Mapping the energy and diffusion landscapes of membrane proteins at the cell surface using high-density single-molecule imaging and Bayesian inference: application to the multi-scale dynamics of glycine receptors in the neuronal membrane

Protein mobility is conventionally analyzed in terms of an effective diffusion. Yet, this description often fails to properly distinguish and evaluate the physical parameters (such as the membrane friction) and the biochemical interactions governing the motion. Here, we present a method combining high-density single-molecule imaging and statistical inference to separately map the diffusion and energy landscapes of membrane proteins across the cell surface at ~100 nm resolution (with acquisition of a few minutes). When applying these analytical tools to glycine neurotransmitter receptors (GlyRs) at inhibitory synapses, we find that gephyrin scaffolds act as shallow energy traps (~3 kBT) for GlyRs, with a depth modulated by the biochemical properties of the receptor-gephyrin interaction loop. In turn, the inferred maps can be used to simulate the dynamics of proteins in the membrane, from the level of individual receptors to that of the population, and thereby, to model the stochastic fluctuations of physiological parameters (such as the number of receptors at synapses). Overall, our approach provides a powerful and comprehensive framework with which to analyze biochemical interactions in living cells and to decipher the multi-scale dynamics of biomolecules in complex cellular environments.Comment: 23 pages, 4 figure

Acoustic emphasis in four year olds

Acoustic emphasis may convey a range of subtle discourse distinctions, yet little is known about how this complex ability develops in children. This paper presents a first investigation of the factors which influence the production of acoustic prominence in young children’s spontaneous speech. In a production experiment, SVO sentences were elicited from 4 year olds who were asked to describe events in a video. Children were found to place more acoustic prominence both on ‘new’ words and on words that were ‘given’ but had shifted to a more accessible position within the discourse. This effect of accessibility concurs with recent studies of adult speech. We conclude that, by age four, children show appropriate, adult-like use of acoustic prominence, suggesting sensitivity to a variety of discourse distinctions

Predicting Fracture in the Proximal Humerus using Phase Field Models

Proximal humerus impacted fractures are of clinical concern in the elderly population. Prediction of such fractures by CT-based finite element methods encounters several major obstacles such as heterogeneous mechanical properties and fracture due to compressive strains. We herein propose to investigate a variation of the phase field method (PFM) embedded into the finite cell method (FCM) to simulate impacted humeral fractures in fresh frozen human humeri. The force-strain response, failure loads and the fracture path are compared to experimental observations for validation purposes. The PFM (by means of the regularization parameter $l_0$) is first calibrated by one experiment and thereafter used for the prediction of the mechanical response of two other human fresh frozen humeri. All humeri are fractured at the surgical neck and strains are monitored by Digital Image Correlation (DIC). Experimental strains in the elastic regime are reproduced with good agreement ($R^2 = 0.726$), similarly to the validated finite element method [9]. The failure pattern and fracture evolution at the surgical neck predicted by the PFM mimic extremely well the experimental observations for all three humeri. The maximum relative error in the computed failure loads is $3.8\%$. To the best of our knowledge this is the first method that can predict well the experimental compressive failure pattern as well as the force-strain relationship in proximal humerus fractures

A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202)

PD-L1 inhibitor; Anal cancer; RetifanlimabInhibidor de PD-L1; Cáncer anal; RetifanlimabInhibidor de PD-L1; Càncer anal; RetifanlimabBackground Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC. Patients and methods Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class. Conclusions Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.This work was supported by Incyte Corporation (Wilmington, DE, USA) (no grant number)

Theoretical analysis of quantum dynamics in 1D lattices: Wannier-Stark description

This papers presents a formalism describing the dynamics of a quantum particle in a one-dimensional tilted time-dependent lattice. The description uses the Wannier-Stark states, which are localized in each site of the lattice and provides a simple framework leading to fully-analytical developments. Particular attention is devoted to the case of a time-dependent potential, which results in a rich variety of quantum coherent dynamics is found.Comment: 8 pages, 6 figures, submitted to PR

Sub-quadratic time for Riemann-Roch spaces. The case of smooth divisors over nodal plane projective curves

International audienceWe revisit the seminal Brill-Noether algorithm in the rather generic situation of smooth divisors over a nodal plane projective curve. Our approach takes advantage of fast algorithms for polynomials and structured matrices. We reach sub-quadratic time for computing a basis of a Riemann-Roch space. This improves upon previously known complexity bounds

Gravity-induced Wannier-Stark ladder in an optical lattice

We discuss the dynamics of ultracold atoms in an optical potential accelerated by gravity. The positions and widths of the Wannier-Stark ladder of resonances are obtained as metastable states. The metastable Wannier-Bloch states oscillate in a single band with the Bloch period. The width of the resonance gives the rate transition to the continuum.Comment: 5 pages + 8 eps figures, submitted to Phys. Rev.

Forecasting in the light of Big Data

Predicting the future state of a system has always been a natural motivation for science and practical applications. Such a topic, beyond its obvious technical and societal relevance, is also interesting from a conceptual point of view. This owes to the fact that forecasting lends itself to two equally radical, yet opposite methodologies. A reductionist one, based on the first principles, and the naive inductivist one, based only on data. This latter view has recently gained some attention in response to the availability of unprecedented amounts of data and increasingly sophisticated algorithmic analytic techniques. The purpose of this note is to assess critically the role of big data in reshaping the key aspects of forecasting and in particular the claim that bigger data leads to better predictions. Drawing on the representative example of weather forecasts we argue that this is not generally the case. We conclude by suggesting that a clever and context-dependent compromise between modelling and quantitative analysis stands out as the best forecasting strategy, as anticipated nearly a century ago by Richardson and von Neumann

Eye movements and lexical access in spoken-language comprehension: evaluating a linking hypothesis between fixations and linguistic processing.

A growing number of researchers in the sentence processing community are using eye movements to address issues in spoken language comprehension. Experiments using this paradigm have shown that visually presented referential information, including properties of referents relevant to specific actions, influences even the earliest moments of syntactic processing. Methodological concerns about task-specific strategies and the linking hypothesis between eye movements and linguistic processing are identified and discussed. These concerns are addressed in a review of recent studies of spoken word recognition which introduce and evaluate a detailed linking hypothesis between eye movements and lexical access. The results provide evidence about the time course of lexical activation that resolves some important theoretical issues in spoken-word recognition. They also demonstrate that fixations are sensitive to properties of the normal language-processing system that cannot be attributed to task-specific strategie