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排序方式: 共有160条查询结果,搜索用时 15 毫秒
1.
Yurii S. Borovikov Daria D. Andreeva Stanislava V. Avrova Vladimir V. Sirenko Armen O. Simonyan Charles S. Redwood Olga E. Karpicheva 《International journal of molecular sciences》2021,22(12)
Point mutations in the genes encoding the skeletal muscle isoforms of tropomyosin can cause a range of muscle diseases. The amino acid substitution of Arg for Pro residue in the 90th position (R90P) in γ-tropomyosin (Tpm3.12) is associated with congenital fiber type disproportion and muscle weakness. The molecular mechanisms underlying muscle dysfunction in this disease remain unclear. Here, we observed that this mutation causes an abnormally high Ca2+-sensitivity of myofilaments in vitro and in muscle fibers. To determine the critical conformational changes that myosin, actin, and tropomyosin undergo during the ATPase cycle and the alterations in these changes caused by R90P replacement in Tpm3.12, we used polarized fluorimetry. It was shown that the R90P mutation inhibits the ability of tropomyosin to shift towards the outer domains of actin, which is accompanied by the almost complete depression of troponin’s ability to switch actin monomers off and to reduce the amount of the myosin heads weakly bound to F-actin at a low Ca2+. These changes in the behavior of tropomyosin and the troponin–tropomyosin complex, as well as in the balance of strongly and weakly bound myosin heads in the ATPase cycle may underlie the occurrence of both abnormally high Ca2+-sensitivity and muscle weakness. BDM, an inhibitor of myosin ATPase activity, and W7, a troponin C antagonist, restore the ability of tropomyosin for Ca2+-dependent movement and the ability of the troponin–tropomyosin complex to switch actin monomers off, demonstrating a weakening of the damaging effect of the R90P mutation on muscle contractility. 相似文献
2.
The actin containing tropomyosin and troponin decorated thin filaments form one of the crucial components of the contractile apparatus in muscles. The thin filaments are organized into densely packed lattices interdigitated with myosin-based thick filaments. The crossbridge interactions between these myofilaments drive muscle contraction, and the degree of myofilament overlap is a key factor of contractile force determination. As such, the optimal length of the thin filaments is critical for efficient activity, therefore, this parameter is precisely controlled according to the workload of a given muscle. Thin filament length is thought to be regulated by two major, but only partially understood mechanisms: it is set by (i) factors that mediate the assembly of filaments from monomers and catalyze their elongation, and (ii) by factors that specify their length and uniformity. Mutations affecting these factors can alter the length of thin filaments, and in human cases, many of them are linked to debilitating diseases such as nemaline myopathy and dilated cardiomyopathy. 相似文献
3.
Sandra Brasil Mariateresa Allocca Salvador C. M. Magrinho Inês Santos Madalena Raposo Rita Francisco Carlota Pascoal Tiago Martins Paula A. Videira Florbela Pereira Giuseppina Andreotti Jaak Jaeken Kristin A. Kantautas Ethan O. Perlstein Vanessa dos Reis Ferreira 《International journal of molecular sciences》2022,23(15)
Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid glycosylation and glycosylphosphatidylinositol anchor biosynthesis. The (re)use of known drugs for novel medical purposes, known as drug repositioning, is growing for both common and rare disorders. The latest innovation concerns the rational search for repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, drug repositioning accelerates the overall drug discovery process while saving costs. This is particularly valuable for rare diseases. AI tools have proven their worth in diagnosis, in disease classification and characterization, and ultimately in therapy discovery in rare diseases. The availability of biomarkers and reliable disease models is critical for research and development of new drugs, especially for rare and heterogeneous diseases such as CDG. This work reviews the literature related to repositioned drugs for CDG, discovered by serendipity or through a systemic approach. Recent advances in biomarkers and disease models are also outlined as well as stakeholders’ views on AI for therapy discovery in CDG. 相似文献
4.
Dilatation of the aorta is a constantly evolving condition that can lead to the ultimate life-threatening event, acute aortic dissection. Recent research has tried to identify quantifiable biomarkers, with both diagnostic and prognostic roles in different aortopathies. Most studies have focused on the bicuspid aortic valve, the most frequent congenital heart disease (CHD), and majorly evolved around matrix metalloproteinases (MMPs). Other candidate biomarkers, such as asymmetric dimethylarginine, soluble receptor for advanced glycation end-products or transforming growth factor beta have also gained a lot of attention recently. Most of the aortic anomalies and dilatation-related studies have reported expression variation of tissular biomarkers. The ultimate goal remains, though, the identification of biomarkers among the serum plasma, with the upregulation of circulating MMP-1, MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), asymmetric dimethylarginine (ADMA), soluble receptor for advanced glycation end-products (sRAGE) and transforming growth factor beta (TGF-β) being reported in association to several aortopathies and related complications in recent research. These molecules are apparently quantifiable from the early ages and have been linked to several CHDs and hereditary aortopathies. Pediatric data on the matter is still limited, and further studies are warranted to elucidate the role of plasmatic biomarkers in the long term follow-up of potentially evolving congenital aortopathies. 相似文献
5.
6.
Barbara Eleni Rosato Roberta Marra Vanessa DOnofrio Federica Del Giudice Simone Della Monica Achille Iolascon Immacolata Andolfo Roberta Russo 《International journal of molecular sciences》2022,23(3)
Biallelic pathogenic variants in the SEC23B gene cause congenital dyserythropoietic anemia type II (CDA II), a rare hereditary disorder hallmarked by ineffective erythropoiesis, hemolysis, erythroblast morphological abnormalities, and hypo-glycosylation of some red blood cell membrane proteins. Abnormalities in SEC23B, which encodes the homonymous cytoplasmic COPII (coat protein complex II) component, disturb the endoplasmic reticulum to Golgi trafficking and affect different glycosylation pathways. The most harmful complication of CDA II is the severe iron overload. Within our case series (28 CDA II patients), approximately 36% of them exhibit severe iron overload despite mild degree of anemia and slightly increased levels of ERFE (the only erythroid regulator of hepcidin suppression). Thus, we hypothesized a direct role of SEC23B loss-of-function in the pathomechanism of hepatic iron overload. We established a hepatic cell line, HuH7, stably silenced for SEC23B. In silenced cells, we observed significant alterations of the iron status, due to both the alteration in BMP/SMADs pathway effectors and a reduced capability to sense BMP6 stimulus. We demonstrated that the loss-of-function of SEC23B is responsible of the impairment in glycosylation of the membrane proteins involved in the activation of the BMP/SMADs pathway with subsequent hepcidin suppression. Most of these data were confirmed in another hepatic cell line, HepG2, stably silenced for SEC23B. Our findings suggested that the pathogenic mechanism of iron overload in CDA II is associated to both ineffective erythropoiesis and to a specific involvement of SEC23B pathogenic variants at hepatic level. Finally, we demonstrated the ability of SEC23B paralog, i.e., SEC23A, to rescue the hepcidin suppression, highlighting the functional overlap between the two SEC23 paralogs in human hepatic cells. 相似文献
7.
Seyyed Reza Pishva Ramachandran Vasudevan Ali Etemad Farzad Heidari Makanko Komara Patimah Ismail Fauziah Othman Abdollah Karimi Mohammad Reza Sabri 《International journal of molecular sciences》2013,14(2):2739-2752
Ventricular septal defect (VSD) is one of the most common types of congenital heart defects (CHD). There are vivid multifactorial causes for VSD in which both genetic and environmental risk factors are consequential in the development of CHD. Methionine synthase reductase (MTRR) and methylenetetrahydrofolate reductase (MTHFR) are two of the key regulatory enzymes involved in the metabolic pathway of homocysteine. Genes involved in homocysteine/folate metabolism may play an important role in CHDs. In this study; we determined the association of A66G and C524T polymorphisms of the MTRR gene and C677T polymorphism of the MTHFR gene in Iranian VSD subjects. A total of 123 children with VSDs and 125 healthy children were included in this study. Genomic DNA was extracted from the buccal cells of all the subjects. The restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method was carried out to amplify the A66G and C524T polymorphism of MTRR and C677T polymorphism of MTHFR genes digested with Hinf1, Xho1 and Nde1 enzymes, respectively. The genotype frequencies of CC, CT and TT of MTRR gene among the studied cases were 43.1%, 40.7% and 16.3%, respectively, compared to 52.8%, 43.2% and 4.0%, respectively among the controls. For the MTRR A66G gene polymorphism, the genotypes frequencies of AA, AG and GG among the cases were 33.3%, 43.9% and 22.8%, respectively, while the frequencies were 49.6%, 42.4% and 8.0%, respectively, among control subjects. The frequencies for CC and CT genotypes of the MTHFR gene were 51.2% and 48.8%, respectively, in VSD patients compared to 56.8% and 43.2% respectively, in control subjects. Apart from MTHFR C677T polymorphism, significant differences were noticed (p < 0.05) in C524T and A66G polymorphisms of the MTRR gene between cases and control subjects. 相似文献
8.
Objective: To examine the relationship between adult attachment style and physical disability in intimate romantic relationships. Method: Participants were 50 individuals with adult-onset spinal cord injuries (SCI) and 50 individuals with congenital disabilities (CON) living in the community. The main outcome measures were adult attachment style and dyadic relationship adjustment. Results: Participants with SCI and CON did not differ in rates of secure versus insecure attachment, and the rates of neither group differed significantly from rates reported for persons without disability. Dyadic adjustment was clearly predicted by attachment variables and differed between the participants with SCI and those with CON; individuals with SCI reported greater total dyadic adjustment. Avoidance showed a strong negative association with dyadic satisfaction, but no association was found with dyadic cohesion. Social participation variables were associated with dyadic adjustment. For instance, mobility was positively associated with dyadic satisfaction. Conclusions: Dyadic adjustment in people with disabilities, as in other groups, is affected by attachment style, but disability and social participation variables may also affect dyadic adjustment. Clinicians should consider differences in attachment styles among persons with disabilities and their implications for intimate close relationships. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
9.
目的观察室间隔缺损先天性心脏病患儿心功能水平、心衰情况与血清脑利钠肽(BNP)水平变化,评价二者之间的相关性。方法选取先天性心脏病室间隔缺损患儿49例,根据患儿超声心动图肺体循环血流比大小分为大分流组和小分流组,并根据患儿症状体征分为无心衰症状组和有心衰症状组;同时选取无心功能损害患儿20例为对照组。同时采血检测各组患儿血清BNP水平,比较各组患儿血清BNP水平差异并分析患儿血清BNP水平与心衰、分流量之间的相关性。结果大、小分流组患儿血清BNP水平均有升高,大分流组患儿血清BNP水平与小分流组及对照组相比,差异均有统计学意义(P〈0.05或P〈0.01);小分流组患儿血清BNP水平与对照组相比,差异有统计学意义(P〈0.05)。心衰情况与患儿血清BNP水平呈正相关(r=1.512,P=0.037);患儿心脏分流量(LVEF、LVSF)与血BNP水平均存正相关(r=0.395、P=0.010,r=0.128、P=0.023)。结论血清BNP水平与先天性室间隔缺损心脏病患儿病情严重程度相关,血清BNP水平可作为评价室间隔缺损先天性心脏病患儿心功能水平的可靠指标。 相似文献
10.
目的探讨谷氨酰胺(Gln)对先天性心脏病心内直视手术患儿的血清特异性神经元烯醇化酶(NSE)的影响和可能脑保护机制。方法将择期行体外循环(CPB)下先天性心脏病(VSD/ASD)心内直视手术患儿20例随机分为2组,小儿氨基酸+Gln组(G组)和小儿氨基酸+生理盐水组(P组),每组10例。2组患儿统一进行术前用药、麻醉诱导、麻醉维持、CPB以及术后管理。于术前30 min(T0)、主动脉开放后10 min(T1)以及CPB结束后1 h(T2)、6 h(T3)、24 h(T4)分别采集颈内静脉球部静脉血检测一氧化氮合酶(NOS)、乳酸(LD)和NSE水平变化。结果 2组血清学指标在T0时差异无显著性意义(P〉0.05);T2-T4时间点NOS活性G组与P组比较有所上升、LD有所下降(P〈0.05或P〈0.01);NSE值G组在T3时点与P组比较在有所下降(P〈0.05)。结论外源性补充Gln能够安全有效地调节先天性室间隔缺损/房间隔缺损心内直视手术患儿血清NOS活性,降低LD和NSE水平,具有一定的脑保护作用。 相似文献