Computational Transport Modeling of High-Energy Neutrons Found in the Space Environment

The high charge and high energy (HZE) particle radiation environment in space interacts with spacecraft materials and the human body to create a population of neutrons encompassing a broad kinetic energy spectrum. As an HZE ion penetrates matter, there is an increasing chance of fragmentation as penetration depth increases. When an ion fragments, secondary neutrons are released with velocities up to that of the primary ion, giving some neutrons very long penetration ranges. These secondary neutrons have a high relative biological effectiveness, are difficult to effectively shield, and can cause more biological damage than the primary ions in some scenarios. Ground-based irradiation experiments that simulate the space radiation environment must account for this spectrum of neutrons. Using the Particle and Heavy Ion Transport Code System (PHITS), it is possible to simulate a neutron environment that is characteristic of that found in spaceflight. Considering neutron dosimetry, the focus lies on the broad spectrum of recoil protons that are produced in biological targets. In a biological target, dose at a certain penetration depth is primarily dependent upon recoil proton tracks. The PHITS code can be used to simulate a broad-energy neutron spectrum traversing biological targets, and it account for the recoil particle population. This project focuses on modeling a neutron beamline irradiation scenario for determining dose at increasing depth in water targets. Energy-deposition events and particle fluence can be simulated by establishing cross-sectional scoring routines at different depths in a target. This type of model is useful for correlating theoretical data with actual beamline radiobiology experiments. Other work exposed human fibroblast cells to a high-energy neutron source to study micronuclei induction in cells at increasing depth behind water shielding. Those findings provide supporting data describing dose vs. depth across a water-equivalent medium. This poster presents PHITS data suggesting an increase in dose, up to roughly 10 cm depth, followed by a continual decrease as neutrons come to a stop in the target

Everolimus (RAD001) sensitizes prostate cancer cells to docetaxel by down-regulation of HIF-1α and sphingosine kinase 1

Resistance to docetaxel is a key problem in current prostate cancer management. Sphingosine kinase 1 (SK1) and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways have been implicated in prostate cancer chemoresistance. Here we investigated whether their combined targeting may re-sensitize prostate cancer cells to docetaxel. In hormone-insensitive PC-3 and DU145 prostate cancer cells the mTOR inhibitor everolimus (RAD001) alone did not lead to significant cell death, however, it strongly sensitized cells to low levels (5 nM) of docetaxel. We show that mTOR inhibition has led to a decrease in hypoxia-inducible factor-1α (HIF-1α) protein levels and SK1 mRNA. HIF-1α accumulation induced by CoCl2 has led to a partial chemoresistance to RAD001/docetaxel combination. SK1 overexpression has completely protected prostate cancer cells from RAD001/docetaxel effects. Using gene knockdown and CoCl2 treatment we showed that SK1 mRNA expression is downstream of HIF-1α. In a human xenograft model in nude mice single RAD001 and docetaxel therapies induced 23% and 15% reduction in prostate tumor volume, respectively, while their combination led to a 58% reduction. RAD001 alone or in combination with docetaxel has suppressed intratumoral mTOR and SK1 signaling, however as evidenced by tumor size, it required docetaxel for clinical efficacy. Combination therapy was well tolerated and had similar levels of toxicity to docetaxel alone. Overall, our data demonstrate a new mechanism of docetaxel sensitization in prostate cancer. This provides a mechanistic basis for further clinical application of RAD001/docetaxel combination in prostate cancer therapy

Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence

Vigorous proliferative CD4+ T cell responses are the hallmark of spontaneous clearance of acute hepatitis C virus (HCV) infection, whereas comparable responses are absent in chronically evolving infection. Here, we comprehensively characterized the breadth, specificity, and quality of the HCV-specific CD4+ T cell response in 31 patients with acute HCV infection and varying clinical outcomes. We analyzed in vitro T cell expansion in the presence of interleukin-2, and ex vivo staining with HCV peptide-loaded MHC class II tetramers. Surprisingly, broadly directed HCV-specific CD4+ T cell responses were universally detectable at early stages of infection, regardless of the clinical outcome. However, persistent viremia was associated with early proliferative defects of the HCV-specific CD4+ T cells, followed by rapid deletion of the HCV-specific response. Only early initiation of antiviral therapy was able to preserve CD4+ T cell responses in acute, chronically evolving infection. Our results challenge the paradigm that HCV persistence is the result of a failure to prime HCV-specific CD4+ T cells. Instead, broadly directed HCV-specific CD4+ T cell responses are usually generated, but rapid exhaustion and deletion of these cells occurs in the majority of patients. The data further suggest a short window of opportunity to prevent the loss of CD4+ T cell responses through antiviral therapy

Divalent and Multivalent Activation in Phosphate Triesters: A Versatile Method for the Synthesis of Advanced Polyol Synthons

This is the peer reviewed version of the following article: Thomas, C. D., McParland, J. P. and Hanson, P. R. (2009), Divalent and Multivalent Activation in Phosphate Triesters: A Versatile Method for the Synthesis of Advanced Polyol Synthons. Eur. J. Org. Chem., 2009: 5487–5500. doi:10.1002/ejoc.200900560, which has been published in final form at http://doi.org/10.1002/ejoc.200900560. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.The construction of mono- and bicyclic phosphate trimesters possessing divalent and multivalent activation and their subsequent use in the production of advanced polyol synthons is presented. The method highlights efforts to employ phosphate tethers as removable, functionally active tethers capable of multipositional activation and their subsequent role as leaving groups in selective cleavage reactions. The development of phosphate tethers represents an integrated platform for a new and versatile tether for natural product synthesis and sheds light on new approaches to the facile construction of small molecules

Genital herpes evaluation by quantitative TaqMan PCR: correlating single detection and quantity of HSV-2 DNA in cervicovaginal lavage fluids with cross-sectional and longitudinal clinical data

Abstract Objective To evaluate the utility of a single quantitative PCR (qPCR) measurement of HSV (HSV-1&2) DNA in cervicovaginal lavage (CVL) specimens collected from women with predominantly chronic HSV-2 infection in assessing genital HSV shedding and the clinical course of genital herpes (GH) within a cohort with semiannual schedule of follow up and collection of specimens. Methods Two previously described methods used for detection of HSV DNA in mucocutaneous swab samples were adapted for quantification of HSV DNA in CVLs. Single CVL specimens from 509 women were tested. Presence and quantity of CVL HSV DNA were explored in relation to observed cross-sectional and longitudinal clinical data. Results The PCR assay was sensitive and reproducible with a limit of quantification of ~50 copies per milliliter of CVL. Overall, 7% of the samples were positive for HSV-2 DNA with median log10 HSV-2 DNA copy number of 3.9 (IQR: 2.6-5.7). No HSV-1 was detected. Presence and quantity of HSV-2 DNA in CVL directly correlated with the clinical signs and symptoms of presence of active symptomatic disease with frequent recurrences. Conclusion Single qPCR measurement of HSV DNA in CVL fluids of women with chronic HSV-2 infection provided useful information for assessing GH in the setting of infrequent sampling of specimens. Observed positive correlation of the presence and quantity of HSV-2 DNA with the presence of active and more severe course of HSV-2 infection may have clinical significance in the evaluation and management of HSV-2 infected patients

Leukotriene B4 mediates p47phox phosphorylation and membrane translocation in polyunsaturated fatty acidâ stimulated neutrophils

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142119/1/jlb0976.pd

The Monarch Initiative in 2024: an analytic platform integrating phenotypes, genes and diseases across species.

Bridging the gap between genetic variations, environmental determinants, and phenotypic outcomes is critical for supporting clinical diagnosis and understanding mechanisms of diseases. It requires integrating open data at a global scale. The Monarch Initiative advances these goals by developing open ontologies, semantic data models, and knowledge graphs for translational research. The Monarch App is an integrated platform combining data about genes, phenotypes, and diseases across species. Monarch\u27s APIs enable access to carefully curated datasets and advanced analysis tools that support the understanding and diagnosis of disease for diverse applications such as variant prioritization, deep phenotyping, and patient profile-matching. We have migrated our system into a scalable, cloud-based infrastructure; simplified Monarch\u27s data ingestion and knowledge graph integration systems; enhanced data mapping and integration standards; and developed a new user interface with novel search and graph navigation features. Furthermore, we advanced Monarch\u27s analytic tools by developing a customized plugin for OpenAI\u27s ChatGPT to increase the reliability of its responses about phenotypic data, allowing us to interrogate the knowledge in the Monarch graph using state-of-the-art Large Language Models. The resources of the Monarch Initiative can be found at monarchinitiative.org and its corresponding code repository at github.com/monarch-initiative/monarch-app