Experiencing spaces – a different approache of the architectural space

In today's society, where visualization predominate, there is little spatial experiences that can stimulate the entire repertoire of human senses. Architecture is the only art that is capable of producing inhabited spaces and provides spatial boundaries in which we, as human beings, can experiencespace. By virtue of this, the most of the experiences on a space can be reduced to a single sensory experience, the visual one.info:eu-repo/semantics/publishedVersio

Spatial Patterns of Regional Inequalities: Empirical Evidence from a Large Panel of Countries

This paper investigates regional inequality from two standpoints. First, it explores them from a global perspective by assessing the incidence of economic growth for 2867 regions from 161 countries. Results show that middle income regions had the highest growth rates after the Great Recession, whilst regions from deciles 9 and, to a lower extent, those from decile 10 had suffered the most negative impact. Hence, the incidence of regional growth resembles the ``elephant curve'' of global inter-personal inequality. Second, the paper explores within-country regional inequality for a panel of 25 countries, over the period 2000\textendash2018. Using OECD data and following both cross-sectional and time series approaches, results show that, while regional inequality decreases with growing GDPPC, regional polarization is more persistent and does not necessarily follow the same rule. The paper also delivers a first systematic assessment of sigma-convergence and regional polarization for a considerable number of countries, with findings pinpointing the importance of spatial clustering (which is contributing considerably to regional inequality levels), but also its complementarity with sigma-convergence measures (as regional inequality trajectories are not necessary associated with spatial clustering trajectories). Overall, findings also suggest that convergence approaches cannot provide an adequate theoretical background for understanding regional problems as long as they remain aspatial. \textcopyright 2022 Elsevier Lt

A New Signaling Pathway for HCV Inhibition by Estrogen: GPR30 Activation Leads to Cleavage of Occludin by MMP-9.

Poor outcome in response to hepatitis C virus, including higher viral load, hepatocellular carcinoma and cirrhosis, is more associated with men and postmenopausal women than with premenopausal women and women receiving hormone replacement therapy, suggesting that β-estradiol plays an innate role in preventing viral infection and liver disease. Consequently, most research in the field has concluded that estrogen affects HCV replication through viral interactions with estrogen receptor-α. Previously, estrogen-like antagonists, including Tamoxifen, were shown to reduce HCV RNA production and prevent viral entry, although the authors did not identify host factors involved. Estrogen can act alternatively through the membrane-bound G-protein-coupled estrogen receptor, GPR30. Here, human hepatoma Huh7.5 cells were infected with HCV J6/JFH-1 and treated with estrogen or Tamoxifen, resulting in a marked decrease in detectable virus. The effect was mimicked by G1, a GPR30-specific agonist, and was reversed by the GPR30-specific antagonist, G15. While previous studies have demonstrated that estrogen down-regulated occludin in cervical cancer cells, its action on liver cells was unknown. Occludin is a tight junction protein and HCV receptor and here we report that activation and cellular export of MMP-9 led to the cleavage of occludin upon estrogen treatment of liver cells. This is the first report of the cleavage of an HCV receptor in response to estrogen. We also identify the occludin cleavage site in extracellular Domain D; the motif required for HCV entry and spread. This pathway gives new insight into a novel innate antiviral pathway and the suboptimal environment that estrogen provides for the proliferation of the virus. It may also explain the disparate host-virus responses to HCV demonstrated by the two sexes. Moreover, these data suggest that hormone replacement therapy may have beneficial antiviral enhancement properties for HCV-infected postmenopausal women and show promise for new antiviral treatments for both men and women

Estrogen abrogates HCV infection.

<p>(A) Huh7.5 cells respond to estrogen treatment measured by cyclin-D1 expression. (B) HCV core protein in J6/JFH1-infected Huh7.5 cells treated with E2 or Universal Type I IFN. (C) HCV intracellular core protein in J6/JFH1-infected Huh7.5 cells treated with E2, as measured by Flow Cytometry. (D) HCV RNA quantitated relative to GAPDH RNA levels from infected Huh7.5 cells treated with E2 or IFN. (E) Virus growth measured by absolute mean focus forming units (FFU). Error bars indicate the statistical standard deviation from the mean (±SD). Statistical significance is indicated by asterisks where: (*** = P ≤ 0.001; **** = P ≤ 0.0001). (F) Representative images of foci after 48 hr of E2 treatment. Magnification 40X (<i>below</i>); 100X (<i>above</i>).</p

Schematic of the E2 signaling pathway controlling HCV entry and spread in liver cells.

<p>The nuclear receptor mediated pathway is activated by E2 and blocked by Tamoxifen (Tam) in most cell types. Activation of GPR30 is inhibited by G15 and initiated by E2, Tam or G1, leading to activation/secretion of MMP-9, which cleaves occludin in extracellular Domain D, resulting in a defective HCV receptor.</p

E2 modulates matrix metalloproteinase to inhibit HCV growth.

<p>(<i>A</i>) Response of increasing concentrations of the broad-spectrum MMP inhibitor, ONO-4817 on J6/JFH1-infected Huh7.5 cells, in the presence or absence of E2 (<i>center panel</i>), and G1 (<i>right panel</i>) on HCV growth. Increasing concentrations of the broad spectrum MMP inhibitors (<i>B</i>) CP471,474 (C) Ilomastat (D) MMP408 or (E) SB-3CT. Data represent the absolute mean foci number of three independent experiments and error bars represent the standard deviation from the mean (±SD). Statistical significance is expressed as asterisks where; (* = P≤ 0.05; ** = P ≤ 0.01; **** = P ≤ 0.0001).</p

MMP-9 activation mediated by E2 modulates occludin.

<p>(A) Immunoblot of occludin down-regulation by G1, reversed by ONO-4817 (ONO). Protein expression relative to GAPDH was quantitated in a SyngeneG:box (<i>right</i>). (B) Immunoblot of full-length and truncated forms of occludin in Huh7.5 cells treated with G1 and ONO-4817 and the percentage of occludin forms were calculated relative to GAPDH protein levels (values below each band). (C) Schematic representation of occludin (504 amino acids). (D) Immunoblot of pro-MMP-9 (92 KDa) and active MMP-9 (~64 KDa) in Huh7.5 cell membranes and conditioned media (extracellular) following E2 treatment. (E) Immunoblot of MMP-9 in supernatant (extracellular) after siRNA transfection and E2 treatment (0, 1, 100, 10,000 nM). Cleaved occludin (38 KDa) is shown and GAPDH is shown as a gel loading control.</p

E2 treatment leads to occludin cleavage in Huh7.5 cells.

<p>(A) Detection of full-length (59 KDa) and truncated (38 KDa) occludin in Huh7.5 cells after treatment with increasing amounts of E2 for 24 hr. (B) Occludin and GAPDH cDNA in Huh7.5 cells following treatment with increasing levels of E2 for 24 hr. NR, RNA/no cDNA control; NC, no RNA/no cDNA control. (C) Immunoblot of full-length and truncated occludin in G15- and E2-treated cells. Intensity of immunoblot bands was quantified by imaging analysis and the percentage of total occludin was calculated relative to GAPDH protein levels. The percentage of truncated (38 KDa) occludin was determined as relative to corrected total occludin, <i>right</i>.</p