ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-β/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC

Chronic stress and impaired glutamate function elicit a depressive-like phenotype and common changes in gene expression in the mouse frontal cortex

Major depression might originate from both environmental and genetic risk factors. The environmental chronic mild stress (CMS) model mimics some environmental factors contributing to human depression and induces anhedonia and helplessness. Mice heterozygous for the synaptic vesicle protein (SVP) vesicular glutamate transporter 1 (VGLUT1) have been proposed as a genetic model of deficient glutamate function linked to depressive-like behaviour. Here, we aimed to identify, in these two experimental models, gene expression changes in the frontal cortex, common to stress and impaired glutamate function. Both VGLUT1+/- and CMS mice showed helpless and anhedonic-like behavior. Microarray studies in VGLUT1+/- mice revealed regulation of genes involved in apoptosis, neurogenesis, synaptic transmission, protein metabolic process or learning and memory. In addition, RT-PCR studies confirmed gene expression changes in several glutamate, GABA, dopamine and serotonin neurotransmitter receptors. On the other hand, CMS affected the regulation of 147 transcripts, some of them involved in response to stress and oxidoreductase activity. Interestingly, 52 genes were similarly regulated in both models. Specifically, a dowregulation in genes that promote cell proliferation (Anapc7), cell growth (CsnK1g1), cell survival (Hdac3), inhibition of apoptosis (Dido1) was observed. Genes linked to cytoskeleton (Hspg2, Invs), psychiatric disorders (Grin1, MapK12) or an antioxidant enzyme (Gpx2) were also downregulated. Moreover, genes that inhibit the MAPK pathways (Dusp14), stimulate oxidative metabolism (Eif4a2) and enhance glutamate transmission (Rab8b) were upregulated. We suggest that these genes could form part of the altered “molecular context” underlying depressive-like behaviour in animal models. The clinical relevance of these findings is discussed

INTERVENCIÓN CON MENORES EN RECURSOS DE ACOGIDA

Extracto del informe inéditoEl análisis de los trabajos sobre intervención con madres maltratadas y sus hijos, nos ha permitido estructurar las áreas que se pueden desarrollar utilizando como instrumento mediador la lectura, sin olvidar fomentar el hábito lector y las lecturas compartidas madres-hijos. El trabajo se ha concentrado en la elaboración de materiales a partir de libros infantiles. Estos materiales están dirigidos a los educadores de las casas de acogida y a las madres. Se han seleccionado dos álbumes de literatura infantil para cada una de las áreas de intervención. Las propuestas de trabajo de los álbumes pretenden emplear la lectura como herramienta para poder entrar en el mundo interior de los hijos e hijas de las mujeres maltratadas y abrir una puerta para que puedan expresarse libremente

The Cadiz Contourite Channel: Sandy contourites, bedforms and dynamic current interaction

The Cadiz Contourite Channel is the largest and most prominent contourite channel in the middle slope of the Gulf of Cadiz, and is known to channelise the southern branch of the Lower Core of Mediterranean Outflow Water (MOW) as it flows westwards from the Gibraltar Gateway. The channel lies in water depth between 650 and 1500 m, is 150 km long, 2–12 km wide, up to 120 m deep, and broadly s-shaped in plan view. It has several associated subparallel marginal channels and shorter spillover channel segments. Its geometry is controlled by the interaction of a strong bottom current with the seafloor morphology, affected by neotectonic deformation and diapiric intrusion. Bottom photographs and dredge hauls reveal a channel floor shaped by high-energy flow, in places with bare rock, boulders and gravel, and elsewhere covered with sandy contourites. The rocky substrate and derived clasts are formed of authigenic iron-rich carbonates, testifying the high degree of fluid escape from adjacent diapiric ridges and mud volcanoes. The sandy substrate shows a wide range of current-induced bedforms including small, straight-crested ripples, large sinuous sand waves and dunes (wavelength 3.5–5 m, height 0.3–0.9 m), weak surface lineation on sands, and aligned gravel stringers and deep erosive scours around large boulders. Bedform orientation indicates flows directed to the south/south-west (main channel) and west (spillover channel), which can be related to MOW bottom currents, and current velocities that vary between about 0.2 and 0.8 m s− 1, even in the same channel location. However, current vane orientation was clearly responding, at least in part, to tidal effects and periodicity in the Gulf of Cadiz at the time the photographs were taken. Maximum current velocities are achieved by a combination of barotropic and internal tides (probably generated at the continental slope) that reinforce the normal MOW flow. In addition, meteorologically-induced internal waves with periods shorter than tidal ones may exert an even greater influence on current intensity, especially when they occur at times of sudden changes of meteorological forcing. This effect further influences MOW variability. In all cases, the funnelling effect of the Cadiz Channel amplifies tidal or meteorologically-induced bottom currents

Does posterior capsule opacification affect the results of diagnostic technologies to evaluate the retina and the optic disc?

The visual outcome obtained after cataract removal may progressively decline because of posterior capsular opacification (PCO). This condition can be treated by creating an opening in the posterior lens capsule by Nd:YAG laser capsulotomy. PCO optical imperfections cause several light reflection, refraction, and diffraction phenomena, which may interfere with the functional and structural tests performed in different ocular locations for the diagnosis and follow-up of ocular disease, like macular and optic nerve diseases. Some parameters measured by visual field examinations, scanning laser polarimetry, and optical coherence tomography (OCT) have changed after PCO removal. Imaging quality also changes following capsulotomy. Consequently, the results of ancillary tests in pseudophakic eyes for studying ocular diseases like glaucoma or maculopathies should be correlated with other clinical examinations, for example, slit-lamp biomicroscopy or funduscopy. If PCO is clinically significant, a new baseline should be set for future comparisons following capsulotomy when using automated perimetry and scanning laser polarimetry. To perform OCT in the presence of PCO, reliable examinations (considering signal strength) apparently guarantee that measurements are not influenced by PCO

Increased vulnerability to depressive-like behaviour of mice with decreased expression of VGLUT1

Background: Many studies have linked depression to an increase in the excitatory-inhibitory ratio in the forebrain. Presynaptic alterations in a shared pathway of the glutamate/GABA cycle may account for this imbalance. Recent evidence suggests that decreased vesicular glutamate transporter 1 (VGLUT1) levels in the forebrain affects the glutamate/GABA cycle and induces helpless behaviour. Here we studied decreased VGLUT1 as a potencial factor enhancing a depressive-like phenotype in an animal model. Methods: Glutamate and GABA synthesis as well as oxidative metabolism were studied in heterozygous mice for the vesicular glutamate transporter 1 (VGLUT1+/-) and WT. Subsequently, the regulation of neurotransmitter levels, proteins involved in the glutamate/GABA cycle and behaviour by both genotype and chronic mild stress (CMS) was studied. Finally, the effect of chronic imipramine on VGLUT1 control and CMS mice was also studied. Results: VGLUT1+/- mice showed increased neuronal synthesis of glutamate, decreased cortical and hippocampal GABA, VGLUT1 and EAAT1, as well as helplessness and anhedonia. CMS induced an increase of glutamate and a decrease of GABA, VGAT and GAD65 in both areas and led to upregulation EAAT1 in the hippocampus. Moreover, CMS induced anhedonia, helplessness, anxiety and impaired recognition memory. VGLUT1+/- CMS mice showed a combined phenotype (genotype plus stress) and specific alterations, such as an upregulation of VGLUT2 and hyperlocomotion. Moreover, an increased vulnerability to anhedonia and helplessness reversible by chronic imipramine was shown. Conclusions: These studies highlight a crucial role for decreased VGLUT1 in the forebrain as a biological mediator of increased vulnerability to chronic mild stress

Update on the effects of antioxidants on diabetic retinopathy : In vitro experiments, animal studies and clinical trials

Current therapies for diabetic retinopathy (DR) incorporate blood glucose and blood pressure control, vitrectomy, photocoagulation, and intravitreal injections of anti-vascular endothelial growth factors or corticosteroids. Nonetheless, these techniques have not been demonstrated to completely stop the evolution of this disorder. The pathophysiology of DR is not fully known, but there is more and more evidence indicating that oxidative stress is an important mechanism in the progression of DR. In this sense, antioxidants have been suggested as a possible therapy to reduce the complications of DR. In this review we aim to assemble updated information in relation to in vitro experiments, animal studies and clinical trials dealing with the effect of the antioxidants on DR

Regulation of markers of synaptic function in mouse models of depression: chronic mild stress and decreased expression of VGLUT1

Depression has been linked to failure in synaptic plasticity originating from environmental and/or genetic risk factors. The chronic mild stress (CMS) model regulates the expression of synaptic markers of neurotransmitter function and associated depressive-like behaviour. Moreover, mice heterozygous for the synaptic vesicle protein (SVP) vesicular glutamate transporter 1 (VGLUT1), have been proposed as a genetic model of deficient glutamate function linked to depressive-like behaviour. Here, we aimed to identify, in these two experimental models, mechanisms of failure in synaptic plasticity, common to stress and impaired glutamate function. First, we show that CMS induced a transient decrease of different plasticity markers (VGLUT1, synapsin 1, sinaptophysin, rab3A and activity regulated cytoskeletal protein Arc) but a long-lasting decrease of the brain derived neurotrophic factor (BDNF) as well as depressive-like behaviour. The immediate early gene (IEG) Arc was also downregulated in VGLUT1+/- heterozygous mice. In contrast, an opposite regulation of synapsin 1 was observed. Finally, both models showed a marked increase of cortical Arc response to novelty. Increased Arc response to novelty could be suggested as a molecular mechanism underlying failure to adapt to environmental changes, common to chronic stress and altered glutamate function. Further studies should investigate whether these changes are associated to depressive-like behaviour both in animal models and in depressed patients

In Utero p,p′-DDE Exposure and Infant Neurodevelopment: A Perinatal Cohort in Mexico

BACKGROUND: Evidence suggests that p,p′-dichlorodiphenyldichloroethene (DDE) affects neurodevelopment in infants, although a critical exposure window has not yet been identified. OBJECTIVES: Our goal was to assess the prenatal DDE exposure window and its effect on the psychomotor development index (PDI) and mental development index (MDI) during the first year of life. METHODS: We recruited 244 children whose pregnancies and deliveries were uncomplicated, and whose mothers were monitored throughout the pregnancy. Participating mothers were not occupationally exposed to DDT (dichlorodiphenyltrichloroethane) but were residents of a zone in Mexico with endemic malaria. We measured serum levels of DDE before pregnancy and during each trimester of the pregnancy. We evaluated PDI and MDI of the Bayley Scales for Infant Development (BSID-II), at 1, 3, 6, and 12 months of age. We adjusted for quality of the home environment and maternal intellectual coefficient (IQ). We used generalized mixed-effects models for statistical analysis. RESULTS: Third-trimester DDE level (7.8 ± 2.8 ppb) was significantly higher than the level at baseline, first, and second trimesters, but the differences never exceeded 20%. Only DDE levels during the first trimester of pregnancy were associated with a significant reduction in PDI (every doubled increase of DDE level reduced the PDI 0.5 points). DDE was not associated with MDI. CONCLUSIONS: A critical window of exposure to DDE in utero may be the first trimester of the pregnancy, and psychomotor development is a target of this compound. Residues of DDT metabolites may present a risk of developmental delay for years after termination of DDT use