96 research outputs found
A proteogenomic view of Parkinson’s disease causality and heterogeneity
No full textAbstract The pathogenesis and clinical heterogeneity of Parkinson’s disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into “endotypes”. The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration
A Global Analysis on Microgrids through the PESTEL Framework
No full textMicrogrids enable distribution of electricity with higher shares of variable renewables, higher power quality, greater reliability and higher efficiency. There are a large number of factors in addition to the technology, which affect their shift towards market competitiveness and widespread adoption. The PESTEL framework, covering Political, Economic, Social, Technical, Environmental and Legislative factors, is used to identify and describe the drivers and barriers for microgrid development at the global level. The framework enables a broader approach to describe potential for microgrid applications. The results aim to provide engineers, project developers and microgrid specialists with an overview of the prospects for microgrid deployment.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Energy Technolog
Persisters show heritable phenotype and generate bacterial heterogeneity and noise in protein expression
No full textPersisters are a small subpopulation of bacteria that survive a lethal concentration of antibiotic without antibiotic resistance genes. Isolation of persisters from normally dividing population is considered difficult due to their slow growth, low numbers and phenotypic shift i.e. when re-grown in antibiotic free medium, they revert to parent population. Inability to isolate persisters is a major hindrance in this field of research. Here we reject the ‘phenotypic shift’ phenomenon exhibited by persisters. Persisters, on the other hand, exhibit a heritable phenotype and can be easily isolated from a normally dividing population that allows their selective growth. Rather than a single subset, they comprise many distinct subgroups each exhibiting different growth rates, colony sizes, antibiotic tolerance and protein expression levels. Clearly, they are one of the sources of bacterial heterogeneity and noise in protein expression. Existence of persisters in normally dividing population can explain some of the unsolved puzzles like antibiotic tolerance, post-antibiotic effect and viable but non-culturable bacterial state. We hypothesize that persisters are aging bacteria
Persisters show heritable phenotype and generate bacterial heterogeneity and noise in protein expression
No full textPersisters are a small subpopulation of bacteria that survive a lethal concentration of antibiotic without antibiotic resistance genes. Isolation of persisters from normally dividing population is considered difficult due to their slow growth, low numbers and phenotypic shift i.e. when re-grown in antibiotic free medium, they revert to parent population. Inability to isolate persisters is a major hindrance in this field of research. Here we reject the ‘phenotypic shift’ phenomenon exhibited by persisters. Persisters, on the other hand, exhibit a heritable phenotype and can be easily isolated from a normally dividing population that allows their selective growth. Rather than a single subset, they comprise many distinct subgroups each exhibiting different growth rates, colony sizes, antibiotic tolerance and protein expression levels. Clearly, they are one of the sources of bacterial heterogeneity and noise in protein expression. Existence of persisters in normally dividing population can explain some of the unsolved puzzles like antibiotic tolerance, post-antibiotic effect and viable but non-culturable bacterial state. We hypothesize that persisters are aging bacteria
The potential role of butyrophilin and xanthine oxidoreductase in controlling the amount and size of milk-fat droplets
No full textThe secretion of fat droplets from mammary epithelial cells requires the expression of two major proteins, butyrophilin1A1 (BTN) and xanthine oxidoreductase (XOR). Ablation of the BTN or XOR gene in mice results in the accumulation of large fat droplets suggesting a reciprocal relationship between BTN/XOR concentration and milk-fat droplet size. We tested this hypothesis by correlating BTN/XOR concentrations in cow and mouse with their fat droplet size. The amount of BTN in mouse was 75 times less than in bovine samples. The size of fat droplets in mice was larger than in cow, but no correlation was found between fat-droplet size and the amount of BTN/XOR. Experimental reduction in fat-droplet size in mice did not change the concentration of BTN. We propose that a low amount of BTN is sufficient to mediate its role in milk-fat secretion and that it may have additional functions to its potential role as a structural protein
Small Colony Variants and Senescent Bacteria
No full textSmall colony variants (SCVs) are bacterial subpopulation that grow slowly and form smaller colonies. They have been described for a wide range of bacterial species, but most extensively studied for Staphylococci. They are considered as mutants that are auxotrophic to hemin, thiamine or thymidine. In the presence of auxotrophic agents, they revert to normal growth. They are tolerant to many antibiotics and are implicated in chronic and persistent infections. In this presentation, it is proposed that most of them are normal senescent bacteria that do not revert in the presence of auxotrophic agents. SCVs can explain the concentration dependent killing property, long post-antibiotic effect and increased resistance to aminoglycosides
Design Guidelines for Exploring Relationships in a Connected Big Data Environment
No full textPart 5: Case StudiesInternational audienceReimagining the ‘SAP Investigative Case Management’ frame-work from a log-based register of events to a direct interaction environment with the possibility to search, explore relationships between multiple entities in one or more cases/incidents. This case study is about our approach in conceptualizing a generic network visualization method by deconstructing the existing data models. We devised a set of guidelines that can be employed to represent a large number of entities with the intention of examining their relationships
Energy-aware Application Mapping onto 3D Mesh-Based Network-on-Chip using Heuristic Mapping Algorithms
No full textNetwork-on-chip (NoC) architectures have emerged as a potential solution for facilitating communication between processing elements (PEs) in modern multi-core systems. The design and optimization of NoC architectures are critical for achieving efficient communication, reduced energy consumption, and improved overall system performance. In this study, we investigate and compare the performance of two prominent optimization algorithms, like Genetic Algorithm (GA) and CastNet Algorithm, for 2D and 3D mesh NoC architectures. The study’s objective is to estimate these algorithms’ effectiveness in optimizing communication cost, communication energy, and CPU run time in both 2D and 3D mesh NoC architectures. Performance metrics such as communication cost, communication energy consumption, and CPU run time are measured and compared between the two algorithms and carried out on real and custom benchmark applications like MWD, VOPD and MPEG4
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