1983 research outputs found
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Internal state modulation of striatal dopamine signaling
No full textDopamine (DA) concentration in the striatum fluctuates on two timescales: fast, sub-second
“phasic” changes, and slow, minutes to hours long, shifts in the “tonic” baseline. Phasic striatal DA
fluctuations may represent a prediction error signal, or the difference between what an agent expects
to happen and what actually happens. Animals are thought to implement this prediction error in a
temporal difference learning framework to update policies mapping states to actions to learn how
to attain rewards and avoid threats in the environment. Although much progress has been made
to understand the heterogeneity of this phasic signal across striatal subregions and how different
stimuli evoke different phasic dopaminergic signals, much less is known on the role that internal
state of the agent plays in shaping phasic and tonic DA signaling.
To investigate how internal state modulates phasic and tonic DA signaling, I employed fluorescence
lifetime photometry at high temporal resolution (FLiP-R) coupled with novel DA sensors to measure
absolute levels of DA in the striatum. I conducted recordings and manipulations of DA signaling
in two striatal subregions - the nucleus accumbens core (NAC) in which phasic DA signaling
is thought to represent a reward-prediction error, and the tail of striatum (TS) in which phasic DA
signaling is thought to represent a threat-prediction error. In the TS, hunger increases tonic DA
while suppressing the phasic TS DA response to modulate exploration of novel, potentially threatening
stimuli. The hunger signal that modulates the phasic TS DA signaling pathway derives from
the activity of hypothalamic agouti-related peptide (AgRP) neurons. In the NAC, hunger increases
the tonic DA level, which in turn modulates an animal’s motivation to work for a fixed reward. I
thus delineate how phasic and tonic DA signaling integrates internal state across different striatal
subregions to modulate different aspects of behavior.Neuroscienc
Tank Imaginaries! Rethinking Water Infrastructure Design in Bengaluru
No full textScattered across Bengaluru is a vast network of manmade lakes (also called “tanks” or keres). Over the last fifty years, this once provisional water infrastructure has been disrupted by rapid urbanization. Under the pretext of conservation, many lakes are currently being restored, however this same narrative is also used to limit access, regulate usage, and diminish holistic spaces. This thesis uses Bengaluru to investigate how water infrastructure can become a central protagonist in the city—an organizing force in fostering new imaginations of public space, civic engagement, and ecological awareness. The first written component skewers current approaches to the tanks, suggesting alternative models of polyfunctional use. The second component presents design scenarios for Bellandur lake at different scales, producing typology toolkits and mechanisms of governance for each. Combined, these are presented as an instrument of advocacy for not just redesigning Bengaluru’s lakes, but critically reimagining urban water infrastructure more broadly.Department of Urban Planning and Desig
The Role of Trade Imbalance and Asymmetry in Interstate Wars
No full textWhile liberal international relations theory often emphasizes that trade interdependence fosters peace, recent patterns of violent interstate conflicts challenge this assumption. According to the Global Peace Index 2024, there are currently 56 active conflicts globally, most of which are ongoing since the end of WWII, and with fewer conflicts being resolved (The Institute for Economics & Peace, 2024).
This thesis investigates the complex relationship between trade interdependence and interstate conflict, with particular attention to how imbalances and asymmetries in bilateral trade (dyads) can exacerbate rather than reduce conflict risks. Drawing on the Hague Centre for Strategic Studies’ (HCSS) dangerous dyads model and the Heidelberg Institute for International Conflict Research’s (HIIK) Conflict Barometer 2023, the study examines six high-risk dyads: Russia - Ukraine, Russia - Georgia, Afghanistan - Pakistan, China - India, Rwanda - Uganda, and Syria - Türkiye.
The findings of this thesis challenge the liberal assumption that economic interdependence universally fosters peace and demonstrate that trade interdependence is not inherently pacifying. A hypothesis is proposed to explain the various political, economic, and social conditions under which trade interdependence transitions from peace to conflict. This thesis also contributes to the broader debate on trade and peace by suggesting that trade positions and outlooks are critical in understanding whether economic ties stabilize or destabilize interstate relations.Extension Studie
Mimicking the Structure and Polymerization Behavior of Clathrin Using DNA Origami
No full textDNA origami is a recently developed nanotechnology paradigm that has demonstrated significant convenience and utility for its ability to self-assemble nanostructures with exquisite control over shape and behavior. Controlling the polymerization and self-assembly properties of DNA origami monomers and polymers would allow for the triggered assembly of large-scale structures with applications in diagnostics and nanofabrication. To that end, we developed a DNA origami system that mimics the structure and polymerization activity of the cellular protein clathrin, which is known for its finely tuned nucleation behavior based on interactions between non-nearest neighbor monomers. We designed triskelion-shaped DNA origami monomers that folded into clathrin-shaped structures with polymerization functionality and multiple distinct binding domains that could engage in non-nearest neighbor interactions. We experimentally verified multi-domain monomer folding using agarose gel electrophoresis and transmission electron microscopy. Guided by a set of abstract models and physical intuitions that incorporated principles from thermodynamics and graph theory, we then designed polymers to recreate the hexagonal lattices formed by clathrin, and progressively improved lattice formation using an iterative process. Hexagonal clathrin-like polymer lattices were successfully formed using a set of 14 rationally designed and unique monomers. This research lays key groundwork for expanding the control that can be exerted over nanoscale self-assembly and nucleation behavior in a biologically inspired fashion.Biomedical Engineering A
Exploiting Genomic Instability to Improve Immunogenicity of Colorectal Cancer
No full textThe vast majority of colorectal cancer patients (~85%) present with tumors that exhibit minimal
immune cell infiltration and are consequently unresponsive to immunotherapy1. Therefore, it is
crucial to develop strategies that enable these patients to benefit from immunotherapy by priming
the immune system to recognize and attack cold tumors. We propose a strategy to induce tumor
cell genomic instability to make immunologically unresponsive tumors sensitive to immune
control. Tumor genomic instability leads to the mislocalization of nuclear chromosomal DNA
into micronuclei that are extruded into the cytoplasm. Upon rupture of the fragile micronuclear
envelope, the released chromosomal fragments activate innate immune nucleic acid sensors and
trigger downstream inflammatory pathways that cause immunogenic cell death. In our studies,
treatment with mitotic spindle checkpoint protein MPS1 inhibitor, BAY-1217389, did not
enhance antitumor efficacy, due to the low basal expression of inflammation-related genes in
tumor cells. However, by combining the MPS1 inhibitor with decitabine, a clinically approved
DNA methyltransferase inhibitor that derepresses the expression of innate immune genes in
murine models of colorectal cancer, tumor growth was controlled without systemic toxicity and
the antitumor immune response to immunotherapy was enhanced. Our findings suggest that
augmenting tumor genomic instability, coupled with a DNA hypomethylating drug decitabine,
could improve colorectal cancer responsiveness to immunotherapy.Graduate Educatio
Structural Characterization of Outer Membrane Protein Folding Intermediates
No full textTransmembrane proteins with a β-barrel topology are found in the outer membranes of mitochondria, chloroplasts, and Gram-negative bacteria. These proteins are folded by a conserved protein complex termed the β-barrel assembly machine (BAM). Structural evidence has demonstrated that the central component of the complex, BamA – itself a β-barrel, interacts with substrates via β-augmentation. However, the mechanism by which BAM allows a substrate to fold is unclear, and what features of the machine allow it to effectively fold many different substrate barrels of varying size and shape is unknown.
First, we develop a disulfide crosslinking assay that we use to identify folding intermediates of substrate barrels as they are assembled on BAM. We use this assay to show that two β-barrel substrates, BamA and LptD, pass through multiple shared intermediates during their folding on the BAM complex.
Next, we structurally characterize three of these sequential folding intermediates of a BamA barrel substrate folding on BAM using cryo-electron microscopy. This “movie” of snapshots shows that β-strands are added to the nascent substrate barrel from a disordered state within the machine BamA lumen. The snapshots also show how the machine BamA barrel variably distorts according to the stage of folding of a single barrel, and suggest that a substrate’s efficient release from the machine requires a properly ordered global substrate architecture.
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Finally, we structurally characterize two large substrate barrels, LptD and FimD, in the process of folding on the BAM complex. These structures suggest that BamA barrel distortion and β-templating of substrate strands from the BamA lumen are general folding features. They also present twists on this general folding mechanism, and allow us to propose models for how BAM folds large barrels which contain soluble plug domains.
Together, these results provide a detailed structural picture of outer membrane protein folding, show how substrates grow via sequential addition of β-strands, and suggest that BAM’s ability to fold many different barrels is rooted in its ability to variably distort, allowing a substrate to find its thermodynamic minimum structure no matter the substrate barrel’s ultimate shape.Chemistry and Chemical Biolog
Emperor and Physician: Plague, Politics, and Healing in the Justinianic Novels
No full textThe first bubonic plague outbreak, the “Plague of Justinian,” has been subject to scrutiny to determine how it impacted the cultural, political, and economic trajectory of the Byzantine Empire. Central to this debate is the question of the plague’s minimal mention in non-literary sources, particularly the “Novels,” a series of laws released by Emperor Justinian throughout his reign. In recent years, the emperor’s relative silence on the matter has been cited as evidence that the plague was not significant enough to merit a robust imperial response. While the Novels make virtually no explicit reference to plague, this paper identifies a shift in legal language during the early years of the pandemic wherein the emperor offered a series of allusions likening himself to a physician practicing his craft. These allusions are forceful in their comparative quality, declaring an equivalency of lawmaking and healing. It is the position of this paper that the emperor used his legislation as a vehicle to modify his public image, embodying the mindset of a physician to underline his virtuous philanthropy and offset criticism throughout the plague. Compared especially to his successors, Justinian’s language was uniquely deployed and represents an understudied political effect of the pandemic.Extension Studie
Creating fiscal space for health in 30 low- and middle-income countries
No full textThis policy brief was developed as part of the collaboration between the Harvard Health Systems Innovation Lab and the Changing Diabetes in Children (CDiC) program, in collaboration with and supported by Novo Nordisk. The analysis currently focuses on the 30 countries where CDiC is active. The brief presents results on opportunities to expand fiscal space for health. A technical report and manuscript with detailed methodology and findings are forthcoming.Version of Recor
Democratic transitions and party institutionalization
No full textThis dissertation argues that variation in the party and party system institutionalization of Third Wave regimes is attributable to the mode of transition.
The first paper distinguishes between modes of transition according to the relative strength of incumbent and opposition party organizations. It categorizes 55 Third Wave transitions (1974-2001) into impositions, pacts, and collapses, showing that modes of transition are associated with distinct rules and party-voter linkage structures. Imposed transitions led by strong authoritarian incumbents put oppositions under high levels of adversity, incentivizing investment in strong party organizations and producing stable, institutionalized party systems. Conversely, pacted transitions where incumbents and oppositions agree to share power guarantee entrants easy access to votes and finance, disincentivizing investment in and adaptation of party organizations.
The second paper argues that political pacts are deleterious to party-building by incentivizing parties to collude, rely on inherited resources, and dilute their party brands. Brand dilution has negative consequences for parties’ internal cohesion, the level of mass partisanship, and parties’ public legitimacy. Evidence is marshalled from Latinobarómetro data and case studies of six parties in Mexico and Chile.
The third paper argues that political pacts are deleterious to party-building by disincentivizing investment in complex, autonomous intraparty organizations. When parties depend on state finance, hand their leaders outsized authority, and demobilize mass actors, they are unlikely to cultivate mass memberships, adhere to intraparty institutions and norms, or descriptively represent salient social groups. Evidence is marshalled from party-financial disclosures, candidates’ lists, and Asia Barometer data from South Korea and Taiwan.
The fourth paper investigates the relationship between modes of transition, party organizations, and party brands across a wide range of Third Wave democracies. Using data from 163 parties in 40 countries, I find the mode of transition durably conditions the organization- building and party-branding strategies of both authoritarian successor and opposition parties.Governmen
Elucidating Novel Immunomodulatory Mechanisms in the Metastatic Cascade
No full textEvery step of the metastatic cascade, from invasion to colonization, is modulated by the immune system. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy of the pancreas, and the mechanisms regulating its propensity to metastasize remain mostly elusive. We sought to investigate the contribution of the fibroinflammatory responses in the PDAC tumor microenvironment (TME) to metastasis. Type 2 (Th2) immune responses evolved for anti-parasite defense and cause allergic disease, but thus far have been minimally linked to cancer. We found that eosinophils, effector cells of a Th2 response, are abundant in pancreatic cancer in mice and humans. Genetic loss of eosinophils in mice does not affect primary tumor growth but increases rates of spontaneous metastasis. Treatment with the Th2 alarmin IL-33 or the allergen papain increases intratumoral eosinophil activation and decreases metastasis. Tumor-resident eosinophils in humans and mice produce IL-4, which prevent epithelial-to-mesenchymal transition, preserving tumor cells in an epithelial state and thus stopping their egress from the primary tumor. Systemic delivery of extended half-life IL-4 or a computationally designed IL-4 mimic ameliorates PDAC prognosis, by reducing primary tumor burden and preventing metastasis to liver and lung.
Besides metastasis in major organs, lymphatic colonization has been linked to worse prognosis in several cancers, as lymph nodes act as a reservoir of malignant cells, allowing their dissemination to distant organs. More recently, lymph node metastasis was found to promote systemic immunosuppression, further highlighting the need for a better understanding of the mechanisms supporting its formation. To this end, we investigated the transcriptional profiling of immune cells in pre-metastatic tumor-draining lymph nodes and observed a phenotypic change in the activation state of B cells. We developed a mouse model of trackable PDAC highly metastatic to the draining lymph node and investigated the contribution of B cells to the metastatic cascade. We observed that metastatic PDAC cells fail to successfully colonize lymph nodes when B cells are depleted either genetically, in μMT-/- mice, or following αCD20 therapy. Similar findings replicated in metastatic melanoma. We found that a role for B cells in supporting metastasis is through antigen presentation to CD4+ T cells, as absence of MHCII on B cells led to a reduction in lymph node metastasis. We analyzed CD4+ T cells in the tumor-draining lymph node of μMT-/- mice and observed a deficit in T regulatory cells, which correlated with stronger systemic anti-tumor responses.
Collectively, these findings elucidate novel immunomodulatory mechanisms in the suppression or support of the metastatic cascade.Immunolog