Canonical transforming growth factor-β signaling regulates disintegrin metalloprotease expression in experimental renal fibrosis via miR-29

Fibrosis pathophysiology is critically regulated by Smad 2– and Smad 3–mediated transforming growth factor-β (TGF-β) signaling. Disintegrin metalloproteases (Adam) can manipulate the signaling environment, however, the role and regulation of ADAMs in renal fibrosis remain unclear. TGF-β stimulation of renal cells results in a significant up-regulation of Adams 10, 17, 12, and 19. The selective Smad2/3 inhibitor SB 525334 reversed these TGF-β–induced changes. In vivo, using ureteral obstruction to model renal fibrosis, we observed increased Adams gene expression that was blocked by oral administration of SB 525334. Similar increases in Adam gene expression also occurred in preclinical models of hypertension-induced renal damage and glomerulonephritis. miRNAs are a recently discovered second level of regulation of gene expression. Analysis of 3′ untranslated regions of Adam12 and Adam19 mRNAs showed multiple binding sites for miR-29a, miR-29b, and miR-29c. We show that miR-29 family expression is decreased after unilateral ureter obstruction and this significant decrease in miR-29 family expression was observed consistently in preclinical models of renal dysfunction and correlated with an increase in Adam12 and Adam19 expression. Exogenous overexpression of the miR-29 family blocked TGF-β–mediated up-regulation of Adam12 and Adam19 gene expression. This study shows that Adams are involved in renal fibrosis and are regulated by canonical TGF-β signaling and miR-29. Therefore, both Adams and the miR-29 family represent therapeutic targets for renal fibrosis

Stuck in the Thicket: Struggling with Interpretation and Application of California\u27s Anti-Gang STEP Act

California’s Street Terrorism Enforcement and Prevention Act (Penal Code Sections 186.20 et seq.) was enacted in 1988 in response to a perceived “state of crisis . . . caused by violent street gangs” throughout the state. The “STEP” Act created a distinct crime of active participation in a criminal street gang, as well as providing enhanced penalties for any crime committed with the intent to facilitate criminal gang activity. Since its enactment, the poorly drafted Act—described by the California Supreme Court as a “thicket of statutory construction”—has produced an array of conflicting and vague appellate opinions. This article examines the interpretive and constitutional problems inherent in the STEP Act as revealed by recent case law, and proposes ways in which the Act might still be applied constitutionally and consistently

Information-Sharing and Strategy by Food Industry Firms

This study investigates the strategic behaviour of food industry firms. Its two goals are to: (i) characterise strategies being employed; and (ii) identify distinct approaches to information-sharing Data from an interview-format survey of Danish food industry firms are used to characterise strategy at two levels: 11 “strategic orientations”; each of which is composed of 3-6 of a total 57 “strategic actions”. Principal components were identified and two complementary cluster analysis techniques were used to assemble clusters that are composed of firms either with distinct strategies, or sets of strategies occurring in distinct combinations. Eight clusters emerge, with reasonable procedural performance. The clusters are distinct in a surprisingly large number of ways, including their strategies for market share, pricing, approach and response to regulation, exports and use of retailers’ own-label brands. Information-sharing strategies are closely linked to both marketing strategy and regulation response/anticipation. Individual clusters identify distinct sets of behaviour regarding information-sharing up and/or down the value chain, their approach to quality and other aspects of market segmentation, targeting of export markets, and willingness to compete on price. Clusters’ distinct strategies regarding regulation featured anticipation, as opposed to several diverse means of passing on compliance costs: to buyers or to sellers. Such activities were linked to information-sharing strategies in different ways by different clusters.Agribusiness, Agricultural and Food Policy, Farm Management, Food Consumption/Nutrition/Food Safety, Industrial Organization,

The Phenomenon of Belonging

A central problem facing humanity is that we have forgotten our sense of belonging. We no longer feel like we belong to ourselves, each other, and the world in deep and meaningful ways. Modern culture has uprooted the heart felt bonds of authentic connection and replaced them with false experiences of belonging through the addictive qualities of materialism, narcissism, and rationalism. As a result we suffer from our lost experiences of soul, spirit, and the aliveness of the world. In this article, we will explore belonging as the process of growth, forever pushing away the old and pulling towards new ways of being. The qualities of belonging explored herein reveal a heroic journey of remembrance from the innocence of being in childhood to the wounds of betrayal, alienation, and growth. This narrative exploration guides us from disillusionment and isolation to a remembering of what more authentic belonging feels like and how we are called to it as a homecoming to ourselves

An Investigation of Engineering Majors: Graduates\u27 Enrollment Timelines and First-Year Students\u27 Perceptions and Exploration

The selection of a specific engineering major can substantially impact a student’s undergraduate experience and can also impact future career opportunities. This work is divided into complementary studies of Enrollment, Perception, and Exploration. Together, the three studies seek to answer six research questions related to (i) when and where students enroll in their graduation majors in different matriculation models, (ii) how students perceive both engineering in general and the engineering majors, and (iii) the impacts of a major exploration course on confidence in major choice, major changes, and fit and satisfaction in engineering in general and in the engineering majors. Primarily using the Attraction-Selection-Attrition Framework and the Student Integration Model, the Study of Enrollment investigates time to enrollment in graduation major and persistence using institutional records from multiple institutions. The results of this study indicate different patterns in enrollment in graduation major based on the institutions’ matriculation model. Generally, students at direct matriculation institutions enroll in their graduation major more quickly, but those students have more major changes than students at institutions with first-year engineering programs. Using a framework of Social Cognitive Career Theory and Expectancy-Value Theory, the Study of Perception uses free-response survey questions from a major exploration course to investigate changes in students’ perceptions of engineering in general and in the engineering majors. The results of this study show that students’ perceptions of engineering in general and their intended engineering majors are expanded during an optional major exploration course. Responses often become more specific at the end of the course compared to the beginning. Framed with the Attraction-Selection-Attrition Framework and the Student Integration Model, the Study of Exploration uses propensity score matching to create two matched groups to investigate the effects of a major exploration course on first-year engineering students’ confidence in major choice, major changes, and fit and satisfaction in engineering. The results of this study show significant differences in the frequency of major changes among students who enrolled in the major exploration course compared with those that do not. Other metrics, while not significant, have differences that are favorable for the major exploration course that highlight its value for helping students make a more informed major choice. The results of this work provide evidence that students are willing to change their engineering majors after matriculation. Students likely make changes to improve academic and social fit and integration and because of changes in perceptions of the engineering majors during their first year. Some changes in perception are likely the result of dedicated major exploration courses which also has a positive (but not statistically significant) impact on confidence in major selection as well as fit and satisfaction in engineering majors

Dysregulation of cadherins in the intercalated disc of the spontaneously hypertensive stroke-prone rat

The structural integrity of cardiac cells is maintained by the Ca2+-dependent homophilic cell-cell adhesion of cadherins. N-cadherin is responsible for this adhesion under normal physiological conditions. The role of cadherins in adverse cardiac pathology is less clear. We studied the hearts of the stroke-prone spontaneously hypertensive (SHRSP) rat as a genetic model of cardiac hypertrophy and compared them to Wistar-Kyoto control animals. Western blotting of protein homogenates from 12-week old SHRSP animals indicated that similar levels of [beta], [gamma]-, and [alpha]-catenin and T, N and R-cadherin were expressed in the control and SHRSP animals. However, dramatically higher levels of E-cadherin were detected in SHRSP animals compared to controls at 6, 12 and 18áweeks of age. This was confirmed by quantitative Taqman PCR and immunohistochemistry. E-cadherin was located at the intercalated disc of the myocytes in co-localisation with connexin 43. Adenoviral overexpression of E-cadherin in rat H9c2 cells and primary rabbit myocytes resulted in a significant reduction in myocyte cell diameter and breadth. E-cadherin overexpression resulted in re-localisation of [beta]-catenin to the cell surface particularly to cell-cell junctions. Subsequent immunohistochemistry of the hearts of WKY and SHRSP animals also revealed increased levels of [beta]-catenin in the intercalated disc in the SHRSP compared to WKY. Therefore, remodelling of the intercalated disc in the hearts of SHRSP animals may contribute to the altered function observed in these animal

A study for systematic errors of the GLA forecast model in tropical regions

From the sensitivity studies performed with the Goddard Laboratory for Atmospheres (GLA) analysis/forecast system, it was revealed that the forecast errors in the tropics affect the ability to forecast midlatitude weather in some cases. Apparently, the forecast errors occurring in the tropics can propagate to midlatitudes. Therefore, the systematic error analysis of the GLA forecast system becomes a necessary step in improving the model's forecast performance. The major effort of this study is to examine the possible impact of the hydrological-cycle forecast error on dynamical fields in the GLA forecast system

Guide to Creative Commons for humanities and social science monograph authors

A booklet for authors in the humanities and social sciences specifically designed to help them understand the Creative Commons licenses