Pharmacologic inhibition of RGD-binding integrins ameliorates fibrosis and improves function following kidney injury

Fibrosis is a final common pathway for many causes of progressive chronic kidney disease (CKD). Arginine-glycine-aspartic acid (RGD)-binding integrins are important mediators of the pro-fibrotic response by activating latent TGF-β at sites of injury and by providing myofibroblasts information about the composition and stiffness of the extracellular matrix. Therefore, blockade of RGD-binding integrins may have therapeutic potential for CKD. To test this idea, we used small-molecule peptidomimetics that potently inhibit a subset of RGD-binding integrins in a murine model of kidney fibrosis. Acute kidney injury leading to fibrosis was induced by administration of aristolochic acid. Continuous subcutaneous administration of CWHM-12, an RGD integrin antagonist, for 28 days improved kidney function as measured by serum creatinine. CWHM-12 significantly reduced Collagen 1 (Col1a1) mRNA expression and scar collagen deposition in the kidney. Protein and gene expression markers of activated myofibroblasts, a major source of extracellular matrix deposition in kidney fibrosis, were diminished by treatment. RNA sequencing revealed that inhibition of RGD integrins influenced multiple pathways that determine the outcome of the response to injury and of repair processes. A second RGD integrin antagonist, CWHM-680, administered once daily by oral gavage was also effective in ameliorating fibrosis. We conclude that targeting RGD integrins with such small-molecule antagonists is a promising therapeutic approach in fibrotic kidney disease

GIS-Based Forage Species Adaptation Mapping

Selecting forage crops adapted to the climatic and edaphic conditions of specific locations is essential for economic sustainability and environmental protection. Yet, currently, proper selection is difficult due to the absence of advanced selection tools. Significant improvements are being made in the process through Geographic Information System (GIS)-based mapping. Climate and soil GIS layers are being matched with forage characteristics through rules describing species tolerances. Better matching will reduce economic risks and environmental hazards associated with sub-optimal crop selection and subsequent performance. Once developed, these forage crop selection strategies and tools can be adapted for use with other crops. A matrix of species characteristics is being assembled for 6 major forage crops. GIS-based climate and soils maps are being developed and reviewed. Base layer climate and soils maps and the species adaptation maps will be placed on a CD-ROM to help educators, consultants, farmers, and ranchers match their conditions to suitable forage crop species. A WWW segment is being developed to provide a source of current information and links to original data and supplementary materials

CD73 (ecto‐5′‐nucleotidase) hepatocyte levels differ across mouse strains and contribute to mallory‐denk body formation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100334/1/hep26525.pd

Selective αv integrin depletion identifies a core, targetable molecular pathway that regulates fibrosis across solid organs

Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not existed. We report that Pdgfrb-Cre inactivates genes in murine HSCs with high efficiency. We used this system to delete the αv integrin subunit because of the suggested role of multiple αv integrins as central mediators of fibrosis in multiple organs. Depletion of the αv integrin subunit in HSCs protected mice from CCl4-induced hepatic fibrosis, whereas global loss of αvβ3, αvβ5 or αvβ6 or conditional loss of αvβ8 on HSCs did not. Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of αv integrins using this system was also protective in models of pulmonary and renal fibrosis. Critically, pharmacological blockade of αv integrins by a novel small molecule (CWHM 12) attenuated both liver and lung fibrosis, even when administered after fibrosis was established. These data identify a core pathway that regulates fibrosis, and suggest that pharmacological targeting of all αv integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases

Developing a National Alfalfa Information System

Using state-of-the-art telecommunication technologies, this project is developing a comprehensive knowledge resource for alfalfa (Medicago sativa L.); the National Alfalfa Information System (NAIS). This project will serve as an improved model for Extension educational programs. Alfalfa is the most important forage crop in the USA and grown worldwide for feeding millions of livestock and in many cropping systems. As a legume, it is important in sustaining the environment and the productivity of agriculture. Information needs are present in every state and internationally. The NAIS is being developed through national and international cooperation, putting the best science-based alfalfa information and expertise at the fingertips of producers, consultants, extension workers, instructors, researchers, and users. Collaboratively developed materials will reduce duplication of effort. To make the knowledge easy-to-use, educational design, communication, and information science professionals are working with alfalfa experts in creating a WWW system and Web-aware CD-ROM. To ensure content quality, peer-review by members of multiple professional societies is included. A significant result will be around-the-clock availability of up-to-date, easy-to-use, and peerreviewed information. Shared workload and the peer-review process can influence faculty morale, efficiency, and effectiveness, an adjunct to maximizing the utilization of alfalfa worldwide by making the best information readily available

The Vehicle, 1967, Vol. 9 no. 2

Table of Contents Commentarypage 3 SketchAnn Butlerpage 4 I Take A Long-Out-of-Use BookAnthony Griggspage 5 The Leaf StemDianne Cochranpage 6 The Four MusketeersJim Courterpage 7 Status QuoAdrian Beardpage 7 SketchAnn Butlerpage 8 NocturneMike Baldwinpage 9 Oh Impatient HeartK. H. Shariffpage 9 Letter to a FianceeMaurice Snivelypage 10 Listen!Bonnie Blackpage 11 The Water\u27s EdgeStephen W. Gibbspage 12 TogetherDavid Reifpage 13 SketchAnn Butlerpage 14 Evening TimeSharon Nelsonpage 15 Japanese HaikuBev Hensonpage 15 Of Love and WarBruce Czeluscinskipage 16 Always AloneKib Voorheespage 17 the end of loveJackie Bratcherpage 18 1-20-66Sharon Nelsonpage 19 Blessed Are WeBonnie Marie Beckpage 19 The Time To LiveNeil Tracypage 20 Imminent AwakeningHelen Coxpage 21 The Dead Panther LairMolly J. Evanspage 21 Good SheepMike Tilfordpage 22 The Flame of LifeJacki Jacquespage 23 Then Arrives The Day Of DarkMolly J. Evanspage 23 Sketch: To love is to rememberAnn Butlerpage 24 Hidden RiversCharles J. Mertzpage 25 SilenceLinda G. Phillipspage 26 December - 1964Bonnie Blackpage 26 LoveHazel Thomaspage 27 To Praise A Good Man Neil Tracypage 28 Definitions \u2767Sharon Nelsonpage 29 To Wish Is a CrimeBonnie Marie Beckpage 30 College MadhatterMaurice Snivelypage 31 No. 8Sharon Nelsonpage 32 The Open FireSusan Williamspage 32https://thekeep.eiu.edu/vehicle/1017/thumbnail.jp

A macrophage-pericyte axis directs tissue restoration via amphiregulin-induced transforming growth factor beta activation

The epidermal growth factor receptor ligand Amphiregulin has a well-documented role in the restoration of tissue homeostasis after injury; however, the mechanism by which Amphiregulin contributes to wound repair remains unknown. Here we show that Amphiregulin functioned by releasing bioactive transforming growth factor beta (TGF-β) from latent complexes via integrin-αV activation. Using acute injury models in two different tissues, we found that by inducing TGF-β activation on mesenchymal stromal cells (pericytes), Amphiregulin induced their differentiation into myofibroblasts, thereby selectively contributing to the restoration of vascular barrier function within injured tissue. Furthermore, we identified macrophages as a critical source of Amphiregulin, revealing a direct effector mechanism by which these cells contribute to tissue restoration after acute injury. Combined, these observations expose a so far under-appreciated mechanism of how cells of the immune system selectively control the differentiation of tissue progenitor cells during tissue repair and inflammation

Comorbidity, age, race and stage at diagnosis in colorectal cancer: a retrospective, parallel analysis of two health systems

© 2008 Zafar et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background : Stage at diagnosis plays a significant role in colorectal cancer (CRC) survival. Understanding which factors contribute to a more advanced stage at diagnosis is vital to improving overall survival. Comorbidity, race, and age are known to impact receipt of cancer therapy and survival, but the relationship of these factors to stage at diagnosis of CRC is less clear. The objective of this study is to investigate how comorbidity, race and age influence stage of CRC diagnosis. Methods : Two distinct healthcare populations in the United States (US) were retrospectively studied. Using the Cancer Care Outcomes Research and Surveillance Consortium database, we identified CRC patients treated at 15 Veterans Administration (VA) hospitals from 2003–2007. We assessed metastatic CRC patients treated from 2003–2006 at 10 non-VA, fee-for-service (FFS) practices. Stage at diagnosis was dichotomized (non-metastatic, metastatic). Race was dichotomized (white, non-white). Charlson comorbidity index and age at diagnosis were calculated. Associations between stage, comorbidity, race, and age were determined by logistic regression. Results : 342 VA and 340 FFS patients were included. Populations differed by the proportion of patients with metastatic CRC at diagnosis (VA 27% and FFS 77%) reflecting differences in eligibility criteria for inclusion. VA patients were mean (standard deviation; SD) age 67 (11), Charlson index 2.0 (1.0), and were 63% white. FFS patients were mean age 61 (13), Charlson index 1.6 (1.0), and were 73% white. In the VA cohort, higher comorbidity was associated with earlier stage at diagnosis after adjusting for age and race (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.58–1.00; p = 0.045); no such significant relationship was identified in the FFS cohort (OR 1.09, 95% CI 0.82–1.44; p = 0.57). In both cohorts, no association was found between stage at diagnosis and either age or race. Conclusion : Higher comorbidity may lead to earlier stage of CRC diagnosis. Multiple factors, perhaps including increased interactions with the healthcare system due to comorbidity, might contribute to this finding. Such increased interactions are seen among patients within a healthcare system like the VA system in the US versus sporadic interactions which may be seen with FFS healthcare

Plasticity in dendroclimatic response across the distribution range of Aleppo pine (Pinus halepensis)

We investigated the variability of the climate-growth relationship of Aleppo pine across its distribution range in the Mediterranean Basin. We constructed a network of tree-ring index chronologies from 63 sites across the region. Correlation function analysis identified the relationships of tree-ring index to climate factors for each site. We also estimated the dominant climatic gradients of the region using principal component analysis of monthly, seasonal, and annual mean temperature and total precipitation from 1,068 climatic gridpoints. Variation in ring width index was primarily related to precipitation and secondarily to temperature. However, we found that the dendroclimatic relationship depended on the position of the site along the climatic gradient. In the southern part of the distribution range, where temperature was generally higher and precipitation lower than the regional average, reduced growth was also associated with warm and dry conditions. In the northern part, where the average temperature was lower and the precipitation more abundant than the regional average, reduced growth was associated with cool conditions. Thus, our study highlights the substantial plasticity of Aleppo pine in response to different climatic conditions. These results do not resolve the source of response variability as being due to either genetic variation in provenance, to phenotypic plasticity, or a combination of factors. However, as current growth responses to inter-annual climate variability vary spatially across existing climate gradients, future climate-growth relationships will also likely be determined by differential adaptation and/or acclimation responses to spatial climatic variation. The contribution of local adaptation and/or phenotypic plasticity across populations to the persistence of species under global warming could be decisive for prediction of climate change impacts across populations. In this sense, a more complex forest dynamics modeling approach that includes the contribution of genetic variation and phenotypic plasticity can improve the reliability of the ecological inferences derived from the climate-growth relationships.This work was partially supported by Spanish Ministry of Education and Science co-funded by FEDER program (CGL2012-31668), the European Union and the National Ministry of Education and Religion of Greece (EPEAEK- Environment – Archimedes), the Slovenian Research Agency (program P4-0015), and the USDA Forest Service. The cooperation among international partners was supported by the COST Action FP1106, STREeSS