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Although the Nile is one of the largest rivers in the world and played a central role in ancient Egyptian life, little is known about its response to climatic change during the Holocene. Here we present a framework for the evolution of the Egyptian Nile, demonstrating how climatic and environmental changes have shaped the landscape of the Egyptian Nile Valley over the past 11,500 years, including the civilization of ancient Egypt (~5,000 to 2,000 years ago). Using data from over 80 sediment cores drilled in a transect spanning the Nile Valley near Luxor, pinned in time by 48 optically stimulated luminescence ages, we reconstruct the dynamics of the Nile River during the Holocene in the vicinity of UNESCO World Heritage sites such as Karnak and Luxor temples. According to our reconstruction, valley incision occurred from the start of the record until approximately 4,000 years ago and then rapidly shifted to massive floodplain aggradation. We argue that this relatively abrupt change in the riverine landscape near Luxor from the Middle to Late Holocene was linked to a shift towards a drier regional hydroclimate around this time. Such a dramatic change in river sediment dynamics could have had local agro-economic consequences.

The present study assesses linguistic and geographic diversity in selected outlets of SLA and multilingualism research. Specifically, we examine over 2,000 articles published in specialized top-tier journals, recording the languages under study and their acquisition order, author affiliations, the country in which the research was conducted, and citations. In the sample, there were 183 unique languages and 174 unique pairings, corresponding to 3 per cent of the world’s 7,000 languages and less than 0.001 per cent of 24.5 million possible language combinations. English was overwhelmingly the most common language, followed by Spanish and Mandarin Chinese. North America and Western Europe were both the main producers of knowledge and the main sites for research on multilingualism in the sample. Crucially, the regions with the highest levels of linguistic diversity and societal multilingualism (typically the Global South) were only marginally represented. The findings also show that studies on English and northern Anglophone settings were likely to elicit more citations than studies on other languages and settings, and that less studied languages were included more frequently in article titles.

Aims: The study investigates the effects of L2 proficiency and L2 exposure on L2-to-L1 cross-language activation (CLA) in L1-dominant bilinguals. In so doing, it tests the predictions made by prominent models of the bilingual lexicon regarding how language experience modulates CLA. Design: The participants (27 L1-dominant L1 English-L2 Afrikaans speakers) completed a visual world eye-tracking task, conducted entirely in English, in which they saw four objects on a screen: a target object, which they were instructed to click on; a competitor object, whose Afrikaans label overlapped phonetically at onset with the English target object label; and two unrelated distractors. Language background data were collected using the Language History Questionnaire 3.0. Analysis: A growth curve analysis was performed to investigate the extent to which the background variables modulated looks to the Afrikaans competitor item versus to the two unrelated distractor items. Findings: Increased L2 exposure was associated with greater CLA, which is consistent with models suggesting that exposure modulates the likelihood and speed with which a linguistic item becomes activated. Moreover, CLA was reduced at higher levels of L2 proficiency, which aligns with accounts of the bilingual lexicon positing that parasitism of the L2 on the L1 is reduced at higher proficiency levels, leading to reduced CLA. Originality: L2 activation during L1 processing and the variables that modulate it are not well documented, particularly among L1 speakers with limited proficiency in and exposure to the L2. Significance: The findings contribute to the evaluation of competing accounts of bilingual lexical organization.

Although the Nile is one of the largest rivers in the world and played a central role in ancient Egyptian life, little is known about its response to climatic change during the Holocene. Here we present a framework for the evolution of the Egyptian Nile, demonstrating how climatic and environmental changes have shaped the landscape of the Egyptian Nile Valley over the past 11,500 years, including the civilization of ancient Egypt (~5,000 to 2,000 years ago). Using data from over 80 sediment cores drilled in a transect spanning the Nile Valley near Luxor, pinned in time by 48 optically stimulated luminescence ages, we reconstruct the dynamics of the Nile River during the Holocene in the vicinity of UNESCO World Heritage sites such as Karnak and Luxor temples. According to our reconstruction, valley incision occurred from the start of the record until approximately 4,000 years ago and then rapidly shifted to massive floodplain aggradation. We argue that this relatively abrupt change in the riverine landscape near Luxor from the Middle to Late Holocene was linked to a shift towards a drier regional hydroclimate around this time. Such a dramatic change in river sediment dynamics could have had local agro-economic consequences.

This document presents a workbook and facilitator's notes designed for use with small groups or with individual students in secondary schools to help them cope with troubling events related to the Gulf War. The material contained in the workbook is designed to help students deal with each of seven stages that the mastery model sees individuals working through in order to minimize the emotional trauma associated with a major crisis: discrimination, coping, restitution, survivor's guilt, reintroduction of structure, insight into relationships between symptoms and trauma, and development/widening of a support system. The facilitator's notes recommend meeting with students over a period of 6 to 8 weeks. The student journal contains the following sections to be completed by the student: (1) About Me; (2) The Military life; (3) Feelings; (4) How I Stay Informed; (5) How I Cope; (6) Helpers; (7) Separations; (8) Problems on the Home Front; (9) More Feelings; and (10) Taking Care of Me. Following the first meeting in which the journal is discussed and the first section completed and discussed, it is suggested that subsequent sessions include a brief meeting followed by time for students to individually complete one section of the journal to be used as the focus of discussion for the rest of the session. Included are 10 separate sections which may be completed individually or in combination and an incomplete letter for students to complete. (NB)

The independence complex $\mathrm{Ind}(G)$ of a graph $G$ is the simplicial complex formed by its independent sets of vertices. We introduce a deformation of the simplicial chain complex of $\mathrm{Ind}(G)$ that gives rise to a spectral sequence which contains on its first page the homology groups of the independence complexes of $G$ and various subgraphs of $G$, obtained by removing independent sets together with their neighborhoods. We show how this can be used to study the homology of $\mathrm{Ind}(G)$. Furthermore, a careful investigation of the sequence's first page exhibits a relation between the cardinality of maximal independent sets in $G$ and the vanishing of certain homology groups of independence complexes of subgraphs of $G$. We show that it holds for all paths and cycles.Mathematics Subject Classifications: 05C69, 55U10

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.

Various mobility applications like advanced driver assistance systems increasingly utilize artificial intelligence (AI) based functionalities. Typically, deep neural networks (DNNs) are used as these provide the best performance on the challenging perception, prediction or planning tasks that occur in real driving environments. However, current regulations like UNECE R 155 or ISO 26262 do not consider AI-related aspects and are only applied to traditional algorithm-based systems. The non-existence of AI-specific standards or norms prevents the practical application and can harm the trust level of users. Hence, it is important to extend existing standardization for security and safety to consider AI-specific challenges and requirements. To take a step towards a suitable regulation we propose 50 technical requirements or best practices that extend existing regulations and address the concrete needs for DNN-based systems. We show the applicability, usefulness and meaningfulness of the proposed requirements by performing an exemplary audit of a DNN-based traffic sign recognition system using three of the proposed requirements., Comment: To appear in Proceedings of the 9th International Conference on Information Systems Security and Privacy

SCOPUS: ed.j, info:eu-repo/semantics/published

Lutz Raphael: Jenseits von Kohle und Stahl: Eine Gesellschaftsgeschichte Westeuropas nach dem Boom. Berlin: Suhrkamp 2019. 978-3-518-58735-5

We prove a relative version of the Picard-Lefschetz theorem, describing the variation of relative homology groups $H_d(Y_t \setminus A_t,B_t\setminus A_t)$ in the fibers of a smooth fiber bundle $Y \to T$ of complex manifolds with $A\cup B \subset Y$ transverse. From this we derive the vanishing of certain iterated variations, a system of constraints dubbed "hierarchy". As applications, we rederive the known analytic structure of Aomoto polylogarithms and massive one loop Feynman integrals. Moreover, we introduce the "simple type" to prove hierarchy constraints in degenerate cases where the Picard-Lefschetz formula does not apply, e.g. the massless triangle or the ice cream cone Feynman diagram. We compare our findings with a "classical" hierarchy of iterated variations (from 1960's $S$-matrix theory) and show how our setup not only explains, but also refines the latter. In order to do so, we need to further resolve the geometry of Feynman motives: We boldly blow up what no one has blown up before., Comment: 85 pages, 27 figures

We derive a variant of the loop-tree duality for Feynman integrals in the Schwinger parametric representation. This is achieved by decomposing the integration domain into a disjoint union of cells, one for each spanning tree of the graph under consideration. Each of these cells is the total space of a fiber bundle with contractible fibers over a cube. Loop-tree duality emerges then as the result of first decomposing the integration domain, then integrating along the fibers of each fiber bundle. As a byproduct we obtain a new proof that the moduli space of graphs is homotopy equivalent to its spine. In addition, we outline a potential application to Kontsevich's graph (co-)homology., Comment: 25 pages. Final version

Background and objectives In 2020, a wide range of hygiene measures was implemented to mitigate infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In consequence, pulmonary infections due to other respiratory pathogens also decreased. Here, we evaluated the number of bacterial and viral meningitis and encephalitis cases during the coronavirus disease 2019 (COVID-19) pandemic. Methods In a multicentre retrospective analysis of data from January 2016 until December 2020, numbers of patients diagnosed with bacterial meningitis and other types of CNS infections (such as viral meningitis and encephalitis) at 26 German hospitals were studied. Furthermore, the number of common meningitis-preceding ear-nose-throat infections (sinusitis, mastoiditis and otitis media) was evaluated. Results Compared to the previous years, the total number of patients diagnosed with pneumococcal meningitis was reduced (n = 64 patients/year in 2020 vs. n = 87 to 120 patients/year between 2016 and 2019, all p < 0.05). Additionally, the total number of patients diagnosed with otolaryngological infections was significantly lower (n = 1181 patients/year in 2020 vs. n = 1525 to 1754 patients/year between 2016 and 2019, all p < 0.001). We also observed a decline in viral meningitis and especially enterovirus meningitis (n = 25 patients/year in 2020 vs. n = 97 to 181 patients/year between 2016 and 2019, all p < 0.001). Discussion This multicentre retrospective analysis demonstrates a decline in the number of patients treated for viral and pneumococcal meningitis as well as otolaryngological infections in 2020 compared to previous years. Since the latter often precedes pneumococcal meningitis, this may point to the significance of the direct spread of pneumococci from an otolaryngological focus such as mastoiditis to the brain as one important pathophysiological route in the development of pneumococcal meningitis.

Predicitions made by neural networks can be fraudulently altered by so-called poisoning attacks. A special case are backdoor poisoning attacks. We study suitable detection methods and introduce a new method called Heatmap Clustering. There, we apply a $k$-means clustering algorithm on heatmaps produced by the state-of-the-art explainable AI method Layer-wise relevance propagation. The goal is to separate poisoned from un-poisoned data in the dataset. We compare this method with a similar method, called Activation Clustering, which also uses $k$-means clustering but applies it on the activation of certain hidden layers of the neural network as input. We test the performance of both approaches for standard backdoor poisoning attacks, label-consistent poisoning attacks and label-consistent poisoning attacks with reduced amplitude stickers. We show that Heatmap Clustering consistently performs better than Activation Clustering. However, when considering label-consistent poisoning attacks, the latter method also yields good detection performance.

Background The bacteriocin nisin is naturally produced by Lactococcus lactis as an inactive prepeptide that is modified posttranslationally resulting in five (methyl-)lanthionine rings characteristic for class Ia bacteriocins. Export and proteolytic cleavage of the leader peptide results in release of active nisin. By targeting the universal peptidoglycan precursor lipid II, nisin has a broad target spectrum including important human pathogens such as Listeria monocytogenes and methicillin-resistant Staphylococcus aureus strains. Industrial nisin production is currently performed using natural producer strains resulting in rather low product purity and limiting its application to preservation of dairy food products. Results We established heterologous nisin production using the biotechnological workhorse organism Corynebacterium glutamicum in a two-step process. We demonstrate successful biosynthesis and export of fully modified prenisin and its activation to mature nisin by a purified, soluble variant of the nisin protease NisP (sNisP) produced in Escherichia coli. Active nisin was detected by a L. lactis sensor strain with strictly nisin-dependent expression of the fluorescent protein mCherry. Following activation by sNisP, supernatants of the recombinant C. glutamicum producer strain cultivated in standard batch fermentations contained at least 1.25 mg/l active nisin. Conclusions We demonstrate successful implementation of a two-step process for recombinant production of active nisin with C. glutamicum. This extends the spectrum of bioactive compounds that may be produced using C. glutamicum to a bacteriocin harboring complex posttranslational modifications. Our results provide a basis for further studies to optimize product yields, transfer production to sustainable substrates and purification of pharmaceutical grade nisin.

Considers how educators from different disciplines create semiotic cycles of inquiry where teachers learn about the arts and through the arts. Believes that their students had to experience cycles of inquiry wherein they learned about the arts and through the arts, and that they needed to see teachers of different disciplines collaborate. Argues that integrated, arts-infused curriculum is a viable way to prepare teachers to create democratic learning communities. (SG)

Discusses how students in the author's classroom are challenged to think critically in a curriculum that focuses specifically on the health of the environment. Discovers that her own convictions about the importance of stewardship for the environment stood in stark contrast to the competitive, consumer-oriented values of the preadolescents in her urban classroom. (SC)

Three professors share techniques for helping students focus on assessments required in classes. Charts are used to show students the specific concepts, principles, and problems that will be included on multiple-choice tests; rubrics developed for assigned work are used to increase student expectations and direct their explorations; and negotiated rubrics are used to involve students in setting standards for work. (Author/MSE)

"Le quartier des prêtres est un quartier résidentiel situé dans le sanctuaire d'Amon à Karnak, à l'est du lac Sacré. Au cours du premier millénaire avant notre ère, il a été presque continuellement occupé par des prêtres le temps de leur service cultuel. Un programme de recherche lancé en 2001 par le Centre franco-égyptien d'étude des temples de Karnak (Cfeetk) complète et révise les résultats de fouilles de sauvetage menées dans ce secteur dans les années 1970, jusqu'alors partiellement publiés. L'histoire et l'évolution de ce quartier, ainsi que l'identité, la culture matérielle, la vie quotidienne et le régime alimentaire de ses habitants, ont été établis au moyen d'une collaboration pluridisciplinaire pendant de nouvelles fouilles et des missions d'études du matériel. Cette recherche explore la manière dont cet habitat s'intègre dans le contexte plus large du temple, en particulier son environnement religieux et architectural direct sur la rive sud du lac Sacré qui jadis abritait de grands secteurs économiques et peut-être artisanaux. L'étude de ces annexes offre un témoignage unique et éloquent des activités quotidiennes au sein du temple d'Amon à Karnak et de la vie des serviteurs des dieux égyptiens." --Provided by publisher., In English: The Priests' Quarter is a housing quarter located within the sanctuary of Amun in Karnak, to the east of the Sacred Lake. For almost all of the first millennium BC, it was occupied by priests performing their cultic service. A research programme initiated in 2001 by the Centre franco-égyptien d'étude des Temples de Karnak (Cfeetk) completes and revises the results of rescue excavations led in this area in the 1970s, which had so far never been fully published. The history and evolution of this quarter, as well as the identity, material culture, daily life and diet of its inhabitants, have been established through a multidisciplinary collaboration during excavation and post-excavation studies. This research explores how this settlement fits into the larger context of the temple, particularly its direct religious and architectural environment on the southern bank on the Sacred Lake where once stood large economic and possibly artisanal sectors. The study of these temple annexes offers a unique and eloquent testimony on the day-to-day activities within the temple of Amun in Karnak itself and the life of ancient Egyptian priests in general., Includes bibliographical references and indexes., "Le quartier des prêtres est un quartier résidentiel situé dans le sanctuaire d'Amon à Karnak, à l'est du lac Sacré. Au cours du premier millénaire avant notre ère, il a été presque continuellement occupé par des prêtres le temps de leur service cultuel. Un programme de recherche lancé en 2001 par le Centre franco-égyptien d'étude des temples de Karnak (Cfeetk) complète et révise les résultats de fouilles de sauvetage menées dans ce secteur dans les années 1970, jusqu'alors partiellement publiés. L'histoire et l'évolution de ce quartier, ainsi que l'identité, la culture matérielle, la vie quotidienne et le régime alimentaire de ses habitants, ont été établis au moyen d'une collaboration pluridisciplinaire pendant de nouvelles fouilles et des missions d'études du matériel. Cette recherche explore la manière dont cet habitat s'intègre dans le contexte plus large du temple, en particulier son environnement religieux et architectural direct sur la rive sud du lac Sacré qui jadis abritait de grands secteurs économiques et peut-être artisanaux. L'étude de ces annexes offre un témoignage unique et éloquent des activités quotidiennes au sein du temple d'Amon à Karnak et de la vie des serviteurs des dieux égyptiens." --Provided by publisher., In English: The Priests' Quarter is a housing quarter located within the sanctuary of Amun in Karnak, to the east of the Sacred Lake. For almost all of the first millennium BC, it was occupied by priests performing their cultic service. A research programme initiated in 2001 by the Centre franco-égyptien d'étude des Temples de Karnak (Cfeetk) completes and revises the results of rescue excavations led in this area in the 1970s, which had so far never been fully published. The history and evolution of this quarter, as well as the identity, material culture, daily life and diet of its inhabitants, have been established through a multidisciplinary collaboration during excavation and post-excavation studies. This research explores how this settlement fits into the larger context of the temple, particularly its direct religious and architectural environment on the southern bank on the Sacred Lake where once stood large economic and possibly artisanal sectors. The study of these temple annexes offers a unique and eloquent testimony on the day-to-day activities within the temple of Amun in Karnak itself and the life of ancient Egyptian priests in general.

The prediction of the individual prognosis of low-grade glioma (LGG) patients is limited in routine clinical practice. Nowadays, 5-aminolevulinic acid (5-ALA) fluorescence is primarily applied for improved intraoperative visualization of high-grade gliomas. However, visible fluorescence is also observed in rare cases despite LGG histopathology and might be an indicator for aggressive tumor behavior. The aim of this study was thus to investigate the value of intraoperative 5-ALA fluorescence for prognosis in LGG patients. We performed a retrospective analysis of patients with newly diagnosed histopathologically confirmed LGG and preoperative 5-ALA administration at two independent specialized centers. In this cohort, we correlated the visible intraoperative fluorescence status with progression-free survival (PFS), malignant transformation-free survival (MTFS) and overall survival (OS). Altogether, visible fluorescence was detected in 7 (12%) of 59 included patients in focal intratumoral areas. At a mean follow-up time of 5.3 ± 2.9 years, patients with fluorescing LGG had significantly shorter PFS (2.3 ± 0.7 vs. 5.0 ± 0.4 years; p = 0.01), MTFS (3.9 ± 0.7 vs. 8.0 ± 0.6 years; p = 0.03), and OS (5.4 ± 1.0 vs. 10.3 ± 0.5 years; p = 0.01) than non-fluorescing tumors. Our data indicate that visible 5-ALA fluorescence during surgery of pure LGG might be an already intraoperatively available marker of unfavorable patient outcome and thus close imaging follow-up might be considered.

We greatly appreciate Dr. Stummer's and Dr. Thomas's interest in our study and their important comments [...].

Contains fulltext : 232010.pdf (Publisher’s version ) (Open Access), BACKGROUND: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. METHODS: Adult patients with advanced solid tumours received peposertib 100-200 mg once daily or 150-400 mg twice daily (BID) in 21-day cycles. RESULTS: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median T(max) 1.1-2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3-6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. CONCLUSIONS: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. CLINICAL TRIAL REGISTRATION: NCT02316197.

Background: Advances in systemic treatment and in brain imaging have led to a higher incidence of diagnosed brain metastases. In the treatment of brain metastases, stereotactic radiotherapy and radiosurgery, systemic immunotherapy, and targeted drug therapy are important evidence-based options. In this review. we summarize the available evidence on the treatment of brain metastases of the three main types of cancer that give rise to them: non-small-cell lung cancer, breast cancer, and malignant melanoma. Methods: This narrative review is based on pertinent original articles. meta-analyses. and systematic reviews that were retrieved by a selective search in PubMed. These publications were evaluated and discussed by an expert panel including radiation oncologists. neurosurgeons. and oncologists. Results: There have not yet been any prospective randomized trials concerning the optimal combination of local stereotactic radiotherapy/radiosurgery and systemic immunotherapy or targeted therapy. Retrospective studies have consistently shown a benefit from early combined treatment with systemic therapy and (in particular) focal radiotherapy. compared to sequential treatment. Two meta-analyses of retrospective data from cohorts consisting mainly of patients with non-small-cell lung cancer and melanoma revealed longer overall survival after combined treatment with focal radiotherapy and checkpoint inhibitor therapy (rate of 12-month overall survival for combined versus non-combined treatment: 64.6% vs. 51.6%, p <0.001). In selected patients with small, asymptomatic brain metastases in non-critical locations. systemic therapy without focal radiotherapy can be considered, as long as follow-up with cranial magnetic resonance imaging can be performed at close intervals. Conclusion: Brain metastases should be treated by a multidisciplinary team, so that the optimal sequence of local and systemic therapies can be determined for each individual patient.

Despite women being the backbone of the agricultural sector in India, the patriarchal agrarian system poses major obstacles and challenges specific to women farmers with consequences well beyond the individual. This research aims to explore how mobile phones can empower rural women vis-à-vis agriculture. Taking the lens of Feminist Theory, the ambition of this research is to study real-life experiences and realities of often invisible women farmers. A mixed-methods case study design allowed to capture a holistic and at the same time nuanced understanding of technology in the rural context of Andhra Pradesh, Karnataka and Maharashtra. The findings of two focus group discussions and a telephone survey of 231 observations conclude that mobile phones enable rural women farmers to feel more independent, self-sufficient, and safe. Towards empowerment in agriculture, mobile phones promote change across all five domains under study: production, resources, income, leadership and time. Mobile phones provide women farmers with invaluable access to information and resources, allowing them to enter previously male-dominated steps along the agricultural value chain.

The repair of inflamed, demyelinated lesions as in multiple sclerosis (MS) necessitates the clearance of cholesterol-rich myelin debris by microglia/macrophages and the switch from a pro-inflammatory to an anti-inflammatory lesion environment. Subsequently, oligodendrocytes increase cholesterol levels as a prerequisite for synthesizing new myelin membranes. We hypothesized that lesion resolution is regulated by the fate of cholesterol from damaged myelin and oligodendroglial sterol synthesis. By integrating gene expression profiling, genetics and comprehensive phenotyping, we found that, paradoxically, sterol synthesis in myelin-phagocytosing microglia/macrophages determines the repair of acutely demyelinated lesions. Rather than producing cholesterol, microglia/macrophages synthesized desmosterol, the immediate cholesterol precursor. Desmosterol activated liver X receptor (LXR) signaling to resolve inflammation, creating a permissive environment for oligodendrocyte differentiation. Moreover, LXR target gene products facilitated the efflux of lipid and cholesterol from lipid-laden microglia/macrophages to support remyelination by oligodendrocytes. Consequently, pharmacological stimulation of sterol synthesis boosted the repair of demyelinated lesions, suggesting novel therapeutic strategies for myelin repair in MS.

"So darf es nicht weitergehen", forderten im September 2019 hunderte deutsche Ärzte und Verbände des Gesundheitssektors. Sie formulierten eine flammende Anklage gegen "das Diktat der Ökonomie" und gegen eine "Enthumanisierung der Medizin" in Krankenhäusern und Arztpraxen. Dieser "Ärzte-Appell" ist ein aktueller Beitrag zu einer langjährigen intensiven Debatte um das Verhältnis von Gesundheit und Ökonomie. In der Öffentlichkeit stehen die "Folgen der Ökonomisierung des Gesundheitswesens" meist als Menetekel für eine "Medizin ohne Empathie" und für die Verschärfung sozialer Ungleichheiten am Krankenbett: Kinder, aber auch Migranten, Alte und Arme seien die Leidtragenden, wenn es "an Geld, Ärzten und Pflegern" fehle. Die Binnenperspektive eröffnet nicht minder alarmierende Einblicke. In einer Studie wurden 2018 zahlreiche Geschäftsführer und Ärzte an Kliniken zu betriebswirtschaftlichen Einflüssen auf ihre Arbeit befragt. Sie zeichneten ein bedrückendes Bild, das die Autoren der Studie wie folgt zusammenfassten: "Die Krankenhausmedizin nimmt fabrikmäßige Züge an, die medizinische Arbeit wird für das ärztliche und pflegerische Personal tendenziell als fremdbestimmt erlebt. [...] Insofern verändert die Ökonomisierung auch mittelbar den Charakter der Medizin."

In der Bundesrepublik und in der gesamten westlichen Welt außerhalb der USA wurde Auslandsbestechung bis Ende der 1980er-Jahre als ein legales Mittel der Exportförderung behandelt. Sie war straffrei und sogar steuerlich absetzbar. Das änderte sich erst im Zuge der "Compliance Revolution" der 1990er-Jahre. Der Beitrag analysiert diesen Wandel für die Bundesrepublik und untersucht die Debatten um die Auslandskorruption. Er konzentriert sich dabei auf die Positionen der Unternehmerschaft und der im Bundestag vertretenen Parteien. Ausgangspunkt ist der stabile Korruptionskonsens der Bonner Republik, der zunächst auch noch in der Berliner Republik Bestand hatte, dann aber unter dem Einfluss einer zunehmend kritischen Zivilgesellschaft und der internationalen Staatengemeinschaft zerbrach. Nachdem es unausweichlich geworden war, die Auslandskorruption zu ächten, wurde hartnäckig darum gerungen, mit welchen juristischen Mitteln sie zu bekämpfen sei. Am Ende eines von vielen Blockaden und Umleitungen verzögerten Prozesses stand ab 2002 die Strafbarkeit aller Arten von Auslandskorruption. Welche Ermittlungsinstrumente eingesetzt werden durften und wie effektiv die Strafverfolgung sein sollte, blieb jedoch weiter strittig. Der Aufsatz zeigt nicht zuletzt die Rückwirkungen internationaler Rechtsnormen für die nationalstaatliche Ebene., In the Federal Republic of Germany and in the entire Western world with the exception of the USA, bribery abroad was treated as a lawful instrument of export promotion until the end of the 1980s. It was not indictable, and was even tax deductible. This only changed in the course of the "Compliance Revolution" of the 1990s. The article analyzes this process as it pertained to the Federal Republic of Germany and examines the debates on foreign corruption. It focuses on the attitudes of economic elites and the parties represented in the Bundestag. The starting point is the unquestioned acceptance of foreign corruption in the Bonn Republic, which initially lasted well into the Berlin Republic, but then crumbled under the influence of an increasingly critical civil society and the international community. After outlawing foreign corruption had become inevitable, there was a persistent struggle over the exact design of the legislation and the vigor of its implementation. At the end of a long drawn-out process delayed by many obstructions and diversions, all types of foreign corruption became punishable by 2002. Which investigation tools were permissible and how stringent prosecution should be, however, remained contentious. Crucially, the article also reveals the repercussions of international legal norms for nation states.

It is well established that access to the bilingual lexicon is non-selective: even in an entirely monolingual context, elements of the non-target language are active. Research has also shown that activation of the non-target language is greater at higher proficiency levels, suggesting that it may be proficiency that drives cross-language lexical activation. At the same time, the potential role of age of acquisition (AoA) in cross-language activation has gone largely unexplored, as most studies have either focused on adult L2 learners or have conflated AoA with L2 proficiency. The present study examines the roles of AoA and L2 proficiency in L2 lexical processing using the visual world paradigm. Participants were a group of early L1 Afrikaans-L2 English bilinguals (AoA 1-9 years) and a control group of L1 English speakers. Importantly, in the bilingual group, AoA and proficiency were not correlated. In the task, participants viewed a screen with four objects on it: a target object, a competitor object whose Afrikaans translation overlapped phonetically with the target object, and two unrelated distractor objects. The results show that the L2 English group was significantly more likely to look at the cross-language competitor than the L1 English group, thus providing evidence of cross-language activation. Importantly, the extent to which this activation occurred was modulated by both L2 proficiency and AoA. These findings suggest that while these two variables may have been confounded in previous research, they actually both exert effects on cross-language activation. The locus of this parallel activation effect is discussed in terms of connectionist models of bilingualism.

Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemother-apy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (Odomzo™, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be trans-lated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.

WHO grade II-III gliomas are rare primary brain tumors occurring at a median age of about 35–55 years. Median survival is longer in WHO grade II-III glioma compared with WHO grade IV glioblastoma as survival times of up to 10 years and longer can be observed. Maximal safe resection and adjuvant therapies including chemotherapy and radiotherapy are the mainstay of treatment. Clinical trials in WHO grade II-III tumors are challenging due to the rarity and the long follow up times. The 2016 WHO Classification of Central Nervous Tumours introduced a new diagnostic framework relying on molecular characteristics, providing the definition of prognostically more homogenous subgroups compared to the histopathological analysis. Most available evidence on the adjuvant treatment of WHO II-III gliomas was generated in the pre-molecular era, challenging the interpretation of study results. The present review therefore summarizes the available data from prospective trials on systemic treatment options in WHO grade II-III glioma, considering molecular markers, recently published results and future outlooks in the field.

SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

Background: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. Methods: Adult patients with advanced solid tumours received peposertib 100–200 mg once daily or 150–400 mg twice daily (BID) in 21-day cycles. Results: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median Tmax 1.1–2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3–6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. Conclusions: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. Clinical trial registration: NCT02316197.

In the last years, AI systems, in particular neural networks, have seen a tremendous increase in performance, and they are now used in a broad range of applications. Unlike classical symbolic AI systems, neural networks are trained using large data sets and their inner structure containing possibly billions of parameters does not lend itself to human interpretation. As a consequence, it is so far not feasible to provide broad guarantees for the correct behaviour of neural networks during operation if they process input data that significantly differ from those seen during training. However, many applications of AI systems are security- or safety-critical, and hence require obtaining statements on the robustness of the systems when facing unexpected events, whether they occur naturally or are induced by an attacker in a targeted way. As a step towards developing robust AI systems for such applications, this paper presents how the robustness of AI systems can be practically examined and which methods and metrics can be used to do so. The robustness testing methodology is described and analysed for the example use case of traffic sign recognition in autonomous driving., Comment: 12 pages, 7 figures. The final publication is available at Springer via https://doi.org/10.1007/978-3-030-79150-6_21

BACKGROUND The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) from solid cancers based on clinical, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) cytology presentation. MRI patterns are classified as linear, nodular, both, or neither. Type I LM is defined by positive CSF cytology (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the clinical utility of these LM subtypes. PATIENTS AND METHODS We retrospectively assembled data from 254 patients with newly diagnosed LM from solid tumors. Survival curves were derived using the Kaplan-Meier method and compared by Log-rank test. RESULTS Median age at LM diagnosis was 56 years. Typical clinical LM features were noted in 225 patients (89%); 13 patients (5%) were clinically asymptomatic. Tumor cells in the CSF were observed in 186 patients (73%) whereas the CSF was equivocal in 24 patients (9.5%) and negative in 44 patients (17.5%). Patients with confirmed LM had inferior outcome compared with patients with probable or possible LM (P = 0.006). Type I patients had inferior outcome than type II patients (P = 0.002). Nodular disease on MRI was a negative prognostic factor in type II LM (P = 0.014), but not in type I LM. Administration of either intrathecal pharmacotherapy (P = 0.020) or systemic pharmacotherapy (P = 0.0004) was associated with improved outcome in type I LM, but not in type II LM. CONCLUSION The EANO ESMO LM subtypes are highly prognostic and should be considered for stratification and overall design of clinical trials.

PURPOSE: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established (CDKN2A/B and TERT), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference P = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnos

We investigate Feynman graphs and their Feynman rules from the viewpoint of graph complexes. We focus on graph homology and on the appearance of cubical complexes when either reducing internal edges or when removing them by putting them on the massshell., Comment: 48 p, 15 Figures, as to appear in CNTP

The paper presents an analysis of the Afrikaans degree modifier baie ‘very/much/many’. Baie appears to be a single lexical item with a wide distribution in terms of the categories of gradable predicate with which it can combine. However, the paper shows that two syntactically distinct instances of baie should be distinguished. These instances of baie portion out the modification of different grammatical categories between them: one, a head, exclusively modifies gradable adjectives, and the other, an adjunct, modifies the remaining categories of gradable predicate.

We review the gauge and ghost cyle graph complexes as defined by Kreimer, Sars and van Suijlekom in “Quantization of gauge fields, graph polynomials and graph homology” and compute their cohomology. These complexes are generated by labelings on the edges or cycles of graphs and the differentials act by exchanging these labels. We show that both cases are instances of a more general construction of double complexes associated with graphs. Furthermore, we describe a universal model for these kinds of complexes which allows to treat all of them in a unified way., Peer Reviewed