Wound Healing in the α2β1 Integrin-Deficient Mouse: Altered Keratinocyte Biology and Dysregulated Matrix Metalloproteinase Expression

The alpha2beta1 integrin, a collagen/laminin receptor, is expressed at high level in the basal cell layer of the epidermis. To define the role of the alpha2beta1 integrin in wound healing, wound repair was extensively evaluated in wild-type and alpha2-null mice in vivo. In addition, the impact of alpha2beta1 integrin-deficiency on the function of primary murine keratinocytes in vitro was analyzed. Our in vivo findings demonstrate that genetic deletion of the alpha2beta1 integrin does not significantly alter the rate of re-epithelialization, collagen deposition, or tensile strength during wound closure in mice. In marked contrast to the observed similarities in wound healing, deletion of the alpha2beta1 integrin resulted in a dramatic increase in neoangiogenesis in the wound microenvironment. In contrast to in vivo studies, primary keratinocytes from alpha2-null mice adhered poorly and displayed impaired migration on type I collagen in vitro. We demonstrate that alpha2beta1 integrin-ligation negatively regulates expression of genes including matrix metalloproteinases both in vivo and in vitro. Furthermore, the changes in gene expression could potentially account for relatively normal wound healing in the alpha2-deficient mouse and our recent observation that suggests an antiangiogenic role for the alpha2beta1 integrin in vivo

Birc2/Iap1 regulates endothelial cell integrity and blood vessel homeostasis.

none4noneM. SANTORO; TEMESGEN SAMUEL; TRACY MITCHEL; JOHN C. REED AND DIDIER Y. STAINIERSantoro, Massimo; Temesgen, Samuel; Tracy, Mitchel; JOHN C. REED AND DIDIER Y., Stainie

eHabitat: A Contribution to the Model Web for Habitat Assessments and Ecological Forecasting

In striving to improve the predictive capabilities of ecological forecasting we face three basic choices ¿ develop new models, improve existing ones or increase the connectivity of models so they can work together. The latter approach of chaining different interoperable models is of particular interest, as technical developments have made it increasingly viable to combine models that can answer more questions than the individual models alone, allowing users to address complex questions, often of a multi-disciplinary nature. This concept of a Model Web encourages the setting up of a dynamic network of interoperating models, communicating with each other using standardized web services. It is the purpose of this paper to introduce the potential contribution of e-Habitat to the Model Web. e-Habitat is conceived as a Web Processing Service for computing the likelihood of finding ecosystems with equal properties. By developing e-Habitat according to Model Web principles, end-users can define the thematic layers for input to the model from various sources. These input layers are discovered using standards-based catalogues, which are a fundamental component of Model Web and generic Spatial Data Infrastructures. e-Habitat integrates data ranging from remote sensing data to socio-economical indicators, thus offering a huge potential for multi-disciplinary modelling. We will show that e-Habitat can be used for the identification of habitats that are most vulnerable or of the optimal locations for monitoring stations or, when coupled with climate change model services, for ecological forecasting. As such, it is an excellent example of the Model Web in practice.JRC.H.3-Global environement monitorin

po 8580 treatment response among cameroonian adolescents receiving antiretroviral therapy in urban and rural settings preliminary findings from the ready study

BackgroundTransitioning from paediatric to adult healthcare requires successful antiretroviral treatment (ART) for adolescents living with HIV (ADLHIV). Implementing such a policy implies monitoring ART response and selecting for therapeutic options for ADLHIV in resource-limited settings (RLS) like Cameroon.MethodsThe Ready study (EDCTP-CDF-1027) is conducted amongst ART-experienced ADLHIV (10–19 years old) in the Centre region, Cameroon. WHO-clinical staging, CD4-counts and viraemia were determined; in case of virological failure [VF] (viraemia ≥1000 copies/ml), HIV drug resistance (HIVDR) and subtyping were performed, and p<0.05 considered significant.ResultsOut of 279 ADLHIV (212 urban vs 67 rural), the gender distribution was similar (54.5% female); median age was higher in urban (15 [IQR: 13–17] years) compared to rural (13 [IQR: 11–17] years), as well as the median duration on ART (7 [IQR: 3–10] years compared to 4 [IQR: 2–7] years, respectively); and the majority was on first-line ART (79.4% [162/204] urban vs 98.5% [66/67] rural, p<0.0004). Following treatment response, clinical failure (WHO-stage 3/4) was similarly low in both urban (5.7% [12/210]) and rural (4.5% [3/67]), p=0.938; CD4 increased similarly (p=0.298) from ART-initiation (370 cells/mm3[urban] vs 332 cells/mm3[rural]) to 6 years after initiation (938 cells/mm3[urban] vs 548 cells/mm3[rural]) and rate of immunodeficiency (<500 CD4 cells/mm3) was 41.0% (87/208) in urban vs 47.5% (29/61) in rural, p=0.428. VF was 43.2% (41/95) in urban vs 60.9% (14/23) in rural, p=0.126. Among nine (9) sequences available from those experiencing VF, overall HIVDR was found in 88.8%, with 77.7% NNRTI, 55.6% NRTI and 22.2% PI/r. All were HIV-1 group M, with 55.6% CRF02_AG, 22.0% F1 and 22.4% others.ConclusionADLHIV appear clinically asymptomatic, with considerable immune recovery overtime. Despite differences in ART duration between urban and rural settings, VF was similarly high, associated with HIVDR mainly to NNRTI-based regimens. Thus, NNRTI-sparing regimens might be highly convenient when transitioning ADLHIV to adult ART-regimens in RLS like Cameroon

Metastatic osteosarcoma of craniovertebral junction with cervicalgia and torticollis an a pediatric patient

Abstract Background Primary osteosarcoma of craniovertebral junction is extremely rare and reports in paediatric patients are limited. The symptoms are subtle and mostly underestimated. Case presentation. We present an unusual case of a 11-years old girl affected by an extensive and metastatic osteosarcoma of the atlas presented with cervicalgia and right torticollis refractory to medical treatment. The patient underwent open biopsy confirming the malignant histology. Conclusions Cervicalgia with or without a torticollis refractory to medical treatment, in absence of history of fell or trauma, is highly suspicious and should be considered as a warning sign for a severe pathology and it should not be neglected

Tumor cell α3β1 integrin and vascular laminin-5 mediate pulmonary arrest and metastasis

Arrest of circulating tumor cells in distant organs is required for hematogenous metastasis, but the tumor cell surface molecules responsible have not been identified. Here, we show that the tumor cell α3β1 integrin makes an important contribution to arrest in the lung and to early colony formation. These analyses indicated that pulmonary arrest does not occur merely due to size restriction, and raised the question of how the tumor cell α3β1 integrin contacts its best-defined ligand, laminin (LN)-5, a basement membrane (BM) component. Further analyses revealed that LN-5 is available to the tumor cell in preexisting patches of exposed BM in the pulmonary vasculature. The early arrest of tumor cells in the pulmonary vasculature through interaction of α3β1 integrin with LN-5 in exposed BM provides both a molecular and a structural basis for cell arrest during pulmonary metastasis

Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported

Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through α2β1 integrin

Endorepellin, the COOH-terminal domain of the heparan sulfate proteoglycan perlecan, inhibits several aspects of angiogenesis. We provide evidence for a novel biological axis that links a soluble fragment of perlecan protein core to the major cell surface receptor for collagen I, α2β1 integrin, and provide an initial investigation of the intracellular signaling events that lead to endorepellin antiangiogenic activity. The interaction between endorepellin and α2β1 integrin triggers a unique signaling pathway that causes an increase in the second messenger cAMP; activation of two proximal kinases, protein kinase A and focal adhesion kinase; transient activation of p38 mitogen-activated protein kinase and heat shock protein 27, followed by a rapid down-regulation of the latter two proteins; and ultimately disassembly of actin stress fibers and focal adhesions. The end result is a profound block of endothelial cell migration and angiogenesis. Because perlecan is present in both endothelial and smooth muscle cell basement membranes, proteolytic activity during the initial stages of angiogenesis could liberate antiangiogenic fragments from blood vessels' walls, including endorepellin