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Ancient metabolic switches underpinning organismal longevity
No full textBiguanides, including metformin, the world’s most prescribed drug for the treatment of type 2 diabetes mellitus, robustly extend lifespan and health-span across multiple invertebrate and vertebrate species. Given the safety, efficacy, and well-tolerated nature of metformin, there is an urgent need to identify how biguanides exert their favorable pro-longevity effects, to illuminate novel geroprotective targets and heretofore underappreciated molecular and cellular mechanisms that modulate aging. In this dissertation, we integrated functional genetic strategies with molecular metabolic assessment across metazoans to identify a series of genetic elements required for biguanide-mediated lifespan extension and the enabling of diverse pro-longevity paradigms.
First, through curated genetic screening in the nematode roundworm Caenorhabditis elegans, we highlight ether lipid biosynthesis as a critical effector of the biological action of biguanides and further demonstrate that key ether lipid-producing enzymes are required to enable the pro-longevity effects of multiple conserved geroprotective interventions.
Second, we leveraged translatomics, metabolomics, and unbiased functional genetics to highlight post-transcriptional protection of de novo fatty acid biosynthesis as an ancient, conserved compensatory metabolic response that buffers against the onset of reductive stress, an underappreciated toxicity associated with chronic biguanide administration. We further demonstrate that inactivation of de novo fatty acid biosynthesis during biguanide treatment drives NADPH toxicity, resulting in aggravated electron spillover across NADH/GSH redox pools and subsequent acceleration of death. Moreover, we find that multiple NADPH-producing metabolic insults require de novo fatty acid biosynthesis to prevent accelerated death outcomes, suggesting that its compensatory protection is broadly mobilized across intervention and species. We thus propose that mRNA translation of de novo fatty acid biosynthesis functions as a tunable rheostat to minimize biguanide-induced reductive stress whilst reciprocally maximizing its geroprotective effects.
Finally, we demonstrate through unbiased classic genetic screening in C. elegans that activation of a cytoprotective nucleolar stress response through a conserved rRNA surveillance pathway may uncouple reductive-stress toxicity from the geroprotective action of biguanides. Combined, these studies illuminate a series of ancient metabolic pathways that may be leveraged to maximize the geroprotective action of biguanides and other related pro-longevity interventions across metazoans.Medical Science
The Versatility and Applicability of Droplet Microfluidics
No full textNew drugs are currently being developed to cure once incurable diseases through medications that involve gene and antibody therapies. These therapies won't work without targeted delivery systems. We need to identify the lock and key mechanism for such systems. An effective model for developing a drug delivery system must take into account the requirements of size, stability, and targeting ability. My thesis presents a model system using droplet microfluidics to produce a tuneable capsule that can be used for drug delivery systems. I use emulsion science and with microfluidics to produce multilayered capsules that are used as a model drug delivery system. In the first chapter of my thesis, I describe the fundamentals of emulsions--how they are formed and stabilized. In chapter 2, I write about a new rapidly prototyped microfluidic device that I developed throughout my thesis. In order to produce the capsules for drug delivery systems using emulsion templates it was essential that I use organic solvents as the oil phase. However, the most commonly used microfluidics device which uses a soft elastomer, PDMS, as its main material, swells immediately upon contact with any organic solvent. My solution replaces PDMS with an organic solvent compatible material whilst maintaining the simplicity of rapid prototyping associated with PDMS. Chapter 3 addresses the challenge of trying to make double emulsion templates that produce membrane enclosed vesicles. Existing formulations allowed for the production of double emulsions, but most of the double emulsions did not survive the transition phase from a template to a vesicle. We report a formulation that generated a high yield of vesicles from double emulsion templates. We found that the formula combined with a microfluidics technique produced nearly 100\% yield of vesicles. Chapter 4 discusses using droplet microfluidics as a tool for high throughput screening assays. As part as of an industrial collaboration, we partnered with BASF to develop an acoustic picoinjector. This technology is used to inject preexisting droplets with additional material. We designed a new acoustic picoinjector that can inject 1000 droplets per second with a uniform volume of injection material. This chapter also describes the physics behind Traveling Surface Acoustic Waves (TSAW) and how it can be integrated into a microfluidics device to inject fluids into droplets.Engineering and Applied Sciences - Engineering Science
FL* theory of the pseudogap, and the transition to d-wave superconductivity in the cuprates
No full textPhysicsAuthor's Origina
Acute undernutrition and child development in low- and middle-income countries: a meta-analysis
No full textContext: The association between linear growth faltering and child development outcomes is generally well-recognized; however, the relationship between metrics of acute undernutrition and development has received less attention.
Objectives: We aimed to quantify the association between acute undernutrition in childhood with development outcomes in low- and middle-income countries (LMIC).
Methods: We conducted a systematic literature review of observational studies that assessed the association between metrics of acute undernutrition, including body mass index-for-age z-score (BMIZ), mid-upper arm circumference (MUAC), weight-for-height/length z-score (WHZ/WLZ), wasting (WHZ/ WLZ <-2), and severe acute malnutrition (SAM) among children under 5 years of age with cognitive, motor, language, and socio-emotional development assessed to 19 years of age. We estimated the pooled correlation and standardized mean difference (SMD) for cross-sectional and longitudinal studies.
Results: A total of 113 studies from 40 LMICs were identified. Metrics of acute undernutrition were associated with lower cognitive and motor development outcomes. In longitudinal studies that reported multivariable-adjusted estimates for the cognitive domain, SAM was associated with -1.06 SD lower scores (95% CI: -1.41, -0.72) as compared to non-SAM children. SAM was also associated with lower motor scores in longitudinal studies with unadjusted estimates (SMD: -0.42; 95% CI: -0.68, -0.15). In longitudinal studies with multivariable estimates, wasting was associated with lower motor scores (SMD: -0.30; 95% CI: -0.54, -0.06), but there was no association with language (SMD: -0.08; 95% CI: -0.24, 0.07) and prosocial development scores (SMD: -0.18; 95% CI: -0.38, 0.02).
Conclusion: Metrics of acute undernutrition in childhood were consistently associated with lower development scores, and the magnitude appeared stronger for children with SAM or wasting.Accepted Manuscrip
Private Benefits from Public Investment in Climate Adaptation and Resilience
No full textFlood protection infrastructure investments, such as Army Corps of Engineers levees, can enhance resilience to flood risks amplified by climate change. We estimate levees’ benefits by exploiting repeat residential property transactions. In areas protected by levees, home values increase 3-4 percent. Levees impose adverse spillover flood risks that reduce home values in nearby areas by 1-5 percent. Capitalized benefits in protected areas are progressive, but adverse spillover impacts are regressive. Capitalized benefits at levee construction do not vary by race, but racial sorting occurs post-construction. The local political economy of levee construction can explain the distribution of winners and losers.Author's Origina
Lectures on insulating and conducting quantum spin liquids
No full textTwo of the iconic phases of the hole-doped cuprate materials are the intermediate temperature pseudogap metal and the lower temperature d-wave superconductor. Following the prescient suggestion of P.~W.~Anderson, there were numerous early theories of these phases as doped quantum spin liquids. However, these theories have had difficulties with two prominent observations:
(i) angle-dependent magnetoresistance measurements (ADMR), including observation of the Yamaji effect, present convincing evidence of small hole pockets which can tunnel coherently between square lattice layers, and
(ii) the velocities of the nodal Bogoliubov quasiparticles in the d-wave superconductor are highly anisotropic, with v_F >> v_\Delta.
These lecture notes review how the fractionalized Fermi Liquid (FL*) state, which dopes quantum spin liquids with gauge-neutral electron-like quasiparticles, resolves both difficulties. Theories of quantum spin liquids employing fractionalization of the electron spin into bosonic and fermionic partons are reviewed. In the early theories, upon doping, the bosonic parton theory leads to a candidate holon metal theory of the pseudogap, while the fermionic parton theory leads to a d-wave superconductor. The construction of the FL* state is described using a quantum dimer model, followed by a more realistic description using the Ancilla Layer Model (ALM). Computations using the ALM resolve the difficulties in both the pseudogap metal and the d-wave superconductor.PhysicsAuthor's Origina
Stagecraft / Statecraft: The Military “Mock Village” and the Fabrication of American Empire, 1941-1945
No full textFocused on the period between the United States’ entry into the Second World War and the surrender of the Axis Powers (1941-1945), this dissertation investigates the entanglement of US wartime governance and global geopolitics, racial tensions, and design expertise that led to the invention and proliferation of military “mock villages.” As so-called “laboratories of war,” mock villages were (and continue to be) replicas of foreign and domestic cities, constructed on US soil, where the US military simulated urban warfare operations. The first examples were overseen by the US Army and the US Office of Civilian Defense in collaboration with architects and staging experts from the Broadway theater industry, the Ringling Bros and Barnum & Bailey Circus, and Hollywood film studios like Walt Disney and Twentieth Century Fox. Together, they produced hundreds of cityscapes representative of Germany, Japan, China, the Pacific Islands, and even the US itself.
Each chapter investigates one example of what I have identified as four distinct ways that the US military used these initial mock villages: as instruments of visual deception; as public propaganda; as military-scientific objects; and as mechanisms for psychologically conditioning troops. As I show, with mock villages, the US military manipulated the built environment to perform less like buildings and cities and more like immersive forms of propagandic media. These implements not only empowered the development of illicit chemical weapons like napalm, for example, but they were also armaments themselves: architectures made to disorient, disinform, and control both soldiers and civilians, foreign and domestic. But while mock villages arose during the Second World War to stop the spread of fascism, they have since become the very tools of imperialism and empire, mirroring US-occupied territories from Korea and Vietnam to Iraq and Afghanistan. That is, from World War II to today, these imitations have been continuously altered and aestheticized to represent new adversaries. What has remained the same, I contend, is the production of a visual field in which foreign nations are parodied as inferior and inherently hostile environments worthy of US military intervention and control.
At the heart of this dissertation, then, are two overlapping lines of inquiry that weave American military, political, and urban history with global studies of media, conflict, and empire. I show how, as products of the American entertainment industry and the military gaze, mock villages figured centrally in the visual and material culture of the mid-twentieth century United States and the nation’s rise as a global superpower. At the same time, I show how the invention of these military tools demanded novel ways of envisioning, constructing, and instrumentalizing the built environment that coincided with the production of new and persistent forms of state-sanctioned disinformation, oppression, and violence.Architecture, Landscape Architecture and Urban Plannin
Gallium Nitride-Based Moiré Photonic Crystals for Applications in Microcavity Lasing
No full textGallium Nitride (GaN) microcavity lasers are powerful devices with applications in lighting, optical communication, and sensing. In conventional microcavities, GaN-based emitters in the visible wavelength range have been shown to exhibit ultralow thresholds lasing despite containing significant levels of growth-related defects. In unconventional microcavities, GaN’s highly efficient light emission presents an opportunity to demonstrate novel light localization mechanisms that can be utilized in lasing. Moiré photonic crystals are unconventional microcavities that slow and localize light propagation via coupling between two stacked, twisted photonic crystal layers. The two layers in the stack provide design degrees of freedom that can enable active tunability of the cavity. This work probes the feasibility of moiré photonic crystal lasers with GaN-based emitting materials. Lasing is demonstrated in a single layer, merged moiré photonic crystal at wavelengths of 450 and 451nm with a threshold of 30μJ/cm2. A fabrication protocol is developed to realize true bilayer GaN photonic crystal systems, paving a way for active tunability. Finally, to be realized in a compact piece of technology, GaN-based microcavities must be able to be controlled electrically. The last chapter of this work explores electrical control of microdisk cavities in GaN, developing a fabrication protocol and identifying key design challenges in electrical injection.Engineering and Applied Sciences - Engineering Science