Differentially Expressed Circular RNA Profile in an Intracranial Aneurysm Group Compared with a Healthy Control Group.

OBJECTIVE: Intracranial aneurysm (IA) is a fatal disease owing to vascular rupture and subarachnoid hemorrhage. Much attention has been given to circular RNAs (circRNAs) because they may be potential biomarkers for many diseases, but their mechanism in the formation of IA remains unknown. METHODS: circRNA expression profile analysis of blood samples was conducted between patients with IA and controls. Overall, 235 differentially expressed circRNAs were confirmed between IA patients and the control group. The reliability of the microarray results was demonstrated by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Of 235 differentially expressed genes, 150 were upregulated, while the other 85 were downregulated. Five miRNAs matched to every differential expression of circRNAs, and related MREs were predicted. We performed gene ontology (GO) analysis to identify the functions of their targeted genes, with the terms "Homophilic cell adhesion via plasma membrane adhesion molecules" and "Positive regulation of cellular process" showing the highest fold enrichment. CONCLUSIONS: This study demonstrated the role of circRNA expression profiling in the formation of IA and revealed that the mTOR pathway can be a latent therapeutic strategy for IA.

A synthetic method to assay adhesion-family G-protein coupled receptors. Determination of the G-protein coupling profile of ADGRG6(GPR126).

G-protein coupled receptors (GPCRs) are the largest family of membrane-spanning receptors in metazoans and mediate diverse biological processes such as chemotaxis, vision, and neurotransmission. Adhesion GPCRs represent an understudied class of GPCRs. Adhesion GPCRs (ADGRs) are activated by an intrinsic proteolytic mechanism executed by the G-protein autoproteolysis inducing domain that defines this class of GPCRs. It is hypothesized that agonist ligands modulate the proteolyzed receptor to regulate the activity of a tethered agonist peptide that is an intramolecular activator of ADGRs. The mechanism of activation of ADGRs in physiological settings is unclear and the toolbox for interrogating ADGR physiology in cellular models is limited. Therefore, we generated a novel enterokinase-activated tethered ligand system for ADGRG6(GPR126). Enterokinase addition to cells expressing a synthetic ADGRG6 protein induced potent and efficacious signal transduction through heterotrimeric G-protein coupled second messenger pathways including cyclic nucleotide production, intracellular calcium mobilization, and GPCR-pathway linked reporter gene induction. These studies support the hypothesis that ADGRG6(GPR126) is coupled to multiple heterotrimeric G-proteins: including Gαs, Gαq, and Gα12. This novel assay method is robust, specific, and compatible with numerous cell pharmacology approaches. We present a new tool for determination of the biological function of ADGRs and the identification of ligands that engage these receptors.

The Impact of Spaceflight and Simulated Microgravity on Cell Adhesion.

Microgravity induces a number of significant physiological changes in the cardiovascular, nervous, immune systems, as well as the bone tissue of astronauts. Changes in cell adhesion properties are one aspect affected during long-term spaceflights in mammalian cells. Cellular adhesion behaviors can be divided into cell-cell and cell-matrix adhesion. These behaviors trigger cell-cell recognition, conjugation, migration, cytoskeletal rearrangement, and signal transduction. Cellular adhesion molecule (CAM) is a general term for macromolecules that mediate the contact and binding between cells or between cells and the extracellular matrix (ECM). In this review, we summarize the four major classes of adhesion molecules that regulate cell adhesion, including integrins, immunoglobulin superfamily (Ig-SF), cadherins, and selectin. Moreover, we discuss the effects of spaceflight and simulated microgravity on the adhesion of endothelial cells, immune cells, tumor cells, stem cells, osteoblasts, muscle cells, and other types of cells. Further studies on the effects of microgravity on cell adhesion and the corresponding physiological behaviors may help increase the safety and improve the health of astronauts in space.

Revisiting Dscam diversity: lessons from clustered protocadherins.

The complexity of neuronal wiring relies on the extraordinary recognition diversity of cell surface molecules. Drosophila Dscam1 and vertebrate clustered protocadherins (Pcdhs) are two classic examples of the striking diversity from a complex genomic locus, wherein the former encodes more than 10,000 distinct isoforms via alternative splicing, while the latter employs alternative promoters to attain isoform diversity. These structurally unrelated families show remarkably striking molecular parallels and even similar functions. Recent studies revealed a novel Dscam gene family with tandemly arrayed 5' cassettes in Chelicerata (e.g., the scorpion Mesobuthus martensii and the tick Ixodes scapularis), similar to vertebrate clustered Pcdhs. Likewise, octopus shows a more remarkable expansion of the Pcdh isoform repertoire than human. These discoveries of Dscam and Pcdh diversification reshape the evolutionary landscape of recognition molecule diversity and provide a greater understanding of convergent molecular strategies for isoform diversity. This article reviews new insights into the evolution, regulatory mechanisms, and functions of Dscam and Pcdh isoform diversity. In particular, the convergence of clustered Dscams and Pcdhs is highlighted.

A chelicerate-specific burst of nonclassical Dscam diversity.

BACKGROUND: The immunoglobulin (Ig) superfamily receptor Down syndrome cell adhesion molecule (Dscam) gene can generate tens of thousands of isoforms via alternative splicing, which is essential for both nervous and immune systems in insects. However, further information is required to develop a comprehensive view of Dscam diversification across the broad spectrum of Chelicerata clades, a basal branch of arthropods and the second largest group of terrestrial animals. RESULTS: In this study, a genome-wide comprehensive analysis of Dscam genes across Chelicerata species revealed a burst of nonclassical Dscams, categorised into four types-mDscam, sDscamα, sDscamß, and sDscamγ-based on their size and structure. Although the mDscam gene class includes the highest number of Dscam genes, the sDscam genes utilise alternative promoters to expand protein diversity. Furthermore, we indicated that the 5' cassette duplicate is inversely correlated with the sDscam gene duplicate. We showed differential and sDscam- biased expression of nonclassical Dscam isoforms. Thus, the Dscam isoform repertoire across Chelicerata is entirely dominated by the number and expression levels of nonclassical Dscams. Taken together, these data show that Chelicerata evolved a large conserved and lineage-specific repertoire of nonclassical Dscams. CONCLUSIONS: This study showed that arthropods have a large diversified Chelicerata-specific repertoire of nonclassical Dscam isoforms, which are structurally and mechanistically distinct from those of insects. These findings provide a global framework for the evolution of Dscam diversity in arthropods and offer mechanistic insights into the diversification of the clade-specific Ig superfamily repertoire.

The semaphorins and their receptors as modulators of tumor progression.

The semaphorins were initially characterized as repulsive axon guidance factors. However, they are currently also recognized as important regulators of diverse biological processes which include regulation of immune responses, angiogenesis, organogenesis, and a variety of additional physiological and developmental functions. The semaphorin family consists of more than 20 genes divided into seven subfamilies, all of which contain the sema domain signature. They usually transduce signals by activation of receptors belonging to the plexin family, either directly, or indirectly following the binding of some semaphorins to receptors of the neuropilin family which subsequently associate with plexins. Additional receptors which form complexes with these primary semaphorin receptors are also frequently involved in semaphorin signalling, and can strongly influence the nature of the biological responses of cells to semaphorins. Recent evidence suggests that semaphorins play important roles in the etiology of multiple forms of cancer. Some semaphorins such as some semaphorins belonging to the class-3 semaphorin subfamily, have been found to function as bona fide tumor suppressors and to inhibit tumor progression by various mechanisms. Because these class-3 semaphorins are secreted proteins, these semaphorins may potentially be used as anti-tumorigenic drugs. Other semaphorins, such as semaphorin-4D, function as inducers of tumor progression and represent targets for the development of novel anti-tumorigenic drugs. The mechanisms by which semaphorins affect tumor progression are diverse, ranging from direct effects on tumor cells to modulation of accessory processes such as modulation of immune responses and inhibition or promotion of tumor angiogenesis and tumor lymphangiogenesis. This review focuses on the diverse mechanisms by which semaphorins affect tumor progression.

Coevolution of paired receptors in Xenopus carcinoembryonic antigen-related cell adhesion molecule families suggests appropriation as pathogen receptors.

BACKGROUND: In mammals, CEACAM1 and closely related members represent paired receptors with similar extracellular ligand-binding regions and cytoplasmic domains with opposing functions. Human CEACAM1 and CEACAM3 which have inhibitory ITIM/ITSM and activating ITAM-like motifs, respectively, in their cytoplasmic regions are such paired receptors. Various bacterial pathogens bind to CEACAM1 on epithelial and immune cells facilitating both entry into the host and down-regulation of the immune response whereas interaction with granulocyte-specific CEACAM3 leads to their uptake and destruction. It is unclear whether paired CEACAM receptors also exist in other vertebrate clades. RESULTS: We identified more than 80 ceacam genes in Xenopus tropicalis and X. laevis. They consist of two subgroups containing one or two putative paired receptor pairs each. Analysis of genomic sequences of paired receptors provide evidence that their highly similar ligand binding domains were adjusted by recent gene conversion events. In contrast, selection for diversification is observed among inhibitory receptor orthologs of the two frogs which split some 60 million years ago. The allotetraploid X. laevis arose later by hybridization of two closely related species. Interestingly, despite the conservation of the genomic landscape surrounding the homeologous ceacam loci only one locus resembles the one found in X. tropicalis. From the second X. laevis locus more than 80 % of the ceacam genes were lost including 5 of the 6 paired receptor genes. This suggests that once the gene for one of the paired receptors is lost the remaining gene cluster degrades rapidly probably due to lack of selection pressure exerted by pathogens. CONCLUSIONS: The presence of paired receptors and selection for diversification suggests that also in amphibians CEACAM1-related inhibitory proteins are or were used as pathogen receptors.

Adhesion Molecules: Master Controllers of the Circulatory System.

This manuscript will review our current understanding of cellular adhesion molecules (CAMs) relevant to the circulatory system, their physiological role in control of vascular homeostasis, innate and adaptive immune responses, and their importance in pathophysiological (disease) processes such as acute lung injury, atherosclerosis, and pulmonary hypertension. This is a complex and rapidly changing area of research that is incompletely understood. By design, we will begin with a brief overview of the structure and classification of the major groups of adhesion molecules and their physiological functions including cellular adhesion and signaling. The role of specific CAMs in the process of platelet aggregation and hemostasis and leukocyte adhesion and transendothelial migration will be reviewed as examples of the complex and cooperative interplay between CAMs during physiological and pathophysiological processes. The role of the endothelial glycocalyx and the glycobiology of this complex system related to inflammatory states such as sepsis will be reviewed. We will then focus on the role of adhesion molecules in the pathogenesis of specific disease processes involving the lungs and cardiovascular system. The potential of targeting adhesion molecules in the treatment of immune and inflammatory diseases will be highlighted in the relevant sections throughout the manuscript.

A large family of Dscam genes with tandemly arrayed 5' cassettes in Chelicerata.

Drosophila Dscam1 (Down Syndrome Cell Adhesion Molecules) and vertebrate clustered protocadherins (Pcdhs) are two classic examples of the extraordinary isoform diversity from a single genomic locus. Dscam1 encodes 38,016 distinct isoforms via mutually exclusive splicing in D. melanogaster, while the vertebrate clustered Pcdhs utilize alternative promoters to generate isoform diversity. Here we reveal a shortened Dscam gene family with tandemly arrayed 5' cassettes in Chelicerata. These cassette repeats generally comprise two or four exons, corresponding to variable Immunoglobulin 7 (Ig7) or Ig7-8 domains of Drosophila Dscam1. Furthermore, extraordinary isoform diversity has been generated through a combination of alternating promoter and alternative splicing. These sDscams have a high sequence similarity with Drosophila Dscam1, and share striking organizational resemblance to the 5' variable regions of vertebrate clustered Pcdhs. Hence, our findings have important implications for understanding the functional similarities between Drosophila Dscam1 and vertebrate Pcdhs, and may provide further mechanistic insights into the regulation of isoform diversity.

Human cell adhesion molecules: annotated functional subtypes and overrepresentation of addiction-associated genes.

Human cell adhesion molecules (CAMs) are essential for proper development, modulation, and maintenance of interactions between cells and cell-to-cell (and matrix-to-cell) communication about these interactions. Despite the differential functional significance of these roles, there have been surprisingly few systematic studies to enumerate the universe of CAMs and identify specific CAMs in distinct functions. In this paper, we update and review the set of human genes likely to encode CAMs with searches of databases, literature reviews, and annotations. We describe likely CAMs and functional subclasses, including CAMs that have a primary function in information exchange (iCAMs), CAMs involved in focal adhesions, CAM gene products that are preferentially involved with stereotyped and morphologically identifiable connections between cells (e.g., adherens junctions, gap junctions), and smaller numbers of CAM genes in other classes. We discuss a novel proposed mechanism involving selective anchoring of the constituents of iCAM-containing lipid rafts in zones of close neuronal apposition to membranes expressing iCAM binding partners. We also discuss data from genetic and genomic studies of addiction in humans and mouse models to highlight the ways in which CAM variation may contribute to a specific brain-based disorder such as addiction. Specific examples include changes in CAM mRNA splicing mediated by differences in the addiction-associated splicing regulator RBFOX1/A2BP1 and CAM expression in dopamine neurons.

Ciona intestinalis peroxinectin is a novel component of the peroxidase-cyclooxygenase gene superfamily upregulated by LPS.

Peroxinectins function as hemoperoxidase and cell adhesion factor involved in invertebrate immune reaction. In this study, the ascidian (Ciona intestinalis) peroxinectin gene (CiPxt) and its expression during the inflammatory response have been examined. CiPxt is a new member of the peroxidase-cyclooxygenase gene superfamily that contains both the peroxidase domain and the integrin KGD (Lys-Gly-Asp) binding motif. A phylogenetic tree showed that CiPxt is very close to the chordate group and appears to be the outgroup of mammalian MPO, EPO and TPO clades. The CiPxt molecular structure model resulted superimposable to the human myeloperoxidase. The CiPxt mRNA expression is upregulated by LPS inoculation suggesting it is involved in C. intestinalis inflammatory response. The CiPxt was expressed in hemocytes (compartment/morula cells), vessel epithelium, and unilocular refractile granulocytes populating the inflamed tunic matrix and in the zones 7, 8 and 9 of the endostyle, a special pharynx organs homolog to the vertebrate thyroid gland.

Variability in the insect and plant adhesins, Mad1 and Mad2, within the fungal genus metarhizium suggest plant adaptation as an evolutionary force.

Several species of the insect pathogenic fungus Metarhizium are associated with certain plant types and genome analyses suggested a bifunctional lifestyle; as an insect pathogen and as a plant symbiont. Here we wanted to explore whether there was more variation in genes devoted to plant association (Mad2) or to insect association (Mad1) overall in the genus Metarhizium. Greater divergence within the genus Metarhizium in one of these genes may provide evidence for whether host insect or plant is a driving force in adaptation and evolution in the genus Metarhizium. We compared differences in variation in the insect adhesin gene, Mad1, which enables attachment to insect cuticle, and the plant adhesin gene, Mad2, which enables attachment to plants. Overall variation for the Mad1 promoter region (7.1%), Mad1 open reading frame (6.7%), and Mad2 open reading frame (7.4%) were similar, while it was higher in the Mad2 promoter region (9.9%). Analysis of the transcriptional elements within the Mad2 promoter region revealed variable STRE, PDS, degenerative TATA box, and TATA box-like regions, while this level of variation was not found for Mad1. Sequences were also phylogenetically compared to EF-1α, which is used for species identification, in 14 isolates representing 7 different species in the genus Metarhizium. Phylogenetic analysis demonstrated that the Mad2 phylogeny is more congruent with 5' EF-1α than Mad1. This would suggest that Mad2 has diverged among Metarhizium lineages, contributing to clade- and species-specific variation, while it appears that Mad1 has been largely conserved. While other abiotic and biotic factors cannot be excluded in contributing to divergence, these results suggest that plant relationships, rather than insect host, have been a major driving factor in the divergence of the genus Metarhizium.

Discordant immunophenotypic profiles of adhesion molecules and cytokines in acute myeloid leukemia involving bone marrow and skin.

We investigated the role of adhesion molecules in skin involvement by acute myeloid leukemia (AML) using immunohistochemical analysis. Ten paired cases of skin and bone marrow biopsy specimens from patients with myeloid leukemia cutis (MLC) and 15 bone marrow biopsy specimens from patients without MLC were studied with antibodies directed against CD29, CD34, CD54, CD62-L, CD183, and cutaneous lymphocyte antigen (CLA). CLA was expressed in all cases of leukemia whereas CD54 was negative within blasts. CD62-L was expressed in 4 of 10 specimens of marrow infiltrates with MLC and 6 of 10 specimens of matching skin infiltrates; in marrows without MLC, only 2 of 15 were positive. CD29 was expressed in 1 of 10 marrow infiltrate specimens with MLC and 4 of 10 matching skin infiltrate specimens; in marrows without MLC, only 1 of 15 were positive. CD183 was expressed in 1 of 10 marrow infiltrate specimens with MLC and 4 of 10 matching skin infiltrate specimens; in marrows without MLC, CD183 was negative. The gain of CD62-L, CD29, and CD183 expression in bone marrow and skin infiltrates in leukemia cutis, relative to bone marrow infiltrates of cases without MLC, suggests a role for these markers in AML homing to skin.

Synaptic cell adhesion molecules.

During development of the nervous system following axon pathfinding, synaptic connections are established between neurons. Specific cell adhesion molecules (CAMs) accumulate at pre- and postsynaptic sites and trigger synaptic differentiation through interactions with intra- and extracellular scaffolds. These interactions are important to align pre- and postsynaptic transduction machineries and to couple the sites of cell-to-cell adhesion to the cytoskeleton and signaling complexes necessary to accumulate and recycle presynaptic vesicles, components of exo- and endocytic zones, and postsynaptic receptors. In mature brains, CAMs contribute to regulation of synaptic efficacy and plasticity, partially via direct interactions with postsynaptic neurotransmitter receptors and presynaptic voltage-gated ion channels. This chapter is to highlight the major classes of synaptic CAMs, their multiple functions, and the multistage concerted interactions between different CAMs and other components of synapses.

Adaptations to endosymbiosis in a cnidarian-dinoflagellate association: differential gene expression and specific gene duplications.

Trophic endosymbiosis between anthozoans and photosynthetic dinoflagellates forms the key foundation of reef ecosystems. Dysfunction and collapse of symbiosis lead to bleaching (symbiont expulsion), which is responsible for the severe worldwide decline of coral reefs. Molecular signals are central to the stability of this partnership and are therefore closely related to coral health. To decipher inter-partner signaling, we developed genomic resources (cDNA library and microarrays) from the symbiotic sea anemone Anemonia viridis. Here we describe differential expression between symbiotic (also called zooxanthellate anemones) or aposymbiotic (also called bleached) A. viridis specimens, using microarray hybridizations and qPCR experiments. We mapped, for the first time, transcript abundance separately in the epidermal cell layer and the gastrodermal cells that host photosynthetic symbionts. Transcriptomic profiles showed large inter-individual variability, indicating that aposymbiosis could be induced by different pathways. We defined a restricted subset of 39 common genes that are characteristic of the symbiotic or aposymbiotic states. We demonstrated that transcription of many genes belonging to this set is specifically enhanced in the symbiotic cells (gastroderm). A model is proposed where the aposymbiotic and therefore heterotrophic state triggers vesicular trafficking, whereas the symbiotic and therefore autotrophic state favors metabolic exchanges between host and symbiont. Several genetic pathways were investigated in more detail: i) a key vitamin K-dependant process involved in the dinoflagellate-cnidarian recognition; ii) two cnidarian tissue-specific carbonic anhydrases involved in the carbon transfer from the environment to the intracellular symbionts; iii) host collagen synthesis, mostly supported by the symbiotic tissue. Further, we identified specific gene duplications and showed that the cnidarian-specific isoform was also up-regulated both in the symbiotic state and in the gastroderm. Our results thus offer new insight into the inter-partner signaling required for the physiological mechanisms of the symbiosis that is crucial for coral health.

Effects of ozone on nasal mucosa (endothelial cells).

After exposure to ozone, humans develop neutrophil infiltration of the nasal mucosa. To investigate the events contributing to inflammatory cell recruitment in the nasal mucosa we exposed 10 healthy nonsmoking volunteers to 400 ppb ozone or filtered air for 2h at rest on two separate occasions. Nasal biopsies were performed 6h after ozone/filtered air exposure. The nasal biopsies were embedded in glycol mathacrylate and immunostained for inflammatory cells, including neutrophils, mast cells, total T-cells (CD3), T-cell subsets CD8 and CD4, macrophages, eosinophils adhesion molecules (P-selectin, E-selectin, ICAM-1, VCAM-1), cytokines (TNF-α, IL-1ß, GM-CSF, IL-6), chemokines (IL-8 and RANTES), and nuclear factor NF-κB. No significant changes were seen in the number of T-cells, and T-cell subsets, eosinophils, macrophages, or percentages of vessels expressing P-selectin, VCAM-1, GM-CSF, IL-6 and RANTES in the biopsies. The number of neutrophils and mast cells in the submucosa was significantly higher after ozone exposure (p=0.009 and p=0.005 respectively). The percentage of vessels expressing E-selectin (p=0.01), ICAM-1 (p=0.005), IL-8 (p=0.02), TNF-α (p=0.02), IL-1ß (p=0.009), and NF-κB (p=0.05) increased significantly after ozone exposure as compared to filtered air exposure. Exposure of normal subjects to ozone increases the expression of proinflammatory cytokines resulting in upregulation of IL-8 and adhesion molecules via activation of NF-κB, leading to neutrophil inflitration in the nasal mucosa.

Drosophila dscam proteins regulate postsynaptic specificity at multiple-contact synapses.

In both vertebrate and invertebrate visual systems, neurons form multiple-contact synapses at which a single presynaptic site releases neurotransmitter upon a discrete combination of different postsynaptic cells. Recognition mechanisms underlying the assembly of such synapses are not known. In Drosophila, photoreceptor terminals form tetrad synapses that incorporate an invariable pair of postsynaptic elements, one each from lamina interneuron L1 and L2, and two elements from other cells. Here, we demonstrate that Drosophila Dscam1 and Dscam2, genes encoding homophilic repulsive proteins, act redundantly to ensure the invariable combination of L1 and L2 postsynaptic elements at all tetrads. We demonstrate that this strict pairing is lost in Dscam1;Dscam2 double mutants. Thus, removing these two repulsive proteins allows elements from the same cell to incorporate into the same postsynaptic tetrad, altering the specificity of photoreceptor transmission. We propose that Dscams regulate synaptic specificity by excluding inappropriate partners at multiple-contact synapses.

Conservation, expression, and knockdown of zebrafish plxnb2a and plxnb2b.

In mice lacking Plexin B2, a receptor of the axon guidance molecules Semaphorin 4C and Semaphorin 4D, the closure of the neural tube and structural organization of the cerebellum are severely impaired. We cloned two Plexin B2 orthologs, plxnb2a and plxnb2b, in zebrafish, which is a widely used model for the development of the vertebrate central nervous system (CNS). The predicted proteins, Plexin B2a and Plexin B2b, contain all the conserved and functional domains of the plexin B-subfamily. During embryonic development, plxnb2a is expressed, e.g., in pharyngeal arches while plxnb2b expression is more confined to neuronal structures like the cerebellum. However, both plxnb2a and plxnb2b are expressed at the midbrain-hindbrain boundary, in the otic vesicles, facial ganglia, and pectoral fins. Knockdown of both plxnb2a and plxnb2b simultaneously (>95% and 45%, respectively) resulted in normal CNS structure, axon guidance and swimming performance of the morphants.

Identification and expression analysis of splice variants of mouse enabled homologue during development and in adult tissues.

BACKGROUND: The Enabled/Vasodilator stimulated phosphoprotein (Ena/VASP) gene family comprises three genes in vertebrates: Vasp, Enabled homologue (Enah) and Ena-VASP like (Evl). Enah has the most complex gene structure. It has extra alternatively included exons compared to Vasp and Evl, and possibly one alternatively excluded intron S. The aim of this mapping study was to probe the occurrence of combinations of exon usage in Enah thereby identifying possible vertebrate ENAH splice variants. We investigated this via an in silico analysis and by performing a reverse transcription-polymerase chain reaction (RT-PCR) screen on mouse samples. We further probed the expression pattern of mouse Enah splice variants during development and in a selection of mouse adult tissues and mouse cell lines. RESULTS: In silico analysis of the vertebrate Ena/VASP gene family reveals that birds do not have Vasp, while fish have two Evl genes. Analysis of expressed sequence tags of vertebrate Enah splice variants confirms that an Enah transcript without alternative exons is ubiquitously expressed, but yields only limited information about the existence of other possible alternatively spliced Enah transcripts. Via a RT-PCR screen, we provide evidence that during mouse development and in adult mice at least eight and maximally sixteen different Enah transcripts are expressed. We also show that tissues and cell lines display specific expression profiles of these different transcripts. Exons previously associated with neuronal expression of Enah splice variants are also present in other tissues, in particular in heart. CONCLUSIONS: We propose a more uniform nomenclature for alternative exons in Enah. We provide an overview of distinct expression profiles of mouse Enah splice variants during mouse development, in adult mouse tissues and in a subset of mouse cell lines.

[Adhesion molecules and diabetes mellitus]. / Molecole di adesione e malattia diabetica.

Adhesion molecules play a significant role in leukocyte migration across the endothelium and are also involved in regulating immune system. It is shown that diabetic patients have an increase of soluble adhesion molecules (sICAM-1, sICAM-2, sVCAM-1, sE-selectin, sL-selectin, sP-selectin) considered an integral part of inflammatory state. This inflammation is responsible for the increased cardiovascular risk of these patients. There is a close link between hyperglycemia, oxidative stress, coagulopathy and inflammation and between these factors and the vascular damage. Various studies have showed the potential role of adhesion molecules in the pathogenesis of diabetic vasculopathy. They promote leukocyte recruitment, which is one of the initial steps in the genesis of atherosclerotic plaque. Adhesion molecules are also involved in the pathogenesis of diabetes mellitus type 1; sICAM-1 would have a particular immunomodulatory role in the process of destroying beta-cells and could be used as a subclinical marker of insulitis. Plasma levels of soluble adhesion molecules correlate with hyperglycemia, insulin resistance, dyslipidemia and obesity; they are associated with the development of nephropathy, retinopathy, myocardial infarction, stroke and obliterant peripheral arterial disease in diabetic type 1 and 2. Given the role of these molecules in endothelial dysfunction genesis and tissue damage associated with diabetes, they could constitute a therapeutic target for the prevention of genesis and progression of chronic complications of diabetic disease.