University of California Research Initiatives

Combining a T cell-targeting mRNA vaccine encoding the conserved SARS-CoV-2 RNA-dependent RNA polymerase, RdRp, with a Spike-encoding mRNA vaccine may offer an additional pathway toward COVID-19 protection. Here, we show that a nucleoside-modified RdRp mRNA vaccine raises robust and durable CD8+ T cell responses in mice. Immunization drives a CD8+ T cell response enriched toward a specific RdRp epitope. Unexpectedly, coadministration of mRNA vaccines encoding RdRp or the Spike Receptor Binding Domain (RBD) dampens RBD-specific immune responses. Contralateral administration reduces the suppression of RBD-specific T cell responses while type I interferon signaling blockade restores RBD-specific antibodies. A staggered immunization strategy maintains both RBD vaccine-mediated antibody and T cell responses as well as protection against lethal SARS-CoV-2 challenge in human ACE2 transgenic mice. In HLA-A2.1 transgenic mice, the RdRp vaccine elicits CD8+ T cell responses against HLA-A*02:01-restricted epitopes recognized by human donor T cells. These results highlight RdRp as a candidate antigen for COVID-19 vaccines. The findings also offer insights into crafting effective multivalent mRNA vaccines to broaden CD8+ T cell responses against SARS-CoV-2 and potentially other viruses with pandemic potential.

Objective: Distinctive stressors facing pregnant and postpartum individuals during the COVID-19 pandemic may have affected their emergency department (ED) care-seeking for behavioral health concerns and violence victimization. We tested whether the incidence of postpartum behavioral health and assault injury ED visits differed for individuals according to their months of postpartum pandemic exposure. Methods: We used statewide, longitudinally linked hospital and ED administrative claims data from California to classify all individuals with hospital deliveries between January 1, 2016, and December 31, 2020, according to their months of postpartum pandemic exposure. Outcomes comprised 12-month incidence of any ED visit for a psychiatric disorder, drug use disorder/overdose, alcohol use disorder/intoxication, or assault injury, defined using International Classification of Diseases-Clinical Modification, version 10 codes. Risk ratios compared the incidence of each outcome among people with 1-12 months of postpartum pandemic exposure to those with 0 months of exposure. Results: Compared to people with 0 months of postpartum pandemic exposure (n = 1,163,215), delivering people with 1-12 month' exposure (range: n = 26,836 to n = 273,561) were approximately equally likely to have a postpartum ED visit for a psychiatric disorder, drug use disorder, or alcohol use disorder, after adjusting for demographic differences (most p > 0.10). The incidence of assault injury was significantly lower among delivering individuals with 11 or 12 months of pandemic exposure (RR_adj = 0.70 and 0.91, respectively; both p < 0.01) compared to those with 0 months. Conclusions: Contrary to expectations, the pandemic did not appear to have affected ED utilization for most behavioral health conditions among postpartum individuals, but assault injury ED visits declined.

Manipulating physical properties through ion migration in complex oxide thin films is an emerging research direction to achieve tunable materials for advanced applications. While the reduction of complex oxides has been widely reported, few reports exist on the modulation of physical properties through a direct hydrogenation process. Here, we report an unusual mechanism for hydrogen-induced topotactic phase transitions in perovskite La_0.7Sr_0.3CoO₃ thin films. Hydrogenation is performed upon annealing in a pure hydrogen gas environment, offering a direct understanding of the role that hydrogen plays at the atomic scale in these transitions. Topotactic phase transformations from the perovskite (P) to hydrogenated-brownmillerite (H-BM) phase can be induced at temperatures as low as 220 °C, while at higher hydrogenation temperatures (320-400 °C), the progression toward more reduced phases is hindered. Density functional theory calculations suggest that hydroxyl bonds are formed with the introduction of hydrogen ions, which lower the formation energy of oxygen vacancies of the neighboring oxygen, enabling the transition from the P to H-BM phase at low temperatures. Furthermore, the impact on the magnetic and electronic properties of the hydrogenation temperature is investigated. Our research provides a potential pathway for utilizing hydrogen as a basis for low-temperature modulation of complex oxide thin films, with potential applications in neuromorphic computing.

Diet is a robust entrainment cue that regulates diurnal rhythms of the gut microbiome. We and others have shown that disruption of the circadian clock drives the progression of colorectal cancer (CRC). While certain bacterial species have been suggested to play driver roles in CRC, it is unknown whether the intestinal clock impinges on the microbiome to accelerate CRC pathogenesis. To address this, genetic disruption of the circadian clock, in an Apc-driven mouse model of CRC, was used to define the impact on the gut microbiome. When clock disruption is combined with CRC, metagenomic sequencing identified dysregulation of many bacterial genera including Bacteroides, Helicobacter, and Megasphaera. We identify functional changes to microbial pathways including dysregulated nucleic acid, amino acid, and carbohydrate metabolism, as well as disruption of intestinal barrier function. Our findings suggest that clock disruption impinges on microbiota composition and intestinal permeability that may contribute to CRC pathogenesis.

Enzymatic biocatalysis typically generates less waste, uses less water, and minimizes energy consumption compared to traditional chemical methods. Efficient, cell-free biosynthesis relies on the reuse of its valuable biocatalysts. Immobilization of enzymes on solid supports, such as enzyme carrier resins (ECRs), offers a reliable and widely deployed approach to maximize enzyme turnover in cell-free biosynthesis. We focus on two major bottlenecks associated with optimizing cell-free biocatalysis. First, we apply our lab's 3D-printed labware to screen ECRs in 96-well mini-reactors to optimize enzyme immobilization conditions. Second, we introduce inline infrared spectroscopy to monitor bioreactor output and maximize enzyme productivity. Urease provides a model system for examining immobilization conditions and continuous assessment of biocatalyst performance. As required for the high substrate concentrations to improve process efficiency and minimize waste, urease was studied in unusually high concentrations of its substrate – molar concentrations of urea. The optimized reactor processed 3.24 L of 4.00 M urea at an average volumetric productivity of 13 g ⋅ L−1 ⋅ h−1 over 18 h and achieved an estimated productivity number of >17.4 kg urea processed per g of immobilized urease Type-IX. This workflow can be generalized to most biocatalytic processes and could accelerate adoption of cell-free biosynthesis for greater chemical sustainability.

Restrictive immigration policies harm the mental health of undocumented immigrants and their U.S. citizen family members. As a sociopolitical stressor, threat to family due to immigration policy can heighten anxiety, yet it is unclear whether political engagement helps immigrant-origin students to cope. We used a cross-sectional survey of college students from immigrant families (N = 2,511) to investigate whether anxiety symptomatology was associated with perceived threat to family and if political engagement moderated this relationship. We stratified analyses by self/parental immigration statuses-undocumented students, U.S. citizens with undocumented parents, and U.S. citizens with lawfully present parents-to examine family members' legal vulnerability. Family threat was significantly associated with anxiety; higher levels of political engagement reduced the strength of this relationship. However, this moderation effect was significant only for U.S. citizens with lawfully present parents. These findings emphasize the importance of the family immigration context in shaping individuals' mental health outcomes.

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

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Recent research has shown that membrane trafficking plays an important role in canonical Wnt signaling through sequestration of the β-catenin destruction complex inside multivesicular bodies (MVBs) and lysosomes. In this study, we introduce Ouabain, an inhibitor of the Na,K-ATPase pump that establishes electric potentials across membranes, as a potent inhibitor of Wnt signaling. We find that Na,K-ATPase levels are elevated in advanced colon carcinoma, that this enzyme is elevated in cancer cells with constitutively activated Wnt pathway and is activated by GSK3 inhibitors that increase macropinocytosis. Ouabain blocks macropinocytosis, which is an essential step in Wnt signaling, probably explaining the strong effects of Ouabain on this pathway. In Xenopus embryos, brief Ouabain treatment at the 32-cell stage, critical for the earliest Wnt signal in development-inhibited brains, could be reversed by treatment with Lithium chloride, a Wnt mimic. Inhibiting membrane trafficking may provide a way of targeting Wnt-driven cancers.

Abstract: Structure elucidation plays a critical role across the landscape of medicinal chemistry, including medicinal inorganic chemistry. Herein, we discuss the importance of structure elucidation in drug development and then provide three vignettes that capture key instances of its relevance in the development of biologically active inorganic compounds. In the first, we describe the exploration of the biological activity of the trinuclear Ru compound called ruthenium red and the realization that this activity derived from a dinuclear impurity. We next explore the development of Au‐based antitubercular and antiarthritic drugs, which features a key step whereby ligands were discovered to bind to Au through S atoms. The third exposition traces the development of As‐based antiparasitic drugs, a key step of which was the realization that the reaction of arsenic acid and aniline does not produce an anilide of arsenic acid, as originally thought, but rather an amino arsonic acid. These case studies provide the motivation for an outlook in which the development of Sb‐based antiparasitic drugs is described. Although antileishmanial pentavalent antimonial drugs remain in widespread use to this day, their chemical structures remain unknown.