查看更多>>摘要：Ventricular arrhythmogenesis is a key cause of sudden cardiac death following myocardial infarction(Ml).Accumulating data show that ischemia,sympathetic activation,and inflammation contribute to arrhythmogenesis.However,the role and mechanisms of abnormal mechanical stress in ventricular arrhythmia following Ml remain undefined.We aimed to examine the impact of increased mechanical stress and identify the role of the key sensor Piezo1 in ventricular arrhythmogenesis in Ml.Concomitant with increased ventricular pressure,Piezo1,as a newly recognized mechano-sensitive cation channel,was the most up-regulated mechanosensor in the myocardium of patients with advanced heart failure.Piezo1 was mainly located at the intercalated discs and T-tubules of cardiomyocytes,which are responsible for intracellular calcium homeostasis and intercellular communication.Cardiomyocyte-conditional Piezo1 knockout mice(Piezo1Cko)exhibited preserved cardiac function after Ml.Piezo1Cko mice also displayed a dramatically decreased mortality in response to the programmed electrical stimulation after Ml with a markedly reduced incidence of ventricular tachycardia.In contrast,activation of Piezo1 in mouse myocardium increased the electrical instability as indicated by prolonged QT interval and sagging ST segment.Mechanistically,Piezo1 impaired intracellular calcium cycling dynamics by mediating the intracellular Ca2+overload and increasing the activation of Ca2+-modulated signaling,CaMKⅡ,and calpain,which led to the enhancement of phosphorylation of RyR2 and further increment of Ca2+leaking,finally provoking cardiac arrhythmias.Furthermore,in human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs),Piezo1 activation remarkably triggered cellular arrhythmogenic remodeling by significantly shortening the duration of the action potential,inducing early afterdepolarization,and enhancing triggered activity.This study uncovered a proarrhythmic role of Piezo1 during cardiac remodeling,which is achieved by regulating Ca2+handling,implying a promising therapeutic target in sudden cardiac death and heart failure.
查看更多>>摘要：Interorganelle contacts and communications are increasingly recognized to play a vital role in cellular function and homeostasis.In particular,the mitochondria-endoplasmic reticulum(ER)membrane contact site(MAM)is known to regulate ion and lipid transfer,as well as signaling and organelle dynamics.However,the regulatory mechanisms of MAM formation and their function are still elusive.Here,we identify mitochondrial Lon protease(LonP1),a highly conserved mitochondrial matrix protease,as a new MAM tethering protein.The removal of LonP1 substantially reduces MAM formation and causes mitochondrial fragmentation.Furthermore,deletion of LonP1 in the cardiomyocytes of mouse heart impairs MAM integrity and mitochondrial fusion and activates the unfolded protein response within the ER(UPRER).Consequently,cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming and pathological heart remodeling.These findings demonstrate that LonP1 is a novel MAM-localized protein orchestrating MAM integrity,mitochondrial dynamics,and UPRER,offering exciting new insights into the potential therapeutic strategy for heart failure.
查看更多>>摘要：Natural tactile sensation is complex,which involves not only contact force intensity detection but also the perception of the force direction,the surface texture,and other mechanical parameters.Nevertheless,the vast majority of the developed tactile sensors can only detect the normal force,but usually cannot resolve shear force or even distinguish the directions of the force.Here,we present a new paradigm of bioinspired tactile sensors for resolving both the intensity and the directions of mechanical stimulations via synergistic microcrack-bristle structure design and cross-shaped configuration engineering.The microcrack sensing structure gives high mechanical sensitivity to the tactile sensors,and the synergistic bristle structure further amplifies the sensitivity of the sensors.The cross-shaped configuration engineering of the synergistic microcrack-bristle structure further endows the tactile sensors with good capability to detect and distinguish the directions of the applied mechanical forces.The as-fabricated tactile sensors exhibit a high sensitivity(25.76 N-1),low detection limit(5.4 mN),desirable stability(over 2,500 cycles),and good capability to resolve both mechanical intensity and directional features.As promising application scenarios,surface texture recognition and biomimetic path explorations are successfully demonstrated with these tactile sensors.This newly proposed tactile sensation strategy and technology have great potential applications in ingenious tactile sensation and construction of various robotic and bionic prostheses with high operational dexterity.
查看更多>>摘要：Small-molecule photothermal agents(PTAs)with intense second near-infrared(NIR-Ⅱ,1,000 to 1,700 nm)absorption and high photothermal conversion efficiencies(PCEs)are promising candidates for treating deep-seated tumors such as osteosarcoma.To date,the development of small-molecule NIR-Ⅱ PTAs has largely relied on fabricating donor-acceptor-donor(D-A-D/D')structures and limited success has been achieved.Herein,through acceptor engineering,a donor-acceptor-acceptor(D-A-A')-structured NIR-Ⅱ aza-boron-dipyrromethene(aza-BODIPY)PTA(SW8)was readily developed for the 1,064-nm laser-mediated phototheranostic treatment of osteosarcoma.Changing the donor groups to acceptor groups produced remarkable red-shifts of absorption maximums from first near-infrared(NIR-Ⅰ)regions(～808 nm)to NIR-Ⅱ ones(～1,064 nm)for aza-BODIPYs(SW1 to SW8).Furthermore,SW8 self-assembled into nanoparticles(SW8@NPs)with intense NIR-Ⅱ absorption and an ultrahigh PCE(75％,1,064 nm).This ultrahigh PCE primarily originated from an additional nonradiative decay pathway,which showed a 100-fold enhanced decay rate compared to that shown by conventional pathways such as internal conversion and vibrational relaxation.Eventually,SW8@NPs performed highly efficient 1,064-nm laser-mediated NIR-Ⅱ photothermal therapy of osteosarcoma via concurrent apoptosis and pyroptosis.This work not only illustrates a remote approach for treating deep-seated tumors with high spatiotemporal control but also provides a new strategy for building high-performance small-molecule NIR-Ⅱ PTAs.
查看更多>>摘要：Neuromuscular dysfunction is tightly associated with muscle wasting that occurs with age or due to degenerative diseases.However,the molecular mechanisms underlying neuromuscular dysfunction are currently unclear.Recent studies have proposed important roles of Protein arginine methyltransferase 1(Prmt1)in muscle stem cell function and muscle maintenance.In the current study,we set out to determine the role of Prmt1 in neuromuscular function by generating mice with motor neuron-specific ablation of Prmt1(mnKO)using Hb9-Cre.mnKO exhibited age-related motor neuron degeneration and neuromuscular dysfunction leading to premature muscle loss and lethality.Prmt1 deficiency also impaired motor function recovery and muscle reinnervation after sciatic nerve injury.The transcriptome analysis of aged mnKO lumbar spinal cords revealed alterations in genes related to inflammation,cell death,oxidative stress,and mitochondria.Consistently,mnKO lumbar spinal cords of sciatic nerve injury model or aged mice exhibited elevated cellular stress response in motor neurons.Furthermore,Prmt1 inhibition in motor neurons elicited mitochondrial dysfunction.Our findings demonstrate that Prmt1 ablation in motor neurons causes age-related motor neuron degeneration attributing to muscle loss.Thus,Prmt1 is a potential target for the prevention or intervention of sarcopenia and neuromuscular dysfunction related to aging.
查看更多>>摘要：Capacitive mixing is a promising blue energy technology due to its membrane-free electricity generation and long electrode life cycle.However,because of limited performance,existing systems do not lend themselves to practical implementation.Although it is a crucial factor directly influencing electrode behavior,surface chemistry has largely been overlooked in capacitive mixing.Here,we show that manipulating surface functionalization alone can tune the responses of electrodes to produce a high voltage rise without altering the pore structure of the electrodes.Our findings reveal that the spontaneous electrode potential of a surface-modified carbon electrode shifts negatively proportional to the surface charge due to the surface groups,which explains why and how manipulating the surface chemistry can improve the power generation capacity.Using electrodes fabricated with identical activated carbon material but with different surface treatments,we have achieved a remarkably high power density of 166 mW/m2 delivered to an electrical load under a 0.6 M to 0.01 M salinity gradient,with the total power generated of 225 mW/m2.The corresponding volumetric power densities were 0.88 kW/m3 net and 1.17 kW/m3 total.The volumetric power density of our prototype is comparable to or better than those of prevailing membrane technologies,such as pressure retarded osmosis and reverse electrolysis,whose volumetric power density values are 1.1 kW/m3 and 0.16 kW/m3,respectively.In the seawater stage,the net power density reached 432 mW/m2 or 2.3 kW/m3.Such performance far exceeds existing membrane-free systems,with the highest reported power density of 65 mW/m2 under a 0.5 M to 0.02 M salinity gradient(121 mW/m2 in this work).The device demonstrated unparalleled durability,maintaining 90％of the maximum energy capacity after 54,000 charge-discharge cycles.
查看更多>>摘要：Anaplastic lymphoma kinase(ALK),a tyrosine receptor kinase,has been proven to be associated with the occurrence of numerous malignancies.Although there have been already at least 3 generations of ALK inhibitors approved by FDA or in clinical trials,the occurrence of various mutations seriously attenuates the effectiveness of the drugs.Unfortunately,most of the drug resistance mechanisms still remain obscure.Therefore,it is necessary to reveal the bottom reasons of the drug resistance mechanisms caused by the mutations.In this work,on the basis of verifying the accuracy of 2 main kinds of binding free energy calculation methodologies[end-point method of Molecular Mechanics with Poisson-Boltzmann/Generalized Born and Surface Area(MM/PB(GB)SA)and alchemical method of Thermodynamic Integration(TI)],we performed a systematic analysis on the ALK systems to explore the underlying shared and specific drug resistance mechanisms,covering the one-drug-multiple-mutation and multiple-drug-one-mutation cases.Through conventional molecular dynamics(cMD)simulation in conjunction with MM/PB(GB)SA and umbrella sampling(US)in conjunction with contact network analysis(CNA),the resistance mechanisms of the in-pocket,out-pocket,and multiple-site mutations were revealed.Especially for the out-pocket mutation,a possible transfer chain of the mutation effect was revealed,and the reason why different drugs exhibited various sensitivities to the same mutation was also uncovered.The proposed mechanisms may be prevalent in various drug resistance cases.
查看更多>>摘要：Miniature magnetic-driven robots with multimode motions and high-precision pose sensing capacity(position and orientation)are greatly demanded in insitu manipulation in narrow opaque enclosed spaces.Various magnetic robots have been carried out,whereas their deformations normally remain in single mode,and the lack of the robot's real-time status leads to its beyond-sight remagnetization and manipulation being impossible.The function integration of pose sensing and multimode motion is still of challenge.Here,a multimotion thin-film robot is created in a novel multilayer structure with a magnetic-driven layer covered by a heating-sensing conductive layer.Such a heating-sensing layer not only can segmentally and on-demand heat the magnetic-driven layer for insitu magnetization reprogramming and multimode motions but also can precisely detect the robot's pose(position and orientation)from its electrical-resistance effect by creating a small deformation under preset magnetic fields.Under the integration of reprogramming and sensing,necessary multimode motions,i.e.,swimming,rolling,crawling,and obstacle-crossing,are achieved under a reprogramming field BRepr of 10 mT,and high-precision poses sensing with an accuracy of±3 mm in position and±2.5° in orientation is obtained even under a low magnetic strength of BSens of 5 mT,which combined help realize accurate out-of-sight manipulations in the enclosed space environment.Finally,a gastroscope robot for stomach drug delivery has been demonstrated for more gastrointestinal medical treatments.
查看更多>>摘要：Inflammatory responses,manifested in excessive oxidative stress and microglia overactivation,together with metal ion-triggered amyloid-beta(Aβ)deposition,are critical hallmarks of Alzheimer's disease(AD).The intricate pathogenesis causes severe impairment of neurons,which,in turn,exacerbates Aβaggregation and facilitates AD progression.Herein,multifunctional melanin-like metal ion chelators and neuroinflammation regulators(named PDA@K)were constructed for targeted treatment of AD.In this platform,intrinsically bioactive material polydopamine nanoparticles(PDA)with potent metal ion chelating and ROS scavenging effects were decorated with the KLVFF peptide,endowing the system with the capacity of enhanced pathological blood-brain barrier(BBB)crossing and lesion site accumulation via Aβ hitchhiking.In vitro and in vivo experiment revealed that PDA@K had high affinity toward Aβ and were able to hitch a ride on Aβ to achieve increased pathological BBB crossing.The engineered PDA@K effectively mitigated Aβ aggregate and alleviated neuroinflammation.The modulated inflammatory microenvironment by PDA@K promoted microglial polarization toward the M2-like phenotype,which restored their critical functions for neuron care and plaque removal.After 3-week treatment of PDA@K,spatial learning and memory deficit as well as neurologic changes of FAD4T transgenic mice were largely rescued.Transcriptomics analysis further revealed the therapeutic mechanism of PDA@K.Our study provided an appealing paradigm for directly utilizing intrinsic properties of nanomaterials as therapeutics for AD instead of just using them as nanocarriers,which largely widen the application of nanomaterials in AD therapy.
查看更多>>摘要：Data-independent acquisition(DIA)technology for protein identification from mass spectrometry and related algorithms is developing rapidly.The spectrum-centric analysis of DIA data without the use of spectra library from data-dependent acquisition data represents a promising direction.In this paper,we proposed an untargeted analysis method,Dear-DIAXMBD,for direct analysis of DIA data.Dear-DIAXMBD first integrates the deep variational autoencoder and triplet loss to learn the representations of the extracted fragment ion chromatograms,then uses the k-means clustering algorithm to aggregate fragments with similar representations into the same classes,and finally establishes the inverted index tables to determine the precursors of fragment clusters between precursors and peptides and between fragments and peptides.We show that Dear-DIAXMBD performs superiorly with the highly complicated DIA data of different species obtained by different instrument platforms.Dear-DIAXMBD is publicly available at https://github.com/jianweishuai/Dear-DIA-XMBD.
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