Emerging studies suggest that antibiotics can disrupt the gut microbiome and alter vaccine-induced immune responses. However, the specific consequences of early-life exposure on neonatal immune development remain poorly understood. Here, we examined how two antibiotics frequently used in perinatal care, broad-spectrum ampicillin (AMP) and the extended-spectrum combination amoxicillin/clavulanate (AMOX/CLAV), administered during gestation and lactation, influence neonatal gut microbiome composition, fecal metabolome profiles, and responses to the 20-valent pneumococcal conjugate vaccine (PCV20). Maternal treatment with AMOX/CLAV, but not AMP, significantly reduced PCV-specific IgG titers at 4 and 6 weeks post-prime immunization compared to untreated controls. Exclusive exposure to AMOX/CLAV also impaired neutrophil-mediated opsonophagocytic killing, indicating reduced antibody functionality. These effects were transient, with immune parameters normalizing by 8 weeks post-prime immunization. Metabolomic and microbiome profiling revealed that maternal AMP and AMOX/CLAV differentially perturbed specific metabolite classes, including bile acids, N-acyl lipids, and indole derivatives. Key commensal taxa, including Bacteroidales and Coriobacteriales were also impacted within the gut microbiota. Together, these findings reveal a previously underappreciated maternal-offspring route of antibiotic influence that is transiently associated with neonatal vaccine responsiveness and microbiome and metabolome alterations. These results highlight maternal antibiotic exposure as a possible modifiable factor shaping early-life immunity.
Background. There are limited data on the impact of azole antifungal use on the appropriate dose conversion strategy from immediate-release tacrolimus (IR-Tac) to once-daily extended-release tacrolimus (LCP-Tacro tablets [LCPT]). The purpose of this study was to determine whether the initial IR-Tac–to-LCPT conversion ratio is affected by azole antifungal use. Methods. This single-center, retrospective cohort study included adult non–kidney transplant recipients who were converted from IR-Tac to LCPT between 2015 and 2022. Patients were grouped by azole antifungal use. The primary outcome was the IR-Tac–to-LCPT conversion ratio for those at goal tacrolimus trough, stratified by azole antifungal use. Secondary outcomes included conversion indications, acute kidney injury, neurological adverse effects, and rejection. Results. A total of 113 transplant recipients were included (liver 23 [20.4%], heart 70 [61.9%], lung 9 [8.0%], and multiorgan 11 [9.8%]). Twenty-two patients (19.5%) were on azole antifungals. A larger proportion of lung transplant recipients were on azole therapy compared with non–lung allograft recipients (27.3% versus 3.3%, P = 0.004). Conversion ratios were significantly higher for patients on azoles at 7 d ( P = 0.031), 30 d ( P = 0.038), and 90 d ( P = 0.001). Azole use was associated with lower LCPT doses at 7 d. There was no difference in patients at goal concentration or in the incidence of acute kidney injury between cohorts. Neurologic adverse effects related to IR-Tac prompted conversion in 55 patients, with 79.3% reporting improvement on LCPT. Conclusions. LCPT may be safely used in non–kidney transplant recipients regardless of azole antifungal use. Patients converting from IR-Tac to LCPT taking azole antifungals may warrant a higher dose conversion ratio, closer to 1, to achieve comparable tacrolimus trough concentrations.
Alpha B-crystallin (CryAB) is a small heat-shock protein highly expressed in cardiac tissue, where it functions as a molecular chaperone that helps prevent protein aggregation, particularly under stress conditions. A missense mutation in CryAB (R120G) causes autosomal dominant cardiomyopathy in humans and is characterized by extensive protein aggregation in cardiomyocytes. To better understand the pathogenic mechanisms underlying CryABR120G-associated cardiomyopathy, appropriate in vivo models are essential. Genetic mouse models are valuable tools for investigating disease pathogenesis and evaluating potential therapeutic strategies. In this study, we characterized a homozygous CryABR120G knock-in (KI) mouse model to assess the impact of this mutation on cardiac function. CryABR120G KI mice exhibited no overt changes in cardiac structure and function up to 12 months of age, with minimal changes in cardiac and proteotoxic stress markers, except for an increased atrial natriuretic peptide expression at 12 months. Protein quality control pathways remained largely unchanged. Although mitochondrial respiration was normal in young CryABR120G KI mice, it was reduced at 12 months of age. Despite the presence of insoluble protein aggregates, homozygous CryABR120G KI mice did not develop overt structural or functional cardiomyopathy through 12 months of age. These findings indicate that, within the age range examined, the CryABR120G KI model does not reproduce the overt cardiomyopathic phenotype associated with the CRYABR120G mutation in patients.
Natural products have an unparalleled track record as sources of clinical drugs. Among them, nonribosomal peptides (NRPs) stand as one of the most therapeutically significant classes, encompassing numerous approved anti-infective and anticancer agents. Yet, discovering bioactive NRPs remains profoundly challenging due to their complex biosynthesis and chemical architecture. Here, we present NPDiscover, a pathogen-oriented, scalable bioinformatics platform that integrates genome mining, metabolomics, and machine learning to identify NRPs active against drug-resistant pathogens. Applying NPDiscover to Actinobacteria datasets, we discovered edaphochelin A, a previously unreported NRP that kills multi-drug-resistant Candida auris and Candida glabrata by disrupting respiratory chain proteins. Structural elucidation via nuclear magnetic resonance and mass spectrometry, alongside in vitro and in vivo validation, confirmed its efficacy, safety, and a mode of action distinct from existing antifungals-establishing edaphochelin A as a compelling drug candidate and NPDiscover as a powerful engine for scalable natural product discovery.
The structure of the catalytic subunit of cAMP-dependent protein kinase (PKA-C), a prototype for the protein kinase superfamily, laid the foundation for the development of targeted kinase inhibitors. Here we describe the structure and biophysical characterization of a PKA-C complex with BLU0588, a small PKA-selective inhibitor. The high-resolution crystal structure not only captures the inhibitor's unusual T-shaped geometry, but also shows how the four rings of BLU0588 serve as surrogates for ATP's adenosine and phosphate-organizing sites. Each site contains two subsites. BLU0588's planar azaindole and pyridine rings, which are buried beneath the glycine-rich loop in a hydrophobic shell at the base of the active site cleft, fill the adenine and ribose subsites. In contrast, BLU0588's indane and pyrrolidine rings fill the phosphate-organizing site. The indane ring occupies the α/β-phosphate organizing site while the pyrrolidine ring fills the Mg/γ-phosphate organizing site. The structure also shows how BLU0588 nucleates an open but stable conformation of the entire hydrophobic architecture of the N- and C-lobes. In addition to potently blocking phosphoryl transfer activity, BLU0588 also abolishes the synergistic high-affinity binding of the physiological pseudosubstrate inhibitor, protein kinase inhibitor. The residence time of BLU0588, measured by surface plasmon residence, contributes to its picomolar affinity and is distinct from H89, a commonly used but more promiscuous PKA inhibitor. These molecular insights provide a valuable framework for dissecting the organization of the active site cleft as well as different strategies for the rational design of more potent and selective kinase inhibitors in general.
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 (p = 0.002), workplace joy (p = 0.005), and supportive work environment (p = 0.003) improved. Meditation frequency increased from T1 to T2 (p < 0.001) and remained higher at T3 (p = 0.006). CONCLUSIONS: A brief compassion program was feasible and improved over-identification and work-climate measures, supporting further evaluation of compassion support training in palliative and end-of-life research settings.
The intrinsic drug resistance of Mycobacterium tuberculosis (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 mice, underscoring its physiological relevance. These findings highlight FecB, Rv3035, and AftB as promising therapeutic targets.
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.
