Recent ucri items

Electron thermalization in TDDFT and Ehrenfest molecular dynamics

Wed, 24 Jun 2026 00:00:00 +0000

A non-equilibrium electronic state will, in general, thermalize toward an equilibrium state due to electron-electron interactions as well as interactions with ions. The description of such processes has remained unclear and controversial in time-dependent density functional theory (TDDFT), given that the occupation numbers remain fixed over time and that adiabatic functionals do not include explicit dissipation. Here, we study the explicit time propagation of graphene after ultrafast laser pulses, using the Octopus real-space code, with and without ionic motion in Ehrenfest molecular dynamics. This work has implications for the treatment of statistical mechanics in a TDDFT framework.

Sustainable Agriculture Engagement And Adoption On The Central Coast

Sun, 12 Apr 2026 00:00:00 +0000

The following report chronicles the professional project completed in partial fulfillment for the degree of Master of Science in Environmental Sciences and Management at California Polytechnic State University, San Luis Obispo. This professional project spanned fifteen months and was conducted with the support of the Sustainable Land Initiative under the supervision of Professor Nicholas Babin. Two educational workshops resulted from the endeavor, thus contributing to the Central Coast’s agriculture community through increased knowledge access and professional networks. Additionally, a two-year road map was developed for future Sustainable Land Initiative events. This plan was intended to be used as a reference point as the organization continues to develop and uplift regenerative farming practices within the region. This report provides the context of the development of the workshops through a literature review, whereas the future outreach plan was informed by survey results...

Navigating Complex Dynamics: Power, Structures, Institutions, And Access In California Climate-Smart Agriculture Programs

Sun, 12 Apr 2026 00:00:00 +0000

The United States agriculture sector needs to adapt to and mitigate its contributions to climate change, especially with adverse impacts such as intense and frequent drought, flooding, wildfire, and extreme heat that affect crop yields, livestock health, farm infrastructure, and farmer incomes. Recently, federal and state governments have introduced new ‘climate-smart agriculture’ (CSA) policies and programs to help farmers mitigate greenhouse gas (GHG) emissions from farming operations. However, farmers face persistent barriers to accessing government resources, which necessitates an understanding of power dynamics among CSA program actors and existing institutions and structures in the agricultural sector. I used the California Department of Food and Agriculture (CDFA) CSA incentive programs to investigate these dynamics. I examined how farmer access to CSA programs and the broader program goal of GHG mitigation are enabled or constrained by program actors involved in program...

Wine Environmental Portfolio Under Different Price Scenarios

Thu, 9 Apr 2026 00:00:00 +0000

Between 1995 and 2014, California wine production increased by 79%. While the industry has made significant efforts to improve environmental performance, existing data on water consumption and $CO_2$ emissions often rely on studies from foreign regions, which may not accurately reflect California's specific production schemes. Because environmental profiles vary widely based on life-cycle factors, this study utilizes Life Cycle Analysis (LCA) to assess the impact of red wine produced on the Central Coast of California under various production scenarios.The cradle-to-gate analysis examined variables including bottle weight reduction, transportation distances, and varying ratios of machine versus hand-harvesting. Results revealed that the bottling process contributes the most significant environmental impacts, accounting for 82.6% of total global warming potential (GWP) and 65.4% of eutrophication potential. Furthermore, transportation and bottle weight are critical factors, contributing...

From Field to Pellets: Life-Cycle Environmental Performance of Aroma Hops and Opportunities for Impact Reduction

Thu, 9 Apr 2026 00:00:00 +0000

The hop industry is culturally and economically significant in the United States due to its central role in beer production, yet its environmental impacts remain understudied. To address this gap, this study conducts a cradle-to-gate life cycle assessment (LCA) of aroma hop production, beginning with seedling propagation via tissue culture and ending with packaged hop pellets ready for shipment. Results show that producing 1 kg of aroma hop pellets generates 5.19 kg CO₂-equivalent (kgCO₂e) of potential global warming impact (GWP) and eutrophication (EP) of 15.61 g N-equivalent (gNeq). Farm cultivation represents the largest contributor, accounting for nearly 60% of GWP and over 63% of EP. Scenario analysis indicates that shifting irrigation methods can reduce EP by 17–34% and GWP by 11–20% relative to the baseline. Air drying of hops can further reduce GWP by 24%, while complete reliance on solar energy decreases EP and GWP by 13% and 5%, respectively. The substantial contribution...

Enantioselective Alkylation of Fused Bicyclic Pyridines Enabled by Chiral Lithium Amides as Traceless Auxiliaries

Thu, 9 Apr 2026 00:00:00 +0000

Pyridines and nitrogen containing heterocycles comprise a large portion of pharmaceutical compounds and have many practical applications. Herein, we describe a straightforward, enantioselective method for direct alkylation of fused bicyclic pyridines, using chiral lithium amides as traceless auxiliaries. This method is tolerant of a variety of activated electrophiles which can allow for further functionalization.

Sustaining Sustainable Farming: An Evaluation of the Reasoned Action and Comprehensive Action Determination Frameworks for Persistence

Thu, 9 Apr 2026 00:00:00 +0000

This paper investigates the persistence of agricultural practices funded by the California Department of Food and Agriculture's Office of Environmental Farming and Innovation (CDFA OEFI). The central inquiry revolves around determining the most effective behavior model for analyzing persistence, comparing the Reasoned Action Approach (RAA), Comprehensive Action Determination Model (CADM), and CADM augmented with structural variables. The study's methodology integrates literature review, analysis of OEFI-funded practices, and statistical modeling to assess persistence levels. Contrary to existing literature, our findings reveal significantly higher levels of persistence than anticipated. Moreover, through model comparison, CADM augmented with political economic variables emerges as the superior model for analyzing and predicting persistence in agricultural practices funded by CDFA OEFI. These results contribute to a deeper understanding of behavioral determinants in sustainable agricultural...

San Luis Obispo’s Commitment To Agricultural Land Conservation

Thu, 9 Apr 2026 00:00:00 +0000

This is a case study of City Farm SLO.

Ib Lub Chaw Tso Pa/“A Place to Exhale”: Unsilencing Hmong Women Through Neej Neeg Storytelling

Thu, 26 Mar 2026 00:00:00 +0000

This paper analyzes the “Hmong Story” YouTube channel as a site of care and activism where Hmong women address violence in their communities through neej neeg storytelling. Situating “Hmong Story” within the genealogy of Hmong oral traditions, the paper reimagines storytelling and listening as a form of Hmong feminist practice that enacts anti-violence work rooted in cultural knowledge and community care. “Hmong Story,” through the storytelling practices of the host and her community of listeners, creates space for Hmong women to creatively counter and transform conditions of violence through culturally grounded feminist care practices.

The Politics of the Anti: Beyond Victimizing Hate Through State Recognition for Asian Americans

Wed, 25 Mar 2026 00:00:00 +0000

The essay discusses the pro-policing agendas of anti-Asian hate political frameworks. Abolition feminist theory and community advocacy practices have shown that policy solutions today primarily rely on policing to save women from gender and sexual violence. These political approaches are largely embraced by white feminist carceral agendas, but end up criminalizing survivors of color and their communities. Drawing on these insights, the essay centers its critique around the discursive production of the “hate-crime-victim” in Asian American political responses to incidences of harm during the COVID-19 pandemic.

Anti-Asian Violence: Origins and Trajectories

Wed, 25 Mar 2026 00:00:00 +0000

Responding to the problematic of anti-Asian violence at this tumultuous historical juncture, this special issue highlights underexplored and multifaceted genealogies and trajectories of anti-Asian violence. Our contributors map how the concepts of anti-Asian violence and “Asian hate” have been mobilized, problematize the construction of hate, consider how anti-Asian violence has been documented, and think through reconstructive approaches to anti-Asian violence.

Synergizing Chemical and AI Communities for Advancing Laboratories of the Future

Thu, 12 Feb 2026 00:00:00 +0000

The development of automated experimental facilities and the digitization of experimental data have introduced numerous opportunities to radically advance chemical laboratories. As many laboratory tasks involve predicting and understanding previously unknown chemical relationships, machine learning (ML) approaches trained on experimental data can substantially accelerate the conventional design-build-test-learn process. This outlook article aims to help chemists understand and begin to adopt ML predictive models for a variety of laboratory tasks, including experimental design, synthesis optimization, and materials characterization. Furthermore, this article introduces how artificial intelligence (AI) agents based on large language models can help researchers acquire background knowledge in chemical or data science and accelerate various aspects of the discovery process. We present three case studies in distinct areas to illustrate how ML models and AI agents can be leveraged to...

Temperature and stagnation effects on ozone sensitivity to NOx and VOC: an adjoint modeling study in central California

Tue, 20 Jan 2026 00:00:00 +0000

Abstract. Extreme weather events like heatwaves and stagnation are increasing with climate change. While their effects on ozone levels have been extensively studied, how extreme weather alters O3-NOx-VOC sensitivity and optimal mitigation strategies is less explored. Here, we apply the CMAQ adjoint model over central California to quantify ozone sensitivity to spatiotemporally resolved precursor emissions under three meteorological scenarios (baseline, high-T, and stagnation) and three emission years (2000, 2012, and 2022). Results show that meteorology-induced changes in sensitivity are comparable in magnitude to those from decadal emission reductions. Higher temperature (+5 °C) amplifies ozone sensitivity to both NOx and VOC, with the largest relative increase in biogenic VOC sources. High-T conditions shift ozone chemistry toward NOx limitation under a VOC-limited emission scenario, but increase the relative importance of VOC control for a NOx-limited scenario. Stagnation consistently...

Assessing Indoor versus Outdoor PM2.5 Concentrations during the 2025 Los Angeles Fires Using the PurpleAir Sensor Network

Tue, 20 Jan 2026 00:00:00 +0000

In January 2025, a series of fast-moving wildland-urban-interface (WUI) fires swept through the Los Angeles (LA) metropolitan area, causing severe air pollution. While the impacts of WUI fires on outdoor air quality have been extensively studied, indoor exposure remains less understood, despite most people sheltering indoors during WUI fires. This study investigates the spatial and temporal patterns of indoor and outdoor PM_2.5 concentrations across the South Coast Air Basin, with a focus on LA County during the LA fires. Using high-resolution data from co-located indoor and outdoor PurpleAir (PA) sensors, we analyze hourly PM_2.5 levels and indoor/outdoor ratios. Outdoor PM_2.5 concentrations spiked sharply during the fires, reaching unhealthy levels exceeding 130 μg/m³, compared to the mean concentration (12 μg/m³) during non-fire hours. Indoor concentrations also increased, though to a lesser extent, peaking around 60 μg/m³...

Phytoremediation potential of Nerium oleander and Salix alba for heavy metal removal in rock-amended soils: a natural and cost-effective approach

Thu, 15 Jan 2026 00:00:00 +0000

Enhanced weathering (EW) through the application of ground rock is a competitive carbon removal strategy. Adoption of this technology at a meaningful scale requires a systematic assessment of its long-term feasibility, especially with regard to soil quality from the application of rock amendments that contain varying levels of heavy metal (loid)s (HM) such as Cu, Ni, Cr, Co, and Pb. The potential accumulation of these metal (loid)s could be an unintended consequence of repeated large-scale EW applications, necessitating careful evaluation for use in croplands. This study explores the idea of using phytoremediation as a natural, low-cost means of remediating rock-amended soils. Specifically, we examined the ability of Nerium oleander and Salix alba species to remove HM from rock-amended soils in their tissues (i.e., leaves, stems, and roots). In this study, the relative abundance of HM accumulation in hyperaccumulator plants followed the order: Si > Rb > Cu > Sn > Cr...

Modelling the Effects of Wetland Restoration on Coastal Hydrology: A Case Study of Elkhorn Slough Watershed, California

Tue, 16 Dec 2025 00:00:00 +0000

ABSTRACT Coastal wetlands, some of the most productive ecosystems on Earth, provide critical ecosystem services, including support of biodiversity, carbon sequestration and flood protection. In recent decades, these ecosystems have experienced extensive coastal wetland loss. Coastal wetland restoration provides a beacon of hope, offering a chance to reclaim these important habitats. However, even with billions of dollars invested worldwide in restoring coastal wetlands, we still lack comprehensive knowledge about the effectiveness of these restoration efforts in recovering wetland ecosystem functions and how future climate change may affect these efforts. The ability to evaluate how these ecosystems will function in the future is vital for examining current investments and developing future protection and management plans. We selected Elkhorn Slough, a tidal estuary, in California, to investigate the impact of wetland restoration and sea level rise (SLR) on coastal hydrology using...

Attitudes of fire service personnel toward respiratory protection in wildland firefighting

Thu, 20 Nov 2025 00:00:00 +0000

Wildland and wildland-urban interface (W/WUI) fires are increasing in frequency and intensity, increasing concerns about firefighters' exposure to hazardous smoke and the need for respiratory protection. This qualitative study explored the perspectives of California fire service personnel on the use of respiratory protective devices (RPDs), particularly powered air-purifying respirators, and a potential Cal/OSHA regulation mandating their use in W/WUI firefighting. Participants were experienced in W/WUI firefighting and had some role in their fire department related to respiratory protection or other aspect of firefighter safety. While all participants recognized the health risks associated with smoke exposure, including cancer and acute respiratory symptoms, and that RPDs would reduce their exposures, participants had concerns that RPDs would negatively affect fatigue, comfort, communication, mobility, and situational awareness. Some concerns specifically relate to the design...

Social Media Recruitment in Indigenous and Native American Populations: Challenges in the AI Age

Mon, 17 Nov 2025 00:00:00 +0000

Unlabelled: Using social media recruitment for public health research presents both opportunities and challenges. Despite its increased use, few studies have detailed the practical issues, challenges encountered, and alternative strategies available for social media recruitment. This paper explores strategies for recruiting Indigenous and Native American populations in California for a study on COVID-19 vaccination and social networks. We describe different recruitment approaches, challenges faced, and pros and cons of strategies used to enhance data quality and efficiency, including survey design considerations, Facebook targeting versus use of research panels, quality assurance checks, and decisions around participant incentives. Our local setting involved recruiting Native American and Mesoamerican Indigenous individuals living in California through social media platforms. We highlight key adaptations to survey design, recruitment strategies, and data cleaning processes, noting...

Repair of Mutated NF1 mRNA with Trans-Splicing Group I Intron Ribozymes

Thu, 25 Sep 2025 00:00:00 +0000

BACKGROUND/OBJECTIVES: Therapeutic strategies for Neurofibromatosis Type I (NF1) that correct the underlying pathogenic NF1 variant hold promise for restoring neurofibromin function, reducing tumor burden, and improving patient outcomes by addressing the root cause of the disease rather than its symptoms. Beyond gene editing, transcript reprogramming via RNA trans-splicing has gained attention, particularly with the recent FDA approval of two trans-splicing-based drugs for IND phase 1/2a trials. This study tests whether trans-splicing group I intron ribozymes from Tetrahymena thermophila can be used to repair pathogenic variants of NF1 (pre-)mRNA by 3'-tail replacement. METHODS: Splice sites on the NF1 mRNA were identified computationally and validated biochemically, and an efficiency-enhancing Extended Guide Sequence (EGS) of the corresponding ribozyme was identified in a combinatorial experiment. RESULTS: The correct trans-splicing product of this...

Policy stakeholders' perspectives and use of data, research evidence, and misinformation in three counties in California, USA during the COVID-19 pandemic, 2020–2022

Wed, 24 Sep 2025 00:00:00 +0000

Objective: This study investigates how local policy stakeholders viewed and used research evidence, data, and (mis)information in county policy discussions during the COVID-19 pandemic. Method: We employed document and exploratory content analysis methods to examine Board of Supervisor materials (N = 534 policy documents) from general and special/emergency meetings (March 2020 - December 2022). We purposefully selected three jurisdictions from California, USA with varying socio-demographic, political, and health care characteristics as case studies. Results: Many residents who commented during local policy discussions contested the: 1) validity of health data provided (i.e., mortality rates), and 2) efficacy of proposed preventive measures like mask wearing and vaccine receipt. While government officials and healthcare personnel referenced research evidence and data as justification for these measures, several stakeholders expressed skepticism about the information...

Pausing ultrafast melting by timed multiple femtosecond-laser pulses

Thu, 11 Sep 2025 00:00:00 +0000

An intense femtosecond-laser excitation of a solid induces highly nonthermal conditions. In materials like silicon, laser-induced bond-softening leads to a highly incoherent ionic motion and eventually nonthermal melting. But is this outcome an inevitable consequence, or can it be controlled? Here, we performed ab initio molecular dynamics simulations of crystalline silicon after timed multiple femtosecond-laser pulse excitations with fluence above the nonthermal melting threshold. Our results demonstrate an excitation mechanism that pauses nonthermal melting and creates a metastable state instead, with an electronic structure similar to the ground state. This mechanism can be generalized to other materials, potentially enabling structural and/or electronic transitions to metastable phases in the high-excitation regime. In addition, our approach could be used to switch off nonthermal contributions in experiments, allowing reliable electron-phonon coupling constants to be obtained...

Factors affecting heat resilience of drone honey bees (Apis mellifera) and their sperm

Thu, 28 Aug 2025 00:00:00 +0000

Extreme temperatures associated with climate change are expected to impact the physiology and fertility of a variety of insects, including honey bees. Most previous work on this topic has focused on female honey bees (workers and queens), and comparatively little research has investigated how heat exposure affects males (drones). To address this gap, we tested body mass, viral infections, and population origin as predictors of drone survival and sperm viability in a series of heat challenge assays. We found that individual body mass was highly influential, with heavier drones being more likely to survive a heat challenge (4 h at 42°C) than smaller drones. In a separate experiment, we compared the survival of Northern California and Southern California drones in response to the same heat challenge (4 h at 42°C), and found that Southern Californian drones - which are enriched for African ancestry - were more likely to survive a heat challenge than drones originating from Northern...

Environmental cues rather than quality of supplemented pollen drive the foraging behaviour of honey bees during avocado pollination

Thu, 28 Aug 2025 00:00:00 +0000

Honey bee colonies adapt their foraging behaviours to the availability of floral resources to meet their nutritional needs. However, it is unknown if the nutritional quality of stored or supplemented pollen can influence the floral choices of bees during commercial crop pollination. The foraging behaviour of bees from 40 colonies was studied during avocado pollination in southern Western Australia. A pollen database of the orchard was built and used to assess the floral preference of the bees. Pollen collectors and nectar foragers showed different foraging behaviour as indicated by their Dominance Candidate Index (DCI). The foraging choices were partially affected by the type of supplemented pollen that consisted of agricultural and forest species. Aside from nutritional cues, floral source abundance and attractiveness played a role in influencing the foraging behaviour for pollen and nectar. Both pollen and nectar foragers chose a sub-set of flowers available at the avocado orchard....

Hypoparathyroidism After Total Thyroidectomy: A Population-Based Analysis of California Databases

Fri, 23 May 2025 00:00:00 +0000

INTRODUCTION: Postthyroidectomy hypoparathyroidism is common and usually managed as an outpatient. A better understanding of patients at risk for an emergency department (ED) visit can improve health-care utilization and patient care. METHODS: The California Cancer Registry and Health Care Access and Information Databases were linked to identify patients who underwent a thyroidectomy for thyroid cancer 2005-2018 and had an ED visit for hypoparathyroidism within 2 y of surgery. Cumulative incidence and multivariable Cox proportional hazards models were used to identify factors associated with an ED visit. RESULTS: Among 41,502 thyroidectomy patients, 588 (1.42%) presented to the ED for hypoparathyroidism, with a median time between thyroidectomy and first ED visit of 4 ds. Two-year cumulative incidence was highest for women (1.56%), Hispanic patients (2.04%), younger adults aged 18-40 y (1.97%), higher Charlson comorbidity index score (2.43%), lowest neighborhood socioeconomic...

Cover Feature: Sustainability‐Driven Accelerated Shear‐Mediated Immunoassay for Amyotrophic Lateral Sclerosis Detection (ChemSusChem 21/2024)

Fri, 25 Apr 2025 00:00:00 +0000

The Cover Feature shows plasticware for biomarker measurement, which constitutes a notable portion of the plastic waste stream from medical consumables. We have developed a portable vortex fluidic device (P‐VFD) with a membrane array to initiate fast reaction, detection and analysis of a clinically relevant protein biomarker, p75ECD. It shows significant potential to replace traditional assay plates with a membrane, providing a greener and more sustainable alternative in biofluid biomarker measurement. More information can be found in the Research Article by X. Luo, M.‐L. Rogers, C. L. Raston and co‐workers.

TRAF-like Proteins Regulate Cellular Survival in the Planarian Schmidtea mediterranea

Mon, 14 Apr 2025 00:00:00 +0000

Tissue homeostasis relies on the timely renewal of cells that have been damaged or have surpassed their biological age. Nonetheless, the underlying molecular mechanism coordinating tissue renewal is unknown. The planarian Schmidtea mediterranea harbors a large population of stem cells that continuously divide to support the restoration of tissues throughout the body. Here, we identify that TNF Receptor Associated Factors (TRAFs) play critical roles in cellular survival during tissue repair in S. mediterranea. Disruption with RNA-interference of TRAF signaling results in rapid morphological defects and lethality within 2 weeks. The TRAF phenotype is accompanied by an increased number of mitoses and cell death. Our results also reveal TRAF signaling is required for proper regeneration of the nervous system. Taken together, we find functional conservation of TRAF-like proteins in S. mediterranea as they act as crucial regulators of cellular...

Direct Current Electric Stimulation Alters the Frequency and the Distribution of Mitotic Cells in Planarians

Sun, 13 Apr 2025 00:00:00 +0000

Background: The use of direct current electric stimulation (DCS) is an effective strategy to treat disease and enhance body functionality. Thus, treatment with DCS is an attractive biomedical alternative, but the molecular underpinnings remain mostly unknown. The lack of experimental models to dissect the effects of DCS from molecular to organismal levels is an important caveat. Here, we introduce the planarian flatworm Schmidtea mediterranea as a tractable organism for in vivo studies of DCS. We developed an experimental method that facilitates the application of direct current electrical stimulation to the whole planarian body (pDCS). Materials and Methods: Planarian immobilization was achieved by combining treatment with anesthesia, agar embedding, and low temperature via a dedicated thermoelectric cooling unit. Electric currents for pDCS were delivered using pulled glass microelectrodes. The electric potential was supplied through...

Measuring protein levels in planarians using western blotting

Sun, 13 Apr 2025 00:00:00 +0000

In the planarian field, two techniques are mostly used for protein detection: immunohistochemistry (IHC) and western blotting. While IHC is great for visualizing the spatial distribution of proteins in whole organisms, it has limitations in antibody availability and issues related to nonspecific expression. The use of western blotting can circumvent nonspecific expression, providing a dependable way to quantify proteins of interest. Here, we present a standardized, easily reproducible protocol with details on protein extractions of whole planarians and western blotting. For complete details on the use and execution of this protocol, please refer to Ziman et al. (2020a).

Building materials could store more than 16 billion tonnes of CO2 annually

Sun, 30 Mar 2025 00:00:00 +0000

Achieving net-zero greenhouse gas emissions likely entails not only lowering emissions but also deploying carbon dioxide (CO₂) removal technologies. We explored the annual potential to store CO₂ in building materials. We found that fully replacing conventional building materials with CO₂-storing alternatives in new infrastructure could store as much as 16.6 ± 2.8 billion tonnes of CO₂ each year-roughly 50% of anthropogenic CO₂ emissions in 2021. The total storage potential is far more sensitive to the scale of materials used than the quantity of carbon stored per unit mass of materials. Moreover, the carbon storage reservoir of building materials will grow in proportion to demand for such materials, which could reduce demand for more costly or environmentally risky geological, terrestrial, or ocean storage.

Reward and Inhibitory Control as Mechanisms and Treatment Targets for Binge Eating Disorder

Fri, 28 Feb 2025 00:00:00 +0000

Purpose of ReviewRecent research has highlighted alterations in reward and inhibitory control among individuals with binge eating disorder, identifying both constructs as potential targets for treatment. Treatments targeting reward and inhibitory control for binge eating disorder are emerging. This review aims to summarize the recent literature evaluating reward and inhibitory control in binge eating disorder compared to weight-matched controls using behavioral paradigms and neuroimaging. This review also aims to summarize recent literature evaluating treatments for binge eating targeting these mechanisms and highlights additional work needed in these areas.Recent FindingsReward hypersensitivity and impaired inhibitory control are mechanisms underlying binge eating disorder. Individuals with binge eating disorder experience higher initial reward to food, and later, higher anticipatory reward but lower experienced food reward which maintains binge eating behavior. Treatments targeting...

Staggered immunization with mRNA vaccines encoding SARS-CoV-2 polymerase or spike antigens broadens the T cell epitope repertoire

Thu, 26 Dec 2024 00:00:00 +0000

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...

Barriers to Implementation of Teleretinal Diabetic Retinopathy Screening Programs Across the University of California

Fri, 6 Dec 2024 00:00:00 +0000

Aim: To describe barriers to implementation of diabetic retinopathy (DR) teleretinal screening programs and artificial intelligence (AI) integration at the University of California (UC). Methods: Institutional representatives from UC Los Angeles, San Diego, San Francisco, Irvine, and Davis were surveyed for the year of their program's initiation, active status at the time of survey (December 2021), number of primary care clinics involved, screening image quality, types of eye providers, image interpretation turnaround time, and billing codes used. Representatives were asked to rate perceptions toward barriers to teleretinal DR screening and AI implementation using a 5-point Likert scale. Results: Four UC campuses had active DR teleretinal screening programs at the time of survey and screened between 246 and 2,123 patients at 1-6 clinics per campus. Sites reported variation between poor-quality photos (<5% to 15%) and...

Emergency Department Utilization for Postpartum Behavioral Health Problems and Assault Injury During the COVID-19 Pandemic

Thu, 21 Nov 2024 00:00:00 +0000
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...

Optimization of Campesterol-Producing Yeast Strains as a Feasible Platform for the Functional Reconstitution of Plant Membrane-Bound Enzymes

Tue, 19 Nov 2024 00:00:00 +0000
Campesterol is a major phytosterol that plays important roles in regulating membrane properties and serves as the precursor to multiple specialized metabolites, such as the phytohormone brassinosteroids. Recently, we established a campesterol-producing yeast strain and extended the bioproduction to 22-hydroxycampesterol and 22-hydroxycampest-4-en-3-one, the precursors to brassinolide. However, there is a trade-off in growth due to the disrupted sterol metabolism. In this study, we enhanced the growth of the campesterol-producing yeast by partially restoring the activity of the sterol acyltransferase and engineering upstream FPP supply. Furthermore, genome sequencing analysis also revealed a pool of genes possibly associated with the altered sterol metabolism. Retro engineering implies an essential role of ASG1, especially the C-terminal asparagine-rich domain of ASG1, in the sterol metabolism of yeast especially under stress. The performance of the campesterol-producing yeast...

The Effect of Hive Type on Colony Homeostasis and Performance in the Honey Bee (Apis mellifera)

Thu, 7 Nov 2024 00:00:00 +0000
The colonies of honey bees are mostly sessile organisms. Consequently, the type of nest boxes that beekeepers provide to their bees should impact a colony's ability to maintain homeostasis, which is a key determinant of performance and fitness. Here, we used European honey bees (Apis mellifera) and provided them with two hive setups widely used and known as Langstroth and Warré. We compared colony performance in a Mediterranean climate for five months from late spring to early autumn, which covered the most active time of bees and included periods of heat and drought. We found that irrespective of hive type or season, honey bees kept hive temperature and humidity within a remarkably narrow range. Nevertheless, the hive type impacted the daily fluctuations in temperature and humidity. In Warré hives, where bees have more autonomy to build and maintain their combs, we found that bees were able to reduce daily fluctuations in temperature and humidity and kept both measures...

Hydrogen-Induced Topotactic Phase Transformations of Cobaltite Thin Films

Sat, 2 Nov 2024 00:00:00 +0000
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...

Disruption of the intestinal clock drives dysbiosis and impaired barrier function in colorectal cancer

Wed, 30 Oct 2024 00:00:00 +0000
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...

Anxious Activists? Examining Immigration Policy Threat, Political Engagement, and Anxiety among College Students with Different Self/Parental Immigration Statuses

Mon, 23 Sep 2024 00:00:00 +0000
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...

Optimizing Continuous‐Flow Biocatalysis with 3D‐Printing and Inline IR Monitoring

Thu, 29 Aug 2024 00:00:00 +0000
Abstract 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...

Influence of soil characteristics and metal(loid)s on antibiotic resistance genes in green stormwater infrastructure in Southern California

Thu, 15 Aug 2024 00:00:00 +0000
The synergetic effects of metal(loid)s and soil characteristics on bacterial antibiotic resistance genes (ARGs) in green stormwater infrastructure (GSI) has been relatively understudied. Surface soil samples from six GSIs in Southern California over three time periods were assessed for selected ARGs, class 1 integron-integrase genes (intI1), 16S rRNA genes, and bioavailable and total concentrations of nine metal(loid)s, to investigate the relationships among ARGs, soil characteristics, and co-occurring metal(loid)s. Significant correlations existed among relative gene abundances (sul1, sul2, tetW, and intI1), total metal(loid)s (arsenic, copper, lead, vanadium, and zinc), and bioavailable metal(loid) (arsenic) (r = 0.29-0.61, p_adj < 0.05). Additionally, soil texture, organic matter, and nutrients within GSI appeared to be significantly correlated with relative gene abundances of sul1, sul2, and tetW (r = -0.57 to 0.59, p_adj < 0.05)....

Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Wed, 24 Jul 2024 00:00:00 +0000
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...

Honeybees (Apis mellifera) decrease the fitness of plants they pollinate

Sat, 6 Jul 2024 00:00:00 +0000
Most flowering plants require animal pollination and are visited by multiple pollinator species. Historically, the effects of pollinators on plant fitness have been compared using the number of pollen grains they deposit, and the number of seeds or fruits produced following a visit to a virgin flower. While useful, these methods fail to consider differences in pollen quality and the fitness of zygotes resulting from pollination by different floral visitors. Here we show that, for three common native self-compatible plants in Southern California, super-abundant, non-native honeybees (Apis mellifera L.) visit more flowers on an individual before moving to the next plant compared with the suite of native insect visitors. This probably increases the transfer of self-pollen. Offspring produced after honeybee pollination have similar fitness to those resulting from hand self-pollination and both are far less fit than those produced after pollination by native insects or by cross-pollination....

Na,K-ATPase activity promotes macropinocytosis in colon cancer via Wnt signaling

Wed, 26 Jun 2024 00:00:00 +0000
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...

Identification of a novel gene signature for neuroblastoma differentiation using a Boolean implication network

Mon, 17 Jun 2024 00:00:00 +0000
Although induction of differentiation represents an effective strategy for neuroblastoma treatment, the mechanisms underlying neuroblastoma differentiation are poorly understood. We generated a computational model of neuroblastoma differentiation consisting of interconnected gene clusters identified based on symmetric and asymmetric gene expression relationships. We identified a differentiation signature consisting of series of gene clusters comprised of 1251 independent genes that predicted neuroblastoma differentiation in independent datasets and in neuroblastoma cell lines treated with agents known to induce differentiation. This differentiation signature was associated with patient outcomes in multiple independent patient cohorts and validated the role of MYCN expression as a marker of neuroblastoma differentiation. Our results further identified novel genes associated with MYCN via asymmetric Boolean implication relationships that would not have been identified using symmetric...

Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations

Sat, 27 Apr 2024 00:00:00 +0000
DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA methylation that may contribute to the pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the mutation-induced functional misregulation of DNMT3A remains unclear. Here, we report the crystal structures of the DNMT3A methyltransferase domain, revealing a molecular basis for its oligomerization behavior distinct to DNMT3B, and the enhanced intermolecular contacts caused by the R882H or R882C mutation. Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells....

Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation

Fri, 12 Apr 2024 00:00:00 +0000
Host-directed therapy (HDT) is an emerging approach to overcome antimicrobial resistance in pathogenic microorganisms. Specifically, HDT targets host-encoded factors required for pathogen replication and survival without interfering with microbial growth or metabolism, thereby eliminating the risk of resistance development. By applying HDT and a drug repurposing approach, we demonstrate that (R)-DI-87, a clinical-stage anti-cancer drug and potent inhibitor of mammalian deoxycytidine kinase (dCK), mitigates Staphylococcus aureus abscess formation in organ tissues upon invasive bloodstream infection. Mechanistically, (R)-DI-87 shields phagocytes from staphylococcal death-effector deoxyribonucleosides that target dCK and the mammalian purine salvage pathway-apoptosis axis. In this manner, (R)-DI-87-mediated protection of immune cells amplifies macrophage infiltration into deep-seated abscesses, a phenomenon coupled with enhanced pathogen control, ameliorated...

Abstract 3180: Suppression of the CPEB3 ribozyme modulates the progression of glioblastoma

Thu, 11 Apr 2024 00:00:00 +0000
Abstract Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain tumor in adults, with a poor prognosis that highlights a dire clinical need for innovative therapeutic interventions. Despite significant advances in diagnoses and multimodality therapies, the overall prognosis for patients with GBM remains poor, with a median survival time of 15-18 months. Therefore, there is an unmet medical need to develop alternative treatment strategies to improve clinical outcomes. Dysregulation of post-transcriptional control and translational machinery have been implicated in malignant tumor development. Cytoplasmic polyadenylation element binding proteins (CPEB1-CPEB4) are RNA-binding proteins that regulate poly(A) tail elongation of target mRNAs and subsequently contribute to phenotypic changes in cancer cells. Notably, a self-cleaving ribozyme was identified in the CPEB3 gene, but its role in cancer is wholly unexplored. Considering the role of CPEB3 as a tumor suppressor...

Higher order divergence-free and curl-free interpolation on MAC grids

Thu, 11 Apr 2024 00:00:00 +0000
Divergence-free vector fields and curl-free vector fields play an important role in many types of problems, including the incompressible Navier-Stokes equations, Maxwell's equations, the equations for magnetohydrodynamics, and surface reconstruction. In practice, these fields are often obtained by projection, resulting in a discrete approximation of the continuous field that is discretely divergence-free or discretely curl-free. This field can then be interpolated to non-grid locations, which is required for many algorithms such as particle tracing or semi-Lagrangian advection. This interpolated field will not generally be divergence-free or curl-free in the analytic sense. In this work, we assume these fields are stored on a MAC grid layout and that the divergence and curl operators are discretized using finite differences. This work builds on and extends [39] in multiple ways: (1) we design a divergence-free interpolation scheme that preserves the discrete flux, (2) we adapt...

Light-Induced GFP Expression in Zebrafish Embryos using the Optogenetic TAEL/C120 System

Mon, 1 Apr 2024 00:00:00 +0000
Light-Induced GFP Expression in Zebrafish Embryos using the Optogenetic TAEL/C120 System

Management dampens seasonal variability in soil microclimates and alters its chemical and physical properties in a semi-arid region

Mon, 25 Mar 2024 00:00:00 +0000
Abstract The urbanization process substantially alters every aspect of the soil environment. In this study, we compared soil microclimate, chemistry, and physical characteristics of unmanaged natural soils with managed soils of three common urban land uses (stormwater natural treatment systems, ornamentally landscaped areas, and lawns) across three University of California campuses. Over the course of 1-year, average monthly soil temperatures among land uses showed fewer than expected differences. Average monthly soil moisture reflected wet and dry seasonal changes, but this pattern was muted in managed land uses compared to natural soils due to irrigation. From April through December, lawns and landscaped areas were significantly wetter than natural soils (e.g. 1.5–3 times higher in August and September). Soil organic matter, total carbon, and total nitrogen were significantly higher in lawns compared to other land uses, while their bulk density was significantly lower. Principle...

Chemical Structure Elucidation in the Development of Inorganic Drugs: Evidence from Ru‐, Au‐, As‐, and Sb‐based Medicines

Thu, 29 Feb 2024 00:00:00 +0000
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...

Establishment of xenografts of urological cancers on chicken chorioallantoic membrane (CAM) to study metastasis

Sun, 25 Feb 2024 00:00:00 +0000
Cancer of the urological system commonly occurs in the kidney, bladder, and prostate gland. The clear cell subtype of renal cell carcinoma (ccRCC) constitutes the great majority of kidney cancer. Metastatic ccRCC portends a very poor outcome with no effective treatment available. Prostate cancer is the most common cancer in males in the US. Despite recent advances in selective kinase inhibitors and immunotherapies, the rate of developing new treatment from bench to bedside is slow. A time-consuming step is at the animal drug testing stage, in which the mouse model is the gold standard. In the pursuit to streamline the in vivo cancer biology research and drug development, we explored the feasibility of the chicken chorioallantoic membrane (CAM) model to establish xenografts. The CAM model greatly shortens the time of tumor growth and lowers the cost comparing to immunocompromised mice. We generated CAM xenografts from ccRCC, bladder and prostate cancer, with established...

Perfluorocarbon nanomaterials for photodynamic therapy

Tue, 30 Jan 2024 00:00:00 +0000
Photodynamic therapy (PDT) is a treatment modality in which a photosensitizer is irradiated with light, producing reactive oxygen species, often via energy transfer with oxygen. As it is common for tumors to be hypoxic, methods to deliver photosensitizer and oxygen are desirable. One such approach is the use of perfluorocarbons, molecules in which all C-H bonds are replaced with C-F bonds, to co-deliver oxygen because of the high solubility of gases in perfluorocarbons. This review highlights the benefits and limitations of several fluorinated nanomaterial architectures for use in PDT.

A Reduction-Sensitive Fluorous Fluorogenic Coumarin

Tue, 30 Jan 2024 00:00:00 +0000
Fluorophores that are sensitive to their environment are useful tools for sensing chemical changes and probing biological systems. Here, we extend responsive fluorophores to the fluorous phase with the synthesis of a reduction-sensitive fluorous-soluble fluorogenic coumarin. We demonstrate that this fluorophore responds to various reducing agents, most notably glutathione, a key biological reductant. The fluorous solubility of this probe allows for its encapsulation into two different fluorous nanomaterials: perfluorocarbon nanoemulsions and fluorous core-shell micelles. The fluorogenic coumarin allows us to study how efficiently these vehicles protect the contents of their interior from the external environment. In the presence of glutathione, we observe different degrees of release for micelles and emulsions. This understanding will help guide future applications of fluorous nanomaterials as drug delivery vehicles.

Perfluorocarbons in Chemical Biology

Tue, 30 Jan 2024 00:00:00 +0000
Perfluorocarbons, saturated carbon chains in which all the hydrogen atoms are replaced with fluorine, form a separate phase from both organic and aqueous solutions. Though perfluorinated compounds are not found in living systems, they can be used to modify biomolecules to confer orthogonal behavior within natural systems, such as improved stability, engineered assembly, and cell-permeability. Perfluorinated groups also provide handles for purification, mass spectrometry, and ¹⁹ F NMR studies in complex environments. Herein, we describe how the unique properties of perfluorocarbons have been employed to understand and manipulate biological systems.

Redox‐Responsive Gene Delivery from Perfluorocarbon Nanoemulsions through Cleavable Poly(2‐oxazoline) Surfactants

Tue, 30 Jan 2024 00:00:00 +0000
The clinical utility of emulsions as delivery vehicles is hindered by a dependence on passive release. Stimuli-responsive emulsions overcome this limitation but rely on external triggers or are composed of nanoparticle-stabilized droplets that preclude sizes necessary for biomedical applications. Here, we employ cleavable poly(2-oxazoline) diblock copolymer surfactants to form perfluorocarbon (PFC) nanoemulsions that release cargo upon exposure to glutathione. These surfactants allow for the first example of redox-responsive nanoemulsions in cellulo. A noncovalent fluorous tagging strategy is leveraged to solubilize a GFP plasmid inside the PFC nanoemulsions, whereupon protein expression is achieved selectively when employing a stimuli-responsive surfactant. This work contributes a methodology for non-viral gene delivery and represents a general approach to nanoemulsions that respond to endogenous stimuli.

Coccidioidomycosis Emergence in South America: Exploring Northeastern Brazil's Epidemiological, Clinical, and Genomic Landscape

Thu, 18 Jan 2024 00:00:00 +0000

Coccidioidomycosis is an invasive mycosis included in WHO’s priority list. It is endemic and notifiable in the United States but neglected in Central and South America. We used a multi-institutional approach to assess whether disease characteristics, genetic variation in the pathogen or environmental factors affects the epidemiology of coccidioidomycosis and disease outcomes throughout the American continent. We identified 292 patients with coccidioidomycosis between 1978 and 2021 in the Piauí and Maranhão states of Brazil; the largest cases series reported outside the US/Mexico epidemic range. The male-to-female ratio was 57.4:1 and the main risk factor was armadillo hunting (91.1%) 4 to 30 days before symptom onset. Forty-two outbreaks involving two to six patients were observed. Most patients (92.8%) presented typical acute pulmonary disease, followed by disseminated (3.4%), chronic pulmonary (2.4%) and regressive pulmonary (1.4%). The most frequent clinical symptoms were...

Strand-specific single-cell methylomics reveals distinct modes of DNA demethylation dynamics during early mammalian development

Tue, 9 Jan 2024 00:00:00 +0000
DNA methylation (5mC) is central to cellular identity. The global erasure of 5mC from the parental genomes during preimplantation mammalian development is critical to reset the methylome of gametes to the cells in the blastocyst. While active and passive modes of demethylation have both been suggested to play a role in this process, the relative contribution of these two mechanisms to 5mC erasure remains unclear. Here, we report a single-cell method (scMspJI-seq) that enables strand-specific quantification of 5mC, allowing us to systematically probe the dynamics of global demethylation. When applied to mouse embryonic stem cells, we identified substantial cell-to-cell strand-specific 5mC heterogeneity, with a small group of cells displaying asymmetric levels of 5mCpG between the two DNA strands of a chromosome suggesting loss of maintenance methylation. Next, in preimplantation mouse embryos, we discovered that methylation maintenance is active till the 16-cell stage followed...

Phosphorylation of the novel mTOR substrate Unkempt regulates cellular morphogenesis

Wed, 3 Jan 2024 00:00:00 +0000
Mechanistic target of rapamycin (mTOR) is a protein kinase that integrates multiple inputs to regulate anabolic cellular processes. For example, mTOR complex 1 (mTORC1) has key functions in growth control, autophagy, and metabolism. However, much less is known about the signaling components that act downstream of mTORC1 to regulate cellular morphogenesis. Here, we show that the RNA-binding protein Unkempt, a key regulator of cellular morphogenesis, is a novel substrate of mTORC1. We show that Unkempt phosphorylation is regulated by nutrient levels and growth factors via mTORC1. To analyze Unkempt phosphorylation, we immunoprecipitated Unkempt from cells in the presence or the absence of the mTORC1 inhibitor rapamycin and used mass spectrometry to identify mTORC1-dependent phosphorylated residues. This analysis showed that mTORC1-dependent phosphorylation is concentrated in a serine-rich intrinsically disordered region in the C-terminal half of Unkempt. We also found that Unkempt...

Probabilistic forecast of nonlinear dynamical systems with uncertainty quantification

Tue, 2 Jan 2024 00:00:00 +0000
Data-driven modeling is useful for reconstructing nonlinear dynamical systems when the underlying process is unknown or too expensive to compute. Having reliable uncertainty assessment of the forecast enables tools to be deployed to predict new scenarios unobserved before. In this work, we first extend parallel partial Gaussian processes for predicting the vector-valued transition function that links the observations between the current and next time points, and quantify the uncertainty of predictions by posterior sampling. Second, we show the equivalence between the dynamic mode decomposition and the maximum likelihood estimator of the linear mapping matrix in the linear state space model. The connection provides a probabilistic generative model of dynamic mode decomposition and thus, uncertainty of predictions can be obtained. Furthermore, we draw close connections between different data-driven models for approximating nonlinear dynamics, through a unified view of generative...

Beyond nature's base pairs: machine learning-enabled design of DNA-stabilized silver nanoclusters

Tue, 2 Jan 2024 00:00:00 +0000
Sequence-encoded biomolecules such as DNA and peptides are powerful programmable building blocks for nanomaterials. This paradigm is enabled by decades of prior research into how nucleic acid and amino acid sequences dictate biomolecular interactions. The properties of biomolecular materials can be significantly expanded with non-natural interactions, including metal ion coordination of nucleic acids and amino acids. However, these approaches present design challenges because it is often not well-understood how biomolecular sequence dictates such non-natural interactions. This Feature Article presents a case study in overcoming challenges in biomolecular materials with emerging approaches in data mining and machine learning for chemical design. We review progress in this area for a specific class of DNA-templated metal nanomaterials with complex sequence-to-property relationships: DNA-stabilized silver nanoclusters (Ag_N-DNAs) with bright, sequence-tuned fluorescence...

Data-Driven Model Construction for Anisotropic Dynamics of Active Matter

Tue, 2 Jan 2024 00:00:00 +0000
Data-Driven Model Construction for Anisotropic Dynamics of Active Matter

Exogenous detection of 13C-glucose metabolism in tumor and diet-induced obesity models

Thu, 30 Nov 2023 00:00:00 +0000
Metabolic rewiring is a hallmark feature prevalent in cancer cells as well as insulin resistance (IR) associated with diet-induced obesity (DIO). For instance, tumor metabolism shifts towards an enhanced glycolytic state even under aerobic conditions. In contrast, DIO triggers lipid-induced IR by impairing insulin signaling and reducing insulin-stimulated glucose uptake. Based on physiological differences in systemic metabolism, we used a breath analysis approach to discriminate between different pathological states using glucose oxidation as a readout. We assessed glucose utilization in lung cancer-induced cachexia and DIO mouse models using a U-¹³C glucose tracer and stable isotope sensors integrated into an indirect calorimetry system. Our data showed increased ¹³CO₂ expired by tumor-bearing (TB) mice and a reduction in exhaled ¹³CO₂ in the DIO model. Taken together, our findings illustrate high glucose uptake and consumption...

Community Engagement Practices at Research Centers in U.S. Minority Institutions: Priority Populations and Innovative Approaches to Advancing Health Disparities Research

Mon, 27 Nov 2023 00:00:00 +0000
This paper details U.S. Research Centers in Minority Institutions (RCMI) Community Engagement Cores (CECs): (1) unique and cross-cutting components, focus areas, specific aims, and target populations; and (2) approaches utilized to build or sustain trust towards community participation in research. A mixed-method data collection approach was employed for this cross-sectional study of current or previously funded RCMIs. A total of 18 of the 25 institutions spanning 13 U.S. states and territories participated. CEC specific aims were to support community engaged research (94%); to translate and disseminate research findings (88%); to develop partnerships (82%); and to build capacity around community research (71%). Four open-ended questions, qualitative analysis, and comparison of the categories led to the emergence of two supporting themes: (1) establishing trust between the community-academic collaborators and within the community and (2) building collaborative relationships. An...

River Delta Morphotypes Emerge From Multiscale Characterization of Shorelines

Mon, 20 Nov 2023 00:00:00 +0000
Abstract Delta shoreline structure has long been hypothesized to encode information on the relative influence of fluvial, wave, and tidal processes on delta formation and evolution. We introduce here a novel multiscale characterization of shorelines by defining three process‐informed morphological metrics. We show that this characterization yields self‐emerging classes of morphologically similar deltas, that is, delta morphotypes, and also predicts the dominant forcing of each morphotype. Then we show that the dominant forcings inferred from shoreline structure generally align with those estimated via relative sediment fluxes, while positing that misalignments arise from spatiotemporal heterogeneity in deltaic sediment fluxes not captured in their estimates. The proposed framework for shoreline characterization advances our quantitative understanding of how shoreline features reflect delta forcings, and may aid in deciphering paleoclimate from images of ancient deposits and projecting...

Scale‐Dependent Influence of Permafrost on Riverbank Erosion Rates

Mon, 20 Nov 2023 00:00:00 +0000
Abstract Whether permafrost systematically alters the rate of riverbank erosion is a fundamental geomorphic question with significant importance to infrastructure, water quality, and biogeochemistry of high‐latitude watersheds. For over four decades, this question has remained unanswered due to a lack of data. Using remotely sensed imagery, we addressed this knowledge gap by quantifying riverbank erosion rates across the Arctic and subarctic. To compare these rates to non‐permafrost rivers, we assembled a global data set of published riverbank erosion rates. We found that erosion rates in rivers influenced by permafrost are on average nine times lower than non‐permafrost systems; erosion rate differences increase up to 40 times for the largest rivers. To test alternative hypotheses for the observed erosion rate difference, we examined differences in total water yield and erosional efficiency between these rivers and non‐permafrost rivers. Neither of these factors nor differences...

First‐Order River Delta Morphology Is Explained by the Sediment Flux Balance From Rivers, Waves, and Tides

Mon, 20 Nov 2023 00:00:00 +0000
Abstract We present a novel quantitative test of a 50‐year‐old hypothesis which asserts that river delta morphology is determined by the balance between river and marine influence. We define three metrics to capture the first‐order morphology of deltas (shoreline roughness, number of distributary channel mouths, and presence/absence of spits), and use a recently developed sediment flux framework to quantify the river‐marine influence. Through analysis of simulated and field deltas we quantitatively demonstrate the relationship between sediment flux balance and delta morphology and show that the flux balance accounts for at least 35% of the variance in the number of distributary channel mouths and 42% of the variance in the shoreline roughness for real‐world and simulated deltas. We identify a tipping point in the flux balance where wave influence halts distributary channel formation and show how this explains morphological transitions in real world deltas. Plain Language Summary...

Integrating Non-Targeted Ecosystem Services into Assessment of Natural Stormwater Treatment Systems

Thu, 9 Nov 2023 00:00:00 +0000
Natural stormwater treatment systems (NTS) are built ecosystems designed to capture and treat stormwater runoff via natural processes. Although NTS design typically targets water services, the biological communities associated with NTS (i.e., plants, animals, and microbes) can provide non-targeted functions that can result in ecosystem services, such as biodiversity, pollination, and climate regulation, or in some cases disservices. Additional co-benefits of NTS include recreation, education and outreach opportunities, and aesthetic value. A review of NTS ecosystem services and co-benefits is provided with specific examples from Los Angeles County, highlighting the need for ecosystem services indicators, standard measurements, and monitoring. As NTS become globally widespread, best practices must include the ability to holistically assess NTS performance in ways that extend beyond water treatment services. Three models are presented that can be used to evaluate NTS performance....

Liver and muscle circadian clocks cooperate to support glucose tolerance in mice

Thu, 9 Nov 2023 00:00:00 +0000
Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting...

Reconsidering short-range order in complex concentrated alloys

Tue, 7 Nov 2023 00:00:00 +0000
The seemingly contradictory state of research on short-range order in many-component alloys is addressed through a critical review of the characterization of face-centered-cubic 3d systems. Despite the paucity of direct observations, the ordering of many widely studied alloys is argued to be primarily interesting for its potential ubiquity. To clarify this situation, future research directions are proposed with reference to historical results, including a review of the fundamental principles of ordering and clustering.Graphical abstract

Barrier-free predictions of short-range ordering/clustering kinetics in binary FCC solid solutions

Tue, 7 Nov 2023 00:00:00 +0000
We present comparisons of kinetic Monte Carlo (kMC) simulations of isothermal short-range ordering (SRO) and clustering (SRC) kinetics in binary FCC alloys with a mean-field concentration wave (CW) model. We find that the CW model is able to give order-of-magnitude agreement with kMC simulations for ordering/clustering relaxation times over a wide range of temperatures and compositions. The advantage of the CW model is that it does not require parameterization of vacancy hopping energy barriers, which, for a concentrated alloy, becomes prohibitive. We assess limits in the accuracy of the model, and discuss the effect of cooling rates as well as the extension to multi-component systems. Ultimately, the simplicity and performance of the CW model compared to kMC simulations suggests that it is a useful tool to connect with models of properties dependent on SRO/SRC as well as for designing thermal treatments to control formation of SRO/SRC.

Isolation and Analysis of B-cell Progenitors from Bone Marrow by Flow Cytometry

Wed, 25 Oct 2023 00:00:00 +0000
B cells play a critical role in host defense, producing antibodies in response to microbial infection. An inability to produce an effective antibody response leaves affected individuals prone to serious infection; therefore, proper B-cell development is essential to human health. B-cell development begins in the bone marrow and progresses through various stages until maturation occurs in the spleen. This process involves several sequential, complex events, starting with pre- and pro-B cells, which rearrange the heavy and light chain genes responsible for producing clonally diverse immunoglobulin (Ig) molecules. These cells then differentiate into immature B cells, followed by mature B cells. The bone marrow is a complex ecological niche of supporting stromal cells, extracellular matrix components, macrophages, and hematopoietic precursor cells influencing B-cell development, maturation, and differentiation. Once fully mature, B cells circulate in peripheral lymphoid organs and...

The Phenotypes of Proliferating Glioblastoma Cells Reside on a Single Axis of Variation

Sun, 15 Oct 2023 00:00:00 +0000
Although tumor-propagating cells can be derived from glioblastomas (GBM) of the proneural and mesenchymal subtypes, a glioma stem-like cell (GSC) of the classic subtype has not been identified. It is unclear whether mesenchymal GSCs (mGSC) and/or proneural GSCs (pGSC) alone are sufficient to generate the heterogeneity observed in GBM. We performed single-cell/single-nucleus RNA sequencing of 28 gliomas, and single-cell ATAC sequencing for 8 cases. We found that GBM GSCs reside on a single axis of variation, ranging from proneural to mesenchymal. In silico lineage tracing using both transcriptomics and genetics supports mGSCs as the progenitors of pGSCs. Dual inhibition of pGSC-enriched and mGSC-enriched growth and survival pathways provides a more complete treatment than combinations targeting one GSC phenotype alone. This study sheds light on a long-standing debate regarding lineage relationships among GSCs and presents a paradigm by which personalized combination therapies...

Entropic Stabilization of Water at Graphitic Interfaces

Thu, 12 Oct 2023 00:00:00 +0000
The thermodynamic stability of water next to graphitic surfaces is of fundamental interest, as it underlies several natural phenomena and important industrial processes. It is commonly assumed that water wets graphite more than graphene due to increased, favorable van der Waals interactions between the interfacial water molecules with multiple carbon sheets. Here, we employed extensive computer simulations and analysis of the molecular correlation functions to show that the interfacial water thermodynamics is in fact dominated by surface entropy. We show that on graphite, destabilization of the interfacial hydrogen bond network leads to an overcompensating increase in population of low frequency translational and librational modes, which is ultimately responsible for the increased interfacial stability compared to graphene. The spectroscopic signature of this effect is an enhancement of the modes near 100 and 300 cm^-1. This subtle interplay between entropy and surface...

Polarization-Resolved Extreme Ultraviolet Second Harmonic Generation from LiNbO$_3$

Thu, 12 Oct 2023 00:00:00 +0000
Second harmonic generation (SHG) spectroscopy ubiquitously enables the investigation of surface chemistry, interfacial chemistry as well as symmetry properties in solids. Polarization-resolved SHG spectroscopy in the visible to infrared regime is regularly used to investigate electronic and magnetic orders through their angular anisotropies within the crystal structure. However, the increasing complexity of novel materials and emerging phenomena hamper the interpretation of experiments solely based on the investigation of hybridized valence states. Here, polarization-resolved SHG in the extreme ultraviolet (XUV-SHG) is demonstrated for the first time, enabling element-resolved angular anisotropy investigations. In non-centrosymmetric LiNbO$_3$, elemental contributions by lithium and niobium are clearly distinguished by energy dependent XUV-SHG measurements. This element-resolved and symmetry-sensitive experiment suggests that the displacement of Li ions in LiNbO$_3$, which is...

Bidding strategy for wireless charging roads with energy storage in real-time electricity markets

Thu, 28 Sep 2023 00:00:00 +0000
The combination of wireless charging roads and energy storage systems is a promising option for electric vehicle charging because of their capabilities in mitigating range anxiety of electric vehicle drivers. Wireless charging road operators can purchase electric energy by submitting price-sensitive demand bids in real-time electricity markets. Efficient bidding strategies are crucial to minimizing the energy costs for providing wireless charging services. In this study, we first propose a composite statistical model based on graph signal processing and linear regression to forecast the future locational marginal prices (LMPs) in a power network. Then an estimate of future electric load on each wireless charging road is derived by simulating its traffic flow using a point queue-based traffic flow model. An efficient price-sensitive bidding strategy for each individual wireless charging road is developed based on its LMP forecast, wireless charging load estimate, and a model predictive...

Model-free voltage control of active distribution system with PVs using surrogate model-based deep reinforcement learning

Thu, 28 Sep 2023 00:00:00 +0000
Accurate knowledge of the distribution system topology and parameters is required to achieve good voltage control performance, but this is difficult to obtain in practice. This paper proposes a physical-model-free voltage control method based on a surrogate-model-enabled deep reinforcement learning approach. Specifically, a surrogate model is trained in a supervised manner using the recorded limited number of historical data to learn the relationship between the power injections and voltage fluctuations of each node. Then, the deep reinforcement learning algorithm is applied to learn an optimal control strategy from the experiences obtained by continuous interactions with the surrogate model. The proposed method can achieve physical-model-free control of unbalanced distribution network and inform real-time decisions to deal with fast voltage fluctuations caused by the rapid variation of PV generation. Simulation results on an unbalance IEEE 123-bus system show that the proposed...

Wnt Antagonists in Hematopoietic and Immune Cell Fate: Implications for Osteoporosis Therapies

Wed, 20 Sep 2023 00:00:00 +0000
Purpose of ReviewWe reviewed the current literature on the roles of the Wnt antagonists sclerostin (Sost) and sclerostin-containing domain protein 1 (Sostdc1) on bone homeostasis, the relationship of the hypoxia-inducible factor (Hif) and von Hippel-Lindau (Vhl) pathways on Sost expression, and how changes in bone induced by depletion of Sost, Sostdc1, and Vhl affect hematopoietic cells.Recent FindingsB cell development is adversely affected in Sost-knockout mice and is more severely affected in Vhl-knockout mice. Inflammation in the Sost−/− bone microenvironment could alter hematopoietic stem cell behavior. Sostdc1−/− mice display defects in natural killer cell development and cytotoxicity.SummaryDepletion of Sost and Sostdc1 have effects on immune cell function that warrant investigation in patients receiving Wnt antagonist-depleting therapies for treatment of bone diseases. Additional clinical applications for manipulation of Wnt antagonists include cancer immunotherapies,...

Metabolic shift in density-dependent stem cell differentiation

Tue, 19 Sep 2023 00:00:00 +0000
BackgroundVascular progenitor cells (VPCs) derived from embryonic stem cells (ESCs) are a valuable source for cell- and tissue-based therapeutic strategies. During the optimization of endothelial cell (EC) inductions from mouse ESCs using our staged and chemically-defined induction methods, we found that cell seeding density but not VEGF treatment between 10 ng/mL and 40 ng/mL was a significant variable directing ESCs into FLK1+ VPCs during stage 1 induction. Here, we examine potential contributions from cell-to-cell signaling or cellular metabolism in the production of VPCs from ESCs seeded at different cell densities.MethodsUsing 1D 1H-NMR spectroscopy, transcriptomic arrays, and flow cytometry, we observed that the density-dependent differentiation of ESCs into FLK1+ VPCs positively correlated with a shift in metabolism and cellular growth.ResultsSpecifically, cell differentiation correlated with an earlier plateauing of exhaustive glycolysis, decreased lactate production,...

Water, environment, and socioeconomic justice in California: A multi-benefit cropland repurposing framework

Sun, 20 Aug 2023 00:00:00 +0000
Low-income, rural frontline communities of California's Central Valley experience environmental and socioeconomic injustice, water insecurity, extremely poor air quality, and lack of fundamental infrastructure (sewage, green areas, health services), which makes them less resilient. Many communities depend financially on agriculture, while water scarcity and associated policy may trigger farmland retirement further hindering socioeconomic opportunities. Here we propose a multi-benefit framework to repurpose cropland in buffers inside and around (400-m and 1600-m buffers) 154 rural disadvantaged communities of the Central Valley to promote socioeconomic opportunities, environmental benefits, and business diversification. We estimate the potential for (1) reductions in water and pesticide use, nitrogen leaching, and nitrogen gas emissions, (2) managed aquifer recharge, and (3) economic and employment impacts associated with clean industries and solar energy. Retiring cropland within...

Highly Mobile Excitons in Single Crystal Methylammonium Lead Tribromide Perovskite Microribbons

Sat, 22 Jul 2023 00:00:00 +0000
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...

Surface Effects on Anisotropic Photoluminescence in One‐Dimensional Organic Metal Halide Hybrids

Fri, 21 Jul 2023 00:00:00 +0000
1D organic metal halide hybrids (OMHHs) exhibit strongly anisotropic optical properties, highly efficient light emission, and large Stokes shift, holding promise for novel photodetection and lighting applications. However, the fundamental mechanisms governing their unique optical properties and in particular the impacts of surface effects are not understood. Herein, 1D C 4 N 2 H 14 PbBr 4 by polarization‐dependent time‐averaged and time‐resolved photoluminescence (TRPL) spectroscopy, as a function of photoexcitation energy, is investigated. Surprisingly, it is found that the emission under photoexcitation polarized parallel to the 1D metal halide chains can be either stronger or weaker than that under perpendicular polarization, depending on the excitation energy. The excitation‐energy‐dependent anisotropic emission is attributed to fast surface recombination, supported by first‐principles calculations of optical absorption in this material. The fast surface recombination is directly...

The impact and outcomes of cancer-macrophage fusion

Tue, 18 Jul 2023 00:00:00 +0000
BackgroundCancer’s hallmark feature is its ability to evolve, leading to metastasis and recurrence. Although genetic mutations and epigenetic changes have been implicated, they don’t fully explain the leukocytic traits that many cancers develop. Cell fusion between cancer and somatic cells, particularly macrophages, has been suggested as an alternative pathway for cancer cells to obtain new traits by acquiring exogenous genetic material.MethodsThis study aims to investigate the potential biological outcomes of tumor-myeloid cell fusion by generating tumor-macrophage hybrid cells. Two clones with markedly different tumorigenicity were selected, and RNA-seq was used to compare their RNA expressions with that of the control cells. Based on the results that the hybrid cells showed differential activation in several upstream regulator pathways that impact their biological behaviors, the hybrid cells’ abilities to recruit stromal cells and establish angiogenesis as well as their cell...

Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma

Sat, 15 Jul 2023 00:00:00 +0000
Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL+) cells. Renal tumors with either VHL+ or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL+ cells. Periostin (POSTN), a...

Scalable Total Synthesis, IP3R Inhibitory Activity ofDesmethylxestospongin B, and Effect on Mitochondrial Function andCancer Cell Survival

Tue, 11 Jul 2023 00:00:00 +0000
Scalable Total Synthesis, IP3R Inhibitory Activity ofDesmethylxestospongin B, and Effect on Mitochondrial Function andCancer Cell Survival

Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination

Sat, 8 Jul 2023 00:00:00 +0000
Class switch recombination generates distinct antibody isotypes critical to a robust adaptive immune system, and defects are associated with autoimmune disorders and lymphomagenesis. Transcription is required during class switch recombination to recruit the cytidine deaminase AID-an essential step for the formation of DNA double-strand breaks-and strongly induces the formation of R loops within the immunoglobulin heavy-chain locus. However, the impact of R loops on double-strand break formation and repair during class switch recombination remains unclear. Here, we report that cells lacking two enzymes involved in R loop removal-senataxin and RNase H2-exhibit increased R loop formation and genome instability at the immunoglobulin heavy-chain locus without impacting its transcriptional activity, AID recruitment, or class switch recombination efficiency. Senataxin and RNase H2-deficient cells also exhibit increased insertion mutations at switch junctions, a hallmark of alternative...

A single-cell atlas of glioblastoma evolution under therapy reveals cell-intrinsic and cell-extrinsic therapeutic targets

Sat, 8 Jul 2023 00:00:00 +0000
Recent longitudinal studies of glioblastoma (GBM) have demonstrated a lack of apparent selection pressure for specific DNA mutations in recurrent disease. Single-cell lineage tracing has shown that GBM cells possess a high degree of plasticity. Together this suggests that phenotype switching, as opposed to genetic evolution, may be the escape mechanism that explains the failure of precision therapies to date. We profiled 86 primary-recurrent patient-matched paired GBM specimens with single-nucleus RNA, single-cell open-chromatin, DNA and spatial transcriptomic/proteomic assays. We found that recurrent GBMs are characterized by a shift to a mesenchymal phenotype. We show that the mesenchymal state is mediated by activator protein 1. Increased T-cell abundance at recurrence was prognostic and correlated with hypermutation status. We identified tumor-supportive networks of paracrine and autocrine signals between GBM cells, nonmalignant neuroglia and immune cells. We present cell-intrinsic...

Stage at diagnosis and survival among adolescents and young adults with lymphomas following the Affordable Care Act implementation in California

Tue, 27 Jun 2023 00:00:00 +0000
Adolescents and young adults (AYAs, 15-39 years) are the largest uninsured population in the Unites States, increasing the likelihood of late-stage cancer diagnosis and poor survival. We evaluated the associations between the Affordable Care Act (ACA), insurance coverage, stage at diagnosis and survival among AYAs with lymphoma. We used data from the California Cancer Registry linked to Medicaid enrollment files on AYAs diagnosed with a primary non-Hodgkin (NHL; n = 5959) or Hodgkin (n = 5378) lymphoma pre-ACA and in the early and full ACA eras. Health insurance was categorized as continuous Medicaid, discontinuous Medicaid, Medicaid enrollment at diagnosis/uninsurance, other public and private. We used multivariable regression models for statistical analyses. The proportion of AYAs uninsured/Medicaid enrolled at diagnosis decreased from 13.4% pre-ACA to 9.7% with full ACA implementation, while continuous Medicaid increased from 9.3% to 29.6% during this time...

Rational design strategies for functional reconstitution of plant cytochrome P450s in microbial systems

Sat, 24 Jun 2023 00:00:00 +0000
Plant natural products (NPs) are of pharmaceutical and agricultural significance, yet the low abundance is largely impeding the broad investigation and utilization. Microbial bioproduction is a promising alternative sourcing to plant NPs. Cytochrome P450s (CYPs) play an essential role in plant secondary metabolism, and functional reconstitution of plant CYPs in the microbial system is one of the major challenges in establishing efficient microbial plant NP bioproduction. In this review, we briefly summarized the recent progress in rational engineering strategies for enhanced activity of plant CYPs in Escherichia coli and Saccharomyces cerevisiae, two commonly used microbial hosts. We believe that in-depth foundational investigations on the native microenvironment of plant CYPs are necessary to adapt the microbial systems for more efficient functional reconstitution of plant CYPs.

Calibration-free analysis of surface proteins on single extracellular vesicles enabled by DNA nanostructure

Fri, 23 Jun 2023 00:00:00 +0000
Extracellular vesicles (EVs) are essential intercellular communicators that are of increasing interest as diagnostic biomarkers. Exploring their biological functions and clinical values, however, remains challenging due to their small sizes and high heterogeneity. Herein, we report an ultrasensitive method that employs target-initiated construction of DNA nanostructure to detect single EVs with an input as low as 100 vesicles/μL. Taking advantage of both DNA nanostructure labeling and EV membrane staining, the method can also permit calibration-free analysis of the protein profiles among different EV samples, leading to clear EV differentiation by their cell of origin. Moreover, this method allows co-localization of dual protein markers on the same EV, and the increased number of EVs carrying dual tumor proteins present in human serum could differentiate cancer patients at the early developmental stage from healthy controls. Our results demonstrate the great potential of this...

Rational Design of RNA Editing Guide Strands: Cytidine Analogs at the Orphan Position

Wed, 21 Jun 2023 00:00:00 +0000
Adenosine Deaminases Acting on RNA (ADARs) convert adenosine to inosine in double stranded RNA. Human ADARs can be directed to predetermined target sites in the transcriptome by complementary guide strands, allowing for the correction of disease-causing mutations at the RNA level. Here we use structural information available for ADAR2-RNA complexes to guide the design of nucleoside analogs for the position in the guide strand that contacts a conserved glutamic acid residue in ADARs (E488 in human ADAR2), which flips the adenosine into the ADAR active site for deamination. Mutating this residue to glutamine (E488Q) results in higher activity because of the hydrogen bond donating ability of Q488 to N3 of the orphan cytidine on the guide strand. We describe the evaluation of cytidine analogs for this position that stabilize an activated conformation of the enzyme-RNA complex and increase catalytic rate for deamination by the wild-type enzyme. A new crystal structure of ADAR2 bound...

Scalable Total Synthesis, IP3R Inhibitory Activity of Desmethylxestospongin B, and Effect on Mitochondrial Function and Cancer Cell Survival

Tue, 20 Jun 2023 00:00:00 +0000
The scalable synthesis of the oxaquinolizidine marine natural product desmethylxestospongin B is based on the early application of Ireland-Claisen rearrangement, macrolactamization, and a late-stage installation of the oxaquinolizidine units by lactam reduction. The synthesis serves as the source of material to investigate calcium signaling and its effect on mitochondrial metabolism in various cell types, including cancer cells.

Effects of residual disinfectants on the redox speciation of lead( ii )/( iv ) minerals in drinking water distribution systems

Thu, 15 Jun 2023 00:00:00 +0000
This study investigated the reaction kinetics on the oxidative transformation of lead(ii) minerals by free chlorine (HOCl) and free bromine (HOBr) in drinking water distribution systems. According to chemical equilibrium predictions, lead(ii) carbonate minerals, cerussite PbCO_3(s) and hydrocerussite Pb₃(CO₃)₂(OH)_2(s), and lead(ii) phosphate mineral, chloropyromorphite Pb₅(PO₄)₃Cl_(s) are formed in drinking water distribution systems in the absence and presence of phosphate, respectively. X-ray absorption near edge spectroscopy (XANES) data showed that at pH 7 and a 10 mM alkalinity, the majority of cerussite and hydrocerussite was oxidized to lead(iv) mineral PbO_2(s) within 120 minutes of reaction with chlorine (3 : 1 Cl₂ : Pb(ii) molar ratio). In contrast, very little oxidation of chloropyromorphite occurred. Under similar conditions, oxidation of lead(ii) carbonate...

Iodide-doped precious metal nanoparticles: measuring oxidative stress in vivo via photoacoustic imaging

Thu, 8 Jun 2023 00:00:00 +0000
Accumulation of reactive oxygen and nitrogen species (RONS) can induce cell damage and even cell death. RONS are short-lived species, which makes direct, precise, and real-time measurement difficult. Biologically-relevant RONS levels are in the nM-μM scale; hence, there is a need for highly sensitive RONS probes. We previously used hybrid gold-core silver-shell nanoparticles with mM sensitivity to H2O2. These particles reported the presence of RONS via spectral shifts which could easily be quantified via photoacoustic imaging. Here, we used halide doping to tune the electrochemical properties of these materials to better match the oxidation potential of RONS. This work describes the synthesis, characterization, and application of these AgI-coated gold nanorods (AgI/AuNR). The I : Ag molar ratio, pH, and initial Ag shell thickness were optimized for good RONS detection limits. Halide doping lowers the reduction potential of Ag from to resulting in a 1000-fold increase in H2O2 and...

Redirecting extracellular proteases to molecularly guide radiosensitizing drugs to tumors

Thu, 8 Jun 2023 00:00:00 +0000
Patients with advanced cancers are treated with combined radiotherapy and chemotherapy, however curability is poor and treatment side effects severe. Drugs sensitizing tumors to radiotherapy have been developed to improve cell kill, but tumor specificity remains challenging. To achieve tumor selectivity of small molecule radiosensitizers, we tested as a strategy active tumor targeting using peptide-based drug conjugates. We attached an inhibitor of the DNA damage response to antibody or cell penetrating peptides. Antibody drug conjugates honed in on tumor overexpressed cell surface receptors with high specificity but lacked efficacy when conjugated to the DNA damage checkpoint kinase inhibitor AZD7762. As an alternative approach, we synthesized activatable cell penetrating peptide scaffolds that accumulated within tumors based on matrix metalloproteinase cleavage. While matrix metalloproteinases are integral to tumor progression, they have proven therapeutically elusive. We harnessed...

Ensemble learning for classifying single-cell data and projection across reference atlases

Wed, 7 Jun 2023 00:00:00 +0000
SUMMARY: Single-cell data are being generated at an accelerating pace. How best to project data across single-cell atlases is an open problem. We developed a boosted learner that overcomes the greatest challenge with status quo classifiers: low sensitivity, especially when dealing with rare cell types. By comparing novel and published data from distinct scRNA-seq modalities that were acquired from the same tissues, we show that this approach preserves cell-type labels when mapping across diverse platforms. AVAILABILITY AND IMPLEMENTATION: https://github.com/diazlab/ELSA. CONTACT: aaron.diaz@ucsf.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Physical and chemical template-blocking strategies in the exponential amplification reaction of circulating microRNAs

Wed, 7 Jun 2023 00:00:00 +0000
The detection of circulating miRNA through isothermal amplification wields many attractive advantages over traditional methods, such as reverse transcription RT-qPCR. However, it is challenging to control the background signal produced in the absence of target, which severely hampers applications of such methods for detecting low abundance targets in complex biological samples. In the present work, we employed both the cobalt oxyhydroxide (CoOOH) nanoflakes and the chemical modification of hexanediol to block non-specific template elongation in exponential amplification reaction (EXPAR). Adsorption by the CoOOH nanoflakes and the hexanediol modification at the 3′ end effectively prevented no-target polymerization on the template itself and thus greatly improved the performance of EXPAR, detecting as low as 10 aM of several miRNA targets, including miR-16, miR-21, and miR-122, with the fluorescent DNA staining dye of SYBR Gold™. Little to no cross-reactivity was observed from...

Precision Chemoradiotherapy for HER2 Tumors Using Antibody Conjugates of an Auristatin Derivative with Reduced Cell Permeability

Fri, 2 Jun 2023 00:00:00 +0000
The most successful therapeutic strategies for locally advanced cancers continue to combine decades-old classical radiosensitizing chemotherapies with radiotherapy. Molecular targeted radiosensitizers offer the potential to improve the therapeutic ratio by increasing tumor-specific kill while minimizing drug delivery and toxicity to surrounding normal tissue. Auristatins are a potent class of anti-tubulins that sensitize cells to ionizing radiation damage and are chemically amenable to antibody conjugation. To achieve tumor-selective radiosensitization, we synthesized and tested anti-HER2 antibody-drug conjugates of two auristatin derivatives with ionizing radiation. Monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) were attached to the anti-HER2 antibodies trastuzumab and pertuzumab through a cleavable linker. While MMAE is cell permeable, MMAF has limited cell permeability as free drug resulting in diminished cytotoxicity and radiosensitization. However, when...

Differential activation of hepatic iNKT cell subsets plays a key role in progression of nonalcoholic steatohepatitis

Tue, 23 May 2023 00:00:00 +0000
Innate immune mechanisms play an important role in inflammatory chronic liver diseases. In this study, we investigated the role of type I or invariant NKT (iNKT) cell subsets in the progression of nonalcoholic steatohepatitis (NASH). We used α-galactosylceramide/CD1d tetramers and clonotypic mAb together with intracytoplasmic cytokine staining to analyze iNKT cells in choline-deficient l-amino acid-defined (CDAA)-induced murine NASH model and in human PBMCs, respectively. Cytokine secretion of hepatic iNKT cells in CDAA-fed C57BL/6 mice altered from predominantly IL-17⁺ to IFN-γ⁺ and IL-4⁺ during NASH progression along with the downmodulation of TCR and NK1.1 expression. Importantly, steatosis, steatohepatitis, and fibrosis were dependent upon the presence of iNKT cells. Hepatic stellate cell activation and infiltration of neutrophils, Kupffer cells, and CD8⁺ T cells as well as expression of key proinflammatory and fibrogenic genes were...

Using Search Engine Data as a Tool to Predict Syphilis

Sat, 20 May 2023 00:00:00 +0000
BACKGROUND: Researchers have suggested that social media and online search data might be used to monitor and predict syphilis and other sexually transmitted diseases. Because people at risk for syphilis might seek sexual health and risk-related information on the internet, we investigated associations between internet state-level search query data (e.g., Google Trends) and reported weekly syphilis cases. METHODS: We obtained weekly counts of reported primary and secondary syphilis for 50 states from 2012 to 2014 from the US Centers for Disease Control and Prevention. We collected weekly internet search query data regarding 25 risk-related keywords from 2012 to 2014 for 50 states using Google Trends. We joined 155 weeks of Google Trends data with 1-week lag to weekly syphilis data for a total of 7750 data points. Using the least absolute shrinkage and selection operator, we trained three linear mixed models on the first 10 weeks of each year. We validated models for 2012 and 2014...