and 83.9%, and 90.9% and 88.9% for the training and validation cohorts, respectively. The decision curves indicated that if the threshold probability is above 0.1, using the rad-score in the current study on G1/2 NF-pNETs is more beneficial than the treat-all-patients scheme or the treat-none scheme. CONCLUSION: Radiomics developed with a combination of nonenhanced and portal venous phases can achieve favorable predictive accuracy for histological grade for G1/G2 NF-pNETs.