24036 research outputs found
Sort by
Calbindin-containing CA1 pyramidal cells support cognitive flexibility in spatial task in mice
No full textThe hippocampus, and particularly the dorsal CA1, is essential for spatial memory consolidation through sharp-wave ripple events (SWRs) that enable the transfer of information to cortical areas. Within the dorsal CA1, distinct pyramidal cell sub-populations of the deep and superficial layer may play distinct roles in the processing and updating of spatial information. Using a Cre-dependent mouseline, we were able to precisely target the superficial, Calbindin (CALB1+) PCs of the CA1. This allowed us to gain a deeper understanding of the connectivity of CALB1+ CA1 PCs to their SWR-propagating excitatory output partners within the Subiculum (SUB), the burst-firing SUB PCs and their functional relevance in spatial memory consolidation and recall. Retrograde rabies tracing revealed heterogeneous innervation of the VGlut2+ bursting PCs by both CA1 PC sub-layers, and showed that the majority of presynaptic inputs are located in the superficial CA1 PC layer. We were able to observe that this anatomically confirmed connection between CALB1+ CA1 PCs and both SUB PC subtypes is able to induce spiking more reliably in burst- than regular-firing SUB PCs. CNO-induced inhibition in a Barnes Maze task revealed that the experimental group showed reduced cognitive flexibility and were slower to adapt to re-location of the goal when CALB1+ CA1 PCs were inhibited during the recall (test), while both groups behaved similarly when consolidation was manipulated (training). Inhibition did not impact overall learning, strategy development or locomotor control. This suggests that CALB1+ CA1 PCs preferentially connect to bursting SUB PCs, and support cognitive flexibility needed to adapt to a changing environment, adding further proof to the functional relevance of laminar segregation of the CA1 and the hippocampus in spatial memory processes
Remodelling of the endothelial extracellular matrix promotes smooth muscle cell hyperplasia in pulmonary hypertension due to left heart disease
Get PDFAIMS: Hyperplasia of pulmonary arterial smooth muscle cells (SMCs) contributes to the progression of pulmonary hypertension (PH), yet the underlying pathomechanism of this process in PH secondary to left heart disease (PH-LHD) is poorly understood. We aimed to investigate the role of the endothelial extracellular matrix (ECM), specifically the pulmonary arterial basement membrane (BM), in influencing SMC proliferation and phenotypic changes in PH-LHD. METHODS AND RESULTS: SMC hyperplasia and endothelial ECM remodelling were characterized histologically on human pulmonary arterial samples, and by mass spectrometry, and atomic force microscopy on decellularized ECM (dECM) produced in vitro by endothelial cells isolated from pulmonary arteries (PA) of LHD patients without pulmonary hypertension (LHD w/o PH), PH-LHD patients, or healthy-heart controls. Proliferation and migration rates of SMC cultured on endothelial dECM were assessed by Ki67 immunostaining and by wound-healing assay, respectively. The role of mechanosensitive YAP1 in SMC hyperplasia was addressed in human cells and in an aortic-banding rat model of PH-LHD by analysing YAP1 activation and the effect of YAP1 inhibition. PA of LHD w/o PH and PH-LHD patients showed extensive remodelling of the BM. This was confirmed in vitro as altered composition and stiffening of dECM generated by respective patient endothelial cells. ECM remodelling was associated with SMC accumulation in the pulmonary arterial intima in patient samples and promoted SMC migration and proliferation in vitro. Conversely, dECM generated by healthy human endothelial cells reduced the hypermigration and hyperproliferation of SMC from LHD w/o PH and PH-LHD patients. Remodelling of the endothelial ECM in LHD w/o PH and PH-LHD patients also activated YAP1 in SMC, inhibition of which reduced SMC migration and proliferation in vitro. These findings were reproduced in vivo in a rat model of PH-LHD induced by aortic-banding. CONCLUSION: Here, we report endothelial ECM remodelling as a key mechanism driving SMC hyperplasia in PH-LHD. Notably, endothelial ECM remodelling is evident in both patients with LHD w/o PH and those with PH-LHD, raising the possibility that it may reflect an early event in LHD-induced pulmonary vascular remodelling. This ECM remodelling is associated with YAP1 in adjacent SMC, promoting their migration and proliferation and contributing to SMC hyperplasia. Consequently, targeting ECM remodelling and YAP1 activation may offer promising therapeutic strategies for preventing of PA remodelling in PH-LHD
Genetic alterations of SENP6 in multiple myeloma disrupt genome and proteome stability, sensitizing to proteasome inhibition
No full textIdentification of full-length circular RNAs linked with therapy resistance of pediatric cancers
Get PDFResistance to cancer treatment remains the leading cause of cancer-related deaths. In tumors with low mutational burden such as pediatric cancers, alternative transcripts, including circular RNAs (circRNAs), have been identified as involved in treatment resistance. However, their isoforms are often missed by commonly used short-read sequencing. Here, we employ long-read sequencing to identify full-length circRNA isoforms associated with resistance in ALK-driven pediatric cancers. Using cell models and a cohort of ALK-translocated anaplastic large-cell lymphoma (ALK+ ALCL) patients, two circRNAs were detected as specifically upregulated in resistant cases and associated with worse disease outcomes. Similar findings were observed in the pediatric cancer neuroblastoma. These circRNAs were also more abundant in liquid biopsies from ALKi-resistant ALK+ ALCL and neuroblastoma patients. This demonstrates that long-read sequencing allows for uncovering disease-relevant circRNA isoforms that could serve as biomarkers for resistance detection in a clinical setting
InCURA: integrative gene clustering based on transcription factor binding sites
Get PDFBiologically meaningful interpretation of transcriptomic datasets remains challenging, particularly when context-specific gene sets are either unavailable or too generic to capture the underlying biology. We here present InCURA, an integrative clustering strategy based on transcription factor (TF) motif occurrence patterns in gene promoters. InCURA takes as input lists of (i) all expressed genes, used solely to identify dataset-specific expressed TFs, and (ii) differentially regulated genes (DRGs) used for clustering. Promoter sequences of DRGs are scanned for TF binding motifs, and the resulting counts are compiled into a gene-by-TFBS matrix. InCURA then uses unsupervised clustering to infer gene modules with shared predicted regulatory input. Applying InCURA to diverse biological datasets, we uncovered functionally coherent gene modules revealing upstream regulators and regulatory programs that standard enrichment or co-expression analyses fail to detect. In summary, InCURA provides a user-friendly, regulation-centric tool for dissecting transcriptional responses, particularly in settings lacking context-specific gene sets
Application of the 2024 McDonald criteria in the International Acute Optic Neuritis Network
No full textBACKGROUND: The 2024 McDonald criteria for multiple sclerosis (MS) incorporate optic nerve lesions as a fifth topography for dissemination in space (DIS), and other additional diagnostic features. We evaluated their performance in acute optic neuritis (ON) patients within the global Acute Optic Neuritis Network (ACON). METHODS: In this ongoing, prospective, multicenter study (clinicaltrials.gov, identifier: NCT05605951), we applied the 2024 McDonald criteria to 250 patients with a first-ever ON (enrolment period August 2020 – December 2024) from 22 centers in 14 countries across six continents. We included 61 patients with idiopathic ON (iON), 53 with clinically isolated syndrome and 64 with MS according to 2017 McDonald criteria (2017-CIS, 2017-MS), 22 with aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD), and 50 with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). We assessed the sensitivity of the 2017 and 2024 McDonald criteria using the MS ”at-risk” population (defined by criteria specific for DIS or dissemination in time (DIT) using MRI). Specificity was measured using the AQP4-IgG+NMOSD and MOGAD cohorts. FINDINGS: All 2017-MS patients (64/64, 100%) fulfilled the 2024 criteria and 33/53 (62%) 2017-CIS patients were reclassified as MS by the 2024 criteria. Additionally, 18% of AQP4-IgG+NMOSD and 14% of MOGAD patients met the 2024 McDonald criteria. The sensitivity of the 2017 and 2024 criteria were 55% (95%-CI 45-64) and 83% (95%-CI 75-89); specificity was 100% (95%-CI 95-100) and 85% (74-92), and diagnostic accuracy was 72% (95%-CI 65-78) and 84% (95%-CI 76-89), respectively. Visual evoked potentials and optic coherence tomography demonstrated higher sensitivity than MRI for the detection of DIS using the 2024 criteria; however, MRI yielded higher specificity. Due to limited use, the impact of new MRI metrics and KFLC were not assessed. INTERPRETATION: The 2024 McDonald criteria enhance diagnostic sensitivity in ON-related CIS, enabling earlier MS diagnosis, but reduce specificity in AQP4-IgG+NMOSD and MOGAD
Deep cardiac phenotyping by cardiovascular magnetic resonance reveals subclinical focal and diffuse myocardial injury in patients with psoriasis (PSOR‑COR study)
Get PDFBACKGROUND: Psoriasis vulgaris (PV) is a chronic inflammatory disorder frequently associated with cardiovascular disease (CVD). This study aims to provide a prospective tissue characterization in patients with PV without major CVD using cardiovascular magnetic resonance (CMR). METHODS: Patients with PV underwent laboratory assessment, a 12-lead and 24-h ECG, and a CMR exam at a 1.5-T scanner. Scan protocol included assessment of left (LV) and right (RV) ventricular function and strain analysis, native and post-contrast T1 mapping, T2 mapping and late gadolinium enhancement (LGE). RESULTS: In total, 60 PV patients (median(IQR) age in years: 50.0 (36.0–60.8); 34 men (56.7%)) were recruited and compared to 40 healthy volunteers (age in years: 49.5 (37.3–57.8); 21 men (53.0%)). No differences were found regarding LV and RV function (p = 0.78 and p = 0.75). Global radial and circumferential strains were lower in patients (p < 0.001 and p < 0.001, respectively). PV had higher global T1 times (1001 (982–1026) ms vs. 991 (968–1005) ms; p = 0.01) and lower global T2 times (48 (47–49) ms vs. 50 (48–51) ms; p < 0.001); however, all values were within local reference ranges. Focal non-ischemic fibrosis was observed in 17 (28.3%) PV patients. CONCLUSION: Deep cardiac phenotyping by CMR revealed subclinical myocardial injury in patients with PV without major CVD, despite preserved LV and RV function. Diffuse and focal fibrosis might be the first detectable signs of adverse tissue remodeling leading to reduced circumferential and radial myocardial deformation. In the background of local and systemic immunomodulatory therapy, no signs of myocardial inflammation were detected. The exact impact of immunomodulatory therapies on the myocardium needs to be addressed in future studies
Therapy adherence after interdisciplinary tumour board discussion is associated with improved outcome in soft tissue sarcoma: a Charité Comprehensive Cancer Centre analysis
Get PDFCentralising soft tissue sarcoma (STS) treatment in expert centres and implementing comprehensive therapy concepts through interdisciplinary tumour boards (ITB) has led to significant treatment progress. However, our knowledge on the implementation of the ITB recommendations and its impact on patient outcome is limited. In this retrospective analysis, we examined a cohort of 222 adult patients (pts) with primary STS who were presented to the ITB of the Charité Comprehensive Cancer Centre between 2015 and 2020. In localised disease (n = 188), resection was recommended in 71% (n = 134) of pts. The treatment modalities chemotherapy with or without regional deep hyperthermia, and radiotherapy were recommended in 37% (n = 69), 26% (n = 48) and 52% (n = 97), respectively. Complex multidisciplinary concepts were established in 29% (n = 54) including ≥3 treatment modalities. Only partial adherence, either by choice of patient or treating physician, was associated with a higher risk of both progression (HR 4.0 95%-CI 1.6-9.7 p < .01) and mortality (HR 5.3 95%-CI 1.7-16.4 p < .01). Pts inable to follow the ITB recommendations due to complications or rapid progression showed a high-risk profile with increased mortality and progression rates (HR 18.1 95%-CI 8.5-38.2 p < .001; HR 21.5 95%-CI 8.5-54.7 p < .001). To our knowledge, this represents the first German Comprehensive Cancer Centre analysis of therapy adherence in STS. It provides further real-world evidence that full adherence to ITB recommendations and the ability to adhere to them are of prognostic value for patient outcome and underlines the importance of interdisciplinary decision-making and treatment planning for STS patients
Challenges and opportunities in the clinical translation of high-resolution spatial transcriptomics
Get PDFPathology has always been fueled by technological advances. Histology powered the study of tissue architecture at single-cell resolution and remains a cornerstone of clinical pathology today. In the last decade, next-generation sequencing has become informative for the targeted treatment of many diseases, demonstrating the importance of genome-scale molecular information for personalized medicine. Today, revolutionary developments in spatial transcriptomics technologies digitalize gene expression at subcellular resolution in intact tissue sections, enabling the computational analysis of cell types, cellular phenotypes, and cell-cell communication in routinely collected and archival clinical samples. Here we review how such molecular microscopes work, highlight their potential to identify disease mechanisms and guide personalized therapies, and provide guidance for clinical study design. Finally, we discuss remaining challenges to the swift translation of high-resolution spatial transcriptomics technologies and how integration of multimodal readouts and deep learning approaches is bringing us closer to a holistic understanding of tissue biology and pathology
Concurrent profiling of localized transcriptome and RNA dynamics in neurons by spatial SLAMseq
No full textThe asymmetric distribution of RNA within a cell plays a pivotal biological role, ensuring the distinctive shapes and functionality of subcellular compartments. In neurons, these mechanisms are fundamental to cellular growth, synaptic plasticity, and information processing. To understand these mechanisms, diverse methods have been developed to analyze localized transcripts. Here, we outline our optimized method for measurement of mRNA half-lives in subcellular neuronal compartments-neurites, and cytoplasmic and nuclear fractions of cell bodies. We call this method spatial SLAMseq, as it combines SLAMseq with subcellular compartment separation techniques. Spatial SLAMseq facilitates the concurrent measurement of mRNA dynamics and steady-state RNA levels within neuronal subcellular compartments