Transglutaminase inhibition ameliorates experimental diabetic nephropathy

Diabetic nephropathy is characterized by excessive extracellular matrix accumulation resulting in renal scarring and end-stage renal disease. Previous studies have suggested that transglutaminase type 2, by formation of its protein crosslink product epsilon-(gamma-glutamyl)lysine, alters extracellular matrix homeostasis, causing basement membrane thickening and expansion of the mesangium and interstitium. To determine whether transglutaminase inhibition can slow the progression of chronic experimental diabetic nephropathy over an extended treatment period, the inhibitor NTU281 was given to uninephrectomized streptozotocin-induced diabetic rats for up to 8 months. Effective transglutaminase inhibition significantly reversed the increased serum creatinine and albuminuria in the diabetic rats. These improvements were accompanied by a fivefold decrease in glomerulosclerosis and a sixfold reduction in tubulointerstitial scarring. This was associated with reductions in collagen IV accumulation by 4 months, along with reductions in collagens I and III by 8 months. This inhibition also decreased the number of myofibroblasts, suggesting that tissue transglutaminase may play a role in myofibroblast transformation. Our study suggests that transglutaminase inhibition ameliorates the progression of experimental diabetic nephropathy and can be considered for clinical application.

Do changes in transglutaminase activity alter latent transforming growth factor beta activation in experimental diabetic nephropathy?

Background. Diabetic nephropathy is the leading cause of end-stage kidney failure worldwide. It is characterized by excessive extracellular matrix accumulation. Transforming growth factor beta 1 (TGF-ß1) is a fibrogenic cytokine playing a major role in the healing process and scarring by regulating extracellular matrix turnover, cell proliferation and epithelial mesanchymal transdifferentiation. Newly synthesized TGF-ß is released as a latent, biologically inactive complex. The cross-linking of the large latent TGF-ß to the extracellular matrix by transglutaminase 2 (TG2) is one of the key mechanisms of recruitment and activation of this cytokine. TG2 is an enzyme catalyzing an acyl transfer reaction leading to the formation of a stable e(?-glutamyl)-lysine cross-link between peptides.Methods. To investigate if changes in TG activity can modulate TGF-ß1 activation, we used the mink lung cell bioassay to assess TGF-ß activity in the streptozotocin model of diabetic nephropathy treated with TG inhibitor NTU281 and in TG2 overexpressing opossum kidney (OK) proximal tubular epithelial cells.Results. Application of the site-directed TG inhibitor NTU281 caused a 25% reduction in kidney levels of active TGF-ß1. Specific upregulation of TG2 in OK proximal tubular epithelial cells increased latent TGF-ß recruitment and activation by 20.7% and 19.7%, respectively, in co-cultures with latent TGF-ß binding protein producing fibroblasts.Conclusions. Regulation of TG2 directly influences the level of active TGF-ß1, and thus, TG inhibition may exert a renoprotective effect by targeting not only a direct extracellular matrix deposition but also TGF-ß1 activation and recruitment.

Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease

Progressive tissue fibrosis is involved in debilitating diseases that affect organs including the lungs, liver, heart, skin, and kidneys. Recent evidence suggests that tissue transglutaminase, an enzyme that crosslinks proteins, may be involved in tissue fibrosis by crosslinking and stabilizing the extracellular matrix or by recruiting and activating the large latent transforming growth factor (TGF)-β1 complex. We treated rats that had undergone 5/6-nephrectomy with two different irreversible inhibitors of transglutaminase and found that both prevented a decline in kidney function and reduced the development of glomerulosclerosis and tubulointerstitial fibrosis by up to 77% and 92%, respectively. Treatment reduced the accumulation of collagen I and collagen III, with the primary mechanism of action being direct interference with the crosslinking of extracellular matrix rather than altered regulation of TGFβ1. We conclude that inhibition of transglutaminase offers a potential therapeutic option for chronic kidney disease and other conditions that result from tissue fibrosis. Copyright © 2007 by the American Society of Nephrology.

Identifying a novel functional domain within the p115 tethering factor required for Golgi ribbon assembly and membrane trafficking

The tethering factor p115 has been shown to facilitate Golgi biogenesis and membrane traffic in cells in culture. However, the role of p115 within an intact animal is largely unknown. Here, we document that RNAi-mediated depletion of p115 in C. elegans causes accumulation of the yolk protein (YP170) in body cavity and the retention of the yolk receptor RME-2 in the ER and the Golgi within oocytes.Structure-function analyses of p115 have identified two homology (H1-2) regions within the N-terminal globular head and the coiled-coil 1 (CC1) domain as essential for p115 function. We identify a novel C-terminal domain of p115 as necessary for Golgi ribbon formation and cargo trafficking. We show that p115 mutants lacking the fourth CC domain (CC4) act in a dominant negative manner to disrupt Golgi and prevent cargo trafficking in cells containing endogenous p115. Furthermore, using RNAi-mediated "replacement" strategy we show that CC4 is necessary for Golgi ribbon formation and membrane trafficking in cells depleted of endogenous p115.p115 has been shown to bind a subset of ER-Golgi SNAREs through CC1 and CC4 domains (Shorter et al., 2002). Our findings show that CC4 is required for p115 function and suggest that both the CC1 and the CC4 SNARE-binding motifs may participate in p115-mediated membrane tethering.

Theoretical perspectives in purchasing and supply chain management:an analysis of the literature

Purpose – This paper attempts to seek answers to four questions. Two of these questions have been borrowed (but adapted) from the work of Defee et al.: RQ1. To what extent is theory used in purchasing and supply chain management (P&SCM) research? RQ2. What are the prevalent theories to be found in P&SCM research? Following on from these questions an additional question is posed: RQ3. Are theory-based papers more highly cited than papers with no theoretical foundation? Finally, drawing on the work of Harland et al., the authors have added a fourth question: RQ4. To what extent does P&SCM meet the tests of coherence, breadth and depth, and quality necessary to make it a scientific discipline? Design/methodology/approach – A systematic literature review was conducted in accordance with the model outlined by Tranfield et al. for three journals within the field of “purchasing and supply chain management”. In total 1,113 articles were reviewed. In addition a citation analysis was completed covering 806 articles in total. Findings – The headline features from the results suggest that nearly a decade-and-a-half on from its development, the field still lacks coherence. There is the absence of theory in much of the work and although theory-based articles achieved on average a higher number of citations than non-theoretical papers, there is no obvious contender as an emergent paradigm for the discipline. Furthermore, it is evident that P&SCM does not meet Fabian's test necessary to make it a scientific discipline and is still some way from being a normal science. Research limitations/implications – This study would have benefited from the analysis of further journals, however the analysis of 1,113 articles from three leading journals in the field of P&SCM was deemed sufficient in scope. In addition, a further significant line of enquiry to follow is the rigour vs relevance debate. Practical implications – This article is of interest to both an academic and practitioner audience as it highlights the use theories in P&SCM. Furthermore, this article raises a number of important questions. Should research in this area draw more heavily on theory and if so which theories are appropriate? Social implications – The broader social implications relate to the discussion of how a scientific discipline develops and builds on the work of Fabian and Amundson. Originality/value – The data set for this study is significant and builds on a number of previous literature reviews. This review is both greater in scope than previous reviews and is broader in its subject focus. In addition, the citation analysis (not previously conducted in any of the reviews) and statistical test highlights that theory-based articles are more highly cited than non-theoretically based papers. This could indicate that researchers are attempting to build on one another's work.

Gender comparisons of fat talk in the United Kingdom and the United States

This study compared different forms of body talk, including "fat talk," among 231 university men and women in central England (UK; n = 93) and the southeastern United States (US; n = 138). A 2 (gender) by 2 (country) repeated measures ANOVA across types of body talk (negative, self-accepting, positive) and additional Chi-square analyses revealed that there were differences across gender and between the UK and US cultures. Specifically, UK and US women were more likely to report frequently hearing or perceiving pressure to engage in fat talk than men. US women and men were also more likely to report pressure to join in self-accepting body talk than UK women and men. © 2010 Springer Science+Business Media, LLC.

Redefining neuromarketing as an integrated science of influence

Multiple transformative forces target marketing, many of which derive from new technologies that allow us to sample thinking in real time (i.e., brain imaging), or to look at large aggregations of decisions (i.e., big data). There has been an inclination to refer to the intersection of these technologies with the general topic of marketing as “neuromarketing”. There has not been a serious effort to frame neuromarketing, which is the goal of this paper. Neuromarketing can be compared to neuroeconomics, wherein neuroeconomics is generally focused on how individuals make “choices”, and represent distributions of choices. Neuromarketing, in contrast, focuses on how a distribution of choices can be shifted or “influenced”, which can occur at multiple “scales” of behavior (e.g., individual, group, or market/society). Given influence can affect choice through many cognitive modalities, and not just that of valuation of choice options, a science of influence also implies a need to develop a model of cognitive function integrating attention, memory, and reward/aversion function. The paper concludes with a brief description of three domains of neuromarketing application for studying influence, and their caveats.

Theoretical perspectives in operations management:an analysis of the literature

Purpose - It is important to advance operations management (OM) knowledge while being mindful of the theoretical developments of the discipline. The purpose of this paper is to explore which theoretical perspectives have dominated the OM field. This analysis allows the authors to identify theory trends and gaps in the literature and to identify fruitful areas for future research. A reflection on theory is also practical, given that it guides research toward important questions and enlightens OM practitioners. Design/methodology/approach - The authors provide an analysis of OM theory developments in the last 30 years. The study encompasses three decades of OM publications across three OM journals and contains an analysis of over 3,000 articles so as to identify which theories, over time, have been adopted by authors in order to understand OM topics. Findings - The authors find that the majority of studies are atheoretical, empirical, and focussed upon theory testing rather than on theory development. Some theories, such as the resource-based view and contingency theory, have an enduring relevance within OM. The authors also identify theories from psychology, economics, sociology, and organizational behavior that may, in the future, have salience to explain burgeoning OM research areas such as servitization and sustainability. Research limitations/implications - The study makes a novel contribution by exploring which main theories have been adopted or developed in OM, doing so by systematically analyzing articles from the three main journals in the field (the Journal of Operations Management, Production and Operations Management, and the International Journal of Operations and Production Management), which encompass three decades of OM publications. In order to focus the study, the authors may have missed important OM articles in other journals. Practical implications - A reflection on theories is important because theories inform how a researcher or practicing manager interprets and solves OM problems. This study allows the authors to reflect on the collective OM journey to date, to spot trends and gaps in the literature, and to identify fruitful areas for future research. Originality/value - As far as the authors are aware, there has not been an assessment of the main theoretical perspectives in OM. The research also identifies which topics are published in OM journals, and which theories are adopted to investigate them. The authors also reflect on whether the most cited papers and those winning best paper awards are theoretical. This gives the authors a richer understanding of the current state of OM research.

Identifying spatially overlapping local cortical networks with MEG

Recent modelling studies (Hadjipapas et al. [2009]: Neuroimage 44:1290-1303) have shown that it may be possible to distinguish between different neuronal populations on the basis of their macroscopically measured (EEG/MEG) mean field. We set out to test whether the different orientation columns contributing to a signal at a specific cortical location could be identified based on the measured MEG signal. We used 1.5deg square, static, obliquely oriented grating stimuli to generate sustained gamma oscillations in a focal region of primary visual cortex. We then used multivariate classifier methods to predict the orientation (left or right oblique) of the stimuli based purely on the time-series data from this one location. Both the single trial evoked response (0-300 ms) and induced post-transient power spectra (300-2,300 ms, 20-70 Hz band) due to the different stimuli were classifiable significantly above chance in 11/12 and 10/12 datasets respectively. Interestingly, stimulus-specific information is preserved in the sustained part of the gamma oscillation, long after perception has occurred and all neuronal transients have decayed. Importantly, the classification of this induced oscillation was still possible even when the power spectra were rank-transformed showing that the different underlying networks give rise to different characteristic temporal signatures. © 2009 Wiley-Liss, Inc.