Senescent-like microglia limit remyelination through the senescence associated secretory phenotype.

The capacity to regenerate myelin in the central nervous system (CNS) diminishes with age. This decline is particularly evident in multiple sclerosis (MS), which has been suggested to exhibit features of accelerated biological aging. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells (SCs) accumulate within demyelinated lesions after injury, and their elimination enhances remyelination in young mice but not in aged mice. In young mice, we observed the upregulation of senescence-associated transcripts primarily in microglia after demyelination, followed by their reduction during remyelination. However, in aged mice, senescence-associated factors persisted within lesions, correlating with inefficient remyelination. We found that SC elimination enhanced remyelination in young mice but was ineffective in aged mice. Proteomic analysis of senescence-associated secretory phenotype (SASP) revealed elevated levels of CCL11/Eotaxin-1 in lesions, which was found to inhibit efficient oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.

Procedure-Focused Escape Room: A Pilot Study on Teaching High-Stakes Technical Skills in Anesthesia Residents.

Background: High-stakes yet clinically infrequent procedures are challenging to teach. Escape rooms may offer an innovative solution through game-based learning. There is limited guidance on how to design an escape room focused on physical puzzles. We designed and implemented a procedure-focused escape room to teach high-stakes procedures to anesthesiology residents. Methods: We selected 5 procedural skills relevant to anesthesiology residents through a modified Delphi technique: fiberoptic intubation, rapid infuser setup, intraosseous line placement, flexible bronchoscopy, and supraglottic airway exchange. We designed associated skills stations and linked them in sequence using an elaborate series of puzzles, locks, keys, and codes. The total cost of puzzle equipment was $169.53. After pilot testing, we implemented the escape room from July to November 2022. We assessed residents using a single group pretest-posttest study design. Results: Forty-three of 55 (78%) eligible anesthesiology residents participated in the escape room. Thirty-one residents completed the surveys. Resident self-efficacy significantly improved for each of the 5 procedures. Twenty-six of 27 (96%) residents preferred the escape room over a typical procedural skills workshop. Conclusions: This pilot study demonstrated the feasibility of a procedure-focused escape room for teaching high-stakes technical skills. We identified 3 lessons in procedure-focused escape room design: set participant caps intentionally, optimize resource usage, and maximize reproducibility. Participating in a single escape room session significantly increased resident self-efficacy. Residents strongly preferred the escape room format over a traditional procedural skills workshop.

The synergistic interplay of artificial intelligence and digital twin in environmentally planning sustainable smart cities: A comprehensive systematic review.

The dynamic landscape of sustainable smart cities is witnessing a significant transformation due to the integration of emerging computational technologies and innovative models. These advancements are reshaping data-driven planning strategies, practices, and approaches, thereby facilitating the achievement of environmental sustainability goals. This transformative wave signals a fundamental shift - marked by the synergistic operation of artificial intelligence (AI), artificial intelligence of things (AIoT), and urban digital twin (UDT) technologies. While previous research has largely explored urban AI, urban AIoT, and UDT in isolation, a significant knowledge gap exists regarding their synergistic interplay, collaborative integration, and collective impact on data-driven environmental planning in the dynamic context of sustainable smart cities. To address this gap, this study conducts a comprehensive systematic review to uncover the intricate interactions among these interconnected technologies, models, and domains while elucidating the nuanced dynamics and untapped synergies in the complex ecosystem of sustainable smart cities. Central to this study are four guiding research questions: 1. What theoretical and practical foundations underpin the convergence of AI, AIoT, UDT, data-driven planning, and environmental sustainability in sustainable smart cities, and how can these components be synthesized into a novel comprehensive framework? 2. How does integrating AI and AIoT reshape the landscape of data-driven planning to improve the environmental performance of sustainable smart cities? 3. How can AI and AIoT augment the capabilities of UDT to enhance data-driven environmental planning processes in sustainable smart cities? 4. What challenges and barriers arise in integrating and implementing AI, AIoT, and UDT in data-driven environmental urban planning, and what strategies can be devised to surmount or mitigate them? Methodologically, this study involves a rigorous analysis and synthesis of studies published between January 2019 and December 2023, comprising an extensive body of literature totaling 185 studies. The findings of this study surpass mere interdisciplinary theoretical enrichment, offering valuable insights into the transformative potential of integrating AI, AIoT, and UDT technologies to advance sustainable urban development practices. By enhancing data-driven environmental planning processes, these integrated technologies and models offer innovative solutions to address complex environmental challenges. However, this endeavor is fraught with formidable challenges and complexities that require careful navigation and mitigation to achieve desired outcomes. This study serves as a comprehensive reference guide, spurring groundbreaking research endeavors, stimulating practical implementations, informing strategic initiatives, and shaping policy formulations in sustainable urban development. These insights have profound implications for researchers, practitioners, and policymakers, providing a roadmap for fostering resiliently designed, technologically advanced, and environmentally conscious urban environments.

Airway IL-1ß is related to disease severity and mucociliary function in bronchiectasis.

RATIONALE: The inflammasome is a key regulatory complex of the inflammatory response leading to IL-1ß release and activation. IL-1ß amplifies inflammatory responses and induces mucus secretion and hyperconcentration in other diseases. The role of IL-1ß in bronchiectasis has not been investigated. OBJECTIVES: To characterize the role of airway IL-1ß in bronchiectasis including the association with mucus properties, ciliary function, airway inflammation, microbiome and disease severity. METHODS: Stable bronchiectasis patients were enrolled in an international cohort study (n=269). IL-1ß was measured in sputum supernatant. A validation cohort also had sputum rheology and hydration measured (n=53). For analysis, patients were stratified according to the median value of IL-1ß in the population (High versus Low) to compare disease severity, airway infection, microbiome (16S rRNA sequencing), inflammation and caspase-1 activity. Primary human nasal epithelial cells grown in air-liquid interface culture were used to study IL-1ß effect on cilia function. MEASUREMENTS AND MAIN RESULTS: Patients with high sputum IL-1ß had more severe disease, increased caspase-1 activity and increased Th1, Th2 and neutrophil inflammatory response compared with patients with low IL-1ß. The active-dominant form of IL-1ß was associated with increased disease severity. High IL-1ß was related to higher relative abundance of Proteobacteria in the microbiome and increased mucus solid content and viscoelastic properties. Chronic IL-1ß treatment reduced the functionality of cilia and tight junctions of epithelial cells in-vitro. CONCLUSIONS: A subset of stable bronchiectasis patients show increased airway IL-1ß, suggesting pulmonary inflammasome activation is linked with more severe disease, airway infection, mucus dehydration and epithelial dysfunction.

Mapping the cellular biogeography of human bone marrow niches using single-cell transcriptomics and proteomic imaging.

Non-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely uncharacterized. We used single-cell RNA sequencing (scRNA-seq) to profile 29,325 non-hematopoietic cells and discovered nine transcriptionally distinct subtypes. We simultaneously profiled 53,417 hematopoietic cells and predicted their interactions with non-hematopoietic subsets. We employed co-detection by indexing (CODEX) to spatially profile over 1.2 million cells. We integrated scRNA-seq and CODEX data to link predicted cellular signaling with spatial proximity. Our analysis revealed a hyperoxygenated arterio-endosteal neighborhood for early myelopoiesis, and an adipocytic localization for early hematopoietic stem and progenitor cells (HSPCs). We used our CODEX atlas to annotate new images and uncovered mesenchymal stromal cell (MSC) expansion and spatial neighborhoods co-enriched for leukemic blasts and MSCs in acute myeloid leukemia (AML) patient samples. This spatially resolved, multiomic atlas of human bone marrow provides a reference for investigation of cellular interactions that drive hematopoiesis.

Endotypes of Exacerbation in Bronchiectasis: An Observational Cohort Study.

RATIONALE: Bronchiectasis is characterised by acute exacerbations but the biological mechanisms underlying these events is poorly characterised. Objectives To investigate the inflammatory and microbial characteristics of exacerbations of bronchiectasis. METHODS: 120 patients with bronchiectasis were enrolled and presented with acute exacerbations within 12 months. Spontaneous sputum samples were obtained during a period of clinical stability and again at exacerbation prior to receipt of antibiotic treatment. A validated rapid PCR assay for bacteria and viruses was used to classify exacerbations as bacterial, viral or both. Sputum inflammatory assessments included label free Liquid chromography/mass spectrometry and measurement of sputum cytokines and neutrophil elastase activity. 16s rRNA sequencing was used to characterise the microbiome. MEASUREMENTS AND MAIN RESULTS: Bronchiectasis exacerbations showed profound molecular heterogeneity. At least one bacteria was identified in 103 samples (86%) and a high bacterial load (total bacterial load >10(7) copies/g) was observed in 81 patients (68%). Respiratory viruses were identified in 55 (46%) patients with rhinovirus being the most common virus (31%). PCR was more sensitive than culture. No consistent change in the microbiome was observed at exacerbation. Exacerbations were associated with increased neutrophil elastase, proteinase-3, Il-1beta and CXCL8. There markers were particularly associated with bacterial and bacterial+viral exacerbations. Distinct inflammatory and microbiome profiles were seen between different exacerbation subtypes, including bacterial, viral and eosinophilic events in both hypothesis led, and hypothesis-free analysis using integrated microbiome and proteomics, demonstrating 4 subtypes of exacerbation. CONCLUSION: Bronchiectasis exacerbations are heterogeneous events with contributions from bacteria, viruses and inflammatory dysregulation.

The establishment of a multiple myeloma clinical registry in the Asia-Pacific region: The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR).

BACKGROUND: Multiple myeloma (MM) is the second most common haematological cancer worldwide. Along with related diseases including monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukaemia (PCL) and plasmacytoma, MM incidence is rising, yet it remains incurable and represents a significant disease burden. Clinical registries can provide important information on management and outcomes, and are vital platforms for clinical trials and other research. The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR) was developed to monitor and explore variation in epidemiology, treatment regimens and their impact on clinical outcomes across this region. Here we describe the registry's design and development, initial data, progress and future plans. METHODS: The APAC MRDR was established in 2018 as a multicentre collaboration across the Asia-Pacific, collecting prospective data on patients newly diagnosed with MM, MGUS, PCL and plasmacytoma in Korea, Singapore, Malaysia and Taiwan, with China recently joining. Development of the registry required a multidisciplinary team of clinicians, researchers, legal and information technology support, and financial resources, as well as local clinical context from key opinion leaders in the APAC region. Written informed consent is obtained and data are routinely collected throughout treatment by hospital staff. Data are stored securely, meeting all local privacy and ethics requirements. Data were collected from October 2018 to March 2024. RESULTS: Over 1700 patients from 24 hospitals have been enrolled onto the APAC MRDR to date, with the majority (86%) being newly diagnosed with MM. Bortezomib with an immunomodulatory drug was most frequently used in first-line MM therapy, and lenalidomide-based therapy was most common in second-line. Establishment and implementation challenges include regulatory and a range of operational issues. CONCLUSION: The APAC MRDR is providing 'real-world' data to participating sites, clinicians and policy-makers to explore factors influencing outcomes and survival, and to support high quality studies. It is already a valuable resource that will continue to grow and support research and clinical collaboration in MM and related diseases across the APAC region.

Mapping the Cellular Biogeography of Human Bone Marrow Niches Using Single-Cell Transcriptomics and Proteomic Imaging.

The bone marrow is the organ responsible for blood production. Diverse non-hematopoietic cells contribute essentially to hematopoiesis. However, these cells and their spatial organization remain largely uncharacterized as they have been technically challenging to study in humans. Here, we used fresh femoral head samples and performed single-cell RNA sequencing (scRNA-Seq) to profile 29,325 enriched non-hematopoietic bone marrow cells and discover nine transcriptionally distinct subtypes. We next employed CO-detection by inDEXing (CODEX) multiplexed imaging of 18 individuals, including both healthy and acute myeloid leukemia (AML) samples, to spatially profile over one million single cells with a novel 53-antibody panel. We discovered a relatively hyperoxygenated arterio-endosteal niche for early myelopoiesis, and an adipocytic, but not endosteal or perivascular, niche for early hematopoietic stem and progenitor cells. We used our atlas to predict cell type labels in new bone marrow images and used these predictions to uncover mesenchymal stromal cell (MSC) expansion and leukemic blast/MSC-enriched spatial neighborhoods in AML patient samples. Our work represents the first comprehensive, spatially-resolved multiomic atlas of human bone marrow and will serve as a reference for future investigation of cellular interactions that drive hematopoiesis.

The splicing regulators RBM5 and RBM10 are subunits of the U2 snRNP engaged with intron branch sites on chromatin.

Understanding the mechanisms of pre-mRNA splicing is limited by the technical challenges to examining spliceosomes in vivo. Here, we report the isolation of RNP complexes derived from precatalytic A or B-like spliceosomes solubilized from the chromatin pellet of mammalian cell nuclei. We found that these complexes contain U2 snRNP proteins and a portion of the U2 snRNA bound with protected RNA fragments that precisely map to intronic branch sites across the transcriptome. These U2 complexes also contained the splicing regulators RBM5 and RBM10. We found RBM5 and RBM10 bound to nearly all branch site complexes and not simply those at regulated exons. The deletion of a conserved RBM5/RBM10 peptide sequence, including a zinc finger motif, disrupted U2 interaction and rendered the proteins inactive for the repression of many alternative exons. We propose a model where RBM5 and RBM10 regulate splicing as components of the U2 snRNP complex following branch site base pairing.

The efficacy and safety of ketamine for depression in patients with cancer: A systematic review / La eficacia y seguridad de la ketamina para la depresión en pacientes con cáncer: una revisión sistemática

Background: Management of depression in the oncology population includes supportive psychotherapeutic interventions with or without psychotropic medication, which take time to demonstrate effectiveness. Fast-acting interventions, like ketamine, can provide a rapid antidepressant effect; however, there has been limited research on effects of ketamine among cancer patients. The objective of this review is to provide an overview of research on the efficacy and safety of ketamine on depression in patients with cancer. Methods: We reviewed the published literature in MEDLINE® (via PubMed®), EMBASE, and Scopus from 1 January 1982 to 20 October 2022. We screened the retrieved abstracts against inclusion criteria and conducted a full‐text review of eligible studies. Following extraction of data from included studies, we used a framework analysis approach to summarize the evidence on using ketamine in patients with cancer. Results: All 5 included studies were randomized clinical trials conducted in inpatient settings in China. In all included studies ketamine was administered intravenously. Three studies used only racemic ketamine, and two studies used both S-ketamine and racemic ketamine. All included studies reported ketamine a tolerable and effective drug to control depression symptoms. Conclusion: Included studies showed administration of sub-anesthesia ketamine significantly improves postoperative depression among patients with cancer.(AU)

Accelerated elastin degradation by age-disease interaction: a common feature in age-related diseases.

Aging is a major driving force for many diseases but the relationship between chronological age, the aging process and age-related diseases is not fully understood. Fragmentation and loss of ultra-long-lived elastin are key features in aging and several age-related diseases leading to increased mortality. By comparing the relationship between age and elastin turnover with healthy volunteers, we show that accelerated elastin turnover by age-disease interaction is a common feature of age-related diseases.

The efficacy and safety of ketamine for depression in patients with cancer: A systematic review.

Background: Management of depression in the oncology population includes supportive psychotherapeutic interventions with or without psychotropic medication, which take time to demonstrate effectiveness. Fast-acting interventions, like ketamine, can provide a rapid antidepressant effect; however, there has been limited research on effects of ketamine among cancer patients. The objective of this review is to provide an overview of research on the efficacy and safety of ketamine on depression in patients with cancer. Methods: We reviewed the published literature in MEDLINE® (via PubMed®), EMBASE, and Scopus from 1 January 1982 to 20 October 2022. We screened the retrieved abstracts against inclusion criteria and conducted a full-text review of eligible studies. Following extraction of data from included studies, we used a framework analysis approach to summarize the evidence on using ketamine in patients with cancer. Results: All 5 included studies were randomized clinical trials conducted in inpatient settings in China. In all included studies ketamine was administered intravenously. Three studies used only racemic ketamine, and two studies used both S-ketamine and racemic ketamine. All included studies reported ketamine a tolerable and effective drug to control depression symptoms. Conclusion: Included studies showed administration of sub-anesthesia ketamine significantly improves postoperative depression among patients with cancer.

Myeloid cell-associated aromatic amino acid metabolism facilitates CNS myelin regeneration.

Regulation of myeloid cell activity is critical for successful myelin regeneration (remyelination) in demyelinating diseases, such as multiple sclerosis (MS). Here, we show aromatic alpha-keto acids (AKAs) generated from the amino acid oxidase, interleukin-4 induced 1 (IL4I1), promote efficient remyelination in mouse models of MS. During remyelination, myeloid cells upregulated the expression of IL4I1. Conditionally knocking out IL4I1 in myeloid cells impaired remyelination efficiency. Mice lacking IL4I1 expression exhibited a reduction in the AKAs, phenylpyruvate, indole-3-pyruvate, and 4-hydroxyphenylpyruvate, in remyelinating lesions. Decreased AKA levels were also observed in people with MS, particularly in the progressive phase when remyelination is impaired. Oral administration of AKAs modulated myeloid cell-associated inflammation, promoted oligodendrocyte maturation, and enhanced remyelination in mice with focal demyelinated lesions. Transcriptomic analysis revealed AKA treatment induced a shift in metabolic pathways in myeloid cells and upregulated aryl hydrocarbon receptor activity in lesions. Our results suggest myeloid cell-associated aromatic amino acid metabolism via IL4I1 produces AKAs in demyelinated lesions to enable efficient remyelination. Increasing AKA levels or targeting related pathways may serve as a strategy to facilitate the regeneration of myelin in inflammatory demyelinating conditions.

The chemotherapeutic agent doxorubicin induces brain senescence, with modulation by APOE genotype.

Many cancer patients experience serious cognitive problems related to their treatment, which can greatly affect their quality of life. The molecular mechanisms of this cancer chemotherapy-induced cognitive impairment (CICI) are unknown, thus slowing the development of preventative approaches. We hypothesized that cancer chemotherapies could induce cellular senescence in the brain, creating a pro-inflammatory environment and damaging normal brain communication. We tested this hypothesis using the common chemotherapeutic agent doxorubicin in two independent mouse models. In the first model, we used mice that express tdTomato under the pdkn2a (p16) promoter; p16 is a regulator of cellular senescence, and its upregulation is denoted by the presence of fluorescently tagged cells. Two weeks after exposure to three doses of 5 mg/kg doxorubicin, the number of tdTomato positive cells were increased nearly three-fold in both the cerebral cortex and the hippocampus. tdTomato staining co-localized with neurons, microglia, oligodendrocyte precursor cells, and endothelial cells, but not astrocytes. In the second model, we used APOE knock-in mice, since the APOE4 allele is a risk factor for CICI in humans and mouse models. We isolated RNA from the cerebral cortex of APOE3 and APOE4 mice from one to 21 days after a single dose of 10 mg/kg doxorubicin. Using NanoString analysis of over 700 genes related to neuroinflammation and RT-qPCR analysis of cerebral cortex transcripts, we found two-fold induction of four senescence-related genes at three weeks in the APOE4 mice compared to the APOE3 control mice: p21(cdkn1a), p16, Gadd45a, and Egr1. We conclude that doxorubicin promotes cellular senescence pathways in the brain, supporting the hypothesis that drugs to eliminate senescent cells could be useful in preventing CICI.

Anesthetic Management for a Patient with Rosai-Dorfman Disease, Cowden Syndrome, and Lhermitte-Duclos Disease: An Extremely Rare Disease Combination.

Rosai-Dorfman disease (RDD) is a rare condition that causes massive lymphadenopathy, most commonly in the cervical area. Cowden syndrome (CS) causes hamartomas in the skin and mucosa and predisposes individuals to various malignancies. Lhermitte-Duclos disease (LDD), or dysplastic cerebellar gangliocytoma, is often associated with CS. A 41-year-old female with all three conditions presented with abnormal uterine bleeding and endometrial intraepithelial neoplasia (EIN). Precautions should be considered when evaluating patients with RDD and CS preoperatively and during airway management owing to the potential for multisystem involvement, anatomical distortion, and difficult airways. The likelihood of having all three conditions is extremely rare.

The apoptotic splicing regulators RBM5 and RBM10 are subunits of the U2 snRNP engaged with intron branch sites on chromatin.

Understanding the mechanisms of pre-mRNA splicing and spliceosome assembly is limited by technical challenges to examining spliceosomes in vivo. Here we report the isolation of RNP complexes derived from precatalytic A or B-like spliceosomes solubilized from the chromatin pellet of lysed nuclei. We found that these complexes contain U2 snRNP proteins and a portion of the U2 snRNA, bound with intronic branch sites prior to the first catalytic step of splicing. Sequencing these pre-mRNA fragments allowed the transcriptome-wide mapping of branch sites with high sensitivity. In addition to known U2 snRNP proteins, these complexes contained the proteins RBM5 and RBM10. RBM5 and RBM10 are alternative splicing regulators that control exons affecting apoptosis and cell proliferation in cancer, but were not previously shown to associate with the U2 snRNP or to play roles in branch site selection. We delineate a common segment of RBM5 and RBM10, separate from their known functional domains, that is required for their interaction with the U2 snRNP. We identify a large set of splicing events regulated by RBM5 and RBM10 and find that they predominantly act as splicing silencers. Disruption of their U2 interaction renders the proteins inactive for repression of many alternative exons. We further find that these proteins assemble on branch sites of nearly all exons across the transcriptome, including those whose splicing is not altered by them. We propose a model where RBM5 and RBM10 act as components of the U2 snRNP complex. From within this complex, they sense structural features of branchpoint recognition to either allow progression to functional spliceosome or rejection of the complex to inhibit splicing.

Exaggerated elastin turnover in young individuals with Marfan syndrome: new insights from the AIMS trial.

Aims: The fragmentation and loss of elastic fibre in the tunica media of the aorta are pathological hallmarks of Marfan syndrome (MFS) but the dynamics of elastin degradation and its relationship to aortic size and physiological growth remain poorly understood. Methods and results: In this post hoc analysis of the AIMS randomized controlled trial, the association of plasma desmosine (pDES)-a specific biomarker of mature elastin degradation-with age and aortic size was analysed in 113 patients with MFS and compared to 109 healthy controls. There was a strong association between age and pDES in both groups, with higher pDES levels in the lower age groups compared to adults. During childhood, pDES increased and peaked during early adolescence, and thereafter decreased to lower adult levels. This trend was exaggerated in young individuals with MFS but in those above 25 years of age, pDES levels were comparable to controls despite the presence of aortic root dilation. In MFS children, increased aortic diameter relative to controls was seen at an early age and although the increase in diameter was less after adolescence, aortic root size continued to increase steadily with age. In MFS participants, there was an indication of a positive association between baseline pDES levels and aortic root dilatation during up to 5 years of follow-up. Conclusion: This study has shown that developmental age has a significant effect on levels of elastin turnover as measured by pDES in MFS individuals as well as healthy controls. This effect is exaggerated in those with MFS with increased levels seen during the period of physiologic development that plateaus towards adulthood. This suggests an early onset of pathophysiology that may present an important opportunity for disease-modifying intervention.

Base editing corrects the common Salla disease SLC17A5 c.115C>T variant.

Free sialic acid storage disorders (FSASDs) result from pathogenic variations in the SLC17A5 gene, which encodes the lysosomal transmembrane protein sialin. Loss or deficiency of sialin impairs FSA transport out of the lysosome, leading to cellular dysfunction and neurological impairment, with the most severe form of FSASD resulting in death during early childhood. There are currently no therapies for FSASDs. Here, we evaluated the efficacy of CRISPR-Cas9-mediated homology directed repair (HDR) and adenine base editing (ABE) targeting the founder variant, SLC17A5 c.115C>T (p.Arg39Cys) in human dermal fibroblasts. We observed minimal correction of the pathogenic variant in HDR samples with a high frequency of undesired insertions/deletions (indels) and significant levels of correction for ABE-treated samples with no detectable indels, supporting previous work showing that CRISPR-Cas9-mediated ABE outperforms HDR. Furthermore, ABE treatment of either homozygous or compound heterozygous SLC17A5 c.115C>T human dermal fibroblasts demonstrated significant FSA reduction, supporting amelioration of disease pathology. Translation of this ABE strategy to mouse embryonic fibroblasts harboring the Slc17a5 c.115C>T variant in homozygosity recapitulated these results. Our study demonstrates the feasibility of base editing as a therapeutic approach for the FSASD variant SLC17A5 c.115C>T and highlights the usefulness of base editing in monogenic diseases where transmembrane protein function is impaired.