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Mini social cognition and emotional assessment: diagnostic performance and neural correlates in behavioural-variant frontotemporal dementia
Get PDFWe aimed at validating the Mini Social Cognition and Emotional Assessment (Mini-SEA) in a German cohort of mildly impaired behavioural-variant frontotemporal dementia (bvFTD) patients and healthy controls. The Mini-SEA comprises the Facial Emotion Recognition Test (FERT) and the Faux Pas Test (FPT) measuring Theory of Mind (ToM) abilities in social norm-related real-life stories. We examined the diagnostic performance of the Mini-SEA alongside other neuropsychological assessments and investigated its structural neural correlates. We included 32 bvFTD patients and 54 controls in logistic regression models with forward-stepwise selection containing demographics, standard neuropsychological battery (CERAD-NAB+) and the Mini-SEA scores to identify the most relevant variables. Demographic, neuropsychological and daily-life activity associations were explored. Voxel-based morphometry analysis was conducted in a subsample (14 bvFTD and 14 controls) on regions previously linked to emotion processing and ToM functions. The Mini-SEA yielded a very good performance, being in the best-fitting model with a high odds ratio alongside the executive-language and memory measures. Specifically, the FERT indicated the strongest effect in the group differentiation. Mini-SEA showed significant associations with executive-language tests and daily-life activities. In canonical emotion processing brain regions, we found associations of the Mini-SEA composite and the FERT with grey matter volumes in the left insula and lentiform nucleus of putamen. Within ToM regions, associations were found for the Mini-SEA composite and the FPT in cerebellar regions. The German Mini-SEA discriminates well between mildly impaired bvFTD patients and controls. We also demonstrated its significant value for neuropsychological assessment and neuro-behavioural associations in regions underlying emotion processing and ToM
Spermidine supplementation and protein restriction protect from organismal and brain aging independently
Get PDFBrain aging and cognitive decline are significant biomedical and societal concerns. Both dietary restriction, such as limiting protein intake, and fasting, which restricts the timing of food consumption, have been proposed as strategies to delay aspects of aging. Recent studies suggest that intermittent fasting effects are mediated by the endogenous polyamine spermidine. Spermidine supplementation promotes mitochondrial integrity and functionality in aging brains by supporting hypusination of the translational initiation factor eIF5A. However, how molecular mechanisms underlying fasting mimicking interventions and protein restriction converge remain unclear, yet biomedically relevant. In this study, we combined low- and high-protein diets (2% versus 12% yeast in food) with spermidine supplementation in aging Drosophila fruit flies. Effective hypusination was essential for normal life expectancy on both 2% and 12% yeast diets. Spermidine supplementation increased longevity, protected against age-related locomotion decline on both diets and improved memory scores in older flies regardless of protein intake. Notably, spermidine did not reduce the positive effects of the 12% protein diet on fecundity. Our findings suggest that while both protein restriction and spermidine supplementation improve brain mitochondrial function, they largely operate through distinct mechanisms in modulating Drosophila brain aging. These results offer a basis for potential synergistic lifestyle interventions targeting age-related brain decline
The economic burden of subjective cognitive decline, mild cognitive impairment and Alzheimer's dementia: excess costs and associated clinical and risk factors
Get PDFBACKGROUND: With the availability of first disease-modifying treatments, evidence on costs across the entire Alzheimer's Continuum, especially for early disease stages, becomes increasingly important to inform healthcare planning, resource allocation, and policy decisions. This study assessed costs and cost-associated factors in patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI) and Alzheimer's Disease (AD) dementia compared to healthy controls. METHODS: The German DELCODE cohort study assessed clinical data, healthcare resource use, and informal care provision. Costs were calculated from payer and societal perspectives using standardized unit costs, and multivariate regression analyses identified cost-associated factors. RESULTS: From a payer perspective, costs were elevated by 26% for SCD (adjusted mean 5,976€ [95%CI 4,598-7,355€]), 85% for MCI (8,795€ [6,200-11,391€]) and 36% for AD (6,454€ [2,796-10,111€]) compared to controls (4,754€ [3,586-5,922€]). Societal costs were elevated by 52% for SCD (adjusted mean 8,377€ [95%CI 6,009-10,746€]), 170% for MCI (14,886€ [9,524-20,248€]) and 307% for AD (22,481€ [9,994-34,969€]) compared to controls (5,522€ [3,814-7,230€]). APOE e4 negative patients showed higher costs compared to APOE e4 positive patients. Hypertension was associated with higher costs. CONCLUSIONS: Healthcare costs are already elevated in early subjective and objective cognitive impairment, driven by formal and informal care. The study emphasizes the importance of early interventions to reduce the economic burden and delay progression
Mechanosensitive PIEZO2 channels shape coronary artery development
Get PDFCoronary arteries develop under constant mechanical stress. However, the role of mechanosensitive ion channels in this process remains poorly understood. Here we show that the ion channel PIEZO2, which responds to mechanical stimuli, is expressed in specific coronary endothelial cell populations during a critical phase of coronary vasculature remodeling. These Piezo2(+) coronary endothelial cells show distinct transcriptional profiles and have mechanically activated ionic currents. Strikingly, PIEZO2 loss-of-function mouse embryos and mice with human pathogenic variants of PIEZO2 show abnormal coronary vessel development and cardiac left ventricular hyperplasia. We conclude that an optimal balance of PIEZO2 channel function contributes to proper coronary vessel formation, structural integrity and remodeling, and is likely to support normal cardiac function. Our study highlights the importance of mechanical cues in cardiovascular development and suggests that defects in this mechanosensing pathway may contribute to congenital heart conditions
SARS-CoV-2 neutralization and protection of hamsters via nasal administration of a humanized neutralizing antibody
Get PDFMonoclonal antibodies are widely used for the treatment of infectious human diseases, including COVID-19. Since the start of the pandemic, eight monoclonal antibodies against SARS-CoV-2 were granted emergency use authorization. The high mutation rate of the SARS-CoV-2 virus has led to the emergence of highly transmissible variants that can evade vaccine-induced immunity. In this study, we generated a panel of murine monoclonal antibodies (mAb) to identify a subset that broadly neutralized SARS-CoV-2 variants and explored whether mucosal administration of such antibodies could protect against infection. Intranasal delivery of XR10, the most promising murine mAb, protected hamsters against infection by Delta variant. We next humanized XR10 mAb using a combination of CDR-grafting and Vernier zones preservation approaches (CRVZ) to create a panel of humanized XR10 variants. We ranked the variants based on their spike binding ability and virus neutralization. Of these, XR10v48 demonstrated the best ability to neutralize SARS-CoV-2 variants and was protective in hamsters when given as a single 50 μg/kg intranasal dose at the time of viral challenge. XR10v48 featured 34 key amino acid residues retained from the murine progenitor. With SARS-CoV-2 escape mutants continuing to emerge this work highlights a potential workflow to generate humanized broadly cross-neutralizing mAb for potential use as a nasal spray for SARS-CoV-2 prophylaxis
Differentiation and Dexamethasone Atrophy on C2C12 myotubes
No full textSkeletal muscle atrophy and weakness are major contributors to morbidity, prolonged recovery, and long-term disability across a wide range of diseases. Atrophy is caused by breakdown of sarcomeric proteins resulting in loss of muscle mass and strength. Molecular mechanism underlying the onset of muscle atrophy and its progression have been analysed in patients, mice, and cell culture but the complementarity of these model systems remains to be explored. Here, we applied deep-coverage transcriptomic and proteomic profiling to characterize dynamic changes during dexamethasone-induced atrophy in the widely used murine skeletal muscle cell line C2C12. Comparison with published datasets confirmed that muscle differentiation is well recapitulated in C2C12 myotubes. Under dexamethasone-induced treatment, this model was particularly suited to capture early atrophy events, prior to disassembly and degradation of sarcomeric proteins. We also identified alterations in mitochondrial gene expression and differential alternative splicing events during early-stage myotube atrophy. This dataset complements existing in vivo data and provides novel insights into the regulatory processes during skeletal muscle wasting
Differentiation and Dexamethasone Atrophy on C2C12 myotubes (house mouse)
No full textSkeletal muscle atrophy and weakness are major contributors to morbidity, prolonged recovery, and long-term disability across a wide range of diseases. Atrophy is caused by breakdown of sarcomeric proteins resulting in loss of muscle mass and strength. Molecular mechanism underlying the onset of muscle atrophy and its progression have been analysed in patients, mice, and cell culture but the complementarity of these model systems remains to be explored. Here, we applied deep-coverage transcriptomic and proteomic profiling to characterize dynamic changes during dexamethasone-induced atrophy in the widely used murine skeletal muscle cell line C2C12. Comparison with published datasets confirmed that muscle differentiation is well recapitulated in C2C12 myotubes. Under dexamethasone-induced treatment, this model was particularly suited to capture early atrophy events, prior to disassembly and degradation of sarcomeric proteins. We also identified alterations in mitochondrial gene expression and differential alternative splicing events during early-stage myotube atrophy. This dataset complements existing in vivo data and provides novel insights into the regulatory processes during skeletal muscle wasting. Overall design: mRNA-seq of undifferentiated C2C12 cells (day 0), differentiated cells (day 7), vehicle treated controls (day 8, day 10) and 100 µM Dexamethasone treated cells (day 8, day 10
Picrosirius Red staining of LV myocardium
No full textPicrosirius Red staining of LV myocardium (2025-05-18
The protein deacetylase SIRT2 exerts metabolic control over adaptive β cell proliferation
Get PDFSelective and controlled expansion of endogenous β cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of β cell proliferation to avoid excessive β cell expansion. Here, we identified a regulator of β cell proliferation whose inactivation resulted in controlled β cell expansion: the protein deacetylase sirtuin 2 (SIRT2). Sirt2 deletion in β cells of mice increased β cell proliferation during hyperglycemia with little effect under homeostatic conditions, indicating preservation of feedback control of β cell mass. SIRT2 restrains proliferation of human islet β cells, demonstrating conserved SIRT2 function. Analysis of acetylated proteins in islets treated with a SIRT2 inhibitor revealed that SIRT2 deacetylates enzymes involved in oxidative phosphorylation, dampening the adaptive increase in oxygen consumption during hyperglycemia. At the transcriptomic level, Sirt2 inactivation has context-dependent effects on β cells, with Sirt2 controlling how β cells interpret hyperglycemia as a stress. Finally, we provide proof of principle that systemic administration of a glucagon-like peptide 1–coupled (GLP1-coupled), Sirt2-targeting antisense oligonucleotide achieves β cell Sirt2 inactivation and stimulates β cell proliferation during hyperglycemia. Overall, these studies identify a therapeutic strategy for increasing β cell mass in diabetes without circumventing feedback control of β cell proliferation. Future work should test the extent to which these findings translate to human β cells from individuals with or without diabetes
Ultra-high scale cytometry-based cellular interaction mapping - Data repository
No full textThis is the repository for datasets used in Vonficht, Jopp-Saile, Yousefian, Flore et al. Ultra-high scale cytometry-based cellular interaction mapping, Nature Methods (2025) https://doi.org/10.1038/s41592-025-02744-w. Associated analysis code can be found at https://github.com/agSHaas/ultra-high-scale-cytometry-based-cellular-interaction-mapping, and the repository for the accompanying R package is hosted at https://github.com/agSHaas/PICtR