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In the era of constantly increasing amounts of the available protein data, a relevant and interpretable visualization becomes crucial, especially for tasks requiring human expertise. Poincaré disk projection has previously demonstrated its important efficiency for visualization of biological data such as single-cell RNAseq data. Here, we develop a new method PoincaréMSA for visual representation of complex relationships between protein sequences based on Poincaré maps embedding. We demonstrate its efficiency and potential for visualization of protein family topology as well as evolutionary and functional annotation of uncharacterized sequences. PoincaréMSA is implemented in open source Python code with available interactive Google Colab notebooks as described at https://www.dsimb.inserm.fr/POINCARE_MSA.

Статья посвящена описанию конспекта-занятия педагога-психолога ДОУ с элементами тренинга для старших дошкольников. Авторы приводят свой опыт работы со старшими дошкольниками по познавательному развитию.

В статье рассматривается опыты «семейной лаборатории» как формы развития познавательно-исследовательской деятельности старших дошкольников. Авторы статьи подробно описывают план родительских собраний и выявляют их значение в воспитании ребенка.

В статье рассмотрена тема образовательной среды в дошкольном образовательном учреждении. Основное внимание уделено компонентам образовательной среды, ведущая роль в формировании которой принадлежит участникам образовательного процесса: педагогам, детям, родителям.

В статье рассматриваются основы духовно-нравственного воспитания, которое является одной из важнейших задач в становлении подрастающего поколения. Авторами статьи раскрываются основополагающие принципы дошкольного воспитания, а также изложены направления духовно-нравственного воспитания детей.

В статье рассматриваются формы развития творческих способностей детей дошкольного возраста. Авторами отмечена интеграция игровой и изобразительной деятельности.

В статье рассматривается опыты «семейной лаборатории», как формы развития познавательно-исследовательской деятельности старших дошкольников.

The photon beam lines and instruments at the European XFEL (EuXFEL) are operated using the Karabo* control system that has been developed in house since 2011. Monitoring and incident analysis requires quick access to historic values of control data. While Karabo���s original custom-built text-file-based data logging system suits well for small systems, a time series data base offers in general a faster data access, as well as advanced data filtering, aggregation and reduction options. EuXFEL has chosen InfluxDB** as backend that is operated since summer 2020. Historic data can be displayed as before via the Karabo GUI or now also via the powerful Grafana*** web interface. The latter is e.g. used heavily in the new Data Operation Center of the EuXFEL. This contribution describes the InfluxDB setup, its transparent integration into Karabo and the experiences gained since it is in operation., Proceedings of the 18th International Conference on Accelerator and Large Experimental Physics Control Systems, ICALEPCS2021, Shanghai, China

В статье обсуждается такое игровое пособие как «волшебные счетные палочки». Поднимается вопрос об их функции, задачи и практическом применении с детьми в ДОУ.

В данной работе авторами были рассмотрены различные здоровьесберегающие технологии в образовательно-воспитательном процессе МДОУ.

Статья рассматривает проблематику использования здоровье сберегающих технологий в образовательной деятельности ДОУ.

Nature methods 2020(17), 73–78 (2019). doi:10.1038/s41592-019-0628-z, The European XFEL (EuXFEL) is a 3.4-km long X-ray source, which produces femtosecond, ultrabrilliant and spatially coherent X-ray pulses at megahertz (MHz) repetition rates. This X-ray source has been designed to enable the observation of ultrafast processes with near-atomic spatial resolution. Time-resolved crystallographic investigations on biological macromolecules belong to an important class of experiments that explore fundamental and functional structural displacements in these molecules. Due to the unusual MHz X-ray pulse structure at the EuXFEL, these experiments are challenging. Here, we demonstrate how a biological reaction can be followed on ultrafast timescales at the EuXFEL. We investigate the picosecond time range in the photocycle of photoactive yellow protein (PYP) with MHz X-ray pulse rates. We show that difference electron density maps of excellent quality can be obtained. The results connect the previously explored femtosecond PYP dynamics to timescales accessible at synchrotrons. This opens the door to a wide range of time-resolved studies at the EuXFEL., Published by Nature Publishing Group, London [u.a.]

The most common ureagenesis defect is X-linked ornithine transcarbamylase (OTC) deficiency which is a main target for novel therapeutic interventions. The spf ash mouse model carries a variant (c.386G>A, p.Arg129His) that is also found in patients. Male spf ash mice have a mild biochemical phenotype with low OTC activity (5%-10% of wild-type), resulting in elevated urinary orotic acid but no hyperammonemia. We recently established a dried blood spot method for in vivo quantification of ureagenesis by Gas chromatography-mass spectrometry (GC-MS) using stable isotopes. Here, we applied this assay to wild-type and spf ash mice to assess ureagenesis at different ages. Unexpectedly, we found an age-dependency with a higher capacity for ammonia detoxification in young mice after weaning. A parallel pattern was observed for carbamoylphosphate synthetase 1 and OTC enzyme expression and activities, which may act as pacemaker of this ammonia detoxification pathway. Moreover, high ureagenesis in younger mice was accompanied by elevated periportal expression of hepatic glutamine synthetase, another main enzyme required for ammonia detoxification. These observations led us to perform a more extensive analysis of the spf ash mouse in comparison to the wild-type, including characterization of the corresponding metabolites, enzyme activities in the liver and plasma and the gut microbiota. In conclusion, the comprehensive enzymatic and metabolic analysis of ureagenesis performed in the presented depth was only possible in animals. Our findings suggest such analyses being essential when using the mouse as a model and revealed age-dependent activity of ammonia detoxification.

Recent advances in multiplexed single-cell transcriptomics experiments are facilitating the high-throughput study of drug and genetic perturbations. However, an exhaustive exploration of the combinatorial perturbation space is experimentally unfeasible, so computational methods are needed to predict, interpret, and prioritize perturbations. Here, we present the compositional perturbation autoencoder (CPA), which combines the interpretability of linear models with the flexibility of deep-learning approaches for single-cell response modeling. CPA encodes and learns transcriptional drug responses across different cell type, dose, and drug combinations. The model produces easy-to-interpret embeddings for drugs and cell types, which enables drug similarity analysis and predictions for unseen dosage and drug combinations. We show that CPA accurately models single-cell perturbations across compounds, doses, species, and time. We further demonstrate that CPA predicts combinatorial genetic interactions of several types, implying that it captures features that distinguish different interaction programs. Finally, we demonstrate that CPA can generate in-silico 5,329 missing genetic combination perturbations (97.6% of all possibilities) with diverse genetic interactions. We envision our model will facilitate efficient experimental design and hypothesis generation by enabling in-silico response prediction at the single-cell level, and thus accelerate therapeutic applications using single-cell technologies.

В статье поднимаются вопросы формирования навыков безопасного поведения на дороге у дошкольников с применением интерактивных форм взаимодействия. Обосновывается необходимость развития знаний и навыков о поведении дошкольников на дороге. Авторы статьи делятся анализом результатов мониторинга включения интерактивных форм взаимодействия с детьми.

In this study, we follow the diffusion and buildup of occupancy of the substrate ceftriaxone inM. tuberculosisβ-lactamase BlaC microcrystals by structural analysis of the enzyme substrate complex at single millisecond time resolution. We also show the binding and the reaction of an inhibitor, sulbactam, on a slower millisecond time scale. We use the ‘mix-and-inject’ technique to initiate these reactions by diffusion, and determine the resulting structures by serial crystallography using ultrafast, intense X-ray pulses from the European XFEL (EuXFEL) arriving at MHz repetition rates. Here, we show how to use the EuXFEL pulse structure to dramatically increase the size of the data set and thereby the quality and time resolution of “molecular movies” which unravel ligand binding and enzymatically catalyzed reactions. This shows the great potential for the EuXFEL as a tool for biomedically relevant research, particularly, as shown here, for investigating bacterial antibiotic resistance.One Sentence SummaryDirect observation of fast ligand binding in a biomedically relevant enzyme at near atomic resolution with MHz X-ray pulses at the European XFEL.

The need to understand cell developmental processes spawned a plethora of computational methods for discovering hierarchies from scRNAseq data. However, existing techniques are based on Euclidean geometry, a suboptimal choice for modeling complex cell trajectories with multiple branches. To overcome this fundamental representation issue we propose Poincaré maps, a method that harness the power of hyperbolic geometry into the realm of single-cell data analysis. Often understood as a continuous extension of trees, hyperbolic geometry enables the embedding of complex hierarchical data in only two dimensions while preserving the pairwise distances between points in the hierarchy. This enables the use of our embeddings in a wide variety of downstream data analysis tasks, such as visualization, clustering, lineage detection and pseudotime inference. When compared to existing methods — unable to address all these important tasks using a single embedding — Poincaré maps produce state-of-the-art two-dimensional representations of cell trajectories on multiple scRNAseq datasets., The discovery of hierarchies in biological processes is central to developmental biology. Here the authors propose Poincaré maps, a method based on hyperbolic geometry to discover continuous hierarchies from pairwise similarities.

To achieve a tight integration of instrument control and (online) data analysis, the European XFEL decided in 2011 to develop Karabo*, a custom control and data processing system. Karabo provides control via event-driven communication. Signal/slot and request/reply patterns are implemented via a central message broker. Data pipelines for e.g. scientific workflows or detector calibration are implemented as direct TCP/IP connections. The core entities of Karabo are self-describing devices written in C++ or Python. They represent hardware, orchestrate other devices, or provide system services like data logging and configuration storage. To operate Karabo, a Python command line interface and a generic GUI written in PyQt are provided. Control and data widgets compose Karabo scenes that are provided by devices or are manually customized and stored together with device configurations in a central database. Since 2016, Karabo is used to commission and operate the currently three photon beam lines and six scientific instruments at the European XFEL. This contribution summarizes the status of Karabo, highlights achievements and lessons learned, and gives an outlook for future directions., Proceedings of the 17th International Conference on Accelerator and Large Experimental Physics Control Systems, ICALEPCS2019, New York, NY, USA

The XrayFeed device of Karabo [1, 2] is designed to provide spatial X-ray beam stability in terms of drift compensation utilizing different diagnostic components at the European XFEL (EuXFEL). Our feedback systems proved to be indispensable in cutting-edge pump-probe experiments at EuXFEL. The feedback mechanism is based on a closed loop PID control algorithm [3] to steer the beam position measured by a so-called diagnostic devices to the desired centered position via defined actuator adjusting the alignment of X-ray optical elements, in our case a flat X-ray mirror system. Several diagnostic devices and actuators can be selected according to the specific experimental area where a beam position feedback is needed. In this contribution, we analyze the improvement of pointing stability of X-rays using different diagnostic devices as an input source for our feedback system. Different types of photon diagnostic devices such as gas-based X-ray monitors [4], quadrant detectors based on avalanche photo diodes [5] and optical cameras imaging the X-ray footprint on scintillator screens have been evaluated in our pointing stability studies., Proceedings of the 17th International Conference on Accelerator and Large Experimental Physics Control Systems, ICALEPCS2019, New York, NY, USA

Agile Project Management (Agile PM), coupled with the DevOps concept, has been worked out as a fundamental approach in a highly uncertain and unpredictable environment to achieve mature software development and to efficiently support concurrent operation*. At the European XFEL**, Agile PM and DevOps have been applied to provide adaptability and efficiency in the development and operation of its control system: Karabo***. In this context, the Control and Analysis Software Group (CAS) has developed in-house a management platform composed of the following macro-artefacts: (1) Agile Process; (2) Release Planning; (3) Testing Infrastructure; (4) Roll-out and Deployment Strategy; (5) Automated tools for Monitoring Control Points (i.e. Configuration Items****) and; (6) Incident Management*****. The software engineering management platform is also integrated with User Relationship Management to establish and maintain a proper feedback loop with our scientists who set up the requirements. This article aims to briefly describe the above points and show how agile project management has guided the software strategy, development and operation of the Karabo control system at the European XFEL., Proceedings of the 17th International Conference on Accelerator and Large Experimental Physics Control Systems, ICALEPCS2019, New York, NY, USA

Jupyter notebooks are executable documents that are displayed in a web browser. The notebook elements consist of human-authored contextual elements and computer code, and computer-generated output from executing the computer code. Such outputs can include tables and plots. The notebook elements can be executed interactively, and the whole notebook can be saved, re-loaded and re-executed, or converted to read-only formats such as HTML, LaTeX and PDF. Exploiting these characteristics, Jupyter notebooks can be used to improve the effectiveness of computational and data exploration, documentation, communication, reproducibility and re-usability of scientific research results. They also serve as building blocks of remote data access and analysis as is required for facilities hosting large data sets and initiatives such as the European Open Science Cloud (EOSC). In this contribution we report from our experience of using Jupyter notebooks for data analysis at research facilities, and outline opportunities and future plans., Proceedings of the 17th International Conference on Accelerator and Large Experimental Physics Control Systems, ICALEPCS2019, New York, NY, USA

Journal of synchrotron radiation 26(5), 1448 - 1461 (2019). doi:10.1107/S1600577519006696, The Karabo distributed control system has been developed to address the challenging requirements of the European X-ray Free Electron Laser facility, including complex and custom-made hardware, high data rates and volumes, and close integration of data analysis for distributed processing and rapid feedback. Karabo is a pluggable, distributed application management system forming a supervisory control and data acquisition environment as part of a distributed control system. Karabo provides integrated control of hardware, monitoring, data acquisition and data analysis on distributed hardware, allowing rapid control feedback based on complex algorithms. Services exist for access control, data logging, configuration management and situational awareness through alarm indicators. The flexible framework enables quick response to the changing requirements in control and analysis, and provides an efficient environment for development, and a single interface to make all changes immediately available to operators and experimentalists., Published by Wiley-Blackwell, [S.l.]

The most common ureagenesis defect is X-linked ornithine transcarbamylase (OTC) deficiency which is a main target for novel therapeutic interventions. The spf ash mouse model carries a variant (c.386G>A, p.Arg129His) that is also found in patients. Male spf ash mice have a mild biochemical phenotype with low OTC activity (5%-10% of wild-type), resulting in elevated urinary orotic acid but no hyperammonemia. We recently established a dried blood spot method for in vivo quantification of ureagenesis by Gas chromatography-mass spectrometry (GC-MS) using stable isotopes. Here, we applied this assay to wild-type and spf ash mice to assess ureagenesis at different ages. Unexpectedly, we found an age-dependency with a higher capacity for ammonia detoxification in young mice after weaning. A parallel pattern was observed for carbamoylphosphate synthetase 1 and OTC enzyme expression and activities, which may act as pacemaker of this ammonia detoxification pathway. Moreover, high ureagenesis in younger mice was accompanied by elevated periportal expression of hepatic glutamine synthetase, another main enzyme required for ammonia detoxification. These observations led us to perform a more extensive analysis of the spf ash mouse in comparison to the wild-type, including characterization of the corresponding metabolites, enzyme activities in the liver and plasma and the gut microbiota. In conclusion, the comprehensive enzymatic and metabolic analysis of ureagenesis performed in the presented depth was only possible in animals. Our findings suggest such analyses being essential when using the mouse as a model and revealed age-dependent activity of ammonia detoxification.

The most common ureagenesis defect is X-linked ornithine transcarbamylase (OTC) deficiency which is a main target for novel therapeutic interventions. The spf

Causal discovery algorithms infer causal relations from data based on several assumptions, including notably the absence of measurement error. However, this assumption is most likely violated in practical applications, which may result in erroneous, irreproducible results. In this work we show how to obtain an upper bound for the variance of random measurement error from the covariance matrix of measured variables and how to use this upper bound as a correction for constraint-based causal discovery. We demonstrate a practical application of our approach on both simulated data and real-world protein signaling data.

Cyber security aspects are often not thoroughly addressed in the design of light source SCADA system. In general the focus remains on building a reliable and fully-functional ecosystem. The underlying assumption is that a SCADA infrastructure is a closed ecosystem of sufficiently complex technologies to provide some security through trust and obscurity. However, considering the number of internal users, engineers, visiting scientists, students going in and out light source facilities cyber security threats can no longer be minored. At the European XFEL, we envision a comprehensive security layer for the entire SCADA infrastructure. There, Karabo [1], the control, data acquisition and analysis software shall implement these security paradigms known in IT but not applicable off-the-shelf to the FEL context. The challenges are considerable: (i) securing access to photon science hardware that has not been designed with security in mind; (ii) granting limited fine-grained permissions to external users; (iii) truly securing Control and Data acquisition APIs while preserving performance. Only tailored solution strategies, as presented in this paper, can fulfill these requirements., Proceedings of the 16th Int. Conf. on Accelerator and Large Experimental Control Systems, ICALEPCS2017, Barcelona, Spain

We describe the data analysis structure that is integrated into the Karabo framework [1] to support scientific experiments and data analysis at European XFEL GmbH. The photon science experiments have a range of data analysis requirements, including online (i.e. near real-time during the actual measurement) and offline data analysis. The Karabo data analysis framework supports execution of automatic data analysis for routine tasks, supports complex experiment protocols including data analysis feedback integration to instrument control, and supports integration of external applications. The online data analysis is carried out using distributed and accelerator hardware (such as GPUs) where required to balance load and achieve near real-time data analysis throughput. Analysis routines provided by Karabo are implemented in C++ and Python, and make use of established scientific libraries. The XFEL control and analysis software team collaborates with users to integrate experiment specific analysis codes, protocols and requirements into this framework, and to make it available for the experiments and subsequent offline data analysis., Proceedings of the 16th Int. Conf. on Accelerator and Large Experimental Control Systems, ICALEPCS2017, Barcelona, Spain