PGE1 stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases

There is a growing appreciation that the cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) signaling pathway is organized to form transduction units that function to deliver specific messages. Such organization results in the local activation of PKA subsets through the generation of confined intracellular gradients of cAMP, but the mechanisms responsible for limiting the diffusion of cAMP largely remain to be clarified. In this study, by performing real-time imaging of cAMP, we show that prostaglandin 1 stimulation generates multiple contiguous, intracellular domains with different cAMP concentration in human embryonic kidney 293 cells. By using pharmacological and genetic manipulation of phosphodiesterases (PDEs), we demonstrate that compartmentalized PDE4B and PDE4D are responsible for selectively modulating the concentration of cAMP in individual subcellular compartments. We propose a model whereby compartmentalized PDEs, rather than representing an enzymatic barrier to cAMP diffusion, act as a sink to drain the second messenger from discrete locations, resulting in multiple and simultaneous domains with different cAMP concentrations irrespective of their distance from the site of cAMP synthesis

Cirugía robótica en patología quirúrgica benigna y maligna: urología, cirugía general y digestiva, cirugía cardiotorácica, ginecología, endocrinología, oftalmología y cirugía de cabeza y cuello. Capítulo II: cirugía urológica, ginecológica, general y digestiva

Cirurgia robòtica; Tècniques quirúrgiques; InnovacióCirugía robótica; Técnicas quirúrgicas; InnovaciónRobotic surgery; Surgical techniques; InnovationS'ha avaluat, de manera específica, l’eficàcia o l’efectivitat, la seguretat i l’eficiència de la cirurgia assistida per robot en comparació amb la cirurgia oberta o la cirurgia laparoscòpica en un grup d’indicacions de patologia benigna o maligna en les especialitats de cirurgia urològica, ginecològica i general i digestiva. De manera addicional, s’ha analitzat l’activitat de la cirurgia robòtica a Espanya per a les indicacions ginecològiques en els últims cinc anys.Se ha evaluado, de forma específica, la eficacia o la efectividad, la seguridad y la eficiencia de la cirugía asistida por robot en comparación con la cirugía abierta o la cirugía laparoscópica en un grupo de indicaciones de patología benigna o maligna en las especialidades de cirugía urológica, ginecológica y general y digestiva. De forma adicional, se ha analizado la actividad de la cirugía robótica en España para las indicaciones ginecológicas en los últimos cinco años.The aim of the study is to determine whether robot-assisted surgery has sufficient evidence to be included in the common portfolio of the UK NHS healthcare services. To this end, the efficacy or effectiveness, safety and efficiency of robot-assisted surgery compared to open surgery or laparoscopic surgery in a group of indications of benign or malignant pathology in the specialities of urological, gynaecological and general and digestive surgery has been specifically evaluated. In addition, the activity of robotic surgery in Spain for gynaecological indications in the last five years has been analysed.Este documento ha sido realizado por la Agència de Qualitat i Avaluació Sanitàries de Catalunya en el marco de la financiación del Ministerio de Sanidad para el desarrollo de las actividades del Plan anual de Trabajo de la Red Española de Agencias de Evaluación de Tecnologías Sanitarias y Prestaciones del SNS, aprobado en el Pleno del Consejo Interterritorial del SNS de 28 de octubre de 2020 (conforme al Acuerdo del Consejo de Ministros de 9 de diciembre de 2020)

Una rappresentazione varsaviense della goldoniana "Donna di garbo"

Due to the interest in the Italian Theater by the Court of Saxony in the mid-18th century, some comedies by Carlo Goldoni were exported from Venice to Dresden and Warsaw. For greater ease of the German and Polish public, the plot of the comedies was summarised in special printed brochures, many of which are now kept at the Landesbibliothek and the Staatsarchiv in Dresden. The leaflet of La Donna di garbo, which is studied here, presents interesting differences compared to the comedy that Goldoni printed since 1750. These differences allow us to partially reconstruct how the comedy was actually represented between the date of its composition, 1742, and the first printed edition controlled by Goldoni

Minocycline alters behavior, microglia and the gut microbiome in a trait-anxiety-dependent manner

Major depressive disorder is the main cause of disability worldwide with imperfect treatment options. However, novel therapeutic approaches are currently discussed, from augmentation strategies to novel treatments targeting the immune system or the microbiome-gut-brain axis. Therefore, we examined the potential beneficial effects of minocycline, a tetracycline antibiotic with pleiotropic, immunomodulatory action, alone or as augmentation of escitalopram on behavior, prefrontal microglial density, and the gut microbiome in rats selectively bred for high anxiety-like behavior (HAB). We show that concomitant with their high innate anxiety and depression, HABs have lower microglial numbers in the infralimbic and prelimbic prefrontal cortex and an altered gut microbiota composition compared with controls. Three weeks of minocycline treatment alleviated the depressive-like phenotype, further reduced microglial density, exclusively in male HAB rats, and reduced plasma concentrations of pro-inflammatory cytokines. However, coadministration of escitalopram, which had no effect alone, prevented these minocycline-induced effects. Moreover, minocycline led to a robust shift in cecal microbial composition in both HABs and rats nonselected for anxiety-like behavior. Minocycline markedly increased relative abundance of Lachnospiraceae and Clostridiales Family XIII, families known for their butyrate production, with a corresponding increase and positive correlation in plasma 3-OH-butyrate levels in a trait-dependent manner. Thus, our data suggest that the antidepressant effect of minocycline is sex- and trait-dependent, associated with a reduced microglial number in the prefrontal cortex, and with changes in microbial composition and their metabolites. These results further support the microbiomegut-brain axis as potential target in the treatment of depression

New Insights into Mutable Collagenous Tissue: Correlations between the Microstructure and Mechanical State of a Sea-Urchin Ligament

The mutable collagenous tissue (MCT) of echinoderms has the ability to undergo rapid and reversible changes in passive mechanical properties that are initiated and modulated by the nervous system. Since the mechanism of MCT mutability is poorly understood, the aim of this work was to provide a detailed morphological analysis of a typical mutable collagenous structure in its different mechanical states. The model studied was the compass depressor ligament (CDL) of a sea urchin (Paracentrotus lividus), which was characterized in different functional states mimicking MCT mutability. Transmission electron microscopy, histochemistry, cryo-scanning electron microscopy, focused ion beam/scanning electron microscopy, and field emission gun-environmental scanning electron microscopy were used to visualize CDLs at the micro- and nano-scales. This investigation has revealed previously unreported differences in both extracellular and cellular constituents, expanding the current knowledge of the relationship between the organization of the CDL and its mechanical state. Scanning electron microscopies in particular provided a three-dimensional overview of CDL architecture at the micro- and nano-scales, and clarified the micro-organization of the ECM components that are involved in mutability. Further evidence that the juxtaligamental cells are the effectors of these changes in mechanical properties was provided by a correlation between their cytology and the tensile state of the CDLs

Delayed diagnosis of coeliac disease increases cancer risk

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Autoimmunity in gestational diabetes mellitus in Sardinia: a preliminary case-control report

<p>Abstract</p> <p>Background</p> <p>We previously reported a high prevalence (22.3%) of gestational diabetes mellitus (GDM) in a large group of Sardinian women, in contrast with the prevalence of Type 2 diabetes. Sardinia has an unusual distribution of haplotypes and genotypes, with the highest population frequency of HLA DR3 in the world, and after Finland, the highest prevalence of Type 1 diabetes and Autoimmune-related Diseases. In this study we preliminarily tested the prevalence of serological markers of Type 1 diabetes in a group of Sardinian GDM patients.</p> <p>Methods</p> <p>We determined glutamic decarboxylase antibodies (anti-GAD65), protein tyrosine phosphatase ICA 512 (IA2) antibodies (anti-IA2), and IAA in 62 GDM patients, and in 56 controls with matching age, gestational age and parity.</p> <p>Results</p> <p>We found a high prevalence and very unusual distribution of antibodies in GDM patients (38.8%), the anti-IA2 being the most frequent antibody. Out of all our GDM patients, 38.8% (24 of 62) were positive for at least one antibody. Anti-IA2 was present in 29.0 % (18 out of 62) vs. 7.1% (4 out of 56) in the controls (P < 0.001). IAA was present in 14.5% (9 out of 62) of our GDM patients, and absent in the control subjects (P < 0.001). Anti-GAD65 was also present in GDM patients, with a prevalence of 3.2% (2 out of 62) while it was absent in the control group (P = NS). Pre-gestational weight was significantly lower (57.78 ± 9.8 vs 65.9 ± 17.3 <it>P </it>= 0.04) in auto-antibodies- positive GDM patients.</p> <p>Conclusion</p> <p>These results are in contrast with the very low prevalence of all antibodies reported in Italy. If confirmed, they could indicate that a large proportion of GDM patients in Sardinia have an autoimmune origin, in accordance with the high prevalence of Type 1 diabetes.</p

Increased expression of urokinase plasminogen activator and its cognate receptor in human seminomas

<p>Abstract</p> <p>Background</p> <p>The urokinase plasminogen activating system (uPAS) is implicated in neoplastic progression and high tissue levels of uPAS components correlate with a poor prognosis in different human cancers. Despite that, relative few studies are available on the expression and function of the uPAS components in human seminomas. In the present study we characterized the expression of the urokinase plasminogen activator (uPA), its cognate receptor (uPAR) and the uPA inhibitors PAI-1 and PAI-2 in normal human testis and seminomas.</p> <p>Methods</p> <p>The expression of the above genes was evaluated by means of quantitative RT-PCR, western blot, zymographic analysis and immunohistochemistry.</p> <p>Results</p> <p>Quantitative RT-PCR analysis of 14 seminomas demonstrated that uPA and uPAR mRNAs were, with respect to control tissues, increased in tumor tissues by 3.80 ± 0.74 (p < 0.01) and 6.25 ± 1.18 (p < 0.01) fold, respectively. On the other hand, PAI-1 mRNA level was unchanged (1.02 ± 0.24 fold), while that of PAI-2 was significantly reduced to 0.34 ± 0.18 (p < 0.01) fold. Western blot experiments performed with protein extracts of three seminomas and normal tissues from the same patients showed that uPA protein levels were low or undetectable in normal tissues and induced in tumor tissues. On the same samples, zymographic analysis demonstrated increased uPA activity in tumor tissue extracts. Western blot experiments showed that also the uPAR protein was increased in tumor tissues by 1.83 ± 0.15 fold (p < 0.01). The increased expression of uPA and uPAR was further confirmed by immunohistochemical staining performed in 10 seminomas and autologous uninvolved peritumoral tissues. Finally, variation in the mRNA level of PAI-1 significantly correlated with tumor size.</p> <p>Conclusions</p> <p>We demonstrated the increased expression of uPA and uPAR in human seminomas with respect to normal testis tissues, which may be relevant in testicular cancer progression.</p