Objective:Artemether is a semi-synthetic derivative of artemisinin and is widely used in the treatment of Plasmodium(P.)falciparum malaria.This study aimed to characterize the safety profile of artemether based on 15-...Objective:Artemether is a semi-synthetic derivative of artemisinin and is widely used in the treatment of Plasmodium(P.)falciparum malaria.This study aimed to characterize the safety profile of artemether based on 15-year data retrived from FDA adverse event reporting system(FAERS).Methods:This is a retrospective analysis on 15-year data of artemether-related adverse effects(AEs)retrieved from the FAERS.AEs were classified according to System Organ Class(SOC)and Preferred Terms(PT).Signal detection was performed using Reporting Odds Ratios(ROR),Proportional Reporting Ratios(PRR),and Empirical Bayes Geometric Mean(EBGM).Stratified analyses examined the impact of demographic factors such as sex,age,and time-to-onset.Temporal patterns and associated risk factors were also investigated.Results:Haemolytic anaemia and haemolysis emerged as the most frequently reported AEs,exhibiting significantly elevated RORs(males:ROR 381.36,95%CI 247.06-588.60;females:ROR 455.11,95%CI 286.43-723.12).Sex-specific differences were evident,with females showing a higher incidence of reproductive-related AEs,including spontaneous abortion and premature labour.Temporal trend analysis revealed that the majority of AEs occurred within the first 30 days after the initiation of artemether administration,indicating a rapid onset.The most affected SOCs were blood and lymphatic system disorders and hepatobiliary disorders.Conclusions:Artemether is associated with a notable frequency of early-onset AEs,particularly hematological and hepatobiliary disorders.The observed sex-specific vulnerability to reproductive AEs highlights the need for sex-conscious clinical approaches.Enhanced post-treatment monitoring and further investigations into the drug’s pharmacokinetics and mechanistic pathways are recommended.展开更多
AIM To summarize clinical presentations and treatment optionsof spinal gout in the literature from 2000 to 2014, and present theories for possible mechanism of spinal gout formation.METHODS The authors reviewed 68 pub...AIM To summarize clinical presentations and treatment optionsof spinal gout in the literature from 2000 to 2014, and present theories for possible mechanism of spinal gout formation.METHODS The authors reviewed 68 published cases of spinal gout, which were collected by searching "spinal gout" on Pub Med from 2000 to 2014. The data were analyzed for clinical features, anatomical location of spinal gout, laboratory studies, imaging studies, and treatment choices. RESULTS Of the 68 patients reviewed, the most common clinical presentation was back or neck pain in 69.1% of patients. The most common laboratory study was elevated uric acid levels in 66.2% of patients. The most common diagnostic image finding was hypointense lesion of the gout tophi on the T1-weighted magnetic resonance imaging scan. The most common surgical treatment performed was a laminectomy in 51.5% and non-surgical treatment was performed in 29.4% of patients.CONCLUSION Spinal gout most commonly present as back or neck pain with majority of reported patients with elevated uric acid. The diagnosis of spinal gout is confirmed with the presence of negatively birefringent monosodium urate crystals in tissue. Treatment for spinal gout involves medication for the reduction of uric acid level and surgery if patient symptoms failed to respond to medical treatment.展开更多
Coating polymer on the surface is an effective way to realize functional modification of the materials for diverse applications,which has been proved to enhance the stability of metal anodes in batteries.However,given...Coating polymer on the surface is an effective way to realize functional modification of the materials for diverse applications,which has been proved to enhance the stability of metal anodes in batteries.However,given the limited operability of coating from polymer dispersions,it is imperative to develop simple aqueous-based strategies from monomers for versatile polymer coating.Herein,a Ti_(3)C_(2)Tx MXene-assisted approach is proposed to construct polymer coating on zinc metal surfaces directly from the aqueous solution of monomers in an ice bath.By combining a doctor-blading method with spontaneous polymerization of monomers on the substrates at room temperature,a uniform,adhesive,and versatile coating layer assisted by a small amount of MXene is produced in one step.Additionally,MXene nanosheets serve as nanofillers to further enhance the mechanical strength and ionic conductivity of the polymer coating.Benefiting from good film formation and improved interfacial contact,the coated zinc anode exhibits a long cycling lifespan of over 1900 h.The assembled full cells show excellent cycling stability with a high capacity retention of 85.0%at 16 A g^(-1)over 2600 cycles.This work provides a simple and efficient way to produce polymer coatings directly from monomers,which may give new insights into design multifunctional polymer coatings for various applications.展开更多
There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as ...There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as a promising target pathway for developing novel bone anabolic drugs. Although neutralizing antibodies against the Wnt antagonist sclerostin have been tested,Wnt ligands themselves have not been fully explored as a potential therapy. Previous work has demonstrated Wnt7b as an endogenous ligand upregulated during osteoblast differentiation, and that Wnt7b overexpression potently stimulates bone accrual in the mouse. The earlier studies however did not address whether Wnt7b could promote bone formation when specifically applied to aged or fractured bones. Here we have developed a doxycycline-inducible strategy where Wnt7b is temporally induced in the bones of aged mice or during fracture healing. We report that forced expression of Wnt7b for 1 month starting at 15 months of age greatly stimulated trabecular and endosteal bone formation, resulting in a marked increase in bone mass. We further tested the effect of Wnt7b on bone healing in a murine closed femur fracture model. Induced expression of Wnt7b at the onset of fracture did not affect the initial cartilage formation but promoted mineralization of the subsequent bone callus. Thus, targeted delivery of Wnt7b to aged bones or fracture sites may be explored as a potential therapy.展开更多
Aim: To study the antitumor mechanism of OSW-1 in hepatocellular carcinoma. Materials and Methods: The expression profiling microarray was carried out to extract RNA from SK-Hep-1 which suffered from OSW-1. ρ0-SK-Hep...Aim: To study the antitumor mechanism of OSW-1 in hepatocellular carcinoma. Materials and Methods: The expression profiling microarray was carried out to extract RNA from SK-Hep-1 which suffered from OSW-1. ρ0-SK-Hep-1 was maintained SK-Hep-1 in MEM containing 100 μg/L ethidium bromide (EB), 1 mM sodium pyruvate and 50 μg/ml uridine for 40 days. Then confirmed COX-I and COX-II of mitochondrial DNA were knocked out. Cells suffered from OSW-1 or doxorubicin. Then cells were washed twice with cold PBS and incubated with DCFH-DA. Fluorescent signal was recorded by using Infinite 200 Pro multimode Plate readers. Results: OSW-1 elevates generation of ROS and Cytochrome C which are associated with the induction of apoptosis in SK-Hep-1 cells. We also demonstrate that OSW-1 does not depend on p53 to up-regulate the BH3-only protein Noxa. What is more noteworthy that the Caspase-9 and FADD are down-regulated in above process. Conclusion: OSW-1 induced special apoptosis is different from the mitochondrial death pathway and the death receptor pathway and final result is not Caspase family’s activating. This provides a novel theory that nonmalignant cells are significantly less sensitive to OSW-1 than cancer cell lines.展开更多
Hainan Island is located in the northwestern South China Sea at the boundary of two tectonic plates.Surface features and actual drilling have confirmed that there are rich geothermal resources in the area,with predict...Hainan Island is located in the northwestern South China Sea at the boundary of two tectonic plates.Surface features and actual drilling have confirmed that there are rich geothermal resources in the area,with predicted resources of 480 million GWh.On the basis of the 1:200,000 gravity and 1:10 aeromagnetic data and constrained by the well-explored Fushan Depression and Baocheng Rock Mass,we conducted a sys-tematic study of hot dry rocks and evaluated the development potential of the geothermal resources of the medium-depth and deep hot dry rocks in Hainan Island for thefirst time.The island is structurally active,with extensive granites,strong volcanic and earthquake activities,and many hot springs,indicating that the geothermal geological conditions are favorable.There are two types of hot dry rocks,sedimentary basin type and uplifted mountain type,on the island.The sedimentary basin-type hot dry rocks are mainly found in the north of the island and have an area of 2657 km^(2),an average depth of 2480 m,and an average heat reservoir temperature of 230℃ at 6000 m depth.Uplifted mountain-type hot dry rocks with a total area of 13,000 km^(2) mainly occur in Danzhou in the north of the island and Baocheng in the south.The heat reservoirs of these rocks are Yanshanian intrusive plutons and the average temperature is 236℃ at 6000 m depth.Nine favorable hot dry rock targets are identified,of whichfive are sedimentary basin types and four are uplifted mountain types.The Fushan and Eman depressions in north Hainan Island and the Baocheng Rock Mass in the south of the island are the preferred exploration targets.展开更多
At low Reynolds numbers,the variable flexibility of flapping insect wings is considered essential in improving the favorable aerodynamic forces.To further explore whether significant aerodynamic coupling exists betwee...At low Reynolds numbers,the variable flexibility of flapping insect wings is considered essential in improving the favorable aerodynamic forces.To further explore whether significant aerodynamic coupling exists between the microstructure and passive flexible deformation,this paper proposes three technical comparison airfoils:a corrugated wing with deformation,a symmetric flat plate wing with deformation,and a corrugated wing without deformation.Based on STAR-CCM+software,this paper numerically solves the Navier-Stokes equations using the fluid-structure interaction method.The results show that the aerodynamic performance of the flexible corrugated wing is better than that of the rigid corrugated wing,and its lift and thrust are both improved to a certain extent,and the thrust efficiency of the flexible corrugated wing is significantly higher than that of the flexible flat plate.Although the thrust is improved,a part of the lift is lost,and as the flapping amplitude increases past 35°,the disparity gradually increases.A comparison of the flexible technical airfoils shows that the corrugated structure promotes thrust and retards lift,which is closely related to the formation and dissipation of strong vortex rings during the downstroke phase.On the premise of maintaining typical flapping without falling,dragonflies can fly with skillful efficiency by adjusting the way they flap their wings.The results of this work provide new insight into the formation and role of thrust in flapping maneuvering flight and provide a specific reference for developing new bionic flapping-wing aircraft.展开更多
As an important promising biomarker,high frequency oscillations(HFOs)can be used to track epileptic activity and localize epileptogenic zones.However,visual marking of HFOs from a large amount of intracranial electroe...As an important promising biomarker,high frequency oscillations(HFOs)can be used to track epileptic activity and localize epileptogenic zones.However,visual marking of HFOs from a large amount of intracranial electroencephalogram(iEEG)data requires a great deal of time and effort from researchers,and is also very dependent on visual features and easily influenced by subjective factors.Therefore,we proposed an automatic epileptic HFO detection method based on visual features and non-intuitive multi-domain features.To eliminate the interference of continuous oscillatory activity in detected sporadic short HFO events,the iEEG signals adjacent to the detected events were set as the neighboring environmental range while the number of oscillations and the peak–valley differences were calculated as the environmental reference features.The proposed method was developed as a MatLab-based HFO detector to automatically detect HFOs in multi-channel,long-distance iEEG signals.The performance of our detector was evaluated on iEEG recordings from epileptic mice and patients with intractable epilepsy.More than 90%of the HFO events detected by this method were confirmed by experts,while the average missed-detection rate was<10%.Compared with recent related research,the proposed method achieved a synchronous improvement of sensitivity and specificity,and a balance between low false-alarm rate and high detection rate.Detection results demonstrated that the proposed method performs well in sensitivity,specificity,and precision.As an auxiliary tool,our detector can greatly improve the efficiency of clinical experts in inspecting HFO events during the diagnosis and treatment of epilepsy.展开更多
Traditional topology optimization methods often suffer from the“dimension curse”problem,wherein the com-putation time increases exponentially with the degrees of freedom in the background grid.Overcoming this challe...Traditional topology optimization methods often suffer from the“dimension curse”problem,wherein the com-putation time increases exponentially with the degrees of freedom in the background grid.Overcoming this challenge,we introduce a real-time topology optimization approach leveraging Conditional Generative Adversarial Networks with Gradient Penalty(CGAN-GP).This innovative method allows for nearly instantaneous prediction of optimized structures.Given a specific boundary condition,the network can produce a unique optimized structure in a one-to-one manner.The process begins by establishing a dataset using simulation data generated through the Solid Isotropic Material with Penalization(SIMP)method.Subsequently,we design a conditional generative adversarial network and train it to generate optimized structures.To further enhance the quality of the optimized structures produced by CGAN-GP,we incorporate Pix2pixGAN.This augmentation results in sharper topologies,yielding structures with enhanced clarity,de-blurring,and edge smoothing.Our proposed method yields a significant reduction in computational time when compared to traditional topology optimization algorithms,all while maintaining an impressive accuracy rate of up to 85%,as demonstrated through numerical examples.展开更多
RAC1 is a small-molecule G protein that regulates multiple cell cycle, cytoskeletal reorganization, cell migration, and apoptosis. FADD-dependent TRAIL can promote tumor metastasis through RAC1 and PI3K, and down-regu...RAC1 is a small-molecule G protein that regulates multiple cell cycle, cytoskeletal reorganization, cell migration, and apoptosis. FADD-dependent TRAIL can promote tumor metastasis through RAC1 and PI3K, and down-regulating RAC1 expression can reduce FasL-induced apoptosis. In addition, RIP1 bound to GTP acts as an activating protein for RAC1 and is involved in cytoskeletal reorganization. TRAF6 promotes migration and metastasis by regulating the RAS pathway in tumors. Thus, it is necessary to understand the interaction between RAC1 and TRAF6 as well as FADD and RIP1. In this study, we cultured hepatoma SK-Hep1 cells in vitro, specifically blocked the necroptosis pathway with Nec-1, and silenced FADD, RIP1 and TRAF6 gene expression using RNAi technology. At the same time, the expression of RAC1 was evaluated separately using RT-PCR and Western blot. The hepatoma SK-Hep1 cells survival rate was highest when the concentration of Nec-1 was 60 μM and the concentration of Z-vad-fmk was 20 μM. And the apoptosis rate of the transfected RAC1 siRNA cells was 3.59% compared with transfected siRNA cells 10.01% which was significantly decreased (P < 0.01). RAC1 could promote the occurrence of apoptosis in SK-Hep1 cells. RAC1 expression was suppressed in both protein and gene level in SK-Hep1 cells when the TRAF6 gene was silenced, but there was no significant change in RAC1 gene and protein expression when FADD and RIP1 genes were silenced. TRAF6 affects RAC1 expression and apoptosis in SK-Hep1 cells, while the FADD and RIP1 genes do not affect the role of RAC1. The TRAF6 gene is an important target in liver cancer cells.展开更多
Interleukin I receptor associated kinase 1 (IRAK1) is a downstream signal molecule of activated MyD88 recruitment, which can activate Fas associated death domain protein (FADD) to induce apoptosis. IRAK1 can also acti...Interleukin I receptor associated kinase 1 (IRAK1) is a downstream signal molecule of activated MyD88 recruitment, which can activate Fas associated death domain protein (FADD) to induce apoptosis. IRAK1 can also activate tumor necrosis factor-related factor 6 (TRAF6) and induce the expression of a series of downstream specific genes. IRAK1 is an essential factor in the induction of mitochondrial division and necroptosis. In the current study, RNAi technique was used to silence IRAK1, and the apoptosis and necroptosis rate of SK-Hep1 cells were detected by flow cytometry. The apoptosis and the necroptosis pathway of hepatoma SK-Hep1 cells were blocked separately, and the expressions of FADD, RIP1 and TRAF6 genes were silenced separately. The results showed when the expression of IRAK1 was down-regulated, the apoptosis and necroptosis rate of SK-Hep1 cells were significantly increased. With silenced FADD, RIP1 and TRAF6, respectively, the expression of IRAK1 protein had no significant change. However, the expression of IRAK1 mRNA decreased significantly (p < 0.01) after the silencing of RIP1 and TRAF6 genes, while the IRAK1 mRNA did not change significantly after the silencing of FADD genes;when z-VAD-FMK was interfered, the expression of IRAK1 mRNA decreased significantly after the silencing of TRAF6 genes, while the IRAK1 mRNA did not change significantly after the silencing of FADD and RIP1genes. The study shows that RAK1 gene inhibits apoptosis and necroptosis in SK-Hep1 cells. TRAF6 gene affected the role of IRAK1 in apoptosis and necroptosis, RIP1 gene affected the role of IRAK1 in apoptosis, while FADD gene did not affect the role of IRAK1 in apoptosis and necroptosis.展开更多
Flexible resources(FRs)in power systems serve as a critical enabler for integration of high share renewable energy.Conventional planning practices mainly focus on supplyside FRs while neglecting demand-side flexibilit...Flexible resources(FRs)in power systems serve as a critical enabler for integration of high share renewable energy.Conventional planning practices mainly focus on supplyside FRs while neglecting demand-side flexibility potential,which challenges the coordination of multi-source flexibility contributions.This paper presents a comprehensive flexibility evaluation framework integrating both supply-and demand-side resources.First,operational models characterize supply-side FRs(thermal,hydro and pumped storage)and demand-side FRs-including centralized air-conditioning systems with cold storage(CACCS),plug-in electric vehicles(PEVs),distributed battery storage(DBS),and time-shiftable appliances(TSA)-with parameters extracted from multi-source datasets.Second,a tri-dimensional flexibility metric system encompassing energy shifting,power balancing,and ramp rate is proposed,anchored by baseline net load.Third,a case study of a provincial power system reveals three key trends as the renewable penetration ratio(REPR)rises to 50%:1)increasing system flexibility requirements dominated by power surplus and upward net load ramping;2)shifting roles of coal plants toward deficit injection(surplus metrics dropping by>80%)and enhanced pumped storage utilization(4-10 times rise in surplus and ramping metrics);3)PEV and CACCS account for approximately 50%energy shifting flexibility in each season and show similar variation trends in metrics to pumped storage.The framework enables coordinated source-load flexibility planning,demonstrating demand-side FRs’capacity to offset conventional flexibility limitations and support renewable integration targets.展开更多
Gas wells often encounter blockages in gas recovery channels owing to fluid accumulation during the later stages of extraction,which adversely affects subsequent recovery efforts.These undesirable conditions(e.g.,high...Gas wells often encounter blockages in gas recovery channels owing to fluid accumulation during the later stages of extraction,which adversely affects subsequent recovery efforts.These undesirable conditions(e.g.,high condensate content,high temperature,and high salinity)often affect foaming agent performance.In this study,surfactants were screened using an airflow method that closely resembles field treatment method.Notably,alcohol ether sulfates(AE_(n)S)with various polyoxyethylene(EO)units demonstrated exceptional performance in terms of liquid unloading efficiency and foam stability.At 80℃,the unloading efficiency of AE_(n)S with two EO units(AE_(2)S)in a high NaCl mass concentration(up to 200 g/L)and high condensate volume fraction(up to 20%)reached 84%.The dynamic surface tension and interfacial tension measured at the same temperature were used to analyze the influence of the diffusion rate and interfacial characteristics on the AE_(n)S foam,while the viscosity and liquid film thickness measurements reflected the mechanical strength and liquid-carrying capacity.In addition,transmission electron microscopy(TEM)revealed that AE_(2)S formed“dendritic”micellar aggregates at a high NaCl mass concentration,which significantly enhanced the viscosity and stability of the foam.The interactions among AE_(n)S,NaCl,and H2O were analyzed using molecular dynamics,and it was confirmed from a molecular mechanics perspective that a stable structure can form among the three,contributing to the foam stability.These findings demonstrate the significant potential of the AE_(2)S foam for gas well deliquification.展开更多
The natural environment provides material essentials for human survival and development. The characteristics,processes, regional differentiation and forcing mechanisms of the elements of the natural environment(e.g. g...The natural environment provides material essentials for human survival and development. The characteristics,processes, regional differentiation and forcing mechanisms of the elements of the natural environment(e.g. geomorphology,climate, hydrology, soil, etc.) are the main objects of research in physical geography. China has a complex natural environment and huge regional differentiation and therefore it provides outstanding reserach opportunities in physical geography. This review summarizes the most important developments and the main contributions of research in the physical geography and human living environment in China during the past 70 years. The major topics addressed are the uplift of the Tibetan Plateau and the evolution of its cryosphere, the development of fluvial systems, the acidification of the vast arid region of the Asian interior, variations in the monsoon and westerly climate systems on multiple timescales, the development of lakes and wetlands, the watershed system model, soil erosion, past human-environment interactions, biogeography, and physical geographic zonality. After briefly introducing international research developments, we review the history of research in physical geography in China, focusing on the major achievements and major academic debates, and finally we summarize the status of current research and the future prospects. We propose that in the context of the national demand for the construction of an ecological civilization, we should make full use of the research findings of physical geography, and determine the patterns and mechanisms of natural environmental processes in order to continue to promote the continued contribution of physical geography to national development strategies, and to further contribute to the theory of physical geography from a global perspective.展开更多
For a future carbon-neutral society,it is a great challenge to coordinate between the demand and supply sides of a power grid with high penetration of renewable energy sources.In this paper,a general power distributio...For a future carbon-neutral society,it is a great challenge to coordinate between the demand and supply sides of a power grid with high penetration of renewable energy sources.In this paper,a general power distribution system of buildings,namely,PEDF(photovoltaics,energy storage,direct current,flexibility),is proposed to provide an effective solution from the demand side.A PEDF system integrates distributed photovoltaics,energy storages(including traditional and virtual energy storage),and a direct current distribution system into a building to provide flexible services for the external power grid.System topology and control strategies at the grid,building,and device levels are introduced and analyzed.We select representative work about key technologies of the PEDF system in recent years,analyze research focuses,and summarize their major challenges&future opportunities.Then,we introduce three real application cases of the PEDF system.On-site measurement results demonstrate its feasibility and advantages.With the rapid growth of renewable power production and electric vehicles,the PEDF system is a potential and promising approach for largescale integration of renewable energy in a carbon-neutral future.展开更多
In recent years,the developed hemostatic technologies are still difficult to be applied to the hemostasis of massive arterial and visceral hemorrhage,owing to their weak hemostatic function,inferior wet tissue adhesio...In recent years,the developed hemostatic technologies are still difficult to be applied to the hemostasis of massive arterial and visceral hemorrhage,owing to their weak hemostatic function,inferior wet tissue adhesion,and low mechanical properties.Herein,a mussel-inspired supramolecular interaction-cross-linked hydrogel with robust mechanical property(308.47±29.20 kPa)and excellent hemostatic efficiency(96.5%±2.1%)was constructed as a hemostatic sealant.Typically,we combined chitosan(CS)with silk fibroin(SF)by cross-linking them through tannic acid(TA)to maintain the structural stability of the hydrogel,especially for wet tissue adhesion ability(shear adhesive strength=29.66±0.36 kPa).Compared with other materials reported previously,the obtained CS/TA/SF hydrogel yielded a lower amount of blood loss and shorter time to hemostasis in various arterial and visceral bleeding models,which could be ascribed to the synergistic effect of wound closure under wet state as well as intrinsic hemostatic activity of CS.As a superior hemostatic sealant,the unique hydrogel proposed in this work can be exploited to offer significant advantages in the acute wound and massive hemorrhage with the restrictive access of therapeutic moieties.展开更多
As a dioxygenase. Ten-Eleven Translocation 2 （TET2） catalyzes subsequent steps of 5-methylcytosine （5mC） oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hei-natopoi...As a dioxygenase. Ten-Eleven Translocation 2 （TET2） catalyzes subsequent steps of 5-methylcytosine （5mC） oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hei-natopoietic stem cells, but its impact on mature hematopoietic cells is not well-characterized. Here we show that Tet2 plays an essential role in osteoclastogenesis. Dele- tion of Tet2 impairs the differentiation of osteoclast precursor cells （macrophages） and their matu- ration into bone-resorbing osteoclasts in vitro. Furthermore, Tet2 / mice exhibit mild osteopetrosis, accompanied by decreased number of osteoclasts in vivo. Tet2 loss in macrophages results in the altered expression of a set of genes implicated in osteoclast differentiation, such as Cehpa, Mafb, and Nfkbiz. Tet2 deletion also leads to a genome-wide alteration in the level of 5-hydroxymethylcytosine （ShmC） and altered expression of a specific subset of macrophage genes associated with osteoclast differentiation. Furthermore, Tet2 interacts with Runxl and negatively modulates its transcriptional activity. Our studies demonstrate a novel molecular mechanism controlling osteoclast differentiation and function by Tet2, that is, through interactions with Runxl and the maintenance of genomie 5hmC. Targeting Tet2 and its pathway could be a potential therapeutic strategy for the prevention and t,＇eatment of abnormal bone mass caused by the deregulation of osteoclast activities.展开更多
Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes.Through metabolic engineering,bioorthogonal groups can be tagged onto cell membranes,which se...Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes.Through metabolic engineering,bioorthogonal groups can be tagged onto cell membranes,which selectively attach to cargos with paired groups via bioorthogonal reactions.Due to its simplicity,high efficiency,and specificity,bioorthogonal chemistry has demonstrated great application potential in drug delivery.On the one hand,bioorthogonal reactions improve therapeutic agent delivery to target sites,overcoming off-target distribution.On the other hand,nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions,providing approaches to developing multi-functional drug delivery systems(DDSs).In this review,we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal groups.We then highlight recent breakthroughs in developing active targeting DDSs to tumors,immune systems,or bacteria by bioorthogonal chemistry,as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs(biomimetic DDSs,cell-based DDSs,bacteria-based and phage-based DDSs)and hydrogels.Finally,we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug delivery.We expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment.展开更多
Deficiency of natural killer(NK)cells shows a significant impact on tumor progression and failure of immunotherapy.It is highly desirable to boost NK cell immunity by upregulating active receptors and relieving the im...Deficiency of natural killer(NK)cells shows a significant impact on tumor progression and failure of immunotherapy.It is highly desirable to boost NK cell immunity by upregulating active receptors and relieving the immunosuppressive tumor microenvironment.Unfortunately,mobilization of NK cells is hampered by poor accumulation and short retention of drugs in tumors,thus declining antitumor efficiency.Herein,we develop an acid-switchable nanoparticle with self-adaptive aggregation property for co-delivering galunisertib and interleukin 15(IL-15).The nanoparticles induce morphology switch by a decomposition-metal coordination cascade reaction,which provides a new methodology to trigger aggregation.It shows self-adaptive size-enlargement upon acidity,thus improving drug retention in tumor to over 120 h.The diameter of agglomerates is increased and drug release is effectively promoted following reduced p H values.The nanoparticles activate both NK cell and CD8+T cell immunity in vivo.It significantly suppresses CT26 tumor in immune-deficient BALB/c mice,and the efficiency is further improved in immunocompetent mice,indicating that the nanoparticles can not only boost innate NK cell immunity but also adaptive T cell immunity.The approach reported here provides an innovative strategy to improve drug retention in tumors,which will enhance cancer immunotherapy by boosting NK cells.展开更多
文摘Objective:Artemether is a semi-synthetic derivative of artemisinin and is widely used in the treatment of Plasmodium(P.)falciparum malaria.This study aimed to characterize the safety profile of artemether based on 15-year data retrived from FDA adverse event reporting system(FAERS).Methods:This is a retrospective analysis on 15-year data of artemether-related adverse effects(AEs)retrieved from the FAERS.AEs were classified according to System Organ Class(SOC)and Preferred Terms(PT).Signal detection was performed using Reporting Odds Ratios(ROR),Proportional Reporting Ratios(PRR),and Empirical Bayes Geometric Mean(EBGM).Stratified analyses examined the impact of demographic factors such as sex,age,and time-to-onset.Temporal patterns and associated risk factors were also investigated.Results:Haemolytic anaemia and haemolysis emerged as the most frequently reported AEs,exhibiting significantly elevated RORs(males:ROR 381.36,95%CI 247.06-588.60;females:ROR 455.11,95%CI 286.43-723.12).Sex-specific differences were evident,with females showing a higher incidence of reproductive-related AEs,including spontaneous abortion and premature labour.Temporal trend analysis revealed that the majority of AEs occurred within the first 30 days after the initiation of artemether administration,indicating a rapid onset.The most affected SOCs were blood and lymphatic system disorders and hepatobiliary disorders.Conclusions:Artemether is associated with a notable frequency of early-onset AEs,particularly hematological and hepatobiliary disorders.The observed sex-specific vulnerability to reproductive AEs highlights the need for sex-conscious clinical approaches.Enhanced post-treatment monitoring and further investigations into the drug’s pharmacokinetics and mechanistic pathways are recommended.
文摘AIM To summarize clinical presentations and treatment optionsof spinal gout in the literature from 2000 to 2014, and present theories for possible mechanism of spinal gout formation.METHODS The authors reviewed 68 published cases of spinal gout, which were collected by searching "spinal gout" on Pub Med from 2000 to 2014. The data were analyzed for clinical features, anatomical location of spinal gout, laboratory studies, imaging studies, and treatment choices. RESULTS Of the 68 patients reviewed, the most common clinical presentation was back or neck pain in 69.1% of patients. The most common laboratory study was elevated uric acid levels in 66.2% of patients. The most common diagnostic image finding was hypointense lesion of the gout tophi on the T1-weighted magnetic resonance imaging scan. The most common surgical treatment performed was a laminectomy in 51.5% and non-surgical treatment was performed in 29.4% of patients.CONCLUSION Spinal gout most commonly present as back or neck pain with majority of reported patients with elevated uric acid. The diagnosis of spinal gout is confirmed with the presence of negatively birefringent monosodium urate crystals in tissue. Treatment for spinal gout involves medication for the reduction of uric acid level and surgery if patient symptoms failed to respond to medical treatment.
基金the support from the National Natural Science Foundation of China(51972228 and 22109116)the TJU Nanoyang-Neware Joint Laboratory for Energy Innovation。
文摘Coating polymer on the surface is an effective way to realize functional modification of the materials for diverse applications,which has been proved to enhance the stability of metal anodes in batteries.However,given the limited operability of coating from polymer dispersions,it is imperative to develop simple aqueous-based strategies from monomers for versatile polymer coating.Herein,a Ti_(3)C_(2)Tx MXene-assisted approach is proposed to construct polymer coating on zinc metal surfaces directly from the aqueous solution of monomers in an ice bath.By combining a doctor-blading method with spontaneous polymerization of monomers on the substrates at room temperature,a uniform,adhesive,and versatile coating layer assisted by a small amount of MXene is produced in one step.Additionally,MXene nanosheets serve as nanofillers to further enhance the mechanical strength and ionic conductivity of the polymer coating.Benefiting from good film formation and improved interfacial contact,the coated zinc anode exhibits a long cycling lifespan of over 1900 h.The assembled full cells show excellent cycling stability with a high capacity retention of 85.0%at 16 A g^(-1)over 2600 cycles.This work provides a simple and efficient way to produce polymer coatings directly from monomers,which may give new insights into design multifunctional polymer coatings for various applications.
基金supported by AR060456 (F.L.), AR047867 (M.J.S.)the Washington University Musculoskeletal Research Center (NIH P30 AR057235)
文摘There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as a promising target pathway for developing novel bone anabolic drugs. Although neutralizing antibodies against the Wnt antagonist sclerostin have been tested,Wnt ligands themselves have not been fully explored as a potential therapy. Previous work has demonstrated Wnt7b as an endogenous ligand upregulated during osteoblast differentiation, and that Wnt7b overexpression potently stimulates bone accrual in the mouse. The earlier studies however did not address whether Wnt7b could promote bone formation when specifically applied to aged or fractured bones. Here we have developed a doxycycline-inducible strategy where Wnt7b is temporally induced in the bones of aged mice or during fracture healing. We report that forced expression of Wnt7b for 1 month starting at 15 months of age greatly stimulated trabecular and endosteal bone formation, resulting in a marked increase in bone mass. We further tested the effect of Wnt7b on bone healing in a murine closed femur fracture model. Induced expression of Wnt7b at the onset of fracture did not affect the initial cartilage formation but promoted mineralization of the subsequent bone callus. Thus, targeted delivery of Wnt7b to aged bones or fracture sites may be explored as a potential therapy.
文摘Aim: To study the antitumor mechanism of OSW-1 in hepatocellular carcinoma. Materials and Methods: The expression profiling microarray was carried out to extract RNA from SK-Hep-1 which suffered from OSW-1. ρ0-SK-Hep-1 was maintained SK-Hep-1 in MEM containing 100 μg/L ethidium bromide (EB), 1 mM sodium pyruvate and 50 μg/ml uridine for 40 days. Then confirmed COX-I and COX-II of mitochondrial DNA were knocked out. Cells suffered from OSW-1 or doxorubicin. Then cells were washed twice with cold PBS and incubated with DCFH-DA. Fluorescent signal was recorded by using Infinite 200 Pro multimode Plate readers. Results: OSW-1 elevates generation of ROS and Cytochrome C which are associated with the induction of apoptosis in SK-Hep-1 cells. We also demonstrate that OSW-1 does not depend on p53 to up-regulate the BH3-only protein Noxa. What is more noteworthy that the Caspase-9 and FADD are down-regulated in above process. Conclusion: OSW-1 induced special apoptosis is different from the mitochondrial death pathway and the death receptor pathway and final result is not Caspase family’s activating. This provides a novel theory that nonmalignant cells are significantly less sensitive to OSW-1 than cancer cell lines.
基金Research on Exploration and Evaluation of hot dry rock Resources and Target Area Preference(No.2023-HNKT-001)This article is sponsored by the New Energy Technology Development and Application Research Project No.2022DJ5503.
文摘Hainan Island is located in the northwestern South China Sea at the boundary of two tectonic plates.Surface features and actual drilling have confirmed that there are rich geothermal resources in the area,with predicted resources of 480 million GWh.On the basis of the 1:200,000 gravity and 1:10 aeromagnetic data and constrained by the well-explored Fushan Depression and Baocheng Rock Mass,we conducted a sys-tematic study of hot dry rocks and evaluated the development potential of the geothermal resources of the medium-depth and deep hot dry rocks in Hainan Island for thefirst time.The island is structurally active,with extensive granites,strong volcanic and earthquake activities,and many hot springs,indicating that the geothermal geological conditions are favorable.There are two types of hot dry rocks,sedimentary basin type and uplifted mountain type,on the island.The sedimentary basin-type hot dry rocks are mainly found in the north of the island and have an area of 2657 km^(2),an average depth of 2480 m,and an average heat reservoir temperature of 230℃ at 6000 m depth.Uplifted mountain-type hot dry rocks with a total area of 13,000 km^(2) mainly occur in Danzhou in the north of the island and Baocheng in the south.The heat reservoirs of these rocks are Yanshanian intrusive plutons and the average temperature is 236℃ at 6000 m depth.Nine favorable hot dry rock targets are identified,of whichfive are sedimentary basin types and four are uplifted mountain types.The Fushan and Eman depressions in north Hainan Island and the Baocheng Rock Mass in the south of the island are the preferred exploration targets.
基金the National Natural Science Foundation of China(Grant No.11862017).
文摘At low Reynolds numbers,the variable flexibility of flapping insect wings is considered essential in improving the favorable aerodynamic forces.To further explore whether significant aerodynamic coupling exists between the microstructure and passive flexible deformation,this paper proposes three technical comparison airfoils:a corrugated wing with deformation,a symmetric flat plate wing with deformation,and a corrugated wing without deformation.Based on STAR-CCM+software,this paper numerically solves the Navier-Stokes equations using the fluid-structure interaction method.The results show that the aerodynamic performance of the flexible corrugated wing is better than that of the rigid corrugated wing,and its lift and thrust are both improved to a certain extent,and the thrust efficiency of the flexible corrugated wing is significantly higher than that of the flexible flat plate.Although the thrust is improved,a part of the lift is lost,and as the flapping amplitude increases past 35°,the disparity gradually increases.A comparison of the flexible technical airfoils shows that the corrugated structure promotes thrust and retards lift,which is closely related to the formation and dissipation of strong vortex rings during the downstroke phase.On the premise of maintaining typical flapping without falling,dragonflies can fly with skillful efficiency by adjusting the way they flap their wings.The results of this work provide new insight into the formation and role of thrust in flapping maneuvering flight and provide a specific reference for developing new bionic flapping-wing aircraft.
基金This work was supported by the National Natural Science Foundation of China(81630098,81671282,and 61471314).
文摘As an important promising biomarker,high frequency oscillations(HFOs)can be used to track epileptic activity and localize epileptogenic zones.However,visual marking of HFOs from a large amount of intracranial electroencephalogram(iEEG)data requires a great deal of time and effort from researchers,and is also very dependent on visual features and easily influenced by subjective factors.Therefore,we proposed an automatic epileptic HFO detection method based on visual features and non-intuitive multi-domain features.To eliminate the interference of continuous oscillatory activity in detected sporadic short HFO events,the iEEG signals adjacent to the detected events were set as the neighboring environmental range while the number of oscillations and the peak–valley differences were calculated as the environmental reference features.The proposed method was developed as a MatLab-based HFO detector to automatically detect HFOs in multi-channel,long-distance iEEG signals.The performance of our detector was evaluated on iEEG recordings from epileptic mice and patients with intractable epilepsy.More than 90%of the HFO events detected by this method were confirmed by experts,while the average missed-detection rate was<10%.Compared with recent related research,the proposed method achieved a synchronous improvement of sensitivity and specificity,and a balance between low false-alarm rate and high detection rate.Detection results demonstrated that the proposed method performs well in sensitivity,specificity,and precision.As an auxiliary tool,our detector can greatly improve the efficiency of clinical experts in inspecting HFO events during the diagnosis and treatment of epilepsy.
基金supported by the National Key Research and Development Projects (Grant Nos.2021YFB3300601,2021YFB3300603,2021YFB3300604)Fundamental Research Funds for the Central Universities (No.DUT22QN241).
文摘Traditional topology optimization methods often suffer from the“dimension curse”problem,wherein the com-putation time increases exponentially with the degrees of freedom in the background grid.Overcoming this challenge,we introduce a real-time topology optimization approach leveraging Conditional Generative Adversarial Networks with Gradient Penalty(CGAN-GP).This innovative method allows for nearly instantaneous prediction of optimized structures.Given a specific boundary condition,the network can produce a unique optimized structure in a one-to-one manner.The process begins by establishing a dataset using simulation data generated through the Solid Isotropic Material with Penalization(SIMP)method.Subsequently,we design a conditional generative adversarial network and train it to generate optimized structures.To further enhance the quality of the optimized structures produced by CGAN-GP,we incorporate Pix2pixGAN.This augmentation results in sharper topologies,yielding structures with enhanced clarity,de-blurring,and edge smoothing.Our proposed method yields a significant reduction in computational time when compared to traditional topology optimization algorithms,all while maintaining an impressive accuracy rate of up to 85%,as demonstrated through numerical examples.
文摘RAC1 is a small-molecule G protein that regulates multiple cell cycle, cytoskeletal reorganization, cell migration, and apoptosis. FADD-dependent TRAIL can promote tumor metastasis through RAC1 and PI3K, and down-regulating RAC1 expression can reduce FasL-induced apoptosis. In addition, RIP1 bound to GTP acts as an activating protein for RAC1 and is involved in cytoskeletal reorganization. TRAF6 promotes migration and metastasis by regulating the RAS pathway in tumors. Thus, it is necessary to understand the interaction between RAC1 and TRAF6 as well as FADD and RIP1. In this study, we cultured hepatoma SK-Hep1 cells in vitro, specifically blocked the necroptosis pathway with Nec-1, and silenced FADD, RIP1 and TRAF6 gene expression using RNAi technology. At the same time, the expression of RAC1 was evaluated separately using RT-PCR and Western blot. The hepatoma SK-Hep1 cells survival rate was highest when the concentration of Nec-1 was 60 μM and the concentration of Z-vad-fmk was 20 μM. And the apoptosis rate of the transfected RAC1 siRNA cells was 3.59% compared with transfected siRNA cells 10.01% which was significantly decreased (P < 0.01). RAC1 could promote the occurrence of apoptosis in SK-Hep1 cells. RAC1 expression was suppressed in both protein and gene level in SK-Hep1 cells when the TRAF6 gene was silenced, but there was no significant change in RAC1 gene and protein expression when FADD and RIP1 genes were silenced. TRAF6 affects RAC1 expression and apoptosis in SK-Hep1 cells, while the FADD and RIP1 genes do not affect the role of RAC1. The TRAF6 gene is an important target in liver cancer cells.
文摘Interleukin I receptor associated kinase 1 (IRAK1) is a downstream signal molecule of activated MyD88 recruitment, which can activate Fas associated death domain protein (FADD) to induce apoptosis. IRAK1 can also activate tumor necrosis factor-related factor 6 (TRAF6) and induce the expression of a series of downstream specific genes. IRAK1 is an essential factor in the induction of mitochondrial division and necroptosis. In the current study, RNAi technique was used to silence IRAK1, and the apoptosis and necroptosis rate of SK-Hep1 cells were detected by flow cytometry. The apoptosis and the necroptosis pathway of hepatoma SK-Hep1 cells were blocked separately, and the expressions of FADD, RIP1 and TRAF6 genes were silenced separately. The results showed when the expression of IRAK1 was down-regulated, the apoptosis and necroptosis rate of SK-Hep1 cells were significantly increased. With silenced FADD, RIP1 and TRAF6, respectively, the expression of IRAK1 protein had no significant change. However, the expression of IRAK1 mRNA decreased significantly (p < 0.01) after the silencing of RIP1 and TRAF6 genes, while the IRAK1 mRNA did not change significantly after the silencing of FADD genes;when z-VAD-FMK was interfered, the expression of IRAK1 mRNA decreased significantly after the silencing of TRAF6 genes, while the IRAK1 mRNA did not change significantly after the silencing of FADD and RIP1genes. The study shows that RAK1 gene inhibits apoptosis and necroptosis in SK-Hep1 cells. TRAF6 gene affected the role of IRAK1 in apoptosis and necroptosis, RIP1 gene affected the role of IRAK1 in apoptosis, while FADD gene did not affect the role of IRAK1 in apoptosis and necroptosis.
基金supported in part by the National Key Research and Development Program of China(2024YFC3810101)the National Natural Science Foundation of China(52394223)Beijing Municipal Science&Technology Commission,and Administrative Commission of Zhongguancun Science Park(No.Z231100006123004).
文摘Flexible resources(FRs)in power systems serve as a critical enabler for integration of high share renewable energy.Conventional planning practices mainly focus on supplyside FRs while neglecting demand-side flexibility potential,which challenges the coordination of multi-source flexibility contributions.This paper presents a comprehensive flexibility evaluation framework integrating both supply-and demand-side resources.First,operational models characterize supply-side FRs(thermal,hydro and pumped storage)and demand-side FRs-including centralized air-conditioning systems with cold storage(CACCS),plug-in electric vehicles(PEVs),distributed battery storage(DBS),and time-shiftable appliances(TSA)-with parameters extracted from multi-source datasets.Second,a tri-dimensional flexibility metric system encompassing energy shifting,power balancing,and ramp rate is proposed,anchored by baseline net load.Third,a case study of a provincial power system reveals three key trends as the renewable penetration ratio(REPR)rises to 50%:1)increasing system flexibility requirements dominated by power surplus and upward net load ramping;2)shifting roles of coal plants toward deficit injection(surplus metrics dropping by>80%)and enhanced pumped storage utilization(4-10 times rise in surplus and ramping metrics);3)PEV and CACCS account for approximately 50%energy shifting flexibility in each season and show similar variation trends in metrics to pumped storage.The framework enables coordinated source-load flexibility planning,demonstrating demand-side FRs’capacity to offset conventional flexibility limitations and support renewable integration targets.
文摘Gas wells often encounter blockages in gas recovery channels owing to fluid accumulation during the later stages of extraction,which adversely affects subsequent recovery efforts.These undesirable conditions(e.g.,high condensate content,high temperature,and high salinity)often affect foaming agent performance.In this study,surfactants were screened using an airflow method that closely resembles field treatment method.Notably,alcohol ether sulfates(AE_(n)S)with various polyoxyethylene(EO)units demonstrated exceptional performance in terms of liquid unloading efficiency and foam stability.At 80℃,the unloading efficiency of AE_(n)S with two EO units(AE_(2)S)in a high NaCl mass concentration(up to 200 g/L)and high condensate volume fraction(up to 20%)reached 84%.The dynamic surface tension and interfacial tension measured at the same temperature were used to analyze the influence of the diffusion rate and interfacial characteristics on the AE_(n)S foam,while the viscosity and liquid film thickness measurements reflected the mechanical strength and liquid-carrying capacity.In addition,transmission electron microscopy(TEM)revealed that AE_(2)S formed“dendritic”micellar aggregates at a high NaCl mass concentration,which significantly enhanced the viscosity and stability of the foam.The interactions among AE_(n)S,NaCl,and H2O were analyzed using molecular dynamics,and it was confirmed from a molecular mechanics perspective that a stable structure can form among the three,contributing to the foam stability.These findings demonstrate the significant potential of the AE_(2)S foam for gas well deliquification.
基金supported by the National Natural Science Foundation of China (Grant No. 41842050)
文摘The natural environment provides material essentials for human survival and development. The characteristics,processes, regional differentiation and forcing mechanisms of the elements of the natural environment(e.g. geomorphology,climate, hydrology, soil, etc.) are the main objects of research in physical geography. China has a complex natural environment and huge regional differentiation and therefore it provides outstanding reserach opportunities in physical geography. This review summarizes the most important developments and the main contributions of research in the physical geography and human living environment in China during the past 70 years. The major topics addressed are the uplift of the Tibetan Plateau and the evolution of its cryosphere, the development of fluvial systems, the acidification of the vast arid region of the Asian interior, variations in the monsoon and westerly climate systems on multiple timescales, the development of lakes and wetlands, the watershed system model, soil erosion, past human-environment interactions, biogeography, and physical geographic zonality. After briefly introducing international research developments, we review the history of research in physical geography in China, focusing on the major achievements and major academic debates, and finally we summarize the status of current research and the future prospects. We propose that in the context of the national demand for the construction of an ecological civilization, we should make full use of the research findings of physical geography, and determine the patterns and mechanisms of natural environmental processes in order to continue to promote the continued contribution of physical geography to national development strategies, and to further contribute to the theory of physical geography from a global perspective.
基金supported in part by the National Natural Science Foundation of China(No.52208112)the major consulting project of the Chinese Academy of Engineering(52021-HYZD-16)+1 种基金the Energy Foundation(No.G-2209-34123),the China Postdoctoral Science Foundation(2021M701935)the Shuimu Tsinghua Scholar Program of Tsinghua University(2021SM001).
文摘For a future carbon-neutral society,it is a great challenge to coordinate between the demand and supply sides of a power grid with high penetration of renewable energy sources.In this paper,a general power distribution system of buildings,namely,PEDF(photovoltaics,energy storage,direct current,flexibility),is proposed to provide an effective solution from the demand side.A PEDF system integrates distributed photovoltaics,energy storages(including traditional and virtual energy storage),and a direct current distribution system into a building to provide flexible services for the external power grid.System topology and control strategies at the grid,building,and device levels are introduced and analyzed.We select representative work about key technologies of the PEDF system in recent years,analyze research focuses,and summarize their major challenges&future opportunities.Then,we introduce three real application cases of the PEDF system.On-site measurement results demonstrate its feasibility and advantages.With the rapid growth of renewable power production and electric vehicles,the PEDF system is a potential and promising approach for largescale integration of renewable energy in a carbon-neutral future.
基金This work was financially supported by the National Natural Science Foundation of China(Grant No 51903050)the Natural Science Foundation of Fujian Province(Grant No.2019J01258)+2 种基金the Opening Project of State Key Laboratory of Polymer Materials Engineering(Sichuan University,Grant No.sklpme2019-4-34)the Key Program of Qingyuan Innovation Laboratory(Grant No.00221002)the Fuzhou University Testing Fund of Precious Apparatus(Grant No.2021T025).
文摘In recent years,the developed hemostatic technologies are still difficult to be applied to the hemostasis of massive arterial and visceral hemorrhage,owing to their weak hemostatic function,inferior wet tissue adhesion,and low mechanical properties.Herein,a mussel-inspired supramolecular interaction-cross-linked hydrogel with robust mechanical property(308.47±29.20 kPa)and excellent hemostatic efficiency(96.5%±2.1%)was constructed as a hemostatic sealant.Typically,we combined chitosan(CS)with silk fibroin(SF)by cross-linking them through tannic acid(TA)to maintain the structural stability of the hydrogel,especially for wet tissue adhesion ability(shear adhesive strength=29.66±0.36 kPa).Compared with other materials reported previously,the obtained CS/TA/SF hydrogel yielded a lower amount of blood loss and shorter time to hemostasis in various arterial and visceral bleeding models,which could be ascribed to the synergistic effect of wound closure under wet state as well as intrinsic hemostatic activity of CS.As a superior hemostatic sealant,the unique hydrogel proposed in this work can be exploited to offer significant advantages in the acute wound and massive hemorrhage with the restrictive access of therapeutic moieties.
基金supported by grants from the National Institutes of Health (Grant No. CA172408 to MX and FCY, Grant No. HL112294 to MX)the Leukemia & Lymphoma Society (LLS) (SCOR program to SN, FCY, and MX+7 种基金 translational grant to SN)University of Miami Sylvester Comprehensive Cancer Center (SCCC to MX and FCY), the United Statessupported by the Ministry of Science and Technology of China (Grant Nos. 2017YFA0103402to WY)National Natural Science Foundation of China (Grant Nos. 81629001 to MX, 81670102 to ZZ, 81600136 to YC, and 81421002 to WY)CAMS Innovation Fund for Medical Sciences (Grant Nos. 2017-I2M-3-015 to WY and 2016-I2M-1-017 to YC)Tianjin Application Foundation and Advanced Technology Research Program (Grant Nos. 16JCYBJC25200 to ZZ and 17JCQNJC09800 to YC)SKLEH-Pilot Research Grand (Grant No. ZK16-3 to ZZ)Peking Union Medical College Youth Fund (Grant No. 3332016092 to YC), China
文摘As a dioxygenase. Ten-Eleven Translocation 2 （TET2） catalyzes subsequent steps of 5-methylcytosine （5mC） oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hei-natopoietic stem cells, but its impact on mature hematopoietic cells is not well-characterized. Here we show that Tet2 plays an essential role in osteoclastogenesis. Dele- tion of Tet2 impairs the differentiation of osteoclast precursor cells （macrophages） and their matu- ration into bone-resorbing osteoclasts in vitro. Furthermore, Tet2 / mice exhibit mild osteopetrosis, accompanied by decreased number of osteoclasts in vivo. Tet2 loss in macrophages results in the altered expression of a set of genes implicated in osteoclast differentiation, such as Cehpa, Mafb, and Nfkbiz. Tet2 deletion also leads to a genome-wide alteration in the level of 5-hydroxymethylcytosine （ShmC） and altered expression of a specific subset of macrophage genes associated with osteoclast differentiation. Furthermore, Tet2 interacts with Runxl and negatively modulates its transcriptional activity. Our studies demonstrate a novel molecular mechanism controlling osteoclast differentiation and function by Tet2, that is, through interactions with Runxl and the maintenance of genomie 5hmC. Targeting Tet2 and its pathway could be a potential therapeutic strategy for the prevention and t,＇eatment of abnormal bone mass caused by the deregulation of osteoclast activities.
基金Financial supports from the National Natural Science Foundation of China(81903548,32170935,32070927 and 81690265)the Strategic Priority Research Program of CAS(XDA12050307)the Youth Innovation Promotion Association of CAS(2019283)are gratefully acknowledged.
文摘Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes.Through metabolic engineering,bioorthogonal groups can be tagged onto cell membranes,which selectively attach to cargos with paired groups via bioorthogonal reactions.Due to its simplicity,high efficiency,and specificity,bioorthogonal chemistry has demonstrated great application potential in drug delivery.On the one hand,bioorthogonal reactions improve therapeutic agent delivery to target sites,overcoming off-target distribution.On the other hand,nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions,providing approaches to developing multi-functional drug delivery systems(DDSs).In this review,we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal groups.We then highlight recent breakthroughs in developing active targeting DDSs to tumors,immune systems,or bacteria by bioorthogonal chemistry,as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs(biomimetic DDSs,cell-based DDSs,bacteria-based and phage-based DDSs)and hydrogels.Finally,we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug delivery.We expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment.
基金Financial supports from the National Natural Science Foundation of China(32170935,81903548,and31930066)the Youth Innovation Promotion Association of CAS(2019283,China)Shandong Provincial Natural Science Foundation(ZR2019PH013,China)are gratefully acknowledged。
文摘Deficiency of natural killer(NK)cells shows a significant impact on tumor progression and failure of immunotherapy.It is highly desirable to boost NK cell immunity by upregulating active receptors and relieving the immunosuppressive tumor microenvironment.Unfortunately,mobilization of NK cells is hampered by poor accumulation and short retention of drugs in tumors,thus declining antitumor efficiency.Herein,we develop an acid-switchable nanoparticle with self-adaptive aggregation property for co-delivering galunisertib and interleukin 15(IL-15).The nanoparticles induce morphology switch by a decomposition-metal coordination cascade reaction,which provides a new methodology to trigger aggregation.It shows self-adaptive size-enlargement upon acidity,thus improving drug retention in tumor to over 120 h.The diameter of agglomerates is increased and drug release is effectively promoted following reduced p H values.The nanoparticles activate both NK cell and CD8+T cell immunity in vivo.It significantly suppresses CT26 tumor in immune-deficient BALB/c mice,and the efficiency is further improved in immunocompetent mice,indicating that the nanoparticles can not only boost innate NK cell immunity but also adaptive T cell immunity.The approach reported here provides an innovative strategy to improve drug retention in tumors,which will enhance cancer immunotherapy by boosting NK cells.
