1,720,991 research outputs found
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Large-scale omics-based assessments of aging trajectories in flies and mice
No full textThe significant increase in life expectancy over the past two centuries can be attributed to advancements in public health, including improved sanitation, access to clean drinking water, widespread immunization, and the development of antibiotics. However, the expansion of human lifespan has led to a rise in chronic diseases typically linked to advanced age, thus shifting the burden of illness to later stages of life. The hallmarks of aging encompass biological processes such as genomic instability, telomere attrition, epigenetic alterations, and several factors. Conventional methods of measuring aging, like relying on lifespan as a proxy for aging, are not sufficient to sufficiently address the complex nature of aging. Therefore, it is necessary to adopt a more comprehensive approach that takes into account the many facets of aging and age-dependent change in physiological function. This thesis utilizes proteomics and transcriptomics to uncover a specific set of age-sensitive biomarkers and investigate their dynamic expression patterns. The research is organized into three interrelated chapters: the first chapter examines the proteomic landscape of normal aging across mouse tissues, the second chapter investigates genetic expression patterns associated with the stabilization of mortality in late life, and the third chapter explores the effects of environmental temperature on aging.
Our findings reveal distinct age-dependent proteomic changes across various organs, emphasizing the dynamic and organ-specific nature of aging. The identification of ASPs and their unique expression patterns provides deeper insights into the molecular mechanisms of aging, with implications for potential biomarkers of age-related diseases. Additionally, the study of Drosophila melanogaster demonstrates a stabilization phase in gene expression associated with a mortality plateau, suggesting biological mechanisms that limit further aging-related deterioration. This phenomenon is further validated by the evaluation of GFP reporter line-Drosomycin as one of the ASGs, offering a deeper perspective on plateau phase at the individual level. To ensure this is a convincing finding, more investigations into the GFP reporter lines are ongoing. Lastly, our investigation into the effects of ambient temperature on lifespan highlights the enduring influence of environmental factors, with transient exposure to low temperature extending lifespan and improving motor performance in later life stages. As previously said, lifespan is not an accurate proxy of aging due to its susceptibility to age-related pathologies like cancer. Proteome analysis will be conducted to evaluate the effect of transient exposure to low temperature on aging extending beyond the lifespan. In summary, this thesis improves our comprehension of age-dependent changes in the multi-omics profiles over time, shedding light on the nature of the aging progress. These findings provide a solid foundation for future studies that aim to understand a wide range of molecular processes involved in aging and find ways to support healthy aging and examine the effect of potential anti-aging therapies on age-related illnesses
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Late-life aging dynamics in <em>C. elegans</em>
No full textAging is a complex biological process marked by a progressive decline in physiological function, leading to increased vulnerability for diseases and mortality. While early and mid-life aging dynamics are well-characterized, less is known about the physiological changes that occur in late life. This thesis investigates the dynamics of aging in the model organism C. elegans, focusing on whether late life presents a deceleration in age-related changes, akin to the mortality plateau observed in many species. Our aim was to characterize proteomic and transcriptomic changes in C. elegans across the lifespan, including late life, thus contributing to a deeper understanding of the aging process.
Our methods included RNA-seq and mass spectrometry to profile age-sensitive genes (ASGs) and age-sensitive proteins (ASPs). Lifespan assays were used to identify critical periods in the aging trajectory, allowing for targeted sample collection in early, middle, and late life phases.
Our transcriptomic and proteomic analyses identified 3686 ASGs and 658 ASPs, respectively, that were used to study the kinetics of age-dependent phenotypic change across the lifespan in C. elegans. These analyses revealed two distinct phases: an initial period of age-related change, followed by a plateau phase in late life as demonstrated by a stabilization of changes in ASGs and ASPs expression. This late-life phase is also associated with a plateau in mortality rates, suggesting a biological transition where some age-sensitive pathways stabilize or even reverse.
Additionally, we used these datasets to identify genes that feature stability across a range of conditions and that may therefore be useful as reference genes in C. elegans. Our work identified 7 stable reference genes (pmp-3, orc-2, praf-3, aars-2, unc-16, gtf-2F1, and ZK1307.8) that maintain consistent gene expression across various conditions, including multiple age groups (days 6, 8, 12, 14, 18, 20, 24), different mutant strains (WT, age-1, daf-2, isp-1), and a range of temperatures (15°C, 20°C and 25°C), whereas previous studies typically focused on a limited set of time points.
To our knowledge, these findings represent the first study to systematically demonstrate, beyond mere lifespan data, that age-dependent changes follow a dynamic that entails a plateau phase in late life, indicating that aging-associated changes stop progressing and stabilize at advanced ages. Future studies need to address the generality of this finding by incorporating longitudinal analysis approaches and extending the assessments to additional biological systems
Somatic cell-derived extracellular vesicles and phenotypic outcomes in the next generation
Full text linkEvidence from both human and animal studies demonstrate that paternal experiences and exposures can cause phenotypic changes in the next generation. Extracellular vesicles (EVs) released by somatic cells are hypothesised to play a role in these paternal effects by acting as a messenger between somatic cells, including those of the male reproductive tract, and germ cells. To date, evidence acquired mainly from in vitro and a few in vivo studies confirm this EV-sperm interaction and information transfer. In this thesis, we aimed to establish an in vivo model system, in the mouse and in the fly, with inhibited secretion of EVs from somatic cells of the male reproductive tract, with the intention to utilise this model to study the impact of EVs on phenotypic outcomes in the next generation and their role as potential mediators of paternal intergenerational effects.
Within the epididymis of the male mouse reproductive tract, the knock-out of three different genes encoding proteins shown in in vitro studies to be involved in EV secretion or biogenesis did not change the number or size of EVs isolated from the epididymal fluid. This finding demonstrates the difficulty of transferability between model organisms in the EV field. Notably, mRNA sequencing analysis of the epididymal EVs from Rab27-DKO mice suggests a potential involvement of the EV mRNA in the sperm maturation process.
Using the UAS-Gal4 system, we established a Drosophila melanogaster model with an inhibited secretion of CD63-GFP from secondary cells, by expressing RNAis against known components of the EV pathway. Prior to mating, these F0 flies were exposed to dietary interventions. Phenotypic and transcriptomic analyses of the generated F1 flies demonstrate paternal genotype and paternal diet dependent changes. These paternal intergenerational effects are firstly sex-specific and age-dependent, and secondly influenced by somatic cell-derived EVs. Furthermore, we are the first to observe that the exposure of male flies expressing Rab11-RNAi under dve-Gal4 control to high sugar and high fat diet cause pernicious sex-specific intergenerational effects. This finding is suggested to be caused by the combined vulnerability of paternal midgut cells and the exposure to energy dense foods, a so far unexplored paternal condition that causes phenotypic changes to the next generation
Charakterisierung von perivaskulärem Fettgewebe
Full text linkDie Prävalenz von Übergewicht hat sich laut World Health Organization weltweit seit 1975 nahezu verdreifacht und hat in den letzten Jahren pandemische Ausmaße erreicht. Adipositas geht mit verschiedenen Komorbiditäten einher wie Diabetes mellitus Typ 2, verschiedenen Krebserkrankungen und kardiovaskulären Erkrankungen. Das in dieser Dissertation näher zu untersuchende perivaskuläre Fettgewebe (PVAT) befindet sich in direkter anatomischer Nachbarschaft zur Adventitia, der äußeren Schicht der Gefäßwand. Fettgewebe ist ein sekretorisch aktives Organ und auch PVAT schüttet Botenstoffe aus, die möglicherweise die Gefäße und deren Funktionalität beeinflussen können, was eine mögliche interessante Verbindung zwischen Adipositas und kardiovaskulären Erkrankungen darstellt.
Ziel dieser Arbeit ist die Charakterisierung sowie der Vergleich von PVAT unterschiedlicher anatomischer Herkunft sowie der Vergleich der verschiedenen PVAT-Depots mit anderen Fettgewebe-Depots auch unter verschiedenen experimentellen Bedingungen (Hochfettdiät (HFD), Kälteexposition, Thermoneutralität). Hierzu wurde PVAT von drei verschiedenen Stellen der murinen Aorta entnommen (Aorta ascendens thoracalis, Aorta descendens thoracalis und Aorta abdominalis). Zudem wurde interscapulär gelegenes braunes Fettgewebe (BAT) sowie inguinal und gonadal gelegenes weißes Fettgewebe (WAT) entnommen. Die Morphologie von PVAT wurde mittels histologischen Färbungen (HE- und UCP-1-Antikörper-Färbung) untersucht. Darüber hinaus wurden mRNA-Analysen (quantitativen Polymerase-Kettenreaktion) durchgeführt, um PVAT bezüglich der thermogenen Eigenschaften sowie exprimierter Botenstoffe näher zu untersuchen. Darüber hinaus wurde PVAT verschiedener Mauslinien (C57/BL6j, 129/Sv und BALB/c) bezüglich Morphologie und thermogener Marker untersucht.
In dieser Arbeit konnte gezeigt werden, dass PVAT der A. ascendens thoracalis, A. descendens thoracalis und A. abdominalis unter verschiedenen Konditionen sowie in verschiedenen Mauslinien einen BAT-ähnlichen Phänotyp besitzt und wurde somit als braunes Fettgewebe charakterisiert. Dennoch scheint es zwischen diesen drei PVAT-Depots Unterschiede sowohl morphologisch als auch bezüglich der thermogenen Eigenschaften zu geben. Außerdem kam es sowohl nach Kälteexposition als auch nach HFD in PVAT zu einem Vorgang der als „Browning“ bezeichnet wird. Was diese Ergebnisse im Hinblick auf den Gefäßtonus und das inflammatorische Profil von PVAT im Zusammenhang mit Adipositas und weiteren assoziierten Erkrankungen wie kardiovaskulären Erkrankungen bedeutet, bedarf weiterer ausgiebiger Analysen
Tissue cell-type composition changes during aging in mice
No full textAging is linked to progressive alterations in organ functionality and a heightened susceptibility to various diseases. These age-related functional deteriorations are likely, in part, due to microstructural changes within organs, even in the absence of pathological conditions. Examining cellular composition at the organ-level across tissues traditionally posed significant challenges due to the high workload associated with the application of unbiased cell counting methods across a range of histological samples. Here, we employed bulk RNA-sequencing, coupled with deconvolution based on celltype specific markers, to generate datasets and derive estimates regarding agingassociated changes in cell-type composition across multiple tissues (brain, heart, lung, skeletal muscle, kidney, testis) in male C57BL/6J mice, covering much of their lifespan (3, 5, 8, 14, 20 and 26 month). We show that with advanced age, immune cell types showed predominant changes among all tested tissues. Across organs, most immune cells increased with advancing age while parenchymal cells showed a decreasing trend during aging. In addition, we mined publicly available RNA-seq datasets in mice to identify experimental conditions that either counteract or phenocopy aging-associated changes in cellular tissue composition. These analyses revealed, for instance, that diabetes phenocopies aging associated changes in the mouse kidney, and calorie restriction counteract aging in mice muscle. Additional well-established cell counting methodologies were used to confirm findings obtained using our deconvolution approach
Immunotherapy-based targeting of senescent cells
Full text linkCellular senescence is a state of permanent cell cycle arrest, characterized by substantial macromolecular alterations and senescence-associated secretory phenotype (SASP) in response to various stressors. The accumulation of senescent cells is thought to play a crucial role in aging-associated physiological decline and the pathogenesis of various age-related diseases. Clearance of senescent cells by transgenic or pharmaceutical strategies has been reported to attenuate various age-related pathologies and extend lifespan in mice. However, current senolytics still have limitations in terms of potency and specificity. Immunotherapy, particularly chimeric antigen receptor (CAR)-T cell therapy, emerges as a promising avenue to selectively eliminate senescent cells. Despite its potential, the effectiveness of this therapy hinges on the precise identification of senescence-associated surface antigens (senoantigens). Even though some surface markers for cellular senescence have been first identified in human fibroblasts, the translational potential of these findings is constrained by the limited senescent cell models previously established. The comprehensive identification of senescence-associated surface proteins remains to be achieved.
First, to investigate the efficacy of CAR-T cells in targeting and eliminating senescent cells in vitro, we focused on the Natural killer group 2D (NKG2D) receptor, which binds to NKG2D ligands (NKG2DLs) expressed on the surface of senescent cells, providing a target for CAR-T cells. Employing mouse embryonic fibroblasts (MEFs) and astrocytes (AST) as senescence models, we demonstrate the elevated expression of NKG2DLs in response to genotoxic and oxidative stress. NKG2D-CAR T cells displayed potent cytotoxicity against these senescent cells, with minimal effects on non-senescent cells, suggesting their potential as targeted senolytics. Our research presents the first evidence of NKG2D-CAR T cells’ ability to target senescent brain cells, offering a novel approach to manage senescence-associated diseases. The findings pave the way for future investigations into the therapeutic applicability of NKG2D-targeting CAR-T cells in naturally aged organisms and models of aging-associated brain diseases in vivo.
Furthermore, to identify novel cell surface markers for potential senotherapeutic targeting, we conducted an extensive analysis of the cell surface proteome, or “surfaceome”, in senescent cells, spanning various senescence induction regimes and encompassing both murine and human cell types. Utilizing quantitative mass spectrometry, we investigated enriched cell surface proteins across eight distinct models of senescence. Our results uncover significant changes in surfaceome expression profiles during senescence, highlighting extensive modifications in cell mechanics and extracellular matrix remodeling. Our research also reveals substantive heterogeneity of senescence, predominantly influenced by cell type and senescence inducer. We identified four cell surface proteins with extracellular epitopes, namely PLXNA1, PLXNA3, PTK7, and CYB5R1. These proteins are expressed in senescent cells, absent or present at low levels in their proliferating counterparts, and notably upregulated in tissues from aged mice and an Alzheimer's disease mouse model. These proteins emerge as promising candidates for senotherapeutic targeting, offering potential pathways for identifying and selectively targeting senescent cell populations in aging and age-related diseases
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