24036 research outputs found
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Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage
Full text linkmTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms un-derlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugsare senomorphic, that is, they mitigate cellular senescence, but whether they protect genome stability itself has been unclear.Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we testedwhether mTOR inhibition enhances genome stability. In human T cells exposed to acute genotoxic stress, we found that rapamy-cin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating au-tophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex vivo analysis of aged immune cells fromhealthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggestingthat human immune ageing may be amenable to intervention by low-dose mTOR inhibition. To test this in vivo, we conducteda placebo-controlled experimental medicine study in older adults administered with low-dose rapamycin. p21, a marker of DNAdamage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. Thesefindings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explainrapamycin's exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drivespathology, ranging from healthy ageing, clinical radiation exposure and even the hazards of cosmic radiation in space travel
ET(B) receptor deficiency amplifies allergic airway inflammation and hyperresponsiveness
Full text linkBACKGROUND: Endothelin-1 (ET-1) is a proinflammatory mediator that plays a crucial role in regulating airway tone by activating G protein-coupled endothelin receptors A (ET(A)) and B (ET(B)). The endothelin system has been linked to asthma, but the impact of ET(B) receptor deficiency on allergic airway inflammation remains uncharted. This study explores how the endothelin system influences allergic airway inflammation and hyperresponsiveness. METHODS: We used rescued ET(B) receptor-deficient (ET(B)(−/−)) mice to obviate lethal inherited Hirschsprung disease, prepro-ET-1 overexpressing ((pre)ET(tg)), and wild-type (WT) mice. Basal airway resistance and responsiveness to broncho-constrictive stimuli were assessed in isolated, perfused and ventilated lungs of naïve mice. Additionally, we analysed the humoral immune response and airway hyperresponsiveness following induction of type 2 airway inflammation induced by systemic ovalbumin (OVA) sensitisation and repeated airway challenge with aerosolised OVA. RESULTS: Naïve ET(B)(−/−) mice exhibited significantly heightened airway responsiveness compared to naïve WT mice. After OVA sensitisation and challenge, ET(B)(−/−) mice displayed increased OVA-specific immunoglobulin E levels, intensified allergic airway inflammation and hyperresponsiveness compared to WT mice. Conversely, (pre)ET(tg) mice displayed reduced immunoglobulin E levels, airway inflammation and hyperresponsiveness. CONCLUSION: Our findings suggest ET(B) receptors have a protective role in asthma-associated allergic airway inflammation and hyperresponsiveness. The increased asthma phenotype in sensitised and challenged ET(B)(−/−) mice is attributed to ET(B)-specific immunomodulatory mechanisms, rather than to elevated levels of ET-1 resulting from impaired ET(B)-mediated ET-1 clearance. This conclusion is supported by the diminished asthma-phenotype observed in sensitised and challenged (pre)ET(tg) mice. Therefore, adjusting endothelin signalling could offer a promising approach to managing asthma
Engineered CCR7 overexpression enhances nodal CAR-T cell homing and cytotoxicity toward B cell lymphoma
No full textAnti-CD19 chimeric antigen receptor (CAR) therapy demonstrated remarkable efficacy against hematological malignancies. However, B cell malignancies with lymph node (LN) involvement frequently remain resistant. Here, we show that CAR T cells downregulated the chemokine receptor CCR7, crucial for nodal homing, during manufacturing. Consequently, in vitro migration toward the respective chemokines and in vivo migration to LNs was severely impaired. To improve nodal CAR T-cell trafficking, we engineered anti-CXCR5 CAR T cells, targeting mature lymphoma, with stable CCR7 expression (CAR.CCR7). CCR7 engineering of human and mouse CAR T cells restored migratory capacity and LN homing. Additionally, we observed enhanced CAR-mediated killing in CCR7-engineered anti-CXCR5 and antiCD19-CARs alike, a process that was independent of increased cytokine secretion. Mechanistically, CCR7 overexpression was associated with an altered expression of genes involved in cytoskeletal rearrangement and faster killing kinetics. CCR7 accumulated in mature CAR synapses, supporting the costimulatory role of CCR7 within immunological synapses. Therapeutically, improved LN-recruitment and enhanced killing of CAR.CCR7 T cells improved lymphoma eradication in mice
Single-cell profiling of immune reset in patients with refractory generalized myasthenia gravis receiving autologous CD19/BCMA CAR-T cell therapy
No full textBACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD19 or B cell maturation antigen (BCMA) hold great promise to treat neuroimmune disorders, but the efficacy of CD19/BCMA dual-targeting CAR-T cells and their impact on systemic immunity are poorly understood. METHODS: In this phase 1 study (ClinicalTrials.gov: NCT06371040), patients with refractory generalized myasthenia gravis (gMG) received autologous CD19/BCMA CAR-T cells without prior lymphodepletion. The primary endpoint was the frequency and severity of treatment-emergent adverse events at week 4. Secondary endpoints included changes in MG-specific scale scores. Single-cell RNA sequencing and flow cytometry were performed to characterize longitudinal changes in B cell, plasma cell, and T cell compartments following CAR-T cell infusion. FINDINGS: CD19/BCMA CAR-T cells expanded in vivo, leading to depletion of B cells and plasma cells. All six patients had a favorable safety profile. Minimal symptom expression (MG Activities of Daily Living Score [MG-ADL] = 0) was achieved in five patients by day 90, with responses sustained through day 120–150, and all patients discontinued glucocorticoids while reducing immunosuppressant use. Immune profiling revealed a transient decline in memory B cells and plasma cells. The repopulated B cells exhibited attenuated B cell receptor signaling and increased inhibitory signals derived from bone marrow niche cells. Further, clonal expansion of T and B cells was significantly reduced. CONCLUSIONS: CD19/BCMA CAR-T cell therapy is safe and effective in refractory gMG without lymphodepletion, leading to systemic immune reset that warrants future investigations in larger clinical trials. FUNDING: This study was supported by the National Key Research and Development Program and the National Natural Science Foundation of China
Analysis of retroviral MLT1 enhancer-driven genes identifies over-expression of EPS8L1 as an early-stage initiator of both oxidative stress and poor trophoblast invasiveness in the pregnancy disorder preeclampsia
No full textIn the human-specific disorder of pregnancy preeclampsia (PE) we find dysregulation of multiple genes associated with the cis-regulatory elements (CREs) derived from mammalian-specific endogenous retrovirus (ERV3-MLT1
The future of cardiac magnetic resonance: navigating ultra-high and low-field imaging (Part 2)
No full textSelfAdapt: unsupervised domain adaptation of cell segmentation models
No full textDeep neural networks have become the go-to method for biomedical instance segmentation. Generalist models like Cellpose demonstrate state-of-the-art performance across diverse cellular data, though their effectiveness often degrades on domains that differ from their training data. While supervised fine-tuning can address this limitation, it requires annotated data that may not be readily available. We propose SelfAdapt, a method that enables the adaptation of pre-trained cell segmentation models without the need for labels. Our approach builds upon student-teacher augmentation consistency training, introducing L2-SP regularization and label-free stopping criteria. We evaluate our method on the LiveCell and TissueNet datasets, demonstrating relative improvements in AP(0.5) of up to 29.64% over baseline Cellpose. Additionally, we show that our unsupervised adaptation can further improve models that were previously fine-tuned with supervision. We release SelfAdapt as an easy-to-use extension of the Cellpose framework. The code for our method is publicly available at https://github.com/Kainmueller-Lab/self_adapt
Beyond autoantibodies: accelerating differential diagnosis in neuroimmunological diseases
No full textThis scientific commentary refers to ‘Granulocyte and astrocyte markers distinguish MOG antibody disease and neuromyelitis optica from multiple sclerosis’ by Furlan et al. (https://doi.org/10.1093/brain/awaf345)
Structuring of the yeast endolysosomal pathway by the Rab5 guanine nucleotide exchange factors Muk1 and Vps9
No full textThe endolysosomal pathway, with its interconnected endosomes and lysosomes, has key functions in cellular nutrient and ion uptake, metabolic adaptation, as well as protein and organelle turnover via autophagy. Rab5 GTPases are organelle identity markers on endosomes, though it remains unclear why cells have several Rab5 isoforms and guanine nucleotide exchange factors (GEFs) as their activators. Using yeast, we demonstrate that the key Rab5 GEFs Vps9 and Muk1 overlap in their Rab5 specificity in vitro but cover distinct cellular territories in vivo. Vps9 functions between the Golgi and endosomes, while Muk1 is primarily found in the early endocytic pathway. Using targeting approaches, we show that Rab5 GEFs can only partially replace each other, demonstrating that each GEF is specific for its cellular niche. Intriguingly, Muk1 functions in vivo as an oligomer through its C-terminal domain, which is sufficient to also oligomerize a chimeric Vps9. Overall, our data suggest the spatial distribution of Rab5 GEFs and their substrate Rab5s fine-tune the endolysosomal system for cellular needs and metabolic cues
Integrative modelling reveals the structure of the human Mic60-Mic19 subcomplex and its role as a diffusion barrier in mitochondria
Full text linkMitochondrial crista junctions (CJs) operate as regulated gateways into the cristae microenvironment, whose protein, metabolite, and ion compositions are finely tuned for mitochondrial function. The Mic60-Mic19 complex of the mitochondrial contact site and cristae organizing system (MICOS) complex was suggested to span across CJs and act as a diffusion barrier, but little is known of how its dynamic architecture facilitates this task. To address this open question, we determined the crystal structure of an amino-terminal dimeric helical bundle of human Mic60. These and previous structural and biochemical data were harnessed in molecular dynamic (MD) simulations to develop a dynamic model of the human tetrameric Mic60-Mic19 subcomplex in the CJ environment, to validate its architecture using in organello cross-linking data and to computationally characterize its function as a diffusion barrier. Our integrative structural biology approach enables the functional investigation of flexible, multidomain protein complexes which escape conventional structural biology methods