Miracle-dz/UniFAR-FTUs huggingface dataset:
Extracellular matrix remodelling in human aortic valve disease: the role of matrix metalloproteinases and their tissue inhibitors.

AIMS Aortic valve diseases are characterized by pathological remodelling of valvular tissue but the cellular and molecular effectors involved in these processes are not well known. The role of matrix metalloproteinase (MMP)-2, MMP-9, MMP-3, MMP-7, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 and TIMP-2 are investigated here. METHODS AND RESULTS Histological analysis of pathological valves [aortic stenosis (AS) (n=49), aortic regurgitation (AR) (n=23)] and control valves (n=8) was performed. The main tissue abnormalities (calcification, inflammatory cells, and capillaries) observed in AS were less severe or absent in AR. However, both groups of pathological valves displayed similar histological signs of extracellular matrix (ECM) remodelling. Biochemical analysis of MMPs and TIMPs (gelatin and casein zymography and ELISA) was performed on valve extracts. MMP-2 activity was not significantly different in control and pathological valves. Increases in MMP-9 and MMP-3 in AS demonstrated an inflammatory state. Finally, there was a four- to seven-fold increase of TIMP-1 in pathological valves. TIMP-1, TIMP-2, and MMP-2 were synthesized by the valvular interstitial cells in primary culture. CONCLUSION This study demonstrates the involvement of the MMP/TIMP system in ECM remodelling of both AS and AR. These findings provide evidence of inflammatory injury more severe in AS than in AR and involvement of mesenchymal cell response.
Interleukin-6, High Sensitivity C-Reactive Protein, and the Development of Type 2 Diabetes Among HIV-Positive Patients Taking Antiretroviral Therapy

Background:HIV infection is associated with increased levels of inflammatory markers. Inflammation is hypothesized to play a role in the development of type 2 diabetes. Data addressing this issue among HIV-positive participants are limited. Methods:A cohort of 3695 participants without diabetes, taking antiretroviral therapy and with an average CD4+ count of 523 cells/mm3, were followed for an average of 4.6 years. Diabetes risk associated with baseline levels of high sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) was assessed using Cox proportional hazards regression models. Analyses considered baseline levels of factors associated with diabetes risk and HIV-related measures. Results:One hundred thirty-seven patients developed diabetes requiring drug treatment during follow-up (8.18 per 1000 person-years). Median levels of IL-6 and hsCRP were significantly higher among those who developed diabetes compared with those who did not: 3.45 versus 2.50 pg/mL for IL-6 and 4.91 versus 3.29 µg/mL for hsCRP (P < 0.001). Adjusted hazard ratios associated with a doubling of IL-6 and hsCRP were 1.29 (95% confidence interval: 1.08 to 1.55; P = 0.005) and 1.22 (95% confidence interval: 1.10 to 1.36; P < 0.001), respectively. Body mass index (P < 0.001), age (P = 0.013), coinfection with hepatitis B or C (P = 0.03), nonsmoking status (P = 0.034), and use of lipid-lowering treatment (P = 0.008) were also associated with an increased risk of diabetes. Conclusions:These findings indicate that low-grade systemic inflammation is an underlying factor in the pathogenesis of diabetes.
Study of the Relationship Between Glucose and Insulin Responses to an Oral Glucose Load in Man

Oral glucose tolerance tests have been performed on 125 patients, and the ensuing changes in plasma glucose and insulin concentrations have been measured. The possible effects of factors which could modify the nature of these responses (obesity, age, sex, family history of diabetes, and indications for performing the tolerance test) have been extensively evaluated. None of these variables were found to have a statistically significant effect on the plasma glucose and insulin responses. Two general relationships between glucose and insulin responses have been defined within the population studied. One, based on the quantitative aspects of the glucose and insulin responses, indicated that there was at first an increase, and then, a decrease in the insulin response to progressive degrees of hyperglycemia. The second relationship was independent of the absolute concentrations of either glucose and insulin, and states that the pattern of glucose response during the three hours of the tolerance test determines the pattern of the insulin response during this same time interval.
A threading-based method (FINDSITE) for ligand-binding site prediction and functional annotation

The detection of ligand-binding sites is often the starting point for protein function identification and drug discovery. Because of inaccuracies in predicted protein structures, extant binding pocket-detection methods are limited to experimentally solved structures. Here, FINDSITE, a method for ligand-binding site prediction and functional annotation based on binding-site similarity across groups of weakly homologous template structures identified from threading, is described. For crystal structures, considering a cutoff distance of 4 Å as the hit criterion, the success rate is 70.9% for identifying the best of top five predicted ligand-binding sites with a ranking accuracy of 76.0%. Both high prediction accuracy and ability to correctly rank identified binding sites are sustained when approximate protein models (<35% sequence identity to the closest template structure) are used, showing a 67.3% success rate with 75.5% ranking accuracy. In practice, FINDSITE tolerates structural inaccuracies in protein models up to a rmsd from the crystal structure of 8–10 Å. This is because analysis of weakly homologous protein models reveals that about half have a rmsd from the native binding site <2 Å. Furthermore, the chemical properties of template-bound ligands can be used to select ligand templates associated with the binding site. In most cases, FINDSITE can accurately assign a molecular function to the protein model.
Attenuated microglial activation mediates tolerance to the neurotoxic effects of methamphetamine

Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. Repeated, intermittent treatment of mice with low doses of methamphetamine leads to the development of tolerance to its neurotoxic effects. The mechanisms underlying tolerance are not understood but clearly involve more than alterations in drug bioavailability or reductions in the hyperthermia caused by methamphetamine. Microglia have been implicated recently as mediators of methamphetamine‐induced neurotoxicity. The purpose of the present studies was to determine if a tolerance regimen of methamphetamine would attenuate the microglial response to a neurotoxic challenge. Mice treated with a low‐dose methamphetamine tolerance regimen showed minor reductions in striatal dopamine content and low levels of microglial activation. When the tolerance regimen preceded a neurotoxic challenge of methamphetamine, the depletion of dopamine normally seen was significantly attenuated. The microglial activation that occurs after a toxic methamphetamine challenge was blunted likewise. Despite the induction of tolerance against drug‐induced toxicity and microglial activation, a neurotoxic challenge with methamphetamine still caused hyperthermia. These results suggest that tolerance to methamphetamine neurotoxicity is associated with attenuated microglial activation and they further dissociate its neurotoxicity from drug‐induced hyperthermia.
Perineurioma: a distinctive and underrecognized peripheral nerve sheath neoplasm.

CONTEXT Perineuriomas are benign peripheral nerve sheath neoplasms composed of perineurial cells with characteristic immunohistochemical and ultrastructural features. They have been traditionally classified into two main types according to their location--intraneural and extraneural--and overlap histologically with many other tumors, which may be diagnostically challenging to general surgical pathologists. OBJECTIVE To review the clinical, morphologic, immunohistochemical, ultrastructural, cytogenetic, and molecular genetic aspects of perineurioma, as well as to discuss its clinicopathologic variants and differential diagnosis. DATA SOURCES English-language literature published between 1966 and 2005 was reviewed. CONCLUSIONS The correct identification of perineuriomas is important to avoid unnecessary overtreatment. The histologic diagnosis should be confirmed through immunohistochemical studies (including epithelial membrane antigen, S100 protein, and more recently described antibodies such as claudin-1 and GLUT1) or electron microscopy. Cytogenetic and molecular genetic studies are still of limited value for the diagnosis of perineuriomas but may play a fundamental role in excluding important differential diagnoses and also in helping elucidate the biology of these poorly known neoplasms.
ImmuKnow as a diagnostic tool for predicting infection and acute rejection in adult liver transplant recipients: A systematic review and meta‐analysis

Immune status monitoring of transplant recipients could identify patients at risk of acute rejection, infection, and cancer, which are important sources of morbidity and mortality in these patients. The ImmuKnow assay provides an objective assessment of the cellular immune function of immunosuppressed patients. Inconclusive results concerning the ability of the ImmuKnow test to predict acute rejection and infection have raised concerns about the predictive value of ImmuKnow in liver transplant recipients. We conducted a systematic literature review to identify studies published up to March 2012 that documented the use of ImmuKnow for monitoring immune function in liver transplant recipients. The study quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 score. We identified 5 studies analyzing ImmuKnow performance for infection and 5 studies analyzing ImmuKnow performance for acute rejection. The pooled sensitivity, specificity, positive likelihood ratio, diagnostic odds ratio, and area under the summary receiver operating characteristic curve were 83.8% [95% confidence interval (CI) = 78.5%‐88.3%], 75.3% (95% CI = 70.9%‐79.4%), 3.3 (95% CI = 2.8‐4.0), 14.6 (95% CI = 9.6‐22.3), and 0.824 ± 0.034, respectively, for infection and 65.6% (95% CI = 55.0%‐75.1%), 80.4% (95% CI = 76.4%‐83.9%), 3.4 (95% CI = 2.4‐4.7), 8.8 (95% CI = 3.1‐24.8), and 0.835 ± 0.060, respectively, for acute rejection. Heterogeneity was low for infection studies and high for acute rejection studies. In conclusion, the ImmuKnow test is a valid tool for determining the risk of further infection in adult liver transplant recipients. Significant heterogeneity across studies precludes the conclusion that ImmuKnow identifies liver transplant patients at risk for rejection. Liver Transpl 18:1245–1253, 2012. © 2012 AASLD.
Expression of miR-142-5p in Peripheral Blood Mononuclear Cells from Renal Transplant Patients with Chronic Antibody-Mediated Rejection

In renal transplantation, the unresponsiveness of patients undergoing chronic antibody mediated rejection (CAMR) to classical treatment stress on the need for accurate biomarkers to improve its diagnosis. We aim to determine whether microRNA expression patterns may be associated with a diagnosis of CAMR. We performed expression profiling of miRNAs in peripheral blood mononuclear cells (PBMC) of kidney transplant recipients with CAMR or stable graft function. Among 257 expressed miRNAs, 10 miRNAs associated with CAMR were selected. Among them, miR-142-5p was increased in PBMC and biopsies of patients with CAMR as well as in a rodent model of CAMR. The lack of modulation of miR-142-5p in PBMC of patients with renal failure, suggests that its over-expression in CAMR was associated with immunological disorders rather than renal dysfunction. A ROC curve analysis performed on independent samples showed that miR-142-5p is a potential biomarker of CAMR allowing a very good discrimination of the patients with CAMR (AUC = 0.74; p = 0.0056). Moreover, its expression was decreased in PHA-activated blood cells and was not modulated in PBMC from patients with acute rejection, excluding a non-specific T cell activation expression. The absence of modulation of this miRNA in immunosuppressed patients suggests that its expression was not influenced by treatment. Finally, the analysis of miR-142-5p predicted targets under-expressed in CAMR PBMC in a published microarray dataset revealed an enrichment of immune-related genes. Altogether, these data suggest that miR-142-5p could be used as a biomarker in CAMR and these finding may improve our understanding of chronic rejection mechanisms.
Surface Modification of Ti6Al4V Open Porous Structures Produced by Additive Manufacturing

Additive manufacturing techniques can be used to produce micro‐porous structures with global morphological properties that are highly controlled through robust computer design. Despite these advantages, most of these techniques still hold several functional constraints, resulting from present technical device limits and consequently the inability to control surface morphology at a microscale level. In this study, a novel protocol for surface modification of 3D titanium alloy‐based open porous structures is developed, which applies a combination of chemical etching (CHE) and electrochemical polishing (ECP) using HF‐based solutions. This protocol achieves significant and controllable roughness reduction of additive manufactured 3D Ti6Al4V open porous structures. Chemical etching mainly removes the attached powder grains, while ECP further decreases the roughness. In this way the heterogeneity of the strut surface roughness throughout the full 3D structure is effectively removed.
Why insulin sensitizers but not secretagogues should be retained when initiating insulin in type 2 diabetes

The stringent targets set for HbA1c levels in type 2 diabetes are currently achieved by fewer than half the patients in the United States. Failure to manage hyperglycaemia in the early stages of disease results in progressive loss of β‐cell function, which ultimately necessitates the initiation of insulin therapy. At this point, choices have to be made on whether to continue oral anti‐diabetic drug therapy and, if so, with which agent(s). Historically, sulfonylureas have been the mainstay of oral anti‐diabetic drug therapy; however, their long‐term efficacy in patients with depleted β‐cell capacity is doubtful, and other classes of oral anti‐diabetic drugs, notably the insulin sensitizers, may prove more reliable. These agents (metformin and thiazolidinediones) appear to provide various benefits over and above sustained glycaemic control, which may variably include reduced loss of β‐cell function as well as improvements to cardiovascular risk factors, morbidity, and mortality. Metformin also limits weight gain associated with insulin therapy. This manuscript presents the case that when insulin therapy is initiated it should be tailored to individual needs through combination with one or more insulin sensitizers rather than a secretagogue. Copyright © 2007 John Wiley & Sons, Ltd.
Mast cells and basophils.

No wonder you activities are, reading will be always needed. It is not only to fulfil the duties that you need to finish in deadline time. Reading will encourage your mind and thoughts. Of course, reading will greatly develop your experiences about everything. Reading mast cells and basophils is also a way as one of the collective books that gives many advantages. The advantages are not only for you, but for the other peoples with those meaningful benefits.
Interdicting Gq Activation in Airway Disease by Receptor-Dependent and Receptor-Independent Mechanisms

Gαqβγ heterotrimer (Gq), an important mediator in the pathology of airway disease, plays a central role in bronchoconstriction and airway remodeling, including airway smooth muscle growth and inflammation. Current therapeutic strategies to treat airway disease include the use of muscarinic and leukotriene receptor antagonists; however, these pharmaceuticals demonstrate a limited clinical efficacy as multiple Gq-coupled receptor subtypes contribute to these pathologies. Thus, broadly inhibiting the activation of Gq may be an advantageous therapeutic approach. Here, we investigated the effects of broadly inhibiting Gq activation in vitro and ex vivo using receptor-dependent and receptor-independent strategies. P4pal-10 is a protease activated receptor 4–derived pepducin that exhibits efficacy toward multiple Gq-coupled receptors. Mechanistic studies demonstrated that P4pal-10 selectively inhibits all G protein coupling to several Gq-coupled receptors, including protease activated receptor 1, muscarinic acetylcholine M3, and histamine H1 receptors, while demonstrating no direct effect on Gq. We also evaluated the ability of FR900359, also known as UBO-QIC, to directly inhibit Gq activation. FR900359 inhibited spontaneous Gαq nucleotide exchange, while having little effect on Gαsβγ, Gαiβγ, or Gα12/13βγ heterotrimer activity. Both P4pal-10 and FR900359 inhibited Gq-mediated intracellular signaling and primary human airway smooth muscle growth, whereas only FR900359 effectively interdicted agonist-promoted airway contraction in human precision cut lung slices. These studies serve as a proof of concept that the broad-based inhibition of Gq activation may be a useful therapeutic approach to treat multiple common pathologies of airway disease.
Mitral Leaflet Changes Following Myocardial Infarction: Clinical Evidence for Maladaptive Valvular Remodeling

Background— Ischemic mitral regurgitation (MR) is classically ascribed to functional restriction of normal leaflets, but recent studies have suggested post–myocardial infarction (MI) mitral valve (MV) leaflet fibrosis and thickening, challenging valve normality. Progression of leaflet thickness post-MI has not been studied. We hypothesized that excessive MV remodeling post-MI contributes to MR. Our objectives are to characterize MV changes after MI and relate them to MR. Methods and Results— Three groups of 40 patients with serial echocardiograms over a mean of 23.4 months were identified from an echocardiography database: patients first studied early (6±12 days) and late (12±7 years) after an inferior MI and normal controls. MV thickness was correlated with MR. We studied the mechanisms for MV changes in a sheep model (6 apical MI versus 6 controls) followed for 8 weeks, with MV cellular and histopathologic analyses. Early post-MI, leaflet thickness was found to be similar to controls (2.6±0.5 vs 2.5±0.4 mm; P=0.23) but significantly increased over time (2.5±0.4 to 2.9±0.4 mm; P<0.01). In this group, patients tolerating maximal doses of renin–angiotensin blocking agents had less thickening (25% of patients; P<0.01). The late-MI group had increased thickness (3.2±0.5 vs 2.5±0.4 mm; P<0.01) without progression. At follow-up, 48% of post-MI patients had more than mild MR. Increased thickness was independently associated with MR. Experimentally, 8 weeks post-MI, MVs were 2-fold thicker than controls, with increased collagen, profibrotic transforming growth factor-&bgr;, and endothelial-to-mesenchymal transformation, confirmed by flow cytometry. Conclusions— MV thickness increases post-MI and correlates with MR, suggesting an organic component to ischemic MR. MV fibrotic remodeling can indicate directions for future therapy.
A Flexible Control Strategy for Grid-Connected and Islanded Microgrids With Enhanced Stability Using Nonlinear Microgrid Stabilizer

The energy sector is moving into the era of distributed generation (DG) and microgrids (MGs). The stability and operation aspects of converter-dominated DG MGs, however, are faced by many challenges. Important among these, are: 1) the absence of physical inertia; 2) comparable size of power converters; 3) mutual interactions among generators; 4) islanding detection delays; and 5) large sudden disturbances associated with transition to islanded mode, grid restoration, and load power changes. To overcome these difficulties, this paper presents a new large-signal-based control topology for DG power converters that is suitable for both grid-connected and islanding modes of operation without any need to reconfigure the control system and without islanding detection. To improve MG stability, the proposed control structure is realized via two steps. First, an emulated inertia and damping functions are adopted. Second, to guarantee stability and high performance of the MG system during sudden harsh transients such as islanding, grid reconnection, and large load power changes, a nonlinear MG stabilizer is proposed. An augmented converter model is developed and used to design the MG stabilizer via the adaptive backstepping (AB) technique to guarantee large-angle stability and robustness against unmodeled dynamics. Theoretical analysis and evaluation results are presented to show the effectiveness of the proposed control scheme in achieving stable and smooth operation of a MG system in grid-connected, islanding, and transition modes.
Endocrine disruption by di‐(2‐ethylhexyl)‐phthalate in Chinese rare minnow (Gobiocypris rarus)

Great concern has been raised over the potential impact of environmental contaminants on fish populations that inhabit the Three Gorge Reservoir. The present study investigated the endocrine‐disrupting effects of di‐(2‐ethylhexyl)‐phthalate (DEHP) on the Chinese rare minnow (Gobiocypris rarus), an endemic fish distributed in upstream waters in the Yangtze River. Adult rare minnow were exposed to environmentally relevant concentrations of DEHP (0 µg/L, 3.6 µg/L, 12.8 µg/L, 39.4 µg/L, and 117.6 µg/L) for a 21‐d period. Then, concentrations of sex hormones in the plasma and relative transcription of various associated genes were measured in the hypothalamic–pituitary–gonadal (HPG) axis and liver of the fish. Exposure to DEHP resulted in greater circulating concentrations of testosterone (T) and lower concentrations of estradiol (E2), which were accompanied by upregulation of Cyp17 mRNA and downregulation of Cyp19a mRNA in the gonads of females. In males, increases of T and E2 levels were consistent with upregulation of Cyp17 and Cyp19a in the gonads. Furthermore, the T/E2 ratio was increased in females but reduced in males. A significant increase in the levels of hepatic vitellogenin (VTG) gene transcription was observed in both females and males. The present study showed that waterborne exposure to DEHP altered plasma sex hormone levels and modulated gene transcription profiles of associated genes in the HPG axis and liver, occurring mostly at higher concentrations (>39.4 µg/L), which suggests that environmental concentration of DEHP (5.4 µg/L) alone might not disturb the endocrine system of the rare minnow in the TGR. Environ Toxicol Chem 2013;32:1846–1854. © 2013 SETAC
Canonical Wnt signalling regulates epithelial patterning by modulating levels of laminins in zebrafish appendages

The patterning and morphogenesis of body appendages – such as limbs and fins – is orchestrated by the activities of several developmental pathways.Wnt signalling is essential for the induction of limbs. However, it is unclear whether a canonical Wnt signalling gradient exists and regulates the patterning of epithelium in vertebrate appendages. Using an evolutionarily old appendage – the median fin in zebrafish – as a model, we show that the fin epithelium exhibits graded changes in cellular morphology along the proximo-distal axis. This epithelial pattern is strictly correlated with the gradient of canonical Wnt signalling activity. By combining genetic analyses with cellular imaging, we show that canonical Wnt signalling regulates epithelial cell morphology by modulating the levels of laminins, which are extracellular matrix components. We have unravelled a hitherto unknown mechanism involved in epithelial patterning, which is also conserved in the pectoral fins – evolutionarily recent appendages that are homologous to tetrapod limbs.