In-Silico Analysis of rSNPsin miRNA:mRNA Duplex Involved in Insulin Signaling Genes Shows a Possible Pathogenesis of Insulin Resistance

Background: Insulin resistance is a condition in which the body produces insulin but is unable to use it effectively. Aberrations in insulin signaling are known to play a crucial role in pathogenesis of this disease state. Eventually patients will have glucose build up in their blood instead of being absorbed by the cells, leading to type 2 diabetes. Objective: In the current study we focus on understanding the role of rSNP mediated miRNA:mRNA dysregulation and its impact on the above metabolic condition. Methods: More than 30 genes involved in insulin signaling pathway were found using KEGG database. The 3’UTR end of genes was studied by using RegRNA and Ensembl, whereas TargetScan along with miRbase were used to identify their target miRNAs.Binding free energy was used as a parameter to analyze the affect of polymorphism on the miRNA:mRNA duplex formation.Further, UNA fold was used to determine the heat capacity changes. Results: The following genes INSR, INS, GLUT4, FOXO1, IL6, TRIB3 and SREBF1 were selected for analysis. Multiple miRNAs, hsa-miR-16-5p, hsa-miR-15a-15p were identified in the SNP occurring region for INSR. INS too showed similar results.INSR, INS and TRIB3 were found to have the maximum change in their binding free energy due to rSNP variation. A destabilisation in the heat capacity values was observed too, contributed due to rSNP induction. Conclusion: A direct relationship between miRNA target polymorphism and the stability of the miRNA:mRNA duplex was observed. The current methodology used to study insulin resistance pathogenesis could elaborate on our existing knowledge of miRNA mediated disease states.

Revealing thermodynamics of DNA origami folding via affine transformations

Structural DNA nanotechnology, as exemplified by DNA origami, has enabled the design and construction of molecularly-precise objects for a myriad of applications. However, limitations in imaging, and other characterization approaches, make a quantitative understanding of the folding process challenging. Such an understanding is necessary to determine the origins of structural defects, which constrain the practical use of these nanostructures. Here, we combine careful fluorescent reporter design with a novel affine transformation technique that, together, permit the rigorous measurement of folding thermodynamics. This method removes sources of systematic uncertainty and resolves problems with typical background-correction schemes. This in turn allows us to examine entropic corrections associated with folding and potential secondary and tertiary structure of the scaffold. Our approach also highlights the importance of heat-capacity changes during DNA melting. In addition to yielding insight into DNA origami folding, it is well-suited to probing fundamental processes in related self-assembling systems.

Thermodynamics of DNA: heat capacity changes on duplex unfolding

The heat capacity change, ΔCp, accompanying the folding/unfolding of macromolecules reflects their changing state of hydration. Thermal denaturation of the DNA duplex is characterized by an increase in ΔCp but of much lower magnitude than observed for proteins. To understand this difference, the changes in solvent accessible surface area (ΔASA) have been determined for unfolding the B-form DNA duplex into disordered single strands. These showed that the polar component represents ~ 55% of the total increase in ASA, in contrast to globular proteins of similar molecular weight for which the polar component is only about 1/3rd of the total. As the exposure of polar surface results in a decrease of ΔCp, this explains the much reduced heat capacity increase observed for DNA and emphasizes the enhanced role of polar interactions in maintaining duplex structure. Appreciation of a non-zero ΔCp for DNA has important consequences for the calculation of duplex melting temperatures (Tm). A modified approach to Tm prediction is required and comparison is made of current methods with an alternative protocol.

Whole-body cryostimulation impact on blood serum thermal denaturation profiles of cross-country skiers

Blood plasma and serum are important diagnostic materials as they clearly reflect an individual’s metabolism. The study has evaluated the effect of whole-body cryostimulation (WBC) on the blood serum of professional cross-country skiers. The experiment involved eight athletes (two women and six men) who underwent a series of ten WBC treatments. Aqueous solutions of human blood serum samples before WBC procedures, after one treatment and after a series of ten treatments were measured by means of differential scanning calorimetry (DSC), a relatively novel diagnostic tool. DSC results showed rather little impact of cryostimulation on heat capacity changes accompanying the process of thermal denaturation of blood serum proteins in elite athletes. However, the statistically significant reduction in the intensity of the serum denaturation transition in its low temperature range has been observed after ten WBC treatments. The results have been interpreted by changes in the serum proteome profile, notably in the ratio of ligated to unligated albumin molecules. As a side result, the relationships between the relative change in body fat mass after ten WBC treatments and the levels of alpha2-globulins and beta2-globulins fractions have been found.

A conformationally adaptive macrocycle: conformational complexity and host–guest chemistry of zorb[4]arene

Large amplitude conformational change is one of the features of biomolecular recognition and is also the basis for allosteric effects and signal transduction in functional biological systems. However, synthetic receptors with controllable conformational changes are rare. In this article, we present a thorough study on the host–guest chemistry of a conformationally adaptive macrocycle, namely per-O-ethoxyzorb[4]arene (ZB4). Similar to per-O-ethoxyoxatub[4]arene, ZB4 is capable of accommodating a wide range of organic cations. However, ZB4 does not show large amplitude conformational responses to the electronic substituents on the guests. Instead of a linear free-energy relationship, ZB4 follows a parabolic free-energy relationship. This is explained by invoking the influence of secondary C–H···O hydrogen bonds on the primary cation···π interactions based on the information obtained from four representative crystal structures. In addition, heat capacity changes (ΔC p) and enthalpy–entropy compensation phenomena both indicate that solvent reorganization is also involved during the binding. This research further deepens our understanding on the binding behavior of ZB4 and lays the basis for the construction of stimuli-responsive materials with ZB4 as a major component.