The cleavage property of hemagglutinin (HA) by different proteases was the prime determinant for influenza A virus pathogenicity. In order to understand the cleavage mechanism, molecular modeling ...tools were utilized to study the coupled model systems of the proteases, i.e., trypsin and furin and peptides of the cleavage sites specific to H5N1 and H1 HAs, which constitute models of HA precursor in complex with cleavage proteases. The peptide segments 'RERRRKKR downward arrow G' and 'SIQSR downward arrow G' from the high pathogenic H5N1 H5 and the low pathogenic H1N1 H1 cleavage sites were docking to the trypsin and furin active pockets, respectively. It was observed through the docking studies that trypsin was able to recognize and cleave both the high pathogenic and low pathogenic hemagglutinin, while furin could only cleave the high pathogenic hemagglutinin. An analysis of binding energies indicated that furin got most of its selectivity due to the interactions with P₁, P₄, and P₆, while having less interaction with P₂ and little interactions with P₃, P₅, P₇, and P₈. Some mutations of H5N1 H5 cleavage sequence fitted less well into furin and would reduce high pathogenicity of the virus. These findings hint that we should focus at the subsites P₁, P₄, and P₆ for developing drugs against H5N1 viruses.
Introduction: Advanced biliary tract carcinoma (BTC) has a poor prognosis and few treatment options. We compared the efficacy of the PD-1 monoclonal antibody (PD-1-mAb) combined regimens with the ...standard chemotherapy in the first-line and second-line treatment of advanced BTC. Methods: We retrospectively assessed the patients with advanced BTC, who received treatment at the First Affiliated Hospital of Sun Yat-Sen University and the Sun Yat-Sen University Cancer Center. The patients were treated with PD-1-mAb combined regimens or standard chemotherapy at the first line or treated with PD-1-mAb combined regimens or systematic therapy at the second line. Further subgroup analyses were assessed to identify superior regimens. Results: This study included 210 patients. The first-line PD-1-mAb combination group (n = 83) achieved longer median PFS (mPFS) (7.3 vs 5.3 months, p=0.001) and median OS (mOS) (15.6 vs 11.4 months, p=0.002) than the first-line standard chemotherapy group (n=76). Similarly, the second-line PD-1-mAb combination group (n=50) yielded longer mPFS (6.1 vs 2.6 months, p< 0.001) and mOS (11.7 vs 7.2 months, p=0.008) than the second-line systematic therapy group (n=51). Subgroup analyses showed that the PD-1-mAb combined with TKI group achieved better mPFS than the chemotherapy group whether in the first-line (HR = 0.468, p=0.005) or the second-line setting (HR = 0.45, p=0.009), but did not achieve superiority in mOS (both p> 0.05). Compared with the chemotherapy group, the PD-1-mAb combined with chemotherapy group achieved longer mOS (HR = 0.53, p=0.023) in the first-line setting and longer mPFS in the second-line setting (HR = 0.54, p=0.044). Conclusion: The PD-1-mAb combination therapy is superior to the standard chemotherapy in advanced or unresectable BTC, whether as a first-line or second-line treatment. Among the combination therapy, both the PD-1-mAb combined with TKI and combined with standard chemotherapy were promising options for advanced BTC patients.
While recent advances in band theory and sample growth have expanded the series of extremely large magnetoresistance (XMR) semimetals in transition-metal dipnictides TmPn2 (Tm=Ta, Nb; Pn=P, As, Sb), ...the experimental study on their electronic structure and the origin of XMR is still absent. Here, using angle-resolved photoemission spectroscopy combined with first-principles calculations and magnetotransport measurements, we performed a comprehensive investigation on MoAs2, which is isostructural to the TmPn2 family and also exhibits quadratic XMR. We resolve a clear band structure well agreeing with the predictions. Intriguingly, the unambiguously observed Fermi surfaces (FSs) are dominated by an open-orbit topology extending along both the 100 and 001 directions in the three-dimensional Brillouin zone. We further reveal the trivial topological nature of MoAs2 by bulk parity analysis. Based on these results, we examine the proposed XMR mechanisms in other semimetals, and conclusively ascribe the origin of quadratic XMR in MoAs2 to the carriers motion on the FSs with dominant open-orbit topology, innovating in the understanding of quadratic XMR in semimetals.
FIP-gsi, a fungal immunomodulatory protein found in Ganoderma sinense, has antitumour, anti-allergy and immunomodulatory activities and is regulated by the fip-gsi gene. In this study, we aimed to ...express the fip-gsi gene from G. sinense in Coprinopsis cinerea to increase yield of FIPs-gsi. A fungal expression vector pBfip-gsi containing the gpd promoter from Agaricus bisporus and the fip-gsi gene from the G. sinense was constructed and transformed into C. cinerea. PCR and Southern blotting analysis verified the successful integration of the exogenous gene fip-gsi into the genome of C. cinerea. RT-PCR and Northern blotting analysis confirmed that the fip-gsi gene was transcribed in C. cinerea. The yield of the FIP-gsi protein reached 314 mg kg⁻¹ fresh mycelia. The molecular weight of the FIP-gsi was 13 kDa, and the FIP-gsi was capable of hemagglutinating mouse red blood cells, but no such activity was observed towards human red blood cells in vitro. The fip-gsi from G. sinense has been successfully translated in C. cinerea, and the yield of bioactive FIP-gsi protein was high. This is the first report using the C. cinerea for the heterologous expression of FIP-gsi protein and it might supply a basis for large-scale production of the protein.
► The study paper reports stated a novel tunable millimeter-wave lowpass filter. ► The proposed concept can be satisfied the requirement of integrated RF Front–End system on the chip. ► It is ...possible to achieve miniaturization of filter. It is important for the next generation wireless communications.
In this paper, fully monolithic tunable millimeter-wave filters with tapped-line feedings are proposed using the CPW-based periodic structures with novel multiple-contact MEMS switches. Millimeter-wave low-pass filters were designed, fabricated, and tested. The cascaded CPW-based periodic structures, with low-pass intrinsic filtering characteristics, are reconfigured into a self-similar single unit cell by the operation of the novel multiple-contact MEMS switches with single actuation. The measured results of the reconfigurable low-pass filter show the 3-dB cutoff frequency change from 19 to 11
GHz with very small change in the average insertion loss from 1.3 to 1.9
dB. The chip size of the low-pass is 4.0
mm
×
1.6
mm.
Micro-channels have been widely used in variety of devices including bipolar plate, micro-chemical reactor, and micro-heat pipe. Electrochemical machining (ECM) is a promising approach to manufacture ...such structure on metallic surface. This paper proposed a modified jet-ECM for generating micro-channels. A flexible insulated mask with micro-through-holes was covered on the head surface of a metallic nozzle. During machining, the mask on the modified nozzle was contacted with the workpiece, and the jetting electrolyte in the nozzle was divided into different machining regions by the micro-through-holes in the mask; then, the micro-channels could be generated by moving the workpiece with an effective voltage applied between the nozzle and workpiece. Compared with traditional jet-ECM, the machining region in this method could be confined by the micro-through-hole, which was efficient for generating channel in micro-scale. In addition, multiple micro-channels could be generated by using a mask with a single row of micro-through-holes rather than assembling multiple nozzles. The experimental results showed that the pulse duty cycle has a significant influence on the dimension of micro-channel, while the pulse frequency has slight influence in contrast. In addition, the material removal rate (MRR), effective material removal rate (MRR
e
), and current efficiency (CE) were investigated with different machining parameters. The results indicated that although MRR was increased with the increasing pulse duty cycle, both MRR
e
and CE were reduced, leading to a deviation between the theory and experiment. The moving speed of workpiece also has a significant influence on CE. Increasing moving speed was useful for enhancing the CE, from 0.48 to 0.66 with the moving speed increasing from 20 to 80 μm/s. Finally, several kinds of micro-channels such as multiple micro-channels, micro-reactor, and cross micro-channels were well manufactured with this method, demonstrating a flexible and efficient process.
Ceramic coatings were formed on a Ti6Al4V alloy in a Na
2SiO
3–KOH–(NaPO
3)
6 aqueous solution, using the pulsating microarc oxidation method. A constant voltage (500
V) was applied to reveal the ...effect of the positive-pulse duty cycle on the growth rate, microstructure and phase composition of the coating. To obtain the optimum process, a constant current density (60
mA
cm
−2) combined with a stepped adjusting of the positive-pulse duty cycle was also proposed. The coatings are mainly composed of anatase and rutile (TiO
2). As the duty cycle increases, rutile increases and becomes the predominant phase. The coating formed at a duty cycle of 8% indicates an optimum combination of structure and thickness. When applying a constant current density, the growth rate of coatings is significantly increased compared with the application of a constant voltage. Further, using the stepped adjusting of the duty cycle, the microstructure of the coatings is improved obviously.
Although there is difficulty in growing a Ti-33Nb-4Sn single crystal due to its ultralow beta -phase stability, the single-crystal elastic constants of metastable beta -type Ti-33Nb-4Sn (wt%) alloy ...were extracted successfully from its polycrystal by in-situ synchrotron X-ray diffraction technique, to clarify the origin of the ultralow Young's modulus in its polycrystal. It is indicated that compared to binary TiCr, TiV and TiNb alloys, the Ti-33Nb-4Sn alloy possesses slightly lower beta -phase stability with respect to {110} super(-) shear (i.e., C') but much lower beta -phase stability regarding to {001} shear (i.e., C sub(44)). An analysis by the Hill approximation suggests that the ultralow isotropic polycrystalline Young's modulus (E sub(H)) of Ti-33Nb-4Sn alloy originates from the extremely low shear modulus C sub(44) as well as the relatively low C'. This indicates that in addition to C', C sub(44) has a significant contribution to the Young's modulus of polycrystal, which challenges a conventional understanding that the Young's modulus of beta -type Ti alloys is predominantly determined by C'.
Ceramic coatings were formed on the surface of Ti6Al4Valloy by microarc oxidation (MAO) in a Na2SiO3 system solution using a pulsed bipolar power supply. The microstructure, phase and elemental ...composition of the ceramic coatings were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The distribution of mechanical properties across the coating and its adhesion strength were determined by a nanoindentation and a shear test respectively. The tribological properties were evaluated using a pin-on-disk wear tester. The results show that the coatings are mainly composed of rutile and a small amount of anatase TiO2, with amorphous compounds from electrolyte components incorporated. The hardness and elastic modulus are about 8.5 GPa and 87.4 GPa for the compact region of the coating, and about 4 GPa and 150 GPa for the substrate. Similar profiles of hardness and elastic modulus along the coating of about 45 mum thickness is found, and both values in the compact region remain mainly constant before finally declining to below those of the substrate in the outer loose region. The adhesion strength is about 70 MPa. The friction coefficient of the coating against steel is as low as 0.2-0.3 at < 1 N load and at < 2500 sliding cycles. However, the oxidation wear mechanism occurring at the later stage of wear tests leads to a gradual increase of friction coefficient.
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