Genomic variations associated with attenuation in Mycobacterium avium subsp paratuberculosis vaccine strains

BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) whole cell vaccines have been widely used tools in the control of Johne's disease in animals despite being unable to provide complete protection. Current vaccine strains derive from stocks created many decades ago; however their genotypes, underlying mechanisms and relative degree of their attenuation are largely unknown. RESULTS: Using mouse virulence studies we confirm that MAP vaccine strains 316 F, II and 2e have diverse but clearly attenuated survival and persistence characteristics compared with wild type strains. Using a pan genomic microarray we characterise the genomic variations in a panel of vaccine strains sourced from stocks spanning over 40 years of maintenance. We describe multiple genomic variations specific for individual vaccine stocks in both deletion (26-32 Kbp) and tandem duplicated (11-40 Kbp) large variable genomic islands and insertion sequence copy numbers. We show individual differences suitable for diagnostic differentiation between vaccine and wild type genotypes and provide evidence for functionality of some of the deleted MAP-specific genes and their possible relation to attenuation. CONCLUSIONS: This study shows how culture environments have influenced MAP genome diversity resulting in large tandem genomic duplications, deletions and transposable element activity. In combination with classical selective systematic subculture this has led to fixation of specific MAP genomic alterations in some vaccine strain lineages which link the resulting attenuated phenotypes with deficiencies in high reactive oxygen species handling

Expression of interleukin 2 receptors on activated human B cells.

Using anti-Tac, a monoclonal anti-interleukin 2 (IL-2) receptor antibody, we have explored the possibility that certain activated B cells display receptors for IL-2. Resting normal B cells and unselected B cell lines established from normal individuals were Tac antigen negative. In contrast, the cell surface Tac antigen expression was demonstrable on 6 of 10 B cell lines from patients with Burkitt's lymphoma, 5 of 6 B cell lines derived from patients with HTLV-I-associated adult T cell leukemia (including all four that had integrated HTLV-I into their genome), and on certain normal B cells activated with pokeweed mitogen. Furthermore, cloned Epstein-Barr virus-transformed B cell lines derived from Tac-positive normal B cells continued to express the Tac antigen in long-term cultures and manifested high affinity IL-2 receptors identified in binding studies with purified radiolabeled IL-2. The line 5B4 developed in the present study could be induced with purified JURKAT-derived or recombinant IL-2 to express a larger number of IL-2 receptors. Furthermore, the addition of IL-2 to the 5B4 B cell line augmented IgM synthesis, which could be blocked by the addition of anti-Tac. The size of the IL-2 receptors expressed on the cloned normal B cell lines was similar (53,000-57,000 daltons) to that of receptors on phytohemagglutinin-stimulated T cell lymphoblasts. Thus, certain malignant and activated normal B cells display the Tac antigen and manifest high affinity receptors for IL-2. These data suggest that IL-2 may play a role in the differentiation of activated B cells into immunoglobulin-synthesizing and -secreting cells

Robust Estimation for Linear Panel Data Models

In different fields of applications including, but not limited to, behavioral, environmental, medical sciences and econometrics, the use of panel data regression models has become increasingly popular as a general framework for making meaningful statistical inferences. However, when the ordinary least squares (OLS) method is used to estimate the model parameters, presence of outliers may significantly alter the adequacy of such models by producing biased and inefficient estimates. In this work we propose a new, weighted likelihood based robust estimation procedure for linear panel data models with fixed and random effects. The finite sample performances of the proposed estimators have been illustrated through an extensive simulation study as well as with an application to blood pressure data set. Our thorough study demonstrates that the proposed estimators show significantly better performances over the traditional methods in the presence of outliers and produce competitive results to the OLS based estimates when no outliers are present in the data set

Epithelial dynamics shed light on mechanisms underlying ear canal defects

Defects in ear canal development can cause severe hearing loss as sound waves fail to reach the middle ear. Here we reveal new mechanisms that control human canal development and highlight for the first time the complex system of canal closure and reopening. These processes can be perturbed in mutant mice and in explant culture, mimicking the defects associated with canal aplasia. The more superficial part of the canal forms from an open primary canal that closes and then reopens. In contrast, the deeper part of the canal forms from an extending solid meatal plate that opens later. Closure and fusion of the primary canal was linked to loss of periderm, with failure in periderm formation in Grhl3 mutant mice associated with premature closure of the canal. Conversely, inhibition of cell death in the periderm resulted in an arrest of closure. Once closed, re-opening of the canal occurred in a wave, triggered by terminal differentiation of the epithelium. Understanding these complex processes involved in canal development sheds light on the underlying causes of canal aplasia

The elliptic genus from split flows and Donaldson-Thomas invariants

We analyze a mixed ensemble of low charge D4-D2-D0 brane states on the quintic and show that these can be successfully enumerated using attractor flow tree techniques and Donaldson-Thomas invariants. In this low charge regime one needs to take into account worldsheet instanton corrections to the central charges, which is accomplished by making use of mirror symmetry. All the charges considered can be realized as fluxed D6-D2-D0 and anti-D6-D2-D0 pairs which we enumerate using DT invariants. Our procedure uses the low charge counterpart of the picture developed Denef and Moore. By establishing the existence of flow trees numerically and refining the index factorization scheme, we reproduce and improve some results obtained by Gaiotto, Strominger and Yin. Our results provide appealing evidence that the strong split flow tree conjecture holds and allows to compute exact results for an important sector of the theory. Our refined scheme for computing indices might shed some light on how to improve index computations for systems with larger charges.Comment: 37 pages, 12 figure

In situ evidence for the structure of the magnetic null in a 3D reconnection event in the Earth's magnetotail

Magnetic reconnection is one of the most important processes in astrophysical, space and laboratory plasmas. Identifying the structure around the point at which the magnetic field lines break and subsequently reform, known as the magnetic null point, is crucial to improving our understanding reconnection. But owing to the inherently three-dimensional nature of this process, magnetic nulls are only detectable through measurements obtained simultaneously from at least four points in space. Using data collected by the four spacecraft of the Cluster constellation as they traversed a diffusion region in the Earth's magnetotail on 15 September, 2001, we report here the first in situ evidence for the structure of an isolated magnetic null. The results indicate that it has a positive-spiral structure whose spatial extent is of the same order as the local ion inertial length scale, suggesting that the Hall effect could play an important role in 3D reconnection dynamics.Comment: 14 pages, 4 figure

Evolution in the number of authors of computer science publications

This article analyses the evolution in the number of authors of scientific publications in computer science (CS). This analysis is based on a framework that structures CS into 17 constituent areas, proposed by Wainer et al. (Commun ACM 56(8):67–63, 2013), so that indicators can be calculated for each one in order to make comparisons. We collected and mined over 200,000 article references from 81 conferences and journals in the considered CS areas, spanning a 60-year period (1954–2014). The main insights of this article are that all CS areas witness an increase in the average number of authors, in every decade, with just one slight exception. We ordered the article references by number of authors, in ascending chronological order and grouped them into decades. For each CS area, we provide a perspective of how many groups (1-author papers, 2-author papers and so on) must be considered to reach certain proportions of the total for that CS area, e.g., the 90th and 95th percentiles. Different CS areas require different number of groups to reach those percentiles. For all 17 CS areas, an analysis of the point in time in which publications with n+1 authors overtake the publications with n authors is presented. Finally, we analyse the average number of authors and their rate of increase.This work was supported by FCT - Fundação para a Ciência e Tecnologia within the Project Scope UID/CEC/00319/2013

Supply driven mortgage choice

Variable mortgage contracts dominate the UK mortgage market (Miles, 2004). The dominance of the variable rate mortgage contracts has important consequences for the transmission mechanism of monetary policy decisions and systemic risks (Khandani et al., 2012; Fuster and Vickery, 2013). This raises an obvious concern that a mortgage market such as that in the UK, where the major proportion of mortgage debt is either at a variable or fixed for less than two years rate (Badarinza, et al., 2013; CML, 2012), is vulnerable to alterations in the interest rate regime. Theoretically, mortgage choice is determined by demand and supply factors. So far, most of the existing literature has focused on the demand side perspective, and what is limited is consideration of supply side factors in empirical investigation on mortgage choice decisions. This paper uniquely explores whether supply side factors may partially explain observed/ex-post mortgage type decisions. Empirical results detect that lenders’ profit motives and mortgage funding/pricing issues may have assisted in preferences toward variable rate contracts. Securitisation is found to positively impact upon gross mortgage lending volumes while negatively impacting upon the share of variable lending flows. This shows that an increase in securitisation not only improves liquidity in the supply of mortgage funds, but also has the potential to shift mortgage choices toward fixed mortgage debt. The policy implications may involve a number of measures, including reconsideration of the capital requirements for the fixed, as opposed to the variable rate mortgage debt, growing securitisation and optimisation of the mortgage pricing policies

Black Hole Meiosis

The enumeration of BPS bound states in string theory needs refinement. Studying partition functions of particles made from D-branes wrapped on algebraic Calabi-Yau 3-folds, and classifying states using split attractor flow trees, we extend the method for computing a refined BPS index, arXiv:0810.4301. For certain D-particles, a finite number of microstates, namely polar states, exclusively realized as bound states, determine an entire partition function (elliptic genus). This underlines their crucial importance: one might call them the `chromosomes' of a D-particle or a black hole. As polar states also can be affected by our refinement, previous predictions on elliptic genera are modified. This can be metaphorically interpreted as `crossing-over in the meiosis of a D-particle'. Our results improve on hep-th/0702012, provide non-trivial evidence for a strong split attractor flow tree conjecture, and thus suggest that we indeed exhaust the BPS spectrum. In the D-brane description of a bound state, the necessity for refinement results from the fact that tachyonic strings split up constituent states into `generic' and `special' states. These are enumerated separately by topological invariants, which turn out to be partitions of Donaldson-Thomas invariants. As modular predictions provide a check on many of our results, we have compelling evidence that our computations are correct.Comment: 46 pages, 8 figures. v2: minor changes. v3: minor changes and reference adde