嚢胞性線維症

Pseudomonas aeruginosa is a widespread Gram-negative opportunistic pathogen in environmental and hospital settings, frequently causing respiratory diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disorder (COPD) and ventilator-associated pneumonia. In our previous study, a galU-deleted clinical P. aeruginosa was found to exhibit increased susceptibility to polymyxins. The galU gene plays an important role in the biosynthesis of lipopolysaccharide (LPS) O-antigen. Here, we systematically evaluated the effects of galU deletion on the phenotype and virulence of P. aeruginosa PAO1. A galU deletion mutant was successfully constructed in P. aeruginosa PAO1 by CRISPR/Cas9, and the complementation was accomplished by pUCP18 plasmid carrying wildtype galU. The changes in phenotype, virulence and pathogenicity were systemically studied. The results revealed that knockout of galU led to the loss of O-antigen, which affected growth, virulence and pathogenicity through various ways in P. aeruginosa, and significantly affected the susceptibility of P. aeruginosa to polymyxins. Mechanism study suggested the involvements of quorum sensing, Entner-Doudoroff pathway and tyrosine metabolism, etc on bacterial virulence, antibiotic susceptibility changes after galU deletion. galU and the related pathways may serve as effective targets for treatment of P. aeruginosa infection, providing a theoretical basis for the development of novel antibacterial drugs.

BACKGROUND: Despite high symptom burden and limited lifespan associated with sickle cell disease (SCD), specialty palliative care (PC) services remain underutilized in this marginalized population.1,2 The extent of routine involvement, barriers to care, and training in the care of SCD patients at academic PC programs in the United States has not been quantified. OBJECTIVE: To assess PC involvement and training in SCD care, identify barriers to access, and inform integration strategies. DESIGN/SETTING: An anonymous Qualtrics survey, developed through literature review and expert panel, was emailed to 180 palliative medicine fellowship program directors or surrogates (June 18-July 25, 2025) in the United States. The survey included demographics, program practices regarding SCD and other chronic conditions (cystic fibrosis, amyotrophic lateral sclerosis, and chronic nonmalignant pain), frequency of routine SCD education, and perceived barriers to providing care to these patients. RESULTS: Fifty-one responses were received (28.3% response rate). Only 37% of programs routinely care for SCD patients (31.5% inpatient only, 10.5% outpatient, 58% both). Among these, 68% regularly prescribed opioids. Programs not routinely involved reported exceptions for patients with limited prognosis, comorbidities such as active cancer, or imminent end-of-life needs. The most common reported barriers to seeing patients with SCD were lack of outpatient resources (46%) and staffing constraints (44%). Free-text responses cited limited referrals, competing specialty ownership (hematology), institutional restrictions, and scope-of-practice limitations. Only 38% of programs included SCD in their fellowship curriculum, and 20% offered routine training for all PC team members. CONCLUSIONS: Fewer than half of academic PC programs routinely care for SCD patients, and most programs lack formal SCD training. Institutional and systemic barriers limit access, highlighting the need for resources and education to expand PC integration into SCD care. There is a need for consensus guidelines stratifying PC involvement in SCD patients.

Accurate prediction of drug-target binding affinity plays an important role in structure-based drug discovery, yet existing approaches are constrained by their reliance on scarce experimentally determined protein-ligand complex structures. In this context, recent advances in biomolecular structure prediction models, such as AlphaFold3, have emerged as a promising approach to alleviate the scarcity of experimentally determined protein-ligand complex structures. In this study, we introduce AlphaDTA, a framework that integrates AlphaFold3-predicted structures and embeddings for drug-target binding affinity prediction. AlphaDTA processes two types of AlphaFold3 embeddings, single and pair embeddings. We utilized the single embeddings at both fine-grained and coarse-grained levels to capture local interaction patterns and global binding context, and used the pair embeddings to encode cross-molecular relational features. The AlphaFold3-predicted structures are further processed by a three-dimensional structure-based geometric encoder to produce corresponding structural embedding representations. The resulting single, pair, and structural embeddings are then integrated through adaptive fusion for affinity prediction. When we evaluated AlphaDTA using recently proposed PDBbind data splits designed to reduce train-test structural overlap, AlphaDTA achieved state-of-the-art or competitive performance across multiple independent benchmarks. In a case study on the cystic fibrosis transmembrane conductance regulator, AlphaDTA correctly identifies a clinically approved potentiator and suggests a potential repurposing candidate among FDA-approved drugs.Scientific contribution AlphaDTA enables accurate drug-target binding affinity prediction without relying on experimentally determined protein-ligand complex structures. By integrating AlphaFold3-derived single, pair, and structure-based embeddings through adaptive fusion, AlphaDTA improves generalization on structurally nonredundant benchmarks and demonstrates utility for target-specific drug repurposing.

Non-cystic fibrosis bronchiectasis is associated with many causes including post-infectious damage, immunodeficiency, connective tissue disease and ciliary dysfunction and can also overlap with chronic obstructive pulmonary disease and asthma. Renal transplantation (RT) is the most common solid-organ transplantation worldwide. Since 2004, bronchiectasis associated with RT has been described in case reports and series involving children and adult patients. The pathogenesis remains unclear and may combine underlying renal diseases, immunodeficiency, direct toxicity of immunosuppressive drugs and lower tract infections. This narrative review, supported by the extensive literature in PubMed, Cochrane Library and Web of Science, provides a state-of-the-art of current knowledge regarding the epidemiology, pathophysiology and clinical impact of bronchiectasis in renal transplant patients. Finally, we provide management proposals for RT-associated bronchiectasis in clinical practice.