Innovation or Imitation? The effect of spillovers and competitive pressure on firms' R&D strategy choice

This article provides a theoretical and empirical analysis of a firm's optimal R&D strategy choice. In this paper a firm's R&D strategy is assumed to be endogenous and allowed to depend on both internal firms. characteristics and external factors. Firms choose between two strategies, either they engage in R&D or abstain from own R&D and imitate the outcomes of innovators. In the theoretical model this yields three types of equilibria in which either all firms innovate, some firms innovate and others imitate, or no firm innovates. Firms'equilibrium strategies crucially depend on external factors. We find that the efficiency of intellectual property rights protection positively affects firms'incentives to engage in R&D, while competitive pressure has a negative effect. In addition, smaller firms are found to be more likely to become imitators when the product is homogeneous and the level of spillovers is high. These results are supported by empirical evidence for German .rms from manufacturing and services sectors. Regarding social welfare our results indicate that strengthening intellectual property protection can have an ambiguous effect. In markets characterized by a high rate of innovation a reduction of intellectual property rights protection can discourage innovative performance substantially. However, a reduction of patent protection can also increase social welfare because it may induce imitation. This indicates that policy issues such as the optimal length and breadth of patent protection cannot be resolved without taking into account specific market and firm characteristics. Journal of Economic Literature Classification Numbers: C35, D43, L13, L22, O31. Keywords: Innovation; imitation; spillovers; product differentiation; market competition; intellectual property rights protection.

Possible competitive displacement of planorbids by Melanoides tuberculata in Minas Gerais, Brazil

Several species of snails, including Pomacea haustrum, Marisa cornuarietis and Helisoma duryi, have been identified as probable competitors and/or predators of planorbid intermediate hosts of Schistosoma. During the last few years, studies carried out in the Caribbean region have shown reductions and even disappearances of populations of Biomphalaria glabrata and B. straminea in breeding places where the snail Melanoides tuberculata was introduced. Observations made over a period of 10 years in two lakes close to Belo Horizonte, MG, showed that there were marked reductions in autochthonous populations of B. glabrata and B. straminea after the arrival of M. tuberculata, both Biomphalaria species disappearing completely after eight years.

Dynamics of the recruitment of lateral amygdala neurons following successive fear learning to different conditional stimuli

In fear conditioning, an animal learns to associate an unconditioned stimulus (US), such as a shock, and a conditioned stimulus (CS), such as a tone, so that the presentation of the CS alone can trigger conditioned responses. Recent research on the lateral amygdala has shown that following cued fear conditioning, only a subset of higher-excitable neurons are recruited in the memory trace. Their selective deletion after fear conditioning results in a selective erasure of the fearful memory. I hypothesize that the recruitment of highly excitable neurons depends on responsiveness to stimuli, intrinsic excitability and local connectivity. In addition, I hypothesize that neurons recruited for an initial memory also participate in subsequent memories, and that changes in neuronal excitability affect secondary fear learning. To address these hypotheses, I will show that A) a rat can learn to associate two successive short-term fearful memories; B) neuronal populations in the LA are competitively recruited in the memory traces depending on individual neuronal advantages, as well as advantages granted by the local network. By performing two successive cued fear conditioning experiments, I found that rats were able to learn and extinguish the two successive short-term memories, when tested 1 hour after learning for each memory. These rats were equipped with a system of stable extracellular recordings that I developed, which allowed to monitor neuronal activity during fear learning. 233 individual putative pyramidal neurons could modulate their firing rate in response to the conditioned tone (conditioned neurons) and/or non- conditioned tones (generalizing neurons). Out of these recorded putative pyramidal neurons 86 (37%) neurons were conditioned to one or both tones. More precisely, one population of neurons encoded for a shared memory while another group of neurons likely encoded the memories' new features. Notably, in spite of a successful behavioral extinction, the firing rate of those conditioned neurons in response to the conditioned tone remained unchanged throughout memory testing. Furthermore, by analyzing the pre-conditioning characteristics of the conditioned neurons, I determined that it was possible to predict neuronal recruitment based on three factors: 1) initial sensitivity to auditory inputs, with tone-sensitive neurons being more easily recruited than tone- insensitive neurons; 2) baseline excitability levels, with more highly excitable neurons being more likely to become conditioned; and 3) the number of afferent connections received from local neurons, with neurons destined to become conditioned receiving more connections than non-conditioned neurons. - En conditionnement de la peur, un animal apprend à associer un stimulus inconditionnel (SI), tel un choc électrique, et un stimulus conditionné (SC), comme un son, de sorte que la présentation du SC seul suffit pour déclencher des réflexes conditionnés. Des recherches récentes sur l'amygdale latérale (AL) ont montré que, suite au conditionnement à la peur, seul un sous-ensemble de neurones plus excitables sont recrutés pour constituer la trace mnésique. Pour apprendre à associer deux sons au même SI, je fais l'hypothèse que les neurones entrent en compétition afin d'être sélectionnés lors du recrutement pour coder la trace mnésique. Ce recrutement dépendrait d'un part à une activation facilité des neurones ainsi qu'une activation facilité de réseaux de neurones locaux. En outre, je fais l'hypothèse que l'activation de ces réseaux de l'AL, en soi, est suffisante pour induire une mémoire effrayante. Pour répondre à ces hypothèses, je vais montrer que A) selon un processus de mémoire à court terme, un rat peut apprendre à associer deux mémoires effrayantes apprises successivement; B) des populations neuronales dans l'AL sont compétitivement recrutées dans les traces mnésiques en fonction des avantages neuronaux individuels, ainsi que les avantages consentis par le réseau local. En effectuant deux expériences successives de conditionnement à la peur, des rats étaient capables d'apprendre, ainsi que de subir un processus d'extinction, pour les deux souvenirs effrayants. La mesure de l'efficacité du conditionnement à la peur a été effectuée 1 heure après l'apprentissage pour chaque souvenir. Ces rats ont été équipés d'un système d'enregistrements extracellulaires stables que j'ai développé, ce qui a permis de suivre l'activité neuronale pendant l'apprentissage de la peur. 233 neurones pyramidaux individuels pouvaient moduler leur taux d'activité en réponse au son conditionné (neurones conditionnés) et/ou au son non conditionné (neurones généralisant). Sur les 233 neurones pyramidaux putatifs enregistrés 86 (37%) d'entre eux ont été conditionnés à un ou deux tons. Plus précisément, une population de neurones code conjointement pour un souvenir partagé, alors qu'un groupe de neurones différent code pour de nouvelles caractéristiques de nouveaux souvenirs. En particulier, en dépit d'une extinction du comportement réussie, le taux de décharge de ces neurones conditionné en réponse à la tonalité conditionnée est resté inchangée tout au long de la mesure d'apprentissage. En outre, en analysant les caractéristiques de pré-conditionnement des neurones conditionnés, j'ai déterminé qu'il était possible de prévoir le recrutement neuronal basé sur trois facteurs : 1) la sensibilité initiale aux entrées auditives, avec les neurones sensibles aux sons étant plus facilement recrutés que les neurones ne répondant pas aux stimuli auditifs; 2) les niveaux d'excitabilité des neurones, avec les neurones plus facilement excitables étant plus susceptibles d'être conditionnés au son ; et 3) le nombre de connexions reçues, puisque les neurones conditionné reçoivent plus de connexions que les neurones non-conditionnés. Enfin, nous avons constaté qu'il était possible de remplacer de façon satisfaisante le SI lors d'un conditionnement à la peur par des injections bilatérales de bicuculline, un antagoniste des récepteurs de l'acide y-Aminobutirique.

The Nursing and Midwifery Resource - Guidance for Best Practice on the Recruitment of Overseas Nurses and Midwives

Guidance for Best Practice on the Recruitment of Overseas Nurses and Midwives is prepared specifically for employers. The document includes a set of principles which are fundamental to the development of a model of transcultural nursing and midwifery. The document is based on the assumption that each potential employee has the qualifications and experience required to meet the criteria for registration as a nurse or midwife in Ireland Download the Report here

Neutrophil-derived CCL3 is essential for the rapid recruitment of dendritic cells to the site of Leishmania major inoculation in resistant mice.

Neutrophils are rapidly and massively recruited to sites of microbial infection, where they can influence the recruitment of dendritic cells. Here, we have analyzed the role of neutrophil released chemokines in the early recruitment of dendritic cells (DCs) in an experimental model of Leishmania major infection. We show in vitro, as well as during infection, that the parasite induced the expression of CCL3 selectively in neutrophils from L. major resistant mice. Neutrophil-secreted CCL3 was critical in chemotaxis of immature DCs, an effect lost upon CCL3 neutralisation. Depletion of neutrophils prior to infection, as well as pharmacological or genetic inhibition of CCL3, resulted in a significant decrease in DC recruitment at the site of parasite inoculation. Decreased DC recruitment in CCL3(-/-) mice was corrected by the transfer of wild type neutrophils at the time of infection. The early release of CCL3 by neutrophils was further shown to have a transient impact on the development of a protective immune response. Altogether, we identified a novel role for neutrophil-secreted CCL3 in the first wave of DC recruitment to the site of infection with L. major, suggesting that the selective release of neutrophil-secreted chemokines may regulate the development of immune response to pathogens.

8-Methoxy-naphtho[2,3-b]thiophen-4,9-quinone, a non-competitive inhibitor of trypanothione reductase

The enzyme trypanothione reductase is a recognised drug target in trypanosomatids and has been used in the search of new compounds with potential activity against diseases such as leishmaniasis, Chagas disease and African trypanosomiasis. 8-Methoxy-naphtho [2,3-b] thiophen-4,9-quinone was selected in a screening of natural and synthetic compounds using an in vitro assay with the recombinant enzyme from Trypanosoma cruzi. Its mode of inhibition fits a non-competitive model with respect to the substrate (trypanothione) and to the co-factor (NADPH), with Ki-values of 5 and 3.6 µM, respectively. When tested against human glutathione reductase, this compound did not display any significant inhibition at 100 µM, indicating a good selectivity against the parasite enzyme.

Selective suppression of leukocyte recruitment in allergic inflammation

Allergic diseases result in a considerable socioeconomic burden. The incidence of allergic diseases, notably allergic asthma, has risen to high levels for reasons that are not entirely understood. With an increasing knowledge of underlying mechanisms, there is now more potential to target the inflammatory process rather than the overt symptoms. This focuses attention on the role of leukocytes especially Th2 lymphocytes that regulate allergic inflammation and effector cells where eosinophils have received much attention. Eosinophils are thought to be important based on the high numbers that are recruited to sites of allergic inflammation and the potential of these cells to effect both tissue injury and remodelling. It is hoped that future therapy will be directed towards specific leukocyte types, without overtly compromising essential host defence responses. One obvious target is leukocyte recruitment. This necessitates a detailed understanding of underlying mechanisms, particularly those involving soluble che-moattractants signals and cell-cell adhesion molecules.

Addressing High Level ICT Skills Recruitment Needs

Ireland is a successful major centre for ICT operations with ten of the top ICT companies in the world having substantial operations here. The large talent pool of ICT professionals that exists here is valuable both for foreign-owned and Irish companies. The cluster of internationally renowned firms and Irish companies offer a range of attractive career opportunities for professionals. A range of skills recruitment difficulties have been raised through the work of the Expert Group on Future Skills Needs (EGFSN), specifically the immediate issue of high-level ICT skills within both the ICT sector and from other sectors such as international financial services, banking and business services. Forfs, with the support of IDA Ireland and Enterprise Ireland, engaged in discussions with a selected range of foreign–owned and Irish companies employing approximately 30,000 employees to establish the nature of positions involved, the reasons for recruitment difficulties and to identify measures to help address them. Consultations were also held with key stakeholders including IDA Ireland, Enterprise Ireland, ICT Ireland, Software Ireland, IT@Cork, Engineers Ireland and Dublin Chambers of Commerce. Discussions were held with the heads of the computing departments of all Universities and Institutes of Technology at a meeting chaired by the Higher Education Authority. An in-depth analysis of third-level ICT supply statistics and trends was undertaken to inform the research.

Fas ligand-induced proinflammatory transcriptional responses in reconstructed human epidermis. Recruitment of the epidermal growth factor receptor and activation of MAP kinases.

Fas ligand (FasL) exerts potent proapoptotic and proinflammatory actions on epidermal keratinocytes and has been implicated in the pathogenesis of eczema, toxic epidermal necrolysis, and drug-induced skin eruptions. We used reconstructed human epidermis to investigate the mechanisms of FasL-induced inflammatory responses and their relationships with FasL-triggered caspase activity. Caspase activity was a potent antagonist of the pro-inflammatory gene expression triggered by FasL prior to the onset of cell death. Furthermore, we found that FasL-stimulated autocrine production of epidermal growth factor receptor (EGFR) ligands, and the subsequent activation of EGFR and ERK1 and ERK2 mitogen-activated protein kinases, were obligatory extracellular steps for the FasL-induced expression of a subset of inflammatory mediators, including CXCL8/interleukin (IL)-8, ICAM-1, IL-1alpha, IL-1beta, CCL20/MIP-3alpha, and thymic stromal lymphopoietin. These results expand the known physiological role of EGFR and its ligands from promoting keratinocyte mitogenesis and survival to mediating FasL-induced epidermal inflammation.

Compliance with dietary and nutrient recommendations in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Granada cohort at recruitment

BACKGROUND: The overall intake of energy and nutrients in the Granada EPIC-cohort (European Prospective Investigation into Cancer and Nutrition) is examined in order to assess compliance with the Spanish Nutritional Objectives (NO) and the Recommended Intakes (RI). METHODS: During recruitment (1992-1996), 7,789 participants, aged 35-69, were asked about diet through a validated diet history questionnaire. Nutrient intake is compared to the NO and RI that were valid at that time. Risk of inadequate intake is estimated as the percentage of the sample with intakes: ≤ 1/3 RI (high risk), ≤ 2/3 RI- > 1/3 RI (moderate risk), ≤ RI- > 2/3 RI, > RI. Differences in intakes have been analyzed by sex and age, and by smoking status and BMI. RESULTS: The daily intake of nutrients did not meet the NO as the total contribution of energy from proteins and fats exceeded these guidelines. Whilst intake of most nutrients was above the RI, the amount of iron, magnesium and vitamins D and E provided by the diet was not enough to meet the RI: in women aged 20-49 years, about 55% were at moderate risk for iron inadequacy, and a 20% of women for magnesium. Both sexes were at high risk of inadequacy for vitamin D, although sunlight exposure may supply adequate amounts. Never smokers showed a higher compliance to the NO. CONCLUSION: At recruitment, the nutrient profile of the diet was unbalanced. The observed nutrient inadequacy for iron, magnesium and vitamin E might be attributed to inappropriate dietary habits, and may have implications for future disease risk.

Twitch potentia induced by two different modalities of neuromuscular electrical stimulation: implications for motor unit recruitment.

INTRODUCTION: We tested the hypothesis that twitch potentiation would be greater following conventional (CONV) neuromuscular electrical stimulation (50-µs pulse width and 25-Hz frequency) compared with wide-pulse high-frequency (WPHF) neuromuscular electrical stimulation (1-ms, 100-Hz) and voluntary (VOL) contractions, because of specificities in motor unit recruitment (random in CONV vs. random and orderly in WPHF vs. orderly in VOL). METHODS: A single twitch was evoked by means of tibial nerve stimulation before and 2 s after CONV, WPHF, and VOL conditioning contractions of the plantar flexors (intensity: 10% maximal voluntary contraction; duration: 10 s) in 13 young healthy subjects. RESULTS: Peak twitch increased (P<0.05) after CONV (+4.5±4.0%) and WPHF (+3.3±5.9%), with no difference between the 2 modalities, whereas no changes were observed after VOL (+0.8±2.6%). CONCLUSIONS: Our results demonstrate that presumed differences in motor unit recruitment between WPHF and CONV do not seem to influence twitch potentiation results.

Fab antibodies capable of blocking T cells by competitive binding have the identical specificity but a higher affinity to the MHC-peptide-complex than the T cell receptor.

In transplant rejection, graft versus host or autoimmune diseases T cells are mediating the pathophysiological processes. Compared to unspecific pharmacological immune suppression specific inhibition of those T cells, that are involved in the disease, would be an alternative and attractive approach. T cells are activated after their T cell receptor (TCR) recognizes an antigenic peptide displayed by the Major Histocompatibility Complex (MHC). Molecules that interact with MHC-peptide-complexes in a specific fashion should block T cells with identical specificity. Using the model of the SSX2 (103-111)/HLA-A*0201 complex we investigated a panel of MHC-peptide-specific Fab antibodies for their capacity blocking specific T cell clones. Like TCRs all Fab antibodies reacted with the MHC complex only when the SSX2 (103-111) peptide was displayed. By introducing single amino acid mutations in the HLA-A*0201 heavy chain we identified the K66 residue as the most critical binding similar to that of TCRs. However, some Fab antibodies did not inhibit the reactivity of a specific T cell clone against peptide pulsed, artificial targets, nor cells displaying the peptide after endogenous processing. Measurements of binding kinetics revealed that only those Fab antibodies were capable of blocking T cells that interacted with an affinity in the nanomolar range. Fab antibodies binding like TCRs with affinities on the lower micromolar range did not inhibit T cell reactivity. These results indicate that molecules that block T cells by competitive binding with the TCR must have the same specificity but higher affinity for the MHC-peptide-complex than the TCR.

Malignant pleural mesothelioma: leukocyte recruitment is not required for drug delivery induced by photodynamic therapy in a human xenograft model

Objective: The pre-treatment of tumor neo-vessels by photodynamic therapy (PDT) was shown to improve the distribution of chemotherapy administered subsequently. However, the precise mechanism by which PDT modifies the tumor vasculature is unknown. We have recently shown that leukocyteendothelial cell interaction was essential for PDT induced drug delivery to normal tissue. Our purpose was to determine if PDT could enhance drug distribution in malignant mesothelioma and if a comparable role for leucocytes existed.Methods: We grew human mesothelioma xenografts (H-meso-1) in the dorsal skinfold chambers of nude mice (n = 28). The rolling, sticking and recruitment of leucocytes was assessed in tumor and normal vessels following PDT (Visudyne 0?4 mg/kg, fluence rate 200 mW/cm2, fluence 60 J/cm2) using intravital microscopy. In parallel, the distribution of a macromolecule (FITC dextran, 2000 kDa) administered after PDT was determined. We compared these variables in control (no PDT), PDT + IgG (non specific antibody) and PDT + pan-selectin antibody (monoclonal P-E-L selectin antibody).Results: PDT significantly enhanced the distribution of FITC dextran in mesothelioma xenografts compared to controls. Interestingly, PDT enhanced the leukocyte-endothelial interaction significantly (rolling and recruitment)in tumor and surrounding normal vessels compared to controls. Leukocyte recruitment was significantly down-regulated by pan-selectin antibodies in tumor tissues. However, the suppression of leucocyte recruitement did not affect the extravasation of FITC-dextran in tumor tissue.Conclusion:PDTpre-treatment of the mesothelioma vasculature can enhance the distribution of macromolecular drugs administered subsequently. However, unlike normal vessels, leukocyte-endothelial cell interaction is not required for PDT induced leakage.

Selective inhibition of CTL activation by a dipalmitoyl-phospholipid that prevents the recruitment of signaling molecules to lipid rafts.

Antigen-specific T-cell activation implicates a redistribution of plasma membrane-bound molecules in lipid rafts, such as the coreceptors CD8 and CD4, the Src kinases Lek and Fyn, and the linker for activation of T cells (LAT), that results in the formation of signaling complexes. These molecules partition in lipid rafts because of palmitoylation of cytoplasmic, membrane proximal cysteines, which is essential for their functional integrity in T-cell activation. Here, we show that exogenous dipalmitoyl-phosphatidylethanolamine (DPPE), but not the related unsaturated dioleoyl-phosphatidylethanolamine (DOPE), partitions in lipid rafts. DPPE inhibits activation of CD8(+) T lymphocytes by sensitized syngeneic antigen-presenting cells or specific major histocompatibility complex (MHC) peptide tetramers, as indicated by esterase release and intracellular calcium mobilization. Cytotoxic, T lymphocyte (CTL)-target cell conjugate formation is not affected by DPPE, indicating that engagement of the T-cell receptor by its cognate ligand is intact in lipid-treated cells. In contrast to other agents known to block raft-dependent signaling, DPPE efficiently inhibits the MHC peptide-induced recruitment of palmitoylated signaling molecules to lipid rafts and CTL activation without affecting cell viability or lipid raft integrity.

Recruitment of TNF receptor 1 to lipid rafts is essential for TNFalpha-mediated NF-kappaB activation.

Engagement of TNF receptor 1 by TNFalpha activates the transcription factor NF-kappaB but can also induce apoptosis. Here we show that upon TNFalpha binding, TNFR1 translocates to cholesterol- and sphingolipid-enriched membrane microdomains, termed lipid rafts, where it associates with the Ser/Thr kinase RIP and the adaptor proteins TRADD and TRAF2, forming a signaling complex. In lipid rafts, TNFR1 and RIP are ubiquitylated. Furthermore, we provide evidence that translocation to lipid rafts precedes ubiquitylation, which leads to the degradation via the proteasome pathway. Interfering with lipid raft organization not only abolishes ubiquitylation but switches TNFalpha signaling from NF-kappaB activation to apoptosis. We suggest that lipid rafts are crucial for the outcome of TNFalpha-activated signaling pathways.