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Resolving Crystallographic Disorder in Heterobimetallic Clusters via Resonant X-ray Diffraction
No full textProbing the chemical makeup of polynuclear reaction centers is central to understanding how composition imparts functionality. Important chemical machinery (e.g., biological inorganic cofactors, catalysts, energy storage materials) often possesses multi-metallic structural elements essential to driving their function. Introducing different metals to the overall composition enables substitutional disorder within the solid-state structure, convoluting the study of structure-function relationships. Resonant X-ray diffraction leverages the large changes to an atomic scattering factor that occur at spectroscopic absorption edges (K-, L-, or M-edge) to differentiate between two different elements, allowing for the resolution of crystallographic disorder stemming from the mixed occupancy of an atomic position within the crystalline lattice. The stepwise synthesis of heterobimetallic trinuclear clusters on the hexaanilide ligand platform, FtbsLH6 (1,3,5-C6H9(NC6H3-4-F-2-NSiMe2tBu)3), generates samples featuring crystallographic disorder that results in mixed-metal occupancies at each site within the trinuclear cores. The compositional homogeneity of these heterobimetallic clusters enables us to test the limitations of metal occupancy refinement via resonant X-ray diffraction.
In Chapter 1, we introduce the theory and experimental protocols of a single-crystal resonant X-ray diffraction experiment. The classical derivation of the atomic scattering factor is provided along with key insights from quantum mechanics. Following this explanation, we review the information that single-crystal resonant X-ray diffraction experiments provide in the context of inorganic chemistry. Finally, the experimental design and data treatment procedures required to extract resonant scattering perturbations, f'(ω) and f''(ω), from single-crystal X-ray diffraction data are described.
In Chapter 2, we examine the accuracy of determining metal site occupancies in a [Fe2Zn] cluster using resonant X-ray diffraction by directly comparing the result to that obtained from single-crystal neutron diffraction. These studies showcased that resonant X-ray experiments were as accurate at determining metal site occupancies in the heterobimetallic clusters as neutron diffraction. We additionally explored the intrinsic error of single-crystal resonant X-ray diffraction studies when theoretical and experimental f'(ω) references are employed, showcasing that the use of homometallic molecular control samples carries an inherent uncertainty of +/- 5%.
In Chapter 3, we expand the synthesis of heterobimetallic clusters on the FtbsLH6 ligand platform towards [Zn2Ni] clusters. Reduction of the heterobimetallic (FtbsL)Zn2Ni(py) (3.3) cluster and subsequent reaction with the nitrene transfer reagent, N3Ad, generates the bridging μ3-nitrenoid adduct [K(THF)3][(FtbsL)Zn2Ni(μ3-NAd)] (3.5). This cluster can be further reduced by one electron, resulting in an isostructural dianionic cluster. The electronic configurations of these clusters were studied by SQUID magnetometry, EPR spectroscopy, and variable wavelength Ni K-edge XRF. These studies suggest a divalent oxidation state for the Ni centers in both the monoanionic and dianionic [Zn2Ni] nitrenoid complexes.
In Chapter 4, we examine which factors (i.e., resolution, scaling methods, uncertainty propagation, structural modeling) impact the ability to refine resonant scattering perturbations from synchrotron-based diffraction data collected at energies along the Ni and Zn K-edges utilizing the [Zn2Ni] clusters described in Chapter 3. Although the resonant effect is maximized at an element’s absolute absorption edge, perturbations to X-ray scattering are still present when the incident radiation is off-resonance. We found that the closeness of Cu Kα radiation (8042 eV) to the K-edge absorption energy of Ni and Zn is sufficient to accurately refine resonant scattering perturbations. Remarkably, the resonant scattering terms refined from in-house generated Cu Kα X-ray diffraction data replicated occupancies determined via synchrotron-based resonant diffraction.
In Chapter 5, the synthesis and structural characterization of several [Zn2Cr] clusters are explored. Reaction of FtbsLZn2Cr(py) (5.1) with aryl and alkyl azides generates bridging μ3-nitrenoid clusters. Depending on the nitrenoid substituent, these clusters display C1- or C3-molecular symmetry, enabling substitutional disorder within the trimetallic cores. As such, we turned towards two different methods to examine the solid-state Zn and Cr core occupancies: (1) structural refinement via ShelXL using EADP and SUMP constraints, and (2) refinement of the disordered sites’ resonant scattering perturbations when irradiated with Cu Kα radiation. Despite the energetic distance between the Cr K-edge (5990 eV) and Cu Kα X-ray radiation, the refined f'(Cu Kα) values for each core site yielded accurate occupancy estimates when compared against standard structural refinement.
In Chapter 6, the electronic and structural characterization of [Fe2M] (where M = Co or Ni) clusters is explored via elastic and inelastic X-ray scattering. The resonant scattering perturbations of these clusters were refined from Cu Kα and variable wavelength synchrotron X-ray diffraction datasets and used to calculate metal-site occupancies. Additionally, experimental resonant scattering factors were derived from the [Fe3], [Co3], and [Ni3], homometallic analogs to provide reference f'(ω) and f''(ω) values for Fe, Co, and Ni in the occupancy calculations. In addition to the structural characterization conducted via elastic X-ray scattering experiments, we were also interested in obtaining information on the electronic configuration of the [Fe2Co] and [Fe2Ni] cores via inelastic spectroscopy. Variable wavelength XRF and 57Fe Mössbauer studies revealed that the nature of the electronic charge distribution within the trinuclear core is dependent on the identity of the metals residing within.Chemistry and Chemical Biolog
Regulatory Reform
No full textFor many years I have been arguing, in the OECD and elsewhere, that the post-crash crisis of capitalism has extended into a crisis of legitimacy in the institutional and regulatory settlement underpinning it.
Regulators and other public authorities that were once seen as harnessing the forces of capitalism for the public good are increasingly being cast - by the left and the right - as part of the problem: unaccountable guardians of an economic order that serves the few at the expense of the many. This is far more than mere populism. Much of it is widely held to be justified.
Criticism of regulators is increasing across Western economies. Ineffective and excessive regulations are held to create impediments to productivity and growth, often serving the interests of large corporations and retarding innovation and optimal capital allocation.
Policy makers are neither satisfied with the performance of regulation in encouraging growth, nor in protecting consumers from the harms of market power. They are increasingly concerned by the economic and political costs of substandard regulatory performance; it is now widely accepted that the industries which regulators supervise are responsible for weaknesses of the supply side. Such evidence that exists suggests that markets are becoming more concentrated and less dynamic, despite significant antitrust activity. The rate of entries and exits to markets is declining. Technological advances are now widely held to enable some of the biggest platforms to entrench market power and engage in rent-seeking. Research from the developed world documents the productivity and growth benefits of competition-boosting regulation, and the penalties to growth and investment from regulatory barriers to entry.
Macroeconomic consequences are also of concern to policy makers. Many view declining competition as a cause of inflation and inequality. The IMF and others estimate that excessive profit margins contributed to around half of the recent growth of inflation in several economies. Rent-seeking is also associated with increasing inequality, leading many to believe that global capitalism benefits asset-owning elites at the expense of the rest of the population. This has also been held to inflame populist sentiments and to contribute to political instability.
An important task for those who believe that competitive markets within a framework of regulation are the most effective route to prosperity is to contribute to restoring trust, and by demonstrating that markets can continue to serve the interests of millions of people. This will require improvements in regulatory performance.
Governments have responded to criticisms of regulators by pursuing wholesale deregulation, which poses risks to economies and the public. This is most salient in the United States, where President Trump has pursued action to cull regulations and enforcement capacity in the first months of his second administration (see Appendix 1). The UK and EU also intend to pursue deregulation, with the stated intention of achieving higher growth and innovation. Each of these interventions requires assessment on its merits. Sweeping reforms, such as those on which the US appears to be embarking, carry the risk of unintended consequences. European regulators for example, have raised alarms that the Trump administration’s deregulation of cryptocurrencies could lead to another major global financial crisis.
Addressing fundamental problems in the regulatory framework of Western economies is not - despite appearances - a recondite subject best left to technocrats. Nor can it be achieved simply by reducing the number of regulations. Both the causes of regulatory under-performance, and possible remedies, are varied and often complex. The consequences of under-performance, to both their political communities and their wider publics, will need to be explained over a sustained period, and far better than is currently achieved in many jurisdictions. It is a prerequisite for the restoration of public trust in free enterprise. These problems - widely perceived regulatory under-performance, inadequate public explanation and a lack of trust in decision-making - have been less fully examined, and much less subject to public and parliamentary discourse, than their macroeconomic counterparts, post-2008. But, like them, their main characteristics are shared across many jurisdictions. What follows first illustrates some of those characteristics; part two offers some suggestions for making improvements. many years I have been arguing, in the OECD and elsewhere, that the post-crash crisis of capitalism has extended into a crisis of legitimacy in the institutional and regulatory settlement underpinning it.
Regulators and other public authorities that were once seen as harnessing the forces of capitalism for the public good are increasingly being cast - by the left and the right - as part of the problem: unaccountable guardians of an economic order that serves the few at the expense of the many. This is far more than mere populism. Much of it is widely held to be justified.
Criticism of regulators is increasing across Western economies. Ineffective and excessive regulations are held to create impediments to productivity and growth, often serving the interests of large corporations and retarding innovation and optimal capital allocation.
Policy makers are neither satisfied with the performance of regulation in encouraging growth, nor in protecting consumers from the harms of market power. They are increasingly concerned by the economic and political costs of substandard regulatory performance; it is now widely accepted that the industries which regulators supervise are responsible for weaknesses of the supply side. Such evidence that exists suggests that markets are becoming more concentrated and less dynamic, despite significant antitrust activity. The rate of entries and exits to markets is declining. Technological advances are now widely held to enable some of the biggest platforms to entrench market power and engage in rent-seeking. Research from the developed world documents the productivity and growth benefits of competition-boosting regulation, and the penalties to growth and investment from regulatory barriers to entry.
Macroeconomic consequences are also of concern to policy makers. Many view declining competition as a cause of inflation and inequality. The IMF and others estimate that excessive profit margins contributed to around half of the recent growth of inflation in several economies. Rent-seeking is also associated with increasing inequality, leading many to believe that global capitalism benefits asset-owning elites at the expense of the rest of the population. This has also been held to inflame populist sentiments and to contribute to political instability.
An important task for those who believe that competitive markets within a framework of regulation are the most effective route to prosperity is to contribute to restoring trust, and by demonstrating that markets can continue to serve the interests of millions of people. This will require improvements in regulatory performance.
Governments have responded to criticisms of regulators by pursuing wholesale deregulation, which poses risks to economies and the public. This is most salient in the United States, where President Trump has pursued action to cull regulations and enforcement capacity in the first months of his second administration (see Appendix 1). The UK and EU also intend to pursue deregulation, with the stated intention of achieving higher growth and innovation. Each of these interventions requires assessment on its merits. Sweeping reforms, such as those on which the US appears to be embarking, carry the risk of unintended consequences. European regulators for example, have raised alarms that the Trump administration’s deregulation of cryptocurrencies could lead to another major global financial crisis.
Addressing fundamental problems in the regulatory framework of Western economies is not - despite appearances - a recondite subject best left to technocrats. Nor can it be achieved simply by reducing the number of regulations. Both the causes of regulatory under-performance, and possible remedies, are varied and often complex. The consequences of under-performance, to both their political communities and their wider publics, will need to be explained over a sustained period, and far better than is currently achieved in many jurisdictions. It is a prerequisite for the restoration of public trust in free enterprise. These problems - widely perceived regulatory under-performance, inadequate public explanation and a lack of trust in decision-making - have been less fully examined, and much less subject to public and parliamentary discourse, than their macroeconomic counterparts, post-2008. But, like them, their main characteristics are shared across many jurisdictions. What follows first illustrates some of those characteristics; part two offers some suggestions for making improvements.Version of Recor
NOVEL COMPUTATIONAL TOOLS FOR HIGH THROUGHPUT IN- SILICO PROTEIN-PROTEIN INTERACTION SCREENING
No full textCells are complex biochemical systems that have evolved elaborate molecular processes to survive and reproduce. Many of these processes involve multiple proteins working together via direct physical interactions. Historically, identifying protein-protein interactions (PPIs) relied on slow, labor-intensive, and inaccurate experimental methods. Recent advances in deep learning have led to new in-silico approaches that can rapidly and accurately predict the structure of proteins and protein complexes from primary amino acid sequence. One of the most prominent examples is AlphaFold-multimer (AF-M), a neural network developed by DeepMind in 2022. Like others, we have begun using AF-M to perform large scale in-silico screens to uncover new PPIs. In my thesis work, I created tools to efficiently conduct AF-M PPI screens and evaluate the results. A core focus of my efforts was the creation of SPOC, a novel machine learning based classifier that examines structural predictions along with experimental omics data to assess the biological relevance of binary AF-M structure predictions. In addition, I built predictomes.org, a web platform that enables users to interact with and interpret massive AF-M screening datasets.
As an initial proof of principle, I applied these tools to uncover PPIs in human genome maintenance by predicting structures for nearly all possible pairwise combinations among 300 proteins. The predictions were scored with SPOC and released to the community on predictomes.org. This screen uncovered new interactions and helped reveal mechanistic insights into processes ranging from transcription coupled nucleotide excision repair to DNA replication stalling during stress. In a separate collaborative effort with Dr. Lucas Farnung’s lab, I folded the H2A/H2B dimer with nearly all human nuclear proteins to identify proteins that engage with a composite nucleosomal surface known as the acidic patch. I developed an analysis pipeline that identified more than 40 hits, including the E3 ubiquitin ligase SHPRH. The Farnung laboratory used cryo-electron microcopy to solve the structure of SHPRH bound to the nucleosome, revealing an interaction that closely matches the screen’s prediction.
The repeated success of large-scale AF-M screens has demonstrated their value as powerful hypothesis generators, motivating development of a proteome-wide structural interactome. However, generating structural models for all ~200 million possible human protein pairs was computationally prohibitive. To address this, I developed KIRC, a classifier that rapidly scores and prioritizes likely interactors based on experimental omics data. Leveraging a GPU cluster donated by NVIDIA corporation, I used AF-M to model the top 1.5 million KIRC-nominated pairs and evaluated them with SPOC. Preliminary analysis suggests that the pipeline yielded more than 34,000 high-confidence interactions, many of which are uncharacterized.
In summary, my work has produced a suite of computational tools that streamline large- scale in silico PPI screening and help biomedical researchers effectively harness advanced machine learning to accelerate discovery. The all-by-all genome maintenance screen, the acidic patch screen, and several additional collaborative projects with labs at Harvard Medical School collectively highlight the power and versatility of this approach.Biological and Biomedical Science
Sexual Violence Stigma: Construct Development, Multi-Level Measurement, and Psychosocial Consequences
No full textSexual violence (SV) is a stigmatized form of trauma, yet the stigma attached to SV has received limited empirical attention. The SV stigma literature is underdeveloped, fractionalized by SV subtype, and lacks validated and comprehensive measurement approaches for quantifying SV stigma. In this dissertation, I seek to advance this literature by developing the construct of SV stigma using multi-level measurement approaches, connecting SV stigma to numerous adverse psychosocial outcomes, and identifying mechanisms underlying the relationship between SV stigma and psychopathology.
In Study 1, I conducted a scoping review of the available literature (n=63 studies), summarizing available evidence for SV stigmatization and associated psychosocial outcomes and identifying gaps in the literature. In Studies 2-5 of my dissertation, I provide an empirical investigation of four of these identified gaps.
In Study 2, I adapted and tested a new measure of SV stigma, the Sexual Violence Related Stigma Scale (SVRSS), and incorporated this scale into a population-based sample of Swedish young adults (n=453) in order to investigate the associations between SV stigma and symptoms of psychopathology (anxiety, depression, PTSD), alcohol misuse, and treatment need, as well as a behavioral measure of shame. Results indicated that SV stigma burden is associated with more severe symptoms of anxiety, depression, and PTSD as well as an behavioral measure of shame and perceived need for treatment in the past year. Unexpectedly, SV stigma burden was associated with less alcohol misuse.
In Study 3, I replicated these findings from Study 2 using longitudinal data, showing that SV stigma predicted psychopathology outcomes (anxiety, depression, PTSD) at two-year follow-up after controlling for baseline symptoms. In addition, I identified two mechanisms, rumination and event centrality, that mediated this longitudinal relationship. Specifically, rumination was a strong mediator of the relationship between SV stigma and both anxiety and depression (accounting for 51% and 60% of variance explained, respectively) and event centrality was a strong mediator of the relationship between SV stigma and PTSD, accounting for 43% of variance. Our results demonstrate that SV stigma creates risk for psychopathology symptoms through distinct, potentially reinforcing, mechanisms and that targeting SV stigma itself may be an important step forward for improving psychotherapy for patients who have experienced SV.
Next, in Study 4, I extend these findings to the United States by launching the National Sexual Violence Stigma Study (NSVSS), a new population-based sample (n=555) of survivors of multiple forms of SV, including rape, sexual assault, intimate partner sexual violence, childhood sexual abuse, and image based sexual abuse. Results connected SV stigma to a wide range of adverse mental health (e.g., anxiety, depression, PTSD), physical health (e.g., chronic pain, frequent headaches, difficulty sleeping), psychosocial (e.g., hypervigilance, rumination, event centrality), event-related (e.g., disclosure, help-seeking), and treatment-related (e.g., treatment use, treatment preferences) outcomes. Finally, in Study 5, I developed and tested the first multi-indicator composite measure of state-level structural SV stigma, comprising both laws/policies and community attitudes that systematically disadvantage survivors of SV. Integrating this objective structural measure into the NSVSS, I investigated whether survivors’ state-level social context is associated with adverse mental health outcomes, finding that survivors living in high SV states have 19% greater anxiety symptoms than survivors living in low structural SV stigma states. Among birth-assigned female survivors, the effect size is even stronger, with female survivors in high SV stigma states demonstrating 29% more anxiety symptoms, 13% more depression symptoms, and 18% more symptoms of PTSD.
Collectively, results from this set of five studies demonstrate that SV is a stigmatized form of trauma associated with a wide range of adverse health outcomes. I demonstrate this association both cross-sectionally and longitudinally, across two population-based samples in two countries, and among a diverse set of SV experiences. Additionally, I identify two mechanisms that help to explain this relationship. Further, I develop and test two novel multi-level measurement approaches for SV stigma, one subjective and one objective, which are designed to improve the validity and consistency of SV stigma measurement in the literature going forward. I close by arguing for a unifying construct of SV stigma and discussing implications of this work for both treatment and policy.Psycholog
Harnessing Multi-Electron Entanglement in Modern Quantum Materials
No full textPhysicsAuthor's Origina
Critical quantum spin liquids, SYK models, and the cuprate high temperature superconductors
No full textPhysicsAuthor's Origina
Democratic Void Cycles: Echoes of January 6
No full textThis thesis addresses a comparative puzzle: whether the January 6, 2021 assault on the U.S. Capitol produced democratic echoes in Brazil and South Korea, and why the aftershocks diverged. Evidence from media framing, elite rhetoric, and institutional indicators confirms a diffusion effect in both countries, while showing that its trajectory is conditional.
Three filters shape outcomes. First, polarization sets receptivity; Brazil’s intense social and digital fragmentation primed audiences, while Korea’s partisan divide remained bounded by post-1987 procedural norms. Second, media structure governs translation; Brazil’s fragmented ecosystem accelerated permissive reinterpretations, while Korea’s gate-kept press initially treated the breach as uniquely American. Third, institutional guardrails determine speed and unity of response; delayed elite accountability in Brazil prolonged the crisis, while Korea’s parliament reversed emergency measures within hours and initiated impeachment within days. The theoretical contribution is the concept of permissive sanctions, the idea that impunity itself travels and lowers perceived costs of imitation.
A three-phase Signal-Echo model links broadcast, domestic translation, and consequence, and a diffusion quotient is proposed, defined as signal strength times polarization divided by guardrail robustness. The model explains why Brazil experienced a larger and longer aftershock and why Korea’s echo was brief and corrected. Policy horizons follow directly. Brazil should institutionalize agile judicial capacity and pursue depolarization. Korea should narrow emergency authorities and require prior legislative consent for deployments in the capital. The United States bears special responsibility; timely, credible accountability at home functions as external deterrence abroad, particularly where politically framed clemency could otherwise signal tolerance for breaches.Extension Studie
A Novel Peptide Hemostat for Enhanced Platelet Adhesion
No full textUncontrolled hemorrhage is the leading cause of preventable death in trauma, particularly among individuals under 45 years of age. While significant progress has been made in managing external bleeding through pressure-based interventions and topical hemostats, internal, noncompressible hemorrhage at anatomically inaccessible sites continues to present a major clinical challenge. Current treatment strategies—such as transfusion of blood components and surgical intervention—are limited by logistical constraints, donor dependence, and inherent risks including pathogen transmission and immunogenicity. Critically, there are no systemically administered agents approved for point-of-care treatment of internal, non-compressible bleeding that could stabilize patients prior to definitive medical intervention.
To address this urgent unmet need, my PhD research focused on the design and evaluation of Covodutide (Collagen and von Willebrand Factor dual binding peptide), a novel, bivalent peptide designed to enhance hemostasis through targeted platelet adhesion. Covodutide consists of two defined functional domains: a collagen-binding motif and a von Willebrand factor (vWF)-
binding motif, enabling it to localize selectively to sites of vascular injury and reinforce the formation of the primary platelet plug. In contrast to conventional synthetic platforms that suffer from molecular heterogeneity and inconsistent functionalization, Covodutide is synthesized using solid-phase peptide chemistry, resulting in a molecule with fully defined architecture, fixed molecular weight, and exact stoichiometry between its functional units. This structural uniformity supports both predictable biological activity and clinically scalable manufacturing.
The research presented in this thesis is structured around three central aims: (1) to design Covodutide as a uniform agent targeting physiologically relevant surfaces at the injury site; (2) to investigate its mechanism of action in enhancing platelet adhesion and plug formation in vitro; and (3) to evaluate its systemic safety and hemostatic efficacy across multiple preclinical bleeding models. Covodutide’s selective binding to collagen and vWF, by virtue of its carefully designed binding domains was confirmed via microfluidic and flow cytometry assays, while its functional capacity to augment hemostasis was demonstrated in platelet aggregation studies. In vivo, Covodutide showed robust hemostatic activity across four bleeding models including tail transection and femoral artery injury—both as a pre-treatment and as a post-injury rescue agent.
Notably, Covodutide administration did not result in off-target effects, as validated by biodistribution, toxicity, and histopathological analyses. Formulated as a lyophilized powder that is easily reconstituted in saline, Covodutide is stable, rapidly deployable, and amenable to intravenous administration at precise doses in both military and civilian settings.
In summary, Covodutide represents a first-in-class, dual-targeting peptide hemostat that merges molecular precision with rapid-acting hemostatic function.Engineering and Applied Sciences - Engineering Science
Stimulating Clean Hydrogen Demand: The Current Landscape
No full textHydrogen is expected to play an important role in the global energy transition as a chemical feedstock and fuel; when produced with renewable energy, hydrogen offers a means of decarbonizing hard-to-abate industrial processes and the heavy transportation sector.1 To support market growth, current hydrogen programs aim to expand clean2 (also called “green”) hydrogen production by providing substantial subsidies in the form of supply-side funding and tax incentives. In 2023, global public investments in clean hydrogen reached $308 billion, with the vast bulk of funding allocated to production-side support.3
While worldwide clean hydrogen production targets4 reached 27-35 megatons (Mt) in 2023, demand targets have stalled at just 14 Mt.5 This trend reflects regional asymmetries in production and demand uptake. Under current projections, demand for renewable hydrogen in Europe is expected to hit 8.5 Mt by 2030, far behind the region’s planned 20 Mt of supply.6 Similarly, although the passage of the United States’ (U.S.) Inflation Reduction Act (IRA) in 2022 spurred an explosion of announced clean hydrogen projects, project offtake has lagged behind policy ambition. Supply-side incentives alone are insufficient to build robust markets for clean hydrogen; therefore, stakeholders must investigate additional demand-side innovation policies to facilitate market growth and development.
In the remainder of this brief, we summarize the hydrogen policy landscape in the United States and European Union (EU), concluding with an examination of the causes of demand-side stagnation in the clean hydrogen market.Version of Recor