Evidence that distinct states of the integrin alpha6beta1 interact with laminin and an ADAM

Integrins can exist in different functional states with low or high binding capacity for particular ligands. We previously provided evidence that the integrin alpha6beta1, on mouse eggs and on alpha6-transfected cells, interacted with the disintegrin domain of the sperm surface protein ADAM 2 (fertilin beta). In the present study we tested the hypothesis that different states of alpha6beta1 interact with fertilin and laminin, an extracellular matrix ligand for alpha6beta1. Using alpha6-transfected cells we found that treatments (e.g., with phorbol myristate acetate or MnCl2) that increased adhesion to laminin inhibited sperm binding. Conversely, treatments that inhibited laminin adhesion increased sperm binding. Next, we compared the ability of fluorescent beads coated with either fertilin beta or with the laminin E8 fragment to bind to eggs. In Ca2+-containing media, fertilin beta beads bound to eggs via an interaction mediated by the disintegrin loop of fertilin beta and by the alpha6 integrin subunit. In Ca2+-containing media, laminin E8 beads did not bind to eggs. Treatment of eggs with phorbol myristate acetate or with the actin disrupting agent, latrunculin A, inhibited fertilin bead binding, but did not induce laminin E8 bead binding. Treatment of eggs with Mn2+ dramatically increased laminin E8 bead binding, and inhibited fertilin bead binding. Our results provide the first evidence that different states of an integrin (alpha6beta1) can interact with an extracellular matrix ligand (laminin) or a membrane-anchored cell surface ligand (ADAM 2)

Benchmarking Nature-Based Solution and Smart City Assessment Schemes Against the Sustainable Development Goal Indicator Framework

Increasing global urbanization yields substantial potential for enhanced sustainability through careful management of urban development and optimized resource use efficiency. Nature-based solutions (NBS) can provide a means for cities to successfully navigate the water-energy-climate relationship, thus enhancing urban resilience. Implementation of NBS can improve local or regional economic resilience underpinned by the sustainable use of natural resources. The innovative governance, institutional, business, and finance models and frameworks inherent to NBS implementation also provide a wealth of opportunity for social transformation and increased social inclusiveness in cities. The ultimate benefit of NBS implementation in cities is increased livability, which is typically measured as a function of multiple social, economic and environmental variables. Given the range of different interventions classified as NBS and the cross-sectoral character of their co-benefits, different assessment schemes can be used to evaluate NBS performance and impact. Herein, performance and impact indicators within three robust NBS- and Smart City-related assessment schemes—Mapping and Assessment of Ecosystems and their Services (MAES), Knowledge and Learning Mechanism on Biodiversity and Ecosystem Services (EKLIPSE), and Smart City Performance Measurement Framework (CITYkeys)—were critically analyzed with respect to Sustainable Development Goal (SDG) 11, “Make cities and human settlements inclusive, safe, resilient and sustainable.” Each selected assessment scheme was benchmarked with respect to the Inter-Agency Expert Group on SDG Indicators' global indicator framework for the sub-objectives of SDG 11. The alignment between each of the selected NBS assessment schemes and the SDG indicator framework was mapped with particular emphasis on consistency with city-level framework indicators for each SDG 11 sub-objective. The results were illustrated as composite scores describing the alignment of the analyzed NBS and Smart city assessment schemes with the SDG 11 sub-objectives. These results facilitate NBS assessment scheme selection based on alignment between each analyzed assessment scheme and specific SDG 11 sub-objectives. Cities face multiple challenges amidst a complex hierarchy of legislative, regulatory and other stakeholder obligations. The present study showed that strategic selection of an NBS assessment scheme which closely aligns with one or more sub-objectives within SDG 11 can maximize operational efficiency by exploiting synergies between evaluation schemes

TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer

Transforming growth factor β (TGFβ) is a pluripotent cytokine promoting epithelial cell plasticity during morphogenesis and tumour progression. TGFβ binding to type II and type I serine/threonine kinase receptors (TβRII and TβRI) causes activation of different intracellular signaling pathways. TβRI is associated with the ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Here we show that TGFβ, via TRAF6, causes Lys63-linked polyubiquitination of TβRI, promoting cleavage of TβRI by TNF-alpha converting enzyme (TACE), in a PKCζ-dependent manner. The liberated intracellular domain (ICD) of TβRI associates with the transcriptional regulator p300 to activate genes involved in tumour cell invasiveness, such as Snail and MMP2. Moreover, TGFβ-induced invasion of cancer cells is TACE- and PKCζ- dependent and the TβRI ICD is localized in the nuclei of different kinds of tumour cells in tissue sections. Thus, our data reveal a specific role for TβRI in TGFβ mediated tumour invasion

Involvement of a metalloprotease in the shedding of human neutrophil FcγRIIIB

AbstractFcγRIIIb is a glycosylphosphatidylinositol(GPI)-anchored, low-affinity IgG receptor, expressed exclusively on human neutrophils. Upon activation or apoptosis of neutrophils, FcγRIIIb is shed from the cell surface, but the enzyme(s) responsible for this process is (are) still unknown. Recently, metalloproteases have been suggested to mediate the shedding of cell surface proteins such as l-selectin and TNF-α. Using hydroxamic acid-based inhibitors of this class of proteases (BB-3103, Ro31-9790), we have observed a clear inhibitory effect on FcγRIIIb shedding after PMA stimulation of neutrophils or induction of apoptosis. These inhibitors did not affect PMA-induced degranulation or superoxide generation

Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor

The multifunctional signaling protein p75 neurotrophin receptor (p75NTR) is a central regulator and major contributor to the highly invasive nature of malignant gliomas. Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75NTR is required for p75NTR-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy. Expression of cleavage-resistant chimeras of p75NTR or treatment of animals bearing p75NTR-positive intracranial tumors with clinically applicable γ-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival. Importantly, proteolytic processing of p75NTR was observed in p75NTR-positive patient tumor specimens and brain tumor initiating cells. This work highlights the importance of p75NTR as a therapeutic target, suggesting that γ-secretase inhibitors may have direct clinical application for the treatment of malignant glioma

Key performance indicators for the indoor environment

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