查看更多>>摘要：Byzantine agreement,the underlying core of blockchain,aims to make every node in a decentralized network reach consensus.Classical Byzantine agreements unavoidably face two major problems.One is 1/3 fault-tolerance bound,which means that the system to tolerate f malicious players requires at least 3f+1 players.The other is the security loopholes from its classical cryptography methods.Here,we propose a Byzantine agreement framework with unconditional security to break this bound with nearly 1/2 fault tolerance due to multiparty correlation provided by quantum digital signatures.It is intriguing that quantum entanglement is not necessary to break the 1/3 fault-tolerance bound,and we show that weaker correlation,such as asymmetric relationship of quantum digital signature,can also work.Our work strictly obeys two Byzantine conditions and can be extended to any number of players without requirements for multiparticle entanglement.We experimentally demonstrate three-party and five-party consensus for a digital ledger.Our work indicates the quantum advantage in terms of consensus problems and suggests an important avenue for quantum blockchain and quantum consensus networks.
查看更多>>摘要：Cortical organoids represent cutting-edge models for mimic human brain development during the early and even middle stage of pregnancy,while they often fail to recreate the complex microenvironmental factors,such as physiological hypoxia.Herein,to recapitulate fetal brain development,we propose a novel cortical organoid-on-a-chip with physiological hypoxia and further explore the effects of tanshinone ⅡA(Tan ⅡA)in neural differentiation.The microfluidic chip was designed with a micropillar array for the controlled and efficient generation of cortical organoids.With low oxygen,the generated cortical organoids could recapitulate key aspects of early-gestational human brain development.Compared to organoids in normoxic culturing condition,the promoted neurogenesis,synaptogenesis and neuronal maturation were observed in the present microsystem,suggesting the significance of physiological hypoxia in cortical development.Based on this model,we have found that Chinese herbal drug Tan ⅡA could promote neural differentiation and maturation,indicating its potential therapeutic effects on neurodevelopmental disorders as well as congenital neuropsychiatric diseases.These results indicate that the proposed biomimetic cortical organoid-on-a-chip model with physiological hypoxia can offer a promising platform to simulate prenatal environment,explore brain development,and screen natural neuroactive components.
查看更多>>摘要：Fibroblast activation protein(FAP)is among the most popular targets in nuclear medicine imaging and cancer theranostics.Several small-molecule moieties(FAP I-04,FAP I-46,etc.)are used for developing FAP-targeted theranostic agents.Nonetheless,the circulation time of FAP inhibitors is relatively short,resulting in rapid clearance via kidneys,low tumor uptake,and associated unsatisfactory treatment efficacy.To address the existing drawbacks,we engineered 3 peptides named FD1,FD2,and FD3 with different circulation times through solid-phase peptide synthesis.All the 3 reported peptides bind to human and murine FAP with single-digit nanomolar affinity measured by surface plasmon resonance.The diagnostic and therapeutic potential of the agents labeled with 68Ga and 177Lu was assessed in several tumor models exhibiting different levels of FAP expression.While radiolabeled FD1 was rapidly excreted from kidneys,radiolabeled FD2/FD3 have significantly prolonged circulation,increased tumor uptake,and decreased kidney accumulation.Our findings indicated that[68Ga]Ga-DOTA-FD1 positron emission tomography(PET)effectively detected FAP dynamics,whereas[177Lu]Lu-DOTA-FD2 and[177Lu]Lu-DOTA-FD3 exhibited remarkable therapeutic efficacy in FAP-overexpressing tumor models,including pancreatic cancer cell models characterized by abundant stroma.Moreover,a pilot translational investigation demonstrated that[68Ga]Ga-DOTA-FD1 had the capability to identify both primary and metastatic tumors with precision and distinction.In summary,we developed[68Ga]Ga-DOTA-FD1 for same-day PET imaging of FAP dynamics and[177Lu]Lu-DOTA-FD2 and[177Lu]Lu-DOTA-FD3 for effective radioligand therapy of FAP-overexpressing tumors.
查看更多>>摘要：Magnetically actuated mobile robots demonstrate attractive advantages in various medical applications due to their wireless and programmable executions with tiny sizes.Confronted with complex application scenarios,however,it requires more flexible and adaptive deployment and utilization methods to fully exploit the functionalities brought by magnetic robots.Herein,we report a design and utilization strategy of magnetic soft robots using a mixture of magnetic particles and non-Newtonian fluidic soft materials to produce programmable,hardened,adhesive,reconfigurable soft robots.For deployment,their ultrasoft structure and adhesion enable them to be spread on various surfaces,achieving magnetic actuation empowerment.The reported technology can potentially improve the functionality of robotic end-effectors and functional surfaces.Experimental results demonstrate that the proposed robots could help to grasp and actuate objects 300 times heavier than their weight.Furthermore,it is the first time we have enhanced the stiffness of mechanical structures for these soft materials by on-demand programmable hardening,enabling the robots to maximize force outputs.These findings offer a promising path to understanding,designing,and leveraging magnetic robots for more powerful applications.
查看更多>>摘要：Histone deacetylases(HDACs)are epigenetic regulators that play an important role in determining cell fate and maintaining cellular homeostasis.However,whether and how HDACs regulate iron metabolism and ferroptosis(an iron-dependent form of cell death)remain unclear.Here,the putative role of hepatic HDACs in regulating iron metabolism and ferroptosis was investigated using genetic mouse models.Mice lacking Hdac3 expression in the liver(Hdac3-LKO mice)have significantly reduced hepatic Hamp mRNA(encoding the peptide hormone hepcidin)and altered iron homeostasis.Transcription profiling of Hdac3-LKO mice suggests that the Hippo signaling pathway may be downstream of Hdac3.Moreover,using a Hippo pathway inhibitor and overexpressing the transcriptional regulator Yap(Yes-associated protein)significantly reduced Hamp mRNA levels.Using a promoter reporter assay,we then identified 2 Yap-binding repressor sites within the human HAMP promoter region.We also found that inhibiting Hdac3 led to increased translocation of Yap to the nucleus,suggesting activation of Yap.Notably,knock-in mice expressing a constitutively active form of Yap(Yap K342M)phenocopied the altered hepcidin levels observed in Hdac3-LKO mice.Mechanistically,we show that iron-overload-induced ferroptosis underlies the liver injury that develops in Hdac3-LKO mice,and knocking down Yap expression in Hdac3-LKO mice reduces both iron-overload-and ferroptosis-induced liver injury.These results provide compelling evidence supporting the notion that HDAC3 regulates iron homeostasis via the Hippo/Yap pathway and may serve as a target for reducing ferroptosis in iron-overload-related diseases.
查看更多>>摘要：Non-alcoholic fatty liver disease,especially nonalcoholic steatohepatitis(NASH),is a leading cause of cirrhosis and liver cancer worldwide;nevertheless,there are no Food and Drug Administration-approved drugs for treating NASH until now.Peroxisome proliferator-activated receptor alpha(PPARα)is an interesting therapeutic target for treating metabolic disorders in the clinic,including NASH.Herpetrione,a natural lignan compound isolated from Tibetan medicine Herpetospermum caudigerum,exerts various hepatoprotective effects,but its efficacy and molecular mechanism in treating NASH have not yet been elucidated.Here,we discovered that herpetrione lessened lipid accumulation and inflammation in hepatocytes stimulated with oleic acid and lipopolysaccharide,and effectively alleviated NASH caused by a high-fat diet or methionine-choline-deficient diet by regulating glucolipid metabolism,insulin resistance,and inflammation.Mechanistically,RNA-sequencing analyses further showed that herpetrione activated PPAR signaling,which was validated by protein expression.Furthermore,the analysis of molecular interactions illustrated that herpetrione bound directly to the PPARα protein,with binding sites extending to the Arm Ⅲ domain.PPARαdeficiency also abrogated the protective effects of herpetrione against NASH,suggesting that herpetrione protects against hepatic steatosis and inflammation by activation of PPARα signaling,thereby alleviating NASH.Our findings shed light on the efficacy of a natural product for treating NASH,as well as the broader prospects for NASH treatment by targeting PPARα.
查看更多>>摘要：Catheters navigating through complex vessels,such as sharp turns or multiple U-turns,remain challenging for vascular embolization.Here,we propose a novel multistage vascular embolization strategy for hard-to-reach vessels that releases untethered swimming shape-memory magnetic microrobots(SMMs)from the prior catheter to the vessel bifurcation.SMMs,made of organo-gel with magnetic particles,ensure biocompatibility,radiopacity,thrombosis,and fast thermal and magnetic responses.An SMM is initially a linear shape with a 0.5-mm diameter at 20 ℃ inserted in a catheter.It transforms into a predetermined helix within 2 s at 38 ℃ blood temperature after being pushed out of the catheter into the blood.SMMs enable agile swimming in confined and tortuous vessels and can swim upstream using helical propulsion with rotating magnetic fields.Moreover,we validated this multistage vascular embolization in living rabbits,completing 100-cm travel and renal artery embolization in 2 min.After 4 weeks,the SMMs maintained the embolic position,and the kidney volume decreased by 36％.
查看更多>>摘要：Neddylation plays a vital role in post-translational modification,intricately shaping the regulation of diverse biological processes,including those related to cellular immune responses.In fact,neddylation exerts control over both innate and adaptive immune systems via various mechanisms.Specifically,neddylation influences the function and survival of innate immune cells,activation of pattern recognition receptors and GMP-AMP synthase-stimulator of interferon genes pathways,as well as the release of various cytokines in innate immune reactions.Moreover,neddylation also governs the function and survival of antigen-presenting cells,which are crucial for initiating adaptive immune reactions.In addition,neddylation regulates T cell activation,proliferation,differentiation,survival,and their effector functions,thereby ensuring an appropriate adaptive immune response.In this review,we summarize the most recent findings in these aspects and delve into the connection between dysregulated neddylation events and immunological disorders,especially inflammatory diseases.Lastly,we propose future directions and potential treatments for these diseases by targeting neddylation.
查看更多>>摘要：Persistent hepatic cellular metabolic stress and liver inflammatory stimuli are key signatures of nonalcoholic steatohepatitis(NASH).DDX3X is a vital molecule involved in cell fate decisions in both pro-survival stress granule(SG)and pro-death NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome assembly in response to stress signals.However,the role of DDX3X in NASH remains unclear.We characterized the cell type-specific roles of DDX3X in NASH.Human liver tissues from NASH patients and normal control subjects were collected to assess DDX3X expression and distribution.Nutritional steatohepatitis models were constructed by feeding macrophage-specific DDX3X knockout(DDX3XΔMφ),hepatocyte-specific DDX3X knockout(DDX3XΔhep),and wild-type control(DDX3Xfl/fl)mice a high-fat and high-cholesterol(HFHC)diet,a methionine-and choline-deficient(MCD)diet,and a high-fat/high-iron/high-fructose/high-cholesterol,low-methionine,and choline-deficient(HFHIHFHC-MCD)diet.The study demonstrated that DDX3X was predominantly expressed in macrophages and hepatocytes in control liver tissues,and its expression was down-regulated in patients or mice with NASH.Compared to DDX3Xfl/fl littermates,DDX3XΔMφ mice showed improved liver histology in nutritional steatohepatitis models.Loss of macrophage DDX3X inhibited NLRP3 inflammasome-mediated pyroptosis,causing anti-inflammatory M2 polarization and alleviating hepatocyte steatohepatitic changes.DDX3XΔhep mice developed marked steatohepatitis in multiple nutritional steatohepatitis models compared to DDX3Xfl/fl littermates.DDX3X-deleted hepatocytes showed impaired SG assembly,leading to increased sensitivity and intolerance to metabolic stimulation and resultant steatohepatitis.In conclusion,DDX3X plays opposite roles in different cell types during the progression of NASH.A better understanding of the cell-specific differences in the crosstalk between SG formation and NLRP3 activation is crucial for developing prospective targeted DDX3X inhibitors for the treatment of NASH.
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