IGFBP-3 inhibits Wnt signaling in metastatic melanoma cells.

In previous works, we have shown that insulin-like growth factor-binding protein-3 (IGFBP-3), a tissue and circulating protein able to bind to IGFs, decreases drastically in the blood serum of patients with diffuse metastatic melanoma. In agreement with the clinical data, recombinant IGFBP-3 was found to inhibit the motility and invasiveness of cultured metastatic melanoma cells and to prevent growth of grafted melanomas in mice. The present work was aimed at identifying the signal transduction pathways underlying the anti-tumoral effects of IGFBP-3. We show that the anti-tumoral effect of IGFBP-3 is due to inhibition of the Wnt pathway and depends upon the presence of CD44, a receptor protein known to modulate Wnt signaling. Once it has entered the cell, IGFBP-3 binds the Wnt signalosome interacting specifically with its component GSK-3β. As a consequence, the β-catenin destruction complex dissociates from the LRP6 Wnt receptor and GSK-3β is activated through dephosphorylation, becoming free to target cytoplasmic β-catenin which is degraded by the proteasomal pathway. Altogether, the results suggest that IGFBP-3 is a novel and effective inhibitor of Wnt signaling. As IGFBP-3 is a physiological protein which has no detectable toxic effects either on cultured cells or live mice, it might qualify as an interesting new therapeutic agent in melanoma, and potentially many other cancers with a hyperactive Wnt signaling

Open legacy soil survey data in Brazil: geospatial data quality and how to improve it.

Spatial soil data applications require sound geospatial data including coordinates and a coordinate reference system. However, when it comes to legacy soil data we frequently find them to be missing or incorrect. This paper assesses the quality of the geospatial data of legacy soil observations in Brazil, and evaluates geospatial data sources (survey reports, maps, spatial data infrastructures, web mapping services) and expert knowledge as a means to fix inconsistencies. The analyses included several consistency checks performed on 6,195 observations from the Brazilian Soil Information System. The positional accuracy of geospatial data sources was estimated so as to obtain an indication of the quality for fixing inconsistencies. The coordinates of 20 soil observations, estimated using the web mapping service, were validated with the true coordinates measured in the field. Overall, inconsistencies of different types and magnitudes were found in half of the observations, causing mild to severe misplacements. The involuntary substitution of symbols and numeric characters with similar appearance when recording geospatial data was the most common typing mistake. Among the geospatial data sources, the web mapping service was the most useful, due to operational advantages and lower positional error (~6 m). However, the quality of the description of the observation location controls the accuracy of estimated coordinates. Thus, the error of coordinates estimated using the web mapping service ranged between 30 and 1000 m. This is equivalent to coordinates measured from arc-seconds to arc-minutes, respectively. Under this scenario, the feedback from soil survey experts is crucial to improving the quality of geospatial data

SUSCEPTIBILIDAD DE LA PALOMA SILVESTRE (Columba livia) UN VIRUS VELOGÉNICO VISCEROTRÓPICO DE LA ENFERMEDAD DE NEWCASTLE EN CONDICIONES EXPERIMENTALES

El objetivo del presente estudio fue evaluar el grado de susceptibilidad, efecto patológico y respuesta serológica de la paloma silvestre (Columba livia) frente a la inoculación experimental con una cepa de virus velogénico de la enfermedad de Newcastle. Se capturaron 28 aves, donde la mitad se inoculó vía nasal y oral, y la otra mitad se mantuvo como grupo control. Se registró signos clínicos y mortalidad. Se tomaron muestras de sangre para la prueba de inhibición de la hemaglutinación y muestras de tejidos de aves muertas y del grupo control para su análisis histopatológico. Se tomaron muestras de pulmón, tráquea e hisopado de cloaca para la recuperación viral, durante seis semanas post inoculación. El 64% de aves del grupo inoculado presentó signos clínicos y una mortalidad del 42.8%. Se presentaron estornudos a partir del 4"dia; erizamiento de plumas, aislamiento y letargia a partir del 5" día; y opistótonos, tremores de cabeza y cuello a partir del 78 día post inoculación. Los hallazgos a la necropsia consistieron en congestión generalizada de órganos y eesplenomegalia. Las lesiones microscópicas fueron edema, gliosis, manguito perivascular en cerebro y cerebelo, pérdida de cilios, infiltrado de linfocitos en tráquea, congestión en pulmón y proventriculo, infiltración de linfocitos en intestinos y despoblamiento linfoide en bazo. El grupo inoculado incrementó sus títulos de anticuerpos a partir de la 1" semana llegando, a su máximo promedio geométrico de titulo de 4.9 en la segunda semana. Se logro, la recuperación vira1 en muestras de pulmón y tráquea durante las tres primeras semanas. Se demostró que las aves de la especie Columba livia usadas en este experimento fueron susceptibles a la inoculación experimental con una cepa velogénica del virus de la enfermedadde Newcastle.The objective of the study was to asses the susceptibility, pathological effect and serological response of wild pigeons (Columba livia) to Newcastle virus. A total of 28 adult wild pigeons were captured, 14 were inoculated with a velogenic viscerotropic strain of Newcastle virus by oral and nasal route, and the remaining birds were used as a control group. Clinical signs and mortality were recorded. Blood samples were collected for the hemaglutination inhibition technique. Tissue samples from lung and trachea were collected, and cloacal swabs were harvested for virus recovery and histological studies. Birds of the inoculated group showed clinical signs (64%) and mortality (42.8%). The clinical signs (sneezes, ruffled plumage, isolation and lethargy) started at day 4 after inoculation. The 43% of birds showed nervous signs (opisthotonos and tremors of head and neck) and 21% had diarrhea. In the necropsy was observed a widespread congestion and splenomegaly. The microscopic injuries were edema, gliosis, mononuclear perivascular cuffing in brain and cerebellum, loss of cillia, lymphoid infiltration in trachea, lung congestion, proventricular congestion, lymphocitic infiltration in intestines, and lymphoid depletion in spleen. The inoculated group showed the highest antibody titer (4.9) in the second week. The viral recovery was made upon lung and trachea tissues. It was showed that the specie Columba livia was susceptible to the experimental inoculation with a velogenic strain of Newcastle diasease virus

Unveiling Molecular Recognition of Sialoglycans by Human Siglec-10

29 p.-6 fig.-2 tab.-7 fig. supl.-2 tab. supl.-1 graph. abst.Siglec-10 is an inhibitory I-type lectin selectively recognizing sialoglycans exposed on cell surfaces, involved in several patho-physiological processes. The key role Siglec-10 plays in the regulation of immune cell functions has made it a potential target for the development of immunotherapeutics against a broad range of diseases. However, the crystal structure of the protein has not been resolved for the time being and the atomic description of Siglec-10 interactions with complex glycans has not been previously unraveled. We present here the first insights of the molecular mechanisms regulating the interaction between Siglec-10 and naturally occurring sialoglycans. We used combined spectroscopic, computational and biophysical approaches to dissect glycans' epitope mapping and conformation upon binding in order to afford a description of the 3D complexes. Our outcomes provide a structural perspective for the rational design and development of high-affinity ligands to control the receptor functionality.This study was supported by the project ‘‘GLYTUNES’’ funded by MIUR Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN 2017) (2017XZ2ZBK, 2019–2022) to A.S.; by progetto POR SATIN and Progetto POR CampaniaOncoterapia to A.M.; by the European Commission (H2020-MSCA- 814102-SWEET CROSSTALK project) to A.M., R.M., and A.S.. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program under grant agreement No 851356 to R.M. FSE,PON Ricerca e Innovazione 2014–2020, Azione I.1 ‘‘Dottorati Innovativi con caratterizzazione Industriale’’ is acknowledged for funding the PhD grant to R.E.F. Grants by the Spanish Ministry of Science MICINN (CTQ2017-88353-R and fellowship BES 2015–071588 to J.G.-C.) and Wellcome Trust 103744/Z/14/Z to P.R.C. are acknowledged.Peer reviewe

The proliferation marker Chromatin Assembly Factor-1 is of clinical value in predicting the biological behaviour of salivary gland tumours.

Salivary gland tumours (SGT) constitute a diagnostically challenging group of neoplasms with frequently unpredictable clinical outcome. The proliferation rate facilitates the identification of aggressive SGT. The Chromatin Assembly Factor-1 (CAF-1) is a major epigenetic regulator of nuclear chromatin organization during DNA replication. It plays a critical function in human tumourigenesis and has been proposed as a new proliferation and prognostic marker for some malignancies. This study focused on the role of CAF-1/p60 protein as a marker of clinical value for SGT. The expression of CAF-1/p60 was evaluated by immunohistochemistry on a retrospective series of 362 surgically excised benign and malignant SGT with different histogenesis and, when available, on fine-needle pre-surgical cytological biopsies. The resulting data were compared with traditional prognostic parameters, including the expression of the routine proliferation marker ki67/MIB1. CAF-1/p60 was detectable in all SGT, with highest degree of expression in metastasizing malignant tumours. Moreover, the cases of benign tumours which progressed to carcinoma during the follow-up, showed significantly higher CAF-1/p60 expression than non-progressing benign SGT, both on histological sections and cytological smears of the primary tumour. Cox's multiple regression analysis selected CAF-1/p60 expression as the best independent predictor of cancer development for benign SGT (p<0.0001), and the best independent predictor of metastasis onset for malignant tumours (p<0.0004). Overexpression of CAF-1/p60, on histological and/or cytological samples, characterizes malignant SGT with aggressive behaviour, irrespective of their specific histotype, and allows the early diagnosis of progression toward malignancy of morphologically benign tumours

The Multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. We identify four distinct homodimerization interfaces on the GR-LBD surface, which can associate into 20 topologically different homodimers. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution, quantitative fluorescence microscopy in living cells, and transcriptomic analyses. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work illustrates the unique flexibility of GR's LBD and suggests different dimeric conformations within cells. In addition, we unveil pathophysiologically relevant quaternary assemblies of the receptor with important implications for glucocorticoid action and drug design

Bringing together Brazilian soil scientists to share soil data.

Brazilian soil scientists have recently created a soil data repository using community-built standards and following open data policies in an attempt to address the issues mentioned above. The Free Brazilian Repository for Open Soil Data - febr -, accessible through www.ufsm.br/febr, is a centralized repository targeted at storing open soil data and serving it in a standardized and harmonized format, for various applications. This paper describes the features of febr and the opportunities that it creates for soil science.Na publicação: Wenceslau Teixeira

Clinical course of sepsis, severe sepsis, and septic shock in a cohort of infected patients from ten Colombian hospitals

ABSTARCT: Sepsis has several clinical stages, and mortality rates are different for each stage. Our goal was to establish the evolution and the determinants of the progression of clinical stages, from infection to septic shock, over the first week, as well as their relationship to 7-day and 28-day mortality