查看更多>>摘要：The COVID-19 pandemic caused by SARS-CoV-2 virus is an ongoing global health burden.Severe cases of COVID-19 and the rare cases of COVID-19 vaccine-induced-thrombotic-thrombocytopenia(VITT)are both associated with thrombosis and thrombocytopenia;however,the underlying mechanisms remain inadequately understood.Both infection and vaccination utilize the spike protein receptor-binding domain(RBD)of SARS-CoV-2.We found that intravenous injection of recombinant RBD caused significant platelet clearance in mice.Further investigation revealed the RBD could bind platelets,cause platelet activation,and potentiate platelet aggregation,which was exacerbated in the Delta and Kappa variants.The RBD-platelet interaction was partially dependent on the β3 integrin as binding was significantly reduced inβ3-/-mice.Furthermore,RBD binding to human and mouse platelets was significantly reduced with related αⅡbβ3 antagonists and mutation of the RGD(arginine-glycine-aspartate)integrin binding motif to RGE(arginine-glycine-glutamate).We developed anti-RBD polyclonal and several monoclonal antibodies(mAbs)and identified 4F2 and 4H12 for their potent dual inhibition of RBD-induced platelet activation,aggregation,and clearance in vivo,and SARS-CoV-2 infection and replication in Vero E6 cells.Our data show that the RBD can bind platelets partially though αⅡbβ3 and induce platelet activation and clearance,which may contribute to thrombosis and thrombocytopenia observed in COVID-19 and VITT.Our newly developed mAbs 4F2 and 4H12 have potential not only for diagnosis of SARS-CoV-2 virus antigen but also importantly for therapy against COVID-19.
查看更多>>摘要：Thrombosis can cause life-threatening disorders.Unfortunately,current therapeutic methods for thrombosis using injecting thrombolytic medicines systemically resulted in unexpected bleeding complications.Moreover,the absence of practical imaging tools for thrombi raised dangers of undertreatment and overtreatment.This study develops a theranostic drug carrier,Pkr(IR-Ca/Pda-uPA)-cRGD,that enables real-time monitoring of the targeted thrombolytic process of deep vein thrombosis(DVT).Pkr(IR-Ca/Pda-uPA)-cRGD,which is prepared from a Pickering-emulsion-like system,encapsulates both near-infrared-Ⅱ(NIR-Ⅱ)contrast agent(IR-1048 dye,loading capacity:28％)and urokinase plasminogen activators(uPAs,encapsulation efficiency:89％),pioneering the loading of multiple drugs with contrasting hydrophilicity into one single-drug carrier.Upon intravenous injection,Pkr(IR-Ca/Pda-uPA)-cRGD considerably targets to thrombi selectively(targeting rate:91％)and disintegrates in response to acidic thrombi to release IR-1048 dye and uPAfor imaging and thrombolysis,respectively.Investigations indicate that Pkr(IR-Ca/Pda-uPA)-cRGD enabled real-time visualization of targeted thrombolysis using NIR-Ⅱ imaging in DVT models,in which thrombi were eliminated(120 min after drug injection)without bleeding complications.This may be the first study using convenient NIR-Ⅱ imaging for real-time visualization of targeted thrombolysis.It represents the precision medicine that enables rapid response to acquire instantaneous medical images and make necessary real-time adjustments to diagnostic and therapeutic protocols during treatment.
查看更多>>摘要：Platelets are small,versatile blood cells that are critical for hemostasis/thrombosis.Local platelet accumulation is a known contributor to proinflammation in various disease states.However,the anti-inflammatory/immunosuppressive potential of platelets has been poorly explored.Here,we uncovered,unexpectedly,desialylated platelets(dPLTs)down-regulated immune responses against both platelet-associated and-independent antigen challenges.Utilizing multispectral photoacoustic tomography,we tracked dPLT trafficking to gut vasculature and an exclusive Kupffer cell-mediated dPLT clearance in the liver,a process that we identified to be synergistically dependent on platelet glycoprotein Ⅰbα and hepatic Ashwell-Morell receptor.Mechanistically,Kupffer cell clearance of dPLT potentiated a systemic immunosuppressive state with increased anti-inflammatory cytokines and circulating CD4+regulatory T cells,abolishable by Kupffer cell depletion.Last,in a clinically relevant model of hemophilia A,presensitization with dPLT attenuated anti-factor Ⅷ antibody production after factor Ⅷ(infusion.As platelet desialylation commonly occurs in daily-aged and activated platelets,these findings open new avenues toward understanding immune homeostasis and potentiate the therapeutic potential of dPLT and engineered dPLT transfusions in controlling autoimmune and alloimmune diseases.
查看更多>>摘要：Immunosenescence refers to the multifaceted and profound alterations in the immune system brought about by aging,exerting complex influences on the pathophysiological processes of diseases that manifest upon it.Using a combination of single-cell RNA sequencing,cytometry by time of flight,and various immunological assays,we investigated the characteristics of immunosenescence in the peripheral blood of aged mice and its impact on the cerebral immune environment after ischemic stroke.Our results revealed some features of immunosenescence.We observed an increase in neutrophil counts,concurrent with accelerated neutrophil aging,characterized by altered expression of aging-associated markers like CD62Land consequential changes in neutrophil-mediated immune functions.Monocytes/macrophages in aged mice exhibited enhanced antigen-presentation capabilities.T cell profiles shifted from naive to effector or memory states,with a specific rise in T helper 1 cells and T helper 17 cells subpopulations and increased regulatory T cell activation in CD4 T cells,Furthermore,regulatory CD8 T cells marked by Klra decreased with aging,while a subpopulation of exhausted-like CD8T cells expanded,retaining potent immunostimulatory and proinflammatory functions.Critically,these inherent disparities not only persisted but were further amplified within the ischemic hemispheres following stroke.In summary,our comprehensive insights into the key attributes of peripheral immunosenescence provide a vital theoretical foundation for understanding not only ischemic strokes but also other age-associated diseases.
查看更多>>摘要：The majority of atherothrombotic events(e.g.,cerebral or myocardial infarction)often occur as a result of plaque rupture or erosion in the carotid,and thereby it is urgent to assess plaque vulnerability and predict adverse cerebrovascular events.However,the monitoring evolution from stable plaque into life-threatening high-risk plaque in the slender carotid artery is a great challenge,due to not enough spatial resolution for imaging the carotid artery based on most of reported fluorescent probes.Herein,copolymerizing with the small molecules of acceptor-donor-acceptor-donor-acceptor(A-D-A'-D-A)and the electron-donating units(D'),the screened second near-infrared(NIR-Ⅱ)nanoprobe presents high quantum yield and good stability,so that it enables to image slender carotid vessel with enough spatial resolution.Encouragingly,NIR-Ⅱ nanoprobe can effectively target to intraplaque macrophage,meanwhile distinguishing vulnerable plaque in carotid atherosclerosis in living mice.Moreover,the NIR-Ⅱ nanoprobe can dynamically monitor the fresh bleeding spots in carotid plaque,indicating the increased risk of plaque instability.Besides,magnetic resonance imaging is integrated with NIR-Ⅱ fluorescence imaging to provide contrast for subtle structure(e.g.,narrow lumen and lipid pool),via incorporating ultrasmall superparamagnetic iron oxide into the NIR-Ⅱ nanoprobe.Thus,such hybrid NIR-Ⅱ/magnetic resonance imaging multimodal nanoprobe provides an effective tool for assessing carotid plaque burden,selecting high-risk plaque,and imaging intraplaque hemorrhage,which is promising for reducing cerebral/myocardial infarction-associated morbidity and mortality.
查看更多>>摘要：Despite substantial progress in the treatment of castration-resistant prostate cancer(CRPC),including radiation therapy and immunotherapy alone or in combination,the response to treatment remains poor due to the hypoxic and immunosuppressive nature of the tumor microenvironment.Herein,we exploited the bioreactivity of novel polymer-lipid manganese dioxide nanoparticles(PLMDs)to remodel the tumor immune microenvironment(TIME)by increasing the local oxygen levels and extracellular pH and enhancing radiation-induced immunogenic cell death.This study demonstrated that PLMD treatment sensitized hypoxic human and murine CRPC cells to radiation,significantly increasing radiation-induced DNA double-strand breaks and ultimately cell death,which enhanced the secretion of damage-associated molecular patterns,attributable to the induction of autophagy and endoplasmic reticulum stress.Reoxygenation via PLMDs also polarized hypoxic murine RAW264.7 macrophages toward the M1 phenotype,enhancing tumor necrosis factor alpha release,and thus reducing the viability of murine CRPC TRAMP-C2 cells.In a syngeneic TRAMP-C2 tumor model,intravenous injection of PLMDs suppressed,while radiation alone enhanced recruitment of regulatory T cells and myeloid-derived suppressor cells.Pretreatment with PLMDs followed by radiation down-regulated programmed death-ligand 1 and promoted the infiltration of antitumor CD8+T cells and M1 macrophages to tumor sites.Taken together,TIME modulation by PLMDs plus radiation profoundly delayed tumor growth and prolonged median survival compared with radiation alone.These results suggest that PLMDs plus radiation is a promising treatment modality for improving therapeutic efficacy in radioresistant and immunosuppressive solid tumors.
查看更多>>摘要：Organic mechanophores have been widely adopted for polymer mechanotransduction.However,most examples of polymer mechanotransduction inevitably experience macromolecular chain rupture,and few of them mimic mussel's mechanochemical regeneration,a mechanically mediated process from functional units to functional materials in a controlled manner.In this paper,inorganic mechanoluminescent(ML)materials composed of CaZnOS-ZnS-SrZnOS∶Mn2+were used as a mechanotransducer since it features both piezoelectricity and mechanolunimescence.The utilization of ML materials in polymerization enables both mechanochemically controlled radical polymerization and the synthesis of ML polymer composites.This procedure features a mechanochemically controlled manner for the design and synthesis of diverse mechanoresponsive polymer composites.
查看更多>>摘要：The emergence of antibiotic tolerance,characterized by the prolonged survival of bacteria following antibiotic exposure,in natural bacterial populations,especially in pathogens carrying antibiotic resistance genes,has been an increasing threat to public health.However,the major causes contributing to the formation of antibiotic tolerance and underlying molecular mechanisms are yet poorly understood.Herein,we show that potassium sorbate(PS),a widely used food additive,triggers a high level of fluoroquinolone tolerance in bacteria carrying mobile colistin resistance gene mcr.Mechanistic studies demonstrate that PS treatment results in the accumulation of intracellular fumarate,which activates bacterial two-component system and decreases the expression level of outer membrane protein OmpF,thereby reducing the uptake of ciprofloxacin.In addition,the supplementation of PS inhibits aerobic respiration,reduces reactive oxygen species production and alleviates DNA damage caused by bactericidal antibiotics.Furthermore,we demonstrate that succinate,an intermediate product of the tricarboxylic acid cycle,overcomes PS-mediated ciprofloxacin tolerance.In multiple animal models,ciprofloxacin treatment displays failure outcomes in PS preadministrated animals,including comparable survival and bacterial loads with the vehicle group.Taken together,our works offer novel mechanistic insights into the development of antibiotic tolerance and uncover potential risks associated with PS use.
查看更多>>摘要：Improving droplet velocity as much as possible is considered as the key to improving both printing speed and printing distance of the piezoelectric drop-on-demand inkjet printing technology.There are 3 tough and contradictory issues that need to be addressed simultaneously,namely,the actuation pressure of the piezoelectric printhead,satellite droplets,and the air resistance,which seems almost impossible to achieve with classical methods.Herein,a novel solution is introduced.By modulating the positive crosstalk effect inside and outside the printhead,self-tuning can be achieved,including self-reinforcing of the actuation pressure,self-restraining of satellite droplets,and self-weakening of the air resistance,thereby greatly improving droplet velocity.Based on these mechanisms,waveform design methods for different inks and printheads are investigated.The results demonstrate that monodisperse droplet jetting with a maximum velocity of 27.53 m/s can be achieved,reaching 3 to 5 times that of the classical method(5 to 8 m/s).Correspondingly,the printing speed and distance can be simultaneously increased by almost 10 times,demonstrating an ability of direct printing on irregular surface.Meanwhile,the compatibility of ink materials is expanded,as the Ohnesorge number and the viscosity of printable inks for the printhead used are increased from 0.36-0.72 to 0.03-1.18 and from 10-12 cp to 1-40.3 cp,respectively,even breaking the traditional limitations of the piezoelectric printing technology(Ohnesorge number of 0.1 to 1;viscosity of 1 to 25 cp).All the above provide a new perspective for improving droplet velocity and may even offer a game-changing choice for expanding the boundaries of the piezoelectric drop-on-demand inkjet printing technology.
查看更多>>摘要：Near-infrared(NIR)transparent optical filters show great promise in night vision and receiving windows.However,NIR optical filters are generally prepared by laborious,environmentally unfriendly processes that involve metal oxides or petroleum-based polymers.We propose a lignin capturing-fusing approach to manufacturing optical biofilters based on molecular collaboration between lignin and cellulose from waste agricultural biomass.In this process,lignin is captured via self-assembly in a cellulose network;then,the lignin is fused to fill gaps and hold the cellulose fibers tightly.The resulting optical biofilter featured a dense structure and smooth surface with NIR transmittance of～90％,ultralow haze of close to 0％,strong ultraviolet-visible light blocking(～100％at 400 nm and 57.58％to 98.59％at 550 nm).Further,the optical biofilter has comprehensive stability,including water stability,solvent stability,thermal stability,and environmental stability.Because of its unique properties,the optical biofilter demonstrates potential applications in the NIR region,such as an NIR-transmitting window,NIR night vision,and privacy protection.These applications represent a promising route to produce NIR transparent optical filters starting from lignocellulose biomass waste.
NETL
NSTL
万方数据