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Qingqing Li,1,* Tong Su,2,* Xu Zhang,3,* Yanfeng Pan,1,* Shengli Ma,4 Lu Zhang,4 Xianqiang Zhang,1 Xiaojuan Gao1 1Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China; 2Department of Medical, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China; 3Department of Hepatobiliary Pancreatic Surgery, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou city, People’s Republic of China; 4Department of Infectious Diseases, The People’s Hospital of Yongcheng, Yongcheng city, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanfeng Pan, Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Jinshui District, Zhengzhou city, 450000, People’s Republic of China, Tel +8613938448759, Email panfirstfeng@163.comPurpose: To observe the efficacy and safety of anlotinib as a first-line treatment for patients with advanced hepatocellular carcinoma (aHCC) in a real-word environment, explore the optimal treatment regimen for patients with aHCC using anlotinib as a first-line treatment.Patients and Methods: Data from 62 patients with aHCC who received anlotinib single-drug first-line therapy between February 2019 and November 2021. Patients received anlotinib monotherapy, which may be interrupted or discontinued or changed in the event of unacceptable or severe adverse events (AEs) or failure to inhibit tumor progression. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate(ORR), disease control rate (DCR), overall survival (OS), and safety.Results: Among the 62 patients, in the best overall response assessment, there were 12 with complete response (CR; 19.4%), 17 with partial response (PR; 27.4%), 25 with stable disease (SD; 40.3%), and 8 with progressive disease (PD; 14.5%). The ORR and DCR were 46.8% and 87.1%, respectively. Among the 11 patients who received tyrosine kinase inhibitors (TKIs) combined with programmed death 1 (PD-1) inhibitors after disease progression, three (27.3%) had CR, one (9.1%) had PR, three (27.3%) had SD, and four (36.4%) had PD. Therefore, the ORR and DCR were 36.4% and 63.6%, respectively. The median PFS for anlotinib monotherapy was 7.37 months (95% confidence interval [CI]: 5.88– 8.86) and the median OS did not reach. AEs occurred in 95.2% of patients during anlotinib monotherapy, with the most common being thrombocytopenia (51.6%). The incidence of grade ≥ 3 AEs was 38.7%.Conclusion: Anlotinib is effective and well-tolerated as a first-line treatment for patients with aHCC. Treatment with TKIs and PD-1 inhibitors after disease progression has also shown preliminary efficacy and safety; therefore, sequential therapy with anlotinib-TKIs and PD-1 inhibitors may be an effective treatment for patients with aHCC.Keywords: hepatocellular carcinoma, anlotinib, sequential therapy, real world

Generating and manipulating magnon quantum states for quantum information processing is a central topic in quantum magnonics. The conventional strategy amplifies the nonlinear interaction among magnons to manifest their quantum correlations at cryogenic temperatures, which is challenging for magnets with vanishingly small nonlinearities. Here we propose an unconventional approach to prepare entangled states of two distant magnon modes by applying a two-tone Floquet field to each magnet inside a microwave cavity. The Floquet driving can effectively generate parametric interaction between magnons and photons, and thus opens an indirect entanglement channel between the two magnon modes mediated by cavity photons. By optimizing the relative ratio of the magnon-photon coupling and the detuning between the magnon modes, the two magnon modes can reach a stationary and robust entanglement, of which the strength is enhanced compared with entanglement generated via magnetic nonlinearities. Furthermore, one-way steering between the two magnets is realized by engineering unequal damping rates of the two magnets while the steering asymmetry can be efficiently modulated by tuning the coupling strength of magnons and cavity photons. The essential physics of our findings universally applies to a wide class of magnets with small nonlinearities and may find promising applications in engineering robust magnon quantum states for quantum information science.

Fault frictional healing Δμ controls the storage of the elastic strain energy in the fault wall rocks and the re-occurrence of earthquakes in pre-existing faults. In the last 40 years, fault healing has been investigated with laboratory slide-hold-slide (SHS) experiments aimed at reproducing the seismic cycle. Experiments performed with different rocks types (e.g., granite, limestone, basalt) revealed that (1) Δμ increases with hold time th and, (2) the frictional healing rate β =Δμ/log th >0. This increase in fault frictional strength with th is interpreted as due to the increase (1) in the real area of contact or (2) of chemical bond strength. However, most of these experiments were conducted under room conditions, whereas natural earthquakes generally nucleate at ambient temperatures T >150℃ and in the presence of pressurized fluids. Under these ambient conditions, fluid-assisted and thermally-activated processes (pressure-solution transfer, stress corrosion, etc.) may impact on the magnitude of Δμ and on β.In this study, SHS experiments were performed on gabbro-built gouges (grain size 200℃, Δμ decreases and β switches to negative values (300s, and at T=400℃: β= 0.0057±0.0020 for holds 100s.The underlying mechanism responsible for the decrease in Δμ and the transition from β > 0 to β < 0 with the hold time, which could result in the transition from seismic to aseismic fault behavior in nature, is still poorly understood. However, high-resolution microstructural analyses conducted by scanning electron microscopy on experimental fault products rule out the formation of weak minerals (e.g., clays) in the gouge layer. Consequently, the weakening of the fault is probably related to the decrease in bond strength at the asperity contacts.The experimental data presented here suggest that fault healing of natural faults is controlled by the feedback of multiple physico-chemical processes associated with the slip history and type of fluid-rock interaction under hydrothermal conditions.

Lipid nanoparticles (LNPs) are the most widely investigated delivery systems for nucleic acid-based therapeutics and vaccines. Loading efficiency of nucleic acids may vary with formulation conditions, and it is considered one of the critical quality attributes of LNP products. Current analytical methods for quantification of cargo loading in LNPs often require external standard preparations and preseparation of unloaded nucleic acids from LNPs; therefore, they are subject to tedious and lengthy procedures, LNP stability, and unpredictable recovery rates of the separated analytes. Here, we developed a modeling approach, which was based on locally weighted regression (LWR) of ultraviolet (UV) spectra of unpurified samples, to quantify the loading of nucleic acid cargos in LNPs

Motivated by recent advances in quantum dynamics, we investigate the dynamics of the system with $SU(1,1)$ symmetry. Instead of performing the time-ordered integral for the evolution operator of the time-dependent Hamiltonian, we show that the time evolution operator can be expressed as an $SU(1,1)$ group element. Since the $SU(1,1)$ group describes the "rotation" on a hyperbolic surface, the dynamics can be visualized on a Poincar\'e disk, a stereographic projection of the upper hyperboloid. As an example, we present the trajectory of the revival of Bose-Einstein condensation and that of the scale-invariant Fermi gas on the Poincar\'e disk. Further considering the quantum gas in the oscillating lattice, we also study the dynamics of the system with time-dependent single-particle dispersion. Our results are hopefully to be checked in current experiments., Comment: 10 pages,4,figures

The small-scale unmanned aerial vehicle (UAV) helicopter has a complex structure, strong nonlinearity, coupling and open-loop instability, making it shake violently and even produce chaotic oscilla...

The fretting wear characteristics of spherical/spherical lateral contacts under different load conditions, contact angles, and the number of fretting cycles are studied. A spherical/spherical lateral fretting wear model is established in ABAQUS software. A UMESHMOTION subroutine for spherical/spherical contact models is written to simulate the fretting wear based on the energy model and the Fortran language. The results show that as the load increases, the contact width increases significantly and the wear depth decreases. It is also found that the rate of change of the wear depth gradually increases in the central portion of the contact area, and is relatively smooth in the contact edge portion. An increase in the magnitude of the moving load causes a small increase in the contact width and a significant increase in the wear depth. The rate of increase of the wear depth at the edge of the contact area gradually increases and the rate of increase of the wear depth at the center of the contact area changes linearly. As the contact angle increases, the contact form gradually changes to a positive contact. Meanwhile, the wear depth variation shifted from a “U” shape to a “W” shape, which caused the wear depth to decrease significantly at the contact center and eventually approach zero as the adhesive area appeared. In addition, with an increase in the number of fretting cycles, the wear depth was almost unchanged at the contact center portion but significantly increased at the edge portion.

To investigate the clinical value of Tie2-expressing monocytes (TEMs) in the early diagnosis of lung cancer and assess its correlation with angiogenesis, a total of 184 patients with non-small cell lung cancer (NSCLC), 101 patients with benign pulmonary disease (BPD), and 77 healthy controls were enrolled in our study. The distribution of TEMs in lung tissue was determined by immunofluorescence staining. Lung microvascular density was assessed by immunohistochemical staining. Receiver-operating characteristic (ROC) curve analysis was performed to assess the diagnostic value of TEM frequency. Patients with NSCLC were followed up for 26 months. We found that the TEM frequency in peripheral blood monocytes of patients with NSCLC was significantly greater than that in patients with BPD and healthy controls. TEM frequency showed a correlation with NSCLC recurrence. The majority of TEMs in tumor tissues were localized around blood vessels; tumoral TEM frequency showed a positive correlation with microvascular density. High percentage of TEMs in the peripheral blood was associated with poor overall survival. ROC curve analysis revealed the potential diagnostic value of circulating TEM frequency in NSCLC. Thus, we believe that TEM frequency is related to angiogenesis in tumor tissues and may serve as a diagnostic marker for NSCLC.

Fault friction is one of the most significant parameters controlling fault slip behavior and earthquake mechanics. Great success has been achieved in understanding the stability of fault slip, nucleation of earthquake and dynamic weakening mechanism in the past decades by performing low (~1 μm/s, sub-seismic conditions) to high (~1 m/s, seismic conditions) velocity friction experiments. However, extrapolating these experimental results to nature remains limited. In fact, for low velocity experiments, usually performed with tri-axial machines, though the hydrothermal conditions can be imposed, the shear displacement is limited to several millimeters neglecting the effect of cumulative displacement. For high velocity experiments aiming at reproducing coseismic fault slip, the implementation of hydrothermal conditions has been hindered by technical difficulties leaving high-velocity friction property of faults under realistic crustal conditions still ambiguous.Here we exploited a Low to High Velocity rotary shear apparatus (LHV) equipped with a dedicated hydrothermal pressure vessel installed at the Institute of Geology, China Earthquake Administration, to investigate the frictional behavior of gabbro under realistic hydrothermal conditions. The samples were sheared at effective normal stresses of 10 MPa and 20 MPa, velocities (V) spanning from 1 μm/s to 0.1 m/s, displacement up to 3 m, under temperature conditions (T) up to 400 ℃ and pore pressure (Pf) up to 30 MPa. Our results showed that at T = 300 ℃ and Pf = 10 MPa (pore fluid as liquid), dramatic slip weakening happened at all tested velocities. At slip initiation the friction coefficient increased sharply to a peak value (~0.7±0.05), then decayed toward a residual value of ~0.35. Instead at T = 400 ℃ and Pf =10 MPa (pore fluid as vapor), we observed that friction remained high (~0.7) at V < 10 mm/s and slip weakening only occurred for V ≥ 10 mm/s. For experiments at T = 400 ℃ and Pf =30 MPa (pore fluid in supercritical conditions), slip weakening behavior occurred in most cases. The evolution of friction coefficient with displacement was complex, e.g., two peaks, large variations. Moreover, comparative experiments conducted at relatively low temperature suggested that mechanisms leading to the dramatic weakening under such a wide velocity range could be closely linked with both fluid-rock interactions and the physical state of the fluid. However, what exact fluid-rock reactions are involved is still an open question, which will be investigated by further microstructural and mineralogical analysis. The unique frictional behavior observed in this study challenges the results obtained from small-displacements experiments in many aspects and improves our understanding on friction behavior of faults in geothermal applications.

We assessed the seismic potential around the northeastern edge of the Longmenshan fault zone (LFZ) by analyzing the aftershocks of the 2008 Mw 7.9 Wenchuan earthquake, focusing on the right-lateral strike-slip Qingchuan fault (QCF). The data used in the present study were collected from a dense network of broadband seismographs, installed after the Mw 7.9 mainshock by the China Earthquake Administration. We analyzed 440 aftershocks that occurred around the northeastern part of the aftershock area between December 2008 and June 2009, the local magnitudes (ML) of which ranged from 2.0 to 5.2. We determined 127 well-constrained focal mechanism solutions for these aftershocks down to ML 2.5 by using P-wave polarity data in conjunction with body-wave amplitudes. An analysis of the stress tensor inversion revealed that, upon approaching the QCF from the LFZ, the stress field changes from a reverse faulting regime to a mixed regime containing strike-slip components and the orientation of the maximum compressional stress changes from a NW–SE to a WNW–ESE direction. This stress field favors a right-lateral strike-slip movement along the fault. The slip tendency analysis revealed that the QCF is regarded as being favorably oriented to the present-day stress field. The coseismic Coulomb stress changes induced by the mainshock increased along the preferred fault plane in the northeastern half of the QCF, which is further loaded by viscoelastic relaxation. This evidence suggests that the potential for a future earthquake in the QCF is high.

While developing a synthetic route for GDC-0326, a PI3Kα selective inhibitor, a side product was identified which was adversely impacting process chemistry development. To aid in optimization of a viable synthetic pathway for the drug, it was decided to characterize this impurity. Initial efforts using typical high-resolution mass spectrometry data coupled with NMR analysis were unable to unambiguously identify the structure. The NMR analysis was hampered by a severe lack of protons in the core of the structure. While efforts were being made to produce suitable crystals for definitive x-ray analysis, Raman analysis was undertaken. The vibrational data were compared to DFT calculations for the two most likely structures. This data, along with chemical reasoning, eventually led to successful prediction of structure 2, which was ultimately confirmed by single crystal x-ray diffractometry data.

The motion of rigid particles driven by gravity in a viscous fluid is relevant in many natural and industrial processes, and many investigations have been carried out on spheroidal particles. However, many non-spherical particles with complex surface structure exist in nature. So far, only few people have proposed an effective particle-laden flow model for practical engineering applications. Therefore, we put forward a set of models combined with the realistic shape data for practical engineering simulation. We present a systematic approach by researching the three-dimensional sedimentation of realistic shaped particles in a viscous fluid. The DEM-FDM method is used for numerical simulations. The morphology of particles is obtained by micro X-ray computed tomography. The novelty of our present contribution relies on the combination of the Monte Carlo Scheme with FDM to calculate the hydrodynamic force acting on the particles. In addition, a new procedure is proposed using overlapping spheres to reconstruct the particles' micro-morphology in three dimensions. We verify the numerical implementation of our approach and validate it against the analytical solution for ellipsoids in uniform shear flow derived by Jeffery, 1922. We investigate the sedimentation of realistic shaped particles separately and that of four particles with different morphologies in an incompressible fluid. The aspect ratio (AR) ranges from 1.2 to 2.2. The density ratio is 2.6. The results show that the path instability of sedimentation of realistic shaped particles with different morphologies occurs, but the behaviour of their sedimentation is closely related to the particles' AR. The sedimentation velocity of particles with sharp corners is obviously higher than that of flat particles, which have a relatively lower sphericity. For particles with higher AR, the phenomenon of ‘helical sedimentation’ appears. This paper provides an effective method to simulate the interactions of particles and their morphology in an incompressible fluid in engineering applications, with continuous improvements in computer performance.

A new model to accurately obtain the contact stiffness of the mechanical joint surface is established, which satisfies the continuous smooth contact characteristics of the asperity and also considers the influence of the asperity interaction. In order to satisfy the continuous and smooth contact characteristics of the asperity, the interpolation interval of the Hermite polynomial function is improved to make the asperity contact stiffness curve smoothly transition in the elastic, elastoplastic and completely plastic stages. Further, the contact situation of the joint surface considering the asperity interaction is explored through micro-contact analysis and mechanism research. Finally, using statistical principles, the microscopic contact model is extended to the entire joint surface, and the contact stiffness model of the joint surface is established. The simulation results show that the asperity stiffness model satisfies the continuous smooth contact characteristics. Surface roughness is the main factor that affects the contact stiffness, and the influence of the asperity interaction cannot be ignored.

Bradykinin and bradykinin B2 receptors (B2R) play important roles in both the peripheral and central nervous systems. The aim of this study was to explore the changes of bradykinin and B2R in spinal cord ischemic injury (SCII) and whether bradykinin treatment would improve the neurologic function of SCII rats. The rats were divided into the sham group, the SCII group, and three doses of bradykinin (50, 100, 150 μg/kg) groups. The neurologic function was assessed by the Basso, Beattie, and Bresnahan (BBB) score at -1, 1, 3, 5, and 7 days postsurgery. Bradykinin concentration in serum and IL-6, TNF-α, and MCP-1 levels in the spinal cord were detected by ELISA. The mRNA expressions of B2R, IL-6, TNF-α, MCP-1, COX-2, and iNOS in the spinal cord were determined by RT-PCR. The protein expressions of B2R, COX-2, iNOS, p65, and p-p65 were detected by Western blot. Immunohistochemical staining was used to examine B2R expression in the L4-6 segments of the spinal cord. Bradykinin levels in serum and B2R expression in the spinal cord were downregulated in SCII rats. Bradykinin treatment significantly improved the hind limb motor function of SCII rats and increased B2R expression, inhibiting COX-2, iNOS, and p-p65 expression in the spinal cord of SCII rats together with a decrease of the inflammatory mediators of IL-6, TNF-α, and MCP-1 levels. Bradykinin administration activated B2R in the spinal cord of SCII rats, which may improve hind limb locomotor recovery by regulating the NF-κB signaling pathway to inhibit the inflammatory response. These findings may provide a theoretical basis for the clinical application of bradykinin in SCII.

A high-order differential feedback control (HODFC), which is a model free control strategy, is applied to the trajectory tracking of a quadrotor unmanned aerial vehicle (UAV) with unknown uncertainties in this paper. Two virtual control variables are introduced to decouple the quadrotor flight system. The third-order HOD (high-order differentiator) is proposed and used to estimate the differentials of reference input and the states of system. The second-order HODFC is designed to ensure the closed system has desired poles. A controller filter is used to compensate the unknown function and disturbance in the quadrotor system. A comparison between the HODFC and active disturbance rejection control (ADRC) is conducted. The simulation results illustrate that the HODFC method can ensure that the quadrotor output track the desired trajectory asymptotically with a smaller tracking error than the linear ADRC, even with unknown function and disturbance.

An outer-loop model-free controller called high order differential feedback control (HODFC) that can compute the velocity of position and yaw is applied to accomplish the flight tasks based on indoor optical positioning system. A high precision observer called high order differentiator (HOD) is introduced to observe the differential states of the system output and given input. A filtering signal of control output is incorporated in the control law to estimate the information related to system model. The remarkable features of the HODFC includes model-free performance, pole assignment based on theory, the disturbance suppression. Comparison results of the HODFC and the proportional-integral-derivative (PID) trajectory tracking experiment in height, yaw and x – y plane, and the disturbance experiments are presented to illustrate the superior performance of the HODFC method over the PID method.

In this paper, we introduce an optimal bias voltage searching strategy and maintaining method in BOTDA system based on dual sideband modulation. The system utilizes both up shifted and down shifted continuous wave light to generate Brillouin scattering light, while using the amplified pulsed light to boost the signal by stimulated Brillouin scatting effect. In order to obtain a clean Brillouin shifted curve along the fiber under test, the probe light must be in good signal to noise ratio. In addition, the intensity of shifted light should be stable as well. Therefore, we propose a novel control method of frequency shift in sideband modulation of a BOTDA system, which keeps the first order frequency-shifted light at its maximum signal to noise ratio and minimum light intensity fluctuation. We also implement static experiments to verify our proposed scheme. Strain/temperature tests were taken out to evaluate the performance of the BOTDA. Results showed that the resolution of BOTDA system could reach 13μe/0.65°C at 50 km fiber cable with spatial resolution of 0.5m.