Miracle-dz/UniFAR-FTUs huggingface dataset:
Activity-enhancing mutations in an E3 ubiquitin ligase identified by high-throughput mutagenesis

Significance Ubiquitin is a 76 residue protein that is attached to target proteins as a posttranslational modification. This modification is dependent on the successive activity of three enzymes, designated E1, E2, and E3. We developed a high-throughput mutagenesis strategy to probe the mechanism of E3-catalyzed transfer of ubiquitin from the E2 to the target protein. By scoring the effect of nearly 100,000 mutations in an E3, we identified mutations that affect direct and allosteric interactions between the E3 and the E2. These results highlight the general utility of high-throughput mutagenesis in delineating the molecular basis of enzyme activity. Although ubiquitination plays a critical role in virtually all cellular processes, mechanistic details of ubiquitin (Ub) transfer are still being defined. To identify the molecular determinants within E3 ligases that modulate activity, we scored each member of a library of nearly 100,000 protein variants of the murine ubiquitination factor E4B (Ube4b) U-box domain for auto-ubiquitination activity in the presence of the E2 UbcH5c. This assay identified mutations that enhance activity both in vitro and in cellular p53 degradation assays. The activity-enhancing mutations fall into two distinct mechanistic classes: One increases the U-box:E2-binding affinity, and the other allosterically stimulates the formation of catalytically active conformations of the E2∼Ub conjugate. The same mutations enhance E3 activity in the presence of another E2, Ube2w, implying a common allosteric mechanism, and therefore the general applicability of our observations to other E3s. A comparison of the E3 activity with the two different E2s identified an additional variant that exhibits E3:E2 specificity. Our results highlight the general utility of high-throughput mutagenesis in delineating the molecular basis of enzyme activity.
Targeted Disruption of Organic Cation Transporter 3 Attenuates the Pharmacologic Response to Metformin

Metformin, the most widely prescribed antidiabetic drug, requires transporters to enter tissues involved in its pharmacologic action, including liver, kidney, and peripheral tissues. Organic cation transporter 3 (OCT3, SLC22A3), expressed ubiquitously, transports metformin, but its in vivo role in metformin response is not known. Using Oct3 knockout mice, the role of the transporter in metformin pharmacokinetics and pharmacodynamics was determined. After an intravenous dose of metformin, a 2-fold decrease in the apparent volume of distribution and clearance was observed in knockout compared with wild-type mice (P < 0.001), indicating an important role of OCT3 in tissue distribution and elimination of the drug. After oral doses, a significantly lower bioavailability was observed in knockout compared with wild-type mice (0.27 versus 0.58, P < 0.001). Importantly, metformin’s effect on the plasma glucose concentration-time curve was reduced in knockout compared with wild-type mice (12 versus 30% reduction, respectively, P < 0.05) along with its accumulation in skeletal muscle and adipose tissue (P < 0.05). Furthermore, the effect of metformin on phosphorylation of AMP activated protein kinase, and expression of glucose transporter type 4 was absent in the adipose tissue of Oct3−/− mice. Additional analysis revealed that an OCT3 3′ untranslated region variant was associated with reduced activity in luciferase assays and reduced response to metformin in 57 healthy volunteers. These findings suggest that OCT3 plays an important role in the absorption and elimination of metformin and that the transporter is a critical determinant of metformin bioavailability, clearance, and pharmacologic action.
Reflections on the use of Agile practices and associated tools in university settings for an Android project

Agile methods such as Scrum are held to improve the management of software projects. In particular, there is a popular view that such methods, if introduced properly at the university level, could translate into both satisfied and highly skilled future developers. This paper reflects on the perceived effectiveness of implementing recommended Agile software development practices and tools through the use of Scrum for developing an Android app as part of a university semester-long course. The app captures, stores, uploads, retrieves, shares and manages digital receipts, in overcoming the problems associated with misplacement, storing and organization for manual receipts. Evidence in our reflections demonstrates that implementing Agile software development practices and tools for a university project significantly contribute to project success and quality. Our outcomes provide lessons both for the mentoring of students in the use of Agile practices, and for novice developers using Agile methods in real projects.
Utilizing a service-oriented architecture to perform closed-loop diagnostics in network centric support environments

Service-Oriented Architecture (SOA) is one of the latest technology enablers that supports closed-loop diagnostics in Network Centric Support Environments (NCSEs). SOA provides patterns for the architecture, design, implementation, deployment, and management of loosely coupled software services that support the requirements of business processes and software users regardless of the underlying platform or implementation. The focus of this paper will be to examine providing a SOA via Web services. More specifically, this paper will discuss an architecture for developing Web services that perform closed-loop diagnostics in military NCSEs. The military information technology infrastructure is comprised of many diverse systems that together provide to key personnel the processed information necessary to support our war-fighters. When new or upgraded systems are deployed, it is far too costly to rewrite all legacy applications. A more cost effective method is to take a System-of-Systems approach to provide a non-intrusive solution that blends well with existing support processes and leverages existing applications and their data stores. A SOA readily supports implementing a System-of-Systems solution to provide closed-loop diagnostics in NCSEs in which various components reside at multiple levels and within multiple domains. When utilizing a SOA to implement closed-loop diagnostics in NCSEs, there are several key ingredients in developing a suitable architecture. These ingredients include leveraging the architecture defined in the Institute of Electrical and Electronics Engineers (IEEE) STD 1232 -Artificial Intelligence Exchange and Service Tie to All Test Environments (AI-ESTATE) specification, leveraging standard data format specifications such as the IEEE STD P1636.1 Draft Trial-Use Standard for Software Interface for Maintenance Information Collection and Analysis (SIMICA): Exchanging Test Results and Session Information via the Extensible Markup Language (XML) specification, leveraging the XML transaction communication framework, ensuring information assurance compliance, and ensuring 24/7 system availability.
Synchrony-Based Feature Extraction for Robust Automatic Speech Recognition

This letter discusses the application of models of temporal patterns of auditory-nerve firings to enhance robustness of automatic speech recognition systems. Most conventional feature extraction schemes (such as mel-frequency cepstral coefficients and perceptual linear processing coefficients) are based on short-time energy in each frequency band, and the temporal patterns of auditory-nerve activity are discarded. We compare the impact on speech recognition accuracy of several types of feature extraction schemes based on the putative synchrony of auditory-nerve activity, including feature extraction based on a modified version of the generalized synchrony detector proposed by Seneff, and a modified version of the averaged localized synchrony response proposed by Young and Sachs. It was found that the use of features based on auditory-nerve synchrony can indeed improve speech recognition accuracy in the presence of additive noise based on experiments using multiple standard speech databases. Recognition accuracy obtained using the synchrony-based features is further increased if some form of noise removal is applied to the signal before the synchrony measure is estimated. Signal processing for noise removal based on the noise suppression that is a part of PNCC feature extraction is more effective toward this end than conventional spectral subtraction.
Inventario forestal nacional

La superficie poblada con especies arboreas forestales en Espana es de unos 15 millones de hectareas, de las que mas de 13 millones estan sin inventariar. La informacion sobre las existencias maderables y sus crecimientos de esta superficie solo pueden obtenerse en corto plazo mediante la realizacion del inventario forestal nacional. Con el fin de formar un grupo de especialistas y adquirir experiencia propia en este tipo de trabajos, se inventariaron durante los anos 1962 y 1963 las provincias de Segovia y Oviedo. Ahora, merced al Plan de Desarrollo, se podra realizar el inventario en la totalidad de la nacion. La utilizacion de fotografia aerea se estima necesaria, debido a la complejidad de nuestras masas forestales.
The AP2/ERF Transcription Factor DRNL Modulates Gynoecium Development and Affects Its Response to Cytokinin

The gynoecium is the female reproductive system in flowering plants. It is a complex structure formed by different tissues, some that are essential for reproduction and others that facilitate the fertilization process and nurture and protect the developing seeds. The coordinated development of these different tissues during the formation of the gynoecium is important for reproductive success. Both hormones and genetic regulators guide the development of the different tissues. Auxin and cytokinin in particular have been found to play important roles in this process. On the other hand, the AP2/ERF2 transcription factor BOL/DRNL/ESR2/SOB is expressed at very early stages of aerial organ formation and has been proposed to be a marker for organ founder cells. In this work, we found that this gene is also expressed at later stages during gynoecium development, particularly at the lateral regions (the region related to the valves of the ovary). The loss of DRNL function affects gynoecium development. Some of the mutant phenotypes present similarities to those observed in plants treated with exogenous cytokinins, and AHP6 has been previously proposed to be a target of DRNL. Therefore, we explored the response of drnl-2 developing gynoecia to cytokinins, and found that the loss of DRNL function affects the response of the gynoecium to exogenously applied cytokinins in a developmental-stage-dependent manner. In summary, this gene participates during gynoecium development, possibly through the dynamic modulation of cytokinin homeostasis and response.
A comparison of two models of electrodes for ECT simulations

This paper discusses some numerical aspects of the simulation of electroconvulsive therapy (ECT). A realistic finite-element model of the human head is used to discuss two approaches to modeling the electrodes applied to human head skin. The first approach models the electrode by a mixed-boundary condition, while the second one uses additional subdomain imitating electrode-to-skin contact for that purpose [three-dimensional (3-D) model]. An algorithm of grid modification used to add an external subdomain modeling the electrode contact resistance is presented. The authors examine the influence of the electrode model on the convergence speed of the iterative solver. The authors state that the 3-D model is better conditioned, and, thus, it converges faster
Antibody and cytokine responses in a mouse pulmonary model of Shigella flexneri serotype 2a infection

A murine pulmonary model was used to study the mucosal immune response to Shigella flexneri serotype 2a infection. Inoculation of BALB/cJ mice with shigellae via the intranasal route resulted in bacterial invasion of bronchial and alveolar epithelia with concomitant development of acute suppurative bronchiolitis and subsequent development of lethal pneumonia. The pathology of pulmonary lesions resembled the colitis that characterizes shigellosis in humans and primates. Significant protection against a lethal dose of S. flexneri 2a was observed in mice previously infected with two sublethal doses of the homologous strain. Immunity against lethal challenge was associated with decreased bacterial invasion of the mucosal epithelium. Over the course of two sublethal challenges, which constituted primary and secondary immunizations, mice developed pulmonary and serum immunoglobulin G and A antibody recognizing both lipopolysaccharide and invasion plasmid antigens IpaB and IpaC. Immune mice and naive control mice differed in lung lavage cytokine levels following lethal challenge. Immune mice developed significantly elevated levels of pulmonary gamma interferon within 6 h of challenge, while naive control mice developed elevated levels of this cytokine later during the initial 24-h period. Both groups had elevated levels of gamma interferon during the 24- to 48-h period of infection. Both groups also had elevated levels of tumor necrosis factor alpha within 6 h of challenge, but the control mice had significantly higher levels at the 48- and 72-h time points. Elevated levels of interleukin-4 were observed only in immunized mice. This cytokine appeared within 24 h and receded between 48 and 72 h. Fluorescence-activated cell sorter analysis of lung parenchymal cells showed that both groups experienced an initial influx of monocytes, but the proportion of this cell type began to recede in immunized mice after 48 h of infection, while peak levels were maintained in the control animals. These studies suggest that elements of local B lymphocyte activity, as well as Th1 and Th2 lymphocyte activity, may contribute to the survival of immune mice after intranasal challenge with shigellae.
Further Formalization of the Process Algebra CCS in HOL4

In this project, we have extended previous work on the formalization of the process algebra CCS in HOL4. We have added full supports on weak bisimulation equivalence and observation congruence (rooted weak equivalence), with related definitions, theorems and algebraic laws. Some deep lemmas were also formally proved in this project, including Deng Lemma, Hennessy Lemma and several versions of the "Coarsest congruence contained in weak equivalence". For the last theorem, we have proved the full version (without any assumption) based on ordinals.
Thalamic Kv7 channels: pharmacological properties and activity control during noxious signal processing

The existence of functional Kv7 channels in thalamocortical (TC) relay neurons and the effects of the K+‐current termed M‐current (IM) on thalamic signal processing have long been debated. Immunocytochemical evidence suggests their presence in this brain region. Therefore, we aimed to verify their existence, pharmacological properties and function in regulating activity in neurons of the ventrobasal thalamus (VB).
Alteration of hepatocellular antioxidant gene expression pattern and biomarkers of oxidative damage in diazinon-induced acute toxicity in Wistar rat: A time-course mechanistic study

In the present survey, the plasma level of diazinon after acute exposure was measured by HPLC method at a time-course manner. In addition, the impact of diazinon on the expression of the key genes responsible for hepatocellular antioxidative defense, including PON1, GPx and CAT were investigated. The increase in oxidative damages in treated rats was determined by measuring LPO, protein carbonyl content and total antioxidant power in plasma. After administration of 85 mg/kg diazinon in ten groups of male Wistar rats at different time points between 0-24 hours, the activity of AChE enzyme was inhibited to about 77.94 %. Significant increases in carbonyl groups and LPO after 0.75 and 1 hours were also observed while the plasma antioxidant power was significantly decreased. Despite the dramatic reduction of GPX and PON1 gene expression, CAT gene was significantly upregulated in mRNA level by 1.1 fold after 4 hours and 1.5-fold after 24 hours due to diazinon exposure, compared to control group. Furthermore, no significant changes in diazinon plasma levels were found after 4 hours in the treated rats. The limits of detection and quantification were 137.42 and 416.52 ng/mL, respectively. The average percentage recoveries from plasma were between 90.62 % and 95.72 %. In conclusion, acute exposure to diazinon increased oxidative stress markers in a time-dependent manner and the changes were consistent with effects on hepatic antioxidant gene expression pattern. The effect of diazinon even as a non-lethal dose was induced on the gene expression of antioxidant enzymes. The change in antioxidant defense system occurs prior to diazinon plasma peak time. These results provide biochemical and molecular evidence supporting potential acute toxicity of diazinon and is beneficial in the evaluation of acute toxicity of other organophosphorus pesticides as well.
Application of optimal control theory to milling process

A prototype for a supervising controller for machining applications is here proposed. The controller relies on the definition of an optimal control problem that aims at calculating the sequence of controls (feed rate and tool speed) that minimize a multi-objective target function. The target function allows to selectively prioritize terms related to the productivity, energy consumption, tool wear, and surface quality, by individually setting their relative weights (the case of all equal weights represents a balanced optimization.) The implementation of the proposed system on a real machine tool is briefly outlined, and the results of real machining tests are reported and compared to those obtained by typical machining on the same machine tool.
Security requirements modelling for virtualized 5G small cell networks

It is well acknowledged that one of the key enabling factors for the realization of future 5G networks will be the small cell (SC) technology. Furthermore, recent advances in the fields of network functions virtualization (NFV) and software-defined networking (SDN) open up the possibility of deploying advanced services at the network edge. In the context of mobile/cellular networks this is referred to as mobile edge computing (MEC). Within the scope of the EU-funded research project SESAME we perform a comprehensive security modelling of MEC-assisted quality-of-experience (QoE) enhancement of fast moving users in a virtualized SC wireless network, and demonstrate it through a representative scenario toward 5G. Our modelling and analysis is based on a formal security requirements engineering methodology called Secure Tropos which has been extended to support MEC-based SC networks. In the proposed model, critical resources which need protection, and potential security threats are identified. Furthermore, we identify appropriate security constraints and suitable security mechanisms for 5G networks. Thus, we reveal that existing security mechanisms need adaptation to face emerging security threats in 5G networks.
Adaptive indirect model predictive control schemes for boost converters

Boost converters are commonly used as the interface in renewable energy systems. To keep its output voltage at desired values, two adaptive Model Predictive Control (MPC) schemes with uncertainties in resistive load and external input voltage are proposed in this paper. Since the boost converter is characterized as a non-minimum phase system, controllers are not directly aimed at voltage regulation. The first method follows a cascade structure. A PI controller is introduced as the outer loop to generate a current reference, and MPC is designed as the inner loop by solving a finite horizon optimization of current tracking. Meanwhile, an unknown offset free MPC (UOFMPC) is proposed as the other scheme, where an observer is used for constructing an accurate model. Based on this exact model, MPC could realize voltage regulation accurately. Finally, both the proposed controllers are validated by simulation results from Matlab/Simulink.
Novel approaches to automated personality classification: Ideas and their potentials

In this paper, we propose several new research directions regarding the problem of Automated Personality Classification (APC). Firstly, we investigate possible improvements of the existing solutions to the problem of APC, for which we use different combinations of the APC corpora, psychological trait measurements, and learning algorithms. Afterwards, we consider extensions of the APC problem and the related tasks, such as dynamical APC and detecting personality inconsistency in a text. This entire research was performed in the context of social networks and the related datamining mechanisms.
An overview of the pharmacology and clinical efficacy of indapamide sustained release

The relationship between blood pressure (BP) and cardiovascular risk is clearly established; hypertension increases the rate of cardiovascular. High systolic blood pressure (SBP) may be the main parameter involved in cardiovascular morbidity and mortality. The benefit of lowering BP, particularly with diuretics has been proven in many outcome studies. Indapamide, a thiazide‐type diuretic, was available for many years at a dosage of 2.5 mg in an immediate release formulation. A new sustained release (SR) formulation has been developed in order to allow the same antihypertensive efficacy with a better acceptability profile. This paper reviews the pharmacology of indapamide 1.5 mg SR from the bench to the bedside. Indapamide has a dual mechanism of action: diuretic effect at the level of the distal tubule in the kidney and a direct vascular effect, both of which contribute to the antihypertensive efficacy of the drug. The SR formulation contains a hydrophilic matrix, which delivers a smoother pharmacokinetic profile. This avoids unnecessary plasma peak concentrations, which may be associated with side effects. Indapamide SR has now been extensively used in hypertensive patients, including those at increased risk, for example elderly or diabetic patients. It has been shown to decrease BP, particularly SBP, with 24‐h efficacy, allowing a once‐daily dosage. Studies have demonstrated BP lowering to be at least as effective as all major therapeutic classes including the more recent antihypertensive drugs. Beyond BP decrease, indapamide SR has also been shown to protect against hypertensive target‐organ damage in the heart and the kidney and to have a favorable metabolic profile. A broad evidence‐base has accumulated to support the benefit of indapamide 1.5 mg SR in hypertensive patients, alone or as part of combination therapy, as recommended by the majority of guidelines.