95038 research outputs found
Sort by
La via dell'amore nel Machiavelli Oricellare
Full text linkFollowing the conclusion of his term as secretary of the Florentine Republic and the Medici's return to Florence, Machiavelli, unable to engage in politics, devoted himself entirely to producing historical, political, poetic, and theatrical works. During this time, he became involved in the Florentine Orti Oricellari circle and was appointed maître à penser by its young members. The relationship between Machiavelli's intellectual endeavors and this intellectual milieu is an untold chapter in the history of Italian humanism and philosophy. The research project, "The Way of Love in the Oricellarian Machiavelli," aims to examine this topic through the lens of love. During the first season of the Orti meetings (1503-1508), led by the circle's founder, Bernardo Rucellai, Francesco Cattani da Diacceto, a pupil of Marsilio Ficino, played a central role. Even after Machiavelli joined the circle and became a leading figure in the second season of meetings (1515-1522), led by Cosimino Rucellai, Diacceto's influence and his teachings on Platonic love remained strong. Meanwhile, Machiavelli's young students followed his teachings. It is essential to keep this context in mind in order to recognize the central position that the philosophical question of love occupies in Machiavelli's thinking during his Oricellare period. Reflections on love permeate not only his historical and political works from this period, such as The Art of War and Discourses, but also his poetry, with the poem The Ass, and his theater, with Mandragola. Machiavelli's oricellarian work is constructed through a dialogue that is both polemical and fruitful with the dominant Platonic philosophy of love in the circle. In The Ass and the Mandrake, Machiavelli offers an anti-humanist critique of love. He explores the dimensions of lust and boredom that plague human beings due to their inadequacies. He also highlights the impasse of individual desire. This desire is incapable of creating political communities. In The Discourses and The Art of War, however, Machiavelli sheds light on how the amorous impulse can be converted into a creative source of political order and historical operations.Doctor of Philosoph
NICKEL-CATALYZED SITE- AND STEREOSELECTIVE SYNTHESES OF COMPLEX MOLECULAR FRAGMENTS FROM 1,3-DIENES THROUGH USE OF NOVEL P,N LIGANDS
Full text linkAlkenes are abundant feedstock chemicals which can be utilized as platforms for the constructionof complex molecules bearing a variety of functional groups and stereogenic centers. Methods whichfocus on facilitating this rapid development of complexity while exerting site- and stereocontrol are ofgreat importance. Olefin dicarbofunctionalization is a general reaction class which allows for theformation of two new C-C -bonds from an olefin -bond allowing for a step and atom economicalmeans of accessing functionalized molecules. Homoallylation reactions have also received attention as ameans of synthesizing understudied bishomoallyl alcohols and amines from simple dienes and eitheraldehydes or imine substrates.Chapter 1 describes early work conducted on the dicarbofunctionalization of 1,3-alkyl dieneswith aldehydes. While 1,3-alkyl dienes pose numerous challenges for selective couplings due to theirsmaller size, we were able to observe an improvement in site-selectivity when employing a novelpyridylphosphine ligand.Chapter 2 demonstrates the effective use of pyridylphosphine ligands in the site- andstereoselective dicarbofunctionalization of 1,3-dienes with imines and boronic ester coupling partners.We also determined that the site-selectivity of the reaction can be guided by additional substitution of thediene to form all-carbon quaternary centers selectively.Chapter 3 covers our current progress on the homoallylation of aldehydes with 1,3-dienes to formbishomoallylic alcohols. Use of our P,N ligand system allows for use non-polarized dienes for theselective synthesis of all-carbon quaternary center containing alcohol products.Doctor of Philosoph
EFFICIENT SCHEDULING AND ANALYSIS FOR COMPLEX REAL-TIME SYSTEMS
Full text linkReal-time systems typically have two conflicting requirements: computations must provably satisfy application-specific timing constraints, and the system must efficiently utilize the underlying processing resources to meet constraints related to size, weight, power, and cost. Satisfying timing constraints while ensuring high resource utilization requires the formal analysis of such systems to be as tight as possible. Unfortunately, obtaining tight analysis for even simple real-time systems is computationally intractable, often leading to inefficient resource utilization. In today’s artificial-intelligence-powered real-time systems, this challenge is further exacerbated by complex workloads involving parallel real-time tasks, precedence constraints, and non-processing shared resources. Moreover, these workloads are often deployed on multiprocessor platforms augmented with hardware accelerators, introducing additional complexities. The goal of this dissertation is to take a step toward tighter analysis of real-time systems exhibiting complex runtime behaviors due to precedence constraints, shared resources, and parallelism. The analyses presented here focus on two types of resource-management algorithms: scheduling algorithms and synchronization algorithms. The specific contributions of this dissertation are threefold. First, this dissertation presents a polynomial-time tight response-time analysis for a practically common class of sequential tasks under global earliest-deadline-first (GEDF) scheduling and its variants. It also presents an exact response-time analysis for such systems that can be performed in pseudo-polynomial time. Furthermore, the analysis is extended to systems with precedence constraints. Second, this dissertation presents an optimal suspension-based locking protocol for mutual exclusion sharing under first-in-first-out (FIFO) scheduling. It also establishes new lower-bound results to show that existing asymptotically optimal suspension-based locking protocols for mutual exclusion under GEDF and its variants are nearly optimal. Finally, this dissertation presents response-time analysis for parallel tasks with co-scheduling requirements, known as gang tasks, both with and without precedence constraints. It also provides intractability results for scheduling gang tasks—even in systems with soft timing constraints—and demonstrates that GEDF and FIFO are not optimal for such systemsDoctor of Philosoph
Deep post-Newtonian expansions of gravitational and scalar radiation from Kerr extreme-mass-ratio inspirals with inclined or eccentric orbits
Full text linkThe Laser Interferometer Space Antenna (LISA), planned for launch in 2035, offers a look into the millihertz (mHz) gravitational wave regime. Among the different sources of mHz frequency radiation, we focus on extreme-mass-ratio inspirals (EMRIs), highly eccentric and inclined binaries where the mass ratio of the component objects are ≤10−4. EMRIs are expected to be long-lasting, staying for months in LISA’s frequency band, allowing for precise estimation of an EMRI’s properties. To aid in parameter estimation, highly accurate EMRI models are needed. The framework that produces the highest accuracy EMRI models is called self-force theory, which models an EMRI as a particle in forced motion about acentral black hole as a result of its own gravitational field. For my dissertation, I computed analytical expressions for the time-averaged dissipative first-order self-force, given by the gravitational and scalar fluxes, from Kerr EMRIs with inclined or eccentric orbits. The expressions were computed by incorporating a post-Newtonian (PN) expansion in addition to the self-force expansion. The results are deep PN expansions of the fluxes, with the gravitational and scalar fluxes for inclined orbits computed up to 12PN relative order and the gravitational flux from eccentric orbits computed up to 10PN relative order and in an eccentricity series to e20. The flux expressions are therefore characterized in terms of the black hole spin a, inclination parameter x and eccentricity e. Finally, we validated our flux expressions with data from a separate numerical calculation by a Teukolsky code built from the Black Hole Perturbation Toolkit.Doctor of Philosoph
LEWIS ACID INTERACTIONS WITH RUTHENIUM FORMYL AND HYDROXYMETHYL COMPLEXES
Full text linkThe global pursuit of efficient and sustainable energy sources has rekindled interest in the capacity of homogeneous, Fischer-Tropsch (FT) catalytic processes capable of reducing renewable feedstocks such as syngas to liquid fuels. While traditional, heterogeneous FT processes often require extreme conditions and with low product specificity, homogeneous FT processes would be molecularly tunable and mechanistically accessible. This work explores the role of Lewis acidic cations as additives in model FT homogeneous processes, with a focus on their capacity to stabilize and tune the reactivity of possible catalytic intermediates capable of CO reduction to methanol.Chapter 2 focuses on a model formyl complex, [Ru(bpy)2(CO)(CHO)]+ (bpy = 2,2′-bipyridine), involved in the reduction of CO to methanol using [Ru(bpy)2(CO)2]2+ and sacrificial H+/H– donors. NMR spectroscopic techniques revealed that monocationic, alkali cations such as Li+ and Na+ can adduct with [Ru(bpy)2(CO)(CHO)]+ intermediate via association to the nucleophilic formyl oxygen, leading to enhanced carbene character in the complex. The effects of this adduct association on the reactivity and stability of [Ru(bpy)2(CO)(CHO)]+ is demonstrated and explored.Chapter 3 continues the exploration of Lewis acid interactions with [Ru(bpy)2(CO)(CHO)]+, but with a stronger, dicationic [Mg(H2O)x]2+ species. Insights into adduct formation using NMR techniques involving variable temperature and titration studies reveal a 2:1 binding mechanism for the association of [Ru(bpy)2(CO)(CHO)]+ with Mg2+. The dicationic Lewis acids bridges two formyl units and imparts strong carbene character mimicking the multi-site behavior observed in heterogeneous FT processes.Chapter 4 explores the interactions of Lewis acids with reactive hydroxymethyl intermediates. The highly reduced model [Ru(bpy)2(CO)(CH2OH)]+ demonstrates similar 2:1 binding association equilibrium with Mg2+ as [Ru(bpy)2(CO)(CHO)]+. However, these adducts of [Ru(bpy)2(CO)(CH2OH)]+ with Mg2+ show clean generation of formaldehyde. This result highlights with the potential for CO reduction to formaldehyde as a potent C1 synthon and fuel precursor. Doctor of Philosoph
Multifocal Kaposiform Hemangioendothelioma Successfully Treated With Sirolimus Monotherapy
Full text linkKaposiform hemangioendothelioma (KHE) is a rare vascular tumor that typically presents in infancy and may be associated with the Kasabach-Merritt phenomenon (KMP). We present a challenging case of multifocal KHE on the leg of an infant, initially suspected at birth to be a reticulate port wine birthmark. Skin biopsy and imaging supported the rare diagnosis of multifocal KHE. Complicated by KMP, he was started on sirolimus monotherapy with significant improvement in his widespread disease
Persistent Type I Interferon Signaling Impairs Innate Lymphoid Cells During HIV-1 Infection Under Suppressive ART
Full text linkPersistent type I interferon (IFN-I) signaling compromises adaptive anti-HIV-1 T cell immunity and promotes viral reservoir persistence, yet its effects on innate lymphoid cells during chronic infection remain unclear. Through integrated single-cell RNA sequencing and functional validation in HIV-1-infected humanized mice with combination antiretroviral therapy (cART) and IFN-I signaling blockade, we reveal IFN-I-induced dysfunction of natural killer (NK) cells and group 3 innate lymphoid cells (ILC3s). Mechanistically, the IFN-I-CD9 axis drives NK cells toward a decidual NK cell-like phenotype, impairing their cytotoxic activity. Furthermore, IFNAR blockade rescues ILC3 functionality, which is critical for IL-17/IL-22-mediated antimicrobial defense and mucosal barrier maintenance. Our study delineates IFN-I-driven immunosuppression across innate lymphocyte compartments and proposes the targeted modulation of this pathway to enhance antiviral and mucosal immunity in HIV-1 management
The role of Tat in HIV latency and reactivation
Full text linkHIV persists during therapy due the existence of a latently infected reservoir in which viral gene expression is silenced. This reservoir thus represents the primary barrier to a cure for HIV. To eliminate latently infected cells from people with HIV (PWH) on antiretroviral therapy (ART), small molecules that reverse HIV latency (Latency reversing agents – LRAs) have been previously developed and tested, but these lack specificity for HIV and are typically inefficient at promoting broad reservoir reactivation. As such, more potent and selective tools for latency reversal are needed. Recently, delivery of mRNA encoding the viral protein Tat, which promotes transcriptional elongation, has attracted interest as a possible HIV-specific approach to inducing latency reversal. This review will cover the evidence that Tat plays a key role in both establishment of HIV latency and latency reversal, as well as recent developments in which Tat mRNA delivery has been used to enhance latency reversal approaches. Delivery of Tat to infected cells represents a promising avenue to bypass the limitations of small molecule LRAs and achieve broad reactivation of the clinical reservoir
Overexpression of TSG101 causes the development of adenosquamous mammary carcinoma
Full text linkBackground The mammalian Tumor Susceptibility Gene 101 (TSG101) encodes a protein with diverse functions that control the proliferation and survival of cells, but its role in malignant transformation and cancer development has remained enigmatic. Methods To study the pro-tumorigenic functions of TSG101, we developed a bi-transgenic mouse model that expresses exogenous TSG101 along with a luciferase reporter in a ligand-controlled manner in the mammary gland epithelium. We performed a comprehensive histopathologic, biochemical, and molecular characterization of ductal hyperplasia and mammary tumors. Unsupervised hierarchical clustering based on 1,723 intrinsic genes of ten TSG101-overexpressing cancers alongside 251 tissue samples representing 31 reference mammary tumor models and normal mammary glands was conducted. Results Females overexpressing TSG101 develop ductal hyperplasia, adenomyoepitheliomas, and palpable adenosquamous carcinomas at an average latency of approximately ten months. These metaplastic mammary tumors are comprised of transforming basal and luminal epithelial cells. Using a GFP reporter strain to monitor the transgene activation at the single-cell level, we determined that the epithelial heterogeneity within transforming ducts and ensuing carcinomas originated from the luminal epithelium. At the molecular level, TSG101-induced mammary tumors are triple-negative and exhibit gene expression signatures of Wnt and inflammatory cytokine signaling, which are key regulators of epithelial cell fate. The ligand-controlled downregulation of exogenous TSG101 in established carcinomas led to tumor regression. We demonstrated that the TSG101-mediated activation of PI3K/AKT signaling, as well as upregulation of Cyclin D1 and MDM2, are dependent on the perpetual expression of the TSG101 oncoprotein. Conclusions The collective findings of this study provide in vivo evidence that TSG101 possesses pro-tumorigenic properties that extend to cancer progression and maintenance, suggesting that this protein could be a rational molecular target to prevent and treat a subset of mammary tumors
Boosting RNA nanotherapeutics with V-ATPase activating non-inflammatory lipid nanoparticles to treat chronic lung injury
Full text linkLipid nanoparticles (LNPs) are a promising platform for mRNA delivery. However, their use in inflammatory pulmonary diseases is limited by reactogenicity and suboptimal delivery. Here we develop a non-inflammatory LNP (NIF-LNP) by incorporating ursolic acid, identified from a natural product library, into a biodegradable, cationic phosphoramide-derived LNP formulation. NIF-LNPs exhibit a 40-fold enhancement in lung protein expression without causing significant reactogenicity compared to LNPs containing ALC-0315. Our CRISPR-KO mechanistic studies uncover that ursolic acid promote endosome acidification by activating the V-ATPase complex, acting as a central hub for endosomal trafficking of LNPs and inflammation control. Furthermore, we identify an intracellular circadian regulatory gene, NR1D1, encapsulated in NIF-LNPs, showing notable therapeutic efficacy in bronchopulmonary dysplasia and lung fibrosis. To enhance clinical feasibility, we have developed a lyophilized formulation that maintains stability for over 90 days and ensures efficient nebulization in preclinical male mouse, pup rat, and male dog models. Overall, this V-ATPase-activating atomized NIF-LNP presents a viable strategy for treating variable chronic inflammatory lung diseases