dolls/puppets like mensch – dolls/puppets as artificial beings. Part 1.2

Die dritte Ausgabe der Zeitschrift denkste: puppe / just a bit of: doll (de:do), ein multi-disziplinäres Online-Journal für Mensch-Puppen-Diskurse, erscheint als Doppelheft, dessen gemeinsamer Themenschwerpunkt lautet: puppen/dolls like mensch – puppen als künstliche meschen. Mit diesem Fokus wird ein Thema aufgegriffen, das Menschen seit der Antike berührt und bis heute ihren Verstand und ihre Imagination, ihre Bedürfnisse und ihre Gefühle in Unruhe versetzt. In Mythologien, literarischen Fiktionen und Narrativen für Erwachsene und Kinder, in Werken der bildenden Künste, im Film, in mechanisch-technischen Anwendungen und Utopien, in den performativen Künsten, in der (Spiel-)Pädagogik und in den verschiedenen Bereichen der Popkultur wirft das Motiv der Puppe mit seinen unterschiedlichsten Ausdrucksformen immer auch existenzielle Fragen auf: Wer und was ist der Mensch? Die Puppe als künstlicher Mensch ist in gewisser Weise wie mensch, ohne Mensch zu sein. Als von Menschen geschaffene Abbilder, Vorbilder, Nachahmungen und Entwürfe des Menschen spiegeln und bestätigen Puppen vorhandene Lebenswelten und loten gleichzeitig Potenziale und Abgründe des Mensch-Seins zwischen Utopie und Dystopie, zwischen Neugier und Hingabe, zwischen Horror und Glückseligkeit, zwischen Macht und Ohnmacht aus. Puppen/dolls like mensch – der doppelte Wortsinn betont die gegebene Ambiguität der Puppen und die spannenden, ihnen innewohnenden Ambivalenzen. Im ersten Teilband (1.1) wird den Spuren und Erscheinungsformen des Puppenmotivs und der Puppe(n) – als literarisches Narrativ, als künstlerisches Motiv, als materialisiertes Objekt – vor allem im Kontext von bildender Kunst, Literatur, Fotografie, Theater und Androidentechnologien nachgegangen. Im zweiten Teilband (1.2) werden zum einen kinderliterarische und (spiel-)didaktische Texte akzentuiert, zum anderen sind hier verschiedene mediale und popkulturelle Formate aus den Bereichen Computerspiel, Comic-Film-Adaptation, Film (unterschiedlicher Genres) und dem Figurentheater versammelt sowie Thematisierungen der Verknüpfung von materiellen Artefakten und literarischen Narrativen. Rezensionen in Form von Essays über literarische Puppen-Narrative, eine Foto-Ausstellung und ein Ballett runden beide Ausgaben ab. Die zeitliche Spanne reicht vom Mittelalter bis in die Gegenwart und Zukunft und zeigt einmal mehr, wie über das Narrativ der Puppe uralte Menschheitsfragen in Traditionslinien eingebunden werden und sie auf faszinierende Weisen fortschreiben.The third edition of the journal denkste: puppe / just a bit of: doll (de: do), a multidisciplinary online journal for human-doll discourses, is a double issue whose shared thematic focus is: puppen/dolls like mensch – dolls/puppets as artificial beings. With this focus, we take up a topic that has concerned mankind since ancient times and has always upset their 'minds' and 'hearts’, their needs and feelings. In mythologies, literary fictions and narratives for adults as well as for children, in works of the visual arts, in film, in mechanical-technical applications and utopias, in the performative arts, in (play-)pedagogy and in the various fields of pop culture, the motif of the doll with its various forms of expression always raises existential questions: Who is man, what is human? The doll as an artificial human being is in a certain way like mensch without being human. As man-made images, as models, imitations and designs of humans, dolls/puppets reflect and confirm existing worlds and at the same time sound out the potentials and abysses of being human between utopia and dystopia, between curiosity and devotion, between horror and bliss, between power and powerlessness. Dolls/puppets like mensch – the double meaning of these words emphasizes the given ambiguity of the dolls/puppets and the intriguing ambivalences inherent in them. In the first part of volume (1.1) the traces and manifestations of the doll motif and of doll(s) – as literary narrative, as artistic motif, as materialized object – will be explored primarily in the context of the fine arts, of literature, photography, theater and android technologies. In the second part of the volume (1.2), on the one hand, children's literature and (play)didactic texts are accentuated; on the other hand, various media and pop-cultural formats from the fields of computer games, comic-film adaptations, films (of different genres) and puppet theater performances are gathered here, as well as issues that link material artifacts and literary narratives. Reviews in the form of essays on literary doll narratives, a photo exhibition and a ballet round off both editions. The time span extends from the Middle Ages to the present and future and shows once again how age-old questions regarding mankind and humanity are integrated into traditional lines and are carried on continuously in fascinating ways

Tetracycline Inducible Gene Manipulation in Serotonergic Neurons

The serotonergic (5-HT) neuronal system has important and diverse physiological functions throughout development and adulthood. Its dysregulation during development or later in adulthood has been implicated in many neuropsychiatric disorders. Transgenic animal models designed to study the contribution of serotonergic susceptibility genes to a pathological phenotype should ideally allow to study candidate gene overexpression or gene knockout selectively in serotonergic neurons at any desired time during life. For this purpose, conditional expression systems such as the tet-system are preferable. Here, we generated a transactivator (tTA) mouse line (TPH2-tTA) that allows temporal and spatial control of tetracycline (Ptet) controlled transgene expression as well as gene deletion in 5-HT neurons. The tTA cDNA was inserted into a 196 kb PAC containing a genomic mouse Tph2 fragment (177 kb) by homologous recombination in E. coli. For functional analysis of Ptet-controlled transgene expression, TPH2-tTA mice were crossed to a Ptet-regulated lacZ reporter line (Ptet-nLacZ). In adult double-transgenic TPH2-tTA/Ptet-nLacZ mice, TPH2-tTA founder line L62-20 showed strong serotonergic β-galactosidase expression which could be completely suppressed with doxycycline (Dox). Furthermore, Ptet-regulated gene expression could be reversibly activated or inactivated when Dox was either withdrawn or added to the system. For functional analysis of Ptet-controlled, Cre-mediated gene deletion, TPH2-tTA mice (L62-20) were crossed to double transgenic Ptet-Cre/R26R reporter mice to generate TPH2-tTA/Ptet-Cre/R26R mice. Without Dox, 5-HT specific recombination started at E12.5. With permanent Dox administration, Ptet-controlled Cre-mediated recombination was absent. Dox withdrawal either postnatally or during adulthood induced efficient recombination in serotonergic neurons of all raphe nuclei, respectively. In the enteric nervous system, recombination could not be detected. We generated a transgenic mouse tTA line (TPH2-tTA) which allows both inducible and reversible transgene expression and inducible Cre-mediated gene deletion selectively in 5-HT neurons throughout life. This will allow precise delineation of serotonergic gene functions during development and adulthood

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

The LHCb upgrade I

The LHCb upgrade represents a major change of the experiment. The detectors have been almost completely renewed to allow running at an instantaneous luminosity five times larger than that of the previous running periods. Readout of all detectors into an all-software trigger is central to the new design, facilitating the reconstruction of events at the maximum LHC interaction rate, and their selection in real time. The experiment's tracking system has been completely upgraded with a new pixel vertex detector, a silicon tracker upstream of the dipole magnet and three scintillating fibre tracking stations downstream of the magnet. The whole photon detection system of the RICH detectors has been renewed and the readout electronics of the calorimeter and muon systems have been fully overhauled. The first stage of the all-software trigger is implemented on a GPU farm. The output of the trigger provides a combination of totally reconstructed physics objects, such as tracks and vertices, ready for final analysis, and of entire events which need further offline reprocessing. This scheme required a complete revision of the computing model and rewriting of the experiment's software

The ALICE experiment at the CERN LHC

ALICE (A Large Ion Collider Experiment) is a general-purpose, heavy-ion detector at the CERN LHC which focuses on QCD, the strong-interaction sector of the Standard Model. It is designed to address the physics of strongly interacting matter and the quark-gluon plasma at extreme values of energy density and temperature in nucleus-nucleus collisions. Besides running with Pb ions, the physics programme includes collisions with lighter ions, lower energy running and dedicated proton-nucleus runs. ALICE will also take data with proton beams at the top LHC energy to collect reference data for the heavy-ion programme and to address several QCD topics for which ALICE is complementary to the other LHC detectors. The ALICE detector has been built by a collaboration including currently over 1000 physicists and engineers from 105 Institutes in 30 countries. Its overall dimensions are 161626 m3 with a total weight of approximately 10 000 t. The experiment consists of 18 different detector systems each with its own specific technology choice and design constraints, driven both by the physics requirements and the experimental conditions expected at LHC. The most stringent design constraint is to cope with the extreme particle multiplicity anticipated in central Pb-Pb collisions. The different subsystems were optimized to provide high-momentum resolution as well as excellent Particle Identification (PID) over a broad range in momentum, up to the highest multiplicities predicted for LHC. This will allow for comprehensive studies of hadrons, electrons, muons, and photons produced in the collision of heavy nuclei. Most detector systems are scheduled to be installed and ready for data taking by mid-2008 when the LHC is scheduled to start operation, with the exception of parts of the Photon Spectrometer (PHOS), Transition Radiation Detector (TRD) and Electro Magnetic Calorimeter (EMCal). These detectors will be completed for the high-luminosity ion run expected in 2010. This paper describes in detail the detector components as installed for the first data taking in the summer of 2008

Structural and Psychosocial Challenges Among Underserved Patients Receiving Hemodialysis During and Beyond the COVID-19 Pandemic: A Qualitative Study

Rationale & Objective: Racial and ethnic minority groups in the United States are disproportionately affected by chronic kidney disease and progressive kidney failure and face significantly more socioeconomic and psychosocial challenges. However, how such patients’ social environment and stigmatization shape their illness experiences and abilities to cope before and during the coronavirus disease 2019 (COVID-19) pandemic has not been well documented, even as social scientific research predicts these groups’ exponential vulnerability. Study Design: Qualitative study using semistructured interviews to elicit individual patient narratives about their personal illness experiences before and during the COVID-19 pandemic, any challenges they faced, and their sources of support. Setting & Participants: Using purposive sampling, we recruited 20 adult patients receiving maintenance hemodialysis from centers affiliated with a safety-net hospital in Boston, Massachusetts. Analytical Approach: Interviews were audiotaped, transcribed, and analyzed using thematic content analysis to identify patients’ challenges and supports before and during the pandemic. Results: Of the 20 patients in the study, 9 were women, and 18 self-identified as Black or African American. Three main themes emerged, whereby most patients described: (1) stigma and stigmatization as a central element of their life experience; (2) the pandemic as a difficult experience but not a complete rupture from their prepandemic life; and (3) social networks, particularly family, friends, and religious communities, as sources of support crucial to coping with their debilitating illness. Limitations: Whether the findings apply to other settings is unknown, as participants were recruited from centers in a single safety-net urban hospital setting. Conclusions: Psychosocial and environmental factors, including institutional racism and stigmatization, play significant roles in amplifying the burdens shouldered by racial and ethnic minority individuals with kidney disease who now also face the COVID-19 pandemic that has since turned endemic. The results of this study can inform the development of policy interventions aimed at alleviating tensions and structural conditions that impinge on kidney disease patients’ wellbeing and health outcomes. Plain-Language Summary: Members of racial and ethnic minority groups in the United States experience the highest rates of progressive kidney failure and face significantly more socioeconomic and psychosocial challenges. We interviewed 20 patients who receive maintenance hemodialysis treatment from centers affiliated with a safety-net hospital. Patients described stigmatization as a central element of their life experience and the pandemic as a difficult challenge (but not a complete rupture) that added to their struggles with illness-related, race-related, and class-related stigmas. Social networks, particularly family, friends, and religious communities, are key sources of support crucial to coping with illness. Findings from this study can inform health care providers and community workers and guide the development of policy interventions to provide better support for these patients

Circulating Proteins and Mortality in CKD: A Proteomics Study of the AASK and ARIC Cohorts

Rationale &amp; Objective: Proteomics could provide pathophysiologic insight into the increased risk of mortality in patients with chronic kidney disease (CKD). This study aimed to investigate associations between the circulating proteome and all-cause mortality among patients with CKD. Study Design: Observational cohort study. Setting &amp; Participants: Primary analysis in 703 participants in the African American Study of Kidney Disease and Hypertension (AASK) and validation in 1,628 participants with CKD in the Atherosclerosis Risk in Communities (ARIC) study who attended visit 5. Exposure: Circulating proteins. Outcome: All-cause mortality. Analytical Approach: Among AASK participants, we evaluated the associations of 6,790 circulating proteins with all-cause mortality using multivariable Cox proportional hazards models. Proteins with significant associations were further studied in ARIC Visit 5 participants with CKD. Results: In the AASK cohort, the mean age was 54.5 years, 271 (38.5%) were women, and the mean measured glomerular filtration rate (GFR) was 46 mL/min/1.73 m2. The median follow-up was 9.6 years, and 7 distinct proteins were associated with all-cause mortality at the Bonferroni-level threshold (P < 0.05 of the 6,790) after adjustment for demographics and clinical factors, including baseline measured estimated GFR and proteinuria. In the ARIC visit 5 cohort, the mean age was 77.2 years, 903 (55.5%) were women, the mean estimated GFR was 54 mL/min/1.73 m2 and median follow-up was 6.9 years. Of the 7 proteins found in AASK, 3 (β2-microglobulin, spondin-1, and N-terminal pro-brain natriuretic peptide) were available in the ARIC data, with all 3 significantly associated with death in ARIC. Limitations: Possibility of unmeasured confounding. Cause of death was not known. Conclusions: Using large-scale proteomic analysis, proteins were reproducibly associated with mortality in 2 cohorts of participants with CKD. Plain-Language Summary: Patients with chronic kidney disease (CKD) have a high risk of premature death, with various pathophysiological processes contributing to this increased risk of mortality. This observational cohort study aimed to investigate the associations between circulating proteins and all-cause mortality in patients with CKD using large-scale proteomic analysis. The study analyzed data from the African American Study of Kidney Disease and Hypertension (AASK) study and validated the findings in the Atherosclerosis Risk in Communities (ARIC) Study. A total of 6,790 circulating proteins were evaluated in AASK, and 7 proteins were significantly associated with all-cause mortality. Three of these proteins (β2-microglobulin, spondin-1, and N-terminal pro-brain natriuretic peptide (BNP)) were also measured in ARIC and were significantly associated with death. Additional studies assessing biomarkers associated with mortality among patients with CKD are needed to evaluate their use in clinical practice

Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2

SummaryMembers of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1), which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses