Aurora B facilitates cholangiocarcinoma progression by stabilizing c-Myc

Background: Cholangiocarcinoma(CCA), a malignancy that arises from biliary epithelial cells, has a dismal prognosis, and few targeted therapies are available. Aurora B, a key mitotic regulator, has been reported to be involved in the progression of various tumors, yet its role in CCA is still unclarified.Methods: Human CCA tissues and murine spontaneous CCA models were used to assess Aurora B expression in CCA. A loss-of-function model was constructed in CCA cells to determine the role of Aurora B in CCA progression. Subcutaneous and liver orthotopic xenograft models were used to assess the therapeutic potential of Aurora B inhibitors in CCA.Results: In murine spontaneous CCA models, Aurora B was significantly upregulated. Elevated Aurora B expression was also observed in 62.3% of human specimens in our validation cohort(143 CCA specimens), and high Aurora B expression was positively correlated with pathological parameters of tumors and poor survival. Knockdown of Aurora B by siRNA and heteroduplex oligonucleotide(HDO)or an Aurora B kinase inhibitor(AZD1152) significantly suppressed CCA progression via G2/M arrest induction. An interaction between Aurora B and c-Myc was found in CCA cells. Targeting Aurora B significantly reduced this interaction and accelerated the proteasomal degradation of c-Myc, suggesting that Aurora B promoted the malignant properties of CCA by stabilizing c-Myc. Furthermore, sequential application of AZD1152 or Aurora B HDO drastically improved the efficacy of gemcitabine in CCA.Conclusions: Aurora B plays an essential role in CCA progression by modulating c-Myc stability and represents a new target for treatment and chemosensitization in CCA.

A Localization Method of High Energy Transients for All-sky Gamma-ray Monitor

Fast and reliable localization of high-energy transients is crucial for characterizing the burst properties and guiding the follow-up observations.Localization based on the relative counts of different detectors has been widely used for all-sky gamma-ray monitors.There are two major methods for this count distribution localization:χ^(2)minimization method and the Bayesian method.Here we propose a modified Bayesian method that could take advantage of both the accuracy of the Bayesian method and the simplicity of the χ^(2)method.With comprehensive simulations,we find that our Bayesian method with Poisson likelihood is generally more applicable for various bursts than the χ^(2)method,especially for weak bursts.We further proposed a location-spectrum iteration approach based on the Bayesian inference,which could alleviate the problems caused by the spectral difference between the burst and location templates.Our method is very suitable for scenarios with limited computation resources or timesensitive applications,such as in-flight localization software,and low-latency localization for rapidly follow-up observations.

A novel geomagnetic satellite constellation:Science and applications

The European Space Agency(ESA)’s Swarm constellation of a trio of geomagnetic survey satellites in nearly circular polar orbits at altitude about 500 km was launched on 22 November 2013 and has been mapping the Earth’s global magnetic field in unprecedented details,helping scientists better understand how the geomagnetic field is generated and maintained inside the Earth’s fluid core and how the Earth’s external magnetic environment is changing.This review discusses a new novel constellation of the geomagnetic survey satellites that consists of at least four satellites:two satellites are in lower-latitude and nearly circular orbits at altitude about 450 km;two further satellites are marked by nearly polar but strongly eccentric orbits with perigee about 200 km and apogee about 5000 km.The new geomagnetic satellites are equipped with highly stable optical benches,high-precision fluxgate magnetometers and scalar magnetometers which are capable of mapping the Earth’s three-dimensional magnetic field in unprecedented accuracies and details.The new constellation will help elucidate different contributions to the measured geomagnetic field:the core dynamo field,the lithospheric magnetic field,the magnetic fields produced by currents in the ionosphere and the magnetosphere as well as by the currents coupling the ionosphere and magnetosphere,and the magnetic fields induced from the electrically conducting mantle,lithosphere and oceans.In comparison to the Swarm mission,it will provide higher-accuracy,higher-resolution and higher-dimension measurements of the geomagnetic field required for shedding new insights into the core dynamo processes and the Earth’s space magnetic systems along with a wide range of important applications.

A global mantle conductivity model derived from 8 years of Swarm satellite magnetic data

Mantle conductivity imaging is one of the scientific goals of the forthcoming Macao Science Satellite-1(MSS-1).To achieve this goal,we develop a data analysis and inversion scheme for satellite magnetic data to probe global one-dimensional(1D)mantle conductivity structures.Using this scheme,we present a new global mantle conductivity model by analyzing over 8 years of Swarm satellite magnetic data.First,after sophisticated data selection procedures and the removal of core and crustal fields,the inducing and induced spherical harmonic coefficients of magnetic potential due to the magnetospheric ring current are derived.Second,satellite Cresponses are estimated from the time series of these coefficients.Finally,the observed responses are inverted for both smooth and threejump conductivity models using a quasi-Newton algorithm.The obtained conductivity models are in general agreement with previous global mantle conductivity models.A comparison of our conductivity model with the laboratory conductivity model suggests the mean state of the upper mantle and transition zone is relatively dry.This scheme can be used to process the forthcoming Macao Science Satellite-1 magnetic data.

Design of the solar X-ray detector for the Macao Science Satellite-1B

The solar X-ray detector(SXD)onboard the Macao Science Satellite-1B was designed to monitor solar flare bursts and to study the solar activity in the 25th solar cycle.The SXD includes two parts:a soft X-ray detection unit and a hard X-ray detection unit.Both the soft X-ray detection unit and the hard X-ray detection unit include two collimators,two X-ray detectors(a silicon drift detector and a cadmium-zinc-telluride detector),and a processing circuit.Compared with similar instruments,the energy range of the SXD is wider(1–600 ke V)and the energy resolution is better(150 e V at 5.9 ke V,12%at 59.5 ke V,and 3%at 662 keV).

The effect of model errors in ensemble sequential assimilation of geomagnetic field

Earth’s magnetic field is generated in the fluid outer core through the dynamo process.Over the last decade,data assimilation has been used to retrieve the core dynamics and predict the evolution of the geomagnetic field.The presence of model errors in the geomagnetic data assimilation is inevitable because current numerical geodynamo models are still far from realistic core dynamics.In this paper,we investigate the effect of model errors in geomagnetic data assimilation based on ensemble Kalman filter(EnKF).We construct two dynamo models with different control parameters but exhibiting similar force balance and magnetic morphology at the core surface.We then use one dynamo model to generate synthetic observations and the other as the forward model in EnKF.Our test experiments show that the EnKF approach with the pre-setting model errors can nevertheless recover large-scale core surface flow and make a rough short-term(5-year)prediction.However,the data assimilation in the presence of model errors cannot keep improving the core state even though new observations are available.Motivated by the planned Macao Science Satellite-1,which is expected to provide improved internal geomagnetic field model,we also perform a test experiment using synthetic observations up to spherical harmonic degree l=18.Our results indicate that high-resolution observations are crucial in reconstructing small scale flow.

A qualitative study on nurses'reactions to inpatient suicide in a general hospital

Aims:To explore the impact of inpatient suicides on nurses working in front-line,the patterns of regulation and their needs for support.Methods:Data were collected through purposive sampling by conducting semi-structured and individual in-depth interviews in a tertiary referral hospital in China.Colaizzi's sevenstep phenomenological method was simultaneously used by two interviewers.Results:Reactions to inpatient suicides revealed three central themes:(1)inpatients were highly likely to commit suicide,(2)inpatient suicide was difficult to prevent,and(3)nurses lacked the necessary suicide prevention skills.Psychological responses mainly included shock and panic,self-accusation or guilt,sense of fear,and frustration.The impacts on practice were stress,excessive vigilance,and burnout.Avoidance and sharing of feelings played key roles in the regulation patterns of nurses.Conclusions:Nurses who experienced inpatient suicide became stressed.Effective interventions must be implemented to improve the coping mechanisms of nurses against the negative consequences of inpatient suicide.The findings of this study will allow administrators to gain insight into the impacts of inpatient suicides on nurses in general hospitals.Such information can be used to develop effective strategies and provide individual support and ongoing education.Consequently,nurses will acquire suicide prevention skills and help patients achieve swift recovery.

Precise Orbit Determination for the FY-3C Satellite Using Onboard BDS and GPS Observations from 2013, 2015, and 2017

Using the FengYun-3C(FY-3C)onboard BeiDou Navigation Satellite System(BDS)and Global Positioning System(GPS)data from 2013 to 2017,this study investigates the performance and contribution of BDS to precise orbit determination(POD)for a low-Earth orbit(LEO).The overlap comparison result indicates that code bias correction of BDS can improve the POD accuracy by 12.4%.The multi-year averaged one-dimensional(1D)root mean square(RMS)of the overlapping orbit differences(OODs)for the GPS-only solution is 2.0,1.7,and 1.5 cm,respectively,during the 2013,2015,and 2017 periods.The 1D RMS for the BDS-only solution is 150.9,115.0,and 47.4 cm,respectively,during the 2013,2015,and 2017 periods,which is much worse than the GPS-only solution due to the regional system of BDS and the few BDS channels of the FY-3C receiver.For the BDS and GPS combined solution(also known as the GC combined solution),the averaged 1D RMS is 2.5,2.3,and 1.6 cm,respectively,in 2013,2015,and 2017,while the GC combined POD presents a significant accuracy improvement after the exclusion of geostationary Earth orbit(GEO)satellites.The main reason for the improvement seen after this exclusion is the unfavorable satellite tracking geometry and poor orbit accuracy of GEO satellites.The accuracy of BDS-only and GC combined solutions have gradually improved from 2013 to 2017,thanks to improvements in the accuracy of International GNSS Service(IGS)orbit and clock products in recent years,especially the availability of a high-frequency satellite clock product(30 s sampling interval)since 2015.Moreover,the GC POD(without GEO)was able to achieve slightly better accuracy than the GPS-only POD in 2017,indicating that the fusion of BDS and GPS observations can improve the accuracy of LEO POD.GC combined POD can significantly improve the reliability of LEO POD,simply due to system redundancy.An increased contribution of BDS to LEO POD can be expected with the launch of more BDS satellites and with further improvements in the accuracy of BDS satellite products in the near future.

Superplastic Solid-Phase Welding of 40 Cr-T10A Steel

The microstructure of 40Cr and T10A steel sample and its surface to be welded is ultra-fined through salt-bath cyclic quenching and high frequency hardening, then the surface is cleaned. Under non-vacuum and no shielded gas, the welding parameter of isothermal superplastic solidphase welding and the effect of surface microstructure prior to pressure welding on the quality of joint are studied. At the temperature of 730~750℃ and at initial strain rate of (2~4) × 10-4 s-l, the strength of the joint is up to or close to that of 40Cr base metal in 3-5 min pressure welding

Research of UAV Flight Planning Parameters

UAV remote sensing as a digital aerial photography, not only has some basic photogrammetry features, but also has some other features. In this paper, aim at the characteristics of UAV remote sensing, begin with image data acquisition, the various parameter setting in the route planning were introduced, some of the principle was analyzed, the design of control points was described, and some of the considerations when laid control points were summarized.

The effect of the equatorially symmetric zonal winds of Saturn on its gravitational field

The penetration depth of Saturn’s cloud-level winds into its interior is unknown.A possible way of estimating the depth is through measurement of the effect of the winds on the planet’s gravitational field.We use a self-consistent perturbation approach to study how the equatorially symmetric zonal winds of Saturn contribute to its gravitational field.An important advantage of this approach is that the variation of its gravitational field solely caused by the winds can be isolated and identified because the leading-order problem accounts exactly for rotational distortion,thereby determining the irregular shape and internal structure of the hydrostatic Saturn.We assume that（i）the zonal winds are maintained by thermal convection in the form of non-axisymmetric columnar rolls and（ii）the internal structure of the winds,because of the Taylor-Proundman theorem,can be uniquely determined by the observed cloud-level winds.We calculate both the variation △J_n,n=2,4,6...of the axisymmetric gravitational coefficients J_n caused by the zonal winds and the non-axisymmetric gravitational coefficients △J_（nm） produced by the columnar rolls,where m is the azimuthal wavenumber of the rolls.We consider three different cases characterized by the penetration depth 0.36 R_S,0.2 R_S and 0.1 R_S,where R_S is the equatorial radius of Saturn at the 1-bar pressure level.We find that the high-degree gravitational coefficient （ J_（12）＋△J_（12）） is dominated,in all the three cases,by the effect of the zonal flow with ｜△J_（12）/J_（12）｜〉100%and that the size of the non-axisymmetric coefficientsdirectly reflects the depth and scale of the flow taking place in the Saturnian interior.

A model of Saturn inferred from its measured gravitational field

We present an interior model of Saturn with an ice-rock core,a metallic region,an outer molecular envelope and a thin transition layer between the metallic and molecular regions.The shape of Saturn’s 1 bar surface is irregular and determined fully self-consistently by the required equilibrium condition.While the ice-rock core is assumed to have a uniform density,three different equations of state are adopted for the metallic,molecular and transition regions.The Saturnian model is constrained by its known mass,its known equatorial and polar radii,and its known zonal gravitational coefficients,J_（2n）,n=1,2,3.The model produces an ice-rock core with equatorial radius 0.203 R_S,where R_S is the equatorial radius of Saturn at the 1-bar pressure surface;the core densityρ_c=10388.1 kgm^（3）corresponding to 13.06 Earth masses;and an analytical expression describing the Saturnian irregular shape of the 1-bar pressure level.The model also predicts the values of the higher-order gravitational coefficients,J_8,J_10 and J_12,for the hydrostatic Saturn and suggests that Saturn’s convective dynamo operates in the metallic region approximately defined by 0.2 R_S

Saturn＇s gravitational field induced by its equatorially antisymmetric zonal winds

The cloud-level zonal winds of Saturn are marked by a substantial equatorially antisymmetric component with a speed of about 50 m s^-1 which, if they are sufficiently deep, can produce measurable odd zonal gravitational coefficients △J2 k＋1, k = 1, 2, 3, 4. This study, based on solutions of the thermal-gravitational wind equation, provides a theoretical basis for interpreting the odd gravitational coefficients of Saturn in terms of its equatorially antisymmetric zonal flow. We adopt a Saturnian model comprising an ice-rock core, a metallic dynamo region and an outer molecular envelope. We use an equatorially antisymmetric zonal flow that is parameterized, confined in the molecular envelope and satisfies the solvability condition required for the thermal-gravitational wind equation. The structure and amplitude of the zonal flow at the cloud level are chosen to be consistent with observations of Saturn.We calculate the odd zonal gravitational coefficients △J2k＋1, k = 1, 2, 3, 4 by regarding the depth of the equatorially antisymmetric winds as a parameter. It is found that △J3 is-4.197 × 10^-8 if the zonal winds extend about 13 000 km downward from the cloud tops while it is-0.765 × 10^-8 if the depth is about 4000 km. The depth/profile of the equatorially antisymmetric zonal winds can eventually be estimated when the high-precision measurements of the Cassini Grand Finale become available.

Lower-order zonal gravitational coefficients caused by zonal circulations inside gaseous planets: Convective flows and numerical comparison between modeling approaches

To infer the internal equilibrium structure of a gaseous planet, especially the equation of state(EOS) and size of its inner core,requires accurate determination of lower-order zonal gravitational coefficients. Modeling of the gravitational signature associated with deep zonal circulation depends critically upon reliable subtraction of the dynamical components from totally derived gravitational coefficients. In the era of the Juno mission and the Grand Finale phase of the Cassini mission, it is timely and necessary to revisit and examine the so-called ‘Thermal Wind Equation(TWE)’, which has been extensively utilized to diagnose the dynamical parts of the gravitational fields measured by the two spacecrafts. TWE treats as negligible a few terms in the full equation of balance. However, the self-gravitational anomaly of the distorted fluid, unlike oblateness effects of solid-body rotation, is not a priori minor and thus should not be neglected in the name of approximation. Another equation, the ‘Thermal Gravitational Wind Equation(TGWE)’, includes this important additional term;we compare it with the TWE and show that physically the TGWE models a fundamentally different balance from the TWE and delivers numerical results considerably different from models based on the TWE. We conclude that the TWE balance cannot be relied upon to produce realistic convection models. Only after the TGWE balance is obtained can the relative importance of terms be assessed.The calculations we report here are based on two types of zonal circulations that are produced by realistically possible convections inside planets, instead of being constructed or assumed.

Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

Respiratory disease caused by coronavirus infection remains a global health crisis.Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their effcacy on emerging coronaviruses in the future,including SARS-CoV-2 variants,might be compromised.Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses.Cathepsin L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response.Here,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and CAPN1.The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of a-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1.Both showed potent and broad-spectrum anticoronaviral activities in vitro,and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern(VOCs)with ECso values ranging from 0.80 to 161.7 nM in various cells.Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance.Moreover,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in mice.In addition,both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model.And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%.Further evaluation showed that 14a and 14b exhibited excellent antiinflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia.Taken together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

High-precision modeling of tide-induced 3-D magnetic field and analysis of geomagnetic satellite orbit requirements

Ground-based magnetic observatories and geomagnetic satellites can observe the induced magnetic field generated by the motion of seawater containing sodium and chlorine ions.Calculating the three-dimensional(3-D)spatial distribution of tide-induced magnetic fields(TIMF)is crucial for inverting the electrical conductivity structure of the oceanic lithosphere.It also serves as an essential basis for designing optimal geomagnetic observatories and satellite orbits.However,existing methods for simulating TIMF suffer from limitations in inaccurately modeling realistic coastlines,heterogeneous land and sea surface properties,and complex deep Earth structures,thereby the interpretational level of TIMF data is reduced.To overcome this issue,we developed a tetrahedral-based finite element method for simulating TIMF,which can efficiently approximate realistic coastlines,heterogeneous land and sea surface properties,and complex deep Earth structures.Firstly,we derived the boundary value problem for the seawater motion-induced electromagnetic field,which was solved using the vector finite element method based on tetrahedral elements.Secondly,using the latest ocean depth and seafloor sediment layer models,we constructed a 3-D conductivity model of the Earth,which includes realistic coastlines,heterogeneous land and sea conductivity distributions.We then computed the TIMF using the M_(2)tidal source as an example and validated our method by comparing it with results obtained from spherical harmonic finite element and integral equation methods.Finally,utilizing the computed high-precision M_(2),N_(2),and O1 TIMF signals,we marked global observatories capable of observing strong M_(2),N_(2),and O1 TIMF signals and predicted alternative stations suitable for tide signal observations.Additionally,we calculated TIMF at heights of 450 and 200 km for the Macao Science Satellite 1 and its subsequent satellites.The results indicate that the amplitude of the tidal-induced magnetic field at 200 km is approximately twice that at 450 km.The maximum amplitudes of M_(2),N_(2),and O1 TIMF at 200 km are eight,two,and three times the measurement accuracy of the magnetic sensing payload(0.5 nT),respectively.The 200 km orbit has great potential for detecting high-resolution electrical structures of the seafloor lithosphere and asthenosphere in regions such as New Zealand,southern Iceland,the southern Indian Ocean,the Ross Sea region of Antarctica,and the Sea of Okhotsk.It also holds the potential for studying large-scale oceanic dynamic processes and properties.

Determination of global geodetic parameters using satellite laser ranging to Galileo,GLONASS,and BeiDou satellites

The new Global Navigation Satellite System(GNSS)satellites,including GLONASS,Galileo,and BeiDou system,are equipped with Laser Retroreflector Arrays(LRA)to support Satellite Laser Ranging(SLR)tracking,which contributes to the estimation of global geodetic parameters.In this study,we estimate the global geodetic parameters using the SLR observations to GNSS satellites and also investigate the effects of different data processing strategies on the estimated Earth Rotation Parameters(ERP),geocenter motion,and terrestrial scale.The results indicate that setting range bias parameters for each satellite-station pair can effectively account for the satellite-specific biases induced by LRAs,leading to smaller Root Mean Square Errors(RMSE)of the post-fit SLR residuals.Furthermore,estimating the range biases for each satellite-station pair improves the accuracy of the estimated station coordinates and ERP.We also examine the impact of different arc lengths on the estimates of ERP,geocenter motion,and terrestrial scale.The results show that extending arc length can significantly reduce the formal error of ERP.The 7-day strategy produces the smallest RMSEs of 473 microarcseconds and 495 microarcseconds for the estimated X-and Y-component of pole coordinates,and 52 microseconds for length-of-day,respectively.However,the estimated geocenter motion is less affected by the arc length,even the shortest 1-day arc strategy can capture the seasonal variations of geocenter motion in Z component.For scale estimation,extending the arc length notably improves the accuracy of the estimated station coordinates and scale,but this advantage becomes less noticeable in longer arcs.The 7-day solution also obtains the closet scale results compared to ITRF2014,with the RMSE of 2.10×10^(–9).

Orbit and clock products for quad-system satellites with undifferenced ambiguity fixing approach

Integer Ambiguity Resolution(IAR)can significantly improve the accuracy of GNSS Precise Orbit Determination(POD).Traditionally,the IAR in POD is achieved at the Double Differenced(DD)level.In this contribution,we develop an Un-Differenced(UD)IAR method for Global Positioning System(GPS)+BeiDou Navigation Satellite System(BDS)+Galileo navigation satellite system(Galileo)+Global'naya Navigatsionnaya Sputnikovaya Sistema(GLONASS)quad-system POD by calibrating UD ambiguities in the raw carrier phase and generating the so-called carrier range.Based on this method,we generate the UD ambiguity-fixed orbit and clock products for the Wuhan Innovation Application Center(IAC)of the International GNSS Monitoring and Assessment System(iGMAS).One-year observations in 2020 from 150 stations are employed to investigate performance of orbit and clock products.Notably,the UD Ambiguity Resolution(AR)yields more resolved integer ambiguities than the traditional DD AR,scaling up to 9%,attributable to its avoidance of station baseline formation.Benefiting from the removal of ambiguity parameters,the computational efficiency of parameter estimation undergoes a substantial 70%improvement.Compared with the float solution,the orbit consistencies of UD AR solution achieve the accuracy of 1.9,5.2,2.8,2.1,and 2.7 cm for GPS,BeiDou-2 Navigation Satellite System(BDS-2),BeiDou-3 Navigation Satellite System(BDS-3),Galileo,and GLONASS satellites respectively,reflecting enhancements of 40%,24%,54%,34%,and 42%.Moreover,the standard deviations of Satellite Laser Ranging(SLR)residuals are spanning 2.5–3.5 cm,underscoring a comparable accuracy to the DD AR solution,with discrepancies below 5%.A notable advantage of UD AR lies in its capability to produce the Integer Recovered Clock(IRC),facilitating Precise Point Positioning(PPP)AR without requiring additional Uncalibrated Phase Delay(UPD)products.To assess the performance of quad-system kinematic PPP based on IRC,a network comprising 120 stations is utilized.In comparison to the float solution,the IRC-based PPP AR accelerates convergence time by 31%and enhance positioning accuracy in the east component by 54%.

Orbit Determination and Thrust Estimation for Noncooperative Target Using Angle-Only Measurement

The classical interactive multimodel(IMM)algorithm has some disadvantages in tracking a noncooperative continuous thrust maneuvering spacecraft,such as poor steady-state accuracy,difficult selection of subfilter parameters,and mismatched model jump.To address the abovementioned problems,a variable-dimensional adaptive IMM strong tracking filtering algorithm(VAIMM-STEKF)is proposed to estimate the spacecraft’s position,velocity,and maneuvering acceleration state.VAIMM-STEKF contains 2 models,model 1 and model 2,which correspond to the tracking of the spacecraft in maneuvering and nonmaneuvering situations.Model 1 estimates the position and velocity of the spacecraft to ensure tracking accuracy when no maneuver occurs.Model 2 is a strong tracking filter with an augmented state.The adaptive IMM algorithm adjusts the fixed Markov transfer matrix in real time according to the model output probability.According to the different states of the spacecraft,the corresponding model interactive fusion method,together with the strong tracking filter,is adopted to ensure fast tracking when the spacecraft state changes.This method can also adapt to continuous thrust maneuvering spacecraft with different orders of magnitude.Simulation results show that the position accuracy of VAIMM-STEKF can be improved by approximately 27%and the speed accuracy can be enhanced by approximately 17%under different levels of maneuvering acceleration compared with those of the IMM algorithm.The convergence speed of VAIMM-STEKF is also better than the IMM algorithm.

Therapeutic Targeting of PKM2 Ameliorates NASH Fibrosis Progression in a Macrophage-Specific and Liver-Specific Manner

Nonalcoholic steatohepatitis(NASH)may soon become the leading cause of end-stage liver disease worldwide with limited treatment options.Liver fibrosis,which is driven by chronic inflammation and hepatic stellate cell(HSC)activation,critically determines morbidity and mortality in patients with NASH.Pyruvate kinase M2(PKM2)is involved in immune activation and inflammatory liver diseases;however,its role and therapeutic potential in NASH-related fibrosis remain largely unexplored.Bioinformatics screening and analysis of human and murine NASH livers indicated that PKM2 was upregulated in nonparenchymal cells(NPCs),especially macrophages,in the livers of patients with fibrotic NASH.Macrophage-specific PKM2 knockout(PKM2^(FL/FL)LysM-Cre)significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by a methionine-and choline-deficient(MCD)diet,a high-fat high-cholesterol(HFHC)diet,and a western diet plus weekly carbon tetrachloride injection(WD/CCl_(4)).Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophages reduced profibrotic Ly6C^(high) macrophage infiltration.Mechanistically,PKM2-dependent glycolysis promoted NLR family pyrin domain containing 3(NLRP3)activation in proinflammatory macrophages,which induced HSC activation and fibrogenesis.A pharmacological PKM2 agonist efficiently attenuated the profibrotic crosstalk between macrophages and HSCs in vitro and in vivo.Translationally,ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides,a novel oligonucleotide drug that preferentially accumulates in the liver,dose-dependently reversed NASH-related fibrosis without causing observable hepatotoxicity.The present study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis.Thus,therapeutic modulation of PKM2 in a macrophage-specific or liver-specific manner may serve as a novel strategy to combat NASH-related fibrosis.