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Patience, Paper, and Pattern Recognition: How Janet Rowley Became the Mother of Modern Cytogenetics
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Mediterranean Travel, Interconfessional Rivalry, and the Written Languages of Late Mamluk Mount Lebanon
No full textIn the twentieth century, the languages of medieval Mount Lebanon became a subject of contention between Arab and Lebanese nationalists. A largely unstudied manuscript corpus from the fifteenth century illuminates this matter. In this corpus, bilingualism prevails, with Middle Arabic serving as the primary written language and Syriac serving as the language of worship and prestige. This article draws on colophons, chronicles, and the fifteenth-century literary texts to examine the norms governing language in late Mamluk Mount Lebanon. It is centered on the lives and works of Mūsá Ibn ʿAṭshah, Yūḥannā ibn Ḥasan, Nūḥ al-Baqūfānī, and Jibrāyil Ibn al-Qilāʿī. Through these figures, it considers authorial intention, educational background, audience, and dynamics of power as determinants of language choice. From this social history of language, a portrait of Mount Lebanon emerges as the site of Syriac revival and a new Christian Arabic literature at the confluence of Mamluk culture, Eastern Christianity, Franciscan vocation, and the Mediterranean
Reply to Benito et al.: Problems in the Cretaceous evolution of the avian palatobasal joint
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Design of Crystalline Framework Materials for Sustainable Catalysis
No full textCrystalline framework materials, such as metal-organic frameworks (MOFs) and covalent framework materials (COFs), exhibit outstanding porosity, tunability and stability. These advantages make this emerging class of materials a promising and versatile platform for the construction of heterogeneous catalysts with high reactivity, durability and recyclability. My PhD research aims to rationally design crystalline framework materials as sustainable catalysts through a dual molecular and material approach, by establishing novel synthetic protocols, employing rigorous characterization techniques, and developing more efficient and synthetically useful catalytic processes. Chapter 1 of this dissertation aims to introduce basic concepts of crystalline framework materials, including their design principles, synthetic strategies and applications. Because they simultaneously possess well-defined molecular structures and intrinsic material properties, these crystalline framework materials can combine the high reactivity and tunability of homogeneous with the stability and recyclability of heterogeneous catalysts. The first part of the dissertation, including Chapters 2 and 3, focuses on using MOFs as a platform to develop bimetallic systems for sustainable catalysis. These chapters describe post-synthetic strategies for the construction of dual catalytic centers, either homobimetallic or heterobimetallic, that can work synergistically to activate small molecules such as O2 and CO2. These systems demonstrated how synergy between two metal sites can lead to superior reactivity compared to their mononuclear analogs or a simple mixture of two monofunctional catalysts. Moreover, these highly reactive catalytic sites are site-isolated in the framework, inhibiting undesired deactivation processes such as aggregation or nanoparticle formation, which significantly increases the durability and recyclability of these MOF-based catalysts. The second part, including Chapters 4, 5 and 6, presents strategies to design COFs for sustainable photocatalysis. Photosensitizing motifs can be introduced into COF backbones with rational design of structures. Furthermore, a second catalytic site can be installed via post-synthetic linkage modification or metalation to construct bifunctional catalysts. The proximity between the photosensitizing motif and the catalytic site drastically accelerates electron transfer during photocatalysis, and the site-isolation effect prevents catalyst deactivation, improving the sustainability of these catalysts
Circuits, Structure and Behavior in Mouse Early Vision
No full textPrimary visual cortex (V1) in rodents, despite being a central and well-characterized research model for systems and computational neuroscience, still lacks consensus on a correspondence of its functional organization and underlying circuitry, as well as the circuit pathways that merge sensory and non-visual modulatory signals. This dissertation collectively develops experimental and theoretical arguments to refine both aspects. The first and second part of the thesis revisit the long hold view of 'salt-and-pepper' spatial organization of orientation tuning in mouse V1. Using large-scale two-photon imaging we observe a fine spatial scale functional organization in both L2/3 and L4 of mouse V1: neurons within ~20μm exhibit remarkably strongly correlated orientation tuning, yet drops to random, uncorrelated levels beyond this range. We term this pattern 'micro-clusters'. To explain how 'micro-clusters' are inherited and stabilized in L2/3 despite underlying broad lateral connectivity, we develop a spatially extended excitation–inhibition (E/I) recurrent circuit model, and derive two qualitative and testable predictions: extra strong components of connection strength over a comparable fine spatial scale; balanced E/I condition over macro-spatial scales yet imbalanced condition over micro-spatial scales. Furthermore, these predictions are validated by various cell-type specific circuit mapping experiments. We next explore the developmental origin of 'micro-cluster' through thalamo-cortical inputs in L4. We employ a Hebbian/Oja rule learning model for LGN to L4 synaptic connections and via an analytical asymptotic analysis we show that L4 recurrent interactions primarily sets the fine spatial scale of clustered functional organization in L4. The third part of the thesis reassess the sources of non-visual input in mouse V1 and LGN via modulation by free, uninstructed body movement behavior in mouse V1. We collect calcium imaging data of both thalamo-cortical boutons (as feedforward inputs to V1) and V1 cortical neurons with simultaneous measurements of spontaneous facial movements. Using rigorous statistical procedures that control for spurious 'nonsense' correlations from slow trending neurophysiological and behavioral data, we reveal a robust movement behavioral modulation in visual stimulated feedforward pathway rather than exclusively from top-down pathway, which is driven by both eye movement and non-ocular movement features. Our analysis suggests that V1 cortical neurons exhibit a robust integration of non-visual signals from a top-down pathway that is active across visually and non-visually stimulated periods with a stimulus-gated bottom-up dLGN pathway. Population analyses further show that movement- and stimulus-related information occupy intertwined subspaces of V1 population activity, while the stimulus information can be properly and perfectly decoded without interference of behavioral variables. Altogether, these results reconcile the interplay between fine-scale functional organization and underlying circuitry within different theoretical frameworks, and establish the potential circuit pathways that merge sensory and free behavior information, re-framing mouse V1 as a context-aware, fine-grained network
Adjuvant Chemotherapy Use for Hormone Receptor–Positive, <i>ERBB2</i> -Negative Breast Cancer After RxPONDER Trial
No full textImportance: Since 2018, the TAILORx and RxPONDER trials have demonstrated that the 21-gene recurrence score (RS) can be indicative of the benefit of adjuvant chemotherapy in hormone receptor (HR)–positive, ERBB2 (formerly HER2)–negative breast cancer with 3 or fewer positive lymph nodes. However, its applicability to key subgroups with high risk for recurrence, including premenopausal women with positive lymph nodes and racial and ethnic minority individuals, remains unclear. Objective: To assess the temporal patterns of and disparities in adjuvant chemotherapy use in early-stage HR-positive, ERBB2-negative breast cancer by age, genomic risk, and nodal involvement. Design, Setting, and Participants: This retrospective cohort study analyzed clinical data from the 2010 to 2022 National Cancer Database. The cohort included women with stage I to III, HR-positive, ERBB2-negative breast cancer who had undergone a lumpectomy or mastectomy and were eligible for endocrine therapy. Patients were categorized into premenopausal (aged ≤50 years) or postmenopausal (aged >50 years) status. Nodal status (negative or positive) was pathologically confirmed. RS was classified per the TAILORx trial, with RS of 0 to 10 as low genomic risk, RS of 11 to 25 as intermediate genomic risk, and RS of 26 or higher as high genomic risk. Data were analyzed from January 20 to August 11, 2025. Main Outcomes and Measures: Adjuvant systemic therapy, defined as receipt of either endocrine therapy alone or chemoendocrine therapy (chemotherapy plus endocrine therapy), after surgery (lumpectomy or mastectomy). Results: A total of 504 937 women (mean [SD] age, 60.0 [10.7] years; 5.4% Hispanic, 4.3% non-Hispanic Asian or Pacific Islander, 8.1% non-Hispanic Black, 81.3% non-Hispanic White, and 0.9% other race or ethnicity) were included. Among premenopausal patients with node-negative tumors, adjuvant chemotherapy use decreased from 6.5% in 2010 to 0.9% in 2022 for those with low genomic risk and from 29.6% in 2010 to 11.1% in 2022 for those with intermediate genomic risk. However, among premenopausal patients with node-positive disease, chemotherapy use declined from 33.3% in 2010 to 12.7% in 2019 but increased to 25.7% in 2022 for the low genomic risk group. For the intermediate genomic risk group, chemotherapy use declined from 55.8% in 2010 to 38.1% in 2019 but increased to 48.9% in 2022. Among postmenopausal women, chemotherapy use for those with low to intermediate genomic risk continued to decrease from 2010 to 2022 in both node-negative and node-positive disease status. Black women with high genomic risk had lower odds of chemotherapy receipt than White women, regardless of menopausal or nodal status (adjusted odds ratio [AOR], 0.84; 95% CI, 0.78-0.90). Premenopausal Black women with low to intermediate genomic risk also had lower odds of chemotherapy receipt than White women (AOR, 0.85; 95% CI, 0.77-0.94), regardless of nodal status. Conclusions and Relevance: This retrospective cohort study found that adjuvant chemotherapy use almost doubled in premenopausal patients with node-positive tumors and with a low to intermediate genomic risk from 2019 to 2022 but decreased for patients with node-negative disease, coinciding with the publication of the TAILORx and RxPONDER trials. The findings highlight the variability in genomic assay use to facilitate adjuvant therapy recommendations for HR-positive, ERBB2-negative breast cancer.</p
Cryo-EM structure revealed a novel F-actin binding motif in a Legionella pneumophila lysine fatty acyltransferase
No full textLegionella pneumophila is an opportunistic bacterial pathogen that causes Legionnaires’ disease. To establish an intracellular niche conducive to replication, L. pneumophila translocates a diverse array of effector proteins that manipulate various host cellular processes, including the actin cytoskeleton. In a screen for effectors that alter actin dynamics, we identified a Legionella effector, Lfat1 (lpg1387), which colocalizes with the actin cytoskeleton in eukaryotic cells. Lfat1 specifically binds F-actin through a novel actin-binding domain (ABD). High-resolution cryo-electron microscopy (Cryo-EM) analysis revealed that this ABD forms a long α-helix hairpin, with its tip interacting with subdomains I and II of two adjacent actin molecules within the F-actin filament. Interestingly, while individual α-helices of the hairpin fail to bind F-actin, co-expression as separate fusion proteins restores binding activity. Furthermore, we demonstrated that Lfat1 exhibits lysine fatty acyltransferase (KFAT) activity, targeting host small GTPases. These findings establish a foundation for studying the KFAT family of bacterial toxins and uncover a novel F-actin-binding motif, providing an alternative F-actin marker with notable flexibility
Directed Evolution of Enzymes for Bioorthogonal Chemistry Using Acid Chloride Proximity Labeling
No full textCombining bioorthogonal protecting groups with localized catalysts that can unmask them is a powerful approach to spatially and temporally modulate molecular activity. Enzymes are appealing catalysts in this context because they are genetically targetable, but enzymes are not always available to unmask a protecting group of interest. Here, we report a platform for ultrahigh-throughput enzyme evolution by combining yeast surface display with masked acylating probes, which selectively label yeast cells based on target biocatalytic activity. We introduce the phenylcyclopropyl (pCP) ester protecting group, which has improved bioorthogonality compared to existing ester protecting groups, and use our platform to evolve BS2 esterase for enhanced pCP unmasking. Evolved BS2 mutants are up to 232-fold more active toward the pCP group. Taking advantage of the enhanced bioorthogonality of the pCP group, we applied a pCP probe together with evolved BS2 to perform spatially resolved RNA tagging with high spatial specificity, including in mammalian cell lines with high endogenous esterase activity. Overall, this work delivers a new bioorthogonal protecting group and engineered enzymes capable of unmasking it, and more broadly, it provides a platform to rapidly engineer enzymes for protecting group removal, opening opportunities in imaging, proximity tagging, induced cell signaling, and therapeutics
Eviction, Collective Efficacy, and Firearm Violence in Chicago
No full textImportance: Firearm violence is concentrated in structurally marginalized communities. Collective efficacy—a community’s belief in their ability to achieve a shared goal—has been associated with lower rates of firearm violence. It remains unclear whether structural determinants, such as eviction, may be associated with lower collective efficacy and firearm violence. Objective: To understand if eviction is independently associated with firearm violence and if eviction moderates established associations between collective efficacy and firearm violence. Design, Setting, and Participants: This cross-sectional study used participant data from the Healthy Chicago Surveys (HCS) from 2021 to 2023, and neighborhood-level data from the City of Chicago. Participants included respondents to the HCS, and data were analyzed from July to December 2024. Exposures: Primary exposures included personal experience of eviction (self-reported) and neighborhood-level exposure to eviction (census-tract eviction rate). Neighborhood collective efficacy and related neighborhood measures were also examined in moderation analyses, modeling an interaction term between eviction and neighborhood measures. Main Outcome and Measures: The primary outcome was exposure to firearm violence, measured by shooting events within 1000 feet of a participant’s home. Mixed-effects linear regression models were used to examine firearm violence as a function of eviction measures and theoretically-relevant covariates. Results: The sample included 13 916 participants. Most participants were White (5194 [37.7%]), Black (3915 [28.4%]), or Hispanic (3150 [22.9%]); women (8625 [62.5%]) were oversampled relative to men (4923 [35.7%]). Additionally, 3362 individuals (25.2%) lived below the federal poverty line and 7032 (50.8%) had at least a bachelor’s degree. Most participants were age 45 to 64 years (4416 [31.8%]) or 30 to 44 years (4169 [30.0%]). The median (IQR) number of shootings within 1000 feet of a participant’s home was 3 (1-9). Each percentage increase in census tract eviction rate (mean [range], 0.88% [0%-5.33%]) was associated with 2.66 (95% CI, 2.01-3.31) additional shootings within 1000 ft of the participant’s home. Individual experience of eviction was associated with 1.04 (95% CI, 0.46-1.61) additional shootings within 1000 ft. Eviction was a significant moderator of associations of low collective efficacy with firearm violence (0.89; 95% CI, 0.20 to 1.58; P = .01). Conclusions and Relevance: In this cross-sectional study, eviction was associated with increased firearm violence exposure. Eviction augmented associations between low collective efficacy and firearm violence, highlighting the contextual role of structural disadvantage in galvanizing this association. Eviction may be a tangible intervention target for violence prevention in US cities.</p