It is well known that primates, including humans, hardly recover motor function after spinal cord injury (SCI) when compared with non-primate mammals such as rodents. This limited functional recovery is in part due to a non-permissive environment of the central nervous system (CNS) inhibiting axonal regrowth. This inhibitory environment for axonal regrowth is mainly caused by interaction of axon growth inhibitors with their common receptor, Nogo receptor-1 (NgR1). Axon regrowth inhibitors such as Nogo proteins, myelin associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein(OMgp) and B lymphocyte stimulator (BLyS) are derived from glial cells in damaged brain.

一是基础性实践，主要是帮助学生对旅游学原理及相关管理学景区规划基本概念、基础理论有能深刻的掌握理论知识，满足职场所必备的基本素质，如职业行为习惯、职场礼节、表达沟通能力等。这项实践内容通过组织学生参与社会公益、专业形势与政策学习、旅游认知实习、观赏植物学实习、林业资源保护实习、野生动物学实习等方式培养学生基础实践能力。

Previous studies have demonstrated that inhibition of NgR1 activity promotes functional recovery in animal models of CNS injury (GrandPré et al., 2002; Kim et al., 2004; Cafferty et al., 2010). Administration of NEP1–40 peptide, a Nogo-66 antagonist, to rat SCI models resulted in significant axon regrowth in corticospinal tract (CST), and improved motor function (GrandPré et al., 2002). Targeting of NgR1 function showed that deletion of the NgR1 gene in these mice improved motor function following SCI (Kim et al., 2004). Targeting multiple axon regrowth inhibitors also showed greater axonal regrowth and improved motor function after SCI in Nogo,MAG and OMgp triple-knockout mice (Cafferty et al., 2010).Gene targeting of NgR1 also enhanced structural plasticity and spontaneous functional recovery (Cafferty et al., 2010). As such,inhibition of NgR1 function promotes functional recovery in motor activity after SCI and may be one of a main therapeutic approach for neural regeneration.

In parallel, supplying neurotrophic factors such as brain-derived neurotrophic factor to an environment provides neuronal protection and enhances motor axonal regeneration (Novikov et al., 1997) Therefore, treatment with various combinations of neurotrophic factors may have a greater impact on neuronal regeneration after SCI. Transplantation of human iPS cell-derived oligodendrocyte precursor cells has been shown to contribute to remyelination of demyelinated axons (Kawabata et al., 2016).Thus, signi fi cant functional recovery requires repair of neural networks not only by inhibiting NgR1 function, but also by supplying neurotrophic factors and cell transplantation.

The discovery of LOTUS addresses the paradox of why neurons extend their neurites and form a neural network in the developing brain while expressing Nogo and NgR1. A neural circuit formation factor, named lateral olfactory tract (LOT) usher substance (LOTUS) was discovered in our laboratory in 2011.Expressed LOTUS in healthy neurons contributes to the LOT axonal bundle formation through antagonism of Nogo-NgR1 interaction. We therefore identi fi ed LOTUS as an endogenous NgR1 antagonist (Sato et al., 2011). LOTUS is a potent inhibitor of NgR1, as overexpression of LOTUS completely suppressed growth cone collapse and neurite outgrowth inhibition.This was achieved by blocking NgR1 function induced by all fi ve types of its ligand in dorsal root ganglion (DRG) neurons that express little LOTUS (Kurihara et al., 2014, 2017) (Figure 1). LOTUS is abundantly expressed in many regions of the CNS. However, it was observed that neurons hardly regenerate when a potent NgR1 antagonist, LOTUS, is expressed in the CNS. Why is this so? We found that LOTUS expression levels drastically decreased at the injured site in wild type mice about one week after SCI. The down-regulation of LOTUS expression may be associated with perturbation of recovery in motor activity after SCI. We thus proposed that decreased LOTUS expression may give rise to a non-permissive environment in the CNS for neuronal regeneration. Therefore, we hypothesized that the level of LOTUS expression may regulate neuronal regrowth activity by increasing and decreasing its antagonism to NgR1. To address this issue, we fi rst compared functional and histological recovery after SCI in wild type mice to that in lotus-knocking-out (LOTUS-KO) mice. It is well established that rodents such as mice and rats show incomplete but substantial spontaneous motor recovery after SCI. However, the factors involved in this spontaneous improvement remained elusive. We found a remarkable delayed spontaneous functional recovery of behavioral and histological outcome in LOTUS-KO mice when compared with wild type mice (Hirokawa et al., 2017). The data thus suggest that LOTUS is a factor associated with spontaneous motor recovery in rodents. We then speculated that the supply of LOTUS could compensate for the loss of regenerative activity due to decreased LOTUS expression and eventually promote functional recovery with neuronal regeneration after SCI. To examine this possibility, we generated transgenic mice(LOTUS-TG mice) that overexpressed LOTUS specifically in neurons and examined the effect of LOTUS overexpression on functional recovery after SCI. Definitive evidence for continued recovery of motor activity in LOTUS-TG mice after the recovery had reached a plateau in wild type mice. Although LOTUS expression level was down-regulated from the level of overexpression after SCI, the down-regulated level of LOTUS expression in LOTUS-TG mice was almost similar to the level in healthy wild type mice. These findings do suggest that the supply of LOTUS promotes functional recovery after SCI (Hirokawa et al., 2017).

LOTUS has also been shown to contribute to neuronal regeneration in another CNS injury model, ischemia by middle cerebral artery occlusion. In this model, CST axon fi bers sprouting from the non-ischemic side to the contralateral ischemic side were increased in LOTUS-TG mice when compared with wild type mice (Takase et al., 2017). The data suggest that LOTUS enhances neuronal plasticity of CST neurons and thereby improves motor function after ischemia. LOTUS contains both a membrane-bound form and secreted form. The soluble (secreted) form of LOTUS protein shows the same antagonistic activity against NgR1 and promotes axonal regeneration in optic nerve crush injury of mice (Kawakami et al., 2018). Conversely,LOTUS promotes axonal growth not only by antagonism of NgR1 function, but also by promoting intrinsic neurite outgrowth activity (unpublished data). It is thus possible to induce neuronal regeneration by utilizing both LOTUS functions,which are its antagonism of NgR1 function and its neurite outgrowth promoting action. Therefore, LOTUS administration with recombinant protein injection, LOTUS gene transfection and transplantation of LOTUS overexpressing neuronal stem cells may be useful as a therapeutic agent to promote neuronal regeneration. In addition, there is a low probability of side effects as LOTUS is an endogenous protein abundantly expressed in the healthy CNS.

Figure 1 Lateral olfactory tract usher substance (LOTUS) as an endogenous Nogo receptor-1 (NgR1) antagonist.

In the central nervous system (CNS), there are axon growth inhibitors such as Nogo, myelin associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), that are derived from oligodendrocytes,and B lymphocyte stimulator (BLyS) and chondroitin sulphate proteoglycans (CSPGs) derived from astrocytes. These 5 inhibitors are the ligands of NgR1 and ligand binding induces axon growth inhibition,thereby limiting neuronal regeneration after injury. LOTUS interacts with NgR1 and completely suppresses NgR1-mediated axonal growth inhibition, thereby promoting axon regrowth.

Figure 2 Therapeutic approach to neuronal regeneration by lateral olfactory tract usher substance (LOTUS).

After central nervous system (CNS) damage, injection of recombinant LOTUS protein, overexpression of LOTUS by gene transfection or transplantation of LOTUS overexpressing neuronal stem cell may be useful for future therapy for CNS damage, indicating that LOTUS may convert a non-permissive to permissive environment for neuronal regeneration in the CNS.

Accepted: 2018-05-03

Molecular Medical Bioscience Laboratory, Yokohama City University Graduate School of Medical Life Science, Yokohama,Japan

Peer review: Externally peer reviewed.

This work was supported by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by grants for Research and Development project of Yokohama City University.

本试验19个华南型黄瓜材料其中18个优良新组合为四川省农业科学院园艺研究所选育，对照燕白黄瓜为重庆市科光种苗公司产品，所有材料统一种植于四川省郫都区四川省农业科学院科研基地。于 2018年11月22日播种，2月13日定植大棚中，行距65 cm，株距35 cm，试验小区厢宽1.3 m，长3.5 m，种20株，设两重复，顺序排列；栽培管理条件一致；于采收高峰期的4月16日和4月23日分两批提供试验品。参试果实采于植株中部，一致性较好，表面无损伤、无病虫为害。原料采摘后2 h内送达实验室，处理前于10 ℃冷库中放置24 h。

orcid: 0000-0001-6938-0812 (Kohtaro Takei)

As such, LOTUS is a strong candidate to convert a non-permissive to permissive brain environment for neuronal regeneration. It is a potential natural agent for providing a regenerative brain environment by inhibition of NgR1 function. We are currently attempting LOTUS administration to injured CNS by injection of purified recombinant LOTUS protein or LOTUS gene transfection in both acute and chronic phase injury (Figure 2). Combination of treatment with other drug targets on which LOTUS does not act such as Semaphorin 3A inhibitor, pleiotrophin, or a chondroitin sulfate proteoglycan inhibitor, and with rehabilitation may be successful as future therapies. Finally, it is important to develop agents blocking a decrease in LOTUS expression since the decrease of LOTUS expression may be associated with perturbation of functional recovery after SCI.

doi: 10.4103/1673-5374.235030

谣言、臆测充斥在真相披露之间。当情绪成为互联网流量的主要驱动力，当敲击键盘表达立场变得比事实本身更重要，那些为保护海外中国同胞权益而奔波在一线的外交工作人员，则不得不一次又一次跌入被撕裂的舆论漩涡……

Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication.

Open peer review reports:

Tomoko Hirokawa, Kohtaro Takei＊

Open access statement: This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-Non-Commercial-ShareAlike 4.0 License, which allows others to remix, tweak,and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

Plagiarism check: Checked twice by iThenticate.

＊Correspondence to: Kohtaro Takei, Ph.D.,kohtaro@yokohama-cu.ac.jp.

Reviewer 1: Shaoping Hou, Drexel Univesity College of Medicine, USA.

Comments to authors: The manuscript converts a non-permissive to permissive brain environment for axonal regrowth”, is a review about a growth inhibitor in CNS axon regeneration. Authors described the discovery of LOTUS and its major effects on attenuating Nogo receptors. As such, this will help spread knowledge about LOTUS to neuroscience community. Nogo and related factors have been characterized for almost 20 years. Their roles in axon regeneration are much clear: inhibitory factors but not conclusive ones. Therefore, the review should provide not only the positive effects about LOTUS’s, but also the limitations. Indeed, all SCI animal models in cited publications were incomplete injury, which rendered difficulties to evaluate real regeneration, sprouting or others based on their tracing techniques and immunostaining.

聚焦新目标，让党员良好形象更加根深蒂固。雨花军休所的党员们遵循习近平总书记对老同志提出的“忠诚一辈子，奉献一辈子”的期望，以此激励全体党员发挥先锋模范作用。如组织老党员对家庭矛盾、邻里纠纷开展调解工作；先后成立了新潮流书画院、新境界艺术团、新气象影像社、新风格创作室等组织，为离退休干部职工搭建优质文化平台；开展文化扶贫惠老和“银发携手红领巾”等活动。三年来，共组织文化扶贫惠老活动16次，服务对象4000余人；举办青少年思想道德教育等专题讲座100余场，把扶贫惠老和关心下一代工作由基层党支部推向社会，充分发挥老党员引领示范作用。

Reviewer 2: Hao Chen, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong University School of Medicine, China.

在外界看来，对于足球，蔡振华是位“门外汉”，连他自己也说，自己并非足球领域的行家，对于因为输球遭受球迷不理智的骂声，他可以理解。

本文采用数据主要来源于联合国统计署贸易数据库（UN Comrades）（2007年-2016年）按联合国国际贸易标准分类（SITC Rev3）。商品分类方法如下表：

References

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