A brief early intervention for adolescent depression that targets emotional mental images and memories: protocol for a feasibility randomised controlled trial (IMAGINE trial)

This is the final version of the article. Available from BioMed Central via the DOI in this record.Background: Adolescent depression is common and impairing. There is an urgent need to develop early interventions to prevent depression becoming entrenched. However, current psychological interventions are difficult to access and show limited evidence of effectiveness. Schools offer a promising setting to enhance access to interventions, including reducing common barriers such as time away from education. Distressing negative mental images and a deficit in positive future images, alongside overgeneral autobiographical memories, have been implicated in depression across the lifespan, and interventions targeting them in adults have shown promise. Here, we combine techniques targeting these cognitive processes into a novel, brief psychological intervention for adolescent depression. This feasibility randomised controlled trial will test the feasibility and acceptability of delivering this imagery-based cognitive behavioural intervention in schools. Methods/design: Fifty-six adolescents (aged 16-18) with high symptoms of depression will be recruited from schools. Participants will be randomly allocated to the imagery-based cognitive behavioural intervention (ICBI) or the control intervention, non-directive supportive therapy (NDST). Data on feasibility and acceptability will be recorded throughout, including data on recruitment, retention and adherence rates as well as adverse events. In addition, symptom assessment will take place pre-intervention, post-intervention and at 3-month follow-up. Primarily, the trial aims to establish whether it is feasible and acceptable to carry out this project in a school setting. Secondary objectives include collecting data on clinical measures, including depression and anxiety, and measures of the mechanisms proposed to be targeted by the intervention. The acceptability of using technology in assessment and treatment will also be evaluated. Discussion: Feasibility, acceptability and symptom data for this brief intervention will inform whether an efficacy randomised controlled trial is warranted and aid planning of this trial. If this intervention is shown in a subsequent definitive trial to be safe, clinically effective and cost-effective, it has potential to be rolled out as an intervention and so would significantly extend the range of therapies available for adolescent depression. This psychological intervention draws on cognitive mechanism research suggesting a powerful relationship between emotion and memory and uses imagery as a cognitive target in an attempt to improve interventions for adolescent depression. Trial registration: ISRCTN85369879.This study represents independent research from a Clinical Doctoral Research Fellowship (Dr Victoria Pile, ICA-CDRF-2015-01-007) supported by the National Institute for Health Research and Health Education England

Intrinsic Capability of Budding Yeast Cofilin to Promote Turnover of Tropomyosin-Bound Actin Filaments

The ability of actin filaments to function in cell morphogenesis and motility is closely coupled to their dynamic properties. Yeast cells contain two prominent actin structures, cables and patches, both of which are rapidly assembled and disassembled. Although genetic studies have shown that rapid actin turnover in patches and cables depends on cofilin, how cofilin might control cable disassembly remains unclear, because tropomyosin, a component of actin cables, is thought to protect actin filaments against the depolymerizing activity of ADF/cofilin. We have identified cofilin as a yeast tropomyosin (Tpm1) binding protein through Tpm1 affinity column and mass spectrometry. Using a variety of assays, we show that yeast cofilin can efficiently depolymerize and sever yeast actin filaments decorated with either Tpm1 or mouse tropomyosins TM1 and TM4. Our results suggest that yeast cofilin has the intrinsic ability to promote actin cable turnover, and that the severing activity may rely on its ability to bind Tpm1

Sarcomere Formation Occurs by the Assembly of Multiple Latent Protein Complexes

The stereotyped striation of myofibrils is a conserved feature of muscle organization that is critical to its function. Although most components that constitute the basic myofibrils are well-characterized biochemically and are conserved across the animal kingdom, the mechanisms leading to the precise assembly of sarcomeres, the basic units of myofibrils, are poorly understood. To gain insights into this process, we investigated the functional relationships of sarcomeric protein complexes. Specifically, we systematically analyzed, using either RNAi in primary muscle cells or available genetic mutations, the organization of myofibrils in Drosophila muscles that lack one or more sarcomeric proteins. Our study reveals that the thin and thick filaments are mutually dependent on each other for striation. Further, the tension sensor complex comprised of zipper/Zasp/α-actinin is involved in stabilizing the sarcomere but not in its initial formation. Finally, integrins appear essential for the interdigitation of thin and thick filaments that occurs prior to striation. Thus, sarcomere formation occurs by the coordinated assembly of multiple latent protein complexes, as opposed to sequential assembly

Mechanical and kinetic effects of shortened tropomyosin reconstituted into myofibrils

The effects of tropomyosin on muscle mechanics and kinetics were examined in skeletal myofibrils using a novel method to remove tropomyosin (Tm) and troponin (Tn) and then replace these proteins with altered versions. Extraction employed a low ionic strength rigor solution, followed by sequential reconstitution at physiological ionic strength with Tm then Tn. SDS-PAGE analysis was consistent with full reconstitution, and fluorescence imaging after reconstitution using Oregon-green-labeled Tm indicated the expected localization. Myofibrils remained mechanically viable: maximum isometric forces of myofibrils after sTm/sTn reconstitution (control) were comparable (~84%) to the forces generated by non-reconstituted preparations, and the reconstitution minimally affected the rate of isometric activation (kact), calcium sensitivity (pCa50), and cooperativity (nH). Reconstitutions using various combinations of cardiac and skeletal Tm and Tn indicated that isoforms of both Tm and Tn influence calcium sensitivity of force development in opposite directions, but the isoforms do not otherwise alter cross-bridge kinetics. Myofibrils reconstituted with Δ23Tm, a deletion mutant lacking the second and third of Tm’s seven quasi-repeats, exhibited greatly depressed maximal force, moderately slower kact rates and reduced nH. Δ23Tm similarly decreased the cooperativity of calcium binding to the troponin regulatory sites of isolated thin filaments in solution. The mechanisms behind these effects of Δ23Tm also were investigated using Pi and ADP jumps. Pi and ADP kinetics were indistinguishable in Δ23Tm myofibrils compared to controls. The results suggest that the deleted region of tropomyosin is important for cooperative thin filament activation by calcium

A prospective investigation of rumination and executive control in predicting overgeneral autobiographical memory in adolescence

The CaR-FA-X model (Williams et al., 2007), or capture and rumination (CaR), functional avoidance (FA) and impaired executive control (X), is a model of overgeneral autobiographical memory. Two mechanisms of the model, rumination and executive control were examined in isolation and in interaction to investigate overgeneral autobiographical memory over time. Method: Across two time points, six months apart, a total of 149 adolescents (13-16 years) completed a minimal instruction autobiographical memory test, a measure of executive control with emotional and non-emotional stimuli, and measures of brooding rumination and reflective pondering. Results: It was found that executive control for emotional information was negatively associated with OGM, but only when reflective pondering levels were high. Conclusion: In the context of higher levels of reflective pondering, greater switch costs (i.e. lower executive control) when processing emotional information predict a decrease in OGM over time

Genetics of photoreceptor degeneration and regeneration in zebrafish

Zebrafish are unique in that they provide a useful model system for studying two critically important problems in retinal neurobiology, the mechanisms responsible for triggering photoreceptor cell death and the innate stem cell–mediated regenerative response elicited by this death. In this review we highlight recent seminal findings in these two fields. We first focus on zebrafish as a model for studying photoreceptor degeneration. We summarize the genes currently known to cause photoreceptor degeneration, and we describe the phenotype of a few zebrafish mutants in detail, highlighting the usefulness of this model for studying this process. In the second section, we discuss the several different experimental paradigms that are available to study regeneration in the teleost retina. A model outlining the sequence of gene expression starting from the dedifferentiation of Müller glia to the formation of rod and cone precursors is presented

Shape Variation in Aterian Tanged Tools and the Origins of Projectile Technology: A Morphometric Perspective on Stone Tool Function

BACKGROUND: Recent findings suggest that the North African Middle Stone Age technocomplex known as the Aterian is both much older than previously assumed, and certainly associated with fossils exhibiting anatomically modern human morphology and behavior. The Aterian is defined by the presence of 'tanged' or 'stemmed' tools, which have been widely assumed to be among the earliest projectile weapon tips. The present study systematically investigates morphological variation in a large sample of Aterian tools to test the hypothesis that these tools were hafted and/or used as projectile weapons. METHODOLOGY/PRINCIPAL FINDINGS: Both classical morphometrics and Elliptical Fourier Analysis of tool outlines are used to show that the shape variation in the sample exhibits size-dependent patterns consistent with a reduction of the tools from the tip down, with the tang remaining intact. Additionally, the process of reduction led to increasing side-to-side asymmetries as the tools got smaller. Finally, a comparison of shape-change trajectories between Aterian tools and Late Paleolithic arrowheads from the North German site of Stellmoor reveal significant differences in terms of the amount and location of the variation. CONCLUSIONS/SIGNIFICANCE: The patterns of size-dependent shape variation strongly support the functional hypothesis of Aterian tools as hafted knives or scrapers with alternating active edges, rather than as weapon tips. Nevertheless, the same morphological patterns are interpreted as one of the earliest evidences for a hafting modification, and for the successful combination of different raw materials (haft and stone tip) into one implement, in itself an important achievement in the evolution of hominin technologies

Live Recombinant Salmonella Typhi Vaccines Constructed to Investigate the Role of rpoS in Eliciting Immunity to a Heterologous Antigen

We hypothesized that the immunogenicity of live Salmonella enterica serovar Typhi vaccines expressing heterologous antigens depends, at least in part, on its rpoS status. As part of our project to develop a recombinant attenuated S. Typhi vaccine (RASTyV) to prevent pneumococcal diseases in infants and children, we constructed three RASTyV strains synthesizing the Streptococcus pneumoniae surface protein PspA to test this hypothesis. Each vector strain carried ten engineered mutations designed to optimize safety and immunogenicity. Two S. Typhi vector strains (χ9639 and χ9640) were derived from the rpoS mutant strain Ty2 and one (χ9633) from the RpoS+ strain ISP1820. In χ9640, the nonfunctional rpoS gene was replaced with the functional rpoS gene from ISP1820. Plasmid pYA4088, encoding a secreted form of PspA, was moved into the three vector strains. The resulting RASTyV strains were evaluated for safety in vitro and for immunogenicity in mice. All three RASTyV strains were similar to the live attenuated typhoid vaccine Ty21a in their ability to survive in human blood and human monocytes. They were more sensitive to complement and were less able to survive and persist in sewage and surface water than their wild-type counterparts. Adult mice intranasally immunized with any of the RASTyV strains developed immune responses against PspA and Salmonella antigens. The RpoS+ vaccines induced a balanced Th1/Th2 immune response while the RpoS− strain χ9639(pYA4088) induced a strong Th2 immune response. Immunization with any RASTyV provided protection against S. pneumoniae challenge; the RpoS+ strain χ9640(pYA4088) provided significantly greater protection than the ISP1820 derivative, χ9633(pYA4088). In the pre-clinical setting, these strains exhibited a desirable balance between safety and immunogenicity and are currently being evaluated in a Phase 1 clinical trial to determine which of the three RASTyVs has the optimal safety and immunogenicity profile in human hosts

Evidence-based Kernels: Fundamental Units of Behavioral Influence

This paper describes evidence-based kernels, fundamental units of behavioral influence that appear to underlie effective prevention and treatment for children, adults, and families. A kernel is a behavior–influence procedure shown through experimental analysis to affect a specific behavior and that is indivisible in the sense that removing any of its components would render it inert. Existing evidence shows that a variety of kernels can influence behavior in context, and some evidence suggests that frequent use or sufficient use of some kernels may produce longer lasting behavioral shifts. The analysis of kernels could contribute to an empirically based theory of behavioral influence, augment existing prevention or treatment efforts, facilitate the dissemination of effective prevention and treatment practices, clarify the active ingredients in existing interventions, and contribute to efficiently developing interventions that are more effective. Kernels involve one or more of the following mechanisms of behavior influence: reinforcement, altering antecedents, changing verbal relational responding, or changing physiological states directly. The paper describes 52 of these kernels, and details practical, theoretical, and research implications, including calling for a national database of kernels that influence human behavior