Prospects for the convergence of polyphenols with pharmaceutical drugs in Type 2 Diabetes: challenges, risks, and strategies.

Type 2 diabetes mellitus (T2DM) is a complex disease that can lead to a variety of life-threatening secondary health conditions. Current treatment strategies primarily revolve around tight glucose control that is difficult to achieve and often turns out to be dangerous due to possible hypoglycemic events. Numerous long-term studies have demonstrated that complex pathways, including low-grade inflammation due to fluctuating glucose levels, are involved in the progression of the disease and the development of secondary health conditions. Growing clinical evidence supports the effectiveness of using multiple medications, possibly in combination with insulin, to effectively manage T2DM. On the other hand, despite the huge, largely untapped potential therapeutic benefit of 'polyphenols', there remains a general skepticism of the practice. However, for any evidence-based clinical intervention, the balance of benefits and risks takes center stage and is governed by biopharmaceutics principles. In this article, we outline the current clinical perspectives on pharmaceutical drug combinations, rationale for early initiation of insulin, and the advantages of novel dosage forms to meet the pathophysiological changes of T2DM, emphasizing the need for further clinical studies to substantiate these approaches. We also make the case for traditional medicines and their combinations with pharmaceutical drugs and outline the inherent challenges in doing so, while also providing recommendations for future research and clinical practice. Significance Statement Type 2 diabetes is associated with life-threatening secondary health conditions that are often difficult to treat. This review provides an in-depth account of preventing/delaying secondary health conditions through combination therapies and emphasizes the role of effective delivery strategies in realizing the translation of such combinations. We will build the case for the importance of polyphenols in diabetes, determine the reasons for skepticism, and potential combinations with pharmaceutical drugs.

A new oral model of free fatty acid kinetics to assess lipolysis in subjects with and without type 2 diabetes.

Assessing free fatty acids (FFAs) kinetics and the role of insulin and glucose on FFA lipolysis and disposal may improve our understanding of the pathogenesis of type 2 diabetes (T2D). Some models have been proposed to describe FFA kinetics during an intravenous glucose tolerance test and only one during an oral glucose tolerance test. Here, we propose a model of FFA kinetics during a meal tolerance test and use it to assess possible differences in postprandial lipolysis in individuals with type 2 diabetes (T2D) and individuals with obesity without type 2 diabetes (ND). We studied 18 obese ND and 16 T2D undergoing three meal tolerance tests (MTT) on three occasions (breakfast, lunch, and dinner). We used plasma glucose, insulin, and FFA concentrations collected at breakfast to test a battery of models and selected the best one based on physiological plausibility, ability to fit the data, precision of parameter estimates, and the Akaike parsimony criterion. The best model assumes that the postprandial suppression of FFA lipolysis is proportional to the above basal insulin, while FFA disposal is proportional to FFA concentration. It was used to compare FFA kinetics in ND and T2D along the day. The maximum lipolysis suppression occurred significantly earlier in ND than T2D (39 ± 6 min vs. 102 ± 13 min, 36 ± 4 min vs. 78 ± 11 min, and 38 ± 6 min vs. 84 ± 13 min, P < 0.01, at breakfast, lunch, and dinner, respectively), making lipolysis significantly lower in ND than T2D. This is mainly attributable to the lower insulin concentration in the second group. This novel FFA model allows to assess lipolysis and insulin antilipolytic effect in postprandial conditions.NEW & NOTEWORTHY In this study, we propose a new mathematical model able to quantify postprandial FFA kinetics and adipose tissue insulin sensitivity in both subjects with obesity without type 2 diabetes (ND) and subjects with type 2 diabetes (T2D). Results show that the slower postprandial suppression of lipolysis in T2D contributes to the higher free fatty acid (FFA) concentration that, in turn, may contribute to hyperglycemia.

Block copolymer self-assembly to pattern gold nanodots for site-specific placement of DNA origami and attachment of nanomaterials.

Directed placement of DNA origami could play a key role in future integrated nanoelectronic devices. Here we demonstrated the site-selective attachment of DNA origami on gold dots formed using a pattern transfer method through block copolymer self-assembly. First, a random copolymer brush layer is grafted on the Si surface and then poly (styrene-b-methylmethacrylate) block copolymer is spin-coated to give a hexagonal nanoarray after annealing. UV irradiation followed by acetic acid etching is used to remove the PMMA, creating cylindrical holes and then oxygen plasma etching removes the random copolymer layer inside those holes. Next, metal evaporation, followed by lift-off creates a gold dot array. We evaluated different ligand functionalization of Au dots, as well as DNA hybridization to attach DNA origami to the nanodots. DNA-coated Au nanorods are assembled on the DNA origami as a step towards creating nanowires and to facilitate electron microscopy characterization of the attachment of DNA origami on these Au nanodots. The DNA hybridization approach showed better DNA attachment to Au nanodots than localization by electrostatic interaction. This work contributes to the understanding of DNA-templated assembly, nanomaterials, and block copolymer nanolithography. Furthermore, the work shows potential for creating DNA-templated nanodevices and their placement in ordered arrays in future nanoelectronics.

Design of multi neutron-to-gamma converter array for measuring time resolved ion temperature of inertial confinement fusion implosions.

The ion temperature varying during inertial confinement fusion implosions changes the amount of Doppler broadening of the fusion products, creating subtle changes in the fusion neutron pulse as it moves away from the implosion. A diagnostic design to try to measure these subtle effects is introduced-leveraging the fast time resolution of gas Cherenkov detectors along with a multi-puck array that converts a small amount of the neutron pulse into gamma-rays, one can measure multiple snapshots of the neutron pulse at intermediate distances. Precise measurements of the propagating neutron pulse, specifically the variation in the peak location and the skew, could be used to infer time-evolved ion temperature evolved during peak compression.

Bottom-Up Fabrication of DNA-Templated Electronic Nanomaterials and Their Characterization.

Bottom-up fabrication using DNA is a promising approach for the creation of nanoarchitectures. Accordingly, nanomaterials with specific electronic, photonic, or other functions are precisely and programmably positioned on DNA nanostructures from a disordered collection of smaller parts. These self-assembled structures offer significant potential in many domains such as sensing, drug delivery, and electronic device manufacturing. This review describes recent progress in organizing nanoscale morphologies of metals, semiconductors, and carbon nanotubes using DNA templates. We describe common substrates, DNA templates, seeding, plating, nanomaterial placement, and methods for structural and electrical characterization. Finally, our outlook for DNA-enabled bottom-up nanofabrication of materials is presented.

Seeding, Plating and Electrical Characterization of Gold Nanowires Formed on Self-Assembled DNA Nanotubes.

Self-assembly nanofabrication is increasingly appealing in complex nanostructures, as it requires fewer materials and has potential to reduce feature sizes. The use of DNA to control nanoscale and microscale features is promising but not fully developed. In this work, we study self-assembled DNA nanotubes to fabricate gold nanowires for use as interconnects in future nanoelectronic devices. We evaluate two approaches for seeding, gold and palladium, both using gold electroless plating to connect the seeds. These gold nanowires are characterized electrically utilizing electron beam induced deposition of tungsten and four-point probe techniques. Measured resistivity values for 15 successfully studied wires are between 9.3 × 10-6 and 1.2 × 10-3 Ωm. Our work yields new insights into reproducible formation and characterization of metal nanowires on DNA nanotubes, making them promising templates for future nanowires in complex electronic circuitry.

Impact of Polymer-Constrained Annealing on the Properties of DNA Origami-Templated Gold Nanowires.

DNA origami-templated fabrication enables bottom-up fabrication of nanoscale structures from a variety of functional materials, including metal nanowires. We studied the impact of low-temperature annealing on the morphology and conductance of DNA-templated nanowires. Nanowires were formed by selective seeding of gold nanorods on DNA origami and gold electroless plating of the seeded structures. At low annealing temperatures (160 °C for seeded-only and 180 °C for plated), the wires broke up and separated into multiple, isolated islands. Through the use of polymer-constrained annealing, the island formation in plated wires was suppressed up to annealing temperatures of 210 °C. Four-point electrical measurements showed that the wires remained conductive after a polymer-constrained annealing at 200 °C.

Thermo-mechanical characterization of NiTi orthodontic archwires with graded actuating forces.

Functionally graded NiTi orthodontic archwire was tested to assess the evolution of the actuation force as a function of the temperature. Varying actuation forces on the same orthodontic wire allow the optimization of repositioning of the different types of teeth, according its radicular support. The wire was separated into three segments: Incisive, Premolar and Molar. The functionally graded NiTi orthodontic archwire segments have distinct structural and mechanical behavior as confirmed by differential scanning calorimetry, synchrotron-based X-ray diffraction, and thermomechanical analysis. The mechanical behavior was analyzed by three-point bending tests at four different temperatures (5, 20, 25 and 37 °C). In parallel, three-point bending tests were performed by TMA analysis in a temperature range from 5 °C (from cold water) to 40 °C (hot meal). This study showed the comparison of the different segments on the same archwire, providing a better understanding of the behavior of these functionally graded materials.

An ensemble model for forecasting infectious diseases in India.

Time series modelling and forecasting plays an important role in various domains. The objective of this paper is to construct a simple average ensemble method to forecast the number of cases for infectious diseases like dengue and typhoid and compare it by applying models for forecasting. In this paper we have also evaluated the correlation between the number of typhoid and dengue cases with the ecological variables. The monthly data of dengue and typhoid cases from 2014 to 2017 were taken from integrated diseases surveillance programme, Government of India. This data was analysed by three models namely support vector regression, neural network and linear regression. The proposed simple average ensemble model was constructed by ensemble of three applied regression models i.e. SVR, NN and LR. We combine the regression models based upon the error metrics such as Mean Square Error, Root Mean Square Error and Mean Absolute Error. It was found that proposed ensemble method performed better in terms of forecast measures. The finding demonstrates that the proposed model outperforms as compared to already available applied models on the basis of forecast accuracy.

Four-Point Probe Electrical Measurements on Templated Gold Nanowires Formed on Single DNA Origami Tiles.

Bottom-up nanofabrication is increasingly making use of self-assembled DNA to fabricate nanowires and potential integrated circuits, although yields of such electronic nanostructures are inadequate, as is the ability to reliably make electrical measurements on them. In this paper, we report improved yields and unprecedented conductivity measurements for Au nanowires created on DNA origami tile substrates. We created several different self-assembled Au nanowire arrangements on DNA origami tiles that are approximately 70 nm × 90 nm, through anisotropic growth of Au nanorods attached to specific sites. Modifications to the tile design increased yields of the final desired nanostructures as much as 6-fold. In addition, we measured the conductivity of Au nanowires created on these DNA tiles (∼130 nm long, 10 nm diameter, and 40 nm spacing between measurement points) with a four-point measurement technique that utilized electron beam induced metal deposition to form probe electrodes. These nanowires formed on single DNA origami tiles were electrically conductive, having resistivities as low as 4.24 × 10-5 Ω m. This work demonstrates the creation and measurement of inorganic nanowires on single DNA origami tiles as a promising path toward future bottom-up fabrication of nanoelectronics.

Directional Growth of DNA-Functionalized Nanorods to Enable Continuous, Site-Specific Metallization of DNA Origami Templates.

This work examines the anisotropic electroless plating of DNA-functionalized gold nanorods attached to a DNA origami template to fabricate continuous metal structures of rectanglar, square, and T shapes. DNA origami, a versatile method for assembling a variety of 2- and 3-D nanostructures, is utilized to construct the DNA breadboard template used for this study. Staple strands on selective sites of the breadboard template are extended with an additional nucleotide sequence for the attachment of DNA-functionalized gold nanorods to the template via base pairing. The nanorod-seeded DNA templates are then introduced into an electroless gold plating solution to determine the extent to which the anisotropic growth of the nanorods is able to fill the gaps between seeds to create continuous structures. Our results show that the DNA-functionalized nanorods grow anisotropically during plating at a rate that is approximately 4 times faster in the length direction than in the width direction to effectively fill gaps of up to 11-13 nm in length. The feasibility of using this directional growth at specific sites to enable the fabrication of continuous metal nanostructures with diameters as thin as 10 nm is demonstrated and represents important progress toward the creation of devices and systems based on self-assembled biological templates.

Potency dependent activity of homeopathic nanomedicine- classical and quantum electrodynamical approach

The effect of homeopathic medicine on biological and physical system is directly related to its potency [1]. However, from physico-chemical point of view it is difficult to explain this effect at such high dilution, as then the existence of even trace amount of particle is questionable. It has been reported that during the process of potentization, a large amount of mechanical energy gets transferred to the medium due to succussion [2]. This energy in all probability reduces the size of the drug aggregates. The drug then penetrates easily through the membrane barrier, and thereby gives rise to enhanced activity of the medicine. It has been experimentally proved by us and supported by others that indeed a reduction of size of the aggregates takes place with increase in potency [3]. Using five different homeopathic medicines, their sizes at three different potencies have been estimated and a general mathematical expression relating the size of the particle (Y) and the corresponding potency (X) has been derived as follows Y = a X -n. (AU)

Synthesis and characterization of Cu/Ag nanoparticle loaded mullite nanocomposite system: A potential candidate for antimicrobial and therapeutic applications.

BACKGROUND: Microbial resistance to antibiotics has triggered the development of nanoscale materials as an alternative strategy. To stabilize these particles an inert support is needed. METHOD: Porous nanomullite developed by sol-gel route is loaded with copper and silver nanoparticle by simple adsorption method. These nanocomposites are characterized using XRD, FTIR, TEM, SEM, EDAX and UV-visible spectrophotometer. Antibacterial activity of these nanocomposites against Gram positive and Gram negative bacteria are performed by bactericidal kinetics, flow cytometry and MTT assay. The underlying mechanisms behind the antimicrobial property and cell death are also investigated by EPR spectroscopy, intracellular ROS measurement and ß-galactosidase assay. The cytocompatibility of the nanocomposites is investigated by cell viability (MTT), proliferation (Alamar blue) and wound healing assay of mammalian fibroblast cell line. RESULTS: Nanocomposites show a fairly uniform distribution of metal nanoparticle within mullite matrix. They show excellent antibacterial activity. Metal ions/nanoparticle is found to be released from the materials (CM and SM). Treated cells manifested high intracellular oxidative stress and ß-galactosidase activity in the growth medium. The effect of nanocomposites on mammalian cell line depends on exposure time and concentration. The scratch assay shows normal cell migration with respect to control. CONCLUSION: The fabricated nanoparticles possess diverse antimicrobial mechanism and exhibit good cytocompatibility along with wound healing characteristics in mouse fibroblast cell line (L929). GENERAL SIGNIFICANCE: The newly synthesized materials are promising candidates for the development of antimicrobial ceramic coatings for biomedical devices and therapeutic applications.

Studies of nanocomposites of carbon nanotubes and a negative dielectric anisotropy liquid crystal.

It has been widely recognized that the combination of carbon nanotube (CNT) and liquid crystals (LCs) not only provides a useful way to align CNTs, but also dramatically enhances the order in the LC phases, which is especially useful in liquid crystal display (LCD) technology. As the measure of this phase behavior, the complex specific heat is presented over a wide temperature range for a negative dielectric anisotropy alkoxyphenylbenzoate liquid crystal (9OO4) and CNT composites as a function of CNT concentration. The calorimetric scans were performed under near-equilibrium conditions between 25 and 95 °C, first cooling and then followed by heating for CNT weight percent ranging from ϕ(w) = 0 to 0.2. All 9OO4/CNT mesophases have transition temperatures ~1 K higher and a crystallization temperature 4 K higher than that of the pure 9OO4. The crystal phase superheats until a strongly first-order specific heat feature is observed, 0.5 K higher than in the pure 9OO4. The transition enthalpy for the nanocomposite mesophases is 10% lower than that observed in the pure 9OO4. The strongly first-order crystallization and melting transition enthalpies are essentially constant over this range of ϕ(w). Complementary electroclinic measurement on a 0.05 wt. % sample, cooling towards the smectic-C phase from the smectic-A, indicates that the SmA-SmC transition remains mean-field-like in the presence of the CNTs. Given the homogeneous and random distribution of CNTs in these nanocomposites, we interpret these results as arising from the LC-CNT surface interaction pinning the orientational order uniformly along the CNT, without pinning the position of the 9OO4 molecule, leading to a net ordering effect for all phases. These effects of incorporating CNTs into LCs are likely due to "anisotropic orientational" coupling between CNT and LC, the change in the elastic properties of composites and thermal anisotropic properties of the CNTs.

Peripheral and central nervous system inhibition of 11ß-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384.

ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-(2)H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1-50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens ≥2 mg daily maintained peripheral HSD-1 inhibition ≥88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition ≥81%. No CNS formation of D3 cortisol (the mass-labeled product of HSD-1) was detected following ABT-384 ≥2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

Assessment of insulin action on carbohydrate metabolism: physiological and non-physiological methods.

Carbohydrate metabolism in humans is regulated by insulin secretion from pancreatic ß-cells and glucose disposal by insulin-sensitive tissues. Insulin facilitates glucose utilization in peripheral tissues and suppresses hepatic glucose production. Any defects in insulin action predispose an individual to glucose intolerance and Type 2 diabetes mellitus. Early detection of defects in insulin action could provide opportunities to prevent or delay progression of the disease state. There are different approaches to assess insulin action. Initial methods, such as peripheral insulin concentration and simple indices, have several limitations. Subsequently, researchers developed methodologies using intravenous glucose infusion to determine glucose fluxes. However, these methodologies are limited by being non-physiological. Newer, innovative techniques that have been developed are more sophisticated and physiological. By modelling glucose kinetics using isotope dilution techniques, several robust parameters can be obtained that are physiologically relevant and sound. This brief review summarizes most of the non-physiological and physiological methodologies used to measure the variables of insulin action.

Effects of 11ß-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis.

The aim of this study was to determine the effect of prolonged 11ß-hydroxysteroid dehydrogenase-1 (11ß-HSD1) inhibition on basal and hormone-stimulated glucose metabolism in fasted conscious dogs. For 7 days prior to study, either an 11ß-HSD1 inhibitor (HSD1-I; n = 6) or placebo (PBO; n = 6) was administered. After the basal period, a 4-h metabolic challenge followed, where glucagon (3×-basal), epinephrine (5×-basal), and insulin (2×-basal) concentrations were increased. Hepatic glucose fluxes did not differ between groups during the basal period. In response to the metabolic challenge, hepatic glucose production was stimulated in PBO, resulting in hyperglycemia such that exogenous glucose was required in HSD-I (P < 0.05) to match the glycemia between groups. Net hepatic glucose output and endogenous glucose production were decreased by 11ß-HSD1 inhibition (P < 0.05) due to a reduction in net hepatic glycogenolysis (P < 0.05), with no effect on gluconeogenic flux compared with PBO. In addition, glucose utilization (P < 0.05) and the suppression of lipolysis were increased (P < 0.05) in HSD-I compared with PBO. These data suggest that inhibition of 11ß-HSD1 may be of therapeutic value in the treatment of diseases characterized by insulin resistance and excessive hepatic glucose production.

Synchronous x-ray and radio mode switches: a rapid global transformation of the pulsar magnetosphere.

Pulsars emit from low-frequency radio waves up to high-energy gamma-rays, generated anywhere from the stellar surface out to the edge of the magnetosphere. Detecting correlated mode changes across the electromagnetic spectrum is therefore key to understanding the physical relationship among the emission sites. Through simultaneous observations, we detected synchronous switching in the radio and x-ray emission properties of PSR B0943+10. When the pulsar is in a sustained radio-"bright" mode, the x-rays show only an unpulsed, nonthermal component. Conversely, when the pulsar is in a radio-"quiet" mode, the x-ray luminosity more than doubles and a 100% pulsed thermal component is observed along with the nonthermal component. This indicates rapid, global changes to the conditions in the magnetosphere, which challenge all proposed pulsar emission theories.

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis.

AIMS/HYPOTHESIS: Acute hyperglycaemia rapidly suppresses endogenous glucose production (EGP) in non-diabetic individuals, mainly by inhibiting glycogenolysis. Loss of this 'glucose effectiveness' contributes to fasting hyperglycaemia in type 2 diabetes. Elevated NEFA levels characteristic of type 2 diabetes impair glucose effectiveness, although the mechanism is not fully understood. Therefore we examined the impact of increasing NEFA levels on the ability of hyperglycaemia to regulate pathways of EGP. METHODS: We performed 4 h 'pancreatic clamp' studies (somatostatin; basal glucagon/growth hormone/insulin) in seven non-diabetic individuals. Glucose fluxes (D-[6,6-(2)H(2)]glucose) and hepatic glycogen concentrations ((13)C magnetic resonance spectroscopy) were quantified under three conditions: euglycaemia, hyperglycaemia and hyperglycaemia with elevated NEFA (HY-NEFA). RESULTS: EGP was suppressed by hyperglycaemia, but not by HY-NEFA. Hepatic glycogen concentration decreased ~14% with prolonged fasting during euglycaemia and increased by ~12% with hyperglycaemia. In contrast, raising NEFA levels in HY-NEFA caused a substantial ~23% reduction in hepatic glycogen concentration. Moreover, rates of gluconeogenesis were decreased with hyperglycaemia, but increased with HY-NEFA. CONCLUSIONS/INTERPRETATION: Increased NEFA appear to profoundly blunt the ability of hyperglycaemia to inhibit net glycogenolysis under basal hormonal conditions.