Critical role of extracellular vesicles in modulating the cellular effects of cytokines

Under physiological and pathological conditions, extracellular vesicles (EVs) are present in the extracellular compartment simultaneously with soluble mediators. We hypothesized that cytokine effects may be modulated by EVs, the recently recognized conveyors of intercellular messages. In order to test this hypothesis, human monocyte cells were incubated with CCRF acute lymphoblastic leukemia cell line-derived EVs with or without the addition of recombinant human TNF, and global gene expression changes were analyzed. EVs alone regulated the expression of numerous genes related to inflammation and signaling. In combination, the effects of EVs and TNF were additive, antagonistic, or independent. The differential effects of EVs and TNF or their simultaneous presence were also validated by Taqman assays and ELISA, and by testing different populations of purified EVs. In the case of the paramount chemokine IL-8, we were able to demonstrate a synergistic upregulation by purified EVs and TNF. Our data suggest that neglecting the modulating role of EVs on the effects of soluble mediators may skew experimental results. On the other hand, considering the combined effects of cytokines and EVs may prove therapeutically useful by targeting both compartments at the same time.     

Epigenetics: a link between addiction and social environment

The detrimental effects of drug abuse are apparently not limited to individuals but may also impact the vulnerability of their progenies to develop addictive behaviours. Epigenetic signatures, early life experience and environmental factors, converge to influence gene expression patterns in addiction phenotypes and consequently may serve as mediators of behavioural trait transmission between generations. The majority of studies investigating the role of epigenetics in addiction do not consider the influence of social interactions. This shortcoming in current experimental approaches necessitates developing social models that reflect the addictive behaviour in a free-living social environment. Furthermore, this review also reports on the advancement of interventions for drug addiction and takes into account the emerging roles of histone deacetylase (HDAC) inhibitors in the etiology of drug addiction and that HDAC may be a potential therapeutic target at nucleosomal level to improve treatment outcomes.     

Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3

The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC₃, MC₄, and MC₅ receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r?/? mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC₃ PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases.     

Operationalising “Double-Loop” Learning in Service Organisations: A Systems Approach for Creating Knowledge

Learning organisation literature has widely discussed the connections between “double-loop” learning and its significance to organisational performance, but paying little attention to tools and systems that can operationalise “double-loop” learning in organisations. This paper investigates the impact of applying a systems approach for service operations design, expressed as the Vanguard Method (Seddon, Freedom from command and control: a better way to make the work work, 2003), in order to activate “double-loop” learning in service organisations. Two case studies were conducted in the banking mortgage operations and adults’ social care services in the UK, using the dimensions of the learning organisation questionnaire (DLOQ), semi-structured interviews, observations, and documents. The findings of the cross-case analysis support the link of applying the Vanguard Method with operationalising “double-loop” learning through three main factors, namely systematic-operations improvement, organisational capacity development, and outside-in mode of work; that are all embedded into the seven dimensions of the DLOQ. The value of this paper is the introduction of a service operations design tool that can activate “double-loop” learning performance in the fast changing knowledge era. It also provides an impetus for service organisations to creatively influence employees’ competencies to effectively improve internal systems.     

Arboreality predicts Batrachochytrium dendrobatidis infection level in tropical direct-developing frogs

Pathogen-mediated changes in host behaviour can result from hosts altering their habitat preferences. Although infection risk with pathogenic fungus Batrachochytrium dendrobatidis in amphibians is associated with environments favouring its growth, the relationship with microhabitat use has not been examined. Here, we aim to determine if microhabitats used by frogs during their nocturnal activity predict B. dendrobatidis prevalence and infection intensity. Our focal host, Eleutherodactylus coqui, is a habitat generalist that uses multiple habitats from the forest floor to the canopy. We analysed data on B. dendrobatidis occurrence in 157 adults and 122 juveniles at El Yunque National forest in Puerto Rico. We categorized each individual’s nocturnal microhabitat as forest floor, curled palm fronds in the floor, arboreal bromeliads and foliage or tree trunks 50 cm to 2.5 m above ground. We found that frogs on the forest floor had the greatest B. dendrobatidis prevalence (73%), compared with those active in vegetation above ground (55%). Overall, the probability of B. dendrobatidis infection in frogs using microhabitats on the forest floor was twice as great as for those on arboreal substrates. Differences in B. dendrobatidis prevalence and intensity in E. coqui may be explained by specific abiotic conditions of microenvironments (temperature and humidity) affecting both pathogen and host, and by the age-specific ecological requirements of hosts. Adults were found to be most active in microhabitats where individuals had lower infection burdens, suggesting pathogen-modulated habitat choice. This work has important implications for the evolutionary dynamics of enzootic diseases and provides data that may inform potential mitigation strategies against a generalist amphibian pathogen.     

Palaeoclimatic distribution models predict Pleistocene refuges for the Neotropical harvestman Geraeocormobius sylvarum (Arachnida: Opiliones: Gonyleptidae)

This paper primarily aims to test a Pleistocene refuge-type scenario, as previously proposed for the gonyleptid Geraeocormobius sylvarum, a semi-deciduous forests dweller in subtropical Argentina, Brazil and Paraguay. Palaeodistributional models of this species were built using MaxEnt for two Last Glacial Maximum (LGM = 21,000 years ago) simulations – Community Climate System Model (CCSM) and Model for Interdisciplinary Research on Climate (MIROC) – and for 6000 years ago (?6k = HCO, the Holocene climatic optimum). Both LGM models retrieved a fragmented pattern. For CCSM, range was split into multiple, scattered fragments. MIROC resulted in very few patches, with a decided range reduction because of a strong humidity drop. Models for ?6k recovered a moderate range expansion. No past connection between the core area and the yungas was predicted. Analysis of variables importance showed that two precipitation predictors (bc18, precipitation warmest quarter; bc14, precipitation driest month) and two temperature predictors (bc7, temperature annual range; bc9, mean temperature driest quarter) scored as the most influencing overall. The Limiting Factor analysis recognized them as limiting too, in different parts of the species range. LGM palaeomodels of G. sylvarum are compatible with the refuge hypothesis invoked in previous molecular analyses, to explain the high genetic diversity found in the core area. Additionally, the results reinforced the hypothesis of the recent anthropogenic origin of the yungas disjunct populations.