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The establishment of cell-type specific gene regulation in the sea urchin embryo
Get PDFCell-fate commitment in metazoan development relies on precise gene regulatory programs. This study presents a comprehensive single-cell atlas of gene expression (scRNA-seq), nascent transcription (scSLAM-seq), and chromatin accessibility (scATAC-seq) in the purple sea urchin, Strongylocentrotus purpuratus , from early cleavage to pluteus larva stages. Our findings reveal a dynamic regulatory landscape with extensive usage of distal and intronic regulatory elements, which often exhibit cell-type-specific motifs and accessibility profiles that closely track gene expression. We identify a major wave of zygotic genome activation (ZGA) at the 128-cell stage, coinciding with the loss of developmental plasticity, alongside evidence of restricted, lineage-specific gene activation preceding widespread ZGA. Motif analysis highlights distinct regulatory grammars for these early accessible regions. Regulatory element usage largely clusters by germ layer, indicating shared accessibility among related cell types. We delve into the regulatory intricacies of neurons and skeletogenic cells. Sea urchin neurodevelopment proceeds through three distinct lineages, utilizing transcription factors with conserved roles in mammalian neurogenesis. Surprisingly, skeletogenic cells show significant transcriptional and regulatory diversity across their subpopulations, and we identify novel genes associated with calcification. This research offers unprecedented insights into the dynamic regulatory genome of a non-chordate deuterostome, highlighting both conserved principles of gene regulation and unique features that underscore the sea urchin’s importance as a model for understanding developmental and evolutionary genomics in ecologically critical marine species
The use of optical coherence tomography and visual evoked potentials in the 2024 McDonald diagnostic criteria for multiple sclerosis
No full textThe 2024 revisions of the McDonald diagnostic criteria include the optic nerve as a fifth anatomical location within the CNS for the diagnosis of multiple sclerosis, in addition to periventricular, juxtacortical or cortical, infratentorial, and spinal cord lesions. Demonstration of dissemination in space can now be achieved with the detection of typical lesions in at least two of these five locations. We review the evidence supporting the use of optical coherence tomography (OCT) and visual evoked potentials (VEPs) to show optic nerve involvement in the diagnosis of multiple sclerosis. We also report consensus recommendations for their use. Provided there is no better explanation for optic nerve involvement and that rigorous quality control is applied, OCT-derived peripapillary retinal nerve fibre layer inter-eye differences of 6 μm or greater or composite macular ganglion cell and inner plexiform layer inter-eye differences of 4 μm or greater support optic nerve injury. Delayed VEP latency, which depends on technical and methodological factors, and is centre and device dependent, supports demyelinating optic nerve injury when done with appropriate technical knowledge and interpretation
Memory dysfunction and psychiatric outcomes in anti-NMDA receptor encephalitis are linked to altered structural brain complexity
No full textINTRODUCTION: Most patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) experience long-term neuropsychiatric sequelae despite immunotherapy. However, how these residual symptoms relate to structural brain changes in the post-acute phase remains unclear. Recently, fractal dimensionality (FD) has emerged as a sensitive imaging marker of structural brain complexity in related conditions but has not been explored in autoimmune encephalitis. METHODS: This cross-sectional study combined clinical, cognitive, and neuroimaging analyses in 70 patients with post-acute NMDARE (median time from onset: 22 months), and 70 healthy controls matched for age (t=-0.57, p=0.57) and sex (χ2=0, p=1). High-resolution T1-weighted magnetic resonance imaging (MRI) data were analyzed with FreeSurfer and computational fractal analysis. Clinical outcomes were assessed with the modified Rankin Scale (mRS) and Clinical Assessment Scale in Autoimmune Encephalitis (CASE). Psychiatric manifestations underwent phenotypical analyses, and memory performance was assessed with standardized neuropsychological tests. RESULTS: Patients with NMDARE were severely affected at peak illness but showed substantial overall improvement in the post-acute stage (median mRS at peak=5, postacute=1, z=-7.2, p<0.001; median CASE at peak=11, post-acute=1, z=-7.2, p<0.001). However, 67% of patients showed residual CASE symptoms, with memory dysfunction (61%) and psychiatric symptoms (36%) representing the most prevalent domains. Therein, psychiatric symptoms showed a phenotypical shift from a ‘schizophrenia-like’ phenotype at peak illness to an affective phenotype in the post-acute stage. Neuroimaging uncovered a characteristic pattern of reduced structural brain complexity, including the hippocampus bilaterally and a fronto-cingulo-temporal cluster in cortical gray matter and cerebral white matter. Importantly, normative modeling revealed that patients with residual symptoms showed stronger alterations of brain complexity than those without (psychiatric: t=-2.65, p=0.010; memory: t=-3.98, p<0.001; both vs. no symptoms: t=-5.46, p<0.001). Similarly, patients with stronger alterations of brain complexity showed lower scores of visuospatial and verbal memory (all p(FDR)<0.015). DISCUSSION: Post-acute NMDARE is characterized by systematic reductions in structural brain complexity, consistently involving previously implicated regions while identifying changes in the cingulate cortex as a new morphological correlate. These changes are linked to residual psychiatric symptoms and memory dysfunction, highlighting FD as a promising new imaging marker of long-term outcomes. Our findings suggest that current treatment strategies may be insufficient to fully address the residual symptom burden after the acute phase of NMDARE
Predictors of relapse and disability in NMOSD, MOGAD, and double-seronegative demyelinating syndromes: an international multicenter retrospective cohort study
No full textBACKGROUND: This international multicenter retrospective cohort study investigated predictors of relapse, acute attack severity, and six-month disability in patients with AQP4-IgG-positive NMOSD, MOGAD, and double-seronegative demyelinating syndromes. METHODS: We analyzed 238 patients (132 NMOSD, 69 MOGAD, 37 double-seronegative). Clinical features, CSF findings, and timing of acute and maintenance therapies were evaluated as prognostic markers. RESULTS: In NMOSD, female sex, delayed initiation of acute therapy, need for plasma exchange, and inflammatory CSF changes were associated with greater disability at the nadir of the first attack. Older age and longer disease duration predicted higher six-month disability, while oral corticosteroid tapering was protective. Higher EDSS at onset was associated with poorer six-month recovery. No factor significantly predicted relapse. In MOGAD, optic neuritis at onset and early IVMP were associated with lower six-month disability and higher recovery rates, whereas post-IVMP corticosteroid tapering correlated with higher six-month disability. CSF pleocytosis correlated with favorable recovery. Higher EDSS at onset predicted worse six-month outcomes. Early initiation of maintenance therapy reduced relapse risk although overall use versus none was not statistically conclusive. In double-seronegative patients, short steroid tapers, elevated CSF glucose, antecedent infections or vaccinations, and delayed maintenance therapy were associated with worse six-month recovery though no independent predictors were confirmed in multivariable analyses. CONCLUSIONS: Prognostic factors differed across subgroups. NMOSD outcomes were influenced by age, disease duration, and steroid tapering; MOGAD outcomes by onset phenotype, early therapy, and maintenance treatment; and seronegative outcomes by treatment timing and immune antecedents. These findings emphasize early, tailored therapy and distinct subgroup-specific prognostic considerations in antibody-mediated and seronegative demyelinating disorders
Insights, opportunities, and challenges provided by large cell atlases
Get PDFThe field of single-cell biology is growing rapidly, generating large amounts of data from a variety of species, disease conditions, tissues, and organs. Coordinated efforts such as CZI CELLxGENE, HuBMAP, Broad Institute Single Cell Portal, and DISCO allow researchers to access large volumes of curated datasets, including more than just scRNA-seq data. These resources have created an opportunity to build and expand the computational biology ecosystem to develop tools necessary for data reuse and for extracting novel biological insights. We highlight achievements made so far, areas where further development is needed, and specific challenges that need to be overcome
lncRNA IGFL2-AS1 mediates NSCLC chemoresistance via YBX1-induced HSPA1A/RAP1 activation
Get PDFBACKGROUND: The development of drug resistance in cancer is associated with multiple malignant properties, including proliferative progression, metastasis, and stemness. Long noncoding RNAs (lncRNAs) reportedly contribute to multidrug resistance in lung cancer. However, functional and mechanistic studies of key lncRNAs associated with lung cancer are lacking.
METHODS: Candidate lncRNA IGFL2-AS1 and its downstream target, the HSPA1A and RAP1 cascade, were identified using RNA sequencing. In vitro functional assays, including proliferation, clonal formation, Transwell migration, sphere formation, and drug sensitivity test, were conducted to explore the function of the IGFL2-AS1/HSPA1A axis in lung cancer. For in vivo functional validation, subcutaneous implantation and tail vein injection of luciferase-tagged lung cancer cells were performed in mouse models. Moreover, RNA pulldown, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and point/truncated mutations were utilized to dissect the mechanisms underlying the activation of the YBX1-mediated IGFL2-AS1/HSPA1A axis. Pharmacological inhibition of HSPA1A was performed to restore chemotherapy sensitivity and attenuate lung cancer cell metastasis in vivo. Finally, tissue microarray staining was employed to evaluate the expression of the YBX1/IGFL2-AS1/HSPA1A/RAP1 axis in lung cancer specimens and its correlation with prognosis.
RESULTS: IGFL2-AS1, stimulated by C/EBPβ, was aberrantly upregulated in chemoresistant cell lines and lung cancer specimens. IGFL2-AS1 promoted lung cancer proliferation, metastasis, drug resistance, and stemness by upregulating HSPA1A expression both in vitro and in vivo. Mechanistically, IGFL2-AS1 recruited YBX1 to the HSPA1A promoter, facilitating its transcription. Pharmacological inhibition of HSPA1A restored the sensitization of A549 cells resistant to cisplatin and 5-fluorouracil via the downstream RAP1 signaling cascade. Notably, the YBX1/IGFL2-AS1/HSPA1A axis was consistently activated in lung cancer specimens and correlated with poor patient prognosis.
CONCLUSIONS: This study demonstrated that the YBX1-modulated IGFL2-AS1/HSPA1A/RAP1 axis is aberrantly activated in lung cancer cells and is associated with unfavorable prognosis, highlighting its potential as a novel therapeutic target in clinical settings
Compartment-specific NK cell phenotypes reveal distinct maturation and activation states in inflammatory arthritis
Get PDFIntroduction: Synovial natural killer (NK) cells contribute to inflammation in arthritis by secreting cytokines and modulating synovial fibroblast activation. The aim of this study was to describe systemic versus local inflammatory changes of NK cell subsets as well as their physical cell-cell interactions in arthritis patients. Methods: Spectral flow cytometry was used to compare paired peripheral blood (PB) and synovial fluid (SF) immune cells from patients with active inflammatory arthritis and healthy controls. Physical cell-cell interactions within tissues were studied by applying a recently developed cellular interaction mapping framework. Results: Our paired approach revealed significant local enrichment of immature and activated NK cells in SF, characterized by elevated markers of early differentiation, immune-checkpoint regulation, and tissue-residency, highlighting tightly controlled immune activation at inflamed sites. Single-cell analysis confirmed heterogeneity within SF-NK cells, suggesting multiple co-existing activation states and developmental stages. PB-NK cells from patients differed profoundly compared to healthy controls, showing less immature NK cell subsets and an enrichment of mature, pro-inflammatory subsets indicative of systemic immune activation. Cellular interaction mapping revealed mainly NK/neutrophil interactions of patients’ NK cells, while interactions with B-cells, T-cells, or monocytes were negligible. T-cells also displayed profound local and systemic alterations. Cellular interaction mapping revealed that next to NK/neutrophil interactions, interactions between B-cells with monocytes and T-cells with neutrophils characterize joint inflammation. Conclusion: This paired high-dimensional analysis revealed systemic and local alterations in NK cell subsets shaped by co-existing developmental stages and immune regulatory mechanisms. Cellular interaction mapping indicated that neutrophils are a main interaction-partner of NK cells in inflamed joints
A semi-automated quality assurance tool for cardiovascular magnetic resonance imaging: application to outlier detection, artificial intelligence evaluation and trainee feedback
Get PDFBACKGROUND: Cardiovascular magnetic resonance (CMR) offers state-of-the-art volume, function, fibrosis and oedema imaging. Quality assurance (QA) tasks, such as quantitative parameter reproducibility assessments, the evaluation of AI methods, and the assessment of trainees have become essential to CMR. However, the explainability of how qualitative differences impact quantitative differences remains underexplored. Our aim is to demonstrate a semi-automated QA tool, Lazy Luna's (LL) applicability to typical CMR QA application cases. METHODS: A software feature error-tracing is designed that allows for quickly pinpointing qualitative reasons for quantitative differences and outliers. Three QA application cases were designed. First, LL was applied to perform outlier detection for inter- and intraobserver analyses to detect failure cases and provide qualitative explanations. Outlier detection was performed on several typical images types. Second, LL supported an Artificial intelligence (AI) evaluation, in which an AI method was compared to a CMR-expert of 144 patients. LL assessed the acceptability of AI biases for left and right ventricular (LV, RV) end-systolic, -diastolic, and stroke volumes (ESV, EDV, SV), ejection fractions (EF) and the myocardial mass (LVM). Annotations were examined to explain the qualitative differences that resulted in good and poor parameters. The AI investigation was recorded as a video. Third, LL was used to provide a Trainee Feedback to a CMR beginner. The trainee was compared to an expert on several imaging techniques to investigate outliers. RESULTS: For the outlier detection, LL detected segmentation differences that caused parameter differences on multiple sequences. For the AI evaluation calculated clinical parameter biases to be: LVESV:-3.1 ml, LVEDV:2.1 ml, LVSV:6.5 ml, LVEF:3.0 ml, RVESV:0.3 ml, RVEDV:-3.8 ml, RVSV:-4.2 ml, RVEF:-1.4 ml, LVM:-2 g. Inspecting the causes for outlier differences revealed that juxtaposed basal slice failures caused unacceptable LVSV deviations between AI and expert. For the trainee assessment, LL showed that trainee parameters exceeded tolerance ranges. The segmentations could be improved to better mirror expert segmentations and close the parameter gaps. CONCLUSION: Lazy Luna, as a semi-automated quality assurance tool, is applicable to several quality assurance application cases in CMR
Probiotic ice cream influences gut and vaginal microbiota in women at high risk of preterm birth: a randomized controlled study
Get PDFBACKGROUND: Research into probiotic use in pregnancy typically focuses on general probiotic strains. We instead investigated the relation between intake of ice cream with vaginal commensal probiotics (L. crispatus, L. gasseri, L. jensenii, L. rhamnosus GR-1; these may govern a stable microbiota and may carry beneficial functions in the vagina), throughout pregnancy, and the impact on gut and vaginal microbiomes, in women at high risk of preterm birth. METHODS: This was a randomised controlled feasibility trial where the impact on gut and vaginal microbiomes was assessed by using 16 S rRNA gene sequencing and qPCR. In total 43 pregnant women were randomized, with 29 assigned to the intervention group and 14 to the control group. Both groups provided vaginal and rectal swabs by self-sampling at gestational time points. Pregnancy outcomes were registered through hospital records, and ice cream adherence and study experience was recorded. RESULTS: We observed statistically significant gut and vaginal Lactobacillus increase during first half of pregnancy in all women with a continued increase in the second half in women compliant with the intervention. L. crispatus was found more often in the intervention group, and L. gasseri, L. jensenii and L. rhamnosus GR-1 in the ice cream could be recovered in both rectal and vaginal samples. Finally, vaginal Prevotella spp, as well as gut Gardnerella and Atopobium spp, significantly decreased upon intervention. Adherence to the intervention varied but gradually decreased throughout the study with 30.4% displaying excellent adherence in the first time period. CONCLUSIONS: We conclude that vaginal commensal probiotics administered in ice cream can be an effective method of optimizing the vaginal and intestinal health in pregnant women at high risk of preterm birth when administered regularly. We give recommendations for future studies. TRIAL REGISTRATION: Clinicaltrials.gov registration number 18/27209. Date of registration 03/25/2019. Date of first enrolment 04/08/2019