Updike, Morrison, and Roth: The Politics of American Identity

My dissertation analyzes American identity in the works of John Updike, Toni Morrison, and Philip Roth. Specifically, I examine American identity in Updike’s Rabbit tetralogy (1960-1990); Morrison’s trilogy of novels Beloved (1987), Jazz (1992), and Paradise (1998); and Roth’s trilogy comprising the novels American Pastoral (1997), I Married a Communist (1998), and The Human Stain (2000). The studied texts of these three novelists, I argue, attack national myths and undermine exclusive narratives that are incongruent with the nation’s ideal identity as a pluralistic and democratic nation

Accelerated process development for integrated end-to-end biologics manufacturing

With the exception of monoclonal antibodies, biologics typically require bespoke manufacturing processes that vary widely in the type of and number of unit operations. This constraint leads to custom facility designs and unique strategies for process development for every new molecule. To enable flexible, multi-product manufacturing facilities and to reduce the speed to clinic for new molecules, streamlined manufacturing processes and associated strategies for process development are needed. We have developed a bench-scale, integrated and automated manufacturing platform capable of rapidly producing a variety of recombinant proteins with phase-appropriate quality for early development1. The system comprises three modules for fermentation via perfusion, straight-through chromatographic purification, and formulation. To facilitate the production of multiple products on the same system, we have also developed a holistic strategy for process design to manufacture new products in as few as twelve weeks after obtaining the product sequence. While upstream process development in our host (Pichia pastoris) has been relatively straightforward, there are not many tools currently available for developing fully integrated straight-through chromatographic processes. Therefore, we developed an in silico tool for the prediction of fully integrated purification processes based on a one-time collection of host-related data combined with conventional high-throughput chromatographic screening data for each new target molecule2. We used this tool to develop fully integrated, end-to-end production processes for three molecules (hGH, IFNα-2b, and G-CSF) with at least 45% fewer steps than traditional processes. While our in silico tool allows for rapid resin selection, it may not predict the optimal process for each individual molecule since it is based on conventional high-throughput screening techniques which seek to optimize each chromatographic step independently rather than optimizing a fully integrated, multi-column process. To address this limitation, we have also developed a DoE-like framework for the optimization of fully integrated purification processes once the resins have been selected. First, a series of range finding experiments are carried out on each individual column, similar to conventional screening but with limited analytics. Next, we carry out fully integrated (multi-column) testing of the proposed operational area with more extensive analytics, including host cell protein, DNA, and yield measurements. We use this methodology to develop optimized processes for the end-to-end production of a variety of single domain antibodies with high yield and purity. Further, we present a method for predicting the optimal operating conditions for a new molecule within the same class based only on its biophysical characteristics, reducing the timeline from sequence to early stage, phase-appropriate product to only six weeks. Using these holistic strategies for process development, we have produced over ten different recombinant proteins on our manufacturing platform including enzymes, cytokines, singe domain antibodies, and vaccine subunits. We believe that such integrated strategies for process design could enable the rapid translation from sequence to early stage clinical development of products for a variety of molecules and potentially allow clinical testing of a greater number of high quality molecules for vaccines and biopharmaceuticals. 1. Crowell, L. E. et al. On-demand manufacturing of clinical-quality biopharmaceuticals. Nat. Biotechnol. (2018). doi:10.1038/nbt.4262 2. Timmick, S. M. et al. An impurity characterization based approach for the rapid development of integrated downstream purification processes. Biotechnol. Bioeng. 1–13 (2018). doi:10.1002/bit.2671

Mutability and the Determinants of Conceptual Transformability

Features differ in their mutability. For example, a robin could still be a robin even if it lacked a red breast; but it would probably not count as one if it lacked bones. One hypothesis to explain this differential transformability is that having bones is more critical to a biological theory than having a red breast is. W e reject this hypothesis in favor of a theory of mutability based solely on local dependency links and expressed in the form of an iterative equation. W e hypothesize that features are immutable to the extent other features depend on them and offer supporting data

Recognition and Production of Facial Emotion by Autistic Children.

Autistic males ages 8 to 16 made significantly more errors than did chronologically and intellectually age-matched nonautistic normal and mentally retarded males on emotion recognition tasks using audiotaped and videotaped emotion sequences. The audiotape and videotape included happy sad, scared, angry, and no emotion sequences. Emotional sequences included emotionally relevant verbal content and the length of verbalized material in the emotional sequences was limited to between 4 and 10 words. Videotaped sequences showed actors portraying facial expressions and verbal content consistent with the five emotion states. Both tapes were rated by normal adults and children as containing socially valid representations of these basic emotions. No difference was seen between performance on the audiotaped emotions (aural information only) and videotaped emotions (visual plus aural information), although there was a trend towards a higher mean number of correctly identified emotions on the videotape. Subjects\u27 facial expressions of the five emotions were rated by undergraduate students blind to the subjects\u27 diagnosis. Autistic subjects\u27 posed facial expressions, in comparison to those made by normal/mentally retarded subjects, were identified less accurately by raters and were rated as different from normal, as well as less precise in their match with commonly held views of how the basic emotions are represented. Autistic children displayed greater difficulty in producing on demand facial expressions of the negative emotions (i.e., those emotions viewed as subjectively or hedonically less-pleasing to the individual) of sad, scared, and angry. The results are consistent with previous research indicating impairment in autistic children\u27s appreciation and production of basic emotion. Implications of the findings are discussed and future research proposed

Programmable matched filter and Hadamard transform hyperspectral imagers based on micro-mirror arrays

Hyperspectral imaging (HSI), in which each pixel contains a high-resolution spectrum, is a powerful technique that can remotely detect, identify, and quantify a multitude of materials and chemicals. The advent of addressable micro-mirror arrays (MMAs) makes possible a new class of programmable hyperspectral imagers that can perform key spectral processing functions directly in the optical hardware, thus alleviating some of HSI's high computational overhead, as well as offering improved signal-to-noise in certain important regimes (e.g. when using uncooled infrared detectors). We have built and demonstrated a prototype UV-Visible micro-mirror hyperspectral imager that is capable not only of matched-filter imaging, but also of full hyperspectral imagery via the Hadamard transform technique. With this instrument, one can upload a chemical-specific spectral matched filter directly to the MMA, producing an image showing the location of that chemical without further processing. Target chemicals are changeable nearly instantaneously simply by uploading new matched-filter patterns to the MMA. Alternatively, the MMA can implement Hadamard mask functions, yielding a full-spectrum hyperspectral image upon inverting the transform. In either case, the instrument can produce the 2D spatial image either by an internal scan, using the MMA itself, or with a traditional external push-broom scan. The various modes of operation are selectable simply by varying the software driving the MMA. Here the design and performance of the prototype is discussed, along with experimental results confirming the signal-to-noise improvement produced by the Hadamard technique in the noisy-detector regime

Brief of Amici Curiae Public Justice, the Prisoners’ Rights Project of the Legal Aid Society of the City of New York, and the Pennsylvania Institutional Law Project in Support of Plaintiffs-Appellees (Argueta v. United States Immigration and Customs Enforcement)

Public Justice is a national public interest law firm dedicated to preserving access to justice, remedying government and corporate wrongdoing, and holding the powerful accountable in courts. As part of its access-to-justice work, Public Justice created an Iqbal Project in 2009 to combat misuse of the Supreme Court’s decision in Ashcroft v. Iqbal, 129 S. Ct. 1937 (2009). The Project tracks developments in the case law and provides assistance to counsel facing Iqbal-based motions. Public Justice is concerned that overbroad readings of Iqbal threaten to deny justice to many injured plaintiffs with meritorious claims. In addition to Public Justice’s Iqbal-related interest in this case, the firm also represents prisoners, arrestees, other detainees, their family members, and other plaintiffs in a variety of cases involving constitutional claims. See, e.g., Hui v. Castaneda, 130 S. Ct. 1845 (2010); Dillon v. Rogers, 596 F.3d 260 (5th Cir. 2010); Menotti v. City of Seattle, 409 F.3d 1113 (9th Cir. 2005); Everett v. Cherry, No. 08-00622 (E.D. Va.) (case pending). Public Justice is concerned that Appellants’ arguments regarding supervisory liability will, if accepted, prevent many plaintiffs with constitutional claims from obtaining a full remedy. The Legal Aid Society of the City of New York is a private organization that has provided free legal assistance to indigent persons in New York City for over 125 years. Through its Prisoners’ Rights Project, the Society seeks to ensure that 2 prisoners’ constitutional and statutory rights are protected. The Society advocates on behalf of prisoners in the New York City jails and New York state prisons, and conducts litigation on prison conditions. The Society often litigates claims of supervisory liability. The Pennsylvania Institutional Law Project is a private not-for-profit organization created to ensure equal access to justice for indigent institutionalized persons. Part of the Pennsylvania Legal Aid Network, the Institutional Law Project provides direct representation services, self-help and other legal materials, and class representation to eligible low-income residents of Pennsylvania’s prisons, jails, state hospitals, and state centers. The Project also takes part in advocacy and legislative initiatives concerning institutional reform in Pennsylvania

ROSARL: Reward-Only Safe Reinforcement Learning

An important problem in reinforcement learning is designing agents that learn to solve tasks safely in an environment. A common solution is for a human expert to define either a penalty in the reward function or a cost to be minimised when reaching unsafe states. However, this is non-trivial, since too small a penalty may lead to agents that reach unsafe states, while too large a penalty increases the time to convergence. Additionally, the difficulty in designing reward or cost functions can increase with the complexity of the problem. Hence, for a given environment with a given set of unsafe states, we are interested in finding the upper bound of rewards at unsafe states whose optimal policies minimise the probability of reaching those unsafe states, irrespective of task rewards. We refer to this exact upper bound as the "Minmax penalty", and show that it can be obtained by taking into account both the controllability and diameter of an environment. We provide a simple practical model-free algorithm for an agent to learn this Minmax penalty while learning the task policy, and demonstrate that using it leads to agents that learn safe policies in high-dimensional continuous control environments

Glucocorticoid Manipulations in Free-Living Animals: Considerations of Dose Delivery, Life-History Context, and Reproductive State

1. Experimental glucocorticoid (GC) manipulations can be useful for identifying the mechanisms that drive life history and fitness variation in free-living animals, but predicting the effects of GC treatment can be complicated. Much of the uncertainty about the effects of GC manipulations stems from their multi-faceted role in organismal metabolism, and their variable influence with respect to life-history stage, ecological context, age, sex, and individual variation. 2. Glucocorticoid hormones have been implicated in the regulation of parental care in many vertebrate taxa but in two seemingly contradictory ways, which sets up a potential corticosterone-induced “reproductive conflict”. GCs mediate adaptive physiological and behavioural responses to stressful events, and elevated levels can lead to trade-offs between reproductive effort and survival (e.g. the current reproduction versus survival hypothesis). The majority of studies examining the fitness effects of GC manipulations extend from this hypothesis. However, when animals are not stressed (likely most of the time) baseline GCs act as key metabolic regulators of daily energy balance, homeostasis, osmoregulation, and food acquisition, with pleiotropic effects on locomotor activity or foraging behaviour. Slight increases in circulating baseline levels can then have positive effects on reproductive effort (e.g. the corticosterone fitness/adaptation hypotheses), but comparatively few GC manipulation studies have targeted these small, non-stress induced increases. 3. We review studies of GC manipulations and examine the specific hypotheses used to predict the effects of manipulations in breeding wildlife. We argue that given the dichotomous function of GCs the current ‘reproduction versus survival’ paradigm is unnecessarily restrictive and predicts only deleterious GC effects on fitness. Therefore, a broader set of hypotheses should be considered when testing the fitness effects of GC manipulations. 4. When framing experimental manipulation studies, we urge researchers to consider three key points: life-history context (e.g. long- vs. short-lived, semelparous vs. iteroparous, etc), ecological context, and dose delivery. &nbsp

Glucocorticoid manipulations in free-living animals: Considerations of dose delivery, life-history context and reproductive state

Experimental glucocorticoid (GC) manipulations can be useful for identifying the mechanisms that drive life-history and fitness variation in free-living animals, but predicting the effects of GC treatment can be complicated. Much of the uncertainty stems from the multi-faceted role of GCs in organismal metabolism, and their variable influence with respect to life-history stage, ecological context, age, sex and individual variation. Glucocorticoid hormones have been implicated in the regulation of parental care in many vertebrate taxa but in two seemingly contradictory ways, which sets up a potential GC-induced \u27reproductive conflict\u27. Circulating GCs mediate adaptive physiological and behavioural responses to stressful events, and elevated levels can lead to trade offs between reproductive effort and survival (e.g. the current reproduction vs. survival hypothesis). The majority of studies examining the fitness effects of GC manipulations extend from this hypothesis. However, when animals are not stressed (likely most of the time) baseline GCs act as key metabolic regulators of daily energy balance, homoeostasis, osmoregulation and food acquisition, with pleiotropic effects on locomotor activity or foraging behaviour. Slight increases in circulating baseline levels can then have positive effects on reproductive effort (e.g. the \u27cort\u27 fitness/adaptation hypotheses), but comparatively few GC manipulation studies have targeted these small, non-stress induced increases. We review studies of GC manipulations and examine the specific hypotheses used to predict the effects of manipulations in wild, breeding vertebrates. We argue that given the dichotomous function of GCs the current \u27reproduction vs. survival\u27 paradigm is unnecessarily restrictive and predicts only deleterious GC effects on fitness. Therefore, a broader set of hypotheses should be considered when testing the fitness effects of GC manipulations. When framing experimental manipulation studies, we urge researchers to consider three key points: life-history context (e.g. long vs. short lived, semelparous vs. iteroparous, etc.), ecological context and dose delivery

Creating correct aberrations: why blur isn’t always bad in the eye

In optics in general, a sharp aberration-free image is normally the desired goal, and the whole field of adaptive optics has developed with the aim of producing blur-free images. Likewise, in ophthalmic optics we normally aim for a sharp image on the retina. But even with an emmetropic, or well-corrected eye, chromatic and high order aberrations affect the image. We describe two different areas where it is important to take these effects into account and why creating blur correctly via rendering can be advantageous. Firstly we show how rendering chromatic aberration correctly can drive accommodation in the eye and secondly report on matching defocus-l generated using rendering with conventional optical defocus