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61.
Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina 总被引:5,自引:0,他引:5
Mansergh F Orton NC Vessey JP Lalonde MR Stell WK Tremblay F Barnes S Rancourt DE Bech-Hansen NT 《Human molecular genetics》2005,14(20):3035-3046
Retinal neural transmission represents a key function of the eye. Identifying the molecular components of this vital process is helped by studies of selected human genetic eye disorders. For example, mutations in the calcium channel subunit gene CACNA1F cause incomplete X-linked congenital stationary night blindness (CSNB2 or iCSNB), a human retinal disorder with abnormal electrophysiological response and visual impairments consistent with a retinal neurotransmission defect. To understand the subcellular basis of this retinal disorder, we generated a mouse with a loss-of-function mutation by inserting a self-excising Cre-lox-neo cassette into exon 7 of the murine orthologue, Cacna1f. Electroretinography of the mutant mouse revealed a scotopic a-wave of marginally reduced amplitude compared with the wild-type mouse and absence of the post-receptoral b-wave and oscillatory potentials. Cone ERG responses together with visual evoked potentials and multi-unit activity in the superior colliculus were also absent. Calcium imaging in Fluo-4 loaded retinal slices depolarized with KCl showed 90% less peak signal in the photoreceptor synapses of the Cacna1f mutant than in wild-type mice. The absence of post-receptoral ERG responses and the diminished photoreceptor calcium signals are consistent with a loss of Ca((2+)) channel function in photoreceptors. Immunocytochemistry showed no detectable Ca(v)1.4 protein in the outer plexiform layer of Cacna1f-mutant mice, profound loss of photoreceptor synapses, and abnormal dendritic sprouting of second-order neurons in the photoreceptor layer. Together, these findings in the Cacna1f-mutant mouse reveal that the Ca(v)1.4 calcium channel is vital for the functional assembly and/or maintenance and synaptic functions of photoreceptor ribbon synapses. Moreover, the outcome of this study provides critical clues to the pathophysiology of the human retinal channelopathy of X-linked incomplete CSNB. 相似文献
62.
Reciprocal effect of Waardenburg syndrome mutations on DNA binding by the Pax-3 paired domain and homeodomain 总被引:1,自引:1,他引:1
The Pax-3 protein contains two DNA-binding domains, a paired domain and a
homeodomain. Mutations in Pax-3 cause Waardenburg syndrome (WS) in humans
and the mouse Splotch (Sp) phenotype. In the Sp-delayed mouse, a mutation
in the Pax-3 paired domain (G9R) abrogates the DNA-binding activity of both
the paired domain and the homeodomain, suggesting that they may
functionally interact. To investigate this possibility further, we have
analyzed the DNA-binding properties of additional point mutants in the
Pax-3 paired domain and homeodomain that occur in WS patients (F12L, N14H,
G15S, P17L, R23L, G48A, S51F and G66D in the paired domain, V47F and R53G
in the homeodomain), the Pax-1 un mutation (G15A) and a substitution
associated with Peters' anomaly in the PAX-6 gene (R23G). Within the paired
domain, seven of 10 mutations were found to abrogate DNA-binding by the
paired domain. Remarkably, these seven mutations also affected DNA binding
by the homeodomain, causing either a complete loss (P17L and G66D), a
reduction (R23G, R23L, G15S and G15A) or an increase in DNA-binding
activity (N14H). In addition, the effect of paired domain mutations
occurred at the level of monomer formation by the homeodomain, while the
dimerization potential of this domain seemed unaffected in mutants where it
could be analyzed. Furthermore, while both homeodomain mutations were found
to abolish DNA binding by this domain, the R53G mutation also abrogated DNA
binding by the paired domain. The important observation that independent
mutations in either domain can affect DNA binding by the other in the
intact Pax- 3 protein strongly suggests that the two domains are not
functionally independent but bind DNA through cooperative interactions.
Modeling the deleterlous mutations on the three-dimensional structure of
the paired domain of Drosophila Prd shows that these mutations cluster at
the DNA interface, thus suggesting that a series of DNA contacts are
essential for DNA binding by both the paired domain and the homeodomain of
Pax-3.
相似文献
63.
Annie Britton Beverly Milne Therese Butler Adelaida Sanchez-Galvez Martin Shipley Anthony Rudd Charles DA Wolfe Ajay Bhalla Eric J Brunner 《BMC medical research methodology》2012,12(1):1-5
Background
Quantiles are a staple of epidemiologic research: in contemporary epidemiologic practice, continuous variables are typically categorized into tertiles, quartiles and quintiles as a means to illustrate the relationship between a continuous exposure and a binary outcome.Discussion
In this paper we argue that this approach is highly problematic and present several potential alternatives. We also discuss the perceived drawbacks of these newer statistical methods and the possible reasons for their slow adoption by epidemiologists.Summary
The use of quantiles is often inadequate for epidemiologic research with continuous variables. 相似文献64.
65.
66.
L.E. Downie K. Vessey A. Miller M.M. Ward M.J. Pianta A.J. Vingrys J.L. Wilkinson-Berka E.L. Fletcher 《Neuroscience》2009
The bio-active peptide, angiotensin II (Ang II), has been suggested to exert a neuromodulatory effect on inner retinal neurons. In this study, we examined the distribution of angiotensin receptors (ATRs) in the developing and mature rat retina and optic nerve using immunofluorescence immunocytochemistry. Double-labeling experiments were performed with established markers to identify different retinal cell populations. In adult retinae, ATRs were observed on neurons involved in “ON” pathways of neurotransmission. Angiotensin II type 1 receptors (AT1Rs) were expressed by a sub-population of “ON” cone bipolar cells that also labeled for Gα0 and islet-1. Extra-neuronal expression of AT1Rs was evident on retinal astrocytes, Müller cells and blood vessels. Immunoreactivity for the angiotensin II type 2 receptor (AT2R) was observed on conventional and displaced GABAergic amacrine cells. Co-localization studies showed that AT2R-expressing amacrine cells constituted at least two separate sub-populations. Cell counts revealed that all wide-field amacrine cells expressing protein kinase C-alpha were also AT2R-positive; a further subset of amacrine cells expressing AT2Rs and stratifying in sublamina “b” of the inner plexiform layer (IPL) was identified. Developmental expression of AT1Rs was dynamic, involving multiple inner neuronal classes. At postnatal day 8 (P8), AT1R immunoreactivity was observed on putative ganglion cells. The characteristic bipolar cell labeling observed in adults was not evident until P13. In contrast, AT2Rs were detected as early as P2 and localized specifically to amacrine cells from this age onward. These data provide further evidence for the potential role of angiotensin II in the modulation of retinal neurons and glia. The differential pattern of expression of these receptors across these cell types is similar to that observed in the brain and suggests that a similar functional role for Ang II may also exist within the retina. 相似文献
67.
目的:观察槲皮素(quercetin)体外对肝癌SMMC-7721细胞的生长抑制和诱导凋亡作用,并探讨线粒体在诱导凋亡机制中的作用。方法:以10、30、60和100μmol/L槲皮素作用于体外培养的SMMC-7721细胞,MTT法检测细胞生长抑制率;Annexi-V/PI双染流式细胞仪检测细胞凋亡情况;吖啶橙(acridine or-ange,AO)染色法观察细胞凋亡时形态变化;JC-1染色法检测细胞线粒体膜电位(mitochondrial membrane potential)变化。结果:槲皮素体外能抑制肝癌SMMC-7721细胞的生长(P<0.01),诱导细胞发生凋亡,并呈现量效和时效关系。10、30、60和100μmol/L槲皮素作用72h引起的细胞抑制率(F=343.71,P<0.01)和凋亡率(F=234.17,P<0.01)明显高于对照组。槲皮素作用48h后,AO染色图片可见细胞膜呈泡状膨出和凋亡小体等。凋亡过程中线粒体膜电位下降。结论:槲皮素体外能抑制肝癌SMMC-7721细胞生长,诱导细胞凋亡发生,线粒体膜电位下降在细胞凋亡过程中可能起到重要作用。 相似文献
68.
Peripheral nerve disorders may be classified into compressive or entrapment neuropathies and non‐compressive neuropathies. Muscle denervation recognized on MRI may be a useful sign in the diagnosis of peripheral nerve disorders. Acute or subacute denervation results in prolonged T2 relaxation time, producing increased signal in skeletal muscle on short tau inversion‐recovery and fat‐suppressed T2‐weighted images. Chronic denervation produces fatty atrophy of skeletal muscles, resulting in increased muscle signal on T1‐weighted images. This review will outline and illustrate the various ways that muscle denervation as seen on MRI may assist in the diagnosis and localization of peripheral nerve disorders. 相似文献
69.
以肺癌病理案例和语义网络技术为基础,结合了统一医学语言系统(UMLS),研究探讨了语义网络技术在电子病历中的实际应用,并最终实现了加入时序性特征的病理案例语义网络的表示。 相似文献
70.