Cell death is fundamental in animal development, tissue homeostasis, and disease. Approximately 50 billion cells die by apoptosis every day in an adult human. During apoptosis, mitochondrial permeabilization results in the activation of caspase proteases. Caspases cleave hundreds of protein targets killing the cell and fragmenting it into apoptotic bodies for immune clearance. Cell death research has long suggested that once mitochondrial dysfunction and caspase activation are observed, death is inevitable. However, a growing body of research challenges this long-standing assumption. A variety of normal and cancer cell types can survive transient activation of apoptosis in a process termed anastasis.

I study anastasis using human cancer cell lines, representing some of the most prevalent cancer types, as a model. I first document major phenotypic changes following transient treatment of the apoptosis inducer staurosporine (STS). I observed cancer cells recovering from STS induced mitochondrial collapse and damage. From these observations, I discovered that anastatic cancer cells survive with low mitochondrial membrane potential (ΔΨm) and that low ΔΨm correlated with nuclear health. This dissertation provides a cell biological description of anastasis in cervical cancer HeLa cells and reveals a previously unknown connection between anastasis and metabolic reprogramming.

Glial biology has been studied for over a century, yet the existence of dynamic calcium signaling in astrocytes was only discovered in 1990. Early studies used cultured astrocytes to investigate this phenomenon; however, studies in cultured cells are highly vulnerable to artifactual results that do not accurately represent normal physiological conditions. More recent studies in vivo have revealed a broad heterogeneity in astrocyte signaling—the mechanisms that trigger a calcium rise, the sources of that calcium rise, and the downstream effects of astrocyte signaling all vary with different brain regions and types of stimulation. In zebrafish (Danio rerio), the primary glial cell type is radial glia that persist into adulthood, which have previously been shown to perform many of the same roles as mammalian astrocytes, including regulating synaptic glutamate uptake and maintaining CNS water balance. This study establishes that zebrafish are an appropriate model for studying glial calcium signaling, which can be triggered by eliciting an acoustic startle response in awake, behaving fish. The glial calcium signal, measured by the genetically encoded calcium indicator GCaMP5, reliably peaks following an escape response and is mediated by the group I metabotropic glutamate receptor mGluR1.

This dissertation is a media-archaeological inquiry into emergences of holograms, broadly defined, in order to demonstrate how human interaction with a specific style of technical imagery may be seen as a social negotiation of inherent contradictions that haunt ideologies of modernity — tensions between presence and absence, body and spirit, life and death. Throughout this work, I discuss what I have identified as visual forms of technically mediated mortality in order to situate these forms within relevant fields — namely, science and technology studies, media archaeology and media studies, and visual culture studies — and their varied but networked examinations of human-machine social relations that have taken shape since the European Enlightenment.

My analysis is organized around the historical figures of the hologram and the “hologram,” a bifurcated term with differing denotations but similar connotations. By following the transportation of the label from an object of science imagery to one of digital projection, this study traces emergences of dimensional, spectral imagery within situated contexts in which spectators not only wrestle with existential concerns but struggle to negotiate the immateriality of mediated experience. I examine four cases that may appear to be (and are often discussed as) apparatuses that are technically and phenomenologically distinct: the Pepper’s Ghost stage illusion as developed by the Royal Polytechnic Institute in London in the mid-19th century, optical holograms displayed at the Museum of Holography in New York City during the 1970s, the imaginary of science-fiction “holograms” (as depicted mainly in Star Wars and Star Trek), and a posthumous performance by the rapper Tupac Shakur as a “hologram” at a live music festival in 2012. Each example demonstrates the emergence of a specific code of visual communication, which I refer to as the technical image, following from the work of communication philosopher Vilém Flusser. The hologram, in fact, projects forward the essence of Flusser’s category by hailing a different kind of spectator (a holosubject), a mobile viewing body who might “read” imagery from a variety of subjective perspectives. By interacting with 3D image-bodies (reaching out to touch, and failing) the holosubject is hailed by the hologram as a fellow specter within a comingling of the virtual and the visceral — a novel mediated experience I call holopresence, the direct experience of a mixed space that includes the virtual space of the image. Rather than “entering” a separate virtual-reality space, holopresence is an encounter with virtuality amid the real — an interaction with real virtuality.

Alzheimer's   disease   (AD)   is   a   prevalent   degenerative disease that is both idiopathic and highly debilitating, calling for early detection and intervention before extensive irreversible brain damage occurs. Here, a novel functional complexity measure based on information theory was applied to mark a disease-related reduction in stochastic low frequency (0.01-0.08 Hz) BOLD signal fluctuations at rest. As AD progresses, BOLD signal complexity is expected to decrease in affected regions, alongside an overall increase in brain amyloid burden.

In this study, a retrospective analysis was performed on 18F-AV-45 PET and rs-fMRI data from 65 subjects (30 males, 35 females; mean age ± SD: 74 ± 7.4 years), across four clinical groups (Control, Early Mild Cognitive Impairment (EMCI), MCI, and AD). The regional BOLD signal complexity measures, or transient information (TI) values, were determined from the change in uncertainty of BOLD pattern prediction over time (i.e. block entropy growth rate).

The main findings in this study included an expected regional reduction in functional complexity with increasing amyloid burden, as well as an unexpected, albeit non-significant, global increase in functional complexity with increased amyloid burden and disease progression. One third (27 out of 82) of the cortical and subcortical grey matter regions presented a significant (>90% CI) effect of brain amyloid load on BOLD signal complexity, including regions associated with disease-related dysfunction in memory, language processing, attention, behavior, somatosensory functions, and motor functions. With disease diagnosis taken into account, only the EMCI group indicated a decrease in global BOLD signal complexity with increased brain amyloid load.

Analysis of rs-BOLD signal complexity has the potential to provide a more accurate representation of disease state than current amyloid plaque or structural measures, as well as identify the regions altered by disease pathology. Based on the reduced signal complexity reported in regions previously linked to disease pathology (precuneus/posterior cingulate, lateral temporal lobe, and frontal regions), further study of this novel metric is advised. With validation, the BOLD complexity analysis metric can be attuned to use as a cognitive biomarker in the clinical setting, potentially improving disease diagnosis, treatment monitoring, and evaluation of future treatment options.

Enzyme function is ubiquitous in living organisms. Assays and biomarkers utilizing enzyme activity have become a pillar of chemical biology with relevance to the discovery of new biology, clinical diagnostics, and streamlining research and industrial pipelines. This thesis project seeks to develop assays and probes harnessing enzyme activity to expand the current repertoire of biomarkers and inhibitory drugs.Chapter1 describes restricted interaction peptides (RIPs) as a platform technology for tracking protease activity in vivo in real time. We show the proof of concept for this, as we harness the catalytic activity of proteases for tracking various biological events and disease states. This chapter evinces the most characterized and furthest along adaptation of the RIP technology, tracking immune activation via imaging with positron emission tomography (PET) by harnessing granzyme B (GZMB) catalysis Chapter 2 continues the concept of harnessing enzyme activity to aid the field of nuclear medicine and radioimaging by detailing the development of a lipoic acid ligase that conjugates radiofluorine onto proteins of interest that contain a specific peptide substrate sequence. This approach would potentially expand the toolbox and broaden the pipelines of proteins amenable to radioimaging. Chapter 3 describes the inhibition, as opposed to the amplification, of enzyme activity by developing substrates and enzyme functional assays for screening inhibitory drugs against the SARS-CoV-2 major protease (Mpro).

Gad’s Book is a fast-paced, darkly humorous novel that blends philosophical fiction, political satire, and metafiction. The narrative follows an unnamed copywriter and aspiring novelist who—while struggling to navigate the social-technological landscape in present-day Berkeley—unwittingly joins Antifa. When we first meet the narrator, he is awkward, obsessive, and, like so many of his generation, anxious about everything. He (and his counterparts) experience social media anxiety disorder, filter bubbles, the transience of data, the attention deficit, the medicalization of depression, internet culture, the redundancy of technological life, artificial intelligence, and artificial realities. From the very first pages of the novel, the narrator seems to believe that he needs to have an opinion about anything and everything—and, more importantly, that his opinions need to be “correct.” His actions reflect his anxiety: he hides from his ten housemates, whom he has delayed meeting; pretends to smoke cigarettes even when no one is watching; practices making faces on his iPhone camera before going to parties; and spends much of his free time thinking up increasingly bizarre plots for the novel he isn’t writing. And that’s another thing: he’s anxious about (not) writing. Amid growing political tension (it’s an election year), he encounters a cast of characters—enigmatic political activists who offer him an escape from boredom, cynicism, and inertia—and he soon finds himself entangled in dangerous conflicts, complex romantic relationships, and sexual misadventures that first enliven then threaten to destroy his carefully-constructed life.

Fetal alcohol spectrum disorders (FASD) describe the wide array of long-lasting developmental abnormalities in offspring due to prenatal alcohol (ethanol [EtOH]) exposure via maternal gestational drinking. Our laboratory has identified many deleterious effects of prenatal ethanol exposure (PrEE) as well as paternal ethanol exposure (PatEE) prior to conception in a mouse model. Our results indicate that PrEE and PatEE can have substantial effects on the offspring including alterations in gross anatomy, neuroanatomy, gene expression, and behavior. In chapter 1, we show that PrEE can lead to craniofacial anomalies, decreased body weight and length, decreased brain weight and cortical length, as well as structural changes to the cortex and corpus callosum in embryonic development (E12.5, E14.5, E16.5, E18.5). To further explore potential heritable effects of PrEE, we investigated brain and behavioral development in the F1 (directly-exposed), F2 (indirectly-exposed) and F3 (non-exposed) generations in Chapter 2. All generations of PrEE newborns had decreased body weights, brain weights, and neocortical lengths compared to controls, although there were no differences in brain to body weight ratios. Hippocampal CA3 was significantly thinner in all generations of PrEE mice compared to controls. PrEE resulted in a significant rate of agenesis or partial development of the corpus callosum in the majority of F1 cases, with a less frequent, non-significant, occurrence in F2 and F3 mice. Disrupted sensorimotor integration, motor control, and anxiety-like behavior persisted to at least the F2 generation. In Chapter 3, we investigated the transgenerational effects of paternal EtOH exposure (PatEE) on offspring brain and behavioral development. We observed no differences between control and PatEE (F1 and F2) mice in measures of neocortical length. Abnormal patterns of Id2 and RZRβ gene expression were observed in the F1 generation but not the F2 at P0. Additionally, PatEE may generate sex-specific effects on offspring behavior that can last up to two generations after the sire’s initial exposure. We propose that the effects of drinking alcohol during pregnancy or prior to conception may be more serious than previously thought as transgenerational effects were observed in the offspring even though they never consumed alcohol themselves.