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1.
Mutations in CTC1 lead to the telomere syndromes Coats Plus and dyskeratosis congenita (DC), but the molecular mechanisms involved remain unknown. CTC1 forms with STN1 and TEN1 a trimeric complex termed CST, which binds ssDNA, promotes telomere DNA synthesis, and inhibits telomerase-mediated telomere elongation. Here we identify CTC1 disease mutations that disrupt CST complex formation, the physical interaction with DNA polymerase α-primase (polα-primase), telomeric ssDNA binding in vitro, accumulation in the nucleus, and/or telomere association in vivo. While having diverse molecular defects, CTC1 mutations commonly lead to the accumulation of internal single-stranded gaps of telomeric DNA, suggesting telomere DNA replication defects as a primary cause of the disease. Strikingly, mutations in CTC1 may also unleash telomerase repression and telomere length control. Hence, the telomere defect initiated by CTC1 mutations is distinct from the telomerase insufficiencies seen in classical forms of telomere syndromes, which cause short telomeres due to reduced maintenance of distal telomeric ends by telomerase. Our analysis provides molecular evidence that CST collaborates with DNA polα-primase to promote faithful telomere DNA replication. 相似文献
2.
Claudia Eliza Patrocinio de Oliveira Osvaldo Costa Moreira Zoila Marilú Carrión-Yagual Carlos Medina-Pérez José Antonio de Paz 《Archives of physical medicine and rehabilitation》2018,99(5):819-825
Objective
To compare the effects of classic progressive resistance training (PRT) versus eccentric strength-enhanced training (EST) on the performance of functional tests and different strength manifestations in the lower limb of people with multiple sclerosis (PwMS).Design
Experimental trial.Setting
Strength training program.Participants
PwMS (N=52; 19 men, 33 women) belonging to MS associations from the Castilla y León, Spain.Interventions
Participants were assigned to 1 of 2 groups: a control group that performed PRT or an experimental group that performed EST. In both groups, the knee extensor muscles were trained for 12 weeks.Main Outcome Measures
Before and after 12 weeks of training, maximal voluntary isometric contraction and 1 repetition maximum (1RM) of the knee extensors were evaluated, as were the Chair Stand Test (CST) and Timed 8-Foot Up and Go (TUG) functional tests.Results
No differences were found between the groups in the initial values for different tests. Intragroup comparisons found significant differences in CST (F=69.4; P<.001), TUG (F=40.0; P<.001), and 1RM (F=57.8; P<.001). For intergroup comparisons, EST presented better results than PRT in the CST (EST, 4.7%±2.8%; PRT, 1.9%±2.8%; F=13.1; P=.001) and TUG (EST, ?2.9±4.7; PRT, ?.41±5.6; F=5.6; P=.022).Conclusions
In PwMS, EST leads to improvements in 1RM, TUG, and CST that are similar to those of PRT. However, for patients who participated in this study, the EST seems to promote a better transfer of strength adaptations to the functional tests, which are closer to daily-living activities. 相似文献3.
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Variable laterality of corticospinal tract axons that regenerate after spinal cord injury as a result of PTEN deletion or knock‐down
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Rafer Willenberg Katherine Zukor Kai Liu Zhigang He Oswald Steward 《The Journal of comparative neurology》2016,524(13):2654-2676
Corticospinal tract (CST) axons from one hemisphere normally extend and terminate predominantly in the contralateral spinal cord. We previously showed that deleting the gene phosphatase and tensin homolog (PTEN) in the sensorimotor cortex enables CST axons to regenerate after spinal cord injury and that some regenerating axons extend along the “wrong” side. Here, we characterize the degree of specificity of regrowth in terms of laterality. PTEN was selectively deleted via cortical adeno‐associated virus (AAV)‐Cre injections in neonatal PTEN‐floxed mice. As adults, mice received dorsal hemisection injuries at T12 or complete crush injuries at T9. CST axons from one hemisphere were traced by unilateral biotinylated dextran amine (BDA) injections in PTEN‐deleted mice with spinal cord injury and in noninjured PTEN‐floxed mice that had not received AAV‐Cre. In noninjured mice, 97.9 ± 0.7% of BDA‐labeled axons in white matter and 88.5 ± 1.0% of BDA‐labeled axons in gray matter were contralateral to the cortex of origin. In contrast, laterality of CST axons that extended past a lesion due to PTEN deletion varied across animals. In some cases, regenerated axons extended predominantly on the ipsilateral side; in other cases, axons extended predominantly contralaterally, and in others, axons were similar in numbers on both sides. Similar results were seen in analyses of cases from previous studies using short hairpin (sh)RNA‐mediated PTEN knock‐down. These results indicate that CST axons that extend past a lesion due to PTEN deletion or knock‐down do not maintain the contralateral rule of the noninjured CST, highlighting one aspect of how the resultant circuitry from regenerating axons may differ from that of the uninjured CST. J. Comp. Neurol. 524:2654–2676, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
6.
背景:基底核区出血性和缺血性病变,最容易造成相邻皮质脊髓束损伤,从而导致肢体运动功能程度障碍。功能磁共振扩散张量成像技术能真实有效地显示脑内白质结构,尤其是发生病变时,相邻和相关的白质纤维结构受到不同程度的影响和破坏,以扩散张量成像的各向异性指数最为敏感。
目的:应用扩散张量成像技术评估左侧基底核缺血性和出血性病变对皮质脊髓束通路的影响,并比较两种情况下皮质脊髓束通路各向异性指数的差异。
设计、时间及地点:对比观察,于2005-10/2008-12在昆明医学院第一附属医院磁共振室完成。
对象:左侧基底核出血患者20例,左侧基底核缺血性病变患者27例。
方法:利用GE 1.5T扫描仪及SUN工作站行全脑数据收集和后处理,在各向异性指数图像上分别测量延髓、脑桥、大脑脚、基底核、放射冠及半卵圆中心等层面的皮质脊髓束通路走行区各向异性指数的测量。兴趣区大小的确定由个体纤维束轴位图上其结构所决定,以不超出该结构的范围、同时有2人对兴趣区大小进行肯定为准。
主要观察指标:常规磁共振明确基底核区出血和缺血性病变患者,采集扩散张量成像数据并在工作站的扩散张量成像软件进行皮质脊髓束走行区域各向异性指数测量和分析。
结果:左侧基底核区的出血、缺血性病变对左侧皮质脊髓束通路各个水平层面结构的影响程度不同,其各向异性指数的统计学分析,α=0.05。缺血及出血性病变患者延髓水平皮质脊髓束的各向异性指数差异无显著性意义(P=0.05);脑桥水平直至半卵圆中心各层皮质脊髓束的各向异性指数差异有显著性意义(P < 0.001);尤其是基底核层面和放射冠层面的P值最小,又以放射冠层面最明显。
结论:扩散张量成像结果显示,基底核区缺血性病变对大脑脚层面及其以上的皮质脊髓束的影响较出血性病变大。 相似文献
7.
Kyle M. Walsh Veryan Codd Terri Rice Christopher P. Nelson Ivan V. Smirnov Lucie S. McCoy Helen M. Hansen Edward Elhauge Juhi Ojha Stephen S. Francis Nils R. Madsen Paige M. Bracci Alexander R. Pico Annette M. Molinaro Tarik Tihan Mitchel S. Berger Susan M. Chang Michael D. Prados Robert B. Jenkins Joseph L. Wiemels ENGAGE Consortium Telomere Group Nilesh J. Samani John K. Wiencke Margaret R. Wrensch 《Oncotarget》2015,6(40):42468-42477
Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82×10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48×10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83×10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis. 相似文献
8.
Spontaneous functional recovery following injury to the adult central nervous system can be enhanced with increased and focused activity, either through altered behaviour (skill learning, exercise or training) or by artificial stimulation (magnetic or electrical). In terms of training, the choice of paradigm plays a key role in the recovered behaviour. Here we show that task-specific training leads to improved forelimb function that can be translated to a novel forelimb task. Adult Long–Evans rats received a unilateral pyramidotomy and we studied the effects of different post-lesion training paradigms for their ability to recover function in the impaired limb. We trained rats on either the single pellet grasping or the horizontal ladder task. Rats were tested on both tasks regardless of the training paradigm and also on a related, but novel forelimb task, the Staircase. Horizontal ladder training led to full recovery of this task, and also limited recovery on the familiar but untrained single pellet grasping task. In comparison, single pellet grasping training led to a smaller improvement on the horizontal ladder, but interestingly the same degree of recovery on the single pellet grasping task as horizontal ladder trained animals. Both training groups performed equally well on a novel, untrained forelimb grasping task. These results show that task-specific forelimb training can lead to functional recovery also in non-trained, complex, forelimb movements. Anatomically, only single pellet grasping training was associated with enhanced sprouting of the intact corticospinal tract across the cervical spinal cord midline to innervate the denervated side of the spinal cord. 相似文献
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