Cells from icons to symbols molecularising cell biology in the 1980s

This thesis addresses the visual change that began to take place in cell biology by the early 1980’s as manifested in textbooks. From that time onwards images produced by instruments of a different nature to the optical and electronic microscopes began to compete for visual supremacy. An important consequence of this visuality shift has been the creation of epistemic discontinuity inside the discipline. New areas, such as signal transduction, fully dependent on this kind of visuality began to emerge. The thesis places and argues for this visual shift as occurring in the context of the following related co-productive developments during the 1960s to 1980s: The promotion and expansion of the project of molecularisation into cell biology. The occurrence of deep changes in academic institutions, oriented to mimic industrial set ups based on network functioning and more flexible forms of production. The emergence of textbooks to better prepare newcomers to the discipline for the production needs of the laboratory. An extensive use of new techniques mainly from molecular biology, biochemistry and immunology. And last but not least, the emergence of a new type of scientific self armoured with a new set of moral codes and attitudes. The study is based on a visual examination of the images contained in the different editions (from 1983 to 2008) of the textbook Molecular Biology of the Cell (MBC) by Alberts et al, as the book that heralded molecularisation inside cell biology. The imagery displayed in this textbook is compared with the different editions (from 1948 to 1987) of the originally entitled General Cytology textbook of De Robertis et al, the book that belonged to the microscopical tradition of thought. The theoretical framework I am using to understand this visual shift as occurring in textbooks is based on semiotics and simulation theory. This dissertation argues that the visual change that the discipline of cell biology began to endure from the early 1980s entails an overall substitution of signs from iconic to symbolic forms and that the new symbolic imagery builds its authenticity and gains its widespread acceptance not only from its experimental validity, but also from the traces they contain derived from both indexical and iconic forms. In a more explorative tone I argue that this new symbolic cell biology is at risk of becoming a self-referential system with a remote relationship with the experimental arrangement it originates from

MALATTIA DI ALZHEIMER E DEGENERAZIONE LOBARE FRONTOTEMPORALE: RICERCA DI MUTAZIONI AUTOSOMICHE DOMINANTI E ANALISI GENETICA E FUNZIONALE DI GENI CANDIDATI

This PhD study is intended to perform a genetic screening on a population of AD and FTLD patients in order to identify pathogenetic causal mutations (PSEN1, PSEN2 and APP for AD; MAPT, GRN and the GGGGCC repeat expansion one the C9orf72 gene for FTLD) and to investigate the role of several candidate genes (GRN,TMEM106b and OLR1) considered to be risk factors for the two disease. Eighteen patients were carriers of pathogenetic causal mutations: 1 carrier of Ala260Val (g.49964C>T) situated in exon 8 of PSEN1,16 carriers of GRN gene mutations and 1 carrier of a new variant, Gly304Ser (g.123789G>A), located in exon 10 of MAPT gene. The presence of GGGGCC repeat expansion, positioned on the first intron of C9orf72 gene, was analyzed in a larger population (651 FTLD patients, 21 CBD and 31 PSP patients). Thirty nine patients with FTLD were carriers of pathogenetic repeat expansion, whereas none of CBD and PSP patients as well as 222 controls carried the mutation. Several associations studies were performed in the remaining sporadic population of AD and FTLD patients. Regarding the influence of GRN genetic variability on susceptibility to AD, two SNPs rs9897526G>A and rs5848 were investigated. A tendency to an increased frequency of rs5848T allele was found in AD patients as compared with controls, whereas for the rs9897526 SNP, in patients carrying the rs9897526A variant was observed a significant earlier age at disease onset compared with patients carrying the G allele. The case-control study carried out on a populations of FTLD patients was focused on four Tagging SNPs (rs2879096, rs3785817, rs4792938 and rs9897526) as well as on rs5848 SNP, localized in the 3\u2019UTR of GRN gene. A statistically significant association of the rs4792938 CC genotype was observed in FTLD patients compared with healthy controls. Concerning the role of TMEM106b gene on susceptibility to AD, an association analysis was performed on three SNP, rs1020004 A/G, rs6966915 C/T and rs1990622 A/G, but no significant differences in allelic and genotype frequencies were found for all polymorphisms between AD patients and controls. The possible functional importance of genetic variability associated with this gene was tested by plasmatic ELISA detection of GRN on eighty AD patients. Stratifying the results according to rs1990622 SNP status, no significant differences in progranulin plasma levels were found in AD patients. Regarding OLR1, in particular it was analyzed the SNP rs1050283 T/C, located in 3\u2019UTR of the gene. Logistic regression analysis, adjusted for gender and ApoE status, showed a statistically significant association of OLR1 rs1050283 under the assumption of a dominant and a genotypic model. Therefore this SNP could be considered a susceptibility factor for sporadic AD. Given that the SNP rs1050283 is also located in a predicted binding site of the miRNA has-miR369-3p, a preliminary expression analysis was performed on the two transcripts in the PBMC in order to clarify a possible functional role of individual genetic variability on the expression of OLR1 gene. Stratifying the results according to the presence of rs1050283C allele, a significant decrease of relative expression levels of OLR1 was observed in patients carrying at least one polymorphic C allele, despite the normal expression levels of has-miR369-3p. These data suggest that the presence of the polymorphic allele could influence the binding of has-miR369-3p to its 3\u2019UTR consensus sequence, in which the SNP is located

Diasporic Chilean and Argentinean narratives in the UK: the traces of second generation postmemory

This thesis analyses the interrelated concepts of diasporic postmemory and how they apply to the oral narratives of a small group of second generation Chileans and Argentineans living in the UK, whose parents were political exiles and economic migrants linked to the Chilean (1973-1990), and Argentinean (1976-1983) dictatorships. Diasporic postmemory as a ‘multidirectional’ theory is used to discuss these narratives in a ‘delocalised’ context where it is argued that two central memory fields overlap: the first being the field of the ‘politics of memory’ in the Southern Cone, and the second the ‘diaspora field’. It will be argued that these narratives occupy a mobile and situated diasporic ‘in-between’ space, indicative of ‘translocational positionalities’ that shift between a UK context and abroad. By presenting these postmemory narratives together, we can come to explore how the legacies of the dictatorships in Chile and Argentina continue to have resonances beyond the stable boundaries of the field of the politics of memory in those countries. As such, they hold the possibility to move beyond the direct victims of state terrorism and their kin, encompassing a wider ‘affective community’ of diasporic positionalities and subjectivities tied to wider societal responses to the legacy of state terrorism and trauma. Furthermore, I will also discuss how in this diaspora space, the positionalities of the researcher and interviewees are intertwined, and form part of subjectivities that can become ethical and reflexive subjects of postmemory, in mutually articulating alternative possibilities for more diversified and collective forms of multidirectional memories to emerge

Hox proteins drive cell segregation and non-autonomous apical remodelling during hindbrain segmentation

Hox genes encode a conserved family of homeodomain transcription factors regulating development along the major body axis. During embryogenesis, Hox proteins are expressed in segment-specific patterns and control numerous different segment-specific cell fates. It has been unclear, however, whether Hox proteins drive the epithelial cell segregation mechanism that is thought to initiate the segmentation process. Here, we investigate the role of vertebrate Hox proteins during the partitioning of the developing hindbrain into lineage-restricted units called rhombomeres. Loss-of-function mutants and ectopic expression assays reveal that Hoxb4 and its paralogue Hoxd4 are necessary and sufficient for cell segregation, and for the most caudal rhombomere boundary (r6/r7). Hox4 proteins regulate Eph/ephrins and other cell-surface proteins, and can function in a non-cell-autonomous manner to induce apical cell enlargement on both sides of their expression border. Similarly, other Hox proteins expressed at more rostral rhombomere interfaces can also regulate Eph/ephrins, induce apical remodelling and drive cell segregation in ectopic expression assays. However, Krox20, a key segmentation factor expressed in odd rhombomeres (r3 and r5), can largely override Hox proteins at the level of regulation of a cell surface target, Epha4. This study suggests that most, if not all, Hox proteins share a common potential to induce cell segregation but in some contexts this is masked or modulated by other transcription factors

Exosome determinants of physiological aging and age-related neurodegenerative diseases

Aging is consistently reported as the most important independent risk factor for neurodegenerative diseases. As life expectancy has significantly increased during the last decades, neurodegenerative diseases became one of the most critical public health problem in our society. The most investigated neurodegenerative diseases during aging are Alzheimer disease (AD), Frontotemporal Dementia (FTD) and Parkinson disease (PD). The search for biomarkers has been focused so far on cerebrospinal fluid (CSF) and blood. Recently, exosomes emerged as novel biological source with increasing interest for age-related neurodegenerative disease biomarkers. Exosomes are tiny Extracellular vesicles (EVs; 30\u2013100 nm in size) released by all cell types which originate from the endosomal compartment. They constitute important vesicles for the release and transfer of multiple (signaling, toxic, and regulatory) molecules among cells. Initially considered with merely waste disposal function, instead exosomes have been recently recognized as fundamental mediators of intercellular communication. They can move from the site of release by diffusion and be retrieved in several body fluids, where they may dynamically reflect pathological changes of cells present in inaccessible sites such as the brain. Multiple evidence has implicated exosomes in age-associated neurodegenerative processes, which lead to cognitive impairment in later life. Critically, consolidated evidence indicates that pathological protein aggregates, including A\u3b2, tau, and \u3b1-synuclein are released from brain cells in association with exosomes. Importantly, exosomes act as vehicles between cells not only of proteins but also of nucleic acids [DNA, mRNA transcripts, miRNA, and non-coding RNAs (ncRNAs)] thus potentially influencing gene expression in target cells. In this framework, exosomes could contribute to elucidate the molecular mechanisms underneath neurodegenerative diseases and could represent a promising source of biomarkers. Despite the involvement of exosomes in age-associated neurodegeneration, the study of exosomes and their genetic cargo in physiological aging and in neurodegenerative diseases is still in its infancy. Here, we review, the current knowledge on protein and ncRNAs cargo of exosomes in normal aging and in age-related neurodegenerative diseases

A natural antisense RNA derived from the HIV-1 env gene encodes a protein which is recognized by circulating antibodies of HIV+ individuals

AbstractA naturally occurring antisense RNA, transcribed in the opposite direction and complementary to the envelope transcript,was identified in various cell lines chronically infected with HIV-1. In T cells, the antisense transcript is constitutively expressed and enhanced by activation with phorbol myristate acetate. The open reading frame corresponding to the antisense transcript, when expressed in vitro, encodes a protein with an apparent molecular mass of 19 kDa. Antibodies against this protein have been detected in several sera of HIV+ individuals and not in any of the noninfected control sera. These results indicate, for the first time, that expression of an antisense open reading frame most likely accompanies the HIV infection cycle in humans

Role of Genetics and Epigenetics in the Pathogenesis of Alzheimer's Disease and Frontotemporal Dementia

Alzheimer's disease (AD) and frontotemporal dementia (FTD) represent the first cause of dementia in senile and pre-senile population, respectively. A percentage of cases have a genetic cause, inherited with an autosomal dominant pattern of transmission. The majority of cases, however, derive from complex interactions between a number of genetic and environmental factors. Gene variants may act as risk or protective factors. Their combination with a variety of environmental exposures may result in increased susceptibility to these diseases or may influence their course. The scenario is even more complicated considering the effect of epigenetics, which encompasses mechanisms able to alter the expression of genes without altering the DNA sequence. In this review, an overview of the current genetic and epigenetic progresses in AD and FTD will be provided, with particular focus on 1) causative genes, 2) genetic risk factors and disease modifiers, and 3) epigenetics, including methylation, non-coding RNAs and chromatin remodeling

Etching kinetics of nanodiamond seeds in the early stages of CVD diamond growth

We present an experimental study on the etching of detonation nanodiamond (DND) seeds during typical microwave chemical vapor deposition (MWCVD)conditions leading to ultra-thin diamond film formation, which is fundamental for many technological applications. The temporal evolution of the surface density of seeds on the Si(100) substrate has been assessed by scanning electron microscopy (SEM). The resulting kinetics have been explained in the framework of a model based on the effect of the particle size, according to the Young-Laplace equation,on both chemical potential of carbon atoms in DND and activation energy of the reaction with atomic hydrogen. The model describes the experimental kinetics of seeds' disappearance by assuming that nanodiamond particles with a size smaller than a "critical radius", r*, are etched away while those greater than r* can grow. Finally, the model allows to estimate the rate coefficients for growth and etching from the experimental kinetics

Size dependent etching of nanodiamond seeds in the early stages of CVD diamond growth

We present an experimental study on the etching of detonation nanodiamond (DND) seeds during typical microwave chemical vapor deposition (MWCVD) conditions leading to ultra-thin diamond film formation, which is fundamental for many technological applications. The temporal evolution of the surface density of seeds on Si(100) substrate has been assessed by scanning electron microscopy (SEM). The resulting kinetics have been explained in the framework of a model based on the effect of particle size, according to the Young-Laplace equation, on both chemical potential of carbon atoms in DND and activation energy of reaction. We found that seeds with size smaller than a critical radius, r*, are etched away while those greater than r* can grow. Finally, the model allows to estimate the rate coefficients for growth and etching from the experimental kinetics.Comment: 28 pages; 15 Figures, 3 Table