simmer: Discrete-Event Simulation for R

The simmer package brings discrete-event simulation to R. It is designed as a generic yet powerful process-oriented framework. The architecture encloses a robust and fast simulation core written in C++ with automatic monitoring capabilities. It provides a rich and flexible R API (application programming interface) that revolves around the concept of trajectory, a common path in the simulation model for entities of the same type

Dopaminergic and noradrenergic modulation of stress-induced alterations in brain activation associated with goal-directed behaviour

BACKGROUND: Acute stress is thought to reduce goal-directed behaviour, an effect purportedly associated with stress-induced release of catecholamines. In contrast, experimentally increased systemic catecholamine levels have been shown to increase goal-directed behaviour. Whether experimentally increased catecholamine function can modulate stress-induced reductions in goal-directed behaviour and its neural substrates, is currently unknown. AIM: To assess whether and how experimentally induced increases in dopamine and noradrenaline contribute to the acute stress effects on goal-directed behaviour and associated brain activation. METHODS: One hundred participants underwent a stress induction protocol (Maastricht acute stress test; MAST) or a control procedure and received methylphenidate (MPH) (40 mg, oral) or placebo according to a 2 × 2 between-subjects design. In a well-established instrumental learning paradigm, participants learnt stimulus–response–outcome associations, after which rewards were selectively devalued. Participants’ brain activation and associated goal-directed behaviour were assessed in a magnetic resonance imaging scanner at peak cortisol/MPH concentrations. RESULTS: The MAST and MPH increased physiological measures of stress (salivary cortisol and blood pressure), but only MAST increased subjective measures of stress. MPH modulated stress effects on activation of brain areas associated with goal-directed behaviour, including insula, putamen, amygdala, medial prefrontal cortex, frontal pole and orbitofrontal cortex. However, MPH did not modulate the tendency of stress to induce a reduction in goal-directed behaviour. CONCLUSION: Our neuroimaging data suggest that MPH-induced increases in dopamine and noradrenaline reverse stress-induced changes in key brain regions associated with goal-directed behaviour, while behavioural effects were absent. These effects may be relevant for preventing stress-induced maladaptive behaviour like in addiction or binge eating disorder

Unexpected Carbon-Carbon Coupling between Organic Cyanides and an Isopropyl β-Carbon in a Hafnium Ene Diamide Complex

A reaction sequence involving two hydrogen transfers and a C-C coupling on the β-carbon of an isopropyl group leads to formation of a new dianionic tridentate ligand in the reaction of the ene diamide complex Cp*Hf(σ2,π-iPr-DAB)Cl (1; Cp* = η5-C5Me5, iPr-DAB = 1,4-diisopropyl-1,4-diaza-1,3-butadiene) with organic cyanides. The product Cp*Hf [iPrNCH=CHNC(Me)=CHC(tBu)=NH]Cl was structurally characterized (Pbca, a = 13.454 (1) Å, b = 11.470 (1) Å, c = 31.297 (2) Å, 100 K). The reaction sequence is probably initiated by the transfer of the iPr α-H atom to a coordinated cyanide. Such a hydrogen transfer was observed in the reaction of 1 with ketones, producing the ene imine alkoxide complexes Cp*Hf[iPrNCH=CHN=CMe2](OCHR2)Cl, which were identified by NMR spectroscopy

Частотно-регулируемый электропривод вентиляционной установки

Объектом исследования является асинхронный электропривод центробежного вентилятора. Цель работы – исследовать основные характеристики асинхронного электропривода со скалярным управлением. В процессе исследования проводились расчет параметров двигателя, выбор преобразователя частоты, расчет искусственных статических характеристик электропривода со скалярным управлением, исследование и анализ переходных характеристик электропривода при пуске под нагрузкой в заданном диапазоне регулирования скорости.The object of the research is an asynchronous electric drive of a centrifugal fan. The aim of the work is to investigate the main characteristics of an asynchronous electric drive with scalar control. In the course of the study, the engine parameters were calculated, the frequency converter was selected, the artificial static characteristics of the electric drive with scalar control were calculated, the analysis and analysis of the transient characteristics of the electric drive when started under load in a given speed control range

Activity-Induced Fluidization and Arrested Coalescence in Fusion of Cellular Aggregates

At long time scales, tissue spheroids may flow or appear solid depending on their capacity to reorganize their internal structure. Understanding the relationship between intrinsic mechanical properties at the single cell level, and the tissue spheroids dynamics at the long-time scale is key for artificial tissue constructs, which are assembled from multiple tissue spheroids that over time fuse to form coherent structures. The dynamics of this fusion process are frequently analyzed in the framework of liquid theory, wherein the time scale of coalescence of two droplets is governed by its radius, viscosity and surface tension. In this work, we extend this framework to glassy or jammed cell behavior which can be observed in spheroid fusion. Using simulations of an individual-cell based model, we demonstrate how the spheroid fusion process can be steered from liquid to arrested by varying active cell motility and repulsive energy as established by cortical tension. The divergence of visco-elastic relaxation times indicates glassy relaxation near the transition toward arrested coalescence. Finally, we investigate the role of cell growth in spheroid fusion dynamics. We show that the presence of cell division introduces plasticity in the material and thereby increases coalescence during fusion

The N‐terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond

Sorsby fundus dystrophy (SFD) is a macular degeneration caused by mutations in TIMP3, the majority of which introduce a novel cysteine. However, the exact molecular mechanisms underlying SFD remain unknown. We aimed to provide novel insights into the functional consequences of a distinct N-terminal mutation. Haplotype reconstruction in three SFD families revealed that the identified c.113C>G, p.(Ser38Cys) mutation is a founder in Belgian and northern French families with a late-onset SFD phenotype. Functional consequences of the p.(Ser38Cys) mutation were investigated by high-resolution Western blot analysis of wild type and mutant TIMP3 using patient fibroblasts and in vitro generated proteins, and by molecular modeling of TIMP3 and its interaction partners. We could not confirm a previous hypothesis on dimerization of mutant TIMP3 proteins. However, we identified aberrant intramolecular disulfide bonding. Our data provide evidence for disruption of the established Cys36-Cys143 disulfide bond and formation of a novel Cys36-Cys38 bond, possibly associated with increased glycosylation of the protein. In conclusion, we propose a novel pathogenetic mechanism underlying the p.(Ser38Cys) TIMP3 founder mutation involving intramolecular disulfide bonding. These results provide new insights into the pathogenesis of SFD and other retinopathies linked to mutations in TIMP3, such as age-related macular degeneration

Solving microscopic flow problems using Stokes equations in SPH

International audienceStarting from the Smoothed Particle Hydrodynamics method (SPH), we propose an alternative way to solve flow problems at a very low Reynolds number. The method is based on an explicit drop out of the inertial terms in the normal SPH equations, and solves the coupled system to find the velocities of the particles using the conjugate gradient method. The method will be called NSPH which refers to the noninertial character of the equations. Whereas the time-step in standard SPH formulations for low Reynolds numbers is linearly restricted by the inverse of the viscosity and quadratically by the particle resolution, the stability of the NSPH solution benefits from a higher viscosity and is independent of the particle resolution. Since this method allows for a much higher time-step, it solves creeping flow problems with a high resolution and a long timescale up to three orders of magnitude faster than SPH. In this paper, we compare the accuracy and capabilities of the new NSPH method to canonical SPH solutions considering a number of standard problems in fluid dynamics. In addition, we show that NSPH is capable of modeling more complex physical phenomena such as the motion of a red blood cell in plasm

Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

In establishing a genetic diagnosis in heterogeneous neurological disease, clinical characterization and whole exome sequencing (WES) go hand-in-hand. Clinical data are essential, not only to guide WES variant selection and define the clinical severity of a genetic defect but also to identify other patients with defects in the same gene. In an infant patient with sensorineural hearing loss, psychomotor retardation, and epilepsy, WES resulted in identification of a novel homozygous CLPP frameshift mutation (c.21delA). Based on the gene defect and clinical symptoms, the diagnosis Perrault syndrome type 3 (PRLTS3) was established. The patient's brain-MRI revealed specific abnormalities of the subcortical and deep cerebral white matter and the middle blade of the corpus callosum, which was used to identify similar patients in the Amsterdam brain-MRI database, containing over 3000 unclassified leukoencephalopathy cases. In three unrelated patients with similar MRI abnormalities the CLPP gene was sequenced, and in two of them novel missense mutations were identified together with a large deletion that covered part of the CLPP gene on the other allele. The severe neurological and MRI abnormalities in these young patients were due to the drastic impact of the CLPP mutations, correlating with the variation in clinical manifestations among previously reported patients. Our data show that similarity in brain-MRI patterns can be used to identify novel PRLTS3 patients, especially during early disease stages, when only part of the disease manifestations are present. This seems especially applicable to the severely affected cases in which CLPP function is drastically affected and MRI abnormalities are pronounce