Hanoverian F/W-line contributes to segregation of Warmblood fragile foal syndrome type 1 variant PLOD1:c.2032G>A in Warmblood horses.
- 作者列表："Metzger J","Kreft O","Sieme H","Martinsson G","Reineking W","Hewicker-Trautwein M","Distl O
BACKGROUND:Warmblood fragile foal syndrome (WFFS) is a lethal condition detected in Warmblood horses. Its origin and association with performance traits and fertility among horse populations is unknown. OBJECTIVES:To validate the previously identified WFFS type 1 (WFFST1)-associated missense variant PLOD1:c.2032G>A and to investigate its distribution among various horses with particular focus on Hanoverian breed, as well as its pathomorphological picture. The study aimed at identifying the origin of the mutant allele and its correlation with performance and fertility traits in Warmblood horses. STUDY DESIGN:Retrospective case-control and association study. METHODS:WFFST1 variant was validated using whole genome sequencing (WGS) in 78 equids. In an affected foal with a homozygous mutant genotype, necropsy was performed. Skin samples were examined using histology and transmission electron microscopy. Pathway analysis was performed to trace back 81 genetic carriers to the most common recent ancestor. Furthermore, generalised linear model analysis was employed to test estimated breeding values (EBVs) for differences in performance and fertility traits among different genotypes in Hanoverian horses. RESULTS:WFFST1 variant had the lowest minor allele frequency among all variants detected in WGS data in the region of PLOD1. Further genotyping of this variant revealed allele frequencies of 0.14 in Hanoverian horses. Histological investigations of the WFFST1-affected foal showed loosely arranged collagen fibres in the dermis. Ultrastructurally, multifocal areas with degraded collagen fibrils and fibrillar plaques were detected. Further pathway analysis revealed a stallion from the Hanoverian sire F/W line as the most common recent ancestor of all tested genetic carriers. Furthermore, WFFST1 variant was found to be correlated with EBVs for gait-related traits as well as conformation and dressage. MAIN LIMITATIONS:Study evaluated carriers and cases only from Europe. CONCLUSIONS:This study provides a comprehensive evaluation of WFFST1 variant and traces it back to its potential origin.
背景: 温血脆性小马驹综合征 (WFFS) 是在温血马中检测到的一种致死性疾病。它的起源和与马群体中的性能性状和生育力的关联是未知的。 目的: 验证先前鉴定的WFFS 1型 (WFFST1) 相关错义变异PLOD1:c.2032G>A，并研究其在各种马中的分布，特别关注Hanoverian品种，以及其病理形态学图像。该研究旨在鉴定温血马突变等位基因的来源及其与生产性能和育性性状的相关性。 研究设计: 回顾性病例对照和关联研究。 方法: 使用全基因组测序 (WGS) 在78个equids中验证WFFST1变体。在具有纯合突变基因型的受影响的小马驹中，进行尸检。使用组织学和透射电子显微镜检查皮肤样品。进行通路分析以追溯81个遗传携带者到最常见的最近祖先。此外，使用广义线性模型分析来测试评估育种值 (EBVs)，以了解Hanoverian马不同基因型之间的性能和育性性状的差异。 结果: 在plod1区域的WGS数据中检测到的所有变体中，WFFST1变体具有最低的次要等位基因频率。该变异的进一步基因分型揭示了Hanoverian马的等位基因频率为0.14。WFFST1-affected小马驹的组织学研究显示真皮中的胶原纤维排列松散。在超微结构上，检测到具有降解的胶原纤维和纤维性斑块的多焦点区域。进一步的途径分析揭示了来自Hanoverian sire F/W系的种马作为所有测试的遗传携带者的最常见的最近祖先。此外，发现WFFST1变体与步态相关性状以及构象和盛装舞步的ebv相关。 主要局限性: 研究评估了仅来自欧洲的携带者和病例。 结论: 本研究提供了对WFFST1变体的全面评估，并将其追溯到其潜在的起源。
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.