Matrix within cells, the cytoskeleton, and that which surrounds cells,the extracellular matrix (ECM), are connected to one another through a number of receptors including those in primary cilia, serving as an important chemical and physical signaling system: Mechanical forces generated through the matrix play a critical role in determining the form and function of tissues (Hughes et al., 2018). Such forces, even in adult tissues, will be important given that breakdown of the ECM in adults may lead to the tissue changing from an adult phenotype to one of primordial or embryonic (Bhat and Bissell, 2014). As an example, chemical and mechanical signaling from the microenvironment and ECM to the cell can be so powerful as to change cellular phenotype from one of cancer to a normal somatic form (Bhat and Bissell, 2014). Even in development and inheritance, the matrix is important for what embryos receive from egg and sperm upon fertilization. Centrioles, the matrix structures responsible for cell division, are given by the paternal gamete. In the oocytes, the maternal gametes, the centriole is lost through desolvation.Thus, paternal matrix inheritance through the centriole structure is another important example of mechanism of heredity beyond the genome that may have consequences to neural dysfunction.

Although the cilium is a relatively small structure its importance as a structural and chemical bridge between intracellular and extracellular compartments is large. For example, the ciliary membrane is the obligate site of action for receptors of a number of signaling systems that profoundly condition cell growth, morphology, and adhesion, and is a specialized site of action for additional signaling receptors. Cilia arise from most cell types, including neural stem cells where the cilia are involved in the cell’s transition from quiescence (Khatri et al., 2014). Wang and Barr (2016) have proposed that the cilium is a dedicated organelle for extracellular vesicle (EV) biogenesis and EV reception. The basal body and its associated transition-fiber proteins are thought to regulate protein entry and exit from the cilia compartment, including the release of exosomes (Wang and Barr, 2016). Cilia connecting with the ECM, through expression of integrins and NG2 on primary cilia, help to determine the morphology and adhesion properties, and other phenotypes of the cell(Seeger-Nukpezah and Golemis, 2012) (Figure 1).

Breakdown of matrix occurs in neurological diseases, including amyotrophic lateral sclerosis (Maguire and Maguire, 2018). The breakdown of matrix includes the perineuronal nets, a condensed form of ECM that surrounds many types of neurons, especially those with high spike rates, such as retinal ganglion cells and motor neurons.Breakdown of the primary cilia can lead to altered integrin function,ECM, and matrix metalloproteinase (MMP) activity, as well as fi brotic scarring, thought to be a major barrier to central nervous system (CNS)regeneration (Fernández-Klett and Priller, 2014). Fibrosis is a double edge sword during the repair of nervous system in the adult, providing mechanisms that are both positive and negative in the process of neural regeneration (Figure 2).

Breakdown of matrix occurs through a number of environmental regulators: Including one’s exposome (Rappaport, 2016; Maguire,2017). As the ECM breakdowns through environmental insult, the chemical and mechanical signals and connections of the primary cilia to the ECM will be modi fi ed, resulting in an intracellular matrix change. Having lost a normal microenvironment, the result could be that the cell senses a more primordial state, and therefore changes phenotype to one where developmental and embryonic circuits are activated in search of a new identity (Bhat and Bissell, 2014). Furthermore, loss of a normal microenvironment and ECM will mean that neurons no longer receive their normal complement of heat shock protein (HSP) and chaperone proteins from surrounding neural stem cells (Maguire, 2017). In such cases, protein misfolding results and prion-like seeding and spreading of the misfolded proteins occurs.This is a major mechanism underlying neurodegeneration, and does not involve the genome (Maguire and Maguire, 2018).

笔者通过参考陈佑清、陶涛［1］、张瑞方［2］、覃鸿怀［3］、谢永鹏、杨英歌［4］、陈善敏［5］、祝智庭［6］学者的研究文献，结合自己作为高校教师多年来的实训教学实践及思考，基于“以学生为中心，以学习效果论教，凸显过程性监控和应用型人才培养目标实现”的理念，提出了“以学评教”的课程教学质量评价指标体系，如表3所示。

Figure 1 Early onset of matrix breakdown throughout the body in neurodegenerative diseases.

In some cell and tissue types, as in renal tubules, cilia protrude into lumens(left panel), while in others, such as neural tissue, cilia extend towards the extracellular matrix (ECM) (right panel). Multiple receptors for soluble growth factors or for mechanosensory stimuli (e.g., fl uid fl ow) localize to the ciliary membrane, controlling signaling cascades that in fl uence cell proliferation, polarity, and interaction with the ECM. Some canonical cell adhesion receptors, including cadherins, and integrins, have been shown to be themselves localized to the cilium in some cell types. Some basal body-localized proteins with ciliary functions also regulate the actin cytoskeleton(Seeger-Nukpezah and Golemis, 2012).

Figure 2 Types of cilia in lumen and extracellular matrix.

In neurodegenerative diseases, early onset mechanisms underlying the disease include matrix breakdown and gut dysbiosis and leaky gut syndrome.Matrix breakdown occurs in the extracellular matrix and perineuronal net surrounding neurons and the neuromuscular junction, as well in the intestines. Matrix breakdown also occurs intracellularly in neuronal cilia, and the microvilli of the intestine. Matrix breakdown may occur through the exposome as microparticulate and other toxins enter the body through the nasal vasculature, lungs, and the gut. The consequences of matrix breakdown include phenotypic changes in neurons and other cell types, and an inability of chaperone proteins and heat shock protein to repair misfolded proteins leading to the prion-like spreading of the malformed proteins within the nervous system.

In conclusion, I have presented evidence that part of the key early onset of neurodegeneration involves a breakdown of matrix throughout the body, including the ECM and the intracellular matrix, in the nervous system and in the gut. To rebuild the matrix I have laid out a general plan for therapeutic development using a supplement that uses the molecules that stem cells release, along with amino acids and prebiotics, probiotics, and postbiotics that help rebuild the extracellular and intracellular matrix, i.e., the cytoskeleton of the cilia and the villi of the epithethelial cells lining the gut.

Accepted: 2018-05-09

我独爱荷花，更爱画荷，绣荷。但没想到绣了七七四十九天的成果居然换来了白家的声名大赫，皇上钦点我爹为专用皇家刺绣御使。

智商是学生先天形成的，情商是学生后天培养的，情商与智商要相统一协调，学生才能更好发展与进步。激励教育的应用让学生的情商得以发展，智商得以呈现，“双商”共同作用，学生才能全面发展，走向成功。学生的智商多数都是一样的，只是有些学生乐于呈现、善于呈现，激励教育让学生更愿意去呈现，显示自己的能力。在激励教育中，学生被老师、同学所认可，班级的氛围会变得更好，学生在交际中情商也有显著的提升。

The means to rebuild the microvilli is now understood. In patients and animals treated with ionizing irradiation, gastrointestinal toxicity results within the fi rst week of exposure. Using an amino acid rehydration solution ingested as a supplement, Yin et al. (2016) have demonstrated that the surface area of microvilli in such patients can be increased. Parenthetically, while ionizing irradiation treatment for cancer is known to be associated with brain toxicity, even when the brain is not irradiated, the mechanisms underlying this toxicity have not been studied, and thus we cannot conclude the toxicity results from microvilli disruption. Part of the consequences of irradiation is a reduction in Lgr5 labeled stem cells in the gut, reduced microvilli surface area, leaky gut, induce Cl– secretion,and diarrhea (Yin et al., 2016). With a certain amino acid supplement, Yin et al. (2016) were able to signi fi cantly ameliorate these symptoms of irradiation. Therefore the amino acid supplement becomes one component of the neurodegeneration remedy proposed here. Also included in the supplement would be molecules that stem and progenitor cells release that build the ECM and provide chaperone and HSP activities crucial for neural repair, along with prebiotics, probiotics, and postbiotics. These molecules are known to condition the gut, and to absorb into the body(Maguire, 2017) Important dosing parameters have been described by Maguire and Maguire (2018).

当前，大部分电力企业在对电网规划工作进行决策和评估时，通常是参考以往的工作经验，并将电网规划的重心放在了经济性方面，没有对电网规划建设的社会影响、环境影响等方面进行综合考虑。一旦评估依据缺乏全面性，就到造成评估结果存在偏差；缺少完善的智能化评估体系，则会导致在建设新型电网规划体系时无法达到能源持续发展的目标。

Reparation of matrix is accomplished using a combination of stem cell released molecules (S2RM), amino acids, and prebiotics, probiotics, and postbiotics: Because many neurological diseases are a function of proteinopathies, proteostatic renormalization is particularly useful to quelling the disease state. Indeed, proteinopathy will activate microglia and the onset of the neuroinflammatory cascade (Chakrabarty et al.,2015). Such activation is important, for example, in the clearance of amyloid proteins in Alzeheimer’s disease (AD) models. However, we can imagine that ECM breakdown, when occurring chronically because of aging and exposome insult (Rappaport, 2016), will lead to an interruption of proteostasis and an onset of the disruption of immunoproteo-stasis. (Chakrabarty et al., 2015). Therefore without proteostasis, such as in the case of an overabundance of the antiin fl ammmatory cytokine interleukin (IL)-10 for example and an under abundance of proin fl ammatory cytokines, IL-6 for example, neurodegenerative processes may be triggered (Chakrabarty et al., 2015). In astronomy the Goldilocks principle is that planets must revolve about a star in a habitable zone where conditions are suitable for life. In neurodegeneration we may therefore think about a Goldilocks zone where protein content, both pro-in fl ammatory and anti-in fl ammatory, is normalized so that ECM and immune related proteins, including chaperones and HSPs, and those responsible for autophagy, are maintained in a zone suitable for life.

Greg Maguire＊

Peer review: Externally peer reviewed.

＊Correspondence to: Greg Maguire, Ph.D., gregmaguire5@gmail.com.

orcid: 0000-0001-5484-6157 (Greg Maguire)

Stem cells and progenitor cells, such as fi broblasts, are responsible for building the ECM through the secretion of the necessary molecules to build the biochemical scaffold, as well as other proteins, such as HSPs and chaperone proteins that are required for normal neural function.As such, stem cell released molecules (SRM) as a therapeutic are a key means to rebuild ECM and provide the other proteins, such as chaperones and HSP, required for normal protein folding and neural function(Maguire, 2017). Many of the proteins and other molecules necessary for neural repair are packaged into exosomes (Maguire, 2017) that may be released through the control by the stem cell’s cilia (Wang and Barr,2016). Emerging evidence now suggests that the ECM can also be partially built through various molecules, including proteins, tryptophan metabolites, and polysaccharides, released by commensal bacteria in the gut (Ruiz et al., 2014; Maguire and Maguire, 2018). Indeed, ECM that originates from the bacteria in our guts, a form of bacterial bio fi lm, has been shown to have important health bene fi ts (Ruiz et al., 2014). Therefore rebuilding of the ECM in the gut though the use of commensal bacteria, i.e., probiotics, the molecules that feed these commensal bacteria,i.e., prebiotics, and the molecules that these bacteria release, i.e., postbiotics, is important to the therapeutic regimen for neurological disorders(Maguire and Maguire, 2018). Gut alterations are known to be expressed early, before in fl ammation or other symptoms are expressed in a number of neurological diseases such as amyotrophic lateral sclerosis (ALS)and Parkinson’s disease. Without a normal matrix barrier present in the gut, leaky gut syndrome results and the molecules that bacteria make,including amyloids, along with bacteria themselves, may systemically enter the body and travel into the nervous system. Evidence that bacteria have entered the brain of AD patients has recently been published.Whether the bacteria are causative, or involved in the initial AD sequlae,or whether the bacteria enter the brain later as a result of blood brain barrier disruption is not known.

doi: 10.4103/1673-5374.235026

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

Plagiarism check: Checked twice by iThenticate.

One additional component in the gut’s matrix will be important to neural repair; the microvilli of the intestinal epithelial. Microvilli are covered in plasma membrane, which encloses cytoplasm and micro fi laments. Though these are cellular extensions, there are little or no cellular organelles present in the microvilli. Each microvillus has a dense bundle of cross-linked actin fi laments, which serves as its structural core, with about 20 to 30 tightly bundled actin fi laments are cross-linked by bundling proteins fi mbrin (or plastin-1), villin and espin to form the core of the microvilli. Actin fi laments, present in the cytosol, are most abundant near the cell surface. These fi laments are thought to determine the shape and movement of the plasma membrane. Changes in molecular composition of the cytoskeleton can lead to nucleation and a dramatic change in self-assembly of the microvilli, leading to diminution of the microvilli structure, including the glycocalyx, a pericellular matrix important for nutrient uptake. Consequent reductions in mechanical autophagy and nutrient absorption result (Maguire and Maguire, 2018).

BioRegenerative Sciences, Inc., NeoGenesis, Inc., San Diego, CA,USA

观察上述患者护理前后MUIS评分情况,其总分为100分,分值越好,患者的焦虑等不良症状越高。并对患者的满意度进行分析。

Open access statement: This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-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.

Open peer review report:

这时，一声哽咽打破了呼吸声，随之传来一阵啜泣。某个庞大身躯在翻动，床垫弹簧吱呀作响，接着枕头捂住了哭泣声，但还是有声音漏了出来。声音是从我旁边的床铺传来的，原来是诚实派的男孩艾尔——新生里面最高大、最胖的人，他用枕头捂住脸，但哭泣的声音还是断断续续。真没想到，艾尔会是第一个崩溃的人。

Reviewer: Jérôme Braudeau, AgenT, France.

Comments to author: This subject is interesting and often unrecognized by neuroscientists. Especially, the potential interaction between brain and gut (and its bacterial fauna) through the extracellular matrix during neurodegenerative disease progression must be kept in mind. Indeed, it’s important to apprehend neurodegenerative diseases, especially Alzheimer’s disease, as whole body pathology. However, in order to facilitate the reading by non-experts of extracellular matrix, it could be pertinent to simplify secondary information amounts.

References

Bhat R, Bissell MJ (2014) Of plasticity and speci fi city: dialectics of the microenvironment and macroenvironment and the organ phenotype. Wiley Interdiscip Rev Dev Biol 3:147-163.

Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, DiNunno N,Rosario AM, Cruz PE, Verbeeck C, Sacino A, Nix S, Janus C, Price ND, Das P, Golde TE (2015) IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85:519-533.

Fernández-Klett F, Priller J (2014) The fi brotic scar in neurological disorders.Brain Pathol 24:404-413.

Hughes AJ, Miyazaki H, Coyle MC, Zhang J, Laurie MT, Chu D, Vavrušová Z,Schneider RA, Klein OD, Gartner ZJ (2018) Engineered tissue folding by mechanical compaction of the mesenchyme. Dev Cell 44:165-178.e6.

Khatri P, Obernier K, Simeonova IK, Hellwig A, Hölzl-Wenig G, Mandl C,Scholl C, Wol fl S, Winkler J, Gaspar JA, Sachinidis A, Ciccolini F (2014) Proliferation and cilia dynamics in neural stem cells prospectively isolated from the SEZ. Sci Rep 4:3803.

Maguire G (2017) Amyotrophic lateral sclerosis as a protein level, non-genomic disease: Therapy with S2RM exosome released molecules. World J Stem Cells 9:187-202.

Maguire M, Maguire G (2018) Gut dysbiosis, leaky gut, and intestinal epithelial proliferation in neurological disorders: towards the development of a new therapeutic using amino acids, prebiotics, probiotics, and postbiotics. Rev Neurosci. In press.

Rappaport SM (2016) Genetic factors are not the major causes of chronic diseases. PLoS One 11:e0154387.

Ruiz L, Hevia A, Bernardo D, Margolles A, Sánche B (2014) Extracellular molecular effectors mediating probiotic attributes. Fems Microbiol Lett 359:1-11.

Seeger-Nukpezah T, Golemis EA (2012) The extracellular matrix and ciliary signaling. Curr Opin Cell Biol 24:652-661.

Wang J, Barr MM (2016) Ciliary extracellular vesicles: txt msg organelles. Cell Mol Neurobiol 36:449-457.

Yin L, Gupta R, Vaught L, Grosche A, Okunieff P, Vidyasagar S (2016) An amino acid-based oral rehydration solution (AA-ORS) enhanced intestinal epithelial proliferation in mice exposed to radiation. Sci Rep 6:37220.