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Cells can modify their environment by depositing biochemical signals or mechanically remodelling the extracellular matrix; the impact of such self-induced environmental perturbations on cell trajectories at various scales remains unexplored. Here authors show that motile cells leave long-lived physicochemical footprints along their way, which determine their future path.

Abstract Background Although psoriatic arthritis is complex and involves multiple domains, recent advances in treatments have made remission or near-remission of most symptoms a potentially achievable goal for many patients. We sought to evaluate whether achieving minimal disease activity (MDA) criteria represented meaningful improvement from the patient perspective. Methods Data were combined from two randomized, multinational, 24 week clinical studies of ixekizumab, a high-affinity monoclonal antibody selectively targeting interleukin-17A, in biological drug-naïve or experienced adults. MDA required 5 of 7 of: tender joint count ≤1; swollen joint count ≤1; Psoriasis Area and Severity Index total score ≤ 1 or body surface area ≤ 3%; patient’s assessment of pain visual analogue scale (VAS) ≤15; patient’s global assessment of disease activity VAS ≤20; Health Assessment Questionnaire Disability Index ≤0.5; and tender entheseal points ≤ 1. MDA responders and non-responders were compared for mean change from baseline on the 36-Item Short Form Health Survey (SF-36), European Quality of Life 5 Dimension 5 Level Health Questionnaire (EQ-5D-5 L); EQ-5D-5 L VAS; and Work Productivity and Activity Impairment–Specific Health Problem (WPAI-SHP) questionnaire. Results MDA responders had significantly greater improvements versus non-responders in each SF-36 domain and in the SF-36 physical summary score; improvements were also greater in the EQ-5D-5 L and EQ-5D-5 L VAS, and in 3 of the 4 WPAI-SHP domains. MDA responders were more likely to achieve minimal clinically important differences than non-responders. Conclusion These findings support MDA response as being strongly associated with achieving improved disease status based on measures of patient reported health-related quality of life and productivity. Trial registration SPIRIT-P1, NCT01695239, First Posted: September 27, 2012; and SPIRIT-P2, NCT02349295, First Posted: January 28, 2015.

Abstract How long is needed for an observable to exceed its previous highest value and establish a new record? This time, known as the age of a record plays a crucial role in quantifying record statistics. Until now, general methods for determining record age statistics have been limited to observations of either independent random variables or successive positions of a Markovian (memoryless) random walk. Here we develop a theoretical framework to determine record age statistics in the presence of memory effects for continuous non-smooth processes that are asymptotically scale-invariant. Our theoretical predictions are confirmed by numerical simulations and experimental realisations of diverse representative non-Markovian random walk models and real time series with memory effects, in fields as diverse as genomics, climatology, hydrology, geology and computer science. Our results reveal the crucial role of the number of records already achieved in time series and change our view on analysing record statistics.

Random walks are usually characterized by the spatial territory they cover, described by the number of sites visited at a given time. Here the authors propose an approach that accounts the time between visits to distinct sites, for improved analysis of the exploration process for general random walks, including the case of anomalous diffusion in disordered media.

Chemical reactions often require multiple random encounters between reactants, but a general, analytical treatment such imperfect transport-limited/influenced reactions in confined spaces has not yet been proposed. Here, the authors predict the full kinetics of these reactions for Markovian processes in large confining volumes.

Single-file transport, where particles cannot bypass each other, has been observed in various experimental setups. In such systems, the behavior of a tracer particle (TP) is subdiffusive, which originates from strong correlations between particles. These correlations are especially marked when the TP is driven and leads to inhomogeneous density profiles. Determining the impact of this inhomogeneity when several TPs are driven in the system is a key question, related to the general issue of bath-mediated interactions, which are known to induce collective motion and lead to the formation of clusters or lanes in a variety of systems. Quantifying this collective behavior, the emerging interactions, and their dependence on the amplitude of forces driving the TPs remains a challenging but largely unresolved issue. Here, considering dense single-file systems, we analytically determine the entire dynamics of the correlations and reveal out-of-equilibrium cooperativity and competition effects between driven TPs.

We study a minimal model of self-propelled particle in a crowded single-file environment. We extend classical models of exclusion processes (previously analyzed for diffusive and driven tracer particles) to the case where the tracer particle is a run-and-tumble particle (RTP), while all bath particles perform symmetric random walks. In the limit of high density of bath particles, we derive exact expressions for the full distribution ${{ \mathcal P }}_{n}(X)$ of the RTP position X and all its cumulants, valid for arbitrary values of the tumbling probability α and time n . Our results highlight striking effects of crowding on the dynamics: even cumulants of the RTP position are increasing functions of α at intermediate timescales, and display a subdiffusive anomalous scaling $\propto \sqrt{n}$ independent of α in the limit of long times $n\to \infty $ . These analytical results set the ground for a quantitative analysis of experimental trajectories of real biological or artificial microswimmers in extreme confinement.

Gene regulation relies on transcription factors (TFs) exploring the nucleus searching their targets. So far, most studies have focused on how fast TFs diffuse, underestimating the role of nuclear architecture. We implemented a single-molecule tracking assay to determine TFs dynamics. We found that c-Myc is a global explorer of the nucleus. In contrast, the positive transcription elongation factor P-TEFb is a local explorer that oversamples its environment. Consequently, each c-Myc molecule is equally available for all nuclear sites while P-TEFb reaches its targets in a position-dependent manner. Our observations are consistent with a model in which the exploration geometry of TFs is restrained by their interactions with nuclear structures and not by exclusion. The geometry-controlled kinetics of TFs target-search illustrates the influence of nuclear architecture on gene regulation, and has strong implications on how proteins react in the nucleus and how their function can be regulated in space and time.

We describe a tracer in a bath of soft Brownian colloids by a particle coupled to the density field of the other bath particles. From the Dean equation, we derive an exact equation for the evolution of the whole system, and show that the density field evolution can be linearized in the limit of a dense bath. This linearized Dean equation with a tracer taken apart is validated by the reproduction of previous results on the mean-field liquid structure and transport properties. Then, the tracer is submitted to an external force and we compute the density profile around it, its mobility and its diffusion coefficient. Our results exhibit effects such as bias enhanced diffusion that are very similar to those observed in the opposite limit of a hard core lattice gas, indicating the robustness of these effects. Our predictions are successfully tested against Brownian dynamics simulations.

Background: Total hip arthroplasty relieves joint pain in patients with end stage osteoarthritis. However, postoperative muscle atrophy often results in suboptimal lower limb function. There is a need to improve functional recovery after total hip arthroplasty., Objectives: To assess safety and efficacy of LY2495655, a humanized monoclonal antibody targeting myostatin, in patients undergoing elective total hip arthroplasty., Design: Phase 2, randomized, parallel, double-blind, 12-week clinical trial with a 12-week follow-up period., Setting: Forty-two sites in 11 countries., Participants: Individuals (N=400) aged ≥50 years scheduled for elective total hip arthroplasty for osteoarthritis within 10 ± 6 days after randomization., Intervention: Placebo or LY2495655 (35 mg, 105 mg, or 315 mg) subcutaneous injections at weeks 0 (randomization date), 4, 8, and 12 with follow up until week 24., Measurements: Primary endpoint: probability that LY2495655 increases appendicular lean mass (operated limb excluded) by at least 2.5% more than placebo at week 12, using dual-energy x-ray absorptiometry. Exploratory endpoints: muscle strength, performance based and self-reported measures of physical function, and whole body composition over time., Results: Participants: 59% women, aged 69 ± 8 years, BMI 29 ± 5 kg/m2. Groups were comparable at baseline. The primary objective was not reached as LY2495655 changes in lean mass did not meet the superiority threshold at week 12. However, LY2495655 105 and LY2495655 315 experienced progressive increases in appendicular lean mass that were statistically significant versus placebo at weeks 8 and 16. Whole body fat mass decreased in LY2495655 315 versus placebo at weeks 8 and 16. No meaningful differences were detected between groups in other exploratory endpoints. Injection site reactions occurred more often in LY2495655 patients than in placebo patients. No other safety signals were detected., Conclusion: Dose-dependent increases in appendicular lean body mass and decreases in fat mass were observed, although this study did not achieve the threshold of its primary objective.