A Thermal Performance Design Optimization Study for Small Alaskan Rural Schools

1.0 Summary - 1 2.0 Introduction - 3 2.1 Purpose - 5 2.2 Scope - 5 3.0 A Discussion of Thermal Standards - 7 3.1 Recent Federal Government Studies - 8 3.1.1 The ASHRAE Standard - 8 3.1.2 The United States Department of Energy Standard - 11 3.2 Requirements for Standards in Alaska - 18 4.0 Life Cycle Cost Evaluation Technique - 20 4.1 Purpose - 21 4.2 Prototype Building - 26 4.3 Envelope Design Alternatives - 33 4.4 Mechanical System Design Alternatives - 34 4.4.1 Existing Practice - 34 4.4.2 Modeling of Mechanical Systems - 42 4.4.3 Maintenance and Operations Considerations - 55 4.4.4 Cogeneration Concepts - 57 4.5 Electrical System Design Alternatives - 59 4.6 Cost Estimating - 63 4.6.1 Construction Costs for Thermal Envelopes - 63 4.6.2 Construction Costs for Mechanical and Electrical Systems - 64 4.6.3 Analysis of Maintenance Costs - 69 4.7 Statewide Climate and Costs Regions - 71 4.8 Thermal Modeling Techniques - 77 4.8.1 Fuel Inputs - 78 4.8.2 Domestic Hot Water Heating Energy - 78 4.8.3 Internal and Passive Solar Heat Gain - 81 4.8.4 Building Ventilation Scheduling- 83 4.8.5 Model Output - 83 4.8.6 Model Validation - 83 4.9 Methods of Economic Analysis - 84 4.9.1 Analysis of First Costs and Renovation Costs - 86 4.9.2 Analysis of Maintenance and Operations Costs - 86 4.9.3 Analysis of Annual Energy Consumption - 89 4.10 LCC Computer Model T-Load - 89 4.10.1 Program Description - 89 4.10.2 Data Set Organization - 91 4.10.3 Building Cases Considered - 93 4.10.4 Program Output - 94 5.0 Analysis - 97 5.1 Description of Life Cycle Cost Model Results - 98 5.2 Analysis of Results - 102 5.2.1 Design Concepts - 106 5.2.2 Exterior Envelope - 106 5.2.3 Interior Energy Systems -107 5.3 Sensitivity Analysis - 108 6.0 Conclusions - 112 6.1 Optimum Design Concepts -113 6.2 Sensitivity of Results - 114 6.3 Interior Energy Systems - 115 6.4 Applicability of Results - 115 6.5 Summary - 116 7.0 References - 118 8.0 Appendices Appendix A: T-Load Computer Program Output - A-1 T-Load NES-002 - A-2 T-Load NEE-002 - A-10 T-Load NED-002 - A-18 T-Load HES-002 A-26 T-Load HEE-002 - A-34 T-Load HED-002 - A-42 T-Load NHS-004 - A-50 T-Load NHE-004 - A-60 T-Load NHD-004 - A-70 T-Load HHS-004 - A-80 T-Load HHE-004 - A-90 T-Load HHD-004 - A-100 Appendix B: Total Life Cycle Cost Minimum Plots - B-

A Thermal Performance Design Optimization Study for Small Alaskan Rural Schools

1.0 Summary - 1 2.0 Introduction - 2 2.1 Purpose - 3 2.2 Scope - 4 3.0 A Discussion of Thermal Standards - 5 3.1 Recent Federal Government Studies - 5 3.2 Requirements for Standards in Alaska - 15 4.0 Life Cycle Cost Evaluation Technique - 17 4.1 - Prototype Building - 20 4.2 Envelope Design Alternatives - 27 4.3 Mechanical System Design Alternatives - 32 4.4 Electrical System Design Alternatives - 46 4.5 Cost Estimating - 49 4.5.1 Construction Costs for Thermal Envelopes - 49 4.5.2 Construction Costs for Mechanical and Electrical Systems - 52 4.5.3 Analysis of Maintenance Costs - 57 4.6 Statewide Climate and Costs Regions - 59 4.7 Thermal Modeling Techniques - 62 4.8 Methods of Economic Analysis - 66 4.8.1 Analysis of First Costs and Renovation Costs - 68 4.8.2 - Analysis of Maintenance and Operations Costs - 70 4.8.3 Analysis of Annual Energy Consumption - 72 4.9 LCC Computer Model "MAIN" - 74 5.0 Analysis of Results - 77 5.1 Description of Life Cycle Cost Model Results - 77 5.2 Selection of Least Life Cycle Cost Design Alternatives - 112 6.0 Conclusions and Recommendations - 117 6.1 Conclusions - 117 6.2 Recommendations - 119 7.0 References - 120 8.0 Appendices Appendix 1: Electrical Systems Design Appendix 2: Climate Data Appendix 3: Listing of Analysis Program Appendix 4: Listing of Program Variables Appendix 5: Energy Use Summary Appendix 6: Life Cycle Cost Summar

First Results from The GlueX Experiment

The GlueX experiment at Jefferson Lab ran with its first commissioning beam in late 2014 and the spring of 2015. Data were collected on both plastic and liquid hydrogen targets, and much of the detector has been commissioned. All of the detector systems are now performing at or near design specifications and events are being fully reconstructed, including exclusive production of $\pi^{0}$, $\eta$ and $\omega$ mesons. Linearly-polarized photons were successfully produced through coherent bremsstrahlung and polarization transfer to the $\rho$ has been observed.Comment: 8 pages, 6 figures, Invited contribution to the Hadron 2015 Conference, Newport News VA, September 201

Oncostatin M Protects Rod and Cone Photoreceptors and Promotes Regeneration of Cone Outer Segment in a Rat Model of Retinal Degeneration

Retinitis pigmentosa (RP) is a group of photoreceptor degenerative disorders that lead to loss of vision. Typically, rod photoreceptors degenerate first, resulting in loss of night and peripheral vision. Secondary cone degeneration eventually affects central vision, leading to total blindness. Previous studies have shown that photoreceptors could be protected from degeneration by exogenous neurotrophic factors, including ciliary neurotrophic factor (CNTF), a member of the IL-6 family of cytokines. Using a transgenic rat model of retinal degeneration (the S334-ter rat), we investigated the effects of Oncostatin M (OSM), another member of the IL-6 family of cytokines, on photoreceptor protection. We found that exogenous OSM protects both rod and cone photoreceptors. In addition, OSM promotes regeneration of cone outer segments in early stages of cone degeneration. Further investigation showed that OSM treatment induces STAT3 phosphorylation in Müller cells but not in photoreceptors, suggesting that OSM not directly acts on photoreceptors and that the protective effects of OSM on photoreceptors are mediated by Müller cells. These findings support the therapeutic strategy using members of IL-6 family of cytokines for retinal degenerative disorders. They also provide evidence that activation of the STAT3 pathway in Müller cells promotes photoreceptor survival. Our work highlights the importance of Müller cell-photoreceptor interaction in the retina, which may serve as a model of glia-neuron interaction in general

CNS activity of Pokeweed Anti-viral Protein (PAP) in mice infected with Lymphocytic Choriomeningitis Virus (LCMV)

BACKGROUND: Others and we have previously described the potent in vivo and in vitro activity of the broad-spectrum antiviral agent PAP (Pokeweed antiviral protein) against a wide range of viruses. The purpose of the present study was to further elucidate the anti-viral spectrum of PAP by examining its effects on the survival of mice challenged with lymphocytic choriomeningitis virus (LCMV). METHODS: We examined the therapeutic effect of PAP in CBA mice inoculated with intracerebral injections of the WE54 strain of LCMV at a 1000 PFU dose level that is lethal to 100% of mice within 7–9 days. Mice were treated either with vehicle or PAP administered intraperitoneally 24 hours prior to, 1 hour prior to and 24 hours, 48 hours 72 hours and 96 hours after virus inoculation. RESULTS: PAP exhibits significant in vivo anti- LCMV activity in mice challenged intracerebrally with an otherwise invariably fatal dose of LCMV. At non-toxic dose levels, PAP significantly prolonged survival in the absence of the majority of disease-associated symptoms. The median survival time of PAP-treated mice was >21 days as opposed to 7 days median survival for the control (p = 0.0069). CONCLUSION: Our results presented herein provide unprecedented experimental evidence that PAP exhibits antiviral activity in the CNS of LCMV-infected mice

The cellular redox environment alters antigen presentation

Cysteine-containing peptides represent an important class of T cell epitopes, yet their prevalence remains underestimated. We have established and interrogated a database of around 70,000 naturally processed MHC-bound peptides and demonstrate that cysteine-containing peptides are presented on the surface of cells in an MHC allomorph-dependent manner and comprise on average 5-10% of the immunopeptidome. A significant proportion of these peptides are oxidatively modified, most commonly through covalent linkage with the antioxidant glutathione. Unlike some of the previously reported cysteine-based modifications, this represents a true physiological alteration of cysteine residues. Furthermore, our results suggest that alterations in the cellular redox state induced by viral infection are communicated to the immune system through the presentation of S-glutathionylated viral peptides, resulting in altered T cell recognition. Our data provide a structural basis for how the glutathione modification alters recognition by virus-specific T cells. Collectively, these results suggest that oxidative stress represents a mechanism for modulating the virus-specific T cell response.This work was supported, in whole or in part, by National Institutes of Health Grant R01 NS036592. This work was also supported by an infrastructure grant (Grant LE100100036) from the Australian Research Council (ARC) and a project grant from the Juvenile Diabetes Research Foundation (17-2012-134)

Promoter DNA Methylation of Oncostatin M receptor-β as a Novel Diagnostic and Therapeutic Marker in Colon Cancer

In addition to genetic changes, the occurrence of epigenetic alterations is associated with accumulation of both genetic and epigenetic events that promote the development and progression of human cancer. Previously, we reported a set of candidate genes that comprise part of the emerging “cancer methylome”. In the present study, we first tested 23 candidate genes for promoter methylation in a small number of primary colon tumor tissues and controls. Based on these results, we then examined the methylation frequency of Oncostatin M receptor-β (OSMR) in a larger number of tissue and stool DNA samples collected from colon cancer patients and controls. We found that OSMR was frequently methylated in primary colon cancer tissues (80%, 80/100), but not in normal tissues (4%, 4/100). Methylation of OSMR was also detected in stool DNA from colorectal cancer patients (38%, 26/69) (cut-off in TaqMan-MSP, 4). Detection of other methylated markers in stool DNA improved sensitivity with little effect on specificity. Promoter methylation mediated silencing of OSMR in cell lines, and CRC cells with low OSMR expression were resistant to growth inhibition by Oncostatin M. Our data provide a biologic rationale for silencing of OSMR in colon cancer progression and highlight a new therapeutic target in this disease. Moreover, detection and quantification of OSMR promoter methylation in fecal DNA is a highly specific diagnostic biomarker for CRC

Inflammation-Associated Nitrotyrosination Affects TCR Recognition through Reduced Stability and Alteration of the Molecular Surface of the MHC Complex

Nitrotyrosination of proteins, a hallmark of inflammation, may result in the production of MHC-restricted neoantigens that can be recognized by T cells and bypass the constraints of immunological self-tolerance. Here we biochemically and structurally assessed how nitrotyrosination of the lymphocytic choriomeningitis virus (LCMV)-associated immunodominant MHC class I-restricted epitopes gp33 and gp34 alters T cell recognition in the context of both H-2Db and H-2Kb. Comparative analysis of the crystal structures of H-2Kb/gp34 and H-2Kb/NY-gp34 demonstrated that nitrotyrosination of p3Y in gp34 abrogates a hydrogen bond interaction formed with the H-2Kb residue E152. As a consequence the conformation of the TCR-interacting E152 was profoundly altered in H-2Kb/NY-gp34 when compared to H-2Kb/gp34, thereby modifying the surface of the nitrotyrosinated MHC complex. Furthermore, nitrotyrosination of gp34 resulted in structural over-packing, straining the overall conformation and considerably reducing the stability of the H-2Kb/NY-gp34 MHC complex when compared to H-2Kb/gp34. Our structural analysis also indicates that nitrotyrosination of the main TCR-interacting residue p4Y in gp33 abrogates recognition of H-2Db/gp33-NY complexes by H-2Db/gp33-specific T cells through sterical hindrance. In conclusion, this study provides the first structural and biochemical evidence for how MHC class I-restricted nitrotyrosinated neoantigens may enable viral escape and break immune tolerance

Monocytes induce STAT3 activation in human mesenchymal stem cells to promote osteoblast formation

A major therapeutic challenge is how to replace bone once it is lost. Bone loss is a characteristic of chronic inflammatory and degenerative diseases such as rheumatoid arthritis and osteoporosis. Cells and cytokines of the immune system are known to regulate bone turnover by controlling the differentiation and activity of osteoclasts, the bone resorbing cells. However, less is known about the regulation of osteoblasts (OB), the bone forming cells. This study aimed to investigate whether immune cells also regulate OB differentiation. Using in vitro cell cultures of human bone marrow-derived mesenchymal stem cells (MSC), it was shown that monocytes/macrophages potently induced MSC differentiation into OBs. This was evident by increased alkaline phosphatase (ALP) after 7 days and the formation of mineralised bone nodules at 21 days. This monocyte-induced osteogenic effect was mediated by cell contact with MSCs leading to the production of soluble factor(s) by the monocytes. As a consequence of these interactions we observed a rapid activation of STAT3 in the MSCs. Gene profiling of STAT3 constitutively active (STAT3C) infected MSCs using Illumina whole human genome arrays showed that Runx2 and ALP were up-regulated whilst DKK1 was down-regulated in response to STAT3 signalling. STAT3C also led to the up-regulation of the oncostatin M (OSM) and LIF receptors. In the co-cultures, OSM that was produced by monocytes activated STAT3 in MSCs, and neutralising antibodies to OSM reduced ALP by 50%. These data indicate that OSM, in conjunction with other mediators, can drive MSC differentiation into OB. This study establishes a role for monocyte/macrophages as critical regulators of osteogenic differentiation via OSM production and the induction of STAT3 signalling in MSCs. Inducing the local activation of STAT3 in bone cells may be a valuable tool to increase bone formation in osteoporosis and arthritis, and in localised bone remodelling during fracture repair