Cell-Free DNA Fragments as Biomarkers of Islet β-Cell Death in Obesity and Type 2 Diabetes

Type 2 diabetes (T2D) typically occurs in the setting of obesity and insulin resistance, where hyperglycemia is associated with decreased pancreatic β-cell mass and function. Loss of β-cell mass has variably been attributed to β-cell dedifferentiation and/or death. In recent years, it has been proposed that circulating epigenetically modified DNA fragments arising from β cells might be able to report on the potential occurrence of β-cell death in diabetes. Here, we review published literature of DNA-based β-cell death biomarkers that have been evaluated in human cohorts of islet transplantation, type 1 diabetes, and obesity and type 2 diabetes. In addition, we provide new data on the applicability of one of these biomarkers (cell free unmethylated INS DNA) in adult cohorts across a spectrum from obesity to T2D, in which no significant differences were observed, and compare these findings to those previously published in youth cohorts where differences were observed. Our analysis of the literature and our own data suggest that β-cell death may occur in subsets of individuals with obesity and T2D, however a more sensitive method or refined study designs are needed to provide better alignment of sampling with disease progression events.     

Rheological and morphological properties of high‐density polyethylene and poly(ethylene–octene) blends

The rheological and morphological properties of blends based on high‐density polyethylene (HDPE) and a commercial ethylene–octene copolymer (EOC) produced by metallocene technology were investigated. The rheological properties were evaluated in steady and dynamic shear experiments at 190°C in shear rates ranging from 90 s^?1 to 1500 s^?1 and frequency range between 10^?1 rad/s and 10² rad/s, respectively. These blends presented a high level of homogeneity in the molten state and rheological behavior was generally intermediate to those of the pure components. Scanning electron microscopy (SEM) showed that the blends exhibit dispersed morphologies with EOC domains distributed homogeneously and with particle size inferior to 2 μm. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 2240–2246, 2002     

What is "special" about face perception?

There is growing evidence that face recognition is "special" but less certainty concerning the way in which it is special. The authors review and compare previous proposals and their own more recent hypothesis, that faces are recognized "holistically" (i.e., using relatively less part decomposition than other types of objects). This hypothesis, which can account for a variety of data from experiments on face memory, was tested with 4 new experiments on face perception. A selective attention paradigm and a masking paradigm were used to compare the perception of faces with the perception of inverted faces, words, and houses. Evidence was found of relatively less part-based shape representation for faces. The literatures on machine vision and single unit recording in monkey temporal cortex are also reviewed for converging evidence on face representation. The neuropsychological literature is reviewed for-evidence on the question of whether face representation differs in degree or kind from the representation of other types of objects.     

A high-level application using belief functions for exchanging and managing uncertain events on the road in vehicular ad hoc networks

This article introduces a high-level system using belief functions for exchanging and managing imperfect information about events on the road in vehicular ad hoc networks. The main purpose of this application is to provide the most reliable information for the driver from multiple messages received informing the driver about events on the roads. This system and some variants are tested using a MATLAB? simulator. An implementation with Android smartphones using a Bluetooth technology to exchange the messages is also introduced.     

Assessment on the mechanical,structural, and thermal attributes of green graphene-based water soluble polymer electrolyte composites

In the current study, graphene oxide (GO) was prepared using green chemistry with modified Hummer's method without incorporating sodium nitrate (NaNO₃). Solvent casting was employed to fabricate GO-doped poly(ethylene oxide) (PEO), that is, PEO/GO composites with various proportion of Na₂SO₄ and were then subjected to characterization via advanced spectroscopic techniques for different physicochemical aspects to estimate their potential applications as marketable products. XRD analysis explored that fabricated composites are more crystalline than neat PEO. PEO/GO/Na₂SO₄ composite films offered maximum crystallinity. SEM displayed the same trend. TG/DTA thermogram exposed better thermal stability than pristine polymer. FTIR studies confirmed complexation among hybrid's components. Elongation-at-break and Young's modulus displayed an enhancing behavior with an incremental loading of salt and filler. In terms of mechanical performance, composite of PEO with 0.37 wt % GO and 0.08 g salt was found to be an ideal composition during the course of study. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48376.     

Influence of different viscosity grade cellulose-based polymers on the development of valsartan controlled release tablets

This work is based on formulating and optimizing controlled release (CR) valsartan (160 mg) tablets using different viscosity grades of the cellulosic polymer. The objective was to develop an effective once-daily drug delivery system of this cardiovascular agent. Central composite design was used for designing the formulations. Polymers used were Methocel® K4M, K15M and K100M. Compatibility of excipients with active was studied through FT-IR. Micromeritic properties were determined and formulations exhibiting appropriate flow characteristics were compressed. Swelling behavior and in vitro buoyancy effect were studied and response surface curves were constructed to optimize the formulation. Multi-point dissolution profiles of valsartan CR tablets at pH 1.2, 4.5 and 6.8 were obtained. Model-dependent and model-independent methods were performed including f2, stability test as per ICH guidelines and ANOVA. FT-IR studies revealed the compatibility of valsartan with all excipients. Formulation K4T9 (containing 25% K4M polymer) was selected to be the best optimized trial, based on physical properties and controlled release profile (23% at 4 h, 82% at 16 h and 100% at 24 h). Results of buoyancy and swelling behavior indicated that HPMC-K4M polymer exhibited excellent floating lag time and swelling indexes. In vitro drug release kinetics showed that formulation K4T9 displayed Korsmeyer–Peppas drug release pattern with r value > 0.99. The manufacturing process of K4T9 was also found to be reproducible with a shelf life period of 41 and 36 months at room temperature and accelerated conditions, respectively. Valsartan CR matrix-based formulation was successfully prepared with Methocel K4M retardant.     

Genomics and Epigenomics of Gestational Diabetes Mellitus: Understanding the Molecular Pathways of the Disease Pathogenesis

One of the most common complications during pregnancy is gestational diabetes mellitus (GDM), hyperglycemia that occurs for the first time during pregnancy. The condition is multifactorial, caused by an interaction between genetic, epigenetic, and environmental factors. However, the underlying mechanisms responsible for its pathogenesis remain elusive. Moreover, in contrast to several common metabolic disorders, molecular research in GDM is lagging. It is important to recognize that GDM is still commonly diagnosed during the second trimester of pregnancy using the oral glucose tolerance test (OGGT), at a time when both a fetal and maternal pathophysiology is already present, demonstrating the increased blood glucose levels associated with exacerbated insulin resistance. Therefore, early detection of metabolic changes and associated epigenetic and genetic factors that can lead to an improved prediction of adverse pregnancy outcomes and future cardio-metabolic pathologies in GDM women and their children is imperative. Several genomic and epigenetic approaches have been used to identify the genes, genetic variants, metabolic pathways, and epigenetic modifications involved in GDM to determine its etiology. In this article, we explore these factors as well as how their functional effects may contribute to immediate and future pathologies in women with GDM and their offspring from birth to adulthood. We also discuss how these approaches contribute to the changes in different molecular pathways that contribute to the GDM pathogenesis, with a special focus on the development of insulin resistance.     

Differential Metabotypes in Synovial Fibroblasts and Synovial Fluid in Hip Osteoarthritis Patients Support Inflammatory Responses

Changes in cellular metabolism have been implicated in mediating the activated fibroblast phenotype in a number of chronic inflammatory disorders, including pulmonary fibrosis, renal disease and rheumatoid arthritis. The aim of this study was therefore to characterise the metabolic profile of synovial joint fluid and synovial fibroblasts under both basal and inflammatory conditions in a cohort of obese and normal-weight hip OA patients. Furthermore, we sought to ascertain whether modulation of a metabolic pathway in OA synovial fibroblasts could alter their inflammatory activity. Synovium and synovial fluid was obtained from hip OA patients, who were either of normal-weight or obese and were undergoing elective joint replacement surgery. The synovial fluid metabolome was determined by 1H NMR spectroscopy. The metabolic profile of isolated synovial fibroblasts in vitro was characterised by lactate secretion, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using the Seahorse XF Analyser. The effects of a small molecule pharmacological inhibitor and siRNA targeted at glutaminase-1 (GLS1) were assessed to probe the role of glutamine metabolism in OA synovial fibroblast function. Obese OA patient synovial fluid (n = 5) exhibited a different metabotype, compared to normal-weight patient fluid (n = 6), with significantly increased levels of 1, 3-dimethylurate, N-Nitrosodimethylamine, succinate, tyrosine, pyruvate, glucose, glycine and lactate, and enrichment of the glutamine–glutamate metabolic pathway, which correlated with increasing adiposity. In vitro, isolated obese OA fibroblasts exhibited greater basal lactate secretion and aerobic glycolysis, and increased mitochondrial respiration when stimulated with pro-inflammatory cytokine TNFα, compared to fibroblasts from normal-weight patients. Inhibition of GLS1 attenuated the TNFα-induced expression and secretion of IL-6 in OA synovial fibroblasts. These findings suggest that altered cellular metabolism underpins the inflammatory phenotype of OA fibroblasts, and that targeted inhibition of glutamine–glutamate metabolism may provide a route to reducing the pathological effects of joint inflammation in OA patients who are obese.     

Involvement of GPx-3 in the Reciprocal Control of Redox Metabolism in the Leukemic Niche

The bone marrow (BM) microenvironment plays a crucial role in the development and progression of leukemia (AML). Intracellular reactive oxygen species (ROS) are involved in the regulation of the biology of leukemia-initiating cells, where the antioxidant enzyme GPx-3 could be involved as a determinant of cellular self-renewal. Little is known however about the role of the microenvironment in the control of the oxidative metabolism of AML cells. In the present study, a coculture model of BM mesenchymal stromal cells (MSCs) and AML cells (KG1a cell-line and primary BM blasts) was used to explore this metabolic pathway. MSC-contact, rather than culture with MSC-conditioned medium, decreases ROS levels and inhibits the Nrf-2 pathway through overexpression of GPx3 in AML cells. The decrease of ROS levels also inactivates p38MAPK and reduces the proliferation of AML cells. Conversely, contact with AML cells modifies MSCs in that they display an increased oxidative stress and Nrf-2 activation, together with a concomitant lowered expression of GPx-3. Altogether, these experiments suggest that a reciprocal control of oxidative metabolism is initiated by direct cell–cell contact between MSCs and AML cells. GPx-3 expression appears to play a crucial role in this cross-talk and could be involved in the regulation of leukemogenesis.