BPR3P0128, a non-nucleoside RNA-dependent RNA polymerase inhibitor, inhibits SARS-CoV-2 variants of concern and exerts synergistic antiviral activity in combination with remdesivir.

Viral RNA-dependent RNA polymerase (RdRp), a highly conserved molecule in RNA viruses, has recently emerged as a promising drug target for broad-acting inhibitors. Through a Vero E6-based anti-cytopathic effect assay, we found that BPR3P0128, which incorporates a quinoline core similar to hydroxychloroquine, outperformed the adenosine analog remdesivir in inhibiting RdRp activity (EC50 = 0.66 µM and 3 µM, respectively). BPR3P0128 demonstrated broad-spectrum activity against various severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. When introduced after viral adsorption, BPR3P0128 significantly decreased SARS-CoV-2 replication; however, it did not affect the early entry stage, as evidenced by a time-of-drug-addition assay. This suggests that BPR3P0128's primary action takes place during viral replication. We also found that BPR3P0128 effectively reduced the expression of proinflammatory cytokines in human lung epithelial Calu-3 cells infected with SARS-CoV-2. Molecular docking analysis showed that BPR3P0128 targets the RdRp channel, inhibiting substrate entry, which implies it operates differently-but complementary-with remdesivir. Utilizing an optimized cell-based minigenome RdRp reporter assay, we confirmed that BPR3P0128 exhibited potent inhibitory activity. However, an enzyme-based RdRp assay employing purified recombinant nsp12/nsp7/nsp8 failed to corroborate this inhibitory activity. This suggests that BPR3P0128 may inhibit activity by targeting host-related RdRp-associated factors. Moreover, we discovered that a combination of BPR3P0128 and remdesivir had a synergistic effect-a result likely due to both drugs interacting with separate domains of the RdRp. This novel synergy between the two drugs reinforces the potential clinical value of the BPR3P0128-remdesivir combination in combating various SARS-CoV-2 variants of concern.

Antigenicity and immunogenicity of chikungunya virus-like particles from mosquito cells.

The spread of chikungunya virus (CHIKV) is reaching pandemic levels, and vaccines and antivirals to control CHIKV infection have yet to be approved. Virus-like particles (VLPs), a self-assembled native multi-subunit protein structure, could potentially be used as an antigen for serological detection and vaccine development. In the current study, we describe the production of novel CHIKV VLPs from mosquitoes using a Baculovirus/Mosquito (BacMos) system in a simple Biosafety Level-2 laboratory. Substantial envelope and capsid protein secretions were detected in culture medium. Co-fractionation of CHIKV E2, E1, and capsid proteins via sucrose gradient ultracentrifugation provided evidence of VLP formation. Transmission electron microscopy and dynamic light scattering analysis revealed the formation of VLPs in the form of spherical particles with a diameter of roughly 40 nm in transduced cells and culture medium. VLP-based IgM capture ELISA in CHIKV patient sera revealed native epitopes on the VLPs. These non-purified VLPs were shown to act as an antigen in CHIKV-specific IgM capture ELISA. The immunization of CHIKV-VLPs alone in mice induced a balance CHIKV-specific IgG2a/IgG1 antibodies and neutralized antibody responses. The study provides support for the hypothesis that mosquito cell-derived CHIKV VLPs could serve as a novel antigen for serological detection and the development of vaccines against CHIKV infection. KEY POINTS: • CHIKV VLPs secreted from BacMos-CHIKV 26S-transduced mosquito cell. • This CHIKV VLPs potentially serve as an alternative capture antigen for MAC-ELISA. • Unadjuvanted CHIK VLPs induce CHIKV-specific IgG and NT responses in mice.

Corporate governance and financial reporting quality during the COVID-19 pandemic.

This paper analyzes whether COVID-19 affects the financial reporting quality of companies and whether corporate governance has a mitigating effect. Using data from UK listed companies, we show that the quality of companies' financial reporting has been lower during the pandemic. Specifically, companies have engaged in more earnings management through real activities during the pandemic. We also find that a larger board helps to mitigate the negative impact of COVID-19 on financial reporting quality, although we find no mitigating effect for board independence and CEO duality. This paper provides additional evidence on the impact of COVID-19 on financial reporting quality using a strong country-level governance setting. It is also the first study to analyze the mitigating effect of corporate governance on financial reporting quality during the COVID-19 pandemic. The results of this study provide useful suggestions to the practice.

Canine-lateral incisor transposition: Controlling root resorption with a bone-anchored T-loop retraction.

A 12-year-old girl presented with a Class II Division 1 malocclusion, complicated by a complete transposition of the maxillary left canine into the position normally occupied by the left lateral incisor. Dental and medical histories were noncontributory. Brackets were bonded on all maxillary teeth, from first molar to first molar, except for the left lateral incisor. Because the lateral incisor was not engaged on the archwire, the tooth was free to physiologically move out of the path of canine root movement. To prepare the site for canine retraction, a coil spring was used to open space between the left central incisor and the first premolar. A 2 × 12-mm stainless steel miniscrew was placed in the infrazygomatic crest, labial to the mesiodistal cusp of the maxillary left first molar. A 0.019 × 0.025-in titanium-molybdenum alloy T-loop, anchored by the miniscrew, was used to retract the canine root over the labial surface of the root of the distally positioned lateral incisor. In 24 months, this difficult malocclusion, with a Discrepancy Index score of 18, was treated to a Cast-Radiograph Evaluation score of 26.

Up-regulation of galectin-9 induces cell migration in human dendritic cells infected with dengue virus.

Galectin-9 (Gal-9) exerts immunosuppressive effects by inducing apoptosis in T cells that produce interferon-γ and interleukin (IL)-17. However, Gal-9 can be pro-inflammatory in lipopolysaccharide-stimulated monocytes. Using microarray analysis, we observed that Gal-9 was up-regulated in human dendritic cells (DCs) after dengue virus (DV) infection. The investigation into the immunomodulatory effects and mechanisms of Gal-9 in DCs exposed to DV revealed that DV infection specifically increased mRNA and protein levels of Gal-9 but not those of Gal-1 or Gal-3. Blocking p38, but not c-Jun N-terminal kinase or extracellular signal-regulated kinase (ERK), inhibited DV-induced expression of Gal-9. Reduction in Gal-9 by small interference RNA treatment suppressed DV-stimulated migration of DCs towards the chemoattractants CCL19 and CCL21. In addition, DV-induced IL-12p40 production was reduced after knockdown of Gal-9 in DCs. Furthermore, Gal-9 deficiency suppressed DV-induced activation of nuclear factor-κB. Inhibition of DV-induced DC migration under conditions of Gal-9 deficiency was mediated through suppressing ERK activation but not by regulating the expression of CCR7, the receptor for CCL19 and CCL21. Both the reduction in IL-12 production and the suppression of ERK activity might account for the inhibition of DV-induced DC migration after knockdown of Gal-9. In summary, this study reveals the roles of Gal-9 in DV-induced migration of DCs. The findings indicate that Gal-9 might be a therapeutic target for preventing immunopathogenesis induced by DV infection.

Homo- and Heteropolynuclear Clusters of Phosphine Triphenolates.

The synthesis and structural characterization of a series of homo- and heteropolynuclear clusters constructed with a potentially tetradentate phosphine triphenolate ligand are presented. Treatment of tris(3,5-di-tert-butyl-2-hydroxyphenyl)phosphine (H3[O3P]) with 3 equiv of nBuLi in diethyl ether at -35 °C affords hexanuclear Li6[O3P]2(OEt2)2 (1) as colorless crystals. In situ lithiation of H3[O3P] with 3 equiv of nBuLi in THF at -35 °C followed by metathetical reactions with MnCl2 or NiCl2(DME) gives crystals of forest green pentanuclear MnLi4[O3P]2(THF)3 (2) or dark brown tetranuclear Ni2Li2[O3P]2(THF)2 (3), respectively. Alkane elimination of ZnR2 (R = Me, Et) with H3[O3P] in THF at 25 °C generates high yields of colorless crystalline trinuclear Zn3[O3P]2(THF)2 (4). The cluster structures of 1-4 were all determined by single crystal X-ray diffraction studies. These molecules represent the first examples of metal complexes supported by phosphine triphenolate derivatives. The cluster 2 contains a paramagnetic core of high spin Mn(II) (S = 5/2) as indicated by solution and solid state magnetic susceptibility measurements.

Isolation and cytotoxicity evaluation of the chemical constituents from Cephalantheropsis gracilis.

Cephalantheropsis gracilis afforded five new compounds: cephalanthrin-A (1), cephalanthrin-B (2), cephathrene-A (3), cephathrene-B (4), methyl 2-(aminocarbonyl) phenylcarbamate (5), and 52 known compounds. The structures of the new compounds were determined by spectroscopic analysis. Among the compounds isolated, tryptanthrin (6), phaitanthrin A (7), cephalinone D (19), and flavanthrin (30) showed significant cytotoxicity against MCF-7, NCI-H460, and SF-268 cell lines.

Overexpression of T-LAK cell-originated protein kinase predicts poor prognosis in patients with stage I lung adenocarcinoma.

Tumor recurrence is the most common cause of disease failure after surgical resection in early-stage lung adenocarcinoma. Identification of clinically relevant prognostic markers could help to predict patients with high risk of disease recurrence. A meta-analysis of available lung adenocarcinoma microarray datasets revealed that T-LAK cell-originated protein kinase (TOPK), a serine/threonine protein kinase, is overexpressed in lung cancer. Using stable cell lines with overexpression or knockdown of TOPK, we have shown that TOPK can promote cell migration, invasion, and clonogenic activity in lung cancer cells, suggesting its crucial role in lung tumorigenesis. To evaluate the prognostic value of TOPK expression in resected stage I lung adenocarcinoma, a retrospective analysis of 203 patients diagnosed with pathological stage I lung adenocarcinoma was carried out to examine the expression of TOPK by immunohistochemistry (IHC). The prognostic significance of TOPK overexpression was examined. Overexpression of TOPK (IHC score >3) was detected in 67.0% of patients, and these patients were more frequently characterized with disease recurrence and angiolymphatic invasion. Using multivariate analysis, patient age (>65 years old; P = 0.002) and TOPK overexpression (IHC score >3; P < 0.001) significantly predicted a shortened overall survival. Moreover, TOPK overexpression (IHC score >3; P = 0.005) also significantly predicted a reduced time to recurrence in the patients. Our results indicate that overexpression of TOPK could predetermine the metastatic capability of tumors and could serve as a significant prognostic predictor of shortened overall survival and time to recurrence.

Effects of investor sentiment and country governance on unexpected conditional volatility during the COVID-19 pandemic: Evidence from global stock markets.

This paper first investigates the relationship between investor sentiment, captured by internet search behaviour, and the unexpected component of stock market volatility during the COVID-19 pandemic. According to data on 12 major stock markets, our research indicates a positive correlation between the Google search volume index on COVID-19 and the unexpected volatility of stock markets. The result suggests that greater COVID-19-related investor sentiment during this pandemic is associated with higher stock market uncertainty. Our study further examines whether country-level governance plays a role in protecting stock markets during this pandemic and reveals that the unexpected conditional volatility is lower when a country's governance is more effective. The impact of investor sentiment and country governance on unexpected volatility after the initial shock of COVID-19 is also investigated. The findings demonstrate the importance of establishing good country-level governance that can effectively reduce stock market uncertainty in the context of this pandemic, and support continual policy development related to investor protection.

Group 4 complexes of a tert-butylphosphine-bridged biphenolate ligand.

The coordination chemistry of group 4 complexes supported by the tridentate, dianionic biphenolate phosphine ligand that carries a phosphorus-bound tert-butyl group, 2,2'-tert-butylphosphino-bis(4,6-di-tert-butylphenolate) ([(t)Bu-OPO](2-)), is described. Metathetical reactions of {[(t)Bu-OPO]Li(2)(DME)}(2) with 2 or 1 equiv of TiCl(4)(THF)(2) selectively produce [(t)Bu-OPO]TiCl(2)(THF) (1a) and Ti[(t)Bu-OPO](2) (2a), respectively. Protonolysis of Ti(O(i)Pr)(4) with 2 or 1 equiv of H(2)[(t)Bu-OPO] cleanly generates 2a and [(t)Bu-OPO]Ti(O(i)Pr)(2) (3a), respectively. Complex 1a can alternatively be prepared from comproportionation of 2a with 1 equiv of TiCl(4)(THF)(2). Treatment of 1a with 2 equiv of NaO(t)Bu affords [(t)Bu-OPO]Ti(O(t)Bu)(2) (4a). In contrast, reactions of {[(t)Bu-OPO]Li(2)(DME)}(2) with ZrCl(4)(THF)(2) or HfCl(4)(THF)(2), regardless of stoichiometry of the starting materials employed, selectively give bis-ligated M[(t)Bu-OPO](2) [M = Zr (2b), Hf (2c)]. Comproportionation of 2b,c with MCl(4)(THF)(2) (M = Zr, Hf) leads to the formation of [(t)Bu-OPO]MCl(2)(THF) [M = Zr (1b), Hf (1c)], which, upon being treated with 2 equiv of NaO(t)Bu, generates [(t)Bu-OPO]M(O(t)Bu)(2)(THF) (4b,c). These synthetic results are markedly different from those obtained from analogous reactions employing a biphenolate phosphine ligand bearing a phosphorus-bound phenyl group ([Ph-OPO](2-)), highlighting a profound phosphorus substituent effect on complex conformation. The alkoxide complexes 3a and 4a-c are all active initiators for catalytic ring-opening polymerization of ε-caprolactone. To assess the potential phosphorus substituent effect on catalysis, [Ph-OPO]Ti(O(i)Pr)(2) (5a) was prepared, and its reactivity was examined. Interestingly, polymers prepared from 3a are characterized by low polydispersities with molecular weights that are linearly dependent on the monomer-to-initiator ratio, thus featuring a living system. The polydispersitiy indexes of polymers prepared from 5a, however, are relatively larger, indicative of the significance of the phosphorus-bound tert-butyl group in 3a in view of discouraging the undesirable transesterification.

Path Model Validation of Breastfeeding Intention Among Pregnant Women.

OBJECTIVE: To validate a blended health belief model and integrated behavioral model of selected modifiable psychosocial constructs during pregnancy to seek the best-fit path model for breastfeeding intention. DESIGN: A nonexperimental, cross-sectional study. SETTING: A virtual online market research sample aggregator. PARTICIPANTS: Women (N = 300) between 18 and 45 years of age in their second or third trimesters of pregnancy participated in the study in February 2018. METHODS: Based on the health belief model and the integrated behavioral model, we proposed a theoretical framework, including self-efficacy for breastfeeding, knowledge, perceived benefits, perceived barriers, attitude toward breastfeeding, patient-provider interaction, and motivation to breastfeed, to predict breastfeeding intention. We administered a 98-item questionnaire modified from preexisting instruments. We conducted descriptive, bivariate, and regression analyses to help with the formation of the path model. RESULTS: The best-fit path model with all significant paths and effect directions showed that intention to breastfeed is directly influenced by motivation to breastfeed, attitudes toward breastfeeding, and self-efficacy for breastfeeding, which together accounted for 56% (R2) of the variance in intention. We also identified indirect effects from knowledge about breastfeeding, patient-provider interaction, perceived benefits, and perceived barriers and their interrelationships with effect directions. CONCLUSION: Through our findings, we contribute to the emerging body of evidence that shows the significant variables and their effect directions for breastfeeding intention. Incorporating these findings may provide support and evidence for clinical and community interventions focusing on modifiable psychosocial constructs during pregnancy to promote breastfeeding and further investigations using health behavior theories.

Association between renal function and cardiovascular mortality: a retrospective cohort study of elderly from health check-up.

OBJECTIVES: This study aimed to investigate the relationship between cardiovascular mortality in elderly Asians and decline in renal function. DESIGN: A retrospective cohort study. SETTING: Community-based health examination database from Taipei city. PARTICIPANTS: At the beginning, the database included 315 045 health check-up visits of 97 803 elderly persons aged ≥65 years old from 2005 to 2012. After excluding missing values and outliers, there were 64 732 elderly persons with at least two visits retained for further analyses. PRIMARY OUTCOME MEASURES: Kidney function indicators include estimated glomerular filtration rate (eGFR) and urine protein, and rapid decline in eGFR was defined as slope ≤ -5 mL/min/1.73 m2 per year. The endpoint outcome was defined as the cardiovascular deaths registered in the death registry encoded by the International Classification of Diseases. We applied a Cox proportional hazards model to analyse the association between renal function and cardiovascular mortality. RESULTS: In this study, we found 1264 elderly persons died from cardiovascular diseases, for whom the data included 4055 previous health check-up visits. We observed significant and independent associations of eGFR <60 mL/min/1.73 m2 (HR (95% CI) of 60>eGFR≥45 and eGFR<45 in males: 2.85 (1.33 to 6.09) and 3.98 (1.84 to 8.61); in females: 3.66 (1.32 to 10.15) and 6.77 (2.41 to 18.99)), positive proteinuria (HR (95% CI) of +/-, +,++ and +++, ++++ in males: 1.51 (1.29 to 1.78) and 2.31 (1.51 to 3.53); in females: 1.93 (1.54 to 2.42) and 4.23 (2.34 to 7.65)) and rapid decline in eGFR (HR (95% CI) in males: 3.24 (2.73 to 3.85); in females: 2.83 (2.20 to 3.64) with higher risk of cardiovascular mortality. The joint effect of increased concentration of urine protein and reduced eGFR was associated with a higher risk of cardiovascular mortality. CONCLUSIONS: Renal function and rapid decline in renal function are independent risk factors for cardiovascular mortality in the elderly.

Incorporating hybrid models into lysine malonylation sites prediction on mammalian and plant proteins.

Protein malonylation, a reversible post-translational modification of lysine residues, is associated with various biological functions, such as cellular regulation and pathogenesis. In proteomics, to improve our understanding of the mechanisms of malonylation at the molecular level, the identification of malonylation sites via an efficient methodology is essential. However, experimental identification of malonylated substrates via mass spectrometry is time-consuming, labor-intensive, and expensive. Although numerous methods have been developed to predict malonylation sites in mammalian proteins, the computational resource for identifying plant malonylation sites is very limited. In this study, a hybrid model incorporating multiple convolutional neural networks (CNNs) with physicochemical properties, evolutionary information, and sequenced-based features was developed for identifying protein malonylation sites in mammals. For plant malonylation, multiple CNNs and random forests were integrated into a secondary modeling phase using a support vector machine. The independent testing has demonstrated that the mammalian and plant malonylation models can yield the area under the receiver operating characteristic curves (AUC) at 0.943 and 0.772, respectively. The proposed scheme has been implemented as a web-based tool, Kmalo (https://fdblab.csie.ncu.edu.tw/kmalo/home.html), which can help facilitate the functional investigation of protein malonylation on mammals and plants.

Mosquito Cell-Derived Japanese Encephalitis Virus-Like Particles Induce Specific Humoral and Cellular Immune Responses in Mice.

The Japanese encephalitis virus (JEV) is the major cause of an acute encephalitis syndrome in many Asian countries, despite the fact that an effective vaccine has been developed. Virus-like particles (VLPs) are self-assembled multi-subunit protein structures which possess specific epitope antigenicities related to corresponding native viruses. These properties mean that VLPs are considered safe antigens that can be used in clinical applications. In this study, we developed a novel baculovirus/mosquito (BacMos) expression system which potentially enables the scalable production of JEV genotype III (GIII) VLPs (which are secreted from mosquito cells). The mosquito-cell-derived JEV VLPs comprised 30-nm spherical particles as well as precursor membrane protein (prM) and envelope (E) proteins with densities that ranged from 30% to 55% across a sucrose gradient. We used IgM antibody-capture enzyme-linked immunosorbent assays to assess the resemblance between VLPs and authentic virions and thereby characterized the epitope specific antigenicity of VLPs. VLP immunization was found to elicit a specific immune response toward a balanced IgG2a/IgG1 ratio. This response effectively neutralized both JEV GI and GIII and elicited a mixed Th1/Th2 response in mice. This study supports the development of mosquito cell-derived JEV VLPs to serve as candidate vaccines against JEV.

Quarantine Vapor Heat Treatment of Papaya Fruit for Bactrocera dorsalis and Bactrocera cucurbitae (Diptera: Tephritidae).

The presence of quarantine insect pests in fruit export can impede trade with other countries. Therefore, to reduce the risk of possible quarantine pests in exported fruit, postharvest disinfestation treatment is essential. This study investigated the effects of vapor heat treatment (VHT) on oriental fruit fly (Bactrocera dorsalis Hendel (Diptera: Tephritidae)) and melon fly (Bactrocera cucurbitae Coquillett (Diptera: Tephritidae)) which are major pests for papaya fruits. For inoculated papaya fruits weighing 550 ± 100 g, the optimal egg-inoculation density, rearing conditions, and heat tolerance for each developmental stages of both fruit flies were determined, and then analyzed to determine their survival, and assess papaya fruit quality after treatment. Result of VHT of each developmental stage indicated that the eggs of B. dorsalis were the most heat tolerant at 45.6°C. Efficacy test that determined the optimal mortality temperature was performed by subjecting 60 fruits infested with 4,500 eggs to fruit core temperatures of 44.2, 45.2, 46.2, and 47.2°C. It was found that when the papaya fruit core temperature increased at a heating rate of 0.0925°C/min from room temperature to 47.2°C in 3 h, fruit flies showed 100% mortality. Results of the confirmatory test using 300 papaya fruits also indicated 100% mortality at this temperature. Both fruit quality and injury test results demonstrated insignificant differences in color, appearance, soluble solids, or firmness of fruits before and after treatment. Thus, VHT effectively disinfested papaya fruits against both fruit fly species, thus making it a viable quarantine treatment for papaya fruits prior to their export.

Kalanchosides A-C, new cytotoxic bufadienolides from the aerial parts of Kalanchoe gracilis.

[Structure: see text] Three new compounds, kalanchosides A-C (1-3), as well as five known compounds, were isolated from the aerial parts of Kalanchoe gracilis. The compound structures were determined by spectroscopic methods. All eight isolated compounds showed significant cytotoxic activity against a panel of human tumor cell lines, with potency reaching the nanomolar range. However, only bryophyllin B (8) inhibited HIV replication in H9 lymphocyte cells.

Influence of soy aglycon isoflavones on bone-related traits and lens protein characteristics of ovariectomized rats and bioactivity performance of osteoprogenitor cells.

Health benefits of soy isoflavones have attracted the concern of the public and the interest of health-care professionals. In this study, two trials were conducted in characterizing bone-related traits and lens proteins as affected by supplementation of soy aglycon isoflavones (SAI). In trial 1, an in vivo study, 20 Sprague-Dawley rats were ovariectomized (OVX) and randomly distributed into OVX and OVX+SAI (135 mg of SAI/kg of feed; 8.33 mg/kg body weight; 2.5 mg/day) groups. Another group containing 10 rats with a sham operation was control (Sham). The experiment period was 3 months, and the rats were subjected to bone-related traits and lens protein characterization. In trial 2, an in vitro study, osteoprogenitor cells (UMR-106) were divided into SAI-supplemented (0.5 mg of SAI/mL of medium) and unsupplemented groups. Results of the in vivo study indicated that daily BW gains in the OVX and OVX+SAI groups were greater than that of the Sham group (p < 0.05). Bone ash and Ca contents of the Sham and OVX+SAI groups were higher than those of the OVX group (p < 0.05), while bone density, strength, and phosphorus contents among groups varied insignificantly (p > 0.05). When the lens proteins were extracted and analyzed with size-exclusion HPLC, the contents of beta- and gamma-crystallins were lowest in the OVX group and the protein solubility decrease could be recovered by dietary SAI supplementation (shown by OVX+SAI group). Based on Raman spectra of the isolated lens proteins, disulfide bonds were observed more in OVX lens than in the Sham and OVX+SAI lens. Results of in vitro study with osteoprogenitor cells revealed that cell viability, alkaline phosphatase activity, osteocalcin, and Ca contents of the SAI-supplemented group were higher than those of the unsupplemented group (p < 0.05). The likely potency to enhance bone and lens health by SAI supplementation is worth pointing out.

Dengue virus infection induces interferon-lambda1 to facilitate cell migration.

A marked increase in the rate of dengue virus (DENV) infection has resulted in more than 212 deaths in Taiwan since the beginning of 2015, mostly from fatal outcomes such as dengue hemorrhagic fever and dengue shock syndrome. The pathogenic mechanisms of these fatal manifestations are poorly understood. Cytokines induce an overwhelming immune reaction and thus have crucial roles. Interferon-lambda (IFN-λ), a newly identified IFN subtype, has antiviral effects, but its immunologic effects in DENV infection have not been investigated. In the present study, we show that DENV infection preferentially induced production of IFN-λ1 in human dendritic cells (DCs) and human lung epithelial cells. Virus nonstructural 1 (NS1) glycoprotein was responsible for the effect. DENV-induced production of IFN-λ1 was dependent on signaling pathways involving toll-like receptor (TLR)-3, interferon regulation factor (IRF)-3, and nuclear factor-kappaB (NF-κB). Blocking interaction between IFN-λ1 and its receptor IFN-λR1 through siRNA interference reduced DENV-induced DC migration towards the chemoattractants CCL19 and CCL21, by inhibiting CCR7 expression. Furthermore, IFN-λ1 itself induced CCR7 expression and DC migration. Our study presents the first evidence of the mechanisms and effects of IFN-λ1 induction in DENV-infected DCs and highlights the role of this cytokine in the immunopathogenesis of DENV infection.

Carvedilol, a new antioxidative beta-blocker, blocks in vitro human peripheral blood T cell activation by downregulating NF-kappaB activity.

OBJECTIVE: The activation of T lymphocytes contributes to the inflammatory process of atherosclerosis. Here we examined the effects of carvedilol, a new beta-blocker containing an antioxidative property, on the activation of T cells. METHODS: Human peripheral blood T cells were negatively selected from whole blood. Cytokines were measured by ELISA. The NF-kappaB and related protein activity was determined by electrophoretic mobility shift assays, Western blotting, kinase assays and transfection assays. RESULTS: Carvedilol was nontoxic at concentrations /=20 microM) induced T cell apoptosis. We demonstrated that carvedilol inhibited cytokine production from various stimuli-activated T cells. Carvedilol also suppressed the expression of T cell activation markers, including CD25, CD69 and CD71. Molecular investigation indicated that carvedilol specifically downregulated NF-kappaB but not activator protein 1 DNA-binding activity in activated T cells. The inhibitory effect was likely due to its antioxidative property. Meanwhile, carvedilol prevented stimuli-induced IkappaBalpha degradation. Such an effect was mediated through the inhibition of IkappaBalpha kinase activity. The inhibitory specificity on NF-kappaB by carvedilol was also demonstrated in transfection assays. CONCLUSIONS: Our results demonstrated a novel therapeutic mechanism of carvedilol in atherosclerosis, namely the inhibition of T cell activation via downregulating NF-kappaB activity.