12 research outputs found

    Agency and Organisation: The Dialectics of Nature and Life

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    In recent decades, there have been major theoretical changes within evolutionary biology. In this dissertation, I critically reconstruct these developments through philosophy to assess how it may inform these debates. The overall aim is to show the mutual relevance between current trends in biology and the dialectical approach to nature. I argue that the repetition of the neglected tradition of organicism is anticipated both by a dialectical tradition within science and by Hegel’s philosophy – and that these theories may together inform the ongoing shift within evolutionary biology called the Extended Evolutionary Synthesis (EES). I stage the discussion by outlining the tenets and history of the modern synthesis (MS) and the alternative: the extended evolutionary synthesis (EES). It takes us into topics such as autonomy, organisation, reduction, and autopoiesis. Based on these discussions, I make the case that the most promising alternative to the MS is the so-called organisational approach formulated within theoretical biology and apply dialectics to strengthen this claim. In my view, they share a fundamental premise: Biology must surpass the physical worldview and adopt a more complex model to comprehend life as an ongoing regeneration of organisation and an expression of self-determination. To bring out the philosophical stakes of this shift, I take on Hegel’s writings on nature, life, and purposiveness and relate them to contemporary thinkers. The main contribution of this work lies not in a particularly novel reading of any of the theories I examine but in bringing them together – both within philosophy and biology and between them – and systematically mapping how philosophy and the humanities should deal with the natural sciences. The new kind of naturalism suggested here, which places life at its core, also calls for another scientific ideal which strives for unification without subsumption or eradication of differences

    Beyond mammography : an evaluation of complementary modalities in breast imaging

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    Breast cancer is the main cause of cancer death among women worldwide and the goal of mammography screening is to reduce breast cancer-specific mortality. The reduction of the sensitivity of mammography for detecting cancer among women with dense breasts requires the use of complementary methods for this subset of women. Three of the projects in this thesis examine the performance of such complementary methods and a fourth study investigates the association between the biomarker BPE (background parenchymal enhancement) and risk factors for breast cancer. In study 1, we prospectively compared the sensitivity and specificity of Automated Breast Volume Scanner (ABVS) with handheld ultrasound for detection of breast cancer among women with a suspicious mammographic finding who were recalled after attending the population-based mammography screening program. We performed both methods on 113 women and found 26 malignant lesions. Analysis was performed in two categories: breasts with a suspicious screening mammography and breasts with a negative screening mammography. In the first category (n=118) the sensitivity of both methods was 88% (p=1.0), the specificity of handheld ultrasound was 93.5 % and ABVS was 89.2%. The difference in specificity was not statistically significant (p=0.29). For breasts without a suspicious mammographic finding, the sensitivity of handheld ultrasound and ABVS was 100% (p=1.0), the specificity was 100% and 94.1% respectively. The difference in specificity was statistically significant (p=0.03). In summary, ABVS has similar sensitivity to handheld ultrasound, but lower specificity in breasts with a negative mammogram. In study 2, we explored the incremental cancer detection rate when adding a threedimensional infrared imaging (3DIRI) score to screening mammography among women with dense breasts (Volpara volumetric density >6 % on the previous mammography examination) who attended the population-based mammography screening program. Women with a negative mammogram and positive 3DIRI score were triaged for a DCEMRI examination to verify the presence of cancer. Of 1727 participants, 7 women had a mammography-detected breast cancer. Among women with a negative mammogram and a positive infrared imaging (n=219), an additional 6 cancers in 5 women were detected on MRI resulting in an incremental cancer detection rate of 22.5 per 1000. Among women with a negative mammography and infrared examination, one woman was diagnosed with breast cancer during the two-year follow-up. The study does not provide information on the proportion of cancers that might have been detected had MRI been performed among women with a negative mammogram and 3DIRI score. Consequently, this study does not shed light on the diagnostic accuracy of infrared imaging or whether using an infrared risk score is the optimal method for identifying women who would benefit from additional imaging modalities. In study 3, we used MRI examinations of study 2 among women without breast cancer (n=214) to explore the association between BPE at DCE-MRI and a large array of risk factors for breast cancer. Thanks to the Karma database, we had unique access to data from self-reporting questionnaires on risk factors. BPE and mammographic density were assessed visually by three radiologists and BPE was further dichotomized into low and high. We created categorical variables for other risk factors. We calculated the univariable associations between BPE and each risk factor and fitted an adjusted logistic regression model. In the adjusted model, we found a negative association with age (p=0.002), and a positive association with BMI (p=0.03). There was a statistically significant association with systemic progesterone (p=0.03) but since only five participants used progesterone preparations, the result is uncertain. Although the likelihood for high BPE increased with increase in mammographic density, the association was not statistically significant (p=0.23). We were able to confirm earlier findings that BPE is associated with age, BMI and progesterone, but we could not find an association with other risk factors for breast cancer. In study 4, we compared the diagnostic accuracy, reading-time, and inter-rater agreement of an abbreviated protocol (aMRI) to the routine full protocol (fMRI) of contrast-enhanced breast MRI. The MRI examinations were performed before biopsy and among women who were not part of a surveillance program due to an increased familial risk of breast cancer. Analysis was performed on a per breast basis. Aggregated across three readers, the sensitivity and specificity were 93.0% and 91.7% for aMRI, and 92.0% and 94.3% for the fMRI. Using a generalized estimating equations approach to compare the two protocols, the difference in sensitivity was not statistically significant (p=0.840), and the difference in specificity was significant (p=0.003). There was a statistically significant difference in average reading time of 67 seconds for aMRI and 126 seconds for the fMRI (p= 0.000). The inter-rater agreement was 0.79 for aMRI and 0.83 for fMRI. We were able to demonstrate that the abbreviated protocol has similar sensitivity to the full protocol even if MRI is performed before biopsy and the images lack telltale signs of malignancy. In conclusion, this thesis provides new knowledge about the biomarker BPE, broadens our knowledge on the diagnostic accuracy of two different imaging modalities and highlights the importance of good study design for diagnostic accuracy studies

    The Largest Unethical Medical Experiment in Human History

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    This monograph describes the largest unethical medical experiment in human history: the implementation and operation of non-ionizing non-visible EMF radiation (hereafter called wireless radiation) infrastructure for communications, surveillance, weaponry, and other applications. It is unethical because it violates the key ethical medical experiment requirement for “informed consent” by the overwhelming majority of the participants. The monograph provides background on unethical medical research/experimentation, and frames the implementation of wireless radiation within that context. The monograph then identifies a wide spectrum of adverse effects of wireless radiation as reported in the premier biomedical literature for over seven decades. Even though many of these reported adverse effects are extremely severe, the true extent of their severity has been grossly underestimated. Most of the reported laboratory experiments that produced these effects are not reflective of the real-life environment in which wireless radiation operates. Many experiments do not include pulsing and modulation of the carrier signal, and most do not account for synergistic effects of other toxic stimuli acting in concert with the wireless radiation. These two additions greatly exacerbate the severity of the adverse effects from wireless radiation, and their neglect in current (and past) experimentation results in substantial under-estimation of the breadth and severity of adverse effects to be expected in a real-life situation. This lack of credible safety testing, combined with depriving the public of the opportunity to provide informed consent, contextualizes the wireless radiation infrastructure operation as an unethical medical experiment

    WRITING NOISE: THE MAZE AND THE DRONE

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    Computational and conceptual blends: the epistemology of designing with functionally graded materials

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    Operating within the landscape of new materialism and considering recent advances in the field of additive manufacturing, the thesis is proposing a novel method of designing with a new type of material that is known as functionally graded. Two of the additive manufacturing advances that are considered of radical importance and at the same time are central to the research have to do with the progressively increasing scales of the output of 3D printing, as well as with the expanding palette of materials that can now be utilised in the process. Regarding the latter, there are already various industrial research initiatives underway that explore ways that various materials can be combined in order to allow for the additive manufacturing of multi-material (otherwise known as functionally graded material) parts or whole volumes that are continuously fused together. In light of this and pre-empting this architectural-level integration and fusing of materials within one volume, the research initially outlines the anticipated impacts of the new way of building that this technology heralds. Of a total of six main anticipated changes, it then focuses on the impact that functionally graded materiality will have on how design is practiced. In this attempt to deal with the uncertainty of a material realm that is unruly and wilful, an initial criticism posed of the scant existing methods for designing with multi-materials in the computer is that they do not consider the intrinsic behaviour of materials and their natural propensity to structure themselves in space. Additionally, these models essentially follow a similarly arbitrary assignment of sub-materiality within larger multi-materials, to the hylomorphic imposition of form on matter. What is effectively proposed as a counter design technique is to computationally ‘predict’ the way materials will fuse and self-structure, with this self-arrangement being partially instigated by their physical properties. Correspondingly, this approach instigates two main objectives that will be pursued in the thesis: –  The first goal, is to formulate an appropriate epistemology (also known as the epistemology of computer simulations-EOCS), which is directly linked to the use of computer simulations to design with (computational blending). This is effectively the creation of a methodological framework for the way to set out, run, and evaluate the results of the simulations. –  The second goal, concerns the new design methodology proposed, in which the conventional material-less computer aided design methods are replaced by a process of constructing b-rep moulds and allowing digital materials to fuse with one another within these virtual frameworks. Drawing from a specific strand of materialist and cognitive theory (conceptual blending), the theoretical objective in effect is to demonstrate that form and material are not separate at any instance of the proposed process. The resulting original contribution of the design research is a process model that is created in an existing simulation software that can be used in a standard laptop computer in order to design with functionally graded materials. The various ‘stages’ of this model are mapped as a diagrammatic design work ow in the concluding end of the PhD, while its main parts are expanded upon extensively in corresponding chapters in the thesis

    Classificação molecular de tumores mamários felinos e sua relevância clínica

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    Dissertação de Mestrado Integrado em Medicina VeterináriaOs tumores mamários (TM) apresentam uma complexa heterogeneidade morfológica e biológica, o que determina diferentes comportamentos clínicos e distintas respostas terapêuticas. Em 2011, uma nova classificação molecular destes tumores foi aprovada em Oncologia Humana com o intuído de realizar um diagnóstico mais preciso, uma seleção terapêutica mais direcionada e um prognóstico mais assertivo. Esta classificação baseia-se na avaliação da expressão de recetores de estrogénio alfa (RE-α), recetores de progesterona (RP), recetores para o fator de crescimento epidérmico humano tipo II (HER-2) e da proteína Ki-67, de modo a identificar e agrupar os TM em quatro subtipos moleculares que apresentam características específicas: Luminal A (LA), Luminal B (LB), HER-2 positivo e Triplo-negativo (TN). Em Oncologia Felina, a sua aplicação começa a dar os primeiros passos, não existindo, supostamente, nenhum artigo publicado acerca do seu valor prognóstico. Assim, os objetivos desta investigação foram a análise da prevalência, da homogeneidade, das características clinicopatológicas, do tempo de sobrevida (TS) e do tempo livre de doença (TLD) dos quatro subtipos moleculares, bem como o estudo de outros fatores de prognóstico em tumores mamários felinos (TMF). O fenótipo molecular de 80 massas presentes em 21 felinos diagnosticados com carcinoma mamário, seguidos clinicamente entre 18 de março de 2009 e 31 de janeiro de 2015, foi determinado mediante a execução de protocolos imunohistoquímicos para avaliação da expressão de RE-α, RP, HER-2 e apreciação do índice de Ki-67. As associações estatísticas foram avaliadas através do teste exato de Fisher, do método de Kaplan-Meyer e do teste de Log-rank, considerando o valor de prova de 0,05. O subtipo mais prevalente foi o LB (n=16; 76,2%), seguido do HER-2 positivo (n=3; 14,3%), do LA (n=1; 4,75%) e do TN (n=1; 4,75%). A classificação molecular de todas as massas tumorais presentes em cada felino foi concordante em 47,6% dos casos (10/21) e, apesar de não se verificar nenhuma associação significativa entre as características clinicopatológicas e os diferentes subtipos moleculares, o fenótipo LA apresentou um perfil menos agressivo. A análise de sobrevivência revelou uma associação significativa entre a classificação molecular e o TS, com o subtipo HER-2 positivo a apresentar pior prognóstico (p=0,035). Essa associação foi ainda mais forte quando se consideraram apenas os subtipos mais prevalentes, LB e HER-2 positivo (p=0,014). O subtipo LA mostrou um TLD longo (27 meses), enquanto o subtipo TN mostrou um TLD curto (5 meses). O subtipo LB manifestou um TLD médio de 13,3 meses, significativamente superior ao do subtipo HER-2 positivo, que foi de 6 meses (p=0,043). A sobreexpressão de HER-2 demonstrou estar associada à presença de metastização no momento do diagnóstico (p=0,006), a menores TS (p=0,009) e a curtos TLD (p=0,003). Este estudo abriu novas perspetivas em Oncologia Mamária Felina, sobretudo por ter correlacionado, aparentemente, pela primeira vez, a classificação molecular dos TMF com o seu prognóstico, bem como a sua sobreexpressão de HER-2 com menores TLD. Assim, esta nova classificação para além de contribuir para o delineamento de terapêuticas mais eficazes, poderá ajudar a prever a evolução clínica de cada animal, de um modo semelhante ao descrito em Oncologia Mamária Humana.ABSTRACT - MOLECULAR CLASSIFICATION OF FELINE MAMMARY TUMORS AND ITS CLINICAL RELEVANCE - The mammary tumors (MT) display a complex morphological and biological heterogeneity, which determines different clinical behaviors and distinct therapeutic responses. In 2011, a new molecular classification was approved in Human Oncology, allowing a more accurate diagnosis, a more targeted therapy, and a more assertive prognosis. This classification is based on the expression assessment of estrogen receptors alpha (ER-α), progesterone receptors (PR), human epidermal growth factor receptors type II (HER2), and Ki-67 protein, in order to identify and group the MT into four molecular subtypes with specific features, namely: Luminal A (LA), Luminal B (LB), HER2-positive and Triple-negative (TN). In Feline Oncology, its application begins to take its first steps, not existing, supposedly, no article published about its prognostic value. Thus, the main goals of this research project were the analysis of the prevalence, homogeneity, clinicopathological characteristics, overall survival (OS) and disease-free survival (DFS) of the four molecular subtypes, as well as the study of other prognostic factors in feline mammary tumors (FMT). The molecular phenotype of 80 masses identified in 21 felines diagnosed with mammary carcinoma, followed clinically between March 18th, 2009 and January 31st, 2015, was analyzed by immunohistochemistry protocols for the expression assessment of RE-α, PR, HER-2 and for the determination of Ki-67 index. The statistical associations were evaluated using Fisher's exact test, Kaplan-Meier method and Log-rank test, considering a p value of 0.05. The most prevalent subtype was LB (n=16; 76.2%), followed by HER2-positive (n=3; 14.3%), LA (n=1; 4.75%) and TN (n=1; 4.75%). The molecular classification of all tumors identified in the same feline was concordant in 47.6% of all cases (10/21). Moreover, the LA phenotype evinced a less aggressive profile, even though no significant association was observed between clinicopathological characteristics and different molecular subtypes. The survival analysis revealed a significant association between molecular classification and OS, with HER2-positive subtype presenting the worse prognosis (p=0.035). This association was even stronger when considering only the most prevalent subtypes: LB and HER2-positive (p=0.014). The LA subtype revealed a longer DFS (27 months), while the TN subtype showed the shortest DFS (5 months). The LB subtype expressed a mean DFS of 13.3 months, significantly higher than that of HER2-positive subtype, which was 6 months (p=0.043). The HER2 overexpression was associated with the presence of metastasis at the time of diagnosis (p=0.006), a lower OS (p=0.009), and a shorter DFS (p=0.003). In conclusion, this study has opened up new perspectives in Feline Mammary Oncology, especially by having correlated, apparently, for the first time, the FMT molecular classification with its prognosis, as well as its HER-2 overexpression with lower DFS. Therefore, this new classification apart from contribute to the design of more effective therapeutics, can also help predict the clinical evolution of each animal, in a similar way to what is described in Human Mammary Oncology

    Rôle de deux groupes de vésicules dans la transmission synaptique

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    Les synapses formées par les fibres moussues (FM) sur les cellules principales de la région CA3 (FM-CA3) jouent un rôle crucial pour la formation de la mémoire spatiale dans l’hippocampe. Une caractéristique des FM est la grande quantité de zinc localisée avec le glutamate dans les vésicules synaptiques recyclées par la voie d’endocytose dépendante de l’AP3. En combinant l’imagerie calcique et l’électrophysiologie, nous avons étudié le rôle des vésicules contenant le zinc dans la neurotransmission aux synapses FM-CA3. Contrairement aux études précédentes, nous n’avons pas observé de rôle pour le zinc dans l’induction des vagues calciques. Nos expériences ont révélé que les vagues calciques sont dépendantes de l’activation des récepteurs métabotropiques et ionotropiques du glutamate. D’autre part, nos données indiquent que les vésicules dérivées de la voie dépendante de l’AP3 forment un groupe de vésicules possédant des propriétés spécifiques. Elles contribuent principalement au relâchement asynchrone du glutamate. Ainsi, les cellules principales du CA3 de souris n’exprimant pas la protéine AP3 avaient une probabilité inférieure de décharge et une réduction de la synchronie des potentiels d’action lors de la stimulation à fréquences physiologiques. Cette diminution de la synchronie n’était pas associée avec un changement des paramètres quantiques ou de la taille des groupes de vésicules. Ces résultats supportent l’hypothèse que deux groupes de vésicules sont présents dans le même bouton synaptique. Le premier groupe est composé de vésicules recyclées par la voie d’endocytose utilisant la clathrine et participe au relâchement synchrone du glutamate. Le second groupe est constitué de vésicules ayant été recyclées par la voie d’endocytose dépendante de l’AP3 et contribue au relâchement asynchrone du glutamate. Ces deux groupes de vésicules sont nécessaires pour l’encodage de l’information et pourraient être importants pour la formation de la mémoire. Ainsi, les décharges de courte durée à haute fréquence observées lorsque les animaux pénètrent dans les places fields pourraient causer le relâchement asynchrone de glutamate. Finalement, les résultats de mon projet de doctorat valident l’existence et l’importance de deux groupes de vésicules dans les MF qui sont recyclées par des voies d’endocytoses distinctes et relâchées durant différents types d’activités.Mossy fiber-CA3 pyramidal cell synapses play a crucial role in the hippocampal formation of spatial memories. These synaptic connections possess a number of unique features substantial for its role in the information processing and coding. One of these features is presence of zinc co-localized with glutamate within a subpopulation of synaptic vesicles recycling through AP3-dependent bulk endocytosis. Using Ca2+ imaging and electrophysiological recordings we investigated role of these zinc containing vesicles in the neurotransmission. In contrast to previous reports, we did not observe any significant role of vesicular zinc in the induction of large postsynaptic Ca2+ waves triggered by burst stimulation. Moreover, our experiments revealed that Ca2+ waves mediated by Ca2+ release from internal stores are dependent not only on the activation of metabotropic, but also ionotropic glutamate receptors. Nevertheless, subsequent experiments unveiled that the vesicles derived via AP3-dependent endocytosis primary contribute to the asynchronous, but not synchronous mode of glutamate release. Futhermore, knockout mice lacking adaptor protein AP3 had a reduced synchronization of postsynaptic action potentials and impaired information transfer; this was not associated with any changes in the synchronous release quantal parameters and vesicle pool size. These findings strongly support the idea that within a single presynaptic bouton two heterogeneous pools of releasable vesicles are present. One pool of readily releasable vesicles forms via clathrin mediated endocytosis and mainly participates in the synchronous release; a second pool forms through bulk endocytosis and primarily supplies asynchronous release. The existence of two specialized pools is essential for the information coding and transfer within hippocampus. It also might be important for hippocampal memory formation. In contrast to low firing rates at rest, dentate gyrus granule cells tend to fire high frequency bursts once an animal enters a place field. These burst activities, embedded in the lower gamma frequency, should be especially efficient in the triggering of substantial asynchronous glutamate release. Therefore, the results of my PhD project for the first time provide strong evidence for the presence and physiological importance of two vesicle pools with heterogeneous release and recycling properties via separate endocytic pathways within the same mossy fiber bouton

    The Paper, Vol. 4 No. 1

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    May/June 1997https://digitalcommons.csumb.edu/thepaper/1014/thumbnail.jp

    Design and Development of a Cell Marking System in Transgenic Mice

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    The aim of this project was to develop a marker system to analyse cell lineage in mouse skin. This should provide useful information on the usual size and organisation of clones in the epidermis and give some clues as to how cell replacement is normally controlled in the epidermis and to the possible location of the stem and progenitor cells. As there is no marker gene currently available in the murine epidermis a marker gene had to be designed and introduced. This was accomplished by generating transgenic mice with a novel marker gene inserted into their DNA. An Escherichia coli lac Z gene was used as a cell marker and activated in single cells following treating the mice with a chemical mutagen. The marker could be activated by a point mutation in the sequence of an oligonucleotide inserted at the 5' end of the lac Z gene, replacing the ATG initiation codon of the gene. Two different marking strategies were devised. One specific for the chemical mutagen N-nitro-N'-methyl-N-nitosoguanidine (MNNG) and the other for the chemical mutagen acetoxyaminofluorene (AAF). Oligonucleotides were designed, synthesised and cloned in front of the lac Z gene to generate oligollac Z fusion marker genes. Test constructs without initiation codons and control constructs with initiation codons were designed and cloned at the same time for both the MNNG and AAF strategies. The fusion genes were then tested in vitro by transfection in to murine epidermal cell lines. No expression was detected in the inactive marker gene designed to be activated by MNNG, whereas high expression was obtained from two control constructs which both contained and in-frame ATG initiation codon in the sequence of the oligonucleotide cloned into the lac Z gene. The MNNG-responsive marker gene was shown to be activated in stably transfected murine epidermal cell lines in response to treatment with MNNG at a frequency of approximately 4.3 x 10-3 per clonogenic cell. Subsequently the work with the AAF strategy was discontinued as there was insufficient time to pursue both strategies and positive results had been obtained with the MNNG construct. Twenty-two transgenic founders were generated with three marker gene constructs (Act-LacZA, K5-LacZD and K5-LacZE by pronuclear microinjection of fertilised embryos. Lines of transgenic mice were bred from the founders and the expression of the marker genes were analysed. Expression from a control lac Z fusion gene driven by a BKIII (keratin 5) promoter was detected by staining skin tissue with the chromogenic beta-galactosidase substrate 5-bromo-4-chloro-3-indolyl beta-D-galactoside (X-gal). The expression of the beta-galactosidase protein was observed in the epidermal basal layer and the hair follicles of transgenic mice. The expression was highest in newborn mice and gradually diminished as the mice reached adulthood. It was subsequently shown that targeting the expression of an activated H-ras oncogene to the epidermis with the same promoter results in a high frequency of malignant tumours. The implications of these results to the biology of the skin are discussed. Expression of the MNNG-activated test marker gene under the control of a beta-actin promoter was also detected. Activation of the marker gene was detected in serial sections of murine brain tissue from transgenic mice treated topically with MNNG at birth. No activation was detected in other tissues probably due to the low level of expression of the marker gene. The explanation of these results and the implications for developing a marker system to work efficiently in the epidermis are discussed
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