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Does a foreign country's prosecution of a family under a law that would be unconstitutional in the United States necessarily provide grounds for a claim of asylum upon arrival in the United States?...

This study aimed to investigate age-related injury incidence, severity, and burden over a 3-year period in U14 to U19 elite male soccer players in a German youth academy.Descriptive epidemiology study.Time-loss injuries of 166 unique players were prospectively documented and injury incidence, severity, and burden were calculated for each age group, body part, and type of injuries.A total of 562 time-loss injuries were recorded. Across all age groups (U14 to U19), injury incidence was 42.2 per squad season (ranging from 30.5 in the U19 to 67.7 in the U15), severity was 11.0 days lost (ranging from 8.0 in the U15 to 17.0 in the U17), and burden was 464.1 days lost per squad season (ranging from 304.9 in the U19 to 756.7 in the U14). The thigh, knee and ankle were the body parts with the highest injury incidence (9.2; 5.9; 5.9), severity (11.0; 16.0; 13.0), and burden (101.6; 94.9; 76.1). Cruciate ligament injuries had both the highest burden (164.4) and severity (137.0), and muscle injuries the highest incidence (11.0) of all types of injuries. U15 had the highest injury incidence (67.7) of all age groups. U14 and U17 had both the highest injury severity (15.0; 17.0) and burden (756.7; 618.8) of all age groups. Age-related patterns were observed for selected types of injuries such as muscle injuries, tendinopathy, bone-stress injury, and fractures.Injury incidence, severity, and burden substantially differed descriptively between age groups and clear age-related patterns for selected types of injuries were evident.

To investigate the influence of geographical origin, age, and sex on toxicologically relevant spontaneous histopathology findings in cynomolgus macaques ( Macaca fascicularis), we performed a comparative analysis of historical control data (HCD) from 13 test sites that included 3351 animals (1645 females and 1706 males) sourced from Mauritius, China, Vietnam, and Cambodia, aged from 2 to 9.5 years, and from 446 toxicology studies evaluated between 2016 and 2021. The most common findings were mononuclear infiltrates in the kidney, liver, brain, and lung, which showed highest incidences in Mauritian macaques, and heart, salivary glands, and gastrointestinal tract (GIT), which showed highest incidences of mononuclear infiltrates in mainland Asian macaques. Developmental and degenerative findings were more common in Mauritian macaques, while lymphoid hyperplasia and lung pigment showed higher incidences in Asian macaques. Various sex and age-related differences were also present. Despite origin-related differences, the similarities in the nature and distribution of background lesions indicate that macaques from all geographical regions are suitable for toxicity testing and show comparable lesion spectrum. However, in a toxicity study, it is strongly recommended to use animals from a single geographical origin and to follow published guidelines when using HCD to evaluate and interpretate commonly diagnosed spontaneous lesions.

Cell fate transitions depend on balanced rewiring of transcription and translation programs to mediate ordered developmental progression. Components of the nonsense-mediated mRNA decay (NMD) pathway have been implicated in regulating embryonic stem cell (ESC) differentiation, but the exact mechanism is unclear. Here we show that NMD controls expression levels of the translation initiation factor Eif4a2 and its premature termination codon-encoding isoform (Eif4a2PTC). NMD deficiency leads to translation of the truncated eIF4A2PTC protein. eIF4A2PTC elicits increased mTORC1 activity and translation rates and causes differentiation delays. This establishes a previously unknown feedback loop between NMD and translation initiation. Furthermore, our results show a clear hierarchy in the severity of target deregulation and differentiation phenotypes between NMD effector KOs (Smg5 KO > Smg6 KO > Smg7 KO), which highlights heterodimer-independent functions for SMG5 and SMG7. Together, our findings expose an intricate link between mRNA homeostasis and mTORC1 activity that must be maintained for normal dynamics of cell state transitions.

Technological advances in the context of digital transformation are the basis for rapid developments in the field of artificial intelligence (AI). Although AI is not a new topic in computer science (CS), recent developments are having an immense impact on everyday life and society. In consequence, everyone needs competencies to be able to adequately and competently analyze, discuss and help shape the impact, opportunities, and limits of artificial intelligence on their personal lives and our society. As a result, an increasing number of CS curricula are being extended to include the topic of AI. However, in order to integrate AI into existing CS curricula, what students can and should learn in the context of AI needs to be clarified. This has proven to be particularly difficult, considering that so far CS education research on central concepts and principles of AI lacks sufficient elaboration. Therefore, in this paper, we present a curriculum of learning objectives that addresses digital literacy and the societal perspective in particular. The learning objectives can be used to comprehensively design curricula, but also allow for analyzing current curricula and teaching materials and provide insights into the central concepts and corresponding competencies of AI., Comment: To be published in the proceedings of the proceedings of World Conference on Computers in Education, WCCE 2022

Written reflective practice is a regular exercise pre-service teachers perform during their higher education. Usually, their lecturers are expected to provide individual feedback, which can be a challenging task to perform on a regular basis. In this paper, we present the first open-source automated feedback tool based on didactic theory and implemented as a hybrid AI system. We describe the components and discuss the advantages and disadvantages of our system compared to the state-of-art generative large language models. The main objective of our work is to enable better learning outcomes for students and to complement the teaching activities of lecturers., Comment: 2 figures

Sequencing of the human genome and numerous advances in molecular techniques have launched the era of genetic medicine. Increasingly precise technologies for genetic modification, manufacturing, and administration of pharmaceutical-grade biologics have proved the viability of in vivo gene therapy (GTx) as a therapeutic modality as shown in several thousand clinical trials and recent approval of several GTx products for treating rare diseases and cancers. In recognition of the rapidly advancing knowledge in this field, the regulatory landscape has evolved considerably to maintain appropriate monitoring of safety concerns associated with this modality. Nonetheless, GTx safety assessment remains complex and is designed on a case-by-case basis that is determined by the disease indication and product attributes. This article describes our current understanding of fundamental biological principles and possible procedures (emphasizing those related to toxicology and toxicologic pathology) needed to support research and development of in vivo GTx products. This article is not intended to provide comprehensive guidance on all GTx modalities but instead provides an overview relevant to in vivo GTx generally by utilizing recombinant adeno-associated virus-based GTx—the most common in vivo GTx platform—to exemplify the main points to be considered in nonclinical research and development of GTx products.

Banken, Versicherungen, Asset Manager und weitere Finanzdienstleister spielen bei der Unterstützung der Transformation zu einer nachhaltigen Wirtschaft eine substantielle Rolle. Dabei werden sie von ökologischen, sozialen und politischen Risikofeldern herausgefordert. Wie Sie Ihr Risikomanagement unter diesen ESG-Kriterien (Environmental, Social, Governance) optimal ausrichten können, beleuchtet das innovative Praxisbuch systematisch – mit Beiträgen führender Finanzdienstleister, Aufsichtsbehörden, Hochschulen, Think Tanks und Beratungsgesellschaften: ein wichtiges, hochaktuelles Schlüsselthema für die gesamte Branche.

Hepatitis A virus (HAV) infects humans and non-human primates causing an acute self-limited illness. Three HAV genotypes have been described for humans and three genotypes have been described for non-human primates. We observed transiently elevated liver enzymes in Mauritius-origin laboratory-housed macaques in Germany and were not able to demonstrate HAV by serology and PCR. Using deep sequencing, we have identified a new HAV genotype with 86% nucleotide sequence homology to HAV genotype IV capsid proteins and approximately 80% nucleotide homology to other HAV genotypes. In situ hybridization indicates persistence in the biliary epithelium up to 3 months after liver enzymes were elevated. Vaccination using a commercial vaccine against human HAV prevented reoccurrence of liver enzyme elevations. Since available assays for HAV did not detect this new variant, knowledge of its existence may ameliorate potential significant epidemiological and research implications in laboratories globally.Article Summary LineA new genotype of hepatitis A virus, that was not identifiable by available diagnostic assays, caused liver enzyme elevations in laboratory-housed Mauritius-origin Cynomolgus macaques.

This article describes the Society of Toxicologic Pathology’s (STP) five recommended (“best”) practices for appropriate use of informed (non-blinded) versus masked (blinded) microscopic evaluation in animal toxicity studies intended for regulatory review. (1) Informed microscopic evaluation is the default approach for animal toxicity studies. (2) Masked microscopic evaluation has merit for confirming preliminary diagnoses for target organs and/or defining thresholds (“no observed adverse effect level” and similar values) identified during an initial informed evaluation, addressing focused hypotheses, or satisfying guidance or requests from regulatory agencies. (3) If used as the approach for an animal toxicity study to investigate a specific research question, masking of the initial microscopic evaluation should be limited to withholding only information about the group (control or test article-treated) and dose equivalents. (4) The decision regarding whether or not to perform a masked microscopic evaluation is best made by a toxicologic pathologist with relevant experience. (5) Pathology peer review, performed to verify the microscopic diagnoses and interpretations by the study pathologist, should use an informed evaluation approach. The STP maintains that implementing these five best practices has and will continue to consistently deliver robust microscopic data with high sensitivity for animal toxicity studies intended for regulatory review. Consequently, when conducting animal toxicity studies, the advantages of informed microscopic evaluation for maximizing sensitivity outweigh the perceived advantages of minimizing bias through masked microscopic examination.

Nonclinical toxicology studies that are required to support human clinical trials of new drug candidates are generally conducted in a rodent and a non-rodent species. These studies typically contain a vehicle control group and low, intermediate, and high dose test article groups. In addition, a dosing-free recovery phase is sometimes included to determine reversibility of potential toxicities observed during the dosing phase and may include additional animals in the vehicle control and one or more dose groups. Typically, reversibility is determined by comparing the test article–related changes in the dosing phase animals to concurrent recovery phase animals at the same dose level. Therefore, for interpretation of reversibility, it is not always essential to euthanize the recovery vehicle control animals. In the absence of recovery vehicle control tissues, the pathologist’s experience, historical control database, digital or glass slide repositories, or literature can be used to interpret the findings in the context of background pathology of the species/strain/age. Therefore, in most studies, the default approach could be not to euthanize recovery vehicle control animals. This article provides opinions on scenarios that may or may not necessitate euthanasia of recovery phase vehicle control animals in nonclinical toxicology studies involving dogs and nonhuman primates.

Supplemental material, sj-docx-2-tpx-10.1177_01926233211041962 for Scientific and Regulatory Policy Committee Points to Consider: Nonclinical Research and Development of In Vivo Gene Therapy Products, Emphasizing Adeno-Associated Virus Vectors by Julie A. Hutt, Basel T. Assaf, Brad Bolon, Joy Cavagnaro, Elizabeth Galbreath, Branka Grubor, Lisa M. Kattenhorn, Annette Romeike and Laurence O. Whiteley in Toxicologic Pathology

Supplemental material, sj-docx-1-tpx-10.1177_01926233211041962 for Scientific and Regulatory Policy Committee Points to Consider: Nonclinical Research and Development of In Vivo Gene Therapy Products, Emphasizing Adeno-Associated Virus Vectors by Julie A. Hutt, Basel T. Assaf, Brad Bolon, Joy Cavagnaro, Elizabeth Galbreath, Branka Grubor, Lisa M. Kattenhorn, Annette Romeike and Laurence O. Whiteley in Toxicologic Pathology

Supplemental material, sj-pdf-1-tpx-10.1177_01926233221096424 for The Influence of Geographical Origin, Age, Sex, and Animal Husbandry on the Spontaneous Histopathology of Laboratory Cynomolgus Macaques (Macaca Fascicularis): A Contemporary Global and Multisite Review of Historical Control Data by Ronnie Chamanza, Stuart W. Naylor, Michela Gregori, Molly Boyle, Marcia E. Pereira Bacares, Elodie Drevon-Gaillot, Annette Romeike, Cynthia Courtney, Kelsey Johnson, Julie Turner, Nadine Swierzawski and Alok K. Sharma in Toxicologic Pathology

Stem cells intrinsically express a subset of genes which are normally associated with interferon stimulation and the innate immune response. However, the expression of these interferon-stimulated genes (ISG) in stem cells is independent from external stimuli such as viral infection. Here, we show that the interferon regulatory factor 1, Irf1, is directly controlled by the murine formative pluripotency gene regulatory network and transiently upregulated during the transition from naive to formative pluripotency. IRF1 binds to regulatory regions of a conserved set of ISGs and is required for their faithful expression upon exit from naive pluripotency. We show that in the absence of IRF1, cells exiting the naive pluripotent stem cell state are more susceptible to viral infection. Irf1 therefore acts as a link between the formative pluripotency network, regulation of innate immunity genes, and defense against viral infections during formative pluripotency.

Toxicologic Pathology is the official journal of the Society of Toxicologic Pathology (STP), the British Society of Toxicological Pathology (BSTP), and the European Society of Toxicologic Pathology (ESTP). Toxicologic Pathology publishes articles related to topics in various aspects of toxicologic pathology such as anatomic pathology, clinical pathology, experimental pathology, and biomarker research. Publications include society-endorsed Best Practice/Position and Points to Consider publications and ESTP Expert Workshop articles that are relevant to toxicologic pathology and scientific regulatory processes, Opinion articles under the banner of the STP Toxicologic Pathology Forum, Original Articles, Review Articles (unsolicited/contributed, mini, and invited), Brief Communications, Letters to the Editor, Meeting Reports, and Book Reviews. This article provides details on the various publication categories in Toxicologic Pathology and will serve as a reference for authors and readers.

Many potential drugs for treatment of neurodegenerative diseases, particularly antisense oligonucleotides (ASOs), are administered via lumbar intrathecal injection, because these drugs do not cross the blood–brain barrier. Intrathecal injection is a well-established method in cynomolgus monkeys, a species that is used in preclinical safety assessment when other nonrodent species cannot be used. The authors completed intrathecal ASO administration in over 30 preclinical safety studies (>1000 animals and >4500 dose administrations) during which we observed 3 cases of procedure-related spinal cord necrosis (incidence

p. 77-94.

Stem cells intrinsically express a subset of genes which are normally associated with interferon stimulation, and thus the innate immunity response. Expression of these interferon stimulated genes (ISG) in stem cells is independent of external stimuli such as viral infection. Here we show that the interferon regulatory factor 1, Irf1, is directly controlled by the murine formative pluripotency gene regulatory network and therefore upregulated in the transition from naive to formative pluripotency. IRF1 in turn binds to regulatory regions of a conserved set of ISGs and is required for their faithful expression in formative pluripotent cells. IRF1 also binds to an enhancer of the formative pluripotency transcription factor Oct6 and is partially required for upregulation of Oct6. IRF1 therefore acts as a link between the formative pluripotency network and the regulation of innate immunity genes in formative pluripotency.

Supplemental Material, sj-docx-2-tpx-10.1177_01926233211041962 for Scientific and Regulatory Policy Committee Points to Consider: Nonclinical Research and Development of In Vivo Gene Therapy Products, Emphasizing Adeno-Associated Virus Vectors by Julie A. Hutt, Basel T. Assaf, Brad Bolon, Joy Cavagnaro, Elizabeth Galbreath, Branka Grubor, Lisa M. Kattenhorn, Annette Romeike and Laurence O. Whiteley in Toxicologic Pathology

Supplemental Material, sj-docx-1-tpx-10.1177_01926233211041962 for Scientific and Regulatory Policy Committee Points to Consider: Nonclinical Research and Development of In Vivo Gene Therapy Products, Emphasizing Adeno-Associated Virus Vectors by Julie A. Hutt, Basel T. Assaf, Brad Bolon, Joy Cavagnaro, Elizabeth Galbreath, Branka Grubor, Lisa M. Kattenhorn, Annette Romeike and Laurence O. Whiteley in Toxicologic Pathology

Being able to use data and AI technologies responsibly is considered increasingly relevant to all school subjects. Despite this trend, existing AI literacy frameworks used to design educational activities often barely cover data literacy. However, AI cannot be appropriately grasped without data literacy, and working with data requires knowledge of AI on multiple levels. To date, though, no framework has been created that considers AI and data literacy holistically. To address this gap, we examine the relationship between AI and data literacy competencies in existing educational frameworks and propose a preliminary approach that utilizes the data lifecycle to reflect on data literacy competencies relevant to AI. The findings provide a basis for developing a comprehensive approach to the education of K-12 teachers of all subjects in AI and data literacy.

Quantum technologies are currently among the most promising technological developments, with quantum computing, in particular, playing a crucial role. This is accompanied by promising opportunities, but also new challenges for our society. However, quantum computing as a subject of computer science education is still at the very beginning. This paper aims to discuss quantum computing as a topic in computer science education and to make a first approach to central terms and ideas as well as their explanatory approaches. With the help of an explorative focus group interview with experts, five core ideas of quantum computer science are identified in this study. A literature review is then used to identify, categorize, and contrast different explanatory approaches for these ideas. The results thus contribute to making quantum computer science accessible for computing education and raise further questions for the computing education research community.

Artificial Intelligence (AI) has found its popularity in many fields of our life, ranging from song recommendation to lung cancer identification. CSE can impart AI knowledge to all people (including teachers) so that they can make an informed decision about AI. Besides, AI technologies can support tailoring the education to the students’ needs or unload teachers by doing routine work for them and leaving more space for creativity. However, despite the growing potential of AI applications in education, some skepticism or even rejection can be observed. It could be especially critical for teacher education: by being a role model for pupils, teachers could multiply their attitude towards AI while transferring it to the pupils. Although AI acceptance is broadly investigated in the marketing context, there is not much prior research on AI acceptance among teachers. Besides, AI acceptance as a term is questionable due to the heterogeneity of the AI field. We highlight the research gap, propose an instrument for the data collection, and introduce the idea of the acceptance spectrum. The proposed concept is exemplified by the case study of acceptance of the AI-supported homework assessment among pre-service teachers.

Single cell biology has the potential to elucidate many critical biological processes and diseases, from development and regeneration to cancer. Single cell analyses are uncovering the molecular diversity of cells, revealing a clearer picture of the variation among and between different cell types. New techniques are beginning to unravel how differences in cell state-transcriptional, epigenetic, and other characteristics-can lead to different cell fates among genetically identical cells, which underlies complex processes such as embryonic development, drug resistance, response to injury, and cellular reprogramming. Single cell technologies also pose significant challenges relating to processing and analyzing vast amounts of data collected. To realize the potential of single cell technologies, new computational approaches are needed. On March 17-19, 2021, experts in single cell biology met virtually for the Keystone eSymposium "Single Cell Biology" to discuss advances both in single cell applications and technologies.

Debugging code is a central skill in learning to program. Nevertheless, debugging poses a major hurdle in the K12 classroom, as students are often rather helpless and rely on the teacher hurrying from one student-PC to the other. Despite this, debugging is an underrepresented topic in the classroom as well as in computer science education research, as only few studies, materials and concepts discuss the explicit teaching of debugging. According to the constructivist learning theory, teaching and developing concepts and materials for the classroom have to take learners’ preexisting experience into account. Students’ preexisting debugging experience is built through troubleshooting, where they frequently find and fix errors in their daily lives – before they learn to program – for example when repairing their bicycle or if “the internet” stops working. Debugging is a special case of general troubleshooting and shares common characteristics, such as the overall process or particular strategies. Thus, the aim of this study is to develop an instrument for assessing preexisting debugging experience in the form of a real-world escape room consisting of debugging-related troubleshooting tasks. This allows us to observe students’ troubleshooting process, strategies, and overall behavior in a natural environment and thus assess preexisting debugging experience. To this end, a design-based research process was conducted and a real-world escape room consisting of various troubleshooting tasks was developed. Those tasks and the escape room setting provide an innovative methodological approach to study students troubleshooting behavior and assess their preexisting debugging experience.

3D printing has been a popular topic in general media in recent years and is increasingly being used by computer science teachers in the classroom. However, while the motivational benefits of 3D printing – especially for novices – are indisputable, the educational value of previous approaches is either rather low or, at the other extreme, a high level of prior knowledge of programming and mathematics is required. For this reason, this paper investigates in an empirical classroom study of an innovative teaching approach to 3D printing as an introduction to programming for novices: Modern 3D printing technology is combined with turtle geometry in Seymour Papert's tradition – transformed into the third dimension. The results show that students are motivated and empowered to create their own artifacts. Remarkably, the personal aesthetics of the objects created are more important to the students than their practical use in everyday life.

Supplemental Material, sj-docx-1-tpx-10.1177_0192623320920590 for Opinion on Current Use of Non-Blinded Versus Blinded Histopathologic Evaluation in Animal Toxicity Studies by Brad Bolon, Jessica M. Caverly Rae, Karyn Colman, Sabine Francke, Karl Jensen, Kevin Keane, Elizabeth F. McInnes, Kyoko Nakano-Ito, Rick Perry, Evelyne Polack, Karen S. Regan, Annette Romeike, Jamie K. Young and Elizabeth J. Galbreath in Toxicologic Pathology

Mithilfe der Sensitivitatsanalyse wird berechnet, wie hoch der Einfluss einer Input-Grose (ein einzelnes Risiko) auf eine Ergebnisgrose (beispielsweise auf das Betriebsergebnis oder den Deckungsbeitrag) ist. Die Sensitivitatsanalyse wird sowohl im Bereich der Physik, der Mathematik und der Betriebswirtschaft angewendet. Es wird eine mogliche Auswirkung an der Zielgrose, dem Erlos oder EBIT eines Unternehmens oder einer anderen aggregierten Grose untersucht, die aufgrund einer Veranderung der Einflussgrose, der Konjunktur, der Rohstoffpreise oder moglicher Ereignisrisiken, verursacht werden kann. Werner Gladen beschreibt in seinem Buch „Performance Management“ (vgl. [1]) die Sensitivitatsanalyse als ein wichtiges Verfahren, mit deren Hilfe Unternehmen die kritischen Werte und Einflussfaktoren einzelner Risiken auf okonomische Zielgrosen analysieren, finden und reihen konnen. Diese Analyse kann als weiterfuhrende Methode der Bow-Tie-Ergebnisse (siehe Abschn. 8.1.1.2) betrachtet werden. Eine Bow-Tie-Analyse liefert eine Reihe moglicher Konsequenzen von Risiken, die Veranderungen an der Zielgrose verursachen konnen. Mit der Sensitivitatsanalyse lassen sich diese Konsequenzen ihrer Auswirkung entsprechend priorisieren und daraus Masnahmen ableiten. Werden alle Konsequenzen ihrer Sensitivitat entsprechend absteigend gereiht, konnen beispielsweise dem Pareto-Prinzip (siehe Abschn. 4.3.2.9) entsprechend jene 20 % der erforderlichen Masnahmen abgeleitet werden, deren Wirksamkeit 80 % der moglichen, unvorteilhaften Abweichungen abmildern konnen.

Warum findet die Zukunft nicht in einer einzelnen Excel-Zelle Platz? Warum werden Risiken immer noch in einer zweidimensionalen und dreifarbigen Matrix mit roten, gelben und grunen Feldern in Form eines Punktes beschrieben, obwohl sich Risiken nicht als ein einzelner Punkt abbilden lassen? Beide Fragen konnen nur aus der Einfachheit, eine einzige Zahl eintragen zu mussen und der Scheu, eine Bandbreite moglicher Auspragungen eines Risikos – beispielsweise mithilfe stochastischer Methoden – zu beschreiben, beantwortet werden. Risiken sind in der Zukunft liegende Unsicherheiten, die sowohl vorteilhafte als auch unvorteilhafte Abweichungen vom Erwarteten mit deren Auftretenswahrscheinlichkeiten oder Haufigkeiten beschrieben werden mussen. Der „Zufall“ im taglichen Leben oder das „Zufallsexperiment“ in der Statistik und Stochastik beschreiben ein nicht vorhersagbares, nicht deterministisches und in der Zukunft liegendes Ereignis. Auch im Risikomanagement fuhrt der Zufall Regie. Erst die Menge vieler vermuteter, vor uns liegender Zufalle, auch als Zufallsexperimente bezeichnet, beschreiben die Zukunft.

Mit dem abschliesenden Kapitel liefern wir Ihnen keinen Kurzlehrgang in die Programmumgebung „R“. Das wurde den Rahmen des Buches absolut sprengen. Und auserdem existieren hierfur bereits exzellente Buch- und Onlinepublikationen. Geben Sie in Ihrem Web-Browser „R for Beginners“ ein und schon werden Sie mit sehr vielen und hilfreichen Beitragen und Hinweisen versorgt, die Ihnen den Einstieg in R erleichtern werden. Dennoch mochten wir Ihnen ein paar Worte uber R selbst, eine kurze Beschreibung fur den Download der Software und der Entwicklungsumgebung R-Studio sowie eine Ubersicht uber die wichtigsten R-Befehle mit auf den Weg geben. Damit sollten erste Hurden im Schreiben eines R-Programmcodes auf kleine und einfach zu bewaltigende Herausforderungen reduziert werden.