The therapeutic potential of oligonucleotides (oligos) is limited by insufficient delivery to extrahepatic tissues. In vitro assays often fail to accurately predict in vivo behavior, while testing each oligo candidate in animals remains inherently low throughput. Here, we conceive a barcoded oligonucleotide system (BOLT), a platform that enables high-throughput in vivo evaluations of small-molecule ligands and identifies tissue-specific oligo delivery. BOLT integrates rational design of oligo barcodes, modular conjugation chemistry, and next-generation sequencing (NGS)-based quantification, allowing simultaneous evaluation of many chemically diverse ligand-oligo conjugates within a single animal. Notably, this platform is applicable in both mice and nonhuman primates (NHPs). Using BOLT, we discovered ligands with tropism for tissues such as the brain, lung, and muscle. Collectively, these results indicate that the BOLT platform can accelerate the discovery of tissue-targeting ligands for broad oligo therapeutics.
The National Institutes of Health (NIH) Office of Dietary Supplements hosted a workshop titled Advancing the Biomedical Science of Resilience: A Discussion of Measures and Metrics on September 24-25, 2024. The workshop convened NIH program staff and researchers from academia and federal agencies to propose and identify measures and metrics that capture protective factors contributing to resilience across the lifespan. Various perspectives on resilience were thoroughly discussed, including those related to cellular, physiological, psychosocial, community, and environmental domains, reflecting the complexity and multidimensionality of resilience science. Central to the workshop were discussions to examine characteristics of resilience studies across domains and to explore outcome-specific measures and metrics and study designs needed to validate those outcomes and accurately measure resilience in biomedical research. The workshop concluded with a panel discussion on the challenges of advancing the science of resilience and the need for robust frameworks for studying the concept. This article presents the proceedings from that workshop and outlines strategies for advancing and strengthening the science of resilience through greater integration across research domains. Leadership in convening diverse perspectives and fostering multidisciplinary dialogue, such as through consensus-building activities and collaborative forums, will be important for advancing shared frameworks and understanding resilience across the lifespan.
This review examines the unique cardiovascular disease patterns in older women, focusing on sex and age-specific pathophysiology, diagnostic challenges, and disparities in management. We aim to clarify how aging and hormonal transitions influence disease presentation and outcomes among women, and to identify gaps in cardiovascular care. Emerging data demonstrate that older women are disproportionately affected by HFpEF, coronary microvascular dysfunction, atrial fibrillation, and valvular heart disease. These conditions are influenced by vascular stiffness, myocardial remodeling, and systemic inflammation and often present with atypical symptoms leading to diagnosis delays. Contemporary studies highlight persistent gaps in timely diagnosis, referral for advanced therapies, and representation in clinical trials. Increasing attention is being directed toward frailty, multimorbidity, and patient-centered care models in this population. Recognizing age and sex-specific characteristics, increasing representation of older women in clinical trials, improving equitable access to diagnostic and therapeutic resources, and aligning treatment decisions with patient priorities are critical to narrowing existing gaps and improving long-term outcomes for older women with cardiovascular disease.
Recent advances in regenerative medicine have highlighted the pivotal role of stem cell-derived exosomes (SC-Exos) as promising acellular therapeutics for joint regeneration. These nanosized extracellular vesicles, which are secreted by mesenchymal stem cells (MSCs) and other progenitor cells, encapsulate bioactive molecules such as proteins, lipids, and nucleic acids, which can modulate inflammation, promote chondrogenesis, and enhance cartilage and bone repair. Unlike their cellular counterparts, SC-Exos offer advantages including lower immunogenicity, improved safety profiles, and easier storage and handling. PubMed, Scopus, and ScienceDirect were searched through 2025 for preclinical and clinical studies on stem cell-derived exosomes in joint regeneration, with reference screening and independent reviewer selection by consensus. Emerging preclinical studies have demonstrated their potential in treating osteoarthritis, rheumatoid arthritis, and traumatic joint injuries by promoting matrix synthesis, reducing apoptosis, and modulating immune responses. Innovations in bioengineering, including exosome modification and targeted delivery systems, further enhance therapeutic efficacy. However, challenges such as standardization of isolation methods, optimization of dosing strategies, and long-term safety evaluations remain. This review discusses the biological mechanisms underlying SC-Exo-mediated joint regeneration; recent advances in their application for cartilage, bone, and synovial tissue repair; and the integration of nanotechnology and biomaterials to increase regenerative capacity. Moreover, ongoing clinical trials, current hurdles in clinical translation, and future perspectives aimed at refining SC-Exo-based therapies for joint diseases are highlighted. Overcoming these barriers will be critical for advancing exosome-based regenerative strategies toward clinical practice and minimally invasive treatments for joint disorders.
BACKGROUND:The global prevalence of autism spectrum diagnosis (ASD) is increasing. Fetal and early-life exposure to trace elements has been associated with increased likelihood of ASD, but evidence regarding timing of exposure remains limited. AIM:This study investigates prenatal and early-life exposure to non-essential and essential elements, individually and as mixtures, in children with and without ASD, stratified by child sex. METHODS:The sample included 170 children from the Norwegian Mother, Father and Child Cohort Study (MoBa), of whom 75 were clinically diagnosed with ASD and 95 were not. Elemental levels were measured in primary tooth dentine using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to investigate case-control differences in levels of pre-and postnatal non-essential and essential elements as well as their mixtures. RESULTS:Significant differences in lead (Pb) levels were observed between ASD case and control groups: The ASD male group had lower Pb levels from 15 to 11 weeks prenatally, while ASD female group had lower levels from birth to 4 weeks postnatally, compared to controls. Males with ASD had higher prenatal magnesium (Mg) and lower postnatal Mg levels, as well as lower prenatal lithium (Li) levels and higher postnatal Li levels compared to controls. Additionally, males with ASD had higher prenatal and lower postnatal essential element mixture levels than controls. DISCUSSION:These findings suggest that there may be differential patterns of exposure to non-essential and essential element levels during specific developmental windows in fetal and early postnatal life in children with and without ASD.
