pH-dependent mechanism of nitric oxide release in nitrophorins 2 and 4

Nitrophorins are NO carrier proteins that transport and release NO through a pH-dependent conformational change. They bind NO tightly in a low pH environment and release it in a higher pH environment. Experimental evidence shows that the increase in the NO dissociation equilibrium constant, K d, is due mainly to an increase in the NO release rate. Structural and kinetic data strongly suggest that NPs control NO escape by modulating its migration from the active site to the solvent through a pH-dependent conformational change. NP2 and NP4 are two representative proteins of the family displaying a 39% overall sequence identity, and interestingly, NP2 releases NO slower than NP4. The proposal that NPs' NO release relies mainly on the NO escape rate makes NPs a very peculiar case among typical heme proteins. The connection between the pH-dependent conformational change and ligand release mechanism is not fully understood and the structural basis for the pH induced structural transition and the different NO release patterns in NPs are unresolved, yet interesting issues. In this work, we have used state of the art molecular dynamics simulations to study the NO escape process in NP2 and NP4 in both the low and high pH states. Our results show that both NPs modulate NO release by switching between a "closed" conformation in a low pH environment and an "open" conformation at higher pH. In both proteins, the change is caused by the differential protonation of a common residue Asp30 in NP4 and Asp29 in NP2, and the NO escape route is conserved. Finally, our results show that, in NP2, the conformational change to the "open" conformation is smaller than that for NP4 which results in a higher barrier for NO release.Fil: Swails, Jason M.. University of Florida; Estados UnidosFil: Meng, Yilin. University of Florida; Estados UnidosFil: Walker, F. Ann. University of Arizona; Estados UnidosFil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Roitberg, Adrián. University of Florida; Estados Unido

iQIST : An open source continuous-time quantum Monte Carlo impurity solver toolkit

Quantum impurity solvers have a broad range of applications in theoretical studies of strongly correlated electron systems. Especially, they play a key role in dynamical mean-field theory calculations of correlated lattice models and realistic materials. Therefore, the development and implementation of efficient quantum impurity solvers is an important task. In this paper, we present an open source interacting quantum impurity solver toolkit (dubbed iQIST). This package contains several highly optimized quantum impurity solvers which are based on the hybridization expansion continuous-time quantum Monte Carlo algorithm, as well as some essential pre- and post-processing tools. We first introduce the basic principle of continuous-time quantum Monte Carlo algorithm and then discuss the implementation details and optimization strategies. The software framework, major features, and installation procedure for iQIST are also explained. Finally, several simple tutorials are presented in order to demonstrate the usage and power of iQIST

Degradation or excretion of quantum dots in mouse embryonic stem cells

<p>Abstract</p> <p>Background</p> <p>Quantum dots (QDs) have been considered as a new and efficient probe for labeling cells non-invasively in vitro and in vivo, but fairly little is known about how QDs are eliminated from cells after labeling. The purpose of this study is to investigate the metabolism of QDs in different type of cells.</p> <p>Results</p> <p>Mouse embryonic stem cells (ESCs) and mouse embryonic fibroblasts (MEFs) were labeled with QD 655. QD-labeling was monitored by fluorescence microscopy and flow cytometry for 72 hours. Both types of cells were labeled efficiently, but a quick loss of QD-labeling in ESCs was observed within 48 hours, which was not prevented by inhibiting cell proliferation. Transmission electron microscope analysis showed a dramatic decrease of QD number in vesicles of ESCs at 24 hours post-labeling, suggesting that QDs might be degraded. In addition, supernatants collected from labeled ESCs in culture were used to label cells again, indicating that some QDs were excreted from cells.</p> <p>Conclusion</p> <p>This is the first study to demonstrate that the metabolism of QDs in different type of cells is different. QDs were quickly degraded or excreted from ESCs after labeling.</p

Vertical deformation monitoring of the suspension bridge tower using GNSS: a case study of the Forth Road Bridge in the UK

The vertical deformation monitoring of a suspension bridge tower is of paramount importance to maintain the operational safety since nearly all forces are eventually transferred as the vertical stress on the tower. This paper analyses the components affecting the vertical deformation and attempts to reveal its deformation mechanism. Firstly, we designed a strategy for high-precision GNSS data processing aiming at facilitating deformation extraction and analysis. Then, 33 months of vertical deformation time series of the southern tower of the Forth Road Bridge (FRB) in the UK were processed, and the accurate subsidence and the parameters of seasonal signals were estimated based on a classic function model that has been widely studied to analyse GNSS coordinate time series. We found that the subsidence rate is about 4.7 mm/year, with 0.1 mm uncertainty. Meanwhile, a 15-month meteorological dataset was utilised with a thermal expansion model (TEM) to explain the effects of seasonal signals on tower deformation. The amplitude of the annual signals correlated quite well that obtained by the TEM, with the consistency reaching 98.9%, demonstrating that the thermal effect contributes significantly to the annual signals. The amplitude of daily signals displays poor consistency with the ambient temperature data. However, the phase variation tendencies between the daily signals of the vertical deformation and the ambient temperature are highly consistent after February 2016. Finally, the potential contribution of the North Atlantic Drift (NAD) to the characteristics of annual and daily signals is discussed because of the special geographical location of the FRB. Meanwhile, this paper emphasizes the importance of collecting more detailed meteorological and other loading data for the investigation of the vertical deformation mechanism of the bridge towers over time with the support of GNSS

Application of GeoSHM System in Monitoring Extreme Wind Events at the Forth Road Bridge

© 2019 by the authors. Implementation of Structural Health Monitoring systems on long-span bridges has become mandatory in many countries to ascertain the safety of these structures and the public, taking into account an increase in usage and threats due to extreme loading conditions. However, the successful delivery of such a system is facing many challenges including the failure to extract damage and reliability information from monitoring data to assist bridge operators with their maintenance planning and activities. Supported by the European Space Agency under the Integrated Applications Promotion scheme, the project 'GNSS and Earth Observation for Structural Health Monitoring of Long-span Bridges' or GeoSHM aims to address some of these shortcomings (GNSS stands for Global Navigation Satellite System). In this paper, the background of the GeoSHM project as well as the GeoSHM sensor system on the Forth Road Bridge (FRB) in Scotland will be briefly described. The bridge response and wind data collected over a two-year period from 15 October 2015 to 15 October 2017 will be analysed to demonstrate the high susceptibility of the bridge to wind loads. Close examination of the data associated with an extreme wind event in 2018-Storm Ali-will be conducted to reveal the relationship between the wind speed and some monitored parameters such as the bridge response and modal frequencies

An observation of non-stationary response to non-synoptic wind on the Forth Road Bridge

© 2020 Elsevier Ltd The GeoSHM project feasibility study for monitoring the Forth Road Bridge is briefly introduced and the instrumentation summarised. The events of January 9th, 2015 are described, when the bridge was struck by storm Elon, which caused widespread damage across Scotland and led to the temporary closure of the bridge when a van was blown over. During this storm an anomalous large amplitude response was observed. The data for January 9th, 2015 are analysed to show that the extreme response and the corresponding wind are non-stationary and non-Gaussian. Further analysis of the rainfall radar data for the same time shows a line of intense rainfall extending for over 100 ​km, which passes the site of the bridge at exactly the time of the peak response. The rainfall intensity was high enough to indicate that this feature was caused by convective activity and this observation was corroborated by records of lightning strikes. It is concluded that non-stationary wind events can give rise to large response of long span bridge structures and that this response can exceed that observed from the stationary wind field. Furthermore, historical data confirm that energetic squall lines are not uncommon in the UK. Therefore, the assumption of stationarity in predicting the wind induced response of long span bridges may be non-conservative and the climatology of large convective systems, such as squall lines, should be considered in assessing the wind hazard for these structures

Research and development of a pilot project using GNSS and Earth observation (GeoSHM) for structural health monitoring of the Forth Road Bridge in Scotland

GeoSHM (GNSS and Earth Observation for Structural Health Monitoring) is a feasibility study project funded under the Integrated Application Promotion (IAP) program of the European Space Agency (ESA) in August 2013. Through integrated use of GNSS, Remote Sensing technologies and environmental data, GeoSHM can offer bridge owners an effective tool to assess the operational conditions of their assets. A reference system that consists of four GNSS receivers and two anemometers was installed on the Forth Road Bridge (FRB) in Scotland. This first stage monitoring system is producing precise 3D real-time displacements under different loading conditions. It can also provide essential land movement information to assess potential threats due to underground water extraction, geo-hazards and other industrial activities. The GeoSHM Feasibility Study has proved that even a small scale monitoring system can make possible for the Bridgemaster of the FRB to fully understand the loading and response effect of the bridge, and identify unusual deformations under extreme weather conditions (wind gust, etc.). Furthermore, EO data has proved to be extremely useful for the subsidence detection, as the SAR interferometry images have shown that there is no significant subsidence of the towers of the FRB or in the surrounding area. Gathering real-time GNSS data has produced continuous and accurate estimation of the displacement time-series of the structure. The issues and gaps identified from GeoSHM FS will form a solid foundation for the next stage development of GeoSHM service – demonstration, which is a two-year project and have started in February 2016. A new consortium of GeoSHM has been formed, focusing on significant refinements to the system reliability, sensor integration, data acquisition, data transmission, data fusion and SHM information extraction. This further developed GeoSHM system will be installed on a few Chinese bridges and the reference monitoring system on the FRB will be expanded as a pre-operational system

Design and implementation of a new system for large bridge monitoring—GeoSHM

Structural Health Monitoring (SHM) is a relatively new branch of civil engineering that focuses on assessing the health status of infrastructure, such as long-span bridges. Using a broad range of in-situ monitoring instruments, the purpose of the SHM is to help engineers understand the behaviour of structures, ensuring their structural integrity and the safety of the public. Under the Integrated Applications Promotion (IAP) scheme of the European Space Agency (ESA), a feasibility study (FS) project that used the Global Navigation Satellite Systems (GNSS) and Earth Observation (EO) for Structural Health Monitoring of Long-span Bridges (GeoSHM) was initiated in 2013. The GeoSHM FS Project was led by University of Nottingham and the Forth Road Bridge (Scotland, UK), which is a 2.5 km long suspension bridge across the Firth of Forth connecting Edinburgh and the Northern part of Scotland, was selected as the test structure for the GeoSHM FS project. Initial results have shown the significant potential of the GNSS and EO technologies. With these successes, the FS project was further extended to the demonstration stage, which is called the GeoSHM Demo project where two other long-span bridges in China were included as test structures. Led by UbiPOS UK Ltd. (Nottingham, UK), a Nottingham Hi-tech company, this stage focuses on addressing limitations identified during the feasibility study and developing an innovative data strategy to process, store, and interpret monitoring data. This paper will present an overview of the motivation and challenges of the GeoSHM Demo Project, a description of the software and hardware architecture and a discussion of some primary results that were obtained in the last three years

Effects of the SNAP-25 Mnll variant on hippocampal functional connectivity in children with attention deficit/hyperactivity disorder

ObjectivesAttention-deficit/hyperactivity disorder (ADHD) is one of the most widespread and highly heritable neurodevelopmental disorders affecting children worldwide. Although synaptosomal-associated protein 25 (SNAP-25) is a possible gene hypothesized to be associated with working memory deficits in ADHD, little is known about its specific impact on the hippocampus. The goal of the current study was to determine how variations in ADHD’s SNAP-25 Mnll polymorphism (rs3746544) affect hippocampal functional connectivity (FC).MethodsA total of 88 boys between the ages of 7 and 10 years were recruited for the study, including 60 patients with ADHD and 28 healthy controls (HCs). Data from resting-state functional magnetic resonance imaging (rs-fMRI) and clinical information were acquired and assessed. Two single nucleotide polymorphisms (SNP) in the SNAP-25 gene were genotyped, according to which the study’s findings separated ADHD patients into two groups: TT homozygotes (TT = 35) and G-allele carriers (TG = 25).ResultsBased on the rs-fMRI data, the FC of the right hippocampus and left frontal gyrus was evaluated using group-based comparisons. The corresponding sensitivities and specificities were assessed. Following comparisons between the patient groups, different hippocampal FCs were identified. When compared to TT patients, children with TG had a lower FC between the right precuneus and the right hippocampus, and a higher FC between the right hippocampus and the left middle frontal gyrus.ConclusionThe fundamental neurological pathways connecting the SNAP-25 Mnll polymorphism with ADHD via the FC of the hippocampus were newly revealed in this study. As a result, the hippocampal FC may further serve as an imaging biomarker for ADHD