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Polyethylene glycol fusion repair of severed rat sciatic nerves reestablishes axonal continuity and reorganizes sensory terminal fields in the spinal cord

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Neural Regeneration Research 2025年第7期20卷 2095-2107页

作者： Emily A.Hibbard Liwen Zhou Cathy Z.Yang Karthik Venkudusamy Yessenia Montoya Alexa Olivarez George D.Bittner Dale R.Sengelaub program in Neuroscience Indiana UniversityBloomingtonINUSA Department of Neuroscience University of Texas at AustinAustinTXUSA

Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions;behavioral recovery is typically *** used a plasmalemmal fusogen,polyethylene glycol(PEG),to immediately fuse closely apposed open ends of severed proximal and distal axons in rat sciatic *** have previously reported that sciatic nerve axons repaired by PEG-fusion do not undergo Wallerian degeneration,and PEG-fused animals exhibit rapid(within 2–6 weeks)and extensive locomotor ***,our previous report showed that PEG-fusion of severed sciatic motor axons was non-specific,i.e.,spinal motoneurons in PEG-fused animals were found to project to appropriate as well as inappropriate target *** this study,we examined the consequences of PEG-fusion for sensory axons of the sciatic *** adult male and female rats(Sprague–Dawley)received either a unilateral single cut or ablation injury to the sciatic nerve and subsequent repair with or without(Negative Control)the application of *** action potentials recorded immediately after PEG-fusion repair confirmed conduction across the injury *** success of PEG-fusion was confirmed through Sciatic Functional Index testing with PEG-fused animals showing improvement in locomotor function beginning at 35 days *** 2–42 days postoperatively,we anterogradely labeled sensory afferents from the dorsal aspect of the hindpaw following bilateral intradermal injection of wheat germ agglutinin conjugated horseradish ***-fusion repair reestablished axonal *** to unoperated animals,labeled sensory afferents ipsilateral to the injury in PEG-fused animals were found in the appropriate area of the dorsal horn,as well as inappropriate mediolateral and rostrocaudal ***,despite having intact peripheral nerves,similar reorganizations of labeled sensory afferents were also observed contralateral to the injury and repa

关键词： axotomy dorsal horn peripheral nerve injury plasticity polyethylene glycol(PEG) sciatic nerve sensory terminals wheat germ agglutinin horseradish peroxidase

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Treatment of spinal cord injury with biomaterials and stem cell therapy in non-human primates and humans

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Neural Regeneration Research 2025年第2期20卷 343-353页

作者： Ana Milena Silva Olaya Fernanda Martins Almeida Ana Maria Blanco Martinez Suelen Adriani Marques PhD program in Pathological Anatomy Federal University of Rio de JaneiroRio de JaneiroBrazil Biomedical Science Institute Federal University of Rio de JaneiroRio de JaneiroBrazil Graduate program in Pathological Anatomy Federal University of Rio de JaneiroRio de JaneiroBrazil Graduate program in Pathological Anatomy(PPGAP/UFRJ) Department of Neurobiology/Institute of BiologyCampus do GragoatáNiteróiRio de JaneiroBrazil

Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical ***,in the search for more effective treatments than those already applied for years,which are not entirely efficient,researches have been able to demonstrate the potential of biological strategies using biomaterials to tissue manufacturing through bioengineering and stem cell therapy as a neuroregenerative approach,seeking to promote neuronal recovery after spinal cord *** of these strategies has been developed and meticulously evaluated in several animal models with the aim of analyzing the potential of interventions for neuronal repair and,consequently,boosting functional *** the majority of experimental research has been conducted in rodents,there is increasing recognition of the importance,and need,of evaluating the safety and efficacy of these interventions in non-human primates before moving to clinical trials involving therapies potentially promising in *** article is a literature review from databases(PubMed,Science Direct,Elsevier,Scielo,Redalyc,Cochrane,and NCBI)from 10 years ago to date,using keywords(spinal cord injury,cell therapy,non-human primates,humans,and bioengineering in spinal cord injury).From 110 retrieved articles,after two selection rounds based on inclusion and exclusion criteria,21 articles were ***,this review arises from the need to recognize the experimental therapeutic advances applied in non-human primates and even humans,aimed at deepening these strategies and identifying the advantages and influence of the results on extrapolation for clinical applicability in humans.

关键词： bioengineering biomaterials cell therapy humans non-human primates spinal cord injury stem cell therapy

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Functions of nuclear factor Y in nervous system development,function and health

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Neural Regeneration Research 2025年第10期20卷 2887-2894页

作者： Pedro Moreira Roger Pocock Development and Stem Cells program Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental BiologyMonash UniversityMelbourneVICAustralia

Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes,one of the most common motifs found in gene promoters and *** the last 30 years,research has revealed that the nuclear factor Y complex controls many aspects of brain development,including differentiation,axon guidance,homeostasis,disease,and most recently ***,a complete understanding of transcriptional regulatory networks,including how the nuclear factor Y complex binds to specific CCAAT boxes to perform its function remains *** this review,we explore the nuclear factor Y complex’s role and mode of action during brain development,as well as how genomic technologies may expand understanding of this key regulator of gene expression.

关键词： axon guidance CCAAT boxes neuronal degeneration neuronal differentiation neuronal regeneration nuclear factor Y complex transcription factor transcriptional regulation

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Polyethylene glycol fusion repair of severed sciatic nerves accelerates recovery of nociceptive sensory perceptions in male and female rats of different strains

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Neural Regeneration Research 2025年第9期20卷 2667-2681页

作者： Liwen Zhou Karthik Venkudusamy Emily A.Hibbard Yessenia Montoya Alexa Olivarez Cathy Z.Yang Adelaide Leung Varun Gokhale Guhan Periyasamy Zeal Pathak Dale R.Sengelaub George D.Bittner Department of Neuroscience University of TexasAustinTXUSA program in Neuroscience Indiana UniversityBloomingtonINUSA Department of Molecular Biosciences University of TexasAustinTXUSA

Successful polyethylene glycol fusion(PEG-fusion)of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to:(1)rapidly restore electrophysiological continuity;(2)prevent distal Wallerian Degeneration and maintain their myelin sheaths;(3)promote primarily motor,voluntary behavioral recoveries as assessed by the Sciatic Functional Index;and,(4)rapidly produce correct and incorrect connections in many possible combinations that produce rapid and extensive recovery of functional peripheral nervous system/central nervous system connections and reflex(e.g.,toe twitch)or voluntary *** preceding companion paper describes sensory terminal field reo rganization following PEG-fusion repair of sciatic nerve transections or ablations;howeve r,sensory behavioral recovery has not been explicitly explored following PEG-fusion *** the current study,we confirmed the success of PEG-fusion surgeries according to criteria(1-3)above and more extensively investigated whether PEG-fusion enhanced mechanical nociceptive recovery following sciatic transection in male and female outbred Sprague-Dawley and inbred Lewis *** nociceptive responses were assessed by measuring withdrawal thresholds using von Frey filaments on the dorsal and midplantar regions of the *** von Frey filament tests were a more reliable method than plantar von Frey filament tests to assess mechanical nociceptive sensitivity following sciatic nerve *** withdrawal thresholds of the sciatic-mediated lateral dorsal region differed significantly across strain but not *** thresholds did not change significantly from baseline in chronic Unoperated and Sham-operated *** sciatic transection,all rats exhibited severe hyposensitivity to stimuli at the lateral dorsal region of the hindpaw ipsilateral to the ***,PEG-fused rats exhibited significantly earlier return to baseline withdrawal thresholds than Negative

关键词： autophagia axotomy collateral sprouting neuropathic pain peripheral nerve repair polyethylene glycol fusion(PEG-fusion) saphenous nerve sensory neurons sex and strain Wallerian degeneration

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Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

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Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong Miao Michael S.Wolfe Computational Medicine program and Department of Pharmacology University of North Carolina–Chapel HillChapel HillNCUSA Department of Medicinal Chemistry University of KansasLawrenceKSUSA

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

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

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Neural Regeneration Research 2025年第1期20卷 291-304页

作者： Simeon C.Daeschler Katelyn J.W.So Konstantin Feinberg Marina Manoraj Jenny Cheung Jennifer Zhang Kaveh Mirmoeini JPaul Santerre Tessa Gordon Gregory HBorschel SickKids Research Institute Neuroscience and Mental Health ProgramTorontoONCanada Institute of Biomaterials and Biomedical Engineering University of TorontoTorontoONCanada Indiana University School of Medicine IndianapolisINUSA Division of Plastic and Reconstructive Surgery the Hospital for Sick ChildrenTorontoONCanada Translational Biology and Engineering program Ted Rogers Centre for Heart ResearchInstitute of Biomedical EngineeringFaculty of DentistryUniversity of TorontoTorontoONCanada

Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong ***,there are no FDA-approved therapies available to promote nerve *** accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve *** 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 *** is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 *** and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible *** 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 *** 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.

关键词： biodegradable local drug delivery nerve injury nerve regeneration nerve wrap tacrolimus

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Bringing epigenetics into the diagnostics of the andrology laboratory： challenges and perspectives

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Asian Journal of andrology 2014年第5期16卷 669-674,I0006页

作者： Ruth Klaver Jorg Gromoll Centre of Reproductive Medicine and andrology University Clinics of MOnster MOnster Germany

Recent studies have shown significant associations of aberrant DNA methylation in spermatozoa with idiopathic male infertility, increased frequency of spontaneous abortions and imprinting disorders. Thus, the analysis of DNA methylation of specific genes in spermatozoa has the potential to become a new valuable diagnostic marker in clinical andrology. This perspective article discusses the current state and value of DNA methylation analysis in the diagnostic setup of infertile men and outlines challenges and perspectives. It highlights the potential of DNA methylation in andrological diagnostics and its putative benefit in the examination of hitherto idiopathic infertile patients is described.

关键词： DNA methylation male infertility spermatogenesis

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Seminal vesicles and diabetic neuropathy： ultrasound evaluation in patients with couple infertility and different levels of glycaemic control

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Asian Journal of andrology 2011年第6期13卷 872-876页

作者： Sandro La Vignera Rosita A Condorelli Enzo Vicari Rosario D＇Agata Aldo E Calogero Section of Endocrinology Andrology and Internal Medicine and Master＇s Program in Andrological Human Reproduction and Biotechnology Sciences Department of Interna Medicine and Systemic Diseases University of Catania Catania 95123 Italy

The aim of this study was to evaluate the ultrasound characteristics of the seminal vesicles （SVs） of infertile patients with diabetes mellitus （DM） and diabetic neuropathy （DN） and to investigate possible changes in ultrasound characteristics related to glycaemic control. To accomplish this, 45 infertile patients with type 2 DM and symptomatic DN were selected. Twenty healthy fertile men and 20 patients with idiopathic oligoasthenoteratozoospermia without DM represented the control groups. DM patients were arbitrarily divided into three groups according to glycaemic control level （A=glycosylated haemoglobin 〈7%; B =glycosylated haemoglobin between 7% and 10%; C=glycosylated haemoglobin 〉 10%）. Patients underwent prostate-vesicular transrectal ultrasonography and sperm analysis. The following SV ultrasound parameters were recorded：（i） body antero-posterior diameter （APD）; （ii） fundus APD; （iii） parietal thicknesses of the right and left SVs; and （iv） the number of polycyclic areas within both SVs. We then calculated the following parameters：（i） fundus/body （F/B） ratio; （ii） difference of the parietal thickness between the right and the left SV; and （iii） pre- and post-ejaculatory APD difference. All DM patients had a higher FIB ratio compared to controls （P〈0.05）. Group C had a higher FIB ratio compared to the other DM groups （P〈0.05）. All DM patients had a lower pre- and post-ejaculatory difference of the body SV APD compared to controls （P〈0.05）. Groups A and B had a similar pre- and post-ejaculatory difference of the body SV APD, whereas this difference was lower in Group C （P〈0.05）. In conclusion, infertile DM patients with DN showed peculiar SV ultrasound features suggestive of functional atony, and low glycaemic control was associated with greater expression of these features.

关键词： diabetes glycaemic control infertility neuropathy seminal vesicles

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Induced pluripotent stem cell-related approaches to generate dopaminergic neurons for Parkinson's disease

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Neural Regeneration Research 2025年第11期20卷 3193-3206页

作者： Ling-Xiao Yi Hui Ren Woon Genevieve Saw Li Zeng Eng King Tan Zhi Dong Zhou National Neuroscience Institute Singapore Nanyang Technology University Singapore Department of Neurology Singapore General HospitalSingapore Signature Research program in Neuroscience and Behavioral Disorders Duke-NUS Medical SchoolSingapore

The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative *** the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and *** induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease *** current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem *** benefits of induced pluripotent stem cell-based research are *** dopaminergic neuron differentiation protocols from induced pluripotent stem cells are *** emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are ***,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.

关键词： dopaminergic neurons induced pluripotent stem cells Parkinson's disease stem cell approaches

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A lead role for a“secondary”axonal injury response

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Neural Regeneration Research 2025年第2期20卷 469-470页

作者： Melissa A.Rudy Trent A.Watkins Division of Neuroimmunology and Glial Biology Department of NeurologyUniversity of California at San FranciscoSan FranciscoCAUSA Development Disease Modelsand Therapeutics Graduate ProgramBaylor College of MedicineHoustonTXUSA

Stress signaling following axon injury stimulates a transcriptional program for regeneration that might be exploited to promote central nervous system ***,this stress response drives neuronal apoptosis in non-regenerative *** duality presents a quandary for the development of therapeutic interventions:manipulating stress signaling to enhance recovery of damaged neurons risks accelerating neurodegeneration or restricting regenerative *** dichotomy is well illustrated by the fates of retinal ganglion cells(RGCs)following optic nerve *** this central nervous system injury model,disruption of a stress-activated MAP kinase(MAPK)cascade blocks the extensive apoptosis of RGCs that occurs in wild-type mice(Watkins et al.,2013;Welsbie et al.,2017).

关键词： injury axonal stress

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