Agent-based simulation of reactions in the crowded and structured intracellular environment: Influence of mobility and location of the reactants

<p>Abstract</p> <p>Background</p> <p>In this paper we apply a novel agent-based simulation method in order to model intracellular reactions in detail. The simulations are performed within a virtual cytoskeleton enriched with further crowding elements, which allows the analysis of molecular crowding effects on intracellular diffusion and reaction rates. The cytoskeleton network leads to a reduction in the mobility of molecules. Molecules can also unspecifically bind to membranes or the cytoskeleton affecting (i) the fraction of unbound molecules in the cytosol and (ii) furthermore reducing the mobility. Binding of molecules to intracellular structures or scaffolds can in turn lead to a microcompartmentalization of the cell. Especially the formation of enzyme complexes promoting metabolic channeling, e.g. in glycolysis, depends on the co-localization of the proteins.</p> <p>Results</p> <p>While the co-localization of enzymes leads to faster reaction rates, the reduced mobility decreases the collision rate of reactants, hence reducing the reaction rate, as expected. This effect is most prominent in diffusion limited reactions. Furthermore, anomalous diffusion can occur due to molecular crowding in the cell. In the context of diffusion controlled reactions, anomalous diffusion leads to fractal reaction kinetics. The simulation framework is used to quantify and separate the effects originating from molecular crowding or the reduced mobility of the reactants. We were able to define three factors which describe the effective reaction rate, namely <it>f ^diff</it>for the diffusion effect, <it>f ^volume</it>for the crowding, and <it>f ^access</it>for the reduced accessibility of the molecules.</p> <p>Conclusions</p> <p>Molecule distributions, reaction rate constants and structural parameters can be adjusted separately in the simulation allowing a comprehensive study of individual effects in the context of a realistic cell environment. As such, the present simulation can help to bridge the gap between <it>in vivo </it>and <it>in vitro </it>kinetics.</p

Supporting Inclusive Design of Mobile Devices with a Context Model

The aim of inclusive product design is to successfully integrate a broad range of diverse human factors in the product development process with the intention of making products accessible to and usable by the largest possible group of users. However, the main barriers for adopting inclusive product design include technical complexity, lack of time, lack of knowledge and techniques, and lack of guidelines. Although manufacturers of consumer products are nowadays more likely to invest efforts in user studies, consumer products in general only nominally fulfill, if at all, the accessibility requirements of as many users as they potentially could. The main reason is that any user-centered design prototyping or testing aiming to incorporate real user input, is often done at a rather late stage of the product development process. Thus, the more progressed a product design has evolved - the more time-consuming and costly it will be to alter the design. This is increasingly the case for contemporary mobile devices such as mobile phones or remote controls

Chapter Supporting Inclusive Design of Mobile Devices with a Context Model

Embedded system

Dysregulation of the mTOR Pathway Mediates Impairment of Synaptic Plasticity in a Mouse Model of Alzheimer's Disease

Background: The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase that plays a pivotal role in multiple fundamental biological processes, including synaptic plasticity. We explored the relationship between the mTOR pathway and b-amyloid (Ab)-induced synaptic dysfunction, which is considered to be critical in the pathogenesis of Alzheimer’s disease (AD). Methodology/Principal Findings: We provide evidence that inhibition of mTOR signaling correlates with impairment in synaptic plasticity in hippocampal slices from an AD mouse model and in wild-type slices exposed to exogenous Ab1-42. Importantly, by up-regulating mTOR signaling, glycogen synthase kinase 3 (GSK3) inhibitors rescued LTP in the AD mouse model, and genetic deletion of FK506-binding protein 12 (FKBP12) prevented Ab-induced impairment in long-term potentiation (LTP). In addition, confocal microscopy demonstrated co-localization of intraneuronal Ab42 with mTOR. Conclusions/Significance: These data support the notion that the mTOR pathway modulates Ab-related synaptic dysfunctio

The National COVID Cohort Collaborative (N3C): Rationale, design, infrastructure, and deployment.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) poses societal challenges that require expeditious data and knowledge sharing. Though organizational clinical data are abundant, these are largely inaccessible to outside researchers. Statistical, machine learning, and causal analyses are most successful with large-scale data beyond what is available in any given organization. Here, we introduce the National COVID Cohort Collaborative (N3C), an open science community focused on analyzing patient-level data from many centers. MATERIALS AND METHODS: The Clinical and Translational Science Award Program and scientific community created N3C to overcome technical, regulatory, policy, and governance barriers to sharing and harmonizing individual-level clinical data. We developed solutions to extract, aggregate, and harmonize data across organizations and data models, and created a secure data enclave to enable efficient, transparent, and reproducible collaborative analytics. RESULTS: Organized in inclusive workstreams, we created legal agreements and governance for organizations and researchers; data extraction scripts to identify and ingest positive, negative, and possible COVID-19 cases; a data quality assurance and harmonization pipeline to create a single harmonized dataset; population of the secure data enclave with data, machine learning, and statistical analytics tools; dissemination mechanisms; and a synthetic data pilot to democratize data access. CONCLUSIONS: The N3C has demonstrated that a multisite collaborative learning health network can overcome barriers to rapidly build a scalable infrastructure incorporating multiorganizational clinical data for COVID-19 analytics. We expect this effort to save lives by enabling rapid collaboration among clinicians, researchers, and data scientists to identify treatments and specialized care and thereby reduce the immediate and long-term impacts of COVID-19

SNAPSHOT USA 2019 : a coordinated national camera trap survey of the United States

This article is protected by copyright. All rights reserved.With the accelerating pace of global change, it is imperative that we obtain rapid inventories of the status and distribution of wildlife for ecological inferences and conservation planning. To address this challenge, we launched the SNAPSHOT USA project, a collaborative survey of terrestrial wildlife populations using camera traps across the United States. For our first annual survey, we compiled data across all 50 states during a 14-week period (17 August - 24 November of 2019). We sampled wildlife at 1509 camera trap sites from 110 camera trap arrays covering 12 different ecoregions across four development zones. This effort resulted in 166,036 unique detections of 83 species of mammals and 17 species of birds. All images were processed through the Smithsonian's eMammal camera trap data repository and included an expert review phase to ensure taxonomic accuracy of data, resulting in each picture being reviewed at least twice. The results represent a timely and standardized camera trap survey of the USA. All of the 2019 survey data are made available herein. We are currently repeating surveys in fall 2020, opening up the opportunity to other institutions and cooperators to expand coverage of all the urban-wild gradients and ecophysiographic regions of the country. Future data will be available as the database is updated at eMammal.si.edu/snapshot-usa, as well as future data paper submissions. These data will be useful for local and macroecological research including the examination of community assembly, effects of environmental and anthropogenic landscape variables, effects of fragmentation and extinction debt dynamics, as well as species-specific population dynamics and conservation action plans. There are no copyright restrictions; please cite this paper when using the data for publication.Publisher PDFPeer reviewe

Stochastic Simulation of Signal Transduction: Impact of the Cellular Architecture on Diffusion

The transduction of signals depends on the translocation of signaling molecules to specific targets. Undirected diffusion processes play a key role in the bridging of spaces between different cellular compartments. The diffusion of the molecules is, in turn, governed by the intracellular architecture. Molecular crowding and the cytoskeleton decrease macroscopic diffusion. This article shows the use of a stochastic simulation method to study the effects of the cytoskeleton structure on the mobility of macromolecules. Brownian dynamics and single particle tracking were used to simulate the diffusion process of individual molecules through a model cytoskeleton. The resulting average effective diffusion is in line with data obtained in the in vitro and in vivo experiments. It shows that the cytoskeleton structure strongly influences the diffusion of macromolecules. The simulation method used also allows the inclusion of reactions in order to model complete signaling pathways in their spatio-temporal dynamics, taking into account the effects of the cellular architecture

Electron transfer in porphyrin−quinone cyclophanes studied on the pico− and femto−second time scale

Electron transfer in porphyrin−quinone cyclophanes is investigated by fluorescence and absorption spectroscopy with pico− and femto−second pulses. In nonpolar solvents, the S1 state of the porphyrin shows a lifetime from 300 ps up to several nanoseconds, depending upon the number of quinones and upon their electron affinity. Comparative measurements in polar solvents demonstrate very fast electron transfer on a time scale between 1 and 10 ps. The results are analyzed with the aid of quantum−chemical calculations which give the energy of the charge transfer states and the relevant coupling strengths. For nonpolar solvents, theory suggests fluctuation−induced charge separation and/or direct radiationless internal conversion from the porphyrin S1 to the ground state. In polar solution, the molecules exist in a tilted configuration with strong electronic coupling and charge transfer states well below the S1 level, resulting in fast electron transfer and subsequent charge recombination within 10−40 p

Non-Destructive Spent Fuel Characterization with Semi-Conducting Gallium Arsinde Neutron Imaging Arrays

High resistivity bulk grown GaAs has been used to produce thermal neutron imaging devices for use in neutron radiography and characterizing burnup in spent fuel. The basic scheme utilizes a portable Sb/Be source for monoenergetic (24 keV) neutron radiation source coupled to an Fe filter with a radiation hard B-coated pixellated GaAs detector array as the primary neutron detector. The coated neutron detectors have been tested for efficiency and radiation hardness in order to determine their fitness for the harsh environments imposed by spent fuel. Theoretical and experimental results are presented, showing detector radiation hardness, expected detection efficiency and the spatial resolution from such a scheme. A variety of advanced neutron detector designs have been explored, with experimental results achieving 13% thermal neutron detection efficiency while projecting the possibility of over 30% thermal neutron detection efficiency