Publications

Metal-based nanoparticles are a promising class of materials for diagnosis and treatment of cancer and other diseases. However, mechanisms of action of these nanomedicines remain insufficiently understood due in large part to our limited understanding of the dynamic equilibria between solid metal nanoparticles and labile metal ions generated from these nanoparticles within complex biological milieus. Here we apply activity-based sensing to directly identify and investigate the fate of labile copper pools with metal and oxidation state-specificity generated by anticancer copper nanomedicines. We found that treatment of cells with copper-releasing CuFe2O4 and Cu2Fe(CN)6 nanoparticles alter labile Cu(I)/Cu(II) ratios through an increase in labile Cu(II), while overall labile copper levels decrease. Labile copper release triggers compensatory responses in two major antioxidant pathways, glutathione (GSH) and nuclear factor erythroid 2–related factor 2 (NRF2), as well as in metal homeostasis to limit copper availability via synergistic upregulation of copper export (ATP7B) and downregulation of copper import (CTR1) proteins. These findings establish the value of activity-based sensing as a generalizable approach for labile metal imaging to help decipher molecular mechanisms of bioactive metal nanoparticles and guide the development of more effective nanomedicine diagnostics and therapies to target metal-dependent disease vulnerabilities.

ABSTRACT MCA-1B (also called UIT003) is a luminous hot star in the western outskirts of M33, classified over 20 yr ago with a spectral type of Ofpe/WN9 and identified then as a candidate luminous blue variable (LBV). Palomar Transient Factory data reveal that this star brightened in 2010, with a light curve resembling that of the classic LBV star AF And in M31. Other Ofpe/WN9 stars have erupted as LBVs, but MCA-1B was unusual because it remained hot. It showed a WN-type spectrum throughout its eruption, whereas LBVs usually get much cooler. MCA-1B showed an almost four-fold increase in bolometric luminosity and a doubling of its radius, but its temperature stayed ≳29 kK. As it faded, it shifted to even hotter temperatures, exhibiting a WN7/WN8-type spectrum, and doubling its wind speed. MCA-1B is reminiscent of some supernova impostors, and its location resembles the isolated environment of SN 2009ip. It is most similar to HD 5980 (in the Small Magellanic Cloud) and GR 290 (also in M33). Whereas these two LBVs exhibited B-type spectra in eruption, MCA-1B is the first clear case where a Wolf–Rayet (WR) spectrum persisted at all times. Together, MCA-1B, HD 5980, and GR 290 constitute a class of WN-type LBVs, distinct from S Doradus LBVs. They are most interesting in the context of LBVs at low metallicity, a possible post-LBV/WR transition in binaries, and as likely Type Ibn supernova progenitors.

We investigated the endocarp of the fruit of Cocos nucifera (i.e., the inner coconut shell), examining the structure across multiple length scales through advanced characterization techniques and in situ testing of mechanical properties. Like many biological materials, the coconut shell possesses a hierarchical structure with distinct features at different length scales that depend on orientation and age. Aged coconut was found to have a significantly stronger (ultimate tensile strength, UTS = 48.5MPa), stiffer (Young's modulus, E = 1.92GPa), and tougher (fracture resistance (R-curve) peak of K J = 3.2MPa m1/2) endocarp than the younger fruit for loading in the latitudinal orientation. While the mechanical properties of coconut shell were observed to improve with age, they also become more anisotropic: the young coconut shell had the same strength (17MPa) and modulus (0.64GPa) values and similar R-curves for both longitudinal and latitudinal loading configurations, whereas the old coconut had 82% higher strength for loading in the latitudinal orientation, and >50% higher crack growth toughness for cracking on the latitudinal plane. Structural aspects affecting the mechanical properties across multiple length scales with aging were identified as improved load transfer to the cellulose crystalline nanostructure (identified by synchrotron x-ray diffraction) and sclerification of the endocarp, the latter of which included closing of the cell lumens and lignification of the cell walls. The structural changes gave a denser and mechanically superior micro and nanostructure to the old coconut shell. Additionally, the development of anisotropy was attributed to the formation of an anisotropic open channel structure throughout the shell of the old coconut that affected both crack initiation during uniaxial tensile tests and the toughening mechanisms of crack trapping and deflection during crack propagation.

Copper plays critical roles as a metal active site cofactor and metalloallosteric signal for enzymes involved in cell proliferation and metabolism, making it an attractive target for cancer therapy. In this study, we investigated the efficacy of polydopamine nanoparticles (PDA NPs), classically applied for metal removal from water, as a therapeutic strategy for depleting intracellular labile copper pools in triple-negative breast cancer models through the metal-chelating groups present on the PDA surface. By using the activity-based sensing probe FCP-1, we could track the PDA-induced labile copper depletion while leaving total copper levels unchanged and link it to the selective MDA-MB-231 cell death. Further mechanistic investigations revealed that PDA NPs increased reactive oxygen species (ROS) levels, potentially through the inactivation of superoxide dismutase 1 (SOD1), a copper-dependent antioxidant enzyme. Additionally, PDA NPs were found to interact with the mitochondrial membrane, resulting in an increase in the mitochondrial membrane potential, which may contribute to enhanced ROS production. We employed an <i>in vivo</i> tumor model to validate the therapeutic efficacy of PDA NPs. Remarkably, in the absence of any additional treatment, the presence of PDA NPs alone led to a significant reduction in tumor volume by a factor of 1.66 after 22 days of tumor growth. Our findings highlight the potential of PDA NPs as a promising therapeutic approach for selectively targeting cancer by modulating copper levels and inducing oxidative stress, leading to tumor growth inhibition as shown in these triple-negative breast cancer models.

In this work, an accident tolerant fuel cladding system with Cr coating deposited using physical vapour deposition (PVD) method onto commercial Optimized ZIRLO™ was studied. The cladding tubes were machined into C-rings and loaded to failure under compression with real-time synchrotron micro-X-ray computed tomography (XCT) imaging at room temperature (RT), 345 °C, 650 °C and 950 °C in argon (Ar) atmosphere. The mechanical behaviour and failure processes were found strongly temperature-dependent where the Cr coating showed brittle fracture at RT and 345 °C, ductile fracture at 650 °C and a reversion to brittle fracture at 950 °C. Nanoindentation measurements and scanning electron microscopy (SEM) imaging were conducted on the materials after high temperature testing. It was found that recrystallisation of the Cr coating occurred at elevated temperatures, which significantly affected its local properties hence the failure behaviour at different temperatures. This work represents the first in situ 3D XCT observation of progressive failure processes in PVD Cr-coated ZIRLO claddings up to 950 °C providing critical insights into its brittle-to-ductile transition (BDTT) behaviour and subsequent ductile-to-brittle reversion with the increase in temperature. Moreover, results are compared with other PVD Cr-coated Zircaloy materials from open literature; the influences of the coating microstructure and local properties on the failure stress/strain and fracture processes are discussed.

Strong and abundant magnetic anomalies imaged beneath the West Antarctic Ice Sheet by aerogeophysical surveys have been interpreted as evidence of widespread Late Cenozoic basaltic volcanism, perhaps even a large igneous province. Petrological and geochemical composition of subglacial sediment samples from West Antarctica supports crustal provenance and does not provide positive evidence for the existence of the proposed mafic Late Cenozoic large igneous province. The only two identified basaltic pebbles, out of a total of &gt;500 examined pebbles, are of Mesozoic to Cambrian age. We conjecture that the subglacial large igneous province does not exist or is blanketed by an at least Miocene age sedimentary drape.