"I Am a Total...Loser" - The Role of Interpretation Biases in Youth Depression

Negative interpretation biases have been found to characterize adults with depression and to be involved in the development and maintenance of the disorder. However, less is known about their role in youth depression. The present study investigated i) whether negative interpretation biases characterize children and adolescents with depression and ii) to what extent these biases are more pronounced in currently depressed youth compared to youth at risk for depression (as some negative interpretation biases have been found already in high-risk youth before disorder onset). After a negative mood induction interpretation biases were assessed with two experimental tasks: Ambiguous Scenarios Task (AST) and Scrambled Sentences Task (SST) in three groups of 9-14-year-olds: children and adolescents with a diagnosis of major depression (n = 32), children and adolescents with a high risk for depression (children of depressed parents; n = 48), as well as low-risk children and adolescents (n = 42). Depressed youth exhibited substantially more negative interpretation biases than both high-risk and low-risk groups (as assessed with both tasks), while the high-risk group showed more negative interpretation biases than the low-risk group only as assessed via the SST. The results indicate that the negative interpretation biases that are to some extent already present in high-risk populations before disorder onset are strongly amplified in currently depressed youth. The different findings for the two tasks suggest that more implicit interpretation biases (assessed with the SST) might represent cognitive vulnerabilities for depression whereas more explicit interpretation biases (assessed with the AST) may arise as a consequence of depressive symptomatology

An Eye-Tracking Study of Attention Biases in Children at High Familial Risk for Depression and Their Parents with Depression

Attention biases (AB) are a core component of cognitive models of depression yet it is unclear what role they play in the transgenerational transmission of depression. 44 children (9-14 years) with a high familial risk of depression (HR) were compared on multiple measures of AB with 36 children with a low familial risk of depression (LR). Their parents: 44 adults with a history of depression (HD) and 36 adults with no history of psychiatric disorder (ND) were also compared. There was no evidence of group differences in AB; neither between the HR and LR children, nor between HD and ND parents. There was no evidence of a correlation between parent and child AB. The internal consistency of the tasks varied greatly. The Dot-Probe Task showed unacceptable reliability whereas the behavioral index of the Visual-Search Task and an eye-tracking index of the Passive-Viewing Task showed better reliability. There was little correlation between the AB tasks and the tasks showed minimal convergence with symptoms of depression or anxiety. The null-findings of the current study contradict our expectations and much of the previous literature. They may be due to the poor psychometric properties associated with some of the AB indices, the unreliability of AB in general, or the relatively modest sample size. The poor reliability of the tasks in our sample suggest caution should be taken when interpreting the positive findings of previous studies which have used similar methods and populations

Electron Tomography of Fusiform Vesicles and Their Organization in Urothelial Cells

The formation of fusiform vesicles (FVs) is one of the most distinctive features in the urothelium of the urinary bladder. FVs represent compartments for intracellular transport of urothelial plaques, which modulate the surface area of the superficial urothelial (umbrella) cells during the distension-contraction cycle. We have analysed the three-dimensional (3D) structure of FVs and their organization in umbrella cells of mouse urinary bladders. Compared to chemical fixation, high pressure freezing gave a new insight into the ultrastructure of urothelial cells. Electron tomography on serial sections revealed that mature FVs had a shape of flattened discs, with a diameter of up to 1.2 µm. The lumen between the two opposing asymmetrically thickened membranes was very narrow, ranging from 5 nm to 10 nm. Freeze-fracturing and immunolabelling confirmed that FVs contain two opposing urothelial plaques connected by a hinge region that made an omega shaped curvature. In the central cytoplasm, 4–15 FVs were often organized into stacks. In the subapical cytoplasm, FVs were mainly organized as individual vesicles. Distension-contraction cycles did not affect the shape of mature FVs; however, their orientation changed from parallel in distended to perpendicular in contracted bladder with respect to the apical plasma membrane. In the intermediate cells, shorter and more dilated immature FVs were present. The salient outcome from this research is the first comprehensive, high resolution 3D view of the ultrastructure of FVs and how they are organized differently depending on their location in the cytoplasm of umbrella cells. The shape of mature FVs and their organization into tightly packed stacks makes them a perfect storage compartment, which transports large amounts of urothelial plaques while occupying a small volume of umbrella cell cytoplasm

A model of the PI cycle reveals the regulating roles of lipid-binding proteins and pitfalls of using mosaic biological data

The phosphatidylinositol (PI) cycle is central to eukaryotic cell signaling. Its complexity, due to the number of reactions and lipid and inositol phosphate intermediates involved makes it difficult to analyze experimentally. Computational modelling approaches are seen as a way forward to elucidate complex biological regulatory mechanisms when this cannot be achieved solely through experimental approaches. Whilst mathematical modelling is well established in informing biological systems, many models are often informed by data sourced from multiple unrelated cell types (mosaic data) or from purified enzyme data. In this work, we develop a model of the PI cycle informed by experimental and omics data taken from a single cell type, namely platelets. We were able to make a number of predictions regarding the regulation of PI cycle enzymes, the importance of the number of receptors required for successful GPCR signaling and the importance of lipid- and protein-binding proteins in regulating second messenger outputs. We then consider how pathway behavior differs, when fully informed by data for HeLa cells and show that model predictions remain consistent. However, when informed by mosaic experimental data model predictions greatly vary illustrating the risks of using mosaic datasets from unrelated cell types

Urothelial Plaque Formation in Post-Golgi Compartments

Urothelial plaques are specialized membrane domains in urothelial superficial (umbrella) cells, composed of highly ordered uroplakin particles. We investigated membrane compartments involved in the formation of urothelial plaques in mouse umbrella cells. The Golgi apparatus did not contain uroplakins organized into plaques. In the post-Golgi region, three distinct membrane compartments containing uroplakins were characterized: i) Small rounded vesicles, located close to the Golgi apparatus, were labelled weakly with anti-uroplakin antibodies and they possessed no plaques; we termed them “uroplakin-positive transporting vesicles” (UPTVs). ii) Spherical-to-flattened vesicles, termed “immature fusiform vesicles” (iFVs), were uroplakin-positive in their central regions and contained small urothelial plaques. iii) Flattened “mature fusiform vesicles” (mFVs) contained large plaques, which were densely labelled with anti-uroplakin antibodies. Endoytotic marker horseradish peroxidase was not found in these post-Golgi compartments. We propose a detailed model of de novo urothelial plaque formation in post-Golgi compartments: UPTVs carrying individual 16-nm particles detach from the Golgi apparatus and subsequently fuse into iFV. Concentration of 16-nm particles into plaques and removal of uroplakin-negative membranes takes place in iFVs. With additional fusions and buddings, iFVs mature into mFVs, each carrying two urothelial plaques toward the apical surface of the umbrella cell

Retrograde traffic in the biosynthetic-secretory route

In the biosynthetic-secretory route from the rough endoplasmic reticulum, across the pre-Golgi intermediate compartments, the Golgi apparatus stacks, trans Golgi network, and post-Golgi organelles, anterograde transport is accompanied and counterbalanced by retrograde traffic of both membranes and contents. In the physiologic dynamics of cells, retrograde flow is necessary for retrieval of molecules that escaped from their compartments of function, for keeping the compartments’ balances, and maintenance of the functional integrities of organelles and compartments along the secretory route, for repeated use of molecules, and molecule repair. Internalized molecules may be transported in retrograde direction along certain sections of the secretory route, and compartments and machineries of the secretory pathway may be misused by toxins. An important example is the toxin of Shigella dysenteriae, which has been shown to travel from the cell surface across endosomes, and the Golgi apparatus en route to the endoplasmic reticulum, and the cytosol, where it exerts its deleterious effects. Most importantly in medical research, knowledge about the retrograde cellular pathways is increasingly being utilized for the development of strategies for targeted delivery of drugs to the interior of cells. Multiple details about the molecular transport machineries involved in retrograde traffic are known; a high number of the molecular constituents have been characterized, and the complicated fine structural architectures of the compartments involved become more and more visible. However, multiple contradictions exist, and already established traffic models again are in question by contradictory results obtained with diverse cell systems, and/or different techniques. Additional problems arise by the fact that the conditions used in the experimental protocols frequently do not reflect the physiologic situations of the cells. Regular and pathologic situations often are intermingled, and experimental treatments by themselves change cell organizations. This review addresses physiologic and pathologic situations, tries to correlate results obtained by different cell biologic techniques, and asks questions, which may be the basis and starting point for further investigations