B-1a cells acquire their unique characteristics by bypassing the pre-BCR selection stage

B-1a cells are long-lived, self-renewing innate-like B cells that predominantly inhabit the peritoneal and pleural cavities. In contrast to conventional B-2 cells, B-1a cells have a receptor repertoire that is biased towards bacterial and self-antigens, promoting a rapid response to infection and clearing of apoptotic cells. Although B-1a cells are known to primarily originate from fetal tissues, the mechanisms by which they arise has been a topic of debate for many years. Here we show that in the fetal liver versus bone marrow environment, reduced IL-7R/STAT5 levels promote immunoglobulin kappa gene recombination at the early pro-B cell stage. As a result, differentiating B cells can directly generate a mature B cell receptor (BCR) and bypass the requirement for a pre-BCR and pairing with surrogate light chain. This 'alternate pathway' of development enables the production of B cells with self-reactive, skewed specificity receptors that are peculiar to the B-1a compartment. Together our findings connect seemingly opposing lineage and selection models of B-1a cell development and explain how these cells acquire their unique properties

A new geodemographic classification of commuting flows for England and Wales

This paper aims to contribute to the area of geodemographic research through the development of a new and novel flow-based classification of commuting for England and Wales. In doing so, it applies an approach to the analysis of commuting in which origin-destination flow-data, collected as part of the 2011 census of England and Wales, are segmented into groups based on shared similarities across multiple demographic and socioeconomic attributes. K-means clustering was applied to 49 flow-based commuter variables for 513,892 interactions that captured 18.4 million of the 26.5 million workers recorded as part of the 2011 census of England and Wales. The final classification resulted in an upper-tier of nine ‘Supergroups’ which were subsequently partitioned to derive a lower-tier of 40 ‘Groups’. A nomenclature was developed and associated pen-portraits derived to provide basic signposting to the dominant characteristics of each cluster. Analysis of a selection of patterns underlying the nine-fold Supergroup configuration revealed a highly variegated structure of commuting in England and Wales. The classification has potentially wide-ranging descriptive and analytical applications within research and policy domains and the approach would be equally transferable to other countries and contexts where origin-destination data is disaggregated based on commuter characteristics

Accuracy and Stability of Computing High-Order Derivatives of Analytic Functions by Cauchy Integrals

High-order derivatives of analytic functions are expressible as Cauchy integrals over circular contours, which can very effectively be approximated, e.g., by trapezoidal sums. Whereas analytically each radius r up to the radius of convergence is equal, numerical stability strongly depends on r. We give a comprehensive study of this effect; in particular we show that there is a unique radius that minimizes the loss of accuracy caused by round-off errors. For large classes of functions, though not for all, this radius actually gives about full accuracy; a remarkable fact that we explain by the theory of Hardy spaces, by the Wiman-Valiron and Levin-Pfluger theory of entire functions, and by the saddle-point method of asymptotic analysis. Many examples and non-trivial applications are discussed in detail.Comment: Version 4 has some references and a discussion of other quadrature rules added; 57 pages, 7 figures, 6 tables; to appear in Found. Comput. Mat

Predictive approaches to heterogeneous treatment effects: a scoping review

Background: Recent evidence suggests that there is often substantial variation in the benefits and harms across a trial population. We aimed to identify regression modeling approaches that assess heterogeneity of treatment effect within a randomized clinical trial. Methods: We performed a literature review using a broad search strategy, complemented by suggestions of a technical expert panel. Results: The approaches are classified into 3 categories: 1) Risk-based methods (11 papers) use only prognostic factors to define patient subgroups, relying on the mathematical dependency of the absolute risk difference on baseline risk; 2) Treatment effect modeling methods (9 papers) use both prognostic factors and treatment effect modifiers to explore characteristics that interact with the effects of therapy on a relative scale. These methods couple data-driven subgroup identification with approaches to prevent overfitting, such as penalization or use of separate data sets for subgroup identification and effect estimation. 3) Optimal treatment regime methods (12 papers) focus primarily on treatment effect modifiers to classify the trial population into those who benefit from treatment and those who do not. Finally, we also identified papers which describe model evaluation methods (4 papers). Conclusions: Three classes of approaches were identified to assess heterogeneity of treatment effect. Methodological research, including both simulations and empirical evaluations, is required to compare the available methods in different settings and to derive well-informed guidance for their application in RCT analysis

Supersymmetric Regularization, Two-Loop QCD Amplitudes and Coupling Shifts

We present a definition of the four-dimensional helicity (FDH) regularization scheme valid for two or more loops. This scheme was previously defined and utilized at one loop. It amounts to a variation on the standard 't Hooft-Veltman scheme and is designed to be compatible with the use of helicity states for "observed" particles. It is similar to dimensional reduction in that it maintains an equal number of bosonic and fermionic states, as required for preserving supersymmetry. Supersymmetry Ward identities relate different helicity amplitudes in supersymmetric theories. As a check that the FDH scheme preserves supersymmetry, at least through two loops, we explicitly verify a number of these identities for gluon-gluon scattering (gg to gg) in supersymmetric QCD. These results also cross-check recent non-trivial two-loop calculations in ordinary QCD. Finally, we compute the two-loop shift between the FDH coupling and the standard MS-bar coupling, alpha_s. The FDH shift is identical to the one for dimensional reduction. The two-loop coupling shifts are then used to obtain the three-loop QCD beta function in the FDH and dimensional reduction schemes.Comment: 44 pages, minor corrections and clarifications include