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Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases
No full textAbstract Accurate diagnosis and monitoring of neurodegenerative diseases require reliable biomarkers. Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the levels of 69 pre-selected proteins in cerebrospinal fluid using antibody-based suspension bead array technology in a multi-disease cohort of 499 individuals with neurodegenerative disorders including Alzheimer’s disease (AD), behavioral variant frontotemporal dementia, primary progressive aphasias, amyotrophic lateral sclerosis (ALS), corticobasal syndrome, primary supranuclear palsy, along with healthy controls. We identify significant inter-individual variability in overall CSF levels of brain-derived proteins, which could not be attributed to specific disease associations. Using linear modelling, we show that adjusting for median CSF levels of brain-derived proteins increases the diagnostic accuracy of proteins previously identified as altered in CSF in the context of neurodegenerative disorders. We further demonstrate a simplified approach for the adjustment using pairs of correlated proteins with opposite alteration in the diseases. With this approach, the proteins adjust for each other and further increase the biomarker performance through additive effect. When comparing the diseases, two proteins—neurofilament medium and myelin basic protein—showed increased levels in ALS compared to other diseases, and neurogranin showed a specific increase in AD. Several other proteins showed similar trends across the studied diseases, indicating that these proteins likely reflect shared processes related to neurodegeneration. Overall, our findings suggest that accounting for inter-individual variability is crucial in future studies to improve the identification and performance of relevant biomarkers. Importantly, we highlight the need for multi-disease studies to identify disease-specific biomarkers
Genomic analysis of three medieval parchments from German monasteries
No full textAbstract In the last two decades there has been growing interest in the analysis of ancient DNA obtained from the parchment used in historic documents. The genetic insight that this data provides makes collections of historic documents an invaluable source for studying the development and spread of historical livestock populations. Additionally, the biological data may provide new information for the historical analysis that could be used to determine the provenance as well as the authenticity of these documents. In this study, we extracted DNA from three medieval parchments that were written in German monasteries in the twelfth century. The source animal of the parchments could be identified as cattle and we compared their genome sequences with those of modern populations that are part of the 1000 Bull Genomes Project. The three animals were found to carry mtDNA haplogroup T3 and show a closer genetic relationship to other historic animals than to modern breeds. We further identified 39 haplotypes and 132 SNPs variants, which are rare ( < 0.1 ) or even non-existent in modern breeds. Finally, the genetic distances between the parchment samples show a putative association with the dates when the documents were written, indicating the usefulness of genetic analysis for provenance research.Open-Access-Publikationsfonds 202
I. Assembly history, environment, and redshift evolution
No full textContext . The evolution of galaxies within a self-consistent cosmological context remains one of the most outstanding and challenging topics in modern galaxy formation theory. Investigating the assembly history and various formation scenarios of the most massive and passive galaxies, particularly those found in the densest clusters, will enhance understanding of why galaxies exhibit such a remarkable diversity in structure and morphology. Aims . In this paper, we simultaneously investigate the assembly history and redshift evolution of semi-analytically modelled galaxy properties of luminous and massive central galaxies between 0.56 < z < 4.15 alongside their connection to their halos as a function of large-scale environment. Methods . We extracted sub-samples of galaxies from a mock catalogue representative of the well-known BOSS-CMASS sample, which includes the most massive and passively evolving system known today. Utilising typical galaxy properties such as star formation rate, ( ɡ -i) colour, and cold gas-phase metallicity ( Z cold ), we tracked the redshift evolution of these properties across the main progenitor trees. Results . We present results on galaxy and halo properties, including their growth and clustering functions, for each of our sub-samples. Our findings indicate that galaxies in the highest stellar and halo mass regimes are the least metal enriched (using Z cold as a proxy) and consistently exhibit significantly larger black hole masses and higher clustering amplitudes compared to sub-samples selected by such properties as colour or star formation rate. This population forms later and retains large reservoirs of cold gas. In contrast, galaxies in the intermediate and lower stellar or halo mass regimes consume their cold gas at a higher redshift and were among the earliest and quickest to assemble their stellar and black hole masses. In addition, we observed a clear trend where the clustering of the galaxies selected according to their Z cold -values (either low- Z cold or high- Z cold ) depends on the density of their location within the large-scale environment. Conclusions . We assume that the galaxies in the low- Z cold and high- Z cold sub-samples form and evolve through distinct evolutionary channels that are predetermined by their location within the large-scale environment of the cosmic web. Furthermore, their clustering dependence on the environment could be an important area for further investigation
Cryo-ET suggests tubulin chaperones form a subset of microtubule lumenal particles with a role in maintaining neuronal microtubules
No full textThe functional architecture of the long-lived neuronal microtubule (MT) cytoskeleton is maintained by various MT-associated proteins (MAPs), most of which are known to bind to the MT outer surface. However, electron microscopy (EM) has long ago revealed the presence of particles inside the lumens of neuronal MTs, of yet unknown identity and function. Here, we use cryogenic electron tomography (cryo-ET) to analyze the three-dimensional (3D) organization and structures of MT lumenal particles in primary hippocampal neurons, human induced pluripotent stem cell–derived neurons, and pluripotent and differentiated P19 cells. We obtain in situ density maps of several lumenal particles from the respective cells and detect common structural features underscoring their potential overarching functions. Mass spectrometry-based proteomics combined with structural modeling suggest that a subset of lumenal particles could be tubulin-binding cofactors (TBCs) bound to tubulin monomers. A different subset of smaller particles, which remains unidentified, exhibits densities that bridge across the MT protofilaments. We show that increased lumenal particle concentration within MTs is concomitant with neuronal differentiation and correlates with higher MT curvatures. Enrichment of lumenal particles around MT lattice defects and at freshly polymerized MT open-ends suggests a MT protective role. Together with the identified structural resemblance of a subset of particles to TBCs, these results hint at a role in local tubulin proteostasis for the maintenance of long-lived neuronal MTs.Deutsche Forschungsgemeinschaft 501100001659European Molecular Biology Laboratory 10001306
Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes
No full textAbstract Prions are assemblies of misfolded prion protein that cause several fatal and transmissible neurodegenerative diseases, with the most common phenotype in humans being sporadic Creutzfeldt-Jakob disease (sCJD). Aside from variation of the prion protein itself, molecular risk factors are not well understood. Prion and prion-like mechanisms are thought to underpin common neurodegenerative disorders meaning that the elucidation of mechanisms could have broad relevance. Herein we sought to further develop our understanding of the factors that confer risk of sCJD using a systematic gene prioritization and functional interpretation pipeline based on multiomic integrative analyses. We integrated the published sCJD genome-wide association study (GWAS) summary statistics with publicly available bulk brain and brain cell type gene and protein expression datasets. We performed multiple transcriptome and proteome-wide association studies (TWAS & PWAS) and Bayesian genetic colocalization analyses between sCJD risk association signals and multiple brain molecular quantitative trait loci signals. We then applied our systematic gene prioritization pipeline on the obtained results and nominated prioritized sCJD risk genes with risk-associated molecular mechanisms in a transcriptome and proteome-wide manner. Genetic upregulation of both gene and protein expression of syntaxin-6 (STX6) in the brain was associated with sCJD risk in multiple datasets, with a risk-associated gene expression regulation specific to oligodendrocytes. Similarly, increased gene and protein expression of protein disulfide isomerase family A member 4 (PDIA4), involved in the unfolded protein response, was linked to increased disease risk, particularly in excitatory neurons. Protein expression of mesencephalic astrocyte derived neurotrophic factor (MANF), involved in protection against endoplasmic reticulum stress and sulfatide binding (linking to the enzyme in the final step of sulfatide synthesis, encoded by sCJD risk gene GAL3ST1), was identified as protective against sCJD. In total 32 genes were prioritized into two tiers based on the level of evidence and confidence for further studies. This study provides insights into the genetically-associated molecular mechanisms underlying sCJD susceptibility and prioritizes several specific hypotheses for exploration beyond the prion protein itself and beyond the previously highlighted sCJD risk loci through the newly prioritized sCJD risk genes and mechanisms. These findings highlight the importance of glial cells, sulfatides and the excitatory neuron unfolded protein response in sCJD pathogenesis
Unexpected recombination at the polled locus in a horned Holstein calf from the mating of a homozygous polled sire and a heterozygous polled cow
No full textAbstract In this study, I report an unexpected case of a Holstein calf that developed horns even though the sire was homozygous and the dam was heterozygous for polledness. After verifying and confirming the correct parentage, the parents and offspring were genotyped with the Illumina EuroG_MD BeadChip and the SNPs in the polled region on chromosome 1 were evaluated. In addition, the father was sequenced with next generation sequencing to identify possible, previously unknown variants. The deletion of two base pairs within the causative 80‐kb duplication described for the Friesian polled variant was verified by melting curve analysis and the 80‐kb duplication by droplet digital PCR. Analysis of all data showed that, as expected, the calf was heterozygous for all SNP positions flanking the 80‐kb duplication but was homozygous wild type in the 80‐kb duplication region and therefore carried horns. This is certainly a very rare case of a recombination within the highly conserved polled region, which on the one hand confirms that only the 80‐kb duplication is responsible for the expression of the Friesian polled variant, but on the other hand also shows that caution is required when interpreting the usual routine genotyping of the horn status based on linked single nucleotide polymorphisms in the polled region on chromosome 1. Based on the present case, it is recommended that, in addition to the evaluation of the SNP data of the BeadChip, an extended diagnosis with direct detection of the 2‐bp deletion (1:g.2629156_2629158delGT) should be carried out in any case when detecting the Friesian polled variant
Increased Mineral‐Associated Organic Carbon and Persistent Molecules in Allochthonous Blue Carbon Ecosystems
No full textABSTRACT Coastal wetlands contain very large carbon (C) stocks—termed as blue C—and their management has emerged as a promising nature‐based solution for climate adaptation and mitigation. The interactions among sources, pools, and molecular compositions of soil organic C (SOC) within blue C ecosystems (BCEs) remain elusive. Here, we explore these interactions along an 18,000 km long coastal line of salt marshes, mangroves, and seagrasses in China. We found that mineral‐associated organic C (MAOC) is enriched in BCEs dominated by allochthonous inputs and abundant active minerals, leading to an increased proportion of persistent organic molecules. Specifically, soils with large allochthonous inputs (> 50%) are characterized by a substantial contribution of MAOC (> 70%) to total SOC with a notable preservation of lipids (36%) across salt marshes, mangroves, and seagrasses. The burial of allochthonous particles, derived from external sources such as rivers or tidal influxes, facilitates the formation of stable MAOC through binding to mineral surfaces or occlusion within microaggregates. The proportions of particulate organic C (POC) and MAOC are important predictors for molecular compositions of soil organic matter. Lipid proportions within molecular composition decrease as POC and autochthonous C proportions increase. These findings provide new insights into the coupled control over SOC sequestration in BCEs, emphasizing the role of allochthonous inputs, proportions of carbon pools, and persistent organic components.National Natural Science Foundation of China https://doi.org/10.13039/501100001809National Key Research and Development Program of China https://doi.org/10.13039/501100012166Natural Science Foundation of Shandong Province https://doi.org/10.13039/50110000712
Endovascular versus Best Medical Treatment for Acute Carotid Occlusion BelOw Circle of Willis (ACOBOW): The ACOBOW Study
No full textFor patients with symptomatic acute occlusions of the internal carotid artery below the circle of Willis, endovascular and best medical treatment were both effective and safe therapeutic options.Background Symptomatic acute occlusions of the internal carotid artery (ICA) below the circle of Willis can cause a variety of stroke symptoms, even if the major intracranial cerebral arteries remain patent; however, outcome and safety data are limited. Purpose To compare treatment effects and procedural safety of endovascular treatment (EVT) and best medical treatment (BMT) in patients with symptomatic acute occlusions of the ICA below the circle of Willis. Materials and Methods This retrospective, multicenter cohort study from 22 comprehensive stroke centers in Europe and Asia includes patients treated between January 1, 2008, and December 31, 2022. Functional (modified Rankin Scale [mRS]) and clinical (National Institutes of Health Stroke Scale [NIHSS]) outcomes, safety measures (symptomatic intracerebral hemorrhage), mortality, and procedural complications were assessed. Results A total 354 patients met the inclusion criteria (median age, 72 years [IQR, 60–81 years]; median NIHSS, 13 [IQR, 7–19]). Most frequent occlusions were in the C1 segment (243 of 354; 68.6%). Of 354 patients, 82.2% (291 patients) were administered EVT. In the overall population, favorable outcomes (mRS 0–2), mortality, and symptomatic intracerebral hemorrhage occurred in 40.6% (108 of 266 patients), 25.2% (67 of 266 patients), and 7.1% (25 of 350 patients), respectively. After adjustment, no statistically significant difference in functional outcome was observed (adjusted odds ratio [AOR], 0.82 [95% CI: 0.31, 2.12]; average treatment effect, −12.7%; P = .19) in the EVT compared with BMT group. Symptomatic intracerebral hemorrhage (average treatment effect, −0.28%; P = .95) and mortality did not differ between both groups (average treatment effect, −17.1%; P = .07). EVT resulted in complete recanalization of the occlusion in 80.9% (229 of 283) of cases. Periprocedural distal embolization occurred in 27.8% (81 of 291 patients) and was associated with poor outcomes (AOR, 0.41; 95% CI: 0.18, 0.93; P = .03). Conclusion EVT did not reveal a favorable treatment effect over BMT, and both therapies were safe. EVT had a risk for periprocedural distal embolization associated with poor outcomes. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Daou and Chaudhary in this issue.For patients with symptomatic acute occlusions of the internal carotid artery below the circle of Willis, endovascular and best medical treatment were both effective and safe therapeutic options.Background Symptomatic acute occlusions of the internal carotid artery (ICA) below the circle of Willis can cause a variety of stroke symptoms, even if the major intracranial cerebral arteries remain patent; however, outcome and safety data are limited. Purpose To compare treatment effects and procedural safety of endovascular treatment (EVT) and best medical treatment (BMT) in patients with symptomatic acute occlusions of the ICA below the circle of Willis. Materials and Methods This retrospective, multicenter cohort study from 22 comprehensive stroke centers in Europe and Asia includes patients treated between January 1, 2008, and December 31, 2022. Functional (modified Rankin Scale [mRS]) and clinical (National Institutes of Health Stroke Scale [NIHSS]) outcomes, safety measures (symptomatic intracerebral hemorrhage), mortality, and procedural complications were assessed. Results A total 354 patients met the inclusion criteria (median age, 72 years [IQR, 60–81 years]; median NIHSS, 13 [IQR, 7–19]). Most frequent occlusions were in the C1 segment (243 of 354; 68.6%). Of 354 patients, 82.2% (291 patients) were administered EVT. In the overall population, favorable outcomes (mRS 0–2), mortality, and symptomatic intracerebral hemorrhage occurred in 40.6% (108 of 266 patients), 25.2% (67 of 266 patients), and 7.1% (25 of 350 patients), respectively. After adjustment, no statistically significant difference in functional outcome was observed (adjusted odds ratio [AOR], 0.82 [95% CI: 0.31, 2.12]; average treatment effect, −12.7%; P = .19) in the EVT compared with BMT group. Symptomatic intracerebral hemorrhage (average treatment effect, −0.28%; P = .95) and mortality did not differ between both groups (average treatment effect, −17.1%; P = .07). EVT resulted in complete recanalization of the occlusion in 80.9% (229 of 283) of cases. Periprocedural distal embolization occurred in 27.8% (81 of 291 patients) and was associated with poor outcomes (AOR, 0.41; 95% CI: 0.18, 0.93; P = .03). Conclusion EVT did not reveal a favorable treatment effect over BMT, and both therapies were safe. EVT had a risk for periprocedural distal embolization associated with poor outcomes. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Daou and Chaudhary in this issue
Metabolic profiling of endophytic fungi acting as antagonists of the banana pathogen Colletotrichum musae
No full textThree endophytic strains, Phomopsis sp., Fusarium proliferatum , and Tinctoporellus epimiltinus , isolated from various plants in the rainforest of the Philippines, were investigated regarding their ability to repress growth of the pathogenic fungus Colletotrichum musae on banana fruits causing anthracnose disease. An in vitro plate-to-plate assay and an in vivo sealed box assay were conducted, using commercial versus natural potato dextrose medium (PDA). All tested endophytes were able to significantly reduce C . musae growth compared to the control. However, the type of medium had no significant effect on lesion size of C . musae on banana. An interaction effect between fungal strain and medium could be shown. On the commercial medium, no differences between the biocontrol ability of the fungi and control treatments could be found, while there were significant differences between the fungal strains on natural medium. Lesions on banana incubated with Phomopsis sp. on natural medium were significantly but only slightly larger than those on banana incubated with F . proliferatum . Volatiles released by these two strains and one pathogenic strain of F . graminearum were collected using polydimethylsiloxane tubes and analyzed via gas chromatography mass spectrometry (GC-MS). Twelve volatile metabolites were detected. Benzaldehyde was the most prominent volatile emitted from the commercial and plain medium. 2-Undecanone, 2-nonanone, and phenylethyl-alcohol were detected in individual samples in both media. 1-Decanol and acoradiene were exclusive to the commercial medium, with acoradiene also being unique to F . proliferatum . Five volatileorganic compounds (VOCs)were emitted from all tested fungal species: 2-heptanone, 2-nonanone, 2-undecanone, 2-tridecanone, and phenylethyl-alcohol. Beta-acorenol was detected in F . proliferatum grown on both media. To reveal whether the medium (commercial PDA versus potato extract) affected the metabolism of the fungi, metabolic footprints were assessed via high performance liquid chromatography with quadrupole time of flight mass spectrometry MS (HPLC-QTOF-MS). A total of 388 metabolic signals were recorded. The intensities of 80–90% of these signals differed significantly between the two types of media. Metabolic footprints varied in response to different potato dextrose medium preparations. The two promising fungal strains may be used to reduce postharvest decay and losses in fruits
Diagnosis and treatment of autonomic failure, pain and sleep disturbances in Parkinson’s disease: guideline “Parkinson’s disease” of the German Society of Neurology
No full textAbstract Background and objective Non-motor symptoms frequently develop throughout the disease course of Parkinson’s disease (PD), and pose affected individuals at risk of complications, more rapid disease progression and poorer quality of life. Addressing such symptom burden, the 2023 revised “Parkinson’s disease” guideline of the German Society of Neurology aimed at providing evidence-based recommendations for managing PD non-motor symptoms, including autonomic failure, pain and sleep disturbances. Methods Key PICO (Patient, Intervention, Comparison, Outcome) questions were formulated by the steering committee and refined by the assigned authors. Recommendations were drafted based on relevant studies, systematic reviews, meta-analyses and high-quality guidelines identified by the literature search. They were subsequently reviewed, revised, and voted by the Guideline Group in online consensus conferences. Consensus was achieved in case of > 75% agreement among the group members. The consensus was considered strong, if agreement was > 95%. Results The guideline entails: (i) 10 PICOs and 23 recommendations on the diagnosis and treatment of urogenital, cardiovascular and gastrointestinal autonomic failure; (ii) four PICOs and four recommendations on the possible types of pain in PD individuals, their diagnosis and treatment; (iii) 11 PICOs and 11 recommendations on the screening, diagnosis and treatment of sleep disturbances and excessive daytime sleepiness in PD individuals, as well as on their prognostic implications. Thirty-one out of 38 recommendations achieved a strong consensus. Conclusion The current German PD guideline provides a practice-oriented and etiology-driven stepwise approach to the diagnosis and treatment of autonomic failure, pain and sleep disturbances in PD individuals