The mechanisms of human renal epithelial cell modulation of autologous dendritic cell phenotype and function

Proximal tubule epithelial cells (PTEC) of the kidney line the proximal tubule downstream of the glomerulus and play a major role in the re-absorption of small molecular weight proteins that may pass through the glomerular filtration process. In the perturbed disease state PTEC also contribute to the inflammatory disease process via both positive and negative mechanisms via the production of inflammatory cytokines which chemo-attract leukocytes and the subsequent down-modulation of these cells to prevent uncontrolled inflammatory responses. It is well established that dendritic cells are responsible for the initiation and direction of adaptive immune responses. Both resident and infiltrating dendritic cells are localised within the tubulointerstitium of the renal cortex, in close apposition to PTEC, in inflammatory disease states. We previously demonstrated that inflammatory PTEC are able to modulate autologous human dendritic cell phenotype and functional responses. Here we extend these findings to characterise the mechanisms of this PTEC immune-modulation using primary human PTEC and autologous monocyte-derived dendritic cells (MoDC) as the model system. We demonstrate that PTEC express three inhibitory molecules: (i) cell surface PD-L1 that induces MoDC expression of PD-L1; (ii) intracellular IDO that maintains the expression of MoDC CD14, drives the expression of CD80, PD-L1 and IL-10 by MoDC and inhibits T cell stimulatory capacity; and (iii) soluble HLA-G (sHLA-G) that inhibits HLA-DR and induces IL-10 expression by MoDC. Collectively the results demonstrate that primary human PTEC are able to modulate autologous DC phenotype and function via multiple complex pathways. Further dissection of these pathways is essential to target therapeutic strategies in the treatment of inflammatory kidney disorders.

FTO genotype is associated with phenotypic variability of body mass index

There is evidence across several species for genetic control of phenotypic variation of complex traits1, 2, 3, 4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ~170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5, 6, 7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ~0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9, 10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

Selling surf, sun and fitness: Queensland's mass-market fashion

How two powerhouse brands, Billabong and Lorna Jane, took the quintessential Queensland lifestyle to the world stage.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and approximately 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-)(8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Age-related changes in hepatic function: An update on implications for drug therapy

The accumulation of deficits with increasing age results in a decline in the functional capacity of multiple organs and systems. These changes can have a significant influence on the pharmacokinetics and pharmacodynamics of prescribed drugs. Although alterations in body composition and worsening renal clearance are important considerations, for most drugs the liver has the greatest effect on metabolism. Age-related change in hepatic function thereby causes much of the variability in older people’s responses to medication. In this review, we propose that a decline in the ability of the liver to inactivate toxins may contribute to a proinflammatory state in which frailty can develop. Since inflammation also downregulates drug metabolism, medication prescribed to frail older people in accordance with disease-specific guidelines may undergo reduced systemic clearance, leading to adverse drug reactions, further functional decline and increasing polypharmacy, exacerbating rather than ameliorating frailty status. We also describe how increasing chronological age and frailty status impact liver size, blood flow and protein binding and enzymes of drug metabolism. This is used to contextualise our discussion of appropriate prescribing practices. For example, while the general axiom of ‘start low, go slow’ should underpin the initiation of medication (titrating to a defined therapeutic goal), it is important to consider whether drug clearance is flow or capacity-limited. By summarising the effect of age-related changes in hepatic function on medications commonly used in older people, we aim to provide a guide that will have high clinical utility for practising geriatricians.

Structural characterization of γ-terpinene thin films using mass spectroscopy and X-Ray photoelectron spectroscopy

Understanding the polymerization mechanism of a precursor is indispensable to enhance the requisite material properties. In situ mass spectroscopy and X-ray photoelectron spectroscopy is used in this study to understand the RF plasma polymerization of γ-terpinene. High-resolution mass spectra positive ion mass spectrometry data of the plasma phase demonstrates the presence of oligomeric species of the type [M+H]+ and [2M+H]+, where M represents a unit of the starting material. In addition, there is abundant fragmented species, with most dominant being [M+] (136 m/z), C10H13+ (133 m/z), C9H11+ (119 m/z), and C7H9+ (93 m/z). The results reported in this manuscript enables to comprehend the relationship between the degree of incorporation of oxygen and the rate of deposition with the input RF power.

Time evolution of graphene growth on SiC as a function of annealing temperature

We followed by X-ray Photoelectron Spectroscopy (XPS) the time evolution of graphene layers obtained by annealing 3C SiC(111)/Si(111) crystals at different temperatures. The intensity of the carbon signal provides a quantification of the graphene thickness as a function of the annealing time, which follows a power law with exponent 0.5. We show that a kinetic model, based on a bottom-up growth mechanism, provides a full explanation to the evolution of the graphene thickness as a function of time, allowing to calculate the effective activation energy of the process and the energy barriers, in excellent agreement with previous theoretical results. Our study provides a complete and exhaustive picture of Si diffusion into the SiC matrix, establishing the conditions for a perfect control of the graphene growth by Si sublimation.

Exercise and vascular function in child obesity: A meta-analysis

CONTEXT: Conduit artery flow-mediated dilation (FMD) is a noninvasive index of preclinical atherosclerosis in humans. Exercise interventions can improve FMD in both healthy and clinical populations. OBJECTIVE: This systematic review and meta-analysis aimed to summarize the effect of exercise training on FMD in overweight and obese children and adolescents as well as investigate the role of cardiorespiratory fitness (peak oxygen consumption [Vo2peak]) on effects observed. DATA SOURCES: PubMed, Medline, Embase, and Cinahl databases were searched from the earliest available date to February 2015. STUDY SELECTION: Studies of children and/or adolescents who were overweight or obese were included. DATA EXTRACTION: Standardized data extraction forms were used for patient and intervention characteristics, control/comparator groups, and key outcomes. Procedural quality of the studies was assessed using a modified version of the Physiotherapy Evidence Base Database scale. RESULTS: A meta-analysis involving 219 participants compared the mean difference of pre- versus postintervention vascular function (FMD) and Vo2peak between an exercise training intervention and a control condition. There was a significantly greater improvement in FMD (mean difference 1.54%, P < .05) and Vo2peak (mean difference 3.64 mL/kg/min, P < .05) after exercise training compared with controls. LIMITATIONS: Given the diversity of exercise prescriptions, participant characteristics, and FMD measurement protocols, varying FMD effect size was noted between trials. CONCLUSIONS: Exercise training improves vascular function in overweight and obese children, as indicated by enhanced FMD. Further research is required to establish the optimum exercise program for maintenance of healthy vascular function in this at-risk pediatric population.

Novel fluorinated surfactants tentatively identified in firefighters using liquid chromatography quadrupole time-of flight tandem mass spectrometry and a case-control approach

Fluorinated surfactant-based aqueous film-forming foams (AFFFs) are made up of per- and polyfluorinated alkyl substances (PFAS) and are used to extinguish fires involving highly flammable liquids. The use of perfluorooctanesulfonic acid (PFOS) and other perfluoroalkyl acids (PFAAs) in some AFFF formulations has been linked to substantial environmental contamination. Recent studies have identified a large number of novel and infrequently reported fluorinated surfactants in different AFFF formulations. In this study, a strategy based on a case-control approach using quadrupole time-of-flight tandem mass spectrometry (QTOF-MS/MS) and advanced statistical methods has been used to extract and identify known and unknown PFAS in human serum associated with AFFF-exposed firefighters. Two target sulfonic acids [PFOS and perfluorohexanesulfonic acid (PFHxS)], three non-target acids [perfluoropentanesulfonic acid (PFPeS), perfluoroheptanesulfonic acid (PFHpS), and perfluorononanesulfonic acid (PFNS)], and four unknown sulfonic acids (Cl-PFOS, ketone-PFOS, ether-PFHxS, and Cl-PFHxS) were exclusively or significantly more frequently detected at higher levels in firefighters compared to controls. The application of this strategy has allowed for identification of previously unreported fluorinated chemicals in a timely and cost-efficient way.

A Bayesian latent class safety performance function for identifying motor vehicle crash blackspots

The current state of the practice in Blackspot Identification (BSI) utilizes safety performance functions based on total crash counts to identify transport system sites with potentially high crash risk. This paper postulates that total crash count variation over a transport network is a result of multiple distinct crash generating processes including geometric characteristics of the road, spatial features of the surrounding environment, and driver behaviour factors. However, these multiple sources are ignored in current modelling methodologies in both trying to explain or predict crash frequencies across sites. Instead, current practice employs models that imply that a single underlying crash generating process exists. The model mis-specification may lead to correlating crashes with the incorrect sources of contributing factors (e.g. concluding a crash is predominately caused by a geometric feature when it is a behavioural issue), which may ultimately lead to inefficient use of public funds and misidentification of true blackspots. This study aims to propose a latent class model consistent with a multiple crash process theory, and to investigate the influence this model has on correctly identifying crash blackspots. We first present the theoretical and corresponding methodological approach in which a Bayesian Latent Class (BLC) model is estimated assuming that crashes arise from two distinct risk generating processes including engineering and unobserved spatial factors. The Bayesian model is used to incorporate prior information about the contribution of each underlying process to the total crash count. The methodology is applied to the state-controlled roads in Queensland, Australia and the results are compared to an Empirical Bayesian Negative Binomial (EB-NB) model. A comparison of goodness of fit measures illustrates significantly improved performance of the proposed model compared to the NB model. The detection of blackspots was also improved when compared to the EB-NB model. In addition, modelling crashes as the result of two fundamentally separate underlying processes reveals more detailed information about unobserved crash causes.

Cognitive function in schizophrenia: Conflicting findings and future directions

Introduction Schizophrenia is a severe mental disorder with multiple psychopathological domains being affected. Several lines of evidence indicate that cognitive impairment serves as the key component of schizophrenia psychopathology. Although there have been a multitude of cognitive studies in schizophrenia, there are many conflicting results. We reasoned that this could be due to individual differences among the patients (i.e. variation in the severity of positive vs. negative symptoms), different task designs, and/or the administration of different antipsychotics. Methods We thus review existing data concentrating on these dimensions, specifically in relation to dopamine function. We focus on most commonly used cognitive domains: learning, working memory, and attention. Results We found that the type of cognitive domain under investigation, medication state and type, and severity of positive and negative symptoms can explain the conflicting results in the literature. Conclusions This review points to future studies investigating individual differences among schizophrenia patients in order to reveal the exact relationship between cognitive function, clinical features, and antipsychotic treatment.

Excel’s Sumif and Sumifs function

As accountants, we are all familiar with the SUM function, which calculates the sum in a range of numbers. However, there are instances where we might want to sum numbers in a given range based on a specified criteria. In this instance the SUM IF function can achieve this objective.

The effect of internal audit function quality and internal audit contribution to external audit on audit fees

Corporate governance mandates and listing rules identify internal audit functions (IAF) as a central internal control mechanism. External audits are expected to assess the quality of IAF before placing reliance on its work. We provide evidence on the effect of IAF quality and IAF contribution to external audit on audit fees. Using data from a matched survey of both external and internal audits, we extend prior research which is based mainly on internal audits' assessment and conducted predominantly in highly developed markets. We find a positive relationship between IAF quality and audit fees as well as a reduction in audit fees as a result of external auditors' reliance on IAF. The interaction between IAF quality and IAF contribution to external audit suggests that high quality IAF induces greater external auditor reliance on internal auditors' work and thus result in lower external audit fees.

Targeting antigen to diverse APCs inactivates memory CD8+ T cells without eliciting tissue-destructive effector function

Memory T cells develop early during the preclinical stages of autoimmune diseases and have traditionally been considered resistant to tolerance induction. As such, they may represent a potent barrier to the successful immunotherapy of established autoimmune diseases. It was recently shown that memory CD8+ T cell responses are terminated when Ag is genetically targeted to steady-state dendritic cells. However, under these conditions, inactivation of memory CD8+ T cells is slow, allowing transiently expanded memory CD8+ T cells to exert tissue-destructive effector function. In this study, we compared different Ag-targeting strategies and show, using an MHC class II promoter to drive Ag expression in a diverse range of APCs, that CD8+ memory T cells can be rapidly inactivated by MHC class II+ hematopoietic APCs through a mechanism that involves a rapid and sustained downregulation of TCR, in which the effector response of CD8+ memory cells is rapidly truncated and Ag-expressing target tissue destruction is prevented. Our data provide the first demonstration that genetically targeting Ag to a broad range of MHC class II+ APC types is a highly efficient way to terminate memory CD8+ T cell responses to prevent tissue-destructive effector function and potentially established autoimmune diseases. Copyright © 2010 by The American Association of Immunologists, Inc.