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

Gene Therapy for Cardiovascular Disease

The last decade has seen substantial advances in the development of gene therapy strategies and vector technology for the treatment of a diverse number of diseases, with a view to translating the successes observed in animal models into the clinic. Perhaps the overwhelming drive for the increase in vascular gene transfer studies is the current lack of successful long-term pharmacological treatments for complex cardiovascular diseases. The increase in cardiovascular disease to epidemic proportions has also led many to conclude that drug therapy may have reached a plateau in its efficacy and that gene therapy may represent a realistic solution to a long-term problem. Here, we discuss gene delivery approaches and target diseases

Water Conservation: Extension Agents’ Perceptions of Issue Importance, Professional Abilities, and Landowner Needs

The Extension Service is one of many agencies charged with increasing awareness and knowledge of research-based agricultural conservation practices. A regional survey of Extension agents with agriculture and natural resources responsibilities was conducted to assess the need for in-service training on 11 water resource conservation topics. The highest priority training needs were for topics related to complex interactions and drivers of agricultural water pollution. This article highlights the implications of these results and offers broader perspective on bringing the Borich model of needs assessment into the agricultural and natural resources realm of subject matter expertise

Development of a digital toolkit to improve quality of life of patients with systemic lupus erythematosus

OBJECTIVE: The purpose of this manuscript is to detail development and initial usability testing of an e-toolkit designed to provide skills and knowledge around self-management behaviors for individuals living with systemic lupus erythematosus. METHODS: Researchers worked with a steering committee of patients and providers to (1) develop a clickable prototype of an e-toolkit and (2) conduct alpha (individuals not affiliated with an academic clinic as patient or provider) and beta (individual patients with systemic lupus erythematosus as well as members of the clinic healthcare team and individuals who work in patient advocacy organizations) usability testing through semistructured interviews. RESULTS: During the review of the e-toolkit, the feedback provided by participants in both alpha and beta groups centered on two overarching themes: (1) improving user interface and materials and (2) integration of information and supports between toolkit and clinical personnel. CONCLUSION: Digital approaches that are tailored to individual symptom variation and integrated with a clinical system have the opportunity to enhance ongoing clinical care. These findings support movement toward integrated, team-based care models, tailored digital resources, and use of expanded virtual interaction options to ensure on-going engagement between healthcare providers and systemic lupus erythematosus patients

Distinguishing the cold conveyor belt and sting jet air streams in an intense extratropical cyclone

Strong winds equatorwards and rearwards of a cyclone core have often been associated with two phenomena, the cold conveyor belt (CCB) jet and sting jets. Here, detailed observations of the mesoscale structure in this region of an intense cyclone are analysed. The {\it in-situ} and dropsonde observations were obtained during two research flights through the cyclone during the DIAMET (DIAbatic influences on Mesoscale structures in ExTratropical storms) field campaign. A numerical weather prediction model is used to link the strong wind regions with three types of ``air streams'', or coherent ensembles of trajectories: two types are identified with the CCB, hooking around the cyclone center, while the third is identified with a sting jet, descending from the cloud head to the west of the cyclone. Chemical tracer observations show for the first time that the CCB and sting jet air streams are distinct air masses even when the associated low-level wind maxima are not spatially distinct. In the model, the CCB experiences slow latent heating through weak resolved ascent and convection, while the sting jet experiences weak cooling associated with microphysics during its subsaturated descent. Diagnosis of mesoscale instabilities in the model shows that the CCB passes through largely stable regions, while the sting jet spends relatively long periods in locations characterized by conditional symmetric instability (CSI). The relation of CSI to the observed mesoscale structure of the bent-back front and its possible role in the cloud banding is discussed

Use of in vivo phage display to engineer novel adenoviruses for targeted delivery to the cardiac vasculature

We performed in vivo phage display in the stroke prone spontaneously hypertensive rat, a cardiovascular disease model, and the normotensive Wistar Kyoto rat to identify cardiac targeting peptides, and then assessed each in the context of viral gene delivery. We identified both common and strain-selective peptides, potentially indicating ubiquitous markers and those found selectively in dysfunctional microvasculature of the heart. We show the utility of the peptide, DDTRHWG, for targeted gene delivery in human cells and rats in vivo when cloned into the fiber protein of subgroup D adenovirus 19p. This study therefore identifies cardiac targeting peptides by in vivo phage display and the potential of a candidate peptide for vector targeting strategies

Deciphering endothelial heterogeneity in health and disease at single cell resolution: progress and perspectives

Endothelial cells (ECs) constitute the inner lining of vascular beds in mammals and are crucial for homeostatic regulation of blood vessel physiology, but also play a key role in pathogenesis of many diseases, thereby representing realistic therapeutic targets. However, it has become evident that ECs are heterogeneous, encompassing several subtypes with distinct functions, which makes EC targeting and modulation in the disease-context challenging. The rise of the new single cell era has led to an emergence of studies aimed at interrogating transcriptome diversity along the vascular tree, and has revolutionized our understanding of EC heterogeneity from both a physiological and pathophysiological context. Here, we discuss recent landmark studies aimed at teasing apart the heterogeneous nature of ECs. We cover driving (epi)genetic, transcriptomic and metabolic forces underlying EC heterogeneity in health and disease, as well as current strategies used to combat disease-enriched EC phenotypes, and propose strategies to transcend largely descriptive heterogeneity towards prioritization and functional validation of therapeutically targetable drivers of EC diversity. Lastly, we provide an overview of the most recent advances and hurdles in single EC OMICs

Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline

<b>Objective</b>: MicroRNAs (miRNAs) are small noncoding RNAs that have the capacity to control protein production through binding "seed" sequences within a target mRNA. Each miRNA is capable of potentially controlling hundreds of genes. The regulation of miRNAs in the lung during the development of pulmonary arterial hypertension (PAH) is unknown.<p></p> <b>Methods and Results</b>: We screened lung miRNA profiles in a longitudinal and crossover design during the development of PAH caused by chronic hypoxia or monocrotaline in rats. We identified reduced expression of Dicer, involved in miRNA processing, during the onset of PAH after hypoxia. MiR-22, miR-30, and let-7f were downregulated, whereas miR-322 and miR-451 were upregulated significantly during the development of PAH in both models. Differences were observed between monocrotaline and chronic hypoxia. For example, miR-21 and let-7a were significantly reduced only in monocrotaline-treated rats. MiRNAs that were significantly regulated were validated by quantitative polymerase chain reaction. By using in vitro studies, we demonstrated that hypoxia and growth factors implicated in PAH induced similar changes in miRNA expression. Furthermore, we confirmed miR-21 downregulation in human lung tissue and serum from patients with idiopathic PAH.<p></p> <b>Conclusion</b>: Defined miRNAs are regulated during the development of PAH in rats. Therefore, miRNAs may contribute to the pathogenesis of PAH and represent a novel opportunity for therapeutic intervention.<p></p&gt

Book Reviews

Book reviews of: Armies of Deliverance: A New History of the Civil War By Elizabeth R. Varon. College Edition. (New York: Oxford University Press, 2021. Maps, acknowledgments, timeline, notes, suggested readings, glossary, index. Pp. xxv, 531. $29.99 paper. ISBN: 978-0-19-933539-8.) Hurtin’ Words: Debating Family Problems in the Twentieth-Century South. By Ted Ownby. (Chapel Hill: The University of North Carolina Press, 2018. Acknowledgements, illustrations, notes, index. Pp. xiv, 334.$90 cloth, $29.95 paper,$22.99 electronic. ISBN: 978-1-46964-700-5.) Illusions of Emancipation: The Pursuit of Freedom & Equality in the Twilight of Slavery. By Joseph P. Reidy. (Chapel Hill: University of North Carolina Press, 2019. Acknowledgements, illustrations, map, notes, index. Pp. 1, 506. $39.95 Hardcover,$29.99 E-Book. ISBN: 978-1-4696-4836-1.) Civil War Monuments and the Militarization of America. By Thomas J. Brown. (Chapel Hill: University of North Carolina Press, 2019. 384 pp., 6.125 x 9.25, 87 halftones, notes, bibl., index, Paper, $29.97, 978-1-4696-5374-7.) Reconstruction Politics in a Deep South State: Alabama, 1865–1874. By William Warren Rogers, Jr. (Tuscaloosa: University of Alabama Press, 2021. Acknowledgments, illustrations, notes, bibliography. Pp. 1, 439.$54.95 cloth. ISBN: 978-0817320744.) Fugitivism: Escaping Slavery in the Lower Mississippi Valley, 1820–1860. By S. Charles Bolton. (Fayetteville: The University of Arkansas Press, 2019. Acknowledgements, appendix, notes, index. Pp. x, 302. $34.95 cloth. ISBN: 978-1-68226-009-9.) Bernardo de Gálvez: Spanish Hero of the American Revolution. By Gonzalo M. Quintero Saravia. (Chapel Hill: University of North Carolina Press, 2018. Acknowledgements, appendix, notes, bibliography, index. Pp. xi, 602,$38.00 cloth. ISBN: 9781469640792.