Understanding the Impact of Trampling on Rodent Bones

Experiments based on the premise of uniformitarism are an effective tool to establish patterns of taphonomic processes acting either before, or after, burial. One process that has been extensively investigated experimentally is the impact of trampling to large mammal bones. Since trampling marks caused by sedimentary friction strongly mimic cut marks made by humans using stone tools during butchery, distinguishing the origin of such modifications is especially relevant to the study of human evolution. In contrast, damage resulting from trampling on small mammal fossil bones has received less attention, despite the fact that it may solve interesting problems relating to site formation processes. While it has been observed that the impact of compression depends on the type of substrate and dryness of the skeletal elements, the fragility of small mammal bones may imply that they will break as a response to compression. Here, we have undertaken a controlled experiment using material resistance compression equipment to simulate a preliminary experiment, previously devised by one of us, on human trampling of owl pellets. Our results demonstrate that different patterns of breakage can be distinguished under wet and dry conditions in mandibles, skulls and long bones that deform or break in a consistent way. Further, small compact bones almost always remain intact, resisting breakage under compression. The pattern obtained here was applied to a Pleistocene small mammal fossil assemblage from Wonderwerk Cave (South Africa). This collection showed unusually extensive breakage and skeletal element representation that could not be entirely explained by excavation procedures or digestion by the predator. We propose that trampling was a significant factor in small mammal bone destruction at Wonderwerk Cave, partly the product of trampling caused by the raptor that introduced the microfauna into the cave, as well as by hominins and other terrestrial animals that entered the cave and trampled pellets covering the cave floor

Comparative Oncogenomic Analysis of Copy Number Alterations in Human and Zebrafish Tumors Enables Cancer Driver Discovery

The identification of cancer drivers is a major goal of current cancer research. Finding driver genes within large chromosomal events is especially challenging because such alterations encompass many genes. Previously, we demonstrated that zebrafish malignant peripheral nerve sheath tumors (MPNSTs) are highly aneuploid, much like human tumors. In this study, we examined 147 zebrafish MPNSTs by massively parallel sequencing and identified both large and focal copy number alterations (CNAs). Given the low degree of conserved synteny between fish and mammals, we reasoned that comparative analyses of CNAs from fish versus human MPNSTs would enable elimination of a large proportion of passenger mutations, especially on large CNAs. We established a list of orthologous genes between human and zebrafish, which includes approximately two-thirds of human protein-coding genes. For the subset of these genes found in human MPNST CNAs, only one quarter of their orthologues were co-gained or co-lost in zebrafish, dramatically narrowing the list of candidate cancer drivers for both focal and large CNAs. We conclude that zebrafish-human comparative analysis represents a powerful, and broadly applicable, tool to enrich for evolutionarily conserved cancer drivers.Kathy and Curt Marble Cancer Research FundArthur C. MerrillNational Institutes of Health (U.S.) (Grant CA106416)National Institutes of Health (U.S.) (Grant ROI RR020833)National Institutes of Health (U.S.) (Grant 1F32GM095213-01

DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Peer reviewe

Linking erythropoietin to Treg-dependent allograft survival through myeloid cells

Erythropoietin (EPO) has multiple nonerythropoietic functions, including immune modulation, but EPO's effects in transplantation remain incompletely understood. We tested the mechanisms linking EPO administration to prolongation of murine heterotopic heart transplantation using WT and conditional EPO receptor-knockout (EPOR-knockout) mice as recipients. In WT controls, peritransplant administration of EPO synergized with CTLA4-Ig to prolong allograft survival (P <0.001), reduce frequencies of donor-reactive effector CD8(+). T cells in the spleen (P <0.001) and in the graft (P <0.05), and increase frequencies and total numbers of donor-reactive Tregs (P < 0.01 for each) versus CTLA4-Ig alone. Studies performed in conditional EPOR-knockout recipients showed that each of these differences required EPOR expression in myeloid cells but not in T cells. Analysis of mRNA isolated from spleen monocytes showed that EPO/EPOR ligation upregulated macrophage-expressed, antiinflammatory, regulatory, and pro-efferocytosis genes and downregulated selected proinflammatory genes. Taken together, the data support the conclusion that EPO promotes Treg-dependent murine cardiac allograft survival by crucially altering the phenotype and function of macrophages. Coupled with our previous documentation that EPO promotes Treg expansion in humans, the data support the need for testing the addition of EPO to costimulatory blockade-containing immunosuppression regimens in an effort to prolong human transplant survival

Erythropoietin inhibits SGK1-dependent TH17 induction and TH17-dependent kidney disease

IL-17-producing CD4(+) (Th17) cells are pathogenically linked to autoimmunity and, specifically, to autoimmune kidney disease. The newly recognized immunoregulatory functions of erythropoietin (EPO) and its predominant intrarenal source suggested that EPO physiologically regulates Th17 cell differentiation, thereby serving as a barrier to development of autoimmune kidney disease. Using in vitro studies of human and murine cells and in vivo models, we show that EPO ligation of its receptor (EPO-R) on CD4(+) T cells directly inhibits Th17 cell generation and promotes transdifferentiation of Th17 cells into IL-17 FOXP3(+)CD4(+) T cells. Mechanistically, EPO/EPO-R ligation abrogates upregulation of SGK1 gene expression and blocks p38 activity to prevent SCK1 phosphorylation, thereby inhibiting RORC-mediated transcription of IL17and IL23 receptor genes. In a murine model of Th17 cell-dependent aristolochic acid-induced interstitial kidney disease associated with reduced renal EPO production, we demonstrate that transgenic EPO overexpression or recombinant EPO (rEPO) administration limits Th17 cell formation and clinical/histological disease expression. EPO/EPO-R ligations on CD4(+) T cells abrogate, while absence of T cell-expressed EPO-R augments, Th17 cell induction and clinical/histological expression of pristane-induced glomerulonephritis (associated with decreased intrarenal EPO). rEPO prevents spontaneous glomerulonephritis and Th17 cell generation in MRL-lpr mice. Together, our findings indicate that EPO physiologically and therapeutically modulates Th17 cells to limit expression of Th17 cell-associated autoimmune kidney disease