The Role of Gtl2 in Hepatocarcinogenesis

Carcinogenesis is a progressive multistep progress comprising various genetic alterations such as mutations in tumor suppressor genes and oncogenes. Non-genotoxic carcinogens (NGC) induce tumor formation by mechanisms other than changes in the underlying DNA sequence. Phenobarbital (PB) is a classic non-genotoxic carcinogen leading to perturbations in gene expression and DNA methylation. In mice, PB selects for Ctnnb1 (encoding β-catenin) mutated liver tumors. Recently, non-coding RNAs from the Dlk1 Dio3 cluster were identified as potential biomarkers for mouse liver tumor promotion caused by PB. One gene within this imprinted region is named Gtl2/ Meg3. We could show that Gtl2 expression was elevated in mice treated with substances of the PB type like PCB 153 and conazole funizides. But the transferability of the biomarker potential of Gtl2 to rats was limited. Using a switchable Gtl2 expressing hepatoma cell line, we found out that the expression of several microRNAs, immune system genes and olfactory receptors were altered with enforced Gtl2 expression. A supposable mechanism to regulate olfactory receptor and immune system gene expression could be via the polycomb repressive complex 2. Due to the lack of an appropriate Gtl2 knockout mouse model, Gtl2 was constitutively overexpressed in murine liver by the use of adenoviral Gtl2. There, Gtl2 was found to regulate cell cycle genes. No final decision could be made whether Gtl2 serves as a tumor suppressor as proposed in literature or as a tumor promoter suggested by members of the MARCAR consortium. There were supports for both characteristics. An initiation promotion study in a mouse constitutively overexpressing Gtl2 would help to answer this question. The second part of this work was to generate a glutamine synthetase (GS) gene expression “atlas” in a GS reporter mouse, which indirectly predicts in which organs/ cells Wnt signaling is active. Most GS promoter activity was found in brain, liver, kidney, testis and heart. In addition, the growth of GS positive liver tumors was pursued non-invasively in the GS reporter mouse by MRI, whereas PET failed to visualize small GS positive liver tumors.Karzinogenese ist einen fortschreitender, mehrstufiger Prozess, der verschiedene genetische Veränderungen wie Mutationen in Tumorsuppressorgenen und Onkogenen umfasst. Nicht-genotoxische Karzinogene (NGC) induzieren die Tumorbildung durch Mechanismen ohne die zugrundeliegende DNA Sequenz zu verändern. Phenobarbital (PB) ist ein klassischer Vertreter der nicht-genotoxischen Karzinogene, das zu Veränderungen in der Genexpression und DNA Methylierung führt. In Mäusen selektiert PB für Ctnnb1 (codiert für β-Catenin) mutierte Lebertumore. Kürzlich wurden nicht-kodierende RNAs aus dem Dlk1-Dio3 Cluster als potentielle Biomarker für Lebertumore der Maus identifiziert, die durch PB verursacht wurden. Ein Gen innerhalb dieser imprinteten Region ist Gtl2/ Meg3. Wir konnten zeigen, dass die Gtl2 Expression in Mäusen erhöht war, die mit Substanzen des PB Typs wie PCB 153 und Conazol Fungiziden behandelt wurden. Jedoch war die Übertragbarkeit des Biomarkerpotentials von Gtl2 auf Ratten begrenzt. Durch Verwendung einer schaltbaren, Gtl2 exprimierenden Leberkrebs-Zelllinie fanden wir heraus, dass die Expression von mehreren microRNAs, von Genen des Immunsystems und olfaktorischen Rezeptoren durch verstärkte Gtl2 Expression verändert war. Ein denkbarer Mechanismus für die Regulation der Expression von olfaktorischen Rezeptoren und Genen des Immunsystems könnte über den polycomb repressive complex 2 ablaufen. Aufgrund des Mangels an einem geeigneten Gtl2 knockout Mausmodell wurde Gtl2 durch adenovirales Gtl2 in der Mausleber konstitutiv überexprimiert. Dabei wurde Gtl2 als Regulator der Gene des Zellzyklus identifiziert. Es konnte aber keine abschließende Entscheidung getroffen werden, ob Gtl2 als Tumorsuppressor fungiert, wie in der Literatur vorgeschlagen, oder aber als Tumorpromoter, wie Mitglieder des MARCAR Konsortiums annehmen. Es gab Hinweise für beide Möglichkeiten. Ein Initiations-Promotions-Experiment in Mäusen, die Gtl2 konstitutiv überexprimieren, würde helfen, diese Frage zu beantworten. Der zweite Teil dieser Arbeit befasste sich mit dem Anlegen eines Glutaminsythetase (GS) Expressions-Atlases in einer GS Reportermaus, wodurch indirekt vorausgesagt werden kann, in welchen Organen/ Zellen der Wnt Signalweg aktiv ist. Am meisten GS Promoteraktivität wurde in Gehirn, Leber, Niere, Hoden und Herz gefunden. Zusätzlich wurde das Wachstum GS positiver Lebertumore in der GS Reportermaus durch MRT nicht-invasiv verfolgt, wohingegen es misslang, kleine GS positive Lebertumore mit PET sichtbar zu machen

The INSPIRE Population Survey: development, dissemination and respondent characteristics

BACKGROUND Most older adults prefer to continue living at home despite increasing care needs and demand for services. To aid in maintaining independence, integrated care models for community-dwelling older people are promoted as the most cost-effective approach. The implementation of such care models is challenging and often the end-users are not involved or their needs are not considered. We conducted a population survey in order to understand the needs and preferences of home-dwelling older adults living in Canton Basel-Landschaft, Switzerland. The aims of this paper are to chronicle the development of the INSPIRE Population Survey, outline its variables and measurements, describe the marketing strategy utilized for survey dissemination and report on the response rate and respondent characteristics. METHODS The INSPIRE Population Survey, conducted between March and August 2019, is a cross-sectional survey of older adults aged 75 and older living at home in Canton Basel-Landschaft. The questionnaire was developed by expert input and stakeholder involvement. Its readability and acceptability were pilot-tested with older people. To ensure the likelihood of a high and representative response rate, a meticulous step-by-step marketing strategy was developed prior to the dissemination of the questionnaire. RESULTS The overall response rate was 30.7% (n = 8,846), with variations between 20.6 and 34.5% across the different care regions in the canton. A generally higher response rate was found in the care regions with a higher density and which bordered the urban city of Basel. We received support from local stakeholders, policy makers and media through using a broad combination of marketing channels and targeting our community partners who have a strong relationship with our target audience. CONCLUSIONS Although recruiting older adults in research is challenging, our study shows that a high response rate can be achieved by developing the survey through expert input and by involving all important stakeholders, including older adults, throughout the entire process

Factors associated with health-related quality of life among home-dwelling older adults aged 75 or older in Switzerland: a cross-sectional study

HRQoL is an indicator of individuals' perception of their overall health, including social and environmental aspects. As a multidimensional concept, HRQoL can be influenced by a multitude of factors. Studies of HRQoL and factors associated with it among home-dwelling older adults have often been limited to inpatient settings or to a sub-population with a chronic disease. Studying HRQoL and its correlating factors among this population, by providing an ecological lens on factors beyond the individual level, can provide a better understanding of the construct and the role of the environment on how they perceive their HRQoL. Thus, we aimed to assess the HRQoL and investigate the correlates of HRQOL among home-dwelling older adults, guided by the levels of the ecological model.; This is a cross-sectional population survey conducted in 2019 in Canton Basel-Landschaft, in northwestern Switzerland, and includes a sample of 8786 home-dwelling older adults aged 75 and above. We assessed HRQoL by using the EQ-index and the EQ-VAS. The influence of independent variables at the macro, meso and micro level on HRQoL was tested using Tobit multiple linear regression modelling.; We found that having a better socio-economic status as denoted by higher income, having supplementary insurance and a higher level of education were all associated with a better HRQoL among home-dwelling older adults. Furthermore, being engaged in social activities was also related to an improved HRQoL. On the other hand, older age, female gender, presence of multimorbidity and polypharmacy as well as social isolation and loneliness were found to all have a negative impact on HRQoL.; Understanding factors related to HRQoL by using an ecological lens can help identify factors beyond the individual level that impact the HRQoL of home-dwelling older adults. Our study emphasises the importance of social determinants of health and potential disparities that exists, encouraging policymakers to focus on policies to reduce socio-economic disparities using a life-course approach, which consequently could also impact HRQoL in later stages of life

Optimal treatment intensity in children with Down syndrome and myeloid leukaemia: data from 56 children treated on NOPHO-AML protocols and a review of the literature

Abstract Children with Down syndrome (DS) and myeloid leukaemia have a significantly higher survival rate than other children, but they also experience considerable treatment-related toxicity. We analysed data on 56 children with DS who were treated on the Nordic Society for Paediatric Haematology and Oncology-acute myeloid leukaemia (NOPHO-AML)88 and NOPHO-AML93 protocols and reviewed the literature. In the dose-intensive NOPHO-AML88 protocol, 8 out of 15 patients (53%) experienced an event. In the less dose-intensive NOPHO-AML93 protocol, 7 out of 41 patients (17%) had an event. Therapy was reduced in 29 patients (52%) with in average 75% and 67% of the scheduled dose of anthracycline and cytarabine, respectively. Treatment-related death occurred in seven who all received full treatment. Relapse and resistant disease occurred at a similar rate in those receiving full and reduced treatment. Review of major series of myeloid leukaemia of DS showed no clear relationship between dose and survival; however, it appears that both a reduction in treatment dose and a less intensively timed treatment regimen improved the outcome. Further studies are needed to define the optimal regimen for treating myeloid leukaemia of DS

The bouba/kiki effect is robust across cultures and writing systems

The bouba/kiki effect-the association of the nonce word bouba with a round shape and kiki with a spiky shape-is a type of correspondence between speech sounds and visual properties with potentially deep implications for the evolution of spoken language. However, there is debate over the robustness of the effect across cultures and the influence of orthography. We report an online experiment that tested the bouba/kiki effect across speakers of 25 languages representing nine language families and 10 writing systems. Overall, we found strong evidence for the effect across languages, with bouba eliciting more congruent responses than kiki. Participants who spoke languages with Roman scripts were only marginally more likely to show the effect, and analysis of the orthographic shape of the words in different scripts showed that the effect was no stronger for scripts that use rounder forms for bouba and spikier forms for kiki. These results confirm that the bouba/kiki phenomenon is rooted in crossmodal correspondence between aspects of the voice and visual shape, largely independent of orthography. They provide the strongest demonstration to date that the bouba/kiki effect is robust across cultures and writing systems. This article is part of the theme issue 'Voice modulation: from origin and mechanism to social impact (Part II)'.Peer reviewe

Novel vocalizations are understood across cultures

Linguistic communication requires speakers to mutually agree on the meanings of words, but how does such a system first get off the ground? One solution is to rely on iconic gestures: visual signs whose form directly resembles or otherwise cues their meaning without any previously established correspondence. However, it is debated whether vocalizations could have played a similar role. We report the first extensive cross-cultural study investigating whether people from diverse linguistic backgrounds can understand novel vocalizations for a range of meanings. In two comprehension experiments, we tested whether vocalizations produced by English speakers could be understood by listeners from 28 languages from 12 language families. Listeners from each language were more accurate than chance at guessing the intended referent of the vocalizations for each of the meanings tested. Our findings challenge the often-cited idea that vocalizations have limited potential for iconic representation, demonstrating that in the absence of words people can use vocalizations to communicate a variety of meanings.Peer reviewe

Proceedings in Marine Biology

“Proceedings in Marine Biology” is an international journal publishing original research by graduate students on all aspects of marine biology. Subjects covered include: ecological surveys and population studies of oceanic, coastal and shore communities; physiology and experimental biology; taxonomy, morphology and life history of marine animals and plants. Papers are also published on techniques em - ployed at sea for sampling, recording, capture and observation of marine organisms.Zeitschrift zur Kursabschlussreise der Humboldt-Universität zu Berlin (Deutschland) im Bereich Elektronenmikroskopie.Peer Reviewe

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Extensive alterations of the whole-blood transcriptome are associated with body mass index: results of an mRNA profiling study involving two large population-based cohorts

Background: Obesity, defined as pathologically increased body mass index (BMI),is strongly related to an increased risk for numerous common cardiovascular and metabolic diseases. It is particularly associated with insulin resistance, hyperglycemia, and systemic oxidative stress and represents the most important risk factor for type 2 diabetes (T2D). However, the pathophysiological mechanisms underlying these associations are still not completely understood. Therefore, in order to identify potentially disease-relevant BMI-associated gene expression signatures, a transcriptome-wide association study (TWAS) on BMI was performed. Methods: Whole-blood mRNA levels determined by array-based transcriptional profiling were correlated with BMI in two large independent population-based cohort studies (KORA F4 and SHIP-TREND) comprising a total of 1977 individuals. Results: Extensive alterations of the whole-blood transcriptome were associated with BMI: More than 3500 transcripts exhibited significant positive or negative BMI-correlation. Three major whole-blood gene expression signatures associated with increased BMI were identified. The three signatures suggested: i) a ratio shift from mature erythrocytes towards reticulocytes, ii) decreased expression of several genes essentially involved in the transmission and amplification of the insulin signal, and iii) reduced expression of several key genes involved in the defence against reactive oxygen species (ROS). Conclusions: Whereas the first signature confirms published results, the other two provide possible mechanistic explanations for well-known epidemiological findings under conditions of increased BMI, namely attenuated insulin signaling and increased oxidative stress. The putatively causative BMI-dependent down-regulation of the expression of numerous genes on the mRNA level represents a novel finding. BMI-associated negative transcriptional regulation of insulin signaling and oxidative stress management provide new insights into the pathogenesis of metabolic syndrome and T2D