[Show abstract][Hide abstract] ABSTRACT: Aims:
In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown.
Methods and results:
We characterized cardiac expression of WDR12, used adenovirus-mediated WDR12 gene delivery to examine effects of WDR12 on left ventricular (LV) remodeling, and analyzed relationship between MI associated WDR12 allele and cardiac function in human subjects. LV WDR12 protein levels were increased in patients with dilated cardiomyopathy and rats post-infarction. In normal adult rat hearts, WDR12 gene delivery into the anterior wall of the LV decreased interventricular septum diastolic and systolic thickness and increased the diastolic and systolic diameters of the LV. Moreover, LV ejection fraction (9.1%, P<0.05) and fractional shortening (12.2%, P<0.05) were declined. The adverse effects of WDR12 gene delivery on cardiac function were associated with decreased cellular proliferation, activation of p38 mitogen-activated protein kinase (MAPK)/heat shock protein (HSP) 27 pathway, and increased protein levels of Block of proliferation 1 (BOP1), essential for ribosome biogenesis. Post-infarction WDR12 gene delivery decreased E/A ratio (32%, P<0.05) suggesting worsening of diastolic function. In human subjects, MI associated WDR12 allele was associated significantly with diastolic dysfunction and left atrial size.
WDR12 triggers distinct deterioration of cardiac function in adult rat heart and the MI associated WDR12 variant is associated with diastolic dysfunction in human subjects.
PLoS ONE 04/2015; 10(4):e0124907. DOI:10.1371/journal.pone.0124907 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The benefits and barriers that software development companies face when moving beyond agile development practices are identified in a multiplecase study in five Finnish companies. The practices that companies need to adopt when moving towards innovation experiment systems are recognised. The background of the study is the Stairway to Heaven (StH) model that describes the path that many software development companies take when advancing their development practices. The development practices in each case are investigated and analysed in relation to the StH model. At first the results of the analysis strengthened the validity of the StH model as a path taken by software development companies to advance their development practices. Based on the findings, the StH model was extended with a set of additional practices and their adoption levels for each step of the model. The extended model was validated in five case companies.
Lecture Notes in Business Information Processing 01/2015; 210:117-131. DOI:10.1007/978-3-319-19593-3_10
[Show abstract][Hide abstract] ABSTRACT: Continuous deployment (CD) is an essential method as software development companies move towards real-time business and continuous experiments. Powered by the lean and agile methods, CD aims for continuous deployment of valuable software. This doctoral research investigates what it will take to enable CD. The findings will be collected to generate a CD reference model. The research is initiated by studying existing literature and models for organisational assessment in relation to lean and agile approaches. Next, the focus is sharpened to capabilities that are required for enabling CD in information and communication technologies (ICT) industry. The research will apply literature reviews, case studies and the design science research (DSR) framework.
Lecture Notes in Business Information Processing 01/2015; 212:354-355.
[Show abstract][Hide abstract] ABSTRACT: Lean principles have attracted the attention of software development companies due to their potential to improve competitiveness. However, the application of such principles in the software domain is still in its infancy. This paper presents a proposal for adapting the Lean Enterprise Self-Assessment Tool (LESAT) to guide the transformation of software development companies toward Lean. LESAT, developed by the Lean Advancement Initiative (LAI) at the Massachusetts Institute of Technology (MIT), has been widely used in other domains. In this study, concepts and expressions of LESAT were analyzed and mapped to software development following the ISO/IEC 12207 standard. Seven assessment items concerning life-cycle processes were modified from the original LESAT. The modified LESAT for software was compared with a lean assessment approach called "Lean amplifier, " which has been developed and successfully used in practice by Ericsson R&D in Finland. The results indicated that LESAT may complement lean assessment in the software domain at enterprise level, involving the entire value stream. Moreover, they clearly emphasized the role of leadership in the transformation.
[Show abstract][Hide abstract] ABSTRACT: Persistent controversy underlies the functional roles of specific p38 MAPK isoforms in cardiac biology and regulation of hypertrophy-associated genes. Here we show that adenoviral gene transfer of p38β but not p38α increased B-type natriuretic peptide (BNP) mRNA levels in vitro as well as atrial natriuretic peptide mRNA levels both in vitro and in vivo. Overexpression of p38α, in turn, augmented the expression fibrosis-related genes connective tissue growth factor, basic fibroblast growth factor and matrix metalloproteinase-9 both in vitro and in vivo. p38β-induced BNP transcription was diminished by mutation of GATA-4 binding site, whereas overexpression of MKK6b, an upstream regulator of p38α and p38β, activated BNP transcription through both GATA-4 and AP-1. Overexpression of MKK3, upstream regulator of p38α, induced BNP transcription independently from AP-1 and GATA-4. These data provide new evidence for diversity in downstream targets and functional roles of p38 pathway kinases in regulation of hypertrophy-associated cardiac genes.