Exploring the novel role of oligodendrocyte precursor cells in phagocytosis:beyond myelinogenesis

Roles of oligodendrocyte precursor cells in the central nervous system:Oligodendrocyte precursor cells(OPCs)have long been recognized for their critical role as precursors to oligodendrocytes,the primary myelin-producing cells.As precursors,OPCs mature and differentiate into oligodendrocytes,which contribute significantly to the formation of myelin sheaths around axons.This myelination,which is critical for the conduction of salutatory nerve impulses in the cerebral white matter,underscores the classical role of oligodendrocytes in central nervous system(CNS)functionality.Importantly,because oligodendrocytes are differentiated cells that cannot proliferate.

Oncogenic BRAF^(V600E) induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase

Activating V600E in v-Raf murine sarcoma viral oncogene homolog B(BRAF)is a common driver mutation in cancers of multiple tissue origins,including melanoma and glioma.BRAF^(V600E) has also been implicated in neurodegeneration.The present study aims to characterize BRAF^(V600E) during cell death and proliferation of three major cell types of the central nervous system:neurons,astrocytes,and microglia.Multiple primary cultures(primary cortical mixed culture)and cell lines of glial cells(BV2)and neurons(SH-SY5Y)were employed.BRAF^(V600E) and BRAF^(WT) expression was mediated by lentivirus or retrovirus.Blockage of downstream effectors(extracellular signal-regulated kinase 1/2 and JNK1/2)were achieved by siRNA.In astrocytes and microglia,BRAF^(V600E) induces cell proliferation,and the proliferative effect in microglia is mediated by activated extracellular signal-regulated kinase,but not c-Jun N-terminal kinase.Conditioned medium from BRAF^(V600E)-expressing microglia induced neuronal death.In neuronal cells,BRAF^(V600E) directly induces neuronal death,through c-Jun N-terminal kinase but not extracellular signal-regulated kinase.We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease.Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity.It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.

针刺太冲穴得气及疼痛激发相对抗的脑功能网络效应fMRI研究

目的:采用磁共振脑功能成像技术,比较针刺太冲穴得气及针刺疼痛时所激发的脑功能网络效应异同。方法:47例初次接受针刺的志愿者参加手针右侧太冲穴fMRI实验。针刺时脑fMRI扫描10min,共2次捻针,各2min,间隔3min。其中17例接受体表触觉刺激作为针刺对照,分为3组:①针刺得气组;②针刺得气合并尖锐性疼痛组(简称针刺疼痛组);③触觉对照组。采用Fisher’s精确检验和t检验分析感觉频率及强度;用AFNI处理fMRI数据,得到激活、负激活脑区;用种子相关分析法,以前扣带回膝部为种子点,分析其与全脑的功能网络联系图谱,并比较得气与疼痛组之间的差异。结果:针刺2组的酸痛、酸感、压感、麻感、钝痛等得气感觉的频率和强度均明显强于触觉刺激组;针刺2组间除尖锐性疼痛及酸痛外,各种感觉差异无统计学意义。针刺得气及疼痛2组均激活了体感及丘脑岛叶皮层,重要的是,针刺得气时在大脑边缘叶-旁边缘叶-新皮层系统(LPNN)产生了较强而广泛的负激活区,加强了负激活区之间的脑功能网络联系。此网络包括杏仁核、海马、旁海马、颞极、前额叶腹内侧回、前扣带回膝及下部、前楔叶内侧回和后扣带回(BA31,23_腹侧核,29,30),另外,小脑蚓部、导水管周围灰质及脑干网状结构也见负激活现象。然而,在针刺疼痛时,这些脑区负激活程度减低且区域缩小,大部分脑区fMRI信号逆转为激活信号,被疼痛激活的脑区之间功能网络明显增强。这些脑区参与了疼痛、镇痛(如感觉、情感、认知、自主性、内源性镇痛)功能调制环路。结合既往研究表明,负激活与脑血氧消耗及血流量下降呈正相关。本结果支持针刺通过调制LPNN和疼痛中枢网络的活动,产生其镇痛、抗焦虑和其他调节效应的假说。结论:针刺得气及针刺得气伴随疼痛产生了相对抗的脑功能网络效应。针刺得气对LPNN及疼痛脑中枢网络(Pain matrix)的负激活效应,可能与针刺镇痛脑中枢机制相关。LPNN和静息态默认网络(Default mode)之间的相似性,提示针刺需通过这一内在脑功能网络系统发挥其广泛的调制作用。

家族性肌萎缩侧索硬化症转基因鼠的繁殖和鉴定

目的建立家族性肌萎缩侧索硬化症(FALS)转基因模型鼠的繁育方法,并对其子代鼠进行基因鉴定。方法(1)以6只B6SJL SOD1G93A/+半合子雄鼠与6只B6SJLF1/J+/+雌鼠(1∶1)交配;(2)由鼠尾血提取基因组DNA,PCR扩增hmSOD1基因的片段,电泳后观察结果;(3)对PCR产物进行纯化测序,并通过BLAST验证。结果6对种鼠交配产鼠仔53只,存活率为98%(52/53);G93A hmSOD1阳性鼠约占44.2%(23/52);PCR扩增产物分别为内对照(IL-2):324 bp;Tg(hmSOD1):236 bp;测序证实PCR产物的基因序列和hmSOD1基因片段中的序列一致,并存在G93A突变。结论B6SJL-Tg(SOD1-G93A)1Gur/J雄鼠与B6SJLF1/J雌鼠配种能成功繁育出Tg(hmSOD1)阳性的ALS半合子子代鼠;本实验的PCR法能准确鉴定hmSOD1基因阳性鼠,并证实该转入的基因按近似孟德尔方式遗传,为ALS实验研究奠定了基础。

中国大陆麻醉住院医师毕业后教育的探讨

经过近几年在全国部分省市试点后,2015年教育部和卫计委正式通知在全国范围内改变医学教育的现有模式,新的规范化培养（简称规培）已经逐步开展并日渐规范。各专科住院医师规范化培训的目的是培养具有现代医学素质的专职人员,能够胜任现代医学的临床要求。同时对住院医师进行评估和考核已经日趋重要,同样需要通过规范化的方式进行。现将美国麻醉住院医师培训考核模式与国内麻醉住院医师考核方式进行比较。

Helminth infections and intestinal inflammation

Evidence from epidemiological studies indicates an inverse correlation between the incidence of certain immune-mediated diseases, including inflammatory bowel diseases (IBD), and exposure to helminths. Helminth parasites are the classic inducers of Th2 responses. The Th2-polarized T cell response driven by helminth infection has been linked to the attenuation of some damaging Th1 driven inflammatory responses, preventing some Th1-mediated autoimmune diseases in the host, including experimentally induced colitis. Helminth parasites (the porcine whipworm, Trichuris suis ) have been tested for treating IBD patients, resulting in clinical amelioration of the disease. As a result, there is a great deal of interest in the research community in exploring the therapeutic use of helminth parasites for the control of immune-mediated diseases, including IBD. However, recent studies have provided evidence indicating the exacerbating effects of helminths on bacterial as well as non-infectious colitis in animal models. Therefore, a better understanding of mechanisms by which helminths modulate host immune responses in the gut may reveal novel, more effective and safer approaches to helminth-based therapy of IBD.

癌症启动中Kras的特异性功能

三种密切相关的Ras蛋白，即Kras、Hras和Nras构成了小分子GTP酶的Ras超家族成员，它们可以作为分子开关，传递细胞外信号从而引发一系列基本的细胞过程．包括增殖、存活和分化。癌症生物学家发现在人类肿瘤细胞中，编码这些蛋白的基因突变率较高。大约30％的人类肿瘤细胞中出现Ras基因突变，也有一系列参与Ras途径的基因发生突变。由于GTP水解作用可灭活蛋白，因此RasGTP酶信号转导通常具有自限性，

Effect of electroacupuncture on glial fibrillary acidic protein and nerve growth factor in the hippocampus of rats with hyperlipidemia and middle cerebral artery thrombus

Electroacupuncture(EA)has been shown to reduce blood lipid level and improve cerebral ischemia in rats with hyperlipemia complicated by cerebral ischemia.However,there are few studies on the results and mechanism of the effect of EA in reducing blood lipid level or promoting neural repair after stroke in hyperlipidemic subjects.In this study,EA was applied to a rat model of hyperlipidemia and middle cerebral artery thrombosis and the condition of neurons and astrocytes after hippocampal injury was assessed.Except for the normal group,rats in other groups were fed a high-fat diet throughout the whole experiment.Hyperlipidemia models were established in rats fed a high-fat diet for 6 weeks.Middle cerebral artery thrombus models were induced by pasting 50%FeCl3 filter paper on the left middle cerebral artery for 20 minutes on day 50 as the model group.EA1 group rats received EA at bilateral ST40(Fenglong)for 7 days before the thrombosis.Rats in the EA1 and EA2 groups received EA at GV20(Baihui)and bilateral ST40 for 14 days after model establishment.Neuronal health was assessed by hematoxylin-eosin staining in the brain.Hyperlipidemia was assessed by biochemical methods that measured total cholesterol,triglyceride,low-density lipoprotein and high-density lipoprotein in blood sera.Behavioral analysis was used to confirm the establishment of the model.Immunohistochemical methods were used to detect the expression of glial fibrillary acidic protein and nerve growth factor in the hippocampal CA1 region.The results demonstrated that,compared with the model group,blood lipid levels significantly decreased,glial fibrillary acidic protein immunoreactivity was significantly weakened and nerve growth factor immunoreactivity was significantly enhanced in the EA1 and EA2 groups.The repair effect was superior in the EA1 group than in the EA2 group.These findings confirm that EA can reduce blood lipid,inhibit glial fibrillary acidic protein expression and promote nerve growth factor expression in the hippocampal CA1 region after hyperlipidemia and middle cerebral artery thrombosis.All experimental procedures and protocols were approved by the Animal Use and Management Committee of Beijing University of Chinese Medicine,China(approval No.BUCM-3-2018022802-1002)on April 12,2018.

Therapeutic potential of prophylactic exercise for intracerebral hemorrhage

Exercise and brain health:Physical activity helps promote and maintain our brain health,including memory and cognitive performance.Research has shown that exercise is a safe behavioral intervention that reduces the risk of hypokinetic diseases,such as hypertension,diabetes,and lipid metabolic disorders.In addition.

Motor tract reorganization after acute central nervous system injury: a translational perspective

Acute central nervous system injuries are among the most common causes of disability worldwide,with widespread social and economic implications.Motor tract injury accounts for the majority of this disability;therefore,there is impetus to understand mechanisms underlying the pathophysiology of injury and subsequent reorganization of the motor tract that may lead to recovery.After acute central nervous system injury,there are changes in the microenvironment and structure of the motor tract.For example,ischemic stroke involves decreased local blood flow and tissue death from lack of oxygen and nutrients.Traumatic injury,in contrast,causes stretching and shearing injury to microstructures,including myelinated axons and their surrounding vessels.Both involve blood-brain barrier dysfunction,which is an important initial event.After acute central nervous system injury,motor tract reorganization occurs in the form of cortical remapping in the gray matter and axonal regeneration and rewiring in the white matter.Cortical remapping involves one cortical region taking on the role of another.cAMP-response-element binding protein is a key transcription factor that can enhance plasticity in the peri-infarct cortex.Axonal regeneration and rewiring depend on complex cell-cell interactions between axons,oligodendrocytes,and other cells.The RhoA/Rho-associated coiled-coil containing kinase signaling pathway plays a central role in axon growth/regeneration through interactions with myelin-derived axonal growth inhibitors and regulation of actin cytoskeletal dynamics.Oligodendrocytes and their precursors play a role in myelination,and neurons are involved through their voltage-gated calcium channels.Understanding the pathophysiology of injury and the biology of motor tract reorganization may allow the development of therapies to enhance recovery after acute central nervous system injury.These include targeted rehabilitation,novel pharmacotherapies,such as growth factors and axonal growth inhibitor blockade,and the implementation of neurotechnologies,such as central nervous system stimulators and robotics.The translation of these advances depends on careful alignment of preclinical studies and human clinical trials.As experimental data mount,the future is one of optimism.

Single Nucleotide Polymorphisms in a Male Infertility-Related Gene CatSper

Objective To identify single nucleotide polymorphisms (SNPs) of human CatSper gene, themouse homologous gene product, which plays a crucial role in mouse male sterility.Methods We demonstrated a systematic screening of SNPs in coding regions and flankingintronic regions of human CatSper gene in a sample subset from a total 210 male individuals byDNA sequencing. Then we used PCR single-strand conformation polymorphism (SSCP) analy-sis to determine the allele frequencies of the possible SNPs among the whole 210 Chinese Hanmale individuals.Results Three SNPs, including two novels, were identified and their allele frequencies weredetermined in the 210 Chinese Han male individuals. These SNPs were assembled into largeSNP database that promises to enable the dissection of the genetic basis of disease.

Probiotic Therapy for Treating Behavioral and Gastrointestinal Symptoms in Autism Spectrum Disorder:A Systematic Review of Clinical Trials

The therapeutic potentials of probiotics in autism spectrum disorder(ASD)remains controversial,with the only existing systematic review on this topic published in 2015.Results from new trials have become available in recent years.We therefore conducted an updated systematic review,to assess the efficacy of probiotics in relieving behavioral symptoms of ASD and gastrointestinal comorbidities.Our review includes two randomized controlled trials,which showed improvement of ASD behaviors,and three open trials,all which exhibited a trend of improvement.Four of these trials concluded from subjective measures that gastrointestinal function indices showed a trend of improvement with probiotic therapy.Additional rigorous trials are needed to evaluate the effects of probiotic supplements in ASD.

Targeted principle component analysis:A new motion artifact correction approach for near-infrared spectroscopy

As near-infrared spectroscopy(NIRS)broadens its application area to diferent age and diseasegroups,motion artifacts in the NIRS signal due to subject movement is becoming an importantchallenge.Motion artifacts generally produce signal fiuctuations that are larger than physio-logical NIRS signals,thus it is cruciai to corect for them before obtaining an cstimate ofstimulusevoked hemodynamic responses.,There are various methods for correction such as principlecomponent analy sis(P CA),wavelet-based filt ering and spline int erpolation.Here,we introduce anew approach to motion artifact correction,targeted principle component analysis(PCA),which incorporates a PCA filter only on the segments of data identified as motion artifacts.Itis expected that this will overcome the issues of filtering desired signals that plagues standardPCA fitering of entire data sets.We compared the new approach with the most efiective motionartifact correction algorithms on a set of data acquired simultaneously with a collodion-fixedprobe(low motion artifact content)and a standard Velcro probe(high motion artifact content).Our results show that tPCA gives statistically better results in recovering hemodynamic responsefunction(HRF)as compared to wavelet-based fltering and spline interpolation for the Velcroprobe.It resulis in a significant reduction in mean-squauared'error(MSE)and significant en-hancement in Pearson's correlation coeficient to the true HRF,The collodion-fixed fiber probewith no motion correction performed better than the Velcro probe corrected for motion artifactsin terms of MSE and Pearson's correlation coefficient.Thus,if the experimental study permits,the use of a collodion-fixed fiber probe may be desirable.I the use of a collodion-fixed probe is notfeasible,then we suggest the use of tP CA in the processing of motion artifact contaminated data.

Hypo-Anxious Phenotype of Adolescent Offspring Prenatally Exposed to LPS Is Associated with Reduced mGluR5 Expression in Hippocampus

Many studies have reported long-term modulation of metabotropic glutamate receptor 5 (mGluR5) by inflammatory processes and a pharmacological modulation of mGluR5 is known to regulate anxiety level. However, it is not known if non-pharmacological modulation of mGluR5 by inflammation impaired the unconditional level of anxiety. In this study, we investigated this relation in LPS prenatal immune challenge (120 μg/kg, 3x i.p. injection in late gestation), a developmental model of neuroinflammation in which some studies have reported hypo-anxious phenotype. Using positron emission tomographic imaging (PET) approaches, we have demonstrated a decrease in the binding potential of [18F]fluoro-5-(2-pyridinylethynyl)benzonitrile([18F]FPEB, a radioligand for mGluR5) in hippocampus of adolescent offspring prenatally exposed to LPS, without significant change in the binding of [11C]peripheral benzodiazepine receptor 28 ([11C]PBR28), an inflammatory marker. In addition, dark-light box emergence test revealed a lower level of anxiety in LPS-exposed offspring and this behavioural phenotype was associated with the binding potential of [18F]FPEB in hippocampus. These results confirm that neuroinflammation during developmental phase modulates the physiology of mGluR5 and this alteration can be associated with behavioural phenotype related to anxiety. In addition, this study supports a hypotheses that mGluR5 could be used as a diagnostic target in anxiety.

Protective effects of organic extracts of Alpinia oxyphylla against hydrogen peroxide-induced cvtotoxicitv in PC12 cells

Alpinia oxyphylla,a traditional herb,is widely used for its neuroprotective,antioxidant and memory-improving effects.However,the neuroprotective mechanisms of action of its active ingredients are unclear.In this study,we investigated the neuroprotective effects of various organic extracts of Alpinia oxyphylla on PC12 cells exposed to hydrogen peroxide-induced oxidative injury in vitro.Alpinia oxyphylla was extracted three times with 95%ethanol(representing extracts 1–3).The third 95%ethanol extract was dried and resuspended in water,and then extracted successively with petroleum ether,ethyl acetate and n-butanol(representing extracts 4–6).The cell counting kit-8 assay and microscopy were used to evaluate cell viability and observe the morphology of PC12 cells.The protective effect of the three ethanol extracts(at tested concentrations of 50,100 and 200μg/mL)against cytotoxicity to PC12 cells increased in a concentration-dependent manner.The ethyl acetate,petroleum ether and n-butanol extracts(each tested at 100,150 and 200μg/mL)had neuroprotective effects as well.The optimum effective concentration ranged from 50–200μg/mL,and the protective effect of the ethyl acetate extract was comparatively robust.These results demonstrate that organic extracts of Alpinia oxyphylla protect PC12 cells against apoptosis induced by hydrogen peroxide.Our findings should help identify the bioactive neuroprotective components in Alpinia oxyphylla.

Electro-acupuncture therapy to improve spatial learning and memory in APPswe/ PS1dE9 transgenic mice through the inhibition of the TLR4/MyD88 signaling pathway

Objective:To determine whether electro-acupuncture (EA) therapy could improve the cognitive functions of amyloid precursor protein Swedish mutation (APPswe)/presenilin 1 deleted in exon 9 (PS1dE9) mice and examine whether EA treatment could attenuate neuroinflammation by targeting the toll-like receptor 4 (TLR4)/myeloid differentiation primary response factor 88 (MyD88) signaling pathway.Methods:Twenty-seven double transgenic APPswe/PS1dE9 mice were randomly allocated into three groups:an Alzheimer's disease model group (AD group),a medication group (M group) and an EA treatment group (EA group).Each group contained nine mice,and nine wild-type mice were used in a normal group (N group).The animals in the M group were treated with oral administrations of 0.92 mg/kg donepezil hydrochloride for 15 days.For animals in the EA group,EA treatments were used on the Yintang (GV 29) and Baihui (GV 20) acupoints for 20 minutes,and the Shuigou (GV 26) acupoint was pricked without needle retention following EA treatments.Following treatments,the spatial learning and memory of the mice were measured using the Morris water maze test.The expression levels of TLR4,MyD88,nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) were analyzed by immunohistochemical staining and western blot.Results:The escape latencies of the M and EA groups were significantly lower than those of the AD group (vs M,P =.002;vs EA,P <.001).Moreover,compared with the AD group,the numbers of platform crossings was higher (vs M,P =.038;vs EA,P =.008) and the latency time for target quadrants was longer (vs M,P =.002;vs EA,P =.001) in the M and EA groups (P <.05).Furthermore,in the M and EA groups,the expression levels of TLR4,MyD88,NF-κB and iNOS decreased significantly compared with those of the AD group (all P <.01).Conclusion:EA treatment enhanced the memory and learning abilities of APPswe/PS1dE9 mice by regulating the TLR4/MyD88 inflammatory signaling pathway.

Preclinical stem cell therapy in Chagas Disease: Perspectives for future research

Chagas cardiomyopathy still remains a challenging problem that is responsible for high morbidity and mortality in Central and Latin America. Chagas disease disrupts blood microcirculation via various autoimmune mechanisms, causing loss of cardiomyocytes and severe impairment of heart function. Different cell types and delivery approaches in Chagas Disease have been studied in both preclinical models and clinical trials. The main objective of this article is to clarify the reasons why the benefits that have been seen with cell therapy in preclinical models fail to translate to the clinical setting. This can be explained by crucial differences between the cellular types and pathophysiological mechanisms of the disease, as well as the differences between human patients and animal models. We discuss examples that demonstrate how the results from preclinical trials might have overestimated the efficacy of myocardial regeneration therapies. Future research should focus, not only on studying the best cell type to use but, very importantly, understanding the levels of safety and cellular interaction that can elicit efficient therapeutic effects in human tissue. Addressing the challenges associated with future research may ensure the success of stem cell therapy in improving preclinical models and the treatment of Chagas disease.

Do phagocytotic mechanisms regulate soluble factor secretion in microglia?

Microglia are responsible for phagocytosis in the brain:Phagocytosis,one of the major mechanisms of innate immune defense,is the process by which several types of cells in the immune system recognize,engulf,and digest large particles,such as pathogens and cell debris.In the brain,microglia play phagocytotic roles to regulate the micro-environment of brains under both physiological and pathological conditions.