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Ub-POD: A Ubiquitin-Specific Proximity-Dependent Labeling Technique to Identify E3 Ubiquitin Ligase Substrates in Human Cells
No full textAm I in control? The dynamics of sensory information, performance feedback, and personality in shaping the sense of control
No full textSense of control (SoC) over our actions is crucial for regulating our behavior. SoC arises from low-level processes, such as immediate sensory feedback, and high-level processes, such as performance evaluation. Studies using simple action-effect tasks suggest that people rely more on low-level sensory than on high-level cues of control. Yet, it remains unclear how these cues interact to shape the SoC in complex, goal-directed environments that require continuous behavioral adaptation. To investigate this, 50 participants performed a challenging motor control task akin to a video game, steering a spaceship along a continuously changing path. Sensorimotor control was manipulated by varying task difficulty via input noise across experimental blocks. After each trial, participants received negative, neutral, or positive feedback, followed by rating of their SoC. Linear mixed model analyses revealed that both sensory and evaluative feedback influenced the SoC. SoC decreased with increasing task difficulty. Furthermore, independent of difficulty, negative feedback reduced the SoC whereas positive feedback enhanced it, with a stronger effect for negative feedback. Notably, the effects of task difficulty and negative feedback were influenced by participants’ depressive symptoms and their external locus of control, suggesting that generalized control beliefs modulate task-specific control experience. These findings indicate that SoC is informed by both low-level sensorimotor cues and high-level affective feedback, suggesting an integration of multiple types of information to assess control in dynamic task contexts where action-effect contingencies are extended over time. Crucially, these effects depend on trait-like control beliefs, highlighting the need to account for individual differences when investigating situated control experience
Mitotane treatment of adrenocortical carcinoma induces tumoural secretion of GDF-15: impact on poor prognosis and impaired responsiveness to immunotherapy
No full textPurpose: Treatment options for adrenocortical carcinoma (ACC), where mitotane remains a mainstay of therapy, are unsatisfactory. Response rates of ACC to immune checkpoint inhibition (ICI) are disappointing, and immune cells are scarce in ACC. Growth/differentiation factor 15 (GDF-15) is a cytokine impairing tumoural immune infiltration. We here aimed to assess the value of serum GDF-15 for the prognosis of ACC and as a predictor of response to ICI.
Methods: GDF-15 was measured in serum samples of 151 patients and correlated with clinical data. Serum GDF-15 was analysed in a second cohort of 46 ACC patients who received ICI, including 14 responders. mRNA expression of GDF15 and genes related to immune response was quantified in 58 ACC tumour samples.
Results: We found GDF-15 induction in ACC cells and patients upon mitotane treatment. In ACC patients, serum GDF-15 concentration below the median was associated with significantly longer patient survival. GDF-15 levels in responders to ICI were significantly lower than in non-responders (P = .0379), and patients with low GDF-15 levels had a significant longer progression-free survival than patients with higher GDF-15 serum levels (P = .036). Expression of pro-inflammatory immune-related genes was lower in ACC tissue with GDF-15 expression above the median.
Conclusions: Mitotane increases GDF-15 levels and is associated with poor response to ICI. GDF-15 may mediate reduced infiltration with immune cells in ACC
PACIC: patient activation and problem solving not related to age in patients with depressive symptoms
No full textThe Patient Assessment of Chronic Illness Care (PACIC) assesses alignment of chronic care with the Chronic Care Model (CCM). We analysed PACIC subscales in patients with depressive symptoms to identify gaps in patient-centred care. A total of N = 2741 patients (59.5% women, mean age 45.3 ± 16.9) were assessed for depression (PHQ-9), anxiety (GAD-7) and socioeconomic data. PACIC data from 1210 patients (62.7% women, mean age 47.2 years ± 16.8) revealed low scores in subscales patient activation, goal setting, problem-solving, and follow-up. Patient activation and problem-solving were age-independent. Overall, the low PACIC scores highlight poor CCM alignment in German depression care
Associations of lifestyle factors with amyloid pathology in persons without dementia
No full textBackground
The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood.
Objective
The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology.
Methods
For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology.
Results
We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66–0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73–0.99, p = 0.029; OR = 0.62, 95%CI 0.45–0.86, p = 0.004).
Conclusions
In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages
An unsupervised XAI framework for dementia detection with context enrichment
No full textExplainable Artificial Intelligence (XAI) methods enhance the diagnostic efficiency of clinical decision support systems by making the predictions of a convolutional neural network’s (CNN) on brain imaging more transparent and trustworthy. However, their clinical adoption is limited due to limited validation of the explanation quality. Our study introduces a framework that evaluates XAI methods by integrating neuroanatomical morphological features with CNN-generated relevance maps for disease classification. We trained a CNN using brain MRI scans from six cohorts: ADNI, AIBL, DELCODE, DESCRIBE, EDSD, and NIFD (N = 3253), including participants that were cognitively normal, with amnestic mild cognitive impairment, dementia due to Alzheimer’s disease and frontotemporal dementia. Clustering analysis benchmarked different explanation space configurations by using morphological features as proxy-ground truth. We implemented three post-hoc explanations methods: (i) by simplifying model decisions, (ii) explanation-by-example, and (iii) textual explanations. A qualitative evaluation by clinicians (N = 6) was performed to assess their clinical validity. Clustering performance improved in morphology enriched explanation spaces, improving both homogeneity and completeness of the clusters. Post hoc explanations by model simplification largely delineated converters and stable participants, while explanation-by-example presented possible cognition trajectories. Textual explanations gave rule-based summarization of pathological findings. Clinicians’ qualitative evaluation highlighted challenges and opportunities of XAI for different clinical applications. Our study refines XAI explanation spaces and applies various approaches for generating explanations. Within the context of AI-based decision support system in dementia research we found the explanations methods to be promising towards enhancing diagnostic efficiency, backed up by the clinical assessments
Differential DNA methylation 7 months after SARS-CoV-2 infection
Get PDFBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), and SARS-CoV-2 has been linked to changes in DNA methylation (DNAm) patterns. Studies focused on post-SARS-CoV-2 infection and DNAm have been mainly carried out among severe COVID-19 cases or without distinguishing the severity of cases. However, investigations into mild and asymptomatic cases after SARS-CoV-2 infection are limited. In this study, we analyzed DNAm patterns of mild and asymptomatic cases seven months after SARS-CoV-2 infection in a household setting by conducting epigenome-wide association studies (EWAS).
Results: We identified DNAm changes at 42 CpG sites associated with anti-SARS-CoV-2 antibody levels. We additionally report EWAS between COVID-19 cases and controls, with the case status being confirmed by either an antibody test or a PCR test. The EWAS with an antibody test case definition identified 172 CpG sites to be differentially methylated, while the EWAS with a PCR test case definition identified 502 CpG sites. Two common sites, namely cg17126990 (annotated to AFAP1L2) and cg25483596 (annotated to PC), were identified to be hypermethylated across the three EWAS. Both CpG sites have been reported to be involved in molecular pathways after SARS-CoV-2 infection. While AFAP1L2 has been found to be upregulated after SARS-CoV-2 infection, the pyruvate carboxylase (PC) activity seems to be affected by SARS-CoV-2 infection resulting in changes to the host cell metabolism. Additionally, an EWAS to assess persistent health restrictions among PCR-confirmed cases showed 40 CpG sites to be differentially methylated.
Conclusions: We detected associations between DNAm in individuals who had asymptomatic and mild SARS-CoV-2 infections as compared to their household controls. These findings contribute to our understanding of the molecular consequences of SARS-CoV-2 infection observed months after infection
Reliable delineation of Bacillus cytotoxicus from other members of the Bacillus cereus group by MALDI-TOF MS – An extensive validation study
Get PDFReliable infarction of the middle cerebral artery territory in C57BL/6 mice using pterygopalatine artery ligation and filament optimization – The PURE-MCAo model
Get PDFCurrent techniques for inducing intraluminal filamentous middle cerebral artery occlusion (fMCAo) in mice produce highly variable results and often cause additional infarcts in the posterior cerebral artery (PCA) territory. The aim of the current study was to develop a novel procedure to overcome these shortcomings. Male C57BL/6 mice were subjected to 60 min of fMCAo with cerebral blood flow monitored by laser Doppler flowmetry. The influence of the length of the occlusion filament coating and the combination of common carotid artery (CCA) or pterygopalatine artery (PPA) ligation on lesion volume and functional outcome 24 h after reperfusion was evaluated. The use of appropriate filament and PPA ligation while maintaining CCA perfusion prevented the development of infarcts in the PCA area, resulted in pure MCA infarcts (68.3 ± 14.5 mm3) and reduced the variability of infarct volumes by more than half (from 26–38% to 14% standard deviation/mean). Using an improved fMCAo procedure, we were able to produce PCA area-unaffected reproducible (PURE) infarcts exclusively in the MCA territory. Thus PURE-MCAo reduced outcome variability by more than 50%. Our results may thus help to reduce the number of animals in preclinical stroke research and to increase the reproducibility of the fMCAo model
