CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration

In developed countries, age-related macular degeneration is a common cause of blindness in the elderly. A common polymorphism, encoding the sequence variation Y402H in complement factor H (CFH), has been strongly associated with disease susceptibility. Here, we examined 84 polymorphisms in and around CFH in 726 affected individuals (including 544 unrelated individuals) and 268 unrelated controls. In this sample, 20 of these polymorphisms showed stronger association with disease susceptibility than the Y402H variant. Further, no single polymorphism could account for the contribution of the CFH locus to disease susceptibility. Instead, multiple polymorphisms defined a set of four common haplotypes (of which two were associated with disease susceptibility and two seemed to be protective) and multiple rare haplotypes (associated with increased susceptibility in aggregate). Our results suggest that there are multiple disease susceptibility alleles in the region and that noncoding CFH variants play a role in disease susceptibility.     

Detailed analysis of the plasma extracellular vesicle proteome after separation from lipoproteins

The isolation of extracellular vesicles (EVs) from blood is of great importance to understand the biological role of circulating EVs and to develop EVs as biomarkers of disease. Due to the concurrent presence of lipoprotein particles, however, blood is one of the most difficult body fluids to isolate EVs from. The aim of this study was to develop a robust method to isolate and characterise EVs from blood with minimal contamination by plasma proteins and lipoprotein particles. Plasma and serum were collected from healthy subjects, and EVs were isolated by size-exclusion chromatography (SEC), with most particles being present in fractions 8–12, while the bulk of the plasma proteins was present in fractions 11–28. Vesicle markers peaked in fractions 7–11; however, the same fractions also contained lipoprotein particles. The purity of EVs was improved by combining a density cushion with SEC to further separate lipoprotein particles from the vesicles, which reduced the contamination of lipoprotein particles by 100-fold. Using this novel isolation procedure, a total of 1187 proteins were identified in plasma EVs by mass spectrometry, of which several proteins are known as EV-associated proteins but have hitherto not been identified in the previous proteomic studies of plasma EVs. This study shows that SEC alone is unable to completely separate plasma EVs from lipoprotein particles. However, combining SEC with a density cushion significantly improved the separation of EVs from lipoproteins and allowed for a detailed analysis of the proteome of plasma EVs, thus making blood a viable source for EV biomarker discovery.     

Experimental verification of a conserved intronic microRNA located in the human <Emphasis Type="Italic">TrkC</Emphasis> gene with a cell type-dependent apoptotic function

Tropomyosin receptor kinase C (TrkC) is involved in cell survival, apoptosis induction and tumorigenesis. We hypothesized that, similar to p75^NTR receptor, some of the diverse functions of TrkC could be mediated by a microRNA (miRNA) embedded within the gene. Here, we experimentally verified the expression and processing of two bioinformatically predicted miRNAs named TrkC-miR1-5p and TrkC-miR1-3p. Transfecting a DNA fragment corresponding to the TrkC-premir1 sequence in HEK293t cells caused ~300-fold elevation in the level of mature TrkC-miR1 and also a significant downregulation of its predicted target genes. Furthermore, endogenous TrkC-miR1 was detected in several cell lines and brain tumors confirming its endogenous generation. Furthermore, its orthologous miRNA was detected in developing rat brain. Accordingly, TrkC-miR1 expression was increased during the course of neural differentiation of NT2 cell, whereas its suppression attenuated NT2 differentiation. Consistent with opposite functions of TrkC, TrkC-miR1 overexpression promoted survival and apoptosis in U87 and HEK293t cell lines, respectively. In conclusion, our data report the discovery of a new miRNA with overlapping function to TrkC.     

A Systemic Framework for Business Model Design and Development -Part A: Theorizing Perspective

Developing innovative business models is one of the complicated issues. Owing to the multiplicity of stakeholders with diverse worldviews about value creation and dynamic markets, the development of innovative business models has turned out to be a complex issue. Therefore, this research seeks to: (1) examine the complicated nature of the development of business model problem and, (2) provide a holistic and systemic framework for the development of business models. The proposed framework employs the Soft Systems Methodology (SSM). This framework is composed of 18 phases, which ranges from the phase of finding out the problem of developing a business model to the phase of its implementation. This methodology is characterized by taking into account the considerations of rational positioning views, evolutionary views, and cognitive views in designing and developing business models.     

在亚稳奥氏体不锈钢中进行温度跳跃拉伸试验以诱导最佳TRIP/TWIP效应

本文通过将AISI 304L奥氏体不锈钢的变形温度控制在0~200oC范围内,初步调整了其塑性变形机制以优化强塑性协同效应。研究表明,孪生诱发塑性效应（TWIP）/相变诱导塑性效应（TRIP）的协同效应和通过调节变形温度将TRIP效应的应变范围扩大到更高的应变范围,是提高亚稳不锈钢强塑性协同性的有效策略。在这方面,考虑到观察到的塑性变形的温度依赖性,通过预先设计的温度跳跃拉伸试验,实现TWIP和TRIP效应的受控序列,以实现良好的强度–延性权衡。因此,在应变的后期,通过利用100oC下的TWIP效应和25oC时的TRIP效应的优势,这种方法获得了846 MJ/m3的拉伸韧性和133%的总伸长率。此外,基于加工硬化分析,发现变形诱发的α′-马氏体屈服是制约塑性和强化性能进一步提高的主要原因。     

A Systemic Framework for Business Model Design and Development -Part B: Practical Perspective

Systemic Practice and Action Research - Profit-making requires innovation in the design of a successful business model that brings about sustainable competitive advantage for the organization....