The causality between C-reactive protein and asthma: a two-sample Mendelian randomization analysis.

PURPOSE: This study sought to investigate the causal effects of circulating C-reactive protein (CRP) level on risk of asthma and its subtypes by two-sample Mendelian randomization (MR) analysis. METHODS: We utilized single nucleotide polymorphisms (SNPs) associated with both CRP and outcomes of asthma, allergic asthma, and obesity-related asthma as genetic variables via a genome-wide summary association study (GWAS). MR analysis mainly based on the inverse variance weighted (IVW) method was performed to infer the causal relationship between exposure and outcomes. Cochran's Q test and MR-Egger regression analysis were performed to determine respectively the heterogeneity and pleiotropy among instrumental variables (IVs), and leave-one-out analysis was conducted to determine the stability of the MR results. RESULTS: In our study, 42 SNPs were identified as IVs for MR analyses. According to the primary inference results by IVW methods, circulating CRP was demonstrated to be significantly associated with risk of asthma [odds ratio (OR): 1.046; 95% confidence interval (95% CI): 1.004-1.090; P = .030] and obesity-related asthma (OR: 1.072; 95% CI: 1.009-1.138; P = 0.025), whereas no distinct causality with allergic asthma was found (OR: 1.051; 95% CI: 0.994-1.112; P = .081). Sensitivity analyses indicated that there was no horizontal pleiotropy among IVs, and the MR results were proved to be robust by leave-one-out sensitivity analysis, despite the presence of heterogeneity. CONCLUSION: The present study suggested that higher CRP might genetically predict an increased risk of developing asthma and obesity-related asthma, without causality with allergic asthma.

Inhibition of Bcl-6 Expression Ameliorates Asthmatic Characteristics in Mice.

OBJECTIVE: The function of Bcl-6 in T follicular helper (Tfh) cell maturation is indispensable, and Tfh cells play a pivotal role in asthma. This study investigated the impact of Bcl-6 on asthmatic traits. METHODS: The microscopic pathological alterations, airway resistance (AR), and lung compliance (LC) were determined in asthmatic mice and Bcl-6 interference mice. The surface molecular markers of Tfh cells and the Bcl-6 mRNA and protein expression were determined by flow cytometry, RT-qPCR, and Western blotting, respectively. The relationships between the Tfh cell ratio and the IgE and IgG1 concentrations in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage fluid (BALF) were determined. RESULTS: Asthmatic inflammatory changes were observed in the lung tissue and were attenuated by Bcl-6 siRNA and dexamethasone (DXM). Asthmatic mice exhibited an increased AR and a decreased LC, while Bcl-6 siRNA or DXM mitigated these changes. The percentages of Tfh cells and eosinophils were significantly increased in the asthmatic mice, and they significantly decreased after Bcl-6 inhibition or DXM treatment. RT-qPCR and Western blotting analyses revealed that the Bcl-6 expression level in PBMCs was significantly higher in asthmatic mice, and it decreased following Bcl-6 inhibition or DXM treatment. The IgE expression in the serum and BALF and the B cell expression in PBMCs exhibited a similar trend. In asthmatic mice, the ratio of Tfh cells in the peripheral blood showed a strong positive correlation with the IgE levels in the serum and BALF, but not with the IgG1 levels. CONCLUSION: The amelioration of airway inflammation and airway hyper-responsiveness is achieved through Bcl-6 suppression, which effectively hinders Tfh cell differentiation, ultimately resulting in a concurrent reduction in IgE production.

Enterovirus A71 utilizes host cell lipid ß-oxidation to promote its replication.

Enterovirus A71 (EV-A71) is a major pathogen that causes severe and fatal cases of hand-foot-and-mouth disease (HFMD), which is an infectious disease that endangers children's health. However, the pathogenic mechanisms underlying these severe clinical and pathological features remain incompletely understood. Metabolism and stress are known to play critical roles in multiple stages of the replication of viruses. Lipid metabolism and ER stress is an important characterization post viral infection. EV-A71 infection alters the perturbations of intracellular lipid homeostasis and induces ER stress. The characterizations induced by viral infections are essential for optimal virus replication and may be potential antiviral targets. In this study, we found that the addition of the chemical drug of ER stress, PKR IN, an inhibitor, or Tunicamycin, an activator, could significantly reduce viral replication with the decrease of lipid. The replication of viruses was reduced by Chemical reagent TOFA, an inhibitor of acetyl-CoA carboxylase (ACC) or C75, an inhibitor of fatty acid synthase (FASN), while enhanced by oleic acid (OA), which is a kind of exogenous supplement of triacylglycerol. The pharmacochemical reagent of carnitine palmitoyltransferase 1 (CPT1) called Etomoxir could knock down CPT1 to induce EV-A71 replication to decrease. This suggests that lipid, rather than ER stress, is the main factor affecting EV-A71 replication. In conclusion, this study revealed that it is the ß-oxidation of lipid that plays a core role, not ER stress, which is only a concomitant change without restrictive effect, on virus replication.

Severe Acute Respiratory Syndrome Coronavirus 2 ORF8 Protein Inhibits Type I Interferon Production by Targeting HSP90B1 Signaling.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has currently infected over 430 million individuals worldwide. With the variant strains of SARS-CoV-2 emerging, a region of high mutation rates in ORF8 was identified during the early pandemic, which resulted in a mutation from leucine (L) to serine (S) at amino acid 84. A typical feature of ORF8 is the immune evasion by suppressing interferon response; however, the mechanisms by which the two variants of ORF8 antagonize the type I interferon (IFN-I) pathway have not yet been clearly investigated. Here, we reported that SARS-CoV-2 ORF8L and ORF8S with no difference inhibit the production of IFN-ß, MDA5, RIG-I, ISG15, ISG56, IRF3, and other IFN-related genes induced by poly(I:C). In addition, both ORF8L and ORF8S proteins were found to suppress the nuclear translocation of IRF3. Mechanistically, the SARS-CoV-2 ORF8 protein interacts with HSP90B1, which was later investigated to induce the production of IFN-ß and IRF3. Taken together, these results indicate that SARS-CoV-2 ORF8 antagonizes the RIG-I/MDA-5 signaling pathway by targeting HSP90B1, which subsequently exhibits an inhibitory effect on the production of IFN-I. These functions appeared not to be influenced by the genotypes of ORF8L and ORF8S. Our study provides an explanation for the antiviral immune suppression of SARS-CoV-2 and suggests implications for the pathogenic mechanism and treatment of COVID-19.

Spatial distribution and influencing factors of litter in urban areas based on machine learning - A case study of Beijing.

Littering in urban areas negatively affects their appearance, is harmful to the environment and increases pollution. It is a typical urban problem looming large upon Beijing and other megacities striving for liveability and harmony in economy, society and environment. This study analyzed the amount and spatial distribution of urban litter generation in Beijing based on the Kernel Density Estimation method and Anselin's Local Moran I method. We analyzed multiple factors affecting littering in urban areas based on the random forest machine learning method. The results show that the density distribution of litter presents a typical core edge diffusion spatial distribution pattern. High clusters of litter were found in most regions of Dongcheng District and central regions of Haidian District. We have verified that littering in urban areas is mostly affected by population, POIs (interest points), road networks, and the management of the city environment. Among these, permanent population, level of road cleaning, the presence of branch roads and commercial places are the four most important influencing factors. This study is of great significance to the prevention and treatment of littering in urban areas and can help city managers better address this problem.

Characteristics and DGT Based Bioavailability of Cadmium in the Soil-Crop Systems from the East Edge of the Dongting Lake, China.

Contamination of heavy metals (including the cadmium, Cd) in agricultural soils has become an increased issue, posing a threat to the crop safety and human health. In order to evaluate the contamination characteristics and bioavailability of Cd in the soil−crop systems from the East edge of the Dongting Lake, four kinds of agricultural products for typical crops (rice, peanut, sweet potato, and corn) and corresponding rhizosphere soils were collected and analyzed for the Cd concentrations. The technique of diffusive gradients in thin-films (DGT) was applied to evaluate the Cd bioavailability in the rhizosphere soils. Concentrations of Cd ranged from 0.04 to 2.95 mg/kg (average 0.24 mg/kg) with 73.9% sites above the background levels, especially for paddy soils. Cd concentrations in the agricultural products ranged from 0.01 to 2.19 mg/kg (average 0.18 mg/kg), with Cd enrichment observed in the peanut samples. No obvious correlations (R2 < 0.25) were observed between the Cd concentrations in the agricultural products and total Cd concentrations in the rhizosphere soils, this indicated that the total Cd concentrations in the soils cannot predict the concentrations in the agricultural products of crops. While the DGT measured Cd concentrations showed good correlations (R2 = 0.64−0.90) with the concentrations in the most agricultural products of crops, which may be used to evaluate the safety of the soil and further safety of the agricultural products of crops. Overall, DGT showed a good potential for prediction of heavy metal bioavailability in soil since the DGT technique can simulate the sustained supply of heavy metals from solid to liquid in the soils.

Evaluation of ceftazidime/avibactam alone and in combination with amikacin, colistin and tigecycline against Klebsiella pneumoniae carbapenemase-producing K. pneumoniae by in vitro time-kill experiment.

Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) poses a major threat to human health worldwide. Combination therapies of antibiotics with different mechanisms have been recommended in literatures. This study assessed in vitro antibacterial activities and synergistic activities of ceftazidime/avibactam alone and in combinations against KPC-Kp. In total, 70 isolates from 2 hospitals in Beijing were examined in our study. By using the agar dilution method and broth dilution method, we determined the minimum inhibitory concentration (MIC) of candidate antibiotics. Ceftazidime/avibactam demonstrated promising susceptibility against KPC-Kp (97.14%). Synergistic activities testing was achieved by checkerboard method and found ceftazidime/avibactam-amikacin displayed synergism in 90% isolates. Ceftazidime/avibactam-colistin displayed partial synergistic in 43% isolates, and ceftazidime/avibactam-tigecycline displayed indifference in 67% isolates. In time-kill assays, antibiotics at 1-fold MIC were mixed with bacteria at 1 × 105 CFU/ml and Mueller-Hinton broth (MHB). Combinations of ceftazidime/avibactam with amikacin and tigecycline displayed better antibacterial effects than single drug. Ceftazidime/avibactam-colistin combination did not exhibit better effect than single drug. In KPC-Kp infections, susceptibility testing suggested that ceftazidime/avibactam may be considered as first-line choice. However, monotherapy is often inadequate in infection management. Thus, our study revealed that combination therapy including ceftazidime/avibactam colistin and ceftazidime/avibactam tigecycline may benefit than monotherapy in KPC-Kp treatment. Further pharmacokinetic/pharmacodynamic and mutant prevention concentration studies should be performed to optimize multidrug-regimens.

Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19.

An outbreak of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that started in Wuhan, China, at the end of 2019 has become a global pandemic. Both SARS-CoV-2 and SARS-CoV enter host cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in various human organs. We have reviewed previously published studies on SARS and recent studies on SARS-CoV-2 infection, named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO), confirming that many other organs besides the lungs are vulnerable to the virus. ACE2 catalyzes angiotensin II conversion to angiotensin-(1-7), and the ACE2/angiotensin-(1-7)/MAS axis counteracts the negative effects of the renin-angiotensin system (RAS), which plays important roles in maintaining the physiological and pathophysiological balance of the body. In addition to the direct viral effects and inflammatory and immune factors associated with COVID-19 pathogenesis, ACE2 downregulation and the imbalance between the RAS and ACE2/angiotensin-(1-7)/MAS after infection may also contribute to multiple organ injury in COVID-19. The SARS-CoV-2 spike glycoprotein, which binds to ACE2, is a potential target for developing specific drugs, antibodies, and vaccines. Restoring the balance between the RAS and ACE2/angiotensin-(1-7)/MAS may help attenuate organ injuries. SARS-CoV-2 enters lung cells via the ACE2 receptor. The cell-free and macrophage-phagocytosed virus can spread to other organs and infect ACE2-expressing cells at local sites, causing multi-organ injury.

Novel naphtho[2,1-d]oxazole-4,5-diones as NQO1 substrates with improved aqueous solubility: Design, synthesis, and in vivo antitumor evaluation.

A new series of ortho-naphthoquinone analogs of ß-lapachone were designed, synthesized and evaluated. The biological results indicated that most of our compounds were efficient substrates for NQO1. The new scaffold with water-soluble side chain resulted in greater solubility under acidic condition compared to ß-lapachone. Thus avoiding the use of hydroxylpropyl ß-cyclodextrin which would finally cause the rapid drug clearance from the blood and dose-limiting toxicity in the form of hemolytic anemia. The most soluble and promising compound in this series was 2-((4-benzylpiperazin-1-yl)methyl)naphtho[2,1-d]oxazole-4,5-dione (3k), which inhibited cancer cell (NQO1-rich A549 cell line) growth at IC50 values of 4.6±1.0µmol·L(-1). Furthermore, compound 3k had in vivo antitumor activity in an A549 tumor xenografts mouse model comparable to the activity obtained with ß-lapachone. The results indicated that these ortho-naphthoquinones could serve as promising leads for further optimization as novel substrates for NQO1.

Synthesis and evaluation of (±)-dunnione and its ortho-quinone analogues as substrates for NAD(P)H:quinone oxidoreductase 1 (NQO1).

Natural product (±)-dunnione (2) and its ortho-quinone analogues (3-8) were synthesized and found to be substrates for NQO1. The structure-activity relationship study revealed that the biological activity was favored by the presence of methyl group at the C ring and methoxy group at the A ring. The docking studies supported the rationalization of the metabolic studies. Deeper location in the active site of NQO1, interactions with hydrophobic pocket and C-H…π interactions with the adjacent Phe178 residue contributed to the better catalytic efficiency and specificity to NQO1. Cytotoxicity studies and determination of superoxide (O2(-)) production in the presence and absence of the NOQ1 inhibitor dicoumarol confirmed that the ortho-quinones exerted their antitumor activity through NQO1-mediated ROS production by redox cycling.

Application of a low impedance contactless conductometric detector for the determination of inorganic cations in capillary monolithic column chromatography.

Poly(glycidyl methacrylate) cation exchange monolithic column was prepared in fused-silica capillaries of 320 µm i.d. by thermally initiated radical polymerization and utilized in capillary ion chromatography. With 15 mM methanesulfonic acid as the mobile phase, the separations of a mixture of inorganic cations (Li(+), Na(+), NH(4)(+), K(+)) was tested by using a capacitively coupled contactless conductivity detector (C(4)D) and a low impedance C(4)D (LIC(4)D). The LIC(4)D is the series combination of a C(4)D and a quartz crystal resonator. At the resonant frequency of the series combination, the capacitor impedance from capillary wall was offset by the inductance impedance from the quartz crystal resonator. A minimum impedance was obtained in the impedance-frequency curve of the combination. The responses of the C(4)D and LIC(4)D were analyzed based on an equivalent circuit model. It was shown that the sensitivity of the C(4)D to the change in analyte concentration is rather poor due to the high ratio of the impedance from the capillary wall capacitor to the solution impedance. The LIC(4)D has the similar sensitivity as a contact conductivity detector but a much smaller cell volume. The on-column detection model was realized by LiC(4)D without preparation of optical detection window in monolithic column.

Effects of Chinese herbal medicine combined with He-Ne laser on lipoperoxide and superoxide dismutase in chloasma patients.

OBJECTIVE: To observe the effects of Chinese decoction and ligustrazin hydrochloride injection combined with He-Ne laser on lipoperoxide (LPO) and Superoxide dismutase (SOD) in patients with chloasma. METHODS: 90 cases of chloasma were randomly divided into the following two groups: a treatment group (of 54 cases) treated by a self-prepared prescription for toning the kidneys and relieving the depressed liver to remove blood stasis, ligustrazin hydrochloricde injection and He-Ne laser therapy, and a control group (of 36 cases) treated with oral administration of Vitamin E and Vitamin C plus external application of 20% Azelaic acid cream. RESULTS: The total effective rate in the treatment group was 79.6%, which was significantly higher than that of the control group (P < 0.05). After treatment, the LPO level in the treatment group was significantly lowered (P < 0.01), and the SOD level was significantly elevated (P < 0.05). CONCLUSION: The therapeutic methods adopted in the treatment group may show the action of antioxidation, providing good clinical effects for treating chloasma.

[Cortical activation induced by intraoral stimulation with water in humans with functional magnetic resonance imaging].

OBJECTIVE: To investigate the neural representations of normal humans intraoral water stimulation using non-invasive functional magnetic resonance imaging (fMRI) measurement, provide information for intraoral thermosensory study. METHODS: 13 healthy right-handed subjects (of which 6 were males) participated in the study to receive 23 degrees C deionized distilled water stimuli in mouth. The experimental protocol consisted of a block-design using 5 stimulus. Water stimuli were delivered to the subject's mouth through self-made polythene tubes that were held between lips. Functional MRI scan covering the whole brain was carried out. The fMRI data was analyzed by SPM99 software with statistic t-test to generate the activation map. RESULTS: Significant activations existed in peri-sylvian including pre/ post-central gyrus, insular, orbitalfrontal cortex (OFC), anterior cingulate cortex (ACC), frontal gyrus, parietal lobule, midbrain and parietal lobule. CONCLUSION: Water's ability to activate nonspecific somatosensory, thermal or taste processing. The findings highlight the complex and distributed processing of different aspects of intraoral perception, and emphasize the importance of controlling for the effects of water when investigating the functional neuroanatomy of taste or temperature.