Gut Microbiota and Short Chain Fatty Acids: Implications in Glucose Homeostasis

Gut microbiota encompasses a wide variety of commensal microorganisms consisting of trillions of bacteria, fungi, and viruses. This microbial population coexists in symbiosis with the host, and related metabolites have profound effects on human health. In this respect, gut microbiota plays a pivotal role in the regulation of metabolic, endocrine, and immune functions. Bacterial metabolites include the short chain fatty acids (SCFAs) acetate (C2), propionate (C3), and butyrate (C4), which are the most abundant SCFAs in the human body and the most abundant anions in the colon. SCFAs are made from fermentation of dietary fiber and resistant starch in the gut. They modulate several metabolic pathways and are involved in obesity, insulin resistance, and type 2 diabetes. Thus, diet might influence gut microbiota composition and activity, SCFAs production, and metabolic effects. In this narrative review, we discuss the relevant research focusing on the relationship between gut microbiota, SCFAs, and glucose metabolism.     

Deep Resequencing of 9 Candidate Genes Identifies a Role for ARAP1 and IGF2BP2 in Modulating Insulin Secretion Adjusted for Insulin Resistance in Obese Southern Europeans

Type 2 diabetes is characterized by impairment in insulin secretion, with an established genetic contribution. We aimed to evaluate common and low-frequency (1–5%) variants in nine genes strongly associated with insulin secretion by targeted sequencing in subjects selected from the extremes of insulin release measured by the disposition index. Collapsing data by gene and/or function, the association between disposition index and nonsense variants were significant, also after adjustment for confounding factors (OR = 0.25, 95% CI = 0.11–0.59, p = 0.001). Evaluating variants individually, three novel variants in ARAP1, IGF2BP2 and GCK, out of eight reaching significance singularly, remained associated after adjustment. Constructing a genetic risk model combining the effects of the three variants, only carriers of the ARAP1 and IGF2BP2 variants were significantly associated with a reduced probability to be in the lower, worst, extreme of insulin secretion (OR = 0.223, 95% CI = 0.105–0.473, p < 0.001). Observing a high number of normal glucose tolerance between carriers, a regression posthoc analysis was performed. Carriers of genetic risk model variants had higher probability to be normoglycemic, also after adjustment (OR = 2.411, 95% CI = 1.136–5.116, p = 0.022). Thus, in our southern European cohort, nonsense variants in all nine candidate genes showed association with better insulin secretion adjusted for insulin resistance, and we established the role of ARAP1 and IGF2BP2 in modulating insulin secretion.     

The Genetic Basis of Primary Myelofibrosis and Its Clinical Relevance

Among classical BCR-ABL-negative myeloproliferative neoplasms (MPN), primary myelofibrosis (PMF) is the most aggressive subtype from a clinical standpoint, posing a great challenge to clinicians. Whilst the biological consequences of the three MPN driver gene mutations (JAK2, CALR, and MPL) have been well described, recent data has shed light on the complex and dynamic structure of PMF, that involves competing disease subclones, sequentially acquired genomic events, mostly in genes that are recurrently mutated in several myeloid neoplasms and in clonal hematopoiesis, and biological interactions between clonal hematopoietic stem cells and abnormal bone marrow niches. These observations may contribute to explain the wide heterogeneity in patients’ clinical presentation and prognosis, and support the recent effort to include molecular information in prognostic scoring systems used for therapeutic decision-making, leading to promising clinical translation. In this review, we aim to address the topic of PMF molecular genetics, focusing on four questions: (1) what is the role of mutations on disease pathogenesis? (2) what is their impact on patients’ clinical phenotype? (3) how do we integrate gene mutations in the risk stratification process? (4) how do we take advantage of molecular genetics when it comes to treatment decisions?     

A DNA Methyltransferase Modulator Inspired by Peyssonenyne Natural Product Structures

A novel epigenetic modulator that displays a DNMT1 inhibition and DNMT3A activation profile was characterized (compound 8 ). This compound is a derivative of palmitic acid that incorporates the putative reactive functional group (diynone) of the peyssonenyne natural products. Other analogues containing the diynone or an acetoxyenediyne did not show the same biological profile. In U937 human leukemia cells, diynone 8 induced cell differentiation and apoptosis, which correlated with the expression of Fas protein. Very surprisingly, diynone 8 was toxic to normal human fibroblasts (BJ) and mouse embryo fibroblasts (MEF), but not to immortalized human fibroblasts (BJEL); this unique effect was not observed with the classical DNMT inhibitor 5‐azacytidine. Therefore, compound 8 interferes in a very specific manner with signaling pathways, the activities of which differ between normal and immortalized cell types. This toxicity is reminiscent of the effects of Dnmt1 ablation on mouse fibroblasts. In fact, some of the genes deregulated by the loss of Dnmt1 are similarly deregulated by 8 , but not by the DNMT inhibitor SGI‐1027.     

Electroactive Ionic Soft Actuators with Monolithically Integrated Gold Nanocomposite Electrodes

Electroactive ionic gel/metal nanocomposites are produced by implanting supersonically accelerated neutral gold nanoparticles into a novel chemically crosslinked ion conductive soft polymer. The ionic gel consists of chemically crosslinked poly(acrylic acid) and polyacrylonitrile networks, blended with halloysite nanoclays and imidazolium‐based ionic liquid. The material exhibits mechanical properties similar to that of elastomers (Young's modulus ≈ 0.35 MPa) together with high ionic conductivity. The fabrication of thin (≈100 nm thick) nanostructured compliant electrodes by means of supersonic cluster beam implantation (SCBI) does not significantly alter the mechanical properties of the soft polymer and provides controlled electrical properties and large surface area for ions storage. SCBI is cost effective and suitable for the scaleup manufacturing of electroactive soft actuators. This study reports the high‐strain electromechanical actuation performance of the novel ionic gel/metal nanocomposites in a low‐voltage regime (from 0.1 to 5 V), with long‐term stability up to 76 000 cycles with no electrode delamination or deterioration. The observed behavior is due to both the intrinsic features of the ionic gel (elasticity and ionic transport capability) and the electrical and morphological features of the electrodes, providing low specific resistance (<100 Ω cm^?2), high electrochemical capacitance (≈mF g^?1), and minimal mechanical stress at the polymer/metal composite interface upon deformation.     

Multi-hazard loss analysis of tall buildings under wind and seismic loads

This paper presents a framework for life-cycle loss estimation for non-structural damage in tall buildings under wind and seismic loads. Life-cycle cost analysis is a useful design tool for decision- makers, aimed at predicting monetary losses over the lifetime of a structure, accounting for uncertainties involved in the problem definition. For tall buildings, sensitive to dynamic excitations like earthquake and wind, it can be particularly suitable to base design decisions not only on initial cost and performance but also on future repair expenses. The proposed approach harmonises the procedures for intervention costs evaluation of structures subjected to multiple-hazards, taking into account the peculiar differences of wind and earthquake, in terms of load characterisation, type and evolution of damage. Relative effect of the two hazards on damage to drift- and acceleration-sensitive non-structural elements are examined. The influence of uncertainty in structural damping is also taken into account. It is shown that, although it is commonly believed that the design of a given structure is usually dominated by either winds or earthquakes, when LCC-based design is performed, both winds and earthquakes may be important.     

Effectiveness of rank correlations in curvilinear relationships

Behaviormetrika - In cases where only linear relationships are suspected, Pearson’s correlation is generally used to measure the strength of the association between variables. It is...     

Risks and benefits related to alimentary exposure to xenoestrogens

Xenoestrogens are widely diffused in the environment and in food, thus a large portion of human population worldwide is exposed to them. Among alimentary xenoestrogens, phytoestrogens (PhyEs) are increasingly being consumed because of their potential health benefits, although there are also important risks associated to their ingestion. Furthermore, other xenoestrogens that may be present in food are represented by other chemicals possessing estrogenic activities, that are commonly defined as endocrine disrupting chemicals (EDCs). EDCs pose a serious health concern since they may cause a wide range of health problems, starting from pre-birth till adult lifelong exposure. We herein provide an overview of the main classes of xenoestrogens, which are classified on the basis of their origin, their structures and their occurrence in the food chain. Furthermore, their either beneficial or toxic effects on human health are discussed in this review.     

Effect of geometry and green density on the anisotropic sintering shrinkage of axisymmetric iron parts

Sintering shrinkage of prior cold compacted iron rings with different geometry (height to wall thickness ratio) and green density in the 6.5–7.3?g/cm³ range was investigated. It displays a minimum at an intermediate green density. Axial, tangential and radial shrinkages are different, due to the gradients of green density along the axial and the radial directions. Therefore, the effect of height on shrinkage and its anisotropy is the result of their effect on the stress distribution in the green parts during cold compaction, and the resulting green density and deformation experienced by the powder. Anisotropy decreases on increasing shrinkage.