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An improved winding function theory (IWFT) is presented in this article, which can be also used to calculate the self-inductance and mutual inductance of large air-gap electric machines, while accurately considering the air-gap length function and the magnetic saturation in iron parts, simultaneously. In IWFT, the radial length of flux path in different points inside air gap is calculated using the conformal mappings (CMs). The total air-gap length is the resultant of air-gap length at differential elements in the radial direction. A modified inverse air-gap function is then presented for a typical cage-rotor induction motor (CRIM) and a typical surface permanent magnet synchronous motor (SPMSM), which considers the real paths of flux lines in the slotted air gap. The high accuracy of these modified inverse air-gap functions is verified by comparing with the corresponding results obtained through the finite element method (FEM). To consider the magnetic saturation, a virtual winding function as a 2-D function is introduced in this article, which can consider the magneto-motive force (MMF) drops in iron parts of stator and rotor obtained through the magnetic equivalent circuit (MEC) model. By using IWFT, dependent on the structure of the relevant motor, a 2-D or 3-D lookup table is pre-calculated and stored for self/mutual inductances and their derivatives, and they are then used to model the running condition of CRIM and SPMSM under different loading conditions. Finally, the accuracy of IWFT results is verified by comparing them with the corresponding results obtained through FEM.

Enhanced understanding of bio-nano interaction requires recognition of hidden factors such as protein corona, a layer of adsorbed protein around nano-systems. This study compares the biological identity and fingerprint profile of adsorbed proteins on PLGA-based nanoparticles through nano-liquid chromatography-tandem mass spectrometry. The total proteins identified in the corona of nanoparticles (NPs) with different in size, charge and compositions were classified based on molecular mass, isoelectric point and protein function. A higher abundance of complement proteins was observed in modified NPs with an increased size, while NPs with a positive surface charge exhibited the minimum adsorption for immunoglobulin proteins. A correlation of dysopsonin/opsonin ratio was found with cellular uptake of NPs exposed to two positive and negative Fc receptor cell lines. Although the higher abundance of dysopsonins such as apolipoproteins may cover the active sites of opsonins causing a lower uptake, the correlation of adsorbed dysopsonin/opsonin proteins on the NPs surface has an opposite trend with the intensity of cell uptake. Despite the reduced uptake of corona-coated NPs in comparison with pristine NPs, the dysopsonin/opsonin ratio controlled by the physicochemistry properties of NPs could potentially be used to tune up the cellular delivery of polymeric NPs. (C) 2019 Elsevier Inc. All rights reserved.

Bio-nano interface investigation models are mainly based on the type of proteins present on corona, bio-nano interaction responses and the evaluation of final outcomes. Due to the extensive diversity in correlative models for investigation of nanoparticles biological responses, a comprehensive model considering different aspects of bio-nano interface from nanoparticles properties to protein corona fingerprints appeared to be essential and cannot be ignored. In order to minimize divergence in studies in the era of bio-nano interface and protein corona with following therapeutic implications, a useful investigation model on the basis of RADAR concept is suggested. The contents of RADAR concept consist of five modules: 1- Reshape of our strategy for synthesis of nanoparticles (NPs), 2- Application of NPs selected based on human fluid, 3- Delivery strategy of NPs selected based on target tissue, 4- Analysis of proteins present on corona using correct procedures and 5- Risk assessment and risk reduction upon the collection and analysis of results to increase drug delivery efficiency and drug efficacy. RADAR grouping strategy for revisiting protein corona phenomenon as a key of success will be discussed with respect to the current state of knowledge.

In this study the role of nicotine (NCT) administration on the intensity of rat testicular tissue alterations induced by quinine (QU) was evaluated.Forty adult Wistar rats were divided into four groups. Control (CON), NCT administrated (4 mg/kg) (NCT), QU treated (25 mg/kg for 7 days) (QU), and nicotine with quinine received (NCT+QU). After 28 days, serum testosterone and malondialdehyde (MDA) levels were measured. Testes and epididymides samples were prepared for determining tissue MDA levels, histomorphometry, microscopic indices of spermatogenesis, immunohistochemistry of p53 and sperm analysis.Testosterone levels were decreased significantly (P = .0004) in treated groups compared to CON group. Serum MDA levels were increased significantly (P = .0004) in NCT and QU groups compared to CON group. Tissue MDA levels were increased significantly (P = .0012) in NCT+QU group in comparison to CON group. These parameters were changed significantly in NCT+QU group compared to QU group. Seminiferous tubules diameter decreased significantly (P.0001) in treated groups compared to CON group and in NCT+QU group compared to QU group. The height of germinal epithelium decreased significantly (P = .0001) in NCT and NCT+QU groups compared to CON and QU groups. The number of Sertoli cells, spermatocytes, and spermatids decreased significantly in treated groups compared to CON group. The number of spermatogonia decreased significantly (P = .0017) in NCT and NCT+QU groups compared to CON group. The number of Sertoli cells, spermatogonia, and spermatocytes decreased significantly in NCT+QU group compared to QU group. All indices of spermatogenesis decreased in treated groups compared to CON group. The lowest mean of these indices was observed in NCT+QU group. The sperm viability decreased significantly (P.0001) in treated groups compared to CON group. Sperm count and motility decreased significantly in NCT and NCT+QU groups compared to CON group. All experimental groups showed the over-expression of p53 compared to CON group.The administration of nicotine could be involved in the exacerbation of testicular tissue alterations related to quinine therapy.

BACKGROUND/OBJECTIVES: Mutations in the Tubby gene (TUB) cause late-onset obesity and insulin resistance in mice and syndromic obesity in humans. Although TUB gene function has not yet been fully elucidated, studies in rodents indicate that TUB is involved in the hypothalamic pathways regulating food intake and adiposity. Aside from the function in central nervous system, TUB has also been implicated in energy metabolism in adipose tissue in rodents. We aimed to determine the expression and distribution patterns of TUB in man as well as its potential association with obesity. SUBJECTS/METHODS: In situ hybridization was used to localize the hypothalamic regions and cells expressing TUB mRNA. Using RT-PCR, we determined the mRNA expression level of the two TUB gene alternative splicing isoforms, the short and the long transcript variants, in the hypothalami of 12 obese and 12 normal-weight subjects, and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissues from 53 severely obese and 24 non-obese control subjects, and correlated TUB expression with parameters of obesity and metabolic health. RESULTS: Expression of both TUB transcripts was detected in the hypothalamus, while only the short TUB isoform was found in both VAT and SAT. TUB mRNA was detected in several hypothalamic regions involved in body weight regulation, including the nucleus basalis of Meynert and the paraventricular, supraoptic and tuberomammillary nuclei. We found no difference in the hypothalamic TUB expression between obese and control groups, while the level of TUB mRNA was significantly lower in adipose tissue of obese subjects as compared to controls. Also, TUB expression was negatively correlated with indices of body weight and obesity in a fat-depot-specific manner. CONCLUSIONS: Our results indicate high expression of TUB in the hypothalamus, especially in areas involved in body weight regulation, and the correlation between TUB expression in adipose tissue and obesity. These findings suggest a role for TUB in human obesity.International Journal of Obesity accepted article preview online, 30 August 2017. doi:10.1038/ijo.2017.214.

Item does not contain fulltext Acute rejection is one of the major immunological determinants of kidney graft function and survival. Early biomarkers to predict rejection are lacking. Emerging evidence reveals a crucial role for the monocyte/macrophage lineage cells in the pathogenesis of rejection. We hypothesized that higher pretransplant numbers of proinflammatory CD16+ monocytes can predict rejection. The study cohort consisted of 104 kidney transplant recipients (58 with no rejection and 46 with biopsy-proven rejection) and 33 healthy persons. Posttransplant median follow-up time was 14.7 mo (interquartile range 0.3-34 mo). Pretransplantation blood samples were analyzed by flow cytometry for monocyte immunophenotypes. Groups were compared by Cox regression models for the occurrence of acute rejection. We documented a significantly increased absolute number of pretransplant CD16+ monocytes in patients who developed biopsy-proven rejection after transplantation compared with those with no rejection (hazard ratio [HR] 1.60, 95% CI 1.28-2.00, p < 0.001) and healthy persons (HR 1.47, 95% CI 1.18-1.82, p < 0.001). In parallel, significantly fewer absolute numbers of CD16- monocytes were observed at pretransplant time points in rejectors versus nonrejectors (HR 0.74, 95% CI 0.58-0.94, p < 0,014). A higher pretransplant number of CD16+ monocytes is significantly associated with a higher risk of acute rejection after kidney transplantation.

Alzheimer's disease (AD) is a type of dementia that causes major issues for patients' memory, thinking, and behavior. Despite efforts to advance AD diagnostic and therapeutic tools, AD remains incurable due to its complex and multifactorial nature and lack of effective diagnostics/therapeutics. Nanoparticles (NPs) have demonstrated the potential to overcome the challenges and limitations associated with traditional diagnostics/therapeutics. Nanotechnology is now offering new tools and insights to advance our understanding of AD and eventually may offer new hope to AD patients. Here, we review the key roles of nanotechnologies in the recent literature, in both diagnostic and therapeutic aspects of AD, and discuss how these achievements may improve patient prognosis and quality of life.

Purpose The purpose of this paper is to present an improved conformal mapping (ICM) method that simultaneously considers the influence of relative recoil permeability of PMs, the armature reaction, the stator slotting, and the magnetic saturation on determination of the PM operating point in its different parts. Design/methodology/approach The ICM method is a time-effective method that considers the magnetic saturation by suitable increments in air-gap length under each tooth and also the width of slot openings. In this paper, the analytical and numerical conformal mappings such as the Schwarz-Christoffel (SC) mapping are used for magnetic field analysis due to the permanent magnets and the armature reaction in one slotted air gap. The field solution in the slotted air gap is obtained through the modulation of field solution in one slotless air-gap using the complex air-gap permeance. Findings The ICM method can consider the magnetic saturation in different electric loadings, and also the variation of PM operating points in its different parts. Practical implications The ICM method is applied to one surface mounted permanent magnet (SMPM) motor and is verified by comparing with the corresponding results obtained through finite element method (FEM), and frozen permeability finite element method (FP-FEM). Originality/value This paper presents an ICM method with a new technique for saturation effect modeling, which can be used to separate and calculate the on-load components of air-gap field and torque.

This paper introduces an improved conformal mapping (ICM) method for the calculation and analysis of unbalanced magnetic force (UMF) in eccentric surface-mounted permanent-magnet (SMPM) motors considering the static, dynamic, and mixed rotor eccentricities. Having the on-load air gap field components obtained through ICM, and by using the Maxwell Stress Tensor method, the ICM method accurately predicts the on-load components of magnetic local traction and UMF due to PMs, the armature reaction, and the mutual interaction between both fields under the rotor eccentricity. The other purpose of this paper is to illustrate the difference between the influences of static, dynamic, and mixed rotor eccentricities on the UMF using the ICM method. The influence of initial eccentricity angle and the magnitude of eccentricity on the UMF are also investigated under the static, dynamic, and mixed rotor eccentricities. The predicted results obtained through ICM are verified by comparing with the corresponding results obtained through finite element method and the frozen permeability method. The ICM method is also validated by the experiment.

Adipose tissue is a primary site of obesity-induced inflammation, which has been emerging as an important contributor to obesity associated disorders. The factors influencing adipose tissue-induced inflammation and the resulting pathophysiological events remain poorly understood. However, dietary fiber consumptions appear to be protective. Short-chain fatty acids such as propionic acid (PA) are the principal products of the dietary fiber fermentation by microbiota. Therefore, we aim to investigate the influence of PA on inflammation, lipogenesis and glucose uptake markers from human subcutaneous adipose tissue (SAT). We showed that the treatment of SAT with PA resulted in a significant downregulation of inflammatory parameters (e.g. TNF-α and IP-10) and macrophage markers (e.g. CD163 and MMP-9). The expression levels of PA receptors (i.e. G protein coupled receptor-41 and -43) in human primary adipocytes were very low in comparison with SAT and macrophages. Upon PA treatment, no anti-inflammatory effect was observed in human adipocytes. PA significantly upregulated the expression of lipoprotein lipase (LPL), sterol regulatory-element-binding protein-1c (SREBP-1c) and glucose transporter 4 (GLUT-4), which are associated with lipogenesis and glucose uptake. We also showed that the observed anti-inflammatory effects of PA on SAT were partly mediated by Gi/o protein coupled receptor. Our data suggests that PA anti-inflammatory effects on SAT are mediated partly via Gi/o proteins, leading to the improved expression of factors associated with lipogenesis and glucose uptake. These responses appeared to be not mediated by adipocytes; but most probably by macrophages. The current study provides new knowledge, which can be used as a potential new avenue for drug development in preventing obesity-related inflammation and metabolic disorders in future. Graphical abstract Schematic presentation of study flow and the components of the investigation. In this study the effect of propionic acid (PA) on inflammation investigated in human subcutaneous adipose tissue (SAT), human primary adipocytes and the expression of a few hallmark inflammatory components produced by SAT and human adipocytes.

Using a family of cationic gold nanoparticles (NPs) with similar size and charge, we demonstrate that proper surface engineering can control the nature and identity of protein corona in physiological serum conditions. The protein coronas were highly dependent on the hydrophobicity and arrangement of chemical motifs on NP surface. The NPs were uptaken in macrophages in a corona-dependent manner, predominantly through recognition of specific complement proteins in the NP corona. Taken together, this study shows that surface functionality can be used to tune the protein corona formed on NP surface, dictating the interaction of NPs with macrophages.

This paper introduces an improved conformal mapping (ICM) method for the separation of the on-load air-gap magnetic field components in surface-mounted permanent-magnet (SPM) motors under loading conditions. The ICM method can model the magnetic induction inside a permanent magnet (PM) due to the armature reaction and the relative recoil permeability. The ICM method can also consider the simultaneous influences of the armature reaction, the slotting effect, the magnetic saturation, and the relative recoil permeability in the determination of operating points of the PM in its different parts. Therefore, this proposed method can be useful for an on-load performance analysis of SPM motors. Three conformal mappings are used to reach the main canonical domain: two logarithmic complex functions and the Schwarz–Christoffel (SC) mapping. The field solution in the slotless domain is then mapped back into the slotted domain using the complex air-gap permeance. The field solution in the slotted domain is used to calculate the on-load air-gap field components due to the PMs and the armature reaction. These on-load field components allow the calculation of the on-load PM flux linkage, the on-load PM back-EMF, and the on-load torque components. The influences of electric loading on the on-load torque components and the on-load PM back-EMF are studied using the ICM method. The on-load cogging torque periodicity is confirmed to change due to the magnetic saturation, and the harmonic content of torque components and the PM back-EMF is also altered due to the electric loading. The accuracy of this developed model is verified by comparing the results obtained through the ICM method with the respective results obtained through the finite-element analysis and the frozen permeability method.

Aims Cannabinoids are the chemical compounds with a high affinity for cannabinoid receptors affecting the central nervous system through the release of neurotransmitters. However, the current knowledge related to the role of such compounds in the regulation of cellular aging is limited. This study aimed to investigate the effect of cannabidiol and tetrahydrocannabinol on the function of aged pancreatic islets. Main methods The expression of p53, p38, p21, p16, and Glut2 genes and β-galactosidase activity were measured as hallmarks of cell aging applying real-time PCR, ELISA, and immunocytochemistry techniques. Pdx1 protein expression, insulin release, and oxidative stress markers were compared between young and aged rat pancreatic islet cells. Key findings Upon the treatment of aged pancreatic islets cells with cannabidiol and tetrahydrocannabinol, the expression of p53, p38, p21 and the activity of β-galactosidase were reduced. Cannabidiol and tetrahydrocannabinol increase insulin release, Pdx1, Glut2, and thiol molecules expression, while the oxidative stress parameters were decreased. The enhanced expression of Pdx1 and insulin release in aged pancreatic islet cells reflects the extension of cell healthy aging due to the significant reduction of ROS. Significance This study provides evidence for the involvement of cannabidiol and tetrahydrocannabinol in the oxidation process of cellular aging.

Background and Aims: Starting from the cytotoxic effects of monosodium glutamate (MSG), the aim of this study was to evaluate the protective effects of quince leaf extract as natural antioxidant on the reproductive dysfunction induced by monosodium glutamate in rats. Material and methods: Monosodium glutamate was administrated with a dose of 30 and 60 mg/kg and quince leaf extract was administrated with a dose of 500 mg/kg. At the end of study, body and testicular weight measurement, hormonal and epididymal sperm analysis were performed. Results: Follicle stimulating hormone (FSH) and testosterone levels were reduced after administration of monosodium glutamate. The levels of luteinizing hormone (LH) exhibited no significant changes. Treatment with quince leaf extract led to improvement in follicle stimulating hormone and testosterone levels. Epididymal sperm population was reduced after administration of monosodium glutamate and treatment with quince leaf extract. The increased sperm motility rate induced by monosodium glutamate was reduced after treatment with quince leaf extract. Administration of monosodium glutamate led to more body weight gain in comparison to combined administration monosodium glutamate and quince leaf extract. Conclusions: The quince leaf extract can be effective in reduction of functional alterations of reproductive system induced by monosodium glutamate.

Contains fulltext : 153710.pdf (Publisher’s version ) (Open Access) Despite numerous developed drugs based on glucose metabolism interventions for treatment of age-related diseases such as diabetes neuropathies (DNs), DNs are still increasing in patients with type 1 or type 2 diabetes (T1D, T2D). We aimed to identify novel candidates in adipose tissue (AT) and pancreas with T2D for targeting to develop new drugs for DNs therapy.AT-T2D displayed 15 (e.g. SYT4 up-regulated and VGF down-regulated) and pancreas-T2D showed 10 (e.g. BAG3 up-regulated, VAV3 and APOA1 down-regulated) highly differentially expressed genes with neuronal functions as compared to control tissues. ELISA was blindly performed to measure proteins of 5 most differentially expressed genes in 41 human subjects. SYT4 protein was upregulated, VAV3 and APOA1 were down-regulated, and BAG3 remained unchanged in 1- Obese and 2- Obese-T2D without insulin, VGF protein was higher in these two groups as well as in group 3- Obese-T2D receiving insulin than 4-lean subjects. Interaction networks analysis of these 5 genes showed several metabolic pathways (e.g. lipid metabolism and insulin signaling).Pancreas is a novel site for APOA1 synthesis. VGF is synthesized in AT and could be considered as good diagnostic, and even prognostic, marker for age-induced diseases obesity and T2D. This study provides new targets for rational drugs development for the therapy of age-related DNs.

Background and Aims: Various types of infertility are associated with uncontrolled hyperglycemia and diabetes. Development of oxidative stress is one the most important factors in the alteration of spermatogenesis in diabetic conditions. Consequently, the reduction of oxidative stress with antioxidant compounds can be effective in the reduction of tissue alterations. The aim of this study was to evaluate the efficacy of coenzyme Q10 in improvement of spermatogenesis in adult diabetic rats. Material and Methods: 32 adult rats were divided into four groups of control and treatment. Coenzyme Q10 (10 mg/kg body weight - b.w.) was administrated to one control and one diabetic (intraperitoneal injection of 45 mg/kg b.w. of Streptozotocin) groups. Blood concentrations of FSH, LH and Testosterone were measured. Histology of testicular tissue and sperm analysis were considered for evaluation of spermatogenesis. Results: Administration of Coenzyme Q10 led to increase of pituitary gonadotropins levels in diabetic rats. Testosterone levels were not changed significantly. Testicular morphology, spermatogenic indices and sperm analysis were improved in treated diabetic rats. Conclusions: The results of this study suggest that the use of Coenzyme Q10 has positive effects in reduction of spermatogenic alterations following induction of experimental diabetes in rats.

Idiopathic pulmonary fibrosis (IPF) is a destructive disease in part resulting from premature or mature cellular aging. Protease-activated receptor-1 (PAR-1) recently emerged as a critical component in the context of fibrotic lung diseases. Therefore, we aimed to study the role of macrophages in PAR-1-mediated idiopathic pulmonary fibrosis. The number of macrophages were significantly reduced in lungs of PAR-1 antagonist (P1pal-12) treated animals upon bleomycin instillation. In line with these data, PAR-1 stimulation increased monocyte / macrophage recruitment in response to epithelium injury in in vitro trans-well assays. Moreover, macrophages induced fibroblasts migration, differentiation and secretion of collagen, which were inhibited in the presence of TGF-beta receptor inhibitors. Interestingly, these profibrotic effects were partially inhibited by treatment with the PAR-1 inhibitor P1pal-12. Using shRNA mediated PAR-1 knock down in fibroblasts, we demonstrate that fibroblast PAR-1 contributes to TGF-beta activation and production. Finally, we show that the macrophage-dependent induction of PAR-1 driven TGF-beta activation was mediated by FXa. Our data identify novel mechanisms by which PAR-1 stimulation on different cell types can contribute to IPF and identify macrophages as key players in PAR-1 dependent development of this devastating disease. IPF may result from cellular senescence mediated by macrophages in the lung.

Microbiota in human is a "mixture society" of different species (i.e. bacteria, viruses, funguses) populations with a different way of relationship classification to Human. Human GUT serves as the host of the majority of different bacterial populations (GUT flora, more than 500 species), which are with us ("from the beginning") in an innate manner known as the commensal (no harm to each other) and symbiotic (mutual benefit) relationship. A homeostatic balance of host-bacteria relationship is very important and vital for a normal health process. However, this beneficial relationship and delicate homeostatic state can be disrupted by the imbalance of microbiome-composition of gut microbiota, expressing a pathogenic state. A strict homeostatic balance of microbiome-composition strongly depends on several factors; 1- lifestyle, 2- geography, 3- ethnicities, 4- "mom" as prime of the type of bacterial colonization in infant and 5- the disease. With such diversity in individuals combined with huge number of different bacterial species and their interactions, it is wise to perform an in-depth systems biology (e.g. genomics, proteomics, glycomics, and etcetera) analysis of personalized microbiome. Only in this way, we are able to generate a map of complete GUT microbiota and, in turn, to determine its interaction with host and intra-interaction with pathogenic bacteria. A specific microbiome analysis provides us the knowledge to decipher the nature of interactions between the GUT microbiota and the host and its response to the invading bacteria in a pathogenic state. The GUT-bacteria composition is independent of geography and ethnicity but lifestyle well affects GUT-bacteria composition and function. Microbiome knowledge obtained by systems biology also helps us to change the behavior of GUT microbiota in response to the pathogenic microbes as protection. Functional microbiome changes in response to environmental factors will be discussed in this review. (C) 2017 Elsevier Ltd. All rights reserved.

A modified non-cross-linking gold-nanoparticles (Au-NPs) aggregation strategy has been developed for the label free colorimetric detection of DNAs/RNAs based on self-assembling target species in the presence of thiolated probes. Two complementary thiol- modified probes, each of which specifically binds at one half of the target introduced SH groups at both ends of dsDNA. Continuous disulfide bond formation at 3′ and 5′ terminals of targets leads to the self-assembly of dsDNAs into the sulfur- rich and flexible products with different lengths. These products have a high affinity for the surface of Au-NPs and efficiently protect the surface from salt induced aggregation. To evaluate the assay efficacy, a small part of the citrus tristeza virus (CTV) genome was targeted, leading to a detection limit of about 5 × 10−9 mol.L−1 over a linear ranged from 20 × 10−9 to 10 × 10−7 mol.L−1. This approach also exhibits good reproducibility and recovery levels in the presence of plant total RNA or human plasma total circulating RNA extracts. Self-assembled targets can be then sensitively distinguished from non-assembled or mismatched targets after gel electrophoresis. The disulfide reaction method and integrating self-assembled DNAs/RNAs targets with bare AuNPs as a sensitive indicator provide us a powerful and simple visual detection tool for a wide range of applications.

—The necessity of using a 3D model is one of the main problems for modeling Roebel bar transposition in turbo-generators by the finite-element method. This article proposes a 2D dual model for computing strand current distribution in the Roebel bar of turbo-generators. Considering the leakage and mutual inductances for each strand and the coupling inductances between them, the end winding region is modeled in this 2D dual model. In this article, the Roebel bar structure including 16 strands was considered, and these distributions are calculated for different transpositions using the finite-element method. In the finite-element method model, the circulating currents are calculated by subtracting a load current at each strand from the total of strand current. Also, for different transpositions, such as 90°, 180°, 360°, and 540°, the circulating currents are calculated using an analytical method. The obtained strand current distributions from the 2D dual model have good agreement with the obtained re...

Representing a crucial T-helper 1 cytokine, IFN-gamma acts as an important bridge between innate and adaptive immunity and is involved in many acute and chronic pathologic states, such as autoimmune diseases and solid organ transplant rejection. At present, debate still prevails about the ability of human monocytes to produce IFN-gamma. We aimed to investigate whether human monocytes possess the capacity to produce IFN-gamma at mRNA and protein level. Using real time PCR, flow cytometric analysis and ELISA, we investigated the capacity of freshly isolated CD14+ monocytes of healthy individuals and kidney transplant recipients to produce IFN-gamma after stimulation with IFN-gamma and LPS or LPS alone. We observed increased IFN-gamma mRNA levels in CD14+ monocytes after stimulation as compared to the unstimulated controls in both populations. In addition, stimulation with IFN-gamma and LPS or LPS alone led to a significant increase in the percentage of CD14+ monocytes producing TNF-alpha and IFN-gamma at protein level (p

SummaryApart from transporting lipids through the body, the human plasma lipoproteins very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) are also thought to serve as a modality for intra-organismal protein transfer, shipping proteins with important roles in inflammation and thrombosis from the site of synthesis to effector locations. To better understand the role of VLDL and LDL in the transport of proteins, we applied a combination of LTQ ORBITRAP-XL (nLC-MS/MS) with both in-SDS-PAGE gel and in-solution tryptic digestion of pure and defined VLDL and LDL fractions. We identified the presence of 95 VLDL-and 51 LDL-associated proteins including all known apolipoproteins and lipid transport proteins, and intriguingly a set of coagulation proteins, complement system and anti-microbial proteins. Prothrombin, protein S, fibrinogen γ, PLTP, CETP, CD14 and LBP were present on VLDL but not on LDL. Prenylcysteine oxidase 1, dermcidin, cathelicidin antimicrobial peptide, TFPI-1 and fibrinogen α chain were associated with both VLDL and LDL. Apo A-V is only present on VLDL and not on LDL. Collectively, this study provides a wealth of knowledge on the protein constituents of the human plasma lipoprotein system and strongly supports the notion that protein shuttling through this system is involved in the regulation of biological processes. Human diseases related to proteins carried by VLDL and LDL can be divided in three major categories: 1 – dyslipidaemia, 2 – atherosclerosis and vascular disease, and 3 – coagulation disorders.

International audience; The toxicity of two types of ultra-small zeolites (8-18 nm) with LTL-and EMT-type structures is reported. Both the LTL- and EMT-type zeolites belong to the same group of molecular sieves; they have large pores (7.1-7.5 angstrom) and low silica content (Si/Al = 1.2-2.3). The zeolites are prepared by an environmentally friendly synthetic approach from precursor suspensions without using any organic template. Cellular interactions with the two types of zeolite nanocrystals are evaluated by cell viability, reactive oxygen species and cell life cycle assays. It is found that various concentrations of zeolites have negligible effects on the cell life cycle. Moreover, the LTL- and EMT-types zeolites did not cause extensive oxidative stress on the cells. Although it is seen that the zeolites extensively entered in the cells, there is no sign of toxicity for all employed concentrations of ultra-small EMT and LTL zeolites. Additionally, no abnormality in DNA replication while exposed to the zeolites is observed. Very importantly, the zeolite corona shows a high affinity for fibrinogen, moderate affinity for apoA-II and complement factor 3, and trace affinity for albumin, which is the most abundant protein of human plasma. Thus the zeolite nanoparticles can be considered as very promising material for purification of fibrinogen and lipoproteins. Since fibrinogen is considered as acute phase protein and found to be the most associated biomolecule in the composition of corona at the surface of zeolites, we propose that these nanoparticles can be potentially pro-inflammatory for in vivo applications.

Tolerance induction is the basis of a successful transplantation with the goal being the re-establishment of homeostasis after transplantation. Non-autograft transplantation disrupts this maintenance drastically which would be avoided by administration of a novel procedure. At present, the blood group antigens and the genotypes of the donor and recipient are cross-matched before transplantation combined with a drug regimen that confers general immunosuppression. But the 'specific' unresponsiveness of the recipient to the donor organ, implied by 'tolerance', is not achieved in this process. This article introduces the 'donor chimera model' via the concept of the 'closed transplantation loop' approach for tolerance induction which seeks to limit the use of immunosuppressive therapy after transplantation. (C) 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC). Cellular senescence contributes to age-related tissue dysfunction, but the epigenetic basis underlying drug-induced senescence remains unclear. macroH2A1, a variant of histone H2A, is a marker of senescence-associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. In this study, we investigated the relationship between macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, and liver carcinogenesis. We found that protein levels of both macroH2A1 isoforms were increased in the livers of very elderly rodents and humans, and were robust immunohistochemical markers of human cirrhosis and HCC. In response to the chemotherapeutic and DNA-demethylating agent 5-aza-deoxycytidine (5-aza-dC), transgenic expression of macroH2A1 isoforms in HCC cell lines prevented the emergence of a senescent-like phenotype and induced synergistic global DNA hypomethylation. Conversely, macroH2A1 depletion amplified the antiproliferative effects of 5-aza-dC in HCC cells, but failed to enhance senescence. Senescence-associated secretory phenotype and whole-transcriptome analyses implicated the p38 MAPK/IL8 pathway in mediating macroH2A1-dependent escape of HCC cells from chemotherapy-induced senescence. Furthermore, chromatin immunoprecipitation sequencing revealed that this hepatic antisenescence state also required active transcription that could not be attributed to genomic occupancy of these histones. Collectively, our findings reveal a new mechanism by which drug-induced senescence is epigenetically regulated by macroH2A1 and DNA methylation and suggest macroH2A1 as a novel biomarker of hepatic senescence that could potentially predict prognosis and disease progression. Cancer Res; 76(3); 594–606. ©2016 AACR.

Background Adipose tissue is a primary site of obesity-induced inflammation, which is emerging as an important contributor to obesity-related diseases such as type 2 diabetes. Dietary fibre consumption appears to be protective. Short-chain fatty acids, e.g. propionic acid, are the principal products of the colonic fermentation of dietary fibre and may have beneficial effects on adipose tissue inflammation. Materials and methods Human omental adipose tissue explants were obtained from overweight (mean BMI 28·8) gynaecological patients who underwent surgery. Explants were incubated for 24h with propionic acid. Human THP-1 monocytic cells were differentiated to macrophages and incubated with LPS in the presence and absence of propionic acid. Cytokine and chemokine production were determined by multiplex-ELISA, and mRNA expression of metabolic and macrophages genes was determined by RT-PCR. Results Treatment of adipose tissue explants with propionic acid results in a significant down-regulation of several inflammatory cytokines and chemokines such as TNF-α and CCL5. In addition, expression of lipoprotein lipase and GLUT4, associated with lipogenesis and glucose uptake, respectively, increased. Similar effects on cytokine and chemokine production by macrophages were observed. Conclusion We show that propionic acid, normally produced in the colon, may have a direct beneficial effect on visceral adipose tissue, reducing obesity-associated inflammation and increasing lipogenesis and glucose uptake. Effects on adipose tissue as a whole are at least partially explained by effects on macrophages but likely also adipocytes are involved. This suggests that, in vivo, propionic acid and dietary fibres may have potential in preventing obesity-related inflammation and associated diseases. © 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.

Hedgehog is one of the major morphogens and fulfils critical functions in both the development and maintenance of the vasculature. Hedgehog is highly hydrophobic and its diffusion toward target tissues remains only partly understood. In Drosophila, hedgehog transport via lipophorins is relevant for development, but neither the presence nor a function for a mammalian Hedgehog carried by human plasma lipoproteins has been established. We investigated the presence of Hedgehog on lipoprotein particles and determined its importance for maintaining the endothelium. LTQ-Orbitrap XL analysis of defined plasma lipoproteins revealed that Indian Hedgehog (Ihh) is present in the human very low density lipoprotein (VLDL) fraction but not in other plasma lipoprotein fractions (low density lipoprotein (LDL) and high density lipoprotein (HDL)). Using the same approach, neither Sonic Hedgehog nor Desert Hedgehog could be detected in plasma lipoprotein fractions. Most likely, primary white adipocytes are the source of Ihh loading on VLDL as both transcriptome as well as immunofluorescence analysis showed high expression of lhh in these cells. Additionally, we show that the endothelial compartment is most likely to be affected by the presence of Ihh on VLDL. Indeed, VLDL increased survival of primary endothelial cells, suggesting that Ihh transport by VLDL is important for maintaining the human endothelium. In conclusion, our study shows that VLDL carries Ihh throughout the body in mammals and Hedgehog signaling by human plasma VLDL particles may affect blood vessel pathophysiology. A combination of three state-of-the-art technologies, proteomics, genomics, and confocal microscopy, appeared to be a powerful tool for analyzing plasma lipoprotein-associated proteins.

Background Dietary fibre (DF) has been shown to be protective for the development of obesity, insulin resistance and type 2 diabetes. Short-chain fatty acids, produced by colonic fermentation of DF might mediate this beneficial effect. Adipose tissue plays a key role in the regulation of energy homeostasis, therefore, we investigated the influence of the short-chain fatty acid propionic acid (PA) on leptin, adiponectin and resistin production by human omental (OAT) and subcutaneous adipose tissue (SAT). As PA has been shown to be a ligand for G-protein coupled receptor (GPCR) 41 and 43, we investigated the role of GPCR's in PA signalling. Materials and methods Human OAT and SAT explants were obtained from gynaecological patients who underwent surgery. Explants were incubated for 24 h with PA. Adipokine secretion and mRNA expression were determined using ELISA and RT-PCR respectively. Results We found that PA significantly stimulated leptin mRNA expression and secretion by OAT and SAT, whereas it had no effect on adiponectin. Furthermore, PA reduced resistin mRNA expression. Leptin induction, but not resistin reduction, was abolished by inhibition of Gi/o-coupled GPCR signalling. Moreover, GPCR41 and GPCR43 mRNA levels were considerably higher in SAT than in OAT. Conclusions We demonstrate that PA stimulates expression of the anorexigenic hormone leptin and reduces the pro-inflammatory factor resistin in human adipose tissue depots. This suggests that PA is involved in regulation of human energy metabolism and inflammation and in this way may influence the development of obesity and type 2 diabetes. © 2010 Stichting European Society for Clinical Investigation Journal Foundation.

Pancytopenia, hepatosplenomegaly and skeletal complications are hallmarks of Gaucher disease. Monitoring of the outcome of therapy on skeletal status of Gaucher patients is problematic since currently available imaging techniques are expensive and not widely accessible. The availability of a blood test that relates to skeletal manifestations would be very valuable. We here report that macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta, both implicated in skeletal complications in multiple myeloma (MM), are significantly elevated in plasma of Gaucher patients. Plasma MIP-1 alpha of patients (median 78 pg/ml, range 21-550 pg/ml, n = 48) is elevated (normal median 9 pg/ml, range 0-208 pg/ml, n = 39). Plasma MIP-1 beta of patients (median 201 pg/ml, range 59-647 pg/ml, n = 49) is even more pronouncedly increased (non-nal median 17 pg/ ml, range 1-41 pg/ml, n = 39; one outlier: 122 pg/ml). The increase in plasma MIP-1 beta levels of Gaucher patients is associated with skeletal disease. The plasma levels of both chemokines decrease upon effective therapy. Lack of reduction of plasma MIP-1 beta below 85 pg/ml during 5 years of therapy was observed in patients with ongoing skeletal disease. In conclusion, MIP-1 alpha and MIP-1 beta are elevated in plasma of Gaucher patients and remaining high levels of MIP-1 beta during therapy seem associated with ongoing skeletal disease. (c) 2007 Elsevier B.V. All rights reserved

Aims: We aimed to investigate the physicochemical effects of superparamagnetic iron oxide nanoparticles (SPIONs) on the composition of the protein corona and their correspondence toxicological issues. Materials & methods: SPIONs of different sizes and surface charges were exposed to fetal bovine serum. The structure/composition and biological effects of the protein corona–SPION complexes were probed. Results & discussion: The affinity and level of adsorption of specific proteins is strongly dependent on the size and surface charge of the SPIONs. In vivo experiments on the mouse blood–brain barrier model revealed that nontargeted SPIONs containing specific proteins will enter the brain endothelial barrier cells. Conclusion: Some commercially available nanoparticles used for target-specific applications may have unintended uptake in the body (e.g., brain tissue) with potential cytotoxity.

Lipid droplets (LDs) hypertrophy in adipocytes is the main cause of energy metabolic system dysfunction, obesity and its afflictions such as T2D. However, the role of adipocytes in linking energy metabolic disorders with insulin regulation is unknown in humans. Human adipocytes constitutively synthesize and secrete insulin, which is biologically functional. Insulin concentrations and release are fat mass- and LDs-dependent respectively. Fat reduction mediated by bariatric surgery repairs obesity-associated T2D. The expression of genes, like PCSK1 (proinsulin conversion enzyme), GCG (Glucagon), GPLD1, CD38 and NNAT, involved in insulin regulation/release were differentially expressed in pancreas and adipose tissue (AT). INS (insulin) and GCG expression reduced in human AT-T2D as compared to AT-control, but remained unchanged in pancreas in either state. Insulin levels (mRNA/protein) were higher in AT derived from prediabetes BB rats with destructed pancreatic β-cells and controls than pancreas derived from the same rats respectively. Insulin expression in 10 human primary cell types including adipocytes and macrophages is an evidence for extrapancreatic insulin-producing cells. The data suggest a crosstalk between AT and pancreas to fine-tune energy metabolic system or may minimize the metabolic damage during diabetes. This study opens new avenues towards T2D therapy with a great impact on public health.

Plasma lipoproteins, such as high-density lipoprotein (HDL), can serve as carriers for a wide range of proteins that are involved in processes such as lipid metabolism, thrombosis, inflammation and atherosclerosis. The identification of HDL-associated proteins is essential with regards to understanding these processes at the molecular level. In this study, a combination of proteomic approaches including 1-DE and 2-DE MALDI-TOF, isotope-coded affinity tag and Western blot analysis were employed to identify proteins associated with human HDL. To minimize potential losses of HDL-associated proteins during isolation, a one-step ultracentrifugation technique was applied and the quality of purified HDL was confirmed by nephelometry, high-performance gel chromatography, and Western blot analysis. MS analysis revealed the presence of 56 HDL-associated proteins including all known apolipoproteins and lipid transport proteins. Furthermore, proteins involved in hemostasis and thrombosis, the immune and complement system were found. In addition, growth factors, receptors, hormone-associated proteins and many other proteins were found to be associated with HDL. Our approach thus resulted in the identification of a large number of proteins associated with HDL. The combination of proteomic technologies proved to be a powerful and comprehensive tool for the identification of proteins on HDL.

SummaryAlthough many epidemiological studies have shown an association between hyperfibrinogenemia and atherosclerosis, it is not established whether elevated fibrinogen has an etiological role in the pathogenesis or is only a reflection of the ongoing disease.We have studied the contribution of fibrinogen to the development of atherosclerosis in atherosclerosis-prone ApoE*3-Leiden mice that have been cross-bred with transgenic mice overexpressing fibrinogen. Genetic compound offspring were used to evaluate the progression of atherosclerotic lesions after being fed an atherogenic diet for 7 weeks. It was observed that the lesion area of the plaques as well as the severity of the lesions in the aortic valve was comparable in control single transgenic ApoE*3-Leiden mice and in double transgenic apoE*3-Leiden mice overexpressing fibrinogen. No thrombus or fibrin deposition was observed in atherosclerotic lesions in either group of mice.These results indicate that elevated plasma fibrinogen concentrations in ApoE*3-Leiden transgenic mice do not affect the progression of diet-induced atherosclerotic lesions.

Due to its high energy density, NdFeB permanentmagnets (PM) are very often used in the rotors of radial-flux PM machines. As the NdFeB-magnets are good electric conductive, electric currents are induced in the magnets when they are exposed to a varying magnetic field. This varying magnetic field has two causes: variation of the air-gap reluctance due to the effect of stator slots, and armature reaction due to the stator currents when the machine is supplied with invertor. The rise of temperature due to eddy current loss in the PM leads to serious deterioration of the PM, especially in high speed operation. This paper describes an original analysis of the eddy current loss in the PM of a surface-mounted PM synchronous machines (PMSM) for electric vehicles, and also harmonic analysis of eddy current loss is carried out to calculate PM eddy current loss due to carrier harmonics of the PWM inverter. And then segmentation of magnets was proposed to reduce magnet eddy current loss, and finally a new structure based on segmentation was proposed to optimize the eddy current loss.

SummaryHyperfibrinogenemia is a risk predictor in several diseases, including cardiovascular disease. Nevertheless, it remains unknown whether elevated fibrinogen has an etiologic role in or is a reflection of disease pathogenesis, or both. To examine this question, we generated a mouse model of hyperfibrinogenemia. We isolated the mouse fibrinogen locus, containing the three fibrinogen genes, in a single P1 clone. This ~ 100 kb clone was injected into C57Bl/6J zygotes. Three transgenic lines were identified, two with elevated fibrinogen, 1.4- and 1.7-fold relative to normal. We characterized the line with the higher level. Northern blots of total RNA showed transgene expression was liver specific, and the message levels were 2- to 3-fold enhanced. Fibrinogen in transgenic mice was normal in both immunologic and clotting assays. Our data indicate that over-expression of all three fibrinogen genes is necessary to achieve hyperfibrinogenemia. We saw no increase in mortality or morbidity, no gross abnormalities in the organs, and no histologic differences in lung, liver, spleen or kidney, in transgenic mice relative to normal littermates. We conclude that elevated fibrinogen did not cause disease in mice. We anticipate that breeding these mice to other mouse models of disease will demonstrate whether hyper-fibrinogenemia has a role in the initiation or progression of symptomatic disease.