Ion Energy Measurements in Plasma Immersion Ion Implantation

This thesis investigates ion energy distributions (IEDs) during plasma immersion ion implantation (PIII). PIII is a surface modification technique where an object is placed in a plasma and pulse biased with large negative voltages. The energy distribution of implanted ions is important in determining the extent of surface modifications. IED measurements were made during PIII using a pulse biased retarding field energy analyser (RFEA) in a capacitive RF plasma. Experimental results were compared with those obtained from a two dimensional numerical simulation to help explain the origins of features in the IEDs. Time resolved IED measurements were made during PIII of metal and insulator materials and investigated the effects of the use of a metal mesh over the surface and the effects of insulator surface charging. When the pulse was applied to the RFEA, the ion flux rapidly increased above the pulse-off value and then slowly decreased during the pulse. The ion density during the pulse decreased below values measured when no pulse was applied to the RFEA. This indicates that the depletion of ions by the pulsed RFEA is greater than the generation of ions in the plasma. IEDs measured during pulse biasing showed a peak close to the maximum sheath potential energy and a spread of ions with energies between zero and the maximum ion energy. Simulations showed that the peak is produced by ions from the sheath edge directly above the RFEA inlet and that the spread of ions is produced by ions which collide in the sheath and/or arrive at the RFEA with trajectories not perpendicular to the RFEA front surface. The RFEA discriminates ions based only on the component of their velocity perpendicular to the RFEA front surface. To minimise the effects of surface charging during PIII of an insulator, a metal mesh can be placed over the insulator and pulse biased together with the object. Measurements were made with metal mesh cylinders fixed to the metal RFEA front surface. The use of a mesh gave a larger ion flux compared to the use of no mesh. The larger ion flux is attributed to the larger plasma-sheath surface area around the mesh. The measured IEDs showed a low, medium and high energy peak. Simulation results show that the high energy peak is produced by ions from the sheath above the mesh top. The low energy peak is produced by ions trapped by the space charge potential hump which forms inside the mesh. The medium energy peak is produced by ions from the sheath above the mesh corners. Simulations showed that the IED is dependent on measurement position under the mesh. To investigate the effects of insulator surface charging during PIII, IED measurements were made through an orifice cut into a Mylar insulator on the RFEA front surface. With no mesh, during the pulse, an increasing number of lower energy ions were measured. Simulation results show that this is due to the increase in the curvature of the sheath over the orifice region as the insulator potential increases due to surface charging. The surface charging observed at the insulator would reduce the average energy of ions implanted into the insulator during the pulse. Compared to the case with no mesh, the use of a mesh increases the total ion flux and the ion flux during the early stages of the pulse but does not eliminate surface charging. During the pulse, compared to the no mesh case, a larger number of lower energy ions are measured. Simulation results show that this is caused by the potential in the mesh region which affects the trajectories of ions from the sheaths above the mesh top and corners and results in more ions being measured with trajectories less than ninety degrees to the RFEA front surface

Dietary iron intakes based on food composition data may underestimate the contribution of potentially exchangeable contaminant iron from soil

Iron intakes calculated from one-day weighed records were compared with those from same day analyzed duplicate diet composites collected from 120 Malawian women living in two rural districts with contrasting soil mineralogy and where threshing may contaminate cereals with soil iron. Soils and diet composites from the two districts were then subjected to a simulated gastrointestinal digestion and iron availability in the digests measured using a Caco-2 cell model. Median analyzed iron intakes (mg/d) were higher (p < 0.001) than calculated intakes in both Zombwe (16.6 vs. 10.1 mg/d) and Mikalango (29.6 vs. 19.1 mg/d), attributed to some soil contaminant iron based on high Al and Ti concentrations in diet composites. A small portion of iron in acidic soil from Zombwe, but not Mikalango calcareous soil, was bioavailable, as it induced ferritin expression in the cells, and may have contributed to higher plasma ferritin and total body iron for the Zombwe women reported earlier, despite lower iron intakes. In conclusion, iron intakes calculated from food composition data were underestimated, highlighting the importance of analyzing duplicate diet composites where extraneous contaminant iron from soil is likely. Acidic contaminant soil may make a small but useful contribution to iron nutrition

Modelling carbonaceous aerosol from residential solid fuel burning with different assumptions for emissions

Evidence is accumulating that emissions of primary particulate matter (PM) from residential wood and coal combustion in the UK may be underestimated and/or spatially misclassified. In this study, different assumptions for the spatial distribution and total emission of PM from solid fuel (wood and coal) burning in the UK were tested using an atmospheric chemical transport model. Modelled concentrations of the PM components were compared with measurements from aerosol mass spectrometers at four sites in central and Greater London (ClearfLo campaign, 2012), as well as with measurements from the UK black carbon network. The two main alternative emission scenarios modelled were Base4x and combRedist. For Base4x, officially reported PM2.5 from the residential and other non-industrial combustion source sector were increased by a factor of four. For the combRedist experiment, half of the baseline emissions from this same source were redistributed by residential population density to simulate the effect of allocating some emissions to the smoke control areas (that are assumed in the national inventory to have no emissions from this source). The Base4x scenario yielded better daily and hourly correlations with measurements than the combRedist scenario for year-long comparisons of the solid fuel organic aerosol (SFOA) component at the two London sites. However, the latter scenario better captured mean measured concentrations across all four sites. A third experiment, Redist – all emissions redistributed linearly to population density, is also presented as an indicator of the maximum concentrations an assumption like this could yield. The modelled elemental carbon (EC) concentrations derived from the combRedist experiments also compared well with seasonal average concentrations of black carbon observed across the network of UK sites. Together, the two model scenario simulations of SFOA and EC suggest both that residential solid fuel emissions may be higher than inventory estimates and that the spatial distribution of residential solid fuel burning emissions, particularly in smoke control areas, needs re-evaluation. The model results also suggest the assumed temporal profiles for residential emissions may require review to place greater emphasis on evening (including “discretionary”) solid fuel burning

Terrestrial Reserve Networks Do Not Adequately Represent Aquatic Ecosystems

Las áreas protegidas son una piedra angular de la conservación y han sido diseñadas principalmente alrededor de atributos terrestres. Las especies y ecosistemas dulceacuícolas se encuentran en peligro, pero la efectividad de las áreas protegidas existentes para representar las características dulceacuícolas es poco conocida. Utilizando las aguas interiores de Michigan como un caso de prueba, cuantificamos la cobertura de cuatro atributos dulceacuícolas clave (humedales, zonas ribereñas, recarga de agua subterránea y especies raras) en las tierras conservadas y las comparamos con la representación de los atributos terrestres. Los humedales estaban incluidos en las áreas protegidas más a menudo que lo esperado por azar, pero las zonas ribereñas estuvieron insuficientemente representadas en todas las tierras protegidas (GAP1–3), particularmente en manantiales y ríos grandes. Sin embargo, las zonas ribereñas estuvieron bien representadas en las tierras con protección estricta (GAP 1–2) debido a la contribución del Programa Nacional de Ríos Silvestres y Escénicos. La representación de áreas de recarga de aguas subterráneas generalmente fue proporcional al área de la red de reservas dentro de cuencas hidrológicas, aunque un sitio importante de recarga asociado con algunos de los ríos más valiosos en Michigan estaba casi totalmente desprotegido. La representación de especies en áreas protegidas difirió significativamente entre las especies acuáticas obligadas, de humedales y terrestres, con una representación generalmente mayor para las especies terrestres y menor para las acuáticas. Nuestros resultados ilustran la necesidad de evaluar y atender la representación de los atributos dulceacuícolas dentro de las áreas protegidas y el valor de ampliar el análisis de brechas y otras evaluaciones de áreas protegidas para incluir los procesos ecosistémicos claves que son requisito para la conservación a largo plazo de especies y ecosistemas. Concluimos que las redes de áreas protegidas orientadas al medio terrestre proporcionan una red de seguridad débil para los atributos acuáticos, lo que significa que se requiere planeación y manejo complementario tanto para objetivos de conservación dulceacuícolas como terrestres.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79138/1/COBI_1460_sm_AppendixS3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/79138/2/COBI_1460_sm_AppendixS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/79138/3/j.1523-1739.2010.01460.x.pd

The International Consortium Investigating Neurocognition in Bipolar Disorder (ICONICâ BD)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148257/1/bdi12748.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148257/2/bdi12748_am.pd

Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses.

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.KLG is supported by the Victorian Cancer Agency (MCRF15013) and the Australian National Health and Medical Research Council (APP1045783 and #628434). This study was supported by the Peter MacCallum Cancer Foundation. CS is supported by a University of Melbourne Postgraduate Scholarship. DDB is supported by National Health and Medical Research Council of Australia (NHMRC) grants APP1092856 and APP1117044 and by the US National Cancer Institute U54 programme (U54CA209978-04). ELG and SHK are supported through P50 CA136393-10. The following cohorts that contributed to the GAMuT study were supported as follows: CASCADE: Supported by the Peter MacCallum Cancer Foundation AOCS: The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania and The Cancer Foundation of Western Australia (Multi-State Applications 191, 211 and 182) and the National Health and Medical Research Council of Australia (NHMRC; ID400413 and ID400281). The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation. The AOCS also acknowledges the cooperation of the participating institutions in Australia and acknowledges the contribution of the study nurses, research assistants and all clinical and scientific collaborators to the study. The complete AOCS Study Group can be found at www.aocstudy.org. We would like to thank all of the women who participated in these research programs. OVCARE receives core funding from The BC Cancer Foundation and the VGH and UBC Hospital Foundation. The Gynaecological Oncology Biobank at Westmead is a member of the Australasian Biospecimen Network-Oncology group, which was funded by the National Health and Medical Research Council Enabling Grants ID 310670 & ID 628903 and the Cancer Institute NSW Grants ID 12/RIG/1-17 & 15/RIG/1-16. COEUR: This study uses resources provided by the Canadian Ovarian Cancer Research Consortium’s - COEUR biobank funded by the Terry Fox Research Institute and managed and supervised by the Centre hospitalier de l’Université de Montréal (CRCHUM). The Consortium acknowledges contributions to its COEUR biobank from Institutions across Canada (for a full list see http://www.tfri.ca/en/research/translational-research/coeur/coeur_biobanks.aspx). The following cohorts that contributed to OTTA were supported as follows: AOV: Canadian Institutes of Health Research (MOP-86727), Cancer Research Society (19319). BAV: ELAN Funds of the University of Erlangen-Nuremberg; DOV: NCI/NIH R01CA168758. Huntsman Cancer Foundation and the National Cancer Institute of the National Institutes of Health under Award Number P30CA042014. HAW: U.S. National 19 Institutes of Health (R01-CA58598, N01-CN-55424 and N01-PC-67001); MAY: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; SEA: SEARCH team: Mitul Shah, Jennifer Alsopp, Mercedes Jiminez-Linan SEARCH funding: Cancer Research UK (C490/A16561), the Cancer Research UK Cambridge Cancer Centre and the National Institute for Health Research Cambridge Biomedical Research Centres. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. JBD: Cancer Research UK Institute Group Award UK A22905 and A15601; STA: NIH grants U01 CA71966 and U01 CA69417; SWE: Swedish Cancer foundation, WeCanCureCancer and årKampMotCancer foundation; TVA: Canadian Institutes of Health Research grant (MOP-86727) and NIH/NCI 1 R01CA160669- 01A1; VAN: M.S. Anglesio is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars program managed by the BC Cancer Foundation. The Vancouver study cohort (TVAN) is supported by BC’s Ovarian Cancer Research team (OVCARE), the BC Cancer Foundation and The VGH+UBC Hospital Foundation. WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 & ID 628903. Cancer Institute NSW Grants 12/RIG/1-17 & 15/RIG/1-16

Dietary mineral supplies in Africa

Dietary micronutrient deficiencies (MNDs) are widespread, yet their prevalence can be difficult to assess. Here, we estimate MND risks due to inadequate intakes for seven minerals in Africa using food supply and composition data, and consider the potential of food-based and agricultural interventions. Food Balance Sheets (FBSs) for 46 countries were integrated with food composition data to estimate per capita supply of calcium (Ca), copper (Cu), iron (Fe), iodine (I), magnesium (Mg), selenium (Se) and zinc (Zn), and also phytate. Deficiency risks were quantified using an estimated average requirement (EAR) ‘cut-point’ approach. Deficiency risks are highest for Ca (54% of the population), followed by Zn (40%), Se (28%) and I (19%, after accounting for iodized salt consumption). The risk of Cu (1%) and Mg (<1%) deficiency are low. Deficiency risks are generally lower in the north and west of Africa. Multiple MND risks are high in many countries. The population-weighted mean phytate supply is 2770 mg capita−1 day−1. Deficiency risks for Fe are lower than expected (5%). However, ‘cut-point’ approaches for Fe are sensitive to assumptions regarding requirements; e.g. estimates of Fe deficiency risks are 43% under very low bioavailability scenarios consistent with high-phytate, low-animal protein diets. Fertilization and breeding strategies could greatly reduce certain MNDs. For example, meeting HarvestPlus breeding targets for Zn would reduce dietary Zn deficiency risk by 90% based on supply data. Dietary diversification or direct fortification is likely to be needed to address Ca deficiency risks

The risk of selenium deficiency in Malawi is large and varies over multiple spatial scales

Selenium (Se) is an essential human micronutrient. Deficiency of Se decreases the activity of selenoproteins and can compromise immune and thyroid function and cognitive development, and increase risks from non-communicable diseases. The prevalence of Se deficiency is unknown in many countries, especially in sub-Saharan Africa (SSA). Here we report that the risk of Se deficiency in Malawi is large among a nationally representative population of 2,761 people. For example, 62.5% and 29.6% of women of reproductive age (WRA, n = 802) had plasma Se concentrations below the thresholds for the optimal activity of the selenoproteins glutathione peroxidase 3 (GPx3

The risk of selenium deficiency in Malawi is large and varies over multiple spatial scales

Selenium (Se) is an essential human micronutrient. Deficiency of Se decreases the activity of selenoproteins and can compromise immune and thyroid function and cognitive development, and increase risks from non-communicable diseases. The prevalence of Se deficiency is unknown in many countries, especially in sub-Saharan Africa (SSA). Here we report that the risk of Se deficiency in Malawi is large among a nationally representative population of 2,761 people. For example, 62.5% and 29.6% of women of reproductive age (WRA, n = 802) had plasma Se concentrations below the thresholds for the optimal activity of the selenoproteins glutathione peroxidase 3 (GPx3; <86.9 ng mL−1) and iodothyronine deiodinase (IDI; <64.8 ng mL−1), respectively. This is the first nationally representative evidence of widespread Se deficiency in SSA. Geostatistical modelling shows that Se deficiency risks are influenced by soil type, and also by proximity to Lake Malawi where more fish is likely to be consumed. Selenium deficiency should be quantified more widely in existing national micronutrient surveillance programmes in SSA given the marginal additional cost this would incur

Modeling Signal Propagation Mechanisms and Ligand-Based Conformational Dynamics of the Hsp90 Molecular Chaperone Full-Length Dimer

Hsp90 is a molecular chaperone essential for protein folding and activation in normal homeostasis and stress response. ATP binding and hydrolysis facilitate Hsp90 conformational changes required for client activation. Hsp90 plays an important role in disease states, particularly in cancer, where chaperoning of the mutated and overexpressed oncoproteins is important for function. Recent studies have illuminated mechanisms related to the chaperone function. However, an atomic resolution view of Hsp90 conformational dynamics, determined by the presence of different binding partners, is critical to define communication pathways between remote residues in different domains intimately affecting the chaperone cycle. Here, we present a computational analysis of signal propagation and long-range communication pathways in Hsp90. We carried out molecular dynamics simulations of the full-length Hsp90 dimer, combined with essential dynamics, correlation analysis, and a signal propagation model. All-atom MD simulations with timescales of 70 ns have been performed for complexes with the natural substrates ATP and ADP and for the unliganded dimer. We elucidate the mechanisms of signal propagation and determine “hot spots” involved in interdomain communication pathways from the nucleotide-binding site to the C-terminal domain interface. A comprehensive computational analysis of the Hsp90 communication pathways and dynamics at atomic resolution has revealed the role of the nucleotide in effecting conformational changes, elucidating the mechanisms of signal propagation. Functionally important residues and secondary structure elements emerge as effective mediators of communication between the nucleotide-binding site and the C-terminal interface. Furthermore, we show that specific interdomain signal propagation pathways may be activated as a function of the ligand. Our results support a “conformational selection model” of the Hsp90 mechanism, whereby the protein may exist in a dynamic equilibrium between different conformational states available on the energy landscape and binding of a specific partner can bias the equilibrium toward functionally relevant complexes