Retromer and Its Role in Regulating Signaling at Endosomes.

The retromer complex is a key element of the endosomal protein sorting machinery being involved in trafficking of proteins from endosomes to the Golgi and also endosomes to the cell surface. There is now accumulating evidence that retromer also has a prominent role in regulating the activity of many diverse signaling proteins that traffic through endosomes and this activity has profound implications for the functioning of many different cell and tissue types from neuronal cells to cells of the immune system to specialized polarized epithelial cells of the retina. In this review, the protein composition of the retromer complex will be described along with many of the accessory factors that facilitate retromer-mediated endosomal protein sorting to detail how retromer activity contributes to the regulation of several distinct signaling pathways

Nutrition and cancer: A review of the evidence for an anti-cancer diet

It has been estimated that 30–40 percent of all cancers can be prevented by lifestyle and dietary measures alone. Obesity, nutrient sparse foods such as concentrated sugars and refined flour products that contribute to impaired glucose metabolism (which leads to diabetes), low fiber intake, consumption of red meat, and imbalance of omega 3 and omega 6 fats all contribute to excess cancer risk. Intake of flax seed, especially its lignan fraction, and abundant portions of fruits and vegetables will lower cancer risk. Allium and cruciferous vegetables are especially beneficial, with broccoli sprouts being the densest source of sulforophane. Protective elements in a cancer prevention diet include selenium, folic acid, vitamin B-12, vitamin D, chlorophyll, and antioxidants such as the carotenoids (α-carotene, β-carotene, lycopene, lutein, cryptoxanthin). Ascorbic acid has limited benefits orally, but could be very beneficial intravenously. Supplementary use of oral digestive enzymes and probiotics also has merit as anticancer dietary measures. When a diet is compiled according to the guidelines here it is likely that there would be at least a 60–70 percent decrease in breast, colorectal, and prostate cancers, and even a 40–50 percent decrease in lung cancer, along with similar reductions in cancers at other sites. Such a diet would be conducive to preventing cancer and would favor recovery from cancer as well

Toward cost-effective staffing mixes for Veterans Affairs substance use disorder treatment programs

BACKGROUND: In fiscal year (FY) 2008, 133,658 patients were provided services within substance use disorders treatment programs (SUDTPs) in the U.S. Department of Veterans Affairs (VA) health care system. To improve the effectiveness and cost-effectiveness of SUDTPs, we analyze the impacts of staffing mix on the benefits and costs of specialty SUD services. This study demonstrates how cost-effective staffing mixes for each type of VA SUDTPs can be defined empirically. METHODS: We used a stepwise method to derive prediction functions for benefits and costs based on patients’ treatment outcomes at VA SUDTPs nationally from 2001 to 2003, and used them to formulate optimization problems to determine recommended staffing mixes that maximize net benefits per patient for four types of SUDTPs by using the solver function with the Generalized Reduced Gradient algorithm in Microsoft Excel 2010 while conforming to limits of current practice. We conducted sensitivity analyses by varying the baseline severity of addiction problems between lower (2.5 %) and higher (97.5 %) values derived from bootstrapping. RESULTS AND CONCLUSIONS: Compared to the actual staffing mixes in FY01-FY03, the recommended staffing mixes would lower treatment costs while improving patients’ outcomes, and improved net benefits are estimated from $1472 to$17,743 per patient

Sorting nexin 27 couples PTHR trafficking to retromer for signal regulation in osteoblasts during bone growth

The parathyroid hormone 1 receptor (PTHR) is central to the process of bone formation and remodeling. PTHR signaling requires receptor internalization into endosomes, which is then terminated by recycling or degradation. Here we show that sorting nexin 27 (SNX27) functions as an adaptor that couples PTHR to the retromer trafficking complex. SNX27 binds directly to the C-terminal PDZ-binding motif of PTHR, wiring it to retromer for endosomal sorting. The structure of SNX27 bound to the PTHR motif reveals a high-affinity interface involving conserved electrostatic interactions. Mechanistically, depletion of SNX27 or retromer augments intracellular PTHR signaling in endosomes. Osteoblasts genetically lacking SNX27 show similar disruptions in PTHR signaling and greatly reduced capacity for bone mineralization, contributing to profound skeletal deficits in SNX27-knockout mice. Taken together, our data support a critical role for SNX27-retromer mediated transport of PTHR in normal bone development

A reactive transport benchmark on heavy metal cycling in lake sediments

Sediments are active recipients of anthropogenic inputs, including heavy metals, but may be difficult to interpret without the use of numerical models that capture sediment-metal interactions and provide an accurate representation of the intricately coupled sedimentological, geochemical, and biological processes. The focus of this study is to present a benchmark problem on heavy metal cycling in lake sediments and to compare reactive transport models (RTMs) in their treatment of the local-scale physical and biogeochemical processes. This benchmark problem has been developed based on a previously published reactive-diffusive model of metal transport in the sediments of Lake Coeur d'Alene, Idaho. Key processes included in this model are microbial reductive dissolution of iron hydroxides (i.e., ferrihydrite), the release of sorbed metals into pore water, reaction of these metals with biogenic sulfide to form sulfide minerals, and sedimentation driving the burial of ferrihydrite and other minerals. This benchmark thus considers a multicomponent biotic reaction network with multiple terminal electron acceptors (TEAs), Fickian diffusive transport, kinetic and equilibrium mineral precipitation and dissolution, aqueous and surface complexation, as well as (optionally) sedimentation. To test the accuracy of the reactive transport problem solution, four RTMs-TOUGHREACT (TR), CrunchFlow (CF), PHREEQC, and PHT3D-have been used. Without sedimentation, all four models are able to predict similar trends of TEAs and dissolved metal concentrations, as well as mineral abundances. TR and CF are further used to compare sedimentation and compaction test cases. Results with different sedimentation rates are captured by both models, but since the codes do not use the same formulation for compaction, the results differ for this test case. Although, both TR and CF adequately capture the trends of aqueous concentrations and mineral abundances, the difference in results highlights the need to consider further the conceptual and numerical models that link transport, biogeochemical reactions, and sedimentation