Characterization of glycan substrates accumulating in GM1 Gangliosidosis

Introduction: GM1 gangliosidosis is a rare autosomal recessive genetic disorder caused by the disruption of the GLB1 gene that encodes β-galactosidase, a lysosomal hydrolase that removes β-linked galactose from the non-reducing end of glycans. Deficiency of this catabolic enzyme leads to the lysosomal accumulation of GM1 and its asialo derivative GA1 in β-galactosidase deficient patients and animal models. In addition to GM1 and GA1, there are other glycoconjugates that contain β-linked galactose whose metabolites are substrates for β-galactosidase. For example, a number of N-linked glycan structures that have galactose at their non-reducing end have been shown to accumulate in GM1 gangliosidosis patient tissues and biological fluids. Objective: In this study, we attempt to fully characterize the broad array of GLB1 substrates that require GLB1 for their lysosomal turnover. Results: Using tandem mass spectrometry and glycan reductive isotope labeling with data-dependent mass spectrometry, we have confirmed the accumulation of glycolipids (GM1 and GA1) and N-linked glycans with terminal beta-linked galactose. We have also discovered a novel set of core 1 and 2 O-linked glycan metabolites, many of which are part of structurally-related isobaric series that accumulate in disease. In the brain of GLB1 null mice, the levels of these glycan metabolites increased along with those of both GM1 and GA1 as a function of age. In addition to brain tissue, we found elevated levels of both N-linked and O-linked glycan metabolites in a number of peripheral tissues and in urine. Both brain and urine samples from human GM1 gangliosidosis patients exhibited large increases in steady state levels for the same glycan metabolites, demonstrating their correlation with this disease in humans as well. Conclusions: Our studies illustrate that GLB1 deficiency is not purely a ganglioside accumulation disorder, but instead a broad oligosaccharidosis that include representatives of many β-linked galactose containing glycans and glycoconjugates including glycolipids, N-linked glycans, and various O-linked glycans. Accounting for all β-galactosidase substrates that accumulate when this enzyme is deficient increases our understanding of this severe disorder by identifying metabolites that may drive certain aspects of the disease and may also serve as informative disease biomarkers to fully evaluate the efficacy of future therapies

James Hutton’s geological tours of Scotland : romanticism, literary strategies, and the scientific quest

This article explores a somewhat neglected part of the story of the emergence of geology as a science and discourse in the late eighteenth century – James Hutton’s posthumously published accounts of the geological tours of Scotland that he undertook in the years 1785 to 1788 in search of empirical evidence in support of his theory of the Earth and that he intended to include in the projected third volume of his Theory of the Earth of 1795. The article brings some of the assumptions and techniques of literary criticism to bear on Hutton’s scientific travel writing in order to open up new connections between geology, Romantic aesthetics and eighteenth-century travel writing about Scotland. Close analysis of Hutton’s accounts of his field trips to Glen Tilt, Galloway and Arran, supplemented by later accounts of the discoveries at Jedburgh and Siccar Point, reveals the interplay between desire, travel and the scientific quest and foregrounds the textual strategies that Hutton uses to persuade his readers that they share in the experience of geological discovery and interpretation as ‘virtual witnesses’. As well as allowing us to revisit the interrelation between scientific theory and discovery, this article concludes that Hutton was a much better writer than he has been given credit for and suggests that if these geological tours had been published in 1795 they would have made it impossible for critics to dismiss him as an armchair geologist

In vitro culturing of porcine tracheal mucosa as an ideal model for investigating the influence of drugs on human respiratory mucosa

It has been previously shown that fresh mucosa from different mammals could serve as raw material for in vitro culturing with the differentiation of cilia, which are the most important morphological structures for the function of the mucociliary system. Increasing legal restrictions on the removal of human tissue and changing surgical techniques have led to a lack of fresh human mucosa for culturing. Most of the animals that have been used as donors up to now are genetically not very close to human beings and must all be sacrificed for such studies. We, therefore, established a modified system of culturing mucosa cells from the trachea of pigs, which is available as a regular by-product after slaughtering. With respect to the possibility of developing “beating” cilia, it could be shown that the speed of cell proliferation until adhesion to the coated culture dishes, the formation of conjunctions of cell clusters and the proliferation of cilia were comparable for porcine and human mucosa. Moreover, it could be demonstrated that the porcine cilia beat frequency of 7.57 ± 1.39 Hz was comparable to the human mucosa cells beat frequency of 7.3 ± 1.4 Hz and that this beat frequency was absolutely constant over the investigation time of 360 min. In order to prove whether the reaction to different drugs is comparable between the porcine and human cilia, we initially tested benzalkonium chloride, which is known to be toxic for human cells, followed by naphazoline, which we found in previous studies on human mucosa to be non-toxic. The results clearly showed that the functional and morphological reactions of the porcine ciliated cells to these substances were similar to the reaction we found in the in vitro cultured human mucosa

Combining estimates of interest in prognostic modelling studies after multiple imputation: current practice and guidelines

Background: Multiple imputation (MI) provides an effective approach to handle missing covariate data within prognostic modelling studies, as it can properly account for the missing data uncertainty. The multiply imputed datasets are each analysed using standard prognostic modelling techniques to obtain the estimates of interest. The estimates from each imputed dataset are then combined into one overall estimate and variance, incorporating both the within and between imputation variability. Rubin's rules for combining these multiply imputed estimates are based on asymptotic theory. The resulting combined estimates may be more accurate if the posterior distribution of the population parameter of interest is better approximated by the normal distribution. However, the normality assumption may not be appropriate for all the parameters of interest when analysing prognostic modelling studies, such as predicted survival probabilities and model performance measures. Methods: Guidelines for combining the estimates of interest when analysing prognostic modelling studies are provided. A literature review is performed to identify current practice for combining such estimates in prognostic modelling studies. Results: Methods for combining all reported estimates after MI were not well reported in the current literature. Rubin's rules without applying any transformations were the standard approach used, when any method was stated. Conclusion: The proposed simple guidelines for combining estimates after MI may lead to a wider and more appropriate use of MI in future prognostic modelling studies

Statistical Inference for Valued-Edge Networks: Generalized Exponential Random Graph Models

Across the sciences, the statistical analysis of networks is central to the production of knowledge on relational phenomena. Because of their ability to model the structural generation of networks, exponential random graph models are a ubiquitous means of analysis. However, they are limited by an inability to model networks with valued edges. We solve this problem by introducing a class of generalized exponential random graph models capable of modeling networks whose edges are valued, thus greatly expanding the scope of networks applied researchers can subject to statistical analysis

“There was something very peculiar about Doc…”: Deciphering Queer Intimacy in Representations of Doc Holliday

This is an Accepted Manuscript of an article published by Taylor & Francis in American Nineteenth-Century History on 8-12-14, available online: http://dx.doi.org/10.1080/14664658.2014.971481This essay discusses representations of male intimacy in life-writing about consumptive gunfighter John Henry “Doc” Holliday (1851-1887). I argue that twentieth-century commentators rarely appreciated the historical specificity of Holliday’s friendships in a frontier culture that not only normalized but actively celebrated same-sex intimacy. Indeed, Holliday lived on the frayed edges of known nineteenth-century socio-sexual norms, and his interactions with other men were further complicated by his vicious reputation and his disability. His short life and eventful afterlife exposes the gaps in available evidence – and the flaws in our ability to interpret it. Yet something may still be gleaned from the early newspaper accounts of Holliday. Having argued that there is insufficient evidence to justify positioning him within modern categories of hetero/homosexuality, I analyze the language used in pre-1900 descriptions of first-hand encounters with Holliday to illuminate the consumptive gunfighter’s experience of intimacy, if not its meaning

Talking Less during Social Interactions Predicts Enjoyment: A Mobile Sensing Pilot Study

Can we predict which conversations are enjoyable without hearing the words that are spoken? A total of 36 participants used a mobile app, My Social Ties, which collected data about 473 conversations that the participants engaged in as they went about their daily lives. We tested whether conversational properties (conversation length, rate of turn taking, proportion of speaking time) and acoustical properties (volume, pitch) could predict enjoyment of a conversation. Surprisingly, people enjoyed their conversations more when they spoke a smaller proportion of the time. This pilot study demonstrates how conversational properties of social interactions can predict psychologically meaningful outcomes, such as how much a person enjoys the conversation. It also illustrates how mobile phones can provide a window into everyday social experiences and well-being

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

Search for Kaluza-Klein Graviton Emission in ppˉp\bar{p} Collisions at s=1.8\sqrt{s}=1.8 TeV using the Missing Energy Signature

We report on a search for direct Kaluza-Klein graviton production in a data sample of 84 ${pb}^{-1}$ of \ppb collisions at $\sqrt{s}$ = 1.8 TeV, recorded by the Collider Detector at Fermilab. We investigate the final state of large missing transverse energy and one or two high energy jets. We compare the data with the predictions from a $3+1+n$-dimensional Kaluza-Klein scenario in which gravity becomes strong at the TeV scale. At 95% confidence level (C.L.) for $n$=2, 4, and 6 we exclude an effective Planck scale below 1.0, 0.77, and 0.71 TeV, respectively.Comment: Submitted to PRL, 7 pages 4 figures/Revision includes 5 figure

Measurement of the Lifetime Difference Between B_s Mass Eigenstates

We present measurements of the lifetimes and polarization amplitudes for B_s --> J/psi phi and B_d --> J/psi K*0 decays. Lifetimes of the heavy (H) and light (L) mass eigenstates in the B_s system are separately measured for the first time by determining the relative contributions of amplitudes with definite CP as a function of the decay time. Using 203 +/- 15 B_s decays, we obtain tau_L = (1.05 +{0.16}/-{0.13} +/- 0.02) ps and tau_H = (2.07 +{0.58}/-{0.46} +/- 0.03) ps. Expressed in terms of the difference DeltaGamma_s and average Gamma_s, of the decay rates of the two eigenstates, the results are DeltaGamma_s/Gamma_s = (65 +{25}/-{33} +/- 1)%, and DeltaGamma_s = (0.47 +{0.19}/-{0.24} +/- 0.01) inverse ps.Comment: 8 pages, 3 figures, 2 tables; as published in Physical Review Letters on 16 March 2005; revisions are for length and typesetting only, no changes in results or conclusion