Artykuły w czasopismach na temat „Olivier Beaud”

Abstract Oliver Goldsmith’s representation of two English gentlemen visiting a country house allegorizes Irish expatriate experience in She Stoops to Conquer. The play mocks a distinctive urban masculinity, the macaroni, by showing how ridiculous such fashionable characters become when removed from London. Resembling expatriates in this new, uncomfortable setting, the self-exiled gentlemen prompt Tony Lumpkin’s waggery, which is enhanced by Kate Hardcastle’s mockery of Marlow, her prospective husband. Goldsmith adapted elements of his plot from The Beaux Stratagem, a comedy by his Irish expatriate precursor George Farquhar, and he also incorporates autobiographical aspects of his Irish youth and recent English past. The laughter evoked by his fine gentlemen includes self-mockery, the result of Goldsmith’s double perspective on balancing the roles of outsider and insider, comic Irishman and fashionable Londoner.

Inner Solar System bodies are depleted in volatile elements relative to chondrite meteorites, yet the source(s) and mechanism(s) of volatile-element depletion and/or enrichment are poorly constrained. The timing, mechanisms and quantities of volatile elements present in the early inner Solar System have vast implications for diverse processes, from planetary differentiation to the emergence of life. We report major, trace and volatile-element contents of a glass bead derived from the D'Orbigny angrite, the hydrogen isotopic composition of this glass bead and that of coexisting olivine and silicophosphates, and the 207 Pb– 206 Pb age of the silicophosphates, 4568 ± 20 Ma. We use volatile saturation models to demonstrate that the angrite parent body must have been a major body in the early inner Solar System. We further show via mixing calculations that all inner Solar System bodies accreted volatile elements with carbonaceous chondrite H and N isotope signatures extremely early in Solar System history. Only a small portion (if any) of comets and gaseous nebular H species contributed to the volatile content of the inner Solar System bodies. This article is part of the themed issue ‘The origin, history and role of water in the evolution of the inner Solar System’.

Understanding the dynamics and patterns of biodiversity in transition forests is vital in promoting conservation and addressing environmental change issues. This work focused on elucidating the diversity, structure, and carbon potentials of a forest-savannah ecosystem. To achieve this, 8 forest plots that measured 50 m × 50 m each was set up in a forest-savannah landscape and used to identify and measure tree species ≥ 10 cm diameter at breast height (DBH measured at 130 cm). Species importance value was used to summarize the biodiversity patterns and the aboveground carbon estimates were elicited with the allometric equation. 43 species within 22 families were enumerated and the diversity was generally low (ranging from 1.82-2.5). Species such as Daniellia oliveri (Rolfe) Hutch. & Dalziel, Pyrostria guinnensis Comm. ex A. Juss, Dialium guineense Willd. and Margariteria discoidea (Baill.) G.L Webster were the dominant species, and had the highest importance values of 113.06, 55.13, 28.16 and 16.95, respectively, while Allophlus africanus P. Beauv., Annona senegalensis Pers., Anthonatha macrophylla P. Beauv., Ficus capensis Thumb. and Lecaniodiscus cupanioides Planch had the least importance values of 0.16 each. Carbon estimates ranged from 16.43172-42.9298 t/Ha. Most frequent species with higher basal areas no doubt contributed much to the carbon estimates, but did not have higher capacities in storing carbon. Managing the ecosystem with more carbon-dense species was seen as a suitable strategy for addressing environmental change in the ecosystem and region.

O estudo realizado na temática política pública, intitulada como: “Abordagem Reflexiva do Desenvolvimento do Amapá no Período de 1988 a 2018: Trinta Anos de Estado” apresenta a realidade de um Estado após a emancipação e elevação a categoria de unidade federada do Brasil, com levantamento de dados que apontam o grau de evolução conquistado nesse período, objetivando entender a condição de subdesenvolvimento, considerando todas as potencialidades dos recursos naturais e projetos de investimento, bem como a busca da compreensão que levou ao desequilíbrio das contas públicas fragilizando a economia e ampliando as desigualdades sociais.O método dialético foi utilizado numa perspectiva de busca de dados quantitativos para servir de base para qualificar a análise reflexiva da abordagem, tendo como fontes obras literárias, indicadores socioeconômicos de órgãos e oficiais, documentos e relatórios do Governo do Estado do Amapá, por meio da Secretaria de Estado da Fazenda e da Secretaria de Estado do Planejamento. Os teóricos abordados, entre outros, são: Gil (2008); Oliveira (2004); Teixeira (2005); Vergara (2005); Lima (2019); Vidal et al (2019); Santiago (2015); Beaud (2004); Weber (2006); Campos (2018). Os resultados demonstram a necessidade de reestruturação administrativa do Governo para reorganização e execução das políticas públicas com maior eficiência e consciência nos gastos públicos.

BackgroundAutoantibodies are found in up to 80% of patients with idiopathic inflammatory myopathies (IIM) and are associated with distinct clinical phenotypes [1]. Autoantibodies targeting cytosolic 5´-nucleotidase 1A (anti-cN1A) are currently the only known serum biomarker for the subgroup inclusion body myositis (IBM) (2), although detected even in other autoimmune diseases.ObjectivesTo identify new autoimmune targets in IIM by antigen bead array assay.MethodsIn a first cross-sectional exploratory study, 357 antigens representing 268 proteins were incubated with plasma samples from 219 IIM (108 Polymyositis (PM), 80 Dermatomyositis (DM) and 31 IBM) patients, 349 Systemic Lupus Erythematosus (SLE) patients and 306 population controls for screening of IgG reactivity by antigen bead array. All samples were identified in the local biobank of the Rheumatology clinic, Karolinska University Hospital. Interesting results obtained for the IBM subgroup were then validated in an independent larger cohort of 287 patients with IBM followed at nine European rheumatological or neurological centers. IBM serum samples were explored by antigen bead array and results validated by western blot. As controls, serum samples from 30 patients with PM and 30 with DM, HLA-matched with the IBM Swedish cohort, were included. Demographics, laboratory, clinical, and muscle biopsy data of the IBM cohort was retrieved.ResultsIn the exploratory study IgG reactivity towards NADH dehydrogenase 1 α subcomplex 11 (NDUFA11), a subunit of the membrane-bound mitochondrial respiratory chain complex I, was discovered with higher frequency in the IBM (9,7%) than PM (2,8%) and DM samples (2,5%), although the difference was not statistically significant. Anti-NDUFA11 IgG was also found in 2,3% of SLE and 2,6% of population control samples. In the validation study anti-NDUFA11 autoantibodies were detected in 11/287 IBM patients (3,8%), 0/30 PM and 0/30 DM patients. Reactivity against NDUFA11 could be confirmed by western blot (Table 1, Figure 1). The eleven anti-NDUFA11 positive patients showed a trend of lower frequency of wheelchair/walker ever use and higher creatine kinase levels at time of IBM diagnosis compared to the anti-NDUFA11 negative group. Ragged red fibers were significantly more prevalent in anti-NDUFA11 positive than negative patients (p=0.04). Anti-cN1A autoantibodies were detected in 98/287 (34,1%) of IBM, 3/30 (10%) DM and 9/29 (31%) PM patients, p=0.03. Coexistence of anti NDUFA11 and anti-cN1A antibodies was observed in 3 IBM patients.ConclusionOur results reveal a new autoimmune target in the mitochondrial respiratory chain complex I that might be specifically associated with IBM. This is of particular interest as mitochondrial abnormalities are known histological findings in muscle biopsies of IBM patients.References[1]Galindo-Feria AS, Wang G, Lundberg IE. Autoantibodies: Pathogenic or epiphenomenon. Best Pract Res Clin Rheumatol. 2022;36(2):101767.[2]Herbert MK,et al. Disease specificity of autoantibodies to cytosolic 5’-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases. Ann Rheum Dis. 2016;75(4):696-701.Table 1.NDUFA11 protein fragments (PrESTs)NDUFA11Amino acid sequence (excluding His6ABP)PrEST molecular weight (Da) (including His6ABP)PrEST 1ASLVKMGRLEGWEVFAKPKV19833,4PrEST 2MAPKVFRQYWDIPDGTDCHRKAYST20574,06PrEST 3TLNPPGTFLEGVAKVGQYTFT19828,23LegendAmino acid sequence and molecular weight of the protein fragments loaded on the western blot gel. NDUFA11, NADH dehydrogenase 1 α subcomplex 11; His6ABP, six histidine and albumin binding protein.Figure 1.Validation of bead array assay results with western blotLegendWestern blot showing the reactivity of two IBM patients against the NDUFA11 protein fragments (PrEST1,2,3) expressed with a His6ABP tag. Patient#1 was reactive to PrEST1 and not to PrEST2 and 3 in the bead array assay while patient#2 did not display any reactivity. NDUFA11, NADH dehydrogenase 1 α subcomplex 11; His6ABP, six histidine and albumin binding protein.Disclosure of InterestsAntonella Notarnicola: None declared, Cecilia Hellstrom: None declared, Begum Horuluoglu: None declared, Charlotta Preger: None declared, Francesco Bonomi: None declared, Boel De Paepe: None declared, Jan De Bleecker: None declared, Anneke J. van der Kooi: None declared, Marianne de Visser: None declared, Sabrina Sacconi: None declared, Pedro Machado: None declared, Umesh A. Badrising: None declared, Anke Rietveld: None declared, Ger Pruijn: None declared, Simon Rothwell: None declared, James B. Lilleker: None declared, Hector Chinoy: None declared, Olivier Benveniste: None declared, Elisabet Svenungsson: None declared, Helena Idborg: None declared, Per-Johan Jakobsson: None declared, Peter Nilsson: None declared, Ingrid E. Lundberg Shareholder of: stock shares in Roche and Novartis, Consultant of: Consulting fees from Corbus Pharmaceuticals, Inc and research grants from Astra Zeneca and has been serving on the advisory board for Astra Zeneca, Bristol Myers Squibb, EMD Serono Research & Development Institute, Argenx, Octapharma, Kezaar, Orphazyme, Pfizer and Janssen.

Abstract The superior clinical therapeutic effects and broad applications of bispecific T cell engagers (BiTEs) has transformed treatment strategies in oncology. While benefits of the novel immunotherapies are indisputable, the safety aspects require to be intensively investigated. Considering challenges of animal models for accessing efficacy and safety of biologics leading to failed clinical trials, there is unmet need for human disease relevant systems, which facilitate development of new clinical candidates. We developed a high-throughput, 384-well-format co-culturing platform for combined assessment of anti-tumor efficacy and liver safety of immunotherapeutics. As a model of liver we employed 3D spheroids composed of primary human hepatocytes and Kupffer cells with preserved metabolic and inflammatory functions. In parallel, the solid tumor model was aggerated of human cancer cell lines (HCT116-GFP) and primary cancer associated fibroblasts, mimicking the tumor microenvironment. Both models were cultured in automation-friendly wells pairwise interconnected with microfluidic channels. Gravity-driven tubeless flow ensured tissue-tissue interaction. To evaluate our system, we treated 3D spheroid models with runimotamab (HER2xCD3 BiTE) in the presence of peripheral blood mononuclear cells (PBMCs). Tumor viability and growth was assessed by fluorescence measurements, while liver toxicity and function were monitored by release of liver aminotransferases ALT/AST, albumin secretion and live confocal microscopy. Immune cell activation was assessed by a cytokine bead array. The treatment with runimotamab resulted in a significant decrease of fluorescence and size of tumor spheroids. At the same time, we observed an induced secretion of cytokines with a peak of expression of IL-2, TNFα after 24h and INFγ, IL-6 and IL-17A after 48h. Cytokine release was coupled with elevated levels of clinically relevant liver damage biomarkers ALT and AST with peak at 72h timepoint. This data suggests potential risk of cytokine release syndrome (CRS) followed by liver damage. Interestingly, redosing of the antibody was not followed by another release of liver enzymes, similarly to clinical observations. In summary, we have developed a human disease relevant, high-throughput platform for the evaluation of novel immunotherapies closely emulating clinical results. Automation-compatible with up to 192 co-culture conditions per plate it represents a powerful tool for clinical candidate development. Citation Format: Michal Rudnik, Ozlem Yavaş Grining, Simon Hutter, Frauke Greve, Daniela Ortiz Franyuti, Ramona Matheis, Ekaterina Breous-Nystrom, Olivier Frey. Combined investigation of anti-tumor efficacy and liver safety of bispecific T cell engagers in immune-competent high-throughput co-culturing platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2747.

Abstract Emerging studies have demonstrated that innate immune checkpoints, regulating Tumor-associated Macrophage (TAM) phagocytic activity, play a crucial role in immune escape and survival of cancer cells. CD47-SIRPα axis is the best studied example of the “don’t eat me” signal, frequently overexpressed on cancer cell. Targeting of CD47 protein has shown impressive results in clinical trials in hematologic malignancies but remained challenging for solid tumors therapy. Therefore, tools facilitating the development of novel innate immune checkpoint inhibitors are of great interest. To address that unmet need, we established a high-throughput, 384-well-format assay for efficacy assessment of compounds inducing macrophage phagocytosis. As a model of solid tumor, we employed 3D spheroids aggregated of human cancer cell lines (A375, HCT116, MCF7, SKOV3) expressing GFP or PDX material (LXFA1647 lung adenocarcinoma, MEXF2106 melanoma) and cancer associated fibroblasts, as well as Monocyte-Derived Macrophages (MDMs) which altogether were co-aggregated to form spheroids mimicking the tumor microenvironment and immune-competence. In parallel MDMs were co-cultured with matured spheroid to emulate tumor infiltration. Both models were cultured in automation and High Content imaging compatible Akura™ 384-well plate. To evaluate our system, we targeted CD47-SIRPα axis by treatment of 3D spheroid models with αCD47 antibody (H6D12) in combination with atezolizumab (αPD-L1 antibody). Tumor viability and growth were assessed by fluorescence measurements and ATP level. Phagocytosis of fluorescently labeled tumor cells was imaged by confocal microscopy and quantified by inhouse developed analysis pipeline. Immune cell activation was evaluated by a cytokine bead array. The treatment of cell line-based 3D models with αCD47 antibody resulted in an increased number of phagocytic macrophages followed by a decrease of fluorescence and size of tumor spheroids in a dose-dependent manner. Moreover, we observed an induced secretion of TNFα, IL-6, IL-10 and IL-RA after 48h. Similarly, in PDX-based models, we observed decreased spheroid size and ATP level at day 7. Notably, αCD47 antibody-induced level of cytokines was further increased in combination with atezolizumab. To conclude, we have developed a human disease relevant, high-throughput assay for the evaluation of novel therapeutic modalities targeting phagocytosis. Due to compatibility with microscopy and most of the biochemical assays, it represents a powerful tool for clinical candidate development. Citation Format: Michal Rudnik, Özlem Yavaş Grining, Nadezhda Rotankova, Silvan Strebel, Francesca Chiovaro, Olivier Frey, Irina Agarkova, Wolfgang Moritz. High-throughput, high content Imaging assay for assessing solid tumor phagocytosis in 3D spheroid model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4558.

BackgroundAbatacept (ABA), a biologic treatment for rheumatoid arthritis (RA), is a recombinant fusion protein composed of the extracellular domain of human CTLA-4 combined with the Fc portion of human IgG1. Lack of response to treatment occurs in 30 % of RA patients, highlighting the need to better understanding its mechanism of action and to identify predictive factors of response. Although ABA is considered to interrupt the costimulatory signal, the importance of this mechanism on the drug effect lacks evidence. Moreover, therapies targeting T cells were disappointing in RA [1]. In contrast, ABA has been shown to induce reverse signaling in antigen-presenting cells, by activating the indolamine 2,3-dioxygenase (IDO) pathway (a strong tolerogenic enzyme) in macrophages and dendritic cells [2]. ABA also acts on nitric oxide (NO) production, a proinflammatory molecule capable of inhibiting IDO action, although conflicting data have been reported.ObjectivesThe objective of this study was to evaluate the importance of direct mechanisms on antigen-presenting cells and identify biomarkers of the response to ABA.MethodsSera (n = 71) and RNA from whole blood (n = 57) were collected from RA patients before treatment by ABA. Abundance of GM-CSF, gamma interferon (IFNg), IL-10, IDO, iNOS were quantified using ELISA and addressable laser bead assay (ALBIA). RT-qPCR was performed onIDO1transcript. Response to ABA was assessed 6 months after its introduction, using EULAR response criteria. A costimulationin vitromodel was developed: monocytes-derived macrophages (using GM-CSF or M-CSF) from healthy donors were polarized 8 days with LP, with or without IFNg. T cells were cocultured with anti-CD3, with or without ABA, anti-CD28 antibodies or IDO inhibitor (1-MTDT). Proliferation was assessed using CFSE.ResultsBefore ABA therapy, GM-CSF, IFNg and IL-10 in sera were increased in serum of good responders compared to non-responders. Our costimulation model showed that in macrophages exposed to GM-CSF, IFNg, LPS, ABA inhibited lymphocyte proliferation by 53%. Inhibition by ABA was only 10% when macrophages has not been exposed to IFNg, suggesting a central role of this cytokines. Furthermore, inhibition was only achieved when both GM-CSF + IFNγ were used, highlighting the need for a combination of these two factors. In presence of GM-CSF with IFNg + LPS + ABA, IDO was increased in macrophages. ABA increased iNOS production in macrophages when either IFNg or GM-CSF were not involved in their polarisation, neutralising IDO and leading to T cell proliferation. These results show a balance between iNOS and IDO in macrophages, modulated by IFNγ and GM-CSF. In RA patients, ABA could release the tolerogenic potential of polarized macrophages, decreasing T cell proliferation. Accordingly, iNOS increased in non-responders‘ sera after 6 months of ABA treatment whileIDO1expression increased in good responders whole blood RNA. In fact, in ABA responders, IDO increase in macrophages enabling a tolerogenic effect since iNOS is not induced.Conclusion:Figure 1.Abatacept direct signaling on antigen presenting cells.Specific macrophage polarisation with IFNg and GM-CSF, leading to an increase in IDO production without increasing iNOS after treatment, could be the key to achieving a good response to ABA. This finding supports the macrophage-mediated action of ABA and may contribute to the development of a prediction system for abatacept response based on macrophage polarisation.References[1]Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 Costimulatory Pathways in Autoimmunity and Transplantation. Annu Rev Immunol 2001;19:225–52. doi:10.1146/annurev.immunol.19.1.225[2]Bozec A, Luo Y, Engdahl C, et al. Abatacept blocks anti-citrullinated protein antibody and rheumatoid factor mediated cytokine production in human macrophages in IDO-dependent manner. Arthritis Res Ther 2018;20:24. doi:10.1186/s13075-018-1527-xAcknowledgementsStudy conducted with the financial support of the Société Française de Rhumatologie.Disclosure of InterestsBaptiste de Maleprade: None declared, Baptiste Gerard: None declared, Pauline Brevet: None declared, Sophie Candon: None declared, Olivier VITTECOQ Consultant of: AbbVie, Bristol-Myers Squibb, Gilead, Lilly, Merck, Novartis, Pfizer, Roche- Chugai, Mylan and Sanofi, Grant/research support from: Novartis, Pfizer, Merck and Bristol-Myers Squibb, Manuel Freret: None declared, Thierry Lequerre Speakers bureau: AbbVie, Boehringer Ingelheim, BMS, Fresenius, Galapagos, Lilly, MEDAC, MSD, Nordic Pharma, Novartis, Pfizer, Roche – Chugai, UCB.

BackgroundChimeric antigen receptors (CAR) have demonstrated remarkable efficacy in licensing T cells for antitumor responses against hematopoietic malignancies but have had limited success against solid tumors. Macrophages, both archetypic phagocytes and professional antigen presenting cells, may exert profound effector functions which complement adaptive cellular immunity.1 Recently, it was shown that human macrophages engineered to express CARs (CAR-Ms) demonstrated antigen-specific phagocytosis, inhibited solid xenograph tumors, and induced an inflammatory tumor microenvironment boosting antitumor T cell responses.2 Kimura et al. previously completed the first prophylactic cancer vaccine trial based on a non-viral antigen, tumor-associated hypoglycosylated Mucin 1 (MUC1).3 A panel of fully-human affinity-matured MUC1-specific antibodies raised in healthy subjects following immunization was identified from these patients.4 Using these MUC1-specific scFv domains for CAR generation, we have now engineered MUC1-targeting CAR-Ms that may potentially possess reduced off-target specificities.MethodsLentiviral CAR expression vectors containing the scFv domains of three unique hypoglycosylated MUC1-specific antibodies or a CD20-specific antibody, the CD3zeta signaling domain, and CD28 and OX40 co-stimulatory domains were constructed. The human monocyte/macrophage U937, SC, and THP-1 lines were stably transduced and flow-sort purified to generate MUC1- or CD20-specific CAR-Ms. CAR-Ms were differentiated into macrophages via 48 hour PMA treatment, and subsequently evaluated for antigen-specific function against MUC1- and/or CD20-expressing K562, ZR-75-1, and Raji cells or cancer cells isolated from solid lung tumors or malignant pleural effusions. CAR-M phenotype was evaluated by flow cytometry following in vitro differentiation and polarization with conventional ‘M1’ and ‘M2’ stimuli. Phagocytosis and lysosomal processing of phagocytosed cargo were evaluated by fluorescence microscopy of GFP/CellTrace labeled targets or detection of pH-sensitive pHrodo expression following CAR-M and tumor cell co-culture, respectively. Antigen-specific cytokine production was determined via cytometric bead array following co-culture of CAR-Ms with MUC1- or CD20-expressing tumor cells or 100mer MUC1 peptide.ResultsDifferentiated CAR-Ms possessed an inflammatory phenotype expressing IL-8 and CD86 which was further enhanced by IFNgamma or LPS treatment and was resistant to ‘M2’ polarization with conventional stimuli. CAR-Ms exhibited phagocytosis and subsequent lysosomal processing in an antigen-specific manner, with minimal reactivity against tumor cell targets in the absence of the corresponding MUC1 or CD20 antigen. MUC1-specific CAR-Ms stimulated with MUC1 peptide or MUC1+ tumor cells secreted robust levels of pro-inflammatory IL-8, TNFa, and IL-1beta, but not immunosuppressive IL-10.ConclusionsMUC1-targeting CAR-Ms exert potent tumor-restricted effector function in vitro and may provide a novel treatment strategy either alone or in potential synergistic combination with T cell-mediated immunotherapies.AcknowledgementsThe authors would like to thank Dr. Olivera J. Finn for generously providing reagents and guidance and Dr. Michael T. Lotze for his mentorship. This study was supported by funding from the University of Pittsburgh’s Department of Cardiothoracic Surgery to ACS and RD.ReferencesWilliams CB, Yeh ES, Soloff AC. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy. Npj Breast Cancer [Internet]. Breast Cancer Research Foundation/Macmillan Publishers Limited; 2016;2:15025. Available from: http://dx.doi.org/10.1038/npjbcancer.2015.25Klichinsky M, Ruella M, Shestova O, Lu XM, Best A, Zeeman M, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol 2020;38:947–53.Kimura T, McKolanis JR, Dzubinski LA, Islam K, Potter DM, Salazar AM, et al. MUC1 Vaccine for Individuals with Advanced Adenoma of the Colon: A Cancer Immunoprevention Feasibility Study. Cancer Prev Res [Internet] 2013;6:18–26. Available from: http://cancerpreventionresearch.aacrjournals.org/content/6/1/18.abstractLohmueller JJ, Sato S, Popova L, Chu IM, Tucker MA, Barberena R, et al. Antibodies elicited by the first non-viral prophylactic cancer vaccine show tumor-specificity and immunotherapeutic potential. Sci Rep 2016;6:31740.Ethics ApprovalThe study was approved by the University of Pittsburgh’s Institutional Review Board approval number CR19120172-005.

O primeiro número da Mare Nostrum reúne artigos, resenhas e ensaios produzidos no segundo semestre de 2009, cujos temas, objetos e problemas de pesquisa estão associados a experiências de pesquisas voltadas, em maior ou menor medida, para as questões relativas aos processos de integração no Mediterrâneo Antigo. Este primeiro número tem como principal objetivo iniciar um debate de longo prazo com estudiosos sobre a questão do papel do Mediterrâneo Antigo nos estudos sobre a Antiguidade. A maior parte dos textos aqui publicados, criados em meio ao trabalho de pesquisa e às discussões no Laboratório de Estudos do Império Romano, não têm como objeto principal o problema da integração do Mediterrâneo, mesmo assim, de uma forma ou de outra, este problema está presente neles tangencial, implícita ou até mesmo explicitamente. Este é o espírito com o qual a Revista Mare Nostrum buscará abordar sua questão central: como espaço de publicação de estudos de diversas naturezas e formas sobre a Antiguidade, que possam contribuir direta ou indiretamente para a realização de debates e para a compreensão dos processos de integração das sociedades do Mediterrâneo Antigo. Os sete artigos podem ser divididos em dois grupos: estudos historiográficos e análises de fonte textual. No primeiro grupo encontramos o artigo de Joana Campos Clímaco, que analisa alguns debates da historiografia contemporânea sobre a cidade de Alexandria, particularmente no que diz respeito à natureza grega, egípcia, sincrética ou “original” de sua inserção no mundo egípcio e no Mediterrâneo como um todo; também sobre historiografia versa o artigo de Bruno dos Santos Silva, que procura sumariar os estudos mais recentes acerca da obra de Estrabão e apontar alguns caminhos de pesquisa, especialmente sobre os modos de classificação dos povos da Pensínsula Ibérica; o artigo de Fábio Augusto Morales analisa o modo pelo qual a historiografia contemporânea interpretou a natureza e a inserção social dos metecos na pólis de Atenas durante o período clássico, criticando as visões economicistas e propondo uma abordagem propriamente política; por fim, o artigo de Deivid Valério Gaia busca realizar uma reflexão a respeito da investigação da Economia Antiga, revendo o debate entre primitivistas e modernistas e a necessidade de uma espacialização dos conceitos de história econômica. No segundo grupo de artigos está o de Rafael Costa Campos, sobre a caracterização do imperador Tibério nos Anais de Tácito, discutindo as formatações narrativas da fonte à luz das polêmicas historiográficas contemporâneas; o texto de Gustavo Junqueira Duarte Oliveira, por sua vez, estuda as relações entre o herói e a multidão na Ilíada à luz das categorias de “identidade” e de “efeito-plateia”, refletindo assim sobre o caráter ativo dos guerreiros “que não são os melhores” (a plateia dos feitos heroicos) na identificação e julgamento dos heróis; o artigo de Victor Sá Ramalho Antonio, por sua vez, propõe uma discussão das termas e banhos públicos romanos em termos de processos de construções identitárias, realizando um estudo comparativo de três casos pompeianos e a validade do uso do conceito de romanização. Em seguida, na seção "Laboratório", dedicada a textos experimentais, temos um ensaio de Norberto Guarinello. Neste é desenvolvido de forma ensaística um ângulo de visão do Império Romano que tenta associar a compreensão na longa duração com a necessidade de compreender a realidade social romana como processo em construção e reconstrução, mas que também está baseado em relações de dominação e exploração. Para isso, resgata as principais interpretações que os historiadores modernos apresentaram a respeito do Império Romano (assim como suas conjunturas modernas de desenvolvimento), para em seguida propor o uso das noções de ordem, fronteiras e integração como resposta à recente interpretação baseada nos conceitos de conectividade e fluxos tão sintonizada com a modalidade de Globalização vivenciada a partir dos anos 1990. A Revista fecha com três resenhas: a de Fábio Augusto Morales analisa a obra de Kostas Vassopoulos, Unthinking the Greek Polis; a resenha de Victor Sá Ramalho Antonio analisa Pompeii, the life of a Roman town de Mary Beard; a resenha de Uiran Gebara da Silva analisa a obra de Peter Heather, The Fall of the Roman Empire. Esperamos, portanto, que esse modesto número inicial seja seguido por outros com contribuições mais variadas e pautados por efetivos debates e experimentos intelectuais sobre o problema dos processos de integração social do Mediterrâneo Antigo.

Abstract Introduction Breast cancer is uncommon in men. Almost all male breast cancers are hormone receptor-positive, HER2-negative, although the pathogenesis is not always attributable to an endocrine condition. A few studies have compared biological characteristics or molecular signatures with breast cancers in women. We sought to evaluate whether hormone receptor-related gene expression is different in cancers from men compared to equivalent cancers from women. SET2,3 index measures non-proliferative hormone receptor-related transcriptional activity in the cancer (SET-ER/PR index) and adjusts this for a Baseline Prognosis Index (BPI) that combines the measurements of tumor and nodal stage with a 4-gene molecular subtype (ESR1, PGR, ERBB2, and AURKA). Methods We received aliquots of total RNA from male patients with breast cancer included in the retrospective cohort study of the EORTC 10085/BCG/TBCRC/BIG/NCTN International Male Breast Cancer Program (NCT01101425). SET2,3 assay was performed using the QuantiGene assay (Thermo Fisher) using bead-based hybridization and laser spectroscopy (Luminex). The statistical analyses were performed by the EORTC statistician. The primary objective of the study was the assessment of the prognostic value of the SET2,3 index score in patients with early-stage hormone receptor-positive, HER2-negative male breast cancer, treated with endocrine therapy. Clinical outcomes (recurrence-free survival – RFS; overall survival – OS) were estimated by Kaplan-Meier curves and secondarily compared using multivariable Cox models adjusted for continuous SET2,3 index, tumor size, nodal status, age, and chemotherapy and radiotherapy use. An exploratory analysis to compare the SET2,3 index scores distribution in female and male breast cancer patients was also performed using results from the same assay performed on cancers from women selected on the same inclusion criteria. Due to the low numbers of male patients treated with neoadjuvant treatment (N=6), this analysis was restricted to patients treated with adjuvant treatment (n=315 male and 660 female). Results Of the 321 male patients with breast cancer analyzed, treated between 1990 and 2010, 211 (65.7%) were categorized as high SET2,3 index score, reflecting a high endocrine activity in the cancer and low risk of recurrence, and 110 patients (34.3%) categorized as being low score, reflecting low endocrine activity and high risk of recurrence. At 5 years, the RFS was 75.0% (95% CI, 67.4-81.1) in the high SET2,3 group versus 60.7% (95% CI, 49.1-70.5) in the low SET2,3 group (HR univariate, 0.49; 95% CI, 0.34-0.70; P< 0.0001). The 5-year OS rate among patients with a high SET2,3 index was 84.3% (95% CI, 45.5-73.8), in contrast of 67.8% (95% CI, 56.6-76.7) in the low SET2,3 group (HR univariate, 0.44; 95% CI, 0.30-0.65; P< 0.0001). SET2,3 was independently prognostic for OS, but not RFS in multivariable Cox models. In patients classified as low SET2,3, the addition of neo/adjuvant chemotherapy to adjuvant endocrine therapy was associated with 5-year OS of 76.0% (95% CI, 59.5-86.4) and in patients who received endocrine therapy alone the 5-year OS was 61.3% (95% CI, 45.5-73.8), an absolute difference of 14.7 percentage points. Overall, we did not observe a difference in the distributions (median, interquartile range) of SET2,3 index between men (2.4, 1.9–2.6) and women (2.3, 2.0–2.7). Conclusion SET2,3 index measurements of endocrine-related transcriptional activity in male patients with breast cancer were not different from measurements in female patients with breast cancer. SET2,3 was prognostic in male breast cancer and our exploratory analysis suggests that chemotherapy might improve the poor prognosis for men with breast cancer that has low SET2,3 index. This study was funded by the Breast Cancer Research Foundation (BCRF). Citation Format: Danielle B. Zakon, Coralie Poncet, Fatima Cardoso, Neven Anouk, Vicente Valero, Stefan Aebi, Kim Benstead, Oliver Bogler, Lissandra Dal Lago, Judith Fraser, Carmela Caballero, Ingrid A. Hedenfalk, Larissa A. Korde, Barbro Linderholm, John WM Martens, Lavinia P. Middleton, Melissa Murray, Catherine M. Kelly, Cecilia Nilsson, Monika Nowaczyk, Stephanie Peeters, Melanie Beauvois, Peggy Porter, Carolien P. Schroder, Isabel T. Rubio, Kathryn Ruddy, Christi van Asperen, Danielle Van Den Weyngaert, Carolien HM van Deurzen, Elise van Leeuwen-Stok, Joanna M. Vermeij, John MS Bartlett, Antonio C. Wolff, Sharon H. Giordano, W. Fraser Symmans. PD6-11 Evaluation of the Sensitivity to Endocrine Therapy Index (SET2,3) in Early Male Breast Cancer: Results from an analysis in the EORTC 10085/TBCRC/BIG/NCTN International Male Breast Cancer Program [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD6-11.

Abstract Background: Leukocyte Adhesion Deficiency-I (LAD-I) is a rare disorder of neutrophil adhesion resulting from ITGB2 mutations encoding for the β2-integrin component, CD18. Severe LAD-I (CD18 <2% of polymorphonuclear [PMN] cells) is characterized by severe infections, impaired wound healing, and childhood mortality. Allogeneic hematopoietic stem cell transplant (alloHSCT) is potentially curative; however, its efficacy is limited by donor availability and risk of graft-versus-host disease (GVHD) and graft failure. RP-L201-0318 (NCT03812263), a phase 1/2 open-label trial currently underway, employs autologous CD34+ cells transduced with a lentiviral vector (LV) carrying the ITGB2 gene (cDNA) Methods: Pediatric patients ≥ 3 months old with severe LAD-I are eligible. HSCs are collected via apheresis after mobilization with granulocyte-colony stimulating factor (G-CSF) and plerixafor and transduced with Chim-CD18-WPRE-LV. Myeloablative therapeutic drug monitoring (TDM) busulfan conditioning precedes RP-L201 infusion. Patients are followed for safety and efficacy (i.e., survival to age 2 and at least 1-year post-infusion, increase in PMN leukocyte CD18 expression to at least 10%, peripheral blood [PB] vector copy number [VCN], decrease in infections/hospitalizations, and resolution of skin or periodontal abnormalities). Results: Seven patients (ages 5mos-9yrs) have received RP-L201; all with follow-up ≥3 to 18 months. RP-L201 cell doses ranged from 2.8x106 to 6.5x106 CD34+ cells/kg with VCN from 1.8-3.8 copies/cell. No serious RP-L201 related treatment-emergent adverse events were reported. PB PMN CD18 expression in Patient 1 at 18-months post-treatment was 40% (vs. < 1% at baseline), with PB VCN of 1.44. Baseline skin lesions resolved with no new lesions reported. CD18 expression in the subsequent 6 patients has been 25-80% in neutrophils and stable for each patient from 3 to up to 18 months post-treatment. No new infections have been reported in patients post-infusion. The safety profile of RP-L102 remains highly favorable with no serious adverse events (SAEs) attributed to the investigational product (IP). Conclusion: RP-L201 leads to durable neutrophil CD18 expression and improved clinical course. Additional patient treatment is ongoing in 2021. Disclosures Kohn: UC Regents: Patents & Royalties; Pluto Immunotherapeutics: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; ImmunoVec: Membership on an entity's Board of Directors or advisory committees; Lyrik Therapeutics: Membership on an entity's Board of Directors or advisory committees; MyoGene Bio: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Sangamo Biosciences: Membership on an entity's Board of Directors or advisory committees. Booth: GSK: Honoraria; Takeda: Honoraria; SOBI: Consultancy, Honoraria; Orchard Therapeutics: Consultancy, Honoraria; Rocket Pharmaceuticals, Inc.: Consultancy. Sevilla: Miltenyi: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Rocket Pharmaceuticals, Inc.: Consultancy, Other: J.Sevilla is an inventor on patents on lentiviral vectors filed by CIEMAT, CIBERER and Fundación Jiménez Díaz, and may be entitled to receive financial benefits from the licensing of such patents.; SOBI: Consultancy. Rao: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Almarza: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Nicoletti: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. de Oliveira: Orchard Therapeutics: Research Funding; Bluebird Bio: Research Funding. Law: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Beard: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Choi: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zeini: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Thrasher: Orchard Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bueren: Rocket Pharmaceuticals, Inc.: Consultancy, Other: J.Bueren is an inventor on patents on lentiviral vectors filed by CIEMAT, CIBERER and Fundación Jiménez Díaz, may be entitled to receive financial benefits from the licensing of such patents and receives funding for research., Patents & Royalties, Research Funding. Schwartz: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company.

BackgroundBecause conventional single-cell strategies rely on dissociating tissues into suspensions that lose spatial context,1 we developed Slide-TCR-seq to sequence both whole transcriptomes and TCRs with 10µm-spatial resolution, & applied it to renal cell carcinoma (ccRCC) treated with immune checkpoint inhibitors (ICI).MethodsSlide-TCR-seq combines Slide-seqV22 3—a 10µm-resolution spatial approach utilizing mRNA capture and DNA-barcoded beads—with sensitive targeted capture of TCR sequences (rhTCRseq,4 previously developed by our group), thereby enabling amplification of segments extending from upstream of CDR3 to the 3’-end of the TCR transcript (figure 1A). We tested Slide-TCR-seq first on OT-I murine spleen and then applied this methodology to 3 patients‘ pre-αPD-1 ccRCC samples5 and a post-αPD-1 metastasis to investigate the spatial, functional, and clonotypic organization of T cells in relationship to tumor using RCTD,6 spatial enrichment, and spatial expression analyses.ResultsUsing Slide-TCR-seq, we first recapitulated native spatial structure of OT-I mouse spleen (figure 1B-G). TCRα/β CDR3 sequences were detected on 37.1% of beads with Trac/Trbc2 constant sequences—comparable to other scTCRseq methods. Because the clonal and spatial context of TILs have been increasingly implicated in immunotherapy resistance, we used Slide-TCR-seq to analyze a lung ccRCC metastasis following αPD-1 therapy. We employed unsupervised clustering to delineate the tumor, intervening boundary, and lung compartments, and RCTD analyses to spatially map individual cell types; together recapitulating the architecture observed in corresponding histology (figure 2). We identified 1,132 unique clonotypes, with distinct spatial distributions spanning the tissue compartments. Eight clonotypes were significantly enriched in tumor, whereas 5 were depleted (all p<0.05) (figure 3). We then analyzed the relationships between the T cells’ clonotype, gene expression, and tumor infiltration depth among clonotypes. Using a T-cell geneset associated with poor response to ICI,7 we dichotomized T-clonotype beads by geneset expression, and found spatial segregation of this geneset’s expression both within and across clonotypes (figure 4). TCR-4—the most significantly tumor-enriched clonotype—and TCR-2 displayed high expression of the poor ICI response geneset near the tumor’s edge, but low expression deeper in the tumor compartment; indicating that there are transcriptionally distinct subpopulations of these clonotypes, which depended on the extent of their tumor infiltration.Abstract 76 Figure 1Slide-TCR-seq spatially localizes T cell receptors and transcriptome information. a. Schematic of Slide-TCR-seq, in which tissue is placed onto an in situ barcoded bead array. cDNA libraries prepared with Slide-seqV2 are split prior to fragmentation with one portion used for targeted amplification via rhTCRseq optimized for use with Slide-seq libraries. Slide-TCR-seq provides gene expression, cell type, and clonotype information in space. b. Serial sections of the OT-1 mouse spleen with hematoxylin and eosin stain show characteristic architecture of red pulp and white pulp separation. c. Spatial reconstruction of Slide-TCR-seq array for a corresponding section of OT-I mouse spleen, with RCTD immune cell type assignment. NK = natural killer. d. Gene expression gaussian-filtered heatmap for visualizing the spatial distribution of gene markers for marginal zone (Marco), red blood cells (RBCs; Gypa), and CD8 T cells (Cd8a). e and f. Comparing the spatial distribution of constant (left) and variable (right) sequences for TCRα (e) and TCRβ (f), with superimposed density plot. g. The fraction of beads that capture CDR3 variable sequences (y-axis) when constant UMIs are captured (x-axis) for TCRα (left, light blue) and TCRβ (right, dark blue), with the number of corresponding beads along the top axis. All scale bars: 500 µm.Abstract 76 Figure 2Slide-TCR-seq identifies spatial differences between T cell clonotypes in renal cell carcinoma. (a) H&E stain of a ccRCC metastasis to the lung following PD-1 blockade therapy. (b) The compartment assignment of lung (green), immune cell boundary (orange), and tumor (blue) by applying K-nearest neighbors to cell types determined by unsupervised clustering from Slide-TCR-seq of a sequential tissue section. (c) Spatial reconstruction of cell type identifies using RCTD anaysis of the Slide-TCR-seq data. (d) Spatial localization of T cell clonotypes (n=447 clonotypes, colored by clonotype) from the the Slide-TCR-seq data.Abstract 76 Figure 3Top: y-axis Significance of clonotype spatial distributions compared against all other clonotypes with at least ten beads per array from the ccRCC lung metastasis plotted against an x-axis of magnitude of tumor enrichment or depletion (data from n=3 replicate arrays, two one-tailed K-S tests). Bottom: Visualization of selected significant clonotypes, ordered by tumor enrichment, in tissue compartments for a single array (T cells within the tumor compartment are displayed as opaque, T cells within other compartments are displayed as translucent).Abstract 76 Figure 4Spatial and molecular heterogeneity in clonotype gene expression and tumor infiltration. a. The three axes — spatial localization, gene expression, and T cell clonotype — that Slide-TCR-seq can relate. b. Top: distribution of poor response to immune checkpoint inhibitor treatment (’PRI’) geneset7 expression across all clonotypes in the tumor region of the same post-PD1 inhibitor RCC lung metastasis from figures 2–3 (from a single replicate) with kernel density estimation. Yellow = clonotypes with lower than median PRI expression; purple = clonotypes with PRI expression greater than or equal to the median value. Bottom: localization of low (yellow) and high (purple) PRI geneset expression clonotypes within the tumor region (light blue) from the Slide-TCR-seq array shows their distinct spatial separation (light blue = tumor region, orange = boundary region, green = lung region). Scale bar: 500 µm. c. Smoothed histograms comparing the distance infiltrated into tumor by two-tailed K-S test comparing low (yellow) and high (purple) expression clonotypes, as dichotomized by median expression of PRI. d. Comparing distance infiltrated into tumor by two-tailed K-S test between low and high PRI expression T cells across those clonotypes with at least 20 beads (n=7 clonotypes).ConclusionsSlide-TCR-seq effectively integrates spatial transcriptomics with TCR detection at 10µm resolution, thereby relating T cells’ clonality and gene expression to their spatial organization in tumors. Our findings suggest that a clonotype’s T cells may exhibit mixed responses to ICI depending on their spatial localization. The heterogeneity among clonotypes, in both gene expression and organization, underscores the importance of studying the TCR repertoire with spatial resolution.AcknowledgementsWe are grateful to Irving A. Barrera-Lopez, Zoe N. Garcia, and Aziz Al’Khafaji for technical assistance.ReferencesGohil S, Iorgulescu JB, Braun D, Keskin D, Livak K. Applying high-dimensional single-cell technologies to the analysis of cancer immunotherapy. Nat Rev Clin Oncol 2021; 18:244–256.Stickels RR, Murray E, Kumar P, Li J, Marshall JL, Di Bella DJ, Arlotta P, Macosko EZ, Chen F. Highly sensitive spatial transcriptomics at near-cellular resolution with Slide-seqV2. Nat Biotechnol 2021 Mar;39(3):313–319.Rodriques SG, Stickels RR, Goeva A, Martin CA, Murray E, Vanderburg CR, Welch J, Chen LM, Chen F, Macosko EZ. Slide-seq: A scalable technology for measuring genome-wide expression at high spatial resolution. Science 2019 Mar 29;363(6434):1463–1467.Li S, Sun J, Allesøe R, Datta K, Bao Y, Oliveira G, Forman J, Jin R, Olsen LR, Keskin DB, Shukla SA, Wu CJ, Livak KJ. RNase H-dependent PCR-enabled T-cell receptor sequencing for highly specific and efficient targeted sequencing of T-cell receptor mRNA for single-cell and repertoire analysis. Nat Protoc 2019 Aug;14(8):2571–2594.Braun DA, Street K, Burke KP, Cookmeyer DL, Denize T, Pedersen CB, Gohil SH, Schindler N, Pomerance L, Hirsch L, Bakouny Z, Hou Y, Forman J, Huang T, Li S, Cui A, Keskin DB, Steinharter J, Bouchard G, Sun M, Pimenta EM, Xu W, Mahoney KM, McGregor BA, Hirsch MS, Chang SL, Livak KJ, McDermott DF, Shukla SA, Olsen LR, Signoretti S, Sharpe AH, Irizarry RA, Choueiri TK, Wu CJ. Progressive immune dysfunction with advancing disease stage in renal cell carcinoma. Cancer Cell 2021 May 10;39(5):632–648.Cable DM, Murray E, Zou LS, Goeva A, Macosko EZ, Chen F, Irizarry RA. Robust decomposition of cell type mixtures in spatial transcriptomics. Nat Biotechnol 2021 Feb 18. doi: 10.1038/s41587-021-00830-w. Epub ahead of print. PMID: 33603203.Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins RW, Lieb DJ, Chen JH, Frederick DT, Barzily-Rokni M, Freeman SS, Reuben A, Hoover PJ, Villani AC, Ivanova E, Portell A, Lizotte PH, Aref AR, Eliane JP, Hammond MR, Vitzthum H, Blackmon SM, Li B, Gopalakrishnan V, Reddy SM, Cooper ZA, Paweletz CP, Barbie DA, Stemmer-Rachamimov A, Flaherty KT, Wargo JA, Boland GM, Sullivan RJ, Getz G, Hacohen N. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 2018 Nov 1;175(4):998–1013Ethics ApprovalThis study was approved by MGB/DFCI/Broad institution’s Ethics Board; approval number 2019P000017.

Cet article est un compte-rendu du livre : Olivier Beaud, Les Libertés universitaires à l’abandon ? Pour une reconnaissance pleine et entière de la liberté académique, Paris : Dalloz, coll. « Les Sens du droit », 2010, 345 p., EAN 9782247104772.

Grimm, Dieter, Verfassung und Privatrecht im 19. Jahrhundert. Die Formationsphase (= Jus Publicum. Beiträge zum öffentlichen Recht, Bd. 269). Mohr Siebeck, Tübingen 2017, 229 S. (Thomas Simon, Wien) Beaud, Olivier/Guérin-Bargues, Cécile, L’état d’urgence – Une étude constitutionnelle, historique et critique, 2. Auflage, LGDJ, Lextenso éditions, Issy-les-Moulineaux 2018, 200 S. (Tristan Barczak, Münster) Frankenberg, Günter, Comparative Law as Critique. Edgar Elgar Publishing, Cheltenham 2016, 281 S. – und ders., Comparative Constitutional Studies: Between Magic and Deceit. Ebd., 2018, 343 S. (Philipp Dann, Berlin) Kästle-Lamparter, David, Welt der Kommentare. Struktur, Funktion und Stellenwert juristischer Kommentare in Geschichte und Gegenwart (Grundlagen der Rechtswissenschaft 30). Mohr Siebeck, Tübingen 2016, XVIII, 416 S. (Miloš Vec, Wien) Dişçi, Duygu, Der Grundsatz politischer Neutralität. Grenzen der Äußerungsbefugnis politischer Amtsträger (Schriften zum Öffentlichen Recht, Bd. 1398). Duncker &amp; Humblot, Berlin 2019, 285 S. (David Kuch, Würzburg)

AbstractThe study of lunar magma evolution holds significant importance within the scientific community due to its relevance in understanding the Moon's thermal and geological history. However, the intricate task of unraveling the history of early volcanic activity on the Moon is hindered by the high flux of impactors, which have substantially changed the morphology of pristine volcanic constructs. In this study, we focus on a unique volcanic glass found in the lunar meteorite Northwest Africa 11801. This kind of volcanic glass is bead‐like in shape and compositionally similar to the Apollo‐14 and Apollo‐17 very low‐Ti glass. Our research approach involves conducting a comprehensive analysis of the petrology and mineralogy of the volcanic glass, coupled with multiple thermodynamic modeling techniques. Through the investigation, we aim to shed light on the petrological characteristics and evolutionary history of the glass. The results indicate that the primitive magma of the glass was created at 1398–1436°C and 8.3–11.9 kbar (166–238 km) from an olivine+orthopyroxene mantle source region. Then, the magma ascended toward the surface along a non‐adiabatic path with an ascent rate of ~40 m s−1 or 0.2 MPa s−1. During the magma ascent, only olivine crystallized and the onset of magma eruption occurred at ~1320–1343°C. Finally, the glass cooled rapidly on the lunar surface with a cooling rate ranging between 20 and 200 K min−1. Considerable evidence from petrology, mineralogy, cooling rate, and the eruption rate of the glass beads strongly supports the occurrence of ancient explosive volcanism on the Moon.

Introduction It has frequently been noted that ICTs and social networking applications have blurred the once-clear boundary between work, leisure and entertainment, just as they have collapsed the distinction between public and private space. While each individual has a sense of what “home” means, both in terms of personal experience and more conceptually, the following three examples of online interaction (based on participants’ interest, or involvement, in activities traditionally associated with the home: pet care, craft and cooking) suggest that the utilisation of online communication technologies can lead to refined and extended definitions of what “home” is. These examples show how online communication can assist in meeting the basic human needs for love, companionship, shelter and food – needs traditionally supplied by the home environment. They also provide individuals with a considerably expanded range of opportunities for personal expression and emotional connection, as well as creative and commercial production, than that provided by the purely physical (and, no doubt, sometimes isolated and isolating) domestic environment. In this way, these case studies demonstrate the interplay and melding of physical and virtual “home” as domestic practices leach from the most private spaces of the physical home into the public space of the Internet (for discussion, see Gorman-Murray, Moss, and Rose). At the same time, online interaction can assert an influence on activity within the physical space of the home, through the sharing of advice about, and modeling of, domestic practices and processes. A Dog’s (Virtual) Life The first case study primarily explores the role of online communities in the formation and expression of affective values and personal identity – as traditionally happens in the domestic environment. Garber described the 1990s as “the decade of the dog” (20), citing a spate of “new anthropomorphic” (22) dog books, Internet “dog chat” sites, remakes of popular classics such as Lassie Come Home, dog friendly urban amenities, and the meteoric rise of services for pampered pets (28-9). Loving pets has become a lifestyle and culture, witnessed and commodified in Pet Superstores as well as in dog collectables and antiques boutiques, and in publications like The Bark (“the New Yorker of Dog Magazines”) and Clean Run, the international agility magazine, Website, online book store and information gateway for agility products and services. Available online resources for dog lovers have similarly increased rapidly during the decade since Garber’s book was published, with the virtual world now catering for serious hobby trainers, exhibitors and professionals as well as the home-based pet lover. At a recent survey, Yahoo Groups – a personal communication portal that facilitates social networking, in this case enabling users to set up electronic mailing lists and Internet forums – boasted just over 9,600 groups servicing dog fanciers and enthusiasts. The list Dogtalk is now an announcement only mailing list, but was a vigorous discussion forum until mid-2006. Members of Dogtalk were Australian-based “clicker-trainers”, serious hobbyist dog trainers, many of whom operated micro-businesses providing dog training or other pet-related services. They shared an online community, but could also engage in “flesh-meets” at seminars, conferences and competitive dog sport meets. An author of this paper (Rutherford) joined this group two years ago because of her interest in clicker training. Clicker training is based on an application of animal learning theory, particularly psychologist E. F. Skinner’s operant conditioning, so called because of the trademark use of a distinctive “click” sound to mark a desired behaviour that is then rewarded. Clicker trainers tend to dismiss anthropomorphic pack theory that positions the human animal as fundamentally opposed to non-human animals and, thus, foster a partnership (rather than a dominator) mode of social and learning relationships. Partnership and nurturance are common themes within the clicker community (as well as in more traditional “home” locations); as is recognising and valuing the specific otherness of other species. Typically, members regard their pets as affective equals or near-equals to the human animals that are recognised members of their kinship networks. A significant function of the episodic biographical narratives and responses posted to this list was thus to affirm and legitimate this intra-specific kinship as part of normative social relationship – a perspective that is not usually validated in the general population. One of the more interesting nexus that evolved within Dogtalk links the narrativisation of the pet in the domestic sphere with the pictorial genre of the family album. Emergent technologies, such as digital cameras together with Web-based image manipulation software and hosting (as provided by portals like Photobucket and Flickr ) democratise high quality image creation and facilitate the sharing of these images. Increasingly, the Dogtalk list linked to images uploaded to free online galleries, discussed digital image composition and aesthetics, and shared technical information about cameras and online image distribution. Much of this cultural production and circulation was concerned with digitally inscribing particular relationships with individual animals into cultural memory: a form of family group biography (for a discussion of the family photograph as a display of extended domestic space, see Rose). The other major non-training thread of the community involves the sharing and witnessing of the trauma suffered due to the illness and loss of pets. While mourning for human family members is supported in the off-line world – with social infrastructure, such as compassionate leave and/or bereavement counselling, part of professional entitlements – public mourning for pets is not similarly supported. Yet, both cultural studies (in its emphasis on cultural memory) and trauma theory have highlighted the importance of social witnessing, whereby traumatic memories must be narratively integrated into memory and legitimised by the presence of a witness in order to loosen their debilitating hold (Felman and Laub 57). Postings on the progress of a beloved animal’s illness or other misfortune and death were thus witnessed and affirmed by other Dogtalk list members – the sick or deceased pet becoming, in the process, a feature of community memory, not simply an individual loss. In terms of such biographical narratives, memory and history are not identical: “Any memories capable of being formed, retained or articulated by an individual are always a function of socially constituted forms, narratives and relations … Memory is always subject to active social manipulation and revision” (Halbwachs qtd. in Crewe 75). In this way, emergent technologies and social software provide sites, akin to that of physical homes, for family members to process individual memories into cultural memory. Dogzonline, the Australian Gateway site for purebred dog enthusiasts, has a forum entitled “Rainbow Bridge” devoted to textual and pictorial memorialisation of deceased pet dogs. Dogster hosts the For the Love of Dogs Weblog, in which images and tributes can be posted, and also provides links to other dog oriented Weblogs and Websites. An interesting combination of both therapeutic narrative and the commodification of affect is found in Lightning Strike Pet Loss Support which, while a memorial and support site, also provides links to the emerging profession of pet bereavement counselling and to suppliers of monuments and tributary urns for home or other use. loobylu and Narratives of Everyday Life The second case study focuses on online interactions between craft enthusiasts who are committed to the production of distinctive objects to decorate and provide comfort in the home, often using traditional methods. In the case of some popular craft Weblogs, online conversations about craft are interspersed with, or become secondary to, the narration of details of family life, the exploration of important life events or the recording of personal histories. As in the previous examples, the offering of advice and encouragement, and expressions of empathy and support, often characterise these interactions. The loobylu Weblog was launched in 2001 by illustrator and domestic crafts enthusiast Claire Robertson. Robertson is a toy maker and illustrator based in Melbourne, Australia, whose clients have included prominent publishing houses, magazines and the New York Public Library (Robertson “Recent Client List” online). She has achieved a measure of public recognition: her loobylu Weblog has won awards and been favourably commented upon in the Australian press (see Robertson “Press for loobylu” online). In 2005, an article in The Age placed Robertson in the context of a contemporary “craft revolution”, reporting her view that this “revolution” is in “reaction to mass consumerism” (Atkinson online). The hand-made craft objects featured in Robertson’s Weblogs certainly do suggest engagement with labour-intensive pursuits and the construction of unique objects that reject processes of mass production and consumption. In this context, loobylu is a vehicle for the display and promotion of Robertson’s work as an illustrator and as a craft practitioner. While skills-based, it also, however, promotes a family-centred lifestyle; it advocates the construction by hand of objects designed to enhance the appearance of the family home and the comfort of its inhabitants. Its specific subject matter extends to related aspects of home and family as, in addition to instructions, ideas and patterns for craft, the Weblog features information on commercially available products for home and family, recipes, child rearing advice and links to 27 other craft and other sites (including Nigella Lawson’s, discussed below). The primary member of its target community is clearly the traditional homemaker – the mother – as well as those who may aspire to this role. Robertson does not have the “celebrity” status of Lawson and Jamie Oliver (discussed below), nor has she achieved their market saturation. Indeed, Robertson’s online presence suggests a modest level of engagement that is placed firmly behind other commitments: in February 2007, she announced an indefinite suspension of her blog postings so that she could spend more time with her family (Robertson loobylu 17 February 2007). Yet, like Lawson and Oliver, Robertson has exploited forms of domestic competence traditionally associated with women and the home, and the non-traditional medium of the Internet has been central to her endeavours. The content of the loobylu blog is, unsurprisingly, embedded in, or an accessory to, a unifying running commentary on Robertson’s domestic life as a parent. Miles, who has described Weblogs as “distributed documentaries of the everyday” (66) sums this up neatly: “the weblogs’ governing discursive quality is the manner in which it is embodied within the life world of its author” (67). Landmark family events are narrated on loobylu and some attract deluges of responses: the 19 June 2006 posting announcing the birth of Robertson’s daughter Lily, for example, drew 478 responses; five days later, one describing the difficult circumstances of her birth drew 232 comments. All of these comments are pithy, with many being simple empathetic expressions or brief autobiographically based commentaries on these events. Robertson’s news of her temporary retirement from her blog elicited 176 comments that both supported her decision and also expressed a sense of loss. Frequent exclamation marks attest visually to the emotional intensity of the responses. By narrating aspects of major life events to which the target audience can relate, the postings represent a form of affective mass production and consumption: they are triggers for a collective outpouring of largely homogeneous emotional reaction (joy, in the case of Lily’s birth). As collections of texts, they can be read as auto/biographic records, arranged thematically, that operate at both the individual and the community levels. Readers of the family narratives and the affirming responses to them engage in a form of mass affirmation and consumerism of domestic experience that is easy, immediate, attractive and free of charge. These personal discourses blend fluidly with those of a commercial nature. Some three weeks after loobylu announced the birth of her daughter, Robertson shared on her Weblog news of her mastitis, Lily’s first smile and the family’s favourite television programs at the time, information that many of us would consider to be quite private details of family life. Three days later, she posted a photograph of a sleeping baby with a caption that skilfully (and negatively) links it to her daughter: “Firstly – I should mention that this is not a photo of Lily”. The accompanying text points out that it is a photo of a baby with the “Zaky Infant Sleeping Pillow” and provides a link to the online pregnancystore.com, from which it can be purchased. A quotation from the manufacturer describing the merits of the pillow follows. Robertson then makes a light-hearted comment on her experiences of baby-induced sleep-deprivation, and the possible consequences of possessing the pillow. Comments from readers also similarly alternate between the personal (sharing of experiences) to the commercial (comments on the product itself). One offshoot of loobylu suggests that the original community grew to an extent that it could support specialised groups within its boundaries. A Month of Softies began in November 2004, describing itself as “a group craft project which takes place every month” and an activity that “might give you a sense of community and kinship with other similar minded crafty types across the Internet and around the world” (Robertson A Month of Softies online). Robertson gave each month a particular theme, and readers were invited to upload a photograph of a craft object they had made that fitted the theme, with a caption. These were then included in the site’s gallery, in the order in which they were received. Added to the majority of captions was also a link to the site (often a business) of the creator of the object; another linking of the personal and the commercial in the home-based “cottage industry” sense. From July 2005, A Month of Softies operated through a Flickr site. Participants continued to submit photos of their craft objects (with captions), but also had access to a group photograph pool and public discussion board. This extension simulates (albeit in an entirely visual way) the often home-based physical meetings of craft enthusiasts that in contemporary Australia take the form of knitting, quilting, weaving or other groups. Chatting with, and about, Celebrity Chefs The previous studies have shown how the Internet has broken down many barriers between what could be understood as the separate spheres of emotional (that is, home-based private) and commercial (public) life. The online environment similarly enables the formation and development of fan communities by facilitating communication between those fans and, sometimes, between fans and the objects of their admiration. The term “fan” is used here in the broadest sense, referring to “a person with enduring involvement with some subject or object, often a celebrity, a sport, TV show, etc.” (Thorne and Bruner 52) rather than focusing on the more obsessive and, indeed, more “fanatical” aspects of such involvement, behaviour which is, increasingly understood as a subculture of more variously constituted fandoms (Jenson 9-29). Our specific interest in fandom in relation to this discussion is how, while marketers and consumer behaviourists study online fan communities for clues on how to more successfully market consumer goods and services to these groups (see, for example, Kozinets, “I Want to Believe” 470-5; “Utopian Enterprise” 67-88; Algesheimer et al. 19-34), fans regularly subvert the efforts of those urging consumer consumption to utilise even the most profit-driven Websites for non-commercial home-based and personal activities. While it is obvious that celebrities use the media to promote themselves, a number of contemporary celebrity chefs employ the media to construct and market widely recognisable personas based on their own, often domestically based, life stories. As examples, Jamie Oliver and Nigella Lawson’s printed books and mass periodical articles, television series and other performances across a range of media continuously draw on, elaborate upon, and ultimately construct their own lives as the major theme of these works. In this, these – as many other – celebrity chefs draw upon this revelation of their private lives to lend authenticity to their cooking, to the point where their work (whether cookbook, television show, advertisement or live chat room session with their fans) could be described as “memoir-illustrated-with-recipes” (Brien and Williamson). This generic tendency influences these celebrities’ communities, to the point where a number of Websites devoted to marketing celebrity chefs as product brands also enable their fans to share their own life stories with large readerships. Oliver and Lawson’s official Websites confirm the privileging of autobiographical and biographical information, but vary in tone and approach. Each is, for instance, deliberately gendered (see Hollows’ articles for a rich exploration of gender, Oliver and Lawson). Oliver’s hip, boyish, friendly, almost frantic site includes the what are purported-to-be self-revelatory “Diary” and “About me” sections, a selection of captioned photographs of the chef, his family, friends, co-workers and sponsors, and his Weblog as well as footage streamed “live from Jamie’s phone”. This self-revelation – which includes significant details about Oliver’s childhood and his domestic life with his “lovely girls, Jools [wife Juliette Norton], Poppy and Daisy” – completely blurs the line between private life and the “Jamie Oliver” brand. While such revelation has been normalised in contemporary culture, this practice stands in great contrast to that of renowned chefs and food writers such as Elizabeth David, Julia Child, James Beard and Margaret Fulton, whose work across various media has largely concentrated on food, cooking and writing about cooking. The difference here is because Oliver’s (supposedly private) life is the brand, used to sell “Jamie Oliver restaurant owner and chef”, “Jamie Oliver cookbook author and TV star”, “Jamie Oliver advertising spokesperson for Sainsbury’s supermarket” (from which he earns an estimated £1.2 million annually) (Meller online) and “Jamie Oliver social activist” (made MBE in 2003 after his first Fifteen restaurant initiative, Oliver was named “Most inspiring political figure” in the 2006 Channel 4 Political Awards for his intervention into the provision of nutritious British school lunches) (see biographies by Hildred and Ewbank, and Smith). Lawson’s site has a more refined, feminine appearance and layout and is more mature in presentation and tone, featuring updates on her (private and public) “News” and forthcoming public appearances, a glamorous selection of photographs of herself from the past 20 years, and a series of print and audio interviews. Although Lawson’s children have featured in some of her television programs and her personal misfortunes are well known and regularly commented upon by both herself and journalists (her mother, sister and husband died of cancer) discussions of these tragedies, and other widely known aspects of her private life such as her second marriage to advertising mogul Charles Saatchi, is not as overt as on Oliver’s site, and the user must delve to find it. The use of Lawson’s personal memoir, as sales tool, is thus both present and controlled. This is in keeping with Lawson’s professional experience prior to becoming the “domestic goddess” (Lawson 2000) as an Oxford graduated journalist on the Spectator and deputy literary editor of the Sunday Times. Both Lawson’s and Oliver’s Websites offer readers various ways to interact with them “personally”. Visitors to Oliver’s site can ask him questions and can access a frequently asked question area, while Lawson holds (once monthly, now irregularly) a question and answer forum. In contrast to this information about, and access to, Oliver and Lawson’s lives, neither of their Websites includes many recipes or other food and cooking focussed information – although there is detailed information profiling their significant number of bestselling cookbooks (Oliver has published 8 cookbooks since 1998, Lawson 5 since 1999), DVDs and videos of their television series and one-off programs, and their name branded product lines of domestic kitchenware (Oliver and Lawson) and foodstuffs (Oliver). Instruction on how to purchase these items is also featured. Both these sites, like Robertson’s, provide various online discussion fora, allowing members to comment upon these chefs’ lives and work, and also to connect with each other through posted texts and images. Oliver’s discussion forum section notes “this is the place for you all to chat to each other, exchange recipe ideas and maybe even help each other out with any problems you might have in the kitchen area”. Lawson’s front page listing states: “You will also find a moderated discussion forum, called Your Page, where our registered members can swap ideas and interact with each other”. The community participants around these celebrity chefs can be, as is the case with loobylu, divided into two groups. The first is “foodie (in Robertson’s case, craft) fans” who appear to largely engage with these Websites to gain, and to share, food, cooking and craft-related information. Such fans on Oliver and Lawson’s discussion lists most frequently discuss these chefs’ television programs and books and the recipes presented therein. They test recipes at home and discuss the results achieved, any problems encountered and possible changes. They also post queries and share information about other recipes, ingredients, utensils, techniques, menus and a wide range of food and cookery-related matters. The second group consists of “celebrity fans” who are attracted to the chefs (as to Robertson as craft maker) as personalities. These fans seek and share biographical information about Oliver and Lawson, their activities and their families. These two areas of fan interest (food/cooking/craft and the personal) are not necessarily or always separated, and individuals can be active members of both types of fandoms. Less foodie-orientated users, however (like users of Dogtalk and loobylu), also frequently post their own auto/biographical narratives to these lists. These narratives, albeit often fragmented, may begin with recipes and cooking queries or issues, but veer off into personal stories that possess only minimal or no relationship to culinary matters. These members also return to the boards to discuss their own revealed life stories with others who have commented on these narratives. Although research into this aspect is in its early stages, it appears that the amount of public personal revelation either encouraged, or allowed, is in direct proportion to the “open” friendliness of these sites. More thus are located in Oliver’s and less in Lawson’s, and – as a kind of “control” in this case study, but not otherwise discussed – none in that of Australian chef Neil Perry, whose coolly sophisticated Website perfectly complements Perry’s professional persona as the epitome of the refined, sophisticated and, importantly in this case, unapproachable, high-end restaurant chef. Moreover, non-cuisine related postings are made despite clear directions to the contrary – Lawson’s site stating: “We ask that postings are restricted to topics relating to food, cooking, the kitchen and, of course, Nigella!” and Oliver making the plea, noted above, for participants to keep their discussions “in the kitchen area”. Of course, all such contemporary celebrity chefs are supported by teams of media specialists who selectively construct the lives that these celebrities share with the public and the postings about others’ lives that are allowed to remain on their discussion lists. The intersection of the findings reported above with the earlier case studies suggests, however, that even these most commercially-oriented sites can provide a fruitful data regarding their function as home-like spaces where domestic practices and processes can be refined, and emotional relationships formed and fostered. In Summary As convergence results in what Turow and Kavanaugh call “the wired homestead”, our case studies show that physically home-based domestic interests and practices – what could be called “home truths” – are also contributing to a refiguration of the private/public interplay of domestic activities through online dialogue. In the case of Dogtalk, domestic space is reconstituted through virtual spaces to include new definitions of family and memory. In the case of loobylu, the virtual interaction facilitates a development of craft-based domestic practices within the physical space of the home, thus transforming domestic routines. Jamie Oliver’s and Nigella Lawson’s sites facilitate development of both skills and gendered identities by means of a bi-directional nexus between domestic practices, sites of home labour/identity production and public media spaces. As participants modify and redefine these online communities to best suit their own needs and desires, even if this is contrary to the stated purposes for which the community was instituted, online communities can be seen to be domesticated, but, equally, these modifications demonstrate that the activities and relationships that have traditionally defined the home are not limited to the physical space of the house. While virtual communities are “passage points for collections of common beliefs and practices that united people who were physically separated” (Stone qtd in Jones 19), these interactions can lead to shared beliefs, for example, through advice about pet-keeping, craft and cooking, that can significantly modify practices and routines in the physical home. Acknowledgments An earlier version of this paper was presented at the Association of Internet Researchers’ International Conference, Brisbane, 27-30 September 2006. 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The Wired Homestead: An MIT Press Sourcebook on the Internet and the Family. Cambridge, MA: MIT Press, 2003. Citation reference for this article MLA Style Brien, Donna Lee, Leonie Rutherford, and Rosemary Williamson. "Hearth and Hotmail: The Domestic Sphere as Commodity and Community in Cyberspace." M/C Journal 10.4 (2007). echo date('d M. Y'); ?> <http://journal.media-culture.org.au/0708/10-brien.php>. APA Style Brien, D., L. Rutherford, and R. Williamson. (Aug. 2007) "Hearth and Hotmail: The Domestic Sphere as Commodity and Community in Cyberspace," M/C Journal, 10(4). Retrieved echo date('d M. Y'); ?> from <http://journal.media-culture.org.au/0708/10-brien.php>.