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 Stochastic Dynamics of an Array of Atomic Force Microscopes in a Viscous Fluid

We consider the stochastic dynamics of an array of two closely spaced atomic force microscope cantilevers in a viscous fluid for use as a possible biomolecule sensor. The cantilevers are not driven externally, as is common in applications of atomic force microscopy, and we explore the stochastic cantilever dynamics due to the constant buffeting of fluid particles by Brownian motion. The stochastic dynamics of two adjacent cantilevers are correlated due to long range effects of the viscous fluid. Using a recently proposed thermodynamic approach the hydrodynamic correlations are quantified for precise experimental conditions through deterministic numerical simulations. Results are presented for an array of two readily available atomic force microscope cantilevers. It is shown that the force on a cantilever due to the fluid correlations with an adjacent cantilever is more than 3 times smaller than the Brownian force on an individual cantilever. Our results indicate that measurements of the correlations in the displacement of an array of atomic force microscopes can detect piconewton forces with microsecond time resolution.Comment: 7 page article with 11 images submitted to the International Journal of Nonlinear Mechanic

Language Learning, Recasts, and Interaction Involving AAC: Background and Potential for Intervention

For children with typical development, language is learned through everyday discursive interaction. Adults mediate child participation in such interactions through the deployment of a range of co-constructive strategies, including repeating, questioning, prompting, expanding, and reformulating the child’s utterances. Adult reformulations of child utterances, also known as recasts, have also been shown to relate to the acquisition of linguistic structures in children with language and learning disabilities and children and adults learning a foreign language. In this paper we discuss the theoretical basis and empirical evidence for the use of different types of recasts as a major language learning catalyst, and what may account for their facilitative effects. We consider the occurrence of different types of recasts in AAC-mediated interactions and their potential for language facilitation, within the typical operational and linguistic constraints of such interactions. We also consider the benefit of explicit and corrective forms of recasts for language facilitation in conversations with children who rely on AAC. We conclude by outlining future research directions

A preview of JWST metallicity studies at cosmic noon: the first detection of auroral [O II] emission at high redshift

Galaxie

Mechanism of polarization of Listeria monocytogenes surface protein ActA

The polar distribution of the ActA protein on the surface of the Gram-positive intracellular bacterial pathogen, Listeria monocytogenes, is required for bacterial actin-based motility and successful infection. ActA spans both the bacterial membrane and the peptidoglycan cell wall. We have directly examined the de novo ActA polarization process in vitro by using an ActA–RFP (red fluorescent protein) fusion. After induction of expression, ActA initially appeared at distinct sites along the sides of bacteria and was then redistributed over the entire cylindrical cell body through helical cell wall growth. The accumulation of ActA at the bacterial poles displayed slower kinetics, occurring over several bacterial generations. ActA accumulated more efficiently at younger, less inert poles, and proper polarization required an optimal balance between protein secretion and bacterial growth rates. Within infected host cells, younger generations of L. monocytogenes initiated motility more quickly than older ones, consistent with our in vitro observations of de novo ActA polarization. We propose a model in which the polarization of ActA, and possibly other Gram-positive cell wall-associated proteins, may be a direct consequence of the differential cell wall growth rates along the bacterium and dependent on the relative rates of protein secretion, protein degradation and bacterial growth