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Characterization of intestinal immune responses in generalized human and murine lipodystrophy
Full text linkAcquired generalized lipodystrophy (AGL) is a rare metabolic disorder frequently associated with autoimmunity. Its etiology is incompletely understood, and the effect of adipose tissue loss on intestinal inflammation in AGL remains unclear. Using mass cytometry and single-cell RNA-seq, we observed an oligoclonal expansion of T cells in the periphery and inflamed intestine in a patient with AGL and Crohn's disease (AGLCD). To explore if loss of adipose tissue triggers lymphoproliferation, we studied lipodystrophic mice as a model for AGL. Unexpectedly, lipodystrophic mice did not show T cell expansion, were protected from colitis, and displayed a defect in the development of proinflammatory T cells, which could be reversed by allogeneic fat transplantations, indicating that clonal T cell expansion in AGLCD is not primarily caused by lipodystrophy. Instead, gene sequencing revealed a T cell-intrinsic de novo neuroblastoma RAS viral oncogene homolog (NRAS) mutation, implicating somatic mosaicism as a facilitator of clonal T cell expansion and intestinal inflammation in AGLCD
Role of kinin B(2) receptor signaling in astrocyte-driven neuroinflammation
Full text linkThe kallikrein–kinin system (KKS) plays a key role in inflammatory responses, but its specific contribution to neuroinf lammation remains to be fully elucidated. The bradykinin B(2) receptor (B(2)R), a principal effector of the KKS, is widely expressed in both neuronal and glial cells in the rodent and human brain. In this study, we investigated the molecular contribution of B(2)R to neuroinflammation using complementary in vitro and in vivo models. Lipopolysaccharide (LPS) stimulation significantly upregulated B(2)R mRNA expression in primary astrocyte cultures and in the cortical tissue of wild-type mice. Pharmacological blockade of B(2)R in astrocytes markedly suppressed the LPS-induced proinflammatory gene expression. In contrast, B(2)R antagonism in vivo resulted in only partial attenuation of the neuroinflammatory response. Together, these findings suggest cell type–specific roles for B(2)R and underscore its key contribution to astrocytemediated neuroinflammation
Transportation noise and self-rated health: Evidence from the German national cohort (NAKO)
Full text linkBACKGROUND: A large proportion of Europeans are exposed to high levels of transportation noise, which can cause physiological and psychological stress, leading to negative health impacts. Few studies have examined the association between transportation noise and self-rated health (SRH), a summary indicator of morbidity. OBJECTIVES: We aimed to assess the associations of SRH with both annual average road traffic noise exposure and nighttime transportation noise annoyance, examine geographic differences, evaluate potential effect modification and interaction by sex, and investigate whether annoyance mediates the relationship between road traffic noise and self-rated health. METHODS: Using NAKO baseline data (n = 174,956), we implemented a cross-sectional study using logistic regression to analyze associations of road traffic noise ≥55 dB(A) Lden and nighttime transportation noise annoyance with poor SRH, adjusting for relevant sociodemographic characteristics and environmental co- exposures, including air pollution and greenness. We examined geographic differences, tested for effect modif ication and interaction by sex, and used path analysis to assess mediation by annoyance. RESULTS: Road traffic noise ≥55 dB(A) (OR 1.06, 95 % CI 1.01; 1.10), and moderate (OR 1.28, 1.23; 1.32) and strong nighttime transportation noise annoyance (OR 1.73, 1.65; 1.81) were associated with higher odds of poor SRH. Associations were similar for males and females, but varied across study regions. The path analysis revealed that road traffic noise was associated with higher odds of poor SRH indirectly via nighttime transportation noise annoyance (indirect effect). CONCLUSIONS: In our study, nighttime transportation noise annoyance was more strongly and consistently associated with poor SRH than road traffic noise. Reducing both transportation noise and related annoyance could help protect population health
Reconstructing the three-dimensional architecture of extrachromosomal DNA with ec3D
No full textHi-C data of the ecDNA cell line MSTO-211H used by ec3
Liver-X-receptor agonism enhances T cell priming and activation to promote anti-tumor immunity
No full textMany cancer patients do not benefit from current immunotherapies. This lack of efficacy may be, in part, due to insufficient priming and activation of T cells. Here, we show that activation of liver-X-receptors (LXRs) promotes adaptive anti-tumor immunity by enhancing priming of T cells. Genetic LXR deletion in the host and depletion of dendritic and CD8+ T cells, but not of macrophages, abrogated anti-tumor effects of LXR-agonistic therapy. In cross-presentation assays, LXR agonism promoted T cell activation upon DC/T cell cross talk. Genetic deletion of LXRs in T cells, but not in dendritic cells, blunted this effect. Dissection of the temporal dynamics of LXR-enhanced T cell effector function showed that LXR agonism rendered T cells more receptive to adopting effector states upon stimulation. Consistently, LXR agonist therapy elicited T cell expansion in cancer patients enrolled in a phase I trial. Our findings establish LXR activation as an effective approach for enhancing T cell priming
YAP1 enhances mesenchymal-type gene expression in human adrenergic-type neuroblastoma cells
Full text linkBACKGROUND/OBJECTIVES: Neuroblastoma cells are phenotypically plastic, transitioning between mesenchymal and adrenergic states. Core functional genes (e.g., YAP1) mark the mesenchymal state, which is linked to unfavorable prognosis. We and others previously demonstrated relapse-specific Hippo-YAP pathway activation in matched primary/relapsed neuroblastomas. Here we explored the role of YAP1 in neuroblastoma aggressiveness and response to therapy. METHODS: RT-qPCR and immunoblotting assessed YAP1 expression in neuroblastoma cell lines. RNA-sequencing detected YAP1-dependent gene signatures in Tet-ON SK-N-AS and SH-EP neuroblastoma cell models expressing wildtype YAP1 or constitutively activated YAP1(S127A). Data from cell models were compared with our published YAP1 expression data from neuroblastomas. Efficacy of commonly used chemotherapeutics was comparatively analyzed in the cell models. RESULTS: YAP1 expression showed marked variability across a panel of neuroblastoma cell lines, assessed by mRNAanalysis in 10 cell lines and protein analysis in a subset of 9 cell lines. RNA sequencing in constitutively activated YAP1(S127A) mutant and wildtype YAP1 models detected 2162 and 1837 significantly differentially expressed genes in the SK-N-AS and SH-EP backgrounds, respectively. Continuously activating YAP1 in SK-N-AS cells upregulated mesenchymal signature genes and mesenchymal-associated transcription factors. Gene expression influenced by YAP1 activity in the cell models significantly overlapped with YAP1-associated genes (e.g., CYR61 and SPRY4) in published tumor data. Functionally, YAP1(S127A) expression rendered neuroblastoma cells resistant to chemotherapy. CONCLUSIONS: Findings corroborate the idea of a mechanistic role for YAP1 in neuroblastoma adrenergic to mesenchymal reprogramming and therapy resistance. The YAP1-mediated plastic switch towards a mesenchymal expression state in neuroblastoma cells may provide the molecular basis for novel therapeutic avenues
Decreased thickness of the individually-mapped genital cortex after childhood sexual abuse exposure in adult women
Full text linkPrevious research suggests interindividual variability in the location of the genital representation field and use-associated structural variation of genital field thickness associated with normative sexual activity in adult women. Using a sensory-tactile fMRI paradigm, we individually mapped genital fields of 128 women with and without exposure to childhood sexual abuse. We assessed whether structural variation of the individual genital field is driven by exposure to childhood sexual abuse or sexual frequency in the past year. We show that exposure to childhood sexual abuse associated with reduced thickness of individually-mapped genital cortex. Earlier abuse onset predicted greater reductions of genital field thickness. There was no effect of sexual frequency in the past year on genital field thickness. Classic neuroplasticity research indicates amplifying effects of stimulation on sensory cortex. In contrast, our results show long-lasting damaging effects of inappropriate stimulation during early development, emphasizing the need to protect children from sexual adversity
Bradykinin contributes to vasogenic edema in murine experimental cerebral malaria
No full textCerebral malaria (CM) due to Plasmodium falciparum (Pf) infection is a major cause of death in African children. Bradykinin (BK) is a mediator of vasogenic edema. It could contribute to the pathogenesis of central nervous system malaria in Kenyan children and P. berghei ANKA (PbA) infected C57BL/6J mice with experimental cerebral malaria. Cleaved plasma high molecular weight kininogen (cHK) is a marker for prior BK release. 40% of children with central nervous system malaria had plasma cHK versus 18% of children with uncomplicated malaria. Wild-type PbA-infected mice had circulating plasma cHK, elevated BK levels, and reduced HK and prekallikrein levels. HK null (Kng1(-/-)), combined BK B1 and B2 receptor null (Bdkrb1(-/-) / Bdkrb2(-/-)), BK B2 (Bdkrb2(-/-)) or BK B1 (Bdkrb1(-/-)) receptor null mice were protected from neurologic deterioration and brain edema compared to wild-type mice. F12(-/-)mice were not protected from neurological deterioration. Prekallikrein null (Klkb1(-/-)), prolylcarboxypeptidase hypomorphs (Prcp(gt/gt)), and brain endothelial cell conditional knockout of PRCP (Prcp(fl/fl) Cre) mice had reduced neurologic deterioration and brain edema. Adjuvant plasma kallikrein inhibition combined with artesunate treatment of PbA-infected mice reversed neurologic deterioration and brain edema and prolonged survival relative to artesunate alone. BK-induced vasogenic edema contributes to human and murine CM
Multiplexed biomarkers dynamically detect heterogeneous residual neuroblastoma cell clone activity in the bone marrow niche
Full text linkMonitoring MYCN-driven high-risk neuroblastoma presents challenges to capture dynamics of all tumor cell clones at their earliest divergence to current clinical course. Not all clones may enter the bone marrow, the most important monitoring site for minimal residual disease (MRD), causing relapse in ~50% of patients. We developed mediator-probe PCR assays to detect up to four multiplexed patient-individual genetic alterations in 37 longitudinally collected bone marrow aspirates from 8 patients with MYCN-amplified disease. Multiplexed biomarkers, including MYCN amplicon breakpoints, detected diverse neuroblastoma clones, surpassing conventional GD2 immunocytology accuracy. We provide proof-of-principle for clonally heterogeneous MRD biomarker detection (1 tumor: 10(6) reference cells). In selected patients, multiplexed biomarkers indicated divergent dynamics, suggesting individual tumor clones differ in their ability to disseminate to the bone marrow and escape therapy. Our pilot data support integrating multiplexed MRD detection in co-clinical trials to monitor the molecular remission state during therapy and follow-up