Wilson disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B gene, resulting in impaired biliary copper excretion and progressive copper accumulation in multiple tissues. Ocular manifestations represent some of the most characteristic and clinically valuable features of the disease, contributing to diagnosis, monitoring, and assessment of neurological involvement. This narrative review summarizes current knowledge regarding the pathophysiology, clinical presentation, and imaging characteristics of ocular involvement in WD. Copper deposition within the eye occurs primarily through the aqueous humor, leading to accumulation in the corneal Descemet membrane and lens capsule. Kayser-Fleischer rings remain the most prevalent ocular sign being strongly associated with neurological disease, while sunflower cataracts represent a less common but highly characteristic manifestation. Anterior segment optical coherence tomography and in vivo confocal microscopy have recently improved the detection and monitoring of these lesions. Beyond copper deposition, growing evidence indicates that WD is associated with retinal and optic nerve neurodegeneration. Optical coherence tomography studies consistently demonstrate thinning of the retinal nerve fiber layer, ganglion cell complex, and macular structures, particularly in patients with neurological involvement. Electrophysiological investigations, including visual evoked potentials and electroretinography, reveal delayed neural conduction and retinal dysfunction, supporting the concept of widespread neuro-ophthalmological impairment. Optical coherence tomography angiography further identifies microvascular alterations affecting retinal and peripapillary capillary networks. Importantly, several ocular abnormalities correlate with neurological severity and may serve as non-invasive biomarkers of disease progression. Current treatments, including copper chelators and zinc therapy, can induce regression of Kayser-Fleischer rings and sunflower cataracts. Ocular assessment therefore provides a valuable window into systemic and neurological disease activity, highlighting the importance of multidisciplinary management and the potential role of emerging imaging biomarkers in Wilson disease.
Diabetic retinopathy (DR) is a leading cause of vision impairment among individuals with diabetes, driven by microvascular damage and retinal degeneration. Recent evidence implicates ceramides-bioactive sphingolipids-as critical mediators in DR pathogenesis. These lipids influence critical cellular processes, including apoptosis, inflammation, and oxidative stress. Emerging data suggests that ceramide accumulation exacerbates retinal neurodegeneration in DR by modulating key molecular pathways. This review synthesizes current knowledge on the role of ceramides in DR development and progression, examines the factors influencing their activity, and explores the therapeutic potential of targeting ceramide metabolism. By integrating recent findings, this article aims to provide insights for future research and clinical strategies in DR management.
Neuromuscular fatigue (NMF) is an inherent consequence of strenuous training and competition. It arises from complex interactions between the central nervous system and peripheral skeletal muscle. Despite decades of research, the interaction between central and peripheral mechanisms of neuromuscular fatigue and their influence on sports performance remains a contentious topic. In addition, translating mechanistic insights into practical strategies for monitoring, training, and recovery in athletes is an ongoing challenge. This review synthesizes contemporary literature to build a central-peripheral integrative model of NMF and proposes an applied framework for athlete monitoring and training design. The review first summarizes central and peripheral fatigue mechanisms, highlighting the bidirectional influence of descending motor drive and afferent feedback, and discusses controversies such as the central-governor theory. It then assesses monitoring tools (subjective ratings, neuromuscular tests, electromyography, heart-rate variability, biochemical and neurochemical markers) and recovery strategies. Finally, the review translates mechanistic knowledge into evidence-based training and recovery recommendations. A conceptual model illustrating the interactions between central and peripheral mechanisms and their monitoring is included. The aim is to inform sports scientists and practitioners about the physiological bases of fatigue and provide guidance for individualized athlete management.
Chromatin remodeling plays a central role in regulating plant development and physiology by shaping the gene expression patterns that drive biological processes. Among epigenetic modifications, histone acetylation is particularly relevant as it alters chromatin structure and influences transcriptional activity. MYST-type histone acetyltransferases (HAT) are evolutionarily conserved components of the Nucleosome Acetyltransferase of histone H4 (NuA4) complex, a key regulator that acetylates histones H4, H2A, and the histone variant H2A.Z. Growing evidence supports the presence of a canonical NuA4-C in plants, similar to that described in yeast. In this review, we summarize recent studies that have begun to uncover its broad role in plant biology, highlighting its involvement in diverse processes such as the skoto- to photomorphogenesis switch, chloroplast development, shade avoidance responses, thermomorphogenesis, the vegetative-to-reproductive transition, plant growth, reproduction and hormonal signalling. In addition, we discuss recent advances in understanding the crosstalk of NuA4-C-mediated H4ac and H2A.Z deposition with other chromatin remodeling complexes in plants. Although significant progress has been made, a full understanding of the complex functions remains unavailable. Current evidence indicates that NuA4-C in yeast and TIP60 in humans are central regulators of transcription, acting not only through histone acetylation but also by influencing transcription elongation and RNA splicing, although direct evidence for similar functions in plant NuA4-C still remains limited. This regulatory role might be critical for integrating developmental programs with environmental signalling pathways. While initial insights into the recruitment of NuA4-C to target genes have emerged, further research is needed to clarify how its activity is controlled and modulated in different biological contexts.
Hispanic/Latino Americans are disproportionately affected by vascular risk factors (VRFs) linked to cognitive decline, yet they remain underrepresented in neuroimaging research. The aim of this study was to determine how white matter (WM) injury imaging biomarkers relate to cognition among Hispanic/Latino adults of different heritage. This study included 2,385 participants from the Study of Latinos-Investigation of Neurocognitive Aging MRI ancillary study, a cohort of self-identified Hispanic/Latino individuals. Cognitive performance was evaluated using standardized, log-transformed scores for Global Cognition Score (GCS), processing speed (Trail Making Test Part A), and executive function (Trail Making Test Part B). MRI data for each participant were acquired using standardized 3T protocols and WM injury measures, including WM hyperintensity (WMH) volume, free water (FW) fraction, and fractional anisotropy (FA). Multivariable regression models adjusted for age at MRI, sex, education, VRFs (diabetes, hypertension, smoking, self-reported history of prevalent stroke/TIA), years of US mainland residency, and heritage were used to assess the associations between imaging biomarkers and cognition. Significant differences in cognitive outcomes were observed across Hispanic/Latino heritage groups (p < 0.001). Compared with Central or South American participants, Dominican participants had lower GCS and TMT-A and TMT-B scores and Mexican participants had higher GCS and TMT-A and TMT-B scores (p < 0.05). Multivariable regression analyses using global diffusion MRI metrics revealed that higher FW and WMH and lower FA were significantly associated with worse global cognition, processing speed, and executive function (p < 0.001). WMH was the only imaging biomarker significantly associated with cognitive status, defined as impaired vs unimpaired (p < 0.001). Voxel-wise analyses identified robust FW-cognition associations in frontoparietal and temporal WM regions, including the corpus callosum, superior longitudinal fasciculus, anterior corona radiata, and retrolenticular internal capsule. In this large and diverse cohort of Hispanic/Latino adults, greater microstructural (FW, FA) and macrostructural (WMH) WM injury was associated with worse cognitive performance. FW was more strongly associated with continuous measures of cognition, whereas WMH was most strongly related to the categorical level of impairment. These results emphasize the complementary roles of microstructural and macrostructural measures of WM pathology in capturing different aspects of cognition.
Isolated REM sleep behavior disorder (iRBD) is recognized as a prodromal stage of α-synucleinopathies. Iron metabolism and inflammation have been implicated in the pathogenesis of neurodegeneration. This study investigated the peripheral iron metabolism and inflammation in relation to prodromal clinical features and disease progression in iRBD. This prospective observational cohort study recruited patients with iRBD at Sleep Medicine Center of West China Hospital. We measured peripheral iron metabolism markers and analyzed their associations with clinical characteristics; REM sleep without atonia (RSWA); and inflammatory markers including C-reactive protein (CRP), interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α. Patients with iRBD were further stratified based on sex-specific ferritin levels. Cox regression was used to assess the risk of neurodegenerative diseases. A total of 113 patients with iRBD (65.33 ± 6.80 years, 23.1% female) and 99 healthy controls (HCs) (64.92 ± 7.12 years, 22.1% female) were enrolled. Patients with iRBD showed dysregulated iron metabolism, with particularly elevated serum ferritin levels compared with HCs (338.48 ± 200.16 vs 238.73 ± 129.50, p < 0.001). Serum ferritin was positively associated with RBD symptom severity, autonomic dysfunction, olfactory impairment, motor symptoms, and RSWA. In the longitudinal analysis, 79 patients with iRBD were included, with a follow-up duration of 4.06 ± 2.1 years. During this period, 23 patients (29.1%) developed neurodegenerative diseases. In a Cox regression model adjusted for age and sex, elevated ferritin levels were significantly associated with an increased risk of phenoconversion (hazard ratio 2.91, 95% CI 1.06-7.99, p = 0.038). Patients with iRBD with high ferritin demonstrated increased IL-10 (3.21 ± 1.71 vs 2.53 ± 1.24, p = 0.029) and TNF-α (4.27 ± 3.41 vs 2.77 ± 2.38, p = 0.046) levels. Serum ferritin levels were positively correlated with CRP (r = 0.204, p = 0.003) and TNF-α (r = 0.160, p = 0.020). This study showed the dysregulation of peripheral iron metabolism in patients with iRBD. Elevated serum ferritin was associated with a more severe prodromal neurodegenerative phenotype in iRBD. Furthermore, our findings indicate that peripheral iron metabolism potentially correlates with inflammation in the neurodegeneration of iRBD.
Despite increasing evidence supporting the validity and utility of pharmacogenomic (PGx)-guided prescribing, clinical PGx testing in oncology remains limited. However, expanding professional guidelines and recommendations have accelerated PGx implementation efforts in the United States. Given the availability of actionable PGx guidelines for several medications commonly prescribed to patients with cancer, this study evaluated US oncologists' knowledge, attitudes, and perceived barriers regarding PGx-guided medication management. A survey focused on oncology-relevant medications with actionable PGx guidelines, including fluoropyrimidines, thiopurines, irinotecan, and opiates/antidepressants, was distributed to clinical oncologists in the United States from December 2023 to August 2024 through ASCO Research Survey Pool, the Association of Northern California Oncologists, and regional ASCO-affiliated groups. A total of 146 providers completed the survey, most through ASCO (n = 125). Opiates and antidepressants were the most frequently prescribed medications in the previous 6 months (92%), followed by fluoropyrimidines (75%). Nearly all respondents (93%) had heard of PGx, although most were only moderately familiar (57%), and PGx awareness for chemotherapies (92%) was much greater than opiates/antidepressants (47%). Reported barriers to PGx testing for chemotherapy management included uncertain utility, concerns for treatment delay, and unclear National Comprehensive Cancer Network recommendations, and barriers for opiate/antidepressant management included uncertain utility, lack of awareness, and uncertainty regarding test ordering and result interpretation. These findings provide valuable insights into the perspectives of oncologists on implementing PGx testing; however, awareness and utilization were higher than previously reported. Importantly, the identified implementation barriers for oncology are both actionable and timely, particularly given the evolving updates to drug labels and professional guidelines supporting PGx testing for medications relevant to patients with cancer.
Many enzymes catalyze chemically complex rearrangement reactions, yet the molecular strategies that enable precise atomic control often remain enigmatic. One of Nature's most intricate examples occurs in the biosynthesis of the molybdenum cofactor (Moco), a pterin-based cofactor essential to all domains of life. Formation of Moco's characteristic pyranopterin requires a remarkable rearrangement of GTP, in which the C8 atom of the guanine base is inserted between the C-2' and C-3' atoms of ribose. Remarkably, this transformation is catalyzed by a single enzyme, MoaC, yet how MoaC orchestrates this rearrangement remains unclear. Here, we show that MoaC employs an unexpected covalent catalytic mechanism. Using chemical trapping, enzyme kinetics, mass spectrometry, and X-ray crystallography, we identified four kinetically relevant covalent intermediates. The transient covalent linkage forms between Lys131 and the substrate-derived C-8 atom and persists across most catalytic steps. While covalent catalysis is classically viewed as a means of substrate activation, the primary function of the transient covalent linkage in MoaC is to govern the spatial trajectory of the reacting carbon center. We term this catalytic strategy guiding covalent catalysis. This mechanism explains the long-standing absence of diffusible intermediates during MoaC catalysis and revises prevailing noncovalent models of Moco and pterin biosynthesis. Together, our findings establish guiding covalent catalysis as a distinct functional mode that enables precise spatial control in complex biochemical transformations and suggest that analogous guiding roles may operate in the biosynthesis of other cofactors.
KRAS mutations are common in colorectal cancer, but the impact of KRAS mutation subtypes on treatment response remains poorly understood. This research aimed to investigate whether different KRAS mutations influence pathological complete response (pCR) rates after neoadjuvant chemoradiotherapy in locally advanced rectal cancer (LARC). A systematic review and meta-analysis of studies describing genetic determinants of response to neoadjuvant chemoradiotherapy in LARC was conducted, searching for manuscripts published up to March 2026. The primary outcome of interest was the odds ratio for KRAS mutations and pCR. A random-effects model estimated the pooled effect size of KRAS mutations within and outside exon 2 on pCR. Genomic data sets were analysed to investigate the molecular characteristics of KRAS exon 2 and non-exon 2 mutant rectal cancers and their impact on overall and disease-free survival. Finally, a transcriptomic data set was analysed to elucidate the underlying response mechanisms. Out of 11 537 manuscripts identified, 15 studies (3354 patients) were included in the meta-analysis. The odds ratio for any KRAS mutation and pCR was 0.48 (95% confidence interval 0.32 to 0.70), indicating reduced odds of pCR in KRAS-mutant LARC. Subgroup analysis revealed that KRAS mutations in exon 2 accounted for this effect, whereas variants outside exon 2 had no influence (odds ratio 0.96, 95% confidence interval 0.11 to 8.49). Analysis confirmed poorer disease-free survival in patients with exon 2 alterations (P = 0.019) as well as poorer overall survival (P = 0.047). Transcriptomic analysis revealed that non-exon 2 KRAS-mutant tumours were enriched for inflammatory signalling pathways, suggesting that these tumours represent a subgroup with high immune infiltration. The presence of KRAS mutations adversely affects pCR odds after neoadjuvant chemoradiotherapy in LARC, but this effect is specific to exon 2 mutations.
Bovine colostrum provides crucial immune and developmental support to newborn calves, yet the roles of non-immunoglobulin bioactive proteins remain underexplored. The objective of this study was to characterize the colostrum proteome and evaluate the effects of parity, prepartum dietary metabolizable energy, and colostral immunoglobulin G (IgG) concentration on its protein composition. Colostrum samples from primiparous and multiparous Angus × Simmental beef cows fed low-, control-, or high-metabolizable-energy diets during the prepartum period were analyzed by quantitative proteomics. We identified distinct proteomic signatures influenced by both parity and dietary energy. Colostrum from multiparous cows consistently exhibited an immune profile characterized by higher levels of lactoferrin, β2-microglobulin, and other immune-related proteins, particularly when fed diets high in metabolizable energy. In contrast, primiparous colostrum was enriched in structural and developmental proteins (e.g., tripartite motif-containing protein 68, growth/differentiation factor 8), with immune-related proteins increasing only under high-energy conditions. Colostrum from cows with higher IgG concentrations also contained proteins involved in innate immunity, cytoskeletal remodeling, and calcium signaling. In contrast, low-IgG colostrum showed compensatory enrichment of transcriptional and metabolic regulators. These findings reveal the interplay among parity, energy intake, and colostrum bioactivity, suggesting that cow parity and nutritional strategies should be considered to enhance colostrum quality and improve neonatal health outcomes.
The Arabian Gulf is a semi-enclosed sea with shallow waters. Its marine fauna must cope with extreme and recurring environmental conditions (high summer temperatures, hypersalinity, hypoxia). In addition, local human activities are very significant and have a marked impact on coastal areas, particularly in urban marine ecosystems (UME). Taken together, the Arabian Gulf's low species richness, its exposure to multiple human-induced stressors, and the proximity of many taxa to their environmental tolerance limits create a particularly concerning situation. Monitoring marine wildlife must be a priority in this context, particularly with respect to marine vertebrates, difficult to study using integrative approaches. The present study aimed to generate relevant data on marine vertebrate biodiversity in the UME of Abu Dhabi, and to provide evidence-based information to inform conservation policy. In addition, investigating marine biodiversity in the world's warmest sea in summer, the Arabian Gulf, will provide us with information of general interest in terms of the adaptation and evolution of marine fauna in the current period of global climate change. We conducted the first environmental DNA (eDNA)-based survey of marine vertebrate diversity in Abu Dhabi's UME. Using a standardized process of water sampling, eDNA metabarcoding using a  ~ 97 bp fragment of the mitochondrial 12S rRNA gene as barcode, and taxonomic assignment, we studied vertebrate biodiversity at four urban sites, including a marina, a newly developed area, a seagrass bed, and a protected urban mangrove. We identified 83 distinct taxa, including five birds, two elasmobranchs, one marine mammal, and 75 teleosts. The specific taxonomic richness did not vary significantly between sites. In contrast, phylogenetic diversity metrics revealed lower diversity than expected for the newly developed area, while the mangrove and, to a lesser extent, the seagrass bed exhibited a phylogenetic structure consistent with their species richness. This approach provides a powerful, non-invasive and integrative framework for long-term monitoring and supports evidence-based conservation planning for marine biodiversity in the Arabian Gulf.
TRK inhibitors (TRKis) have transformed the therapeutic landscape for patients with neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive tumors. However, approval of TRKis is based on evidence derived mainly from small, pooled, single-arm clinical trial cohorts. The REALTRK registry aims to describe real-world molecular diagnostic practices, treatment patterns, and clinical outcomes for adult patients with NTRK fusion-positive cancers. The REALTRK registry was a multicenter cohort study that included adults with advanced solid tumors harboring NTRK1/2/3 fusions, from Germany and Switzerland. Both retrospective and prospective data were collected from diverse clinical settings. NTRK fusions had to be diagnosed via validated assays. Of 88 patients screened, 47 adults with advanced NTRK fusion-positive solid tumors were included in the full analysis set. Across all treatment lines after NTRK fusion diagnosis, 29 patients received TRKi therapy, eight received non-TRKi therapy, and 10 received no therapy. Lung cancer, colorectal cancer, and soft tissue sarcoma were the most common tumor types. Next-generation sequencing was the primary diagnostic method, with a median turnaround time of 2 weeks. After NTRK fusion diagnosis, TRKi therapy was immediately initiated in 26 patients, of whom 13 received TRKi as first-line treatment in the advanced/metastatic setting. About half of the patients responded to TRKi treatment as the first treatment line after NTRK fusion diagnosis (46.2%), with an overall response rate of 46.2% and a disease control rate of 73.1%. The median progression-free survival was 15.7 months, and the overall survival was 27.6 months in TRKi-treated patients. The REALTRK registry provides important real-world insights into the patient path of adult patients with locally advanced or metastatic solid tumors harboring NTRK1/2/3 gene fusions.
Plants rely on cell surface immune receptors to detect microbial patterns and initiate effective defense responses. Although the Asteraceae family is one of the largest and economically important plant groups, little information is available about its pattern-triggered immunity signaling. Cultivated lettuce (Lactuca sativa L.) recognizes a 24-amino acid peptide (nlp24) from necrosis- and ethylene-inducing peptide 1 (Nep1)-like proteins (NLPs) found in bacteria, fungi, and oomycetes. Here, we perform an extensive characterization of nlp24-induced immune responses in lettuce and identify the LETTUCE nlp24 RECEPTOR (LNR) as the leucine-rich repeat receptor-like kinase mediating its recognition. Remarkably, nlp24 recognition in lettuce and subsequent activation of defenses strongly depend on the conserved heptapeptide motif (GHRHDWE). Structural modeling-guided mutagenesis experiments suggest that residues in the nlp24 heptapeptide interact with a hydrophobic pocket in the LNR solenoid structure. Divergent ligand specificities and the absence of sequence homology between LNR and the Arabidopsis nlp24-recognizing receptor RLP23 indicate that NLP recognition in lettuce and Arabidopsis emerged independently, through convergent evolution. Our phylogenetic analysis shows that LNR is closely related to Arabidopsis MALE DISCOVERER 1-INTERACTING RECEPTOR-LIKE KINASE 2 (MIK2) but belongs to a distinct, Asteraceae-specific monophyletic subgroup that has undergone a significant expansion in Lactuca. Our findings provide insights into the mechanisms of pattern-triggered immunity in lettuce and present an example of convergent evolution of plant pattern-recognition receptors.
The last few decades have witnessed a resurgence in pertussis notifications in a number of countries with high vaccine coverage, including Sweden. The underlying causes of the resurgence have been the subject of much scientific debate. To arbitrate among the putative drivers of the resurgence in Sweden, we formulated a mechanistic transmission model which we fit to age-structured time-series notifications data via likelihood maximisation. Given our model, we find the data are best explained by the combined effects of a low basic reproductive number, incomplete (leaky) DTaP-derived immunity, a much lower reporting probability of infections in older individuals and waning of vaccine-derived immunity. In addition, our modelling explains the post-2014 resurgence as a combination of two factors. First, a dynamical transient known as the honeymoon effect, in which a rebound in transmission follows after a rapid decrease in the average population susceptibility. Second, an increase in the infection reporting probability from 2014 onwards, likely due to the use of new laboratory testing methods. Additionally, we used our fitted transmission model to reconstruct indirect protective effects of vaccination. Our results suggest immunization prevents about 50% of potential infections in individuals too young to receive vaccination. However, our statistical inference demonstrates that pertussis elimination is not possible with routine immunization using acellular vaccines due to the combined effects of vaccine leakiness and waning immunity.
This study aimed to evaluate whether the magnesium depletion score (MDS), an indicator of magnesium deficiency, is associated with the development of complex regional pain syndrome type 1 (CRPS-1) in patients with traumatic extremity injuries. Between November 2024 and May 2025, a total of 117 patients who suffered from traumatic extremity injuries were included. Demographic and clinical data of the patients were collected and recorded, and the MDS was calculated. Age, sex, body mass index (BMI), smoking status, alcohol consumption, diabetes, hypertension, duration of immobilization, MDS, and injury-related characteristics were evaluated as potential risk factors for CRPS-1 development. Of the patients, 40 were male and 77 were female with a mean age of 51.9 ± 15.01 (range, 20 to 91 years). In a total of 42.7% of patients with traumatic extremity injuries, CRPS-1 developed. The female-to-male ratio was higher among patients with CRPS-1 than among those without. The MDS, hypertension, diabetes, smoking, and alcohol consumption were not found to be independent risk factors. However, prolonged immobilization (more than one month) was found to be an independent risk factor for the development of CRPS-1. Our study results suggest that the MDS score is not a risk factor for developing CRPS-1, but immobilization for more than one month significantly increases the risk. Taken together, these findings indicate that the duration of immobilization following injury may be a more decisive factor in the development of CRPS-1 than demographic and clinical characteristics.
Mutations in transmembrane channel-like protein 1 (TMC1), the pore-forming component of the mechano-electrical transducer (MET) channel in auditory hair cells, cause cell death and deafness in 3-wk old mice. We studied mice with mutations Tmc1 p.T416K, p.M412K, p.D528N, and p.D569N, which possessed functional MET channels at postnatal day (P)6 but became deaf before P21. These Tmc1 mutants had channels with reduced Ca2+ permeability and lower expression of the PMCA2 calcium pump in outer hair cell (OHC) stereocilia. The reduction in PMCA2 density was directly correlated with reduced Ca2+ entry via the MET channel. Over the first postnatal week, PMCA2 expression decreased in cochlear cultures containing lowered extracellular Ca2+, but after P11, PMCA2 density was insensitive to Ca2+ changes. The lower PMCA2 density in mutants was maintained into adulthood and may contribute to hair cell death. Before the onset of hearing, PMCA2 continuously turns over, and its insertion into stereocilia from an identified vesicular compartment is regulated by cytoplasmic [Ca2+]. PMCA2 turnover was strongly inhibited by the endocytosis blocker, Pitstop2, and by PtdIns(4,5)P2 blockers like phenylarsine oxide (PAO), which was shown to elevate stereociliary [Ca2+]. We argue the effects of PAO on mechanotransduction may be partly due to this Ca2+ increase. OHC bundles also expressed Neuroplastin (NPTN), a PMCA2 accessory protein, whose development paralleled PMCA2, and we propose it stabilizes the pump complex in stereocilia. NPTN expression was delayed about 2 d relative to PMCA2 and was less Ca2+ sensitive, implying it originates from a different internal pool of vesicles.
Extracellular vesicles (EVs) are membrane-bound particles that mediate intercellular communication and are being explored as carriers for antigen delivery in cancer immunotherapy. However, the molecular mechanisms underlying the uptake of antigen-carrying EVs by dendritic cells (DCs) remain unclear. EV uptake is influenced by the recognition of EV surface components by receptors on recipient cells. Phospholipids, including phosphatidylserine (PS), are common structural components of EV membrane. We therefore focused on the TAM receptor tyrosine kinases Tyro3, Axl, and Mertk, which are expressed in antigen-presenting cells and engage PS-exposing membranes through the bridging ligands Growth arrest-specific 6 (Gas6) and Protein S (Pros1). Using the DC2.4 dendritic cell line as a model system, we investigated the involvement of TAM receptors in the uptake of small EVs (sEVs) and subsequent antigen presentation. We found that Tyro3 binding to sEVs was enhanced by Gas6 and Pros1, and that Tyro3 also associated with phosphatidylserine (PS) and phosphatidylglycerol (PG) through these bridging ligands. Among TAM receptors, only Tyro3 markedly enhanced sEV internalization in DC2.4 cells. Deletion analysis indicated that the immunoglobulin C2-type domain (IG2c domain) of Tyro3 is required for efficient sEV association and uptake. Moreover, Tyro3-mediated internalization enabled cross-presentation of sEV-delivered antigens and activation of CD8+ T cells. This function required a 46-amino acid intracellular region of Tyro3, which we designated the Tyro3 antigen presentation-related domain (TAPD); deletion of TAPD impaired cross-presentation of sEV-delivered antigens. Finally, we observed an increase in the frequency of Tyro3 ⁺ DCs in the spleens of tumor-bearing mice. These findings suggest that Tyro3 mediates sEV uptake and antigen cross-presentation in DCs and may represent a candidate molecular target for EV-based cancer immunotherapy.
The dorsal vagal complex (DVC) includes a multi-component brainstem satiety centre which has gained attention as a key target of anti-obesity pharmacotherapies. Our recent studies revealed its circadian timekeeping properties, with molecular and electrophysiological 24 h rhythms persisting independently of the primary hypothalamic clock. However, the factors entraining these brainstem oscillators and the downstream transcriptional targets of the DVC molecular clock remain unclear. Here, using PERIOD2::LUCIFERASE reporter mice and fluorescent in situ hybridisation, we quantitatively demonstrate rhythms in core clock gene expression in the caudal DVC ex vivo and in vivo. We show that the molecular clock is associated with rhythmic expression of numerous neurotransmitter receptor genes in the DVC in vivo, with the phase of both clock and clock-controlled gene expression tightly regulated by meal timing. These findings uncover food-entrained circadian rhythms in the DVC and have important implications for clinical studies targeting brainstem satiety mechanisms.
Primary (genetic) pediatric dystonia, characterized by sustained or intermittent muscle contractions that cause abnormal movements or postures, affects 16.4 in 100,000 children worldwide. It can be caused by various factors, including pathogenic variants in genes such as TOR1A, associated with DYT-TOR1A dystonia. In this report, we present the case of a toddler with DYT-TOR1A treated with deep brain stimulation (DBS) because of his early-onset, rapidly progressive, and refractory status dystonicus. Genetic testing confirmed a maternally inherited pathogenic variant in TOR1A, c.907_909del (p.Glu303del). His dystonia was refractory to multiple optimized medications and continuous infusions. Ultimately, DBS surgery to the bilateral globus pallidus interni (GPi) provided symptomatic relief of his status dystonicus. His atypical presentation and young age made it difficult to predict expected outcomes. Thus, he required unique planning considerations before placement of bilateral GPi DBS. This case highlights challenges in symptom management, anticipatory guidance, and treatment expectations in the complex and refractory condition of status dystonicus for a young patient with DYT-TOR1A.
Degenerative spine conditions and physical inactivity are major public health concerns. Engaging in physical activity before spine surgery may improve postoperative outcomes experienced by patients with lumbar stenosis or lumbar disc herniation. This study aims to identify barriers and facilitators to physical activity among patients with degenerative lumbar spine conditions awaiting surgery. In this qualitative patient-oriented study, guided by a patient partner who contributed to the development of the interview guide and interpretation of findings, we conducted data-prompted semi-structured interviews (a method in which personalised physical activity information is used to stimulate reflection and discussion), with patients diagnosed with lumbar spinal stenosis or lumbar disc herniation on a surgical waiting list. Interviews were structured around the Theoretical Domains Framework (TDF). Patient responses were deductively coded to TDF domains and inductively analyzed to identify subthemes. Key domains were determined through researcher consensus based on the frequency and clarity of specific beliefs within each domain. We interviewed 18 patients (8 female), 11 with lumbar spinal stenosis and 7 with lumbar disc herniation, with a mean (SD) age of 54.7 (17.3) years. Five key TDF domains were identified: skills, beliefs about capabilities, beliefs about consequences, environmental context and resources, and emotion. Barriers to physical activity included a lack of physical capacity, pain and other adverse symptoms, potential for negative consequences, inappropriate environment, and negative emotions. Facilitators to physical activity were motivation, appropriate environment, supportive social influences, positive emotions, alternate strategies, and daily physical activity habits. Physical activity behaviour in patients awaiting spine surgery is shaped by an interplay of physical, emotional and contextual factors. These findings can inform the design of tailored, theory-driven preoperative physical activity interventions, targeting key barriers such as pain, fear of harm, and limited access to resources, while leveraging factors including motivation, professional guidance, social support, and habit formation.