Thiophene-Based Trimers and Their Bioapplications: An Overview

Certainly, the success of polythiophenes is due in the first place to their outstanding electronic properties and superior processability. Nevertheless, there are additional reasons that contribute to arouse the scientific interest around these materials. Among these, the large variety of chemical modifications that is possible to perform on the thiophene ring is a precious aspect. In particular, a turning point was marked by the diffusion of synthetic strategies for the preparation of terthiophenes: the vast richness of approaches today available for the easy customization of these structures allows the finetuning of their chemical, physical, and optical properties. Therefore, terthiophene derivatives have become an extremely versatile class of compounds both for direct application or for the preparation of electronic functional polymers. Moreover, their biocompatibility and ease of functionalization make them appealing for biology and medical research, as it testifies to the blossoming of studies in these fields in which they are involved. It is thus with the willingness to guide the reader through all the possibilities offered by these structures that this review elucidates the synthetic methods and describes the full chemical variety of terthiophenes and their derivatives. In the final part, an in-depth presentation of their numerous bioapplications intends to provide a complete picture of the state of the art.Operational Program Research, Development, and Education Project “MSCAfellow4@MUNI” (No. CZ.02.2.69/0.0/0.0/20_079/0017045) is acknowledged. The European Union is acknowledged for funding this research through Horizon 2020 MSCA-IF-2018 No 838171 (TEXTHIOL)

Characterization of the "diabesity" gene HMG20A in pancreatic islets

Motivation: Type 2 Diabetes (T2D) accounts for 90-95% of diagnosed diabetic patients, which tendency in the next years is also expected to increase. Recent genomic wide association studies showed a correlation of an allelic variation of HMG20A with T2D in some ethnic groups. Up to date, there is no scientific evidence of the role of this gene in pancreatic tissue. But, in central nervous system, HMG20A regulates the expression of NeuroD, common in pancreas and nervous system morphogenesis. Here, our group makes an approach to characterize HMG20A in pancreatic islets, focusing on its involvement in glucose-stimulated insulin secretion (GSIS) and pancreatic islets development. We want to demonstrate that: 1) HMG20A is expressed in endocrine pancreas 2) HMG20A modifies expression of genes involved in pancreas development 3) silencing HMG20A affects expression levels of insulin secretion related genes and functionality.Methods: Qualitative expression of HMG20A is tested out in slides of pancreatic sections obtained from control mice. Co-localization with α or β cells is analyzed by immunofluorescence using anti-HMG20A, anti-insulin/glucagon antibodies and Dapi for nuclei. INS-1E cells are cultured and treated with a specific siRNA against HMG20A or a non-specific siRNA control during 72h. Genes involved in insulin secretion and endocrine pancreas development are assayed via qRT-PCR in INS1-E cells after siRNA treatment. Pdx1, Pax4, MafA and HMG20A expression levels are assessed following 2-ΔΔCt method. Finally, HMG20A silenced mouse islets and INS-1E are cultured at low glucose (2.8 mM) and high glucose medium (22 mM) following quantification of insulin secretion by ELISA.Results: Immunofluorescence confirmed co-localization of HMG20A with insulin (β-cell) and with glucagon (α-cells) producing cells in mouse pancreas. HMG20A expression diminished a 60% after treating INS1-E cells with a specific siRNA for HMG20A. Insulin secretion regulator gene, MafA, is downregulated significantly (50-60%) after HMG20A silencing. Pax4 expression significantly increased meanwhile Pdx1 showed a tendency to decrease. A 40% drop in insulin secretion is obtained in siHMG20A treated mouse islets compared to control.Conclusions: This data confirms HMG20A expression in pancreatic islets and impairment of insulin secretion when it is knocked down. Hence, concluding that HMG20A plays an important role in physiological GSIS and regulating pancreatic development related genes

PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus

[Aims/hypothesis]: A strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7.1 mouse model background and to characterise putative cellular mechanisms associated with preserved BCM. [Methods]: Two groups of RIP-B7.1 mice were genetically engineered to: (1) conditionally express either PAX4 (BPTL) or its diabetes-linked mutant variant R129W (mutBPTL) using doxycycline (DOX); and (2) constitutively express luciferase in beta cells through the use of RIP. Mice were treated or not with DOX, and EAD was induced by immunisation with a murine preproinsulin II cDNA expression plasmid. The development of hyperglycaemia was monitored for up to 4 weeks following immunisation and alterations in the BCM were assessed weekly by non-invasive in vivo bioluminescence intensity (BLI). In parallel, BCM, islet cell proliferation and apoptosis were evaluated by immunocytochemistry. Alterations in PAX4- and PAX4R129W-mediated islet gene expression were investigated by microarray profiling. PAX4 preservation of endoplasmic reticulum (ER) homeostasis was assessed using thapsigargin, electron microscopy and intracellular calcium measurements. [Results]: PAX4 overexpression blunted EAD, whereas the diabetes-linked mutant variant PAX4R129W did not convey protection. PAX4-expressing islets exhibited reduced insulitis and decreased beta cell apoptosis, correlating with diminished DNA damage and increased islet cell proliferation. Microarray profiling revealed that PAX4 but not PAX4R129W targeted expression of genes implicated in cell cycle and ER homeostasis. Consistent with the latter, islets overexpressing PAX4 were protected against thapsigargin-mediated ER-stress-related apoptosis. Luminal swelling associated with ER stress induced by thapsigargin was rescued in PAX4-overexpressing beta cells, correlating with preserved cytosolic calcium oscillations in response to glucose. In contrast, RNA interference mediated repression of PAX4-sensitised MIN6 cells to thapsigargin cell death. [Conclusions/interpretation]: The coordinated regulation of distinct cellular pathways particularly related to ER homeostasis by PAX4 not achieved by the mutant variant PAX4R129W alleviates beta cell degeneration and protects against diabetes mellitus. The raw data for the RNA microarray described herein are accessible in the Gene Expression Omnibus database under accession number GSE62846

Electrochemical deposition of CoNi micro/nanostructures as new materials for electrochemical sensing of glucose

CoNi micro/nanostructures (films and nanowires of different properties) have been synthesised, through a facile and low cost method, as catalysts for glucose electro-oxidation, being promising material for non-enzymatic glucose sensors. The synthesis is a one-step procedure able to prepare, from a single solution, films or nanorods with different composition, shape and morphology. The electrocatalytic activity of the CoNi films and glassy carbon/CoNi nanorods for the glucose oxidation in basic medium has been investigated. The glucose oxidation current is clearly detected over the oxidized alloy. Voltamperometry and chronoamperometry techniques allow sensing the glucose over the CoNi structures prepared. The best catalysts are the films synthesised at -1.0 V and the nanorods at -0.8 V, which moreover minimizes the amount of sensing material

El neolític antic i l"inici de l"edat del bronze a les excavacions del nou conservatori del Liceu

[cat] En aquest article es presenta l"estudi interdisciplinari de les ocupacions prehistòriques recents (neolític i inici de l"edat del bronze) localitzades durant la construcció del Conservatori del Gran Liceu de Barcelona, al barri del Raval de la mateixa ciutat. Les restes ocupacionals corresponen a un assentament amb evidències d"estructures de combustió i diversos elements de suport. Hi destaca la conservació d"alguns magnífics fogars, així com un conjunt de materials abiòtics i biòtics que permeten augmentar el coneixement de les primeres comunitats agrícoles del Pla de Barcelona. [spa] En este artículo se presenta el estudio interdisciplinar de las ocupaciones prehistóricas recientes (Neolítico e inicio de la Edad del Bronce) localizadas durante la construcción del Conservatorio del Gran Liceo de Barcelona, en el barrio del Raval de la misma ciudad. Los restos de ocupación corresponden a un asentamiento con evidencias de estructuras de combustión y otros elementos de soporte. Entre ellos destaca la conservación de algunos magníficos hogares así como un conjunto de materiales abióticos y bióticos que permiten aumentar el conocimiento sobre las primeras comunidades agrícolas del llano de Barcelona. [eng] This paper presents the interdisciplinary study of the recent prehistoric occupations (Neolithic and Early Bronze Age) found during the construction of El Liceu Conservatoire in Barcelona"s El Raval district. Occupational remains correspond to a settlement with traces of combustion structures and several supporting elements. It emphasises the preservation of some magnificent fireplaces and a set of archaeological abitoic and biotic materials that can increase knowledge of the first farming communities in the Barcelona plain. [fra] Cet article présente l"étude interdisciplinaire des occupations préhistoriques récentes (néolithique et début de l"âge du bronze) localisées lors de la construction du Conservatoire du Grand Théâtre du Liceu (opéra) de Barcelone, dans le quartier du Raval. Les vestiges d"occupation correspondent à un établissement présentant des structures de combustion et différents éléments de support. On y remarque la conservation de quelques magnifiques foyers ainsi qu"un ensemble de matériaux abiotiques et biotiques qui peuvent enrichir les connaissances sur les premières communautés agricoles de la plaine de Barcelone

Defective chaperone-mediated autophagy is a hallmark of joint disease in patients with knee osteoarthritis

[Abstract] Objective: Defects in autophagy contribute to joint aging and Osteoarthritis (OA). Identifying specific autophagy types could be useful for developing novel treatments for OA. Design: An autophagy-related gene array was performed in blood from non-OA and knee OA subjects from the Prospective Cohort of A Coruña (PROCOAC). The differential expression of candidate genes was confirmed in blood and knee cartilage and a regression analysis was performed adjusting for age and BMI. HSP90A, a chaperone mediated autophagy (CMA) marker was validated in human knee joint tissues, as well as, in mice with aging-related and surgically-induced OA. The consequences of HSP90AA1 deficiency were evaluated on OA pathogenesis. Finally, the contribution of CMA to homeostasis was studied by assessing the capacity to restore proteostasis upon ATG5-mediated macroautophagy deficiency and genetic HSP90AA1 overexpression. Results: 16 autophagy-related genes were significantly down-regulated in blood from knee OA subjects. Validation studies showed that HSP90AA1 was down-regulated in blood and human OA cartilage and correlated with risk incidence of OA. Moreover, HSP90A was reduced in human OA joints tissues and with aging and OA in mice. HSP90AA1 knockdown was linked to defective macroautophagy, inflammation, oxidative stress, senescence and apoptosis. However, macroautophagy deficiency increased CMA, highlighting the CMA-macroautophagy crosstalk. Remarkably, CMA activation was sufficient to protect chondrocytes from damage. Conclusions: We show that HSP90A is a key chaperone for chondrocyte homeostasis, while defective CMA contributes to joint damage. We propose that CMA deficiency is a relevant disease mechanism and could represent a therapeutic target for OA.Instituto de Salud Carlos III; PI17/02059Instituto de Salud Carlos III; PI20/0064

Use of healthcare REsources and associated COsts in controlled versus uncontrolled carcinoid SYndrome in patients with neuroendocrine tumours: the RECOSY study

Purpose: To report healthcare resource use and associated costs in controlled versus uncontrolled carcinoid syndrome (CS) in patients with neuroendocrine tumours. Methods: A cross-sectional, non-interventional multicentre study was conducted with retrospective data analysis. Resource use was compared between two patient groups: those with controlled CS (> 12 months with no uncontrolled CS episodes) and uncontrolled CS (< 12 months since last uncontrolled episode). Patients were matched for age, sex, and origin and grade of tumour. When no matching patients were available, data from deceased patients were used. Information on healthcare resource use came from review of medical records, patient history and physician reports. Working capacity was assessed using the Work Productivity and Activity Impairment General Health questionnaire. Results: Twenty-six university hospitals in Spain participated, between July 2017 and April 2018. 137 patients were enrolled; 104 were analysed (2 groups of 52). Patients with uncontrolled CS had 10 times more emergency department (ED) visits (mean 1.0 vs 0.10 visits; P = 0.0167), were more likely to have a hospital admission (40.4% vs 19.2%; P = 0.0116) and had longer hospital stays (mean 7.87 vs 2.10 days; P = 0.0178) than those with controlled CS. This corresponded to higher annual hospitalisation costs (mean €5511.59 vs €1457.22; P = 0.028) and ED costs (€161.25 vs €14.85; P = 0.0236). The mean annual total healthcare costs were 60.0% higher in patients with uncontrolled than controlled CS (P = NS). Conclusion: This study quantifies higher health resource use, and higher hospitalisation and ED costs in patients with uncontrolled CS. Better control of CS may result 3in lower medical costs

Superelastic damping at nanoscale in ternary and quaternary Cu-based shape memory alloys

Superelasticity is a characteristic thermomechanical property in shape memory alloys (SMA), which is due to a reversible stress-induced martensitic transformation. Nano-compression experiments made possible the study of this property in Cu–Al–Ni SMA micropillars, showing an outstanding ultra-high mechanical damping capacity reproducible for thousands of cycles and reliable over the years. This scenario motivated the present work, where a comparative study of the damping capacity on four copper-based SMA: Cu–Al–Ni, Cu–Al–Be, Cu–Al–Ni–Be and Cu–Al–Ni–Ga is approached. For this purpose, [001] oriented single-crystal micropillars of comparable dimensions (around 1 µm in diameter) were milled by focused ion beam technique. All micropillars were cycled up to two hundred superelastic cycles, exhibiting a remarkable reproducibility. The damping capacity was evaluated through the dimensionless loss factor η, calculated for each superelastic cycle, representing the dissipated energy per cycle and unit of volume. The calculated loss factor was averaged between three micro-pillars of each alloy, obtaining the following results: Cu–Al–Ni η = 0.20 ± 0.01; Cu–Al–Be η = 0.100 ± 0.006; Cu–Al–Ni–Be η = 0.072 ± 0.004 and Cu–Al–Ni–Ga η = 0.042 ± 0.002. These four alloys exhibit an intrinsic superelastic damping capacity and offer a wide loss factor band, which constitutes a reference for engineering, since this kind of micro/nano structures can potentially be integrated not only as sensors and actuators but also as dampers in the design of MEMS to improve their reliability. In addition, the study of the dependence of the superelastic loss factor on the diameter of the pillar was approached in the Cu–Al–Ni–Ga alloy, and here we demonstrate that there is a size effect on damping at the nanoscale.Fil: Gómez Cortés, J.F.. Universidad del País Vasco; EspañaFil: Fuster, Valeria de Los Angeles. Universidad del País Vasco; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Física de Rosario. Universidad Nacional de Rosario. Instituto de Física de Rosario; ArgentinaFil: Pérez Cerrato, M.. Universidad del País Vasco; EspañaFil: Lorenzo, P.. Universidad del País Vasco; EspañaFil: Ruiz Larrea, I.. Universidad del País Vasco; EspañaFil: Breczewski, T.. Universidad del País Vasco; EspañaFil: Nó, M. L.. Universidad del País Vasco; EspañaFil: San Juan, J. M.. Universidad del País Vasco; Españ