Studies in the Behaviour of Molecular Beams

This thesis describes the design, construction and development of a molecular beam apparatus for the study of interactions of gases with solid surfaces in systems of catalytic interest. The apparatus has been used in an investigation of the displacement, from palladium surfaces, of the surface species resulting from the adsorption of ethylene C-14 by beams of acetylene and ethylene. The apparatus produced ultimate static vacua of about 5 x 10e-9 torr. The palladium was in the form of a film, freshly deposited in vacuo, to which was admitted ethylene C-14 at a pressure of greater than 5 x 10e-2 torr, known to provide saturation of the surface with adsorbed species. The fate of the isotopically labelled surface species was followed in vacuum desorption and in beam-displacement reactions. The detector for radioactivity was, in the final form of the apparatus, a lithium-drifted silicon solid-state detector mounted close to the target inside the beam system. The maximum flux intensity which could be directed on to the surface was 2.5 x 10e13 molecules/cm 2/sec as against a background of scattered beam material of 4.1 x 10e13 molecules/cm 2/sec. The beam was produced from a source whose pressure was 2 x 10e-3 torr and whose temperature could be varied between 1

Receipt, Property tax, 1854

https://egrove.olemiss.edu/aldrichcorr_c/1080/thumbnail.jp

Perspective

The imagery we adopt when recalling the personal past may involve different perspectives. In many cases, we remember the past event from our original point of view. In some cases, however, we remember the past event from an external “observer” perspective and view ourselves in the remembered scene. Are such observer perspective images genuine memories? Are they accurate representations of the personal past? This chapter focuses on such observer perspectives in memory, and outlines and examines proposals about the nature of such imagery

Exposure-age constraints on the extent, timing and rate of retreat of the last Irish Sea ice stream

We report 23 cosmogenic isotope exposure ages (10Be and 36Cl) relating to the maximum extent and deglaciation chronology of the Irish Sea Ice Stream (ISIS), which drained the SW sector of the last British-Irish Ice Sheet. These show that the ISIS failed to reach the Preseli Hills of North Pembrokeshire yet extended southwards to impinge on northern Isles of Scilly (50°N) during the last glacial maximum. Four samples from western Anglesey demonstrate deglaciation of the southern Irish Sea Basin by c. 20-18 ka, and two from the Llŷn Peninsula in northwest Wales, if valid, suggest deglaciation by c. 23-22 ka followed by gradual oscillatory northwards retreat of the ice margin for over 3000 years. An alternative interpretation of our data suggests that ice reached Scilly as late as 22-21 ka then retreated 450 km northwards within the following three millennia, possibly in response to sea level rise and/or intrinsic reorganisation within the last British-Irish Ice Sheet. Samples from upland source areas of the ISIS in NW England and SW Scotland produced exposure ages ≤14.3 ka, suggesting possible persistence of ice in such areas into the Lateglacial Interstade of 14.7-12.9 ka

Reconstructing CNV genotypes using segregation analysis: combining pedigree information with CNV assay

<p>Abstract</p> <p>Background</p> <p>Repeated blocks of genome sequence have been shown to be associated with genetic diversity and disease risk in humans, and with phenotypic diversity in model organisms and domestic animals. Reliable tests are desirable to determine whether individuals are carriers of copy number variants associated with disease risk in humans and livestock, or associated with economically important traits in livestock. In some cases, copy number variants affect the phenotype through a dosage effect but in other cases, allele combinations have non-additive effects. In the latter cases, it has been difficult to develop tests because assays typically return an estimate of the sum of the copy number counts on the maternally and paternally inherited chromosome segments, and this sum does not uniquely determine the allele configuration. In this study, we show that there is an old solution to this new problem: segregation analysis, which has been used for many years to infer alleles in pedigreed populations.</p> <p>Methods</p> <p>Segregation analysis was used to estimate copy number alleles from assay data on simulated half-sib sheep populations. Copy number variation at the Agouti locus, known to be responsible for the recessive self-colour black phenotype, was used as a model for the simulation and an appropriate penetrance function was derived. The precision with which carriers and non-carriers of the undesirable single copy allele could be identified, was used to evaluate the method for various family sizes, assay strategies and assay accuracies.</p> <p>Results</p> <p>Using relationship data and segregation analysis, the probabilities of carrying the copy number alleles responsible for black or white fleece were estimated with much greater precision than by analyzing assay results for animals individually. The proportion of lambs correctly identified as non-carriers of the undesirable allele increased from 7% when the lambs were analysed alone to 80% when the lambs were analysed in half-sib families.</p> <p>Conclusions</p> <p>When a quantitative assay is used to estimate copy number alleles, segregation analysis of related individuals can greatly improve the precision of the estimates. Existing software for segregation analysis would require little if any change to accommodate the penetrance function for copy number assay data.</p

Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors

There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile

Impaired Autophagy of an Intracellular Pathogen Induced by a Crohn's Disease Associated ATG16L1 Variant

The genetic risk factors predisposing individuals to the development of inflammatory bowel disease are beginning to be deciphered by genome-wide association studies. Surprisingly, these new data point towards a critical role of autophagy in the pathogenesis of Crohn's disease. A single common coding variant in the autophagy protein ATG16L1 predisposes individuals to the development of Crohn's disease: while ATG16L1 encoding threonine at amino acid position 300 (ATG16L1*300T) confers protection, ATG16L1 encoding for alanine instead of threonine (ATG16L1*300A, also known as T300A) mediates risk towards the development of Crohn's disease. Here we report that, in human epithelial cells, the Crohn's disease-associated ATG16L1 coding variant shows impairment in the capture of internalized Salmonella within autophagosomes. Thus, we propose that the association of ATG16L1*300A with increased risk of Crohn's disease is due to impaired bacterial handling and lowered rates of bacterial capture by autophagy

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

How the 22q11.2 deletion predisposes to psychiatric disease is unclear. Here, the authors examine living human neuronal cells and show that 22q11.2 regulates the expression of genes linked to autism during early development, and genes linked to schizophrenia and synaptic biology in neurons. It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.Peer reviewe