E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development.

Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that plays an essential role during brain development. Using genetically engineered mouse model and primary neuronal cells, we identify the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U).

Neurofilament Light Chain under the Lens of Structural Mass Spectrometry.

Neurofilament light chain (NfL) is an early nonspecific biomarker in neurodegenerative diseases and traumatic brain injury, indicating axonal damage. This work describes the detailed structural characterization of a selected primary calibrator with the potential to be used in future reference measurement procedure (RMP) development for the accurate quantification of NfL. As a part of the described workflow, the sequence, higher-order structure as well as solvent accessibility, and hydrogen-bonding profile were assessed under three different conditions in KPBS, artificial cerebrospinal fluid, and artificial cerebrospinal fluid in the presence of human serum albumin.

Blood-based biomarkers and plasma Aβ assays in the differential diagnosis of Alzheimer's disease and behavioral-variant frontotemporal dementia.

Introduction: The differentiation between Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD) can be complicated in the initial phase by shared symptoms and pathophysiological traits. Nevertheless, advancements in understanding AD's diverse pathobiology suggest the potential for establishing blood-based methods for differential diagnosis.

Methods: We devised a novel assay combining immunoprecipitation and mass spectrometry (IP-MS) to quantify Amyloid-beta (Aβ) peptides in plasma.

Glial fibrillary acidic protein in Alzheimer's disease: a narrative review.

Astrocytes are fundamental in neural functioning and homeostasis in the central nervous system. These cells respond to injuries and pathological conditions through astrogliosis, a reactive process associated with neurodegenerative diseases such as Alzheimer's disease. This process is thought to begin in the early stages of these conditions.

SARS-CoV-2 Displays a Suboptimal Codon Usage Bias for Efficient Translation in Human Cells Diverted by Hijacking the tRNA Epitranscriptome.

Codon bias analysis of SARS-CoV-2 reveals suboptimal adaptation for translation in human cells it infects. The detailed examination of the codons preferentially used by SARS-CoV-2 shows a strong preference for Lys, Gln, Glu, and Arg, which are infrequently used in human genes. In the absence of an adapted tRNA pool, efficient decoding of these codons requires a 5-methoxycarbonylmethyl-2-thiouridine (mcms) modification at the U wobble position of the corresponding tRNAs (tLys; tGln; tGlu; tArg).

Ultrasensitive and Tracking of C-Labeled PEG-PLA Degradation Products by MALDI-TOF Mass Spectrometry.

Copolymers of poly(lactic acid) (PLA) and poly(ethylene glycol) (PEG) are widely used in biomedical applications. As inactive ingredients in formulations, tracking their degradation byproducts stands as a major challenge but is a pivotal endeavor to ensure safety and further progress in clinical stages. Current bioanalytical methods used to monitor this degradation lack sensitivity and quantification precision.

Clarifying the association of CSF Aβ, tau, BACE1, and neurogranin with AT(N) stages in Alzheimer disease.

Background: Current AT(N) stratification for Alzheimer's disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy.

Methods: This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Inherited mitochondrial dysfunction triggered by OPA1 mutation impacts the sensory innervation fibre identity, functionality and regenerative potential in the cornea.

Mitochondrial dysfunctions are detrimental to organ metabolism. The cornea, transparent outmost layer of the eye, is prone to environmental aggressions, such as UV light, and therefore dependent on adequate mitochondrial function. While several reports have linked corneal defects to mitochondrial dysfunction, the impact of OPA1 mutation, known to induce such dysfunction, has never been studied in this context.

Enabling population protein dynamics through Bayesian modeling.

Motivation: The knowledge of protein dynamics, or turnover, in patients provides invaluable information related to certain diseases, drug efficacy, or biological processes. A great corpus of experimental and computational methods has been developed, including by us, in the case of human patients followed in vivo. Moving one step further, we propose a novel modeling approach to capture population protein dynamics using Bayesian methods.

Serum NfL and GFAP are weak predictors of long-term multiple sclerosis prognosis: A 6-year follow-up.

Background: Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising biomarkers that might be associated with clinical and radiological markers of multiple sclerosis (MS) severity. However, it is not known whether they can accurately identify patients at risk of disability progression in the medium and long term.

Objectives: We wanted to determine the association between sNfL and sGFAP, Expanded Disability Status Scale score changes, and conversion to secondary progressive MS (SPMS) in a cohort of 133 patients with relapsing remitting MS.

A candidate reference measurement procedure for the quantification of α-synuclein in cerebrospinal fluid using an SI traceable primary calibrator and multiple reaction monitoring.

α-synuclein aggregation is an important hallmark of neurodegenerative diseases such as Parkinson's disease (PD) and Lewy body dementia. α-synuclein has been increasingly used as a diagnostic biomarker in PD and other synucleinopathies. Current clinical assays rely on antibody-based immunoassays to detect α-synuclein, which possess high sensitivity, afford high throughput and require small sample volumes.

Modeling the Simultaneous Dynamics of Proteins in Blood Plasma and the Cerebrospinal Fluid in Human .

The analysis of protein dynamics or turnover in patients has the potential to reveal altered protein recycling, such as in Alzheimer's disease, and to provide informative data regarding drug efficacy or certain biological processes. The observed protein dynamics in a solid tissue or a fluid is the net result of not only protein synthesis and degradation but also transport across biological compartments. We report an accurate 3-biological compartment model able to simultaneously account for the protein dynamics observed in blood plasma and the cerebrospinal fluid (CSF) including a hidden central nervous system (CNS) compartment.

Surfaceome: a new era in the discovery of immune evasion mechanisms of circulating tumor cells.

Circulating tumor cells (CTCs) are cancer cells that detach from the original site and reach the bloodstream. The most aggressive CTCs survive various immune system attacks and initiate metastasis formation. Importantly, CTCs are not specifically targeted by the current immunotherapies due to the limited knowledge on specific targets.

Inflammation biomarkers in the intracranial blood are associated with outcome in patients with ischemic stroke.

Background: Performing endovascular treatment (EVT) in patients with acute ischemic stroke (AIS) allows a port of entry for intracranial biological sampling.

Objective: To test the hypothesis that specific immune players are molecular contributors to disease, outcome biomarkers, and potential targets for modifying AIS.

Methods: We examined 75 subjects presenting with large vessel occlusion of the anterior circulation and undergoing EVT.

Increasing the sensitivity of Simoa via bead count reduction facilitates the quantification of pTau-181 in dried plasma spots.

Introduction: The exclusion of affected populations from Alzheimer's disease (AD) clinical research limits our understanding of disease heterogeneity and its impact on clinical care. While micro sampling with dried plasma spots (DPS) can promote inclusivity by enabling sample collection in remote areas, current techniques lack the sensitivity required for the quantification of phosphorylated tau at Thr181 (pTau-181) in DPS extracts.

Methods: We developed an assay for pTau-181 with reduced bead count and improved bead read efficiency (BRE) using a prototype Simoa instrument.

Mass Spectrometry-Based Pipeline for Identifying RNA Modifications Involved in a Functional Process: Application to Cancer Cell Adaptation.

Cancer onset and progression are known to be regulated by genetic and epigenetic events, including RNA modifications (a.k.a.

Use of dried blood spots for monitoring inflammatory and nutritional biomarkers in the elderly.

Objectives: Blood microsampling, particularly dried blood spots (DBSs), is an attractive minimally-invasive approach that is well suited for home sampling and predictive medicine associated with longitudinal follow-up of the elderly. However, diagnostic quantification of biomarkers from DBS poses a major challenge. Clinical mass spectrometry can reliably quantify blood proteins in various research projects.

A sensitive high-resolution mass spectrometry method for quantifying intact M-protein light chains in patients with multiple myeloma.

To determine the disease status and the response to treatment for patients with multiple myeloma, measuring serum M-protein levels is a widely used alternative to invasive punctures to count malignant plasma cells in the bone marrow. However, the quantification of this monoclonal antibody, which varies from patient to patient, poses significant analytical challenges. This paper describes a sensitive and specific mass spectrometry assay that addresses two objectives: to overcome the potential interference of biotherapeutics in the measurement of M-proteins, and to determine the depth of response to treatment by assessing minimal residual disease.

Readthrough isoform of aquaporin-4 (AQP4) as a therapeutic target for Alzheimer's disease and other proteinopathies.

The glymphatic system is a crucial component in preserving brain homeostasis by facilitating waste clearance from the central nervous system (CNS). Aquaporin-4 (AQP4) water channels facilitate the continuous interchange between cerebrospinal fluid and brain interstitial fluid by convective flow movement. This flow is responsible for guiding proteins and metabolites away from the CNS.

Ultrasensitive digital immunoassays for SOD1 conformation in amyotrophic lateral sclerosis.

The aim of this study was to detect misfolded Cu/Zn SOD1 as a potential biomarker for amyotrophic lateral sclerosis (ALS). Two ultrasensitive immunodetection assays were developed for the quantification of total and misfolded SOD1. The detection of total and misfolded SOD1 was possible in human serum and cerebrospinal fluid.

Neurofilament-Light, a Promising Biomarker: Analytical, Metrological and Clinical Challenges.

Neurofilament-light chain (Nf-L) is a non-specific early-stage biomarker widely studied in the context of neurodegenerative diseases (NDD) and traumatic brain injuries (TBI), which can be measured in biofluids after axonal damage. Originally measured by enzyme-linked immunosorbent assay (ELISA) in cerebrospinal fluid (CSF), Nf-L can now be quantified in blood with the emergence of ultrasensitive assays. However, to ensure successful clinical implementation, reliable clinical thresholds and reference measurement procedures (RMP) should be developed.

Lower systemic nitric oxide bioactivity, cerebral hypoperfusion and accelerated cognitive decline in formerly concussed retired rugby union players.

New Findings: What is the central question of this study? What are the molecular, cerebrovascular and cognitive biomarkers of retired rugby union players with concussion history? What is the main finding and its importance? Retired rugby players compared with matched controls exhibited lower systemic nitric oxide bioavailability accompanied by lower middle cerebral artery velocity and mild cognitive impairment. Retired rugby players are more susceptible to accelerated cognitive decline.

Abstract: Following retirement from sport, the chronic consequences of prior-recurrent contact are evident and retired rugby union players may be especially prone to accelerated cognitive decline.