Responsible Innovation in Business

This chapter introduces responsible innovation in a business context. The first part explains the basic terms that constitute responsible innovation from a busi-ness perspective. The second part presents tangible business practices that opera-tionalise responsible innovation and introduces two good practice examples that hint at the variety of ways in which responsible innovation can be implemented in companies

Spin-orbit coupling suppression and singlet-state blocking of spin-triplet Cooper pairs

An inhomogeneous magnetic exchange field at a superconductor/ferromagnet interface converts spin-singlet Cooper pairs to a spin-polarized triplet state. Although the decay envelope of triplet pairs within ferromagnetic materials is well studied, little is known about their decay in nonmagnetic metals and superconductors and, in particular, in the presence of spin-orbit coupling (SOC). Here, we investigate devices in which singlet and triplet supercurrents propagate into the s-wave superconductor Nb. In the normal state of Nb, triplet supercurrents decay over a distance of 5 nm, which is an order of magnitude smaller than the decay of spin-singlet pairs due to the SOC. In the superconducting state of Nb, triplet supercurrents are not able to couple with the singlet wave function and are thus blocked by the absence of available equilibrium states in the singlet gap. The results offer insight into the dynamics between s-wave singlet and s-wave triplet states

Search for CP violation in D0 and D+ decays

A high statistics sample of photoproduced charm particles from the FOCUS (E831) experiment at Fermilab has been used to search for CP violation in the Cabibbo suppressed decay modes D+ to K-K+pi+, D0 to K-K+ and D0 to pi-pi+. We have measured the following CP asymmetry parameters: A_CP(K-K+pi+) = +0.006 +/- 0.011 +/- 0.005, A_CP(K-K+) = -0.001 +/- 0.022 +/- 0.015 and A_CP(pi-pi+) = +0.048 +/- 0.039 +/- 0.025 where the first error is statistical and the second error is systematic. These asymmetries are consistent with zero with smaller errors than previous measurements.Comment: 12 pages, 4 figure

Using indirect methods to constrain symbiotic nitrogen fixation rates : a case study from an Amazonian rain forest

© The Authors 2009. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License. The definitive version was published in Biogeochemistry 99 (2010): 1-13, doi:10.1007/s10533-009-9392-y.Human activities have profoundly altered the global nitrogen (N) cycle. Increases in anthropogenic N have had multiple effects on the atmosphere, on terrestrial, freshwater and marine ecosystems, and even on human health. Unfortunately, methodological limitations challenge our ability to directly measure natural N inputs via biological N fixation (BNF)—the largest natural source of new N to ecosystems. This confounds efforts to quantify the extent of anthropogenic perturbation to the N cycle. To address this gap, we used a pair of indirect methods—analytical modeling and N balance—to generate independent estimates of BNF in a presumed hotspot of N fixation, a tropical rain forest site in central Rondônia in the Brazilian Amazon Basin. Our objectives were to attempt to constrain symbiotic N fixation rates in this site using indirect methods, and to assess strengths and weaknesses of this approach by looking for areas of convergence and disagreement between the estimates. This approach yielded two remarkably similar estimates of N fixation. However, when compared to a previously published bottom-up estimate, our analysis indicated much lower N inputs via symbiotic BNF in the Rondônia site than has been suggested for the tropics as a whole. This discrepancy may reflect errors associated with extrapolating bottom-up fluxes from plot-scale measures, those resulting from the indirect analyses, and/or the relatively low abundance of legumes at the Rondônia site. While indirect methods have some limitations, we suggest that until the technological challenges of directly measuring N fixation are overcome, integrated approaches that employ a combination of model-generated and empirically-derived data offer a promising way of constraining N inputs via BNF in natural ecosystems.We acknowledge and are grateful for financial support from the Andrew W. Mellon Foundation (C.C. and B.H.), the National Science Foundation (NSF DEB-0515744 to C.C. and A.T. and DEB-0315656 to C.N.), and the NASA LBA Program (NCC5-285 to C.N.)

UTP and ATP increase extracellular signal-regulated kinase 1/2 phosphorylation in bovine chromaffin cells through epidermal growth factor receptor transactivation

Adenosine triphosphate (ATP) is coreleased with catecholamines from adrenal medullary chromaffin cells in response to sympathetic nervous system stimulation and may regulate these cells in an autocrine or paracrine manner. Increases in extracellular signal-regulated kinase (ERK) 1/2 phosphorylation were observed in response to ATP stimulation of bovine chromaffin cells. The signaling pathway involved in ATP-mediated ERK1/2 phosphorylation was investigated via Western blot analysis. ATP and uridine 5′-triphosphate (UTP) increased ERK1/2 phosphorylation potently, peaking between 5 and 15 min. The mitogen-activated protein kinase (MAPK/ERK)-activating kinase (MEK) inhibitor PD98059 blocked this response. UTP, which is selective for G-protein-coupled P2Y receptors, was the most potent agonist among several nucleotides tested. Adenosine 5′-O-(3-thio) triphosphate (ATPγS) and ATP were also potent agonists, characteristic of the P2Y2 or P2Y4 receptor subtypes, whereas agonists selective for P2X receptors or other P2Y receptor subtypes were weakly effective. The receptor involved was further characterized by the nonspecific P2 antagonists suramin and reactive blue 2, which each partially inhibited ATP-mediated ERK1/2 phosphorylation. Inhibitors of protein kinase C (PKC), protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and phosphoinositide-3 kinase (PI3K) had no effect on ATP-mediated ERK1/2 phosphorylation. The Src inhibitor PP2, epidermal growth factor receptor (EGFR) inhibitor AG1478, and metalloproteinase inhibitor GM6001 decreased ATP-mediated ERK1/2 phosphorylation. These results suggest nucleotide-mediated ERK1/2 phosphorylation is mediated by a P2Y2 or P2Y4 receptor, which stimulates metalloproteinase-dependent transactivation of the EGFR

The endothelial-specific regulatory mutation, Mvwf1, is a common mouse founder allele

Mvwf1 is a cis-regulatory mutation previously identified in the RIIIS/J mouse strain that causes a unique tissue-specific switch in the expression of an N-acetylgalactosaminyltransferase, B4GALNT2, from intestinal epithelium to vascular endothelium. Vascular B4galnt2 expression results in aberrant glycosylation of von Willebrand Factor (VWF) and accelerated VWF clearance from plasma. We now report that 13 inbred mouse strains share the Mvwf1 tissue-specific switch and low VWF phenotype, including five wild-derived strains. Genomic sequencing identified a highly conserved 97-kb Mvwf1 haplotype block shared by these strains that encompasses a 30-kb region of high nucleotide sequence divergence from C57BL6/J flanking B4galnt2 exon 1. The analysis of a series of bacterial artificial chromosome (BAC) transgenes containing B4galnt2 derived from the RIIIS/J or C57BL6/J inbred mouse strains demonstrates that the corresponding sequences are sufficient to confer the vessel (RIIIS/J) or intestine (C57BL6/J)-specific expression patterns. Taken together, our data suggest that the region responsible for the Mvwf1 regulatory switch lies within an approximately 30-kb genomic interval upstream of the B4galnt2 gene. The observation that Mvwf1 is present in multiple wild-derived strains suggests that this locus may be retained in wild mouse populations due to positive selection. Similar selective pressures could contribute to the high prevalence of von Willebrand disease in humans

Two GCC boxes and AP2/ERF-domain transcription factor ORA59 in jasmonate/ethylene-mediated activation of the PDF1.2 promoter in Arabidopsis

Plant defense against microbial pathogens depends on the action of several endogenously produced hormones, including jasmonic acid (JA) and ethylene (ET). In defense against necrotrophic pathogens, the JA and ET signaling pathways synergize to activate a specific set of defense genes including PLANT DEFENSIN1.2 (PDF1.2). The APETALA2/Ethylene Response Factor (AP2/ERF)-domain transcription factor ORA59 acts as the integrator of the JA and ET signaling pathways and is the key regulator of JA- and ET-responsive PDF1.2 expression. The present study was aimed at the identification of elements in the PDF1.2 promoter conferring the synergistic response to JA/ET and interacting with ORA59. We show that the PDF1.2 promoter was activated synergistically by JA and the ET-releasing agent ethephon due to the activity of two GCC boxes. ORA59 bound in vitro to these GCC boxes and trans-activated the PDF1.2 promoter in transient assays via these two boxes. Using the chromatin immunoprecipitation technique we were able to show that ORA59 bound the PDF1.2 promoter in vivo. Finally, we show that a tetramer of a single GCC box conferred JA/ethephon-responsive expression, demonstrating that the JA and ET signaling pathways converge to a single type of GCC box. Therefore ORA59 and two functionally equivalent GCC box binding sites form the module that enables the PDF1.2 gene to respond synergistically to simultaneous activation of the JA and ET signaling pathways

Segregation distortion of wild-type alleles at the Machado-Joseph disease locus: a study in normal families from the Azores islands (Portugal)

Machado-Joseph disease (MJD) is caused by an expansion of a triplet repeat with a CAG motif at the ATXN3 gene. The putative segregation ratio distortion (SRD) of alleles can play an important role in the non-Mendelian behaviour of triplet repeat loci. To study the stability and infer the segregation patterns of wild-type MJD alleles, the size of the (CAG)(n) tract was analysed in 102 normal sibships, representing 428 meioses. No mutational events were detected during the transmission of alleles. Segregation analysis showed that the smaller alleles were preferentially transmitted (56.9%). Considering maternal meioses alone, such preference was still detected (55.7%) but without statistical significance. A positive correlation was observed for the difference in length between the two alleles constituting the transmitters' genotype (D) and the frequency of transmission of the smaller alleles. The results suggest that small D values are not enough to modify the probability of allele transmission. When transmissions involving genotypes with D <or= 2 were excluded, SRD in favour of the smaller allele became significant for both maternal and paternal transmissions. Therefore, the genotypic composition of the transmitters in a sample to be analysed should influence the ability to detect SRD, acting as a confounding factor.This work was supported by ‘‘Projecto Regional Integrado— DMJ (PRI-DMJ)’’ (funded by Regional Government of the Azores), ‘‘Construyendo una Bio-Región Europea—Biopolis’’ (05/MAC/2.3/ C14, funded by PIC Interreg III B, Azores—Madeira—Canarias) and MANSEEBMO (MI.2.1/004/2005, funded by ‘‘Direcção Regional da Ciência e Tecnologia’’). CB (SFRH/BD/21875/2005) is a recipient of a Ph.D. grant, and RM (SFRH/BPD/32473/2006) and CS (SFRH/BPD/ 20944/2004) are postdoctoral fellows from ‘‘Fundação para a Ciência e a Tecnologia’’ (FCT)

High resolution human leukocyte antigen (HLA) class I and class II allele typing in Mexican mestizo women with sporadic breast cancer: case-control study

<p>Abstract</p> <p>Background</p> <p>The development of breast cancer is multifactorial. Hormonal, environmental factors and genetic predisposition, among others, could interact in the presentation of breast carcinoma. Human leukocyte antigen (HLA) alleles play an important role in immunity (cellular immunity) and may be important genetic traits. HLAAllele-specific interaction has not been well established. Recently, several studies had been conducted in order to do so, but the results are controversial and in some instances contradictory.</p> <p>Methods</p> <p>We designed a case-control study to quantify the association of HLA class I and II genes and breast cancer. HLA typing was performed by high resolution sequence-specific oligotyping after DNA amplification (PCR-SSOP) of 100 breast cancer Mexican mestizo patients and 99 matched healthy controls.</p> <p>Results</p> <p>HLA-A frequencies that we were able to observe that there was no difference between both groups from the statistical viewpoint. HLA-B*1501 was found three times more common in the case group (OR, 3.714; <it>p </it>= 0.031). HLA-Cw is not a marker neither for risk, nor protection for the disease, because we did not find significant statistical differences between the two groups. DRB1*1301, which is expressed in seven cases and in only one control, observing an risk increase of up to seven times and DRB1*1602, which behaves similarly in being present solely in the cases (OR, 16.701; 95% CI, 0.947 – 294.670). DQ*0301-allele expression, which is much more common in the control group and could be protective for the presentation of the disease (OR, 0.078; 95% CI, 0.027–0.223, <it>p </it>= 0.00001).</p> <p>Conclusion</p> <p>Our results reveal the role of the MHC genes in the pathophysiology of breast cancer, suggesting that in the development of breast cancer exists a disorder of immune regulation. The triggering factor seems to be restricted to certain ethnic groups and certain geographical regions since the relevant MHC alleles are highly diverse. This is the first study in Mexican population where high resolutions HLA typing has been performed in order to try to establish an association with malignancy.</p

Mosaic Origins of a Complex Chimeric Mitochondrial Gene in Silene vulgaris

Chimeric genes are significant sources of evolutionary innovation that are normally created when portions of two or more protein coding regions fuse to form a new open reading frame. In plant mitochondria astonishingly high numbers of different novel chimeric genes have been reported, where they are generated through processes of rearrangement and recombination. Nonetheless, because most studies do not find or report nucleotide variation within the same chimeric gene, evolution after the origination of these chimeric genes remains unstudied. Here we identify two alleles of a complex chimera in Silene vulgaris that are divergent in nucleotide sequence, genomic position relative to other mitochondrial genes, and expression patterns. Structural patterns suggest a history partially influenced by gene conversion between the chimeric gene and functional copies of subunit 1 of the mitochondrial ATP synthase gene (atp1). We identified small repeat structures within the chimeras that are likely recombination sites allowing generation of the chimera. These results establish the potential for chimeric gene divergence in different plant mitochondrial lineages within the same species. This result contrasts with the absence of diversity within mitochondrial chimeras found in crop species