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Effect of Polymer Structure on the Thermodynamics of Polyelectrolyte Complex Micelle Formation
No full textPolyelectrolyte complex micelles (PCMs) are nanoparticles that form through the associative phase separation between hydrophilic neutral–charged block copolymers and oppositely charged polyelectrolytes, resulting in a dense, charged core surrounded by a stabilizing neutral corona. Among other applications, these constructs have been studied as nonviral vectors for therapeutic nucleic acid delivery for a variety of potential clinical indications. Although prior research has focused on tailoring PCM morphology and size by modifying block polyelectrolyte characteristics, thermodynamic considerations have received comparatively little attention in the design of PCMs. In this study, we explore the dependencies of PCM complexation thermodynamics, particularly the entropy of complexation, on polyelectrolyte block length and PCM structure. We employ scattering (DLS, SAXS, MALS) to characterize PCM structure, while using isothermal titration calorimetry to provide quantitative thermodynamic data. Compared to complexation between homopolymers, we observe that PCM formation involving block polyelectrolytes introduces an entropic cost related to the neutral corona-forming block. This penalty depends on the sizes of the charged blocks but is relatively insensitive to the neutral block size. Scattering results show that PCM complexation entropy is not correlated with indicators of corona chain conformation, such as brush height and corona surface chain density. Rather, for PCMs composed of polymers with equal charged block lengths, complexation entropy is correlated with monomer density within the core and corona. Our findings also suggest a negligible free polymer concentration in PCM formulations with net neutral charge. These insights advance the rational design of block copolymers for encapsulating a wide array of therapeutically relevant cargos and deepen our understanding of the factors governing PCM formation
Intersubjective Meanings and Oppressive Social Practices
No full textRecently, social philosophers have argued for a practice-based social ontology that can furnish a robustly social account of oppression and, in turn, illuminate the obstacles to and possibilities for social change. This paper argues for an intersubjective approach to oppressive social practices. Oppressive meanings constitute relationships between agents in ways they neither choose nor decide on; agents uphold those meanings through their relationships to others. This approach, I argue, can illuminate a critical case of an oppressive social practice that revolves around struggles for recognition and the dynamics of social change
Genomic profiling of active vitamin D colonic responses in African- and European-Americans identifies an ancestry-related regulatory variant of POLB
No full text We measured genomic responses to active vitamin D, 1α,25-dihydroxyvitamin D (1,25D), in colonic organoids from individuals of African and European ancestry. Given protective effects of 1,25D for gastrointestinal conditions such as colorectal cancer, organoid cultures enabled evaluation of condition-specific responses in relevant target tissue across individuals of diverse ancestries. We found significant alterations in transcriptional and chromatin accessibility responses to 1,25D treatment, including some with ancestry-associated differences, and also elucidated the role of cis- genetic variants on treatment responses. Integration of genomic profiling with genetic mapping found an insertion-deletion variant that explains ancestry-associated differences in 1,25D regulation of POLB, an oxidative DNA repair enzyme involved in colorectal carcinogenesis, which also showed signals of positive natural selection. These findings highlight the importance of including diverse individuals in functional genomics studies to identify potential drivers of population-level differences relevant for clinical outcomes, and to uncover functional mechanisms that may be obscured by ancestry variation.</p
qSIEVE: Efficient qLDPC Memory via Systolic Movement in Atom Arrays
No full textAs quantum machines have scaled up in their number of qubits, significant research has turned towards increasing their fidelity with quantum error correction codes. Although promising results have been shown with the surface code, which only requires near-neighbor connections between qubits, the high qubit overhead of such local codes promises to be problematic. Consequently, recent work has explored non-local quantum LDPC (qLDPC) codes, which have good asymptotic encoding rates. Despite theoretical progress, hardware implementations of these codes have been a longstanding challenge. At the experimental level, demonstrations of movement based communication on atom arrays suggest this is a powerful new primitive to achieve non-local connectivity. Leveraging this, we present a protocol for implementing non-local qLDPC codes in hardware. Our protocol, qSIEVE, is a co-design of such codes with movement in atom arrays. qSIEVE defines a restricted family of qLDPC codes that can be implemented efficiently with systolic movement. We then quantify the utility of qSIEVE in the context of a complete fault tolerant architecture. We compare the cost of implementing benchmark programs in a standard, surface code only architecture and a mixed architecture where data is stored in qLDPC memory with qSIEVE and loaded to surface codes for computation.</p
From Divine Emanation to Government Organization: Tracing the Development of an Ottoman Political Theology
No full textThis dissertation, "From Divine Emanation to Government Organization: Tracing the Development of an Ottoman Political Theology", investigates the intellectual foundations of the early Ottoman state by examining the influence of Akbari Sufi philosophy on political theory. While traditional historiography often treats Ottoman governance as a pragmatic evolution of Central Asian and Islamic legal traditions, this study argues that the metaphysics of the "Unity of Being" (waḥdat al-wujūd) provided a cohesive "political theology" that underpinned the state’s legitimacy and administrative structure from the fourteenth through the sixteenth centuries. The research focuses on the transition from high-level mystical theory to concrete bureaucratic practice through the works of three seminal scholars. The first, Dāvūd-i Ḳayṣerī (d. 1350), the inaugural director of the first Ottoman madrasa, established the ontological necessity of the Caliphate. By framing the ruler as a terrestrial manifestation of Divine Names, Ḳayṣerī provided the nascent Ottoman polity with a metaphysical justification for authority that transcended mere military might. The study then moves to the fifteenth-century polymath ‘Abdurrahman al-Bisṭāmī (d. 1454). Bisṭāmī transformed Akbari thought into a systematic "emanative epistemology," wherein the hierarchy of the state mirrored the hierarchy of existence. His work represents a crucial middle stage, where mystical concepts were used to categorize and organize the various "orders" of society—from the military to the scholars—under a unified spiritual and temporal administration. Finally, the dissertation examines the sixteenth-century work of the judge and litterateur Aşık Çelebī (d. 1572). In his Miʿrācü’l Eyāle, Çelebī integrated earlier metaphysical frameworks with the practical realities of a mature imperial bureaucracy. By examining his focus on the judiciary and provincial administration, the study demonstrates how the diffusion of the Sultan’s power was understood as a continuation of the Divine emanative process. Ultimately, this dissertation demonstrates that the Ottoman ‘ilmiyye (scholarly class) did not view the state as a secular necessity, but as a sacred extension of the cosmos. By tracing this intellectual lineage, the research offers a new perspective on Ottoman "justice" and statecraft, showing how Akbari philosophy served as the essential scaffolding for the empire's political identity. This study contributes to a deeper understanding of how the Ottomans synthesized diverse intellectual currents into a unique and durable model of Islamic sovereignty
“Knowledge of the Three Shone in One”: Contextualizing al-Sakhāwī’s Perceptions of Islamicate Trilingualism in the Ḍawʾ al-Lāmiʿ
No full textThrough biographies pulled from al-Sakhāwī’s Ḍawʾ al-lāmiʿ, this article analyzes the interaction of multilingual proficiency with social mobility, migration, and intellectual life in the fifteenth-century Cairo Sultanate. Focusing on al-Sakhāwī’s presentation of trilingual scholars fluent in Arabic, Persian, and Turkic, the article explores trilingualism as a noteworthy skillset indicative of adaptability. It also considers how linguistic versatility enabled access to patronage, teaching appointments, chancery work, and participation in transregional networks. By focusing on local Egyptian and immigrant scholars, the article demonstrates ways in which language influenced elite identity and contributed to the cosmopolitan milieu of late medieval Egypt and Syria
Beyond Surface Alignment: Grounding the Dynamics of Situational Understanding and Generative Control in LLMs
No full textCurrent alignment tuning prioritizes surface fluency, masking a lack of deep grounding. This thesis proposes "Grounded Alignment," analyzing failures in situational understanding (SitTest, ReCode) and generative control (Branching Factor). We reveal that alignment often induces "stylistic collapse" rather than true comprehension. Finally, we introduce mechanisms like Base-Aligned Model Collaboration to build agents robustly anchored in their context and generation
No Observational Evidence for Dark Matter Nor a Large Metallicity Spread in the Extreme Milky Way Satellite Ursa Major III/UNIONS 1
No full textThe extremely low-luminosity, compact Milky Way satellite Ursa Major III/UNIONS 1 (UMaIII/U1; LV = 11 L⊙, a1/2 = 3 pc) was found to have a substantial velocity dispersion at the time of its discovery , suggesting that it might be an exceptional, highly dark-matter-dominated dwarf galaxy with very few stars. However, significant questions remained about the system’s dark matter content and nature as a dwarf galaxy, due to the small member sample (N = 11), possible spectroscopic binaries, and the lack of any metallicity information. Here, we present new spectroscopic observations covering N = 16 members that both dynamically and chemically test the true nature of UMaIII/U1. From higher-precision Keck/DEIMOS spectra, we find a 95% confidence level velocity dispersion limit of σv < 2.3 km s−1, with a ∼120:1 likelihood ratio favoring the expected stellar-only dispersion of σ* ≈ 0.1 km s−1 over the original 3.7 km s−1 dispersion. There is now no observational evidence for dark matter in the system. From Keck/LRIS spectra targeting the Ca II K line, we also measure the first metallicities for 12 member stars, finding a mean metallicity of [Fe/H] = − 2.65 ± 0.1 (stat.) ±0.3 (zero-point), with a metallicity dispersion limit of σ[Fe/H] < 0.35 dex (at the 95% credible level). Together, these properties are more consistent with UMaIII/U1 being a star cluster, though the dwarf galaxy scenario is not fully ruled out. Under this interpretation, UMaIII/U1 ranks among the faintest and most metal-poor star clusters yet discovered
Deep Learning (nnU-Net)-Based Segmentation of Primary HPV-Positive OPSCC: Contrast-Enhanced T1-Weighted Fat-Suppressed Versus Non-Contrast-Enhanced T2-Weighted Fat-Suppressed MRI (Paired Single-Center Study)
No full textBackground/Objectives: While deep learning-based AI algorithms have been shown to perform well for OPSCC tumor segmentation, the relative value of contrast-enhanced versus T2-weighted sequences for automated segmentation has not been systematically evaluated. In this study, we compared the sequence-specific deep learning performance on contrast-enhanced T1-weighted fat-suppressed and T2-weighted fat-suppressed MRI in HPV-positive OPSCC. Methods: Pretreatment MRI from 39 patients with paired sequences from a single center were retrospectively analyzed. OPSCC primary tumors were manually segmented using both sequences, which served as the ground truth. Three sequence-specific configurations were evaluated: contrast-enhanced (CE), T2-only, and combined CE + T2. Quantitative evaluation was carried out on aggregated out-of-fold predictions using Dice score (primary), Surface-Dice@2mm (secondary), and other boundary and volumetric metrics, and paired comparisons (combined vs. T2-only; CE-only vs. T2-only) were performed using an exact Wilcoxon signed-rank test. Qualitative evaluation was performed on 4-point ordinal acceptability ratings recorded using a blind reader study, and the ratings were compared using the exact Wilcoxon signed-rank test (pairwise) and dichotomized acceptability using the McNemar test.Results: Median Dice was comparable across configurations (0.63 for CE + T2, 0.60 for T2-only, and 0.55 for CE-only). Median Surface-Dice@2mm was highest for the combined configuration (0.62), followed by CE-only (0.6) and T2-only (0.57). Median ASSD were 2.71, 2.98, and 2.98 mm, and median HD95 were 11.39, 15.0, and 11.3 mm for combined, CE, and T2, respectively. The median GTV differences (−1.31, −1.29, and −1.49 mL for combined, T2, and CE, respectively) showed a slight bias toward under-segmentation across all configurations. No significant differences in Dice scores were observed for combined vs. T2 (p = 0.11) or contrast-enhanced vs. T2-only (p = 0.98). Similarly, qualitative analysis also showed no evidence of performance difference for ratings and acceptability rates across sequence configurations (paired Wilcoxon, p ≥ 0.35; McNemar, p = 1.00).Conclusions: In this single-center study, the segmentation performance using non-contrast sequences was comparable to that using both contrast-enhanced and non-contrast sequences. The drop in performance when the contrast-enhanced sequences were excluded from the combination was not significant. These findings justify multi-center validation to support the feasibility of contrast-sparing automated primary OPSCC segmentation when use of contrast agents is contraindicated.</p
Synthetic Biology Approaches for Recording Diffusible Cell-Cell Communications
No full textCells must exchange information via diffusible signals to sustain life. Such cell-cell communications are extracellular, transient, and disseminated by nature, making it incredibly challenging to track in any experimental system. Therefore, many fundamental questions about the structure and function of intercellular signaling cascades mediated by secreted factors remain unanswered. Here, we prototype intracellular sensors to record the release and receipt of cytokine signals, both at the protein (Chapter 2) and RNA (Chapter 3) levels. First, we establish nanobody-DNA writer fusions that become active upon target antigen recognition. We benchmark our sensors in vitro by recording the release and receipt of type I interferons in an inducible cell-cell circuit, which we construct in human lung epithelial cells. We find that sensor-based recordings closely recapitulate the patterns of interferon signaling between sender and receiver cells, as reported by time-lapse microscopy of fluorescent reporters. Next, we apply these tools in vitro and in vivo to capture the release and receipt of type II interferon between T lymphocytes and cancer cells in mouse models of solid and hematologic malignancies. To this end, we employ both retroviral delivery and engineered transgenic mice carrying integrated cytokine-sensing circuits, which enable stable, lineage-resolved recording of interferon-γ signaling events within T-cells. Using these complementary systems, we aim to define how the transcriptional and functional states of T cells and tumor cells evolve as a function of their history of intercellular interferon-γ signaling during tumor initiation, progression, therapeutic response, and relapse. Finally, we develop a new class of gRNAs that couple Cas13, Cas9, and Csy4 activity to enable programmable, transcript-responsive CRISPR editing. Together, these approaches open new avenues for systematic studies of how past intercellular communication shapes the present and future behavior of multicellular systems