Defensive towers and river territories: water architecture in the Zhujiang river basin, Guangdong

[EN] The contribution intends to provide a reading and an in-depth study of the defensive heritage located in the Zhujiang river basin and its delta in Guangdong, China. The paper focuses on the case of diaolou, defensive towers already listed as UNESCO since 2007, built from the sixteenth century until the first half of the twentieth century in Kaiping country. These buildings show an interesting mixture of some local models and typologies and specific characters and styles borrowed from western examples. The research takes as a privileged point of view the relationships that these settlement systems forge with the hydrographic resource, which generates a territorial groove that determines the morphology of the territory and constitutes a historical vehicle of crossings. The arrangement of the fortified towers with respect to the river line is influenced by centripetal and centrifugal actions aimed at responding to defensive needs in the geography of this territory. The heritage of the diaolou seems to respond to two types of defensive demands: one linked to historical facts and the frequent bandit raids that took place in the Guangdong area in the nineteenth century; the other connected to geographical and hydraulic data, as the protection from the phenomenon of inundation and the consequent placement of the towers in the floodplain of the Zhujiang river. The course of the river gets in shape through the architectural technique, in the construction of towers and defensive works and, in the same way, some aspects of the design of this territory are defined through the description of the forms of the river. Architecture, hydraulic engineering and geography work together in defining the form of the settlement and invest the scale of the buildings, generating specific architectural types and morphological characters suitable for responding to the problem of water control, conservation and distribution.Ficarelli, L.; Vacca, V. (2020). Torri difensive e territori fluviali: architetture d’acque nel bacino del fiume Zhujiang, Guangdong. Editorial Universitat Politècnica de València. 907-914. https://doi.org/10.4995/FORTMED2020.2020.11529OCS90791

Heritability of Cardiovascular and Personality Traits in 6,148 Sardinians

In family studies, phenotypic similarities between relatives yield information on the overall contribution of genes to trait variation. Large samples are important for these family studies, especially when comparing heritability between subgroups such as young and old, or males and females. We recruited a cohort of 6,148 participants, aged 14–102 y, from four clustered towns in Sardinia. The cohort includes 34,469 relative pairs. To extract genetic information, we implemented software for variance components heritability analysis, designed to handle large pedigrees, analyze multiple traits simultaneously, and model heterogeneity. Here, we report heritability analyses for 98 quantitative traits, focusing on facets of personality and cardiovascular function. We also summarize results of bivariate analyses for all pairs of traits and of heterogeneity analyses for each trait. We found a significant genetic component for every trait. On average, genetic effects explained 40% of the variance for 38 blood tests, 51% for five anthropometric measures, 25% for 20 measures of cardiovascular function, and 19% for 35 personality traits. Four traits showed significant evidence for an X-linked component. Bivariate analyses suggested overlapping genetic determinants for many traits, including multiple personality facets and several traits related to the metabolic syndrome; but we found no evidence for shared genetic determinants that might underlie the reported association of some personality traits and cardiovascular risk factors. Models allowing for heterogeneity suggested that, in this cohort, the genetic variance was typically larger in females and in younger individuals, but interesting exceptions were observed. For example, narrow heritability of blood pressure was approximately 26% in individuals more than 42 y old, but only approximately 8% in younger individuals. Despite the heterogeneity in effect sizes, the same loci appear to contribute to variance in young and old, and in males and females. In summary, we find significant evidence for heritability of many medically important traits, including cardiovascular function and personality. Evidence for heterogeneity by age and sex suggests that models allowing for these differences will be important in mapping quantitative traits

Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer

Mitochondria are complex intracellular organelles traditionally identified as the powerhouses of eukaryotic cells due to their central role in bioenergetic metabolism. In recent decades, the growing interest in mitochondria research has revealed that these multifunctional organelles are more than just the cell powerhouses, playing many other key roles as signaling platforms that regulate cell metabolism, proliferation, death and immunological response. As key regulators, mitochondria, when dysfunctional, are involved in the pathogenesis of a wide range of metabolic, neurodegenerative, immune and neoplastic disorders. Far more recently, mitochondria attracted renewed attention from the scientific community for their ability of intercellular translocation that can involve whole mitochondria, mitochondrial genome or other mitochondrial components. The intercellular transport of mitochondria, defined as horizontal mitochondrial transfer, can occur in mammalian cells both in vitro and in vivo, and in physiological and pathological conditions. Mitochondrial transfer can provide an exogenous mitochondrial source, replenishing dysfunctional mitochondria, thereby improving mitochondrial faults or, as in in the case of tumor cells, changing their functional skills and response to chemotherapy. In this review, we will provide an overview of the state of the art of the up-to-date knowledge on intercellular trafficking of mitochondria by discussing its biological relevance, mode and mechanisms underlying the process and its involvement in different pathophysiological contexts, highlighting its therapeutic potential for diseases with mitochondrial dysfunction primarily involved in their pathogenesis

Protective effect of pioglitazone, a PPARγ ligand, in a 3 nitropropionic acid model of Huntington's disease

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the PPAR family. PPAR gamma is the target of insulin-sensitising thiazolidinediones (TZDs), drugs used for the treatment of non-insulin-dependent diabetes. Recently, several studies have shown that PPAR gamma activators can also prevent or attenuate neurodegeneration. The PPAR gamma agonist pioglitazone provides neuroprotection to dopaminergic neurons in lipopolysaccharide (LPS) and MPTP-induced Parkinson's disease experimental models. Here, we investigated whether PPAR gamma activation by pioglitazone protected striatal cells from mitochondrial dysfunction and oxidative stress in a 3 nitropropionic acid (3NP)-induced experimental model of Huntington's disease (HD). Our results suggested that pioglitazone has beneficial effects on mitochondrial dysfunction by interfering with the NF-kappa B signalling pathway, which has been implicated in the pathogenesis of HD. Additionally, we demonstrated that the nuclear translocation of HDAC3 is regulated by 3NP via I kappa B alpha and that treatment with pioglitazone prevented these effects. These results suggested that I kappa B alpha-dependent nuclear translocation is responsible for PPAR gamma inhibition by 3NP and pointed to histone modifications as a novel approach for treating HD. (C) 2011 Elsevier Inc. All rights reserved

IL-15 drives the specific migration of CD94+ and TCR-??+ intraepithelial lymphocytes in organ cultures of treated celiac patients

Objectives: Celiac disease (CD) is an under-diagnosed but extremely frequent disease, triggered by the ingestion of gliadin. The pathogenic mechanisms of CD are still poorly understood, but intraepithelial lymphocytes are considered to have a key role. We intended to define the subsets of T lymphocytes migrating upon gliadin challenge in organ cultures of treated celiac patients and establish the type of factor(s) driving such an infiltration.Methods: Duodenum biopsies from 10 treated celiacs and 7 controls were cultured in vitro with/without gliadin digest (1 mg/ml) or interleukin (IL)-15 (10 ng/ml). In 7 treated celiacs IL-7, IL-4, and IL-2 were similarly tested. Intraepithelial CD3, CD8, TCR-??, and CD94 were detected by immunohistochemistry and numbered per mm epithelium.Results: IL-15 but not IL-7, IL-4, or IL-2 induced intraepithelial increase of CD3+ and CD8+ cells in celiac and control intestine (p< 0.001 vs cultures with medium). IL-15 induced increases in the number of intraepithelial TCR-??+ and CD94+ cells only in celiacs (p< 0.001). IL-7 was also effective in increasing intraepithelial TCR-??+ (but not CD94+) cells in celiac biopsies (p< 0.001). Gliadin induced intraepithelial migration of CD3+, CD8+ (p< 0.001), and CD94+ (p< 0.05) cells in celiacs, but not in controls.Conclusions: The results we describe in this report indicate that IL-15 might have a key role in modulating and driving intraepithelial infiltration and ultimately in the pathogenesis of CD

Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease

Background: the adaptive immune system is central to the development of coeliac disease. Adaptive immune responses are, however, controlled by a preceding activation of the innate immune system. We investigated whether gliadin, a protein present in wheat flour, could activate an innate as well as an adaptive immune response in patients with coeliac disease.Methods: duodenal biopsy samples from 42 patients with untreated coeliac disease, 37 treated patients, and 18 controls, were cultured in vitro for 3 h or 24 h, in the presence of either immunodominant gliadin epitopes (p?-2 and p?-9) or a non-immunodominant peptide (p31–43) known to induce small intestine damage in coeliac disease. We also incubated biopsy samples from nine untreated and six treated patients with a non-immunodominant peptide for 3 h, before incubation with immunodominant gliadin epitopes. Different combinations of interleukin-15 or signal transduction inhibitors were added to selected incubations.Findings: only the non-immunodominant peptide induced rapid expression of interleukin-15, cd83, cyclo-oxygenase (COX)-2, and CD25 by CD3– cells (p=O005 vs medium alone) and enterocyte apoptosis (p<0·0001). Only the non-immunodominant peptide induced p38 MAP kinase activation in CD3– cells. Pre-incubation with the non-immunodominant peptide enabled immunodominant epitopes to induce T-cell activation (p=0·001) and enterocyte apoptosis. Inhibition of interleukin-15 or of p38 MAP kinase controlled such activity.Interpretation: a gliadin fragment can activate the innate immune system, affecting the in situ T-cell recognition of dominant gliadin epitopes. Although our findings emphasise the key role of gliadin-specific T cells, they suggest a complex pathogenic situation, and show that inhibition of interleukin-15 or p38 MAP kinase might have the potential to control coeliac disease

Chronic inflammation enhances NGF-β/TrkA system expression via EGFR/MEK/ERK pathway activation in Sjögren’s syndrome

Primary Sjögren's syndrome (pSS) is a chronic autoimmune exocrine disease associated with variable lymphocytic infiltration of the affected organs (primarily salivary and lachrymal glands). To investigate the potential implication of nerve growth factor-β (NGF-β) and its high affinity receptor tyrosine kinase receptor A (TrkA) in the regulation of pSS inflammatory responses, we studied their expression in the human salivary gland epithelial cells (SGEC) cultures from pSS minor salivary glands (MSG) biopsies and their relationship with histopathological disease parameters. Here, we demonstrated an increased expression of the NGF-β/TrkA system in pSS SGEC, correlated with the MSG inflammation grade. The results demonstrate that the pro-inflammatory cytokines TNF-α and IL-6 enhance NGF-β production; on the contrary, NGF-β production was reduced in the presence of both Raf-1 kinase and MEK inhibitors. Furthermore, TNF-α/IL-6 treatment increased ERK1/2 phosphorylation. Inhibition of the EGF/EGFR system also decreased NGF-β release by pSS SGEC, indicating that the chronic inflammatory condition characteristic of pSS enhances NGF-β production via EGFR/Raf-1/MEK/ERK pathway activation. KEY MESSAGE: NGF-β and TrkA expression is elevated in salivary gland epithelial cells of primary Sjögren's syndrome (pSS). Overexpression of NGF-β/TrkA system in pSS occurs via EGFR/Raf-1/MEK/ERK pathway. In pSS, NGF-β overexpression was prevented by EGFR/Raf-1/MEK/ERK pathway inhibition

Foxm1 controls a pro-stemness microRNA network in neural stem cells.

Cerebellar neural stem cells (NSCs) require Hedgehog-Gli (Hh-Gli) signalling for their maintenance and Nanog expression for their self-renewal. To identify novel molecular features of this regulatory pathway, we used next-generation sequencing technology to profile mRNA and microRNA expression in cerebellar NSCs, before and after induced differentiation (Diff-NSCs). Genes with higher transcript levels in NSCs (vs. Diff-NSCs) included Foxm1, which proved to be directly regulated by Gli and Nanog. Foxm1 in turn regulated several microRNAs that were overexpressed in NSCs: miR-130b, miR-301a, and members of the miR-15~16 and miR-17~92 clusters and whose knockdown significantly impaired the neurosphere formation ability. Our results reveal a novel Hh-Gli-Nanog-driven Foxm1-microRNA network that controls the self-renewal capacity of NSCs