http://www.rssboard.org/rss-specification 720 https://escholarship.org/uc/sspps_orw/rss Recent eScholarship items from Other Recent Work Tue, 16 Jun 2026 18:12:19 +0000 https://escholarship.org/uc/item/98g5585v BACKGROUND: End-of-life HIV research places emotional demands on staff, yet evidence for brief compassion training to enhance resilience is limited. OBJECTIVES: To assess the feasibility and impact of a four-week compassion training program on self-compassion and professional well-being. DESIGN: Prospective, single-group, repeated-measures pilot with surveys at baseline (T1), post-program (T2), and 12-week follow-up (T3). SETTING/PARTICIPANTS: Twenty-four professionals from the UC San Diego Last Gift program (83% women, 63% aged 25-44 years). MEASUREMENTS: Validated scales assessed self-compassion, compassion for others, professional quality of life, and work climate; changes were analyzed with Friedman and Bonferroni-adjusted Wilcoxon tests. RESULTS: Over-identification (<i>p</i> = 0.002), workplace joy (<i>p</i> = 0.005), and supportive work environment (<i>p</i> = 0.003) improved. Meditation frequency increased from T1 to T2 (<i>p</i> &lt; 0.001) and remained higher at T3 (<i>p</i>... https://escholarship.org/uc/item/98g5585v Thu, 9 Apr 2026 00:00:00 +0000 Higgins, Niamh https://orcid.org/0000-0002-5947-5209 Ahmed, Ali Tran, Whitney Lau, Rachel Lai, Joyce Ching-Jung Schairer, Sara Gianella, Sara Dubé, Karine https://escholarship.org/uc/item/9cs3g1kn The intrinsic drug resistance of <i>Mycobacterium tuberculosis</i> (Mtb) is a major barrier to effective tuberculosis (TB) treatment and is largely due to its complex, impermeable cell envelope. We identified a periplasmic protein complex comprising FecB and Rv3035 that is essential for maintaining envelope integrity and mediating intrinsic multidrug resistance in Mtb. FecB interacts with Rv3035, forming a stable heterodimer that associates with the cell envelope biosynthesis protein AftB. We report the structures of Rv3035 alone and in complex with FecB and identify critical residues for complex formation and function. Coessentiality and genetic interaction analyses support a functional link between FecB, Rv3035, and AftB, an arabinofuranosyltransferase that synthesizes arabinogalactan and lipoarabinomannan. Loss of FecB or Rv3035 disrupted AftB-mediated arabinan synthesis, suggesting that these proteins support AftB's enzymatic activity. FecB is required for Mtb virulence in... https://escholarship.org/uc/item/9cs3g1kn Mon, 6 Apr 2026 00:00:00 +0000 Klevorn, Thaís Brown, Christopher Hardy, Christine D Cuthbert, Bonnie J Spencer, Amanda Jinich, Adrián Chan, Luming Angala, Shiva K Manzer, Jordan Mendoza, Jessica de Miranda, Rodger Kim, Heather Schnappinger, Dirk Jackson, Mary Rhee, Kyu Goulding, Celia W https://orcid.org/0000-0001-5582-0565 Ehrt, Sabine https://escholarship.org/uc/item/6t82v6xc Is there a principal-agent problem between large retail-chain pharmacy corporations and community pharmacists? https://escholarship.org/uc/item/6t82v6xc Thu, 12 Mar 2026 00:00:00 +0000 Bounthavong, Mark https://orcid.org/0000-0002-7343-9458 https://escholarship.org/uc/item/5c8073wg Host-cell cysteine proteases play an essential role in the processing of the viral spike protein of SARS coronaviruses. K777, an irreversible, covalent inactivator of cysteine proteases that has recently completed phase 1 clinical trials, reduced SARS-CoV-2 viral infectivity in several host cells: Vero E6 (EC₅₀&lt; 74 nM), HeLa/ACE2 (4 nM), Caco-2 (EC₉₀ = 4.3 μM), and A549/ACE2 (&lt;80 nM). Infectivity of Calu-3 cells depended on the cell line assayed. If Calu-3/2B4 was used, EC₅₀ was 7 nM, but in the ATCC Calu-3 cell line without ACE2 enrichment, EC₅₀ was &gt;10 μM. There was no toxicity to any of the host cell lines at 10-100 μM K777 concentration. Kinetic analysis confirmed that K777 was a potent inhibitor of human cathepsin L, whereas no inhibition of the SARS-CoV-2 cysteine proteases (papain-like and 3CL-like protease) was observed. Treatment of Vero E6 cells with a propargyl derivative of K777 as an activity-based probe identified... https://escholarship.org/uc/item/5c8073wg Thu, 15 Jan 2026 00:00:00 +0000 Mellott, Drake M Tseng, Chien-Te Drelich, Aleksandra Fajtová, Pavla Chenna, Bala C Kostomiris, Demetrios H Hsu, Jason Zhu, Jiyun Taylor, Zane W Kocurek, Klaudia I Tat, Vivian Katzfuss, Ardala Li, Linfeng Giardini, Miriam A https://orcid.org/0000-0002-6510-2409 Skinner, Danielle Hirata, Ken Yoon, Michael C https://orcid.org/0000-0002-2900-5257 Beck, Sungjun Carlin, Aaron F https://orcid.org/0000-0002-1669-8066 Clark, Alex E Beretta, Laura Maneval, Daniel Hook, Vivian Frueh, Felix Hurst, Brett L Wang, Hong Raushel, Frank M O’Donoghue, Anthony J de Siqueira-Neto, Jair Lage Meek, Thomas D McKerrow, James H https://escholarship.org/uc/item/8wk2t87f <b>Objective:</b> The purpose of this study is to evaluate obstetric outcomes in pregnant women who received second-generation long-acting injectable antipsychotics (LAIAs) compared to a control group who received second-generation oral antipsychotics. <b>Methods:</b> This was a retrospective study utilizing a global cohort of 148 health care organizations grouped into a network within the TriNetX database. Pregnant patients of any trimester were grouped into 2 cohorts: (1) exposure to long-acting aripiprazole, risperidone, paliperidone, or olanzapine (n=2,082) and (2) exposure to the corresponding oral formulations (n=31,376) and propensity matched. The primary outcome was the occurrence of one of the following obstetric complications: gestational diabetes, preeclampsia, eclampsia, or a newly diagnosed hypertensive disorder. Cesarean section rates were also assessed. <b>Results:</b> After propensity matching, each cohort yielded 2,025 patients. No intergroup differences were... https://escholarship.org/uc/item/8wk2t87f Wed, 14 Jan 2026 00:00:00 +0000 Khorassani, Farah https://orcid.org/0000-0003-2506-2921 Espejo, Gemma Lee, Kelly C https://orcid.org/0000-0002-1674-4210 https://escholarship.org/uc/item/49v5w2g8 Despite extensive efforts, extracting medication exposure information from clinical records remains challenging. To complement this approach, here we show the Global Natural Product Social Molecular Networking (GNPS) Drug Library, a tandem mass spectrometry (MS/MS) based resource designed for drug screening with untargeted metabolomics. This resource integrates MS/MS references of drugs and their metabolites/analogs with standardized vocabularies on their exposure sources, pharmacologic classes, therapeutic indications, and mechanisms of action. It enables direct analysis of drug exposure and metabolism from untargeted metabolomics data, supporting flexible summarization at multiple ontology levels to align with different research goals. We demonstrate its application by stratifying participants in a human immunodeficiency virus (HIV) cohort based on detected drug exposures. We uncover drug-associated alterations in microbiota-derived N-acyl lipids that are not captured when stratifying... https://escholarship.org/uc/item/49v5w2g8 Mon, 15 Dec 2025 00:00:00 +0000 Zhao, Haoqi Nina Kvitne, Kine Eide Brungs, Corinna Mohan, Siddharth Charron-Lamoureux, Vincent Bittremieux, Wout Tang, Runbang Schmid, Robin Lamichhane, Santosh Xing, Shipei El Abiead, Yasin Andalibi, Mohammadsobhan S Mannochio-Russo, Helena Ambre, Madison Avalon, Nicole E Bryant, MacKenzie Burnett, Lindsey A Caraballo-Rodríguez, Andrés Mauricio Maya, Martin Casas Chin, Loryn Corominas, Lluís Ellis, Ronald J Franklin, Donald Girod, Sagan Gomes, Paulo Wender P Hansen, Lauren Heaton, Robert K Iudicello, Jennifer E Jarmusch, Alan K Khatib, Lora Letendre, Scott https://orcid.org/0000-0003-3490-4975 Magyari, Sarolt McDonald, Daniel Mohanty, Ipsita Cumsille, Andrés Moore, David J https://orcid.org/0000-0002-2199-1662 Rajkumar, Prajit Ross, Dylan H Sapre, Harshada Shahneh, Mohammad Reza Zare Gil-Solsona, Ruben Thomas, Sydney P Tribelhorn, Caitlin Tubb, Helena M Walker, Corinn Wang, Crystal X Zemlin, Jasmine Zuffa, Simone https://orcid.org/0000-0001-7237-3402 Wishart, David S Gago-Ferrero, Pablo Kaddurah-Daouk, Rima Wang, Mingxun Raffatellu, Manuela https://orcid.org/0000-0001-6487-4215 Zengler, Karsten Pluskal, Tomáš Xu, Libin Knight, Rob Tsunoda, Shirley M https://orcid.org/0000-0002-3974-8038 Dorrestein, Pieter C https://escholarship.org/uc/item/0pr7f7ks Cyanobacteria are prolific producers of biologically active compounds that are important in influencing ecology, behavior of interacting organisms, and as leads in drug discovery efforts. Here we discuss the challenges faced by all natural product researchers, especially those that focus on cyanobacteria, and then describe progress that has been made in these areas. We also propose some solutions, paths forward, and thoughts for consideration on these challenges. https://escholarship.org/uc/item/0pr7f7ks Tue, 9 Dec 2025 00:00:00 +0000 Philmus, Benjamin Avalon, Nicole E Ding, Yousong Doering, Drew T Eustáquio, Alessandra S Gerwick, William H https://orcid.org/0000-0003-1403-4458 Luesch, Hendrik Orjala, Jimmy Sutherland, Shaz Taton, Arnaud Udwary, Daniel https://orcid.org/0000-0002-3491-0198 https://escholarship.org/uc/item/6p80v9t7 Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei) urgently demand innovative drug development due to their impact on public health worldwide. Their cysteine proteases, Cruzain (CRZ) and the T. brucei Cathepsin L-like protease (TbrCATL) are established drug targets for these parasites. In this study, our coumarin-3-thiosemicarbazones demonstrated nanomolar IC₅₀ values (22-698&nbsp;nM) toward these proteases. Against T. cruzi amastigotes and T. brucei trypomastigotes, LASF-01 displayed a promising result. Herein, MCG-02, the most potent TbrCATL inhibitor, underwent comprehensive analyses, including cytotoxicity assessments and in vitro tests. Molecular dynamics (MD) simulations and a multiscale Quantum Mechanics/Quantum Mechanics (QM/QM) approach were used to generate insights into their binding modes. These suggested that MCG-02 could be a reversible, competitive covalent inhibitor. Further, confirmatory assays were experimentally performed changing different... https://escholarship.org/uc/item/6p80v9t7 Thu, 4 Dec 2025 00:00:00 +0000 Nunes, Jéssica Alves Santos-Júnior, Paulo Fernando da Silva Gomes, Midiane Correa Ferreira, Luiz Alberto Santos Padilha, Emanuelly Karla Araújo Teixeira, Thaiz Rodrigues Stanger, Emily J Kaur, Yashpreet Silva, Elany Barbosa da Costa, Clara Andrezza Crisóstomo Bezerra Freitas, Johnnatan Duarte de Araújo-Júnior, João Xavier de Mendonça-Junior, Francisco Jaime Bezerra Giardini, Miriam A https://orcid.org/0000-0002-6510-2409 Siqueira-Neto, Jair L Caffrey, Conor R Zhan, Peng Cardoso, Sílvia Helena Silva-Júnior, Edeildo Ferreira da https://escholarship.org/uc/item/7626976q Alcohol use disorder (AUD) remains a pervasive public health issue with limited effective treatments. Cannabidiol (CBD), a non-psychotropic constituent of cannabis, shows promise in modulating addictive behaviors. This study investigated the effects of chronic CBD administration on alcohol dependence, withdrawal symptoms, and neurodegeneration using two complementary rodent models: chronic intermittent ethanol (CIE) exposure, which models established alcohol dependence, and ethanol vapor self-administration (EVSA), which captures the volitional aspects of alcohol intake. In the CIE model, CBD reduced alcohol self-administration during acute withdrawal without affecting alcohol metabolism or locomotor activity. CBD decreased motivation for alcohol, somatic withdrawal signs, withdrawal-induced anxiety-like behaviors, and mechanical sensitivity. During extinction, CBD attenuated alcohol-seeking behavior and stress-induced reinstatement. Electrophysiological recordings revealed that... https://escholarship.org/uc/item/7626976q Mon, 1 Dec 2025 00:00:00 +0000 Dirik, Selen Doyle, Michelle R Wood, Courtney P Campo, Paola Martinez, Angelica R Fannon, McKenzie Balaguer, Maria G Seely, Spencer Montoya, Bryan A Cook, Gregory MR Palermo, Gabrielle M Lin, Junjie Sist, Madelyn D Naghshineh, Parsa K Lan, Zihang Rahman, Sara RMU Suhandynata, Raymond Schweitzer, Paul Kallupi, Marsida de Guglielmo, Giordano https://escholarship.org/uc/item/0fj9x5gd The constant emergence of SARS-CoV-2 resistance drives the search for new antivirals. We screened the SARS-CoV-2 cysteine proteases, the main protease (M^pro) and papain-like protease (PL^pro), with 141 peptidyl and peptidomimetic inhibitors designed to target a trypanosome cysteine protease. Five compounds (<b>1a</b>-<b>5a</b>) inhibited M^pro (IC₅₀ of 0.1601-16.42 µM), whereas none inhibited PL^pro. Compounds <b>1a</b>-<b>4a</b> inhibited human cathepsin L (hCatL; 0.184-10.74 µM), which is important for viral entry into human cells. Compounds <b>1a</b> and <b>5a</b>, and its synthesised (R,S) enantiomer, <b>5b</b>, which share a benzyl carbamate moiety, inhibited the M^pro of SARS-CoV/MERS-CoV (0.0732-0.8295 µM). The three compounds were biochemically characterised as covalent reversible inhibitors. Compounds <b>5a</b> and <b>5b</b>, which contain vinyl ketone warheads, were specific for M^pro, and this behaviour... https://escholarship.org/uc/item/0fj9x5gd Sat, 22 Nov 2025 00:00:00 +0000 Serafim, Mateus Sá Magalhães Kronenberger, Thales Francisco, Karol R de Sousa Reis, Erik Vinicius de Oliveira, Ellen Gonçalves Marcelino e Oliveira, Fernanda Kelly Fortes, Isadora Serraglio Fernandes, Thaís Helena Maciel da Silva, Elany Barbosa Fajtova, Pavla Skinner, Danielle E Syed, Rafay O de Siqueira-Neto, Jair Lage Poso, Antti Mota, Bruno Eduardo Fernandes Coelho-dos-Reis, Jordana Grazziela Alves Abrahão, Jônatas Santos Maltarollo, Vinícius Gonçalves O’Donoghue, Anthony J Caffrey, Conor R https://escholarship.org/uc/item/8737x5zf Extracellular vesicles (EVs) are secreted by cells under various conditions and can contribute to the disease progression in tissues. Here, we present a protocol to separate small and large EVs from mouse hearts and cardiac tissues collected from patients. We describe steps for utilizing enzymatic digestion for release of EVs from interstitial space followed by differential centrifugation and immunoaffinity purification. The isolated EVs can be used for various experiments to gain insight into their in&nbsp;vivo functions. For complete details on the use and execution of this protocol, please refer to Liang et&nbsp;al. (2023).¹. https://escholarship.org/uc/item/8737x5zf Tue, 30 Sep 2025 00:00:00 +0000 Liang, Wenjing Najor, Rita H Gustafsson, Åsa B https://escholarship.org/uc/item/3n84f6c6 Acinetobacter baumannii is a high-risk pathogen associated with increased patient morbidity and mortality. Host-pathogen interactions amplify its virulence, in part by promoting biofilm formation-a crucial factor in antimicrobial resistance and persistence. Given the bacterium's strong propensity for acquiring resistance, antimicrobial susceptibility testing (AST) is essential for guiding effective therapeutic interventions. However, discrepancies have been observed between in vitro AST results and therapeutic outcomes, with some antimicrobials being deemed to show in vivo efficacy despite appearing ineffective in vitro. This discordance may stem from traditional AST protocols, which rely on bacteriological media such as Mueller Hinton broth (MHB) optimized for bacterial growth but not for mimicking the host environment. Moreover, conventional AST does not account for virulence traits such as biofilm formation, which further contribute to treatment failure. Incorporating physiologically... https://escholarship.org/uc/item/3n84f6c6 Tue, 30 Sep 2025 00:00:00 +0000 Opoku, Nana Yaa P Sakyi Mishra, Arunima Fletcher, Hansel Nizet, Victor Abdul‐Mutakabbir, Jacinda C https://escholarship.org/uc/item/1676z83d Mitochondria are multifunctional organelles that are important for many different cellular processes, including energy production and biosynthesis of fatty acids, haem and iron–sulfur clusters. Mitochondrial dysfunction leads to a disruption in these processes, the generation of excessive reactive oxygen species, and the activation of inflammatory and cell death pathways. The consequences of mitochondrial dysfunction are particularly harmful in energy-demanding organs such as the heart. Loss of terminally differentiated cardiomyocytes leads to cardiac remodelling and a reduced ability to sustain contraction. Therefore, cardiomyocytes rely on multilayered mitochondrial quality control mechanisms to maintain a healthy population of mitochondria. Mitochondrial chaperones protect against protein misfolding and aggregation, and resident proteases eliminate damaged proteins through proteolysis. Irreparably damaged mitochondria can also be degraded through mitochondrial autophagy (mitophagy)... https://escholarship.org/uc/item/1676z83d Tue, 30 Sep 2025 00:00:00 +0000 Ravindran, Rishith Gustafsson, Åsa B https://escholarship.org/uc/item/689030kw Rational optimization of molecular glue degraders (MGD) remains a challenging and lengthy process even after identification of a promising scaffold. Unlike proteolysis targeting chimeras (PROTAC), MGDs rely on induced protein-protein interactions as opposed to direct binding in order to target a protein of interest for degradation. Here, we report the synthesis of MGDs targeting the transcription factor ZBTB11 guided by protein complex modeling. Exploration of structure-activity-relationships yielded JWJ-01-306 with improved ZBTB11 degradation activity and potent antiproliferative effects against BRAF inhibitor-resistant melanoma cells. Our findings led to the discovery of a novel MGD that targets a previously undrugged transcription factor with the potential to address acquired resistance to cancer therapy. https://escholarship.org/uc/item/689030kw Thu, 25 Sep 2025 00:00:00 +0000 Jiang, Jiewei https://orcid.org/0000-0001-5497-9371 Tran, Nathan L https://orcid.org/0000-0002-7917-3945 Svendsen, Emma Wang, Eric S Ferguson, Fleur M https://orcid.org/0000-0003-4091-7617 https://escholarship.org/uc/item/36v4d69t Kahalalide F is a cyclic depsipeptide with notable anticancer properties, initially discovered from the green alga <i>Bryopsis</i> sp. and its molluscan predator <i>Elysia rufescens</i>. Recent studies have pinpointed a bacterial endosymbiont of the green alga, <i>Candidatus</i> Endobryopsis kahalalidefaciens, as the true producer of kahalalide F. In the present work, we characterize a closely related kahalalide F analog, kahalalide Z₅, from the marine cyanobacterium <i>Limnoraphis</i> sp. collected in the Las Perlas Islands, Panama, and propose the structures of several related compounds by detailed MS analysis. To uncover novel metabolites and prioritize them for targeted isolation from this organism, we employed a robust metabolomics strategy combining LC-MS/MS with SMART NMR and DeepSAT, artificial intelligence platforms trained to infer chemical structures from ¹H-¹³C HSQC NMR data. This integrated approach annotated a compound with structural... https://escholarship.org/uc/item/36v4d69t Thu, 28 Aug 2025 00:00:00 +0000 Ryu, Byeol https://orcid.org/0000-0002-3405-2875 Avalon, Nicole E Cuau, Marine Almaliti, Jehad Din, M Omar Brennan, Caitriona Glukhov, Evgenia Knight, Rob Gerwick, Lena Gerwick, William H https://orcid.org/0000-0003-1403-4458 https://escholarship.org/uc/item/2kt3p937 Enhancing Naloxone Distribution and Academic Detailing Effectiveness: Insights From an Online Priority Panel Report at the United States Veterans Health Administration https://escholarship.org/uc/item/2kt3p937 Thu, 14 Aug 2025 00:00:00 +0000 Bounthavong, Mark https://orcid.org/0000-0002-7343-9458 Harvey, Michael A Kay, Chad L Himstreet, Julie E Popish, Sarah J Morillo, Christina M Lau, Marcos K Christopher, Melissa LD https://escholarship.org/uc/item/3j1093sk OBJECTIVE: SLE is associated with increased risks of maternal cardiovascular events (CVEs) as well as adverse pregnancy outcomes. The influence of maternal CVEs on pregnancy complications in lupus is not clearly known. Our primary aim was to assess the risks of adverse pregnancy outcomes in individuals with SLE, specifically examining the influence of CVEs. METHODS: Using a California population-based birth cohort from 2005 to 2020, pregnant individuals with SLE were identified via International Classification of Diseases codes on maternal discharge records and further subdivided based on whether they had lupus nephritis (LN) or antiphospholipid syndrome (APS). We analysed adjusted relative risks (aRRs) of adverse pregnancy outcomes in SLE subgroups, comparing those with and without CVEs, to the reference group of pregnant individuals without autoimmune rheumatic diseases or APS and CVEs. CVEs were broadly defined to encompass thromboembolic and cardiovascular conditions associated... https://escholarship.org/uc/item/3j1093sk Mon, 11 Aug 2025 00:00:00 +0000 Dhital, Rashmi Baer, Rebecca J https://orcid.org/0000-0001-8485-1977 Kalunian, Kenneth Chambers, Christina https://orcid.org/0000-0003-4675-7722 https://escholarship.org/uc/item/34z8b9cm BACKGROUND: Exclusive breastfeeding for 6 months is recommended, but breastfeeding safety data is insufficient for several medications. AIM: To determine if mothers treated with chronic medications are less likely to breastfeed. METHODS: For this secondary analysis, 6383 pregnant women in the MotherToBaby cohort recruited from the United States and Canada between 2010 and 2022 were included. Participants treated with antirheumatic medications (ARM), selective serotonin reuptake inhibitors (SSRIs), and asthma medications during pregnancy were divided into two groups based on their medication use: continuers and discontinuers. Breastfeeding initiation, supplementation with commercial milk formula, and discontinuation of breastfeeding before 6 months were compared between those exposed and unexposed to medication use. Adjusted risk and hazard ratios (aRR, aHR) and 95% Confidence Intervals (CI) were calculated with modified Poisson and Cox regressions adjusted for year, parity, socioeconomic... https://escholarship.org/uc/item/34z8b9cm Mon, 11 Aug 2025 00:00:00 +0000 Heinonen, Essi Whaites Johnson, Diana L Todd, Alec Chambers, Christina D https://orcid.org/0000-0003-4675-7722 https://escholarship.org/uc/item/68g314ft BackgroundOpioid overdose remains a leading cause of mortality in the USA. Although distributing naloxone to laypersons for use during witnessed opioid overdoses has been shown to effectively reduce overdose deaths, clinician awareness of naloxone prescribing remains low. Academic detailing (AD) has been reported to be an effective strategy to increase naloxone distribution to individuals at risk of opioid-related overdose/death.ObjectiveThis study evaluated the cost effectiveness of an academic detailing program aimed at promoting naloxone prescribing for adults at risk of opioid-related overdose compared to no intervention (non-AD program). MethodsA Markov model with an integrated decision tree was developed to estimate the costs and outcomes associated with the AD program over a lifetime horizon from the US payer perspective. Model robustness was tested using sensitivity and scenario analyses.ResultsThe results indicated that the AD program incurred a total direct cost of... https://escholarship.org/uc/item/68g314ft Thu, 31 Jul 2025 00:00:00 +0000 Yip, Olivia Bounthavong, Mark https://orcid.org/0000-0002-7343-9458 https://escholarship.org/uc/item/0bd742kd The structural basis of inhibitory effect of organic solvent dimethyl sulfoxide (DMSO) on human acetylcholinesterase (EC 3.1.1.7; hAChE) was inferred from the effect of DMSO on kinetics of reversible inhibition of uncharged, heterocyclic bis-oximes to hAChE, from DMSO effect on rates of reactivation of inactive organophosphate (OP)-hAChE conjugates by bis-oximes and by X-ray structures of bis-oxime and DMSO binding to hAChE. The reversible inhibition constant of DMSO for hAChE in 0.1&nbsp;M phosphate buffer pH 7.4&nbsp;at 22&nbsp;°C, was K_i= (0.32&nbsp;±&nbsp;0.04) % (or 45&nbsp;±&nbsp;5&nbsp;mM). The K_i of the bis-oxime LG-703 for hAChE was 3.2-fold larger in 1&nbsp;% DMSO, consistent with direct competition between LG-703 and DMSO. The X-ray structure of the LG-703∗hAChE complex (PDB ID: 6U3P) shows DMSO and LG-703 bound to individual hAChE monomers, LG-703 in the chain A and DMSO in the chain B. In the co-crystallization both small molecules were present... https://escholarship.org/uc/item/0bd742kd Fri, 18 Jul 2025 00:00:00 +0000 Kolić, Dora Gerlits, Oksana Kucharski, Megan Gorecki, Lukas Joiner, Nichole Kovalevsky, Andrey Radić, Zoran https://escholarship.org/uc/item/4xx8p7nh Public untargeted metabolomics data is a growing resource for metabolite and phenotype discovery; however, accessing and utilizing these data across repositories pose significant challenges. Therefore, here we develop pan-repository universal identifiers and harmonized cross-repository metadata. This ecosystem facilitates discovery by integrating diverse data sources from public repositories including MetaboLights, Metabolomics Workbench, and GNPS/MassIVE. Our approach simplified data handling and unlocks previously inaccessible reanalysis workflows, fostering unmatched research opportunities. https://escholarship.org/uc/item/4xx8p7nh Tue, 15 Jul 2025 00:00:00 +0000 El Abiead, Yasin Strobel, Michael Payne, Thomas Fahy, Eoin O’Donovan, Claire Subramamiam, Shankar Vizcaíno, Juan Antonio Yurekten, Ozgur Deleray, Victoria Zuffa, Simone https://orcid.org/0000-0001-7237-3402 Xing, Shipei Mannochio-Russo, Helena Mohanty, Ipsita Zhao, Haoqi Nina Caraballo-Rodriguez, Andres M P. Gomes, Paulo Wender Avalon, Nicole E Northen, Trent R https://orcid.org/0000-0001-8404-3259 Bowen, Benjamin P https://orcid.org/0000-0003-1368-3958 Louie, Katherine B Dorrestein, Pieter C Wang, Mingxun https://orcid.org/0000-0001-7647-6097 https://escholarship.org/uc/item/92v7624z Maeda M., Humber D., Hida E., et al. (2024) Lower doses of carvedilol in Japanese heart failure patients with reduced ejection fraction could show the potential to be non-inferior to higher doses in US patients: An international collaborative observational study. PLoS ONE 19(3.0): e0299510. doi.org/10.1371/journal.pone.0299510. https://escholarship.org/uc/item/92v7624z Mon, 14 Jul 2025 00:00:00 +0000 Maeda, Makiko Humber, Douglas Hida, Eisuke Ohtani, Tomohito Wang, Guannan Wu, Tong Takeda, Shiori Situ, Jacinta N Hayashi, Jun Nonen, Shinpei Takeda, Toshihiro Okamoto, Hiroshi Hori, Masatsugu Sakata, Yasushi Fujio, Yasushi Tsunoda, Shirley M https://orcid.org/0000-0002-3974-8038 https://escholarship.org/uc/item/6kx2k27j Halogenated indole natural products have been isolated from a variety of organisms, including plants, marine algae, marine invertebrates, and bacteria. Aquatic cyanobacteria, in particular, are rich producers of brominated indoles, but their cognate biosynthetic enzymes have only been successfully linked in a limited number of natural products, such as the eagle-killing toxin aetokthonotoxin (AETX). The biosynthetic pathway for AETX involves five enzymes, two of which were previously undescribed due to incomplete annotations as hypothetical proteins. Our recent elucidation of AETX biosynthesis established functions of the two previously unknown proteins as enzymes responsible for tryptophan halogenation (AetF) and nitrile synthesis (AetD). Given their sequence novelty, we queried metagenomic data sets for these two enzymes and identified two new cyanobacterial haloindole biosynthetic gene clusters (BGCs) from marine sediment in Moorea, French Polynesia, and soil-derived samples... https://escholarship.org/uc/item/6kx2k27j Mon, 14 Jul 2025 00:00:00 +0000 Adak, Sanjoy Chase, Alexander B Skrip, Anna E Moore, Bradley S Lukowski, April L https://orcid.org/0000-0003-4865-0910 https://escholarship.org/uc/item/2cc4k1zt Thioesters, rather than oxo-esters, can be tolerated and processed during translation to incorporate unnatural monomers. https://escholarship.org/uc/item/2cc4k1zt Mon, 14 Jul 2025 00:00:00 +0000 Lukowski, April L https://orcid.org/0000-0003-4865-0910 https://escholarship.org/uc/item/2016221k Mammalian α-arrestins are members of the same arrestin family as the ubiquitously expressed and extensively studied β-arrestins. Arrestins share common structural elements, including the conserved N- and C-arrestin-fold domains, polar core, finger loop, and C-terminal tail, all of which mediate protein-protein interactions. In β-arrestins, these domains enable the control of G protein-coupled receptor (GPCR) signaling and scaffolding interactions with various signaling proteins including c-Src. By contrast, the repertoire of α-arrestin scaffolding partners and regulatory mechanisms that control their interactions are not well-understood. α-arrestins differ considerably from β-arrestins in the C-terminal region; β-arrestins contain clathrin adaptor β-adaptin-binding sites, whereas α-arrestins harbor PPxY motifs, demonstrated to interact with WW domains of E3 ubiquitin ligases such as WWP2. Here we report the identification of a novel phosphorylation site, tyrosine (Y) 394, embedded... https://escholarship.org/uc/item/2016221k Tue, 17 Jun 2025 00:00:00 +0000 Caplan, Mika Bardeleben, Carolyne Dhawan, Kanika https://orcid.org/0000-0002-6267-0312 Plawat, Rhea Kufareva, Irina https://orcid.org/0000-0001-9083-7039 Trejo, JoAnn https://orcid.org/0000-0003-4405-6228 https://escholarship.org/uc/item/0xd295q8 Given the current state of academic pharmacy, characterized by constrained resources and heightened expectations for curricular and professional excellence, institutions must strategically employ methods to enhance efficiency. Objective structured clinical examinations (OSCEs) are beneficial for assessing communication skills that are difficult to measure within traditional examinations; however, OSCEs are labor-intensive and costly to administer. In this commentary, we describe the context, process, successes, challenges, and best practices for inter-institutional collaborative OSCE development and implementation. Here we put forth a call to action to all institutions within the Academy to consider forming such collaboratives. https://escholarship.org/uc/item/0xd295q8 Thu, 5 Jun 2025 00:00:00 +0000 Lee, Kelly C https://orcid.org/0000-0002-1674-4210 Gruenberg, Katherine Namba, Jennifer M Valle-Oseguera, Cynthia S Awdishu, Linda https://orcid.org/0000-0002-3187-3264 Assemi, Mitra Corelli, Robin L Zhou, Crystal https://orcid.org/0000-0002-0763-0721 https://escholarship.org/uc/item/9kw4z90p Aetokthonotoxin (AETX) is a cyanobacterial neurotoxin that causes vacuolar myelinopathy, a neurological disease that is particularly deadly to bald eagles in the United States. The recently characterized AETX is structurally unique among cyanotoxins and is composed of a pentabrominated biindole nitrile. Herein we report the discovery of an efficient, five-enzyme biosynthetic pathway that the freshwater cyanobacterium <i>Aetokthonos hydrillicola</i> uses to convert two molecules of tryptophan to AETX. We demonstrate that the biosynthetic pathway follows a convergent route in which two functionalized indole monomers are assembled and then reunited by biaryl coupling catalyzed by the cytochrome P450 AetB. Our results revealed enzymes with novel biochemical functions, including the single-component flavin-dependent tryptophan halogenase AetF and the iron-dependent nitrile synthase AetD. https://escholarship.org/uc/item/9kw4z90p Thu, 22 May 2025 00:00:00 +0000 Adak, Sanjoy Lukowski, April L https://orcid.org/0000-0003-4865-0910 Schäfer, Rebecca JB Moore, Bradley S https://escholarship.org/uc/item/8qp1z8mk A conspicuous roadblock to studying marine bacteria for fundamental research and biotechnology is a lack of modular synthetic biology tools for their genetic manipulation. Here, we applied, and generated new parts for, a modular plasmid toolkit to study marine bacteria in the context of symbioses and host-microbe interactions. To demonstrate the utility of this plasmid system, we genetically manipulated the marine bacterium <i>Pseudoalteromonas luteoviolacea</i>, which stimulates the metamorphosis of the model tubeworm, <i>Hydroides elegans</i>. Using these tools, we quantified constitutive and native promoter expression, developed reporter strains that enable the imaging of host-bacteria interactions, and used CRISPR interference (CRISPRi) to knock down a secondary metabolite and a host-associated gene. We demonstrate the broader utility of this modular system for testing the genetic tractability of marine bacteria that are known to be associated with diverse host-microbe symbioses.... https://escholarship.org/uc/item/8qp1z8mk Thu, 22 May 2025 00:00:00 +0000 Alker, Amanda T Farrell, Morgan V Aspiras, Alpher E Dunbar, Tiffany L Fedoriouk, Andriy Jones, Jeffrey E Mikhail, Sama R Salcedo, Gabriella Y Moore, Bradley S Shikuma, Nicholas J https://escholarship.org/uc/item/73d22793 Reference genomes are key resources in biodiversity conservation. Yet, sequencing efforts are not evenly distributed across the tree of life raising concerns over our ability to enlighten conservation with genomic data. Good-quality reference genomes remain scarce in octocorals while these species are highly relevant targets for conservation. Here, we present the first annotated reference genome in the red coral, Corallium rubrum (Linnaeus, 1758), a habitat-forming octocoral from the Mediterranean and neighboring Atlantic, impacted by overharvesting and anthropogenic warming-induced mass mortality events. Combining long reads from Oxford Nanopore Technologies (ONT), Illumina paired-end reads for improving the base accuracy of the ONT-based genome assembly, and Arima Hi-C contact data to place the sequences into chromosomes, we assembled a genome of 532 Mb (20 chromosomes, 309 scaffolds) with contig and scaffold N50 of 1.6 and 18.5 Mb, respectively. Fifty percent of the sequence... https://escholarship.org/uc/item/73d22793 Thu, 22 May 2025 00:00:00 +0000 Ledoux, Jean-Baptiste Gomez-Garrido, Jessica Cruz, Fernando Ferreira, Francisco Camara Matos, Ana Sarropoulou, Xenia Ramirez-Calero, Sandra Aurelle, Didier Lopez-Sendino, Paula Grayson, Natalie E Moore, Bradley S Antunes, Agostinho Aguilera, Laura Gut, Marta Salces-Ortiz, Judit Fernández, Rosa Linares, Cristina Garrabou, Joaquim Alioto, Tyler https://escholarship.org/uc/item/6q92q256 The implementation of <i>ortho</i>-quinone methide (<i>o</i>-QM) intermediates in complex molecule assembly represents a remarkably efficient strategy designed by Nature and utilized by synthetic chemists. <i>o</i>-QMs have been taken advantage of in biomimetic syntheses for decades, yet relatively few examples of <i>o-</i>QM-generating enzymes in natural product biosynthetic pathways have been reported. The biosynthetic enzymes that have been discovered thus far exhibit tremendous potential for biocatalytic applications, enabling the selective production of desirable compounds that are otherwise intractable or inherently difficult to achieve by traditional synthetic methods. Characterization of this biosynthetic machinery has the potential to shine a light on new enzymes capable of similar chemistry on diverse substrates, thus expanding our knowledge of Nature's catalytic repertoire. The presently known <i>o</i>-QM-generating enzymes include flavin-dependent oxidases, hetero-Diels-Alderases,... https://escholarship.org/uc/item/6q92q256 Thu, 22 May 2025 00:00:00 +0000 Purdy, Trevor N Moore, Bradley S Lukowski, April L https://orcid.org/0000-0003-4865-0910 https://escholarship.org/uc/item/64n754hb Skatole is a pungent heterocyclic compound derived from the essential amino acid l-tryptophan by bacteria in the mammalian digestive tract. The four-step anaerobic conversion of tryptophan to skatole is well-established; though, to date, no aerobic counterpart has been reported. Herein, we report the discovery of the oxygen-dependent skatole synthase SktA that single-handedly converts 5-bromo-l-tryptophan to 5-bromoskatole, obviating the need for a multienzyme process. SktA is part of a three-gene biosynthetic gene cluster (BGC) in the cyanobacterium <i>Nostoc punctiforme</i> NIES-2108 and functions as a nonheme diiron enzyme belonging to the heme oxygenase-like domain-containing oxidase (HDO) superfamily. Our detailed biochemical analyses revealed cyanide and bicarbonate as biosynthetic coproducts, while stopped-flow experiments showed the hallmark formation of a substrate-triggered peroxo Fe₂(III) intermediate. Overall, this work unravels an alternative pathway for... https://escholarship.org/uc/item/64n754hb Thu, 22 May 2025 00:00:00 +0000 Adak, Sanjoy Calderone, Logan A Krueger, August Pandelia, Maria-Eirini Moore, Bradley S https://escholarship.org/uc/item/5v01x3kg Aromatic amines in nature are typically installed with Glu or Gln as the nitrogen donor. Here we report a pathway that features glycyl-tRNA instead. During the biosynthesis of pyrroloiminoquinone-type natural products such as ammosamides, peptide-aminoacyl tRNA ligases append amino acids to the C-terminus of a ribosomally synthesized peptide. First, AmmBCTrp$${\mathrm{Amm}}{{{\mathrm{B}}}}_{{{\mathrm{C}}}}^{{{{\mathrm{Trp}}}}}$$ adds Trp in a Trp-tRNA-dependent reaction and the flavoprotein AmmC1 then carries out three hydroxylations of the indole ring of Trp. After oxidation to the corresponding ortho-hydroxy para-quinone, AmmBDGly$${\mathrm{Amm}}{{{\mathrm{B}}}}_{{{\mathrm{D}}}}^{{{{\mathrm{Gly}}}}}$$ attaches Gly to the indole ring in a Gly-tRNA dependent fashion. Subsequent decarboxylation and hydrolysis results in an amino-substituted indole. Similar transformations are catalysed by orthologous enzymes from Bacillus halodurans. This pathway features three previously unknown... https://escholarship.org/uc/item/5v01x3kg Thu, 22 May 2025 00:00:00 +0000 Daniels, Page N Lee, Hyunji Splain, Rebecca A Ting, Chi P Zhu, Lingyang Zhao, Xiling Moore, Bradley S van der Donk, Wilfred A https://escholarship.org/uc/item/54r195h3 Isonitrile-containing natural products have garnered attention for their manifold bioactivities but are difficult to detect and isolate due to the chemical lability of the isonitrile functional group. Here, we used the isonitrile-chlorooxime ligation (INC) in a reactivity-based screening (RBS) protocol for the detection and isolation of alkaloid and terpene isonitriles in the cyanobacterium Fischerella ambigua and a marine sponge of the order Bubarida, respectively. A trifunctional probe bearing a chlorooxime moiety, a UV active aromatic moiety, and a bromine label facilitated the chemoselective reaction with isonitriles, UV-Vis spectroscopic detection, and mass spectrometric analysis. The INC-based RBS allowed for the detection, isolation, and structural elucidation of isonitriles in microgram quantities. https://escholarship.org/uc/item/54r195h3 Thu, 22 May 2025 00:00:00 +0000 Schäfer, Rebecca JB Wilson, Kayla Biedermann, Maurice Moore, Bradley S Sieber, Simon Wennemers, Helma https://escholarship.org/uc/item/4mn9v582 An important factor dictating coral fitness is the quality of bacteria associated with corals and coral reefs. One way that bacteria benefit corals is by stimulating the larval to juvenile life cycle transition of settlement and metamorphosis. Tetrabromopyrrole (TBP) is a small molecule produced by bacteria that stimulates metamorphosis with and without attachment in a range of coral species. A standing debate remains, however, about whether TBP biosynthesis from live Pseudoalteromonas bacteria is the primary stimulant of coral metamorphosis. In this study, we create a Pseudoalteromonas sp. PS5 mutant lacking the TBP brominase gene, bmp2. Using this mutant, we confirm that the bmp2 gene is critical for TBP biosynthesis in Pseudoalteromonas sp. PS5. Mutation of this gene ablates the bacterium's ability in live cultures to stimulate the metamorphosis of the stony coral Porites astreoides. We further demonstrate that expression of TBP biosynthesis genes is strongest in stationary... https://escholarship.org/uc/item/4mn9v582 Thu, 22 May 2025 00:00:00 +0000 Alker, Amanda T Farrell, Morgan V Demko, Alyssa M Purdy, Trevor N Adak, Sanjoy Moore, Bradley S Sneed, Jennifer M Paul, Valerie J Shikuma, Nicholas J https://escholarship.org/uc/item/3z70t67n Octocorals are the most prolific source of terpenoids in the marine environment, with more than 4000 different compounds known from the phylum to date. However, the biochemical and genetic origin of their production remained elusive until recent studies showed that octocorals encode genes responsible for the biosynthesis of terpenoids in their own chromosomal DNA rather than from microbial symbionts as originally proposed. The identified coral genes include those encoding a new group of class I terpene cyclases (TCs) clustered among other candidate classes of tailoring enzymes. Phylogenetic analyses established octocoral TCs as a monophyletic clade, distinct from TCs of plants, bacteria, and other organisms. The newly discovered group of TCs appears to be ubiquitous in octocorals and is evolutionarily ancient. Given the recent discovery of octocoral terpenoid biochemistry and only limited genomic data presently available, there is substantial potential for discovering new biosynthetic... https://escholarship.org/uc/item/3z70t67n Thu, 22 May 2025 00:00:00 +0000 Burkhardt, Immo https://orcid.org/0000-0001-9515-4042 Dürr, Lara Grayson, Natalie E Moore, Bradley S https://escholarship.org/uc/item/10m29501 Pseudoalteromonas luteoviolacea is a globally distributed marine bacterium that stimulates the metamorphosis of marine animal larvae, an important bacteria-animal interaction that can promote the recruitment of animals to benthic ecosystems. Recently, different P. luteoviolacea isolates have been shown to produce two stimulatory factors that can induce tubeworm and coral metamorphosis; Metamorphosis-Associated Contractile structures (MACs) and tetrabromopyrrole (TBP) respectively. However, it remains unclear what proportion of P. luteoviolacea isolates possess the genes encoding MACs, and what phenotypic effect MACs and TBP have on other larval species. Here, we show that 9 of 19 sequenced P. luteoviolacea genomes genetically encode both MACs and TBP. While P. luteoviolacea biofilms producing MACs stimulate the metamorphosis of the tubeworm Hydroides elegans, TBP biosynthesis genes had no effect under the conditions tested. Although MACs are lethal to larvae of the cnidarian Hydractinia... https://escholarship.org/uc/item/10m29501 Thu, 22 May 2025 00:00:00 +0000 Alker, Amanda T Delherbe, Nathalie Purdy, Trevor N Moore, Bradley S Shikuma, Nicholas J https://escholarship.org/uc/item/5nm6p2z4 CPNP 2019 Annual Meeting Poster Abstracts https://escholarship.org/uc/item/5nm6p2z4 Wed, 7 May 2025 00:00:00 +0000 https://escholarship.org/uc/item/6gr2x12g With diabetes reaching epidemic proportions globally, it is imperative to increase the number of providers equipped to screen, educate, and help patients achieve glycemic control. This study evaluated the long-term results of student pharmacists attending a first-year Diabetes Self-Care Education Program (DSEP) by measuring knowledge retention, confidence, and clinical applicability of skills learned over time. The DSEP, integrated into the early pharmacy curriculum, is a 9-h training program made up of interactive lectures, glucose monitoring assignments, and active-learning workshops. Following DSEP training, two cohorts of first-year student pharmacists were surveyed annually for 3 and 5 years to assess knowledge retention, confidence, and clinical use of the DSEP content in their practice sites. By the year 1 follow-up survey, the response rate from the pre-survey period for cohort 1 was 88% and 78% for cohort 2; over time, the response rate decreased. For the long-term follow-up... https://escholarship.org/uc/item/6gr2x12g Fri, 18 Apr 2025 00:00:00 +0000 Morello, Candis Fricovsky, Eduardo https://escholarship.org/uc/item/34g7130m BACKGROUND: Long-acting injectable cabotegravir and rilpivirine have demonstrated safety, acceptability, and efficacy in adults living with HIV-1. The IMPAACT 2017 study (MOCHA study) was the first to use these injectable formulations in adolescents (aged 12-17 years) living with HIV-1. Herein, we report acceptability and tolerability outcomes in cohort 1 of the study. METHODS: In this a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study, with continuation of pre-study oral combination antiretroviral treatment (ART), 55 adolescents living with HIV-1 were enrolled to receive sequential doses of either long-acting cabotegravir or rilpivirine and 52 received at least two injections. Participants had a body weight greater than 35 kg and BMI less than 31·5 kg/m² and had been on stable ART for at least 90 consecutive days with an HIV-1 viral load of less than 50 copies per mL at a participating IMPAACT study site. Participants had... https://escholarship.org/uc/item/34g7130m Wed, 16 Apr 2025 00:00:00 +0000 Lowenthal, Elizabeth D Chapman, Jennifer Ohrenschall, Rachel Calabrese, Katherine Baltrusaitis, Kristin Heckman, Barbara Yin, Dwight E Agwu, Allison L Harrington, Conn Van Solingen-Ristea, Rodica M McCoig, Cynthia C Adeyeye, Adeola Kneebone, Jared Chounta, Vasiliki Smith-Anderson, Christiana Camacho-Gonzalez, Andres D'Angelo, Jessica Bearden, Allison Crauwels, Herta Huang, Jenny Buisson, Sarah Milligan, Ryan Ward, Shawn Bolton-Moore, Carolyn Gaur, Aditya H Collaborators, IMPAACT 2017 Best, Brookie M https://orcid.org/0000-0001-8569-2293 Capparelli, Edmund V Hanley, Sherika Mathiba, Sisinyana Ruth Naidoo, Megeshinee Ounchanum, Pradthana Patel, Faeezah Paul, Mary E Townley, Ellen Vandermeulen, Kati Whitson, Kyle Zabih, Sara Team, IMPAACT 2017 https://escholarship.org/uc/item/2nx4k31h OBJECTIVE: The diagnoses included within the umbrella term fetal alcohol spectrum disorders (FASD), are based on the documentation of prenatal alcohol exposure (PAE), growth deficits and a pattern of dysmorphic physical features and neurobehavioral impairments. Although 3 key facial features (short palpebral fissures, a smooth philtrum and a thin vermilion of the upper lip) are the only dysmorphic features taken into account for the diagnosis of Fetal Alcohol Syndrome (FAS) or partial FAS (pFAS), several other features are commonly seen in individuals with these diagnoses. The goals of our study were to determine if some of these secondary physical features also occur more frequently in children with alcohol-related neurodevelopmental disorder (ARND) relative to controls, and if a cluster of these features combined in a dysmorphology score could be used to identify those negatively impacted by PAE but who do not have the cardinal physical features that led to a diagnosis of FAS... https://escholarship.org/uc/item/2nx4k31h Tue, 15 Apr 2025 00:00:00 +0000 Del Campo, Miguel Kable, Julie Coles, Claire Suttie, Michael Chambers, Christina Bandoli, Gretchen https://escholarship.org/uc/item/8kk2802g BACKGROUND: Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents. METHODS: In this phase 1/2, multicentre, open-label, non-comparative, dose-finding study, virologically suppressed adolescents (aged 12-17 years; weight ≥35 kg; BMI ≤31·5 kg/m²) with HIV-1 on daily oral ART were enrolled at 15 centres in four countries (Botswana, South Africa, Thailand, and the USA). After 4-6 weeks of oral cabotegravir (cohort 1C) or rilpivirine (cohort 1R), participants received intramuscular long-acting cabotegravir or long-acting rilpivirine every 4 weeks or 8 weeks per the adult dosing regimens, while continuing pre-study ART. The primary outcomes were assessments of safety measures, including... https://escholarship.org/uc/item/8kk2802g Sat, 12 Apr 2025 00:00:00 +0000 Gaur, Aditya H Capparelli, Edmund V Calabrese, Katherine Baltrusaitis, Kristin Marzinke, Mark A McCoig, Cynthia Van Solingen-Ristea, Rodica M Mathiba, Sisinyana Ruth Adeyeye, Adeola Moye, John H Heckman, Barbara Lowenthal, Elizabeth D Ward, Shawn Milligan, Ryan Samson, Pearl Best, Brookie M https://orcid.org/0000-0001-8569-2293 Harrington, Conn M Ford, Susan L Huang, Jenny Crauwels, Herta Vandermeulen, Kati Agwu, Allison L Smith-Anderson, Christiana Camacho-Gonzalez, Andres Ounchanum, Pradthana Kneebone, Jared L Townley, Ellen Moore, Carolyn Bolton Collaborators, IMPAACT 2017 Team, IMPAACT 2017 Buisson, Sarah Cheung, SY Amy Chounta, Vasiliki Deprez, Isabelle Desmond, Alicia Catherine Han, Kelong Hanley, Sherika Lin, Yu-Wei Patel, Faeezah Paul, Mary E Roberts, Gilly Whitson, Kyle Zabih, Sara https://escholarship.org/uc/item/75r2h2ww Recent analyses of genome data indicate that members of the cyanobacterial order Pleurocapsales show tremendous potential for natural product discovery. However, only a few compounds have been reported from this order. Here, we report the isolation of hyellamide (<b>1</b>), a glycosylated N-acyl tyrosine-derived eneamide, from the pleurocapsalean cyanobacterium <i>Hyella patelloides</i> LEGE 07179. The putative biosynthetic gene cluster for <b>1</b> was identified in the genome of the producing organism and a biosynthetic proposal is presented. This work sheds light on the chemistry of the Pleurocapsales and expands the chemical repertoire of cyanobacterial natural products to include N-acyl tyrosine-derived molecules. https://escholarship.org/uc/item/75r2h2ww Sat, 12 Apr 2025 00:00:00 +0000 Brito, Ângela Martins, Teresa Freitas, Sara Branco, Raquel Castelo Rego, Adriana Vasconcelos, Vitor M Gerwick, William H https://orcid.org/0000-0003-1403-4458 Tamagnini, Paula Leão, Pedro N https://escholarship.org/uc/item/6x35f7gz IntroductionThis study compared the calculated vancomycin area under the curve (AUC0–24)&nbsp;using trapezoidal and non-trapezoidal first-order pharmacokinetic equations.MethodsThis retrospective observational study included adult patients with documented MRSA bacteremia who received ≥ 48 h of intravenous vancomycin and had two consecutive serum levels after the first dose. AUC0–24 was calculated using trapezoidal and non-trapezoidal equations. Correlation and agreement between methods were assessed using Pearson’s correlation coefficient (r) and Bland–Altman plots. Significant predictors (p &lt; 0.05) from simple linear regression were included in a multiple linear regression model to evaluate their impact on AUC0–24 for both methods.ResultsFifty-two patients were included. The median age was 63 years (interquartile range [IQR]: 50–73), and the median vancomycin clearance was 4 l/h (IQR: 2–6). Median vancomycin AUC0-24 was 399 mg∙h/l (IQR: 257–674) for the trapezoidal method... https://escholarship.org/uc/item/6x35f7gz Sat, 12 Apr 2025 00:00:00 +0000 Msdi, Abdulwhab Shremo Ravari, Alireza Fakhri Abdul-Mutakabbir, Jacinda C https://orcid.org/0000-0003-4162-6408 Tan, Karen K https://escholarship.org/uc/item/39x597n8 Cathepsin B has been shown to contribute to deficits in traumatic brain injury (TBI), an important risk factor for Alzheimer's disease (AD). Cathepsin B is elevated in TBI and AD patients, as well as in animal models of these conditions. Knockout of the cathepsin B gene results in amelioration of TBI-induced motor dysfunction and improvement of AD memory deficit in mice. The mechanism of cathepsin B pathogenesis in these brain disorders has been hypothesized to involve its translocation to the cytosol from its normal lysosomal location. This study, therefore, evaluated brain cytosolic cathepsin B activity in the controlled cortical impact (CCI) mouse model of TBI. CCI-TBI resulted in motor deficits demonstrated by the rotarod assay, brain tissue lesions, and disorganization of the hippocampus. Significantly, CCI-TBI increased cytosolic cathepsin B activity in the brain cortex in the ipsilateral brain hemisphere that received the CCI-TBI injury, with a concomitant decrease in the... https://escholarship.org/uc/item/39x597n8 Sat, 12 Apr 2025 00:00:00 +0000 Podvin, Sonia Florio, Jazmin Spencer, Brian Mante, Michael Guzman, Estefani Arias, Carlos Mosier, Charles Phan, Von V Yoon, Michael C https://orcid.org/0000-0002-2900-5257 Almaliti, Jehad O’Donoghue, Anthony J Gerwick, William H https://orcid.org/0000-0003-1403-4458 Rissman, Robert A Hook, Vivian https://escholarship.org/uc/item/65f2c8cb Untargeted metabolomics often produce large datasets with missing values. These missing values are derived from biological or technical factors and can undermine statistical analyses and lead to biased biological interpretations. Imputation methods, such as <i>k</i>-Nearest Neighbors (kNN) and Random Forest (RF) regression, are commonly used, but their effects vary depending on the type of missing data, e.g., Missing Completely At Random (MCAR) and Missing Not At Random (MNAR). Here, we determined the impacts of degree and type of missing data on the accuracy of kNN and RF imputation using two datasets: a targeted metabolomic dataset with spiked-in standards and an untargeted metabolomic dataset. We also assessed the effect of compositional data approaches (CoDA), such as the centered log-ratio (CLR) transform, on data interpretation since these methods are increasingly being used in metabolomics. Overall, we found that kNN and RF performed more accurately when the proportion... https://escholarship.org/uc/item/65f2c8cb Fri, 11 Apr 2025 00:00:00 +0000 Krutkin, Dennis D Thomas, Sydney Zuffa, Simone https://orcid.org/0000-0001-7237-3402 Rajkumar, Prajit Knight, Rob https://orcid.org/0000-0002-0975-9019 Dorrestein, Pieter C Kelley, Scott T https://escholarship.org/uc/item/26b21692 OBJECTIVES: To define meropenem plasma concentrations and pharmacodynamic exposure metrics in children with septic shock during the first 3 days of PICU hospitalization. DESIGN: Pharmacokinetic sampling was undertaken in 19 subjects receiving standard meropenem dosing (20 mg/kg/dose, 8 hr) recruited from March 2019 to March 2022. Sampling occurred once each day following meropenem given 24 hours apart, during the first 3 PICU days. Data analysis was completed in 2023 and noncompartmental analysis was performed to assess pharmacodynamic exposure targets for sepsis. Clearance and volume of distribution at 20 mg/kg/dose were used to simulate mean exposures at 40 and 60 mg/kg/dose. SETTING: PICU in a tertiary care center. SUBJECTS: Patients 4 weeks old or older with hypotension requiring fluid resuscitation and vasopressor therapy, receiving meropenem as empiric therapy for sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Augmented renal clearance (ARC) was documented in... https://escholarship.org/uc/item/26b21692 Fri, 11 Apr 2025 00:00:00 +0000 Bradley, John S https://orcid.org/0000-0002-3835-5064 Harvey, Helen Stout, Dayna Momper, Jeremiah Capparelli, Edmund Avedissian, Sean N Barbato, Courtney Mak, Robert H Jones, Tom P Jones, Douglas Le, Jennifer https://orcid.org/0000-0002-6692-0884 https://escholarship.org/uc/item/5gn5w6d6 OBJECTIVES: Health economic models are crucial for health technology assessments to evaluate the value of medical interventions. Open-source models (OSMs), in which source code and calculations are publicly accessible, enhance transparency, efficiency, credibility, and reproducibility. This study systematically reviewed databases to map the landscape of available OSMs in health economics. METHODS: A systematic database review was conducted, informed by guidance from ISPOR's OSM Special Interest Group. Eleven databases and specific OSM repositories were searched using predefined terms. Identified models were screened and duplicates were removed. RESULTS: The search yielded 8664 hits, resulting in 182 unique OSMs. GitHub hosted the majority (74%), followed by Zenodo (11%). R was the predominant software platform (64%). Infectious disease was the most common application domain (29%). Markov models were the most frequent model type (49%). Licensing with Creative Commons was typical.... https://escholarship.org/uc/item/5gn5w6d6 Thu, 10 Apr 2025 00:00:00 +0000 Henderson, Raymond H Sampson, Chris Pouwels, Xavier GLV Harvard, Stephanie Handels, Ron Feenstra, Talitha Bhandari, Ramesh Sepassi, Aryana https://orcid.org/0000-0003-0149-7824 Arnold, Renée https://escholarship.org/uc/item/5359r5jh Abstract: Background: Studies using Alzheimer’s disease (AD) models suggest that gut bacteria contribute to amyloid pathology and systemic inflammation. Further, gut‐derived metabolites serve critical roles in regulating cholesterol, blood‐brain barrier permeability, neuroinflammation, and circadian rhythms. Recent studies from the Alzheimer’s Disease Neuroimaging Initiative have shown that serum‐based gut‐derived metabolites are associated with AD biomarkers and cognitive impairment. We recently reported a time‐restricted feeding (TRF) intervention that restored brain transcription, increased Aβ clearance, reduced amyloid deposition, and improved memory deficits in AD mice (PMID:37607543). Here we investigated gut microbiome alterations in the APP23 mouse stool and terminal ileum and evaluated the role of the microbiome and metabolome in the beneficial effects of TRF. Methods: Adult male and female APP23 transgenic (TG) and littermate non‐transgenic (NTG) mice (n = 3‐4/sex/genotype/condition)... https://escholarship.org/uc/item/5359r5jh Thu, 10 Apr 2025 00:00:00 +0000 Whittaker, Daniel S https://orcid.org/0000-0002-4293-5192 Maissy, Erica S Richter, R Alexander Zuffa, Simone https://orcid.org/0000-0001-7237-3402 Ramos, Stephany Z Flores Zarrinpar, Amir https://orcid.org/0000-0001-6423-5982 Desplats, Paula https://orcid.org/0000-0002-4758-4280 https://escholarship.org/uc/item/4j94r18x Discovery of metabolites prevails amid in-source fragmentation https://escholarship.org/uc/item/4j94r18x Thu, 10 Apr 2025 00:00:00 +0000 El Abiead, Yasin Rutz, Adriano Zuffa, Simone https://orcid.org/0000-0001-7237-3402 Amer, Bashar Xing, Shipei https://orcid.org/0000-0001-6227-6959 Brungs, Corinna Schmid, Robin Correia, Mario SP Caraballo-Rodriguez, Andres Mauricio Zarrinpar, Amir https://orcid.org/0000-0001-6423-5982 Mannochio-Russo, Helena Witting, Michael Mohanty, Ipsita Pluskal, Tomáš Bittremieux, Wout Knight, Rob Patterson, Andrew D van der Hooft, Justin JJ Böcker, Sebastian Dunn, Warwick B Linington, Roger G Wishart, David S Wolfender, Jean-Luc Fiehn, Oliver https://orcid.org/0000-0002-6261-8928 Zamboni, Nicola Dorrestein, Pieter C https://escholarship.org/uc/item/07j2053m Herein we report the finding and structure determination of a natural product based on the methyldeoxaphomin scaffold family from the fungus <i>Trichocladium asperum</i> that shows promising antiplasmodial activity and selectivity against host cells. In vitro evolution and whole genome analysis in <i>Plasmodium falciparum</i> with the most potent member, NPDG-F (EC₅₀ of 550 nM in Dd2; 290 nM in 3D7), shows that parasite resistance to methyldeoxaphomins is strongly associated with mutations in PfActin1 (PF3D7_1246200), a critically essential ATPase needed for all stages of parasite development. Molecular docking study with available PfActin1 crystal structure shows NPDG-F occupies the same allosteric binding pocket as the known actin inhibitor cytochalasin D. The direct PfActin1 target engagement in the allosteric site was supported by cross-resistance studies, isobologram analysis with other PfActin1 inhibitors, and the structure-activity relationships for the methyldeoxaphomin... https://escholarship.org/uc/item/07j2053m Mon, 7 Apr 2025 00:00:00 +0000 Jiang, Tiantian Lee, Jin Woo Collins, Jennifer E Schaefer, Samuel Chen, Daisy Nardella, Flore Wendt, Karen Peramuna, Thilini G Paes, Raphaella McLellan, James L Bhasin, Jasveen Durst, Gregory L Hanson, Kirsten K Chakrabarti, Debopam Cichewicz, Robert H Winzeler, Elizabeth A https://orcid.org/0000-0002-4049-2113 https://escholarship.org/uc/item/19n7p7ns Identification of novel drug targets is a key component of modern drug discovery. While antimalarial targets are often identified through the mechanism of action studies on phenotypically derived inhibitors, this method tends to be time- and resource-consuming. The discoverable target space is also constrained by existing compound libraries and phenotypic assay conditions. Leveraging recent advances in protein structure prediction, we systematically assessed the Plasmodium falciparum genome and identified 867 candidate protein targets with evidence of small-molecule binding and blood-stage essentiality. Of these, 540 proteins showed strong essentiality evidence and lack inhibitors that have progressed to clinical trials. Expert review and rubric-based scoring of this subset based on additional criteria such as selectivity, structural information, and assay developability yielded 27 high-priority antimalarial target candidates. This study also provides a genome-wide data resource... https://escholarship.org/uc/item/19n7p7ns Fri, 4 Apr 2025 00:00:00 +0000 Godinez-Macias, Karla P Chen, Daisy Wallis, J Lincoln Siegel, Miles G Adam, Anna Bopp, Selina Carolino, Krypton Coulson, Lauren B Durst, Greg Thathy, Vandana Esherick, Lisl Farringer, Madeline A Flannery, Erika L Forte, Barbara Liu, Tiqing Godoy Magalhaes, Luma Gupta, Anil K Istvan, Eva S Jiang, Tiantian Kumpornsin, Krittikorn Lobb, Karen McLean, Kyle J Moura, Igor MR Okombo, John Payne, N Connor Plater, Andrew Rao, Srinivasa PS Siqueira-Neto, Jair L Somsen, Bente A Summers, Robert L Zhang, Rumin Gilson, Michael K Gamo, Francisco-Javier Campo, Brice Baragaña, Beatriz Duffy, James Gilbert, Ian H Lukens, Amanda K Dechering, Koen J Niles, Jacquin C McNamara, Case W Cheng, Xiu Birkholtz, Lyn-Marie Bronkhorst, Alfred W Fidock, David A Wirth, Dyann F Goldberg, Daniel E Lee, Marcus CS Winzeler, Elizabeth A https://orcid.org/0000-0002-4049-2113 https://escholarship.org/uc/item/95c0t4q7 Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia/hypercapnia (IHC), affects predominantly obese individuals, and increases atherosclerosis risk. Since we and others have implicated gut microbiota and metabolites in atherogenesis, we dissected their contributions to OSA-induced atherosclerosis. Atherosclerotic lesions were compared between conventionally-reared specific pathogen free (SPF) and germ-free (GF) Apoe^-/- mice following a high fat high cholesterol diet (HFHC), with and without IHC conditions. The fecal microbiota and metabolome were profiled using 16S rRNA gene amplicon sequencing and untargeted tandem mass spectrometry (LC-MS/MS) respectively. Phenotypic data showed that HFHC significantly increased atherosclerosis as compared to regular chow (RC) in both aorta and pulmonary artery (PA) of SPF mice. IHC exacerbated lesions in addition to HFHC. Differential abundance analysis of gut microbiota identified an enrichment of Akkermansiaceae... https://escholarship.org/uc/item/95c0t4q7 Thu, 3 Apr 2025 00:00:00 +0000 Xue, Jin Allaband, Celeste Zuffa, Simone https://orcid.org/0000-0001-7237-3402 Poulsen, Orit Meadows, Jason Zhou, Dan Dorrestein, Pieter C Knight, Rob https://orcid.org/0000-0002-0975-9019 Haddad, Gabriel G https://escholarship.org/uc/item/7rd6j35k Transcription-coupled repair (TCR) is a vital nucleotide excision repair sub-pathway that removes DNA lesions from actively transcribed DNA strands. Binding of CSB to lesion-stalled RNA Polymerase II (Pol II) initiates TCR by triggering the recruitment of downstream repair factors. Yet it remains unknown how transcription factor IIH (TFIIH) is recruited to the intact TCR complex. Combining existing structural data with AlphaFold predictions, we build an integrative model of the initial TFIIH-bound TCR complex. We show how TFIIH can be first recruited in an open repair-inhibited conformation, which requires subsequent CAK module removal and conformational closure to process damaged DNA. In our model, CSB, CSA, UVSSA, elongation factor 1 (ELOF1), and specific Pol II and UVSSA-bound ubiquitin moieties come together to provide interaction interfaces needed for TFIIH recruitment. STK19 acts as a linchpin of the assembly, orienting the incoming TFIIH and bridging Pol II to core TCR... https://escholarship.org/uc/item/7rd6j35k Thu, 3 Apr 2025 00:00:00 +0000 Paul, Tanmoy Yan, Chunli Yu, Jina Tsutakawa, Susan E https://orcid.org/0000-0002-4918-4571 Tainer, John A Wang, Dong https://orcid.org/0000-0002-2829-1546 Ivanov, Ivaylo https://escholarship.org/uc/item/6t68006h Ergosterol biosynthesis inhibitors, such as posaconazole and ravuconazole, have been proposed as drug candidates for Chagas disease, a neglected infectious tropical disease caused by the protozoan parasite Trypanosoma cruzi. To understand better the mechanism of action and resistance to these inhibitors, a clone of the T. cruzi Y strain was cultured under intermittent and increasing concentrations of ravuconazole until phenotypic stability was achieved. The ravuconazole-selected clone exhibited loss in fitness in vitro when compared to the wild-type parental clone, as observed in reduced invasion capacity and slowed population growth in both mammalian and insect stages of the parasite. In drug activity assays, the resistant clone was above 300-fold more tolerant to ravuconazole than the sensitive parental clone, when the half-maximum effective concentration (EC₅₀) was considered. The resistant clones also showed reduced virulence in vivo, when compared to parental sensitive... https://escholarship.org/uc/item/6t68006h Thu, 3 Apr 2025 00:00:00 +0000 Franco, Caio H Warhurst, David C Bhattacharyya, Tapan Au, Ho YA Le, Hai Giardini, Miriam A https://orcid.org/0000-0002-6510-2409 Pascoalino, Bruno S Torrecilhas, Ana Claudia Romera, Lavinia MD Madeira, Rafael Pedro Schenkman, Sergio Freitas-Junior, Lucio H Chatelain, Eric Miles, Michael A Moraes, Carolina B https://escholarship.org/uc/item/95w9z7jw Untargeted metabolomics is frequently performed on human fecal samples in conjunction with sequencing to unravel the gut microbiome functionality. As sample collection efforts are rapidly expanding, with individuals often collecting specimens at home, metabolomics experiments should adapt to accommodate the safety and needs of bulk off-site collections and improve high throughput. Here, we show that a 95% ethanol, safe to be shipped and handled, extraction part of the Matrix Method pipeline recovers comparable amounts of metabolites as a validated 50% methanol extraction, preserving metabolic profile differences between investigated subjects. Additionally, we show that the fecal metabolome remains relatively stable when stored in 95% ethanol for up to 1 week at room temperature. Finally, we suggest a metabolomics data analysis workflow based on robust centered log ratio transformation, which removes the variance introduced by possible different sample weights and concentrations,... https://escholarship.org/uc/item/95w9z7jw Wed, 2 Apr 2025 00:00:00 +0000 Zuffa, Simone https://orcid.org/0000-0001-7237-3402 Charron-Lamoureux, Vincent Brennan, Caitriona Ambre, Madison Knight, Rob https://orcid.org/0000-0002-0975-9019 Dorrestein, Pieter C https://escholarship.org/uc/item/8hn6w75m BackgroundOpioid users across federal poverty levels have varying healthcare consumption, which could influence public health policies to address the opioid crisis. To better understand this relationship, we evaluated the associations between federal poverty level (FPL) with healthcare costs and utilizations among adult opioid users in the United States (US).MethodsA serial cross-sectional study using pooled data (2008–2019) from the Medical Expenditure Panel Survey (MEPS) was used to evaluate the association between FPL with healthcare expenditures among a representative sample of the US adult population with &gt; = 1 opioid prescription. FPL was defined as Poor/Near Poor-Income, Low-Income, Middle-Income, and High-Income. Healthcare expenditures included costs and resource utilization. Survey weights were applied to generate standard errors for the representative sample of the US population. Generalized linear models were constructed to evaluate the association between FPL and... https://escholarship.org/uc/item/8hn6w75m Wed, 2 Apr 2025 00:00:00 +0000 Bounthavong, Mark https://orcid.org/0000-0002-7343-9458 Suh, Kangho Sepassi, Aryana https://orcid.org/0000-0003-0149-7824 Stottlemyer, Britney Spoutz, Patrick Hart, Laura Li, Meng https://escholarship.org/uc/item/3kz7w1wk BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) recently announced the Maximum Fair Price for the first 10 Medicare Part D drugs selected for price negotiation. By February 2025, CMS should announce the list of Part D drugs to be negotiated with implementation of the negotiated prices in 2027. OBJECTIVE: To identify up to 15 Medicare Part D single-source drugs anticipated to be selected by CMS for price negotiation in 2025. METHODS: We followed selection criteria identified in the Inflation Reduction Act and CMS guidance to identify drugs. We projected 2023 Part D gross spending using 2020-2022 data reported by CMS and linear prediction models. We ranked products according to the projected spending figure and identified those not eligible for selection because of (1) number of years since approval, (2) availability of a biosimilar or generic version, (3) approval for a single orphan indication, (4) whole human blood or plasma-derived, or (5) eligibility for the... https://escholarship.org/uc/item/3kz7w1wk Wed, 2 Apr 2025 00:00:00 +0000 Cousin, Emma M Sullivan, Sean D Hansen, Ryan N Gabriel, Nico Kirihennedige, Ayuri S Hernandez, Inmaculada https://escholarship.org/uc/item/32x6223r The configurational analysis of amino acids (AAs) in natural product peptides, often containing nonproteinogenic AAs, is mostly carried out by the venerable Marfey's method using a chiral derivatizing agent (CDA) 1-fluoro-2,4-dinitrophenyl-5-l-alaninamide (l-FDAA)─Marfey's reagent─which undergoes <i>S</i>_NAr reaction of the 1° amino group. The resulting AA-DAA derivatives are mostly well-separated by reversed-phase HPLC, but some DAA derivatives resist resolution. Here, we report the synthesis and characterization of two CDAs: l-FDTA (<b>4</b>) in which the l-alanine-derived auxiliary is replaced by l-tryptophanamide and (<i>S</i>)-FDNE (<b>3</b>) where the auxiliary is <i>S</i>-(6-methoxynaphth-2-yl)-1-ethylamine. Side-by-side comparisons of the two reagents were carried out by AA derivatization and reversed-phase HPLC analysis with variables such as organic solvent, additives, and the ionic strength of the mobile phase. l-DTA derivatives of l- and d-AAs were found... https://escholarship.org/uc/item/32x6223r Wed, 2 Apr 2025 00:00:00 +0000 Salib, Mariam N Molinski, Tadeusz F https://orcid.org/0000-0003-1935-2535 https://escholarship.org/uc/item/9pr723cz The blood-brain barrier (BBB) constitutes a crucial protective anatomical layer with a microenvironment that tightly controls material transit. Constructing an in vitro BBB model to replicate in vivo features requires the sequential layering of constituent cell types. Maintaining heightened integrity in the observed tight junctions during both the establishment and post-experiment phases is crucial to the success of these models. We have developed an in vitro BBB model that replicates the cellular composition and spatial orientation of in vivo BBB observed in humans. The experiment includes comprehensive procedures and steps aimed at enhancing the integration of the four-cell model. Departing from conventional in vitro BBB models, our methodology eliminates the necessity for pre-coated plates to facilitate cell adhesion, thereby improving cell visualization throughout the procedure. An in-house coating strategy and a simple yet effective approach significantly reduce costs and... https://escholarship.org/uc/item/9pr723cz Tue, 1 Apr 2025 00:00:00 +0000 Malik, Johid R Modebelu, Ukamaka O Fletcher, Courtney V Podany, Anthony T Scarsi, Kimberly K Byrareddy, Siddappa N Anand, Robbyn K Buch, Shilpa Sil, Susmia Le, Jennifer https://orcid.org/0000-0002-6692-0884 Bradley, John S Brown, Ashley N Sutar, Debapriya Avedissian, Sean N https://escholarship.org/uc/item/835250wg BACKGROUND: Pediatric brain tumors (PBT) stand as the leading cause of cancer-related deaths in children. Chemoradiation protocols have improved survival rates, even for non-resectable tumors. Nonetheless, radiation therapy carries the risk of numerous adverse effects that can have long-lasting, detrimental effects on the quality of life for survivors. The pursuit of chemotherapeutics that could obviate the need for radiotherapy remains ongoing. Several anti-tumor agents, including sunitinib, valproic acid, carboplatin, and panobinostat, have shown effectiveness in various malignancies but have not proven effective in treating PBT. The presence of the blood-brain barrier (BBB) plays a pivotal role in maintaining suboptimal concentrations of anti-cancer drugs in the central nervous system (CNS). Ongoing research aims to modulate the integrity of the BBB to attain clinically effective drug concentrations in the CNS. However, current findings on the interaction of exogenous chemical... https://escholarship.org/uc/item/835250wg Tue, 1 Apr 2025 00:00:00 +0000 Malik, Johid Reza Podany, Anthony T Khan, Parvez Shaffer, Christopher L Siddiqui, Jawed A Baranowska‐Kortylewicz, Janina Le, Jennifer https://orcid.org/0000-0002-6692-0884 Fletcher, Courtney V Ether, Sadia Afruz Avedissian, Sean N https://escholarship.org/uc/item/7bc8f0sj Neglected tropical diseases such as Chagas disease, human African trypanosomiasis, leishmaniasis, and schistosomiasis have a significant global health impact in predominantly developing countries, although these diseases are spreading due to increased international travel and population migration. Drug repurposing with a focus on increasing antiparasitic potency and drug-like properties is a cost-effective and efficient route to the development of new therapies. Here we identify compounds that have potent activity against <i>Trypanosoma cruzi</i> and <i>Leishmania donovani</i>, and the latter were progressed into the murine model of infection. Despite the potent <i>in vitro</i> activity, there was no effect on parasitemia, necessitating further work to improve the pharmacokinetic properties of this series. Nonetheless, valuable insights have been obtained into the structure-activity and structure-property relationships of this compound series. https://escholarship.org/uc/item/7bc8f0sj Tue, 1 Apr 2025 00:00:00 +0000 Spaulding, Andrew Sharma, Amrita Giardini, Miriam A https://orcid.org/0000-0002-6510-2409 Hoffman, Benjamin Bernatchez, Jean A McCall, Laura-Isobel Calvet, Claudia M Ackermann, Jasmin Souza, Julia M Thomas, Diane Millard, Caroline C Devine, William G Singh, Baljinder Silva, Everton M Leed, Susan E Roncal, Norma E Penn, Erica C Erath, Jessey Kumar, Gaurav Sepulveda, Yadira Garcia, Arnold Rodriguez, Ana El-Sakkary, Nelly Sciotti, Richard J Campbell, Robert F Momper, Jeremiah D McKerrow, James H Caffrey, Conor R Siqueira-Neto, Jair L Pollastri, Michael P Mensa-Wilmot, Kojo Ferrins, Lori https://escholarship.org/uc/item/6p8832td PURPOSE: Administrative data sources are used to describe the epidemiology of chronic hypertension in pregnancy and its consequences. Differences in identification across sources may affect research estimates. We compared identification of chronic hypertension in birth certificate records, hospital discharge records, and Medi-Cal claims in the same individuals. METHODS: We used data from 820 140 2016-2020 California Medi-Cal covered births. We identified chronic hypertension on birth certificates using the prepregnancy hypertension check box and in hospital discharge records and Medi-Cal claims using ICD codes. We compared the prevalence of chronic hypertension and identified predictors of agreement. We also compared absolute and relative estimates of racial/ethnic disparities in chronic hypertension and associations with neonatal outcomes. RESULTS: The prevalence of chronic hypertension was 0.7% in birth records, 2.1% in hospital discharge records, and 3.9% in Medi-Cal claims.... https://escholarship.org/uc/item/6p8832td Tue, 1 Apr 2025 00:00:00 +0000 Delker, Erin Baer, Rebecca J https://orcid.org/0000-0001-8485-1977 Chambers, Christina D https://orcid.org/0000-0003-4675-7722 Bandoli, Gretchen https://orcid.org/0000-0003-2167-8921 https://escholarship.org/uc/item/1hz2h28b Tissue-selective chemoattractants direct lymphocytes to epithelial surfaces to establish local immune environments, regulate immune responses to food antigens and commensal organisms, and protect from pathogens. Homeostatic chemoattractants for small intestines, colon and skin are known1,2, but chemotropic mechanisms selective for respiratory tract and other non-intestinal mucosal tissues remain poorly understood. Here we leveraged diverse omics datasets to identify GPR25 as a lymphocyte receptor for CXCL17, a chemoattractant cytokine whose expression by epithelial cells of airways, upper gastrointestinal and squamous mucosae unifies the non-intestinal mucosal tissues and distinguishes them from intestinal mucosae. Single-cell transcriptomic analyses show that GPR25 is induced on innate lymphocytes before emigration to the periphery, and is imprinted in secondary lymphoid tissues on activated B and T cells responding to immune challenge. GPR25 characterizes B and T tissue resident... https://escholarship.org/uc/item/1hz2h28b Tue, 1 Apr 2025 00:00:00 +0000 Ocón, Borja Xiang, Menglan https://orcid.org/0000-0003-4234-4998 Bi, Yuhan Tan, Serena Brulois, Kevin Ayesha, Aiman Kunte, Manali Zhou, Catherine LaJevic, Melissa Lazarus, Nicole Mengoni, Francesca Sharma, Tanya Montgomery, Stephen Hooper, Jody E Huang, Mian Handel, Tracy Dawson, John RD Kufareva, Irina https://orcid.org/0000-0001-9083-7039 Zabel, Brian A Pan, Junliang Butcher, Eugene C https://escholarship.org/uc/item/1cv305s9 The eukaryotic parasite <i>Trypanosoma cruzi</i> (<i>T. cruzi</i>) is responsible for Chagas disease, which results in heart failure in patients. The disease is more common in Latin America, and is an emerging infection with The Centers for Disease Control estimating that greater than 300,000 people are currently infected in the United States. This disease has also spread from South and Central America, where it is endemic to many other countries, including Australia, Japan, and Spain. Current therapy for Chagas disease is inadequate due to limited efficacy in the indeterminate and chronic phases of the disease, in addition to the adverse effects from nifurtimox and benznidazole, which are nitro-containing drugs used for therapy. There is a clear need for new therapies for the Chagas disease. Using a computational machine learning approach, we have previously shown that the antimalarial pyronaridine tetraphosphate is active against <i>T. cruzi</i> Brazil-luc <i>in vitro</i> against... https://escholarship.org/uc/item/1cv305s9 Tue, 1 Apr 2025 00:00:00 +0000 Siqueira-Neto, Jair Lage Lane, Thomas R Bernatchez, Jean A Alvarez, Claudia Magalhaes Calvet da Silva, Elany Barbosa Giardini, Miriam A https://orcid.org/0000-0002-6510-2409 Ekins, Sean https://escholarship.org/uc/item/0qj9b7gj BACKGROUND: Limited data exist on bictegravir pharmacokinetics in pregnancy among persons with HIV (PWH) and infant washout. SETTING: Nonrandomized, open-label, multicenter phase-IV prospective study of bictegravir pharmacokinetics and safety in pregnant PWH and their infants. METHODS: Steady-state 24-hour pharmacokinetic sampling of oral bictegravir 50 mg once daily (a component of fixed-dose combination bictegravir/emtricitabine/tenofovir alafenamide) during the second and third trimesters and postpartum was performed. Cord blood and infant washout samples were collected. Total and free bictegravir concentrations were measured by validated liquid chromatography with tandem mass spectrometry methods. Within-participant geometric mean ratios (GMR) with 90% confidence intervals (CI) were calculated to compare pharmacokinetics between second and third trimester versus postpartum. Infant HIV testing results were obtained. RESULTS: Twenty-seven maternal-infant pairs were enrolled.... https://escholarship.org/uc/item/0qj9b7gj Tue, 1 Apr 2025 00:00:00 +0000 Powis, Kathleen M Pinilla, Mauricio McMorrow, Flynn Stek, Alice Brooks, Kristina M Shapiro, David E Knowles, Kevin Eke, Ahizechukwu C Greene, Elizabeth Agwu, Allison Topete, Lourdes Browning, Renee Chakhtoura, Nahida Arora, Priyanka Huang, Xiaoying Best, Brookie M https://orcid.org/0000-0001-8569-2293 Mirochnick, Mark Momper, Jeremiah D Team, the IMPAACT 2026 Protocol https://escholarship.org/uc/item/0bb8k7kn A structurally novel metabolite, fatuamide A (<b>1</b>), was discovered from a laboratory cultured strain of the marine cyanobacterium <i>Leptolyngbya</i> sp., collected from Faga'itua Bay, American Samoa. A bioassay-guided approach using NCI-H460 human lung cancer cells directed the isolation of fatuamide A, which was obtained from the most cytotoxic fraction. The planar structure of fatuamide A was elucidated by integrated NMR and MS/MS analysis, and a combination of bioinformatic and computational approaches was used to deduce the absolute configuration at its eight stereocenters. A putative hybrid PKS/NRPS biosynthetic gene cluster responsible for fatuamide A production was identified from the sequenced genomic DNA of the cultured cyanobacterium. The biosynthetic gene cluster possessed elements that suggested fatuamide A binds metals, and this metallophore property was demonstrated by native metabolomics and indicated a preference for binding copper. The producing strain was... https://escholarship.org/uc/item/0bb8k7kn Tue, 1 Apr 2025 00:00:00 +0000 Alexander, Kelsey L Naman, C Benjamin Iwasaki, Arihiro Mangoni, Alfonso Leao, Tiago Reher, Raphael Petras, Daniel Kim, Hyunwoo Ternon, Eva Caro-Diaz, Eduardo JE Glukhov, Evgenia Mitrevska, Jana A Avalon, Nicole E Duggan, Brendan M https://orcid.org/0000-0002-7034-8374 Gerwick, Lena Gerwick, William H https://orcid.org/0000-0003-1403-4458 https://escholarship.org/uc/item/53v9m0nc CYSTAMINE D4 IMPROVES LIVER INFLAMMATION AND FIBROSIS IN A MURINE MODEL OF FIBROSING STEATOHEPATITIS https://escholarship.org/uc/item/53v9m0nc Thu, 27 Mar 2025 00:00:00 +0000 Leszczynska, Ola Kaufmann, Benedikt Alle, Thibault https://orcid.org/0000-0001-8459-6443 Stoess, Christian Sung, Hana Kim, Andrea D Tran, Chelsea Reca, Agustina Ballatore, Carlo Dohil, Ranjan Feldstein, Ariel E https://escholarship.org/uc/item/26p8n9c8 Background: Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are one of the most commonly used drugs for type 2 diabetes mellitus. Clinical guidelines recommend GLP-1 RAs as an adjunct to diabetes therapy in patients with chronic kidney disease, presence or risk of atherosclerotic cardiovascular disease, and obesity. The weight loss observed in clinical trials has been explored further in healthy individuals, putting GLP-1 RAs on track to be the next weight loss treatment. Objective: Although the adverse event profile is relatively safe, most GLP-1 RAs come with a labeled boxed warning for the risk of thyroid cancers, based on animal models and some postmarketing case reports in humans. Considering the increasing popularity of this drug class and its expansion into a new popular indication, a further review of the most recent postmarketing safety data was warranted to quantify thyroid hyperplasia and neoplasm instances. Methods: GLP-1 RA patient reports from the US Food... https://escholarship.org/uc/item/26p8n9c8 Mon, 24 Mar 2025 00:00:00 +0000 Makunts, Tigran Joulfayan, Haroutyun Abagyan, Ruben https://orcid.org/0000-0001-9309-2976 https://escholarship.org/uc/item/7jj5f3jn Background: Health disparities are known to play a role in pediatric cardiac surgery outcomes. Objectives: Risk factors associated with poor clinical outcomes were assessed. Methods: Using Pediatric Health Information System Database, pediatric subjects undergoing cardiac surgery using International Classification of Diseases 10th Revision from October 2015 to December 2020 were evaluated. Subjects were categorized by case complexity using the newly validated Risk Adjustment for Congenital Heart Surgery-2 (RACHS-2). Multivariable regression analyses were conducted to ascertain risk factors. Results: A total of 59,856 subjects, median age 7.4&nbsp;months (IQR: 1.5-61 months) were included; 38,917 (low), 9,833 (medium), and 11,106 (high) RACHS-2. Overall, hospital mortality was 3% and postoperative length of stay (LOS) was 7&nbsp;days (IQR: 4-18 days), with significant increases in both mortality and postoperative LOS from low to high RACHS-2 scores by multivariable analysis, Kaplan-Meier,... https://escholarship.org/uc/item/7jj5f3jn Fri, 21 Mar 2025 00:00:00 +0000 Setty, Shaun P Reynolds, Lauren C Chou, Vanessa C Yu, Maya T Kang, Stephen Allen, Phillip M Tran, Lan Le, Jennifer https://orcid.org/0000-0002-6692-0884 https://escholarship.org/uc/item/1t23r53g INTRODUCTION: Intraneuronal inclusions composed of tau protein are found in Alzheimer's disease (AD) and other tauopathies. Tau normally binds microtubules (MTs), and its disengagement from MTs and misfolding in AD is thought to result in MT abnormalities. We previously identified triazolopyrimidine-containing MT-stabilizing compounds that provided benefit in AD mouse models and herein describe the characterization and efficacy testing of an optimized candidate, CNDR-51997. METHODS: CNDR-51997 underwent pharmacokinetic, pharmacodynamic, safety pharmacology, and mouse tolerability testing. In addition, the compound was examined for efficacy in 5XFAD amyloid beta (Aβ) plaque mice and PS19 tauopathy mice. RESULTS: CNDR-51997 significantly reduced Aβ plaques in 5XFAD mice and tau pathology in PS19 mice, with the latter also showing attenuated axonal dystrophy and gliosis. CNDR-51997 was well tolerated at doses that exceeded efficacy doses, with a good safety pharmacology profile. DISCUSSION:... https://escholarship.org/uc/item/1t23r53g Fri, 21 Mar 2025 00:00:00 +0000 Yao, Yuemang Muench, Megan Alle, Thibault https://orcid.org/0000-0001-8459-6443 Zhang, Bin Lucero, Bobby Perez‐Tremble, Roxanne McGrosso, Dominic Newman, Mira Gonzalez, David J Lee, Virginia M‐Y Ballatore, Carlo Brunden, Kurt R https://escholarship.org/uc/item/9g39392r Petrosamine (<b>1</b>)-a colored pyridoacridine alkaloid from the Belizean sponge, <i>Petrosia</i> sp., that is also a potent inhibitor of acetylcholine esterase (AChE)-was investigated by spectroscopic and computational methods. Analysis of the petrosamine-free energy landscapes, p<i>K</i>_a and tautomerism, revealed an accurate electronic depiction of the molecular structure of <b>1</b> as the di-keto form, with a net charge of <i>q</i> = +1, rather than a dication (<i>q</i> = +2) under ambient conditions of isolation-purification. The pronounced solvatochromism (UV-vis) reported for <b>1</b>, and related analogs were investigated in detail and is best explained by charge delocalization and stabilization of the ground state (HOMO) of <b>1</b> rather than an equilibrium of competing tautomers. Refinement of the molecular structure <b>1</b> by QM methods complements published computational docking studies to define the contact points in the enzyme active site that may... https://escholarship.org/uc/item/9g39392r Tue, 18 Mar 2025 00:00:00 +0000 Gartshore, Christopher J Wang, Xiao Su, Yongxuan Molinski, Tadeusz F https://orcid.org/0000-0003-1935-2535 https://escholarship.org/uc/item/4pj3q1dz Introduction: Leishmaniasis is a parasitic disease that affects more than 1 million people worldwide annually, predominantly in resource-limited settings. The challenge in compound development is to exhibit potent activity against the intracellular stage of the parasite (the stage present in the mammalian host) without harming the infected host cells. We have identified a compound series (pyrazolopyrrolidinones) active against the intracellular parasites of <i>Leishmania donovani</i> and <i>L. major</i>; the causative agents of visceral and cutaneous leishmaniasis in the Old World, respectively. Methods: In this study, we performed medicinal chemistry on a newly discovered antileishmanial chemotype, with over 100 analogs tested. Studies included assessments of antileishmanial potency, toxicity towards host cells, and in vitro ADME screening of key drug properties. Results and discussion: Members of the series showed high potency against the deadliest form, visceral leishmaniasis... https://escholarship.org/uc/item/4pj3q1dz Tue, 18 Mar 2025 00:00:00 +0000 Kavouris, John A McCall, Laura-Isobel Giardini, Miriam A https://orcid.org/0000-0002-6510-2409 De Muylder, Geraldine Thomas, Diane Garcia-Pérez, Adolfo Cantizani, Juan Cotillo, Ignacio Fiandor, Jose M McKerrow, James H De Oliveira, Camila I Siqueira-Neto, Jair L González, Silvia Brown, Lauren E Schaus, Scott E https://escholarship.org/uc/item/2qd5w8jg Oxidative DNA lesions cause significant detrimental effects on a living species. Two major DNA lesions resulting from dG oxidation, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxodGuo) and formamidopyrimidine (Fapy·dG), are produced from a common chemical intermediate. Fapy·dG is formed in comparable yields under oxygen-deficient conditions. Replicative bypass of Fapy·dG in human cells is more mutagenic than that of 8-OxodGuo. Despite the biological importance of transcriptional mutagenesis, there are no reports of the effects of Fapy·dG on RNA polymerase II (Pol II) activity. Here we perform comprehensive kinetic studies to investigate the impact of Fapy·dG on three key transcriptional fidelity checkpoint steps by Pol II: insertion, extension, and proofreading steps. The ratios of error-free versus error-prone incorporation opposite Fapy·dG are significantly reduced in comparison with undamaged dG. Similarly, Fapy·dG:A mispair is extended with comparable efficiency as that of the... https://escholarship.org/uc/item/2qd5w8jg Tue, 18 Mar 2025 00:00:00 +0000 Gao, Shijun Hou, Peini Oh, Juntaek Wang, Dong https://orcid.org/0000-0002-2829-1546 Greenberg, Marc M https://escholarship.org/uc/item/27k2n564 ObjectiveDefine optimal ampicillin dosing for empiric early-onset sepsis (EOS) therapy in preterm neonates.Study designWe simulated ampicillin concentrations in newborns (birthweight &lt; 1500 g; gestational age 22–27 weeks), summarizing three 48 h regimens: high 100 mg/kg Q8hr, medium 100 mg/kg Q12hr, and standard 50 mg/kg Q12hr. Concentration data were analyzed for concentration above minimum inhibitory concentration (MIC), below neurotoxicity threshold (Cmax ≤ 140 mcg/mL), and duration limited to 48 h.ResultsAmong 34,689 newborns, all dosing regimens provided concentrations above MIC through 48 h, but Cmax exceeded the neurotoxicity threshold. With the 4-dose standard regimen, &gt;90% maintained concentrations &gt;MIC beyond 48 h. With the 2-dose regimen, newborns maintained the mean concentration &gt;MIC within the 48 h culture window and below neurotoxicity level. Infants 22–24 weeks’ gestation had higher drug concentrations and more prolonged exposure duration than 25–27... https://escholarship.org/uc/item/27k2n564 Tue, 18 Mar 2025 00:00:00 +0000 Le, Jennifer https://orcid.org/0000-0002-6692-0884 Greenberg, Rachel G Yoo, YoungJun Clark, Reese H Benjamin, Daniel K Zimmerman, Kanecia O Cohen-Wolkowiez, Michael Wade, Kelly C https://escholarship.org/uc/item/8vp5z560 Recent studies have demonstrated that anti-staphylococcal beta-lactam antibiotics, like nafcillin, render methicillin-resistant Staphylococcus aureus (MRSA) more susceptible to killing by innate host defense peptides (HDPs), such as cathelicidin LL-37. We compared the effects of growth in 1/4 minimum inhibitory concentration (MIC) of nafcillin or vancomycin on the LL-37 killing of 92 methicillin-susceptible S. aureus (MSSA) isolates. For three randomly selected strains among these, we examined the effects of nafcillin, vancomycin, daptomycin, or linezolid on LL-37 killing and autolysis. Growth in the presence of subinhibitory nafcillin significantly enhanced LL-37 killing of MSSA compared to vancomycin and antibiotic-free controls. Nafcillin also reduced MSSA production of the golden staphylococcal pigment staphyloxanthin in 39&nbsp;% of pigmented strains vs. 14&nbsp;% for vancomycin. Among the antibiotics tested, only nafcillin resulted in significantly increased MSSA autolysis.... https://escholarship.org/uc/item/8vp5z560 Mon, 17 Mar 2025 00:00:00 +0000 Le, J https://orcid.org/0000-0002-6692-0884 Dam, Q Schweizer, M Thienphrapa, W Nizet, V Sakoulas, G https://escholarship.org/uc/item/6mz6f9vj BACKGROUND: Premature, very low birth weight (VLBW) neonates are at risk for early-onset sepsis and receive ampicillin and gentamicin post-birth. Antimicrobial stewardship supports short-course antibiotics, but how long antibiotic concentrations remain therapeutic post-last dose is unknown. METHODS: Using Monte Carlo simulations (NONMEM 7.3), we analyzed antibiotic exposures in a retrospective cohort of 34 689 neonates (&lt;1500 g, 22-27 weeks of gestation). Therapeutic exposure for ampicillin and gentamicin was evaluated relative to the minimum inhibitory concentration (MIC) for common pathogens (MIC 0.25-8 mcg/mL for group B streptococcus [GBS] and Escherichia coli). Post-discontinuation antibiotic exposure (PDAE) was defined as the time from the last dose to time when concentration decreased below MIC. RESULTS: Neonates had a median (range) gestational age of 26 (22-27) weeks and BW, 790 g (400-1497) . All ampicillin dosing regimens (50-100 mg/kg every 8-12 hours for 2-6 doses)... https://escholarship.org/uc/item/6mz6f9vj Mon, 17 Mar 2025 00:00:00 +0000 Le, Jennifer https://orcid.org/0000-0002-6692-0884 Greenberg, Rachel G Benjamin, Daniel K Yoo, YoungJun Zimmerman, Kanecia O Cohen-Wolkowiez, Michael Wade, Kelly C Benjamin, Daniel K Hornik, Christoph Zimmerman, Kanecia Kennel, Phyllis Beci, Rose Hornik, Chi Dang Kearns, Gregory L Laughon, Matthew Paul, Ian M Sullivan, Janice Wade, Kelly Delmore, Paula Taylor-Zapata, Perdita Lee, June Anand, Ravinder Sharma, Gaurav Simone, Gina Kaneshige, Kim Taylor, Lawrence Green, Thomas https://escholarship.org/uc/item/6bx0c228 Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of self-masked aldehyde inhibitors (SMAIs) for cruzain, the major cysteine protease of the causative agent of Chagas disease-<i>Trypanosoma cruzi</i>. These SMAIs exerted potent, reversible inhibition of cruzain (<i>K_i</i>* = 18-350 nM) while apparently protecting the free aldehyde in cell-based assays. We synthesized prodrugs of the SMAIs that could potentially improve their pharmacokinetic properties. We also elucidated the kinetic and chemical mechanism of SMAIs and applied this strategy to the design of... https://escholarship.org/uc/item/6bx0c228 Mon, 17 Mar 2025 00:00:00 +0000 Li, Linfeng Chenna, Bala C Yang, Kai S Cole, Taylor R Goodall, Zachary T Giardini, Miriam https://orcid.org/0000-0002-6510-2409 Moghadamchargari, Zahra Hernandez, Elizabeth A Gomez, Jana Calvet, Claudia M Bernatchez, Jean A Mellott, Drake M Zhu, Jiyun Rademacher, Andrew Thomas, Diane Blankenship, Lauren R Drelich, Aleksandra Laganowsky, Arthur Tseng, Chien-Te K Liu, Wenshe R Wand, A Joshua Cruz-Reyes, Jorge Siqueira-Neto, Jair L Meek, Thomas D https://escholarship.org/uc/item/52c717km The opioid epidemic is a public health crisis that continues to impact healthcare in the United States of America (USA). While changes in opioid prescribing have curbed the medical use of opioids, the increase in nonmedical use, largely driven by injection drug use (IDU), has contributed to the escalating incidence of opioid use disorder (OUD). Furthermore, IDU is associated with high-risk injection practices that can increase the risk of acquiring viral and bacterial infections. Here in this comprehensive review, we aimed to summarize the epidemiology and management of OUD, along with the screening and antimicrobial treatment of associated infections, specifically focused on human immunodeficiency virus, hepatitis&nbsp;C virus, skin and soft tissue infections, endocarditis, and osteomyelitis. Medication-assisted therapy (MAT) and infection guidelines from the USA will be presented. https://escholarship.org/uc/item/52c717km Mon, 17 Mar 2025 00:00:00 +0000 Jones, Jessica F Legaspi, Jamie Chen, Eric Lee, Kelly https://orcid.org/0000-0002-1674-4210 Le, Jennifer https://orcid.org/0000-0002-6692-0884 https://escholarship.org/uc/item/209907b6 BACKGROUND: The SENTRY Antimicrobial Surveillance Program monitors the frequency of occurrence and antimicrobial susceptibility of organisms from various infection types worldwide. In this investigation, we evaluated the antimicrobial susceptibility of <i>Streptococcus pneumoniae</i> isolates collected worldwide over 20 years (1997-2016). METHODS: A total of 65 993 isolates were consecutively collected (1 per infection episode) from North America (NA; n = 34 626; 2 nations), Europe (EUR; n = 19 123; 23 nations), the Asia-Pacific region (APAC; n = 7111; 10 nations), and Latin America (LATAM; n = 5133; 7 nations) and tested for susceptibility using reference broth microdilution methods. Resistant subgroups included multidrug-resistant (MDR; nonsusceptible to ≥3 classes of agents) and extensively drug-resistant (XDR; nonsusceptible to ≥5 classes). RESULTS: The isolates were collected primarily from respiratory tract infections (77.3%), and 25.4% were from pediatric patients. Penicillin... https://escholarship.org/uc/item/209907b6 Mon, 17 Mar 2025 00:00:00 +0000 Sader, Helio S Mendes, Rodrigo E Le, Jennifer https://orcid.org/0000-0002-6692-0884 Denys, Gerald Flamm, Robert K Jones, Ronald N https://escholarship.org/uc/item/0sc670g5 Augmented renal clearance (ARC) can occur in critically ill pediatric patients receiving aminoglycosides such as gentamicin and tobramycin, yet optimal dosing strategies for ARC are undefined. We evaluated the probability of achieving efficacious or toxic exposures in pediatrics. Parallel population modeling of concentration strategies were pursued using <i>Pmetrics</i> v1.5.2 (nonparametric) and Monolix v2019R2 (parametric). Bayesian exposures were used to classify ARC based on total clearance (CL). The effects of serum creatinine (SCR), creatinine clearance (CRCL), total body weight (TBW), postnatal age (PNA), and ARC were explored as covariates. The probabilities of target attainment (PTA) (i.e., maximum concentration [<i>C</i>_max]/MIC, area under the concentration-time curve [AUC]/MIC) and of toxic exposure (PTE) (i.e., minimum concentration [<i>C</i>_min] &gt; 2 μg/ml) were calculated according to PNA and ARC. A total of 123 patients (1 to 21 years old,... https://escholarship.org/uc/item/0sc670g5 Mon, 17 Mar 2025 00:00:00 +0000 Avedissian, Sean N Rohani, Roxane Bradley, John https://orcid.org/0000-0002-3835-5064 Le, Jennifer https://orcid.org/0000-0002-6692-0884 Rhodes, Nathaniel J https://escholarship.org/uc/item/0f7462j4 Ultra-high resolution band-selective HSQC (bsHSQC) has been employed for detection of ³⁵ Cl-³⁷ Cl isotope shifted ¹³ C NMR signals for assignment of regioisomerism in bromo-chloro natural products. Optimum pulse sequence and instrumental parameters for maximization of detection of the isotope shifts were explored. The chlorine isotope shifts (Δδ) were detected within crosspeaks and were shown to vary with hybridization of ¹³ C, substitution of ¹³ C, presence of β-chloro substituents, and their relative configuration. Deconvolution of Cl-substituted CH bsHSQC crosspeaks may provide other useful information, including a potentially MS-independent method for quantitating ³⁷ Cl/³⁵ C isotopic fractionation during the biosynthesis of halogenated natural products. Copyright © 2016 John Wiley &amp; Sons, Ltd. https://escholarship.org/uc/item/0f7462j4 Fri, 14 Mar 2025 00:00:00 +0000 Wang, Xiao Duggan, Brendan M https://orcid.org/0000-0002-7034-8374 Molinski, Tadeusz F https://orcid.org/0000-0003-1935-2535 https://escholarship.org/uc/item/81n1d451 Background: Specialty societies, including the Infectious Diseases Society of America, strive to address gender and racial inequities in professional advancement. Microaggressions remain a persistent and pervasive barrier to these goals. Nonprofessional speaker introductions are a manifestation of race- and gender-based microaggressions, which have not been previously assessed at IDWeek. We assessed disparities in speaker introductions at IDWeek over a 7-year period that included formal gender equity initiatives introduced in 2016. Methods: We conducted a retrospective observational study of video-recorded IDWeek speaker introductions from 2013 to 2019. Trained coders reviewed presentation video archives to assess a primary outcome of nonprofessional introductions: when a speaker's professional title was not used as the first introduction. We used descriptive statistics, Fisher exact tests, Cochrane-Armitage trend tests, and multivariable logistic regression to characterize relationships... https://escholarship.org/uc/item/81n1d451 Fri, 28 Feb 2025 00:00:00 +0000 Marcelin, Jasmine R Khazanchi, Rohan Lyden, Elizabeth Cawcutt, Kelly A Abdul-Mutakabbir, Jacinda C https://orcid.org/0000-0003-4162-6408 Ha, David R Florez, Narjust Kullar, Ravina Ristagno, Elizabeth H Rajapakse, Nipunie Patel, Megha Miller, Amy M Oeltjen, Erin N Semaj, Sophie Sramek, Kyle T Lindeman, Christopher J Daubach, Eric C Akinmoladun, Oladapo O Wurtz, Paul J Yang, Yuhong https://escholarship.org/uc/item/44r4197v Surveillance of drug resistance and the discovery of novel targets-key objectives in the fight against malaria-rely on identifying resistance-conferring mutations in <i>Plasmodium</i> parasites. Current approaches, while successful, require laborious experimentation or large sample sizes. To elucidate shared determinants of antimalarial resistance that can empower in silico inference, we examined the genomes of 724 <i>Plasmodium falciparum</i> clones, each selected in vitro for resistance to one of 118 compounds. We identified 1448 variants in 128 recurrently mutated genes, including drivers of antimalarial multidrug resistance. In contrast to naturally occurring variants, those selected in vitro are more likely to be missense or frameshift, involve bulky substitutions, and occur in conserved, ordered protein domains. Collectively, our dataset reveals mutation features that predict drug resistance in eukaryotic pathogens. https://escholarship.org/uc/item/44r4197v Fri, 28 Feb 2025 00:00:00 +0000 Luth, Madeline R Godinez-Macias, Karla P Chen, Daisy Okombo, John Thathy, Vandana Cheng, Xiu Daggupati, Sindhu Davies, Heledd Dhingra, Satish K Economy, Jan M Edgar, Rebecca CS Gomez-Lorenzo, Maria G Istvan, Eva S Jado, Juan Carlos LaMonte, Gregory M Melillo, Bruno Mok, Sachel Narwal, Sunil K Ndiaye, Tolla Ottilie, Sabine Diaz, Sara Palomo Park, Heekuk Peña, Stella Rocamora, Frances Sakata-Kato, Tomoyo Small-Saunders, Jennifer L Summers, Robert L Tumwebaze, Patrick K Vanaerschot, Manu Xia, Guoqin Yeo, Tomas You, Ashley Gamo, Francisco-Javier Goldberg, Daniel E Lee, Marcus CS McNamara, Case W Ndiaye, Daouda Rosenthal, Philip J Schreiber, Stuart L Serra, Gloria De Siqueira-Neto, Jair Lage Skinner-Adams, Tina S Uhlemann, Anne-Catrin Kato, Nobutaka Lukens, Amanda K Wirth, Dyann F Fidock, David A Winzeler, Elizabeth A https://orcid.org/0000-0002-4049-2113 https://escholarship.org/uc/item/68k3r7c7 <b><i>Context:</i></b> Pain and symptom management at the end of life (EoL) can pose unique challenges, particularly when symptoms are refractory to conventional methods. Dexmedetomidine, originally approved for sedation in ventilated patients, has been demonstrated to be beneficial in pain management and palliative care settings by functioning as an alpha-2 agonist. <b><i>Methods:</i></b> A retrospective review of inpatient palliative care unit (IPU) records from January 2020 to December 2023 was conducted. Twenty-five adult patients receiving continuous dexmedetomidine for refractory pain at the EoL were identified. These patients were further evaluated for concurrent opioid, benzodiazepine, and chlorpromazine usage. <b><i>Results:</i></b> Patients experienced predominantly cancer-related pain, and had a median infusion duration of 5 days. Dexmedetomidine's initial dosing differed between the intensive care unit (ICU) and IPU settings. There was a trend toward a decreased opioid... https://escholarship.org/uc/item/68k3r7c7 Thu, 27 Feb 2025 00:00:00 +0000 Leslie, Eric A Byrne, Jennifer Mesarwi, Paula Edmonds, Kyle P https://orcid.org/0000-0002-0790-5211 Hirst, Jeremy M Atayee, Rabia S https://orcid.org/0000-0003-0505-8693 https://escholarship.org/uc/item/5fx4j0xj <b><i>Context:</i></b> The growing field of palliative care emphasizes the need for high-quality research, yet the contributions of nonphysician palliative care specialists to studying patient outcomes remain underexplored. <b><i>Methods:</i></b> This national observational study aims to identify barriers to conducting research among chaplains, nurses, pharmacists, and social workers in palliative care settings. An anonymous online survey was conducted across various disciplines. <b><i>Results:</i></b> A total of 173 participants reveal significant differences in research engagement and perceived barriers, with chaplains and pharmacists more likely to have research requirements and training, respectively, but face obstacles including insufficient time and article preparation. Nurse practitioners and social workers reported lower research involvement and higher perceived barriers in study design and mentorship. <b><i>Conclusion:</i></b> The study highlights the need for tailored... https://escholarship.org/uc/item/5fx4j0xj Thu, 27 Feb 2025 00:00:00 +0000 Atayee, Rabia S https://orcid.org/0000-0003-0505-8693 Edmonds, Kyle P https://orcid.org/0000-0002-0790-5211 Kestenbaum, Allison https://orcid.org/0000-0003-4780-4172 Kim, Jennifer Soriano, Karolina Lee, Kelly C https://orcid.org/0000-0002-1674-4210 https://escholarship.org/uc/item/7c36g97g <i>Prymnesium parvum</i> are harmful haptophyte algae that cause massive environmental fish kills. Their polyketide polyether toxins, the prymnesins, are among the largest nonpolymeric compounds in nature and have biosynthetic origins that have remained enigmatic for more than 40 years. In this work, we report the "PKZILLAs," massive <i>P. parvum</i> polyketide synthase (PKS) genes that have evaded previous detection. PKZILLA-1 and -2 encode giant protein products of 4.7 and 3.2 megadaltons that have 140 and 99 enzyme domains. Their predicted polyene product matches the proposed pre-prymnesin precursor of the 90-carbon-backbone A-type prymnesins. We further characterize the variant PKZILLA-B1, which is responsible for the shorter B-type analog prymnesin-B1, from <i>P. parvum</i> RCC3426 and thus establish a general model of haptophyte polyether biosynthetic logic. This work expands expectations of genetic and enzymatic size limits in biology. https://escholarship.org/uc/item/7c36g97g Mon, 17 Feb 2025 00:00:00 +0000 Fallon, Timothy R https://orcid.org/0000-0002-3048-7679 Shende, Vikram V https://orcid.org/0000-0001-8396-6297 Wierzbicki, Igor H Pendleton, Amanda L Watervoort, Nathan F Auber, Robert P Gonzalez, David J Wisecaver, Jennifer H Moore, Bradley S https://escholarship.org/uc/item/45q2d13k Marine sponge diterpenoid isonitriles are exceptional nitrogenous natural products that exhibit antiplasmodial activity. Their biosynthesis presents a biosynthetic puzzle: how do the elements of NC engage terpenyl carbocations in isoprenoid secondary metabolism, and what is the biosynthetic precursor of the NC group? Cyanoformic acid (NC-COOH, <b>B1</b>) is proposed as a plausible delivery vehicle of NC that resolves a paradox in the commonly held proposition that an inorganic cyanide anion, CN^-, terminates terpenoid isonitrile (TI) biosynthesis. DFT calculations of NC-COOH and its conjugate base, cyanoformate, NC-COO^- (<b>B2</b>), support high nucleophilicity at N and explain bond-forming constitutionality: attack at N and formation of an isonitrile over its nitrile isomer. TI biogenesis is compared to the cyanoformamide-containing ceratamines that arise from oxidation of a terminal <i>N</i>-Gly amide precursor. A unifying model links C-NC vs C-CN bond formation... https://escholarship.org/uc/item/45q2d13k Mon, 17 Feb 2025 00:00:00 +0000 Molinski, Tadeusz F https://orcid.org/0000-0003-1935-2535 https://escholarship.org/uc/item/7k87r7fw Molecular networking is a tandem mass spectrometry (MS/MS) data organizational approach that has been recently introduced in the drug discovery, metabolomics, and medical fields. The chemistry of molecules dictates how they will be fragmented by MS/MS in the gas phase and, therefore, two related molecules are likely to display similar fragment ion spectra. Molecular networking organizes the MS/MS data as a relational spectral network thereby mapping the chemistry that was detected in an MS/MS-based metabolomics experiment. Although the wider utility of molecular networking is just beginning to be recognized, in this review we highlight the principles behind molecular networking and its use for the discovery of therapeutic leads, monitoring drug metabolism, clinical diagnostics, and emerging applications in precision medicine. https://escholarship.org/uc/item/7k87r7fw Wed, 12 Feb 2025 00:00:00 +0000 Quinn, Robert A Nothias, Louis-Felix Vining, Oliver Meehan, Michael Esquenazi, Eduardo Dorrestein, Pieter C https://escholarship.org/uc/item/5bd2g6s5 While progress has been made in the effort to eradicate malaria, the disease remains a significant threat to global health. Acquired resistance to frontline treatments is emerging in Africa, urging a need for the development of novel antimalarial agents. Repurposing human kinase inhibitors provides a potential expedited route given the availability of a diverse array of kinase-targeting drugs that are approved or in clinical trials. Phenotypic screening of a library of type II human kinase inhibitors identified compound <b>1</b> as a lead antimalarial, which was initially developed to target human ephrin type A receptor 2 (EphA2). Here, we report a structure-activity relationship study and lead optimization of compound <b>1</b>, which led to compound <b>33,</b> with improved antimalarial activity and selectivity. https://escholarship.org/uc/item/5bd2g6s5 Tue, 11 Feb 2025 00:00:00 +0000 Wang, Lushun Bohmer, Monica J Wang, Jinhua Nardella, Flore Calla, Jaeson De Souza, Mariana Laureano Schindler, Kyra A Montejo, Lukas Mittal, Nimisha Rocamora, Frances Treat, Mayland Charlton, Jordan T Tumwebaze, Patrick K Rosenthal, Philip J Cooper, Roland A Chakrabarti, Ratna Winzeler, Elizabeth A https://orcid.org/0000-0002-4049-2113 Chakrabarti, Debopam Gray, Nathanael S https://escholarship.org/uc/item/40k8r5dn Terrestrial actinomycetes in the genus <i>Streptomyces</i> have long been recognized as prolific producers of small-molecule natural products, including many clinically important antibiotics and cytotoxic agents. Although <i>Streptomyces</i> can also be isolated from marine environments, their potential for natural product biosynthesis remains underexplored. The MAR4 clade of largely marine-derived <i>Streptomyces</i> has been a rich source of novel halogenated natural products of diverse structural classes. To further explore the biosynthetic potential of this group, we applied pattern-based genome mining, leading to the discovery of the first halogenated pyrroloketoindane natural products, indanopyrrole A (<b>1</b>) and B (<b>2</b>), and the bioinformatic linkage of these compounds to an orphan biosynthetic gene cluster (BCG) in 20 MAR4 genomes. Indanopyrrole A displays potent broad-spectrum antibiotic activity against clinically relevant pathogens. A comparison of the putative... https://escholarship.org/uc/item/40k8r5dn Sat, 8 Feb 2025 00:00:00 +0000 Sweeney, Douglas Bogdanov, Alexander Chase, Alexander B Castro-Falcón, Gabriel Trinidad-Javier, Alma Dahesh, Samira Nizet, Victor Jensen, Paul R https://escholarship.org/uc/item/90m6q5tk The Arf GTPase family is involved in a wide range of cellular regulation including membrane trafficking and organelle–structure assembly. Here, we have generated a proximity interaction network for the Arf family using the miniTurboID approach combined with TMT‐based quantitative mass spectrometry. Our interactome confirmed known interactions and identified many novel interactors that provide leads for defining Arf pathway cell biological functions. We explored the unexpected finding that phospholipase D1 (PLD1) preferentially interacts with two closely related but poorly studied Arf family GTPases, ARL11 and ARL14, showing that PLD1 is activated by ARL11/14 and may recruit these GTPases to membrane vesicles, and that PLD1 and ARL11 collaborate to promote macrophage phagocytosis. Moreover, ARL5A and ARL5B were found to interact with and recruit phosphatidylinositol 4‐kinase beta (PI4KB) at trans‐Golgi, thus promoting PI4KB's function in PI4P synthesis and protein secretion. https://escholarship.org/uc/item/90m6q5tk Mon, 3 Feb 2025 00:00:00 +0000 Li, Fu‐Long Wu, Zhengming Gao, Yong‐Qi Bowling, Forrest Z Franklin, J Matthew Hu, Chongze Suhandynata, Raymond T Frohman, Michael A Airola, Michael V Zhou, Huilin Guan, Kun‐Liang https://orcid.org/0000-0003-1892-0174 https://escholarship.org/uc/item/83p9x8mq Large multiprotein machines are central to many biological processes. However, stoichiometric determination of protein complex subunits in their native states presents a significant challenge. This study addresses the limitations of current tools in accuracy and precision by introducing concatemer-assisted stoichiometry analysis (CASA). CASA leverages stable isotope-labeled concatemers and liquid chromatography-parallel reaction monitoring-mass spectrometry (LC-PRM-MS) to achieve robust quantification of proteins with sub-femtomole sensitivity. As a proof of concept, CASA was applied to study budding yeast kinetochores. Stoichiometries were determined for ex vivo reconstituted kinetochore components, including the canonical H3 nucleosomes, centromeric (Cse4^CENP-A) nucleosomes, centromere proximal factors (Cbf1 and CBF3 complex), inner kinetochore proteins (Mif2^CENP-C, Ctf19^CCAN complex), and outer kinetochore proteins (KMN network). Absolute quantification... https://escholarship.org/uc/item/83p9x8mq Mon, 3 Feb 2025 00:00:00 +0000 Cai, Jiaxi Quan, Yun Zhang, Cindy Yuxuan Wang, Ziyi Hinshaw, Stephen M Zhou, Huilin Suhandynata, Raymond T https://escholarship.org/uc/item/7sb6h599 BACKGROUND: Patients with kidney disease are at risk for adverse events due to improper medication prescribing. Few randomized controlled trials of clinical decision support (CDS) utilizing dynamic assessment of patients' kidney function to improve prescribing for patients with kidney disease have been published. METHODS: We developed a CDS tool for 20 medications within a commercial electronic health record. Our system detected scenarios in which drug discontinuation or dosage adjustment was recommended for adult patients with impaired renal function in the ambulatory and acute settings - both at the time of the initial prescription ("prospective" alerts) and by monitoring changes in renal function for patients already receiving one of the study medications ("look-back" alerts). We performed a prospective, cluster randomized controlled trial of physicians receiving clinical decision support for renal dosage adjustments versus those performing their usual workflow. The primary... https://escholarship.org/uc/item/7sb6h599 Mon, 3 Feb 2025 00:00:00 +0000 Awdishu, Linda https://orcid.org/0000-0002-3187-3264 Coates, Carrie R Lyddane, Adam Tran, Kim Daniels, Charles E Lee, Joshua El-Kareh, Robert https://escholarship.org/uc/item/0sb2563s Proteins with nuclear localization sequences (NLSs) are directed into the cell nucleus through interactions between the NLS and importin proteins. NLSs are generally short motifs rich in basic amino acids; however, identifying NLSs can be challenging due to the lack of a universally conserved sequence. In this study, we characterized the sequence specificity of an essential and conserved NLS in Mcm3, a subunit of the replicative DNA helicase. Through mutagenesis and AlphaFold 3 (AF3) modeling, we demonstrate that the precise positioning of basic residues within the NLS is critical for nuclear transport of Mcm3 through optimal interactions with importin. Disrupting these interactions impairs the nuclear import of Mcm3, resulting in defective chromatin loading of the MCM complex and poor cell growth. Our results provide a structure-guided framework for predicting and analyzing monopartite NLSs, which, despite lacking a single consensus sequence, retain key characteristics shared... https://escholarship.org/uc/item/0sb2563s Mon, 3 Feb 2025 00:00:00 +0000 Wang, Ziyi Zhang, Yun Jing Zhang, Qian-yi Bilsborrow, Kate Leslie, Matthew Suhandynata, Raymond T Zhou, Huilin https://escholarship.org/uc/item/3g49q9j9 <b>Background/Objectives:</b> Idecabtagene vicleucel (ide-cel), an anti-B-cell maturation chimeric antigen receptor T-cell therapy, represents an unprecedented treatment option for relapsed/refractory multiple myeloma (R/R MM). Nevertheless, given its limitations, including the risk of adverse effects and unclear durability of efficacy, there remains a need to report the real-world clinical outcomes of ide-cel therapy in patients with R/R MM, as well as explore host predictive factors for therapy. <b>Methods:</b> We performed a single-center retrospective analysis of 25 adult patients with R/R MM who received ide-cel between 2021 and 2023 at the University of California San Diego Health. Data on baseline characteristics, efficacy, safety, and post-relapse outcomes were collected. Treatment responses were assessed using the International Myeloma Working Group criteria while survival analyses were conducted using the Kaplan-Meier and Cox proportional hazards methods. <b>Results:</b>... https://escholarship.org/uc/item/3g49q9j9 Thu, 30 Jan 2025 00:00:00 +0000 Trando, Aaron Ghamsari, Farid Yeung, Philip Costello, Caitlin Saunders, Ila https://orcid.org/0000-0002-8805-3734 Jeong, Ah-Reum https://escholarship.org/uc/item/4kz3d502 BACKGROUND: Prenatal alcohol exposure (PAE), leading to fetal alcohol spectrum disorders (FASD), is a serious public health issue in the United States and globally. Diagnosis of FASD is crucial in obtaining appropriate care, but it is not always possible when PAE cannot be documented. METHODS: Deciduous teeth from a child with known PAE and a child with known absence of PAE were analyzed using liquid chromatography-isotope dilution tandem mass spectrometry (LC-IDMS/MS) in a multiple-reaction monitoring mode for direct markers and LC-high resolution MS in positive and negative mode with hydrophilic interaction liquid chromatography and reverse-phase chromatography, respectively, for indirect markers. RESULTS: Direct markers of PAE (ethyl glucuronide and ethyl sulfate) were detected in prenatal and postnatal dentine from a case tooth but not from a control tooth. Indirect biomarker analysis indicated a dysregulation of amino acids and an increase in cholesterol sulfate in the case... https://escholarship.org/uc/item/4kz3d502 Sat, 25 Jan 2025 00:00:00 +0000 Montag, Annika Chambers, Christina Jones, Kenneth Dassanayake, Priyanthi Andra, Syam Petrick, Lauren Arora, Manish Austin, Christine https://escholarship.org/uc/item/3x69z048 Ubiquitination pathways have crucial roles in protein homeostasis, signalling and innate immunity1–3. In these pathways, an enzymatic cascade of E1, E2 and E3 proteins conjugates ubiquitin or a ubiquitin-like protein (Ubl) to target-protein lysine residues4. Bacteria encode ancient relatives of E1 and Ubl proteins involved in sulfur metabolism5,6, but these proteins do not mediate Ubl–target conjugation, leaving open the question of whether bacteria can perform ubiquitination-like protein conjugation. Here we demonstrate that a bacterial operon associated with phage defence islands encodes a complete ubiquitination pathway. Two structures of a bacterial E1–E2–Ubl complex reveal striking architectural parallels with canonical eukaryotic ubiquitination machinery. The bacterial E1 possesses an amino-terminal inactive adenylation domain and a carboxy-terminal active adenylation domain with a mobile α-helical insertion containing the catalytic cysteine (CYS domain). One structure reveals... https://escholarship.org/uc/item/3x69z048 Tue, 21 Jan 2025 00:00:00 +0000 Chambers, Lydia R Ye, Qiaozhen https://orcid.org/0000-0002-3942-4121 Cai, Jiaxi Gong, Minheng Ledvina, Hannah E Zhou, Huilin Whiteley, Aaron T Suhandynata, Raymond T Corbett, Kevin D https://orcid.org/0000-0001-5854-2388 https://escholarship.org/uc/item/2031g0bj BACKGROUND: For extended-release drug formulations, effective half-life (t 1/2eff ) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t 1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t 1/2eff and terminal half-life (t 1/2z ) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). METHODS: A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using... https://escholarship.org/uc/item/2031g0bj Mon, 20 Jan 2025 00:00:00 +0000 Momper, Jeremiah D Venkataramanan, Raman Jantz, Arin S Cibrik, Diane M Birdwell, Kelly Nguyen, Tk Masters, Brian M Patel, Samir J https://escholarship.org/uc/item/6th891tv Dengue, West Nile, Zika, Yellow fever, and Japanese encephalitis viruses persist as significant global health threats. The development of new therapeutic strategies based on inhibiting essential viral enzymes or viral-host protein interactions is problematic due to the fast mutation rate and rapid emergence of drug resistance. This study focuses on the NS2B-NS3 protease as a promising target for antiviral drug development. Promising allosteric binding sites were identified in two conformationally distinct inactive states and characterized for five flaviviruses and four Dengue virus subtypes. Their shapes, druggability, inter-viral similarity, sequence variation, and susceptibility to drug-resistant mutations have been studied. Two identified allosteric inactive state pockets appear to be feasible alternatives to a larger closed pocket near the active site, and they can be targeted with specific drug-like small-molecule inhibitors. Virus-specific sequence and structure implications... https://escholarship.org/uc/item/6th891tv Thu, 16 Jan 2025 00:00:00 +0000 Grabski, Hovakim Grabska, Siranuysh Abagyan, Ruben https://orcid.org/0000-0001-9309-2976 https://escholarship.org/uc/item/4329527s Red algae or seaweeds produce highly distinctive halogenated terpenoid compounds, including the pentabromochlorinated monoterpene halomon that was once heralded as a promising anticancer agent. The first dedicated step in the biosynthesis of these natural product molecules is expected to be catalyzed by terpene synthase (TS) enzymes. Recent work has demonstrated an emerging class of type I TSs in red algal terpene biosynthesis. However, only one such enzyme from a notoriously haloterpenoid-producing red alga (<i>Laurencia pacifica</i>) has been functionally characterized and the product structure is not related to halogenated terpenoids. Herein, we report 10 new type I TSs from the red algae <i>Portieria hornemannii</i>, <i>Plocamium pacificum</i>, <i>L. pacifica</i>, and <i>Laurencia subopposita</i> that produce a diversity of halogenated mono- and sesquiterpenes. We used a combination of genome sequencing, terpenoid metabolomics, <i>in vitro</i> biochemistry, and bioinformatics... https://escholarship.org/uc/item/4329527s Wed, 15 Jan 2025 00:00:00 +0000 Steele, Taylor S Burkhardt, Immo https://orcid.org/0000-0001-9515-4042 Moore, Malia L de Rond, Tristan Bone, Hannah K Barry, Kerrie https://orcid.org/0000-0002-8999-6785 Bunting, Victoria Mae Grimwood, Jane Handley, Lori H Rajasekar, Shanmugam Talag, Jayson Michael, Todd P Moore, Bradley S