Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of organophosphate hydrolase activity in a bacterial homolog of human cholinesterase

We applied a combination of rational design and directed evolution (DE) to Bacillus subtilis p-nitrobenzyl esterase (pNBE) with the goal of enhancing organophosphorus acid anhydride hydrolase (OPAAH) activity. DE started with a designed variant, pNBE A107H, carrying a histidine homologous with human butyrylcholinesterase G117H to find complementary mutations that further enhance its OPAAH activity. Five sites were selected (G105, G106, A107, A190, and A400) within a 6.7 Å radius of the nucleophilic serine Oγ. All 95 variants were screened for esterase activity with a set of five substrates: pNP-acetate, pNP-butyrate, acetylthiocholine, butyrylthiocholine, or benzoylthiocholine. A microscale assay for OPAAH activity was developed for screening DE libraries. Reductions in esterase activity were generally concomitant with enhancements in OPAAH activity. One variant, A107K, showed an unexpected 7-fold increase in its kcat/Km for benzoylthiocholine, demonstrating that it is also possible to enhance the cholinesterase activity of pNBE. Moreover, DE resulted in at least three variants with modestly enhanced OPAAH activity compared to wild type pNBE. A107H/A190C showed a 50-fold increase in paraoxonase activity and underwent a slow time- and temperature-dependent change affecting the hydrolysis of OPAA and ester substrates. Structural analysis suggests that pNBE may represent a precursor leading to human cholinesterase and carboxylesterase 1 through extension of two vestigial specificity loops; a preliminary attempt to transfer the Ω-loop of BChE into pNBE is described. Unlike butyrylcholinesterase and pNBE, introducing a G143H mutation (equivalent to G117H) did not confer detectable OP hydrolase activity on human carboxylesterase 1 (hCE1). We discuss the use of pNBE as a surrogate scaffold for the mammalian esterases, and the importance of the oxyanion-hole residues for enhancing the OPAAH activity of selected serine hydrolases.
Beyond the dogma: novel β2-adrenoceptor signalling in the airways

β2-Adrenoceptor agonists evoke rapid bronchodilatation and are the mainstay of the treatment of asthma symptoms worldwide. The mechanism of action of this class of compounds is believed to involve the stimulation of adenylyl cyclase and subsequent activation of the cyclic adenosine monosphosphate (cAMP)/cAMP-dependent protein kinase cascade. This classical model of β2-adrenoceptor-mediated signal transduction is deeply entrenched, but there is compelling evidence that agonism of β2-adrenoceptors can lead to the activation of multiple effector pathways, which now compels researchers in academia and the pharmaceutical industry alike to think beyond the traditional dogma. Therefore, the regulation by β2-adrenoceptor agonists of responses, including airways smooth muscle tone and the secretory capacity of the epithelium and pro-inflammatory/immune cells, may be highly complex, involving both cAMP-dependent and -independent mechanisms that, in many cases, may act in concert. In this article, the current status of β2-adrenoceptor-mediated signalling in the airways is reviewed in the context of understanding mechanisms that may underlie both the beneficial and detrimental effects of these drugs in asthma symptom management.
Assembly and Stoichiometry of the AMPA Receptor and Transmembrane AMPA Receptor Regulatory Protein Complex

Glutamate is a major excitatory neurotransmitter in the vertebrate brain. AMPA-type glutamate receptors mediate fast excitatory transmission. AMPA receptors assemble with transmembrane AMPA receptor regulatory protein (TARP) auxiliary subunits and function as native ion channels. However, the assembly and stoichiometry of AMPA receptor and TARP complexes remain unclear. Here, we developed a novel strategy to determine the assembly and stoichiometry of this protein complex and found that functional AMPA receptors indeed assembled as a tetramer in a dimer-of-dimers structure. Furthermore, we found that the AMPA receptor auxiliary subunit, TARP, had a variable stoichiometry (1–4 TARP units) on AMPA receptors and that 1 TARP unit was sufficient to modulate AMPA receptor activity. In neurons, TARP had fixed and minimum stoichiometry on AMPA receptors. This fundamental composition of the AMPA receptor/TARP complex is important for the elucidation of the molecular machinery that underlies synaptic transmission.
Unsupervised Fluorescence Lifetime Imaging Microscopy for High Content and High Throughput Screening *S

Proteomics and cellomics clearly benefit from the molecular insights in cellular biochemical events that can be obtained by advanced quantitative microscopy techniques like fluorescence lifetime imaging microscopy and Förster resonance energy transfer imaging. The spectroscopic information detected at the molecular level can be combined with cellular morphological estimators, the analysis of cellular localization, and the identification of molecular or cellular subpopulations. This allows the creation of powerful assays to gain a detailed understanding of the molecular mechanisms underlying spatiotemporal cellular responses to chemical and physical stimuli. This work demonstrates that the high content offered by these techniques can be combined with the high throughput levels offered by automation of a fluorescence lifetime imaging microscope setup capable of unsupervised operation and image analysis. Systems and software dedicated to image cytometry for analysis and sorting represent important emerging tools for the field of proteomics, interactomics, and cellomics. These techniques could soon become readily available both to academia and the drug screening community by the application of new all-solid-state technologies that may results in cost-effective turnkey systems. Here the application of this screening technique to the investigation of intracellular ubiquitination levels of α-synuclein and its familial mutations that are causative for Parkinson disease is shown. The finding of statistically lower ubiquitination of the mutant α-synuclein forms supports a role for this modification in the mechanism of pathological protein aggregation.
Next Generation Space Telescope Mission Cosmic Ray Management on NGST 1 : The Effect of Cosmic Rays on Near Infrared Imaging Exposure Times

Cosmic rays will play an important role in determining NGST’s maximum exposure time. Based on simulations of a deep L band galaxy imaging program, we find that shorter exposure times may be required than had hitherto been thought when using simple “throw away the hits” cosmic ray rejection strategies. The primary reasons for this are the effects of crosstalk and multi-pixel hits, both of which increase the area of a typical hit. In this paper, we explore a trade space including t=1,000 s, 500 s, 250 s, and 125 s exposures using a 27 μm pixel pitch array. Using existing image combining tools, deep images can be obtained in the L2 radiation environment using all of these exposure times by taking reasonable numbers of extra exposures. However, combining smaller numbers of longer exposures comes at the price of greater pixel-to-pixel sensitivity variation. A potentially important effect that was not modeled is the increase in read noise that accrues as the number of Fowler samples diminishes with shorter exposure times. Based on recent studies, it is likely that NGST’s minimum exposure time will be about t=12 s. This would limit the number of Fowler samples that are possible in some of the shorter exposures considered in this paper. The effect is most pronounced in 27 μm pitch InSb arrays at exposure times shorter than about t=500 s. Likewise, recent research on the cosmic ray environment at L2 suggests that solar protons could substantially increase the cosmic ray flux above the 5 protons cm s considered in this report for much of the NGST mission. To first order, one can scale our suggested exposure times as follows,
Optimized Synthesis of Self-Equalized Microwave Filters

In this paper, a new methodology for synthesizing self-equalized filters is introduced. The methodology consists of optimizing the polynomial transfer and reflection functions considering amplitude and phase constraints simultaneously. The algorithm gives access to a more general class of functions than generalized Chebyshev (also called quasi-elliptic) functions. Two self-equalized filters are designed using this new methodology, and their performances are compared to general Chebyshev filters in order to put into evidence the interest of the proposed optimization algorithm. The first design leads to reduced group-delay variations, and the second one leads to a simplification of the hardware, reducing the number of resonators.
An LMI Approach to D-stable Robust Hinfin Fault Tolerant Control of Uncertain Systems

In this paper, the D-stabilizable robust Hinfin fault tolerant control problem is formulated in an LMI (linear matrix inequality) setting, in which satisfactory performance and guaranteed stability robustness are introduced. The objective is to design a controller that stabilizes an uncertain system while satisfying an Hinfin-norm bound constraint and closed-loop pole placement constraint in the normal condition as well as in the event of actuator failures. To achieve such aims, a multi-objective approach is used to establish a matrix inequality formulation for fault-tolerant control system design. The sufficient condition for the existence of the controller is presented, and furthermore, a parameterized characterization of the robust controllers is given in terms of the feasible solutions to the certain matrix inequalities. In addition, on the premise of guaranteeing the system integrity, the sufficient condition for the consistency of Hinfin-norm specification with D-stabilizable specification is derived.
Relating hygroscopicity and optical properties to chemical composition and structure of secondary organic aerosol particles generated from the ozonolysis of α-pinene

Abstract. Secondary organic aerosol (SOA) were generated from the ozonolysis of α-pinene in the CESAM (French acronym for Experimental Multiphasic Atmospheric Simulation Chamber) simulation chamber. The SOA formation and aging were studied by following their optical, hygroscopic and chemical properties. The optical properties were investigated by determining the particle complex refractive index (CRI). The hygroscopicity was quantified by measuring the effect of relative humidity (RH) on the particle size (size growth factor, GF) and on the scattering coefficient (scattering growth factor, f(RH)). The oxygen to carbon atomic ratios (O : C) of the particle surface and bulk were used as a sensitive parameter to correlate the changes in hygroscopic and optical properties of the SOA composition during their formation and aging in CESAM. The real CRI at 525 nm wavelength decreased from 1.43–1.60 (±0.02) to 1.32–1.38 (±0.02) during the SOA formation. The decrease in the real CRI correlated to the O : C decrease from 0.68 (±0.20) to 0.55 (±0.16). In contrast, the GF remained roughly constant over the reaction time, with values of 1.02–1.07 (±0.02) at 90% (±4.2%) RH. Simultaneous measurements of O : C of the particle surface revealed that the SOA was not composed of a homogeneous mixture, but contained less oxidised species at the surface which may limit water absorption. In addition, an apparent change in both mobility diameter and scattering coefficient with increasing RH from 0 to 30% was observed for SOA after 14 h of reaction. We postulate that this change could be due to a change in the viscosity of the SOA from a predominantly glassy state to a predominantly liquid state.
Stable self-serving personality traits in recreational and dependent cocaine users

Chronic cocaine use has been associated with impairments in social cognition, self-serving and antisocial behavior, and socially relevant personality disorders (PD). Despite the apparent relationship between Machiavellianism and stimulant use, no study has explicitly examined this personality concept in cocaine users so far. In the frame of the longitudinal Zurich Cocaine Cognition Study, the Machiavellianism Questionnaire (MACH-IV) was assessed in 68 recreational and 30 dependent cocaine users as well as in 68 psychostimulant-naïve controls at baseline. Additionally, three closely related personality dimensions from the Temperament and Character Inventory (TCI)–cooperativeness, (social) reward dependence, and self-directedness–and the screening questionnaire of the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) were acquired. At the one-year follow-up, 57 cocaine users and 48 controls were reassessed with the MACH-IV. Finally, MACH-IV scores were correlated with measures of social cognition and interaction (cognitive/emotional empathy, Theory-of-Mind, prosocial behavior) and with SCID-II PD scores assessed at baseline. Both recreational and dependent cocaine users showed significantly higher Machiavellianism than controls, while dependent cocaine users additionally displayed significantly lower levels of TCI cooperativeness and self-directedness. During the one-year interval, MACH-IV scores showed high test-retest reliability and also the significant gap between cocaine users and controls remained. Moreover, in cocaine users, higher Machiavellianism correlated significantly with lower levels of cooperativeness and self-directedness, with less prosocial behavior, and with higher cluster B PD scores. However, Machiavellianism was not correlated with measures of cocaine use severity (r<-.15). Both recreational and dependent cocaine users display pronounced and stable Machiavellian personality traits. The lack of correlations with severity of cocaine use and its temporal stability indicates that a Machiavellian personality trait might represent a predisposition for cocaine use that potentially serves as a predictor for stimulant addiction.
Modified PPPE architecture for two-dimensional Radon Transform computation

In this paper, a modified VLSI architecture for two-dimensional Radon Transform has been presented. The proposed architecture is primarily based on the analytical relationship between the pixels on horizontal and vertical raster scan line and also between the projection angles. The proposed architecture is compared against the existing ‘Parallel Pipeline Projection Engine’ (PPPE) architecture. Implementation of the proposed and PPPE architecture has been done on ‘Field Programmable Gate Array’ (FPGA). It has been observed that the modified architecture reduces the computational complexity, delay and latency as compared to PPPE.
Process Lines: A Product Line Approach Designed for Process Model Development

Standard process models like RUP or the German V-Modell XT are developed to be used in an organizational environment. Yet introducing such a process model into an organization is no simple task. It is usually accompanied by either reorganizing internal processes to comply with a standard process model or by adaptation of the process model to organizational structures. The latter is an approach that can often be found in practice and is subject to this paper.The paper describes a generalization of the process model architecture of the V-Modell XT 1.3. Compared to the previous version 1.2. 1.1, its metamodel has completely been revised with respect to a new adaptation concept. We will see how this concept allows the implementation of a so called process line. Software process lines are derived from software product lines and can be used for the adaptation of standard processes during process model development, project initialization and project runtime.
Infection and Drug Resistance Dovepress Optimizing the Detection of Methicillin-resistant Staphylococcus Aureus with Elevated Vancomycin Minimum Inhibitory Concentrations within the Susceptible Range Nicholas a Wells 4

you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms Background: Determination of vancomycin minimum inhibitory concentration (MIC) can influence the agent used to treat methicillin-resistant Staphylococcus aureus (MRSA) infection. We studied diagnostic accuracy using E-test and VITEK ® 2 against a gold standard broth microdilution (BMD) methodology, the correlation between methods, and associations between vancomycin MIC and MRSA phenotype from clinical isolates. values were determined prospectively on all isolates by gradient diffusion E-test and automated VITEK ® 2. The Clinical and Laboratory Standards Institute reference BMD method was performed retrospectively on thawed frozen isolates. Diagnostic accuracy for detecting less susceptible strains was calculated at each MIC cutoff point for E-Test and VITEK ® 2 using BMD ≥1 µg/mL as a standard. The correlation between methods was assessed using Spearman's rho (r). The association between MRSA phenotype and MIC for the three methods was assessed using Fisher's exact test. Results: Of 148 MRSA isolates, all except one (E-test =3 µg/mL) were susceptible to van-comycin (MIC of ≤2 µg/mL) irrespective of methodology. MICs were ≥1.0 µg/mL for 9.5% of BMD, 50.0% for VITEK ® 2, and 27.7% for E-test. Spearman's r showed weak correlations between methods: 0.29 E-test vs VITEK ® 2 (P=0.003), 0.27 E-test vs BMD (P=0.001), and 0.31 VITEK ® 2 vs BMD (P=0.002). The optimal cutoff points for detecting BMD-defined less susceptible strains were ≥1.0 µg/mL for E-test and VITEK ® 2. E-test sensitivity at this cutoff point was 0.85 and specificity 0.29, while VITEK ® 2 sensitivity and specificity were 0.62 and 0.51, respectively. Multiresistant MRSA strains tended to have higher MIC values compared to nonmultiresistant MRSA or epidemic MRSA 15 phenotypes by E-test (Fisher's exact P<0.001) and VITEK ® 2 (Fisher's exact P<0.001). Conclusion: Overall diagnostic accuracy and correlations between MIC methods used in routine diagnostic laboratories and the gold standard BMD showed limited overall agreement. This study helps optimize guidance on the effective use of vancomycin.
Adherence and rehospitalizations in patients with schizophrenia: evidence from Japanese claims data

Background The aim of this study is to analyze if there is a relationship between adherence to antipsychotic medication and rehospitalization for patients diagnosed with schizophrenia in Japan. Methods Based on Japanese claims data, we constructed three patient groups based on their medication possession ratio (MPR). Controlling for potential confounders, a Cox proportional hazard model was employed to assess if medication adherence affects the risk of rehospitalization. Results Patients with good adherence (MPRs from 0.8–1.1) had the lowest rates of admission. Both poor adherence (MPRs <0.8) and overadherence (MPRs >1.1) were associated with a significant higher risk of rehospitalization with hazard ratios of 4.7 and 2.0, respectively. Conclusion The results of this study support the notion that good adherence to antipsychotic medication reduces the risk of rehospitalization of schizophrenia patients. Appropriate measures should be taken to improve adherence of schizophrenia patients.
Evaluation on Potential Contributions of Protease Activated Receptors Related Mediators in Allergic Inflammation

Protease activated receptors (PARs) have been recognized as a distinctive four-member family of seven transmembrane G protein-coupled receptors (GPCRs) that can be cleaved by certain serine proteases. In recent years, there has been considerable interest in the role of PARs in allergic inflammation, the fundamental pathologic changes of allergy, but the potential roles of PARs in allergy remain obscure. Since many of these proteases are produced and actively involved in the pathologic process of inflammation including exudation of plasma components, inflammatory cell infiltration, and tissue damage and repair, PARs appear to make important contribution to allergy. The aim of the present review is to summarize the expression of PARs in inflammatory and structural cells, the influence of agonists or antagonists of PARs on cell behavior, and the involvement of PARs in allergic disorders, which will help us to better understand the roles of serine proteases and PARs in allergy.
Rate-distortion optimized DCT-domain video transcoder for bit-rate reduction of MPEG videos

In this paper, we propose a rate-distortion optimized video transcoder which converts MPEG videos into a similar form at lower bit-rates. Our transcoder design is characterized by two features: 1) transcoding is performed in the DCT domain and the motion vector information is re-used; and 2) the rate-distortion relationship is optimized in both the frame-level rate allocation and macroblock-level rate control, thus leading to performances even better than the direct encoding and re-encoding methods based on the well-known TM5. In the proposed algorithm, the Lagrangian multiplier plays not only its traditional role in macroblock-level optimization, but also a variable to be optimized in frame-level rate allocation. These two levels of optimization process are highly linked. Experiments show that the R-D optimization is effective in getting better video quality, even the drift errors are ignored. Several speedy schemes were developed to make our transcoder design suitable for real-time video transmission over heterogeneous networks.
Flow-Based Dissection of Network Services

The unprecedented success story of the Internet is largely due to rich and constantly emerging applications such as online social networks, video streaming, etc. To characterize the Internet and its usage, high-level metrics such as traffic volume or topology-related measures have been widely used in the past. However, researchers and network professionals still lack concepts to capture Internet services. Our approach for monitoring applications and services is to be agnostic. Starting at the granularity of flow-level information, we propose a system that can efficiently detect communication end points that offer service to multiple clients. In this technical report, we dive into some details with respect to the data structures and data processing techniques that are needed to achieve our goals.
SIRTOS: A simple real-time operating system

This paper describes the development of a simple, real-time operating system for educational purposes. The system provides soft real-time capabilities to serve real time processes and data and meet deadlines. The main contribution of this paper is a very simple open source operating system that implements different real-time algorithms. The code is kept minimal as the kernel is only 15000 lines long. It supports high definition graphics and easy modification which allows more real-time algorithms to be implemented.
Comparison of Three Electromechanical Oscillation Damping Estimation Methods

This paper describes three data driven methods to monitor electromechanical oscillations in interconnected power system operation. The objective is to compare and contrast the performance of the methods. The accuracy of damping ratio and frequency of oscillations are the measures of the performance of the algorithms. The advantages and disadvantages of various techniques and their limitations to measurement noise have been considered while assessing performance. The target frequency and damping are computed using the Nordic power system simulation model.