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It is well known that induction motors consume active and reactive energy from the utility grid to operate; additionally, when a power converter drives the motor, a high content of current harmonics is produced, and both circumstances decrease the utility grid power factor, which later requires to be improved. To this end, this paper presents a novel complete solution through a robust control system employed in a back-to-back topology power converter to deliver, instead of consuming, regulated reactive power toward the main grid, which comes from a capacitor bank in a DC-bus. This salient feature of delivering reactive power, and simultaneously, regulating the speed for an induction motor, becomes one of the contributions of this work to enhance the power factor. The robust converter controller is synthesized in a cascade form, by applying the linearization block control and state-feedback techniques. These techniques are combined with the super-twisting strategy for canceling the nonlinearities and the effect of the external disturbances. The complete system consists of a back-to-back converter, an LCL filter coupled to the main grid for mitigating the current harmonic content, and an induction motor under variable load conditions. Experimental tests expose the performance and robustness of the proposed controller, where a robust control for the reactive power acts under sudden changes in the active power produced through abrupt variations in the motor load., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 ISA. Published by Elsevier Ltd. All rights reserved.)

Peptides represent an increasingly important class of pharmaceutical products. During the last decade or so, acylation with fatty acids has demonstrated considerable success in prolonging the circulating half-life of therapeutic peptides by exploiting the ability of fatty acids to reversibly bind to human serum albumin (HSA), thus significantly impacting their pharmacological profiles. Employing methyl- 13 C-labeled oleic acid or palmitic acid as probe molecules and exploiting HSA mutants designed to probe fatty acid binding, the signals in two-dimensional (2D) nuclear magnetic resonance (NMR) spectra corresponding to high-affinity fatty acid binding sites in HSA were assigned. Subsequently, using a set of selected acylated peptides, competitive displacement experiments by 2D NMR identified a primary fatty acid binding site in HSA utilized in acylated peptide binding. These results represent an important first step toward understanding the structural basis for acylated peptides binding to HSA.

Objective: Ultra-rapid insulin formulations control postprandial hyperglycemia; however, inadequate understanding of injection site absorption mechanisms is limiting further advancement. We used photoacoustic imaging to investigate the injection site dynamics of dye-labeled insulin lispro in the Humalog® and Lyumjev® formulations using the murine ear cutaneous model and correlated it with results from unlabeled insulin lispro in pig subcutaneous injection model., Methods: We employed dual-wavelength optical-resolution photoacoustic microscopy to study the absorption and diffusion of the near-infrared dye-labeled insulin lispro in the Humalog and Lyumjev formulations in mouse ears. We mathematically modeled the experimental data to calculate the absorption rate constants and diffusion coefficients. We studied the pharmacokinetics of the unlabeled insulin lispro in both the Humalog and Lyumjev formulations as well as a formulation lacking both the zinc and phenolic preservative in pigs. The association state of insulin lispro in each of the formulations was characterized using SV-AUC and NMR spectroscopy., Results: Through experiments using murine and swine models, we show that the hexamer dissociation rate of insulin lispro is not the absorption rate-limiting step. We demonstrated that the excipients in the Lyumjev formulation produce local tissue expansion and speed both insulin diffusion and microvascular absorption. We also show that the diffusion of insulin lispro at the injection site drives its initial absorption; however, the rate at which the insulin lispro crosses the blood vessels is its overall absorption rate-limiting step., Conclusions: This study provides insights into injection site dynamics of insulin lispro and the impact of formulation excipients. It also demonstrates photoacoustic microscopy as a promising tool for studying protein therapeutics. The results from this study address critical questions around the subcutaneous behavior of insulin lispro and the formulation excipients, which could be useful to make faster and better controlled insulin formulations in the future., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Competing Interests: There are no conflicts of interest.

Objective: Members of the insulin/insulin-like growth factor (IGF) superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single-chain (sc), i.e., IGF-1-like, forms of the viral insulin/IGF-1-like peptides (VILPs), we previously showed that they can stimulate human receptors. Because these peptides possess potential cleavage sites to form double chain (dc), i.e., more insulin-like, VILPs, in this study, we have characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1) for the first time., Methods: The dcVILPs were chemically synthesized. Using murine fibroblast cell lines overexpressing insulin receptor (IR-A or IR-B) or IGF1R, we first determined the binding affinity of dcVILPs to the receptors and characterized post-receptor signaling. Further, we used C57BL/6J mice to study the effect of dcVILPs on lowering blood glucose. We designed a 3-h dcVILP in vivo infusion experiment to determine the glucose uptake in different tissues., Results: GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A and IR-B) and to the IGF1R, and for the latter, show higher affinity than human insulin. These dcVILPs stimulate IR and IGF1R phosphorylation and post-receptor signaling in vitro and in vivo. Both GIV and SGIV dcVILPs stimulate glucose uptake in mice. In vivo infusion experiments revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP (0.75 nmol/kg/min) stimulated a comparable glucose uptake in heart and skeletal muscle and brown adipose tissue, GIV dcVILP stimulated 2-fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This was associated with increased Akt phosphorylation and glucose transporter type 4 (GLUT4) gene expression compared to insulin in WAT., Conclusions: Our results show that GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action, design new analogs that specifically target the tissues and provide new insights into their potential role in disease., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objective: The continuous endothelium of skeletal muscle (SkM) capillaries regulates insulin's access to skeletal myocytes. Whether impaired transendothelial insulin transport (EIT) contributes to SkM insulin resistance (IR), however, is unknown., Methods: Male and female C57/Bl6 mice were fed either chow or a high-fat diet for 16 weeks. Intravital microscopy was used to measure EIT in SkM capillaries, electron microscopy to assess endothelial ultrastructure, and glucose tracers to measure indices of glucose metabolism., Results: Diet-induced obesity (DIO) male mice were found to have a ~15% reduction in EIT compared with lean mice. Impaired EIT was associated with a 45% reduction in endothelial vesicles. Despite impaired EIT, hyperinsulinemia sustained delivery of insulin to the interstitial space in DIO male mice. Even with sustained interstitial insulin delivery, DIO male mice still showed SkM IR indicating severe myocellular IR in this model. Interestingly, there was no difference in EIT, endothelial ultrastructure, or SkM insulin sensitivity between lean female mice and female mice fed a high-fat diet., Conclusions: These results suggest that, in male mice, obesity results in ultrastructural alterations to the capillary endothelium that delay EIT. Nonetheless, the myocyte appears to exceed the endothelium as a contributor to SkM IR in DIO male mice., (© 2020 The Authors. Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).)

Bovine leukemia virus (BLV) is a retrovirus that infects cattle and is associated with an increase in secondary infections. The objective of this study was to analyze the effect of BLV infection on cell viability, apoptosis and morphology of a bovine mammary epithelial cell line (MAC-T), as well as Toll like receptors (TLR) and cytokine mRNA expression. Our findings show that BLV infection causes late syncytium formation, a decrease in cell viability, downregulation of the anti-apoptotic gene Bcl-2, and an increase in TLR9 mRNA expression. Moreover, we analyzed how this stably infected cell line respond to the exposure to Staphylococcus aureus (S. aureus), a pathogen known to cause chronic mastitis. In the presence of S. aureus, MAC-T BLV cells had decreased viability and decreased Bcl-2 and TLR2 mRNA expression. The results suggest that mammary epithelial cells infected with BLV have altered the apoptotic and immune pathways, probably affecting their response to bacteria and favoring the development of mastitis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Before insulin can stimulate glucose uptake in muscle, it must be delivered to skeletal muscle (SkM) through the microvasculature. Insulin delivery is determined by SkM perfusion and the rate of movement of insulin across the capillary endothelium. The endothelium therefore plays a central role in regulating insulin access to SkM. Nitric oxide (NO) is a key regulator of endothelial function and stimulates arterial vasodilation, which increases SkM perfusion and the capillary surface area available for insulin exchange. The effects of NO on transendothelial insulin efflux (TIE), however, are unknown. We hypothesized that acute reduction of endothelial NO would reduce TIE. However, intravital imaging of TIE in mice revealed that reduction of NO by l- N G -nitro-l-arginine methyl ester (l-NAME) enhanced the rate of TIE by ∼30% and increased total extravascular insulin delivery. This accelerated TIE was associated with more rapid insulin-stimulated glucose lowering. Sodium nitroprusside, an NO donor, had no effect on TIE in mice. The effects of l-NAME on TIE were not due to changes in blood pressure alone, as a direct-acting vasoconstrictor (phenylephrine) did not affect TIE. These results demonstrate that acute NO synthase inhibition increases the permeability of capillaries to insulin, leading to an increase in delivery of insulin to SkM., (© 2018 by the American Diabetes Association.)

Before insulin can stimulate myocytes to take up glucose, it must first move from the circulation to the interstitial space. The continuous endothelium of skeletal muscle (SkM) capillaries restricts insulin's access to myocytes. The mechanism by which insulin crosses this continuous endothelium is critical to understand insulin action and insulin resistance; however, methodological obstacles have limited understanding of endothelial insulin transport in vivo. Here, we present an intravital microscopy technique to measure the rate of insulin efflux across the endothelium of SkM capillaries. This method involves development of a fully bioactive, fluorescent insulin probe, a gastrocnemius preparation for intravital microscopy, an automated vascular segmentation algorithm, and the use of mathematical models to estimate endothelial transport parameters. We combined direct visualization of insulin efflux from SkM capillaries with modeling of insulin efflux kinetics to identify fluid-phase transport as the major mode of transendothelial insulin efflux in mice. Model-independent experiments demonstrating that insulin movement is neither saturable nor affected by insulin receptor antagonism supported this result. Our finding that insulin enters the SkM interstitium by fluid-phase transport may have implications in the pathophysiology of SkM insulin resistance as well as in the treatment of diabetes with various insulin analogs.

The secretin-like, class B1 subfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and use a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via an N-terminal extracellular domain that forms a hydrophobic ligand-binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogs of several class B1 ligands for therapeutic use. Among the most accepted of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multifunctional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of polypharmacologic ligands. Furthermore, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complexes with either native ligands or multifunctional agonists are provided, supporting the pharmacological basis of such therapeutic agents. [ABSTRACT FROM AUTHOR]

We recently showed that the ratio of capillaries to myofibers in skeletal muscle, which accounts for 80% of insulindirected glucose uptake and metabolism, was reduced in baboon fetuses in which estrogen was suppressed by maternal letrozole administration. Since vascular endothelial growth factor (VEGF) promotes angiogenesis, the present study determined the impact of estrogen deprivation on fetal skeletal muscle VEGF expression, capillary development, and long-term vascular and metabolic function in 4- to 8-year-old adult offspring. Maternal baboons were untreated or treated with letrozole or letrozole plus estradiol on days 100-164 of gestation (term = 184 days). Skeletal muscle VEGF protein expression was suppressed by 45% (P < 0.05) and correlated (P = 0.01) with a 47% reduction (P < 0.05) in the number of capillaries per myofiber area in fetuses of baboons in which serum estradiol levels were suppressed 95% (P < 0.01) by letrozole administration. The reduction in fetal skeletal muscle microvascularization was associated with a 52% decline (P = 0.02) in acetylcholine-induced brachial artery dilation and a 23% increase (P = 0.01) in mean arterial blood pressure in adult progeny of letrozole-treated baboons, which was restored to normal by letrozole plus estradiol. The present study indicates that estrogen upregulates skeletal muscle VEGF expression and systemic microvessel development within the fetus as an essential programming event critical for ontogenesis of systemic vascular function and insulin sensitivity/glucose homeostasis after birth in primate offspring. [ABSTRACT FROM AUTHOR]

Capillary zone electrophoresis was successfully applied, for the first time, to the chiral separation of structurally related sulfonium ions, using sodium phosphate buffer pH 2.5 with β-cyclodextrin (β-CD) or sulfated-β-cyclodextrin (S-β-CD) as the chiral selector with tetrabutylammonium bromide (TBA). For this study, a series of structurally related sulfonium ions in which one of the alkyl chains varied in length were synthesized from a common sulfide. The resolution of the ions was found to be dependent on the type of cyclodextrin used, the presence or absence of TBA, and the structure of the sulfonium ion. β-CD was found to be effective only for ions containing two aromatic groups, while the S-β-CD was effective only for ions containing one aromatic group. The chiral separation of thiophenium ions was also studied under the conditions established. Chiral separation of sulfonium ions in a binary buffer system containing methanol was explored as well. Separations were achieved for all but one sulfonium ion and one thiophenium ion. The data presented show the effectiveness of the enantiomeric separation using CZE with cyclodextrin-modified buffer for these types of ions.

Diabetic nephropathy (DN) is one of the most frequent complications of diabetes. Early stages of DN are associated with hyperinsulinemia and progressive insulin resistance in insulin-sensitive cells, including podocytes. The diabetic environment induces pathological changes, especially in podocyte bioenergetics, which is tightly linked with mitochondrial dynamics. The regulatory role of insulin in mitochondrial morphology in podocytes has not been fully elucidated. Therefore, the main goal of the present study was to investigate effects of insulin on the regulation of mitochondrial dynamics and bioenergetics in human podocytes. Biochemical analyses were performed to assess oxidative phosphorylation efficiency by measuring the oxygen consumption rate (OCR) and glycolysis by measuring the extracellular acidification rate (ECAR). mRNA and protein expression were determined by real-time polymerase chain reaction and Western blot. The intracellular mitochondrial network was visualized by MitoTracker staining. All calculations were conducted using CellProfiler software. Short-term insulin exposure exerted inhibitory effects on various parameters of oxidative respiration and adenosine triphosphate production, and glycolysis flux was elevated. After a longer time of treating cells with insulin, an increase in mitochondrial size was observed, accompanied by a reduction of expression of the mitochondrial fission markers DRP1 and FIS1 and an increase in mitophagy. Overall, we identified a previously unknown role for insulin in the regulation of oxidative respiration and glycolysis and elucidated mitochondrial dynamics in human podocytes. The present results emphasize the importance of the duration of insulin stimulation for its metabolic and molecular effects, which should be considered in clinical and experimental studies of DN. [ABSTRACT FROM AUTHOR]

The assessment of the combined water is a reliable method to monitor the hydration of cement pastes. This method is also being used to screen different SCMs and cement formulations. However, to obtain reliable data it is necessary to stop the hydration of specimens, removing the free water. In this sense, this work evaluates the effect of different hydration stoppage methods on assessing the combined water of cement pastes. Three procedures were investigated, two using solvent exchange (RILEM and CEMtec), including the one recommended by RILEM TC 238, and the other using silica gel (Silica4h). Firstly, two cement formulations (OPC and LC50) were evaluated using thermogravimetric analysis and X-ray diffraction. The results of combined water at 7 and 28 days were similar independently of the hydration stoppage technique. A repeatability test was also conducted and demonstrated that all three methods presented good repeatability with a low coefficient of variation. Then, six Brazilian commercial cements had their hydration stopped at 7 and 28 days using the studied procedures. The results of combined water were comparable regardless of the used method. A qualitative analysis was also carried out indicating that for the assessment of combined water the Silica4h is the most practical and cost-effective method to stop the hydration of cement pastes and RILEM is the fastest procedure. Finally, both procedures with solvent exchange require attention due to their health and safety issues, solvent disposal, and acquisition. [ABSTRACT FROM AUTHOR]

Induction machines are widely utilized in the industry due to their sturdy construction nature and relatively simple maintenance. For the design, control, optimization, and failure analysis procedures of induction machines, equivalent circuit parameters are required. These parameters can be estimated using a variety of techniques, such as traditional testing, experimental research, analytical methods, programming, and machine learning algorithms. However, the aforementioned methods have limitations; experimental methods are laborious and time-consuming, analytical methods require complicated and iterative computations for each machine, and programming algorithms involve writing of lengthy command sequences. The article concentrates on a high precision estimation method based on neural network algorithms to avoid complex calculations, thus, minimizing time and effort, and eliminating errors. In this context, it is aimed to provide a greater reliability compared to studies using small amounts of datasets and to investigate earlier methods, which are not studied vastly, for estimating the parameters of induction machines. In this regard, three distinct artificial neural networks were applied to a large dataset consisting of 1164 machines with power output ranging from 4 to 900 kW and belonging to 7 different manufacturers. RMSE values of 0.0125 were attained in parameter estimation, and artificial neural networks produced encouraging results. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Microvascular dysfunction contributes to insulin resistance. CD36, a fatty acid transporter and modulator of insulin signalling, is abundant in microvascular endothelial cells. Humans carrying the minor allele (G) of CD36 coding variant rs3211938 have 50% reduced CD36 expression and show endothelial dysfunction. We aimed to determine whether G allele carriers have microvascular resistance to insulin and, if so, how this affects glucose disposal., Methods: Our multi-disciplinary approach included hyperinsulinaemic-euglycaemic clamps in Cd36 -/- and wild-type mice, and in individuals with 50% CD36 deficiency, together with control counterparts, in addition to primary human-derived microvascular endothelial cells with/without CD36 depletion., Results: Insulin clamps showed that Cd36 -/- mice have enhanced insulin-stimulated glucose disposal but reduced vascular compliance and capillary perfusion. Intravital microscopy of the gastrocnemius showed unaltered transcapillary insulin flux. CD36-deficient humans had better insulin-stimulated glucose disposal but insulin-unresponsive microvascular blood volume (MBV). Human microvascular cells depleted of CD36 showed impaired insulin activation of Akt, endothelial NO synthase and NO generation. Thus, in CD36 deficiency, microvascular insulin resistance paradoxically associated with enhanced insulin sensitivity of glucose disposal., Conclusions/interpretation: CD36 deficiency was previously shown to reduce muscle/heart fatty acid uptake, whereas here we showed that it reduced vascular compliance and the ability of insulin to increase MBV for optimising glucose and oxygen delivery. The muscle and heart respond to these energy challenges by transcriptional remodelling priming the tissue for insulin-stimulated glycolytic flux. Reduced oxygen delivery activating hypoxia-induced factors, endothelial release of growth factors or small intracellular vesicles might mediate this adaptation. Targeting NO bioavailability in CD36 deficiency could benefit the microvasculature and muscle/heart metabolism., Trial Registration: Clinicaltrials.gov NCT03012386 DATA AVAILABILITY: The RNAseq data generated in this study have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/ ) under accession code GSE235988 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235988 )., (© 2024. The Author(s).)

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The endocrine system relies on the vasculature for delivery of hormones throughout the body, and the capillary microvasculature is the site where the hormones cross from the blood into the target tissue. Once considered an inert wall, various studies have now highlighted the functions of the capillary endothelium to regulate transport and therefore affect or maintain the interstitial environment. The role of the capillary may be clear in areas where there is a continuous endothelium, yet there also appears to be a role of endothelial cells in tissues with a sinusoidal structure. Here we focused on the most common endocrine disorder, diabetes, and several of the target organs associated with the disease, including skeletal muscle, liver and pancreas. However, it is important to note that the ability of hormones to cross the endothelium to reach their target tissue is a component of all endocrine functions. It is also a consideration in organs throughout the body and may have greater impact for larger hormones with target tissues containing a continuous endothelium. We noted that the blood levels do not always equal interstitial levels, which is what the cells are exposed to, and discussed how this may change in diseases such as obesity and insulin resistance. The capillary endothelium is, therefore, an essential and understudied aspect of endocrinology and metabolism that can be altered in disease, which may be an appropriate target for treatment., (© 2019 John Wiley & Sons Australia, Ltd.)

Central response to insulin is suspected to be defective in Alzheimer's disease. As most insulin is secreted in the bloodstream by the pancreas, its capacity to regulate brain functions must, at least partly, be mediated through the cerebral vasculature. However, how insulin interacts with the blood-brain barrier and whether alterations of this interaction could contribute to Alzheimer's disease pathophysiology both remain poorly defined. Here, we show that human and murine cerebral insulin receptors (INSRs), particularly the long isoform INSRα-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSRα-B were lower in the parietal cortex of subjects diagnosed with Alzheimer's disease, positively correlating with cognitive scores, leading to a shift towards a higher INSRα-A/B ratio, consistent with cerebrovascular insulin resistance in the Alzheimer's disease brain. Vascular INSRα was inversely correlated with amyloid-β plaques and β-site APP cleaving enzyme 1, but positively correlated with insulin-degrading enzyme, neprilysin and P-glycoprotein. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the blood-brain barrier remained very low (<0.03 µl/g·s) and was not inhibited by an insulin receptor antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSRβ that was restricted to microvessels. Such an activation of vascular insulin receptor was blunted in 3xTg-AD mice, suggesting that Alzheimer's disease neuropathology induces insulin resistance at the level of the blood-brain barrier. Overall, the present data in post-mortem Alzheimer's disease brains and an animal model of Alzheimer's disease indicate that defects in the insulin receptor localized at the blood-brain barrier strongly contribute to brain insulin resistance in Alzheimer's disease, in association with β-amyloid pathology. [ABSTRACT FROM AUTHOR]

This paper deals with a new design of a hybrid fuzzy super-twisting sliding mode controller (HFSTSMC) for a three-phase induction motor (IM) controlled by the rotor flux orientation technique. Super-twisting sliding mode control is employed as a potential solution to limit the inherent chattering effect in the conventional sliding mode control without affecting the tracking accuracy and robustness. The super-twisting sliding mode control (STSMC) scheme is a modified second-order sliding mode control (SOSMC) scheme that does not need the information of any derivative of the sliding surface, but the experimental control coefficients found in the control law have an obvious effect on limiting chattering and the system response speed. Therefore, a robust hybrid controller was proposed based on the fuzzy logic control (FLC) approach to optimally tuning these coefficients. Whereas, the fuzzy logic controller is used as a supervisory controller to adjust the value of the gains according to the state of the system. Thus, providing high dynamic performance and achieving the highest rates of robustness in transient and uncertain conditions. On the other hand, increasing tracking accuracy and chattering phenomena reduction in steady states. The validation of the suggested scheme is verified by experimental approximating of simulations using MATLAB/SIMULINK and also compared with conventional and advanced controllers. The obtained results confirm the reduction of the chattering phenomenon and thus reduction of the total harmonic distortion (THD) in the motor current, and the effectiveness of the proposed scheme in various operating conditions. [ABSTRACT FROM AUTHOR]

With the gradual decline in global fertility rates, there is a need to identify potential contributing factors, their mechanisms of actions and investigate possible solutions to reverse the trend. Endocrine disrupting compounds (EDCs), such as bisphenol A (BPA), are environmental toxicants that are known to negatively impact reproductive functions. As such, the use of BPA in the manufacturing industry has slowly been replaced by analogs, including bisphenol S (BPS) and bisphenol F (BPF), despite limited knowledge available regarding their impact on health and their safety. The following study investigates the effects of BPA, BPS and BPF at a concentration of 0.5 mg/mL and 50 mg/mL on bovine granulosa cell apoptosis, with the ultimate goal of determining how they may impact oocyte competence and, thus, overall fertility. The underlying hypothesis is that bisphenols disrupt the granulosa cell environment surrounding the oocyte inducing excessive apoptosis via the intrinsic mitochondrial pathway. To test this hypothesis, apoptosis was measured following a time- and dose-dependent exposure to all three bisphenols by flowcytometry paired with annexin V/PI staining as well as by quantification of key genes belonging to the intrinsic apoptotic pathway both at the mRNA and protein levels. The results of this study report that BPA and BPF reduce cell viability through reduced cell counts and increased apoptosis. This increase is due, in part, to the induction of apoptotic genes of the intrinsic pathway of apoptosis. Additionally, this study also suggests that BPS may not act on the intrinsic mitochondrial apoptotic pathway in bovine granulosa cells. Overall, this study allows us to establish potential apoptotic pathways activated by bisphenols as well as compare the relative apoptotic activities of BPA to its most widespread analogs. [ABSTRACT FROM AUTHOR]

Purpose : Oral delivery of therapeutic peptides has been challenging due to multiple physiological factors and physicochemical properties of peptides. We report a systematic approach to identify formulation compositions combining a permeation enhancer and a peptidase inhibitor that minimize proteolytic degradation and increase absorption of a peptide across the small intestine. Methods: An acylated glucagon-like peptide-1/glucagon co-agonist peptide (4.5 kDa) was selected as a model peptide. Proteolytic stability of the peptide was investigated in rat and pig SIF. Effective PEs and multiple component formulations were identified in rats. Relative bioavailability of the peptide was determined in minipigs via intraduodenal administration (ID) of enteric capsules. Results: The peptide degraded rapidly in the rat and pig SIF. Citric acid, SBTI, and SBTCI inhibited the enzymatic degradation. The peptide self-associated into trimers in solution, however, addition of PEs monomerized the peptide. C10 was the most effective PE among tested PEs (DPC, LC, rhamnolipid, C12-maltosides, and SNAC) to improve intestinal absorption of the peptide in the rat IJ-closed loop model. A combination of C10 and SBTI or SBTCI increased the peptide exposure 5–tenfold compared to the exposure with the PE alone in the rat IJ-cannulated model, and achieved 1.06 ± 0.76% bioavailability in minipigs relative to subcutaneous via ID administration using enteric capsules. Conclusion: We identified SBTI and C10 as an effective peptidase inhibitor and PE for intestinal absorption of the peptide. The combination of SBTI and C10 addressed the peptide physiochemical properties and provides a formulation strategy to achieve intestinal delivery of this peptide. [ABSTRACT FROM AUTHOR]

Fluorescently labelling proteins such as insulin have wide ranging applications in a pharmaceutical research and drug delivery. Human insulin (Actrapid®) was labelled with fluorescein isothiocyanate (FITC) and the synthesised conjugate identified using reverse phase high performance liquid chromatography (RP-HPLC) on a C18 column and a gradient method with mobile phase A containing 0.1% trifluoroacetic acid (TFA) in Millipore water and mobile phase B containing 90% Acetonitrile, 10% Millipore water and 0.1% TFA. Syntheses were carried out at varying reaction times between 4 and 20 h. Mono-labelled FITC-insulin conjugate was successfully synthesised with labelling at the B1 position on the insulin chain using a molar ratio of 2:1 (FITC:insulin) at a reaction time of 18 h and confirmed by electrospray mass spectroscopy. Reactions were studied across a pH range of 7–9.8 and the quantities switch from mono-labelled to di-labelled FITC-insulin conjugates at a reaction time of 2 h (2:1 molar ratio) at pH > 8. The conjugates isolated from the studies had biological activities in comparison to native insulin of 99.5% monoB1, 78% monoA1, 51% diA1B1 and 0.06% triA1B1B29 in HUVEC cells by examining AKT phosphorylation levels. MonoB1 FITC-insulin conjugate was also compared to native insulin by examining cell surface GLUT4 in C2C12 skeletal muscle cells. No significant difference in the cellular response was observed for monoB1 produced in-house compared to native insulin. Therefore mono-labelled FITC-insulin at the B1 position showed similar biological activity as native insulin and can potentially be used for future biomedical applications. [ABSTRACT FROM AUTHOR]

The rate-limiting step for skeletal muscle glucose uptake is transport from microcirculation to muscle interstitium. Capillary endothelium poses a barrier that delays the onset of muscle insulin action. Defining physiological barriers that control insulin access to interstitial space is difficult because of technical challenges that confront study of microscopic events in an integrated physiological system. Two physiological variables determine muscle insulin access. These are the number of perfused capillaries and the permeability of capillary walls to insulin. Disease states associated with capillary rarefaction are closely linked to insulin resistance. Insulin permeability through highly resistant capillary walls of muscle poses a significant barrier to insulin access. Insulin may traverse the endothelium through narrow intercellular junctions or vesicular trafficking across the endothelial cell. Insulin is large compared with intercellular junctions, making this an unlikely route. Transport by endothelial vesicular trafficking is likely the primary route of transit. Studies in vivo show movement of insulin is not insulin receptor dependent. This aligns with single-cell transcriptomics that show the insulin receptor is not expressed in muscle capillaries. Work in cultured endothelial cell lines suggest that insulin receptor activation is necessary for endothelial insulin transit. Controversies remain in the understanding of transendothelial insulin transit to muscle. These controversies closely align with experimental approaches. Control of circulating insulin accessibility to skeletal muscle is an area that remains ripe for discovery. Factors that impede insulin access to muscle may contribute to disease and factors that accelerate access may be of therapeutic value for insulin resistance. [ABSTRACT FROM AUTHOR]

Translational medicine, experimental medicine and experimental animal models, in particular mice and rats, represent a multidisciplinary field that has made it possible to achieve, in the last decades, important scientific progress. In this review, we have summarized the most frequently used imaging animal models, such as ultrasound (US), micro-CT, MRI and the optical imaging methods, and their main implications in diagnostic and therapeutic fields, with a particular focus on diabetes mellitus, a multifactorial disease extremely widespread among the general population. [ABSTRACT FROM AUTHOR]

Background: Vascular endothelial dysfunction is an essential part of the pathophysiology of type 2 diabetes and its complications. In type 2 diabetes, endothelial dysfunction is characterized by reduced insulin signaling and increased transendothelial transport of fatty acids (FA). As the Abl kinase inhibitor imatinib was previously shown to reverse type 2 diabetes and to inhibit VEGF signaling via Abl kinases, we studied the effect of imatinib on vascular insulin sensitivity and fatty acid transport in vivo and in vitro. Methods: C57/BL6J mice were fed a chow diet or Western diet (WD), and received daily imatinib injections for two weeks. Insulin-mediated vasoreactivity of resistance arteries was studied using intravital microscopy, and metabolic insulin sensitivity using the hyperinsulinemic-euglycemic clamp. The effect of imatinib on triglyceride content in skeletal muscle and heart in vivo was also determined. In vitro, the effect of imatinib on fatty acid transport was studied in human umbilical vein endothelial cells (HUVECs) by evaluating the effect of imatinib on fluorescently labeled FA uptake both under basal and VEGF-B-stimulated conditions. Results: Imatinib prevented the WD-induced weight gain in mice, independently from food intake. In line with this, imatinib enhanced insulin-mediated vasoreactivity of resistance arteries in the WD-fed mice. However, imatinib did not affect triglyceride content in muscle. In cultured endothelial cells, VEGF-B stimulation resulted in a time-dependent uptake of fatty acids in parallel with increased phosphorylation of the Abl kinase substrate Crk-like protein (CrkL) at Tyr207. Although imatinib effectively prevented VEGF-B-mediated Abl kinase activation, it had no effect on VEGF-B mediated endothelial FA uptake. Conclusion: Imatinib prevents weight gain and preserves insulin-mediated vasodilation in WD-fed mice, but does not affect endothelial FA transport despite inhibiting VEGF-B signaling. The beneficial effect of imatinib on insulin-mediated vasodilation may contribute to the anti-diabetic effects of imatinib. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: It has been proposed that muscle fibre type composition and perfusion are key determinants of insulin-stimulated muscle glucose uptake, and alterations in muscle fibre type composition and perfusion contribute to muscle, and consequently whole-body, insulin resistance in people with obesity. The goal of the study was to evaluate the relationships among muscle fibre type composition, perfusion and insulin-stimulated glucose uptake rates in healthy, lean people and people with obesity. Methods: We measured insulin-stimulated whole-body glucose disposal and glucose uptake and perfusion rates in five major muscle groups (erector spinae, obliques, rectus abdominis, hamstrings, quadriceps) in 15 healthy lean people and 37 people with obesity by using the hyperinsulinaemic–euglycaemic clamp procedure in conjunction with [2H]glucose tracer infusion (to assess whole-body glucose disposal) and positron emission tomography after injections of [15O]H2O (to assess muscle perfusion) and [18F]fluorodeoxyglucose (to assess muscle glucose uptake). A biopsy from the vastus lateralis was obtained to assess fibre type composition. Results: We found: (1) a twofold difference in glucose uptake rates among muscles in both the lean and obese groups (rectus abdominis: 67 [51, 78] and 32 [21, 55] μmol kg−1 min−1 in the lean and obese groups, respectively; erector spinae: 134 [103, 160] and 66 [24, 129] μmol kg−1 min−1, respectively; median [IQR]) that was unrelated to perfusion or fibre type composition (assessed in the vastus only); (2) the impairment in insulin action in the obese compared with the lean group was not different among muscle groups; and (3) insulin-stimulated whole-body glucose disposal expressed per kg fat-free mass was linearly related with muscle glucose uptake rate (r2 = 0.65, p < 0.05). Conclusions/interpretation: Obesity-associated insulin resistance is generalised across all major muscles, and is not caused by alterations in muscle fibre type composition or perfusion. In addition, insulin-stimulated whole-body glucose disposal relative to fat-free mass provides a reliable index of muscle glucose uptake rate. [ABSTRACT FROM AUTHOR]

Calcium aluminum phosphate cement (CAPC) requires a practical composition for biological applications. This research aims to investigate the effect of aluminum hydroxide sources (aluminum hydroxide, boehmite, and hydratable alumina), where SECAR 71 cement and phosphoric acid are in the composition, regarding the mechanical, biological, and microstructural properties of CAPC. In vitro assessments were evaluated by immersing the samples in simulated body fluid (SBF) solution for 7 days, 14 days, and 28 days, and by MTT testing (cytotoxicity of MG-63 cells). The results revealed that the composition including hydratable alumina was superior concerning the lowest final setting time (50 min), in situ formation and growth of hydroxyapatite on its surface, as well as the compressive strength which reaches to 42 ± 10 MPa after 28 days in SBF solution. However, regarding the cytotoxicity, the cements consisting of boehmite have priority. A more detailed biological analysis is recommended to evaluate the clinical application of CAPC. [ABSTRACT FROM AUTHOR]

Background Insulin has to be transported across the capillary endothelium to stimulate muscle glucose uptake. We investigated insulin uptake from the peripheral circulation in non-diabetic (ND) individuals and in type 2 diabetes (T2D) patients. Methods Single-center cross-sectional study involving 40 ND (age 65±11 years) and 30 T2D patients (age 67±8 years). Thirty-six participants were studied in the fasted state (22 ND subjects and 14 T2D patients termed NDF and T2DF) and 34 participants 1-h following a glucose challenge (18 ND subjects and 16 T2D patients indicated as NDG and T2DG). Main outcome measure was fractional extraction (FE) of insulin (FEins) and glucose using the forearm balance method. Results In NDF, FEins was 18 (10–26) % at lower insulin levels (63 51–80] pmol/l), while in NDG at higher insulin levels (776 [543–1176] pmol/l), FEins was 9 (4–16) % (p = 0.01 vs. NDF). In NDF only, a negative correlation was observed between FEins and arterial plasma insulin load (rho = − 0.575;p = 0.006) and fasting plasma glucose levels (rho = − 0.551;p = 0.01). In T2DF FEins was 6 (1–19) % and not different from FEins in T2DG (10 2–14) %), and was not associated to fasting glucose. FEins tended to be higher in NDF compared to T2DF (p = 0.07). Discussion We propose that in ND individuals, besides passive diffusion, an active high-affinity pathway with limited capacity around lower physiologic insulin levels exists for insulin transendothelial transport, contributing to glycemic control. In T2D patients, this mechanism of peripheral insulin uptake is diminished or even absent. Modulation of insulin extraction from the circulation may be a novel target to improve glucose metabolism in T2D. [ABSTRACT FROM AUTHOR]

Bovine leukemia virus (BLV) is a δ-retrovirus responsible for Enzootic Bovine Leukosis (EBL), a lymphoproliferative disease that affects cattle. The virus causes immune system deregulation, favoring the development of secondary infections. In that context, mastitis incidence is believed to be increased in BLV infected cattle. The aim of this study was to analyze the transcriptome profile of a BLV infected mammary epithelial cell line (MAC-T). Our results show that BLV infected MAC-T cells have an altered expression of IFN I signal pathway and genes involved in defense response to virus, as well as a collagen catabolic process and some protooncogenes and tumor suppressor genes. Our results provide evidence to better understand the effect of BLV on bovine mammary epithelial cell's immune response. [ABSTRACT FROM AUTHOR]

The role of the endothelium is not just limited to acting as an inert barrier for facilitating blood transport. Endothelial cells (ECs), through expression of a repertoire of angiocrine molecules, regulate metabolic demands in an organ‐specific manner. Insulin flux across the endothelium to muscle cells is a rate‐limiting process influencing insulin‐mediated lowering of blood glucose. Here, we demonstrate that Notch signaling in ECs regulates insulin transport to muscle. Notch signaling activity was higher in ECs isolated from obese mice compared to non‐obese. Sustained Notch signaling in ECs lowered insulin sensitivity and increased blood glucose levels. On the contrary, EC‐specific inhibition of Notch signaling increased insulin sensitivity and improved glucose tolerance and glucose uptake in muscle in a high‐fat diet‐induced insulin resistance model. This was associated with increased transcription of Cav1, Cav2, and Cavin1, higher number of caveolae in ECs, and insulin uptake rates, as well as increased microvessel density. These data imply that Notch signaling in the endothelium actively controls insulin sensitivity and glucose homeostasis and may therefore represent a therapeutic target for diabetes. Synopsis: Insulin flux from blood plasma to muscle cells across the endothelium is a critical step in insulin‐mediated lowering of blood glucose levels. This study highlights the role of Notch signaling in regulating systemic glucose homeostasis. Notch signaling activity was higher in endothelial cells (ECs) isolated from obese mice compared to non‐obese mice.Sustained Notch signaling in ECs lowered insulin sensitivity and increased blood glucose levels in mice.EC‐specific inhibition of canonical Notch signaling increased insulin sensitivity and improved glucose tolerance in a high‐fat diet‐induced insulin resistance model.Glucose tolerance improvement was associated with increased transcription of genes involved in caveolae formation (Cav1 and Cavin1), higher number of caveolae in ECs and insulin uptake rates. [ABSTRACT FROM AUTHOR]

The drying behavior for various calcium aluminate cement and hydratable alumina‐bonded refractory castables was investigated in the first‐drying temperature range (100°C‐300°C). Using a specialized high‐temperature Nuclear Magnetic Resonance setup, we were able to directly and nondestructively measure the spatially and temporally resolved moisture distribution, while simultaneously measuring the temperature distribution as well. These measurements show that the drying front position is a linear function of time, which can be explained on the basis of a simplified model where only vapor transport is considered. Based on the measurements and the model, one can directly determine the permeability at high temperatures. Moreover, the results demonstrate that the drying front speed and temperature strongly correlates with the control of key material parameters (eg, water demand, binder content, etc). In particular, microsilica fume‐containing low‐cement castables displayed the highest vapor pressures, while regular castables generated the lowest vapor pressures reflecting the permeability of these materials. [ABSTRACT FROM AUTHOR]

These studies test, using intravital microscopy (IVM), the hypotheses that perfusion effects on insulin-stimulated muscle glucose uptake (MGU) are 1) capillary recruitment independent and 2) mediated through the dispersion of glucose rather than insulin. For experiment 1, capillary perfusion was visualized before and after intravenous insulin. No capillary recruitment was observed. For experiment 2, mice were treated with vasoactive compounds (sodium nitroprusside, hyaluronidase, and lipopolysaccharide), and dispersion of fluorophores approximating insulin size (10- kDa dextran) and glucose (2-NBDG) was measured using IVM. Subsequently, insulin and 2[14C]deoxyglucose were injected and muscle phospho-2[14C]deoxyglucose (2[C14]DG) accumulation was used as an index of MGU. Flow velocity and 2-NBDG dispersion, but not perfused surface area or 10-kDa dextran dispersion, predicted phospho-2[14C]DG accumulation. For experiment 3, microspheres of the same size and number as are used for contrast-enhanced ultrasound (CEU) studies of capillary recruitment were visualized using IVM. Due to their low concentration, microspheres were present in only a small fraction of blood-perfused capillaries. Microsphereperfused blood volume correlated to flow velocity. These findings suggest that 1) flow velocity rather than capillary recruitment controls microvascular contributions to MGU, 2) glucose dispersion is more predictive of MGU than dispersion of insulin-sized molecules, and 3) CEU measures regional flow velocity rather than capillary recruitment. [ABSTRACT FROM AUTHOR]

Continuous glucose monitor (CGM) readings are delayed relative to blood glucose, and this delay is usually attributed to the latency of interstitial glucose levels. However, CGM-independent data suggest rapid equilibration of interstitial glucose. This study sought to determine the loci of CGM delays. Electrical current was measured directly from CGM electrodes to define sensor kinetics in the absence of smoothing algorithms. CGMs were implanted in mice, and sensor versus blood glucose responses were measured after an intravenous glucose challenge. Dispersion of a fluorescent glucose analog (2-NBDG) into the CGM microenvironment was observed in vivo using intravital microscopy. Tissue deposited on the sensor and nonimplanted subcutaneous adipose tissue was then collected for histological analysis. The time to half-maximum CGM response in vitro was 35 ± 2 s. In vivo, CGMs took 24 ± 7 min to reach maximum current versus 2 ± 1 min to maximum blood glucose (P = 0.0017). 2-NBDG took 21 ± 7 min to reach maximum fluorescence at the sensor versus 6 ± 6 min in adipose tissue (P = 0.0011). Collagen content was closely correlated with 2-NBDG latency (R = 0.96, P = 0.0004). Diffusion of glucose into the tissue deposited on a CGM is substantially delayed relative to interstitial fluid. A CGM that resists fibrous encapsulation would better approximate real-time deviations in blood glucose. [ABSTRACT FROM AUTHOR]

Summary: In this paper, a new practical robust control scheme is proposed and investigated for the cable‐driven manipulators under lumped uncertainties. There are three parts in the proposed method, ie, a time‐delay estimation (TDE) part, a modified super‐twisting algorithm (STA) part, and a fractional‐order nonsingular terminal sliding mode (FONTSM) error dynamics part. The TDE uses intentionally time‐delayed system signals to estimate the lumped dynamics of the system and ensures an attractive model‐free control structure. The STA is applied to guarantee high performance and chattering suppression simultaneously in the reaching phase. The FONTSM error dynamics is utilized to obtain fast convergence and strong robustness in the sliding mode phase. Thanks to the above three parts, the proposed control scheme is model free and can ensure high control performance under lumped uncertainties. The stability considering the FONTSM error dynamics and modified STA scheme is analyzed. Comparative simulation and experiments were conducted to demonstrate the effectiveness and superiorities of the newly proposed control scheme. Corresponding experimental results show that our newly proposed control scheme can provide more than 20% improvement of the steady control accuracy under three different reference trajectories. [ABSTRACT FROM AUTHOR]

Sepsis costs the healthcare system $23 billion annually and has a mortality rate between 10 and 40%. An early indication of sepsis is the onset of hyperglycemia, which is the result of sepsis-induced insulin resistance in skeletal muscle. Previous investigations have focused on events in the myocyte (e.g., insulin signaling and glucose transport and subsequent metabolism) as the causes for this insulin-resistant state. However, the delivery of insulin to the skeletal muscle is also an important determinant of insulin action. Skeletal muscle microvascular blood flow, which delivers the insulin to the muscle, is known to be decreased during sepsis. Here we test whether the reduced capillary blood flow to skeletal muscle belies the sepsis-induced insulin resistance by reducing insulin delivery to the myocyte. We hypothesize that decreased capillary flow and consequent decrease in insulin delivery is an early event that precedes gross cardiovascular alterations seen with sepsis. This hypothesis was examined in mice treated with either lipopolysaccharide (LPS) or polymicrobial sepsis followed by intravital microscopy of the skeletal muscle microcirculation. We calculated insulin delivery to the myocyte using two independent methods and found that LPS and sepsis rapidly reduce insulin delivery to the skeletal muscle by ~50%; this was driven by decreases in capillary flow velocity and the number of perfused capillaries. Furthermore, the changes in skeletal muscle microcirculation occur before changes in both cardiac output and arterial blood pressure. These data suggest that a rapid reduction in skeletal muscle insulin delivery contributes to the induction of insulin resistance during sepsis. [ABSTRACT FROM AUTHOR]

An endothelial cell monolayer separates interstitia from blood and lymph, and determines the bidirectional transfer of solutes and macromolecules across these biological spaces. We review advances in transport modalities across these endothelial barriers. Glucose is a major fuel for the brain and peripheral tissues, and insulin acts on both central and peripheral tissues to promote whole‐body metabolic signalling and anabolic activity. Blood‐brain barrier endothelial cells display stringent tight junctions and lack pinocytic activity. Delivery of blood glucose and insulin to the brain occurs through their respective carrier (Glucose transporter 1) and receptor (insulin receptor), enacting bona fide transcytosis. At supraphysiological concentrations, insulin is also likely transferred by fluid phase cellular uptake and paracellular transport, especially in peripheral microvascular endothelia. The lymphatic microvasculature also transports insulin but in this case from tissues to lymph and therefrom to blood. This serves to end the hormone's action and to absorb highly concentrated subcutaneously injected insulin in diabetic individuals. The former function may involve receptor‐mediated transcytosis into lymphatic endothelial cells, the latter fluid phase uptake and paracellular transport. Lymphatic capillaries also mediate carrier‐dependent transport of other nutrients and macromolecules. These findings challenge the notion that lymphatic capillaries only transport macromolecules through intercellular flaps. [ABSTRACT FROM AUTHOR]

Due to their osteoconductive and osteoinductive abilities, bioglasses (BGs) have attracted attention in tissue engineering, especially for mineralized tissue. The aim of this study is to review the current state of the art on the effects of BGs produced by sol–gel on cells for dental and periodontal regeneration. The study also discusses associated antibacterial properties. The research was performed by considering the Preferred Reporting Items for Systematic Reviews and the Meta‐Analyses (PRISMA) statement. The research ranged 5 years' window time (from January, 01, 2012, to August, 31, 2017) and the relevant studies were identified based on the inclusion/exclusion criteria. A total of 45 articles were selected from 244 initial returns, plus seven further articles coming from other sources were selected for the same purpose. From this systematic study, it is revealed that only 13 of the 52 articles have proved both the ability of BGs to differentiate dental cells at genetic level and their ability of triggering cell‐mediated mineralization, but only six of them showed, along with cells, the antibacterial properties of the glasses. This review shows that sol–gel BGs are not toxic, can sustain cell proliferation and differentiation at a genetic level, and can keep the bacterial population under control. Moreover, a standard methodology and an ideal material are suggested. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1210–1227, 2019. [ABSTRACT FROM AUTHOR]

Key points: Insulin enters the brain from the blood via a saturable transport system. It is unclear how insulin is transported across the blood–brain barrier (BBB). Using two models of the signalling‐related insulin receptor loss or inhibition, we show insulin transport can occur in vivo without the signalling‐related insulin receptor. Insulin in the brain has multiple roles including acting as a metabolic regulator and improving memory. Understanding how insulin is transported across the BBB will aid in developing therapeutics to further increase CNS concentrations. Abstract: A saturable system transports insulin from blood across the blood–brain barrier (BBB) and into the central nervous system. Whether or not the classic or signalling‐related insulin receptor plays a role in mediating this transport in vivo is controversial. Here, we employed kinetics methods that distinguish between transport across the brain endothelial cell and reversible luminal surface receptor binding. Using a previously established line of mice with endothelial‐specific loss of the signalling‐related insulin receptor (EndoIRKO) or inhibiting the insulin receptor with the selective antagonist S961, we show insulin transport across the BBB is maintained. Rates of insulin transport were similar in all groups and transport was still saturable. Unlike transport, binding of insulin to the brain endothelial cell was decreased with the loss or inhibition of the signalling‐related insulin receptor. These findings demonstrate that the signalling‐related insulin receptor is not required for insulin transport across the BBB. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Changes in microvascular perfusion have been reported in many diseases, yet the functional significance of altered perfusion is often difficult to determine. This is partly because commonly used techniques for perfusion measurement often rely on either indirect or by‐hand approaches. Methods: We developed and validated a fully automated software technique to measure microvascular perfusion in videos acquired by fluorescence microscopy in the mouse gastrocnemius. Acute perfusion responses were recorded following intravenous injections with phenylephrine, SNP, or saline. Results: Software‐measured capillary flow velocity closely correlated with by‐hand measured flow velocity (R2 = 0.91, P < 0.0001). Software estimates of capillary hematocrit also generally agreed with by‐hand measurements (R2 = 0.64, P < 0.0001). Detection limits range from 0 to 2000 μm/s, as compared to an average flow velocity of 326 ± 102 μm/s (mean ± SD) at rest. SNP injection transiently increased capillary flow velocity and hematocrit and made capillary perfusion more steady and homogenous. Phenylephrine injection had the opposite effect in all metrics. Saline injection transiently decreased capillary flow velocity and hematocrit without influencing flow distribution or stability. All perfusion metrics were temporally stable without intervention. Conclusions: These results demonstrate a novel and sensitive technique for reproducible, user‐independent quantification of microvascular perfusion. [ABSTRACT FROM AUTHOR]

Capillary electrophoresis (CE) was used to separate polycyclic aromatic sulfur heterocycles (PASHs), a class of compounds that occurs in fossil fuels and refined products of petroleum. An electric charge was introduced into the compounds through methylation or phenylation of the sulfur atom. Separations of standard PASHs that are expected to be present in industrially desulfurized fuels showed that CE possessed a higher resolution than reversed phase liquid chromatography. The CE method can separate all the monomethylbenzothiophenes; this is not achieved in capillary gas chromatography. A linear relationship was found between migration time and the calculated volume of the compounds. The PASHs in deeply desulfurized diesel were separated after preconcentration, and the electropherogram was compared with the chromatograms from GC and HPLC. Finally, derivatized PASHs are often enantiomeric and the enantiomers can be separated if a suitable cyclodextrin is added to the running buffer. [ABSTRACT FROM AUTHOR]

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