Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

OBJECTIVE OF THE STUDY: Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. METHODOLOGY AND PRINCIPAL FINDINGS: Streptozotocin (STZ)-induced diabetes in apolipoprotein E(-/-) mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. CONCLUSIONS: Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications

Vibrational Relaxation and Redistribution Dynamics in Ruthenium(II) Polypyridyl-Based Charge-Transfer Excited States: A Combined Ultrafast Electronic and Infrared Absorption Study

Ultrafast time-resolved electronic and infrared absorption measurements have been carried out on a series of Ru­(II) polypyridyl complexes in an effort to delineate the dynamics of vibrational relaxation in this class of charge transfer chromophores. Time-dependent density functional theory calculations performed on compounds of the form [Ru­(CN-Me-bpy)x(bpy)3‑x]2+ (x = 1–3 for compounds 1–3, respectively, where CN-Me-bpy is 4,4′-dicyano-5,5′-dimethyl-2,2′-bipyridine and bpy is 2,2′-bipyridine) reveal features in their charge-transfer absorption envelopes that allow for selective excitation of the Ru­(II)–(CN-Me-bpy) moiety, the lowest-energy MLCT state(s) in each compound of the series. Changes in band shape and amplitude of the time-resolved differential electronic absorption data are ascribed to vibrational cooling in the CN-Me-bpy-localized 3MLCT state with a time constant of 8 ± 3 ps in all three compounds. This conclusion was corroborated by picosecond time-resolved infrared absorption measurements; sharpening of the CN stretch in the 3MLCT excited state was observed with a time constant of 3.0 ± 1.5 ps in all three members of the series. Electronic absorption data acquired at higher temporal resolution revealed spectral modulation over the first 2 ps occurring with a time constant of τ = 170 ± 50 fs, in compound 1; corresponding effects are significantly attenuated in compound 2 and virtually absent in compound 3. We assign this feature to intramolecular vibrational redistribution (IVR) within the 3MLCT state and represents a rare example of this process being identified from time-resolved electronic absorption data for this important class of chromophores

Modelling Pricing Policy Based on Shelf-Life of Non Homogeneous Available-To-Promise in Fruit Supply Chains

[EN] Fruit Supply Chains (SCs) are influenced by uncontrollable natural factors causing heterogeneity in their products, as regards certain attributes that are relevant to customers and vary over time because of the shelf-life. As a consequence customers should be served not only with the required quantity and due date as usual, but also with the quality, freshness and homogeneity specified in their orders. The order promising process (OPP) is based on the uncommitted availability of homogeneous product quantities in planned lots (ATP) that are uncertain. Therefore, there is a risk of not being reliable in the commitments because of discrepancies between the real and planned homogeneous quantities. Furthermore, due to the shelf-life (SL), serving customers with the freshest product introduce the risk of increasing waste because of the aging process. To efficiently manage these risks, this work proposes a mathematical model for handling the heterogeneous ATP in fruit SCs and a pricing policy based on the product SL in the moment of delivery. In order to illustrate the application of the modelling approach, a short numerical example is introduced. The example evidences a conflictive situation when optimizing the assignation of homogeneous ATP between serving orders with fresh and more valuable product, what could lead to increase the risk of having waste because of expiration, and consequently, more costs and less profit.This research has been supported by the Ministry of Science, Technology and Telecommunications, government of Costa Rica (MICITT), through the program of innovation and human capital for competitiveness (PINN) (PED-019-2015-1).Grillo-Espinoza, H.; Alemany Díaz, MDM.; Ortiz Bas, Á. (2016). Modelling Pricing Policy Based on Shelf-Life of Non Homogeneous Available-To-Promise in Fruit Supply Chains. IFIP Advances in Information and Communication Technology. 480:608-617. https://doi.org/10.1007/978-3-319-45390-3_52S608617480Alarcon, F., Alemany, M.M.E., Lario, F.C., Oltra, R.F.: The lack of homogeneity in the product (LHP) in the ceramic tile industry and its impact on the reallocation of inventories. Boletin Soc. Espanola Ceram. Vidr. 50, 49–57 (2011). doi: 10.3989/cyv.072011Alemany, M.M.E., Grillo, H., Ortiz, A., Fuertes-Miquel, V.S.: A fuzzy model for shortage planning under uncertainty due to lack of homogeneity in planned production lots. Appl. Math. Model. (2015). doi: 10.1016/j.apm.2014.12.057Alemany, M.M.E., Lario, F.-C., Ortiz, A., Gomez, F.: Available-To-Promise modeling for multi-plant manufacturing characterized by lack of homogeneity in the product: an illustration of a ceramic case. Appl. Math. Model. 37, 3380–3398 (2013). doi: 10.1016/j.apm.2012.07.022Blanco, A.M., Masini, G., Petracci, N., Bandoni, J.A.: Operations management of a packaging plant in the fruit industry. J. Food Eng. 70, 299–307 (2005). doi: 10.1016/j.jfoodeng.2004.05.075Grillo, H., Alemany, M.M.E., Ortiz, A.: A review of mathematical models for supporting the order promising process under Lack of Homogeneity in Product and other sources of uncertainty. Comput. Ind. Eng. 91, 239–261 (2016)Kilic, O.A., van Donk, D.P., Wijngaard, J., Tarim, S.A.: Order acceptance in food processing systems with random raw material requirements. Spectrum 32, 905–925 (2010). doi: 10.1007/s00291-010-0213-4Lin, J.T., Hong, I.H., Wu, C.H., Wang, K.S.: A model for batch available-to-promise in order fulfillment processes for TFT-LCD production chains. Comput. Ind. Eng. 59, 720–729 (2010). doi: 10.1016/j.cie.2010.07.026Maihami, R., Karimi, B.: Optimizing the pricing and replenishment policy for non-instantaneous deteriorating items with stochastic demand and promotional efforts. Comput. Oper. Res. 51, 302–312 (2014). doi: 10.1016/j.cor.2014.05.022Mundi, M.I., Alemany, M.M.E., Poler, R., Fuertes-Miquel, V.S.: Fuzzy sets to model master production effectively in Make to Stock companies with Lack of Homogeneity in the Product. Fuzzy Sets Syst. 293, 95–112 (2016). http://dx.doi.org/10.1016/j.fss.2015.06.009Tsao, Y.-C., Sheen, G.-J.: Dynamic pricing, promotion and replenishment policies for a deteriorating item under permissible delay in payments. Part Spec. Issue Top. Real-Time Supply Chain Manag. 35, 3562–3580 (2008). doi: 10.1016/j.cor.2007.01.02

The effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle-closure glaucoma (EAGLE) : study protocol for a randomized controlled trial

Peer reviewedPublisher PD

EXPERIENCIAS, PERCEPCIONES Y NECESIDADES EN LA UCI: REVISIÓN SISTEMÁTICA DE ESTUDIOS CUALITATIVOS.

Introduction: The intensity of the experience that represents going through an Intensive Care Unit is undeniable. A focus of phenomenological type using qualitative methodology can provide us with a relevant view. The objective of our study is to gather the experiences and patient families and nurses needs in the ICU. Methodology: Qualitative systematic revision meta-study. Presentation of 21 studies. Results: The following categories have been used: Patient experiences, patient needs, stress and confrontation strategies; family experiences, family needs; related nurse-family; nurses regarding the experiences of the patient family; nurses experiences; nurses image. Conclusion: The patient-families demand information, an open visit system, personalized attention, human treatment… Nurses demand a wider training in social abilities. The sanitary administration should also consider the family like an attention nucleus in the ICU, providing resources for it.Introducción. La intensidad de la experiencia que supone pasar por una Unidad de Cuidados Intensivos es innegable. Un enfoque de tipo fenomenológico empleando la metodología cualitativa nos puede proporcionar una acertada visión de la misma. El objetivo de nuestro trabajo es recopilar las vivencias, necesidades de los pacientes-familias y enfermeras de estas unidades. Metodología. Metaestudio tipo revisión sistemática cualitativa. 21 estudios incluidos. Resultados. Se han agrupado en las categorías: experiencias del paciente, necesidades del paciente, estrés y estrategias de afrontamiento; vivencias de la familia, necesidades de la familia; relaciones enfermera-familia; las enfermeras respecto a las vivencias del paciente-familia; vivencias de las enfermeras; imagen de las enfermeras. Conclusión. Los pacientes-familias demandan información, un sistema abierto de visitas, atención personalizada, humanización… Las enfermeras demandamos una formación más amplia en habilidades sociales. La gestión sanitaria debe considerar también a la familia como núcleo de atención en estas unidades, proporcionando recursos para ello

Towards interoperability in the european poetry community: the standardization of philological concepts

This paper stems from the Poetry Standardization and Linked Open Data project (POSTDATA). As its name reveals, one of the main aims of POSTDATA is to provide a means to publish European poetry (EP) data as Linked Open Data (LOD). Thus, developing a metadata application profile (MAP) as a common semantic model to be used by the EP community is a crucial step of this project. This MAP will enhance interoperability among the community members in particular, and among the EP community and other contexts in general (e.g. bibliographic records). This paper presents the methodology followed in the process of defining the concepts of the domain model of this MAP, as well as some issues that arise when labeling philological terms.info:eu-repo/semantics/publishedVersio

Transpiration from subarctic deciduous woodlands: environmental controls and contribution to ecosystem evapotranspiration

Potential land‐climate feedbacks in subarctic regions, where rapid warming is driving forest expansion into the tundra, may be mediated by differences in transpiration of different plant functional types. Here we assess the environmental controls of overstorey transpiration and its relevance for ecosystem evapotranspiration in subarctic deciduous woodlands. We measured overstorey transpiration of mountain birch canopies and ecosystem evapotranspiration in two locations in northern Fennoscandia, having dense (Abisko) and sparse (Kevo) overstories. For Kevo, we also upscale chamber‐measured understorey evapotranspiration from shrubs and lichen using a detailed land cover map. Sub‐daily evaporative fluxes were not affected by soil moisture, and showed similar controls by vapour pressure deficit and radiation across sites. At the daily timescale, increases in evaporative demand led to proportionally higher contributions of overstorey transpiration to ecosystem evapotranspiration. For the entire growing season, the overstorey transpired 33% of ecosystem evapotranspiration in Abisko and only 16% in Kevo. At this latter site, the understorey had a higher leaf area index and contributed more to ecosystem evapotranspiration compared to the overstorey birch canopy. In Abisko, growing season evapotranspiration was 27% higher than precipitation, consistent with a gradual soil moisture depletion over the summer. Our results show that overstorey canopy transpiration in subarctic deciduous woodlands is not the dominant evaporative flux. However, given the observed environmental sensitivity of evapotranspiration components, the role of deciduous trees in driving ecosystem evapotranspiration may increase with the predicted increases in tree cover and evaporative demand across subarctic regions

Evidence-based practice educational intervention studies: A systematic review of what is taught and how it is measured

Abstract Background Despite the established interest in evidence-based practice (EBP) as a core competence for clinicians, evidence for how best to teach and evaluate EBP remains weak. We sought to systematically assess coverage of the five EBP steps, review the outcome domains measured, and assess the properties of the instruments used in studies evaluating EBP educational interventions. Methods We conducted a systematic review of controlled studies (i.e. studies with a separate control group) which had investigated the effect of EBP educational interventions. We used citation analysis technique and tracked the forward and backward citations of the index articles (i.e. the systematic reviews and primary studies included in an overview of the effect of EBP teaching) using Web of Science until May 2017. We extracted information on intervention content (grouped into the five EBP steps), and the outcome domains assessed. We also searched the literature for published reliability and validity data of the EBP instruments used. Results Of 1831 records identified, 302 full-text articles were screened, and 85 included. Of these, 46 (54%) studies were randomised trials, 51 (60%) included postgraduate level participants, and 63 (75%) taught medical professionals. EBP Step 3 (critical appraisal) was the most frequently taught step (63 studies; 74%). Only 10 (12%) of the studies taught content which addressed all five EBP steps. Of the 85 studies, 52 (61%) evaluated EBP skills, 39 (46%) knowledge, 35 (41%) attitudes, 19 (22%) behaviours, 15 (18%) self-efficacy, and 7 (8%) measured reactions to EBP teaching delivery. Of the 24 instruments used in the included studies, 6 were high-quality (achieved ≥3 types of established validity evidence) and these were used in 14 (29%) of the 52 studies that measured EBP skills; 14 (41%) of the 39 studies that measured EBP knowledge; and 8 (26%) of the 35 studies that measured EBP attitude. Conclusions Most EBP educational interventions which have been evaluated in controlled studies focus on teaching only some of the EBP steps (predominantly critically appraisal of evidence) and did not use high-quality instruments to measure outcomes. Educational packages and instruments which address all EBP steps are needed to improve EBP teaching

Variation in Seed Dormancy Quantitative Trait Loci in Arabidopsis thaliana Originating from One Site

A Quantitative Trait Locus (QTL) analysis was performed using two novel Recombinant Inbred Line (RIL) populations, derived from the progeny between two Arabidopsis thaliana genotypes collected at the same site in Kyoto (Japan) crossed with the reference laboratory strain Landsberg erecta (Ler). We used these two RIL populations to determine the genetic basis of seed dormancy and flowering time, which are assumed to be the main traits controlling life history variation in Arabidopsis. The analysis revealed quantitative variation for seed dormancy that is associated with allelic variation at the seed dormancy QTL DOG1 (for Delay Of Germination 1) in one population and at DOG6 in both. These DOG QTL have been previously identified using mapping populations derived from accessions collected at different sites around the world. Genetic variation within a population may enhance its ability to respond accurately to variation within and between seasons. In contrast, variation for flowering time, which also segregated within each mapping population, is mainly governed by the same QTL

Assisted evolution enables HIV-1 to overcome a high trim5α-imposed genetic barrier to rhesus macaque tropism

Diversification of antiretroviral factors during host evolution has erected formidable barriers to cross-species retrovirus transmission. This phenomenon likely protects humans from infection by many modern retroviruses, but it has also impaired the development of primate models of HIV-1 infection. Indeed, rhesus macaques are resistant to HIV-1, in part due to restriction imposed by the TRIM5α protein (rhTRIM5α). Initially, we attempted to derive rhTRIM5α-resistant HIV-1 strains using two strategies. First, HIV-1 was passaged in engineered human cells expressing rhTRIM5α. Second, a library of randomly mutagenized capsid protein (CA) sequences was screened for mutations that reduced rhTRIM5α sensitivity. Both approaches identified several individual mutations in CA that reduced rhTRIM5α sensitivity. However, neither approach yielded mutants that were fully resistant, perhaps because the locations of the mutations suggested that TRIM5α recognizes multiple determinants on the capsid surface. Moreover, even though additive effects of various CA mutations on HIV-1 resistance to rhTRIM5α were observed, combinations that gave full resistance were highly detrimental to fitness. Therefore, we employed an 'assisted evolution' approach in which individual CA mutations that reduced rhTRIM5α sensitivity without fitness penalties were randomly assorted in a library of viral clones containing synthetic CA sequences. Subsequent passage of the viral library in rhTRIM5α-expressing cells resulted in the selection of individual viral species that were fully fit and resistant to rhTRIM5α. These viruses encoded combinations of five mutations in CA that conferred complete or near complete resistance to the disruptive effects of rhTRIM5α on incoming viral cores, by abolishing recognition of the viral capsid. Importantly, HIV-1 variants encoding these CA substitutions and SIVmac239 Vif replicated efficiently in primary rhesus macaque lymphocytes. These findings demonstrate that rhTRIM5α is difficult to but not impossible to evade, and doing so should facilitate the development of primate models of HIV-1 infection