A bright future for the tree shrew in neuroscience research:Summary from the inaugural Tree Shrew Users Meeting

Tree shrews(Tupaia spp.)have been used in neuroscience research since the 1960s due to their evolutionary proximity to primates.The use of and interest in this animal model have recently increased,in part due to the adaptation of modern neuroscience tools in this species.These tools include quantitative behavioral assays,calcium imaging,optogenetics and transgenics.To facilitate the exchange and development of these new technologies and associated research findings,we organized the inaugural“Tree Shrew Users Meeting”which was held online due to the COVID-19 pandemic.Here,we review this meeting and discuss the history of tree shrews as an animal model in neuroscience research and summarize the current themes being investigated using this animal,as well as future directions.

Implications of regional identity for neural stem and progenitor cell transplantation in the injured or diseased nervous system

Neural stem and progenitor cell(NSPC)transpla ntation has emerged as a promising therapeutic strategy for replacing lost neuronal populations and repairing damaged neural circuits following nervous system injury and disease.A great deal of experimental work has investigated the biology of NSPC grafting in preclinical animal models;more recently.

Trophic factors are essential for the survival of grafted oligodendrocyte progenitors and for neuroprotection after perinatal excitotoxicity

The consequences of neonatal white matter injury are devastating and represent a major societal problem as currently there is no cure.Prematurity,low weight birth and maternal pre-natal infection are the most frequent causes of acquired myelin deficiency in the human neonate leading to cerebral palsy and cognitive impairment.In the developing brain,oligodendrocyte(OL)maturation occurs perinatally,and immature OLs are particularly vulnerable.Cell replacement therapy is often considered a viable option to replace progenitors that die due to glutamate excitotoxicity.We previously reported directed specification and mobilization of endogenous committed and uncommitted neural progenitors by the combination of transferrin and insulin growth factor 1(TSC1).Here,considering cell replacement and integration as therapeutic goals,we examined if OL progenitors(OLPs)grafted into the brain parenchyma of mice that were subjected to an excitotoxic insult could rescue white matter injury.For that purpose,we used a well-established model of glutamate excitotoxic injury.Four-day-old mice received a single intraparenchymal injection of the glutamate receptor agonist N-methyl-D-aspartate alone or in conjunction with TSC1 in the presence or absence of OLPs grafted into the brain parenchyma.Energetics and expression of stress proteins and OL developmental specific markers were examined.A comparison of the proteomic profile per treatment was also ascertained.We found that OLPs did not survive in the excitotoxic environment when grafted alone.In contrast,when combined with TSC1,survival and integration of grafted OLPs was observed.Further,energy metabolism in OLPs was significantly increased by N-methyl-D-aspartate and modulated by TSC1.The proteomic profile after the various treatments showed elevated ubiquitination and stress/heat shock protein 90 in response to N-methyl-D-aspartate.These changes were reversed in the presence of TSC1 and ubiquitination was decreased.The results obtained in this pre-clinical study indicate that the use of a combinatorial intervention including both trophic support and healthy OLPs constitutes a promising approach for long-term survival and successful graft integration.We established optimal conditioning of the host brain environment to promote long-term survival and integration of grafted OLPs into an inflamed neonate host brain.Experimental procedures were performed under the United States Public Health Service Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee at(UCLA)(ARC#1992-034-61)on July 1,2010.

The Continuous Relative Deficiency of Intracellular Potassium Is a Core Mechanism for the Occurrence and Metastasis of Tumor Cancer Cells

The core mechanism for occurrence of tumor cancer cells is related to the continuous relative deficiency of potassium ions in the cells of organs and tissues, which results in embryonic like proliferation and differentiation in the affected cells. The purpose of the metastasis of cancer cells is to obtain and utilize the potassium resources in other organs in body. However, if the overall potassium storage in body is obviously insufficient, the metastatic cancer cells still fail to achieve the purpose of obtaining enough potassium and turn into normal cells, further proliferation and differentiation of cancer cells will continue, and finally will lead to functional decline in the organs and tissues affected or death. Therefore, the key means to prevent and treat tumors and cancers is to ensure the normal and balanced potassium ions in cells in various organs and tissues, so as to avoid the formation of tumors and cancer cells caused by obvious deficiency of potassium ions.

Microfluidic systems for axonal growth and regeneration research

Damage to the adult mammalian central nervous system （CNS） often results in persistent neurological deficits with limited recovery of functions. The past decade has seen in- creasing research efforts in neural regeneration research with the ultimate goal of achieving functional recovery. Many studies have focused on prevention of further neural damage and restoration of functional connections that are com- promised after iniurY or pathological damage.

"universe collapse model"and its roles in the unification of four fundamental forces and the origin and the evolution of the universe

To unify the four known fundamental forces and provide an explanation for the origin and the evolution of the universe are two long-term goals of theoretical physics. Here a “universe collapse model” has been proposed. The universe consists of Matter and No-matter. No-matter is the universal energy that constructs a consistent universe field, presenting a spiral wave motion at the speed of light at the small scale. The partial collapse of the universal energy forms the particles of the universal energy in a variety of sizes, which are called as the elementary particles. These elementary particles form atom and matter, which construct the galaxies. The collapse of the universe field induces the formation of the universe collapse potential (UCP) and universe collapse force (UCF), and the later is represented by four different aspects of the fundamental forces at the large or small scales. The mathematical equation and the derivation of UCP and UCF are described, and possible experimental tests are also suggested. Therefore, this new model may give a novel explanation for the unification of four fundamental forces and the origin and the evolution of the universe.

Prior Somatic Stimulation Improves Performance of Acquired Motor Skill by Facilitating Functional Connectivity in Cortico-Subcortical Motor Circuits

Once people have a well-trained motor skill, their performance becomes stabilized and achieving substantial improvement is difficult. Recently, we have shown that even a plateaued hand motor skill can be upgraded with short-period electrical stimulation to the hand prior to the task. Here, we identify the neuronal substrates underlying the improvement of the plateaued skill by examining the enhanced functional connectivity in the sensory-motor regions that are associated with motor learning. We measured brain activity using functional magnetic resonance imaging and performed psychophysiological interaction analysis. We recruited seven right-handed very-well trained participants, whose motor performance of continuously rotating two balls with their right hands became stabilized at higher performance levels. We prepared two experiments, in each of which they repeated an experimental run 16 times. In each run, they performed this cyclic rotation as many times as possible in 16 s. In the thenar-stimulation experiment, we applied 60-s stimulation to the thenar muscle before each of the 5th - 12th runs, and the others were preceded by ineffective sham stimulation. In the control experiment, the sham was always provided. Thenar stimulation enabled the participants to perform the movements at higher cycles. In association with this performance improvement, we found enhanced activity couplings between the primary motor cortex and the sensorimotor territory of the putamen and between the cerebellum and the primary sensorimotor cortices, without any quantitative activity increase. Neither behavioral change nor these increased activity couplings were observed in the control.Thus, in contrast to the stable neuronal states in the cortico-subcortical motor circuits when the well-learned task is repeated at the later stages of motor skill learning, plastic changes in the motor circuits seem to be required when the plateaued skill is upgraded, and the stimulation may entail a state of readiness for the plastic change that allows subsequent performance improvement.

Spiral Wave Law Is Involved in the Unification of Four Fundamental Forces and the Origin and the Evolution of the Universe

A long-term goal of theoretical physics is to develop a single simple theory or model that would unify the four known fundamental forces (or interactions) and give explanations for the origin and the evolution of the Universe. Here a “spiral wave law” has been proposed based on the previous studies that a consistent universe field presents various forms of spiral (helical) wave motions at the speed of light (c), and therefore, a mathematical equation for the relationship between the radius of a spiral wave motion (r) and its wave length (λ) is derived including a simplified formula ( or ), which could provide a novel explanation for the origin and the evolution of the Universe, and the space-time relationships. This model may give a new way for the unification of four fundamental forces and determine the moving properties of galaxies and basic particles, and the propagation characteristics of electromagnetic waves at the large or small scale.

CD4^(+)T细胞相关的细胞因子促使由诱导性多能干细胞衍生的中脑星形胶质细胞表现出慢性促炎症表型

星形胶质细胞是维持稳态的介质,但在帕金森病(Parkinson’s disease,PD)中参与神经炎症。越来越多的证据表明外周免疫细胞参与了PD的发病机制。因此,本研究旨在确定外周免疫细胞分泌的细胞因子在调节中脑星形胶质细胞反应性中的潜在作用。人类诱导性多能干细胞(iPSC)衍生的中脑星形胶质细胞暴露于5%和10%的CD4^(+)T细胞条件培养基(CD4CM)24小时、72小时和7天,以评估长期暴露的影响。此外,星形胶质细胞还暴露于Th17细胞细胞因子IL-17A(10 ng/mL),单独或与TNF-α(0.3 ng/mL)结合,在24小时、72小时和7天评估2种细胞因子可能的协同效应。CD4CM在中脑星形胶质细胞中引起了急性及长期的变化。观察到了NFκB向细胞核的转移增加,以及在24小时时促炎基因IL-1β和CXCL10的表达增加;在24小时和48小时时C3、LCN2和IL-6的表达增加;同时在这些时间点促炎细胞因子IL-6和CXCL10的释放也有所增加。IL-17A和TNF-α的组合对增加促炎基因表达和细胞因子释放产生了协同效应。IL-17A和TNF-α在24小时时增加了S100β的强度,在72小时时减少了细胞核面积并增加了星形胶质细胞的圆度。在72小时时观察到了γH2AX强度的协同效应,并且在7天时观察到了乳酸脱氢酶(LDH)释放的增加。我们的结果表明,IL-17A和TNF-α协同作用,增强了中脑星形胶质细胞的反应性,其程度类似于CD4CM。这突出了外周免疫细胞分泌的细胞因子在增强中脑星形胶质细胞反应状态方面的重要性,并提示了它们在PD发病机制中的可能作用。

Long interspersed nuclear element ORF-1 protein promotes proliferation and resistance to chemotherapy in hepatocellular carcinoma

AIM:To clarify the specific roles and mechanisms of long interspersed nuclear element-1 ORF-1 protein [human long interspersed nuclear element-1(LINE-1),ORF-1p] in chemotherapeutic drug resistance and cell proliferation regulation in hepatocellular carcinoma(HCC) cells.METHODS:MTT assays were performed to identify the effect of the chemotherapeutic drug toxicity on HepG2 cells.Cell proliferation inhibition and the IC 50 were calculated by the Origin 8.0 software.Western blotting assays were performed to investigate whether LINE-1 ORF-1p modulates the expression of some important genes,including p53,p27,p15,Bcl-2,mdr,and p-gp.To corroborate the proliferation and anchor-independent growth results,the HepG2 cells were analyzed by flow cytometry to investigate the effect of LINE-1 ORF1p on the apoptosis regulation.RESULTS:LINE-1 ORF-1p contributed to the resistance to several chemotherapeutic drugs(cisplatin and epirubicin) in HepG2 cells.The IC 50 of the epirubicin and cisplatin increased from 36.04 nmol/L to 59.11 nmol/L or from 37.94 nmol/L to 119.32 nmol/L.Repression of LINE-1 ORF-1p expression by the siRNA could markedly enhance the response of HepG2 cells to the epirubicin and cisplatin.The IC 50 correspondingly decreased from 28.06 nmol/L to 3.83 nmol/L or from 32.04 nmol/L to 2.89 nmol/L.Interestingly,down-regulation of LINE-1 ORF-1p level by siRNA could promote the response of HepG2 cells to the paclitaxel.The IC 50 decreased from 35.90 nmol/L to 7.36 nmol/L.However,overexpression of LINE-1 ORF-1p did not modulate the paclitaxel toxicity in HepG2 cells.Further Western blotting revealed that LINE-1 ORF-1p enhanced mdr and p-gp gene expression.As a protein arrested in the nucleus,LINE-1 ORF-1p may function through modulating transcriptional activity of some important transcription factors.Indeed,LINE-1 ORF-1p promoted HepG2 cell proliferation,anchor-independent growth and protected the cells against apoptosis through modulating the expression of p15,p21,p53,and Bcl-2 genes.CONCLUSION:LINE-1 ORF-1p promotes HepG2 cell proliferation and plays an important role in the resistance of chemotherapeutic drugs.By establishing novel roles and defining the mechanisms of LINE-1 ORF1p in HCC chemotherapeutic drug resistance and cell proliferation regulation,this study indicates that LINE-1 ORF-1p is a potential target for overcoming HCC chemotherapeutic resistance.

Impact of social isolation on behavioral health in elderly: Systematic review

AIM: To examine and compare the effects of subjective and objective social isolation on behavioral health in elderly adults.METHODS: A systematic search of Pub Med was performed for original research articles from peerreviewed journals examining one of the following topics: "Social isolation and sleep disturbance", "social isolation and depression", or "social isolation and fatigue in older adults". Studies were selected following the criteria established based on the aim of this review. Data were extracted from the articles by two independent reviewers. Due to the heterogeneity in study designs and outcome measures of the included studies, qualitative and narrative analyses were conducted.RESULTS: The set criteria were used to select a total of 16 studies for the review. Of the 16, 13 were crosssectional studies. The characteristics of study populations were identified as follows. A total of 12 studies randomly selected subjects irrespective of pre-existing health conditions. Consequently, an unspecified number of the study subjects had chronic diseases in the studies compared. In addition, cultural and ethnic backgrounds of studies in this review were diverse, and included subjects living in North America, South America, Asia, Europe, and Oceania. Both subjective and objective types of social isolation increased behavioral symptoms, such as sleep disturbance, depressive symptoms, and fatigue in older adults. Furthermore, a few recent studies reported stronger effects of subjective social isolation than objective social isolation on sleep disturbance and depressive symptoms.CONCLUSION: Social isolation affects behavioral health in older adults. Compared to the objective social isolation, subjective social isolation contributes more significantly to sleep disturbance and depression.

Modulation of protein tyrosine phosphorylation in gastric mucosa during re-epithelization processes

AIM:To investigate the role of protein tyrosine phosphorylation in gastric wound formation and repair following ulceration. METHODS:Gastric lesions were induced in rats using restraint cold stress.To investigate the effect of oxidative and nitrosative cell stress on tyrosine phosphorylation during wound repair,total activity of protein tyrosine kinase(PTK),protein tyrosine phosphatase (PTP),antioxidant enzymes,nitric oxide synthase (NOS), 2',5'-oligoadenylate synthetase,hydroxyl radical and zinc levels were assayed in parallel. RESULTS:Ulcer provocation induced an immediate decrease in tyrosine kinase(40% in plasma membranes and 56% in cytosol,(P<0.05) and phosphatase activity (threefold in plasma membranes and 3.3-fold in cytosol),followed by 2.3-2.4-fold decrease (P<0.05) in protein phosphotyrosine content in the gastric mucosa. Ulceration induced no immediate change in superoxide dismutase (SOD) activity,30% increase (P<0.05) in catalase activity,2.3-fold inhibition (P<0.05) of glutathione peroxidase,3.3-fold increase (P<0.05) in hydroxyl radical content,and 2.3-fold decrease (P<0.05) in zinc level in gastric mucosa.NOS activity was three times higher in gastric mucosa cells after cold stress. Following ulceration,PTK activity increased in plasma membranes and reached a maximum on day 4 after stress (twofold increase,P<0.05),but remained inhibited(1.6-3-fold decrease on days 3,4 and 5,P<0.05) in the cytosol.Tyrosine phosphatases remained inhibited both in membranes and cytosol(1.5-2.4-fold,P< 0.05).NOS activity remained increased on days 1,2 and 3(3.8-,2.6-,2.2-fold,respectively,P<0.05).Activity of SOD increased 1.6 times(P<0.05)days 4 and 5 after stress.Catalase activity normalized after day 2. Glutathione peroxidase activity and zinc level decreased (3.3-and 2-fold,respectively,P<0.05)on the last day. Activity of 2',5'-oligoadenylate synthethase increased 2.8-fold (P<0.05) at the beginning,and 1.6-2.3-fold (P<0.05) during ulcer recuperation,and normalized on day 5,consistent with slowing of inflammation processes. CONCLUSION:These studies show diverse changes in total tyrosine kinase activity in gastric mucosa during the recovery process.Oxidative and nitrosative stress during lesion formation might lead to the observed reduction in tyrosine phosphorylation during ulceration.

Why Are There So Many Puzzles in Fighting against COVID-19 Pandemic?

The novel coronavirus (SARS-CoV-2) and its variety that causes coronavirus disease 2019 (COVID-19) have had a great impact on human health and society since it was epidemic in 2019. The traditional immunological theories believe that human body resists the invasion of exogenous substances, such as different kinds of pathogenic microorganisms, through natural immunity and acquired immunity. We have greatly understood the underlying mechanisms of these two kinds of immunities, which are achieved through cellular and humoral immunity. Immune cells mainly include B and T cells. B cells produce specific antibodies and participate in the humoral immune response, while T cells have more extensive immune effects related to the cellular immune response. Therefore, such traditional immunological theories allow us habitually believe that the human body can resist the attack of virus as long as we have established the so-called normal cellular and humoral immune functions, however, in fact, this is not the case. The traditional ideas make us ignore the most critical, but simple and important defense system in our body to fight against the attack of foreign microorganisms, and that is the intracellular potassium ions (K+) and extracellular sodium ions (Na+), in particular, the intracellular potassium ions, called “K+/Na+ natural immune system”. The abnormality of this system, in particular, the intracellular relative deficiency of potassium ions, may have a very important relationship with the susceptibility and pathogenesis of the body to viral infection, and could explain a series of confusing phenomena that appeared during SARS-CoV-2 pandemic and provide new ideas for the prevention and treatment of COVID-19.

The Relative Deficiency of Potassium Ions in Nerve Cells Causes Abnormal Functions and Neurological and Mental Diseases

The difference of intracellular potassium (K+) and extracellular sodium (Na+) concentrations in nerve cells plays an important role in the functional activities of the nervous system. The maintenance of this difference mainly depends on the number and efficiency of Na, K-ATPase. However, due to the functional activity of nerve cells, this system often loses its balance. An undetectable phenomenon is the relative deficiency of potassium in nerve cells in specific brain regions or neural network structures, which leads to dysfunction of specific nerve cell populations or brain regions, thus leading to different types of neurological disorders or diseases. The relative deficiency of potassium ions in nerve cells may be caused by the competitive failure of nerve cells to effectively use potassium ions stored in the body, and the core reason may be related to insufficient potassium obtained through diet or effectively absorbed by the digestive system. Therefore, a simple strategy is to treat a patient by taking appropriate potassium orally. This paper presents a case with great success by using such a method to treat a patient with major depression.

Regulatory role of sorting nexin 5 in protein stability and vesicular targeting of vesicular acetylcholine transporter to synaptic vesicle-like vesicles in PC12 cells

Accurate targeting of vesicular acetylcholine transporter(VAChT)to synaptic vesicles(SVs)is indispensable for efficient cholinergic transmission.Previous studies have suggested that the dileucine motif within the C-terminus of the transporter is sufficient for its targeting to SVs.However,the cytosolic machinery underlying specific regulation of VAChT trafficking and targeting to SVs is still unclear.Here we used the C-terminus of VAChT as a bait in a yeast two-hybrid screen to identify sorting nexin 5(SNX5)as its novel interacting protein.SNX5 was detected in the SVs enriched LP2 subcellular fraction of rat brain homogenate and showed strong colocalization with VAChT in both brain sections and PC12 cells.Binding assays suggested that the C-terminal domain of VAChT can interact with both BAR and PX domain of SNX5.Depletion of SNX5 enhanced the degradation of VAChT and the process was mediated through the lysosomal pathway.More importantly,we found that,in PC12 cells,the depletion of SNX5 expression significantly decreased the synaptic vesicle-like vesicles(SVLVs)localization of VAChT.Therefore,the results suggest that SNX5 is a novel regulator for both stability and SV targeting of VAChT.

The Core Mechanism of Traditional Medicine Is the Rational and Effective Use of Potassium Ions

The use of traditional medicines including natural drugs, especially traditional Chinese medicine (TCM), plays an important role in the prevention and treatment of human diseases;however, so far, the mechanism of its prevention, health care and treatment of diseases is unclear. Here, I propose that the core mechanism of traditional medicines is to correct the relative deficiency of potassium ions in body and at the same time improve the utilization efficiency of potassium ions, so as to improve or restore cell functions in organs and tissues, and let the body return to a normal state. In order to achieve such a core goal, the therapeutic effect of natural drugs has an important relationship with the rational matching of prescriptions and the quality of drugs, with particular emphasis on the concentrations and quantum energy levels of potassium ions or their compounds in the formula. The understanding of the core effect of potassium in natural drugs has a specific and important guiding role for the artificial cultivation and rational use of natural drugs. Moreover, these ideas may also provide an important theoretical basis for the development of modern agriculture and medicine, and the rational and comprehensive utilization of potassium resources.

Relative Deficiency of Intracellular Potassium in Relation to the Functional Changes and Diseases in Non-Nervous System

Because of the huge differences in cellular structures and functions in non-nervous system and interaction between the nervous and non-nervous systems in potassium ion absorption, storage and effective utilization, the organs, tissues and tissue cells in non-nervous system have different functional dependence on potassium ion and its characteristics in competitive distribution differences. Therefore, I propose that the relative deficiency of potassium in cells in non-nervous organs and tissues may show very different functional changes and disease characteristics. Some are susceptible to pathogenic microorganisms, some may result in decrease of cell functions, and other may have comprehensive changes such as chronic inflammation. Therefore, the core causes for the functional changes and lesions of these non-nervous organs and tissues are closely related to the relative deficiency of potassium ions in their cells, which provides important ideas for the prevention and treatment of these functional changes and diseases.

miR147b:白细胞介素-1β介导的人类星形胶质细胞炎症中的新型关键调节因子

星形胶质细胞是大脑炎症过程的重要介质,可能在包括癫痫在内的几种神经系统疾病中起重要作用。星形胶质细胞中可生产几种miRNA,是炎症通路的关键调节因子,还可能用作治疗靶标。本研究将探索在体外IL-1β介导的炎症条件下,星形胶质细胞内生成的miRNA及其功能,并在人癫痫脑组织中验证。我们通过测序评估IL-1β刺激的人胎儿星形胶质细胞培养物中的miRNA和mRNA表达。使用miRNA模拟物在细胞培养物中过表达miRNA。使用原位杂交技术检测患有结节性硬化症复合体或颞叶癫痫伴海马硬化患者的切除脑组织中miRNA的表达。我们发现了2种差异表达的miRNA:miR146a和miR147b,它们与免疫/炎症反应相关基因的表达增加有关。既往有研究报道,在星形胶质细胞和结节性硬化复合细胞培养物中使用IL-1β刺激后,miR147b的过表达降低了促炎介质IL-6和COX-2的表达。miR146a和miR147b过表达降低了星形胶质细胞的增殖并促进人神经干细胞的神经元分化。miR147b在致癫痫脑中的星形胶质细胞中表达增加。由于其抗炎和恢复异常星形细胞增殖和促进神经元分化的能力,miR146a和miR147b作为与炎症相关的神经疾病(例如癫痫)的潜在治疗靶标值得进一步研究。

The Core Mechanism of Natural Selection: How the Natural Cycle of Potassium Resources Affects the Biological Evolution and the Change of Human Society

Darwin’s theory of evolution believes that biological evolution is a process of natural selection. This theory has been supported by much evidence, but the internal biological mechanism is not clear. Here, I elaborate on the cycle of potassium resources on the earth and the biological utilization and efficiency, which may be the core mechanism of natural selection and affect the evolution of organisms and the development of human society.