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IntroductionIntegrins are a family of transmembrane heterodimer proteins differentially expressed on the cell surface of many lung cell types. Integrin-mediated activation of the key pro-fibrotic mediator TGF-β1, plays a critical role in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). Both galectin-1 and galectin-3 potentiate this TGF-β1 signaling pathway to promote fibrogenesis, although the exact mechanism is unclear. Integrins are glycoproteins thus their activity can be facilitated by glycan-mediated interactions with N-linked glycosylation the most well studied.1 ObjectiveTo investigate whether galectin-1 and galectin-3 interact directly with αvβ1, αvβ5 and αvβ6 integrins using biophysical methods.MethodsIntegrin-galectin interactions were determined by surface plasmon resonance (SPR) in the presence of divalent cations and the effect of extensive integrin deglycosylation or removal of N-linked oligosaccharides alone explored. SPR was used to assess integrin-galectin interactions in the presence of small molecule galectin inhibitors, GB1107 (galectin-3 selective inhibitor) or GB1490 (galectin-1 selective inhibitor). Binding of both galectins to N-Acetyl-D-glucosamine was assessed by isothermal titration calorimetry (ITC).ResultsSPR data showed that both galectin-1 and galectin-3 bind to recombinant human αvβ1, αvβ5 and αvβ6 in a glycosylation-dependent manner. Minimal integrin-galectin binding was observed following integrin protein deglycosylation or in the presence of small molecule galectin inhibitors which act via the galectin carbohydrate binding domain (CBD). However, the removal of integrin N-linked oligosaccharides alone resulted in only a partial decrease in integrin-galectin binding. Additionally, ITC demonstrated that both galectin-1 and galectin-3 were unable to bind N-Acetyl-D-glucosamine; the α5β1 terminal sugar required for α5β1-fibronectin binding.ConclusionGalectins are able to bind to integrins via their post-translational glycosylation sites. Collectively, these data suggest that the presence of both N-linked and O-linked glycan residues are essential for integrin-galectin binding, and that this binding may occur at the galectin galactoside-binding pocket. Understanding the precise role of galectins in integrin-mediated TGF-β1 activation and IPF pathogenesis may be critical for the continued development of more effective and selective treatments for IPF patients.ReferenceJanik ME, et al. Cell migration-the role of integrin glycosylation. Biochim Biophys Acta. 2010; 1800(6):545–55.Please refer to page A190 for declarations of interest related to this abstract.

RationaleRespiratory tract infection (RTI) is a major issue in athlete health and is the leading cause of training and competition time-loss. The host-defence immunomodulatory factors associated with heightened RTI susceptibility remains unclear.ObjectiveThis prospective study aimed to characterise host immune factors in international athletes exhibiting heightened RTI susceptibility. Methods/measurements: Comprehensive clinical and physiological phenotyping was prospectively undertaken in a cohort of 121 elite athletes. Athletes were characterised using objective retrospective electronic medical record analysis as highly susceptible (HS) (≥5 confirmed RTI over last 18 months) (N=22) or non-susceptible (NS) to RTI (<2 confirmed infections over last 18 months) (N=23). Peripheral blood lymphocyte population phenotyping of HS and NS athletes was performed by flow cytometry, with validation of findings by mass cytometry. The immune response to microbial stimuli was analysed by peripheral blood mononuclear cell (PBMC) stimulation assays. Further immuno-metabolic phenotyping was performed through 16S rRNA microbial sequencing of oropharyngeal swabs and global untargeted plasma metabolomic profiling. Findings were compared to data from a non-athletic healthy control group (N=10).Main ResultsHS athletes had a persistently reduced memory T regulatory cell compartment compared to NS athletes (p=0.005) and healthy controls (p=0.002) (see figure 1) with a T helper 2 skewed PBMC immune response to microbial stimuli additionally seen in HS athletes. 16S rRNA microbial sequencing revealed a reduced bacterial biomass of the oropharyngeal microbiome in athletes compared to healthy controls (p=0.032), with plasma metabolomic profiling showing significant differences in sphingolipid pathway metabolites in HS athletes compared to NS athletes and healthy controls. Immune phenotypic differences were not related to sporting discipline or evidence of underlying asthma or atopy.Abstract S94 Figure 1CD4+ FoxP3 populations in elite athlete cohort. The CD3+ CD4+ T cell population identified using CyTOF was subjected to tSNE analysis using Cytobank. Using heat maps overlaid on tSNE plots, 2 FoxP3+ populations were identified and termed as FoxP3 P1 and FoxP3 P2 (a). Heatmaps were further used to examine differences in CD4 and Treg markers, with FoxP3+ population 2 seen to be CD45ROhiCD45RAdimCD95hi identifying it as a memory Treg subset (b). FoxP3 P2 populations as a total of total CD3+CD4+ T cells were calculated (c) and compared for total athletes (TA), highly susceptible (HS), non-susceptible (NS) athletes and healthy controls (HC)ConclusionElite athletes have evidence of upper airway microbial dysbiosis, with a reduction in circulating memory T regulatory cells, and metabolic dysregulation of the sphingolipid pathway evident in those HS to RTI. Further prospective longitudinal work is needed to explore this novel potential mechanistic link to elite athlete infection susceptibility.Please refer to page A190 for declarations of interest related to this abstract.

Introduction and ObjectivesLung cancer is the commonest cause of cancer-related deaths. Early detection improves outcomes, however, the diagnostic yield of existing sampling techniques is suboptimal. Fluorescence-lifetime imaging microscopy (FLIM), an autofluorescence-based technique which measures endogenous fluorophore decay rates, may aid identification of optimal biopsy sites in suspected lung cancer. We describe the application of a novel fibre-based FLIM system, which utilises 488nm excitation to enable fluorescence intensity and lifetime imaging, to detect changes in freshly resected lung cancer and adjacent healthy tissue. The mechanisms responsible for alterations in lung cancer fluorescence lifetime are not understood. We investigate the contributions of cancer cells and tumour stroma to fluorescence lifetime signatures using fixed unstained lung cancer and benchtop FLIM.MethodsPaired cancer and non-cancerous lung tissues were obtained from resection patients (n=21). A 488nm fibre-based FLIM platform was used to perform high-resolution fluorescence intensity and lifetime imaging (figure 1). Co-registered fixed unstained lung cancer sections were evaluated using benchtop FLIM and image analysis software.ResultsFluorescence lifetime is significantly reduced in fresh ex vivo lung cancer, compared with non-cancerous tissue (mean±SD, 2.15±0.26ns vs. 1.79±0.40ns, p<0.0001). Fibre-based FLIM distinguishes lung cancer, from adjacent tissue, with 81.0% sensitivity and 71.4% specificity. Lifetime-based signatures are retained after fixation, as evidenced by benchtop FLIM of fixed unstained lung cancer, which demonstrates no difference in fluorescence lifetimes compared with fresh cancer (p=0.55). By applying this technique on fixed tissues, we demonstrate that cancer cells have significantly longer lifetimes, compared with tumour stroma (p=0.027). Cancer subtype also influences lifetime signatures (mean±SD, adenocarcinoma 1.55±0.38ns vs. squamous cell carcinoma 2.57±0.47ns, p=0.0005). Mean fluorescence lifetimes of fixed unstained lung cancer positively correlate with the proportion of cancer cells within tissue section area (r=0.80; p=0.033).Abstract S99 Figure 1(a) Translational fibre-based FLIM system, with optical imaging fibre (1.42mm outer diameter) delivered via the working channel of a bronchoscope. Fluorescence lifetime images of (b) non-cancerous and (c) cancerous human lung tissue using fibre-based FLIM. (d) Corresponding haematoxylin and eosin stained sections of non-cancerous and cancerous (adenocarcinoma) lung tissueConclusionsOur novel fibre-based FLIM system discriminates lung cancer from adjacent healthy tissue ex vivo with good performance characteristics. This minimally invasive technique, which is deliverable via endoscopic platforms, may permit advanced in situ diagnostic capabilities in lung cancer. FLIM of fixed unstained tissue enables cellular resolution lifetime characterisation, and highlights the role of cancer cells in determining the overall fluorescence lifetime signature in lung cancer.Please refer to page A190 for declarations of interest related to this abstract.

Introduction and ObjectivesPulmonary arteriovenous malformations (PAVMs) are most commonly caused by hereditary haemorrhagic telangiectasia (HHT). This multisystemic condition, inherited as an autosomal dominant trait, results from a heterozygous loss-of-function variant in ACVRL1, ENG or SMAD4. Heterozygous endothelial cell phenotypes have proved elusive, hindering preclinical testing of potential therapeutic agents. Here, our objective was to define the transcriptional changes occurring in patient-derived blood outgrowth endothelial cells (BOECs).MethodsWith ethical approvals (16/ES/0095), BOECs were established from HHT/PAVM patients heterozygous for a pathogenic variant in ACVRL1, ENG or SMAD4, and from heathy volunteers. HHT gene protein production by patient and control BOECs was evaluated by 35S-methionine pulse chase experiments. Single cell qRT-PCR aimed to verify expression and heterogeneity of 48 transcripts in 40 viable (DRAQ7 negative) BOECs per genotype. Long and short RNA libraries were generated from BOECs prior to Illumina HiSeq sequencing of paired-end reads, and alignment to GRCh38. Differential alignments were used to rank transcripts for discovery gene ontology process identifications.Results24 BOEC lines were established from patients heterozygous for one of 10 different nonsense (stop gain) pathogenic variants in ENG, ACVRL1 and SMAD4, with a median of two donors per genotype. Pulse chase experiments distinguished the genotypes. Blinded analyses of normalised RNASeq alignments also identified the source heterozygous HHT genotypes: ENG alignments were lowest in heterozygous ENG+/- BOECs (Dunn’s p=0.0089); ACVRL1 alignments lowest in heterozygous ACVRL1+/- BOECs (p=0.0040) and SMAD4 alignments lowest in heterozygous SMAD4+/- BOECs (p=0.007). By single cell qRT-PCR, 7/48 (15%) genes were expressed in all BOECs, 7/48 (15%) in no BOECs with 34 genes expressed in a proportion of BOECs. Seven genes displayed differential expression patterns between HHT and control BOECs, confirmed by distribution plots of all 16,807 RNASeq Ensembl transcript alignments in BOECs from different donors. Ranking transcripts by differential alignments in ENG/ACVRL1/SMAD4 compared to control BOECs, identified consistent gene ontology processes enriched compared to equivalent numbers of randomly-selected transcripts.ConclusionsThere are reproducible, transcriptional signatures in pulmonary AVM and HHT patient-derived BOECs distinguishable from healthy volunteer BOEC signatures. Common patterns for ACVRL1, ENG and SMAD4 BOECs suggest a shared HHT transcriptome phenotype.

Objective: To investigate the clinical diversity, genetic bases, diagnostic complexity, and therapeutic approaches of epileptic syndromes, highlighting recent advances in understanding these disorders.   Theoretical Framework: Epileptic syndromes are neurological disorders characterized by recurrent epileptic seizures, resulting from abnormal neuronal activity in the brain, whose classification has evolved towards clinical and genetic criteria.   Method: A systematic approach was employed for bibliographic review on epileptic syndromes, consulting biomedical databases and applying strict selection criteria. Studies addressing clinical diversity, genetic bases, and diagnostic complexity were included, followed by qualitative data analysis to identify patterns and gaps in the literature.   Results and Discussion: Results reveal evident genetic heterogeneity, with some syndromes exhibiting well-defined genetic bases. Advances in genomics and molecular neurobiology have provided insights into pathogenic mechanisms, despite persistent challenges, including resistance to conventional medications.   Implications of the Research: In-depth understanding is crucial for accurate diagnosis and effective therapeutic development, emphasizing the continuous need for research to improve clinical outcomes and quality of life for patients.   Originality/Value: Highlights recent advances in understanding epileptic syndromes, identifying key areas for future research, and contributing to better comprehension and quality of life for affected patients.

The U.S. life science research mission is critical not only to human health and understanding the natural world but also to agriculture and food production, technological innovations, socioeconomic progress, and our national defense and leadership worldwide. A 2025 Research!America survey reveals that 92% of Americans want government to actively work to promote medical progress, in part by funding infectious and chronic disease research. Why? Because biomedical research saves lives, prevents suffering, and increases quality of life for not only Americans but for people throughout the world. While less well appreciated, science also drives enormous economic growth. Indeed, historically there has been widespread bipartisan support for biomedical funding by the federal government. Below we discuss the U.S. scientific research enterprise and provide evidence and arguments we hope the ASM community can use to advocate for science.

Ocean carbon sink is an emerging and interdisciplinary research area that plays a vital role in the global carbon cycle. This paper reviews recent scientific advancements in ocean carbon sink research, focusing on the mechanisms for capturing, utilizing, and sequestering atmospheric CO 2 , and highlights its contribution to climate change mitigation and adaptation. Using bibliometric analysis based on CiteSpace and data from the Web of Science and Scopus, we examine research hotspots and topic evolution through country collaboration, journal co-citation, and keyword co-occurrence networks. The findings show that ocean carbon sink research is shaped by complex scientific uncertainties and the integration of multiple disciplines. Current research hotspots include scientific advances, technological innovation, and governance challenges related to sustainable development. In general, recent studies emphasize the role of carbon sink, the value of nature, and the importance of precautionary management. This paper underlines the need for coordination between scientific and social dimensions of carbon sink functions, and it draws attention to the ethical aspects of carbon sink governance. It advocates for multi-stakeholder participation, precautionary governance, and policy-based financial system to support climate resilience and foster the sustainable development of the oceans.

Synthetic male sling (MS) is considered an effective surgical treatment to restore male stress urinary incontinence. The modern MS can be categorised into adjustable or non-adjustable types, while the surgical techniques can be divided into retropubic or transobturator approaches. This narrative review paper evaluates the contemporary MS devices in the current commercial market regarding clinical outcomes and refinements in surgical techniques. Scientific advances in device design and technology, coupled with further surgical refinements will enhance the clinical outcomes and improve the safety profile of MS surgery. The newer generation of modern MS not only provides direct compression of the bulbar urethra but also allows for proximal urethral relocation by realigning the mobile sphincter complex to provide further urethral sphincter complex coaptation. Strict patient selection, use of MS with proven clinical records, adherence to safe surgical principles and judicious postoperative care are critical to ensure a high continence rate, good patient satisfaction and low postoperative complications.