FLIM as a Promising Tool for Cancer Diagnosis and Treatment Monitoring

Fluorescence lifetime imaging microscopy(FLIM)has been rapidly developed over the past 30 years and widely applied in biomedical engineering.Recent progress in fluorophore-dyed probe design has widened the application prospects of fluorescence.Because fluorescence lifetime is sensitive to microenvironments and molecule alterations,FLIM is promising for the detection of pathological conditions.Current cancer-related FLIM applications can be divided into three main categories:(i)FLIM with autofluorescence molecules in or out of a cell,especially with reduced form of nicotinamide adenine dinucleotide,and flavin adenine dinucleotide for cellular metabolism research;(ii)FLIM with Förster resonance energy transfer for monitoring protein interactions;and(iii)FLIM with fluorophore-dyed probes for specific aberration detection.Advancements in nanomaterial production and efficient calculation systems,as well as novel cancer biomarker discoveries,have promoted FLIM optimization,offering more opportunities for medical research and applications to cancer diagnosis and treatment monitoring.This review summarizes cutting-edge researches from 2015 to 2020 on cancer-related FLIM applications and the potential of FLIM for future cancer diagnosis methods and anti-cancer therapy development.We also highlight current challenges and provide perspectives for further investigation.

Chronic stress as an emerging risk factor for the development and progression of glioma

Gliomas tend to have a poor prognosis and are the most common primary malignant tumors of the central nervous system.Compared with patients with other cancers,glioma patients often suffer from increased levels of psychological stress,such as anxiety and fear.Chronic stress(CS)is thought to impact glioma profoundly.However,because of the complex mechanisms underlying CS and variability in individual tolerance,the role of CS in glioma remains unclear.This review suggests a new proposal to redivide the stress system into two parts.Neuronal activity is dominant upstream.Stress-signaling molecules produced by the neuroendocrine system are dominant downstream.We discuss the underlying molecular mechanisms by which CS impacts glioma.Potential pharmacological treatments are also summarized from the therapeutic perspective of CS.

Cand2 inhibits CRL-mediated ubiquitination and suppresses autophagy to facilitate pathogenicity of phytopathogenic fungi

The ubiquitin–proteasome system and the autophagy system are the two primary mechanisms used by eukaryotes to maintain protein homeostasis,and both are closely related to the pathogenicity of the rice blast fungus.In this research,we identified MoCand2 as an inhibitor of ubiquitination in Magnaporthe oryzae.Through this role,MoCand2 participates in the regulation of autophagy and pathogenicity.Spe-cifically,we found that deletion of MoCand2 increased the ubiquitination level in M.oryzae,whereas overexpression of MoCand2 inhibited the accumulation of ubiquitinated proteins.Interaction analyses showed that MoCand2 is a subunit of Cullin-RING ligases(CRLs).It suppresses ubiquitination by blocking the assembly of CRLs and downregulating the expression of key CRL subunits.Further research indi-cated that MoCand2 regulates autophagy through ubiquitination.MoCand2 knockout led to over-ubiquitination and over-degradation of MoTor,and we confirmed that MoTor content was negatively correlated with autophagy level.In addition,MoCand2 knockout accelerated the K63 ubiquitination of MoAtg6 and strengthened the assembly and activity of the phosphatidylinositol-3-kinase class 3 complex,thus enhancing autophagy.Abnormal ubiquitination and autophagy in DMocand2 resulted in defects in growth,conidiation,stress resistance,and pathogenicity.Finally,sequence alignment and functional an-alyses in other phytopathogenic fungi confirmed the high conservation of fungal Cand2s.Our research thus reveals a novel mechanism by which ubiquitination regulates autophagy and pathogenicity in phyto-pathogenic fungi.

Pattern recognition receptors in health and diseases

Pattern recognition receptors(PRRs)are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens,apoptotic host cells,and damaged senescent cells.PRRs bridge nonspecific immunity and specific immunity.Through the recognition and binding of ligands,PRRs can produce nonspecific anti-infection,antitumor,and other immunoprotective effects.Most PRRs in the innate immune system of vertebrates can be classified into the following five types based on protein domain homology:Toll-like receptors(TLRs),nucleotide oligomerization domain(NOD)-like receptors(NLRs),retinoic acid-inducible gene-1(RIG-1)-like receptors(RLRs),C-type lectin receptors(CLRs),and absent in melanoma-2(AIM2)-like receptors(ALRs).PRRs are basically composed of ligand recognition domains,intermediate domains,and effector domains.PRRs recognize and bind their respective ligands and recruit adaptor molecules with the same structure through their effector domains,initiating downstream signaling pathways to exert effects.In recent years,the increased researches on the recognition and binding of PRRs and their ligands have greatly promoted the understanding of different PRRs signaling pathways and provided ideas for the treatment of immune-related diseases and even tumors.This review describes in detail the history,the structural characteristics,ligand recognition mechanism,the signaling pathway,the related disease,new drugs in clinical trials and clinical therapy of different types of PRRs,and discusses the significance of the research on pattern recognition mechanism for the treatment of PRR-related diseases.

语言经验对听者感知汉语外国口音严重程度和言语理解度的影响

本研究使用定量研究方法考察了听者的语言经验对其感知汉语外国口音严重程度和言语理解度的影响.研究发现,听者的母语会显著影响其对外国口音的感知和言语理解度,教学经验在一定程度上削弱了口音感知和言语理解度的相关性.研究结果对于汉语教师语音教学要求的定位和二语学习者语音习得目标的确定具有一定的启示意义.

Ultrastable MOF-based foams for versatile applications

Metal-organic frameworks(MOFs)are attractive for promising applications but plagued by difficult recovery and deployment due to their intrinsic nano/micro powder nature.Although significant efforts have been made to develop separable solid matrixes for MOF supporting,the poor loading stability and durability of MOFs still challenge their engineering applications.Here,we present a facile and effective approach to fabricate MOF-based melamine foams(MFs)(denoted as MOFiths)with ultrahigh loading stability and operation stability,easy separation,and high-efficient performance for versatile robust applications.By adopting our approach,numbers of typical fragile MOFs characterized with wide ranges of particle size(from~nm to~μm)can be precisely incorporated into MFs with controllable loading ratios(up to~1,600%).Particularly,the produced MOFiths show excellent capacities for the highly effective and durable water purifications and acetalization reactions.100%of organic pollutants can be rapidly destructed within 10 min by MOFiths initiated Fenton or catalytic ozonation processes under five successive cycles while the maximum adsorption capacity of MOFiths toward Pb(II),Cd(II),and Cu(II)reaches to 422,222,and 105 mg·g^(-1),respectively.This study provides a critical solution to substantially facilitate the engineering applications of MOFs for long-term use in practice.

Leucine-rich repeats containing 4 protein(LRRC4)in memory,psychoneurosis,and glioblastoma

Leucine-rich repeats containing 4(LRRC4,also named netrin-G ligand 2[NGL-2])is a member of the NetrinGs ligands(NGLs)family.As a gene with relatively high and specific expression in brain,it is a member of the leucine-rich repeat superfamily and has been proven to be a suppressor gene for gliomas,thus being involved in gliomagenesis.LRRC4 is the core of microRNA-dependent multi-phase regulatory loops that inhibit the proliferation and invasion of glioblastoma(GB)cells,including LRRC4/NGL2-activator protein 2(AP2)-microRNA(miR)182-LRRC4 and LRRC4-miR185-DNA methyltransferase 1(DNMT1)-LRRC4/specific protein 1(SP1)-DNMT1-LRRC4.In this review,we demonstrated LRRC4 as a new member of the partitioning-defective protein(PAR)polarity complex that promotes axon differentiation,mediates the formation and plasticity of synapses,and assists information input to the hippocampus and storage of memory.As an important synapse regulator,aberrant expression of LRRC4 has been detected in autism,spinal injury and GBs.LRRC4 is a candidate susceptibility gene for autism and a neuro-protective factor in spinal nerve damage.In GBs,LRRC4 is a novel inhibitor of autophagy,and an inhibitor of protein–protein interactions involving in temozolomide resistance,tumor immune microenvironment,and formation of circular RNA.

OPTIMAL RISK CONTROL POLICIES FOR DIFFUSION MODELS WITH NON-CHEAP PROPORTIONAL REINSURANCE AND BANKRUPTCY VALUE

This paper considers the problem about optimization of proportional reinsurance in the setting of diffusion models. The authors take into account non-cheap proportional reinsurance and bankruptcy value simultaneously. The objective is to find the risk control policies which maximize the total discounted reserve and the bankruptcy value. Results show that, the optimal risk control policies and corresponding optimal return functions vary, depending both on the range of bankruptcy value and the relationship between the premium rate of insurance and that of reinsurance.

Dispersion of“guava-like”silica/polyacrylate nanocomposite particles in polyacrylate matrix

A series of“guava-like”silica/polyacrylate nanocomposite particles with close silica content and different grafting degrees were prepared via mini-emulsion polymerization using 3-(trimethoxysilyl)propyl methacrylate(TSPM)modified silica/acrylate dispersion.The silica/polyacrylate composite particles were melt-mixed with unfilled polyacrylate(PA)resin to prepare corresponding silica/polyacrylate molded composites and the dispersion mechanism of these silica particles from the“guava-like”composite particles into polyacrylate matrix was studied.It was calculated that about 110 silica particles were accumulated in the bulk of every silica/polyacrylate composite latex particle.Both the solubility tests of silica/polyacrylate composite latex particles in tetrahydrofuran(THF)and the section transmission electron microscope(TEM)micrographs of silica/polyacrylate molded composites indicated that the grafting degree of silica particles played a crucial role in the dispersion of silica/polyacrylate composite particles into the polyacrylate matrix.When the grafting degree of polyacrylate onto silica was in a moderate range(ca.20%-70%),almost all of silica particles in these“guava-like”composite particles were dispersed into the polyacrylate matrix in a primaryparticle-level.However,at a lower grafting degree,massive silica aggregations were found in molded composites because of the lack of steric protection.At a greater grafting degree(i.e.,200%),a cross-linked network was formed in the silica/polyacrylate composite particles,which prevented the dispersion of composite particles in THF and polyacrylate matrix as primary particles.

Phenolic rigid organic filler/isotactic polypropylene composites.I.Preparation

A novel phenolic rigid organic filler(KT)was melt-mixed with an isotactic polypropylene(iPP)to prepare a series of PP/KT composites,with or without maleic anhydride grafted polypropylene(MAPP)as compatilizer.The evolution of filler morphology during melt-mixing and melt-pressure processes was monitored by scanning electron microscope(SEM)and polarized optical microscope(POM).The influences of shear force,pressure time,filler content and MAPP concentration on the final filler dispersion were studied.We found that this rigid organic filler readily melted and dispersed homogenously into the iPP matrix through a fission-fusion process during the melt-mixing process.Thus a balanced dispersion,which was closely related to shear force and MAPP concentration,can be achieved.During the meltpressure process,parts of the filler particles combined gradually through a coalescence process.However,the incorporation of MAPP can effectively inhibit the tendency to coalesce and refine the filler particles sizes into nanoscale.Thus,a series of PP/KT composites with controllable filler particles size and narrow size distribution can be obtained just by adjusting process conditions and MAPP concentration.In addition,due to the in-situ formation mechanism,the filler phase possessed a typical solid true-spherical shape.

Phenolic rigid organic filler/isotactic polypropylene composites. Ⅱ. Tensile properties

A novel phenolic rigid organic filler(KT)was used to modify isotactic polypropylene(iPP).The influence of KT particles on the tensile properties of PP/KT micro-composites was studied by uniaxial tensile test and the mor-phological structures of the stretched specimens were observed by scanning electron microscopy(SEM)and polarized optical microscopy(POM).We found that the Young's modulus of PP/KT specimens increased with filler content,while the yield and break of the specimens are related to the filler particles size.The yield stress,the break-ing stress and the ultimate elongation of PP/KT specimens were close to those of unfilled iPP specimens when the max-imal filler particles size is less than a critical value,which is 7μm at a crosshead speed of 10 mm/min and 3μm at 200 mm/min,close to that of glass bead but far more than those of other rigid inorganic filler particles.The interfacial interaction was further estimated from yield stress,indi-cating that KT particles have a moderate interracial inter-action with iPP matrix.Thus,the incorporation of small KT particles can reinforce iPP matrix and simultaneously cause few detrimental effects on the other excellent tensile properties of iPP matrix,due to their organic nature,higher specific area,solid true-spherical shape and the homogen-ous dispersion of the ROF particles in microcomposites.

Phenolic rigid organic filler/isotactic polypropylene composites. Ⅲ. Impact resistance property

A novel phenolic rigid organic filler(KT)was used to modify isotactic polypropylene(iPP).The influence of KT particles on the impact resistance property of PP/KT specimens(with similar interparticles distance,1.8μm)was studied by notched izod impact tests.It was found that the brittle-ductile transition(BDT)of the PP/KT microcomposites took place at the filler content of about 4%,and the impact strength attains the maximum at 5%(with filler particles size of 1.5μm),which is about 2.5 times that of unfilled iPP specimens.The impact fracture morphology was investigated by scanning electron micro-scopy(SEM).For the PP/KT specimens and the high-density polyethylene/KT(HDPE/KT)specimens in ductile fracture mode,many microfibers could be found on the whole impact fracture surface.It was the filler particles that induced the plastic deformation of interparticles ligament and hence improved the capability of iPP matrix on absorbing impact energy dramatically.The determinants on the BDT were further discussed on the basis of stress concentration and debonding resistance.It can be con-cluded that aside from the interparticle distance,the filler particles size also plays an important role in semicrystal-line polymer toughening.