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Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Decreased hepcidin leads to tissue iron overload, whereas hepcidin overproduction leads to hypoferremia and the anemia of inflammation. Ferroportin is an iron exporter present on the surface of absorptive enterocytes, macrophages, hepatocytes, and placental cells. Here we report that hepcidin bound to ferroportin in tissue culture cells. After binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron. The posttranslational regulation of ferroportin by hepcidin may thus complete a homeostatic loop: Iron regulates the secretion of hepcidin, which in turn controls the concentration of ferroportin on the cell surface.

Hemoproteins are critical for the function and integrity of aerobic cells. However, free heme is toxic. Therefore, cells must balance heme synthesis with its use. We previously demonstrated that the feline leukemia virus, subgroup C, receptor (FLVCR) exports cytoplasmic heme. Here, we show that FLVCR-null mice lack definitive erythropoiesis, have craniofacial and limb deformities resembling those of patients with Diamond-Blackfan anemia, and die in midgestation. Mice with FLVCR that is deleted neonatally develop a severe macrocytic anemia with proerythroblast maturation arrest, which suggests that erythroid precursors export excess heme to ensure survival. We further demonstrate that FLVCR mediates heme export from macrophages that ingest senescent red cells and regulates hepatic iron. Thus, the trafficking of heme, and not just elemental iron, facilitates erythropoiesis and systemic iron balance.

Ferritin is a cytosolic molecule comprised of subunits that self‐assemble into a nanocage capable of containing up to 4500 iron atoms. Iron stored within ferritin can be mobilized for use within cells or exported from cells. Expression of ferroportin (Fpn) results in export of cytosolic iron and ferritin degradation. Fpn‐mediated iron loss from ferritin occurs in the cytosol and precedes ferritin degradation by the proteasome. Depletion of ferritin iron induces the monoubiquitination of ferritin subunits. Ubiquitination is not required for iron release but is required for disassembly of ferritin nanocages, which is followed by degradation of ferritin by the proteasome. Specific mammalian machinery is not required to extract iron from ferritin. Iron can be removed from ferritin when ferritin is expressed in Saccharomyces cerevisiae , which does not have endogenous ferritin. Expressed ferritin is monoubiquitinated and degraded by the proteasome. Exposure of ubiquitination defective mammalian cells to the iron chelator desferrioxamine leads to degradation of ferritin in the lysosome, which can be prevented by inhibitors of autophagy. Thus, ferritin degradation can occur through two different mechanisms.

Mutations in the iron exporter ferroportin (Fpn) (IREG1, SLC40A1, and MTP1) result in hemochromatosis type IV, a disorder with a dominant genetic pattern of inheritance and heterogeneous clinical presentation. Most patients develop iron loading of Kupffer cells with relatively low saturation of plasma transferrin, but others present with high transferrin saturation and iron-loaded hepatocytes. We show that known human mutations introduced into mouse Fpn-GFP generate proteins that either are defective in cell surface localization or have a decreased ability to be internalized and degraded in response to hepcidin. Studies using coimmunoprecipitation of epitope-tagged Fpn and size-exclusion chromatography demonstrated that Fpn is multimeric. Both WT and mutant Fpn participate in the multimer, and mutant Fpn can affect the localization of WT Fpn, its stability, and its response to hepcidin. The behavior of mutant Fpn in cell culture and the ability of mutant Fpn to act as a dominant negative explain the dominant inheritance of the disease as well as the different patient phenotypes.

There is an intrinsic tension between the incentives for developers of commodity software and the desires of users of commodity software. Developers of commodity software must support a multitude of users and use cases, and must often develop and maintain large sets of optional features to address and anticipate diverse use cases. Individual organizations and users often have specific, well-defined use cases that depend only on a subset of a program’s features. From the perspective of the end user, unused features constitute bloat, which has ramifications in terms of program size, performance, and attack surface. Thus, for end-users, it is desirable to have an automated means of producing programs specialized for their use case.One means of performing program specialization, is via a partial evaluator. A partial evaluator takes as input a subset of a program’s input (referred to as static input), and identifies a portion of the program’s text that can be executed safely on the static input. The partial evaluator executes the “safe” portion of the program on the static input, performing an exploration of the partial program’s state-space. In the course of this state-space exploration, the partial evaluator simplifies the the program, using information computed from the static input. Partial evaluation can remove unreachable code, and perform optimizations such as constant propagation, loop-unrolling and function inlining. For low-level languages such as C and machine code, performing partial evaluation on programs of non-trivial complexity requires solving problems related to the state-space exploration of partial programs, particularly (i) saving and restoring program states, and (ii) identifying previously visited states.In this thesis, I describe GenXGen, a system for partially evaluating programs written in C and x86 machine code. With GenXGen, I improve on the state-of-the-art for problem (i) by creating an OS-assisted mechanism to save and restore states. By using additional information made available by the OS, I improve on previous techniques for problem (ii) by using incremental-hashing techniques to implement an O(1) technique for identifying previously visited states (with high probability). In addition, I improve on the scalability of existing tools by using program-slicing techniques to identify the “safely executable” portion of a program’s code. These techniques allow GenXGen to produce specialized versions of real-world Linux programs.

Posner (1976) criticized the US Supreme Court's 1946 decision in American Tobacco Co. versus US in which the Court inferred collusion from pricing behavior, as \"intellectually disastrous.\" Posner argued that a monopolist would lower prices when faced with decreasing demand and falling marginal costs, circumstances the Court used to find the defendants guilty of restraint of trade. A reexamination of the case, however, indicates that Posner's assumption that demand elasticity remains the same before and after the demand shift is overly restrictive. If this assumption is relaxed, conditions exist under which a monopolist would raise prices in the face of decreasing demand and falling marginal costs. The behavior the Court cited thus represents one of the few instances when monopolistic and competitive pricing can be clearly differentiated by empirical observation. The reasoning used by the Court should be given a more important place in antitrust enforcement.

An analysis was made of the reciprocal relationships in the health care sector. It was shown that the allocation of a great deal of modern biotechnology is governed by reciprocity. Perhaps the most enlightening example of the contemporary reliance upon reciprocity and redistribution is the system for the procurement and allocation of transplantable organs for kidney, liver, cornea, heart, and other transplants. One of the most interesting cases of reciprocity in the health care sector involves the duty of physicians to treat patients, even if they place themselves in jeopardy. In the environment of reciprocal health care arrangements, the allocative decisions of physicians are crucial. This indicates that reciprocity may serve as a method for perpetuating physician autonomy.

Intensification of drought and wildfire associated with climate change has triggered widespread ecosystem stress and transformation. Natural resource managers are on the frontline of these changes, yet their perspectives on whether management actions match the scale and align with the severity of ecosystem responses to improve outcomes are not well understood. To provide new insight, a new conceptual framework that linked scale and severity was tested by conducting interviews and surveys of staff associated with natural resource management on the Colorado Plateau in the southwestern United States (U.S.), which contains the highest concentration of public lands in the contiguous U.S. Results indicate that drought was experienced more frequently than wildfire, and both stressors were happening at large scales and moderate to abrupt timeframes with a high degree of impact to ecosystems. Ecosystem responses were perceived to increase in severity under future climate change with limited capacity to recover, and a majority of resource managers expressed that they had low control to shape these trajectories. Although management strategies to address drought and wildfire were well recognized, adaptation-specific actions remained unclear or had limited financial and staffing resources to support implementation. Additional effort could help close a growing misalignment between management actions and natural resource responses, including effective science communication, refined information tailored to meet adaptation goals at management-relevant spatiotemporal scales, and opportunities for adaptive management that can proactively address intensification of drought and wildfire.

Neighborhood characteristics have been associated with various facets of children's health. This study explored whether adverse neighborhood conditions-particularly violence exposure and perceptions of danger-were associated with child health status and health risks across four dimensions: health difficulties (for example, headaches, stomachaches, or breathing problems), chronic physical conditions, developmental disorders, and mental health conditions. Data were derived from the 2016 National Survey of Children's Health, a survey of a cross-sectional weighted probability sample of US children ages 0-17. The findings indicate that neighborhood violence exposure and perceptions of danger yielded the strongest associations with the studied health dimensions and were especially relevant to the occurrence and accumulation of intersecting health problems across dimensions. The findings underscore the need for multiple sectors and agencies to collectively invest in public safety and community violence prevention as a means of promoting health among children.