Integrins, angiogenesis and vascular cell survival

The interactions between integrins and the extracellular matrix have been identified as important regulators of vascular cell survival, proliferation and invasion during the complex process of blood vessel formation by angiogenesis.     

Integrins involved in the adhesion of megakaryocytes to fibronectin and fibrinogen

We studied integrins involved in the adhesion of resting and activated megakaryocytes (MK) to fibronectin (FN) and fibrinogen (FGN). Guinea pig MK were isolated and in some experiments were activated by thrombin. MK adhering to FN or FGN coated on coverslips were quantitated by a computerized image analysis program. The binding of soluble human FN to MK was detected by Western blotting. Anti-integrin antibodies, disintegrins, and cyclic RGD peptides were used to identify integrins involved in the adhesion of MK to FN or FGN. Resting MK adhered to coverslips with immobilized FN. The adhesion of MK to FN was primarily inhibited by an anti-alpha5 antibody and EMF-10, a distintegrin highly specific for alpha5 beta1. However, the adhesion of MK to FN was not blocked by agents that inhibit alphaIIb beta3, alphav beta3 or alpha4 beta1. A beta1 activating antibody increased the number of MK bound to FN due to the activation of alpha5 beta1. The binding of soluble FN was also primarily inhibited by agents that block alpha5 beta1. Resting MK did not adhere to FGN. However, MK activated by thrombin did adhere to FGN. This binding was mediated by alphaIIb beta3, because binding was inhibited by bitistatin, a disintegrin, and a cyclic RGD peptide that are known to block this integrin. The binding of thrombin-activated MK to FN was mediated by both alpha5 beta1 and alphaIIb beta3 based on the additive effect of agents that inhibit these integrins. The study indicates that resting MK bind to FN but not to FGN and that alpha5 beta1 is the major integrin involved in the binding of MK to FN. Activated MK bind to FGN primarily by alphaIIb beta3. However, the binding of activated MK to FN is due to both alpha5 beta1 and alphaIIb beta3. The demonstration that alpha5 beta1 and that alphaIIb beta3 are involved in MK adhesion indicates that these integrins may have a role in MK maturation and platelet production.     

Integrins inhibit angiotensin II-induced contraction in rat aortic rings

Many extracellular matrix proteins contain the tripeptide sequence arginine-glycine-aspartate (RGD). This RGD motif is recognized by integrins, a family of adhesion receptors present on vascular smooth muscle cells. In the present study, we examined the ability of different RGD-containing peptides to affect the contraction of rat aortic rings in response to different agonists. We found that the peptide RGDS inhibited angiotensin-induced contraction in a dose dependent manner. In contrast, the peptides RGDW and RGES had no effect on angiotensin-induced contractility. We show that function-blocking antibodies to the integrins alphavbeta3 and alpha5beta1 also inhibit angiotensin-induced contraction. These effects were observed in the absence of an intact endothelium. In contrast, neither an antibody directed against the beta1 subunit nor the peptide RGDS had an effect on phenylephrine or 5-hydroxytryptamine-induced contraction. These data suggest that interactions of vascular smooth muscle with components of the surrounding extracellular matrix may influence the response of smooth muscle to agonists.     

Integrins: a role for adhesion molecules in olfactory memory

A gene required for short-term memory in Drosophila, Volado, encodes an alpha integrin and is preferentially expressed in the mushroom bodies of the adult brain. Adhesion molecules of this kind may play a role in olfactory memory by altering the strength of synaptic connections in an experience-dependent manner.     

Integrins take partners: cross-talk between integrins and other membrane receptors

This review discusses an emerging theme in the understanding of how an integrin contributes to the life of a cell. Previously, integrins have been thought to 'go it alone', but it is now appreciated that their duties extend beyond that of being 'sticky' receptors. By interacting in cis with other receptors on the cell membrane, integrins and their partner receptors inteact to form distinct membrane complexes that recruit signalling molecules to each receptor's mutual benefit. Here, Joanna Porter and Nancy Hogg discuss a few of the best characterized of these specialist integrin partnerships.     

Integrins and inside-out signal transduction: converging signals from PKC and PIP3

Recent studies have identified molecules that interact with integrins and appear to participate in the signaling pathways that regulate integrin adhesiveness. Clues provided by studies of these molecules point to the integration by integrins of signal transduction pathways implicated in cell division and activation.     

UNIFOLIATA regulates leaf and flower morphogenesis in pea

Signs and symptoms of craniomandibular dysfunction (CMD) and social medical history were reported in 29 subjects, aged 23-68 years, with longstanding (5 years or more) bruxing behaviour. The subjects were selected from answers to an advertisement in the local newspaper. The subjects presented many symptoms of a general character including somatic and psycho-social problems, sleep disorders (72%), and pain (86%). More than half of the subjects (55%) had symptoms every day. Frequent aches in the neck, back, throat or shoulders were reported by 69% and frequent headache by 48% of the subjects. The most common symptoms of CMD were pain in the face or jaws (48%), stiffness in the jaws in the morning (44%), temporomandibular joint (TMJ) sounds (34%) and fatigue in the jaws during chewing (38%) and the most common clinical signs were more than three muscles tender on palpation (76%), TMJ-sounds (55%) and tenderness of TMJ on lateral palpation (66%). There was a statistically significant correlation between frequent tooth clenching and headache, pain in the neck, back, throat or shoulders, sleep disorders and high scores of the clinical dysfunction index (Di). The frequent clenchers had higher score values than the 'non-clenchers' for pain in the face and the jaws; headache; pain in the neck, back, throat or shoulders and the clinical dysfunction index (Di). These findings indicate a causal relationship between frequent tooth clenching and signs and symptoms of CMD, including headache and pain in the neck, back, throat or shoulders and high pathogenicity for frequent clenching. However, the material in this study is small and some precaution must be taken prior to generalized conclusions. More studies are required, especially sleep laboratory investigations, which could perhaps give answers to some of the numerous questions in this unexplored field of odontology.     

Ultrastructure and morphogenesis of human immunodeficiency virus

The ultrastructure and morphogenesis of human immunodeficiency virus (HIV) were elucidated by observation with several techniques including immunoelectron microscopy and cryo-microscopy. The virus particle consists of an envelope, a core and matrix. The virus particles were observed extracellularly as having one of three profiles: (1) a centric or an eccentric electron-dense core, (2) rod-shaped electron-dense core, and (3) doughnut-shaped. HIV-1 particles in the hydrated state were observed by high resolution electron cryo-microscopy to be globular, and the lipid membrane was clearly resolved as a bilayer. Many projections around the circumference were seen to be knob-like. The shapes and sizes of the projections, especially head parts, were found to vary in each projection. By isolation with Nonidet P40 and glutaraldehyde, HIV-1 cores were confirmed to consist of p24 protein by immunogold labeling. When the virus enters the cell, two entry modes were found: membrane fusion and endocytosis. No structures resembling virus particles could be seen in the cytoplasm after viral entry. In HIV-1-infected cells, positive reactions by immuno-labeling suggest that HIV-1 Gag may be produced in membrane-bound structures and transported to the cell surface by cytoskeletons. Then a crescent electron-dense layer was first formed underneath the cell membrane. Finally, the virus particle was released from the cell surface. Several cell clones producing defective particles were isolated from MT-4/HIV-1 cells. Among them, doughnut-shaped or teardrop-shaped particles were seen to be produced in the extracellular space. In the doughnut-shaped particles, Gag p17 and p24 proteins faced each other against the inner electron dense ring, suggesting that the inner ring consists of a precursor Gag protein.     

Human cervico-facial morphogenesis. Evaluation of acquired data and current outlook. Second part: cervical morphogenesis

After having recalled the formation of the so-called "branchial" organisation, each component of the segmentary units constituting this organisation is analysed, as well as their particularities. This lead us to recognize the existence of only five branchial arches in the human embryo, without an intermediary arch between the fourth arch and the pulmonary arch. This question is moreover linked to the signification of the so-called "ultimobranchial" body, which must be connected with the fourth pharyngeal pouch. The question of cervical segmentation is inseparable from the question of cephalic metamerisation. Two segments are individualised in front of the mandibular process: the fronto-nasal process and the maxillary process, corresponding to premandibular arches, which existence is well established in paleontology. In addition to the peripheral expression of this cervico-cephalic segmentation marqued by primitive characters. We observe the paraxial expression of segmentation by the somitomeres and the somites. Recent data provided by the developmental genes confirm that only one process is at the origin of these two expressions which appear distinct, but lead to a unitary organisation. The mutation of the gene Pax 6 affecting in the same time the nasal placode and the optic vesicle confirms the unity of the fronto-nasal process. The pre-eminence of genetic expression on skeletal, muscular and nervous tissues with respect to the vascular system confirms the inadequacy of the criterion given by the aortic arches for the analysis of the cervico-cephalic development, although it is classically linked to the concept of an embryonic "branchial apparatus".     

Architectural patterns in branching morphogenesis in the kidney

During kidney development, several discrete steps generate its three-dimensional pattern including specific branch types, regional differential growth of stems, the specific axes of growth and temporal progression of the pattern. The ureteric bud undergoes three different types of branching. In the first, terminal bifid type, a lateral branch arises and immediately bifurcates to form two terminal branches whose tips induce the formation of nephrons. After 15 such divisions (in humans) of this specifically renal type of branching, several nephrons are induced whose connecting tubules fuse and elongate to form the arcades. Finally, the last generations undergo strictly lateral branching to form the cortical system. The stems of these branches elongate in a highly regulated pattern. The molecular basis of these processes is unknown and we briefly review their potential mediators. Differential growth in three different axes of the kidney (cortico-medullary, dorsoventral and rostro-caudal) generate the characteristic shape of the kidney. Rapid advances in molecular genetics highlight the need for development of specific assays for each of these discrete steps, a prerequisite for identification of the involved pathways. The identification of molecules that control branching (the ultimate determinant of the number of nephrons) has acquired new urgency with the recent suggestion that a reduced nephron number predisposes humans to hypertension and to progression of renal failure.     

VEGF enhances pulmonary vasculogenesis and disrupts lung morphogenesis in vivo

Three approximate free energy calculation methods are examined and applied to an example ligand design problem. The first of the methods uses a single simulation to estimate the relative binding free energies for related ligands that are not simulated. The second method is similar, except that it uses only first derivatives of free energy with respect to atomic parameters (most often charge, van der Waals equilibrium distance, and van der Waals well depth) to calculate free energy differences. The last method PROFEC (Pictorial Representation of Free Energy Components), generates contour maps that show how binding free energy changes when additional particles are added near the ligand. These three methods are applied to a benzamidine/trypsin complex. They each reproduce the general trends in the binding free energies, indicating that they might be useful for suggesting how ligands could be modified to improve binding and, consequently, useful in structure-based drug design.     

Integrins: their structures, functions and gene expressions in the central nervous system. Acta anat

More than ten years have passed since integrin was shown to function in cellular attachment. To date integrin research has been one of major fields in cell biology. Integrin, which functions as an integrator of both extra- and intracellular skeletal molecules, is regarded as one of the essential molecules for cellular signal transduction as well. Thus, integrin appears to be essential and indispensable for many cellular phenomena. Although every type of cell is thought to express a few kinds of integrin molecules, their expression and functional roles in neurons remain to be determined. Both intensive and extensive researches should reveal one by one how integrins are involved in the neural network formation in development, neuronal plasticity and regeneration, higher function of CNS, and also neuronal degeneration in both inflammation and degenerative diseases.     

The morphogenesis of melanotic lesions

A controlled trial of the relative efficacies of procaine penicillin G and pivampicillin for single dose treatment of uncomplicated gonorrhea in female was performed. Confirmation of the disease was obtained by bacteriological isolation of Neisseria gonorrhea from uretral, cervical or rectal exudates inoculated in suitable media. Based upon their previous experience, the authors used probenecid, along with both antibiotics, as a way of increasing the effectiveness of these drugs. Twentynine patients received probenecid 1 g. followed by oral pivampicillin, in a single dose of 1,4 g. Therapeutical results were evaluated in twenty-four, with clinical and bacteriological cure of eighteen. The other group included fifty-two patients treated with probenecid 1 g. followed by a single intramuscular dose of 3.000.000 U. of procaine penicillin G. The therapeutical results in the last group were evaluated in forty patients, with clinical and bacteriological cure of thirty-three. According to the above mentioned results procaine penicillin G seems to offer a slightly superior probability of cure.