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911.
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913.
Johan Simonsson Karl Keijzer Theres Sdereld Angelica Forsberg 《Journal of clinical nursing》2020,29(9-10):1614-1622
914.
Michael J. Power Luke E. Rogerson Timm Schubert Philipp Berens Thomas Euler François Paquet-Durand 《The Journal of comparative neurology》2020,528(7):1113-1139
Calcium (Ca2+) dysregulation has been linked to neuronal cell death, including in hereditary retinal degeneration. Ca2+ dysregulation is thought to cause rod and cone photoreceptor cell death. Spatial and temporal heterogeneities in retinal disease models have hampered validation of this hypothesis. We examined the role of Ca2+ in photoreceptor degeneration, assessing the activation pattern of Ca2+-dependent calpain proteases, generating spatiotemporal maps of the entire retina in the cpfl1 mouse model for primary cone degeneration, and in the rd1 and rd10 models for primary rod degeneration. We used Gaussian process models to distinguish the temporal sequences of degenerative molecular processes from other variability sources.In the rd1 and rd10 models, spatiotemporal pattern of increased calpain activity matched the progression of primary rod degeneration. High calpain activity coincided with activation of the calpain-2 isoform but not with calpain-1, suggesting differential roles for both calpain isoforms. Primary rod loss was linked to upregulation of apoptosis-inducing factor, although only a minute fraction of cells showed activity of the apoptotic marker caspase-3. After primary rod degeneration concluded, caspase-3 activation appeared in cones, suggesting apoptosis as the dominant mechanism for secondary cone loss. Gaussian process models highlighted calpain activity as a key event during primary rod photoreceptor cell death. Our data suggest a causal link between Ca2+ dysregulation and primary, nonapoptotic degeneration of photoreceptors and a role for apoptosis in secondary degeneration of cones, highlighting the importance of the spatial and temporal location of key molecular events, which may guide the evaluation of new therapies. 相似文献
915.
Daisuke Ishibashi Takeshi Ishikawa Satoshi Mizuta Hiroya Tange Takehiro Nakagaki Tsuyoshi Hamada Noriyuki Nishida 《Neurotherapeutics》2020,17(4):1836
The accumulation of abnormal prion protein (PrPSc) produced by the structure conversion of PrP (PrPC) in the brain induces prion disease. Although the conversion process of the protein is still not fully elucidated, it has been known that the intramolecular chemical bridging in the most fragile pocket of PrP, known as the “hot spot,” stabilizes the structure of PrPC and inhibits the conversion process. Using our original structure-based drug discovery algorithm, we identified the low molecular weight compounds that predicted binding to the hot spot. NPR-130 and NPR-162 strongly bound to recombinant PrP in vitro, and fragment molecular orbital (FMO) analysis indicated that the high affinity of those candidates to the PrP is largely dependent on nonpolar interactions, such as van der Waals interactions. Those NPRs showed not only significant reduction of the PrPSc levels but also remarkable decrease of the number of aggresomes in persistently prion-infected cells. Intriguingly, treatment with those candidate compounds significantly prolonged the survival period of prion-infected mice and suppressed prion disease-specific pathological damage, such as vacuole degeneration, PrPSc accumulation, microgliosis, and astrogliosis in the brain, suggesting their possible clinical use. Our results indicate that in silico drug discovery using NUDE/DEGIMA may be widely useful to identify candidate compounds that effectively stabilize the protein.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00903-9) contains supplementary material, which is available to authorized users. 相似文献
916.
917.
918.
Zhipeng Cao Xinqiang Yan John C. Gore William A. Grissom 《Magnetic resonance in medicine》2020,83(6):2331-2342
919.
Michael Loecher Matthew J. Middione Daniel B. Ennis 《Magnetic resonance in medicine》2020,84(6):3234-3245
920.
Age estimation of cadavers from post-mortem “chest plate” using conventional radiography, which involves radiographic assessment of ossification around the sternum and rib ends, has been evaluated without fruitful results. This study examined the value of images of the chest plate obtained by three-dimensional post-mortem CT for estimation of age at time of death in a Japanese population. Five chest plate ossification scores were evaluated in 320 subjects, including ossification of the first costal cartilage (OF), ossification of the second to seventh costal cartilages at the rib (OR) and sternal (OS) ends, fusion of the manubriosternal joint (FM), and fusion of the xiphisternal joint (FX). OS was found to have the highest correlation with age while FM had no significant correlation. The best composite score for age estimation was the summative score for both sides of the OS and the right side of the OF and FX, for which the coefficient of determination (R2) and the standard error of estimation (SEE) were 0.608 and 12.44 years, respectively, for men and 0.590 and 14.65 years for women. The accuracy of the model was tested in a further 26 male and 24 female subjects, and the accuracy rate within the first SEE was 57.69% and 70.83%, respectively. This rapid and non-invasive method of age estimation in the chest plate area is superior to conventional methods and could be useful for estimation of age at time of death in the Japanese population. 相似文献