University of California Research Initiatives

The evolution of the placenta is an excellent model to examine the evolutionary processes underlying adaptive complexity due to the recent, independent derivation of placentation in divergent animal lineages. In fishes, the family Poeciliidae offers the opportunity to study placental evolution with respect to variation in degree of post-fertilization maternal provisioning among closely related sister species. In this study, we present a detailed examination of a new reference transcriptome sequence for the live-bearing, matrotrophic fish, Poeciliopsis prolifica, from multiple-tissue RNA-seq data. We describe the genetic components active in liver, brain, late-stage embryo, and the maternal placental/ovarian complex, as well as associated patterns of positive selection in a suite of orthologous genes found in fishes. Results indicate the expression of many signaling transcripts, "non-coding" sequences and repetitive elements in the maternal placental/ovarian complex. Moreover, patterns of positive selection in protein sequence evolution were found associated with live-bearing fishes, generally, and the placental P. prolifica, specifically, that appear independent of the general live-bearer lifestyle. Much of the observed patterns of gene expression and positive selection are congruent with the evolution of placentation in fish functionally converging with mammalian placental evolution and with the patterns of rapid evolution facilitated by the teleost-specific whole genome duplication event.

Excitons are often given negative connotation in solar energy harvesting in part due to their presumed short diffusion lengths. We investigate exciton transport in single-crystal methylammonium lead tribromide (MAPbBr₃) microribbons via spectrally, spatially, and temporally resolved photocurrent and photoluminescence measurements. Distinct peaks in the photocurrent spectra unambiguously confirm exciton formation and allow for accurate extraction of the low temperature exciton binding energy (39 meV). Photocurrent decays within a few μm at room temperature, while a gate-tunable long-range photocurrent component appears at lower temperatures (about 100 μm below 140 K). Carrier lifetimes of 1.2 μs or shorter exclude the possibility of the long decay length arising from slow trapped-carrier hopping. Free carrier diffusion is also an unlikely source of the highly nonlocal photocurrent, due to their small fraction at low temperatures. We attribute the long-distance transport to high-mobility excitons, which may open up new opportunities for novel exciton-based photovoltaic applications.

Stimuli responsive polymers are an efficient means of targeted therapy.  Compared to conventional agents, they increase bioavailability and efficacy.  In particular, polymer hydrogel nanoparticles (NPs) can be designed to respond when exposed to a specific environmental stimulus such as pH or temperature. However, targeting a specific metabolite as the trigger for stimuli response could further elevate selectivity and create a new class of bioresponsive materials.  In this work we describe an N-isopropylacrylamide (NIPAm) NP that responds to a specific metabolite characteristic of a hypoxic environment found in cancerous tumors.  NIPAm NPs were synthesized by copolymerization with an oxamate derivative, a known inhibitor of lactate dehydrogenase (LDH).  The oxamate functionalized NPs (OxNP) efficiently sequestered LDH to produce an OxNP-protein complex.  When exposed to elevated concentrations of lactic acid, a substrate of LDH and a metabolite characteristic of hypoxic tumor microenvironments, OxNP-LDH complexes swelled (65%).  The OxNP-LDH complexes were not responsive to structurally related small molecules.  This work demonstrates a proof of concept for tuning NP responsiveness by conjugation with a key protein to target a specific metabolite of disease.

Constructs derived from mammalian cells are emerging as a new generation of nano-scale platforms for clinical imaging applications. Herein, we report successful engineering of hybrid nano-structures composed of erythrocyte-derived membranes doped with FDA-approved near infrared (NIR) chromophore, indocyanine green (ICG), and surface-functionalized with antibodies to achieve molecular targeting. We demonstrate that these constructs can be used for targeted imaging of cancer cells in vitro. These erythrocyte-derived optical nano-probes may provide a potential platform for clinical translation, and enable molecular imaging of cancer biomarkers.

Multiple myeloma (MM) is an aggressive hematopoietic cancer of plasma cells. The recent emergence of three effective FDA-approved proteasome-inhibiting drugs, bortezomib (Velcade), carfilzomib (Kyprolis), and ixazomib (Ninlaro) confirms that proteasome inhibitors are therapeutically useful against neoplastic disease, in particular refractory MM and mantle cell lymphoma. This study describes the synthesis, computational affinity assessment, and preclinical evaluation of TIR-199, a natural product-derived syrbactin structural analog. Molecular modeling and simulation suggested TIR-199 covalently binds each of the three catalytic subunits (β1, β2 and β5) and revealed key interaction sites. In vitro and cell culture-based proteasome activity measurements confirmed that TIR-199 inhibits the proteasome in a dose-dependent manner and induces tumor cell death in multiple myeloma and neuroblastoma cells as well as other cancer types in the NCI-60 cell panel. It is particularly effective against kidney cancer cell lines, with more than 250-fold higher anti-tumor activities than observed with the natural product syringolin A (SylA). In vivo studies in mice revealed a maximum tolerated dose (MTD) of TIR-199 at 25 mg/kg. The anti-tumor activity of TIR-199 was confirmed in hollow fiber assays in mice. Adverse drug reaction screens in a kidney panel revealed no off-targets of concern. This is the first study to examine the efficacy of a syrbactin in animals. Taken together, the results suggest that TIR-199 is a potent new proteasome inhibitor with promise for further development into a clinical drug for the treatment of multiple myeloma and other forms of cancer.

The dynamics of relativistic electrons in the intense laser radiation and quasi-static electromagnetic fields both along and across the laser propagating direction are studied in the 3/2 dimensional (3/2D) Hamiltonian framework. It is shown that the unperturbed oscillations of the relativistic electron in these electric fields could exhibit a long tail of the amplitude of harmonics which makes an onset of stochastic electron motion be a primary candidate for electron heating. Chirikov-like mappings which describe the recurrence relations of electron energy and time passing through zero canonical momentum plane are derived, and then, the criteria for instability are obtained. It follows that for both transverse and longitudinal electric fields, there exist upper limits of the stochastic electron energy depending on the laser intensity and electric field strength. These maximum energies could be increased by a weak electric field. However, the maximum energy is reduced for the superluminal phase velocity in both cases. The impacts of the magnetic fields on the electron dynamics are different for these two cases and discussed qualitatively. These analytic results are confirmed by the numerical simulations of solving the 3/2D Hamiltonian equations directly.

The paper examines the legal and administrative history of the Sustainable Groundwater Act and assesses its potential for remedying overdraft.