El análisis de la conectividad funcional mediante resonancia magnética funcional (RMf) puede llevarse a cabo durante la realización de una tarea, la percepción de un estímulo o en estado de reposo. ...Estos análisis han demostrado su fiabilidad y reproducibilidad con diferentes enfoques (matemáticos, estadísticos, físicos) para seleccionar los vóxeles activados. El estudio de la señal de baja frecuencia en la actividad cerebral a través del contraste BOLD en estado de reposo ha revelado patrones de actividad cortical sincronizados, permitiendo describir la arquitectura funcional intrínseca del cerebro humano. La comunidad científica internacional dispone de recursos compartidos que contribuirán mediante este análisis de RMf en estado de reposo a la obtención de diagnósticos y tratamientos más precisos y avanzados en el campo de las neurociencias.
Biological activity of natural retinoids requires the oxidation of retinol to retinoic acid (RA) and its binding to specific nuclear receptors in target tissues. The first step of this pathway, the ...reversible oxidoreduction of retinol to retinaldehyde, is essential to control RA levels. The enzymes of retinol oxidation are NAD-dependent dehydrogenases of the cytosolic medium-chain (MDR) and the membrane-bound short-chain (SDR) dehydrogenases/reductases. Retinaldehyde reduction can be performed by SDR and aldoaketo reductases (AKR), while its oxidation to RA is carried out by aldehyde dehydrogenases (ALDH). In contrast to SDR, AKR and ALDH are cytosolic. A common property of these enzymes is that they only use free retinoid, but not retinoid bound to cellular retinol binding protein (CRBP). The relative contribution of each enzyme type in retinoid metabolism is discussed in terms of the different subcellular localization, topology of membrane-bound enzymes, kinetic constants, binding affinity of CRBP for retinol and retinaldehyde, and partition of retinoid pools between membranes and cytoplasm. The development of selective inhibitors for AKR enzymes 1B1 and 1B10, of clinical relevance in diabetes and cancer, granted the investigation of some structure-activity relationships. Kinetics with the 4-methyl derivatives of retinaldehyde isomers was performed to identify structural features for substrate specificity. Hydrophilic derivatives were better substrates than the more hydrophobic compounds. We also explored the inhibitory properties of some synthetic retinoids, known for binding to retinoic acid receptors (RAR) and retinoid X receptors (RXR). Consistent with its substrate specificity towards retinaldehyde, AKR1B10 was more effectively inhibited by synthetic retinoids than AKR1B1. A RARbeta/gamma agonist (UVI2008) inhibited AKR1B10 with the highest potency and selectivity, and docking simulations predicted that its carboxyl group binds to the anion-binding pocket.
Els temes de bioseguretat, biocontenció i bioprotecció
no són sempre completament entesos per molts científics i
comparteixen, pel públic en general, alguns significats ominosos.
El sentit últim de ...les paraules prèviament esmentades
però també el disseny, la construcció i el funcionament
d'aquests tipus de instal·lacions seran discutides tenint en
compte els significats complementaris. El disseny, la construcció
i la posada en marxa d'una unitat de biocontenció, requereixen
d'equips complementaris (i de vegades oposats) de
persones que juguen els papers d'arquitectes, enginyers,
científics però també de funcionaris.
The effects of the
Mangiferia indica L. (Vimang) extract, and mangiferin (a C-glucosylxanthone of Vimang) on the inducible isoforms of cyclooxygenase (cyclooxygenase-2) and nitric oxide synthase ...(iNOS) expression and on vasoconstrictor responses were investigated in vascular smooth muscle cells and mesenteric resistance arteries, respectively, from Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Vimang (0.5–0.1 mg/ml) and mangiferin (0.025 mg/ml) inhibited the interleukin-1β (1 ng/ml)-induced iNOS expression more in SHR than in WKY, and cyclooxygenase-2 expression more in WKY than in SHR. Vimang (0.25–1 mg/ml) reduced noradrenaline (0.1–30 μM)- and U46619 (1 nM–30 μM)- but not KCl (15–70 mM)-induced contractions. Mangiferin (0.05 mg/ml) did not affect noradrenaline-induced contraction. In conclusion, the antiinflammatory action of Vimang would be related with the inhibition of iNOS and cyclooxygenase-2 expression, but not with its effect on vasoconstrictor responses. Alterations in the regulation of both enzymes in hypertension would explain the differences observed in the Vimang effect.
The transport properties of artificially engineered superlattices （SLs） can be tailored by incorporating a high density of interfaces in them. Specifically, SiGe SLs with low thermal conductivity ...values have great potential for thermoelectric generation and nano-cooling of Si-based devices. Here, we present a novel approach for customizing thermal transport across nanostructures by fabricating Si/Sil-xGex SLs with well-defined compositional gradients across the SiGe layer from x = 0 to 0.60. We demonstrate that the spatial inhomogeneity of the structure has a remarkable effect on the heat-flow propagation, reducing the thermal conductivity to -2.2 W.m-1.K-1, which is significantly less than the values achieved previously with non-optimized long-period SLs. This approach offers further possibilities for future applications in thermoelectricity.
Renin–angiotensin and endothelin systems are involved in the cardiovascular effects produced by treatment with ouabain. We recently demonstrated that the contractile response to phenylephrine is ...decreased in ouabain‐treated rats. The present study investigated whether endothelin‐1 (ET‐1) and angiotensin II (Ang II) contributes to the vascular changes observed in rats chronically treated with ouabain.
Wistar rats were treated with ouabain (8.0 μg day−1, s.c. pellets for 5 weeks) alone or in combination with an endothelin type A receptor (ETA) antagonist, BMS182874 (40 mg kg−1 day−1, per gavage) or an angiotensin type 1 (AT1) receptor antagonist, losartan (15 mg kg−1 day−1, p.o.).
Treatment with ouabain increased systolic blood pressure and treatment with either losartan or BMS182874 prevented the development of ouabain‐induced hypertension.
The sensitivity and maximal response for phenylephrine were reduced in aortic rings from ouabain‐treated rats. Removal of the endothelium or in vitro exposure to an inhibitor of nitric oxide synthase (NOS), N‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μM) increased the responses to phenylephrine, an effect that was more pronounced in aortas from ouabain‐treated rats. Endothelial NOS protein (eNOS) expression was increased after ouabain treatment. Treatment with BMS182874, but not with losartan, prevented the effects of ouabain on the reactivity of phenylephrine and in eNOS protein expression.
Gene expression of pre–pro‐ET‐1 and ETA receptors was increased in aortic rings from ouabain‐treated rats. ETB receptor gene expression was not altered by ouabain treatment.
In conclusion, our results suggest that endothelin and angiotensin systems play an important role in the development of ouabain‐induced hypertension. However, ET‐1, by activation of ETA receptors, but not Ang II, contributes to changes in vascular reactivity to phenylephrine induced by chronic treatment with ouabain.
British Journal of Pharmacology (2004) 143, 794–802. doi:10.1038/sj.bjp.0705994
Proximity to road traffic involves higher health risks because of atmospheric pollutants. In addition to outdoor air, indoor air quality contributes to overall exposure. In the framework of the ...BREATHE study, indoor and outdoor air pollution was assessed in 39 schools in Barcelona. The study quantifies indoor and outdoor air quality during school hours of the BREATHE schools. High levels of fine particles (PM2.5), nitrogen dioxide (NO2), equivalent black carbon (EBC), ultrafine particle (UFP) number concentration and road traffic related trace metals were detected in school playgrounds and indoor environments. PM2.5 almost doubled (factor of 1.7) the usual urban background (UB) levels reported for Barcelona owing to high school-sourced PM2.5 contributions: 1 an indoor-generated source characterised mainly by organic carbon (OC) from organic textile fibres, cooking and other organic emissions, and by calcium and strontium (chalk dust) and; 2 mineral elements from sand-filled playgrounds, detected both indoors and outdoors. The levels of mineral elements are unusually high in PM2.5 because of the breakdown of mineral particles during playground activities. Moreover, anthropogenic PM components (such as OC and arsenic) are dry/wet deposited in this mineral matter. Therefore, PM2.5 cannot be considered a good tracer of traffic emissions in schools despite being influenced by them. On the other hand, outdoor NO2, EBC, UFP, and antimony appear to be good indicators of traffic emissions. The concentrations of NO2 are 1.2 times higher at schools than UB, suggesting the proximity of some schools to road traffic. Indoor levels of these traffic-sourced pollutants are very similar to those detected outdoors, indicating easy penetration of atmospheric pollutants. Spatial variation shows higher levels of EBC, NO2, UFP and, partially, PM2.5 in schools in the centre than in the outskirts of Barcelona, highlighting the influence of traffic emissions. Mean child exposure to pollutants in schools in Barcelona attains intermediate levels between UB and traffic stations.
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•39 schools in Barcelona monitored (indoor and outdoor) for air quality assessment.•Higher levels of traffic pollutants at schools than at urban background station.•OC, Ca & Sr are mainly school sourced: organic emissions, textile fibres and chalk.•Mineral matter (mixed with urban pollutants) is resuspended by children activities.•BC, NO2, UFP & few metals good traffic tracers but not PM2.5 due to school sources.
Around 30-40% of patients with colorectal cancer (CRC) undergoing curative resection of the primary tumour will develop metastases in the subsequent years
. Therapies to prevent disease relapse ...remain an unmet medical need. Here we uncover the identity and features of the residual tumour cells responsible for CRC relapse. An analysis of single-cell transcriptomes of samples from patients with CRC revealed that the majority of genes associated with a poor prognosis are expressed by a unique tumour cell population that we named high-relapse cells (HRCs). We established a human-like mouse model of microsatellite-stable CRC that undergoes metastatic relapse after surgical resection of the primary tumour. Residual HRCs occult in mouse livers after primary CRC surgery gave rise to multiple cell types over time, including LGR5
stem-like tumour cells
, and caused overt metastatic disease. Using Emp1 (encoding epithelial membrane protein 1) as a marker gene for HRCs, we tracked and selectively eliminated this cell population. Genetic ablation of EMP1
cells prevented metastatic recurrence and mice remained disease-free after surgery. We also found that HRC-rich micrometastases were infiltrated with T cells, yet became progressively immune-excluded during outgrowth. Treatment with neoadjuvant immunotherapy eliminated residual metastatic cells and prevented mice from relapsing after surgery. Together, our findings reveal the cell-state dynamics of residual disease in CRC and anticipate that therapies targeting HRCs may help to avoid metastatic relapse.
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