Modelling Climate - Surface Hydrology Interactions in Data Sparse Areas

This thesis develops tools aimed at the study and prediction of climate effects on land-surface hydrology (in particular streamflow), which require a minimum amount of site specific data. This minimum data requirement allows studies to be performed in areas that are data sparse, such as the developing world. ¶ ..

Global Origin of Mycobacterium tuberculosis in the Midlands, UK

DNA fingerprinting data for 4,207 Mycobacterium tuberculosis isolates were combined with data from a computer program (Origins). Largest population groups were from England (n = 1,031) and India (n = 912), and most prevalent strains were the Euro-American (45%) and East African–Indian (34%) lineages. Combining geographic and molecular data can enhance cluster investigation

The Farthest Known Supernova: Support for an Accelerating Universe and a Glimpse of the Epoch of Deceleration

We present photometric observations of an apparent Type Ia supernova (SN Ia) at a redshift of ~1.7, the farthest SN observed to date. SN 1997ff, was discovered in a repeat observation by the HST of the HDF-), and serendipitously monitored with NICMOS on HST throughout the GTO campaign. The SN type can be determined from the host galaxy type:an evolved, red elliptical lacking enough recent star formation to provide a significant population of core-collapse SNe. The class- ification is further supported by diagnostics available from the observed colors and temporal behavior of the SN, both of which match a typical SN Ia. The photo- metric record of the SN includes a dozen flux measurements in the I, J, and H bands spanning 35 days in the observed frame. The redshift derived from the SN photometry, z=1.7+/-0.1, is in excellent agreement with the redshift estimate of z=1.65+/-0.15 derived from the U_300,B_450,V_606,I_814,J_110,J_125,H_160, H_165,K_s photometry of the galaxy. Optical and near-infrared spectra of the host provide a very tentative spectroscopic redshift of 1.755. Fits to observations of the SN provide constraints for the redshift-distance relation of SNe~Ia and a powerful test of the current accelerating Universe hypothesis. The apparent SN brightness is consistent with that expected in the decelerating phase of the preferred cosmological model, Omega_M~1/3, Omega_Lambda~2/3. It is inconsistent with grey dust or simple luminosity evolution, candidate astro- physical effects which could mimic past evidence for an accelerating Universe from SNe Ia at z~0.5.We consider several sources of possible systematic error including lensing, SN misclassification, selection bias, and calibration errors. Currently, none of these effects appears likely to challenge our conclusions.Comment: Accepted to the Astrophysical Journal 38 pages, 15 figures, Pretty version available at http://icarus.stsci.edu/~stefano/ariess.tar.g

A Geographically-Restricted but Prevalent Mycobacterium tuberculosis Strain Identified in the West Midlands Region of the UK between 1995 and 2008

Background: We describe the identification of, and risk factors for, the single most prevalent Mycobacterium tuberculosis strain in the West Midlands region of the UK.Methodology/Principal Findings: Prospective 15-locus MIRU-VNTR genotyping of all M. tuberculosis isolates in the West Midlands between 2004 and 2008 was undertaken. Two retrospective epidemiological investigations were also undertaken using univariable and multivariable logistic regression analysis. The first study of all TB patients in the West Midlands between 2004 and 2008 identified a single prevalent strain in each of the study years (total 155/3,056 (5%) isolates). This prevalent MIRU-VNTR profile (32333 2432515314 434443183) remained clustered after typing with an additional 9-loci MIRU-VNTR and spoligotyping. The majority of these patients (122/155, 79%) resided in three major cities located within a 40 km radius. From the apparent geographical restriction, we have named this the "Mercian" strain. A multivariate analysis of all TB patients in the West Midlands identified that infection with a Mercian strain was significantly associated with being UK-born (OR = 9.03, 95% CI = 4.56-17.87, p 65 years old (OR = 0.25, 95% CI = 0.09-0.67, p < 0.01). A second more detailed investigation analyzed a cohort of 82 patients resident in Wolverhampton between 2003 and 2006. A significant association with being born in the UK remained after a multivariate analysis (OR = 9.68, 95% CI = 2.00-46.78, p < 0.01) and excess alcohol intake and cannabis use (OR = 6.26, 95% CI = 1.45-27.02, p = .01) were observed as social risk factors for infection.Conclusions/Significance: The continued consistent presence of the Mercian strain suggests ongoing community transmission. Whilst significant associations have been found, there may be other common risk factors yet to be identified. Future investigations should focus on targeting the relevant risk groups and elucidating the biological factors that mediate continued transmission of this strain

Comparison of various climate change projections of eastern Australian rainfall

The Australian eastern seaboard is a distinct climate entity from the interior of the continent, with different climatic influences on each side of the Great Dividing Range. Therefore, it is plausible that downscaling of global climate models could reveal meaningful regional detail, or ‘added value’, in the climate change signal of mean rainfall change in eastern Australia un-der future scenarios. However, because downscaling is typically done using a limited set of global climate models and downscaling methods, the results from a downscaling study may not represent the range of uncertainty in plausible projected change for a region suggested by the ensemble of host global climate models. A complete and unbiased representation of the plausible changes in the climate is essential in producing climate projections useful for future planning. As part of this aim it is important to quantify any differences in the change signal between global climate models and downscaling, and understand the cause of these differ-ences in terms of plausible added regional detail in the climate change signal, the impact of sub-sampling global climate models and the effect of the downscaling models themselves. Here we examine rainfall projections in eastern Australia under a high emissions scenario by late in the century from ensembles of global climate models, two dynamical downscaling models and one statistical downscaling model. We find no cases where all three downscaling methods show the same clear regional spatial detail in the change signal that is distinct from the host models. However, some downscaled projections suggest that the eastern seaboard could see little change in spring rainfall, in contrast to the substantial rainfall decrease inland. The change signal in the downscaled outputs is broadly similar at the large scale in the various model outputs, with a few notable exceptions. For example, the model median from dynamical downscaling projects a rainfall increase over the entirety of eastern Australia in autumn that is greater than the global models. Also, there are some instances where a downscaling method produces changes outside the range of host models over eastern Australia as a whole, thus ex-panding the projected range of uncertainty. Results are particularly uncertain for summer, where no two downscaling studies clearly agree. There are also some confounding factors from the model configuration used in downscaling, where the particular zones used for statis-tical models and the model components used in dynamical models have an influence on results and produce additional uncertainty

Bioinformatics Workflow for Clinical Whole Genome Sequencing at Partners HealthCare Personalized Medicine

Effective implementation of precision medicine will be enhanced by a thorough understanding of each patient’s genetic composition to better treat his or her presenting symptoms or mitigate the onset of disease. This ideally includes the sequence information of a complete genome for each individual. At Partners HealthCare Personalized Medicine, we have developed a clinical process for whole genome sequencing (WGS) with application in both healthy individuals and those with disease. In this manuscript, we will describe our bioinformatics strategy to efficiently process and deliver genomic data to geneticists for clinical interpretation. We describe the handling of data from FASTQ to the final variant list for clinical review for the final report. We will also discuss our methodology for validating this workflow and the cost implications of running WGS

Clathrin light chains' role in selective endocytosis influences antibody isotype switching

Clathrin, a cytosolic protein composed of heavy and light chain subunits, assembles into a vesicle coat, controlling receptor-mediated endocytosis. To establish clathrin light chain (CLC) function in vivo, we engineered mice lacking CLCa, the major CLC isoform in B lymphocytes, generating animals with CLC-deficient B cells. In CLCa-null mice, the germinal centers have fewer B cells, and they are enriched for IgA-producing cells. This enhanced switch to IgA production in the absence of CLCa was attributable to increased transforming growth factor β receptor 2 (TGFβR2) signaling resulting from defective endocytosis. Internalization of C-X-C chemokine receptor 4 (CXCR4), but not CXCR5, was affected in CLCa-null B cells, and CLC depletion from cell lines affected endocytosis of the δ-opioid receptor, but not the β2-adrenergic receptor, defining a role for CLCs in the uptake of a subset of signaling receptors. This instance of clathrin subunit deletion in vertebrates demonstrates that CLCs contribute to clathrin’s role in vivo by influencing cargo selectivity, a function previously assigned exclusively to adaptor molecules

Tuberculosis Microepidemics among Dispersed Migrants, Birmingham, UK, 2004-2013

MIRU-VNTR typing was supported by the Public Health England National TB Strain Typing Project. M.M. is funded by the UK Clinical Research Collaboration Modernising Medical Microbiology Consortium. C.B. is funded by the Heart of Birmingham Primary Care Trust and Public Health England