Consequences of Postnatally Elevated Insulin-Like Growth Factor-II in Transgenic Mice: Endocrine Changes and Effects on Body and Organ Growth.

Insulin-like growth factor-II (IGF-II) is an important regulator of embryonic growth and differentiation, but its function in postnatal life is unclear. To address this point, we generated transgenic mice harboring fusion genes in which a human IGF-II complementary DNA is placed under the transcriptional control of the rat phosphoenolpyruvate carboxykinase promoter. Transgene-specific messenger RNA was detected in liver, kidney, and several parts of the gut. Serum IGF-II levels in transgenic mice were 2-3 times higher than those in controls and increased after starvation. Circulating IGF-I correlated negatively and IGF-binding protein-2 (IGFBP-2) positively with IGF-II levels, suggesting that IGF-I is displaced from IGFBPs by IGF-II and that IGFII is a major regulator of IGFBP-2. Serum levels of IGFBP-3 and IGFBP-4 tended to be higher in phosphoenolpyruvate carboxykinase- IGF-II transgenic mice than in controls, as evaluated by ligand blot analysis. Starvation reduced serum IGF-I, but increased IGFBP-2 in transgenic mice more markedly than in controls. Fasting insulin levels were significantly reduced in transgenic mice, whereas glucose levels were not influenced by elevated IGF-II. The body growth of 4- and 12- week-old mice was not significantly influenced by elevated IGF-II, but transgenic mice displayed increased kidney and testis weight at the age of 4 weeks, and increased adrenal weight at the age of 12 weeks. Our results demonstrate that elevated IGF-II in postnatal life has multiple endocrine consequences and subtle time-specific effects on organ growth

Internationalization of New Product Development:Results from a Multiple Case Study on companies with Innovation Processes in Germany and India

A rich body of literature has emerged from research on Western new product development (NPD). However, the impact of country- and culture-specific influences on these processes has not been examined in detail yet. Hence, this study identifies the differences in NPD practices between the Indian and German research and development (R&amp;D) subsidiaries of multinational companies (MNCs). Data have been generated by interviews with R&amp;D executives in both countries across multiple cases. The study samples strategic, organisational, and operational aspects and indicates differences in process coordination, reward systems, NPD creativity techniques, market orientation, and the average age of NPD teams. Other aspects, such as top management support, the use of structured NPD processes, and the use of heterogeneous NPD teams, show no substantial differences between the countries. Our findings suggest that, while some aspects are universally applicable across cultural frontiers, Western companies must understand India's different expectations regarding NPD and adjust their practices accordingly.</jats:p

The noise properties of 42 millisecond pulsars from the European Pulsar Timing Array and their impact on gravitational wave searches

The sensitivity of Pulsar Timing Arrays to gravitational waves depends on the noise present in the individual pulsar timing data. Noise may be either intrinsic or extrinsic to the pulsar. Intrinsic sources of noise will include rotational instabilities, for example. Extrinsic sources of noise include contributions from physical processes which are not sufficiently well modelled, for example, dispersion and scattering effects, analysis errors and instrumental instabilities. We present the results from a noise analysis for 42 millisecond pulsars (MSPs) observed with the European Pulsar Timing Array. For characterising the low-frequency, stochastic and achromatic noise component, or "timing noise", we employ two methods, based on Bayesian and frequentist statistics. For 25 MSPs, we achieve statistically significant measurements of their timing noise parameters and find that the two methods give consistent results. For the remaining 17 MSPs, we place upper limits on the timing noise amplitude at the 95% confidence level. We additionally place an upper limit on the contribution to the pulsar noise budget from errors in the reference terrestrial time standards (below 1%), and we find evidence for a noise component which is present only in the data of one of the four used telescopes. Finally, we estimate that the timing noise of individual pulsars reduces the sensitivity of this data set to an isotropic, stochastic GW background by a factor of >9.1 and by a factor of >2.3 for continuous GWs from resolvable, inspiralling supermassive black-hole binaries with circular orbits.Comment: Accepted for publication by the Monthly Notices of the Royal Astronomical Societ

Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics'

We combined large-scale mRNA expression analysis and gene mapping to identify genes and loci that control hematopoietic stem cell (HSC) function. We measured mRNA expression levels in purified HSCs isolated from a panel of densely genotyped recombinant inbred mouse strains. We mapped quantitative trait loci (QTLs) associated with variation in expression of thousands of transcripts. By comparing the physical transcript position with the location of the controlling QTL, we identified polymorphic cis-acting stem cell genes. We also identified multiple trans-acting control loci that modify expression of large numbers of genes. These groups of coregulated transcripts identify pathways that specify variation in stem cells. We illustrate this concept with the identification of candidate genes involved with HSC turnover. We compared expression QTLs in HSCs and brain from the same mice and identified both shared and tissue-specific QTLs. Our data are accessible through WebQTL, a web-based interface that allows custom genetic linkage analysis and identification of coregulated transcripts.

Intra- and inter-individual genetic differences in gene expression

Genetic variation is known to influence the amount of mRNA produced by a gene. Given that the molecular machines control mRNA levels of multiple genes, we expect genetic variation in the components of these machines would influence multiple genes in a similar fashion. In this study we show that this assumption is correct by using correlation of mRNA levels measured independently in the brain, kidney or liver of multiple, genetically typed, mice strains to detect shared genetic influences. These correlating groups of genes (CGG) have collective properties that account for 40-90% of the variability of their constituent genes and in some cases, but not all, contain genes encoding functionally related proteins. Critically, we show that the genetic influences are essentially tissue specific and consequently the same genetic variations in the one animal may up-regulate a CGG in one tissue but down-regulate the same CGG in a second tissue. We further show similarly paradoxical behaviour of CGGs within the same tissues of different individuals. The implication of this study is that this class of genetic variation can result in complex inter- and intra-individual and tissue differences and that this will create substantial challenges to the investigation of phenotypic outcomes, particularly in humans where multiple tissues are not readily available.&#xd;&#xa;&#xd;&#xa

Spatio-temporal Models of Lymphangiogenesis in Wound Healing

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total

Genome wide analysis of gene expression changes in skin from patients with type 2 diabetes

Non-healing chronic ulcers are a serious complication of diabetes and are a major healthcare problem. While a host of treatments have been explored to heal or prevent these ulcers from forming, these treatments have not been found to be consistently effective in clinical trials. An understanding of the changes in gene expression in the skin of diabetic patients may provide insight into the processes and mechanisms that precede the formation of non-healing ulcers. In this study, we investigated genome wide changes in gene expression in skin between patients with type 2 diabetes and non-diabetic patients using next generation sequencing. We compared the gene expression in skin samples taken from 27 patients (13 with type 2 diabetes and 14 non-diabetic). This information may be useful in identifying the causal factors and potential therapeutic targets for the prevention and treatment of diabetic related diseases