VictorJuiz/thesis huggingface dataset:
Start-ups as Buyers in Technology Markets: Evidence from the Bio-pharmaceutical Industry
Keywords: Entrepreneurial Growth Strategy
Market for Technologies
Start-ups
Technology Acquisition

My dissertation studies start-ups’ strategies in the market for technologies, with a focus on their role as technology buyers, in the context of the bio-pharmaceutical industry. The ﬁrst chapter clariﬁes when and what start-ups are likely to buy. Building on the classic assumption that start-ups are most advantaged in developing early-stage technologies and drawing on research examining M resource reconﬁgurations, I argue that start-ups will have opportunities to buy from sellers that experienced recent M events because M resource reconﬁgurations release early-stage technologies that would otherwise be further developed and sold to incumbents when late-staged. To test the predictions, I exploit a novel data set involving 97,202 U.S. bio-pharmaceutical patents, and adopt a quasi-experimental approach, using M that unexpectedly failed to go through. The results show that sellers’ M events increase the probability that a patent will be bought by a start-up by around 50%, a ﬁnding that is driven primarily by an increase in start-ups’ acquisitions of early-stage technologies. The second chapter studies the possible impact of venture capital (VC) backing for start-ups’ probability of buying external technologies. An analysis of nearly 3,137 U.S. bio-pharmaceutical start-ups founded between 1996 and 2012 suggests that start-ups are about 2% more likely to acquire external technologies after they receive VC funding. To address the concern that a ﬁrm’s VC backing status might not be random, I construct an instrumental variable, capturing exogenous variation in VC funding at the MSA level. IV regression results reveal that VC backing status causes over 30% increase in start-ups’ probability of acquiring external technologies. The third chapter examines a puzzle in the literature explaining technology transaction timing: why some quality signals that reduce information asymmetries promote early licensing (e.g., licensors’ alliance experiences), whereas others do not (e.g., patents). By building a formal model and exploiting a novel data set comprising 124 U.S. exclusive licensing agreements announced between 2009 and 2015, I show that patents, in addition to reducing information asymmetry, induce licensors’ over-optimism regarding buyer competition, which delays licensing timing. Overall, my dissertation contributes to a more comprehensive and nuanced understanding of the market for technologies.
Between Chinese and Western Norms: Local Policy Deliberation and Cross-issue-area Variations in China’s Global Governance Strategies
Keywords: China
climate governance
financial governance
global governance
international development cooperation
norm

As a rising power, China sometimes plays an ideational leadership role in global governance by constructing homegrown norms and policy ideas, but at other times it embraces Western global governance norms and rules and even imports them for domestic reforms. When will China provide alternative global governance ideas, and when will it learn from the West? This study argues that varied Chinese global governance strategies are produced by varied trajectories of the local policy deliberation mechanism. Local policy deliberation is a pragmatic mechanism of ideational change taking place within local policy communities (i.e., communities of ministry-level bureaucrats and their advisors). Its trajectories are shaped by two conditions. First, uncertainty build-up and problematization of local orthodoxy trigger local ideational change and determine the scope of change. Second, local policy communities’ evaluations of local-idea-informed policy experiments determine the outcome of policy selection. While local policy communities facing uncertainty tend to prioritize local-centric policy innovation, idea importation incentives emerge when the governance performance of such local-centric innovations are perceived as negative. The two conditions can be influenced by multiple factors but are profoundly shaped by policy communities’ interpretations and interests. I illustrate the theory using a comparative case study and process tracing. In the international development cooperation (IDC) case, two rounds of local policy deliberations have focused on absorbing novel local ideas for policy innovation, and local-centric policy experiments were politically endorsed by a passive local policy community. The products were homegrown IDC norms and practices. In the climate case, although local policy deliberation initially brought in local ideas (i.e., the command and control measure), the governance performance of local-centric policy experiments was seen as negative. This generated strong incentives for importing foreign ideas (e.g., ET). In the finance case, a lack of local financial governance knowledge gave Western actors more influence over Chinese financial policy community’s beliefs from the very beginning. The local commitment to norm integration has been robust since the 1990s.
Polyurethane Biomaterial-based Strategies toward Anti-infective Gingival Tissue Constructs
Keywords: antimicrobials
biomaterials
drug delivery
electrospinning
in vivo
tissue engineering

Gingival recession is found in 58% of adults over 30 years old regardless of oral hygiene. Tissue engineering strategies have the potential to overcome the limitations of the current standard of treatment, autologous grafts, among which include tissue shortage and co-morbidity. It is proposed that the gingival connective tissues may be tissue engineered using polyurethane-based scaffold platforms. Polyurethane biomaterials have adaptable chemistry, diverse mechanical properties and suitable biocompatibility and biodegradation characteristics for tissue engineering applications. However, the use of a synthetic material in the infectious oral environment has the potential to lead to biomaterial-associated infections. As such, two different anti-infective scaffold systems will be evaluated in this thesis. In the first system, a degradable polycarbonate urethane (PCNU) was co-electrospun with an antimicrobial oligomer (AO) containing the antibiotic ciprofloxacin (CF) to generate antimicrobial nanofibres. Scaffolds with a higher loading of AO were found to have CF localized on the fibre surfaces which led to a fast release of AO (~100% released within 7 days). Loaded drug was found to slow hydrolysis kinetics of the PCNU scaffolds, and the form of CF loaded was found to significantly affect fibroblast cell attachment, wherein CF incorporated in free form increased cell attachment and spreading on the scaffolds relative to scaffolds with AO. In the second system, a polyurethane-based random pore hydrogel sponge, D-PHI, was used as a scaffold for generating prevascularized gingival constructs via perfusion co-culture of gingival fibroblasts and human vascular endothelial cells (HUVECs) in D-PHI. These constructs are potentially anti-infective in that they will be readily perfused upon implantation so that host defense mechanisms can fight colonization of the scaffold material by plaque bacteria. In an in vivo subcutaneous model, a portion of engineered microvessels in D-PHI were found to be functional (i.e. perfused with host blood and non-leaky) at 14 days after implantation. The investigation of this system demonstrated the critical importance of perfusion flow toward generating engineered microvessels in vitro. The two strategies find similarities in that they both apply synthetic polyurethane materials with unique surface chemistries, geometries, and mechanical properties that allowed for control over their performance as anti-infective gingival constructs in terms of degradation, drug release, cell attachment, and tissue morphogenesis in in vitro models. The peer-reviewed work from this thesis furthers the field’s understanding of polymer-drug and polymer-cell interactions toward optimizing soft tissue constructs for regenerative medicine.
Security Entrenchment and the Dynamics of Politicide: Evidence from Indonesia
Keywords: Genocide
Indonesia
Killing
Mass Violence
PKI
Politicide

This dissertation examines variations in violence during politicide. Why do some areas have greater levels of killings and long term detentions than others, controlling for the size of the victim group? Moreover, why do some areas have greater rates of killing relative to detentions? Using process tracing to compare three Indonesian provinces that experienced politicide in 1965-66, I argue these dynamics are shaped by two factors: the degree to which security forces are entrenched at the local level, and the strength of civilian networks willing to collaborate with security forces. The first two chapters develop my theoretical framework, situate it in current debates of mass violence, and outline the methodology used. Chapter three overviews the origins of the Indonesian politicide, in which the Indonesian army killed an estimated 500,000 civilian communist supporters. The following three chapters trace the dynamics of this politicide in Central Java, East Java, and West Java. Through these cases, I demonstrate that low security entrenchment leads to higher levels of violence and higher rates of killing, as security forces lacked the ability to use violence more selectively. The strain of caring for these detainees then poses a logistical problem and incentivizes mass executions. Collaborator networks can further increase killings when security forces are weak by pressuring them to use additional lethal violence or engage in lethal violence unilaterally. I conclude by demonstrating how these findings are likely to apply across cases of politicide more broadly, and reflect on the relationship between security capacity, mass violence, and repression.
Bayes Factor Approaches for Region-Based Analysis of Rare Variants from Next Generation Sequencing Studies
Keywords: Bayesian Analysis
Biostatistical method
False discovery rate
Genome wide association study
Rare genetic variants
Sequencing data

The emergence of new high-throughput genotyping technologies, such as Next Generation Sequencing (NGS), allows the study of the human genome at an unprecedented depth and scale. The discovery of germline rare variants (RVs) through NGS is a very challenging issue in the field of human genetics. Since RVs have extremely low frequencies, traditional strategies that analyze one variant at a time are underpowered for detecting associations with RVs. Gene-level or region-based statistics can provide a first step in the analysis of RVs that can lead to further experimental validation. Bayesian analysis is not well developed for RV analysis. Our goal in this thesis is to develop such approaches and show their interests for germline RV analyses in the context of case-control studies. Chapter 1 gives a general overview about NGS data analysis and methods for association tests with RV data. In Chapter 2, we propose a novel region-based statistical approach based on the Bayes Factor (BF) to assess evidence of association between a set of RVs located on the same genomic region and a disease outcome in the context of case-control design. We derive the theoretical null distribution of the BF under our prior setting. Informative priors are introduced using prior evidence of association from a Kolmogorov-Smirnov test statistic. In Chapter 3, we introduce a Bayesian procedure to control the False Discovery Rate (BFDR) in the context of genome-wide inference. We develop a simulation program, sim1000G, to generate RV data similar to the 1,000 genomes sequencing project and assess our BFDR procedure. Our simulation studies show that the new BF statistic outperforms standard methods (SKAT, SKAT-O, Burden test) in case-control studies with moderate sample sizes and is equivalent to them under large sample size scenarios. Chapter 4 concludes this thesis with an extension of the BF approach that integrates individual-level and variant-level covariates by using a Bayesian regression approach and inference based on the Integrated Nested Laplace Approximation (INLA). Finally, the interests of our methodological developments are illustrated throughout the thesis by real data applications to a lung cancer case-control study seeking RV association with known and novel cancer genes.
MKRN2 Interacts with GLE1 and Negatively Regulates mRNA Nuclear Export and Retinal Development
Keywords: GLE1
MKRN2
mRNA export
Retinal development
RNA binding protein

Canonical mammalian mRNA export is terminated at the cytoplasmic face of the nuclear pore complex. A key factor implicated in mRNA export termination is GLE1, a highly conserved, DEAD-box helicase activator protein. I conducted an affinity-purification mass-spectrometry screen of human RNA-binding E3 ubiquitin ligases from tissue cell cultures, and discovered a novel physical interaction between MKRN2 and a GLE1-containing complex of mRNA export factors. We next assessed GLE1 epistasis with MKRN2 in a genetically tractable zebrafish model. Consistent with an antagonistic relationship between GLE1 and MKRN2, injection of GLE1 morpholinos into zebrafish embryos deficient in MKRN2 rescued or altered the pronounced retinal defects associated with GLE1 depletion. My data therefore implicate MKRN2 as both a novel macromolecular binding partner and putative new negative regulator of GLE1, and by extension mRNA export. To further explore this hypothesis, I subsequently investigated the function of MKRN2 in mRNA processing in human cell lines. Analysis of the RNA-binding activity of MKRN2 by individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) established that MKRN2 binds to specific mRNAs directly and predominantly in their 3' untranslated region (3'UTR) in regions enriched for C-rich sequences. Biochemical fractionation and sequencing of transcripts from MKRN2 knockdown cells also revealed that nuclear export of mRNAs bound by MKRN2 was enhanced upon MKRN2 knockdown. Taken together, these results indicate that MKRN2 interacts physically and functionally with GLE1, and other associated widely conserved mRNA export factors, to negatively regulate mRNA export of select target transcripts.
Coarse Grained Modeling of Intrinsically Disordered Protein Structures and Dynamics
Keywords: IDP
intrinsically disordered proteins
NPC
nuclear pore complex
polymer physics

Contrary to natively folded proteins, which often have a single stable 3D structure, Intrinsically Disordered Protein (IDP) structures dynamically fluctuate between many conformations. This complexity impedes their study and the understanding of their functions. Experimental techniques can probe aspects of the conformations, but often different techniques or conditions offer seemingly contradictory results. In this thesis, I use coarse-grained models and simulations to investigate the structures and dynamics of IDPs. One system I focus on is the Nuclear Pore Complex (NPC): a bidirectional selective gate for cargo traveling across the nuclear envelope of eukaryotic cells. A key functional component of the NPC is the layer of intrinsically disordered FG nucleoporins attached to the interior of the transport channel. Elucidating the mechanism of transport remains elusive due to the size and complexity of the NPC, but will contribute to the understanding of diseases associated with mutations in the NPC, viruses which enter the nucleus via the NPC, and drug delivery into the nucleus, as well as the development of NPC inspired devices for nanotechnological applications. I show how a mean field model for surface grafted FG nups reconciles several conflicting experimental observations and theories of transport. Due to a lack of unique structure, the influence of the amino acid sequence on IDP structures and dynamics is unclear. Various evidence points to the overall importance of general properties of the sequence rather than the atomistic details of the amino acids. Using coarse-grained simulations, I investigate how the effects of several key sequence properties on the polymer dimensions and end-to-end distance dynamics of IDPs. These results have implications for interpreting experimental measurements as well as developing appropriate models of IDPs.
Fabrication of Superhydrophobic Ceramic Coatings via Solution Precursor Plasma Spray Process under Atmospheric and Low-pressure Conditions
Keywords: rare earth oxides
solution precursor plasma spray
superhydrophobic coatings

In this work, superhydrophobic ytterbium oxide coatings were fabricated via the solution precursor plasma spray process under atmospheric and low-pressure conditions. Firstly, Yb2O3 coatings were deposited via the solution precursor atmospheric plasma spray (SPAPS) process by an injection of Yb(NO3)3 solution into atmospheric plasma. The SPAPS coatings exhibited hierarchical columnar structures composed of micron-sized clusters with nanometer-sized splats/particles on the top surface. The SPAPS coating showed a water contact angle (WCA) of ~163o, a roll-off angle (RA) of ~6o, and multiple complete droplet rebound behavior. Based on the SPAPS process, a novel solution precursor vacuum plasma spray (SPVPS) process was developed by injecting Yb(NO3)3 solution into low-pressure plasma. Highly-dense Yb2O3 coatings with relatively consistent microstructures were deposited at different standoff distances at 150 mbar. The coating showed relatively flat topographies, resulting in a WCA of ~155o and a RA of ~28o. The dense SPVPS coating maintained a high microstructural integrity and relatively consistent hydrophobicity after a comprehensive set of mechanical tests, showing a higher mechanical robustness than the SPAPS coatings. By increasing the chamber pressure to 250 mbar and using a glancing angle deposition method, superhydrophobic coatings with bump-structures and inter-bump gaps were deposited via the SPVPS process, showing a WCA of ~160o and a RA of ~7o. The Yb2O3 coatings showed reversible wetting behaviors. The as-deposited coating was superhydrophilic while it became superhydrophobic after vacuum (1-15 Pa) treatment. The superhydrophobic coating again became superhydrophilic after Ar-plasma cleaning or heat treatment, while it regained the superhydrophobicity after another vacuum treatment. The investigation of the surface composition showed that hydrocarbon species increased significantly after vacuum treatment and decreased dramatically after Ar-plasma cleaning or heat treatment, indicating hydrocarbon adsorption/desorption on the surface was the decisive factor for the reversible wettability of the coating. The surface composition of Yb2O3 coatings after long-term (over 10 months) air exposure, Yb2O3 coatings after ultra-high vacuum (~10-7 Pa) treatment and Al2O3 coatings after vacuum treatment (1-15 Pa) were investigated, showing the WCA variation of all the coatings after different treatments was closely related to the amount of hydrocarbon species adsorbed on the surface.
Transcriptional Profiling and Regulation in Survivors of Critical Illness with Muscle Weakness and Meta-analysis across Human Muscle Diseases
Keywords: Biomarkers
Intensive Care Medicine
Muscle disease
Transcriptomics

ICU acquired weakness (ICUAW) is a common complication of critical illness characterized by decreased muscle mass and function with resulting physical impairment that may persist for years after ICU discharge. Transcriptomic profiling of peripheral muscle biopsies in patients with muscle weakness and healthy controls may detect changes in key biological processes related to muscle impairment. We hypothesized that abnormal expression of mRNAs and miRs related to muscle repair may be an important feature of ICUAW compared to controls. In study 1, we integrated clinical data and mRNA transcriptomic data from quadriceps muscle biopsies from patients with ICUAW at day 7 post-ICU discharge and at follow up at month 6 post-ICU discharge and compared to healthy controls. A gene co-expression network analysis method detected groups of co-expressed genes related to muscle repair that were downregulated in ICUAW compared to healthy controls. In study 2, we aimed to identify miRs that are significant regulators of mRNAs and mRNA networks in ICUAW. Mir-424-5p was found to regulate the greatest number of mRNAs in early ICUAW, including downregulated mRNAs related to striated muscle cell differentiation. At month 6 post-ICU, a differentially expressed miR signature was found between patients that increased quadriceps muscle mass (“Improvers”) from those who did not (“Non-improvers”). In study 3, we performed meta-analysis of mRNA transcriptional profiles from muscle biopsies from human muscle diseases and healthy controls to identify a common signature of genes dysregulated across muscle diseases as well as those genes with expression changes that are unique to ICUAW. We detected a common muscle signature of 131 genes similarly expressed across five categories of muscle diseases. Finally, removing the genes common to muscle disease from meta-analysis of only ICUAW cohorts revealed uniquely down-regulated muscle development and contraction genes specific to ICUAW. In summary, dysregulation of mRNAs and miRs related to muscle repair was detected in ICUAW compared to controls. Transcriptional changes unique to ICUAW versus other categories of muscle disease were detected using meta-analysis strategy.
Indexing Cortical Reactivity with TMS in Major Depressive Disorder and Response to Therapeutic Brain Stimulation
Keywords: Biomarkers
Brain Stimulation
EEG
EMG
Major Depressive Disorder
TMS

The neuropathophysiology of Major Depressive Disorder (MDD) appears to be linked to aberrant cortical inhibition and excitation. These processes are mediated by -amino butyric acid (GABA) and glutamate, the main inhibitory and excitatory neurotransmitters of the cortex, and modified by therapeutic brain stimulation, such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS). Cortical inhibition and excitation can be indexed via transcranial magnetic stimulation, affording high potential as biomarkers of illness state and response to brain stimulation. When combined with electromyography (TMS-EMG), the motor cortex response is assessed. When combined with electroencephalography (TMS-EEG), TMS indexes cortical inhibition and excitation over other cortical regions, more closely associated with MDD. In study one, cortical inhibition was indexed with TMS-EMG over the motor cortex before and after a course of ECT. A TMS-EMG measure of GABAB receptor-mediated cortical inhibition, the cortical silent period, was shorter at baseline in patients who responded to ECT, when compared to the non-responder group. Contrary to evidence, neither cortical silent period nor short interval cortical inhibition (both TMS-EMG measures of cortical inhibition) were altered by a course of ECT. In study two, TMS-EEG indexed cortical inhibition and excitation over the dorsolateral prefrontal cortex (DLPFC) in healthy subjects and patients with MDD. MDD patients had larger TMS-EEG amplitudes of markers of cortical inhibition (N45 and N100) and excitation (P60 and GMFA Area Under the Curve). In fact, the N45 predicted illness state with high accuracy, and N100 was associated with illness severity. In study three, DLPFC response to rTMS was indexed via TMS-EEG in patients recruited for a trial comparing active rTMS to sham rTMS. Sham rTMS did not alter TMS-EEG markers. Active rTMS resulted in differences in the markers of cortical inhibition. The N100 amplitude, a marker associated with GABAB receptor mediated inhibition, decreased in amplitude after rTMS in association with improvement in depressive symptoms. Moreover, a local dampening of cortical activity over the DLPFC, where rTMS was applied, was noted only with active rTMS. TMS markers of cortical inhibition and excitation therefore demonstrate high potential as biomarkers of MDD and response to therapeutic brain stimulation.