A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

Progressive kidney diseases are often associated with scarring of the kidney’s filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.National Institutes of Health (U.S.) (Grant DK095045)National Institutes of Health (U.S.) (Grant DK099465)National Institutes of Health (U.S.) (Grant DK103658)National Institutes of Health (U.S.) (Grant DK083511)National Institutes of Health (U.S.) (Grant DK093746

Comparison of the Genesis solar wind regime algorithm results with solar wind composition observed by ACE

Launched on 8 August 2001, the NASA Genesis mission is now collecting samples of the solar wind in various materials, and will return those samples to Earth in 2004 for analysis. A primary science goal of Genesis is the determination of the isotopic and elemental composition of the solar atmosphere from the solar wind material returned. In particular, Genesis will provide measurements of those species that are not provided by solar and in situ observations. We know from in situ measurements that the solar wind exhibits compositional variations across different types of solar wind flows. Therefore, Genesis exposes different collectors to solar wind originating from three flow types: coronal hole, coronal mass ejection (CME), and interstream flows. Flow types are identified using in situ measurements of solar wind protons, alphas, and electrons from electrostatic analyzers carried by Genesis. The flow regime selection algorithm and subsequent collector deployment on Genesis act autonomously. We present an assessment of composition variations of O, He, and Mg ions observed by ACE/SWICS concurrent with Genesis observations, and compare these to the Genesis algorithm decisions. Not only does this serve as a test of the algorithm, the compilation of composition vs. regime will be important for comparison to the abundances determined from sample analysis at the end of the mission

Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review

This review deals with podocyte proteins that play a significant role in the structure and function of the glomerular filter. Genetic linkage studies has identified several genes involved in the development of nephrotic syndrome and contributed to the understanding of the pathophysiology of glomerular proteinuria and/or focal segmental glomerulosclerosis. Here, we describe already well-characterized genetic diseases due to mutations in nephrin, podocin, CD2AP, alpha-actinin-4, WT1, and laminin β2 chain, as well as more recently identified genetic abnormalities in TRPC6, phospholipase C epsilon, and the proteins encoded by the mitochondrial genome. In addition, the role of the proteins which have shown to be important for the structure and functions by gene knockout studies in mice, are also discussed. Furthermore, some rare syndromes with glomerular involvement, in which molecular defects have been recently identified, are briefly described. In summary, this review updates the current knowledge of genetic causes of congenital and childhood nephrotic syndrome and provides new insights into mechanisms of glomerular dysfunction

Coulter, David L., and John R. Weins, eds., Why Do We Educate? Renewing the Conversation. 107th Yearbook of the National Society for the Study of Education, Vol. One. Walden, MA: Wiley Blackwell, 2008.

Presents evocative ideas by more than twenty authors regarding fundamental purposes, ideals, and subject matters for consideration by educational policy-makers, school curriculum planners, and the public; aims at renewing the conversation on these topics

Predation in Insular Plant Dynamics: An Experimental Assessment of Postdispersal Fruit and Seed Survival, Enewetak Atoll, Marshall Islands

We studied predation upon the fruits of four common terrestrial plant species of atolls by excluding: 1) all predators; 2) large predators only; and 3) no predators. Each of these treatments was located within the vegetation at three distances from the shore: beach edge of fringing thicket; middle of the thicket; and inner forest. The plants were Terminalia catappa, Messerschmidia argentea, Scaevola taccada, and Guettarda speciosa. Predation loss over the year was significant (P \u3c 0.01) for all four species. Location contributed significantly only for S. taccada. Amount of loss and predominant type of seed predator for a plant species were related to size and conspicuousness. The largest fruits, those of the widespread tree T. catappa, were destroyed completely at all sites; the damage was done by both insects and terrestrial crabs. The large fruits of G. speciosa were destroyed by insects inland and by crabs at the beach edge. The small fruits of M. argentea, a plant which is common along the beach, tended to have greater losses away from the beach edge; those losses were caused primarily by insects. For S. taccada, which occurred at the beach edge, fruit survival was highest in the middle of the fringe thicket; average damage and disappearance were high and caused primarily by large predators. In sum, the experiment demonstrated that predation by widespread, omnivorous large animals and insects on an atoll island was important in survival of fruits and enclosed seeds. We conclude that this interaction could have a significant influence on the dynamics of plants on atolls

Image_1_Uncovering a novel role of focal adhesion and interferon-gamma in cellular rejection of kidney allografts at single cell resolution.jpeg

BackgroundKidney transplant recipients are currently treated with nonspecific immunosuppressants that cause severe systemic side effects. Current immunosuppressants were developed based on their effect on T-cell activation rather than the underlying mechanisms driving alloimmune responses. Thus, understanding the role of the intragraft microenvironment will help us identify more directed therapies with lower side effects.MethodsTo understand the role of the alloimmune response and the intragraft microenvironment in cellular rejection progression, we conducted a Single nucleus RNA sequencing (snRNA-seq) on one human non-rejecting kidney allograft sample, one borderline sample, and T-cell mediated rejection (TCMR) sample (Banff IIa). We studied the differential gene expression and enriched pathways in different conditions, in addition to ligand-receptor (L-R) interactions.ResultsPathway analysis of T-cells in borderline sample showed enrichment for allograft rejection pathway, suggesting that the borderline sample reflects an early rejection. Hence, this allows for studying the early stages of cellular rejection. Moreover, we showed that focal adhesion (FA), IFNg pathways, and endomucin (EMCN) were significantly upregulated in endothelial cell clusters (ECs) of borderline compared to ECs TCMR. Furthermore, we found that pericytes in TCMR seem to favor endothelial permeability compared to borderline. Similarly, T-cells interaction with ECs in borderline differs from TCMR by involving DAMPS-TLRs interactions.ConclusionOur data revealed novel roles of T-cells, ECs, and pericytes in cellular rejection progression, providing new clues on the pathophysiology of allograft rejection.</p