Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL

Monoclonal antibodies (MAbs) form a central part of chronic lymphocytic leukaemia (CLL) treatment. We therefore evaluated whether complement defects in CLL patients reduced the induction of complement-dependent cytotoxicity (CDC) by using anti-CD20 MAbs rituximab (RTX) and ofatumumab (OFA). Ofatumumab elicited higher CDC levels than RTX in all CLL samples examined, particularly in poor prognosis cohorts (11q− and 17p−). Serum sample analyses revealed that 38.1% of patients were deficient in one or more complement components, correlating with reduced CDC responses. Although a proportion of patients with deficient complement levels initially induced high levels of CDC, on secondary challenge CDC activity in sera was significantly reduced, compared with that in normal human serum (NHS; P<0.01; n=52). In addition, a high CLL cell number contributed to rapid complement exhaustion. Supplementing CLL serum with NHS or individual complement components, particularly C2, restored CDC on secondary challenge to NHS levels (P<0.0001; n=9). In vivo studies revealed that complement components were exhausted in CLL patient sera post RTX treatment, correlating with an inability to elicit CDC. Supplementing MAb treatment with fresh-frozen plasma may therefore maintain CDC levels in CLL patients with a complement deficiency or high white blood cell count. This study has important implications for CLL patients receiving anti-CD20 MAb therapy

The denatured state of N-PGK is compact and predominantly disordered

The Organisation of the structure present in the chemically denatured N-terminal domain of phosphoglycerate kinase (N-PGK) has been determined by paramagnetic relaxation enhancements (PREs) to define the conformational landscape accessible to the domain. Below 2.0 M guanidine hydrochloride (GuHCl), a species of N-PGK (denoted I-b) is detected, distinct from those previously characterised by kinetic experiments [folded (F), kinetic intermediate (I-k) and denatured (D)]. The transition to I-b is never completed at equilibrium, because F predominates below 1.0 M GuHCl. Therefore, the ability of PREs to report on transient or low population species has been exploited to characterise I-b. Five single cysteine variants of N-PGK were labelled with the nitroxide electron spin-label MTSL [(1-oxyl-2,2,5,5-tetramethyl-3-pyrroline-3-methyl)methanesulfonate] and the denaturant dependences of the relaxation properties of the amide NMR signals between 1.2 and 3.6 M GuHCl were determined. Significant PREs for I-b were obtained, but these were distributed almost uniformly throughout the sequence. Furthermore, the PREs indicate that no specific short tertiary contacts persist. The data indicate a collapsed state with no coherent three-dimensional structure, but with a restricted radius beyond which the protein chain rarely reaches. The NMR characteristics Of I-b indicate that it forms from the fully denatured state within 100 mu s, and therefore a rapid collapse is the initial stage of folding of N-PGK from its chemically denatured state. By extrapolation, I-b is the predominant form of the denatured state under native conditions, and the non-specifically collapsed structure implies that many non-native contacts and chain reversals form early in protein folding and must be broken prior to attaining the native state topology. (C) 2008 Elsevier Ltd. All rights reserved

A model of context-dependent component connectors

Recent approaches to component-based software engineering employ coordinat- ing connectors to compose components into software systems. For maximum flexibility and reuse, such connectors can themselves be composed, resulting in an expressive calculus of connectors whose semantics encompasses complex combinations of synchronisation, mutual exclusion, non-deterministic choice and state-dependent behaviour. A more expressive notion of connector includes also context-dependent behaviour, namely, whenever the choices a connector can take change non-monotonically as the context, given by the pending activity on its ports, changes. Context dependency can express notions of priority and inhi- bition. Capturing context-dependent behaviour in formal models is non-trivial, as it is unclear how to propagate context information through composition. In this paper we present an intuitive automata-based formal model of context- dependent connectors, and argue that it is superior to previous attempts at such a model for the coordination language Reo

Monolithic integration of a quantum emitter with a compact on-chip beam-splitter

A fundamental component of an integrated quantum optical circuit is an on-chip beam-splitter operating at the single-photon level. Here, we demonstrate the monolithic integration of an on-demand quantum emitter in the form of a single self-assembled InGaAs quantum dot (QD) with a compact (>10 μm), air clad, free standing directional coupler acting as a beam-splitter for anti-bunched light. The device was tested by using single photons emitted by a QD embedded in one of the input arms of the device. We verified the single-photon nature of the QD signal by performing Hanbury Brown-Twiss measurements and demonstrated single-photon beam splitting by cross-correlating the signal from the separate output ports of the directional coupler

Path-dependent initialization of a single quantum dot exciton spin in a nanophotonic waveguide

We demonstrate a scheme for in-plane initialization of a single exciton spin in an InGaAs quantum dot (QD) coupled to a GaAs nanobeam waveguide. The chiral coupling of the QD and the optical mode of the nanobeam enables spin initialization fidelity approaching unity in magnetic field B=1 T and >0.9 without the field. We further show that this in-plane excitation scheme is independent of the incident excitation laser polarization and depends solely on the excitation direction. This scheme provides a robust in-plane spin excitation basis for a photon-mediated spin network for quantum information applications

What to choose next? A paradigm for testing human sequential decision making

Many of the decisions we make in our everyday lives are sequential and entail sparse rewards. While sequential decision-making has been extensively investigated in theory (e.g., by reinforcement learning models) there is no systematic experimental paradigm to test it. Here, we developed such a paradigm and investigated key components of reinforcement learning models: the eligibility trace (i.e., the memory trace of previous decision steps), the external reward, and the ability to exploit the statistics of the environment's structure (model-free vs. model-based mechanisms). We show that the eligibility trace decays not with sheer time, but rather with the number of discrete decision steps made by the participants. We further show that, unexpectedly, neither monetary rewards nor the environment's spatial regularity significantly modulate behavioral performance. Finally, we found that model-free learning algorithms describe human performance better than model-based algorithms. © 2017 Tartaglia, Clarke and Herzog

Superconducting Quantum Interference in Fractal Percolation Films. Problem of 1/f Noise

An oscillatory magnetic field dependence of the DC voltage is observed when a low-frequency current flows through superconducting Sn-Ge thin-film composites near the percolation threshold. The paper also studies the experimental realisations of temporal voltage fluctuations in these films. Both the structure of the voltage oscillations against the magnetic field and the time series of the electric "noise" possess a fractal pattern. With the help of the fractal analysis procedure, the fluctuations observed have been shown to be neither a noise with a large number of degrees of freedom, nor the realisations of a well defined dynamic system. On the contrary the model of voltage oscillations induced by the weak fluctuations of a magnetic field of arbitrary nature gives the most appropriate description of the phenomenon observed. The imaging function of such a transformation possesses a fractal nature, thus leading to power-law spectra of voltage fluctuations even for the simplest types of magnetic fluctuations including the monochromatic ones. Thus, the paper suggests a new universal mechanism of a "1/f noise" origin. It consists in a passive transformation of any natural fluctuations with a fractal-type transformation function.Comment: 17 pages, 13 eps-figures, Latex; title page and figures include

Anderson-Yuval approach to the multichannel Kondo problem

We analyze the structure of the perturbation expansion of the general multichannel Kondo model with channel anisotropic exchange couplings and in the presence of an external magnetic field, generalizing to this case the Anderson-Yuval technique. For two channels, we are able to map the Kondo model onto a generalized resonant level model. Limiting cases in which the equivalent resonant level model is solvable are identified. The solution correctly captures the properties of the two channel Kondo model, and also allows an analytic description of the cross-over from the non Fermi liquid to the Fermi liquid behavior caused by the channel anisotropy.Comment: 23 pages, ReVTeX, 4 figures av. on reques

On-chip resonantly-driven quantum emitter with enhanced coherence

Advances in nanotechnology provide techniques for the realisation of integrated quantum-optical circuits for on-chip quantum information processing(QIP). The indistinguishable single photons, required for such devices can be generated by parametric down-conversion, or from quantum emitters such as colour centres and quantum dots(QDs). Among these, semiconductor QDs offer distinctive capabilities including on-demand operation, coherent control, frequency tuning and compatibility with semiconductor nanotechnology. Moreover, the coherence of QD photons can be significantly enhanced in resonance fluorescence(RF) approaching at its best the coherence of the excitation laser. However, the implementation of QD RF in scalable on-chip geometries remains challenging due to the need to suppress stray laser photons. Here we report on-chip QD RF coupled into a single-mode waveguide with negligible resonant laser background and show that the coherence is enhanced compared to off-resonant excitation. The results pave the way to a novel class of integrated quantum-optical devices for on-chip QIP with embedded resonantly-driven quantum emitters

On-chip resonantly-driven quantum emitter with enhanced coherence

Advances in nanotechnology provide techniques for the realisation of integrated quantum-optical circuits for on-chip quantum information processing(QIP). The indistinguishable single photons, required for such devices can be generated by parametric down-conversion, or from quantum emitters such as colour centres and quantum dots(QDs). Among these, semiconductor QDs offer distinctive capabilities including on-demand operation, coherent control, frequency tuning and compatibility with semiconductor nanotechnology. Moreover, the coherence of QD photons can be significantly enhanced in resonance fluorescence(RF) approaching at its best the coherence of the excitation laser. However, the implementation of QD RF in scalable on-chip geometries remains challenging due to the need to suppress stray laser photons. Here we report on-chip QD RF coupled into a single-mode waveguide with negligible resonant laser background and show that the coherence is enhanced compared to off-resonant excitation. The results pave the way to a novel class of integrated quantum-optical devices for on-chip QIP with embedded resonantly-driven quantum emitters