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In this preliminary study, the underlying pathophysiology mechanisms of cerebral aneurysms (CAs) in monozygotic twins (MTs) were investigated via a rare pair of MTs (twin A and twin B) involving four reconstructed arterial models using preclinical information. First, dimensions and configurated outlines of three-perspective geometries were compared. Adopting an in-vitro validated numerical CA model, hemodynamic characteristics were investigated in the MTs, respectively. Despite expected genetic similarities, morphological comparisons show that configurations of cerebral arteries exhibit significant differences between the twins. The ICA size of twin A is larger than that in twin B (2.23~25.86%), varying with specific locations, attributing to variations during embryological developments and environmental influences. Numerical modeling indicates the MTs have some hemodynamic similarities such as pressure distributions (~13,400 Pa) and their oscillatory shear index (OSI) (0~0.49), but present significant differences in local regions. Specifically, the difference in blood flow rate in the MTs is from 16% to 221%, varying with specifically compared arteries. The maximum time-averaged wall shear stress (53.6 Pa vs. 37.8 Pa) and different local OSI distributions were also observed between the MTs. The findings revealed that morphological variations in MTs could be generated by embryological and environmental factors, further influencing hemodynamic characteristics on CA pathophysiology.

The influenza A virus is highly contagious and often causes global pandemics. The prevalence of strains of the influenza A virus that are resistant to approved drugs is a huge challenge for the current clinical treatment of influenza A. RNA polymerase is a pivotal enzyme in the replication of the influenza A virus, and it is a promising target for anti-influenza A therapies. In this paper, we report a novel and potent anti-influenza-A-virus inhibitor, ZSP1273, targeting the influenza A virus RNA polymerase, especially for multidrug-resistant strains. The inhibitory activity of ZSP1273 on RNA polymerase activity was 0.562 ± 0.116 nM (IC50 value), which was better than that of the clinical candidate compound VX-787 with the same target. In vitro, the EC50 values of ZSP1273 on normal influenza A virus strains (i.e., H1N1 and H3N2) varied from 0.01 nM to 0.063 nM, which were better than those of the licensed drug oseltamivir. Moreover, oseltamivir-resistant strains, baloxavir-resistant strains, and highly pathogenic avian influenza strains were also sensitive to ZSP1273. In vivo, ZSP1273 effectively reduced influenza A virus titers in a dose-dependent manner in a murine model and maintained a high survival rate in mice. In addition, the inhibitory activity of ZSP1273 on influenza A virus infection was also observed in a ferret model. Pharmacokinetic studies showed the favorable pharmacokinetic characteristics of ZSP1273 in mice, rats, and beagle dogs after single-dose and continuous multiple-dose administration. In conclusion, ZSP1273 is a highly effective anti-influenza A virus replication inhibitor, especially against multidrug-resistant strains. ZSP1273 is currently being studied in phase III clinical trials.

Protein kinases and phosphatases catalyze the phosphorylation and dephosphorylation of their protein substrates, respectively, and these are important mechanisms in cellular signal transduction. The rice blast fungus Magnaporthe oryzae possesses 6 protein phosphatases of type 2C class, including MoPtc1, 2, 5, 6, 7 and 8. However, only very little is known about the roles of these phosphatases in filamentous fungi. Here in, we deployed genetics and molecular biology techniques to identify, characterize and establish the roles of MoPtc5 and MoPtc7 in M. oryzae development and pathogenicity. We found that during pathogen-host interaction, MoPTC7 is differentially expressed. Double deletion of MoPTC7 and MoPTC5 suppressed the fungal vegetative growth, altered its cell wall integrity and reduced its virulence. The two genes were found indispensable for stress tolerance in the phytopathogen. We also demonstrated that disruption of any of the two genes highly affected appressorium turgor generation and Mps1 and Osm1 phosphorylation levels. Lastly, we demonstrated that both MoPtc5 and MoPtc7 are localized to mitochondria of different cellular compartments in the blast fungus. Taken together, our study revealed synergistic coordination of M. oryzae development and pathogenesis by the type 2C protein phosphatases.

Computational fluid dynamics (CFD) is widely employed to predict hemodynamic characteristics in arterial models, while not friendly to clinical applications due to the complexity of numerical simulations. Alternatively, this work proposed a framework to estimate hemodynamics in vessels based on angiography images using machine learning (ML) algorithms. First, the iodine contrast perfusion in blood was mimicked by a flow of dye diffusing into water in the experimentally validated CFD modeling. The generated projective images from simulations imitated the counterpart of light passing through the flow field as an analogy of X-ray imaging. Thus, the CFD simulation provides both the ground truth velocity field and projective images of dye flow patterns. The rough velocity field was estimated using the optical flow method (OFM) based on 53 projective images. ML training with least absolute shrinkage, selection operator and convolutional neural network was conducted with CFD velocity data as the ground truth and OFM velocity estimation as the input. The performance of each model was evaluated based on mean absolute error and mean squared error, where all models achieved or surpassed the criteria of 3 × 10−3 and 5 × 10−7 m/s, respectively, with a standard deviation less than 1 × 10−6 m/s. Finally, the interpretable regression and ML models were validated with over 613 image sets. The validation results showed that the employed ML model significantly reduced the error rate from 53.5% to 2.5% on average for the v-velocity estimation in comparison with CFD. The ML framework provided an alternative pathway to support clinical diagnosis by predicting hemodynamic information with high efficiency and accuracy.

There is an urgent need for a broad-spectrum and protective vaccine due to the emergence and rapid spreading of more contagious SARS-CoV-2 strains. We report the development of RBMRNA-176, a pseudouridine (Ψ) nucleoside-modified mRNA-LNP vaccine encoding pre-fusion stabilized trimeric SARS-CoV-2 spike protein ectodomain, and evaluate its immunogenicity and protection against virus challenge in mice and nonhuman primates. A prime-boost immunization with RBMRNA-176 at intervals of 21 days resulted in high IgG titers (over 1:819,000 endpoint dilution) and a CD4+ Th1-biased immune response in mice. RBMRNA-176 vaccination induced pseudovirus-neutralizing antibodies with IC50 ranging from 1:1020 to 1:2894 against SARS-CoV-2 spike pseudotyped wild-type and variant viruses, including Alpha, Beta, Gamma, and Kappa. Moreover, significant control of viral replication and histopathology in lungs was observed in vaccinated mice. In nonhuman primates, a boost given by RBMRNA-176 on day 21 after the prime induced a persistent and sustained IgG response. RBMRNA-176 vaccination also protected macaques against upper and lower respiratory tract infection, as well as lung injury. Altogether, these findings support RBMRNA-176 as a vaccine candidate for prevention of COVID-19.

The pulsatile flow rate (PFR) in the cerebral artery system and shunt ratios in bifurcated arteries are two patient-specific parameters that may affect the hemodynamic characteristics in the pathobiology of cerebral aneurysms, which needs to be identified comprehensively. Accordingly, a systematic study was employed to study the effects of pulsatile flow rate (i.e., PFR−I, PFR−II, and PFR−III) and shunt ratio (i.e., 75:25 and 64:36) in bifurcated distal arteries, and transient cardiac pulsatile waveform on hemodynamic patterns in two internal carotid artery sidewall aneurysm models using computational fluid dynamics (CFD) modeling. Numerical results indicate that larger PFRs can cause higher wall shear stress (WSS) in some local regions of the aneurysmal dome that may increase the probability of small/secondary aneurysm generation than under smaller PFRs. The low WSS and relatively high oscillatory shear index (OSI) could appear under a smaller PFR, increasing the potential risk of aneurysmal sac growth and rupture. However, the variances in PFRs and bifurcated shunt ratios have rare impacts on the time-average pressure (TAP) distributions on the aneurysmal sac, although a higher PFR can contribute more to the pressure increase in the ICASA−1 dome due to the relatively stronger impingement by the redirected bloodstream than in ICASA−2. CFD simulations also show that the variances of shunt ratios in bifurcated distal arteries have rare impacts on the hemodynamic characteristics in the sacs, mainly because the bifurcated location is not close enough to the sac in present models. Furthermore, it has been found that the vortex location plays a major role in the temporal and spatial distribution of the WSS on the luminal wall, varying significantly with the cardiac period.

Fluid–structure interactions (FSI) play a crucial role in the design, construction, service and maintenance of many engineering applications, e [...]

A 2D numerical simulation was conducted to investigate the effect of an extended rigid trailing edge fringe with a flapping motion on the S833 airfoil and its wake flow field, as an analogy of an owl’s wing. This study aims to characterize the influence of the extended flapping fringe on the aerodynamic performance and the wake flow characteristics downstream of the airfoil. The length (Le) and flapping frequencies (fe) of the fringe are the key parameters that dominate the impact on the airfoil and the flow field, given that the oscillation angular amplitude is fixed at 5°. The simulation results demonstrated that the airfoil with an extended fringe of 10% of the chord at a flapping frequency of fe = 110 Hz showed a substantial effect on the pressure distribution on the airfoil and the flow characteristics downstream of the airfoil. An irregular vortex street was predicted downstream, thus causing attenuations of the vorticities, and shorter streamwise gaps between each pair of vortices. The extended flapping fringe at a lower frequency than the natural shedding vortex frequency can effectively break the large vortex structure up into smaller scales, thus leading to an accelerated attenuation of vorticities in the wake.

Guangdong province, located in South China, is an important economic hub with a large domestic migrant population and was among the earliest areas to report COVID-19 cases outside of Wuhan. We conducted a cross-sectional, age-stratified serosurvey to determine the seroprevalence of antibodies against SARS-CoV-2 after the emergence of COVID-19 in Guangdong. We tested 14,629 residual serum samples that were submitted for clinical testing from 21 prefectures between March and June 2020 for SARS-CoV-2 antibodies using a magnetic particle based chemiluminescent enzyme immunoassay and validated the results using a pseudovirus neutralization assay. We found 21 samples positive for SARS-CoV-2 IgG, resulting in an estimated age- and sex-weighted seroprevalence of 0.15% (95% CI: 0.06–0.24%). The overall age-specific seroprevalence was 0.07% (95% CI: 0.01–0.24%) in persons up to 9 years old, 0.22% (95% CI: 0.03–0.79%) in persons aged 10–19, 0.16% (95% CI: 0.07–0.33%) in persons aged 20–39, 0.13% (95% CI: 0.03–0.33%) in persons aged 40–59 and 0.18% (95% CI: 0.07–0.40%) in persons ≥60 years old. Fourteen (67%) samples had pseudovirus neutralization titers to S-protein, suggesting most of the IgG-positive samples were true-positives. Seroprevalence of antibodies to SARS-CoV-2 was low, indicating that there were no hidden epidemics during this period. Vaccination is urgently needed to increase population immunity to SARS-CoV-2.

An accurate equivalent thermal model is proposed to calculate the equivalent thermal conductivity (ETC) of shield differential through-silicon via (SDTSV). The mathematical expressions of ETC in both horizontal and vertical directions are deduced by considering the anisotropy of SDTSV. The accuracy of the proposed model is verified by the finite element method (FEM), and the average errors of temperature along the X-axis, Y-axis, diagonal line, and vertical directions are 1.37%, 3.42%, 1.76%, and 0.40%, respectively. Compared with COMSOL, the proposed model greatly improves the computational efficiency. Moreover, the effects of different parameters on the thermal distribution of SDTSV are also investigated. The thermal conductivity is decreased with the increase in thickness of SiO2. With the increase in pitch, the maximum temperature of SDTSV increases very slowly when β = 0° , and decreases very slowly when β = 90°. The proposed model can be used to accurately and quickly describe the thermal distribution of SDTSV, which has a great prospect in the design of 3D IC.

A novel tandem catalysis system consisted of salicylaldiminato binuclear/mononuclear titanium and 2,6-bis(imino)pyridyl iron complexes was developed to catalyze ethylene in-situ copolymerization. Linear low-density polyethylene (LLDPE) with varying molecular weight and branching degree was successfully prepared with ethylene as the sole monomer feed. The polymerization conditions, including the reaction temperature, the Fi/Ti molar ratio, and the structures of bi- or mononuclear Ti complexes were found to greatly influence the catalytic performances and the properties of obtained polymers. The polymers were characterized by differential scanning calorimetry (DSC), high temperature gel permeation chromatography (GPC) and high temperature 13C NMR spectroscopy, and found to contain ethyl, butyl, as well as some longer branches. The binuclear titanium complexes demonstrated excellent catalytic activity (up to 8.95 × 106 g/molTi·h·atm) and showed a strong positive comonomer effect when combined with the bisiminopyridyl Fe complex. The branching degree can be tuned from 2.53 to 22.89/1000C by changing the reaction conditions or using different copolymerization pre-catalysts. The melting points, crystallinity and molecular weights of the products can also be modified accordingly. The binuclear complex Ti2L1 with methylthio sidearm showed higher capability for comonomer incorporation and produced polymers with higher branching degree and much higher molecular weight compared with the mononuclear analogue.

Laggera pterodonta (DC.) Benth. is a traditional Chinese medicine. The previous study revealed that the crude extracts of this herb could inhibit influenza virus infection, but its anti-influenza components and underlying mechanism of action remain unknown. Column chromatography was performed to isolate components from the plant. Activity against influenza virus of the compound was determined by CPE inhibition assay. Neuraminidase (NA) inhibition was measured by chemiluminescence assay. The anti-virus and anti-inflammation effects were determined using dual-luciferase reporter assay, immunofluorescence, quantitative real-time PCR and luminex assay. Pterodontic acid was isolated from L. pterodonta, which showed selective anti-viral activities to H1 subtype of human influenza A virus. Meanwhile, the NA activity was not obviously inhibited by the compound. Further experiments exhibited that the compound can suppress the activation of NF-κB signal pathway and export of viral RNP complexes from the nucleus. In addition, it can significantly attenuate expression of the pro-inflammatory molecules IL-6, MIP-1β, MCP-1, and IP-10 induced by human influenza A virus (H1N1) and similarly downregulate expression of cytokines and chemokines induced by avian influenza A virus (H9N2). This study showed that in vitro antiviral activity of pterodontic acid is most probably associated with inhibiting the replication of influenza A virus by blocking nuclear export of viral RNP complexes, and attenuating the inflammatory response by inhibiting activation of the NF-κB pathway. Pterodontic acid might be a potential antiviral agent against influenza A virus.

Influenza remains one of the major epidemic diseases worldwide, and rapid virus replication and collateral lung tissue damage caused by excessive pro-inflammatory host immune cell responses lead to high mortality rates. Thus, novel therapeutic agents that control influenza A virus (IAV) propagation and attenuate excessive pro-inflammatory responses are needed. Polysaccharide extract from Radix isatidis, a traditional Chinese herbal medicine, exerted potent anti-IAV activity against human seasonal influenza viruses (H1N1 and H3N2) and avian influenza viruses (H6N2 and H9N2) in vitro. The polysaccharides also significantly reduced the expression of pro-inflammatory cytokines (IL-6) and chemokines (IP-10, MIG, and CCL-5) stimulated by A/PR/8/34 (H1N1) at a range of doses (7.5 mg/mL, 15 mg/mL, and 30 mg/mL); however, they were only effective against progeny virus at a high dose. Similar activity was detected against inflammation induced by avian influenza virus H9N2. The polysaccharides strongly inhibited the protein expression of TLR-3 induced by PR8, suggesting that they impair the upregulation of pro-inflammatory factors induced by IAV by inhibiting activation of the TLR-3 signaling pathway. The polysaccharide extract from Radix isatidis root therefore has the potential to be used as an adjunct to antiviral therapy for the treatment of IAV infection.