Mechanism by which Rab5 promotes regeneration and functional recovery of zebrafish Mauthner axons

Rab5 is a GTPase protein that is involved in intracellular membrane trafficking. It functions by binding to various effector proteins and regulating cellular responses, including the formation of transport vesicles and their fusion with the cellular membrane. Rab5 has been reported to play an important role in the development of the zebrafish embryo;however, its role in axonal regeneration in the central nervous system remains unclear. In this study, we established a zebrafish Mauthner cell model of axonal injury using single-cell electroporation and two-photon axotomy techniques. We found that overexpression of Rab5 in single Mauthner cells promoted marked axonal regeneration and increased the number of intra-axonal transport vesicles. In contrast, treatment of zebrafish larvae with the Rab kinase inhibitor CID-1067700markedly inhibited axonal regeneration in Mauthner cells. We also found that Rab5 activated phosphatidylinositol 3-kinase(PI3K) during axonal repair of Mauthner cells and promoted the recovery of zebrafish locomotor function. Additionally, rapamycin, an inhibitor of the mechanistic target of rapamycin downstream of PI3K, markedly hindered axonal regeneration. These findings suggest that Rab5 promotes the axonal regeneration of injured zebrafish Mauthner cells by activating the PI3K signaling pathway.

Human induced pluripotent stem cell-derived therapies for regeneration after central nervous system injury

In recent years,the progression of stem cell therapies has shown great promise in advancing the nascent field of regenerative medicine.Considering the non-regenerative nature of the mature central nervous system,the concept that“blank”cells could be reprogrammed and functionally integrated into host neural networks remained intriguing.Previous work has also demonstrated the ability of such cells to stimulate intrinsic growth programs in post-mitotic cells,such as neurons.While embryonic stem cells demonstrated great potential in treating central nervous system pathologies,ethical and technical concerns remained.These barriers,along with the clear necessity for this type of treatment,ultimately prompted the advent of induced pluripotent stem cells.The advantage of pluripotent cells in central nervous system regeneration is multifaceted,permitting differentiation into neural stem cells,neural progenitor cells,glia,and various neuronal subpopulations.The precise spatiotemporal application of extrinsic growth factors in vitro,in addition to microenvironmental signaling in vivo,influences the efficiency of this directed differentiation.While the pluri-or multipotency of these cells is appealing,it also poses the risk of unregulated differentiation and teratoma formation.Cells of the neuroectodermal lineage,such as neuronal subpopulations and glia,have been explored with varying degrees of success.Although the risk of cancer or teratoma formation is greatly reduced,each subpopulation varies in effectiveness and is influenced by a myriad of factors,such as the timing of the transplant,pathology type,and the ratio of accompanying progenitor cells.Furthermore,successful transplantation requires innovative approaches to develop delivery vectors that can mitigate cell death and support integration.Lastly,host immune responses to allogeneic grafts must be thoroughly characterized and further developed to reduce the need for immunosuppression.Translation to a clinical setting will involve careful consideration when assessing both physiologic and functional outcomes.This review will highlight both successes and challenges faced when using human induced pluripotent stem cell-derived cell transplantation therapies to promote endogenous regeneration.

A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair

Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies available to promote nerve regeneration.Tacrolimus accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery.The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure.Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days.Size and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible byproducts.Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic delivery.Given its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

FK506 contributes to peripheral nerve regeneration by inhibiting neuroinflammatory responses and promoting neuron survival

FK506(Tacrolimus)is a systemic immunosuppressant approved by the U.S.Food and Drug Administration.FK506 has been shown to promote peripheral nerve regeneration,however,its precise mechanism of action and its pathways remain unclear.In this study,we established a rat model of sciatic nerve injury and found that FK506 improved the morphology of the injured sciatic nerve,increased the numbers of motor and sensory neurons,reduced inflammatory responses,markedly improved the conduction function of the injured nerve,and promoted motor function recovery.These findings suggest that FK506 promotes peripheral nerve structure recovery and functional regeneration by reducing the intensity of inflammation after neuronal injury and increasing the number of surviving neurons.

A novel flexible nerve guidance conduit promotes nerve regeneration while providing excellent mechanical properties

Autografting is the gold standard for surgical repair of nerve defects>5 mm in length;however,autografting is associated with potential complications at the nerve donor site.As an alternative,nerve guidance conduits may be used.The ideal conduit should be flexible,resistant to kinks and lumen collapse,and provide physical cues to guide nerve regeneration.We designed a novel flexible conduit using electrospinning technology to create fibers on the innermost surface of the nerve guidance conduit and employed melt spinning to align them.Subsequently,we prepared disordered electrospun fibers outside the aligned fibers and helical melt-spun fibers on the outer wall of the electrospun fiber lumen.The presence of aligned fibers on the inner surface can promote the extension of nerve cells along the fibers.The helical melt-spun fibers on the outer surface can enhance resistance to kinking and compression and provide stability.Our novel conduit promoted nerve regeneration and functional recovery in a rat sciatic nerve defect model,suggesting that it has potential for clinical use in human nerve injuries.

Silk-based nerve guidance conduits with macroscopic holes modulate the vascularization of regenerating rat sciatic nerve

Peripheral nerve injuries induce a severe motor and sensory deficit. Since the availability of autologous nerve transplants for nerve repair is very limited, alternative treatment strategies are sought, including the use of tubular nerve guidance conduits(tNGCs). However, the use of tNGCs results in poor functional recovery and central necrosis of the regenerating tissue, which limits their application to short nerve lesion defects(typically shorter than 3 cm). Given the importance of vascularization in nerve regeneration, we hypothesized that enabling the growth of blood vessels from the surrounding tissue into the regenerating nerve within the tNGC would help eliminate necrotic processes and lead to improved regeneration. In this study, we reported the application of macroscopic holes into the tubular walls of silk-based tNGCs and compared the various features of these improved silk^(+) tNGCs with the tubes without holes(silk^(–) tNGCs) and autologous nerve transplants in an 8-mm sciatic nerve defect in rats. Using a combination of micro-computed tomography and histological analyses, we were able to prove that the use of silk^(+) tNGCs induced the growth of blood vessels from the adjacent tissue to the intraluminal neovascular formation. A significantly higher number of blood vessels in the silk^(+) group was found compared with autologous nerve transplants and silk^(–), accompanied by improved axon regeneration at the distal coaptation point compared with the silk^(–) tNGCs at 7 weeks postoperatively. In the 15-mm(critical size) sciatic nerve defect model, we again observed a distinct ingrowth of blood vessels through the tubular walls of silk^(+) tNGCs, but without improved functional recovery at 12 weeks postoperatively. Our data proves that macroporous tNGCs increase the vascular supply of regenerating nerves and facilitate improved axonal regeneration in a short-defect model but not in a critical-size defect model. This study suggests that further optimization of the macroscopic holes silk^(+) tNGC approach containing macroscopic holes might result in improved grafting technology suitable for future clinical use.

High mobility group box 1 in the central nervous system:regeneration hidden beneath inflammation

High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.

FAILURE ANALYSIS AND INSPECTION OF CRACKING OF IN-SERVICE CATALYTIC REGENERATOR

The special subject 'research on life prediction technology of important in-service pressure' mainly analyzes the failure mechanism of large-sized important and criticalin-service pressure vessels under the action of working medium and investigates safety assessmentand life prediction technology with a view to enhance the operation reliability of in-servicepressure vessels in China. Based on a series of accident investigation and test & measuringresearch, the cause of cracking of catalytic regenerator is analyzed and the in-line non-destructiveexamination method and failure prevention measures for the cracking of catalytic regenerator areproposed.

Perturbation Solutions for Thermal Process of Honeycomb Regenerator

A parameter perturbation for the unsteady-state heat-transfer characteristics of honeycomb regenerator is presented. It is limited to the cases where the storage matrix has a small wall thickness so that no temperature variation in the matrix perpendicular to the flow direction is considered. Starting from a two-phase transient thermal model for the gas and storage matrix, an approximate solution for regenerator heat transfer process is derived using the multiple-scale method for the limiting case where the longitudinal heat conduction of solid matrix is far less than the convective heat transfer between the gas and the solid. The regenerator temperature profiles are expressed as Taylor series of the coefficient of solid heat conduction item in the model. The analytical validity is shown by comparing the perturbation solution with the experiment and the numerical solution. The results show that it is possible for the perturbation to improve the effectiveness and economics of thermal research on regenerators.

Resistance characteristics of the ball packed-bed regenerator of the new-type swirl flow hot blast stove

A renovation project of miniaturization and high efficiency is provided for the hot blast stove .The experimental data tested feasibility of the new-type swirl flow hot blast stove. The normal and hot state experiments have been done through changing the angle of gas entering into the regenerator. Factors influencing pressure drop have been studied and analyzed. The experimental results can be formulated in the form of the Ergun equation. The regression equation is obtained. And two modified coefficients are offered to the regenerator pressure drop of the new-type swirl flow hot blast stove.

An Identified Study on the Active Network of a Thermoacoustic Regenerator

An active thermo-acoustic network model of regenerator which is a key component to accomplish the con-version between thermal-and acoustic power in thermo-acoustic system has been established in this paper. The experiment was carried out to quantify the network. A method called least square is employed in order to identify the H matrix describing the system. The results obtained here show that the active thermo-acoustic network can reliably depict the characteristics of a thermo-acoustic system.

“Bad regenerators” die after spinal cord injury:insights from lampreys

In mammalian species, including humans, spinal cord in- jury （SCI） leads to permanent disability. A major cause of disability after SCI is the failure of axotomized descending axons to regenerate across the trauma zone and to reconnect to they appropriate targets distal to the site of injury. Cur- renfly, major research efforts are devoted to find new ways of promoting the regrowth of damaged descending axons. However, activation of axonal regrowth will depend on the survival of the axotomized descending brain neurons.

Foundation of three—dimensional mathematical models for glass furnace regenerator

This paper presents a practical three dimensional mathematical model of circulation and heat transfer in generator of glass melting furnaces. The model was based on the heat transfer between the smoke flow and the lattice units, and between the air flow and the lattice units. This model not only bypassed the difficulty of complicated computation of the heat transfer process in the regenerator of glass furnaces, but also avoided the irrationality of fixing the temperature distribution on the surfaces. Use of the model yielded very important data and also the method for the design of the regenerator of glass furnaces in practical production.

Investigation on porous frequency of regenerator of microminiature thermoacoustic refrigerator

A new method was proposed to directly measure the effective resistance and distinguish the porous frequency in the regenerator of the microminiature thermoacoustic refrigerator. Measured results were compared with the flux gain factor and transmission loss of the real system. The results show that the agreement between the range of the porous frequency and frequency of the system is good, the method can be used to predict the porous frequency of the regenerator in production.

Damage Mechanism and Structure Analysis of Used Clay Checker Bricks for Regenerators of Coke Ovens

During long-term use,the clay checker bricks for regenerators of coke ovens on gas side react with the impurities containing Fe and K20,causing foaming,softening and deformation,which is not only related with the impurity content and properties of the clay checker bricks,but also related with the type and the composition of the dust in the gas.After long term use,the clay checker bricks of coke ovens on air side have relative lower impurities containing Fe and K20.The inferior clay checker bricks,with high impurity content and high porosity,are easy to pulverize and deteriorate due to the oxidationreduction reaction with the iron oxide and the gas.The gas quality shall be concerned for long service life of the coke oven regenerators.

Semiconductor optical amplifier used as regenerator for degraded differential phase-shift keying signals

Phase and amplitude regeneration are necessary for degraded differential phase-shift keying communication sys- tems. This paper proposes a regenerator based on semiconductor optical amplifier for differential phase-shift keying signals. The key regeneration mechanism is theoretically analysed. The effectiveness of semiconductor optical amplifier based regenerator is demonstrated by comparing the bit error rate and eye diagrams before and after regeneration for 40-Cbit/s differential phase-shift keying 1080-km transmission systems. The results show that regeneration effects are very well. Bit error rate is tess than 10-12 with the regenerator.

Heat Saturation Time of Solid Spherical Regenerator of HTAC

In order to control the heat saturation time, the temperature field of the regenerators of high temperature air combustion （HTAC） technology after reheating furnace was studied. A one-dimensional unsteady mathematical model was established and discretized through finite difference method. The relationship between the heat saturation time and some factors was determined through the calculation of a program developed by language C. The heat saturation time decreases with the increase of heat convection coefficient, however, the increase of heat capacity, density and radius of regenerator all increase the heat saturation time approximately linearly.

Optimization of regenerator based on semiconductor optical amplifier for degraded differential phase shift keying signal

Real time phase regeneration is necessary for degraded phase modulation format optical communication systems. A regenerator based on the discrimitive gain effect of a semiconductor optical amplifier was proposed in recent years. In this paper, for this type of regenerator, its optimal working condition is found by solving the dynamic equations which describe the variance of the optical field and carrier density in the semiconductor optical amplifier by the finite difference method. The results show that the optimal improvement of signal Q factor can reach more than 2.2 dB.

Regeneration of the heart:f rom molecular mechanisms to clinical therapeutics

Heart injury such as myocardial infarction leads to cardiomyocyte loss,fibrotic tissue deposition,and scar formation.These changes reduce cardiac contractility,resulting in heart failure,which causes a huge public health burden.Military personnel,compared with civilians,is exposed to more stress,a risk factor for heart diseases,making cardiovascular health management and treatment innovation an important topic for military medicine.So far,medical intervention can slow down cardiovascular disease progression,but not yet induce heart regeneration.In the past decades,studies have focused on mechanisms underlying the regenerative capability of the heart and applicable approaches to reverse heart injury.Insights have emerged from studies in animal models and early clinical trials.Clinical interventions show the potential to reduce scar formation and enhance cardiomyocyte proliferation that counteracts the pathogenesis of heart disease.In this review,we discuss the signaling events controlling the regeneration of heart tissue and summarize current therapeutic approaches to promote heart regeneration after injury.

Preoperative albumin-bilirubin score and liver resection percentage determine postoperative liver regeneration after partial hepatectomy

BACKGROUND The success of liver resection relies on the ability of the remnant liver to regenerate.Most of the knowledge regarding the pathophysiological basis of liver regeneration comes from rodent studies,and data on humans are scarce.Additionally,there is limited knowledge about the preoperative factors that influence postoperative regeneration.AIM To quantify postoperative remnant liver volume by the latest volumetric software and investigate perioperative factors that affect posthepatectomy liver regenera-tion.METHODS A total of 268 patients who received partial hepatectomy were enrolled.Patients were grouped into right hepatectomy/trisegmentectomy(RH/Tri),left hepa-tectomy(LH),segmentectomy(Seg),and subsegmentectomy/nonanatomical hepatectomy(Sub/Non)groups.The regeneration index(RI)and late rege-neration rate were defined as(postoperative liver volume)/[total functional liver volume(TFLV)]×100 and(RI at 6-months-RI at 3-months)/RI at 6-months,respectively.The lower 25th percentile of RI and the higher 25th percentile of late regeneration rate in each group were defined as“low regeneration”and“delayed regeneration”.“Restoration to the original size”was defined as regeneration of the liver volume by more than 90%of the TFLV at 12 months postsurgery.RESULTS The numbers of patients in the RH/Tri,LH,Seg,and Sub/Non groups were 41,53,99 and 75,respectively.The RI plateaued at 3 months in the LH,Seg,and Sub/Non groups,whereas the RI increased until 12 months in the RH/Tri group.According to our multivariate analysis,the preoperative albumin-bilirubin(ALBI)score was an independent factor for low regeneration at 3 months[odds ratio(OR)95%CI=2.80(1.17-6.69),P=0.02;per 1.0 up]and 12 months[OR=2.27(1.01-5.09),P=0.04;per 1.0 up].Multivariate analysis revealed that only liver resection percentage[OR=1.03(1.00-1.05),P=0.04]was associated with delayed regeneration.Furthermore,multivariate analysis demonstrated that the preoperative ALBI score[OR=2.63(1.00-1.05),P=0.02;per 1.0 up]and liver resection percentage[OR=1.02(1.00-1.05),P=0.04;per 1.0 up]were found to be independent risk factors associated with volume restoration failure.CONCLUSION Liver regeneration posthepatectomy was determined by the resection percentage and preoperative ALBI score.This knowledge helps surgeons decide the timing and type of rehepatectomy for recurrent cases.