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可羅素蛋白調控心肌細胞鈣離子恆定與電生理重塑

為了解決Ar js change model的問題，作者洪元 這樣論述：

前言:心房顫動(atrial fibrillation, AF)是一種常見的心律不整，會增加不良心血管事件的風險，例如心衰竭和中風。肺靜脈(pulmonary vein, PV)是誘發AF 異位搏動的重要來源。一些病生理狀況，如衰老、發炎、高血壓、冠狀動脈疾病、心衰竭和慢性腎臟病(chronic kidney disease, CKD)，可能導致細胞內鈣離子調控出現異常和結構重塑，導致AF的發生。可羅素蛋白(Klotho)是一種多功能蛋白，具有顯著的心血管作用，在CKD患者中血清裡的Klotho濃度較低。流行病學研究報導，較高的血清Klotho濃度與較少的AF 發生有關，而較低的血清Klot

ho濃度與終末期腎病患者的AF 發生相關。然而，關於Klotho在AF病理生理學中的作用並未被廣泛研究。磷酸肌醇3-激酶(phosphoinositide 3-kinases, PI3K)是脂質激酶，而PI3K可以透過活化下游Akt等其他訊息傳遞路徑來調節鉀離子、鈉離子和鈣離子通道，在心肌細胞的心律不整中扮演至關重要的角色。部分研究顯示Klotho可以調控PI3K-Akt路徑改變細胞表現與離子流變化。目的:在這項研究中，我們假設Klotho可能透過PI3K-Akt訊息傳遞路徑調節離子電流和鈣離子恆定來調節PV 電生理特性，且這反應在CKD 的兔子中可能更為顯著。材料方法:我們使用傳統的微電極和

全細胞膜片鉗技術來研究Klotho給藥前後大白兔PV心肌組織和單一心肌細胞的動作電位和離子電流。並使用西方點墨法研究了PI3K-Akt訊息傳遞路徑。結果:Klotho在較高濃度（1.0 和 3.0 ng/mL）下顯著降低了PV組織的異位節律自動跳頻率。在存在Akt抑制劑(10 uM)的情況下，Klotho(1.0 和3.0 ng/mL)不會改變PV電生理活動。Klotho(1.0 ng/mL)顯著降低晚鈉離子電流(INa-Late)和L型鈣電流(ICa-L)，與 Akt 抑制劑(10 uM) 相似。西方點墨法顯示，與未經Klotho處理的心肌細胞相比，經Klotho (1.0 ng/mL)處理

的PV心肌細胞的Akt(Ser473)磷酸化較少。 與對照PV相比，低濃度（0.1 和0.3 ng/mL）的Klotho顯著降低了CKD PV的自動跳頻率並降低了去極化後延遲的幅度。結論:Klotho透過抑制PI3K-Akt訊息傳遞路徑來調節離子電流與改變PV 組織電生理活動，這些作用在CKD 組中比對照組更為明顯。這些發現可能為CKD誘導的心律不整發生提供新的見解。

探討在神經退化性疾病中調控核醣核酸結合蛋白MBNL2表現之機轉

為了解決Ar js change model的問題，作者王李馨 這樣論述：

中文摘要 iAbstract iiContents iiiIntroduction 1Myotonic dystrophy type 1 (DM1) 1Cerebral involvement of adult-onset DM1 2Genetic basis of DM1 4Molecular mechanism in DM1 4Mouse models of DM1 with expression of CUG repeats 6RNA-binding protein: Muscleblind-like (MBNL) family

8MBNL1 and MBNL2 knockout mice 9Calcium-dependent cysteine protease: Calpain 11Calpain-1 and -2 11Calpain-1 and -2 deficient mice 12Calpain-1 and -2 in neurodegeneration 13Alzheimer’s disease (AD) 14Disease stages of AD 14Clinical presentations of AD 15Brain atrophy of AD

15Two pathological hallmarks of AD 16The aims of the study 20Materials and methods 211. Animals 212. Primary hippocampal neuron culture, drug treatment, virus infection and transfection 213. Cell culture and transient transfection 234. Total protein extraction and sub

cellular fractionation 245. Immunoprecipitation (IP) 256. Immunoblotting analysis 257. RNA preparation, RT-PCR and splicing analysis 268. Immunofluorescence staining and immunohistochemistry 279. Quantification of fluorescent images of brain sections 2910. Quantif

ication of fluorescent images of neurons 3011. Antibodies 3012. Plasmids 3113. Statistical analysis 31Results 331. Characterize the role of MBNL2 in neuronal maturation1.1. MBNL2 is expressed postnatally and increased as neuronal maturation 331.2. MBNL2 expression

is required for promoting adult pattern of RNA processingand neuronal differentiation 342. Determine how neurodegenerative conditions reduce MBNL2 expression2.1. Glutamate-induced excitotoxicity reduces MBNL2 protein expression viaNMDAR activation 352.2. NMDAR-mediated Calpain-2 acti

vation causes MBNL2 protein degradation 362.3. Calcium-dependent nuclear translocation of CAPN2 is associated with reducedMBNL2 expression 382.4. Dysregulated calcium homeostasis reduces MBNL2 expression 392.5. Enhanced nuclear translocation of CAPN2 occurs in the EpA960/CamKII-Cre

brain 402.6. Enhanced nuclear translocation of CAPN2 in neurodegeneration recapitulates thefetal developmental pattern 413. Explore the possibility of the reduced MBNL2 expression associated re-induced fetalpattern of RNA processing as a common feature among neurodegenerative disorders3.

1. Enhanced nuclear translocation of CAPN2, reduced MBNL2 expression and associated aberrant MBNL2-regulated alternative splicing in the degenerative brains of AD 41Discussion 44Perspective 48References 49List of figuresFigure 1. MBNL2 is expressed postnatally and increased with bra

in maturation 64Figure 2. MBNL2 is expressed in the more differentiated cells during hippocampusmaturation 65Figure 3. MBNL2 is expressed ubiquitously in the adult mouse brain 66Figure 4. MBNL2 is expressed in the neurons, oligodendrocytes and astrocytes 67Figure 5. The knockdown

efficiency of MBNL2 shRNAs in cultured neurons 68Figure 6. The alternative splicing and polyadenylation of MBNL2 targets show a fetal to adult transition during neuronal differentiation 70Figure 7. MBNL2 depletion disrupts the developmental RNA processing transition in cultured neurons

71Figure 8. MBNL2 depletion impairs dendrite maturation in cultured neurons 72Figure 9. Glutamate treatment induces excitotoxicity in mature cultured neurons showing condensed nucleus 74Figure 10. Glutamate-induced excitotoxicity reduces MBNL2 protein level in mature cultured neurons 75

Figure 11. Glutamate reduces MBNL2 level via NMDAR activation in cultured neurons 77Figure 12. NMDAR-mediated MBNL2 reduction is calcium dependent 78Figure 13. The alternative splicing and polyadenylation of MBNL2 targets are disrupted in neurons treated with glutamate or NMDA 79Figure 14.

MBNL2 mRNA level is unchanged in cultured neurons treated with glutamate or NMDA 81Figure 15. MBNL2 protein is stable in the neurons 82Figure 16. NMDAR signaling-mediated MBNL2 reduction requires calpain activity incultured neurons 83Figure 17. Protein expression of CAPN1 and CAPN2 are alte

red in NMDA-treatedneurons 84Figure 18. MBNL2 binds to both CAPN1 and CAPN22 in HEK293 cells 85Figure 19. Knockdown efficiency of CAPN1 or CAPN2 shRNAs in neurons 86Figure 20. NMDAR-mediated calpain-2 activation causes MBNL2 degradation inneurons 87Figure 21. Depletion of CAPN2 preserves

MBNL2-regulated alternative splicing andpolyadenylation in neurons upon NMDA treatment 88Figure 22. CAPN2 is predominantly expressed in the cytoplasm of mature neurons 90Figure 23. NMDA treatment induces the nuclear translocation of CAPN2 in neurons 91Figure 24. NMDAR-mediated MBNL2 reduct

ion requires calpain-2 expression in thenucleus and cytoplasm of neurons 92Figure 25. NMDA-induced nuclear translocation of CAPN2 requires calcium 93Figure 26. Nuclear translocation of CAPN2 involves in MBNL2 degradation 94Figure 27. Dysregulated calcium homeostasis induces the nuclear tran

slocation of CAPN2 and reduced MBNL2 expression in neurons 95Figure 28. CAPN2 depletion preserves MBNL2 expression in the neurons with dysregulated calcium homeostasis 96Figure 29. Effect of CAPN2 depletion on the RNA processing pattern of MBNL2 targets in A23187-treated neurons 97Figure 30

. CAPN2 nuclear translocation is occurred in the EpA960/CaMKII-Cre mouse brains 98Figure 31. Nuclear-to-cytoplasmic distribution of CAPN2 during neuronal differentiation 99Figure 32. Nuclear translocation of CAPN2 occurs in the APP/PS1 and THY-Tau22brains 100Figure 33. Reduced MBNL2 express

ion in the APP/PS1 and THY-Tau22 brains 101Figure 34. Aberrant MBNL2-regulated alternative splicing in the APP/PS1 and THY-Tau22 brains 102