Cumulative phylogenetic, sequence and structural analysis of Insulin superfamily proteins provide unique structure-function insights.

The insulin superfamily proteins (ISPs), in particular, insulin, IGFs and relaxin proteins are key modulators of animal physiology. They are known to have evolved from the same ancestral gene and have diverged into proteins with varied sequences and distinct functions, but maintain a similar structural architecture stabilized by highly conserved disulphide bridges. The recent surge of sequence data and the structures of these proteins prompted a need for a comprehensive analysis, which connects the evolution of these sequences (427 sequences) in the light of available functional and structural information including representative complex structures of ISPs with their cognate receptors. This study reveals (a) unusually high sequence conservation of IGFs (>90 % conservation in 184 sequences) and provides a possible structure-based rationale for such high sequence conservation; (b) provides an updated definition of the receptor-binding signature motif of the functionally diverse relaxin family members (c) provides a probable non-canonical C-peptide cleavage site in a few insulin sequences. The high conservation of IGFs appears to represent a classic case of resistance to sequence diversity exerted by physiologically important interactions with multiple partners. We also propose a probable mechanism for C-peptide cleavage in a few distinct insulin sequences and redefine the receptor-binding signature motif of the relaxin family. Lastly, we provide a basis for minimally modified insulin mutants with potential therapeutic application, inspired by concomitant changes observed in other insulin superfamily protein members supported by molecular dynamics simulation.

Erratum: Exploring HMMR as a therapeutic frontier in breast cancer treatment, its interaction with various cell cycle genes, and targeting its overexpression through specific inhibitors.

[This corrects the article DOI: 10.3389/fphar.2024.1361424.].

Verification of surgical factors affecting the efficiency of stone extraction with one-surgeon basketing technique using a f-URSL simulation model.

PURPOSE: Stone extraction is an important treatment option when performing flexible ureteroscopic lithotripsy (f-URSL) for upper urinary stones. We used a f-URSL simulator model to investigate surgical factors affecting the efficacy of stone extraction with the one-surgeon basketing technique. MATERIALS AND METHODS: This simulator-based study involved eight urologists and eight residents. These participants each performed two tasks, with Flexor (Cook Medical) and Navigator (Boston Scientific) ureteral access sheaths, with and without the M-arm (MC Medical) single-use basket holder, and with models representing both left and right kidneys. The two tasks were to touch each renal calix with the ureteroscope, and to extract stones. As outcomes, we recorded the number of times that the ureteroscope became stuck during insertion, the number of times a stone was dropped during removal, the number of times the basket forceps were opened and closed, and the time required to accomplish each task. RESULTS: The ureteroscope became stuck significantly more often when Navigator was used compared with Flexor overall, and for both urologists and residents (all p<0.01). Stones were dropped significantly more often on the ipsilateral side (kidney on the same side as the operator's hand) than on the contralateral side overall (p=0.01), and the basket forceps were opened and closed significantly more often on the ipsilateral side than on the contralateral side both overall and by residents (all p<0.01). CONCLUSIONS: The efficiency of stone extraction during f-URSL with the one-surgeon basketing technique was affected by differences in ureteral access sheath and the kidney side.

A lever hypothesis for Synaptotagmin-1 action in neurotransmitter release.

Neurotransmitter release is triggered in microseconds by Ca2+-binding to the Synaptotagmin-1 C2 domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca2+-sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 C2B domain to SNARE complexes through a 'primary interface' comprising two regions (I and II). The Synaptotagmin-1 Ca2+-binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers or helping bridge the membranes, but SNARE complex binding orients the Ca2+-binding loops away from the fusion site, hindering these putative activities. Molecular dynamics simulations now suggest that Synaptotagmin-1 C2 domains near the site of fusion hinder SNARE action, providing an explanation for this paradox and arguing against previous models of Sytnaptotagmin-1 action. NMR experiments reveal that binding of C2B domain arginines to SNARE acidic residues at region II remains after disruption of region I. These results and fluorescence resonance energy transfer assays, together with previous data, suggest that Ca2+ causes reorientation of the C2B domain on the membrane and dissociation from the SNAREs at region I but not region II. Based on these results and molecular modeling, we propose that Synaptotagmin-1 acts as a lever that pulls the SNARE complex when Ca2+ causes reorientation of the C2B domain, facilitating linker zippering and fast membrane fusion. This hypothesis is supported by the electrophysiological data described in the accompanying paper.

Psychologists' experience of working with people who hear voices and their views on the idea of voice simulation training: A qualitative study.

OBJECTIVES: Research indicates psychologists typically lack subjective understanding of voice hearing. Voice hearing simulation training has potential to improve understanding, empathy and confidence among clinicians, but psychologists have had limited input into its development. This study investigated psychologists' and a psychotherapist's clinical experience of working with people who hear voices and their views and recommendations for voice hearing simulation training. DESIGN: This was a qualitative study. METHODS: Clinical psychologists and one psychotherapist (N = 17) participated in semi-structured interviews. Thematic analysis was used to analyse transcribed data. RESULTS: The Clinical Experience theme comprised of subthemes Barriers to engagement, Diversity of voice hearing experiences, Lack of subjective understanding, Curiosity about voice hearing, Empathy for voice hearers, Using personal experiences to relate to voices, Clinical experience increases knowledge, Importance of supervision and colleague's support, Benefits of experiential training, Limited training in non-psychosis settings and Clinical experience increases confidence. The Views on Voice Hearing Simulation Training theme comprised of subthemes Improves subjective understanding, Concern about distress, Discomfort as a strength of voice hearing simulations, Artificiality of simulation, Increases empathy and Over-estimation of understanding. The Recommendations theme comprised of subthemes Discuss artificiality, Co-production, Promote voice diversity, Support staff and Maximise inclusivity. CONCLUSIONS: Findings indicate that clinical experience improves psychologists' confidence and knowledge, yet participants reported a lack of subjective understanding of voice hearing. Co-produced simulation training between individuals who hear voices and clinicians was anticipated to improve subjective understanding, empathy and therapeutic relationships, which could support a range of staff and improve quality of care delivered.

Enhanced Interfacial Electron Transfer in Photocatalyst-Natural Enzyme Coupled Artificial Photosynthesis System: Tuning Strategies and Molecular Simulations.

Laccase is capable of catalyzing a vast array of reactions, but its low redox potential limits its potential applications. The use of photocatalytic materials offers a solution to this problem by converting absorbed visible light into electrons to facilitate enzyme catalysis. Herein, MIL-53(Fe) and NH2-MIL-53(Fe) serve as both light absorbers and enzyme immobilization carriers, and laccase is employed for solar-driven chemical conversion. Electron spin resonance spectroscopy results confirm that visible light irradiation causes rapid transfer of photogenerated electrons from MOF excitation to T1 Cu(II) of laccase, significantly increasing the degradation rate constant of tetracycline (TC) from 0.0062 to 0.0127 min-1. Conversely, there is only minimal or no electron transfer between MOF and laccase in the physical mixture state. Theoretical calculations demonstrate that the immobilization of laccase's active site and its covalent binding to the metal-organic framework surface augment the coupled system's activity, reducing the active site accessible from 27.8 to 18.1 Å. The constructed photo-enzyme coupled system successfully combines enzyme catalysis' selectivity with photocatalysis's high reactivity, providing a promising solution for solar energy use.

Study on the dynamic response and roadways stability during mining under the disturbance of hard roof break.

Under the condition that the working face was directly covered with hard roof, the abrupt breaking of hard roof release significant amount of energy, thus prone to triggering dynamic disasters such as roadway instability or rockburst. This paper based on the engineering background of the Xieqiao Coal Mine's 11,618 working face, a numerical simulation method was put forward to study the dynamic response of roadway under the disturbance of hard roof breaking and proposed an evaluation index IC for roadway stability. Research indicates that the elastic energy released during the periodic weighting of the hard roof is higher than that released during the first weighting. Under the dynamic disturbance caused by hard roof breaking, the peak stresses of the roadway was slight decreased, accompanied by a significant increase in the range of stress concentration and plastic zone expansion. Roadway deformation patterns are significantly influenced by hard roof breaking, with noticeable increases in deformation on the roof and right side. During the period of hard roof breaking, the possibility of instability of the roadway increase significantly due to the disturbance caused by the dynamic load. The research results reveal the instability mechanism of roadway under the condition of hard roof, and provide a more reliable basis for evaluating the stability of roadway.

Innovative BIM technology application in the construction management of highway.

Within the global architecture, engineering, and construction industry, the use of Building Information Modeling (BIM) technology has significantly expanded. However, given the unique characteristics of road infrastructure, the application of BIM technology is still being explored. This article focuses on the Yuanchen Expressway, exploring innovative applications of BIM technology in comprehensive construction management. The project employs advanced technologies, including BIM, Geographic Information Systems (GIS), and the Internet of Things (IoT), to precisely identify critical nodes and breakthroughs. Supported by a detailed BIM model and a multi-level, diversified digital management platform, the project effectively addresses construction challenges in multiple tunnels, bridges, and complex interchanges, achieving intelligent construction innovation throughout the Yuanchen Expressway with BIM technology. By guiding construction through BIM models, utilizing a BIM+GIS-based management cloud platform system, and employing VR safety briefings, the project effectively reduces the difficulty of communication and coordination in project management, shortens the project measurement cycle, improves on-site work efficiency, and ensures comprehensive control and safety management. This article provides an exemplary case for the application of full-line construction management using BIM technology in the highway sector both in China and globally, offering new perspectives and strategies for highway construction management.

Effects of packetization on communication dynamics in brain networks.

Computational studies in network neuroscience build models of communication dynamics in the connectome that help us understand the structure-function relationships of the brain. In these models, the dynamics of cortical signal transmission in brain networks are approximated with simple propagation strategies such as random walks and shortest path routing. Furthermore, the signal transmission dynamics in brain networks can be associated with the switching architectures of engineered communication systems (e.g., message switching and packet switching). However, it has been unclear how propagation strategies and switching architectures are related in models of brain network communication. Here, we investigate the effects of the difference between packet switching and message switching (i.e., whether signals are packetized or not) on the transmission completion time of propagation strategies when simulating signal propagation in mammalian brain networks. The results show that packetization in the connectome with hubs increases the time of the random walk strategy and does not change that of the shortest path strategy, but decreases that of more plausible strategies for brain networks that balance between communication speed and information requirements. This finding suggests an advantage of packet-switched communication in the connectome and provides new insights into modeling the communication dynamics in brain networks.

Communication dynamics in brain networks have been modeled with various approximations to signaling in the connectome. These approximations differ in their assumptions about propagation strategies (random walks, shortest path routing) and switching architectures (message switching, packet switching); however, their relationships in brain network communication models have been unclear so far. Here, we link them by investigating how the difference between packet and message switching (whether signals are packetized or not) affects the transmission completion time of propagation strategies in communication simulations in the connectome. We find that packetization selectively reduces the time of physiologically plausible strategies for the connectome that balance communication speed and information requirements. This study sheds light on the utility of packet switching for modeling efficient communication in brain networks.

Simulation and experimental study of InN nanoparticles synthesized by ion implantation technology.

CONTEXT: In order to synthesize InN nanoparticles (NPs), we have simulated the co-implantation of indium (In) and nitrogen (N) ions on silicon (Si) and silicon oxide (SiO2) substrates with flat-top profiles. The choice of flat-top profile is to increase the possibility of creating homogeneous zone with well-distributed InN nanoparticles over the entire implanted layer. In this view and to obtain these flat-top profiles, we must do several implantations with different doses and energies optimized by our program. The simulation results performed on a silicon substrate < 111 > , give an average dose of 4.30 × 1016 at./cm2 and the implantation energies were In (10, 46, and 180 keV) and N (13 and 35 keV). But for the SiO2 substrate, the total mean dose is about 5.20 × 1016at./cm2 for each Indium and nitrogen ion. The respective implantation energies were In (23, 63, and 120 keV) and N (12 and 28 keV) in an average depth of approximately 100 nm. The implantations were performed in a 206-nm-thick (SiO2) layer thermally grown on < 100 > silicon. Subsequent thermal treatments (500-900 °C) lead to the formation of nanoparticles precipitates of the compound semiconductor (InN) and to cure the oxide defects during different periods of time. To verify that indium (In) and nitrogen (N) ions were located according to flat curves, we used RBS technical and study the formation (InN) stoichiometric compound several techniques, were used such as X-ray diffraction, UV-visible-IR, and photoluminescence (PL) spectroscopy. METHODS: The simulated profiles have been chosen with the aim that the implanted element not exceeding 5-10 at %maximum concentration for each species. We have elaborated our program to simulate these profiles using data as input values from SRIM2008 code taking into account the sputtering factor. The optimal conditions are determined, which are the expected depth impact energies (Rp), the standard deviation (ΔRp) and the sputtering corrosion factor (Fs). Through these results, a simulation program has been created which allows building flat "distribution" curves for ion implantation for each element (In and N), so that each curve is obtained from three Gaussian functions whose values are carefully chosen in relation to the optimal experimental conditions.

Understanding stratification and turnover dynamics of a tropical lake using extensive field observations and 3D hydrodynamic simulations.

The stratification and turnover dynamics of a tropical lake were evaluated using field observations and 3D hydrodynamic simulations. Located in the Philippines, Sampaloc Lake is a 104-ha and 27-m deep volcanic crater lake with enclosed watershed, which is at risk of the impacts of intensive aquaculture, rapid urbanization and climate change. Temperature, dissolved oxygen (DO) and chlorophyll-a (Chl-a) were measured at seven sampling stations using a multiprobe. Kruskal-Wallis test revealed that the three parameters are not significantly different among stations, indicating that one sampling station can represent the water quality of the whole lake. Schmidt's Stability Index (SSI) and thermocline strength, together with DO and Chl-a gradients decreased from October 2022 (stratified) to January 2023 (turnover). After successfully verifying the 3D numerical model, sensitivity analyses of water temperature to varying weather, together with particle tracking simulations, were implemented to determine the timing of isothermal state, upwelling, partial mixing, and full turnover. Compared to air temperature, variations in wind speed have more pronounced effects on the delay or progression of isothermal conditions in the lake based on SSI, Lake Number and Wedderburn Number. Isothermal conditions do not necessarily coincide with the timing of full turnover, with the latter being delayed by two days than the former, on average. Results revealed that full turnover can occur several weeks earlier with the decrease in AT and increase in WS. This study can advance the understanding of thermal and turnover dynamics of stratified tropical lakes, leading to better management of the water quality of these water bodies.

Development of in-silico drug cardiac toxicity evaluation system with consideration of inter-individual variability.

Safety pharmacology examines the potential for new drugs to have unusual, rare side effects such as torsade de pointes (TdP). Recently, as a part of the Comprehensive in vitro Proarrhythmia Assay (CiPA) project, techniques for predicting the development of drug-induced TdP through computer simulations have been proposed and verified. However, CiPA assessment generally does not consider the effect of cardiac cell inter-individual variability, especially related to metabolic status. The study aimed to explore whether rare proarrhythmic effects may be linked to the inter-individual variability of cardiac cells and whether incorporating this variability into computational models could alter the prediction of drugs' TdP risks. This study evaluated the contribution of two biological characteristics to the proarrhythmic effects. The first was spermine concentration, which varies with metabolic status; the second was L-type calcium permeability that could occur due to mutations. Twenty-eight drugs were examined throughout this study, and qNet was analyzed as an essential feature. Even though there were some discrepancies of TdP risk predictions from the baseline model, we found that considering the inter-individual variability might change the TdP risk of drugs. Several drugs in the high-risk drugs group were predicted to affect as intermediate and low-risk drugs in some individuals and vice versa. Also, most intermediate-risk drugs were expected to act as low-risk drugs. When compared, the effects of inter-individual variability of L-type calcium were more significant than spermine in altering the TdP risk of compounds. These results emphasize the importance of considering inter-individual variability to assess drugs.

An observer tool to enhance learning of medical students during simulation training of cardiopulmonary resuscitation: a randomised controlled trial.

BACKGROUND: Simulation training in cardiopulmonary resuscitation (CPR) is effective but active practice time is limited given the large number of students and the learning effect size remains small. To improve learning during observation, the use of an observer tool (OT) has been advocated. The aim was to assess the value of OT to improve medical students' learning outcomes during CPR simulation training. METHODS: This prospective, randomized study took place during CPR training of medical students. The workshop targeted recognition of unconsciousness, absence of breathing, call for help, cardiac massage and defibrillation. Students practicing in dyads were randomized to use an OT (i.e., a checklist summarizing CPR skills and step-by-step actions) (OT +) or not (OT-) when observing others. At the end of the training, the global performance of the dyad was assessed by an evaluator using the OT checklist (primary outcome). The non-technical skills (NTS), chest compression quality, perceived improvement in knowledge and skills and knowledge score (MCQ) were also recorded. RESULTS: The student dyads were included (OT + : n = 40 and OT-: n = 41). Immediately after training, the global performance was similar between the two groups: OT + : 24 [23-25] and OT-: 23 [21-24] (out of 25), p = 0.052. However, better learning of breathing assessment and cardiac massage performance, as well as a better knowledge score, were found in the OT + group. No significant difference was observed for NTS or perceived improvement in knowledge and skills. Satisfaction was higher in the OT- group. CONCLUSIONS: The use of an OT during CPR simulation did not show any pedagogical benefit on the global performance of medical students. However, a potential benefit was found for several important secondary outcomes. Further studies are needed to confirm these positive results.

Apigenin inhibits proliferation and differentiation of cardiac fibroblasts through AKT/GSK3ß signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge (S. miltiorrhiza) is an important Traditional Chinese herbal Medicine (TCM) used to treat cardio-cerebrovascular diseases. Based on the pharmacodynamic substance of S. miltiorrhiza, the aim of present study was to investigate the underlying mechanism of S. miltiorrhiza against cardiac fibrosis (CF) through a systematic network pharmacology approach, molecular docking and dynamics simulation as well as experimental investigation in vitro. MATERIALS AND METHODS: A systematic pharmacological analysis was conducted using the Traditional Chinese Medicine Pharmacology (TCMSP) database to screen the effective chemical components of S. miltiorrhiza, then the corresponding potential target genes of the compounds were obtained by the Swiss Target Prediction and TCMSP databases. Meanwhile, GeneCards, DisGeNET, OMIM, and TTD disease databases were used to screen CF targets, and a protein-protein interaction (PPI) network of drug-disease targets was constructed on S. miltiorrhiza/CF targets by Search Tool for the Retrieval of Interacting Genes/Proteins (STING) database. After that, the component-disease-target network was constructed by software Cytoscape 3.7. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed for the intersection targets between drug and disease. The relationship between active ingredient of S. miltiorrhiza and disease targets of CF was assessed via molecular docking and molecular dynamics simulation. Subsequently, the underlying mechanism of the hub compound on CF was experimentally investigated in vitro. RESULTS: 206 corresponding targets to effective chemical components from S. miltiorrhiza were determined, and among them, there were 82 targets that overlapped with targets of CF. Further, through PPI analysis, AKT1 and GSK3ß were the hub targets, and which were both enriched in the PI3K/AKT signaling pathway, it was the sub-pathways of the lipid and atherosclerosis pathway. Subsequently, compound-disease-genes-pathways diagram is constructed, apigenin (APi) was a top ingredients and AKT1 (51) and GSK3ß (22) were the hub genes according to the degree value. The results of molecular docking and dynamics simulation showed that APi has strong affinities with AKT and GSK3ß. The results of cell experiments showed that APi inhibited cells viability, proliferation, proteins expression of α-SMA and collagen I/III, phosphorylation of AKT1 and GSK3ß in MCFs induced by TGFß1. CONCLUSION: Through a systematic network pharmacology approach, molecular docking and dynamics simulation, and confirmed by in vitro cell experiments, these results indicated that APi interacts with AKT and GSK3ß to disrupt the phosphorylation of AKT and GSK3ß, thereby inhibiting the proliferation and differentiation of MCFs induced by TGFß1, which providing new insights into the pharmacological mechanism of S. miltiorrhiza in the treatment of CF.

Investigating the role of flight phase and task difficulty on low-time pilot performance, gaze dynamics and subjective situation awareness during simulated flight.

Gaze behaviour has been used as a proxy for information processing capabilities that underlie complex skill performance in real-world domains such as aviation. These processes are highly influenced by task requirements, expertise and can provide insight into situation awareness (SA). Little research has been done to examine the extent to which gaze behaviour, task performance and SA are impacted by various task manipulations within the confines of early-stage skill development. Accordingly, the current study aimed to understand the impact of task difficulty on landing performance, gaze behaviour and SA across different phases of flight. Twenty-four low-time (<300 hours) pilots completed simulated landing scenarios under visual flight rules conditions. Traditional gaze metrics, entropybased metrics, and blink rate provided meaningful insight about the extent to which information processing is modulated by flight phase and task difficulty. The results also suggested that gaze behavior changes compensated for increased task demands and minimized the impact on task performance. Dynamic gaze analyses were shown to be a robust measure of task difficulty and pilot flight hours. Recommendations for the effective implementation of gaze behaviour metrics and their utility in examining information processing changes are discussed.

ENERGY Pro: Spatially explicit agent-based model on achieving positive energy districts.

This article describes the ENERGY Pro agent-based model using the Overview, Design Concept, and Details + Human Decision-making (ODD+D protocol). The model is empirically explicit and aims to investigate the adoption decisions of homeowners in Amsterdam on different energy-efficient retrofitting (EER) measures. Following the ODD+D protocol, this study uncovers the conceptual framework used for model construction, the spatial microsimulation process of expanding the data, and the model implementation details. The article also describes sensitivity analysis, validation results, and how to use and adapt the model. With this article, the authors aim to make the model replicable and accessible to other researchers and inspire them using the combination of social simulation and spatial microsimulation in studying the energy transition.•The agent-based model is described using the ODD+D protocol.•The combination of simulation methods is used for constructing an empirical model.•The model on energy transition can be adapted for other cities.

Cognitive simulation along with neural adaptation explain effects of suggestions: a novel theoretical framework.

Hypnosis is an effective intervention with proven efficacy that is employed in clinical settings and for investigating various cognitive processes. Despite their practical success, no consensus exists regarding the mechanisms underlying well-established hypnotic phenomena. Here, we suggest a new framework called the Simulation-Adaptation Theory of Hypnosis (SATH). SATH expands the predictive coding framework by focusing on (a) redundancy elimination in generative models using intrinsically generated prediction errors, (b) adaptation due to amplified or prolonged neural activity, and (c) using internally generated predictions as a venue for learning new associations. The core of our treatise is that simulating proprioceptive, interoceptive, and exteroceptive signals, along with the top-down attenuation of the precision of sensory prediction errors due to neural adaptation, can explain objective and subjective hypnotic phenomena. Based on these postulations, we offer mechanistic explanations for critical categories of direct verbal suggestions, including (1) direct-ideomotor, (2) challenge-ideomotor, (3) perceptual, and (4) cognitive suggestions. Notably, we argue that besides explaining objective responses, SATH accounts for the subjective effects of suggestions, i.e., the change in the sense of agency and reality. Finally, we discuss individual differences in hypnotizability and how SATH accommodates them. We believe that SATH is exhaustive and parsimonious in its scope, can explain a wide range of hypnotic phenomena without contradiction, and provides a host of testable predictions for future research.

NoC simulation steered by NEST: McAERsim and a Noxim patch.

Introduction: Great knowledge was gained about the computational substrate of the brain, but the way in which components and entities interact to perform information processing still remains a secret. Complex and large-scale network models have been developed to unveil processes at the ensemble level taking place over a large range of timescales. They challenge any kind of simulation platform, so that efficient implementations need to be developed that gain from focusing on a set of relevant models. With increasing network sizes imposed by these models, low latency inter-node communication becomes a critical aspect. This situation is even accentuated, if slow processes like learning should be covered, that require faster than real-time simulation. Methods: Therefore, this article presents two simulation frameworks, in which network-on-chip simulators are interfaced with the neuroscientific development environment NEST. This combination yields network traffic that is directly defined by the relevant neural network models and used to steer the network-on-chip simulations. As one of the outcomes, instructive statistics on network latencies are obtained. Since time stamps of different granularity are used by the simulators, a conversion is required that can be exploited to emulate an intended acceleration factor. Results: By application of the frameworks to scaled versions of the cortical microcircuit model-selected because of its unique properties as well as challenging demands-performance curves, latency, and traffic distributions could be determined. Discussion: The distinct characteristic of the second framework is its tree-based source-address driven multicast support, which, in connection with the torus topology, always led to the best results. Although currently biased by some inherent assumptions of the network-on-chip simulators, the results suit well to those of previous work dealing with node internals and suggesting accelerated simulations to be in reach.

4D-QSAR, ADMET properties, and molecular dynamics simulations for designing N-substituted urea/thioureas as human glutaminyl cyclase inhibitors.

Human glutaminyl cyclase (hQC) inhibitors have great potential to be used as anti- Alzheimer's disease (AD) agents by reducing the toxic pyroform of ß-amyloid in the brains of AD patients. The four-dimensional quantitative structure activity relationship (4D-QSAR) model of N-substituted urea/thioureas was established with satisfying predictive ability and statistical reliability (Q2 = 0.521, R2 = 0.933, R2prep = 0.619). By utilizing the developed 4D-QSAR model, a set of new N-substituted urea/thioureas was designed and evaluated for their Absorption Distribution Metabolism Excretion and Toxicity (ADMET) properties. The results of molecular dynamics (MD) simulations, Principal component analysis (PCA), free energy landscape (FEL), dynamic cross-correlation matrix (DCCM) and molecular mechanics generalized Born Poisson-Boltzmann surface area (MM-PBSA) free energy calculations, revealed that the designed compounds were remained stable in protein binding pocket and compounds b ∼ f (-35.1 to -44.55 kcal/mol) showed higher binding free energy than that of compound 14 (-33.51 kcal/mol). The findings of this work will be a theoretical foundation for further research and experimental validation of urea/thiourea derivatives as hQC inhibitors.

Optimizing selective withdrawal strategies to mitigate hypoxia under water-level reduction in Germany's largest drinking water reservoir.

Water-level reduction frequently occurs in deep reservoirs, but its effect on dissolved oxygen concentration is not well understood. In this study we used a well-established water quality model to illustrate effects of water level dynamics on oxygen concentration in Rappbode Reservoir, Germany. We then systematically elucidated the potential of selective withdrawal to control hypoxia under changing water levels. Our results documented a gradual decrease of hypolimnetic oxygen concentration under decreasing water level, and hypoxia occurred when the initial level was lower than 410 m a.s.l (71 m relative to the reservoir bottom). We also suggested that changes of hypoxic region, under increasing hypolimnetic withdrawal discharge, followed a unimodal trajectory with the maximum hypoxic area projected under the discharge between 3 m3/sec and 4 m3/sec. Besides, our results illustrated the extent of hypoxia was most effectively inhibited if the withdrawal strategy was applied at the end of stratification with the outlet elevation at the deepest part of the reservoir. Moreover, hypoxia can be totally avoided under a hybrid elevation withdrawal strategy using surface withdrawal during early and mid stratification, and deep withdrawal at the end of stratification. We further confirmed the decisive role of thermal structure in the formation of hypoxia under water-level reduction and withdrawal strategies. We believe the conclusions from this study can be applied to many deep waters in the temperate zone, and the results should guide stakeholders to mitigate negative impacts of hypoxia on aquatic ecosystems.