Acrylamide Neurotoxicity as a Possible Factor Responsible for Inflammation in the Cholinergic Nervous System

Acrylamide (ACR) is a chemical compound that exhibits neurotoxic and genotoxic effects. It causes neurological symptoms such as tremors, general weakness, numbness, tingling in the limbs or ataxia. Numerous scientific studies show the effect of ACR on nerve endings and its close connection with the cholinergic system. The cholinergic system is part of the autonomic nervous system that regulates higher cortical functions related to memory, learning, concentration and attention. Within the cholinergic system, there are cholinergic neurons, anatomical cholinergic structures, the neurotransmitter acetylcholine (ACh) and cholinergic receptors. Some scientific reports suggest a negative effect of ACR on the cholinergic system and inflammatory reactions within the body. The aim of the study was to review the current state of knowledge on the influence of acrylamide on the cholinergic system and to evaluate its possible effect on inflammatory processes. The cholinergic anti-inflammatory pathway (CAP) is a neuroimmunomodulatory pathway that is located in the blood and mucous membranes. The role of CAP is to stop the inflammatory response in the appropriate moment. It prevents the synthesis and the release of pro-inflammatory cytokines and ultimately regulates the local and systemic immune response. The cellular molecular mechanism for inhibiting cytokine synthesis is attributed to acetylcholine (ACh), the major vagal neurotransmitter, and the α7 nicotinic receptor (α7nAChR) subunit is a key receptor for the cholinergic anti-inflammatory pathway. The combination of ACh with α7nAChR results in inhibition of the synthesis and release of pro-inflammatory cytokines. The blood AChE is able to terminate the stimulation of the cholinergic anti-inflammatory pathway due to splitting ACh. Accordingly, cytokine production is essential for pathogen protection and tissue repair, but over-release of cytokines can lead to systemic inflammation, organ failure, and death. Inflammatory responses are precisely regulated to effectively protect against harmful stimuli. The central nervous system dynamically interacts with the immune system, modulating inflammation through the humoral and nervous pathways. The stress-induced rise in acetylcholine (ACh) level acts to ease the inflammatory response and restore homeostasis. This signaling process ends when ACh is hydrolyzed by acetylcholinesterase (AChE). There are many scientific reports indicating the harmful effects of ACR on AChE. Most of them indicate that ACR reduces the concentration and activity of AChE. Due to the neurotoxic effect of acrylamide, which is related to the disturbance of the secretion of neurotransmitters, and its influence on the disturbance of acetylcholinesterase activity, it can be concluded that it disturbs the normal inflammatory response.     

Blood Thiol Redox State in Chronic Kidney Disease

Thiols (sulfhydryl groups) are effective antioxidants that can preserve the correct structure of proteins, and can protect cells and tissues from damage induced by oxidative stress. Abnormal levels of thiols have been measured in the blood of patients with moderate-to-severe chronic kidney disease (CKD) compared to healthy subjects, as well as in end-stage renal disease (ESRD) patients on haemodialysis or peritoneal dialysis. The levels of protein thiols (a measure of the endogenous antioxidant capacity inversely related to protein oxidation) and S-thiolated proteins (mixed disulphides of protein thiols and low molecular mass thiols), and the protein thiolation index (the molar ratio of the S-thiolated proteins to free protein thiols in plasma) have been investigated in the plasma or red blood cells of CKD and ESRD patients as possible biomarkers of oxidative stress. This type of minimally invasive analysis provides valuable information on the redox status of the less-easily accessible tissues and organs, and of the whole organism. This review provides an overview of reversible modifications in protein thiols in the setting of CKD and renal replacement therapy. The evidence suggests that protein thiols, S-thiolated proteins, and the protein thiolation index are promising biomarkers of reversible oxidative stress that could be included in the routine monitoring of CKD and ESRD patients.     

Effect of ALDH1A1 Gene Knockout on Drug Resistance in Paclitaxel and Topotecan Resistant Human Ovarian Cancer Cell Lines in 2D and 3D Model

Ovarian cancer is the most common cause of gynecological cancer death. Cancer Stem Cells (CSCs) characterized by drug transporters and extracellular matrix (ECM) molecules expression are responsible for drug resistance development. The goal of our study was to examine the role of aldehyde dehydrogenase 1A1 (ALDH1A1) expression in paclitaxel (PAC) and topotecan (TOP) resistant ovarian cancer cell lines. In both cell lines, we knocked out the ALDH1A1 gene using the CRISPR/Cas9 technique. Additionally, we derived an ALDH1A1 positive TOP-resistant cell line with ALDH1A1 expression in all cells via clonal selection. The effect of ALDH1A1 gene knockout or clonal selection on the expression of ALDH1A1, drug transporters (P-gp and BCRP), and ECM (COL3A1) was determined by Q-PCR, Western blot and immunofluorescence. Using MTT assay, we compared drug resistance in two-dimensional (2D) and three-dimensional (3D) cell culture conditions. We did not observe any effect of ALDH1A1 gene knockout on MDR1/P-gp expression and drug resistance in the PAC-resistant cell line. The knockout of ALDH1A1 in the TOP-resistant cell line resulted in a moderate decrease of BCRP and COL3A1 expression and weakened TOP resistance. The clonal selection of ALDH1A1 cells resulted in very strong downregulation of BCPR and COL3A1 expression and overexpression of MDR1/P-gp. This finally resulted in decreased resistance to TOP but increased resistance to PAC. All spheroids were more resistant than cells growing as monolayers, but the resistance mechanism differs. The spheroids’ resistance may result from the presence of cell zones with different proliferation paces, the density of the spheroid, ECM expression, and drug capacity to diffuse into the spheroid.     

Experimental Evaluation of Thermal Properties of Grouting Materials

This study is aimed at the thermal analysis of sealant mortar （usually a mixtures of bentonite and cemem with addition of sand） used in geothermal cooling and heating. In particular, thermal conductivity and diffusivity measurements were performed on differem sealant mixtures by using Hot Disk thermal constants analyzer in order to identify the interesting thermal properties of grouting materials. The grouting materials that we considered are of porous nature and, if used in the presence of groundwater, have different levels of imbibitions. It is important to know the thermal behavior of these materials at different water content. A first set of measurements was performed on a not-tinted material at room temperature; then the samples were led to saturation conditions by contact capillary imbibitions with a cotton wool layer moistened in water. The determination of thermal conductivity in these test conditions appears to be critical compared to the measuremems on non-timed sample. The thermal conductivity tests have revealed how the thermal behavior of the samples analyzed is essentially determined by the density and water content of the material： in fact, the thermal conductivity increases of two to three times the value of the not-tinted material.     

Passive adaptation or active engagement? The challenges of Housing First internationally and in the Italian case

In recent years, a peculiar homelessness policy that goes under the name of ‘Housing First’ has become increasingly popular all over the world. Epitomising a quintessential case of policy-mobility, Housing First can today be considered an heterogeneous assemblage of experiences and approaches that sometimes have little in common with each other. Introducing and commenting upon this heterogeneity, the paper critically analyses why and how Housing First has become a planetary success and what are the issues at stake with its widespread implementation. If recent scholarship published in this journal has granted us a fine understanding of Housing First’s functioning in the US, this paper offers something currently absent from the debate: a nuanced and critical understanding of the ambiguities related to the international success of this policy, with specific references to the challenges associated to its translation in the Italian case.     

丹尼尔斯大厦 加拿大多伦多

正多伦多大学丹尼尔斯建筑、景观和设计学院的设计采用了分期的方法,包括修复和扩建以前称为知识学院的标志性建筑,将现有建筑物改造成与教学和需求更相关的框架体系。这个十九世纪遗址的总体规划是通过对预期用途模式和场地生态的分析而制定的,目的是重新定位校园西南角与安大略湖的轴线,并为学院创造新的特性。丹尼尔斯建筑、景观和设计学院需要一个可持续发展的新型工     

Towards the development of technical specifications for the production of lithium–lead alloys for the ITER HCLL TMB

The ITER and DEMO projects are developing new Test Blanket Modules (TBM), where the Pb–Li alloy plays a key role in the new commercial fusion reactors functionality. The Breeding Blanket (BB) has to perform several functions which are essential for the reactor operation. The HCLL TBM is one of the Breeding Blanket concepts to be tested in ITER. It is cooled by He and uses the eutectic liquid metal LLE (Lithium–Lead Eutectic) as breeder material (enriched at 90% in ⁶Li).Pb–Li eutectic alloy has no known uses outside of fusion technology, so the available databases of this material are currently incomplete. It is very important, within the material specifications, to have a complete characterization in order to define their chemical and physical properties, because any variation in the alloy composition has significant consequences in their behaviour, and therefore in their regenerative function inside the blanket.The chemical characterization methodology developed and presented in this paper (useful for both Pb–Li alloys as any Pb alloy) is a key tool that allows performing standard quality control procedures for base material and/or monitoring the alloy during the reactor operation. This report provides a procedure to perform a wide material chemical characterization, assessing the concentrations of major elements, as well as a review of trace level elements that can be found both in the eutectic alloy and in starting materials. In this determination plays an important role the ICP-MS technique because, as a highly sensitive technique, allows very low detection limits.     

Coenzyme Q10 supplementation: Efficacy,safety, and formulation challenges

World population growth and aging are posing unprecedented challenges in sustaining the health of 9.1 billion people that will be occupying the planet by 2050. Although noncommunicable diseases such as cardiovascular and neurodegenerative diseases, cancer, and diabetes are among the top 10 global causes of death, they can be prevented by risk factor reduction, early detection, and adequate treatment. Since a healthy diet along with dietary supplementation could play an important role to reduce morbidity and cut off its associated health care costs, research in the food and nutrition area is required to find solutions to global challenges affecting health. As a result of the healthy living trend, dietary supplements category is growing fast, leading to an urgent need for dietitians, physicians, and policy makers to broaden the scientific evidence on the efficacy and safety of a wide range of active ingredients. Coenzyme Q10 (CoQ10), as the third most consumed dietary supplement, and as a potential candidate for the treatment of various noncommunicable diseases that are among the global top 10 causes of death, has gained interest over years. Scientific evidence regarding mainly CoQ10 efficacy and safety, as well as formulation challenges, is addressed in this review.