The case for formal theory

The article introduces this issue of "Academy of Management Review" which focuses on topics such as the performance differentials between diversified companies and new business enterprises, the prediction of business mortality that is based on the industry conditions at the time of the company's founding, and the free-rider problem

Sex differences in the ability of corticostriatal oscillations to predict rodent alcohol consumption

Background: Although male and female rats differ in their patterns of alcohol use, little is known regarding the neural circuit activity that underlies these differences in behavior. The current study used a machine learning approach to characterize sex differences in local field potential (LFP) oscillations that may relate to sex differences in alcohol-drinking behavior. Methods: LFP oscillations were recorded from the nucleus accumbens shell and the rodent medial prefrontal cortex of adult male and female Sprague-Dawley rats. Recordings occurred before rats were exposed to alcohol (n = 10/sex × 2 recordings/rat) and during sessions of limited access to alcohol (n = 5/sex × 5 recordings/rat). Oscillations were also recorded from each female rat in each phase of estrous prior to alcohol exposure. Using machine learning, we built predictive models with oscillation data to classify rats based on: (1) biological sex, (2) phase of estrous, and (3) alcohol intake levels. We evaluated model performance from real data by comparing it to the performance of models built and tested on permutations of the data. Results: Our data demonstrate that corticostriatal oscillations were able to predict alcohol intake levels in males (p \u3c 0.01), but not in females (p = 0.45). The accuracies of models predicting biological sex and phase of estrous were related to fluctuations observed in alcohol drinking levels; females in diestrus drank more alcohol than males (p = 0.052), and the male vs. diestrus female model had the highest accuracy (71.01%) compared to chance estimates. Conversely, females in estrus drank very similar amounts of alcohol to males (p = 0.702), and the male vs. estrus female model had the lowest accuracy (56.14%) compared to chance estimates. Conclusions: The current data demonstrate that oscillations recorded from corticostriatal circuits contain significant information regarding alcohol drinking in males, but not alcohol drinking in females. Future work will focus on identifying where to record LFP oscillations in order to predict alcohol drinking in females, which may help elucidate sex-specific neural targets for future therapeutic development

The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation

Toll-like receptor (TLR) 7 agonists are known to reduce allergic airway inflammation. Their recently reported ability to rapidly relax airways has further increased their interest in the treatment of pulmonary disease. However, the mechanisms behind this effect are not fully understood. The present study, therefore, aimed to determine whether airway smooth muscle (ASM)-dependent mechanisms could be identified. TLR7 agonists were added to guinea pig airways following precontraction with carbachol in vitro or histamine in vivo. Pharmacological inhibitors were used to dissect conventional pathways of bronchodilation; tetrodotoxin was used or bilateral vagotomy was performed to assess neuronal involvement. Human ASM cells (HASMCs) were employed to determine the effect of TLR7 agonists on intracellular Ca(2+) ([Ca(2+)]i) mobilization. The well-established TLR7 agonist imiquimod rapidly relaxed precontracted airways in vitro and in vivo. This relaxation was demonstrated to be independent of nitric oxide, carbon monoxide, and cAMP signaling, as well as neuronal activity. A limited role for prostanoids could be detected. Imiquimod induced [Ca(2+)]i release from endoplasmic reticulum stores in HASMCs, inhibiting histamine-induced [Ca(2+)]i The TLR7 antagonist IRS661 failed to inhibit relaxation, and the structurally dissimilar agonist CL264 did not relax airways or inhibit [Ca(2+)]i This study shows that imiquimod acts directly on ASM to induce bronchorelaxation, via a TLR7-independent release of [Ca(2+)]i The effect is paralleled by other bronchorelaxant compounds, like chloroquine, which, like imiquimod, but unlike CL264, contains the chemical structure quinoline. Compounds with quinoline moieties may be of interest in the development of multifunctional drugs to treat pulmonary disease.FWN – Publicaties zonder aanstelling Universiteit Leide

The bronchodilatory capacity of imiquimod: the existence of two mechanisms

FWN – Publicaties zonder aanstelling Universiteit Leide

Mannitol triggers mast cell-dependent contractions of human small bronchi and prostacyclin bronchoprotection

BACKGROUND:Clinical research supports that exercise-induced bronchoconstriction (EIB) is caused by hyperosmolar triggering of mast cells. The reaction can be mimicked by inhalation of mannitol, but it has paradoxically previously not been possible to replicate this mode of action of mannitol in isolated airways. OBJECTIVE:We sought to establish an ex vivo model of EIB in human small bronchi. METHODS:Small bronchi (inner diameter, 0.5-2 mm) from macroscopically healthy human lung tissue were obtained from 48 patients and mounted in organ baths. Contractions and mediator release were analyzed after challenge with hyperosmolar mannitol (850 mOsm). RESULTS:Ten minutes of exposure to mannitol caused a small initial contraction (12% ± 1% of maximum) that was followed by a second and much larger contraction (maximum effect [Emax], 47% ± 5%) when mannitol was washed out. The mast cell stabilizer cromolyn reduced the second contraction (Emax, 27% ± 3%). Furthermore, this main contraction was abolished by the combination of antagonists of histamine and cysteinyl leukotrienes in the presence of indomethacin. Mannitol increased the release of the mast cell mediators histamine (9.0-fold), cysteinyl leukotrienes (4.5-fold), and prostaglandin (PG) D2 (5.4-fold), as well as PGE2 (6.3-fold) and the prostacyclin metabolite 6-keto PGF1α (5.7-fold). In contrast, indomethacin alone enhanced the bronchoconstriction (Emax, 68% ± 6%). Likewise, receptor antagonists for PGE2 (EP2 and EP4) and prostacyclin (IP) also enhanced the mannitol-induced bronchoconstriction (Emax, 67% ± 5%, 66% ± 4%, and 68% ± 3%, respectively). In bronchi precontracted by carbachol, the IP receptor agonist cicaprost induced profound relaxation. CONCLUSION:This new protocol established an in vitro model for studies of EIB in isolated human bronchi. The IP receptor might be a new target for asthma treatment.FWN – Publicaties zonder aanstelling Universiteit Leide

When culture meets digital platforms: value creation and stakeholders' alignment in big data use

Research on big data has highlighted that a crucial element to create value from data is the capability of aligning different stakeholders’ interests. However, it has not yet been investigated empirically how this process of alignment can be realized. We conduct a multiple case study on the two leading platforms involved in the online dissemination of cultural heritage – Europeana and Google Arts & Culture. Our findings reveal that a platform overtakes a rival one when it turns on multiple drivers of value creation in such a way that the drivers contribute to realigning the interests expressed by the stakeholders whose strategic objectives and beliefs were formerly divergent – or simply unrelated – to each other. This capability of realigning different stakeholders’ interests is independent of the level of industry-specific knowledge that the platform orchestrator has. The dynamics we document imply that Google has assumed a system integration role in the cultural ecosystem. This generates new trade-offs for museums in the way they generate value for the tourism industry. The paper enriches our understanding of what strategies digital platforms adopt to create value in big data contexts and provides a base to continue the investigation on other ecosystems driven by big data

Intranasal Administration of poly(I:C) and LPS in BALB/c Mice Induces Airway Hyperresponsiveness and Inflammation via Different Pathways

BACKGROUND: Bacterial and viral infections are known to promote airway hyperresponsiveness (AHR) in asthmatic patients. The mechanism behind this reaction is poorly understood, but pattern recognizing Toll-like receptors (TLRs) have recently been suggested to play a role. MATERIALS AND METHODS: To explore the relation between infection-induced airway inflammation and the development of AHR, poly(I:C) activating TLR3 and LPS triggering TLR4, were chosen to represent viral and bacterial induced interactions, respectively. Female BALB/c or MyD88-deficient C57BL/6 mice were treated intranasally with either poly(I:C), LPS or PBS (vehicle for the control group), once a day, during 4 consecutive days. RESULTS: When methacholine challenge was performed on day 5, BALB/c mice responded with an increase in airway resistance. The maximal resistance was higher in the poly(I:C) and LPS treated groups than among the controls, indicating development of AHR in response to repeated TLR activation. The proportion of lymphocytes in broncheoalveolar lavage fluid (BALF) increased after poly(I:C) treatment whereas LPS enhanced the amount of neutrophils. A similar cellular pattern was seen in lung tissue. Analysis of 21 inflammatory mediators in BALF revealed that the TLR response was receptor-specific. MyD88-deficient C57BL/6 mice responded to poly (I:C) with an influx of lymphocytes, whereas LPS caused no inflammation. CONCLUSION: In vivo activation of TLR3 and TLR4 in BALB/c mice both caused AHR in conjunction with a local inflammatory reaction. The AHR appeared to be identical regardless of which TLR that was activated, whereas the inflammation exhibited a receptor specific profile in terms of both recruited cells and inflammatory mediators. The inflammatory response caused by LPS appeared to be dependent on MyD88 pathway. Altogether the presented data indicate that the development of AHR and the induction of local inflammation might be the result of two parallel events, rather than one leading to another

Up-regulation of endothelin type B receptors in the human internal mammary artery in culture is dependent on protein kinase C and mitogen-activated kinase signaling pathways

<p>Abstract</p> <p>Background</p> <p>Up-regulation of vascular endothelin type B (ET_B) receptors is implicated in the pathogenesis of cardiovascular disease. Culture of intact arteries has been shown to induce similar receptor alterations and has therefore been suggested as a suitable method for, <it>ex vivo</it>, in detail delineation of the regulation of endothelin receptors. We hypothesize that mitogen-activated kinases (MAPK) and protein kinase C (PKC) are involved in the regulation of endothelin ET_Breceptors in human internal mammary arteries.</p> <p>Methods</p> <p>Human internal mammary arteries were obtained during coronary artery bypass graft surgery and were studied before and after 24 hours of organ culture, using <it>in vitro </it>pharmacology, real time PCR and Western blot techniques. Sarafotoxin 6c and endothelin-1 were used to examine the endothelin ET_Aand ET_Breceptor effects, respectively. The involvement of PKC and MAPK in the endothelin receptor regulation was examined by culture in the presence of antagonists.</p> <p>Results</p> <p>The endohtelin-1-induced contraction (after endothelin ET_Breceptor desensitization) and the endothelin ET_Areceptor mRNA expression levels were not altered by culture. The sarafotoxin 6c contraction, endothelin ET_Breceptor protein and mRNA expression levels were increased after organ culture. This increase was antagonized by; (1) PKC inhibitors (10 μM bisindolylmaleimide I and 10 μM Ro-32-0432), and (2) inhibitors of the p38, extracellular signal related kinases 1 and 2 (ERK1/2) and C-jun terminal kinase (JNK) MAPK pathways (10 μM SB203580, 10 μM PD98059 and 10 μM SP600125, respectively).</p> <p>Conclusion</p> <p>In conclusion, PKC and MAPK seem to be involved in the up-regulation of endothelin ET_Breceptor expression in human internal mammary arteries. Inhibiting these intracellular signal transduction pathways may provide a future therapeutic target for hindering the development of vascular endothelin ET_Breceptor changes in cardiovascular disease.</p

IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways

BACKGROUND:Specific inflammatory pathways are indicated to contribute to severe asthma, but their individual involvement in the development of airway hyperresponsiveness remains unexplored. OBJECTIVE:This experimental study in human small bronchi aimed to provide insight into which of the type 2 and type 17 cytokines cause hyperresponsiveness of airway smooth muscle. METHODS:Explanted small bronchi isolated from human lung tissue and human airway smooth muscle cells were treated for 2 and 1 day(s), respectively, with 100 ng/mL of IL-4, IL-5, IL-13, or IL-17A, and contractile responses, Ca2+ mobilization, and receptor expression were assessed. RESULTS:Treatment with IL-13 increased the potency of histamine, carbachol, and leukotriene D4 as contractile agonists. IL-4, but not IL-5 or IL-17A, also increased the potency of histamine. In human airway smooth muscle cells, IL-13 and IL-4, but not IL-5 and IL-17A, enhanced the histamine-induced Ca2+ mobilization that was accompanied with increased mRNA expression of histamine H1 and cysteinyl leukotriene CysLT1 receptors. RNA sequencing of isolated bronchi confirmed the IL-13-mediated upregulation of H1 and CysLT1 receptors, without showing an alteration of muscarinic M3 receptors. Dexamethasone had no effects on IL-13-induced hyperresponsiveness in human bronchi, the increased Ca2+ mobilization, or the enhanced receptor expression. In contrast, antagonism of the common receptor for IL-13 and IL-4 by the biologic dupilumab prevented the effects of both IL-13 and IL-4 in human bronchi and human airway smooth muscle cells. CONCLUSIONS:The glucocorticoid-insensitive hyperrresponsiveness in isolated human airways induced by IL-13 and IL-4 provides further evidence that the IL-4Rα pathway should be targeted as a new strategy for the treatment of airway hyperresponsiveness in asthma.FWN – Publicaties zonder aanstelling Universiteit Leide

Back to the future:re-establishing guinea pig in vivo asthma models

Research using animal models of asthma is currently dominated by mouse models. This has been driven by the comprehensive knowledge on inflammatory and immune reactions in mice, as well as tools to produce genetically modified mice. Many of the identified therapeutic targets influencing airway hyper-responsiveness and inflammation in mouse models, have however been disappointing when tested clinically in asthma. It is therefore a great need for new animal models that more closely resemble human asthma. The guinea pig has for decades been used in asthma research and a comprehensive table of different protocols for asthma models is presented. The studies have primarily been focused on the pharmacological aspects of the disease, where the guinea pig undoubtedly is superior to mice. Further reasons are the anatomical and physiological similarities between human and guinea pig airways compared with that of the mouse, especially with respect to airway branching, neurophysiology, pulmonary circulation and smooth muscle distribution, as well as mast cell localization and mediator secretion. Lack of reagents and specific molecular tools to study inflammatory and immunological reactions in the guinea pig has however greatly diminished its use in asthma research. The aim in this position paper is to review and summarize what we know about different aspects of the use of guinea pig in vivo models for asthma research. The associated aim is to highlight the unmet needs that have to be addressed in the future