Publisher Correction: K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8+ T cell activation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8(+) T cell activation.

The key molecular mechanisms that control signaling via T cell antigen receptors (TCRs) remain to be fully elucidated. Here we found that Nrdp1, a ring finger-type E3 ligase, mediated Lys33 (K33)-linked polyubiquitination of the signaling kinase Zap70 and promoted the dephosphorylation of Zap70 by the acidic phosphatase-like proteins Sts1 and Sts2 and thereby terminated early TCR signaling in CD8(+) T cells. Nrdp1 deficiency significantly promoted the activation of naive CD8(+) T cells but not that of naive CD4(+) T cells after engagement of the TCR. Nrdp1 interacted with Zap70 and with Sts1 and Sts2 and connected K33 linkage of Zap70 to Sts1- and Sts2-mediated dephosphorylation. Our study suggests that Nrdp1 terminates early TCR signaling by inactivating Zap70 and provides new mechanistic insights into the non-proteolytic regulation of TCR signaling by E3 ligases.

Engineering an Almost All-Waterborne System for Transparent yet Superhydrophobic Surfaces with High Liquid Impalement Resistance.

Realistically, green manufacturing of transparent superhydrophobic surfaces (SHSs) and high liquid impalement resistance for outdoor engineering are very necessary but pretty challenging. To address this, an almost all-waterborne system composed of synthesized partially open-cage fluorinated polyhedral oligomeric silsesquioxane bearing a pair of -OH (poc-FPOSS-2OH), silica sol, and resin precursor is engineered. The transparent SHSs facilely formed by this system are featured with the exclusive presence of wrapped silica nanoparticle (SiNP) dendritic networks at solid-gas interfaces. The wrapped SiNP dendritic networks have a small aggregation size and low distribution depth, making SHSs highly transparent. The Si-O polymeric wrappers render mechanical flexibility to SiNP dendritic networks and thus enable transparent SHSs to resist high-speed water jet impinging with a Weber number of ≥19 800 in conjunction with the extremely low-surface-energy poc-FPOSS-2OH, which is the highest liquid impalement resistance so far among waterborne SHSs, and can rival the state-of-the-art solventborne SHSs.

Combination therapy with long-acting bronchodilators and the risk of major adverse cardiovascular events in patients with COPD: a systematic review and meta-analysis.

INTRODUCTION: Accumulated high-quality data from randomised controlled trials (RCTs) indicate that long-acting muscarinic antagonist (LAMA)/long-acting ß2 agonist (LABA) combination therapy significantly improves clinical symptoms and health status in patients with chronic obstructive pulmonary disease (COPD) and reduces exacerbation risk. However, there is a growing concern that LAMA/LABA therapy may increase the risk of cardiovascular disease in patients with COPD. The aim of this paper is to determine whether the use of LAMA/LABA combination therapy modifies the risk of cardiovascular disease in patients with COPD. METHODS: Two reviewers independently searched Embase, PubMed and Cochrane Library to identify relevant RCTs of LAMA/LABA or LABA/LAMA/inhaled corticosteroids (ICS) for the management of patients with COPD that reported on cardiovascular end-points. The primary outcome was major adverse cardiovascular events (MACE), which was a composite of cardiovascular death, myocardial infarction or stroke. RESULTS: A total of 51 RCTs enrolling 91 021 subjects were analysed. Both dual LAMA/LABA (1.6% versus 1.3%; relative risk 1.42, 95% CI 1.11-1.81) and triple therapy (1.6% versus 1.4%; relative risk 1.29, 95% CI 1.03-1.61) significantly increased the risk of MACE compared with ICS/LABA. The excess risk was most evident in RCTs in which the average underlying baseline risk for MACE was >1% per year. Compared with LAMA only, LABA only or placebo, dual LAMA/LABA therapy did not significantly increase the risk of MACE, though these comparisons may have lacked sufficient statistical power. CONCLUSION: Compared with ICS/LABA, dual LAMA/LABA or triple therapy increases cardiovascular risk in patients with COPD. This should be considered in the context of the incremental benefits of these therapies for symptoms and exacerbation rates in patients with COPD, especially in those with a MACE risk of >1% per year.

The E3 ubiquitin ligase Nrdp1 'preferentially' promotes TLR-mediated production of type I interferon.

E3 ubiquitin ligases are important in both innate and adaptive immunity. Here we report that Nrdp1, an E3 ubiquitin ligase, inhibited the production of proinflammatory cytokines but increased interferon-beta production in Toll-like receptor-triggered macrophages by suppressing adaptor MyD88-dependent activation of transcription factors NF-kappaB and AP-1 while promoting activation of the kinase TBK1 and transcription factor IRF3. Nrdp1 directly bound and polyubiquitinated MyD88 and TBK1, which led to degradation of MyD88 and activation of TBK1. Knockdown of Nrdp1 inhibited the degradation of MyD88 and the activation of TBK1 and IRF3. Nrdp1-transgenic mice showed resistance to lipopolysaccharide-induced endotoxin shock and to infection with vesicular stomatitis virus. Our data suggest that Nrdp1 functions as both an adaptor protein and an E3 unbiquitin ligase to regulate TLR responses in different ways.

Development of an optical microfiber immunosensor for prostate specific antigen analysis using a high-order-diffraction long period grating.

Fiber-optic biosensors are of great interest to many bio/chemical sensing applications. In this study, we demonstrate a high-order-diffraction long period grating (HOD-LPG) for the detection of prostate specific antigen (PSA). A HOD-LPG with a period number of less than ten and an elongated grating pitch could realize a temperature-insensitive and bending-independent biosensor. The bio-functionalized HOD-LPG was capable of detecting PSA in phosphate buffered saline with concentrations ranging from 5 to 500 ng/ml and exhibited excellent specificity. A limit of detection of 9.9 ng/ml was achieved, which is promising for analysis of the prostate specific antigen.

A universal strategy: Rational construction of noble metal nanoparticle-shell/conducting polymer nanofiber-core electrodes with enhanced electrochemical performances.

To address a challenge for decoration of noble metal nanoparticles (NMNPs)-shell on conducting polymer nanofiber (CPNF) electrodes (i.e. NMNP-shell/CPNF-core electrodes) for boosting electrochemical performances, a two-step strategy comprising chemical pre-deposition and electrochemical deposition is designed. The strategy shows a high universality in terms of the diversity of NMNP-shell elements (single-element: AgNP-shell, AuNP-shell, PtNP-shell, PdNP-shell; multi-element: Au/Pt/PdNP-shell) and the independence of conductive substrates of electrodes. The shells are composed of high-density NMNPs and have strong adhesion to CPNF-cores. It is demonstrated that in response to a specific applied electrical stimulus, the resulting low doping level of CPNFs facilitates the generation of high-density nucleation sites (small NMNPs) by chemical pre-deposition (as high capability of electron transfer and low resistance to electron transfer from CP chains to NM ions), which is indispensable for the formation of NMNP-shells on CPNF-cores by electrochemical deposition. The decoration of NMNP-shells can significantly enhance the electrochemical performances of CPNF electrodes. Moreover, the great practicality and reliability of NMNP-shell/CPNF-core electrodes in use as an electrocatalytic platform are confirmed. This universal strategy opens up a new avenue to construct high-dimension shell/core-nanostructured electrodes.

Association of tiotropium use and the risk of adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a meta-analysis of randomized controlled trials.

BACKGROUND: Tiotropium have been recommended as first-line maintenance therapy for chronic obstructive pulmonary disease (COPD) to reduce the frequency, duration, and severity of exacerbations and improve quality of life. Recently, it was reported that tiotropium use might link to cardiovascular risk in COPD patients. But it is controversial. We aimed to clarify the associations between tiotropium use and cardiovascular risk in patients with COPD. METHODS: We searched PubMed, EMBASE, Cochrane Library, and Clinical Trials.gov to identify potentially relevant articles. We included randomized controlled trials of any inhaled tiotropium versus non-anticholinergic treatment for COPD, with reporting of cardiovascular events as an adverse event. We conducted meta-analyses by the Peto and Mantel-Haenszel approaches with corresponding 95% CIs. RESULTS: Our work included 20 RCTs with more than 27,699 subjects. Pooled results indicated that tiotropium treatment did not increase the risk of cardiovascular events (Peto OR, 0.97, 95% CI, 0.84-1.12; I2 = 0%), overall mortality (RD, 0.00, 95% CI, - 0.00-0.01; I2 = 68%), and cardiovascular mortality (Peto OR, 1.58, 95% CI, 0.92-2.74; I2 = 0%) compared with controls. Then, subgroup analysis was performed according to the type of controls. The pooled results were consistent with the above (tiotropium vs LABA: Peto OR, 0.98, 95% CI, 0.81-1.19; I2 = 17%) (tiotropium vs placebo: Peto OR, 0.92, 95% CI, 0.75-1.44; I2 = 15%). In addition, there was also no association between cardiovascular risk and duration of tiotropium treatment. CONCLUSIONS: Inhaled tiotropium does not increase the risk of cardiovascular events and cardiovascular mortality in patients with COPD.

Benefits and risks of low molecular weight heparin in patients with acute exacerbation of chronic obstructive pulmonary disease: a meta-analysis of randomized controlled trials.

BACKGROUND: Low molecular weight heparin (LMWH) is an anticoagulant that has recently been found benefit in the acute exacerbation stage of chronic obstructive pulmonary disease (COPD). But its efficacy is controversial. The objective of this paper is to compare the harm/benefit of LMWH combined with conventional therapy versus single conventional therapy in the acute exacerbation stage of COPD. METHODS: PubMed, Cochrane Library, EMBASE, CNKI, and Clinical Trials.gov were searched from inception until March 2019. Randomized control trials were included if they reported the use of LMWH for the treatment of COPD. Continuous variable data were reported as mean difference (MD), risk difference (RD), and Peto odds ratio (OR) with corresponding 95% CIs. RESULTS: Twelve RCTs (N = 1086 subjects) were included in the meta-analysis. Pooled results exhibited that LMWH treatment significantly improved the levels of arterial partial pressure of oxygen (PaO2) (MD = 4.58, 95% CI: 1.78-7.39, P = 0.001), forced expiratory volume in 1 s (FEV1) (MD = 0.19, 95% CI: 0.09-0.29, P = 0.0002), and FEV1/forced vital capacity (FVC) (MD = 10.44, 95% CI: 5.40-15.48, P < 0.0001), and significantly reduced the risk of thrombosis (RD, - 0.03; 95% CI, - 0.07 to 0.00; P = 0.05). There was a marginally but nonsignificant improvement in PaCO2 levels vs non-LMWH treatment. Moreover, pooled results exhibited that LMWH may increase the risk of hemorrhage. Subgroup analyses exhibited that LMWH treatment only was associated with a significantly increased risk of minor bleeding but not major hemorrhage. CONCLUSIONS: When compared with single conventional therapy, addition of LMWH to conventional therapy may provide more clinical benefits in the acute exacerbation stage of COPD.

Optical Microfiber Reader for Enzyme-Linked Immunosorbent Assay.

In clinical diagnosis, accurate and reliable measurement technologies for the detection of disease biomarkers at ultralow concentrations can provide guidance for the initiation of treatment and potentially improve survival for patients. Here, we demonstrate an optical microfiber reader for enhanced analytical sensitivity in enzyme-linked immunosorbent assays (ELISA) that enables the detection of tiny changes of the refractive index (RI) induced by the catalyzed oxidation of substrate, owing to the strong interaction between the evanescent field and surrounding medium. By employing the microfiber reader for the C-reaction protein (CRP) and interleukin-6 (IL-6) assays after the enzymatic signal amplification in ELISA, we experimentally investigate the biosensing capacity of the device. As a result, log-linear relations of CRP and IL-6 detection in PBS and human serum between the concentration and spectral response were obtained at both nanogram and picogram levels, respectively, and anti-CRP/HRP detection as low as 9.75 pg/mL was achieved, which was undetectable by the conventional spectrophotometry. With a stable, accurate, and color-free detection capacity, this optical microfiber reader has a promising prospect in early disease diagnosis and clinical treatment.

Ultrasensitive sensing in air based on Sagnac interferometer working at group birefringence turning point.

In this paper, a gas refractometer based on microfiber Sagnac interferometer is demonstrated, which can achieve an ultrahigh sensitivity when operating at the group birefringence turning point. We undertake a theoretical analysis and a simulated calculation to study the device characteristics and obtain the specific parameters of ellipticity and long axis of the elliptic microfiber for the group birefringence turning point. In the experiment, we obtain a positive sensitivity of 0.295 nm/KPa and a negative sensitivity of -0.219 nm/KPa during gas pressure and refractive index (RI) sensing, the obtained highest RI sensitivity can reach 160,938.9 nm/RIU. To further reveal its practical potential in gas detection, we conduct CO2 gas concentration detection and the device also demonstrates ultrahigh sensitivity and good repeatability. Besides, temperature sensing is performed to explore its temperature response wherein it shows a sensitivity of 486.7 pm/ °C. These results show its potential for use in gas- and acoustic-sensing applications.

Ultra-high sensitivity of dual dispersion turning point taper-based Mach-Zehnder interferometer.

We present here a detailed investigation into the sensitivity of the taper-based Mach-Zehnder interferometer as a function of external refractive index, with particular attention to the dispersion turning point (DTP) and possibilities for ultra-sensitive sensors. Our numerical simulation revealed that two DTPs exist with a decrease in the microfiber waist diameter; given this relationship, it is possible to obtain an ultra-sensitive operation. We then conducted experiments with fabricated devices with different waist diameters to achieve both positive and negative sensitivities at two DTPs. In particular, we achieved an ultrahigh refractive index sensitivity of approximately 95,832 nm/RIU at the second DTP when working with a diameter of 1.87 µm around the RI of air. These results show its potential for use in acoustic sensing and biochemical detection.

Inhaled corticosteroids and risk of upper respiratory tract infection in patients with asthma: a meta-analysis.

BACKGROUND: Recent studies have suggested a possible association between respiratory infection and the use of inhaled corticosteroids (ICS). We aimed to ascertain the risk of upper respiratory tract infection (URTI) with long-term inhaled corticosteroid use among patients with asthma. METHODS: Through a comprehensive literature search of PubMed, Cochrane Library, EMBASE, and Google Scholar from inception to May 2018, we included randomized controlled trials of any ICS vs. a control treatment for asthma, with reporting of URTI as an adverse event. We conducted meta-analyses by the Peto approaches to generate summary estimates comparing ICS with non-ICS treatment on the risk of URTI. RESULTS: Seventeen trials (15,336 subjects) were included. Compared with non-ICS treatment, ICSs were associated with a significantly increased risk of URTI (Peto OR, 1.24; 95% CI 1.08-1.42; I2 = 5%, p = 0.002). Subgroup analyses were performed for different dose, both high- and low-dose ICSs were associated with a significantly increased risk of URTI (high dose: Peto OR, 1.46; 95% CI 1.05-2.03; I2 = 0%; p = 0.03) (low dose: Peto OR, 1.20; 95% CI 1.04-1.39; I2 = 25%; p = 0.01). Moreover, fluticasone was observed with an increased risk of URTI (Peto OR, 1.18; 95% CI 1.02-1.38; p = 0.03; heterogeneity: I2 = 21%) but not budesonide, low-dose fluticasone treatment was associated with a significantly higher risk of URTI but not high dose. CONCLUSIONS: This study raises safety concerns about the risk of URTI associated with ICS use in patients with asthma, but it should be further investigated.

Cytoplasmic STAT4 Promotes Antiviral Type I IFN Production by Blocking CHIP-Mediated Degradation of RIG-I.

Retinoic acid-inducible gene I (RIG-I) signaling is critical to host innate immune response against RNA virus infection. Numerous factors use different mechanisms to regulate RIG-I signaling. In this study, we report that STAT family member STAT4 promotes RIG-I-triggered type I IFN production in antiviral innate immunity. Silencing of STAT4 impaired IFN-ß production in macrophages upon RNA virus infection, whereas overexpression of STAT4 enhanced RIG-I-induced IFN-ß promoter activation and IFN-stimulated response element activity. Silencing of STAT4 increased degradation of RIG-I. Interestingly, during RNA virus infection STAT4 was found to be constantly present in cytoplasm of macrophages without Tyr(693) phosphorylation, which is required for its classical activation and nuclear translocation. Mechanistically, cytoplasmic STAT4 could interact with E3 ligase CHIP and block RIG-I and CHIP association, preventing CHIP-mediated proteasomal degradation of RIG-I via K48-linked ubiquitination. Our study provides a new manner for posttranslational regulation of RIG-I signaling and identifies a previously unknown function of cytoplasm-localized STAT4 in antiviral innate immunity.

Long-term use of inhaled corticosteroids and risk of upper respiratory tract infection in chronic obstructive pulmonary disease: a meta-analysis.

Recent studies have suggested that inhaled corticosteroids (ICS) may be associated with higher risks of tuberculosis and pneumonia in patients with COPD. However, it is not known whether ICS increases the risk of upper respiratory tract infection (URTI). Aim of this study was to explore the relationship between ICS and URTI. Through a comprehensive literature search of PubMed, EMBASE, Cochrane Library, and Google Scholar from inception to March 2016, we identified randomized controlled trials of ICS therapy lasting at least 6 months. A meta-analysis by the Peto approach was also conducted to generate summary estimates comparing ICS with non-ICS treatment on the risk of URTI. A total of 14 studies involving 19,777 subjects were considered in the meta-analysis. Compared with non-ICS treatment, ICS were associated with a significantly increased risk of URTI (Peto OR: 1.16; 95% CI: 1.05-1.29; I2 = 9%; p = .004). Subgroup analyzes were performed for different dose, high-dose ICS was associated with a significantly increased risk of URTI (Peto OR: 1.19; 95% CI: 1.05-1.34; I2 = 0%; p = .005), whereas low-dose ICS showed a non-significant increased risk of URTI (Peto OR: 1.10; 95% CI: 0.91-1.33; I2 = 0%; p = .32). Moreover, fluticasone was observed with an increased risk of URTI but not mometasone; high-dose fluticasone treatment was associated with a significantly higher risk of URTI but not low-dose. These results suggested to us that ICS use may increase the risk of URTI in patients with COPD, but it should be further investigated.

Interaction between intestinal flora and gastric cancer in tumor microenvironment.

Gastric Cancer (GC) is a prevalent malignancy globally and is the third leading cause of cancer-related deaths. Recent researches focused on the correlation between intestinal flora and GC. Studies indicate that bacteria can influence the development of gastrointestinal tumors by releasing bacterial extracellular vesicles (BEVs). The Tumor microenvironment (TME) plays an important role in tumor survival, with the interaction between intestinal flora, BEVs, and TME directly impacting tumor progression. Moreover, recent studies have demonstrated that intestinal microflora and BEVs can modify TME to enhance the effectiveness of antitumor drugs. This review article provides an overview and comparison of the biological targets through which the intestinal microbiome regulates TME, laying the groundwork for potential applications in tumor diagnosis, treatment, and prognosis.