The dynamical signature of anhedonia in major depressive disorder: positive emotion dynamics, reactivity, and recovery.

BACKGROUND: Major Depressive Disorder (MDD) is the leading cause of disability worldwide. The cardinal features of MDD are depressed mood and anhedonia. Anhedonia is defined as a "markedly diminished interest or pleasure in all, or almost all, activities of the day", and has generally been investigated on group-level using retrospective data (e.g. via questionnaire/interview). However, inferences based on group-level findings not necessarily generalize to daily life experiences within individuals. METHODS: We repeatedly sampled pleasurable experiences within individuals' daily lives by means of Experience Sampling Methods, and compared how positive affect unfolded in the daily life of healthy controls versus patients diagnosed with MDD and anhedonia. We sampled Positive Affect (PA) and reward experiences on 10 semi-random time points a day, for seven days in the daily lives of 47 MDD patients with anhedonia, and 40 controls. RESULTS: Multilevel models showed that anhedonia was associated with low PA, but not to differences in PA dynamics, nor reward frequency in daily life. In reaction to rewards, MDD patients with anhedonia showed no difference in their increase in PA (i.e., PA reactivity), and showed no signs of a faster return to baseline thereafter (i.e., PA recovery). CONCLUSIONS: Our results suggest that the dynamical signature of anhedonia in MDD can be described best as a lower average level of PA, and "normal" in terms of PA dynamics, daily reward reactivity and reward recovery. Preregistration: https://osf.io/gmfsc/register/565fb3678c5e4a66b5582f67 . Preprint: https://osf.io/cfkts.

The Statistical Specificity of Emotion Dynamics in Borderline Personality Disorder.

Persons with borderline personality disorder (BPD) experience heightened emotional instability. Different components underlie instability, and the relation between instability and well-being could be confounded by average emotionality and within-person standard deviation across emotional states, reflecting variability. Therefore, the goal was to examine which pattern of emotion dynamics parsimoniously captures the emotional trajectories of persons with BPD. Forty persons with BPD, 38 clinical controls in a major depressive episode, and 40 healthy controls rated the intensity of their emotions 10 times a day for 1 week. After correction for differences in average emotionality, persons with BPD showed heightened emotional instability compared to both control groups. When additionally correcting for emotional variability, the authors found that instability indices did not differ between groups anymore. This shows that persons with BPD differ from control groups in the magnitude of emotional deviations from the emotional baseline, and not necessarily in the degree of abruptness of these deviations.

Differential expression of glycosomal and mitochondrial proteins in the two major life-cycle stages of Trypanosoma brucei.

Label-free semi-quantitative differential three-dimensional liquid chromatography coupled to mass spectrometry (3D-LC-MS/MS) was used to compare the glycosomal and mitochondrial proteomes of the bloodstream- and insect-form of Trypanosoma brucei. The abundance of glycosomal marker proteins identified in the two life-cycle stages corresponded well with the relative importance of biochemical pathways present in the glycosomes of the two stages and the peptide spectral count ratios of selected enzymes were in good agreement with published data about their enzymatic specific activities. This approach proved extremely useful for the generation of large scale proteomics data for the comparison of different life-cycle stages. Several proteins involved in oxidative stress protection, sugar-nucleotide synthesis, purine salvage, nucleotide-monophosphate formation and purine-nucleotide cycle were identified as glycosomal proteins.

Experimental and in silico analyses of glycolytic flux control in bloodstream form Trypanosoma brucei.

A mathematical model of glycolysis in bloodstream form Trypanosoma brucei was developed previously on the basis of all available enzyme kinetic data (Bakker, B. M., Michels, P. A. M., Opperdoes, F. R., and Westerhoff, H. V. (1997) J. Biol. Chem. 272, 3207-3215). The model predicted correctly the fluxes and cellular metabolite concentrations as measured in non-growing trypanosomes and the major contribution to the flux control exerted by the plasma membrane glucose transporter. Surprisingly, a large overcapacity was predicted for hexokinase (HXK), phosphofructokinase (PFK), and pyruvate kinase (PYK). Here, we present our further analysis of the control of glycolytic flux in bloodstream form T. brucei. First, the model was optimized and extended with recent information about the kinetics of enzymes and their activities as measured in lysates of in vitro cultured growing trypanosomes. Second, the concentrations of five glycolytic enzymes (HXK, PFK, phosphoglycerate mutase, enolase, and PYK) in trypanosomes were changed by RNA interference. The effects of the knockdown of these enzymes on the growth, activities, and levels of various enzymes and glycolytic flux were studied and compared with model predictions. Data thus obtained support the conclusion from the in silico analysis that HXK, PFK, and PYK are in excess, albeit less than predicted. Interestingly, depletion of PFK and enolase had an effect on the activity (but not, or to a lesser extent, expression) of some other glycolytic enzymes. Enzymes located both in the glycosomes (the peroxisome-like organelles harboring the first seven enzymes of the glycolytic pathway of trypanosomes) and in the cytosol were affected. These data suggest the existence of novel regulatory mechanisms operating in trypanosome glycolysis.

Kinetic characterization, structure modelling studies and crystallization of Trypanosoma brucei enolase.

In this article, we report the results of an analysis of the glycolytic enzyme enolase (2-phospho-d-glycerate hydrolase) of Trypanosoma brucei. Enolase activity was detected in both bloodstream-form and procyclic insect-stage trypanosomes, although a 4.5-fold lower specific activity was found in the cultured procyclic homogenate. Subcellular localization analysis showed that the enzyme is only present in the cytosol. The T. brucei enolase was expressed in Escherichia coli and purified to homogeneity. The kinetic properties of the bacterially expressed enzyme showed strong similarity to those values found for the natural T. brucei enolase present in a cytosolic cell fraction, indicating a proper folding of the enzyme in E. coli. The kinetic properties of T. brucei enolase were also studied in comparison with enolase from rabbit muscle and Saccharomyces cerevisiae. Functionally, similarities were found to exist between the three enzymes: the Michaelis constant (Km) and KA values for the substrates and Mg2+ are very similar. Differences in pH optima for activity, inhibition by excess Mg2+ and susceptibilities to monovalent ions showed that the T. brucei enolase behaves more like the yeast enzyme. Alignment of the amino acid sequences of T. brucei enolase and other eukaryotic and prokaryotic enolases showed that most residues involved in the binding of its ligands are well conserved. Structure modelling of the T. brucei enzyme using the available S. cerevisiae structures as templates indicated that there are some atypical residues (one Lys and two Cys) close to the T. brucei active site. As these residues are absent from the human host enolase and are therefore potentially interesting for drug design, we initiated attempts to determine the three-dimensional structure. T. brucei enolase crystals diffracting at 2.3 A resolution were obtained and will permit us to pursue the determination of structure.