De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes

© 2015 WILEY PERIODICALS, INC. Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ~1%-2% of CdLS-like phenotypes. Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder caused by mutation in five genes encoding subunits or regulators of the cohesin complex. To date, only the clinical features of the unique mildly affected CdLS male with SMC3 mutation have been published. Here, we report a series of 16 probands with 15 different intragenic mutations in SMC3 that provide a significant advance in our understanding of the clinical and molecular basis of Cornelia de Lange syndrome and overlapping phenotypes.CdLS Foundation of UK and Ireland for their long-term help and support. M.A.D. and I.D.K. are indebted to the USA Cornelia de Lange Syndrome FoundationPeer Reviewe

Comparison of several Real-Time PCR kits versus a culture-dependent algorithm to identify enteropathogens in stool samples

This study aims to validate the current diagnostic method for the clinical detection of gastroenteritis. We analyzed 400 stool samples to detect three of the most common enteropathogens: Salmonella spp., Campylobacter spp., and Yersinia enterocolitica. All specimens were tested with a routine clinical diagnosis algorithm and with five real-time PCR assays. A total of 98 specimens (24.5%) were positive for enteropathogens. We found 24 samples positive for Salmonella enterica, 71 positive for Campylobacter spp., and 4 positive for Yersinia enterocolitica. All evaluated methods exhibited a good performance in identifying Salmonella and Yersinia enterocolitica, being the highest positive percent agreement (PPA) value of 95.8% and 100%, respectively. The clinical algorithm showed the highest PPA value identifying Salmonella, due to the enrichment in selenite broth. However, the evaluated methods showed notable differences in the identification of Campylobacter species, obtaining a wide range of PPA values: 59.2%–100%. The clinical algorithm showed the lowest PPA value since it was only able to detect Campylobacter jejuni and Campylobacter coli species. This study revealed the importance of implementing the real-time PCR technique in a clinical algorithm: it improved the accuracy of the diagnosis and provided results in a shorter time compared to routine clinical methods

Siempre UCM! Recorrido de los doctores egresados por la Facultad de Ciencias Políticas y Sociología

Se plantea un proyecto aplicado para mantener el contacto con los egresados en los programas de doctorado de la UCM. Se ha realizado un piloto consistente en la aplicación de un cuestionario. Con esta herramienta se obtiene información sobre publicaciones de egresados que es necesaria para reacreditación y autoinformes, además de información sobre satisfacción con el programa e inserción profesional de utilidad para guiar las decisiones de las comisiones académicas

Compuestos neurogénicos basados en melatonina y su uso en el tratamiento de enfermedades del sistema nervioso

La presente invención, que se incluye en el campo de la investigación e industria farmacéutica, se refiere a nuevas entidades químicas derivadas de melatonina con propiedades neurogénicas, moduladoras de los receptores de melatonina y/o serotonina, antioxidantes y/o colinérgicas. También se refiere a los procedimientos para la preparación de estos nuevos compuestos, a las composiciones farmacéuticas que los contienen y a su uso para la fabricación de un medicamento para el tratamiento de enfermedades del sistema nervioso relacionadas con degeneración neuronal, depresión, trastornos psiquiátricos y cognitivos, trauma o lesión celular, u otro trastorno neurológico relacionado, tratamiento de fatiga diurna, trastornos del sueño, pérdida de eficacia mental, debilidad e irritabilidad y síntomas relacionados con la descompensación horaria (efecto jet-lag o síndrome transoceánico).Peer reviewedConsejo Superior de Investigaciones Científicas, Universidad Autónoma de MadridB1 Patente sin examen previ

Cornelia de Lange syndrome with NIBPL mutation and mosaic Turner syndrome in the same individual

Background: Cornelia de Lange syndrome (CdLS) is a dominantly inherited disorder characterized by facial dysmorphism, growth and cognitive impairment, limb malformations and multiple organ involvement. Mutations in NIPBL gene account for about 60% of patients with CdLS. This gene encodes a key regulator of the Cohesin complex, which controls sister chromatid segregation during both mitosis and meiosis. Turner syndrome (TS) results from the partial or complete absence of one of the X chromosomes, usually associated with congenital lymphedema, short stature, and gonadal dysgenesis. Case presentation: Here we report a four-year-old female with CdLS due to a frameshift mutation in the NIPBL gene (c.1445_1448delGAGA), who also had a tissue-specific mosaic 45,X/46,XX karyotype. The patient showed a severe form of CdLS with craniofacial dysmorphism, pre- and post-natal growth delay, cardiovascular abnormalities, hirsutism and severe psychomotor retardation with behavioural problems. She also presented with minor clinical features consistent with TS, including peripheral lymphedema and webbed neck. The NIPBL mutation was present in the two tissues analysed from different embryonic origins (peripheral blood lymphocytes and oral mucosa epithelial cells). However, the percentage of cells with monosomy X was low and variable in tissues. These findings indicate that, ontogenically, the NIPBL mutation may have appeared before the mosaic monosomy X. Conclusions: The coexistence in several patients of these two rare disorders raises the issue of whether there is indeed a cause-effect association. The detailed clinical descriptions indicate predominant CdLS phenotype, although additional TS manifestations may appear in adolescence

Immunoproteomic analysis of the protective response obtained with subunit and commercial vaccines against Glässer’s disease in pigs

14 p.An immunoproteomic analysis of the protective response of subunit and commercial vaccines in colostrumdeprived pigs against Glässer’s disease was carried out. A mixture of proteins with affinity to porcine transferrin (PAPT) from Haemophilus parasuis Nagasaki strain (serovar 5) was inoculated intramuscularly (PAPTM) and intratracheally (PAPTCp), along with a commercial bacterin. PAPT were separated using 2 dimensional electrophoresis (2DE) gels and with them, 2DE Western blots were carried out. A total of 17 spots were identified as positive with sera of pigs from any of the three vaccinated groups, the highest number of immunoreactive proteins being detected in those having received PAPTCp. Among them, six proteins (FKBP-type peptidyl-prolyl cis-trans isomerase, neuraminidase exo- -sialidase, xanthine-guanine phosphoribosyl transferase, CMP-N-acetylneuraminic acid synthetase, phenylalanyl-tRNA synthetase and glyceraldehyde 3-phosphate dehydrogenase) were found to be novel immunogens in H. parasuis. These proteins showed a high potential as candidates in future subunit vaccines against Glässer’s disease. The three experimental groups developed specific systemic total IgG (IgGt), IgG1, IgG2 and IgM antibodies after immunizations. In addition, those receiving PAPTCp yielded a serum IgA response.S

Nueva enzima para la biosíntesis de isoprenoides.

Se ha encontrado una nueva enzima con actividad 1-desoxi-D-xilulosa 5-fosfato reductoisomerasa que cataliza la reacción de producción de 2-C-metil-D-eritritol 4-fosfato a partir de 1-desoxi-D-xilulosa 5-fosfato, que tiene la secuencia de aminoácidos SEQ ID NO: 41. La enzima es útil en la síntesis de isoprenoides, particularmente en la síntesis de 2-C-metil-D-eritritol 4-fosfato.Solicitud: 201031068 (14.07.2010)Nº Pub. de Solicitud: ES2372942A1 (30.01.2012)Nº de Patente: ES2372942B1 (04.12.2012

Two-step ATP-driven opening of cohesin head.

The cohesin ring is a protein complex composed of four core subunits: Smc1A, Smc3, Rad21 and Stag1/2. It is involved in chromosome segregation, DNA repair, chromatin organization and transcription regulation. Opening of the ring occurs at the “head” structure, formed of the ATPase domains of Smc1A and Smc3 and Rad21. We investigate the mechanisms of the cohesin ring opening using techniques of free molecular dynamics (MD), steered MD and quantum mechanics/molecular mechanics MD (QM/MM MD). The study allows the thorough analysis of the opening events at the atomic scale: i) ATP hydrolysis at the Smc1A site, evaluating the role of the carboxy-terminal domain of Rad21 in the process; ii) the activation of the Smc3 site potentially mediated by the movement of specific amino acids; and iii) opening of the head domains after the two ATP hydrolysis events. Our study suggests that the cohesin ring opening is triggered by a sequential activation of the ATP sites in which ATP hydrolysis at the Smc1A site induces ATPase activity at the Smc3 site. Our analysis also provides an explanation for the effect of pathogenic variants related to cohesinopathies and cancer.post-print4709 K

Dexamethasone and doxycycline functionalized nanoparticles enhance osteogenic properties of titanium surfaces

Objectives: To evaluate the effect of doxycycline and dexamethasone doped nanoparticles covering titanium surfaces, on osteoblasts proliferation and differentiation. Methods: Doxycycline and dexamethasone doped polymeric nanoparticles were applied on titanium discs (Ti- DoxNPs and Ti-DexNPs). Undoped NPs and uncovered Ti discs were used as control. Human MG-63 osteoblast- like cells were cultured. Osteoblasts proliferation was tested by MTT assay. Alkaline phosphatase activity was analyzed. Differentiation gene expression was assessed by real-time quantitative polymerase chain reaction. Scanning Electron Microscopy was performed to assess osteoblasts morphology. Mean comparisons were con- ducted by ANOVA and Wilcoxon or Tukey tests (p < 0.05). Results: No differences in osteoblasts proliferation were found. Osteoblasts grown on Ti-DoxNPs significantly increased alkaline phosphatase activity. Doxycycline and dexamethasone nanoparticles produced an over-ex- pression of the main osteogenic proliferative genes (TGF-β1, TGF-βR1 and TGF-βR2). The expression of Runx-2 was up-regulated. The osteogenic proteins (AP, OSX and OPG) were also overexpressed on osteoblasts cultured on Ti-DoxNPs and Ti-DexNPs. The OPG/RANKL ratio was the highest when DoxNPs were present (75-fold in- crease with respect to the control group). DexNPs also produced a significantly higher OPG/RANKL ratio with respect to the control (20 times higher). Osteoblasts grown on titanium discs were mainly flat and polygonal in shape, with inter-cellular connections. In contrast, osteoblasts cultured on Ti-DoxNPs or Ti-DexNPs were found to be spindle-shaped and had abundant secretions on their surfaces. Significance: DoxNPs and DexNPs were able to stimulate osteoblasts differentiation when applied on titanium surfaces, being considered potential inducers of osteogenic environment when performing regenerative proce- dures around titanium dental implants.Grant PID2020–114694RB-I00 funded by MCIN/AEI 10.13039/501100011033FPU of Ministry of Universities grant FPU20/0045Klockner S.A. for financial support and for providing the titanium disc

Use of seasonal forecasts for water resources management in Spain

Presentación realizada en: 15th Annual Meeting of the European Meteorological Society (EMS) /12th European Conference on Applications of Meteorology (ECAM) celebrado en Sofía, Bulgaria del 7 al 11 de septiembre de 2015