CD137L,a driver of harmful inflammation in the nervous system

CD137 (TNFRSF9,4-1BB) is a member of the tumor necrosis factor (TNF) receptor family and a potent costimulatory molecule.High levels of CD137 are expressed on T cells upon activation.CD137 signaling in T cells,either by cognate interaction with antigen-presenting cells (APC)or by agonistic anti-CD137 antibodies,strongly enhances proliferation,interferon-y secretion,and cytolytic activity of T cells.Thus,CD137 signaling is a main driver of cellular,type 1 helper T cells (Th1)and type 1 cytolytic T cells (Tc1) polarised immune responses.

Intracellular interferon signalling pathways as potential regulators of covalently closed circular DNA in the treatment of chronic hepatitis B

250 million people worldwide continue to be chronically infected with the virus.While patients may be treated with nucleoside/nucleotide analogues,this only suppresses HBV titre to sub-detection levels without eliminating the persistent HBV covalently closed circular DNA(cccDNA)genome.As a result,HBV infection cannot be cured,and the virus reactivates when conditions are favorable.Interferons(IFNs)are cytokines known to induce powerful antiviral mechanisms that clear viruses from infected cells.They have been shown to induce cccDNA clearance,but their use in the treatment of HBV infection is limited as HBVtargeting immune cells are exhausted and HBV has evolved multiple mechanisms to evade and suppress IFN signalling.Thus,to fully utilize IFN-mediated intracellular mechanisms to effectively eliminate HBV,instead of direct IFN administration,novel strategies to sustain IFN-mediated anti-cccDNA and antiviral mechanisms need to be developed.This review will consolidate what is known about how IFNs act to achieve its intracellular antiviral effects and highlight the critical interferon-stimulated gene targets and effector mechanisms with potent anti-cccDNA functions.These include cccDNA degradation by APOBECs and cccDNA silencing and transcription repression by epigenetic modifications.In addition,the mechanisms that HBV employs to disrupt IFN signalling will be discussed.Drugs that have been developed or are in the pipeline for components of the IFN signalling pathway and HBV targets that detract IFN signalling mechanisms will also be identified and discussed for utility in the treatment of HBV infections.Together,these will provide useful insights into design strategies that specifically target cccDNA for the eradication of HBV.

Enhancing single-cell encapsulation in droplet microfluidics with fine-tunable on-chip sample enrichment

Single-cell encapsulation in droplet microfluidics is commonly hindered by the tradeoff between cell suspension density and on-chip focusing performance.In this study,we introduce a novel droplet microfluidic chip to overcome this challenge.The chip comprises a double spiral focusing unit,a flow resistance-based sample enrichment module with fine-tunable outlets,and a crossflow droplet generation unit.Utilizing a low-density cell/bead suspension(2×10^(6) objects/mL),cells/beads are focused into a near-equidistant linear arrangement within the double spiral microchannel.The excess water phase is diverted while cells/beads remain focused and sequentially encapsulated in individual droplets.Focusing performance was assessed through numerical simulations and experiments at three flow rates(40,60,80μL/min),demonstrating successful focusing at 40 and 80μL/min for beads and cells,respectively.In addition,both simulation and experimental results revealed that the flow resistance at the sample enrichment module is adjustable by punching different outlets,allowing over 50%of the aqueous phase to be removed.YOLOv8n-based droplet detection algorithms realized the counting of cells/beads in droplets,statistically demonstrating single-cell and bead encapsulation rates of 72.2%and 79.2%,respectively.All the results indicate that this on-chip sample enrichment approach can be further developed and employed as a critical component in single-cell encapsulation in water-in-oil droplets.

Valley-filling instability and critical magnetic field for interaction-enhanced Zeeman response in doped WSe_(2) monolayers

Carrier-doped transition metal dichalcogenide(TMD)monolayers are of great interest in valleytronics due to the large Zeeman response(g-factors)in these spin-valley-locked materials,arising from many-body interactions.We develop an ab initio approach based on many-body perturbation theory to compute the interaction-enhanced g-factors in carrier-doped materials.We show that the g-factors of doped WSe2 monolayers are enhanced by screened-exchange interactions resulting from magnetic-field-induced changes in band occupancies.Our interaction-enhanced g-factors g*agree well with experiment.Unlike traditional valleytronic materials such as silicon,the enhancement in g-factor vanishes beyond a critical magnetic field Bc achievable in standard laboratories.We identify ranges of g*for which this change in g-factor at Bc leads to a valley-filling instability and Landau level alignment,which is important for the study of quantum phase transitions in doped TMDs.We further demonstrate how to tune the g-factors and optimize the valley-polarization for the valley Hall effect.

A flexible nickel phthalocyanine resistive random access memory with multi-level data storage capability

Metal phthalocyanine is considered one of the most promising candidates for the design and fabrication of flexible resistive random access memory(RRAM)devices due to its intrinsic flexibility and excellent functionality.However,performance degradation and the lack of multi-level capability,which can directly expand the storage capacity in one memory cell without sacrificing additional layout area,are the primary obstacles to the use of metal phthalocyanine RRAMs in information storage.Here,a flexible RRAM with pristine nickel phthalocyanine(Ni Pc)as the resistive layer is reported for multi-level data storage.Due to its high trap-concentration,the charge transport behavior of the device agrees well with classical space charge limited conduction controlled by traps,leading to an excellent performance,including a high on-off current ratio of 10^(7),a long-term retention of 10^(6)s,a reproducible endurance over6000 cycles,long-term flexibility at a bending strain of 0.6%,a write speed of 50 ns under sequential bias pulses and the capability of multi-level data storage with reliable retention and uniformity.

Factorial design analytics on effects of material parameter uncertainties in multiphysics modeling of additive manufacturing

A bottleneck in Laser Powder Bed Fusion(L-PBF)metal additive manufacturing(AM)is the quality inconsistency of its products.To address this issue without costly experimentation,computational multi-physics modeling has been used,but the effectiveness is limited by parameter uncertainties and their interactions.We propose a full factorial design and variable selection approach for the analytics of main and interaction effects arising from material parameter uncertainties in multi-physics models.Data is collected from high-fidelity thermal-fluid simulations based on a 2-level full factorial design for 5 selected material parameters.Crucial physical phenomena of the L-PBF process are analyzed to extract physics-based domain knowledge,which are used to establish a validation checkpoint for our study.Initial data visualization with half-normal probability plots,interaction plots and standard deviation plots,is used to assess if the checkpoint is being met.We then apply the combination of best subset selection and the LASSO method on multiple linear regression models for comprehensive variable selection.Analytics yield statistically and phyiscally validated findings with practical implications,emphasizing the importance of parameter interactions under uncertainty,and their relation to the underlying physics of L-PBF.

Cell-derived nanovesicles from mesenchymal stem cells as extracellular vesicle-mimetics in wound healing

Wound healing is a dynamic process that involves a series of molecular and cellular events aimed at replacing devitalized and missing cellular components and/or tissue layers.Recently,extracellular vesicles(EVs),naturally cell-secreted lipid membrane-bound vesicles laden with biological cargos including proteins,lipids,and nucleic acids,have drawn wide attention due to their ability to promote wound healing and tissue regeneration.However,current exploitation of EVs as therapeutic agents is limited by their low isolation yields and tedious isolation processes.To circumvent these challenges,bioinspired cell-derived nanovesicles(CDNs)that mimic EVs were obtained by shearing mesenchymal stem cells(MSCs)through membranes with different pore sizes.Physical characterisations and highthroughput proteomics confirmed that MSC-CDNs mimicked MSC-EVs.Moreover,these MSC-CDNs were efficiently uptaken by human dermal fibroblasts and demonstrated a dose-dependent activation of MAPK signalling pathway,resulting in enhancement of cell proliferation,cell migration,secretion of growth factors and extracellular matrix proteins,which all promoted tissue regeneration.Of note,MSC-CDNs enhanced angiogenesis in human dermal microvascular endothelial cells in a 3D PEGfibrin scaffold and animal model,accelerating wound healing in vitro and in vivo.These findings suggest that MSC-CDNs could replace both whole cells and EVs in promoting wound healing and tissue regeneration.

Alleviating mechanical degradation of hexacyanoferrate via strain locking during Na^(+) insertion/extraction for full sodium ion battery

Generation of large strains upon Na^(+) intercalation is one of the prime concerns of the mechanical degradation of Prussian blue(PB)and its analogs.Structural construction from the atomic level is imperative to maintain structural stability and ameliorate the long-term stability of PB.Herein,an inter nickel hexacyanoferrate(NNiFCN)is successfully introduced at the out layer of iron hexacyanoferrate(NFFCN)through ion exchange to improve structural stability through compressive stress locking by forming NNiFCN shell.Furthermore,the kinetics of sodium ion diffusion is enhanced through the built-in electric pathway.The electrochemical performance is therefore significantly improved with a remarkable long-term cycling stability over 3,000 cycles at 500 mA·g^(–1) in the full sodium-ion batteries(SIBs)with a maximum energy density of 91.94 Wh·g^(–1),indicating that the core-shell structured NNiFCN/NFFCN could be the low-cost and high-performance cathode for full SIBs in large-scale EES applications.

Reconfigurable nonlinear photonic activation function for photonic neural network based on non-volatile opto-resistive RAM switch

Photonic neural network has been sought as an alternative solution to surpass the efficiency and speed bottlenecks of electronic neural network.Despite that the integrated Mach-Zehnder Interferometer(MZI)mesh can perform vector-matrix multiplication in photonic neural network,a programmable in-situ nonlinear activation function has not been proposed to date,suppressing further advancement of photonic neural network.Here,we demonstrate an efficient in-situ nonlinear accelerator comprising a unique solution-processed two-dimensional(2D)MoS2 Opto-Resistive RAM Switch(ORS),which exhibits tunable nonlinear resistance switching that allow us to introduce nonlinearity to the photonic neuron which overcomes the linear voltage-power relationship of typical photonic components.Our reconfigurable scheme enables implementation of a wide variety of nonlinear responses.Furthermore,we confirm its feasibility and capability for MNIST handwritten digit recognition,achieving a high accuracy of 91.6%.Our accelerator constitutes a major step towards the realization of in-situ photonic neural network and pave the way for the integration of photonic integrated circuits(PIC).

Loss-induced phase transition in mid-infrared plasmonic metamaterials for ultrasensitive vibrational spectroscopy

Metamaterials have proven their ability to possess extraordinary physical properties distinct from naturally available materials,leading to exciting sensing functionalities and applications.However,metamaterial-based sensing applications suffer from severe performance limitations due to noise interference and design constraints.Here,we propose a dual-phase strategy that leverages loss-induced different Fano-resonant phases to access both destructive and constructive signals of molecular vibration.When the two reverse signals are innovatively combined,the noise in the detection system is effectively suppressed,thereby breaking through the noise-related limitations.Additionally,by utilizing loss optimization of the plasmon-molecule coupling system,our dual-phase strategy enhances the efficiency of infrared energy transfer into the molecule without any additional fabrication complex,thereby overcoming the trade-off dilemma between performance and fabrication cost.Thanks to the pioneering breakthroughs in the limitations,our dual-phase strategy possesses an overwhelming competitive advantage in ultrasensitive vibrational spectroscopy over traditional metamaterial technology,including strong signal strength(×4),high sensitivity(×4.2),effective noise suppression(30%),low detection limit(13 ppm),and excellent selectivity among CO_(2),NH_(3),and CH_(4) mixtures.This work not only opens the door to various emerging ultrasensitive detection applications,including ultrasensitive in-breath diagnostics and high-information analysis of molecular information in dynamic reactions,but also gains new insights into the plasmon-molecule interactions in advanced metamaterials.