Background
Cognitive impairment (CI) affects approximately one-third of the patients with early multiple sclerosis (MS) and clinically isolated syndrome (CIS). Little is known about factors ...predicting CI and progression after initial diagnosis.
Methods
Neuropsychological screening data from baseline and 1-year follow-up of a prospective multicenter cohort study (NationMS) involving 1123 patients with newly diagnosed MS or CIS were analyzed. Employing linear multilevel models, we investigated whether demographic, clinical and conventional MRI markers at baseline were predictive for CI and longitudinal cognitive changes.
Results
At baseline, 22% of patients had CI (impairment in ≥2 cognitive domains) with highest frequencies and severity in processing speed and executive functions. Demographics (fewer years of academic education, higher age, male sex), clinical (EDSS, depressive symptoms) but no conventional MRI characteristics were linked to baseline CI. At follow-up, only 14% of patients showed CI suggesting effects of retesting. Neither baseline characteristics nor initiation of treatment between baseline and follow-up was able to predict cognitive changes within the follow-up period of 1 year.
Conclusions
Identification of risk factors for short-term cognitive change in newly diagnosed MS or CIS is insufficient using only demographic, clinical and conventional MRI data. Change-sensitive, re-test reliable cognitive tests and more sophisticated predictors need to be employed in future clinical trials and cohort studies of early-stage MS to improve prediction.
The formylglycine‐generating enzyme (FGE) is a unique copper protein that catalyzes oxygen‐dependent C−H activation. We describe 1.66 Å‐ and 1.28 Å‐resolution crystal structures of FGE from ...Thermomonospora curvata in complex with either AgI or CdII providing definitive evidence for a high‐affinity metal‐binding site in this enzyme. The structures reveal a bis‐cysteine linear coordination of the monovalent metal, and tetrahedral coordination of the bivalent metal. Similar coordination changes may occur in the active enzyme as a result of CuI/II redox cycling. Complexation of copper atoms by two cysteine residues is common among copper‐trafficking proteins, but is unprecedented for redox‐active copper enzymes or synthetic copper catalysts.
Modelle für CuI/II: Kristallstrukturen von Komplexen des Formylglycin erzeugenden Enzyms (FGE) aus Thermomonospora curvata mit AgI oder CdII (1.66 Å bzw. 1.28 Å Auflösung) zeigen eine lineare Bis(cystein)‐Koordination für AgI und eine tetraedrische Koordination für CdII. Ähnliche Änderungen könnten im aktiven, Kupfer‐enthaltenden Enzym während CuI/II‐Redoxzyklen auftreten.
The formylglycine‐generating enzyme (FGE) is a unique copper protein that catalyzes oxygen‐dependent C−H activation. We describe 1.66 Å‐ and 1.28 Å‐resolution crystal structures of FGE from ...Thermomonospora curvata in complex with either AgI or CdII providing definitive evidence for a high‐affinity metal‐binding site in this enzyme. The structures reveal a bis‐cysteine linear coordination of the monovalent metal, and tetrahedral coordination of the bivalent metal. Similar coordination changes may occur in the active enzyme as a result of CuI/II redox cycling. Complexation of copper atoms by two cysteine residues is common among copper‐trafficking proteins, but is unprecedented for redox‐active copper enzymes or synthetic copper catalysts.
Copper like: 1.66 Å‐ and 1.28 Å‐resolution crystal structures of formylglycine‐generating enzyme (FGE) from Thermomonospora curvata in complex with either AgI or CdII reveal a bis‐cysteine linear coordination of AgI, and tetrahedral coordination of CdII. Similar coordination changes may occur in the active copper‐containing enzyme as a result of CuI/II redox cycling.
Interim results from the development of a polycrystalline Co-Al-W based superalloy are presented. Cr has been added to provide oxidation resistance and Ni has then been added to widen and stabilise ...the γ′ phase field. The alloy presented has a solvus of 1010 °C and a density of 8.7 g cm−3. The room temperature flow stress is over 1000 MPa and this reduces dramatically above 800 °C. The flow stress anomaly is observed. A microstructure with both ∼ 50 nm γ′ produced on cooling and larger 100–200 nm γ′ can be obtained. Isothermal oxidation at 800 °C in air for 200 h gave a mass gain of 0.96 mg cm−2. After hot deformation in the 650–850 °C temperature range, both anti phase boundaries (APBs) and stacking faults could be observed. An APB energy of 71 mJ m−2 was measured, which is comparable to that found in commercial nickel superalloys.
Formylglycine‐generating enzyme (FGE) is an O2‐utilizing oxidase that converts specific cysteine residues of client proteins to formylglycine. We show that CuI is an integral cofactor of this enzyme ...and binds with high affinity (KD=of 10−17 m) to a pair of active‐site cysteines. These findings establish FGE as a novel type of copper enzyme.
Biochemical characterization reveals the formylglycine‐generating enzyme as a copper‐dependent oxidase. The enzyme binds copper with attomolar affinity by using two active‐site cysteine residues as ligands. In the absence of reducing agent, the cysteine residues form a disulfide bond and the enzyme looses all metal affinity.
The formylglycine‐generating enzyme (FGE) recognizes proteins with a specific cysteine‐containing six‐amino‐acid motif and converts this cysteine residue into formylglycine. The resulting aldehyde ...function provides a unique handle for selective protein labeling. We have identified two mutations in FGE from Thermomonospora curvata that increase this catalytic efficiency more than 40‐fold. The resulting activity and stability, as well as its ease of recombinant production, make this FGE variant a practical reagent for in vitro protein engineering.
FGE7—an efficient and practical tool for bioconjugation: The formylglycine‐generating enzyme (FGE) converts specific cysteine residues in client proteins into formylglycine. These aldehyde functions provide unique handles for selective protein labeling. We have identified an FGE variant that is thermostable, easy to produce, and 40 times more active than the wild type.
Objective
Fatigue is a frequent and severe symptom in multiple sclerosis (MS), but its pathophysiological origin remains incompletely understood. We aimed to examine the predictive value of ...subcortical gray matter volumes for fatigue severity at disease onset and after 4 years by applying structural equation modeling (SEM).
Methods
This multicenter cohort study included 601 treatment‐naive patients with MS after the first demyelinating event. All patients underwent a standardized 3T magnetic resonance imaging (MRI) protocol. A subgroup of 230 patients with available clinical follow‐up data after 4 years was also analyzed. Associations of subcortical volumes (included into SEM) with MS‐related fatigue were studied regarding their predictive value. In addition, subcortical regions that have a central role in the brain network (hubs) were determined through structural covariance network (SCN) analysis.
Results
Predictive causal modeling identified volumes of the caudate (s standardized path coefficient = 0.763, p = 0.003 left; s = 0.755, p = 0.006 right), putamen (s = 0.614, p = 0.002 left; s = 0.606, p = 0.003 right) and pallidum (s = 0.606, p = 0.012 left; s = 0.606, p = 0.012 right) as prognostic factors for fatigue severity in the cross‐sectional cohort. Moreover, the volume of the pons was additionally predictive for fatigue severity in the longitudinal cohort (s = 0.605, p = 0.013). In the SCN analysis, network hubs in patients with fatigue worsening were detected in the putamen (p = 0.008 left; p = 0.007 right) and pons (p = 0.0001).
Interpretation
We unveiled predictive associations of specific subcortical gray matter volumes with fatigue in an early and initially untreated MS cohort. The colocalization of these subcortical structures with network hubs suggests an early role of these brain regions in terms of fatigue evolution. ANN NEUROL 2022;91:192–202
Formylglycine‐generating enzymes (FGEs) catalyze O2‐dependent conversion of specific cysteine residues of arylsulfatases and alkaline phosphatases into formylglycine. The ability also to introduce ...unique aldehyde functions into recombinant proteins makes FGEs a powerful tool for protein engineering. One limitation of this technology is poor in vitro activity of reconstituted FGEs. Although FGEs have been characterized as cofactor‐free enzymes we report that the addition of one equivalent of CuI increases catalytic efficiency more than 20‐fold and enables the identification of stereoselective C−H bond cleavage at the substrate as the rate‐limiting step. These findings remove previous limitations of FGE‐based protein engineering and also pose new questions about the catalytic mechanism of this O2‐utilizing enzyme.
Copper helps: Formylglycine‐generating enzymes (FGEs) catalyze oxygen‐dependent conversion of specific cysteine residues in substrate proteins into formylglycine. Although FGEs have been characterized as cofactor‐free enzymes, we found that addition of CuI dramatically increases their catalytic activity.
Epigenetic processes, such as DNA methylation, and molecular chaperones, including FK506-binding protein 51 (FKBP51), are independently implicated in stress-related mental disorders and ...antidepressant drug action. FKBP51 associates with cyclin-dependent kinase 5 (CDK5), which is one of several kinases that phosphorylates and activates DNA methyltransferase 1 (DNMT1). We searched for a functional link between FKBP51 (encoded by FKBP5) and DNMT1 in cells from mice and humans, including those from depressed patients, and found that FKBP51 competed with its close homolog FKBP52 for association with CDK5. In human embryonic kidney (HEK) 293 cells, expression of FKBP51 displaced FKBP52 from CDK5, decreased the interaction of CDK5 with DNMT1, reduced the phosphorylation and enzymatic activity of DNMT1, and diminished global DNA methylation. In mouse embryonic fibroblasts and primary mouse astrocytes, FKBP51 mediated several effects of paroxetine, namely, decreased the protein-protein interactions of DNMT1 with CDK5 and FKBP52, reduced phosphorylation of DNMT1, and decreased the methylation and increased the expression of the gene encoding brain-derived neurotrophic factor (Bdnf). In human peripheral blood cells, FKBP5 expression inversely correlated with both global and BDNF methylation. Peripheral blood cells isolated from depressed patients that were then treated ex vivo with paroxetine revealed that the abundance of BDNF positively correlated and phosphorylated DNMT1 inversely correlated with that of FKBP51 in cells and with clinical treatment success in patients, supporting the relevance of this FKBP51-directed pathway that prevents epigenetic suppression of gene expression.
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