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Structural analyses define the molecular basis of clusterin chaperone function
Get PDFClusterin (apolipoprotein J), a conserved glycoprotein abundant in blood and cerebrospinal fluid, functions as a molecular chaperone and apolipoprotein. Dysregulation of clusterin is linked to late-onset Alzheimer disease. Despite its prominent role in extracellular proteostasis, the mechanism of clusterin function remained unclear. Here, we present crystal structures of human clusterin, revealing a discontinuous three-domain architecture. Structure-based mutational analysis demonstrated that two disordered, hydrophobic peptide tails enable diverse activities. Resembling the substrate-binding regions of small heat-shock proteins, these sequences mediate clusterin’s chaperone function in suppressing amyloid-β, tau and α-synuclein aggregation. In conjunction with conserved surface areas, the tail segments also participate in clusterin binding to cell surface receptors and cellular uptake. While contributing to lipoprotein formation, the hydrophobic tails remain accessible for chaperone function in the lipoprotein complex. The remarkable versatility of these sequences allows clusterin to function alone or bound to lipids in maintaining the solubility of aberrant extracellular proteins and facilitating their clearance by endocytosis and lysosomal degradation
Co-occurrence of multiple pathologies in a case of frontotemporal dementia with TBK1 mutation: first in vivo detection of alpha-synuclein and tau co-pathology
No full textWe present the case of a 74-year-old woman with behavioral variant frontotemporal dementia (bvFTD) linked to a pathogenic TANK-binding kinase 1 (TBK1) mutation (c.1349_1352del; p.Ile450Lysfs*15). During clinical workup, the patient underwent comprehensive biomarker analysis, including tau positron emission tomography (PET) and cerebrospinal fluid (CSF) seed amplification assay (SAA) for α-synuclein (αSyn). While CSF biomarkers for Alzheimer’s disease were normal, the αSyn SAA was clearly positive, indicating misfolded αSyn aggregates. Tau PET revealed increased [18F]PI-2620 uptake in the basal ganglia. Genetic testing confirmed autosomal dominant TBK1-associated FTD. The patient’s condition deteriorated over the following year, with rapid cognitive decline and the emergence of cortical signs. Post-mortem neuropathological analysis confirmed multiple proteinopathies: FTLD-TDP43 (subtype A), Lewy body disease (limbic type, Braak stage 5), argyrophilic grain disease (AGD), aging-related tau astrogliopathy (ARTAG), and primary age-related tauopathy (PART). This is the first reported TBK1-FTD case with in vivo detection of αSyn pathology via SAA and in vivo monitoring of tau pathology. The case expands the clinical and neuropathological spectrum of TBK1-associated FTD. Our findings support a broader interpretation of TBK1-associated neurodegeneration and highlight the importance of multimodal diagnostic approaches that integrate molecular, genetic, imaging, and neuropathological tools. This case also underscores the utility of αSyn SAA and tau PET in detecting co-pathologies that may otherwise remain clinically silent and illustrates the need for further studies exploring the molecular cross-talk between TBK1, tau, and αSyn pathologies
Executive Function Deficits in Genetic Frontotemporal Dementia
No full textBackground and Objectives
Executive dysfunction is a core feature of frontotemporal dementia (FTD). While there has been extensive research into such impairments in sporadic FTD, there has been little research in the familial forms.
Methods
Seven hundred fifty-two individuals were recruited in total: 214 C9orf72; 205 progranulin (GRN) and 86 microtubule associated protein tau (MAPT) mutation carriers, stratified into asymptomatic, prodromal, and fully symptomatic; and 247 mutation-negative controls. Attention and executive function were measured using the Weschler Memory Scale-Revised (WMS-R) Digit Span Backwards (DSB), Wechsler Adult Intelligence Scale-Revised Digit Symbol task, Trail Making Test Parts A and B, and the Delis-Kaplan Executive Function System Color Word Interference Test. Linear regression models with bootstrapping were used to assess differences between groups. Correlation of task score with disease severity was also performed, as well as an analysis of the neuroanatomical correlates of each task.
Results
Fully symptomatic C9orf72, GRN, and MAPT mutation carriers were significantly impaired on all tasks compared with controls (all p < 0.001), except on the WMS-R DSB in the MAPT mutation carriers (p = 0.147). While asymptomatic and prodromal C9orf72 individuals also demonstrated differences compared with controls, neither the GRN or MAPT asymptomatic or prodromal mutation carriers showed significant deficits. All tasks were significantly correlated with disease severity in each of the genetic groups (all p < 0.001).
Discussion
Some individuals with C9orf72 mutations show difficulties with executive function from very early on in the disease and this continues to deteriorate with disease severity. By contrast, similar difficulties occur only in the later stages of the disease in GRN and MAPT mutation carriers. This differential performance across the genetic groups will be important in neuropsychological task selection in upcoming clinical trials
Synaptic loss pattern is constrained by brain connectome and modulated by phosphorylated tau in Alzheimer’s disease
No full textWiphala de lucha: El actuar transfronterizo de una bandera aymara ante el agravio estatal
No full textA partir de la descripción de las movilizaciones sociales de Bolivia el 2019 y Perú el 2022-2023, este artículo pretende abordar el carácter interpelador y aglutinador de la Wiphala, una bandera indígena del pueblo aymara que, desde su (re)constitución, entre los años 1970 y 1980 como bandera anticolonial, se ha establecido como uno de los emblemas más reconocidos de los movimientos sociales en los Andes. Mediante un abordaje histórico y etnográfico se busca comprender su cualidad transfronteriza, así como algunos contextos en los que esta bandera emerge y se constituye en una entidad cohesionadora de la identidad étnica traspasando fronteras de los Estados-nación. Se plantea que, pese a que en los últimos años se iniciaron procesos que buscaron incorporarla dentro de la simbología oficial de los Estados, su carácter de “bandera de lucha” prevalece en momentos de convulsión social y persecución, activando emociones y sentimientos de identidad política. De esta manera, este emblema se constituye en un movilizador de acciones colectivas dentro de los Estados y en un garante de los avances políticos e históricos de este pueblo
Health‐Related Quality of Life and Everyday Functioning in the Flood‐Affected Population in Germany ‐ A Case Study of the 2021 Floods in West Germany
No full textFloods lead to adverse impacts not only in financial terms but also on the health of the exposed population. We report on health-related Quality of Life (QoL) and functioning in the population affected by the 2021 flooding in Germany using an empirical survey data set. Health-related QoL and functioning are represented by two scores-(a) The EuroQoL 5D Visual Analog Scale (EQ-5D VAS) and (b) The 12-Item World Health Organization Disability Assessment Schedule (WHODAS 2.0), respectively. By applying an incremental linear regression model and Machine Learning models, we infer that health-related QoL and functioning are strongly negatively related to the psychological burden from those being affected by the flooding. This includes how often they think about the traumatic event. Home owners were found to have worse QoL and functioning than tenants. Household income and the status of repair/reconstruction of flood damages-in specific, insurance benefits, private donation and satisfactory claims compensation are associated with high health-related QoL and functioning. These findings highlight the importance of strengthening the health-related QoL of flood affected populations and emphasizes the strong association between recovery and health-related QoL and functioning of flood-affected populations
Commentary: Regression Models—Efforts Are Required to Improve Statistical Practice and Teaching
No full textUnderstanding non-partner sexual violence perpetration in young Tanzanian men: a cross-sectional study
No full textBackground: The World Health Organisation estimates that worldwide six percent of women aged 15-49 have experienced non-partner sexual violence (NPSV) in their lifetimes. A similar prevalence is found in sub-Saharan Africa. This form of violence is comparatively under-researched, leading to a dearth of knowledge around potential risk factors for male perpetration of NPSV.
Methods: We sought to explore key risk factors for perpetration of non-partner rape, verbal and physical sexual harassment in young Tanzanian men by conducting a cross-sectional survey of 1002 young men aged 18 to 24 living in Mwanza, Tanzania between June 2021 and March 2022. We conducted unadjusted logistic regression for bivariate associations between all three forms of NPSV and risk factors at the sociodemographic, behavioural, and mental health and substance misuse level. The risk factors independently associated with the outcomes were included in three separate multivariable logistic regression models. We then used dominance analysis to determine which factors had the strongest association with all three forms of NPSV perpetration.
Results: Among the young men in our sample, 9% reported having perpetrated non-partner rape (n = 86), 19% having physically harassed a woman (n = 188) and 33% having verbally harassed a woman (n = 330). After adjustment for the other risk factors in the model, pornography consumption, having multiple sexual partners, gambling, and depressive symptoms remained significantly associated with more than one form of NPSV.
Conclusions: The widespread nature of sexual harassment and rape perpetration among young men in our study and the associated risk factors, which are all tied to notions of masculinity encouraging domination, promiscuity, and risky health behaviours, call for harmful gender norms to be addressed to reduce the incidence of NPSV
Primary cardiac sarcoma: insights from two decades of multimodal management at LMU Munich
No full textBackground: Primary cardiac sarcomas (PCS) are rare, aggressive malignancies with poor prognosis and limited evidence guiding optimal management. We aimed to evaluate clinical and histopathological parameters in a single-center PCS cohort.
Methods: Thirty-three patients diagnosed with PCS between 2002 and 2024 were retrospectively reviewed. Clinical outcomes and prognostic factors were analyzed. Event-free survival (EFS) was defined as the time from initial diagnosis to the first occurrence of disease progression, recurrence, or death. Overall survival (OS) was calculated from initial diagnosis to death.
Results: The median age at diagnosis was 45 years, with angiosarcoma representing the most common histological subtype (n = 9, 27%). Most patients presented with localized or regional disease (n = 25, 75%), predominantly involving the right (n = 11, 33%) and left atrium (n = 8, 24%). In patients who underwent comprehensive genomic profiling, MDM2 amplification was the most common molecular alteration (n = 5, 45%). The majority of patients received multimodal treatment: surgical resection in 76% (n = 25), systemic therapy in 73% (n = 24), and radiotherapy in 21% (n = 7). After a median follow-up of 63.4 months, median EFS and OS were 11.7 months (95% CI 9.4–23.7) and 37.5 months (95% CI 21.2–83.2), respectively. Distant metastasis (p = 0.027, HR = 3.74) and angiosarcoma histology (p = 0.014, HR = 6.97) were significantly associated with worse OS, while surgical resection was associated with improved OS (p = 0.0064, HR = 0.086).
Conclusion: Our findings underscore the key clinical and histopathological characteristics of PCS and suggest that surgical resection - even when incomplete - may confer a survival benefit in this aggressive tumor entity. The favorable clinical outcomes observed in this cohort may be attributable to the high proportion of patients undergoing multimodal treatment
Dietary greenhouse gas emissions and resource use among Bavarian adults: associations with sociodemographics and food choices
Get PDFBackground: This study assessed dietary greenhouse gas emission (GHGE), land use (LU), and water footprint (WFP) among Bavarian residents while exploring sociodemographic characteristics, food consumption patterns, sustainability beliefs, and behaviors across GHGE quintiles.
Methods and design: The 3rd Bavarian Food Consumption Survey (BVS III) was conducted from October 2021 to January 2023, involving participants aged 18-75 years. The study employed demographic weighting to represent the Bavarian population. Dietary data (N = 1,100) were linked to sustainability databases.
Results: In Bavaria, the average dietary GHGE is 6.14 kg CO2eq, with LU at 7.50 m2*yr. and WFP at 4.39 kiloliters per 2,500 kcal. Multivariate regression analyses indicated that females had significantly higher GHGE (β = 0.204, p = 0.023) and WFP (β = 0.466, p < 0.001) compared to males. Waist circumference was positively associated with GHGE (β = 0.011, p < 0.001) and LU (β = 0.035, p < 0.001). Participants following vegetarian or vegan diets show significantly lower GHGE, LU, and WFP than omnivores. High CO2eq emitters also consumed more coffee, tea, and most foods of animal origin. Lowest CO2eq emitters are more inclined to reduce meat consumption (91% vs. 61-77%, p = 0.012), while higher emitters focused on purchasing regional foods (93-95% vs. 80%, p = 0.041).
Conclusion: This study provided a view of dietary sustainability metrics in Bavaria. Considering energy-adjusted diets, higher emissions are associated with being female, having a higher waist circumference, and following an omnivorous diet. Increased consumption of animal products, coffee, and tea contributed to greater environmental impacts