Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (BIT1–9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required

The human in the loop Perspectives and challenges for RoboCup 2050

Robotics researchers have been focusing on developing autonomous and human-like intelligent robots that are able to plan, navigate, manipulate objects, and interact with humans in both static and dynamic environments. These capabilities, however, are usually developed for direct interactions with people in controlled environments, and evaluated primarily in terms of human safety. Consequently, human-robot interaction (HRI) in scenarios with no intervention of technical personnel is under-explored. However, in the future, robots will be deployed in unstructured and unsupervised environments where they will be expected to work unsupervised on tasks which require direct interaction with humans and may not necessarily be collaborative. Developing such robots requires comparing the effectiveness and efficiency of similar design approaches and techniques. Yet, issues regarding the reproducibility of results, comparing different approaches between research groups, and creating challenging milestones to measure performance and development over time make this difficult. Here we discuss the international robotics competition called RoboCup as a benchmark for the progress and open challenges in AI and robotics development. The long term goal of RoboCup is developing a robot soccer team that can win against the world’s best human soccer team by 2050. We selected RoboCup because it requires robots to be able to play with and against humans in unstructured environments, such as uneven fields and natural lighting conditions, and it challenges the known accepted dynamics in HRI. Considering the current state of robotics technology, RoboCup’s goal opens up several open research questions to be addressed by roboticists. In this paper, we (a) summarise the current challenges in robotics by using RoboCup development as an evaluation metric, (b) discuss the state-of-the-art approaches to these challenges and how they currently apply to RoboCup, and (c) present a path for future development in the given areas to meet RoboCup’s goal of having robots play soccer against and with humans by 2050.</p

The human in the loop Perspectives and challenges for RoboCup 2050

© 2024 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Robotics researchers have been focusing on developing autonomous and human-like intelligent robots that are able to plan, navigate, manipulate objects, and interact with humans in both static and dynamic environments. These capabilities, however, are usually developed for direct interactions with people in controlled environments, and evaluated primarily in terms of human safety. Consequently, human-robot interaction (HRI) in scenarios with no intervention of technical personnel is under-explored. However, in the future, robots will be deployed in unstructured and unsupervised environments where they will be expected to work unsupervised on tasks which require direct interaction with humans and may not necessarily be collaborative. Developing such robots requires comparing the effectiveness and efficiency of similar design approaches and techniques. Yet, issues regarding the reproducibility of results, comparing different approaches between research groups, and creating challenging milestones to measure performance and development over time make this difficult. Here we discuss the international robotics competition called RoboCup as a benchmark for the progress and open challenges in AI and robotics development. The long term goal of RoboCup is developing a robot soccer team that can win against the world’s best human soccer team by 2050. We selected RoboCup because it requires robots to be able to play with and against humans in unstructured environments, such as uneven fields and natural lighting conditions, and it challenges the known accepted dynamics in HRI. Considering the current state of robotics technology, RoboCup’s goal opens up several open research questions to be addressed by roboticists. In this paper, we (a) summarise the current challenges in robotics by using RoboCup development as an evaluation metric, (b) discuss the state-of-the-art approaches to these challenges and how they currently apply to RoboCup, and (c) present a path for future development in the given areas to meet RoboCup’s goal of having robots play soccer against and with humans by 2050.Peer reviewe

Ep-CAM expression in squamous cell carcinoma of the esophagus: a potential therapeutic target and prognostic marker

BACKGROUND: To evaluate the expression and test the clinical significance of the epithelial cellular adhesion molecule (Ep-CAM) in esophageal squamous cell carcinoma (SCC) to check the suitability of esophageal SCC patients for Ep-CAM directed targeted therapies. METHODS: The Ep-CAM expression was immunohistochemically investigated in 70 primary esophageal SCCs using the monoclonal antibody Ber-EP4. For the interpretation of the staining results, we used a standardized scoring system ranging from 0 to 3+. The survival analysis was calculated from 53 patients without distant metastasis, with R0 resection and at least 2 months of clinical follow-up. RESULTS: Ep-CAM neo-expression was observed in 79% of the tumors with three expression levels, 1+ (26%), 2+ (11%) and 3+ (41%). Heterogeneous expression was observed at all expression levels. Interestingly, tumors with 3+ Ep-CAM expression conferred a significantly decreased median relapse-free survival period (log rank, p = 0.0001) and median overall survival (log rank, p = 0.0003). Multivariate survival analysis disclosed Ep-CAM 3+ expression as independent prognostic factor. CONCLUSION: Our results suggest Ep-CAM as an attractive molecule for targeted therapy in esophageal SCC. Considering the discontenting results of the current adjuvant concepts for esophageal SCC patients, Ep-CAM might provide a promising target for an adjuvant immunotherapeutic intervention

Single-Spin Addressing in an Atomic Mott Insulator

Ultracold atoms in optical lattices are a versatile tool to investigate fundamental properties of quantum many body systems. In particular, the high degree of control of experimental parameters has allowed the study of many interesting phenomena such as quantum phase transitions and quantum spin dynamics. Here we demonstrate how such control can be extended down to the most fundamental level of a single spin at a specific site of an optical lattice. Using a tightly focussed laser beam together with a microwave field, we were able to flip the spin of individual atoms in a Mott insulator with sub-diffraction-limited resolution, well below the lattice spacing. The Mott insulator provided us with a large two-dimensional array of perfectly arranged atoms, in which we created arbitrary spin patterns by sequentially addressing selected lattice sites after freezing out the atom distribution. We directly monitored the tunnelling quantum dynamics of single atoms in the lattice prepared along a single line and observed that our addressing scheme leaves the atoms in the motional ground state. Our results open the path to a wide range of novel applications from quantum dynamics of spin impurities, entropy transport, implementation of novel cooling schemes, and engineering of quantum many-body phases to quantum information processing.Comment: 8 pages, 5 figure

Global fine-resolution data on springtail abundance and community structure

Springtails (Collembola) inhabit soils from the Arctic to the Antarctic and comprise an estimated ~32% of all terrestrial arthropods on Earth. Here, we present a global, spatially-explicit database on springtail communities that includes 249,912 occurrences from 44,999 samples and 2,990 sites. These data are mainly raw sample-level records at the species level collected predominantly from private archives of the authors that were quality-controlled and taxonomically-standardised. Despite covering all continents, most of the sample-level data come from the European continent (82.5% of all samples) and represent four habitats: woodlands (57.4%), grasslands (14.0%), agrosystems (13.7%) and scrublands (9.0%). We included sampling by soil layers, and across seasons and years, representing temporal and spatial within-site variation in springtail communities. We also provided data use and sharing guidelines and R code to facilitate the use of the database by other researchers. This data paper describes a static version of the database at the publication date, but the database will be further expanded to include underrepresented regions and linked with trait data.</p

Globally invariant metabolism but density-diversity mismatch in springtails.

Soil life supports the functioning and biodiversity of terrestrial ecosystems. Springtails (Collembola) are among the most abundant soil arthropods regulating soil fertility and flow of energy through above- and belowground food webs. However, the global distribution of springtail diversity and density, and how these relate to energy fluxes remains unknown. Here, using a global dataset representing 2470 sites, we estimate the total soil springtail biomass at 27.5 megatons carbon, which is threefold higher than wild terrestrial vertebrates, and record peak densities up to 2 million individuals per square meter in the tundra. Despite a 20-fold biomass difference between the tundra and the tropics, springtail energy use (community metabolism) remains similar across the latitudinal gradient, owing to the changes in temperature with latitude. Neither springtail density nor community metabolism is predicted by local species richness, which is high in the tropics, but comparably high in some temperate forests and even tundra. Changes in springtail activity may emerge from latitudinal gradients in temperature, predation and resource limitation in soil communities. Contrasting relationships of biomass, diversity and activity of springtail communities with temperature suggest that climate warming will alter fundamental soil biodiversity metrics in different directions, potentially restructuring terrestrial food webs and affecting soil functioning

Global fine-resolution data on springtail abundance and community structure

CODE AVAILABILITY : Programming R code is openly available together with the database from Figshare.SUPPLEMENTARY MATERIAL 1 : Template for data collectionSUPPLEMENTARY MATERIAL 2 : Data Descriptor WorksheetSpringtails (Collembola) inhabit soils from the Arctic to the Antarctic and comprise an estimated ~32% of all terrestrial arthropods on Earth. Here, we present a global, spatially-explicit database on springtail communities that includes 249,912 occurrences from 44,999 samples and 2,990 sites. These data are mainly raw sample-level records at the species level collected predominantly from private archives of the authors that were quality-controlled and taxonomically-standardised. Despite covering all continents, most of the sample-level data come from the European continent (82.5% of all samples) and represent four habitats: woodlands (57.4%), grasslands (14.0%), agrosystems (13.7%) and scrublands (9.0%). We included sampling by soil layers, and across seasons and years, representing temporal and spatial within-site variation in springtail communities. We also provided data use and sharing guidelines and R code to facilitate the use of the database by other researchers. This data paper describes a static version of the database at the publication date, but the database will be further expanded to include underrepresented regions and linked with trait data.Open Access funding enabled and organized by Projekt DEAL.http://www.nature.com/sdatahj2024Plant Production and Soil ScienceSDG-15:Life on lan

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012

OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients

Vocational Schools in the Federal Republic of Germany (FRG) 1949-2001

The study ‘Vocational Schools and universities in the Federal Republic of Germany (FRG) 1949-2001’ consists of two parts: I: vocational schools; II: universities. In Gesis´s online database HISTAT the data is available in two separated data sets, one for vocational schools and one for universities. The study was published as volume VIII of the data handbook on German educational history, a collaborative research project supported by the Deutsche Forschungsgesellschaft (DFG) which documents German educational statistics of the last 200 years. The data handbook starts with a part in text form on the history of institutions and the functions of these institutions. In the text part there are also nine appendices explaining the methodological procedure. The other part of the study contains data. 535 tables based on this data are available on HISTAT. A selection of tables and numerous graphs illustrate the text part. The data handbook can be used by those who work with the data set from HISTAT and who want further information on previous decisions made on the construction of the data set. The table of contents of the hand book and the register of tables are available here as PDF files. The data tables on vocational schools mainly refer to the pupils of different school types as defined in the sources. Regarding the basic classification of school types we did some standardization and slightly summarized the classifications from the original source. Data tables in HISTAT (topic: education): Vocational schools by school type 1. Vocational schools (incl. vocational special schools) 2. Berufsgrundbildungsjahr (basic vocational training year) 3. Berufsvorbereitungsjahr (occupation preparation year) 4. Vocational colleges 5. Technical colleges and academies 6. Schools in the health care sector 7. Vocational further school 8. Vocational grammar schools 8.1 Specialized secondary schools 8.2 Specialized grammar schools 8.3 Colleges 8.4 Higher vocational schools, technical secondary schoolsDie Studie ´Berufliche Schulen und Hochschulen in der Bundesrepublik Deutschland 1949-2001´ besteht aus zwei Teilen, I: Berufliche Schulen; II: Hochschulen. Die Publikation der Studie als Buch integriert beide Teile. In der GESIS-ZA Online-Datenbank HISTAT sind die Daten, auf denen die Studie beruht, aus technischen Gründen in zwei getrennten Datensätzen zugänglich, für “Berufliche Schulen” oder für “Hochschulen”. Die Studie ist erschienen als Bd. VIII des Datenhandbuchs zur deutschen Bildungsgeschichte, eines arbeitsteiligen, von der DFG seit etwa 20 Jahren geförderten großen Forschungsunternehmens, mit dem die deutsche Bildungsstatistik der letzten 200 Jahre in langen Zeitreihen dokumentiert wird. Das Datenhandbuch ´Berufliche Schulen und Hochschulen in der Bundesrepublik Deutschland 1949-2001´ enthält erstens einen Text-Teil mit Kapiteln zur Institutionengeschichte sowie zur Nutzung dieser Institutionen im Spiegel der Statistik. Ferner finden sich im Text-Teil neun Anhänge, die Rechenschaft ablegen über das methodische Vorgehen (siehe: Anmerkungen). Zweitens enthält die Buchpublikation einen Daten-Teil. Aus dem Datensatz, der hier über HISTAT zur Verfügung steht, sind insgesamt 535 Tabellen konstruiert worden. Sie sind als pdf-Dateien sowie im Excel-Format auf einer CD-ROM gespeichert, die dem Buch beiliegt. Eine Auswahl von Tabellen sowie zahlreiche Grafiken illustrieren den Text-Teil. Das Datenhandbuch stellt in seiner gedruckten Form den “Schlüssel” dar, den konsultieren sollte, wer den Datensatz über HISTAT nutzt und wissen will, welche Entscheidungen in die Konstruktion von Zeitreihen eingegangen sind. Das Inhaltsverzeichnis des Buches ist hier als pdf-Datei zugänglich, ebenso das Tabellenverzeichnis. Die Datentabellen zu den beruflichen Schulen beziehen sich zum größten Teil auf Schüler an den zahlreichen Schularten, wie sie die Quellen unterscheiden. Für diese grundlegende Zuordnung haben wir eine gewisse Vereinheitlichung und leichte Zusammenfassung gegenüber den Quellen vorgenommen. Themen Datentabellen im Downloadsystem HISTAT (Thema: Bildung): Berufliche Schulen nach Schularten 1. Berufsschulen (incl. Berufssonderschulen) 2. Berufsgrundbildungsjahr 3. Berufsvorbereitungsjahr 4. Berufsfachschulen 5. Fachschulen/Fachakademien 6. Schulen des Gesundheitswesens 7. Berufsaufbauschulen 8. Berufliche Oberschulen [Sammelkategorie, kein Quellenbegriff] 8.1 Fachoberschulen 8.2 Fachgymnasien 8.3 Kollegschulen 8.4 Berufsoberschulen/Technische Oberschulen Unter ´Links´ in dieser Studienbeschreibung kann HISTAT aufgerufen werden