The failed components of repairable systems are replaced with spare parts that may have different failure distributions from those of the components that have failed. The spare parts may be either the same as new, bet...The failed components of repairable systems are replaced with spare parts that may have different failure distributions from those of the components that have failed. The spare parts may be either the same as new, better than new, or worse than new. This is the reality in maintenance engineering. Repair with better spare parts is defined as ＂super repair＂. The failure distributions of the spare parts affect the availability of the components and their systems. A novel model is proposed to describe the availability of repairable systems across their operating time, at the level of their components, on the assumption that the failed components are immediately replaced. The model functions with arbitrary failure distributions of spare parts. It can be used to compute the availability of components and systems not only under perfect and imperfect repair but also under super repair.展开更多
This research article is based on a study of optimal frequency to the repairable system due to the failure finding interval to maximize as well as minimize the availability of some components devices. We studied toget...This research article is based on a study of optimal frequency to the repairable system due to the failure finding interval to maximize as well as minimize the availability of some components devices. We studied together maintenance and corrective actions that carried out item of failure and periodic failure finding designed to check whether a system is still working. The model is proved as well as useful application in detecting the problem related to finding failure tasks of different scheme devices by maximization. The model formulated and the numerical application to the relevant mathematical model have been discussed to demonstrate the article quality. Therefore based on probability analytic development, the optimal maintenance policy is then obtained as solution of an optimization problem in which the maintenance cost rate is the objective function and the risk of corrective maintenance is the constraint function. Finally, the solution to the optimal device in the considered development model has been well adjusted due to derivation to the experimental observation rather than theory which will be taken into consideration in the next applied practical design research related and the system device provided that, the proactive device agreed with using the exponential distribution to the survive distribution function which can not be considered as valid.展开更多
Injuries caused by trauma and neurodegenerative diseases can damage the peripheral nervous system and cause functional deficits.Unlike in the central nervous system,damaged axons in peripheral nerves can be induced to...Injuries caused by trauma and neurodegenerative diseases can damage the peripheral nervous system and cause functional deficits.Unlike in the central nervous system,damaged axons in peripheral nerves can be induced to regenerate in response to intrinsic cues after reprogramming or in a growth-promoting microenvironment created by Schwann cells.However,axon regeneration and repair do not automatically result in the restoration of function,which is the ultimate therapeutic goal but also a major clinical challenge.Transforming growth factor(TGF)is a multifunctional cytokine that regulates various biological processes including tissue repair,embryo development,and cell growth and differentiation.There is accumulating evidence that TGF-βfamily proteins participate in peripheral nerve repair through various factors and signaling pathways by regulating the growth and transformation of Schwann cells;recruiting specific immune cells;controlling the permeability of the blood-nerve barrier,thereby stimulating axon growth;and inhibiting remyelination of regenerated axons.TGF-βhas been applied to the treatment of peripheral nerve injury in animal models.In this context,we review the functions of TGF-βin peripheral nerve regeneration and potential clinical applications.展开更多
Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of adv...Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.展开更多
Irregular articular cartilage injury is a common type of joint trauma,often resulting from intense impacts and other factors that lead to irregularly shaped wounds,the limited regenerative capacity of cartilage and th...Irregular articular cartilage injury is a common type of joint trauma,often resulting from intense impacts and other factors that lead to irregularly shaped wounds,the limited regenerative capacity of cartilage and the mismatched shape of the scaffods have contributed to unsatisfactory therapeutic outcomes.While injectable materials are a traditional solution to adapt to irregular cartilage defects,they have limitations,and injectable materials often lack the porous microstructures favorable for the rapid proliferation of cartilage cells.In this study,an injectable porous polyurethane scaffold named PU-BDO-Gelatin-Foam(PUBGF)was prepared.After injection into cartilage defects,PUBGF forms in situ at the site of the defect and exhibits a dynamic microstructure during the initial two weeks.This dynamic microstructure endows the scaffold with the ability to retain substances within its interior,thereby enhancing its capacity to promote chondrogenesis.Furthermore,the chondral repair efficacy of PUBGF was validated by directly injecting it into rat articular cartilage injury sites.The injectable PUBGF scaffold demonstrates a superior potential for promoting the repair of cartilage defects when compared to traditional porous polyurethane scaffolds.The substance retention ability of this injectable porous scaffold makes it a promising option for clinical applications.展开更多
Neuronal injury,aging,and cerebrovascular and neurodegenerative diseases such as cerebral infarction,Alzheimer’s disease,Parkinson’s disease,frontotemporal dementia,amyotrophic lateral sclerosis,and Huntington’s di...Neuronal injury,aging,and cerebrovascular and neurodegenerative diseases such as cerebral infarction,Alzheimer’s disease,Parkinson’s disease,frontotemporal dementia,amyotrophic lateral sclerosis,and Huntington’s disease are characte rized by significant neuronal loss.Unfo rtunately,the neurons of most mammals including humans do not possess the ability to self-regenerate.Replenishment of lost neurons becomes an appealing therapeutic strategy to reve rse the disease phenotype.Transplantation of pluripotent neural stem cells can supplement the missing neurons in the brain,but it carries the risk of causing gene mutation,tumorigenesis,severe inflammation,and obstructive hydrocephalus induced by brain edema.Conversion of neural or non-neural lineage cells into functional neurons is a promising strategy for the diseases involving neuron loss,which may overcome the above-mentioned disadvantages of neural stem cell therapy.Thus far,many strategies to transfo rm astrocytes,fibroblasts,microglia,Muller glia,NG2 cells,and other glial cells to mature and functional neurons,or for the conversion between neuronal subtypes have been developed thro ugh the regulation of transcription factors,polypyrimidine tra ct binding protein 1(PTBP1),and small chemical molecules or are based on a combination of several factors and the location in the central nervous system.However,some recent papers did not obtain expected results,and discrepancies exist.Therefore,in this review,we discuss the history of neuronal transdifferentiation,summarize the strategies for neuronal replenishment and conversion from glia,especially astrocytes,and point out that biosafety,new strategies,and the accurate origin of the truly co nverted neurons in vivo should be focused upon in future studies.It also arises the attention of replenishing the lost neurons from glia by gene therapies such as up-regulation of some transc ription factors or downregulation of PTBP1 or drug interfe rence therapies.展开更多
Skin wounds are characterized by injury to the skin due to trauma,tearing,cuts,or contusions.As such injuries are common to all human groups,they may at times represent a serious socioeconomic burden.Currently,increas...Skin wounds are characterized by injury to the skin due to trauma,tearing,cuts,or contusions.As such injuries are common to all human groups,they may at times represent a serious socioeconomic burden.Currently,increasing numbers of studies have focused on the role of mesenchymal stem cell(MSC)-derived extracellular vesicles(EVs)in skin wound repair.As a cell-free therapy,MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy.Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures,including the regeneration of vessels,nerves,and hair follicles.In addition,MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization,wound angiogenesis,cell proliferation,and cell migration,and by inhibiting excessive extracellular matrix production.Additionally,these structures can serve as a scaffold for components used in wound repair,and they can be developed into bioengineered EVs to support trauma repair.Through the formulation of standardized culture,isolation,purification,and drug delivery strategies,exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair.In conclusion,MSCderived EV-based therapies have important application prospects in wound repair.Here we provide a comprehensive overview of their current status,application potential,and associated drawbacks.展开更多
BACKGROUND Cartilage defects are some of the most common causes of arthritis.Cartilage lesions caused by inflammation,trauma or degenerative disease normally result in osteochondral defects.Previous studies have shown...BACKGROUND Cartilage defects are some of the most common causes of arthritis.Cartilage lesions caused by inflammation,trauma or degenerative disease normally result in osteochondral defects.Previous studies have shown that decellularized extracellular matrix(ECM)derived from autologous,allogenic,or xenogeneic mesenchymal stromal cells(MSCs)can effectively restore osteochondral integrity.AIM To determine whether the decellularized ECM of antler reserve mesenchymal cells(RMCs),a xenogeneic material from antler stem cells,is superior to the currently available treatments for osteochondral defects.METHODS We isolated the RMCs from a 60-d-old sika deer antler and cultured them in vitro to 70%confluence;50 mg/mL L-ascorbic acid was then added to the medium to stimulate ECM deposition.Decellularized sheets of adipocyte-derived MSCs(aMSCs)and antlerogenic periosteal cells(another type of antler stem cells)were used as the controls.Three weeks after ascorbic acid stimulation,the ECM sheets were harvested and applied to the osteochondral defects in rat knee joints.RESULTS The defects were successfully repaired by applying the ECM-sheets.The highest quality of repair was achieved in the RMC-ECM group both in vitro(including cell attachment and proliferation),and in vivo(including the simultaneous regeneration of well-vascularized subchondral bone and avascular articular hyaline cartilage integrated with surrounding native tissues).Notably,the antler-stem-cell-derived ECM(xenogeneic)performed better than the aMSC-ECM(allogenic),while the ECM of the active antler stem cells was superior to that of the quiescent antler stem cells.CONCLUSION Decellularized xenogeneic ECM derived from the antler stem cell,particularly the active form(RMC-ECM),can achieve high quality repair/reconstruction of osteochondral defects,suggesting that selection of decellularized ECM for such repair should be focused more on bioactivity rather than kinship.展开更多
Spares inventory configuration optimization is an effective way to improve readiness and reduce life cycle cost of equipment.Through analyzing two-echelon spares support system,the METRIC model basic theory was used.A...Spares inventory configuration optimization is an effective way to improve readiness and reduce life cycle cost of equipment.Through analyzing two-echelon spares support system,the METRIC model basic theory was used.An inventory configuration optimization model of two-echelon spares support system was proposed which took the spares expected shortfall as the object and made the minimum repairable parts expected shortfall instead of the maximum spares supportability as the objective function.Marginal efficiency analysis algorithm was applied to optimizing the spares configuration and generating a rational spares inventory configuration.Finally,several examples are given to verify the model.展开更多
Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,...Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.展开更多
Loss of plasma membrane integrity can compromise cell functioning and viability.To countera ct this eminent threat,euka ryotic cells have developed efficient repair mechanisms,which seem to have co-evolved with the em...Loss of plasma membrane integrity can compromise cell functioning and viability.To countera ct this eminent threat,euka ryotic cells have developed efficient repair mechanisms,which seem to have co-evolved with the emergence of vital membrane processes(Cooper and McNeil,2015).This relationship between basic cellular functioning and membrane repair highlights the fundamental significance of preserving membrane integrity for cellular life.展开更多
A composite bone cement based onα-TCP with self-reinforcing characteristics is prepared by compounding cellulose whiskers and polyvinyl alcohol in different proportions.In this system,we are inspired by the sea cucum...A composite bone cement based onα-TCP with self-reinforcing characteristics is prepared by compounding cellulose whiskers and polyvinyl alcohol in different proportions.In this system,we are inspired by the sea cucumber,which can alter the stiffness of their inner dermis reversibly.Through the formation of hydrogen bonds between the hydroxyl groups on the cellulose whiskers and PVA,the bone cement matrix can be strengthened during the curing process of cement.In the process of bone cement blending,there is more water,the hydrogen bond connection is destroyed,so the slurry has better fluidity at this time.As the hydration of the bone cement progresses,the reduction of the water phase leads to the formation of a permeable network structure of hydrogen bond connections between the whiskers.The dual-phase action of PVA and whiskers greatly increases the mechanical strength of the bone cement system(5.5 to 23.8 MPa),while the presence of polyvinyl alcohol improves the toughness of the bone cement system.This work was supposed to explore whether the chemoresponsive materials can be adapted to biomedical materials,for example,bone repair.展开更多
A new scour countermeasure using solidified slurry for offshore foundation has been proposed recently.Fluidized solidified slurry is pumped to seabed area around foundation for scour protection or pumped into the deve...A new scour countermeasure using solidified slurry for offshore foundation has been proposed recently.Fluidized solidified slurry is pumped to seabed area around foundation for scour protection or pumped into the developed scour holes for scour repair as the fluidized material solidifies gradually.In the pumping operation and solidification,the engineering behaviors of solidified slurry require to be considered synthetically for the reliable application in scour repair and protection of ocean engineering such as the pumpability related flow value,flow diffusion behavior related rheological property,anti-scour performance related retention rate in solidification and bearing capacity related strength property after solidification.In this study,a series of laboratory tests are conducted to investigate the effects of mix proportion(initial water content and binder content)on the flow value,rheological properties,density,retention rate of solidified slurry and unconfined compressive strength(UCS).The results reveal that the flow value increases with the water content and decreases with the binder amount.All the solidified slurry exhibits Bingham plastic behavior when the shear rate is larger than 5 s^(-1).The Bingham model has been employed to fit the rheology test results,and empirical formulas for obtaining the density,yield stress and viscosity are established,providing scientific support for the numerical assessment of flow and diffusion of solidified slurry.Retention rate of solidified slurry decreases with the water flow velocity and flow value,which means the pumpability of solidified slurry is contrary to anti-scour performance.The unconfined compressive strength after solidification reduces as the water content increases and binder content decreases.A design and application procedure of solidified soil for scour repair and protection is also proposed for engineering reference.展开更多
Neuronal growth, extension, branching, and formation of neural networks are markedly influenced by the extracellular matrix—a complex network composed of proteins and carbohydrates secreted by cells. In addition to p...Neuronal growth, extension, branching, and formation of neural networks are markedly influenced by the extracellular matrix—a complex network composed of proteins and carbohydrates secreted by cells. In addition to providing physical support for cells, the extracellular matrix also conveys critical mechanical stiffness cues. During the development of the nervous system, extracellular matrix stiffness plays a central role in guiding neuronal growth, particularly in the context of axonal extension, which is crucial for the formation of neural networks. In neural tissue engineering, manipulation of biomaterial stiffness is a promising strategy to provide a permissive environment for the repair and regeneration of injured nervous tissue. Recent research has fine-tuned synthetic biomaterials to fabricate scaffolds that closely replicate the stiffness profiles observed in the nervous system. In this review, we highlight the molecular mechanisms by which extracellular matrix stiffness regulates axonal growth and regeneration. We highlight the progress made in the development of stiffness-tunable biomaterials to emulate in vivo extracellular matrix environments, with an emphasis on their application in neural repair and regeneration, along with a discussion of the current limitations and future prospects. The exploration and optimization of the stiffness-tunable biomaterials has the potential to markedly advance the development of neural tissue engineering.展开更多
The conserved DNA damage repair complex,MMS21-SMC5/6(Methyl methane sulfonate 21-Structural maintenance of chromosomes 5/6),has been extensively studied in yeast,animals,and plants.However,its role in phytopathogenic ...The conserved DNA damage repair complex,MMS21-SMC5/6(Methyl methane sulfonate 21-Structural maintenance of chromosomes 5/6),has been extensively studied in yeast,animals,and plants.However,its role in phytopathogenic fungi,particularly in the highly destructive rice blast fungus Magnaporthe oryzae,remains unknown.In this study,we functionally characterized the homologues of this complex,MoMMS21 and MoSMC5,in M.oryzae.We first demonstrated the importance of DNA damage repair in M.oryzae by showing that the DNA damage inducer phleomycin inhibited vegetative growth,infection-related development and pathogenicity in this fungus.Additionally,we discovered that MoMMS21 and MoSMC5 interacted in the nuclei,suggesting that they also function as a complex in M.oryzae.Gene deletion experiments revealed that both MoMMS21 and MoSMC5 are required for infection-related development and pathogenicity in M.oryzae,while only MoMMS21 deletion affected growth and sensitivity to phleomycin,indicating its specific involvement in DNA damage repair.Overall,our results provide insights into the roles of MoMMS21 and MoSMC5 in M.oryzae,highlighting their functions beyond DNA damage repair.展开更多
Tissue engineering technology has advanced rapidly in recent years, offering opportunities to construct biologicallyactive tissues or organ substitutes to repair or even enhance the functions of diseased tissues and o...Tissue engineering technology has advanced rapidly in recent years, offering opportunities to construct biologicallyactive tissues or organ substitutes to repair or even enhance the functions of diseased tissues and organs.Tissue-engineered scaffolds rebuild the extracellular microenvironment by mimicking the extracellular matrix.Fibrin-based scaffolds possess numerous advantages, including hemostasis, high biocompatibility, and gooddegradability. Fibrin scaffolds provide an initial matrix that facilitates cell migration, differentiation, proliferation,and adhesion, and also play a critical role in cell-matrix interactions. Fibrin scaffolds are now widelyrecognized as a key component in tissue engineering, where they can facilitate tissue and organ defect repair.This review introduces the properties of fibrin, including its composition, structure, and biology. In addition, themodification and cross-linking modes of fibrin are discussed, along with various forms commonly used in tissueengineering. We also describe the biofunctionalization of fibrin. This review provides a detailed overview of theuse and applications of fibrin in skin, bone, and nervous tissues, and provides novel insights into future researchdirections for clinical treatment.展开更多
The repair and regeneration of bone defects are highly challenging orthopedic problems.Recently,Mg-based implants have gained popularity due to their unique biodegradation and elastic modulus similar to that of human ...The repair and regeneration of bone defects are highly challenging orthopedic problems.Recently,Mg-based implants have gained popularity due to their unique biodegradation and elastic modulus similar to that of human bone.The aim of our study is to develop a magnesium alloy with a controllable degradation that can closely match bone tissue to help injuries heal in vivo and avoid cytotoxicity caused by a sudden increase in ion concentration.In this study,we prepared and modified Mg-3Zn,Mg-3Zn-1Y,and Mg-2Zn-1Mn by hot extrusion,and used Mg-2.5Y-2.5Nd was as a control.We then investigated the effect of additions of Y and Mn on alloys'properties.Our results show that Mn and Y can improve not only compression strength but also corrosion resistance.The alloy Mg-2Zn-1Mn demonstrated good cytocompatibility in vitro,and for this reason we selected it for implantation in vivo.The degraded Mg-2Zn-1Mn implanted a bone defect area did not cause obvious rejection and inflammatory reaction,and the degradation products left no signs of damage to the heart,liver,kidney,or brain.Furthermore,we find that Mg-2Zn-1Mn can promote an osteoinductive response in vivo and the formation of bone regeneration.展开更多
Objective:Nucleotide excision repair(NER)plays a vital role in maintaining genome stability,and the effect of NER gene polymorphisms on hepatoblastoma susceptibility is still under investigation.This study aimed to ev...Objective:Nucleotide excision repair(NER)plays a vital role in maintaining genome stability,and the effect of NER gene polymorphisms on hepatoblastoma susceptibility is still under investigation.This study aimed to evaluate the relationship between NER gene polymorphisms and the risk of hepatoblastoma in Eastern Chinese Han children.Methods:In this five-center case-control study,we enrolled 966 subjects from East China(193 hepatoblastoma patients and 773 healthy controls).The TaqMan method was used to genotype 19 single nucleotide polymorphisms(SNPs)in NER pathway genes,including ERCC1,XPA,XPC,XPD,XPF,and XPG.Then,multivariate logistic regression analysis was performed,and odds ratios(ORs)and 95%confidence intervals(95%CIs)were utilized to assess the strength of associations.Results:Three SNPs were related to hepatoblastoma risk.XPC rs2229090 and XPD rs3810366 significantly contributed to hepatoblastoma risk according to the dominant model(adjusted OR=1.49,95%CI=1.07−2.08,P=0.019;adjusted OR=1.66,95%CI=1.12−2.45,P=0.012,respectively).However,XPD rs238406 conferred a significantly decreased risk of hepatoblastoma under the dominant model(adjusted OR=0.68,95%CI=0.49−0.95;P=0.024).Stratified analysis demonstrated that these significant associations were more prominent in certain subgroups.Moreover,there was evidence of functional implications of these significant SNPs suggested by online expression quantitative trait loci(eQTLs)and splicing quantitative trait loci(sQTLs)analysis.Conclusions:In summary,NER pathway gene polymorphisms(XPC rs2229090,XPD rs3810366,and XPD rs238406)are significantly associated with hepatoblastoma risk,and further research is required to verify these findings.展开更多
Probiotics participate in various physiological activities and contribute to body health.However,their viability and bioefficacy are adversely affected by gastrointestinal harsh conditions,such as gastric acid,bile sa...Probiotics participate in various physiological activities and contribute to body health.However,their viability and bioefficacy are adversely affected by gastrointestinal harsh conditions,such as gastric acid,bile salts and various enzymes.Fortunately,encapsulation based on various nanomaterials shows tremendous potential to protect probiotics.In this review,we introduced some novel encapsulation technologies involving nanomaterials in view of predesigned stability and viability,selective adhesion,smart release and colonization,and efficacy exertion of encapsulated probiotics.Furthermore,the interactions between encapsulated probiotics and the gastrointestinal tract were summarized and analyzed,with highlighting the regulatory mechanisms of encapsulated probiotics on intestinal mechanical barrier,chemical barrier,biological barrier and immune barrier.This review would benefit the food and pharmaceutical industries in preparation and utilization of multifunctional encapsulated probiotics.展开更多
Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrèsyndrome,mostly related to halted axon regeneration.Cross-linking of cell surface gangliosides by anti-ganglioside a...Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrèsyndrome,mostly related to halted axon regeneration.Cross-linking of cell surface gangliosides by anti-ganglioside antibodies triggers inhibition of nerve repair in in vitro and in vivo paradigms of axon regeneration.These effects involve the activation of the small GTPase Rho A/ROCK signaling pathways,which negatively modulate growth cone cytoskeleton,similarly to well stablished inhibitors of axon regeneration described so far.The aim of this work was to perform a proof of concept study to demonstrate the effectiveness of Y-27632,a selective pharmacological inhibitor of ROCK,in a mouse model of axon regeneration of peripheral nerves,where the passive immunization with a monoclonal antibody targeting gangliosides GD1a and GT1b was previously reported to exert a potent inhibitory effect on regeneration of both myelinated and unmyelinated fibers.Our results demonstrate a differential sensitivity of myelinated and unmyelinated axons to the pro-regenerative effect of Y-27632.Treatment with a total dosage of 9 mg/kg of Y-27632 resulted in a complete prevention of anti-GD1a/GT1b monoclonal antibody-mediated inhibition of axon regeneration of unmyelinated fibers to skin and the functional recovery of mechanical cutaneous sensitivity.In contrast,the same dose showed toxic effects on the regeneration of myelinated fibers.Interestingly,scale down of the dosage of Y-27632 to 5 mg/kg resulted in a significant although not complete recovery of regenerated myelinated axons exposed to anti-GD1a/GT1b monoclonal antibody in the absence of toxicity in animals exposed to only Y-27632.Overall,these findings confirm the in vivo participation of Rho A/ROCK signaling pathways in the molecular mechanisms associated with the inhibition of axon regeneration induced by anti-GD1a/GT1b monoclonal antibody.Our findings open the possibility of therapeutic pharmacological intervention targeting Rho A/Rock pathway in immune neuropathies associated with the presence of anti-ganglioside antibodies and delayed or incomplete clinical recovery after injury in the peripheral nervous system.展开更多
文摘The failed components of repairable systems are replaced with spare parts that may have different failure distributions from those of the components that have failed. The spare parts may be either the same as new, better than new, or worse than new. This is the reality in maintenance engineering. Repair with better spare parts is defined as ＂super repair＂. The failure distributions of the spare parts affect the availability of the components and their systems. A novel model is proposed to describe the availability of repairable systems across their operating time, at the level of their components, on the assumption that the failed components are immediately replaced. The model functions with arbitrary failure distributions of spare parts. It can be used to compute the availability of components and systems not only under perfect and imperfect repair but also under super repair.
文摘This research article is based on a study of optimal frequency to the repairable system due to the failure finding interval to maximize as well as minimize the availability of some components devices. We studied together maintenance and corrective actions that carried out item of failure and periodic failure finding designed to check whether a system is still working. The model is proved as well as useful application in detecting the problem related to finding failure tasks of different scheme devices by maximization. The model formulated and the numerical application to the relevant mathematical model have been discussed to demonstrate the article quality. Therefore based on probability analytic development, the optimal maintenance policy is then obtained as solution of an optimization problem in which the maintenance cost rate is the objective function and the risk of corrective maintenance is the constraint function. Finally, the solution to the optimal device in the considered development model has been well adjusted due to derivation to the experimental observation rather than theory which will be taken into consideration in the next applied practical design research related and the system device provided that, the proactive device agreed with using the exponential distribution to the survive distribution function which can not be considered as valid.
基金supported by the National Natural Science Foundation of China,Nos.31971277 and 31950410551(both to DY)。
文摘Injuries caused by trauma and neurodegenerative diseases can damage the peripheral nervous system and cause functional deficits.Unlike in the central nervous system,damaged axons in peripheral nerves can be induced to regenerate in response to intrinsic cues after reprogramming or in a growth-promoting microenvironment created by Schwann cells.However,axon regeneration and repair do not automatically result in the restoration of function,which is the ultimate therapeutic goal but also a major clinical challenge.Transforming growth factor(TGF)is a multifunctional cytokine that regulates various biological processes including tissue repair,embryo development,and cell growth and differentiation.There is accumulating evidence that TGF-βfamily proteins participate in peripheral nerve repair through various factors and signaling pathways by regulating the growth and transformation of Schwann cells;recruiting specific immune cells;controlling the permeability of the blood-nerve barrier,thereby stimulating axon growth;and inhibiting remyelination of regenerated axons.TGF-βhas been applied to the treatment of peripheral nerve injury in animal models.In this context,we review the functions of TGF-βin peripheral nerve regeneration and potential clinical applications.
基金Supported by IU Simon Comprehensive Cancer Center grant,No.5P30CA082709-24.
文摘Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
基金supported by the National Natural Science Foundation of China(Nos.52273119,51973018 and 81571410)the Beijing Science and Technology Project(Z191100002019017).
文摘Irregular articular cartilage injury is a common type of joint trauma,often resulting from intense impacts and other factors that lead to irregularly shaped wounds,the limited regenerative capacity of cartilage and the mismatched shape of the scaffods have contributed to unsatisfactory therapeutic outcomes.While injectable materials are a traditional solution to adapt to irregular cartilage defects,they have limitations,and injectable materials often lack the porous microstructures favorable for the rapid proliferation of cartilage cells.In this study,an injectable porous polyurethane scaffold named PU-BDO-Gelatin-Foam(PUBGF)was prepared.After injection into cartilage defects,PUBGF forms in situ at the site of the defect and exhibits a dynamic microstructure during the initial two weeks.This dynamic microstructure endows the scaffold with the ability to retain substances within its interior,thereby enhancing its capacity to promote chondrogenesis.Furthermore,the chondral repair efficacy of PUBGF was validated by directly injecting it into rat articular cartilage injury sites.The injectable PUBGF scaffold demonstrates a superior potential for promoting the repair of cartilage defects when compared to traditional porous polyurethane scaffolds.The substance retention ability of this injectable porous scaffold makes it a promising option for clinical applications.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences,No.XDB39050600(to RL)the National Natural Science Foundation of China,No.81971610(to RL)Beijing Rehabilitation Hospital Introduction of Talent Research Start-up Fund,No.2021R-008(to JZ)。
文摘Neuronal injury,aging,and cerebrovascular and neurodegenerative diseases such as cerebral infarction,Alzheimer’s disease,Parkinson’s disease,frontotemporal dementia,amyotrophic lateral sclerosis,and Huntington’s disease are characte rized by significant neuronal loss.Unfo rtunately,the neurons of most mammals including humans do not possess the ability to self-regenerate.Replenishment of lost neurons becomes an appealing therapeutic strategy to reve rse the disease phenotype.Transplantation of pluripotent neural stem cells can supplement the missing neurons in the brain,but it carries the risk of causing gene mutation,tumorigenesis,severe inflammation,and obstructive hydrocephalus induced by brain edema.Conversion of neural or non-neural lineage cells into functional neurons is a promising strategy for the diseases involving neuron loss,which may overcome the above-mentioned disadvantages of neural stem cell therapy.Thus far,many strategies to transfo rm astrocytes,fibroblasts,microglia,Muller glia,NG2 cells,and other glial cells to mature and functional neurons,or for the conversion between neuronal subtypes have been developed thro ugh the regulation of transcription factors,polypyrimidine tra ct binding protein 1(PTBP1),and small chemical molecules or are based on a combination of several factors and the location in the central nervous system.However,some recent papers did not obtain expected results,and discrepancies exist.Therefore,in this review,we discuss the history of neuronal transdifferentiation,summarize the strategies for neuronal replenishment and conversion from glia,especially astrocytes,and point out that biosafety,new strategies,and the accurate origin of the truly co nverted neurons in vivo should be focused upon in future studies.It also arises the attention of replenishing the lost neurons from glia by gene therapies such as up-regulation of some transc ription factors or downregulation of PTBP1 or drug interfe rence therapies.
基金supported by the National Key Research and Development Project Intergovernmental Cooperation in Science and Technology of China(2018YFE0126900)the Key R&D Program of Lishui City(2021ZDYF12)the National Natural Science Foundation of China(82271629)。
文摘Skin wounds are characterized by injury to the skin due to trauma,tearing,cuts,or contusions.As such injuries are common to all human groups,they may at times represent a serious socioeconomic burden.Currently,increasing numbers of studies have focused on the role of mesenchymal stem cell(MSC)-derived extracellular vesicles(EVs)in skin wound repair.As a cell-free therapy,MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy.Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures,including the regeneration of vessels,nerves,and hair follicles.In addition,MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization,wound angiogenesis,cell proliferation,and cell migration,and by inhibiting excessive extracellular matrix production.Additionally,these structures can serve as a scaffold for components used in wound repair,and they can be developed into bioengineered EVs to support trauma repair.Through the formulation of standardized culture,isolation,purification,and drug delivery strategies,exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair.In conclusion,MSCderived EV-based therapies have important application prospects in wound repair.Here we provide a comprehensive overview of their current status,application potential,and associated drawbacks.
基金National Natural Science Foundation of China,No.U20A20403This study was conducted in accordance with the Animal Ethics Committee of the Institute of Antler Science and Product Technology,Changchun Sci-Tech University(AEC No:CKARI202309).
文摘BACKGROUND Cartilage defects are some of the most common causes of arthritis.Cartilage lesions caused by inflammation,trauma or degenerative disease normally result in osteochondral defects.Previous studies have shown that decellularized extracellular matrix(ECM)derived from autologous,allogenic,or xenogeneic mesenchymal stromal cells(MSCs)can effectively restore osteochondral integrity.AIM To determine whether the decellularized ECM of antler reserve mesenchymal cells(RMCs),a xenogeneic material from antler stem cells,is superior to the currently available treatments for osteochondral defects.METHODS We isolated the RMCs from a 60-d-old sika deer antler and cultured them in vitro to 70%confluence;50 mg/mL L-ascorbic acid was then added to the medium to stimulate ECM deposition.Decellularized sheets of adipocyte-derived MSCs(aMSCs)and antlerogenic periosteal cells(another type of antler stem cells)were used as the controls.Three weeks after ascorbic acid stimulation,the ECM sheets were harvested and applied to the osteochondral defects in rat knee joints.RESULTS The defects were successfully repaired by applying the ECM-sheets.The highest quality of repair was achieved in the RMC-ECM group both in vitro(including cell attachment and proliferation),and in vivo(including the simultaneous regeneration of well-vascularized subchondral bone and avascular articular hyaline cartilage integrated with surrounding native tissues).Notably,the antler-stem-cell-derived ECM(xenogeneic)performed better than the aMSC-ECM(allogenic),while the ECM of the active antler stem cells was superior to that of the quiescent antler stem cells.CONCLUSION Decellularized xenogeneic ECM derived from the antler stem cell,particularly the active form(RMC-ECM),can achieve high quality repair/reconstruction of osteochondral defects,suggesting that selection of decellularized ECM for such repair should be focused more on bioactivity rather than kinship.
文摘Spares inventory configuration optimization is an effective way to improve readiness and reduce life cycle cost of equipment.Through analyzing two-echelon spares support system,the METRIC model basic theory was used.An inventory configuration optimization model of two-echelon spares support system was proposed which took the spares expected shortfall as the object and made the minimum repairable parts expected shortfall instead of the maximum spares supportability as the objective function.Marginal efficiency analysis algorithm was applied to optimizing the spares configuration and generating a rational spares inventory configuration.Finally,several examples are given to verify the model.
基金supported by the Heart and Stroke Foundation and Ontario Institute of Regenerative Medicine (New Ideas Grant)Canada First Research Excellence Fund(Medicine by Design)+2 种基金the National Sciences and Engineering Research Councilthe Jurgen Manchot Foundationthe Christiane and Claudia Hempel Foundation for Clinical Stem Cell Research and the James and Elisabeth Cloppenburg,Peek and Cloppenburg Düsseldorf Stiftung (to PK)
文摘Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.
基金supported by the Novo Nordisk Foundation(NNF180C0034936)the Lundbeck Foundation(R380-2021-1262)(to CD and JN)。
文摘Loss of plasma membrane integrity can compromise cell functioning and viability.To countera ct this eminent threat,euka ryotic cells have developed efficient repair mechanisms,which seem to have co-evolved with the emergence of vital membrane processes(Cooper and McNeil,2015).This relationship between basic cellular functioning and membrane repair highlights the fundamental significance of preserving membrane integrity for cellular life.
基金Supported by the National Natural Science Foundation of China(Nos.31670969,82172440)the Fundamental Research Funds for the Central Universities(Nos.21620417,21621103)+2 种基金the Medical Joint Fund of Jinan University(No.YXJC2022005)the National Key Research and Development Program of China(No.2022YFE0206200)the Funding of Science and Technology Projects in Guangzhou(Nos.202206010158,202201020087)。
文摘A composite bone cement based onα-TCP with self-reinforcing characteristics is prepared by compounding cellulose whiskers and polyvinyl alcohol in different proportions.In this system,we are inspired by the sea cucumber,which can alter the stiffness of their inner dermis reversibly.Through the formation of hydrogen bonds between the hydroxyl groups on the cellulose whiskers and PVA,the bone cement matrix can be strengthened during the curing process of cement.In the process of bone cement blending,there is more water,the hydrogen bond connection is destroyed,so the slurry has better fluidity at this time.As the hydration of the bone cement progresses,the reduction of the water phase leads to the formation of a permeable network structure of hydrogen bond connections between the whiskers.The dual-phase action of PVA and whiskers greatly increases the mechanical strength of the bone cement system(5.5 to 23.8 MPa),while the presence of polyvinyl alcohol improves the toughness of the bone cement system.This work was supposed to explore whether the chemoresponsive materials can be adapted to biomedical materials,for example,bone repair.
基金financially supported by the Science and Technology Commission Foundation of Shanghai(Grant Nos.22DZ1208903,20DZ2251900)the National Natural Science Foundation of China(Grant No.51679134)。
文摘A new scour countermeasure using solidified slurry for offshore foundation has been proposed recently.Fluidized solidified slurry is pumped to seabed area around foundation for scour protection or pumped into the developed scour holes for scour repair as the fluidized material solidifies gradually.In the pumping operation and solidification,the engineering behaviors of solidified slurry require to be considered synthetically for the reliable application in scour repair and protection of ocean engineering such as the pumpability related flow value,flow diffusion behavior related rheological property,anti-scour performance related retention rate in solidification and bearing capacity related strength property after solidification.In this study,a series of laboratory tests are conducted to investigate the effects of mix proportion(initial water content and binder content)on the flow value,rheological properties,density,retention rate of solidified slurry and unconfined compressive strength(UCS).The results reveal that the flow value increases with the water content and decreases with the binder amount.All the solidified slurry exhibits Bingham plastic behavior when the shear rate is larger than 5 s^(-1).The Bingham model has been employed to fit the rheology test results,and empirical formulas for obtaining the density,yield stress and viscosity are established,providing scientific support for the numerical assessment of flow and diffusion of solidified slurry.Retention rate of solidified slurry decreases with the water flow velocity and flow value,which means the pumpability of solidified slurry is contrary to anti-scour performance.The unconfined compressive strength after solidification reduces as the water content increases and binder content decreases.A design and application procedure of solidified soil for scour repair and protection is also proposed for engineering reference.
基金supported by the Natio`nal Natural Science Foundation of China,No. 81801241a grant from Sichuan Science and Technology Program,No. 2023NSFSC1578Scientific Research Projects of Southwest Medical University,No. 2022ZD002 (all to JX)。
文摘Neuronal growth, extension, branching, and formation of neural networks are markedly influenced by the extracellular matrix—a complex network composed of proteins and carbohydrates secreted by cells. In addition to providing physical support for cells, the extracellular matrix also conveys critical mechanical stiffness cues. During the development of the nervous system, extracellular matrix stiffness plays a central role in guiding neuronal growth, particularly in the context of axonal extension, which is crucial for the formation of neural networks. In neural tissue engineering, manipulation of biomaterial stiffness is a promising strategy to provide a permissive environment for the repair and regeneration of injured nervous tissue. Recent research has fine-tuned synthetic biomaterials to fabricate scaffolds that closely replicate the stiffness profiles observed in the nervous system. In this review, we highlight the molecular mechanisms by which extracellular matrix stiffness regulates axonal growth and regeneration. We highlight the progress made in the development of stiffness-tunable biomaterials to emulate in vivo extracellular matrix environments, with an emphasis on their application in neural repair and regeneration, along with a discussion of the current limitations and future prospects. The exploration and optimization of the stiffness-tunable biomaterials has the potential to markedly advance the development of neural tissue engineering.
基金Research and Development Program of China(2023YFD1400200)the Natural Science Foundation of Fujian Province,China(2022J01125)+2 种基金the Fujian Key Laboratory for Monitoring and Integrated Management of Crop Pests,China(MIMCP-202301)the Fujian Provincial Science and Technology Key Project,China(2022NZ030014)the National Natural Science Foundation of China(NSFC31871914).
文摘The conserved DNA damage repair complex,MMS21-SMC5/6(Methyl methane sulfonate 21-Structural maintenance of chromosomes 5/6),has been extensively studied in yeast,animals,and plants.However,its role in phytopathogenic fungi,particularly in the highly destructive rice blast fungus Magnaporthe oryzae,remains unknown.In this study,we functionally characterized the homologues of this complex,MoMMS21 and MoSMC5,in M.oryzae.We first demonstrated the importance of DNA damage repair in M.oryzae by showing that the DNA damage inducer phleomycin inhibited vegetative growth,infection-related development and pathogenicity in this fungus.Additionally,we discovered that MoMMS21 and MoSMC5 interacted in the nuclei,suggesting that they also function as a complex in M.oryzae.Gene deletion experiments revealed that both MoMMS21 and MoSMC5 are required for infection-related development and pathogenicity in M.oryzae,while only MoMMS21 deletion affected growth and sensitivity to phleomycin,indicating its specific involvement in DNA damage repair.Overall,our results provide insights into the roles of MoMMS21 and MoSMC5 in M.oryzae,highlighting their functions beyond DNA damage repair.
基金supported by Education Department of Shaanxi Provincial Government(No.YJSZG2023134)Nanjing Medical University Fan Daiming Research Funds for Holistic Integrative Medicine.
文摘Tissue engineering technology has advanced rapidly in recent years, offering opportunities to construct biologicallyactive tissues or organ substitutes to repair or even enhance the functions of diseased tissues and organs.Tissue-engineered scaffolds rebuild the extracellular microenvironment by mimicking the extracellular matrix.Fibrin-based scaffolds possess numerous advantages, including hemostasis, high biocompatibility, and gooddegradability. Fibrin scaffolds provide an initial matrix that facilitates cell migration, differentiation, proliferation,and adhesion, and also play a critical role in cell-matrix interactions. Fibrin scaffolds are now widelyrecognized as a key component in tissue engineering, where they can facilitate tissue and organ defect repair.This review introduces the properties of fibrin, including its composition, structure, and biology. In addition, themodification and cross-linking modes of fibrin are discussed, along with various forms commonly used in tissueengineering. We also describe the biofunctionalization of fibrin. This review provides a detailed overview of theuse and applications of fibrin in skin, bone, and nervous tissues, and provides novel insights into future researchdirections for clinical treatment.
基金supported by the Hunan Provincial Science and Technology Department Project(2015WK3012)the National Natural Science Foundation of China(No.81571021)+3 种基金R&D of Key Project of Hunan Provincial Science and Technology Department(2022SK2010)R&D of Key Technology of Light Metal Air Battery,Transformation and Industrialization of Scientific and Technological Achievements of Hunan Province(2020GK2071)R&D of Key Technology and Materials of Magnesium Air Battery,Transformation of Scientific and Technological Achievements of Changsha City(Kh2005186)Technology Fundation(2021JCJQ-JJ-0432)。
文摘The repair and regeneration of bone defects are highly challenging orthopedic problems.Recently,Mg-based implants have gained popularity due to their unique biodegradation and elastic modulus similar to that of human bone.The aim of our study is to develop a magnesium alloy with a controllable degradation that can closely match bone tissue to help injuries heal in vivo and avoid cytotoxicity caused by a sudden increase in ion concentration.In this study,we prepared and modified Mg-3Zn,Mg-3Zn-1Y,and Mg-2Zn-1Mn by hot extrusion,and used Mg-2.5Y-2.5Nd was as a control.We then investigated the effect of additions of Y and Mn on alloys'properties.Our results show that Mn and Y can improve not only compression strength but also corrosion resistance.The alloy Mg-2Zn-1Mn demonstrated good cytocompatibility in vitro,and for this reason we selected it for implantation in vivo.The degraded Mg-2Zn-1Mn implanted a bone defect area did not cause obvious rejection and inflammatory reaction,and the degradation products left no signs of damage to the heart,liver,kidney,or brain.Furthermore,we find that Mg-2Zn-1Mn can promote an osteoinductive response in vivo and the formation of bone regeneration.
基金supported by grants from the Innovation and Cultivation Fund Project of the Seventh Medical Center,PLA General Hospital(No.QZX-2023-7)Postdoctoral Science Foundation of China(No.2021M691649)Postdoctoral Science Foundation of Jiangsu Province(No.2021K524C).
文摘Objective:Nucleotide excision repair(NER)plays a vital role in maintaining genome stability,and the effect of NER gene polymorphisms on hepatoblastoma susceptibility is still under investigation.This study aimed to evaluate the relationship between NER gene polymorphisms and the risk of hepatoblastoma in Eastern Chinese Han children.Methods:In this five-center case-control study,we enrolled 966 subjects from East China(193 hepatoblastoma patients and 773 healthy controls).The TaqMan method was used to genotype 19 single nucleotide polymorphisms(SNPs)in NER pathway genes,including ERCC1,XPA,XPC,XPD,XPF,and XPG.Then,multivariate logistic regression analysis was performed,and odds ratios(ORs)and 95%confidence intervals(95%CIs)were utilized to assess the strength of associations.Results:Three SNPs were related to hepatoblastoma risk.XPC rs2229090 and XPD rs3810366 significantly contributed to hepatoblastoma risk according to the dominant model(adjusted OR=1.49,95%CI=1.07−2.08,P=0.019;adjusted OR=1.66,95%CI=1.12−2.45,P=0.012,respectively).However,XPD rs238406 conferred a significantly decreased risk of hepatoblastoma under the dominant model(adjusted OR=0.68,95%CI=0.49−0.95;P=0.024).Stratified analysis demonstrated that these significant associations were more prominent in certain subgroups.Moreover,there was evidence of functional implications of these significant SNPs suggested by online expression quantitative trait loci(eQTLs)and splicing quantitative trait loci(sQTLs)analysis.Conclusions:In summary,NER pathway gene polymorphisms(XPC rs2229090,XPD rs3810366,and XPD rs238406)are significantly associated with hepatoblastoma risk,and further research is required to verify these findings.
基金supported by the National Key Research and Development Program(2019YFC1606704)the Key Research and Development Program of Shaanxi Province(2022NY-013)+1 种基金National Natural Science Foundation of China(31801653)the Natural Science Foundation of Shaanxi Province(2019JQ-722).
文摘Probiotics participate in various physiological activities and contribute to body health.However,their viability and bioefficacy are adversely affected by gastrointestinal harsh conditions,such as gastric acid,bile salts and various enzymes.Fortunately,encapsulation based on various nanomaterials shows tremendous potential to protect probiotics.In this review,we introduced some novel encapsulation technologies involving nanomaterials in view of predesigned stability and viability,selective adhesion,smart release and colonization,and efficacy exertion of encapsulated probiotics.Furthermore,the interactions between encapsulated probiotics and the gastrointestinal tract were summarized and analyzed,with highlighting the regulatory mechanisms of encapsulated probiotics on intestinal mechanical barrier,chemical barrier,biological barrier and immune barrier.This review would benefit the food and pharmaceutical industries in preparation and utilization of multifunctional encapsulated probiotics.
基金supported by Fondo para la Investigación Cientifica y Tecnológica(FONCy T),Argentina,grant#PICT 2015-2473(to PHHL)supported by grants from National Institute of Health/National Institute of Neurological Disorders and Stroke(NIH/NINDS,USA)(NS121621)+2 种基金Department of Defense,USA(Do D-CL1)(PR200530)partially financed with a fellowship for Research in Medicine from Fundación Florencio Fiorinisupported with a PhD fellowship from CONICET。
文摘Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrèsyndrome,mostly related to halted axon regeneration.Cross-linking of cell surface gangliosides by anti-ganglioside antibodies triggers inhibition of nerve repair in in vitro and in vivo paradigms of axon regeneration.These effects involve the activation of the small GTPase Rho A/ROCK signaling pathways,which negatively modulate growth cone cytoskeleton,similarly to well stablished inhibitors of axon regeneration described so far.The aim of this work was to perform a proof of concept study to demonstrate the effectiveness of Y-27632,a selective pharmacological inhibitor of ROCK,in a mouse model of axon regeneration of peripheral nerves,where the passive immunization with a monoclonal antibody targeting gangliosides GD1a and GT1b was previously reported to exert a potent inhibitory effect on regeneration of both myelinated and unmyelinated fibers.Our results demonstrate a differential sensitivity of myelinated and unmyelinated axons to the pro-regenerative effect of Y-27632.Treatment with a total dosage of 9 mg/kg of Y-27632 resulted in a complete prevention of anti-GD1a/GT1b monoclonal antibody-mediated inhibition of axon regeneration of unmyelinated fibers to skin and the functional recovery of mechanical cutaneous sensitivity.In contrast,the same dose showed toxic effects on the regeneration of myelinated fibers.Interestingly,scale down of the dosage of Y-27632 to 5 mg/kg resulted in a significant although not complete recovery of regenerated myelinated axons exposed to anti-GD1a/GT1b monoclonal antibody in the absence of toxicity in animals exposed to only Y-27632.Overall,these findings confirm the in vivo participation of Rho A/ROCK signaling pathways in the molecular mechanisms associated with the inhibition of axon regeneration induced by anti-GD1a/GT1b monoclonal antibody.Our findings open the possibility of therapeutic pharmacological intervention targeting Rho A/Rock pathway in immune neuropathies associated with the presence of anti-ganglioside antibodies and delayed or incomplete clinical recovery after injury in the peripheral nervous system.
