Regulation of human beta-cell adhesion, motility, and insulin secretion by collagen IV and its receptor alpha1beta1

Collagens have been shown to influence the survival and function of cultured beta-cells; however, the utilization and function of individual collagen receptors in beta-cells is largely unknown. The integrin superfamily contains up to five collagen receptors, but we have determined that alpha(1)beta(1) is the primary receptor utilized by both fetal and adult beta-cells. Cultured beta-cells adhered to and migrated on collagen type IV (Col-IV), and these responses were mediated almost exclusively by alpha(1)beta(1). The migration of cultured beta-cells to Col-IV significantly exceeded that to other matrix components suggesting that this substrate is of unique importance for beta-cell motility. The interaction of alpha(1)beta(1) with Col-IV also resulted in significant insulin secretion at basal glucose concentrations. A subset of beta-cells in developing islets was confirmed to express alpha(1)beta(1), and this expression co-localized with Col-IV in the basal membranes of juxtaposed endothelial cells. Our findings indicate that alpha(1)beta(1) and Col-IV contribute to beta-cell functions known to be important for islet morphogenesis and glucose homeostasis.     

Broad-scale habitat use by red-legged partridge <Emphasis Type="Italic">(Alectoris rufa</Emphasis>) in a low-density area in northwestern Spain

We developed broad-scale habitat selection models for the distribution of red-legged partridge Alectoris rufa in a low-density area in northwestern Spain, the Baixa-Limia site of community importance (SCI). The fieldwork consisted of ground surveys in 1 × 1 km squares. For habitat selection analysis, we used a 2 × 2 km grid integrating the information obtained in the 1 × 1 km squares. As predictors we used environmental variables measured on digital 1:50,000 scale cartography using a geographical information system (GIS). The red-legged partridge was scarce in the study area. The logistic regression analysis carried out on data from the squares with probable and confirmed breeding included the area of scrubland and pastureland with a positive sign. Using the breeding index category (BIC) three variables produced a slightly positive response: area of scrubland and pastureland, length of border between scrublands and forests, and length of border between forests and dams. The difficulty for modelling the habitat selection of this species could be due to human activities (hunting, habitat loss, restocking of hunt species), and may have modified their habitat preferences. Furthermore, the occupation of suboptimal habitats would distort the real habitat preferences.     

Carbamoyloximes as novel non-competitive mGlu5 receptor antagonists

Hit-to-lead optimization of a HTS hit led to new carbamoyloxime derivatives. After identification of an advanced hit (8d) the CYP enzyme inhibitory activity of this class of compounds was successfully eliminated. Systematic exploration of different parts of the advanced hit led us to some promising lead compounds with mGluR5 affinities comparable to that of MPEP.     

Toward a comprehensive model for induced endoreduplication

Both the biological significance and the molecular mechanism of endoreduplication (END) have been debated for a long time by cytogeneticists and researchers into cell cycle enzymology and dynamics alike. Mainly due to the fact that a wide variety of agents have been reported as able to induce endoreduplication and the diversity of cell types where it has been described, until now no clear or unique mechanism of induction of this phenomenon, rare in animals but otherwise quite common in plants, has been proposed. DNA topoisomerase II (topo II), plays a major role in mitotic chromosome segregation after DNA replication. The classical topo II poisons act by stabilizing the enzyme in the so-called cleavable complex and result in DNA damage as well as END, while the true catalytic inhibitors, which are not cleavable-complex-stabilizers, do induce END without concomitant DNA and chromosome damage. Taking into account these observations on the induction of END by drugs that interfere with topo II, together with our recently obtained evidence that the nature of DNA plays an important role for chromosome segregation [Cortes, F., Pastor, N., Mateos, S., Dominguez, I., 2003. The nature of DNA plays a role in chromosome segregation: endoreduplication in halogen-substituted chromosomes. DNA Repair 2, 719-726.], a straightforward model is proposed in which the different mechanisms leading to induced END are considered.     

Phylogenetic and molecular clock inferences of cyanobacterial strains within Rivulariaceae from distant environments

Heterocyst-forming cyanobacteria are important players at both evolutionary and ecological scales, but to date it has been difficult to establish their phylogenetic affiliations. We present data from a phylogenetic and molecular clock analysis of heterocystous cyanobacteria within the family Rivulariaceae, including the genera Calothrix, Rivularia, Gloeotrichia and Tolypothrix. The strains were isolated from distant geographic regions including fresh and brackish water bodies, microbial mats from beach rock, microbialites, pebble beaches, plus PCC strains 7103 and 7504. Phylogenetic inferences (distance, likelihood and Bayesian) suggested the monophyly of genera Calothrix and Rivularia. Molecular clock estimates indicate that Calothrix and Rivularia originated ～1500 million years ago (MYA) ago and species date back to 400-300 MYA while Tolypothrix and Gloeotrichia are younger genera (600-400 MYA).     

How Accurate are Paleoecological Reconstructions of Early Paleontological and Archaeological Sites?

Paleoecology allows construction of paleoenvironmental models, faunal changes and evolutionary trends of paleontological taxa using modern analogs. However, when linking modern analogs to paleontological taxa in paleoecological reconstruction, differential taxonomic preservation in the fossil record has to be taken into account. Paleontologists have known the biased nature of the fossil record since Efremov’s publication on taphonomy in 1940, yet many ecological models of habitats associated with hominins in paleontological and archaeological sites in Africa and elsewhere barely address the complexity of the fossil record. We use randomly sampled ungulates from modern biomes in a comparative taxonomic abundance to demonstrate how the combination of modern thanatocoenoses and taphocoenoses, when used in reference to habitat-specific biocoenosis, produce better inferences of past habitats in paleontological and archaeological sites than approaches currently used.     

Recognition of the neural chemoattractant Netrin-1 by integrins alpha6beta4 and alpha3beta1 regulates epithelial cell adhesion and migration

Netrins, axon guidance cues in the CNS, have also been detected in epithelial tissues. In this study, using the embryonic pancreas as a model system, we show that Netrin-1 is expressed in a discrete population of epithelial cells, localizes to basal membranes, and specifically associates with elements of the extracellular matrix. We demonstrate that alpha6beta4 integrin mediates pancreatic epithelial cell adhesion to Netrin-1, whereas recruitment of alpha6beta4 and alpha3beta1 regulate the migration of CK19+/PDX1+ putative pancreatic progenitors on Netrin-1. These results provide evidence for the activation of epithelial cell adhesion and migration by a neural chemoattractant, and identify Netrin-1/integrin interactions as adhesive/guidance cues for epithelial cells.     

Pure partial trisomy 6p due to a familial insertion (16;6)(p12;p21.2p23)

There have only been eight patients with 6p pure trisomy involving different segments: four cases resulted from a translocation or insertion and four were due to an intrachromosomal duplication. We report here the first postnatally ascertained patient with a pure 6p partial trisomy due to an interchromosomal insertion (16;6)(p12;p21.2p23)mat. This rearrangement was confirmed by fluorescent in situ hybridization (FISH) with whole chromosome 6 and 16 painting probes. The clinical findings in the present patient were similar to those observed in previous cases, including craniofacial dysmorphism, minor anomalies, and lack of severe anatomical defects; yet, the unspecificity of many of these features prevented us from delineating the 6p pure trisomy syndrome.     

Clinical Characteristics of Preschool Children with Oppositional Defiant Disorder and Callous-Unemotional Traits

There is a need to know whether callous-unemotional (CU) traits identify a more severe group of oppositional defiant children (ODD). The aim of this study is to ascertain cross-sectionally and longitudinally the specific contribution of CU levels and the presence of ODD in the psychological state of preschool children from the general population. A total of 622 children were assessed longitudinally at ages 3 and 5 with a semi-structured diagnostic interview and questionnaires filled out by parents and teachers. In multivariate models simultaneously including ODD diagnosis and CU levels, controlling by socioeconomic status, ethnicity, sex, severity of conduct disorder symptoms and other comorbidity, high CU scores were related to higher levels of aggression, withdrawn, externalizing and global symptomatology, functional impairment and higher probability of comorbid disorders and use of services. The contribution of CU traits on children’s psychological state was not moderated by the presence/absence of ODD. Stability for CU traits and number of ODD-symptoms between ages 3 and 5 was statistically significant but moderate-low (intra-class correlation under .40). Assessment and identification of CU traits from preschool might help to identify a subset of children who could have socialization problems, not only among those with ODD but also among those without a diagnosis of conduct problems.     

Resveratrol Ameliorates the Maturation Process of β-Cell-Like Cells Obtained from an Optimized Differentiation Protocol of Human Embryonic Stem Cells

Human embryonic stem cells (hESCs) retain the extraordinary capacity to differentiate into different cell types of an adult organism, including pancreatic β-cells. For this particular lineage, although a lot of effort has been made in the last ten years to achieve an efficient and reproducible differentiation protocol, it was not until recently that this aim was roughly accomplished. Besides, several studies evidenced the impact of resveratrol (RSV) on insulin secretion, even though the mechanism by which this polyphenol potentiates glucose-stimulated insulin secretion (GSIS) is still not clear. The aim of this study was to optimize an efficient differentiation protocol that mimics in vivo pancreatic organogenesis and to investigate whether RSV may improve the final maturation step to obtain functional insulin-secreting cells. Our results indicate that treatment of hESCs (HS-181) with activin-A induced definitive endoderm differentiation as detected by the expression of SOX17 and FOXA2. Addition of retinoic acid (RA), Noggin and Cyclopamine promoted pancreatic differentiation as indicated by the expression of the early pancreatic progenitor markers ISL1, NGN3 and PDX1. Moreover, during maturation in suspension culture, differentiating cells assembled in islet-like clusters, which expressed specific endocrine markers such as PDX1, SST, GCG and INS. Similar results were confirmed with the human induced Pluripotent Stem Cell (hiPSC) line MSUH-001. Finally, differentiation protocols incorporating RSV treatment yielded numerous insulin-positive cells, induced significantly higher PDX1 expression and were able to transiently normalize glycaemia when transplanted in streptozotocin (STZ) induced diabetic mice thus promoting its survival. In conclusion, our strategy allows the efficient differentiation of hESCs into pancreatic endoderm capable of generating β-cell-like cells and demonstrates that RSV improves the maturation process.