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Microbes use a range of genetic codes and gene structures, yet these are often ignored during metagenomic analysis. This causes spurious protein predictions, preventing functional assignment which limits our understanding of ecosystems. To resolve this, we developed a lineage-specific gene prediction approach that uses the correct genetic code based on the taxonomic assignment of genetic fragments, removes incomplete protein predictions, and optimises prediction of small proteins. Applied to 9634 metagenomes and 3594 genomes from the human gut, this approach increased the landscape of captured expressed microbial proteins by 78.9%, including previously hidden functional groups. Optimised small protein prediction captured 3,772,658 small protein clusters, which form an improved microbial protein catalogue of the human gut (MiProGut). To enable the ecological study of a protein’s prevalence and association with host parameters, we developed InvestiGUT, a tool which integrates both the protein sequences and sample metadata. Accurate prediction of proteins is critical to providing a functional understanding of microbiomes, enhancing our ability to study interactions between microbes and hosts. Microbes within the gut vary in how they encode genes, both in terms of the genetic codes and gene structures, which are often unexplored in metagenomic analysis. Here, the authors develop a lineage-specific gene approach that optimizes prediction of small proteins and apply it to 9,634 metagenomes and 3,594 genomes from the human gut, increasing the landscape of captured expressed microbial proteins by 78.9%, including previously hidden functional groups.

This paper presents the design and implementation of a SLAM-based online mapping and autonomous trajectory execution system for the Nimbulus-e, a concept vehicle designed for agile maneuvering in confined spaces. The Nimbulus-e uses individual steer-by-wire corner modules with in-wheel motors at all four corners. The associated eight joint variables serve as control inputs, allowing precise trajectory following. These control inputs can be derived from the vehicle’s trajectory using nonholonomic constraints. A LiDAR sensor is used to map the environment and detect obstacles. The system processes LiDAR data in real time, continuously updating the environment map and enabling localization within the environment. The inclusion of vehicle odometry data significantly reduces computation time and improves accuracy compared to a purely visual approach. The A* and Hybrid A* algorithms are used for trajectory planning and optimization, ensuring smooth vehicle movement. The implementation is validated through both full vehicle simulations using an ADAMS Car—MATLAB co-simulation and a scaled physical prototype, demonstrating the effectiveness of the system in navigating complex environments. This work contributes to the field of autonomous systems by demonstrating the potential of combining advanced sensor technologies with innovative control algorithms to achieve reliable and efficient navigation. Future developments will focus on improving the robustness of the system by implementing a robust closed-loop controller and exploring additional applications in dense urban traffic and agricultural operations.

The clinical diagnosis of vascular dementia (VaD) is based on imaging criteria, and specific biochemical markers are not available. Here, we investigated the potential of cerebrospinal fluid (CSF) lipocalin 2 (LCN2), a secreted glycoprotein that has been suggested as mediating neuronal damage in vascular brain injuries. The study included four independent cohorts with a total n  = 472 samples. LCN2 was significantly elevated in VaD compared to controls, Alzheimer’s disease (AD), other neurodegenerative dementias, and cognitively unimpaired patients with cerebrovascular disease. LCN2 discriminated VaD from AD without coexisting VaD with high accuracy. The main findings were consistent over all cohorts. Neuropathology disclosed a high percentage of macrophages linked to subacute infarcts, reactive astrocytes, and damaged blood vessels in multi-infarct dementia when compared to AD. We conclude that CSF LCN2 is a promising candidate biochemical marker in the differential diagnosis of VaD and neurodegenerative dementias. Diagnosis of vascular dementia is hampered by the lack of biochemical markers for this disease. Here, the authors show that vascular dementia is associated with increased lipocalin-2 in cerebrospinal fluid, compared to controls and patients with other forms of dementia.

Neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, are identified and characterized by the progressive loss of neurons and neuronal dysfunction, resulting in cognitive and motor impairment. Recent research has shown the importance of PTMs, such as phosphorylation, acetylation, methylation, ubiquitination, sumoylation, nitration, truncation, O-GlcNAcylation, and hydroxylation, in the progression of neurodegenerative disorders. PTMs can alter protein structure and function, affecting protein stability, localization, interactions, and enzymatic activity. Aberrant PTMs can lead to protein misfolding and aggregation, impaired degradation, and clearance, and ultimately, to neuronal dysfunction and death. The main objective of this review is to provide an overview of the PTMs involved in neurodegeneration, their underlying mechanisms, methods to isolate PTMs, and the potential therapeutic targets for these disorders. The PTMs discussed in this article include tau phosphorylation, α-synuclein and Huntingtin ubiquitination, histone acetylation and methylation, and RNA modifications. Understanding the role of PTMs in neurodegenerative diseases may provide new therapeutic strategies for these devastating disorders.

Real-time quaking-induced conversion (RT-QuIC) allows the amplification of miniscule amounts of scrapie prion protein (PrP Sc ). Recent studies applied the RT-QuIC methodology to cerebrospinal fluid (CSF) for diagnosing human prion diseases. However, to date, there has not been a formal multi-centre assessment of the reproducibility, validity and stability of RT-QuIC in this context, an indispensable step for establishment as a diagnostic test in clinical practice. In the present study, we analysed CSF from 110 prion disease patients and 400 control patients using the RT-QuIC method under various conditions. In addition, “blinded” ring trials between different participating sites were performed to estimate reproducibility. Using the previously established cut-off of 10,000 relative fluorescence units (rfu), we obtained a sensitivity of 85 % and a specificity of 99 %. The multi-centre inter-laboratory reproducibility of RT-QuIC revealed a Fleiss’ kappa value of 0.83 (95 % CI: 0.40–1.00) indicating an almost perfect agreement. Moreover, we investigated the impact of short-term CSF storage at different temperatures, long-term storage, repeated freezing and thawing cycles and the contamination of CSF with blood on the RT-QuIC seeding response. Our data indicated that the PrP Sc seed in CSF is stable to any type of storage condition but sensitive to contaminations with blood (>1250 erythrocytes/μL), which results in a false negative RT-QuIC response. Fresh blood-contaminated samples (3 days) can be rescued by removal of erythrocytes. The present study underlines the reproducibility and high stability of RT-QuIC across various CSF storage conditions with a remarkable sensitivity and specificity, suggesting RT-QuIC as an innovative and robust diagnostic method.

Detection of Prion Disease in Tear FluidAbnormally folded prion protein scrapie was detected in tear fluid obtained from 16 of 19 patients with symptomatic or asymptomatic prion disease by means of RT-QuIC testing.

This 96-well-plate ‘real-time quaking-induced conversion’ assay allows the detection of abnormal prion protein in human brain and CSF samples. It can be applied to study many protein misfolding diseases, as well as for drug screening and prion strain discrimination. The development and adaption of in vitro misfolded protein amplification systems has been a major innovation in the detection of abnormally folded prion protein scrapie (PrP Sc ) in human brain and cerebrospinal fluid (CSF) samples. Herein, we describe a fast and efficient protein amplification technique, real-time quaking-induced conversion (RT-QuIC), for the detection of a PrP Sc seed in human brain and CSF. In contrast to other in vitro misfolded protein amplification assays—such as protein misfolding cyclic amplification (PMCA)—which are based on sonication, the RT-QuIC technique is based on prion seed–induced misfolding and aggregation of recombinant prion protein substrate, accelerated by alternating cycles of shaking and rest in fluorescence plate readers. A single RT-QuIC assay typically analyzes up to 32 samples in triplicate, using a 96-well-plate format. From sample preparation to analysis of results, the protocol takes ∼87 h to complete. In addition to diagnostics, this technique has substantial generic analytical applications, including drug screening, prion strain discrimination, biohazard screening (e.g., to reduce transmission risk related to prion diseases) and the study of protein misfolding; in addition, it can potentially be used for the investigation of other protein misfolding diseases such as Alzheimer's and Parkinson's disease.

Background YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing. Methods In the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures. Results YKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer’s disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around β-amyloid plaques, and surrounding vessels with β-amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology. CSF YKL-40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD ( p  < 0.001, AUC = 0.92) and AD ( p  < 0.001, AUC = 0.77) but not in vascular dementia (VaD) ( p  > 0.05, AUC = 0.71) or in DLB/Parkinson’s disease dementia (PDD) ( p  > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP- D178N (Fatal Familial Insomnia) and PRNP- E200K mutations. Conclusions Our results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component.

Background Increased plasma YKL-40 has been reported in Alzheimer’s disease (AD), but its levels in other neurodegenerative diseases are unknown. Here, we aimed to investigate plasma YKL-40 in the spectrum of neurodegenerative dementias. Methods YKL-40 was quantified in the plasma of 315 cases, including healthy controls (HC), neurological disease controls (ND), AD, vascular dementia (VaD), frontotemporal dementia (FTD), sporadic Creutzfeldt-Jakob disease (CJD) and Lewy body dementia (LBD). Diagnostic accuracy in the differential diagnostic context and influence of age and gender was assessed. Results Highest YKL-40 levels were detected in CJD, followed by LBD, VaD, AD, FTD, ND and HC. YKL-40 was associated to age but not to sex. After controlling for age, YKL-40 was significantly elevated in CJD compared to HC ( p  < 0.001), ND, AD and VaD ( p  < 0.01) and in LBD compared to HC ( p  < 0.05). In CJD, YKL-40 concentrations were significantly higher at late disease stages. Conclusions Plasma YKL-40 is significantly elevated in CJD regardless of clinical and genetic parameters, with moderate diagnostic accuracy in the discrimination from control cases. Our study discards a potential use of this biomarker in the differential diagnostic context but opens the possibility to be explored as a marker for CJD monitoring.

The definitive diagnosis of genetic prion diseases (gPrD) requires pathological confirmation. To date, diagnosis has relied upon the finding of the biomarkers 14-3-3 protein and total tau (t-tau) protein in the cerebrospinal fluid (CSF), but many researchers have reported that these markers are not sufficiently elevated in gPrD, especially in Gerstmann-Sträussler-Scheinker syndrome (GSS). We recently developed a new in vitro amplification technology, designated \"real-time quaking-induced conversion (RT-QUIC)\", to detect the abnormal form of prion protein in CSF from sporadic Creutzfeldt-Jakob disease (sCJD) patients. In the present study, we aimed to investigate the presence of biomarkers and evaluate RT-QUIC assay in patients with gPrD, as the utility of RT-QUIC as a diagnostic tool in gPrD has yet to be determined. 56 CSF samples were obtained from gPrD patients, including 20 cases of GSS with P102L mutation, 12 cases of fatal familial insomnia (FFI; D178N), and 24 cases of genetic CJD (gCJD), comprising 22 cases with E200K mutation and 2 with V203I mutation. We subjected all CSF samples to RT-QUIC assay, analyzed 14-3-3 protein by Western blotting, and measured t-tau protein using an ELISA kit. The detection sensitivities of RT-QUIC were as follows: GSS (78%), FFI (100%), gCJD E200K (87%), and gCJD V203I (100%). On the other hand the detection sensitivities of biomarkers were considerably lower: GSS (11%), FFI (0%), gCJD E200K (73%), and gCJD V203I (67%). Thus, RT-QUIC had a much higher detection sensitivity compared with testing for biomarkers, especially in patients with GSS and FFI. RT-QUIC assay is more sensitive than testing for biomarkers in gPrD patients. RT-QUIC method would thus be useful as a diagnostic tool when the patient or the patient's family does not agree to genetic testing, or to confirm the diagnosis in the presence of a positive result for genetic testing.