The role of purinergic receptors in neural repair and regeneration after spinal cord injury

Spinal cord injury is a serious injury of the central nervous system that results in neurological deficits.The pathophysiological mechanisms underlying spinal cord injury,as well as the mechanisms involved in neural repair and regeneration,are highly complex.Although there have been many studies on these mechanisms,there is no effective intervention for such injury.In spinal cord injury,neural repair and regeneration is an important part of improving neurological function after injury,although the low regenerative ability of nerve cells and the difficulty in axonal and myelin regeneration after spinal cord injury hamper functional recovery.Large amounts of ATP and its metabolites are released after spinal cord injury and participate in various aspects of functional regulation by acting on purinergic receptors which are widely expressed in the spinal cord.These processes mediate intracellular and extracellular signalling pathways to improve neural repair and regeneration after spinal cord injury.This article reviews research on the mechanistic roles of purinergic receptors in spinal cord injury,highlighting the potential role of purinergic receptors as interventional targets for neural repair and regeneration after spinal cord injury.

Is glial heme oxygenase-1 suppression in neurodegenerative disorders permissive for neural repair?

＇Core＇ neuropathology of degenerative central nervous system （CNS） disorders The common human neurodegenerative disorders （Alzheimer＇s disease （AD）, Parkinson＇s disease （PD）, amyotrophic lateral sclerosis, etc.） vary with respect to risk factors, ages of onset, sex predilections, neuraxial regions affected, hallmark cellular inclusions, behavioral and neurological symptoms, and responses to treatment. Despite these differences, there appears to be a set of ＇core＇ neuropathological features shared among these and related entities. Common to these conditions are 1） pathological deposition of non-transferrin bound iron, 2） oxidative stress and associated protein, lipid and nucleic acid modifications, 3） mitochondrial membrane damage and bioenergetic failure, and 4） macroautophagy in the affected neural tissues.

“To measure is to know”: how advances in image analysis are supporting neural repair strategies

Neuronal regeneration in the peripheral nervous system arises via a synergistic interplay of neurotrophic factors,integrins,cytoskeletal proteins,mechanical cues,cytokines,stem cells,glial cells and astrocytes.

DDAH1 promotes neurogenesis and neural repair in cerebral ischemia

Choline acetyltransferase(ChAT)-positive neurons in neural stem cell(NSC)niches can evoke adult neurogenesis(AN)and restore impaired brain function after injury,such as acute ischemic stroke(AIS).However,the relevant mechanism by which ChAT+neurons develop in NSC niches is poorly understood.Our RNA-seq analysis revealed that dimethylarginine dimethylaminohydrolase 1(DDAH1),a hydrolase for asymmetric NG,NG-dimethylarginine(ADMA),regulated genes responsible for the synthesis and transportation of acetylcholine(ACh)(Chat,Slc5a7 and Slc18a3)after stroke insult.The dual-luciferase reporter assay further suggested that DDAH1 controlled the activity of ChAT,possibly through hypoxia-inducible factor 1α(HIF-1α).KC7F2,an inhibitor of HIF-1α,abolished DDAH1-induced ChAT expression and suppressed neurogenesis.As expected,DDAH1 was clinically elevated in the blood of AIS patients and was positively correlated with AIS severity.By comparing the results among Ddah1 general knockout(KO)mice,transgenic(TG)mice and wild-type(WT)mice,we discovered that DDAH1 upregulated the proliferation and neural differentiation of NSCs in the subgranular zone(SGZ)under ischemic insult.As a result,DDAH1 may promote cognitive and motor function recovery against stroke impairment,while these neuroprotective effects are dramatically suppressed by NSC conditional knockout of Ddah1 in mice.

Double-target neural circuit-magnetic stimulation improves motor function in spinal cord injury by attenuating astrocyte activation

Multi-target neural circuit-magnetic stimulation has been clinically shown to improve rehabilitation of lower limb motor function after spinal cord injury. However, the precise underlying mechanism remains unclear. In this study, we performed double-target neural circuit-magnetic stimulation on the left motor cortex and bilateral L5 nerve root for 3 successive weeks in a rat model of incomplete spinal cord injury caused by compression at T10. Results showed that in the injured spinal cord, the expression of the astrocyte marker glial fibrillary acidic protein and inflammatory factors interleukin 1β, interleukin-6, and tumor necrosis factor-α had decreased, whereas that of neuronal survival marker microtubule-associated protein 2 and synaptic plasticity markers postsynaptic densification protein 95 and synaptophysin protein had increased. Additionally, neural signaling of the descending corticospinal tract was markedly improved and rat locomotor function recovered significantly. These findings suggest that double-target neural circuit-magnetic stimulation improves rat motor function by attenuating astrocyte activation, thus providing a theoretical basis for application of double-target neural circuit-magnetic stimulation in the clinical treatment of spinal cord injury.

Neural stem cell transplantation in a double-layer collagen membrane with unequal pore sizes for spinal cord injury repair

A novel double-layer collagen membrane with unequal pore sizes in each layer was designed and tested in this study. The inner, loose layer has about 100-μm-diameter pores, while the outer, compact layer has about 10-μm-diameter pores. In a rat model of incomplete spinal cord injury, a large number of neural stem cells were seeded into the loose layer, which was then adhered to the injured side, and the compact layer was placed against the lateral side. The results showed that the transplantation of neural stem cells in a double-layer collagen membrane with unequal pore sizes promoted the differentiation of neural stem cells, attenuated the pathological lesion, and signiifcantly improved the motor function of the rats with incomplete spinal cord injuries. These experimental ifndings suggest that the transplantation of neural stem cells in a double-lay-er collagen membrane with unequal pore sizes is an effective therapeutic strategy to repair an injured spinal cord.

Optimising repetitive transcranial magnetic stimulation for neural circuit repair following traumatic brain injury

While it is well-known that neuronal activity promotes plasticity and connectivity, the success of activity-based neural rehabilitation programs remains extremely limited in human clinical experience because they cannot adequately control neuronal excitability and activity within the injured brain in order to induce repair. However, it is possible to non-invasively modulate brain plasticity using brain stimu- lation techniques such as repetitive transcranial （rTMS） and transcranial direct current stimulation （tDCS） techniques, which show promise for repairing injured neural circuits （Henrich-Noack et al., 2013; Lefaucher et al., 2014）. Yet we are far from having full control of these techniques to repair the brain following neurotrauma and need more fundamen- tal research （Ellaway et al., 2014; Lefaucher et al., 2014）. In this perspective we discuss the mechanisms by which rTMS may facilitate neurorehabilitation and propose experimental techniques with which magnetic stimulation may be investi- gated in order to optimise its treatment potential.

Neural regeneration after peripheral nerve injury repair is a system remodelling process of interaction between nerves and terminal effector

In China, there are approximately 20 million people suffering from peripheral nerve injury and this number is increasing at a rate of 2 million per year. These patients cannot live or work independently and are a heavy responsibility on both family and society because of extreme disability and dysfunction caused by peripheral nerve injury （PNI）. Thus, repair of PNI has become a major public health issue in China.

Repair of spinal cord injury by neural stem cells modified with BDNF gene in rats

Objective To explore repair of spinal cord injury by neural stem cells （NSCs） modified with brain derived neurotrophic factor （BDNF） gene （BDNF-NSCs） in rats. Methods Neural stem cells modified with BDNF gene were transplanted into the complete transection site of spinal cord at the lumbar 4 （L4） level in rats. Motor function of rats＇ hind limbs was observed and HE and X-gal immunoeytochemical staining, in situ hybridization, and retrograde HRP tracing were also performed. Results BDNF-NSCs survived and integrated well with host spinal cord. In the transplant group, some X-gal positive, NF-200 positive, GFAP positive, BDNF positive, and BDNF mRNA positive cells, and many NF-200 positive nerve fibers were observed in the injury site. Retrograde HRP tracing through sciatic nerve showed some HRP positive cells and nerve fibers near the rostral side of the injury one month after transplant and with time, they increased in number. Examinations on rats＇ motor function and behavior demonstrated that motor function of rats＇ hind limbs improved better in the transplant group than the injury group. Conclusion BDNF-NSCs can survive, differentiate, and partially integrate with host spinal cord, and they significantly ameliorate rats＇ motor function of hind limbs, indicating their promising role in repairing spinal cord injury.

Novel conductive polypyrrole/silk fibroin scaffold for neural tissue repair

Three dimensional（3D） bioprinting, which involves depositing bioinks（mixed biomaterials） layer by layer to form computer-aided designs, is an ideal method for fabricating complex 3D biological structures. However, it remains challenging to prepare biomaterials with micro-nanostructures that accurately mimic the nanostructural features of natural tissues. A novel nanotechnological tool, electrospinning, permits the processing and modification of proper nanoscale biomaterials to enhance neural cell adhesion, migration, proliferation, differentiation, and subsequent nerve regeneration. The composite scaffold was prepared by combining 3D bioprinting with subsequent electrochemical deposition of polypyrrole and electrospinning of silk fibroin to form a composite polypyrrole/silk fibroin scaffold. Fourier transform infrared spectroscopy was used to analyze scaffold composition. The surface morphology of the scaffold was observed by light microscopy and scanning electron microscopy. A digital multimeter was used to measure the resistivity of prepared scaffolds. Light microscopy was applied to observe the surface morphology of scaffolds immersed in water or Dulbecco＇s Modified Eagle＇s Medium at 37℃ for 30 days to assess stability. Results showed characteristic peaks of polypyrrole and silk fibroin in the synthesized conductive polypyrrole/silk fibroin scaffold, as well as the structure of the electrospun nanofiber layer on the surface. The electrical conductivity was 1 × 10^-5–1 × 10^-3 S/cm, while stability was 66.67%. A 3-（4,5-dimethyl-2-thiazolyl）-2,5-diphenyl-2-H-tetrazolium bromide assay was employed to measure scaffold cytotoxicity in vitro. Fluorescence microscopy was used to observe Ed U-labeled Schwann cells to quantify cell proliferation. Immunohistochemistry was utilized to detect S100β immunoreactivity, while scanning electron microscopy was applied to observe the morphology of adherent Schwann cells. Results demonstrated that the polypyrrole/silk fibroin scaffold was not cytotoxic and did not affect Schwann cell proliferation. Moreover, filopodia formed on the scaffold and Schwann cells were regularly arranged. Our findings verified that the composite polypyrrole/silk fibroin scaffold has good biocompatibility and may be a suitable material for neural tissue engineering.

Stiffness-tunable biomaterials provide a good extracellular matrix environment for axon growth and regeneration

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.

基于自注意力机制神经机器翻译的软件缺陷自动修复方法

循环神经网络对于代码序列数据有着良好的处理能力,软件缺陷修复的补丁生成模型大多采用循环神经网络实现.然而,基于循环神经网络的补丁生成模型在处理代码序列中长距离依赖问题时仍然具有局限性,其修复成功率和修复效率较低.针对此问题,提出一种基于自注意力神经机器翻译的软件缺陷自动修复方法(Self-attention Neural machine translation based automatic software Repair,SNRepair).首先,为有效缓解源码中的未登录词问题,对数据集引入子词切分技术进行预处理;其次,为解决源代码中棘手的长距离依赖问题并更充分地利用局部信息,构建融合局部建模的Transformer程序补丁生成模型;然后,采用缺陷自动定位技术定位缺陷语句位置,利用参数优化后的Transformer补丁生成模型生成候选补丁;最后,运行测试用例验证候选补丁.在具有395个真实Java软件缺陷的Defects4J缺陷库上实验评估,结果表明SNRepair方法与对比方法比较,修复成功率和修复效率更高.

天然药物调控星形胶质细胞促进缺血性脑卒中后神经修复的研究进展

星形胶质细胞在治疗缺血性脑卒中过程中起到了不可忽视的作用。我国拥有丰厚资源的天然药物,近年来针对星形胶质细胞的天然药物研究逐年增多,为治疗缺血性脑卒中提供了丰富的依据及思路。因此,该文对星形胶质细胞在缺血性脑卒中后对神经修复的影响及机制,以及天然药物对该过程的调控从而促进修复的作用作一阐述。

深度神经网络修复策略综述

随着智能信息时代的发展,深度神经网络在人类社会众多领域中的应用,尤其是在自动驾驶、军事国防等安全攸关系统中的部署,引起了学术界和工业界对神经网络模型可能表现出的错误行为的担忧.虽然神经网络验证和神经网络测试可以提供关于错误行为的定性或者定量结论,但这种事后分析并不能防止错误行为的发生,如何修复表现出错误行为的预训练神经网络模型依然是极具挑战性的问题.为此,深度神经网络修复这一领域应运而生,旨在消除有缺陷的神经网络产生的错误预测,使得神经网络满足特定的规约性质.目前为止,典型的神经网络修复范式有3种:重训练、无错误定位的微调和包含错误定位的微调.介绍深度神经网络的发展和神经网络修复的必要性;厘清相近概念;明确神经网络修复的挑战;详尽地调研目前已有的神经网络修复策略,并对内在联系与区别进行分析和比较;调研整理神经网络修复策略常用的评价指标和基准测试;展望未来神经网络修复领域研究中需要重点关注的可行方向.

神经程序修复领域数据泄露问题的实证研究

修复软件缺陷是软件工程领域一个无法回避的重要问题,而程序自动修复技术则旨在自动、准确且高效地修复存在缺陷的程序,以缓解软件缺陷所带来的问题.近年来,随着深度学习的快速发展,程序自动修复领域兴起了一种使用深度神经网络去自动捕捉缺陷程序及其补丁之间关系的方法,被称为神经程序修复.从在基准测试上被正确修复的缺陷的数量上看,神经程序修复工具的修复性能已经显著超过了非学习的程序自动修复工具.然而,近期有研究发现:神经程序修复系统性能的提升可能得益于测试数据在训练数据中存在,即数据泄露.受此启发,为了进一步探究神经程序修复系统数据泄露的原因及影响,更公平地评估现有的系统:(1)对现有神经程序修复系统进行了系统的分类和总结,根据分类结果定义了神经程序修复系统的数据泄露,并为每个类别的系统设计了数据泄露的检测方法;(2)依照上一步骤中的数据泄露检测方法对现有模型展开了大规模检测,并探究了数据泄露对模型真实性能与评估性能间差异的影响以及对模型本身的影响;(3)分析现有神经程序修复系统数据集的收集和过滤策略,加以改进和补充,在现有流行的数据集上,基于改进后的策略构建了一个纯净的大规模程序修复训练数据集,并验证了该数据集避免数据泄露的有效性.由实验结果发现:调研的10个神经程序修复系统在基准测试集上均出现了数据泄露,其中,神经程序修复系统RewardRepair的数据泄露问题较为严重,在基准测试集Defects4J(v1.2.0)上的数据泄露达24处,泄露比例高达53.33%.此外,数据泄露对神经程序修复系统的鲁棒性也造成了影响,调研的5个神经程序修复系统均因数据泄露产生了鲁棒性降低的问题.由此可见,数据泄露是一个十分常见的问题,且会使神经程序修复系统得到不公平的性能评估结果以及影响系统在基准测试集上的鲁棒性.研究人员在训练神经程序修复模型时,应尽可能避免出现数据泄露,且要考虑数据泄露问题对神经程序修复系统性能评估产生的影响,尽可能更公平地评估系统.

面向边缘部署场景的轻量神经网络修复算法

随着深度学习技术的不断进步,神经网络在各领域得到广泛应用,特别是在边缘计算环境中,例如智能交通和新型电网等典型场景.然而,神经网络的可靠性问题限制了其在真实世界的广泛应用.在复杂的边缘环境中,预训练模型往往因未涵盖所有可能的边缘情况而性能下降.因此,针对部署中的神经网络进行高效修复成为一个关键的研究课题.传统修复方法通常涉及整个模型的重新训练,这在边缘场景中具有诸多局限性.首先,不同地理区域的设备可能面临独特的自然噪声,使得统一模型难以适应所有环境.其次,深度神经网络的大规模参数使得其训练和部署时资源消耗巨大,且更新期间的服务中断将降低系统的可用性.为解决这些问题,本文提出了一种轻量级的补丁式神经网络修复算法.该算法通过引入个性化的补丁来增强神经网络对不同边缘环境中自然噪声和边角案例的鲁棒性.具体的,在故障定位阶段,类比于程序插桩中通过注入代码以检测、改进和分析软件行为,本文提出了神经网络插桩技术.通过将模型探针插桩进神经网络,观测其内部运行情况,实现了对错误样本的故障定位.在故障修复时,通过插入无监督搜索得到的神经网络补丁来纠正原始神经网络的输出.此外,本文提出了故障预测模块以提前预测潜在的错误输出,从而仅在必要时激活补丁.在基于2个数据集、15种噪声以及4个神经网络模型的实验中,与现有修复算法相比,本文方法在修复性能上取得了 6.64%至20.00%的提升.同时,本文方法所需的训练样本量减少了超过90%,而所需更新的参数量最高减少了 91.94%.这种有效且轻量的特性为解决边缘计算环境中神经网络的可靠性问题提供了有效途径.

基于加权组合算法的点云孔洞修补

为了对无人机航测数据中的点云孔洞进行修补,将最小二乘支持向量机算法LS-SVM和遗传算法GA优化的反向传播神经网络算法BP进行线性组合,构建一种加权组合模型,用于散乱点云数据中的孔洞修补。通过两种修补方法的误差进行两者的加权组合,建立出与两种修补方法误差相关的加权组合模型,并将加权组合模型的修补结果与单一使用最小二乘支持向量机、遗传算法优化的BP神经网络两种修补方法的修补结果进行残差和内外符合精度的比较与分析。结果表明:采用加权组合模型得到的点云修补结果内外符合精度较高,且具有更强的稳定性,为无人机获取的点云数据提供了一种有效的孔洞修补方法。

基于指针神经网络的细粒度缺陷定位

软件缺陷定位是指找出与软件失效相关的程序元素.当前的缺陷定位技术仅能产生函数级或语句级的定位结果.这种粗粒度的定位结果会影响人工调试程序和软件缺陷自动修复的效率和效果.专注于细粒度地识别导致软件缺陷的具体代码令牌,为代码令牌建立抽象语法树路径,提出基于指针神经网络的细粒度缺陷定位模型来预测出具体的缺陷代码令牌和修复该令牌的具体操作行为.开源项目中的大量缺陷补丁数据集包含大量可供训练的数据,且基于抽象语法树构建的路径可以有效捕获程序结构信息.实验结果表明所训练出的模型能够准确预测缺陷代码令牌并显著优于基于统计的与基于机器学习的基线方法.另外,为了验证细粒度的缺陷定位结果可以贡献于缺陷自动修复,基于细粒度的缺陷定位结果设计两种程序修复流程,即代码补全工具去预测正确令牌的方法和启发式规则寻找合适代码修复元素的方法,结果表明两种方法都能有效解决软件缺陷自动修复中的过拟合问题.

电力变压器油中溶解气体在线监测数据修复方法

变压器油中溶解气体分析已广泛应用于变电站中。但是一些在线监测装置常常出现数据异常或缺失,影响对变压器状态的实时准确判断,因此亟需对在线监测数据中被剔除的“脏数据”和缺失数据进行修复。在总结现场变压器油中溶解气体在线监测数据特点的基础上,综合考虑数据修复的时效性和准确度要求,提出了由滑动平均、径向基函数神经网络和多项式拟合3种缺失数据修复算法组成的修复策略;利用现场典型数据,分析了这3种方法的修复效果、最佳参数、优缺点和相互配合方式,实现了对油中溶解气体在线监测数据的快速准确修复。

Ischemic long-term-potentiation(iLTP): perspectives to set the threshold of neural plasticity toward therapy

The precise role of neural plasticity under pathological conditions remains not well understood. It appears to be well accepted, however, that changes in the ability of neurons to express plasticity accompany neurological diseases. Here, we discuss recent experimental evidence, which suggests that synaptic plasticity induced by a pathological stimulus, i.e., ischemic long-term-potentiation（i LTP） of excitatory synapses, could play an important role for post-stroke recovery by influencing the post-lesional reorganization of surviving neuronal networks.