Thy-1 binds to integrin beta(3) on astrocytes and triggers formation of focal contact sites.

BACKGROUND: Thy-1 is an abundant neuronal glycoprotein in mammals. Despite such prevalence, Thy-1 function remains largely obscure in the absence of a defined ligand. Astrocytes, ubiquitous cells of the brain, express a putative Thy-1 ligand that prevents neurite outgrowth. In this paper, a ligand molecule for Thy-1 was identified, and the consequences of Thy-1 binding for astrocyte function were investigated. RESULTS: Thy-1 has been implicated in cell adhesion and, indeed, all known Thy-1 sequences were found to contain an integrin binding, RGD-like sequence. Thy-1 interaction with beta3 integrin on astrocytes was demonstrated in an adhesion assay using a thymoma line (EL-4) expressing high levels of Thy-1. EL-4 cells bound to astrocytes five times more readily than EL-4(-f), control cells lacking Thy-1. Binding was blocked by either anti-Thy-1 or anti-beta3 antibodies, by RGD-related peptides, or by soluble Thy-1-Fc chimeras. However, neither RGE/RLE peptides nor Thy-1(RLE)-Fc fusion protein inhibited the interaction. Immobilized Thy-1-Fc, but not Thy-1(RLE)-Fc fusion protein supported the attachment and spreading of astrocytes in a Mn(2+)-dependent manner. Binding to Thy-1-Fc was inhibited by RGD peptides. Moreover, vitronectin, fibrinogen, denatured collagen (dcollagen), and a kistrin-derived peptide, but not fibronectin, also mediated Mn(2+)-dependent adhesion, suggesting the involvement of beta3 integrin. The addition of Thy-1 to matrix-bound astrocytes induced recruitment of paxillin, vinculin, and focal adhesion kinase (FAK) to focal contacts and increased tyrosine phosphorylation of proteins such as p130(Cas) and FAK. Furthermore, astrocyte binding to immobilized Thy-1-Fc alone was sufficient to promote focal adhesion formation and phosphorylation on tyrosine. CONCLUSIONS: Thy-1 binds to beta3 integrin and triggers tyrosine phosphorylation of focal adhesion proteins in astrocytes, thereby promoting focal adhesion formation, cell attachment, and spreading.

Estudi del sistema reptroductor de la guatlla (Coturnix coturnix) i de la hibridació amb la guatlla japonesa (Coturnix japonica) domèstica i híbrids

La guatlla (Coturnix coturnix) és actualment una espècie amb un estat de conservació desfavorable. Una amenaça per a la seva conservació és la hibridació que pot produir-se degut als alliberaments massius amb finalitats cinegètiques de la guatlla japonesa (Coturnix japonica) o híbrids provinents de granges de cria. Els objectius d’estudi són: a) Aprofundir en el sistema sexual de la guatlla, ja que el seu coneixement pot permetre entendre els mecanismes d’hibridació amb la guatlla japonesa o híbrids. b) Conèixer la taxa de supervivència i l’eficàcia biològica dels individus no nadius a àrees de reproducció de la guatlla. c) Buscar evidències directes d’hibridació en condicions naturals i caracteritzar-la. d) Determinar si existeix competència espermàtica interespecífica mitjançant experiments en captivitat. S’ha seguit el comportament en condicions naturals de parelles homospecífiques i heterospecífiques de mascles i femelles de guatlla i de guatlla japonesa o híbrids. S’ha analitzat la paternitat dels polls d’aquestes parelles i s’ha pogut conèixer quins aspectes del comportament (segons l’espècie) es relacionen amb l’eficàcia biològica dels adults. S’han analitzat el mateix tipus de dades obtingudes durant cinc temporades reproductives, en les que hi van participar només individus de guatlla. Així s’ha pogut comparar el comportament de l’espècie en presència i absència dels individus al•lòctons. Els resultats indiquen que existeixen dues estratègies sexuals entre els mascles de guatlla. L’estat físic del mascle en relació al dels altres mascles coetanis i el temps de permanència amb la femella determinen la seva taxa de paternitat. Existeix una fracció relativament petita però significativa de guatlla japonesa de granja que sobreviu en condicions naturals i s’hibrida amb la guatlla silvestre, predominantment de forma unidireccional, entre femella japonesa i mascle de guatlla. Aquestes femelles presenten un sistema d’aparellament majoritàriament monògam. Els anàlisis sobre els experiments de competència espermàtica s’estan realitzant a l’actualitat.

Roles of mGluR5 in synaptic function and plasticity of the mouse thalamocortical pathway.

The group I metabotropic glutamate receptor 5 (mGluR5) has been implicated in the development of cortical sensory maps. However, its precise roles in the synaptic function and plasticity of thalamocortical (TC) connections remain unknown. Here we first show that in mGluR5 knockout (KO) mice bred onto a C57BL6 background cytoarchitectonic differentiation into barrels is missing, but the representations for large whiskers are identifiable as clusters of TC afferents. The altered dendritic morphology of cortical layer IV spiny stellate neurons in mGluR5 KO mice implicates a role for mGluR5 in the dendritic morphogenesis of excitatory neurons. Next, in vivo single-unit recordings of whisker-evoked activity in mGluR5 KO adults demonstrated a preserved topographical organization of the whisker representation, but a significantly diminished temporal discrimination of center to surround whiskers in the responses of individual neurons. To evaluate synaptic function at TC synapses in mGluR5 KO mice, whole-cell voltage-clamp recording was conducted in acute TC brain slices prepared from postnatal day 4-11 mice. At mGluR5 KO TC synapses, N-methyl-D-aspartate (NMDA) currents decayed faster and synaptic strength was more easily reduced, but more difficult to strengthen by Hebbian-type pairing protocols, despite a normal developmental increase in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated currents and presynaptic function. We have therefore demonstrated that mGluR5 is required for synaptic function/plasticity at TC synapses as barrels are forming, and we propose that these functional alterations at the TC synapse are the basis of the abnormal anatomical and functional development of the somatosensory cortex in the mGluR5 KO mouse.

Apparent competition through facilitation between Melanoides tuberculata and Biomphalaria glabrata and the control of schistosomiasis

Interactions between two species that result in reduced growth rates for both and extinction of one of the species are generally considered cases of asymmetric interspecific competition. Exploitative or interference competition is the usual mechanism invoked. Here we describe another mechanism producing the same result, named apparent competition through facilitation (ACF), observed between Melanoides tuberculata and Biomphalaria glabrata populations. The superior competitor actually gives some benefit to the other species, whose population becomes unstable with progressively increasing oscillations, leading to extinction. A model of ACF using difference equations suggests initial dynamics distinct from traditional interspecific competition. The dynamics of two freshwater snails in the field and in laboratory experiments suggest ACF, and these relations should be considered in studies of schistosomiasis control. ACF could occur in natural populations, but might have gone undetected because the final result is similar to traditional interspecific competition.

Disorders of pupillary structure and function.

Neurologists are frequently consulted because of a pupillary abnormality. An unequal size of the pupils, an unusual shape, white colored pupils, or a poorly reactive pupil are common reasons for referral. A directed history and careful observation of the iris and pupil movements can bear out ocular pathology such as congenital or structural anomalies as the cause of abnormal pupils. Thereafter, it is important to evaluate the neurologic causes of anisocoria and poor pupil function. The first part of this article emphasizes pupillary abnormalities frequently encountered in infants and children and discusses some of the more common acquired iris structural defects. The second part focuses on evaluation of lesions in the neural pathways that result in pupillary dysfunction, with particular attention to those conditions having neurologic, systemic, or visual implications.

The Holiness Code between D and P. Some Comments on the Function and Significance of Leviticus 17-26 in the Composition of the Torah.

(Résumé de l'ouvrage) Das Deuteronomium nimmt sowohl in der Literaturgeschichte der alttestamentlichen Geschichtsbücher Josua bis Könige eine Schlüsselstellung ein als auch für die Entstehung des Pentateuchs. Wie lassen sich diese beiden Funktionen vereinbaren? Mit der Verhältnisbestimmung haben sich namhafte Wissenschafter der Arbeitsgruppe »Biblical and Ancient Near Eastern Law« im Rahmen der Internationalen Treffen der Society of Biblical Literature in Berlin (2002) und Cambridge (2003) befasst. Der Band präsentiert die neuesten Forschungsergebnisse. Er enthält Vorträge von E. Otto, K. Schmid, H.-C. Schmitt, T. Römer, W.M. Schniedewind, G.N. Knoppers, R. Achenbach, M.M. Zahn und C. Nihan.

Unraveling the complex network of cuticular structure and function.

A hydrophobic cuticle is deposited at the outermost extracellular matrix of the epidermis in primary tissues of terrestrial plants. Besides forming a protective shield against the environment, the cuticle is potentially involved in several developmental processes during plant growth. A high degree of variation in cuticle composition and structure exists between different plant species and tissues. Lots of progress has been made recently in understanding the different steps of biosynthesis, transport, and deposition of cuticular components. However, the molecular mechanisms that underlie cuticular function remain largely elusive.

An analysis of the components of pain, function, and health-related quality of life in patients with failed back surgery syndrome treated with spinal cord stimulation or conventional medical management

Objectives: Failed back surgery syndrome (FBSS) patients experience pain, functional disability, and reduced health-related quality of life (HRQoL) despite anatomically successful surgery. Examining sub-dimensions of health outcomes measures provides insight into patient well-being. Materials and Methods: The international multicenter PROCESS trial collected detailed HRQoL (EuroQol-5D; Short-Form 36) and function (Oswestry Disability Index) information on 100 FBSS patients. Results: At baseline, patients reported moderate-to-severe leg and back pain adversely affecting all dimensions of function and HRQoL. Compared with conventional medical management alone, patients also receiving spinal cord stimulation (SCS) reported superior pain relief, function, and HRQoL at six months on overall and most sub-component scores. The majority of these improvements with SCS were sustained at 24 months. Nonetheless, 36-40% of patients experienced ongoing marked disability (standing, lifting) and HRQoL problems (pain/discomfort). Conclusions: Longer-term patient management and research must focus on these refractory FBSS patients with persisting poor function and HRQoL outcomes.

Detection of human growth hormone doping in urine: out of competition tests are necessary.

The misuse of human growth hormone (hGH) in sport is deemed to be unethical and dangerous because of various adverse effects. Thus, it has been added to the International Olympic Committee list of banned substances. Until now, the very low concentration of hGH in the urine made its measurement difficult using classical methodology. Indeed, for routine diagnosis, only plasma measurements were available. However, unlike blood samples, urine is generally provided in abundant quantities and is, at present, the only body fluid allowed to be analysed in sport doping controls. A recently developed enzyme-linked immunosorbent assay (Norditest) makes it now possible, without any extraction, to measure urinary hGH (u-hGH) in a dynamic range of 2-50 ng hGH/l. In our protocol, untreated and treated non-athlete volunteers were followed. Some of them received therapeutical doses of recombinant hGH (Norditropin) for one week either intramuscularly (three increasing doses) or subcutaneously (12 i.u. every day). The u-hGH excretion after treatment showed dramatic increases of 50-100 times the basal values and returned to almost the mean normal level after 24 h. u-hGH was also measured in samples provided by the anti-doping controls at major and minor competitions. Depending on the type of efforts made during the competition, the hGH concentration in urine was dramatically increased. Insulin-like growth factor binding proteins and beta 2-microglobulins in urine and/or in blood could be necessary for the correct investigation of any hGH doping test procedure.

Conditioning of stochastic 3-D fracture networks to hydrological and geophysical data

The geometry and connectivity of fractures exert a strong influence on the flow and transport properties of fracture networks. We present a novel approach to stochastically generate three-dimensional discrete networks of connected fractures that are conditioned to hydrological and geophysical data. A hierarchical rejection sampling algorithm is used to draw realizations from the posterior probability density function at different conditioning levels. The method is applied to a well-studied granitic formation using data acquired within two boreholes located 6 m apart. The prior models include 27 fractures with their geometry (position and orientation) bounded by information derived from single-hole ground-penetrating radar (GPR) data acquired during saline tracer tests and optical televiewer logs. Eleven cross-hole hydraulic connections between fractures in neighboring boreholes and the order in which the tracer arrives at different fractures are used for conditioning. Furthermore, the networks are conditioned to the observed relative hydraulic importance of the different hydraulic connections by numerically simulating the flow response. Among the conditioning data considered, constraints on the relative flow contributions were the most effective in determining the variability among the network realizations. Nevertheless, we find that the posterior model space is strongly determined by the imposed prior bounds. Strong prior bounds were derived from GPR measurements and helped to make the approach computationally feasible. We analyze a set of 230 posterior realizations that reproduce all data given their uncertainties assuming the same uniform transmissivity in all fractures. The posterior models provide valuable statistics on length scales and density of connected fractures, as well as their connectivity. In an additional analysis, effective transmissivity estimates of the posterior realizations indicate a strong influence of the DFN structure, in that it induces large variations of equivalent transmissivities between realizations. The transmissivity estimates agree well with previous estimates at the site based on pumping, flowmeter and temperature data.

Decreased PM10 exposure attenuates age-related lung function decline: genetic variants in p53, p21, and CCND1 modify this effect.

BACKGROUND: Decreasing exposure to airborne particulates was previously associated with reduced age-related decline in lung function. However, whether the benefit from improved air quality depends on genetic background is not known. Recent evidence points to the involvement of the genes p53 and p21 and of the cell cycle control gene cyclin D1 (CCND1) in the response of bronchial cells to air pollution. OBJECTIVE: We determined in 4,326 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) whether four single-nucleotide polymorphisms in three genes [CCND1 (rs9344 [P242P], rs667515), p53 (rs1042522 [R72P]), and p21 (rs1801270 [S31R])] modified the previously observed attenuation of the decline in the forced expiratory flow between 25% and 75% of the forced vital capacity (FEF(25-75)) associated with improved air quality. METHODS: Subjects of the prospective population-based SAPALDIA cohort were assessed in 1991 and 2002 by spirometry, questionnaires, and biological sample collection for genotyping. We assigned spatially resolved concentrations of particulate matter with aerodynamic diameter < or = 10 microm (PM(10)) to each participant's residential history 12 months before the baseline and follow-up assessments. RESULTS: The effect of diminishing PM(10) exposure on FEF(25-75) decline appeared to be modified by p53 R72P, CCND1 P242P, and CCND1 rs667515. For example, a 10-microg/m(3) decline in average PM(10) exposure over an 11-year period attenuated the average annual decline in FEF(25-75) by 21.33 mL/year (95% confidence interval, 10.57-32.08) among participants homozygous for the CCND1 (P242P) GG genotype, by 13.72 mL/year (5.38-22.06) among GA genotypes, and by 6.00 mL/year (-4.54 to 16.54) among AA genotypes. CONCLUSIONS: Our results suggest that cell cycle control genes may modify the degree to which improved air quality may benefit respiratory function in adults.

Intracoronary injection of bone marrow-derived mononuclear cells early or late after acute myocardial infarction: effects on global left ventricular function.

BACKGROUND: Intracoronary administration of autologous bone marrow-derived mononuclear cells (BM-MNC) may improve remodeling of the left ventricle (LV) after acute myocardial infarction. The optimal time point of administration of BM-MNC is still uncertain and has rarely been addressed prospectively in randomized clinical trials. METHODS AND RESULTS: In a multicenter study, we randomized 200 patients with large, successfully reperfused ST-segment elevation myocardial infarction in a 1:1:1 pattern into an open-labeled control and 2 BM-MNC treatment groups. In the BM-MNC groups, cells were administered either early (ie, 5 to 7 days) or late (ie, 3 to 4 weeks) after acute myocardial infarction. Cardiac magnetic resonance imaging was performed at baseline and after 4 months. The primary end point was the change from baseline to 4 months in global LV ejection fraction between the 2 treatment groups and the control group. The absolute change in LV ejection fraction from baseline to 4 months was -0.4±8.8% (mean±SD; P=0.74 versus baseline) in the control group, 1.8±8.4% (P=0.12 versus baseline) in the early group, and 0.8±7.6% (P=0.45 versus baseline) in the late group. The treatment effect of BM-MNC as estimated by ANCOVA was 1.25 (95% confidence interval, -1.83 to 4.32; P=0.42) for the early therapy group and 0.55 (95% confidence interval, -2.61 to 3.71; P=0.73) for the late therapy group. CONCLUSIONS: Among patients with ST-segment elevation myocardial infarction and LV dysfunction after successful reperfusion, intracoronary infusion of BM-MNC at either 5 to 7 days or 3 to 4 weeks after acute myocardial infarction did not improve LV function at 4-month follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00355186.

MicroRNA Profile of Circulating CD4-positive Regulatory T Cells in Human Adults and Impact of Differentially Expressed MicroRNAs on Expression of Two Genes Essential to Their Function.

Regulatory T cells (Tregs) are characterized by a high expression of IL-2 receptor α chain (CD25) and of forkhead box P3 (FOXP3), the latter being essential for their development and function. Another major player in the regulatory function is the cytotoxic T-lymphocyte associated molecule-4 (CTLA-4) that inhibits cytotoxic responses. However, the regulation of CTLA-4 expression remains less well explored. We therefore studied the microRNA signature of circulating CD4(+) Tregs isolated from adult healthy donors and identified a signature composed of 15 differentially expressed microRNAs. Among those, miR-24, miR-145, and miR-210 were down-regulated in Tregs compared with controls and were found to have potential target sites in the 3'-UTR of FOXP3 and CTLA-4; miR-24 and miR-210 negatively regulated FOXP3 expression by directly binding to their two target sites in its 3'-UTR. On the other hand, miR-95, which is highly expressed in adult peripheral blood Tregs, positively regulated FOXP3 expression via an indirect mechanism yet to be identified. Finally, we showed that miR-145 negatively regulated CTLA-4 expression in human CD4(+) adult peripheral blood Tregs by binding to its target site in CTLA-4 transcript 3'-UTR. To our knowledge, this is the first identification of a human adult peripheral blood CD4(+) Treg microRNA signature. Moreover, unveiling one mechanism regulating CTLA-4 expression is novel and may lead to a better understanding of the regulation of this crucial gene.

Efecte de la nutrició precoç en el desenvolupament de sibilàncies

Objectiu: provar que, enfront de l’aparició de sibilàncies, l’alletament matern es comporta com a un factor protector i l’alletament artificial com a un factor inductor. Material i mètodes: assaig clínic controlat, randomitzat, a doble cec amb grup control i seguiment de 8 anys, de la submostra espanyola, en el seu 5è any de seguiment, del treball multicèntric europeu EU CHILDHOOD OBESITY PROGRAMME (QLK1-2001-00389). La població es va dividir en 3 grups: nadons alimentats amb lactància artificial amb baix contingut proteic, nadons alimentats amb lactància artificial amb alt contingut proteic i un grup control de nadons alimentats amb llet materna. Per avaluar l’aparició de sibilàncies i la seva evolució en el temps es van realitzar entrevistes als pares a mesura que la població assolia els 6 anys de vida sobre qüestions referides als 3 i als 6 anys i s’havien de realitzar entrevistes als 8 anys de vida sobre qüestions referdies a aquesta mateixa edat. Per comprovar la repercussió en la funció pulmonar i valorar la base atòpica, es tenia previst realitzar, als 8 anys, espirometria, prik test amb aeroalergens, determinació de IgE sèrica total i quantificació dels eosinòfils en sang perifèrica. S’han valorat possibles factors de confusió com antecedents familiars de malalties de base al•lèrgica, nivell socioeconòmic familiar, factors, ambient epidemiològic i s’ha estudiat altra morbiditat associada com episodis de febre, vòmits, diarrea, dermatitis atòpica, refredat de vies respiratòries altes i prescripció mèdica d’antibiòtics. Resultats: només un 20’8% van rebre alletament matern. No s’han trobat diferències estadísticament significatives entre la història d’episodis de sibilàncies i el tipus d’alletament rebut. Tampoc s’han trobat diferències estadísticament significatives entre l’alimentació rebuda i la història de dermatitis atòpica. La llet artificial es va associar, amb significació estadística, a una major prescripció d’antibiòtics i una major incidència de patir diarrees i, sense significació estadística, es va associar a un augment del risc de patir RVA. La lactància materna es va associar amb significació estadística a una menor prescripció d’antibiòtics. La presència de germans grans i un baix nivell d’educació de la mare van contribuir a augmentar la morbiditat durant el primer any de vida. El consum d’alcohol durant l’embaràs es va associar a més episodis de vòmits i el consum de tabac a més episodis de diarrea. Conclusions: l’alletament artificial no predisposa a patir més episodis de sibilàncies ni de dermatitis atòpica. La lactància materna exclusiva durant almenys 3 mesos disminueix el risc de diarrees en els primers 6 mesos de vida i retarda l’aparició d’infeccions aparentment bacterianes que requereixen tractament antibiòtic. L’alletament matern exclusiu durant un mínim de tres mesos no comporta una substancial disminució de la morbiditat durant els primers 12 mesos de vida.