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Twenty years after the entry into force of the German Code of Crimes Against International Law, it is time for a critical assessment of its implementation and impact in practice. While a number of trials have been conducted and a certain prosecutorial practice has been established during the last decade, the law and practice nevertheless leave room for some criticism. This article addresses some of the criticism from the perspective of an NGO with experience in several international crimes cases, and deals with substantive and procedural law, as well as the issue of political case selection and the failure to prosecute corporate involvement in crimes under international law. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this investigation is to evaluate the use of a probe‐format graphite calorimeter, Aerrow, as an absolute and relative dosimeter of high‐energy pulse dose rate (UHPDR) electron beams for in‐water reference and depth–dose‐type measurements, respectively. Methods: In this paper, the calorimeter system is used to investigate the potential influence of dose per pulses delivered up to 5.6 Gy, the number of pulses delivered per measurement, and its potential for relative measurement (depth–dose curve measurement). The calorimeter system is directly compared against an Advanced Markus ion chamber. The finite element method was used to calculate heat transfer corrections along the percentage depth dose of a 20‐MeV electron beam. Monte Carlo–calculated dose conversion factors necessary to calculate absorbed dose‐to‐water at a point from the measured dose‐to‐graphite are also presented. Results: The comparison of Aerrow against a fully calibrated Advanced Markus chamber, corrected for the saturation effect, has shown consistent results in terms of dose‐to‐water determination. The measured reference depth is within 0.5 mm from the expected value from Monte Carlo simulation. The relative standard uncertainty estimated for Aerrow was 1.06%, which is larger compared to alanine dosimetry (McEwen et al. https://doi.org/10.1088/0026‐1394/52/2/272) but has the advantage of being a real‐time detector. Conclusion: In this investigation, it was demonstrated that the Aerrow probe–type graphite calorimeter can be used for relative and absolute dosimetries in water in an UHPDR electron beam. To the author's knowledge, this is the first reported use of an absorbed dose calorimeter for an in‐water percentage depth–dose curve measurement. The use of the Aerrow in quasi‐adiabatic mode has greatly simplified the signal readout, compared to isothermal mode, as the resistance was directly measured with a high‐stability digital multimeter. [ABSTRACT FROM AUTHOR]

Fungal species have the capability of producing an overwhelming diversity of bioactive substances that can have beneficial but also detrimental effects on human health. These so-called secondary metabolites naturally serve as antimicrobial "weapon systems", signaling molecules or developmental effectors for fungi and hence are produced only under very specific environmental conditions or stages in their life cycle. However, as these complex conditions are difficult or even impossible to mimic in laboratory settings, only a small fraction of the true chemical diversity of fungi is known so far. This also implies that a large space for potentially new pharmaceuticals remains unexplored. We here present an overview on current developments in advanced methods that can be used to explore this chemical space. We focus on genetic and genomic methods, how to detect genes that harbor the blueprints for the production of these compounds (i.e., biosynthetic gene clusters, BGCs), and ways to activate these silent chromosomal regions. We provide an in-depth view of the chromatin-level regulation of BGCs and of the potential to use the CRISPR/Cas technology as an activation tool. [ABSTRACT FROM AUTHOR]

Identifying drug–target interactions is a crucial step in discovering novel drugs and for drug repositioning. Network-based methods have shown great potential thanks to the straightforward integration of information from different sources and the possibility of extracting novel information from the graph topology. However, despite recent advances, there is still an urgent need for efficient and robust prediction methods. Here, we present SimSpread, a novel method that combines network-based inference with chemical similarity. This method employs a tripartite drug–drug–target network constructed from protein–ligand interaction annotations and drug–drug chemical similarity on which a resource-spreading algorithm predicts potential biological targets for both known or failed drugs and novel compounds. We describe small molecules as vectors of similarity indices to other compounds, thereby providing a flexible means to explore diverse molecular representations. We show that our proposed method achieves high prediction performance through multiple cross-validation and time-split validation procedures over a series of datasets. In addition, we demonstrate that our method performed a balanced exploration of both chemical ligand space (scaffold hopping) and biological target space (target hopping). Our results suggest robust and balanced performance, and our method may be useful for predicting drug targets, virtual screening, and drug repositioning. [ABSTRACT FROM AUTHOR]

Purpose: A diamond detector prototype was recently proposed by Marinelli et al. (Medical Physics 2022, https://doi.org/10.1002/mp.15473) for applications in ultrahigh‐dose‐per‐pulse (UH‐DPP) and ultrahigh‐dose‐rate (UH‐DR) beams, as used in FLASH radiotherapy (FLASH‐RT). In the present study, such so‐called flashDiamond (fD) was investigated from the dosimetric point of view, under pulsed electron beam irradiation. It was then used for the commissioning of an ElectronFlash linac (SIT S.p.A., Italy) both in conventional and UH‐DPP modalities. Methods: Detector calibration was performed in reference conditions, under 60Co and electron beam irradiation. Its response linearity was investigated in UH‐DPP conditions. For this purpose, the DPP was varied in the 1.2–11.9 Gy range, by changing either the beam applicator or the pulse duration from 1 to 4 μs. Dosimetric validation of the fD detector prototype was then performed in conventional modality, by measuring percentage depth dose (PDD) curves, beam profiles, and output factors (OFs). All such measurements were carried out in a motorized water phantom. The obtained results were compared with the ones from commercially available dosimeters, namely, a microDiamond, an Advanced Markus ionization chamber, a silicon diode detector, and EBT‐XD GAFchromic films. Finally, the fD detector was used to fully characterize the 7 and 9 MeV UH‐DPP electron beams delivered by the ElectronFlash linac. In particular, PDDs, beam profiles, and OFs were measured, for both energies and all the applicators, and compared with the ones from EBT‐XD films irradiated in the same experimental conditions. Results: The fD calibration coefficient resulted to be independent from the investigated beam qualities. The detector response was found to be linear in the whole investigated DPP range. A very good agreement was observed among PDDs, beam profiles, and OFs measured by the fD prototype and reference detectors, both in conventional and UH‐DPP irradiation modalities. Conclusions: The fD detector prototype was validated from the dosimetric point of view against several commercial dosimeters in conventional beams. It was proved to be suitable in UH‐DPP and UH‐DR conditions, for which no other commercial real‐time active detector is available to date. It was shown to be a very useful tool to perform fast and reproducible beam characterizations in standard clinical motorized water phantom setups. All of the previously mentioned demonstrate the suitability of the proposed detector for the commissioning of UH‐DR linac beams for preclinical FLASH‐RT applications. [ABSTRACT FROM AUTHOR]

Background: Conventional air ionization chambers (ICs) exhibit ion recombination correction factors that deviate substantially from unity when irradiated with dose per pulse magnitudes higher than those used in conventional radiotherapy. This fact makes these devices unsuitable for the dosimetric characterization of beams in ultra‐high dose per pulse as used for FLASH radiotherapy. Purpose: We present the design, development, and characterization of an ultra‐thin parallel plate IC that can be used in ultra‐high dose rate (UHDR) deliveries with minimal recombination. Methods: The charge collection efficiency (CCE) of parallel plate ICs was modeled through a numerical solution of the coupled differential equations governing the transport of charged carriers produced by ionizing radiation. It was used to find out the optimal parameters for the purpose of designing an IC capable of exhibiting a linear response with dose (deviation less than 1%) up to 10 Gy per pulse at 4 μ$\umu$s pulse duration. As a proof of concept, two vented parallel plate IC prototypes have been built and tested in different ultra‐high pulse dose rate electron beams. Results: It has been found that by reducing the distance between electrodes to a value of 0.25 mm it is possible to extend the dose rate operating range of parallel plate ICs to ultra‐high dose per pulse range, at standard voltage of clinical grade electrometers, well into several Gy per pulse. The two IC prototypes exhibit behavior as predicted by the numerical simulation. One of the so‐called ultra‐thin parallel plate ionization chamber (UTIC) prototypes was able to measure up to 10 Gy per pulse, 4 μ$\umu$s pulse duration, operated at 300 V with no significant deviation from linearity within the uncertainties (ElectronFlash Linac, SIT). The other prototype was tested up to 5.4 Gy per pulse, 2.5 μ$\umu$s pulse duration, operated at 250 V with CCE higher than 98.6% (Metrological Electron Accelerator Facility, MELAF at Physikalisch‐Technische Bundesanstalt, PTB). Conclusions: This work demonstrates the ability to extend the dose rate operating range of ICs to ultra‐high dose per pulse range by reducing the spacing between electrodes. The results show that UTICs are suitable for measurement in UHDR electron beams. [ABSTRACT FROM AUTHOR]

Purpose: The ion collection efficiency of vented ionization chambers has been investigated in an ultra‐high dose‐per‐pulse (DPP) electron beam. The role of the chamber design and the electric field strength in the sensitive air volume have been evaluated. Methods: An advanced Markus chamber and three specially designed parallel plate air‐filled ionization chambers (EWC: End Window Chamber) with varying electrode distance of 0.5, 1, and 2 mm have been investigated. Their ion collection efficiencies were determined experimentally using two methods: extrapolation of Jaffé plots and comparison against a DPP‐independent reference detector. The latter was achieved by calibrating a current transformer against alanine dosimeters. All measurements were performed in a 24 MeV electron beam with DPP values between 0.01 and 3 Gy. Additionally, the numerical approach introduced by Gotz et al. was implemented taking into account space charge effects at these ultra‐high DPPs. The method has been extended to obtain time‐resolved and position‐dependent electric field distortions within the air cavity. Results: The ion collection efficiency of the investigated ionization chambers drops significantly in the ultra‐high DPP range. The extent of this drop is dependent on the electrode distance, the applied chamber voltage and thus the field strength in the sensitive air volume. For the Advanced Markus chamber, a good agreement between the experimental, numerical and the results of Petersson et al. could be shown. Using the three EWCs with different electrode spacing, an improvement of the ion collection efficiency and a reduction of the polarity effect with decreasing electrode distance could be demonstrated. Furthermore, the results revealed that the determination of the ion collection efficiency from the Jaffé plots and therefore also from two‐voltage method typically underestimate the ion collection efficiency in the region of high dose‐per‐pulse (3 to 130 mGy) and overestimate the ion collection efficiency at ultra‐high dose‐per‐pulse (>1 Gy per pulse). Conclusions: In this work, the ion collection efficiency determined with different methods and ionization chambers have been compared and discussed. As expected, an increase of the electric field in the ionization chamber, either by applying a higher bias voltage or a reduction of the electrode distance, improves the ion collection efficiency and also reduces the polarity effect. For the Advanced Markus chamber, the experimental results obtained by comparison against a reference agree well with the numerical solution. Based on these results, it seems possible to keep the recombination loss less than or equal to 5% up to a dose‐per‐pulse of 3 Gy with an appropriately designed ionization chamber, which corresponds to the level accepted in conventional radiotherapy dosimetry protocols. [ABSTRACT FROM AUTHOR]

Summary Intra- and intermolecular contact surfaces are routinely calculated for a large array of applications in bioinformatics but are typically approximated from differential solvent accessible surface area calculations and not calculated directly. These approximations do not properly take the effects of neighboring atoms into account and tend to deviate considerably from the true contact surface. We implemented an extension of the original Shrake-Rupley algorithm to accurately estimate interatomic contact surface areas of molecular structures and complexes. Our extended algorithm is able to calculate the contact area of an atom to all nearby atoms by directly calculating overlapping surface patches, taking into account the possible shielding effects of neighboring atoms. Here, we present a versatile software tool and web server for the calculation of contact surface areas, as well as buried surface areas and solvent accessible surface areas (SASA) for different types of biomolecules, such as proteins, nucleic acids and small organic molecules. Detailed results are provided in tab-separated values format for analysis and Protein Databank files for visualization. Direct contact surface area calculation resulted in improved accuracy in a benchmark with a non-redundant set of 245 protein–DNA complexes. SASA-based approximations underestimated protein–DNA contact surfaces on average by 40%. This software tool may be useful for surface-based intra- and intermolecular interaction analyses and scoring function development. Availability and implementation A web server, stand-alone binaries for Linux, MacOS and Windows and C++ source code are freely available from http://schuellerlab.org/dr%5fsasa/. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

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Purpose: The aim of this study was to investigate whether a chamber-type-specific radiation quality correction factor kQ can be determined in order to measure the reference air kerma rate of 60Co high-dose-rate (HDR) brachytherapy sources with acceptable uncertainty by means of a well-type ionization chamber calibrated for 192Ir HDR sources. Methods: The calibration coefficients of 35 well-type ionization chambers of two different chamber types for radiation fields of 60Co and 192Ir HDR brachytherapy sources were determined experimentally. A radiation quality correction factor kQ was determined as the ratio of the calibration coefficients for 60Co and 192Ir. The dependence on chamber-to-chamber variations, source-to-source variations, and source strength was investigated. Results: For the PTW Tx33004 (Nucletron source dosimetry system (SDS)) well-type chamber, the type-specific radiation quality correction factor kQ is 1.19. Note that this value is valid for chambers with the serial number, SN ≥ 315 (Nucletron SDS SN ≥ 548) onward only. For the Standard Imaging HDR 1000 Plus well-type chambers, the type-specific correction factor kQ is 1.05. Both kQ values are independent of the source strengths in the complete clinically relevant range. The relative expanded uncertainty (k = 2) of kQ is UkQ = 2.1% for both chamber types. Conclusions: The calibration coefficient of a well-type chamber for radiation fields of 60Co HDR brachytherapy sources can be calculated from a given calibration coefficient for 192 Ir radiation by using a chamber-type-specific radiation quality correction factor kQ. However, the uncertainty of a 60Co calibration coefficient calculated via kQ is at least twice as large as that for a direct calibration with a 60Co source. [ABSTRACT FROM AUTHOR]

Wnt/β-catenin signalling is an important pathway that regulates multiple biological processes, including cell adhesion and determination of cell fate during animal development; in the adult nervous system it regulates the structure and function of synapses. Wnt-signalling dysfunction is associated with several neurodegenerative diseases such as schizophrenia and Alzheimer's disease. The use of natural compounds is an interesting strategy in the search for drugs with the therapeutic potential to activate this signalling pathway. In the present study, we report that andrographolide (ANDRO), a component of Andrographis paniculata, is a potent activator of Wnt signalling. Our results indicate that ANDRO activates this pathway, inducing the transcription of Wnt target genes by a mechanism that bypasses Wnt ligand binding to its receptor. In vitro kinase assays demonstrate that ANDRO inhibits glycogen synthase kinase (GSK)-3β by a non-ATP-competitive, substrate-competitive mode of action. In silico analyses suggest that ANDRO interacts with the substrate-binding site of GSK-3β. Finally, we demonstrated that the increase seen in the levels of GSK-3β phosphorylated at Ser9 is the result of an autoregulatory mechanism of the kinase in vivo, although not through activation of protein phosphatase type 1. Our results suggest that ANDRO could be used as a potential therapeutic drug for disorders caused by Wnt-signalling dysfunction such as neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Eine Prozedur beschreibt allgemein den Verfahrensablauf zur Realisierung eines bestimmten Prozesses. Operativ beschreibt sie den geplanten Steuerungsablauf für eine gegebene Systemumgebung in mehreren Schritten mit entsprechenden Übergangsbedingungen. Die Beschreibung der Prozeduren erfolgt heute typischerweise mit speziell auf die Anwendung zugeschnittenen Sprachen. In diesem Beitrag wird angeregt, ein gemeinsames Metamodell der Prozedurbeschreibung zu entwickeln. Ein solches Metamodell trägt wesentlich zur Standardisierung der Prozedurbeschreibung bei. In dieser Arbeit werden generische Konzepte vorgestellt, auf denen ein Metamodell der Prozedurbeschreibung aufgebaut werden kann. A procedure describes a control sequence that is planned for the realization of a specific process. From an operational perspective, a procedure describes the intended control sequence for a given system environment in multiple steps, which include the respective transition conditions. The description of procedures is nowadays typically realized by using languages that are specially tailored for the given application. In this article, we propose the development of a common meta-model for procedure descriptions. A meta-model of this kind would make a significant contribution to the standardization of procedure descriptions. The meta-model has to take care about certain generic concepts. These concepts are introduced in this work. [ABSTRACT FROM AUTHOR]

In diesem Artikel stellen wir ein Ebenenmodell vor, mit dem Prozesse in Unternehmen strukturiert werden können. Die Trennung zwischen Prozeduren, ausführenden Einheiten und Prozessen ist in der Automatisierungstechnik ein verbreitetes Mittel. Dieses Konzept wird auf Geschäftsprozesse übertragen. Die Modellstruktur führt zu einer stärkeren Verzahnung zwischen Geschäftsprozessen und technischen Prozessen, wie sie im Rahmen der Industrie 4.0-Initiative gefordert wird. Throughout this paper, we will introduce a layer model that is used to structure the processes in companies. The separation of processes, procedures, and execution units is common in automation technology. We are trying to transfer this idea onto business processes. This leads to a greater interlocking of business processes and technical processes. [ABSTRACT FROM AUTHOR]

Currently, about 20 crystal structures per day are released and deposited in the Protein Data Bank. A significant fraction of these structures is produced by research groups associated with the structural genomics consortium. The biological function of many of these proteins is generally unknown or not validated by experiment. Therefore, a growing need for functional prediction of protein structures has emerged. Here we present an integrated bioinformatics method that combines sequence-based relationships and three-dimensional (3D) structural similarity of transcriptional regulators with computer prediction of their cognate DNA binding sequences. We applied this method to the AraC/XylS family of transcription factors, which is a large family of transcriptional regulators found in many bacteria controlling the expression of genes involved in diverse biological functions. Three putative new members of this family with known 3D structure but unknown function were identified for which a probable functional classification is provided. Our bioinformatics analyses suggest that they could be involved in plant cell wall degradation (Lin2118 protein from Listeria innocua, PDB code 3oou), symbiotic nitrogen fixation (protein from Chromobacterium violaceum, PDB code 3oio), and either metabolism of plant-derived biomass or nitrogen fixation (protein from Rhodopseudomonas palustris, PDB code 3mn2). [ABSTRACT FROM AUTHOR]

The Fundamental Standards of Humanity were developed in the 1980s to ensure the protection of individuals in situations where international humanitarian law was not applicable, but derogation of human rights was still possible. To date, there is no binding document that has been adopted that is applicable in situations of internal disturbances and tensions. This article examines whether such a binding document is necessary at all, because developments in international law, especially international criminal law, international humanitarian law, as well as human rights law could have narrowed or closed this gap. Therein, a few provisions are scrutinised as to their applicability in all circumstances. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusion FLASH radiotherapy is an emerging treatment modality using ultra‐high dose rate beams. Much effort has been made to develop suitable dosimeters for reference dosimetry, yet the spatial beam characteristics must also be characterized to enable computerized treatment planning, as well as quality control and service of a treatment delivery device. In conventional radiation therapy, this is commonly achieved by beam profile scans in a water phantom using a point detector. In ultra‐high dose rate beams, the delivered dose needed for a set of beam profile scans may exceed the regulatory dose limit specified for a typical treatment room, or degrade components of the scanning system and scanning detector. Point detector scans also cannot quantify the pulse‐to‐pulse stability of a beam profile. Detector arrays can overcome these challenges, but to date, no detector arrays suitable for ultra‐high dose rate beams are commercially available.The study presents the development and characterization of a two‐dimensional detector array for measuring pulse‐resolved spatial fluence distributions in real‐time and temporal structure of intra‐pulse dose rate of ultra‐high pulsed dose rate (UHPDR) electron beams used in FLASH radiotherapy.The performance of the SunPoint 1 diode was evaluated by measuring the response of the EDGE Detector in a 20 MeV UHPDR electron beam with a dose per pulse of 0.04 Gy – 6 Gy at a pulse duration of 1 µs or 1.9 µs, and instantaneous dose rates of 0.040 – 3.2 MGy·s−1. Based on the findings regarding a suitable signal acquisition technique, a PROFILER 2 detector array made of SunPoint 1 diodes was then modified by minimizing trace resistance, applying a reverse bias, and implementing an RC component to each diode to optimize the transfer of the collected charge during a pulse. The resultant “FLASH Profiler” was then tested in the same UHPDR electron beam.The FLASH Profiler exhibited a linear response within ± 3% deviation over the investigated dose per pulse range. The FLASH Profiler array showed good agreement with the absolute dose measured using a flashDiamond point detector and an integrating current transformer for dose‐per‐pulse values of up to 6 Gy. The FLASH Profiler was able to measure lateral beam profiles in real‐time and on a single‐pulse basis. The ability to capture and display the profiles during steering of UHPDR beams was demonstrated. The SunPoint 1 diode was able to measure the pulse duration and the intra‐pulse dose rate with a time resolution of 4 ns.The FLASH Profiler could be used for characterizing UHPDR electron beams and facilitating quality control and beam steering service of electron FLASH irradiators. [ABSTRACT FROM AUTHOR]

Pinostilbene is a monomethyl ether analog of the well-known nutraceutical resveratrol. Both compounds have health-promoting properties, but the latter undergoes rapid metabolization and has low bioavailability. O-methylation improves the stability and bioavailability of resveratrol. In plants, these reactions are performed by O-methyltransferases (OMTs). Few efficient OMTs that monomethylate resveratrol to yield pinostilbene have been described so far. Here, we report the engineering of a resveratrol OMT from Vitis vinifera (VvROMT), which has the highest catalytic efficiency in di-methylating resveratrol to yield pterostilbene. In the absence of a crystal structure, we constructed a three-dimensional protein model of VvROMT and identified four critical binding site residues by applying different in silico approaches. We performed point mutations in these positions generating W20A, F24A, F311A, and F318A variants, which greatly reduced resveratrol's enzymatic conversion. Then, we rationally designed eight variants through comparison of the binding site residues with other stilbene OMTs. We successfully modified the native substrate selectivity of VvROMT. Variant L117F/F311W showed the highest conversion to pinostilbene, and variant L117F presented an overall increase in enzymatic activity. Our results suggest that VvROMT has potential for the tailor-made production of stilbenes. [ABSTRACT FROM AUTHOR]