Candidate gene expression and coding sequence variants in Warmblood horses with myofibrillar myopathy.
- 作者列表："Williams ZJ","Velez-Irizarry D","Petersen JL","Ochala J","Finno CJ","Valberg SJ
BACKGROUND:Myofibrillar myopathy (MFM) of unknown aetiology has recently been identified in Warmblood (WB) horses. In humans, 16 genes have been implicated in various MFM-like disorders. OBJECTIVES:To identify variants in 16 MFM candidate genes and compare allele frequencies of all variants between MFM WB and non-MFM WB and coding variants with moderate or severe predicted effects in MFM WB with publicly available data of other breeds. To compare differential gene expression and muscle fibre contractile force between MFM and non-MFM WB. STUDY DESIGN:Case-control. ANIMALS:8 MFM WB, 8 non-MFM WB, 33 other WB, 32 Thoroughbreds, 80 Quarter Horses and 77 horses of other breeds in public databases. METHODS:Variants were called within transcripts of 16 candidate genes using gluteal muscle mRNA sequences aligned to EquCab3.0 and allele frequencies compared by Fisher's exact test among MFM WB, non-MFM WB and public sequences across breeds. Candidate gene differential expression was determined between MFM and non-MFM WB by fitting a negative binomial generalised log-linear model per gene (false discovery rate <0.05). The maximal isometric force/cross-sectional area generated by isolated membrane-permeabilised muscle fibres was determined. RESULTS:None of the 426 variants identified in 16 candidate genes were associated with MFM including 26 missense variants. Breed-specific differences existed in allele frequencies. Candidate gene differential expression and muscle fibre-specific force did not differ between MFM WB (143.1 ± 34.7 kPa) and non-MFM WB (140.2 ± 43.7 kPa) (P = .8). MAIN LIMITATIONS:RNA-seq-only assays transcripts expressed in skeletal muscle. Other possible candidate genes were not evaluated. CONCLUSIONS:Evidence for association of variants with a disease is essential because coding sequence variants are common in the equine genome. Variants identified in MFM candidate genes, including two coding variants offered as commercial MFM equine genetic tests, did not associate with the WB MFM phenotype.
背景: 最近在温血 (WB) 马中发现了病因不明的肌原纤维肌病 (MFM)。在人类中，16个基因与各种MFM样病症有关。 目的: 鉴定16个MFM候选基因中的变异，并将MFM WB和非MFM WB之间所有变异的等位基因频率以及MFM WB中具有中度或重度预测效应的编码变异与其他品种的公开数据进行比较。比较MFM与非MFM WB基因表达和肌纤维收缩力的差异。 研究设计: 病例对照。 动物: 8个MFM WB，8个非MFM WB，33个其他WB，32个纯种马，80个四分之一马和77个其他品种的马在公共数据库中。 方法: 使用与EquCab3.0比对的臀肌mRNA序列，在16个候选基因的转录本中调用变体，并通过Fisher精确检验在MFM WB、非MFM WB和跨品种的公共序列中比较等位基因频率。通过拟合每个基因的负二项式广义对数线性模型 (错误发现率 <0.05)，确定MFM和非MFM WB之间的候选基因差异表达。测定由分离的膜透化肌纤维产生的最大等距力/横截面积。 结果: 在16个候选基因中鉴定的426个变体中没有一个与MFM相关，包括26个错义变体。等位基因频率存在品种特异性差异。候选基因差异表达和肌纤维特异性力在MFM WB (143.1 ± 34.7 kPa) 和非MFM WB (140.2 ± 43.7 kPa) 之间没有差异 (P = .8)。 主要局限性: 仅RNA-seq测定在骨骼肌中表达的转录物。未评估其他可能的候选基因。 结论: 变异与疾病关联的证据是必不可少的，因为编码序列变异在马基因组中是常见的。在MFM候选基因中鉴定的变体，包括作为商业MFM马遗传测试提供的两个编码变体，与WB MFM表型不相关。
METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.
METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.
METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.