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

Phytoprotective influence of bacteria on growth and cadmium accumulation in the aquatic plant Lemna minor

Certain plants are known to accumulate heavy metals, and can be used in remediation ofpolluted soil or water. Plant-associated bacteria, especially those that are metal tolerant,may enhance the total amount of metal accumulated by the plant, but this process is stillunclear. In this study, we investigated metal enhancement vs. exclusion by plants, and thephytoprotective role plant-associated bacteria might provide to plants exposed to heavymetal. We isolated cadmium-tolerant bacteria from the roots of the aquatic plant Lemnaminor grown in heavy metal-polluted waters, and tested these isolates for tolerance tocadmium. The efficiency of plants to accumulate heavy metal from their surroundingenvironment was then tested by comparing L. minor plants grown with added metaltolerant bacteria to plants grown axenically to determine, whether bacteria associated withthese plants increase metal accumulation in the plant.Unexpectedly, cadmium tolerance was not seen in all bacterial isolates that had beenexposed to cadmium. Axenic plants accumulated slightly more cadmium than plantsinoculated with bacterial isolates. Certain isolates promoted root growth, but overall,addition of bacterial strains did not enhance plant cadmium uptake, and in some cases,inhibited cadmium accumulation by plants. This suggests that bacteria serve a phytoprotectiverole in their relationship with Lemna minor, preventing toxic cadmium from enteringplants

Genetic Variability in Developing Periodical Cicadas

There are few events in nature that are more predictable than the emergence of periodical cicadas. The insects emerge from the ground after 13 or 17 years (depending on brood and species) of development. Karlin et al., (1991) biochemically examined over 750 Magicicada tredecassini belonging to Brood XIX which emerged during the spring of 1985. In this study they found evidence for rapid deterioration of heterozygosity for two esterase loci,Gi-3-pdh and Gpi, and suggested that this deterioration may be related to differential mating classes. To test this hypothesis, we re-sampled from this same brood at the same location during fall (1993) and winter (1994), nine years into the 13 year development of this brood. The current biochemical data suggest no significant deviations from Hardy-Weinberg expectations for either Est-3, Gl-3- pdh or Pgm-1, but in several cases Est-1 or Est-2 displayed significant departures. Our failure to find excess heterozygosity in the nymphal sample is interpreted to support weakly the size-mediated mating system hypothesis

Impact of an Intravenous Magnesium Shortage on Potassium Doses in Adult Surgical Patients Receiving Parenteral Nutrition

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141001/1/jpen0688.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141001/2/jpen0688-sup-0001.pd

The chromatin landscape of healthy and injured cell types in the human kidney

There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We establish a spatially-anchored epigenomic atlas to define the kidney\u27s active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we note distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3, KLF6, and KLF10 regulates the transition between health and injury, while in thick ascending limb cells this transition is regulated by NR2F1. Further, combined perturbation of ELF3, KLF6, and KLF10 distinguishes two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks

In vivo characterization of connective tissue remodeling using infrared photoacoustic spectra

Premature cervical remodeling is a critical precursor of spontaneous preterm birth, and the remodeling process is characterized by an increase in tissue hydration. Nevertheless, current clinical measurements of cervical remodeling are subjective and detect only late events, such as cervical effacement and dilation. Here, we present a photoacoustic endoscope that can quantify tissue hydration by measuring near-infrared cervical spectra. We quantify the water contents of tissue-mimicking hydrogel phantoms as an analog of cervical connective tissue. Applying this method to pregnant women in vivo, we observed an increase in the water content of the cervix throughout pregnancy. The application of this technique in maternal healthcare may advance our understanding of cervical remodeling and provide a sensitive method for predicting preterm birth

Communities for Growth: Cultivating and Sustaining Service-Learning Teaching and Scholarship in a Faculty Fellows Program

We analyze a two-year Faculty Fellows Program designed to enhance the service-learning pedagogy and scholarship at a regional comprehensive university. The impact of the program was analyzed using initial questionnaires, meeting notes, final reports, and faculty reflective essays. Participation in a faculty fellows cohort program provided a sense of campus community, led to professional and personal development, and improved community and student outcomes. Findings indicated the supportive culture created through the program was central to its powerful impact; other positive outcomes were grounded in the sense of community that developed

Reducing Legionella Colonization of Water Systems with Monochloramine

Monochloramine reduced colonization in building hot water systems

Working in Wonder

Catalog for the exhibition Working in Wonder held at the Seton Hall University Walsh Gallery, January 18 - February 11, 2011. Curated by Erin Gray, Danielle Schallom, and Ed Stapley-Brown. Includes an essay by Erin Gray, Danielle Schallom, and Ed Stapley-Brown. Includes color illustrations