This work presents and experimentally tests the framework used by our context-aware, distributed team of small Unmanned Aerial Systems (SUAS) capable of operating in real time, in an autonomous ...fashion, and under constrained communications. Our framework relies on a three-layered approach: (1) an operational layer, where fast temporal and narrow spatial decisions are made; (2) a tactical layer, where temporal and spatial decisions are made for a team of agents; and (3) a strategical layer, where slow temporal and wide spatial decisions are made for the team of agents. These three layers are coordinated by an ad hoc, software-defined communications network, which ensures sparse but timely delivery of messages amongst groups and teams of agents at each layer, even under constrained communications. Experimental results are presented for a team of 10 small unmanned aerial systems tasked with searching for and monitoring a person in an open area. At the operational layer, our use case presents an agent autonomously performing searching, detection, localization, classification, identification, tracking, and following of the person, while avoiding malicious collisions. At the tactical layer, our experimental use case presents the cooperative interaction of a group of multiple agents that enables the monitoring of the targeted person over wider spatial and temporal regions. At the strategic layer, our use case involves the detection of complex behaviors, i.e., the person being followed enters a car and runs away, or the person being followed exits the car and runs away, which require strategic responses to successfully accomplish the mission.
This work presents and experimentally test the framework used by our context-aware, distributed team of small Unmanned Aerial Systems (SUAS) capable of operating in real-time, in an autonomous ...fashion, and under constrained communications. Our framework relies on three layered approach: (1) Operational layer, where fast temporal and narrow spatial decisions are made; (2) Tactical Layer, where temporal and spatial decisions are made for a team of agents; and (3) Strategical Layer, where slow temporal and wide spatial decisions are made for the team of agents. These three layers are coordinated by an ad-hoc, software-defined communications network, which ensures sparse, but timely delivery of messages amongst groups and teams of agents at each layer even under constrained communications. Experimental results are presented for a team of 10 small unmanned aerial systems tasked with searching and monitoring a person in an open area. At the operational layer, our use case presents an agent autonomously performing searching, detection, localization, classification, identification, tracking, and following of the person, while avoiding malicious collisions. At the tactical layer, our experimental use case presents the cooperative interaction of a group of multiple agents that enable the monitoring of the targeted person over a wider spatial and temporal regions. At the strategic layer, our use case involves the detection of complex behaviors-i.e. the person being followed enters a car and runs away, or the person being followed exits the car and runs away-that requires strategic responses to successfully accomplish the mission.
Macrophages polarize into distinct phenotypes in response to complex environmental cues. We found that the nuclear receptor PPARγ drove robust phenotypic changes in macrophages upon repeated ...stimulation with interleukin (IL)-4. The functions of PPARγ on macrophage polarization in this setting were independent of ligand binding. Ligand-insensitive PPARγ bound DNA and recruited the coactivator P300 and the architectural protein RAD21. This established a permissive chromatin environment that conferred transcriptional memory by facilitating the binding of the transcriptional regulator STAT6 and RNA polymerase II, leading to robust production of enhancer and mRNAs upon IL-4 re-stimulation. Ligand-insensitive PPARγ binding controlled the expression of an extracellular matrix remodeling-related gene network in macrophages. Expression of these genes increased during muscle regeneration in a mouse model of injury, and this increase coincided with the detection of IL-4 and PPARγ in the affected tissue. Thus, a predominantly ligand-insensitive PPARγ:RXR cistrome regulates progressive and/or reinforcing macrophage polarization.
Display omitted
•Ligand-insensitive PPARγ sites are highly abundant in alternatively polarized MQs•PPARγ is recruited to the genome in a ligand-independent manner upon polarization•Ligand-insensitive PPARγ alters chromatin structure and facilitates IL-4 signaling•Ligand-insensitive PPARγ drives progressive polarization via transcriptional memory
Daniel et al. describe that the nuclear receptor PPARγ has a significant ligand-insensitive, genome-bound fraction that affects local chromatin structure upon macrophage polarization. Ligand-insensitive PPARγ mediates the expression of a hidden gene set upon repeated IL-4 exposure, providing transcriptional memory and an epigenomic ratchet mechanism to support progressive polarization.
The resolving power of cryo-EM experiments has dramatically improved in recent years. However, many cryo-EM maps may still not achieve a resolution that is sufficiently high to allow model building ...directly from the map. Instead, it is common practice to fit an initial atomic model to the map and refine this model. Depending on the resolution and whether the structure suffers from inherent flexibility or experimental limitations, different methods can be applied, to obtain high-quality, well-fitted atomic model of the macromolecular assembly represented by the map, and to assess its properties. In this review, we describe some of these methods, with the main focus on those that have been developed in our group over the last decade.
We present a study of multiple sclerosis segmentation algorithms conducted at the international MICCAI 2016 challenge. This challenge was operated using a new open-science computing infrastructure. ...This allowed for the automatic and independent evaluation of a large range of algorithms in a fair and completely automatic manner. This computing infrastructure was used to evaluate thirteen methods of MS lesions segmentation, exploring a broad range of state-of-theart algorithms, against a high-quality database of 53 MS cases coming from four centers following a common definition of the acquisition protocol. Each case was annotated manually by an unprecedented number of seven different experts. Results of the challenge highlighted that automatic algorithms, including the recent machine learning methods (random forests, deep learning, …), are still trailing human expertise on both detection and delineation criteria. In addition, we demonstrate that computing a statistically robust consensus of the algorithms performs closer to human expertise on one score (segmentation) although still trailing on detection scores.
Many individuals hospitalised with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience post-acute sequelae of SARS-CoV-2 infection (PASC), sometimes referred to as "long ...COVID". Our objective was to conduct a systematic literature review and meta-analysis to identify PASC-associated symptoms in previously hospitalised patients and determine the frequency and temporal nature of PASC.
Searches of MEDLINE, Embase, Cochrane Library (2019-2021), World Health Organization International Clinical Trials Registry Platform and reference lists were performed from November to December 2021. Articles were assessed by two reviewers against eligibility criteria and a risk of bias tool. Symptom data were synthesised by random effects meta-analyses.
Of 6942 records, 52 studies with at least 100 patients were analysed; ∼70% were Europe-based studies. Most data were from the first wave of the pandemic. PASC symptoms were analysed from 28 days after hospital discharge. At 1-4 months post-acute SARS-CoV-2 infection, the most frequent individual symptoms were fatigue (29.3% (95% CI 20.1-40.6%)) and dyspnoea (19.6% (95% CI 12.8-28.7%)). Many patients experienced at least one symptom at 4-8 months (73.1% (95% CI 44.2-90.3%)) and 8-12 months (75.0% (95% CI 56.4-87.4%)).
A wide spectrum of persistent PASC-associated symptoms were reported over the 1-year follow-up period in a significant proportion of participants. Further research is needed to better define PASC duration and determine whether factors such as disease severity, vaccination and treatments have an impact on PASC.
Structural determination of molecular complexes by cryo‐EM requires large, often complex processing of the image data that are initially obtained. Here, TEMPy2, an update of the TEMPy package to ...process, optimize and assess cryo‐EM maps and the structures fitted to them, is described. New optimization routines, comprehensive automated checks and workflows to perform these tasks are described.
TEMPy2, an update of the TEMPy package to process, optimize and assess cryo‐EM maps and the structures fitted to them, is presented.
The physiologically based pharmacokinetic (PBPK) model for liver transporter substrates has been established previously and used for predicting drug–drug interactions (DDI) and for clinical practice ...guidance. So far, nearly all the published PBPK models for liver transporter substrates have one or more hepatic clearance processes (
i.e.
, active uptake, passive diffusion, metabolism, and biliary excretion) estimated by fitting observed systemic data. The estimated hepatic clearance processes are then used to predict liver concentrations and DDI involving either systemic or liver concentration. However, the accuracy and precision of such predictions are unclear. In this study, we try to address this question by using the PBPK model to generate simulated compounds for which we know both systemic and liver profiles. We then developed an approach to assess the accuracy and precision of predicted liver concentration. With hepatic clearance processes estimated using plasma data, model predictions of liver are typically accurate (
i.e.
, true value is bounded by predicted maximum and minimum); however, only for a few compounds are predictions also precise. The results of the current study indicate that extra attention is required when using the current PBPK approach to predict liver concentration and DDI for transporter substrates dependent upon liver concentrations.
The power of computer simulations, including machine‐learning, has become an inseparable part of scientific analysis of biological data. This has significantly impacted the field of cryogenic ...electron microscopy (cryo‐EM), which has grown dramatically since the “resolution‐revolution.” Many maps are now solved at 3–4 Å or better resolution, although a significant proportion of maps deposited in the Electron Microscopy Data Bank are still at lower resolution, where the positions of atoms cannot be determined unambiguously. Additionally, cryo‐EM maps are often characterized by a varying local resolution, partly due to conformational heterogeneity of the imaged molecule. To address such problems, many computational methods have been developed for cryo‐EM map reconstruction and atomistic model building. Here, we review the development in algorithms and tools for building models in cryo‐EM maps at different resolutions. We describe methods for model building, including rigid and flexible fitting of known models, model validation, small‐molecule fitting, and model visualization. We provide examples of how these methods have been used to elucidate the structure and function of dynamic macromolecular machines.
This article is categorized under:
Structure and Mechanism > Molecular Structures
Structure and Mechanism > Computational Biochemistry and Biophysics
Software > Molecular Modeling
Combining cryo‐EM data and molecular simulation to understand protein structure and dynamics.
Structural determination of molecular complexes by cryo-EM requires large, often complex processing of the image data that are initially obtained. Here,
TEMPy
2, an update of the
TEMPy
package to ...process, optimize and assess cryo-EM maps and the structures fitted to them, is described. New optimization routines, comprehensive automated checks and workflows to perform these tasks are described.
PDF
