CBT for difficult-to-treat depression: self-regulation model

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for depression but a significant minority of clients do not complete therapy, do not respond to it, or subsequently relapse. Non-responders, and those at risk of relapse, are more likely to have adverse childhood experiences, early-onset depression, co-morbidities, interpersonal problems and heightened risk. This is a heterogeneous group of clients who are currently difficult to treat. AIM: The aim was to develop a CBT model of depression that will be effective for difficult-to-treat clients who have not responded to standard CBT. METHOD: The method was to unify theory, evidence and clinical strategies within the field of CBT to develop an integrated CBT model. Single case methods were used to develop the treatment components. RESULTS: A self-regulation model of depression has been developed. It proposes that depression is maintained by repeated interactions of self-identity disruption, impaired motivation, disengagement, rumination, intrusive memories and passive life goals. Depression is more difficult to treat when these processes become interlocked. Treatment based on the model builds self-regulation skills and restructures self-identity, rather than target negative beliefs. A bespoke therapy plan is formed out of ten treatment components, based on an individual case formulation. CONCLUSIONS: A self-regulation model of depression is proposed that integrates theory, evidence and practice within the field of CBT. It has been developed with difficult-to-treat cases as its primary purpose. A case example is described in a concurrent article (Barton et al., 2022) and further empirical tests are on-going

Recurrent depression and relational trauma: a single case of memory processing

\ua9 2024 The Author(s). Published by Cambridge University Press on behalf of British Association for Behavioural and Cognitive Psychotherapies. Cognitive behavioural therapy (CBT) is an effective treatment for depression, but a significant minority of clients are difficult to treat, including those with histories of relational trauma. The model of Beck et al. (1979) proposes that adverse childhood experiences lead to negative core beliefs, and these create a susceptibility to depression. However, Beck\u27s model does not identify trauma as a subset of adverse experiences. An alternative view is that traumatised clients internalise conflicting representations of self and it is conflict, interacting with trauma memories, that creates a vulnerability for depression. In this formulation, methods from the treatment of post-traumatic stress disorder (PTSD) could be incorporated into the treatment of depression, to emotionally process trauma memories and resolve self-identity conflicts. The aims of this study were to: (1) report the treatment of a 67-year-old man with recurrent depression and a history of prolonged relational trauma, and (2) to explore how memory processing from the treatment of PTSD can be incorporated into the treatment of recurrent depression. A single case observational design was used in the long-term treatment of a depressed traumatised client. The client received 47 individual sessions over 19 months in routine clinical practice in a tertiary CBT service. He completed repeated measures of mood, memory intrusions and sleep disruption. The client responded well to treatment with clinically significant improvements across measures of mood, memory and sleep. The effects were sustained over an 18-month follow-up. Memory processing was successfully integrated into a high-intensity treatment for recurrent depression. This is a promising approach for depressed clients with histories of relational trauma. Key learning aims (1) To consider how imaginal reliving can be incorporated into CBT for recurrent depression, when relational trauma is present. (2) To consider the cognitive processing mode of depressed traumatised clients when appraising beliefs about self and others. (3) To consider vulnerability to depression based on intrusive memories and conflicting self-representations, not only core beliefs

Toxin release by conditional remodelling of ParDE1 from Mycobacterium tuberculosis leads to gyrase inhibition

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.Mycobacterium tuberculosis, the causative agent of tuberculosis, is a growing threat to global health, with recent efforts towards its eradication being reversed in the wake of the COVID-19 pandemic. Increasing resistance to gyrase-targeting second-line fluoroquinolone antibiotics indicates the necessity to develop both novel therapeutics and our understanding of M. tuberculosis growth during infection. ParDE toxin–antitoxin systems also target gyrase and are regulated in response to both host-associated and drug-induced stress during infection. Here, we present microbiological, biochemical, structural, and biophysical analyses exploring the ParDE1 and ParDE2 systems of M. tuberculosis H37Rv. The structures reveal conserved modes of toxin–antitoxin recognition, with complex-specific interactions. ParDE1 forms a novel heterohexameric ParDE complex, supported by antitoxin chains taking on two distinct folds. Curiously, ParDE1 exists in solution as a dynamic equilibrium between heterotetrameric and heterohexameric complexes. Conditional remodelling into higher order complexes can be thermally driven in vitro. Remodelling induces toxin release, tracked through concomitant inhibition and poisoning of gyrase activity. Our work aids our understanding of gyrase inhibition, allowing wider exploration of toxin–antitoxin systems as inspiration for potential therapeutic agents

Confocal microscopy of a dense particle system

We report experiments utilizing confocal microscopy to determine the position of cornflour starch granules in a paste, as a function of distance from a wall. The granules have an average diameter of 15 mum. If a solvent is chosen such as to approximately match the refractive index of the granules then images of them can be obtained to a depth of 120 mum, which is the limit imposed by the working distance of the x40 oil immersion lens used in the experiment. An algorithm is presented which successfully identifies the particle centers in 3D. In addition to experiments on static systems we show how measurements of particle number density and velocity can be obtained from images of a system in pipe flow. We find that particles are depleted from the wall over a range of around 100 mum. (C) 2002 Elsevier Science

Mechanisms of structure formation in particulate gels of beta-lactoglobulin formed near the isoelectric point

Particulate gels are known to be formed by bovine beta-lactoglobulin near the isoelectric point when partial unfolding is allowed to occur under heating. The aggregation process of the protein has been investigated within the context of a nucleation and growth process by preparing gels under precisely controlled thermal histories. This was achieved using a Differential Scanning Calorimeter (DSC) to provide controlled heating rates, and known final temperatures and incubation times. The resulting particulate gels were characterized by their particle size and polydispersity using Environmental Scanning Electron Microscopy (ESEM), which permits hydrated samples to be observed. Particle size was found to decrease with increasing final temperature, with the aggregation taking longer to reach completion for lower temperatures. Particle size was also found to decrease with increasing heating rate. This system could be modelled as evolving via nucleation and growth by taking into account the fact that the concentration of the aggregating species was varying as a function of temperature as well as time. The intrinsic tryptophan fluorescence as a function of temperature was used as a guide to the fraction of unfolded protein in solution, thereby permitting successful comparisons between the model predictions and the particle sizes to be made

Aggregation across the length-scales in beta-lactoglobulin

The protein beta-lactoglobulin (BLG) has been widely studied, in large part because of its importance to the food industry. Following denaturation during heating, under different conditions of pH it has been found to form either particulate (around the isoelectric point at pH 5.1) or fibrillar gels. The nature of the fibrils has recently been suggested to be the same as that identified with amyloid fibrils known for a wide-range of different proteins and implicated in many disease states. We confirm that the BLG fibrils show all the classical signatures of amyloid fibrils. In addition, the fibrils are capable themselves of aggregating further to form large-scale (many microns in size) spherulites. Polarized light microscopy and Environmental scanning electron microscopy (ESEM) have been used to explore the internal structure of these spherulites under conditions in which the solvent has not been dried off. The factors which determine whether or not the spherulites form have also been considered, together with implications for other amyloid-containing systems

Synthetic biology through biomolecular design and engineering

Synthetic biology is a rapidly growing field that has emerged in a global, multidisciplinary effort among biologists, chemists, engineers, physicists, and mathematicians. Broadly, the field has two complementary goals: To improve understanding of biological systems through mimicry and to produce bioorthogonal systems with new functions. Here we review the area specifically with reference to the concept of synthetic biology space, that is, a hierarchy of components for, and approaches to generating new synthetic and functional systems to test, advance, and apply our understanding of biological systems. In keeping with this issue of Current Opinion in Structural Biology, we focus largely on the design and engineering of biomolecule-based components and systems

The binding of thioflavin-T to amyloid fibrils: localisation and implications

Amyloid fibrils are a polymeric form of protein, involving a continuous P-sheet with the strands perpendicular to the long axis of the fibril. Although typically implicated in diseases such as Alzheimer's disease and the transmissible spongiform encephalopathies, non disease-associated protein can also be converted into amyloid fibrils. Traditionally, amyloid fibrils are identified via the use of specific dyes such as Congo red and thioflavin-T, although their specificity is ill understood. Recently, solutions of bovine insulin and bovine beta-lactoglobulin have been found to form spherulites, micron-sized spherical structures containing radially arranged amyloid fibrils. When studied by confocal microscopy using polarised laser light and thioflavin-T, a consistent pattern of emission, rather than a uniform disc, was observed. This suggests the dye binds in a specific, regular fashion to amyloid fibrils. Confocal microscopy studies of thioflavin-T aligned in stretched poly-vinyl alcohol films showed that the dye dipole excitation axis lies parallel to the long molecular axis. Therefore, thioflavin-T binds to amyloid fibrils such that their long axes are parallel. We propose binding occurs in 'channels' that run along the length of the beta-sheet. Steric interactions between dye molecules and side chains indicate why thioflavin-T fluoresces more intensely when bound to amyloid fibrils and can explain why this interaction with amyloid fibrils is specific, but with varying efficiency. (C) 2004 Elsevier Inc. All rights reserved