Expression of Retinoid Acid Receptor-Responsive Genes in Rodent Models of Placental Pathology

In humans, retinoic acid receptor responders (RARRES) have been shown to be altered in third trimester placentas complicated by the pathologies preeclampsia (PE) and PE with intrauterine growth restriction (IUGR). Currently, little is known about the role of placental Rarres in rodents. Therefore, we examined the localization and expression of Rarres1 and 2 in placentas obtained from a Wistar rat model of isocaloric maternal protein restriction (E18.5, IUGR-like features) and from an eNOS-knockout mouse model (E15 and E18.5, PE-like features). In both rodent models, Rarres1 and 2 were mainly localized in the placental spongiotrophoblast and giant cells. Their placental expression, as well as the expression of the Rarres2 receptor chemokine-like receptor 1 (CmklR1), was largely unaltered at the examined gestational ages in both animal models. Our results have shown that RARRES1 and 2 may have different expression and roles in human and rodent placentas, thereby underlining immanent limitations of comparative interspecies placentology. Further functional studies are required to elucidate the potential involvement of these proteins in early placentogenesis

Televisión digital en 2010: El reto de la interoperabilidad

En este artículo se plantea la situación actual de despliegue de la televisión digital en España desde el punto de vista de la necesaria interoperabilidad que debe haber entre los eslabones de la cadena de valor en un mercado horizontal, con especial atención, por una parte, a la navegación y la presentación de la información de programación y, por otra, a la accesibilidad de las personas con discapacidad. Los patentes problemas de interoperabilidad existentes se han producido a pesar de la existencia de un completo conjunto de disposiciones legales y normas técnicas, lo que sugiere la necesidad además de laboratorios de interoperabilidad que supongan un punto de encuentro entre los actores del sector, con el apoyo de las administraciones públicas (Utray 2009: 211‐225

Intrauterine growth restriction promotes vascular remodelling following carotid artery ligation in rats

A B S T R A C T Epidemiological studies revealed an association between IUGR (intrauterine growth restriction) and an increased risk of developing CVDs (cardiovascular diseases), such as atherosclerosis or hypertension, in later life. Whether or not IUGR contributes to the development of atherosclerotic lesions, however, is unclear. We tested the hypothesis that IUGR aggravates experimentally induced vascular remodelling. IUGR was induced in rats by maternal protein restriction during pregnancy (8 % protein diet). To detect possible differences in the development of vascular injury, a model of carotid artery ligation to induce vascular remodelling was applied in 8-week-old intrauterinegrowth-restricted and control rat offspring. Histological and immunohistochemical analyses were performed in the ligated and non-ligated carotid arteries 8 weeks after ligation. IUGR alone neither caused overt histological changes nor significant dedifferentiation of VSMCs (vascular smooth muscle cells). After carotid artery ligation, however, neointima formation, media thickness and media/lumen ratio were significantly increased in rats after IUGR compared with controls. Moreover, dedifferentiation of VSMCs and collagen deposition in the media were more prominent in ligated carotids from rats after IUGR compared with ligated carotids from control rats. We conclude that IUGR aggravates atherosclerotic vascular remodelling induced by a second injury later in life

Асинхронный электропривод агломерационной машины

В выпускной работе предложено заменить морально устаревший и выработавший ресурс электропривод постоянного тока на асинхронный частотно-регулируемый электропривод. По результатам расчета требуемой мощности двигателя выбран электродвигатель фирмы SIEMENS серии 1LG4313-8AB, а также преобразователь частоты типа MICROMACTER 440. В процессе выполнения работы была определена область работы, рассчитаны параметры схемы замещения двигателя и его характеристики. Выполнена оптимизация контуров регулирования электропривода. В ходе имитационных исследований установлено, что обеспечивается требуемый диапазон регулирования 1:10, необходимая точность поддержания скорости не менее 3%, что соответствует техническому заданию.In the final work, it was proposed to replace the obsolete and exhausted resource of a DC electric drive with an asynchronous frequency-controlled electric drive. Based on the results of calculating the required engine power, a SIEMENS electric motor of the 1LG4313-8AB series and a frequency converter of the MICROMACTER 440 type were chosen. During the work, the work area was determined, the parameters of the motor replacement circuit and its characteristics were calculated. Optimization of the control circuits of the electric drive is performed. During simulations it was found that the required control range of 1:10 is provided, the necessary accuracy of maintaining the speed is not less than 3%, which corresponds to the technical specification

Integrin-Linked Kinase Expression in Human Valve Endothelial Cells Plays a Protective Role in Calcific Aortic Valve Disease.

Calcific aortic valve disease (CAVD) is highly prevalent during aging. CAVD initiates with endothelial dysfunction, leading to lipid accumulation, inflammation, and osteogenic transformation. Integrin-linked kinase (ILK) participates in the progression of cardiovascular diseases, such as endothelial dysfunction and atherosclerosis. However, ILK role in CAVD is unknown. First, we determined that ILK expression is downregulated in aortic valves from patients with CAVD compared to non-CAVD, especially at the valve endothelium, and negatively correlated with calcification markers. Silencing ILK expression in human valve endothelial cells (siILK-hVECs) induced endothelial-to-mesenchymal transition (EndMT) and promoted a switch to an osteoblastic phenotype; SiILK-hVECs expressed increased RUNX2 and developed calcified nodules. siILK-hVECs exhibited decreased NO production and increased nitrosative stress, suggesting valvular endothelial dysfunction. NO treatment of siILK-hVECs prevented VEC transdifferentiation, while treatment with an eNOS inhibitor mimicked ILK-silencing induction of EndMT. Accordingly, NO treatment inhibited VEC calcification. Mechanistically, siILK-hVECs showed increased Smad2 phosphorylation, suggesting a TGF-β-dependent mechanism, and NO treatment decreased Smad2 activation and RUNX2. Experiments performed in eNOS KO mice confirmed the involvement of the ILK-eNOS signaling pathway in valve calcification, since aortic valves from these animals showed decreased ILK expression, increased RUNX2, and calcification. Our study demonstrated that ILK endothelial expression participates in human CAVD development by preventing endothelial osteogenic transformationpost-print4615 K

Renal Chemerin Expression is Induced in Models of Hypertensive Nephropathy and Glomerulonephritis and Correlates with Markers of Inflammation and Fibrosis

Chemerin and its receptor, chemokine-like receptor 1 (CmklR1), are associated with chemotaxis, inflammation, and endothelial function, especially in metabolic syndrome, coronary heart disease, and hypertension. In humans, circulating chemerin levels and renal function show an inverse relation. So far, little is known about the potential role of chemerin in hypertensive nephropathy and renal inflammation. Therefore, we determined systemic and renal chemerin levels in 2-kidney-1-clip (2k1c) hypertensive and Thy1.1 nephritic rats, respectively, to explore the correlation between chemerin and markers of renal inflammation and fibrosis. Immunohistochemistry revealed a model-specific induction of chemerin expression at the corresponding site of renal damage (tubular vs. glomerular). In both models, renal expression of chemerin (RT-PCR, Western blot) was increased and correlated positively with markers of inflammation and fibrosis. In contrast, circulating chemerin levels remained unchanged. Taken together, these findings demonstrate that renal chemerin expression is associated with processes of inflammation and fibrosis-related to renal damage. However, its use as circulating biomarker of renal inflammation seems to be limited in our rat models

SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications

Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cells (CSC). The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features of SOX2 have been scarcely investigated in other sarcoma subtypes. Here, we show that SOX2 depletion dramatically reduced the ability of undifferentiated pleomorphic sarcoma (UPS) cells to form tumorspheres and to initiate tumor growth. Conversely, SOX2 overexpression resulted in increased in vivo tumorigenicity. Moreover, using a reporter system (SORE6) which allows to monitor viable cells expressing SOX2 and/or OCT4, we found that SORE6+ cells were significantly more tumorigenic than the SORE6- subpopulation. In agreement with this findings, SOX2 expression in sarcoma patients was associated to tumor grade, differentiation, invasive potential and lower patient survival. Finally, we studied the effect of a panel of anti-tumor drugs on the SORE6+ cells of the UPS model and patient-derived chondrosarcoma lines. We found that the mithramycin analogue EC-8042 was the most efficient in reducing SORE6+ cells in vitro and in vivo. Overall, this study demonstrates that SOX2 is a pro-tumorigenic factor with prognostic potential in sarcoma. Moreover, SORE6 transcriptional activity is a bona fide CSC marker in sarcoma and constitutes an excellent biomarker for evaluating the efficacy of anti-tumor treatments on CSC subpopulations.This work was supported by the Agencia Estatal de Investigación (AEI) [MINECO/Fondo Europeo de Desarrollo Regional (FEDER) (SAF-2016-75286-R to R.R.), ISC III/FEDER (Miguel Servet Program CPII16/00049 to R.R., Sara Borrell Program CD16/00103 to S.T.M. and PI16/00280 and PI19/00560 to J.M.G-P) and Consorcio CIBERONC CB16/12/00390)] and the Plan de Ciencia Tecnología e Innovación del Principado de Asturias/FEDER (IDI/2018/155) to J.P.R and Predoctoral Fellowship Severo Ochoa (BP-17-108) to O.E.S

Intrauterine Growth Restriction following Ligation of the Uterine Arteries Leads to More Severe Glomerulosclerosis after Mesangioproliferative Glomerulonephritis in the Offspring

Background: Low birth weight is a risk factor for the development of a more severe course of secondary renal diseases. We tested the hypothesis that experimental mesangioproliferative glomerulonephritis (GN) shows an aggravated course in rats inflicted with experimental uteroplacental insufficiency during gestation. Methods: Intrauterine growth restriction (IUGR) was induced by ligation of both uterine arteries on day 19 in pregnant Wistar rat dams. GN was induced in male offspring at the age of 9 weeks by intravenous injection of an anti-Thy-1.1 antibody. At day 14 of GN, kidneys were taken and analyzed for glomerular morphometry, markers of inflammation, glomerulosclerosis and tubulointerstitial fibrosis. Results: Despite a similar extent of mesangiolysis, former IUGR animals presented with a higher level of glomerulosclerosis and increased deposition of glomerular collagens I and IV compared to nephritic control animals. Arterial blood pressure, renal function, and proteinuria after 14 days of GN were not influenced by former IUGR. Conclusion: Ligation of the uterine arteries in the rat leads to more pronounced sclerotic changes in the glomerulus in the offspring suffering from acute GN. This finding supports the hypothesis that former IUGR increases the susceptibility for a more severe course of secondary renal diseases

Integrin α8 Is Abundant in Human, Rat, and Mouse Trophoblasts

Objective: Integrins exert regulatory functions in placentogenesis. Null mutation of certain integrin α subunits leads to placental defects with subsequent fetal growth restriction or embryonic lethality in mice. So far, the placental role of α8 integrin remains to be determined. Methods: Localization of α8 integrin and its ligands, fibronectin (FN) and osteopontin (OPN), was studied by immunohistochemistry in human, rat, and mouse placenta. The vascularization of the placental labyrinth layer of α8 integrin-deficient mice was determined by CD31 staining. In humans, α8 integrin expression was assessed via real-time polymerase chain reaction in healthy placentas, in the placental pathologies such as intrauterine growth restriction (IUGR), preeclampsia, and HELLP-syndrome (hemolysis, elevated liver enzymes, low platelet count), as well as in primary extravillous trophoblasts (EVT) and villous trophoblasts. Results: In humans, α8 integrin was detected in first and third trimester syncytiotrophoblast and EVT. Although OPN showed the same localization, FN was observed in EVT only. No expressional changes in α8 integrin were detected in the placental pathologies studied. Rodent placenta showed α8 integrin expression in giant cells and in the labyrinth layer. The localization of OPN and FN, however, showed species-specific differences. Knockout of α8 integrin in mice did not cause IUGR, despite some reduction in labyrinth layer vascularization. Conclusion: α8 Integrin is expressed in functional placental compartments among its ligands, OPN and/or FN, across species. Although this may point to a regulatory role in trophoblast function, our data from α8 integrin-deficient mice indicated only mild placental pathology. Thus, the lack of placental α8 integrin seems to be largely compensated for

Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration

Intestinal organoids capture essential features of the intestinal epithelium such as crypt folding, cellular compartmentalization and collective movements. Each of these processes and their coordination require patterned forces that are at present unknown. Here we map three-dimensional cellular forces in mouse intestinal organoids grown on soft hydrogels. We show that these organoids exhibit a non-monotonic stress distribution that defines mechanical and functional compartments. The stem cell compartment pushes the extracellular matrix and folds through apical constriction, whereas the transit amplifying zone pulls the extracellular matrix and elongates through basal constriction. The size of the stem cell compartment depends on the extracellular-matrix stiffness and endogenous cellular forces. Computational modelling reveals that crypt shape and force distribution rely on cell surface tensions following cortical actomyosin density. Finally, cells are pulled out of the crypt along a gradient of increasing tension. Our study unveils how patterned forces enable compartmentalization, folding and collective migration in the intestinal epithelium