<p> Although most muscle spindle investigations have used the cat model and mvasiVe surgical measurement techniques, several investigators have used microneurography to record from the Ia and II fibres in humans during tendon vibration. In these studies the muscle spindle primary (Ia) endings are stimulated using transverse vibration of the tendon at reflex sub-threshold amplitudes. Others have used low amplitude vibration and the H-reflex (monosynaptic electrical response) to determine reflex properties during both agonist and antagonist voluntary contractions. Both of these methods explore only certain parts of the monosynaptic reflex arc; microneurography focus on the properties and firing characteristics of the muscle spindles themselves, whereas the H-reflex response to vibration is a representation of the response of the spinal cord as well as the muscle spindles. </p> <p> In the past we have developed a PC based instrument that uses Lab VIEW and a linear servomotor to study tendon reflex properties by recording H-reflexes (or stretch reflexes for mechanical stimuli) from single tendon taps or electrical stimuli to the afferent nerve. In this thesis we describe a further development of this system to provide precise vibrations of the tendon at up to 55 Hz with amplitudes up to 4 mm. The resultant vibration stretch reflex train is extracted from 2 major background noise sources, 60 Hz power line noise, and vibration artifact noise, of the EMG recording via phase coherent subtractive filtering. </p> <p> To demonstrate the versatility and efficacy of this system in studying the monosynaptic reflex arc, test results from several pilot studies are presented, using the system to vibrate the human distal flexor carpi radialis tendon: (i) whether stretch reflexes could be entrained with high frequency vibration, as contrary to H-reflexes, (ii) whether the responses were affected by low levels of agonist or antagonist contraction, in agreement with the existing pool of work on the subject using the H-reflex, (iii) whether a separation of the Ia (primary) and II (secondary) ending pathways is observable as individual but delayed responses at low vibration frequencies due to different activation characteristics, and axon diameters, of each ending. Possible physiological mechanisms that explain the resultant behaviour are also discussed. </p> / Thesis / Master of Applied Science (MASc)

The regulation of gene expression at the transcriptional level is one of the paramount mechanisms for maintaining control of growth, development and metabolic homeostasis. The Liver X Receptor (LXRa) is a novel member of the nuclear hormone receptor superfamily of transcription factors, which was originally isolated in our laboratory. Subsequent studies have revealed that LXRa is an essential transcriptional regulator of cholesterol homeostasis and a number of potent LXRa activators, including the oxysterol 22(R)-hydroxycholesterol have also been identified. As other members of the superfamily, LXRa exerts its regulatory control of target genes directly by binding to LXRa-responsive enhancer elements (LXREs), located upstream of the target gene promoter. Our laboratory initially demonstrated that LXRa heterodimerizes with the Retinoid X Receptor (RXRa) and cooperatively binds to a synthetic LXRE (DR4- LXRE), which consists of direct repeats of the hexad core consensus sequence spaced by four nucleotides. Tc date, two naturally occurring LXREs have been identified, including the LXRE--L\MTV element, located in the promoter region of the mouse mammary tumor vims long terminal repeat and the CYP7 A-LXRE element, located in the proximal promoter region of the rat cholesterol a-hydroxylase gene. In order to delineate the mechanism by which LXRa mediates the transcriptional regulation of target genes, a series of highly integrated characterization studies were initiated. Our initial interest was identifying the transactivation properties ofLXRa. Thus, a series of tramient transfection studies were performed, which investigated the effect of various LXREs, ligands/activators and cell lines on LXRa.-mediated transactivation. Ultimately, these studies revealed that the LXRa.-mediated transcriptional response was highly varied and specifically dependent upon the response element, ligand and cell line employed. Thus, these investigations indicate the specificity and great diversity in the nuclear hormone receptor-mediated transcriptional regulation of target genes. Furthermore, these studies resulted in the establishment of a viable and efficient transient transfection assay for further LXRa. in vivo investigations. Nuclear hormone receptors, including LXRa., are comprised of several modular domains termed AlB, C, D and E. A number of recent studies have implicated the highly divergent AlB domain of variety of nuclear receptors, and their isoforms, as a participant in transactivation. Specifically, these nuclear receptors have been shown to posses, within their respective AlB domains, an autonomous ligand-independent transactivation function termed the AF-1 domain, which can either function independently or can synergize with the E domain of the same receptor. Thus, determination of whether or not the 97 amino acid AI B domain of LXRa. participated in LXRa.-mediated transactivation became a main focus; in our investigation of LXRa.. In vitro EMSA analysis revealed that deletion of up to 63 amino acids of the N-terminal region of the LXRa. AlB domain did not effect either LXRa./ RXR.a. heterodimerization nor cooperative binding to LXREs. In vivo transient transfection assays further illustrated that theN-terminal 63 amino acids of the LXR.a. AlB domain were dispensable for LXR.a./RXR.a.-mediated transactivation. Therefore, as determined by the limitations of these assays, theNIV terminal63 amino acids of the LXRa AlB domain do not participate in neither transactivation nor heterodimerization and subsequent binding to LXR.Es. Transcriptional regulation, mediated by members of the nuclear hormone receptor superfamily, has been shown to involve multiple auxiliary co-factors, which modulate receptor-mediated tnmsactivation. These co-factors can either serve to repress (corepressors) or activate (co-activators) transcription not only through blocking or facilitating interactio r1s, respectively, between receptors and the basal transcription machinery but also through chromatin remodeling. Thus, the identification of LXRainteracting co-facton and the subsequent investigation of their ability to modulate LXRamediated transactiva1ion, were of particular interest. We demonstrated, via utilization of in vitro GST-binding assays, that LXRa interacts with RIP 140, SRC-1a and SMRT cofactors in a ligand-independent manner. Furthermore, these studies illustrate that the LXRa AF-2 core domain is necessary for efficient RIP 140 and SRC-1a binding. Surprisingly, this domain appears to impede, although not absolutely, the SMRTILXRa interaction, which has also been observed for the Retinoic Acid Receptor (RAR)/SMRT interaction. Functional studies ofLXRa, RXRa and RIP 140 indicate that RIP 140 antagonizes LXRa/RXR.a-mediated transactivation, which suggests that RIP 140 may serve to attenuate the transcriptional response of nuclear receptors modulated by other, more potent co-activators, as previously suggested in Peroxisome Proliferator-activated receptor a (PPARa);RIP 140 studies. As well, it is apparent that neither'the RIP 140/LXRa interaction nor the RIP 140-mediated repression of LXRa activity is effected upon deletion of the N-terminal 63 amino acids of the LXR.a. AlB domain. Interestingly, functional studies of LXR.a., RXR.a. and the partial SRC-1a clone, which lacks the Nterminal PAS-bHLH domain, indicate that this SRC-1a clone antagonized LXR.a.IRXR.a.mediated transactivation. While this result may simply demonstrate the necessity for a full length SRC-1a clone it may also indicate SRC-1 isoform-specific differences as previously illustrated in Estrogen Receptor (ER)/SRC-1 studies. Lastly, preliminary functional studies of LXR.a., RXR.a. and S:MR.T indicate that S:MR.T has no significant effect on LXR.a./RXR-mediated transactivation. These tentative results indicate that while LXR.a. and SMRT interaction in solution, S:MR.T may not be able to interact with LXR.a. when bound to DNA, and is thus unable to modulate LXR.a.-mediated transcriptional activation as previously demonstrated for the PP ARy and the orphan receptor Rev Erb. Taken together, the investigations presented in this study of LXR.a., further our understanding of not only the mechanism by which LXR.a. mediates its transcriptional response, but also hew nuclear receptors achieve specificity and diversity in the activation of target gene expression. / Thesis / Master of Science (MS)

This thesis is concerned with the responses of human infants to novel visual stimuli. Novelty is defined in terms of a time dimension so that a stimulus which is presented to the subject for a period of time (familiarisation period) is said to be novel relative to a stimulus which has not been so presented. Experiments demonstrated that infants will fixate a novel stimulus longer than they fixate a familiar stimulus. This effect was shown to be greater when familiar and novel stimuli differ from each other in two dimensions than when they differ in only one dimension. The decline in responsiveness to stimuli presented for a familiarisation period was shown to be a linear function of time. / Thesis / Master of Arts (MA)

Thesis advisor: Tim van Opijnen / Thesis advisor: Michelle Meyer / Molecules that have high affinity and specificity for their target are critical for functioning biosensors and effective therapeutics. Aptamers, or single-stranded oligonucleotides, are one type of molecule capable of both high affinity and specificity. Systematic Evolution of Ligands by EXponential enrichment (SELEX) is the iterative in vitro process for identifying aptamers with high affinity and specificity from an initial pool of approximately 1015 randomized nucleotide molecules. There have been a multitude of SELEX variations developed over the years to include incorporation of machine learning algorithms to address the limited success (~30%), cost, and time required to identify high affinity and specific aptamers. While some SELEX variations have been more successful than others in addressing some of the challenges, issues remain. To confront these challenges, the digitalSELEX platform introduces a novel de novo design approach. The platform has two main components. The first component analyzes the target molecule identifying clusters of amino acids along the molecule’s surface based on their accessibility and proximity of atoms relevant to target-aptamer binding. The platform then proposes aptamers built from sequences of nucleotides that paired to the amino acids in the clusters. The second component improves these aptamers sequentially. This is done via simulation-based optimization procedure which uses molecular docking and stochastic optimization techniques. It explores small adjustments made on the starting aptamer that increase the affinity and specificity that is calculated extracting binding related features from the output of the docker. Once in silico counter-selection is complete, the best possible sequences are extracted for in vitro validation. To validate digitalSELEX, aptamers were designed for four different target molecules of varying size ranging from 18 – 140 kDa. Some of the aptamers were designed with specific counter-targets while others did not have counter-target molecules. In total, 19 oligonucleotides were chemically synthesized, and their affinity and specificity tested for five explicit validation problems. All 19 aptamers demonstrated high affinity for their respective target molecules. Sixteen of the 19 oligonucleotides were tested for specificity with nine meeting the 4-times Kd-value difference specificity criteria. Depending on the computational capacity being employed for each problem, the approximate time required from initiating the de novo design to the point of validation was 170 hours. The cost of in silico oligonucleotide design is negligible while validation of a few aptamers is few hundred dollars. The digitalSELEX platform was comprehensively tested examining the initial de novo design through affinity and specificity determination. The digtalSELEX platform is a prototype that has the opportunity for further development such as employing different molecular simulators. / Thesis (PhD) — Boston College, 2023. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

A novel about a reality bomb.

This is a novel about grief.

Longing and avoidance are both in play in the lives of Liv and August, two single people at the cusp of middle age who meet while trying to help Santo, a young illegal immigrant, and his son find a place to live. The two circle about each other and eventually fall in love, but almost as quickly old patterns reassert themselves for both. These challenges must be acknowledged and a new way envisioned before the love Liv and August share can mature into something more durable.

Casa Caracol: A Novella and Stories is a two-genre writing project. The novella is a collection of interconnected stories about two Venezuelan female childhood companions, Zafirah and Tamara, who maintain their friendship despite political upheaval and migration. The protagonist, Zafirah, must reconcile her divided cultural identity through the dynamics of her relationship with a new host country and her far-away homeland. The stories, Migrant Voicings, are language driven cuentos that attempt to render what is happening in a migrant-influenced mind. The voicings aim to challenge how a story is told and disrupt the expectations of what the immigrant story is supposed to be. There are thematic links to the novella--migration, Diaspora, alienation, violence, nostalgia and embodied longing, etc--and a vocal link, too, as some of the voices could belong to a grown-up, alternative Zafirah. / Master of Fine Arts

The dissertation consists of a critical preface and excerpts from the novel Derivation. The preface details how the novel Derivation explores the tension between the artist and the academy in the university, as well as the role memory plays in the construction of fictional narratives. The preface also details how narrative voice is used to expand the scope of Derivation, and ends with a discussion of masculine tropes in the novel. Derivation traces the path of a woman trying to rebuild her life in the wake of the 2008 financial crisis, returning first to her blue collar roots before pursuing a career as an academic.

O objetivo dessa dissertação é a análise da produção ensaística e do conteúdo das aulas ministradas pelo jovem Samuel Beckett no final dos anos 1920 e início dos anos 1930, focando-se nas considerações do irlandês a respeito do romance modernista. O material analisado compreende essencialmente o ensaio Dante...Bruno.Vico..Joyce (1929), a monografia Proust (1931) e as anotações da aluna Rachel Burrows tomadas das aulas ministradas por Beckett na Trinity College de Dublin nos anos 1930 e 1931, compiladas e comentadas no volume crítico Beckett before Beckett (2008) de Brigitte Le Juez. Intentamos enfatizar o que há de particular e de interessado nas leituras do jovem em seu início de carreira literária, buscando dar relevo às tomadas de posições estéticas, explícitas ou implícitas, em suas críticas e em suas aulas. Da influência marcante de seu conterrâneo James Joyce, comentamos o procedimento modernista de adicionar notas intertextuais às obras literárias e a busca por uma linguagem na qual forma e conteúdo encontre máxima fusão. De Proust, realçamos a veia estrategicamente pessimista da leitura beckettiana, analisando sua exposição do conceito de Hábito, as problemáticas da percepção distorcida do objeto pelo sujeito, e a complexidade da construção da personagem literária em constante mutação. Visando ilustrar de que modo tais tomadas de posições estéticas se desenvolveram na prática de sua produção ficcional, lançamos mão também da análise de determinados aspectos de seu primeiro romance, Dream of Fair to Middling Women, escrito em 1932, mas publicado apenas postumamente em 1992. De suas aulas, debatemos a impessoalidade do narrador e a exposição da complexidade incoerente da sucessão de eventos e personagens como critérios que orientam a defesa de Stendhal e Flaubert como precursores do romance modernista e a escolha de Balzac como alvo central de suas críticas à artificialidade da concatenação plausível de eventos do romance e da coerência lógica das personagens. Por fim, debatemos as razões da escolha beckettiana de André Gide como escritor exemplar do romance modernista francês em suas aulas, levando em conta o interesse do irlandês pelas considerações de Gide sobre a obra de Dostoievsky. Concluímos indicando a importância conferida por Beckett à incorporação da crítica e à exposição da incoerência dos elementos do romance como sinais de uma afinidade a uma estética do fracasso. / The purpose of this dissertation is to analyze the critical writings and the content of the lectures ministered by the young Samuel Beckett in the end of the 1920s and the beginning of the 1930s, focusing on the considerations of the Irishman on the modern novel. The material analyzed comprehends essentially the essay Dante...Bruno.Vico..Joyce (1929), the monograph Proust (1931) and the notes taken by Rachel Burrows on Becketts lectures at the Trinity College of Dublin in the years of 1930 and 1931, as compiled and commented by Brigitte Le Juez in her critical volume Beckett before Beckett (2008). We intended to emphasize the particularities and the interests of the young man at the beginning of his literary carrier, stressing the aesthetics positions taken, explicitly as implicitly, on his criticism and his lectures. On the notable influence of his countryman James Joyce, we commented the modernist procedure of the note snatching incorporated on the literary works and the search for a language in which form and content could find its maximum fusion. On Proust, we highlighted the strategic pessimism of Becketts rendering by analyzing his exposure on the concept of Habit, the problematic of the distortive perception of the object by the subject, and the constructions complexity of the literary character constantly evolving. In order to illustrate the way in which the aesthetics positions taken developed in the practice of his fictional work, we also analyzed some aspects of his first novel, Dream of Fair to Middling Women, written in 1932, but only published posthumously. On the subject of his lectures, we discussed the narrators impersonality and the explanation on the incoherent complexity of the chain of events and characters as parameters that orientate the defense of Stendhal and Flaubert as the precursors of the modern novel and the designation of Balzac as the central target of his critics about the artificiality of the plausible concatenation of events and the logical coherence of fictional characters. Finally, we discuss the reasons of Becketts choice of André Gide as the exemplar writer of the French modern novel in his lectures, taking on account the Irishman interest in Gides considerations about Dostoevskys oeuvre. We conclude by indicating the importance conferred by Beckett on the critical incorporation and the exposure of the elements incoherence in the novel as signs of an affinity to an aesthetic of failure.