Search

Objectives: Respiratory and intestinal tract are two primary target organs of SARS-CoV-2 infection. However, detailed characterization of the host-virus interplay in infected human lung and intestinal epithelial cells is lacking.Methods: We utilized immunofluorescence assays, flow cytometry, and RT-qPCR to delineate the virological features and the innate immune response of the host cells against SARS-CoV-2 infection in two prototype human cell lines representing the human lung (Calu3) and intestinal (Caco2) epithelium when compared with SARS-CoV.Results: Lung epithelial cells were significantly more susceptible to SARS-CoV-2 compared to SARS-CoV. However, SARS-CoV-2 infection induced an attenuated pro-inflammatory cytokines/chemokines induction and type I and type II IFN responses. A single dose of 10 U/mL interferon-β (IFNβ) pretreatment potently protected both Calu3 and Caco2 against SARS-CoV-2 infection. Interestingly, SARS-CoV-2 was more sensitive to the pretreatment with IFNβ and IFN inducer than SARS-CoV in Calu3.Conclusions: Despite robust infection in both human lung and intestinal epithelial cells, SARS-CoV-2 could attenuate the virus-induced pro-inflammatory response and IFN response. Pre-activation of the type I IFN signaling pathway primed a highly efficient antiviral response in the host against SARS-CoV-2 infection, which could serve as a potential therapeutic and prophylactic maneuver to COVID-19 patients. [ABSTRACT FROM AUTHOR]

Lesion morphology poorly predicts functional significance of intermediate coronary artery stenosis. The aim of this study was to determine whether a coronary artery-based myocardial segmentation method that quantifies subtended myocardium can improve the diagnostic accuracy of intravascular ultrasound (IVUS)-derived parameters for detecting ischemia-producing lesions. Coronary computed tomography angiography, IVUS, and fractional flow reserve (FFR) data were analyzed in 101 non-left main lesions (20% to 80% angiographic stenosis). Using the coronary artery-based myocardial segmentation method, total left ventricular myocardial volume (Vtotal), myocardial volume subtended by the stenotic coronary segment (Vsub), and Vratio (the ratio of the Vsub to the Vtotal) were assessed. Both Vsub >30.7 cm(3) and Vratio >25.4% were determinants of FFR ≤0.75 (area under the curve = 0.696 and 0.744). Overall, an IVUS-measured minimum lumen area (IVUS-MLA) ≤2.83 mm(2) predicted FFR ≤0.75 with a sensitivity 88% and specificity 73%. Among lesions with IVUS-MLA ≤2.83 mm(2) and FFR >0.75, 89% showed Vsub <30.7 cm(3). In 50 lesions with Vsub >30.7 cm(3), an IVUS-MLA ≤2.85 mm(2) predicted FFR ≤0.75 with sensitivity 85%, specificity 92%, positive predictive value 92%, and negative predictive value 85%. Conversely, in 51 lesions with a Vsub ≤30.7 cm(3), IVUS-MLA ≤2.67 mm(2) showed sensitivity 100%, specificity 69%, positive predictive value 38%, and negative predictive value 100% for predicting FFR ≤0.75. Body surface area, reference lumen diameter, and vessel area had modest correlations with Vsub. In those lesion subsets, IVUS-MLA ≈2.8 mm(2) accurately predicted an FFR ≤0.75, whereas the clinical relevance of assessing and treating lesions with a smaller myocardial territory may be limited (ClinicalTrials.gov number NCT1696006). [ABSTRACT FROM AUTHOR]

Abstract: Eubacterium limosum ZL-II is an anaerobic bacterium with demethylated activity, which was isolated from human intestinal bacteria in our previous work. In this study, the flavonolignan constituents of Silybi Fructus were biotransformed by E. limosum 1 [1] Eubacterium limosum. ZL-II, producing four new transformation products — demethylisosilybin B (T1), demethylisosilybin A (T2), demethylsilybin B (T3) and demethylsilybin A (T4), among which T1 and T2 were new compounds. Their chemical structures were identified by ESI-TOF/MS, 1H NMR, 13C NMR, HMBC and CD spectroscopic data. The bioassay results showed that the transformation products T1–T4 exhibited significant inhibitory activities on Alzheimer's amyloid-? 42 (A?42 2 [2] Amyloid-?. ) aggregation with IC50 values at 7.49?M–10.46?M, which were comparable with that of the positive control (epigallocatechin gallate, EGCG 3 , [3] Epigallocatechin gallate. at 9.01?M) and much lower than those of their parent compounds (at not less than 145.10?M). The method of biotransformation by E. limosum ZL-II explored a way to develop the new and active lead compounds in Alzheimer's disease from Silybi Fructus. However, the transformation products T1–T4 exhibited decreased inhibitory activities against human tumor cell lines comparing with their parent compounds. [Copyright &y& Elsevier]

Abstract: Configuring structured products poses new challenges to the solving technologies for product configuration. This paper presents a novel and direct approach to encoding configuration models into the Dynamic Constraint Satisfaction Problems (DCSP). In the presented approach, components are encoded as DCSP variables while structural relationships are represented as DCSP activity constraints. Furthermore, the configuration constraints such as the requisition and exclusion constraints are treated as DCSP compatibility constraints, which allow a low-level component to join in the solving process only after its high-level component is selected in the configuration. The presented method allows a more compact encoding representation, compared to CSP and generative CSP. Experimental study shows that the presented DCSP encoding approach makes a significant improvement in the performance of product configuration. [Copyright &y& Elsevier]

Abstract: We analyze a single removable and unreliable server in an M/G/1 queueing system operating under the 〈p, N〉-policy. As soon as the system size is greater than N, turn the server on with probability p and leave the server off with probability (1− p). All arriving customers demand the first essential service, where only some of them demand the second optional service. He needs a startup time before providing first essential service until there are no customers in the system. The server is subject to break down according to a Poisson process and his repair time obeys a general distribution. In this queueing system, the steady-state probabilities cannot be derived explicitly. Thus, we employ an improved maximum entropy method with several well-known constraints to estimate the probability distributions of system size and the expected waiting time in the system. By a comparative analysis between the exact and approximate results, we may demonstrate that the improved maximum entropy method is accurate enough for practical purpose, and it is a useful method for solving complex queueing systems. [Copyright &y& Elsevier]

Abstract: The problem addressed in this paper is to compare the minimum cost of the two randomized control policies in the M/G/1 queueing system with an unreliable server, a second optional service, and general startup times. All arrived customers demand the first required service, and only some of the arrived customers demand a second optional service. The server needs a startup time before providing the first required service until the system becomes empty. After all customers are served in the queue, the server immediately takes a vacation and the system operates the (, )-policy or (, )-policy. For those two policies, the expected cost functions are established to determine the joint optimal threshold values of (, ) and (, ), respectively. In addition, we obtain the explicit closed form of the joint optimal solutions for those two policies. Based on the minimal cost, we show that the optimal (, )-policy indeed outperforms the optimal (, )-policy. Numerical examples are also presented for illustrative purposes. [Copyright &y& Elsevier]

Introduction: Cetuximab, a monoclonal antibody to the epidermal growth factor receptor (EGFR), extends survival in combination with standard therapy in head and neck squamous cell carcinoma (HNSCC). However, as effects are modest, and patients experience side effects, a biomarker to predict resistance and personalize therapy is needed. Activation of signaling pathways downstream from receptor tyrosine kinases predicts resistance to such therapies in other cancers. The most common abnormalities downstream from EGFR in HNSCC are in the PI3K pathway, activated via loss of expression of the regulator PTEN, or via PI3K mutation. We studied whether PTEN and/or PI3K abnormalities predict resistance to cetuximab.Methods: Tumor PTEN and PIK3CA/PI3K p110α were analyzed in samples from subjects treated on two trials of cetuximab-based therapy for patients with metastatic or recurrent HNSCC: E5397, a randomized trial of cisplatin plus placebo versus cisplatin plus cetuximab; and NCI-8070, a randomized trial of cetuximab plus sorafenib versus cetuximab. In situ quantification of PTEN and PI3K p110 α was performed using the AQUA™ method of quantitative immunofluorescence. PI3KCA hot spot mutations were determined with BEAMing.Results: For E5397, in multivariable analysis, PTEN expressing/PIK3CA WT patients tended to improve PFS with cetuximab compared to placebo (N = 48; HR = 0.54, Wald p = 0.0502). High PTEN expression was significantly associated with superior PFS among patients treated on NCI-8070 (N = 37; HR = 0.35, p = 0.008).Conclusion: Loss of PTEN expression may be associated with lack of benefit from cetuximab. This analysis is limited by small sample size, and PTEN as a potential predictive biomarker merits validation in larger sample sets. [ABSTRACT FROM AUTHOR]

Background: Deficiency of olfaction is thought to be associated with depression, and type 3 adenylyl cyclase (AC3) genetic knockout and forebrain knockout mice show depression-like behaviours. AC3 is expressed in the main olfactory epithelium (MOE) and hippocampus, which plays an important role in olfactory signal transduction. However, it is unclear whether AC3 in the MOE also plays a role in the pathogenesis of depression. Thus, we aimed to study the relationship between AC3 in the MOE and the pathogenesis of depression.Methods: We obtained anosmic mice by intranasal perfusion of zinc sulphate (ZnSO4) (ZnSO4 mice), and distinctively knocked down AC3 in the MOE (AC3KD/MOE mice) by CRISPR/cas9 technology. Behavioural tests related to depression and anxiety were employed to evaluate the depression- and anxiety-like behaviours of mice. The mRNA and protein expressions of tyrosine hydroxylase (TH), dopamine receptors (Drds), and N-Methyl D-aspartate receptor subunit 2B (GluN2B) in the hippocampus of mice were investigated by qPCR and western blotting to explore the mechanism of depression and anxiety caused by AC3 in the MOE, preliminarily.Results: Compared with NaCl mice, ZnSO4 mice exhibited depression-like behaviours in tail suspension tests (TST), forced swimming tests, and social (FST) interaction tests (SIT), but showed no anxiety-like behaviours in anxiety-related behavioural tests. The mRNA and protein expressions of Drd3 and GluN2B in the hippocampus of ZnSO4 mice were significantly downregulated. Compared with the negative control mice (NC mice), AC3KD / MOE mice showed depression-like behaviours in TST, FST, and SIT tests, anxiety-like behaviours in light/dark transition test, elevated-plus maze test, and novelty-suppressed feeding test. The protein expressions of Drd3, TH, and GluN2B were significantly downregulated in the hippocampus.Limitations: We did not further demonstrate that AC3 in the MOE causes depression through the dopaminergic nervous system with dopamine or dopamine receptor agonists.Conclusions: Our data demonstrate that intranasal infusion of ZnSO4 can cause depression-like behaviours and has no effect on anxiety-like behaviours. Specific knockdown of AC3 in the MOE can cause depression-like and anxiety-like behaviours. The behavioural changes caused by intranasal ZnSO4 and specific knockdown of AC3 in the MOE can be related to the significant downregulation of dopaminergic system and GluN2B expressions in the hippocampus of mice. [ABSTRACT FROM AUTHOR]

Background: Previous randomised trials have shown an overwhelming benefit of mechanical thrombectomy for treating patients with stroke caused by large vessel occlusion of the anterior circulation. Whether endovascular treatment is beneficial for vertebrobasilar artery occlusion remains unknown. In this study, we aimed to investigate the safety and efficacy of endovascular treatment of acute strokes due to vertebrobasilar artery occlusion.Methods: We did a multicentre, randomised, open-label trial, with blinded outcome assessment of thrombectomy in patients presenting within 8 h of vertebrobasilar occlusion at 28 centres in China. Patients were randomly assigned (1:1) to endovascular therapy plus standard medical therapy (intervention group) or standard medical therapy alone (control group). The randomisation sequence was computer-generated and stratified by participating centres. Allocation concealment was implemented by use of sealed envelopes. The primary outcome was a modified Rankin scale (mRS) score of 3 or lower (indicating ability to walk unassisted) at 90 days, assessed on an intention-to-treat basis. The primary safety outcome was mortality at 90 days. Secondary safety endpoints included the rates of symptomatic intracranial haemorrhage, device-related complications, and other severe adverse events. The BEST trial is registered with ClinicalTrials.gov, NCT02441556.Findings: Between April 27, 2015, and Sept 27, 2017, we assessed 288 patients for eligibility. The trial was terminated early after 131 patients had been randomly assigned (66 patients to the intervention group and 65 to the control group) because of high crossover rate and poor recruitment. In the intention-to-treat analysis, there was no evidence of a difference in the proportion of participants with mRS 0-3 at 90 days according to treatment (28 [42%] of 66 patients in the intervention group vs 21 [32%] of 65 in the control group; adjusted odds ratio [OR] 1·74, 95% CI 0·81-3·74). Secondary prespecified analyses of the primary outcome, done to assess the effect of crossovers, showed higher rates of mRS 0-3 at 90 days in patients who actually received the intervention compared with those who received standard medical therapy alone in both per-protocol (28 [44%] of 63 patients with intervention vs 13 [25%] of 51 with standard therapy; adjusted OR 2·90, 95% CI 1·20-7·03) and as-treated (36 [47%] of 77 patients with intervention vs 13 [24%] of 54 with standard therapy; 3·02, 1·31-7·00) populations. The 90-day mortality was similar between groups (22 [33%] of 66 patients in the intervention vs 25 [38%] of 65 in the control group; p=0·54) despite a numerically higher prevalence of symptomatic intracranial haemorrhage in the intervention group.Interpretation: There was no evidence of a difference in favourable outcomes of patients receiving endovascular therapy compared with those receiving standard medical therapy alone. Results might have been confounded by loss of equipoise over the course of the trial, resulting in poor adherence to the assigned study treatment and a reduced sample size due to the early termination of the study.Funding: Jiangsu Provincial Special Program of Medical Science. [ABSTRACT FROM AUTHOR]

The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Numerous mechanisms have been recognized that cause MDR, but one of the most important mechanisms is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters, through which the efflux of various anticancer drugs against their concentration gradients is powered by ATP. In recent years, small molecular tyrosine kinase inhibitors (TKIs) have been developed for treatment in various human cancers overexpressing epidermal growth factor receptor (EGFR). At the same time, some TKIs have been shown to be capable of inhibiting ABC transporter-mediated MDR. Dacomitinib (PF-00299804) is a second generation, irreversible TKI, which has shown positive anticancer activities in some preclinical and clinical trials. As many TKIs are substrates or inhibitors of ABC transporters, this study investigates whether dacomitinib could interact with ABC subfamily members that mediate MDR, including ABCB1 (P-gp), ABCG2 (BCRP) and ABCC1 (MRP1). The results showed that dacomitinib at 1.0 μM significantly reversed drug resistance mediated by ABCB1 and ABCG2, but not ABCC1, doing so by antagonizing the drug efflux function in ABCB1- and ABCG2-overexpressing cell lines. The reversal effect on ABCB1-overexpressing cells is more potent than that on ABCG2-overexpressing cells. In addition, dacomitinib at reversal concentration affected neither the protein expression level nor the localization of ABCB1 and ABCG2. Therefore, the mechanisms of this modulating effect are likely to be the following: first, as an inhibitor of ABCB1 or ABCG2 transporters, dacomitinib binds to drug-substrate site in transmembrane domains (TMD) stably in a noncompetitive manner; or second, dacomitinib inhibits ATPase activity and maintains the stability of TMD conformation in a concentration-dependent manner thereby inhibiting the drug efflux function of ABCB1 or ABCG2 transporter. This study provides a useful combinational therapeutic strategy with dacomitinib and substrates of ABCB1 and/or ABCG2 transporters in ABCB1- or ABCG2-overexpressing cancers. [ABSTRACT FROM AUTHOR]

Luteolin (3,4,5,7-tetrahydroxyflavones), a major dietary flavone, regulates a variety of biological effects including cancer progression, insulin resistance and inflammation. However, its exact actions on adipogenesis and osteogenesis and the underlying molecular mechanisms are yet to be clarified. In this study, we show that luteolin suppresses lipid accumulation but increases osteoblast differentiation. In mechanism studies, luteolin increases the expression of the heat shock proteins (Hsp) 40 (Dnajb1) and Hsp90 (Hsp90b1), but not those of other heat shock proteins including Hsp20, Hsp27, Hsp47, Hsp70, Hsp72, and Hsp90, and another type of Hsp40 (Dnaja1). Silencing Dnajb1 by using small interfering RNAs (siRNAs), but not against Hsp90b1, recapitulates the effects of luteolin in adipocyte and osteoblast differentiation. Consistently, the forced expression of Dnajb1 decreases the lipid accumulation and stimulates alkaline phosphatase (ALPL) activity. The antiadipogenic and proosteogenic effects of luteolin are significantly blunted in Dnajb1-deficient cells, further suggesting that Dnajb1 is, at least in part, required for luteolin's dual actions in adipogenesis and osteogenesis. Together, our data implicate luteolin as an ingredient and Dnajb1 as a molecular target for the development of functional foods and drugs in metabolic and bone-related diseases. [ABSTRACT FROM AUTHOR]

Abstract: Regional atrophy of gray matter (GM) in Alzheimer''s disease (AD) is well known; however, the relationship between macroscopic and microscopic changes of cerebral white matter (WM) is uncertain. The aim of this study was to investigate the pattern of GM, WM atrophy, and microscopic WM changes in the same individuals with AD. All subjects (10AD and 15 healthy controls [HC]) underwent a MRI scanning at 1.5 T, including a 3-dimensional volumetric scan and diffusion tensor imaging (DTI). We performed statistical parametric mapping (SPM) with DTI to evaluate the patterns of the microscopic WM changes, as well as voxel-based morphometry (VBM) for GM and WM volume changes between patients with AD and HC. GM atrophy was detected, mainly in posterior regions, and WM atrophy was similarly distributed, but less involved on VBM analysis. Unlike WM atrophy on VBM analysis, microscopic WM changes were shown in the medial frontal, orbitofrontal, splenium of the corpus callosum, and cingulum on DTI analysis with SPM. We demonstrated that the pattern of macroscopic WM atrophy was similar to GM atrophy, while microscopic WM changes had a different pattern and distribution. Our findings suggest that WM atrophy may preferentially reflect the secondary changes of GM atrophy, while microscopic WM changes start earlier in frontal areas before GM and WM atrophy can be detected macroscopically. [Copyright &y& Elsevier]

Purpose: This study investigated the impact of gender differences on the diagnostic performance of machine-learning based coronary CT angiography (cCTA)-derived fractional flow reserve (CT-FFRML) for the detection of lesion-specific ischemia.Method: Five centers enrolled 351 patients (73.5% male) with 525 vessels in the MACHINE (Machine leArning Based CT angiograpHy derIved FFR: a Multi-ceNtEr) registry. CT-FFRML and invasive FFR ≤ 0.80 were considered hemodynamically significant, whereas cCTA luminal stenosis ≥50% was considered obstructive. The diagnostic performance to assess lesion-specific ischemia in both men and women was assessed on a per-vessel basis.Results: In total, 398 vessels in men and 127 vessels in women were included. Compared to invasive FFR, CT-FFRML reached a sensitivity, specificity, positive predictive value, and negative predictive value of 78% (95%CI 72-84), 79% (95%CI 73-84), 75% (95%CI 69-79), and 82% (95%CI: 76-86) in men vs. 75% (95%CI 58-88), 81 (95%CI 72-89), 61% (95%CI 50-72) and 89% (95%CI 82-94) in women, respectively. CT-FFRML showed no statistically significant difference in the area under the receiver-operating characteristic curve (AUC) in men vs. women (AUC: 0.83 [95%CI 0.79-0.87] vs. 0.83 [95%CI 0.75-0.89], p = 0.89). CT-FFRML was not superior to cCTA alone [AUC: 0.83 (95%CI: 0.75-0.89) vs. 0.74 (95%CI: 0.65-0.81), p = 0.12] in women, but showed a statistically significant improvement in men [0.83 (95%CI: 0.79-0.87) vs. 0.76 (95%CI: 0.71-0.80), p = 0.007].Conclusions: Machine-learning based CT-FFR performs equally in men and women with superior diagnostic performance over cCTA alone for the detection of lesion-specific ischemia. [ABSTRACT FROM AUTHOR]