Dimerization choice and alternative functions of ZBTB transcription factors.

Zinc Finger DNA-binding domain-containing proteins are the most populous family among eukaryotic transcription factors. Among these, members of the BTB domain-containing ZBTB sub-family are mostly known for their transcriptional repressive functions. In this Viewpoint article, we explore molecular mechanisms that potentially diversify the function of ZBTB proteins based on their homo and heterodimerization, alternative splicing and post-translational modifications. We describe how the BTB domain is as much a scaffold for the assembly of co-repressors, as a domain that regulates protein stability. We highlight another mechanism that regulates ZBTB protein stability: phosphorylation in the zinc finger domain. We explore the non-transcriptional, structural roles of ZBTB proteins and highlight novel findings that describe the ability of ZBTB proteins to associate with poly adenosine ribose in the nucleus during the DNA damage response. Herein, we discuss the contribution of BTB domain scaffolds to the formation of transcriptional repressive complexes, to chromosome compartmentalization and their non-transcriptional, purely structural functions in the nucleus.

My Diet Study: protocol for a two-part observational, longitudinal, psycho-biological study of dieting in Australian youth.

Introduction: Self-directed dieting (i.e., unsupervised) is very common among adolescents and young adults but has had almost no direct research. This paper describes the protocol for the My Diet Study, a two-arm observational investigation of the natural progression of dieting among young people over a period of 6-months. The study aims to examine the links between self-directed dieting, general physiological and psychological metrics of wellbeing (e.g., depressive symptoms) and biomarkers of gut-brain axis functions (e.g., microbiome and hormones) that are predicted to influence diet adherence through appetite, mood and metabolism regulation. Methods: Young people aged 16-25, intending to start a diet will be invited to participate in this observational study. For Part 1 (psychological arm), participants will be asked to complete a set of questionnaires and diaries at the beginning of every month for 6 months, to assess overall mental (e.g., psychological distress, disordered eating) and physical (e.g., weight) health, perceived diet success, food intake and gastrointestinal movements. For Part 2 (biological arm), a subsample of 50 participants will be asked to provide feces, blood and saliva for bio-sampling each month for the first 3-months of their participation in Part 1. Discussion: The My Diet Study will be the first longitudinal, observational study of dieting in young people combining in-depth psychological and biological data. It is anticipated that the findings will yield psychological & biological information about the impacts and effectiveness of self-directed dieting in young people, inform a framework for advice on safety in dieting among young people and help to establish the potential for biomarkers for risk management and improvement of diet-based lifestyle interventions.

A randomised controlled trial of clinician supported vs self-help delivery of online cognitive behaviour therapy for Bulimia Nervosa.

High dropout rates and poor adherence associated with digital interventions have prompted research into modifications of these treatments to improve engagement and completion rates. This trial aimed to investigate the added benefit of clinician support when paired alongside a ten-session, online cognitive behaviour therapy (CBT) self-help intervention for bulimia nervosa (BN). As part of a three-arm, phase II randomised controlled trial, 114 participants (16 years or over) with full or subthreshold BN were randomly assigned to complete the intervention in a self-help mode (with administrative researcher contact; n = 38), with adjunct clinician support (weekly 30-minute videoconferencing sessions; n = 37), or a no-treatment waitlist control (WLC; n = 39). Baseline to post-treatment (12-weeks) decreases in objective binge episode frequency were significantly greater for clinician-supported participants as compared to WLC, but not for self-help when compared to WLC. However, due to continued improvements for self-help across follow-up (24-weeks), both arms outperformed WLC when analysed as an overall rate of change across three timepoints. Clinician-supported participants outperformed self-help in regards to laxative use and dietary restraint. Our results demonstrate that good clinical outcomes can be achieved with a relatively brief online CBT-based program even in the absence of structured clinical support, indicating a possible overreliance upon clinician support as a primary adherence-facilitating mechanism.

The acceptability, feasibility, and preliminary efficacy of a supported online self-help treatment program for binge-eating disorder.

Introduction: Studies in transdiagnostic eating disorder (ED) samples suggest supported online self-help programs (eTherapies) are effective and may improve access to treatment; however, their evaluation in those with binge-eating disorder (BED) is limited. Given BED's high prevalence and low levels of treatment uptake, further eTherapy evaluation is needed to broaden access to effective, evidence-based treatment options. The aim of this study was to investigate the acceptability, feasibility, and preliminary efficacy of a supported eTherapy for those with BED or subthreshold BED, and to examine symptom change across the duration of therapy. Method: Nineteen women with BED completed a supported, 10-session Cognitive Behavioural Therapy-based eTherapy in an uncontrolled, pre-post, and 3 months follow up intervention study. Key outcomes were assessed by the Eating Disorder Examination Questionnaire (EDE-Q): objective binge episode (OBE) frequency and ED psychopathology. Feasibility was evaluated via program adherence and dropout, whilst acceptability was assessed through participant feedback post-treatment. Weekly symptom change (ED psychopathology) during treatment was assessed by the Eating Disorder Examination - Questionnaire Short (EDE-QS). Results: Generalised estimating equations showed statistically and clinically significant reductions in OBEs and ED psychopathology (large effects) post-treatment, with these decreases maintained at follow up. Across weekly assessment, a marked slowing in the rate of change in ED psychopathology was observed after four sessions of the program. Program feasibility was high (i.e., 84% of content completed), as was program acceptability (i.e., 93% of participants expressed high levels of satisfaction). Discussion: These results support the acceptability, feasibility, and preliminary efficacy of a supported eTherapy program for those with BED and suggest the variability of symptom change across the duration of therapy. Future research should further investigate findings in an adequately powered randomised controlled trial.

Risk factors for eating disorders: findings from a rapid review.

BACKGROUND: Risk factors represent a range of complex variables associated with the onset, development, and course of eating disorders. Understanding these risk factors is vital for the refinement of aetiological models, which may inform the development of targeted, evidence-based prevention, early intervention, and treatment programs. This Rapid Review aimed to identify and summarise research studies conducted within the last 12 years, focusing on risk factors associated with eating disorders. METHODS: The current review forms part of a series of Rapid Reviews to be published in a special issue in the Journal of Eating Disorders, funded by the Australian Government to inform the development of the National Eating Disorder Research and Translation Strategy 2021-2031. Three databases were searched for studies published between 2009 and 2021, published in English, and comprising high-level evidence studies (meta-analyses, systematic reviews, moderately sized randomised controlled studies, moderately sized controlled-cohort studies, or population studies). Data pertaining to risk factors for eating disorders were synthesised and outlined in the current paper. RESULTS: A total of 284 studies were included. The findings were divided into nine main categories: (1) genetics, (2) gastrointestinal microbiota and autoimmune reactions, (3) childhood and early adolescent exposures, (4) personality traits and comorbid mental health conditions, (5) gender, (6) socio-economic status, (7) ethnic minority, (8) body image and social influence, and (9) elite sports. A substantial amount of research exists supporting the role of inherited genetic risk in the development of eating disorders, with biological risk factors, such as the role of gut microbiota in dysregulation of appetite, an area of emerging evidence. Abuse, trauma and childhood obesity are strongly linked to eating disorders, however less conclusive evidence exists regarding developmental factors such as role of in-utero exposure to hormones. Comorbidities between eating disorders and mental health disorders, including personality and mood disorders, have been found to increase the severity of eating disorder symptomatology. Higher education attainment, body image-related factors, and use of appearance-focused social media are also associated with increased risk of eating disorder symptoms. CONCLUSION: Eating disorders are associated with multiple risk factors. An extensive amount of research has been conducted in the field; however, further studies are required to assess the causal nature of the risk factors identified in the current review. This will assist in understanding the sequelae of eating disorder development and in turn allow for enhancement of existing interventions and ultimately improved outcomes for individuals.

Research into the risk factors associated with eating disorders (EDs) is necessary in order to better understand the reasons why people develop EDs and to inform programs which aim to reduce these risk factors. In the current study we reviewed studies published between 2009 and 2021 which had researched risk factors associated with EDs. This study is one review of a wider Rapid Review series conducted as part the development of Australia's National Eating Disorders Research and Translation Strategy 2021­2031. The findings from this review are grouped into nine main risk factor categories. These include (1) genetics, (2) gastrointestinal microbiota and autoimmune reactions, (3) childhood and early adolescent exposures, (4) personality traits and comorbid mental health conditions, (5) gender, (6) socio-economic status, (7) ethnic minority, (8) body image and social influence, and (9) elite sports. Further research is needed to better understand the relationship between the risk factors, in particular the ways in which they may interact with each other and whether they cause the ED or are just associated with the ED.

Sibling rivalry among the ZBTB transcription factor family: homodimers versus heterodimers.

The BTB domain is an oligomerization domain found in over 300 proteins encoded in the human genome. In the family of BTB domain and zinc finger-containing (ZBTB) transcription factors, 49 members share the same protein architecture. The N-terminal BTB domain is structurally conserved among the family members and serves as the dimerization site, whereas the C-terminal zinc finger motifs mediate DNA binding. The available BTB domain structures from this family reveal a natural inclination for homodimerization. In this study, we investigated the potential for heterodimer formation in the cellular environment. We selected five BTB homodimers and four heterodimer structures. We performed cell-based binding assays with fluorescent protein-BTB domain fusions to assess dimer formation. We tested the binding of several BTB pairs, and we were able to confirm the heterodimeric physical interaction between the BTB domains of PATZ1 and PATZ2, previously reported only in an interactome mapping experiment. We also found this pair to be co-expressed in several immune system cell types. Finally, we used the available structures of BTB domain dimers and newly constructed models in extended molecular dynamics simulations (500 ns) to understand the energetic determinants of homo- and heterodimer formation. We conclude that heterodimer formation, although frequently described as less preferred than homodimers, is a possible mechanism to increase the combinatorial specificity of this transcription factor family.

Evaluating the feasibility and potential efficacy of a brief eTherapy for binge-eating disorder: A pilot study.

OBJECTIVE: For those with binge-eating disorder (BED), access to evidence-based, face-to-face treatment is often constrained by clinician availability and high treatment costs. Emerging evidence suggests online therapy (eTherapy) may navigate these barriers and reduce binge-eating symptomatology; however, less evaluation has been done in those with BED, particularly with briefer programs targeting early change. This study investigated the feasibility and potential efficacy of a brief, supported eTherapy in those with BED or subthreshold BED. METHOD: Participants were 19 women with BED who completed a four-session eTherapy. This was a single-arm, pre-post intervention study, with participants completing weekly content and attending telehealth sessions. Key outcomes were assessed by the Eating Disorder Examination Questionnaire-Short (EDE-QS): objective binge episode days, loss of control over eating days, and eating disorder (ED) psychopathology via a total EDE-QS score. RESULTS: Generalized and linear mixed models showed significantly reduced loss of control over eating days and ED psychopathology. Program feasibility was high, with strong program adherence and a below average attrition rate. DISCUSSION: Pilot results support the feasibility and potential efficacy of a brief, behavioral-focused eTherapy program in reducing ED pathology in those with BED. Future research should further investigate findings in an adequately powered randomized controlled trial. PUBLIC SIGNIFICANCE: This study suggests that a brief, behavioral-focused online therapy, guided by non-expert clinicians, can be successfully administered to those with binge-eating disorder (BED) and may be efficacious at reducing eating disorder and other related symptomatology. Brief eTherapies that are effective, accessible, and rapidly available may facilitate earlier intervention in illness and improve treatment outcomes for individuals who experience this common and distressing disorder.

Nanobodies as molecular imaging probes.

Camelidae derived single-domain antibodies (sdAbs), commonly known as nanobodies (Nbs), are the smallest antibody fragments with full antigen-binding capacity. Owing to their desirable properties such as small size, high specificity, strong affinity, excellent stability, and modularity, nanobodies are on their way to overtake conventional antibodies in terms of popularity. To date, a broad range of nanobodies have been generated against different molecular targets with applications spanning basic research, diagnostics, and therapeutics. In the field of molecular imaging, nanobody-based probes have emerged as a powerful tool. Radioactive or fluorescently labeled nanobodies are now used to detect and track many targets in different biological systems using imaging techniques. In this review, we provide an overview of the use of nanobodies as molecular probes. Additionally, we discuss current techniques for the generation, conjugation, and intracellular delivery of nanobodies.

Accessibility of Psychological Treatments for Bulimia Nervosa: A Review of Efficacy and Engagement in Online Self-Help Treatments.

Bulimia nervosa is an eating disorder characterised by marked impairment to one's physical health and social functioning, as well as high rates of chronicity and comorbidity. This literature review aims to summarise existing academic research related to the symptom profile of BN, the costs and burden imposed by the illness, barriers to the receipt of care, and the evidence base for available psychological treatments. As a consequence of well-documented difficulties in accessing evidence-based treatments for eating disorders, efforts have been made towards developing innovative, diverse channels to deliver treatment, with several of these attempting to harness the potential of digital platforms. In response to the increasing number of trials investigating the utility of online treatments, this paper provides a critical review of previous attempts to examine digital interventions in the treatment of eating disorders. The results of a focused literature review are presented, including a detailed synthesis of a knowledgeable selection of high-quality articles with the aim of providing an update on the current state of research in the field. The results of the review highlight the potential for online self-help treatments to produce moderately sized reductions in core behavioural and cognitive symptoms of eating disorders. However, concern is raised regarding the methodological limitations of previous research in the field, as well as the high rates of dropout and poor adherence reported across most studies. The review suggests directions for future research, including the need to replicate previous findings using rigorous study design and methodology, as well as further investigation regarding the utility of clinician support and interactive digital features as potential mechanisms for offsetting low rates of engagement with online treatments.

Supported online cognitive behavioural therapy for bulimia nervosa: a study protocol of a randomised controlled trial.

BACKGROUND: Despite the availability of effective treatments for bulimia nervosa (BN), a number of barriers to accessibility exist. Examples include access to trained clinicians, the expense of treatment, geographical limitations, and personal limitations such as stigma regarding help seeking. Self-help interventions, delivered via a digital platform, have the potential to overcome treatment gaps by providing patients with standardised, evidence-based treatments that are easily accessible, cost-effective, and require minimal clinician support. Equally, it is important to examine the shortcomings of digital interventions when compared to traditional to face-to-face delivery (e.g., high dropout rates) in order to maximise the therapeutic effectiveness of online, self-help interventions. METHODS: A three-arm, multisite randomised controlled trial will be conducted in Australia examining the effectiveness and cost-effectiveness of a newly developed online self-help intervention, Binge Eating eTherapy (BEeT), in a sample of patients with full or sub-threshold BN. The BEeT program consists of 10, multimedia sessions delivering the core components of cognitive behaviour therapy. Eligible participants will be randomised to one of three groups: independent completion of BEeT as a purely self-help program, completion of BEeT alongside clinician support (in the form of weekly telemedicine sessions), or waitlist control. Assessments will take place at baseline, weekly, post-intervention, and three-month follow up. The primary outcome is frequency of objective binge episodes. Secondary outcomes include frequency of other core eating disorder behavioural symptoms and beliefs, psychological distress, and quality of life. Statistical analyses will examine treatment effectiveness, feasibility, acceptability and cost effectiveness. DISCUSSION: There is limited capacity within the mental health workforce in Australia to meet the demand of people seeking treatment for eating disorders. This imbalance has only worsened following outbreak of the COVID-19 pandemic. Further research is required into innovative digital modes of treatment delivery with the capacity to service mental health needs in an accessible and affordable manner. Self-help programs may also appeal to individuals who are more reluctant to engage in traditional face-to-face treatment formats. This study will provide rigorous evidence on how to diversify treatment options for individuals with BN, ensuring more people with the illness can access evidence-based treatment. The study has been registered with the Australia New Zealand Clinical Trials Registry (ANZCTR Registration Number: ACTRN12619000123145p). Registered 22 January 2019, https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12619000123145 .

Evaluating the role of digital intervention design in treatment outcomes and adherence to eTherapy programs for eating disorders: A systematic review and meta-analysis.

OBJECTIVE: Despite the existence of reviews which document the effectiveness of online therapies, there is little consensus regarding the exact components of online treatment delivery that are most effective in maintaining user engagement and reducing eating disorder (ED) symptomology. The current review and meta-analysis aimed to determine which components of web-based, ED self-help interventions are associated with lower attrition and improved therapeutic outcome. METHOD: A systematic search of electronic databases (PsycINFO, Medline, Web of Science, Scopus) was conducted for published studies of web-based interventions for EDs and a meta-analysis of the final included studies was performed. Each intervention was coded across four dimensions, including the multimedia channels employed (e.g., text, audio, videos), degree of user interactivity (e.g., online self-monitoring, skills exercises), level of automated feedback (e.g., reminders, personalized feedback), and technological device through which the program was accessed (e.g., smartphone, computer). RESULTS: A final 23 papers were included. The results of meta-regressions indicated that higher scores on the multimedia subscale were associated with greater ED symptom improvement in treatment groups. Conversely, a higher degree of feedback in the treatment group was associated with a group difference in ED psychopathology favoring the control group. Other intervention components were not associated with treatment outcome or dropout. DISCUSSION: The results are discussed in relation to limitations of the scale used to quantify digital intervention features, as well as the limited diversity and technological sophistication of available ED digital interventions. Such findings indicate the importance of understanding the digital components, which differentiate online therapeutic programs.

Objetivo: A pesar de las existencia de revisiones que documentan la efectividad de las terapias en línea, hay poco consenso acerca de los componentes exactos de los tratamientos llevados a cabo en línea que son más efectivos en mantener involucrado al usuario y reducir la sintomatología de trastorno de la conducta alimentaria (TCA). La presente revisión y meta-análisis pretende determinar qué componentes de las intervenciones de autoayuda para TCA basadas en la web, están asociadas con menor deserción y resultados terapéuticos mejorados. Método: Una revisión sistemática de las bases de datos electrónicas (PsycINFO, Medline, Web of Science, Scopus) fueron revisadas buscando estudios de intervenciones para TCAs basadas en la web y se realizó un meta-análisis de los estudios finalmente incluidos. Cada intervención fue codificada en cuatro dimensiones, incluyendo los canales multimedia (por ejemplo, texto, audio, videos), grado de interacción con el usuario (por ejemplo, auto monitoreo en línea, ejercicios de habilidades), nivel de retroalimentación automatizada (por ejemplo, recordatorios, retroalimentación personalizada), y aparatos tecnológicos a través de los cuáles se accesó al programa (por ejemplo, teléfonos inteligentes, computadora). Resultados: Al final fueron incluidos 23 estudios. Los resultados de las meta-regresiones indicaron que puntuaciones más elevadas en la subescala de multimedia estaba asociado con mayor mejoría de los síntomas de TCA en los grupos de tratamiento. Por lo contrario, un mayor grado de retroalimentación en el grupo de tratamiento fue asociado con una diferencia grupal en la psicopatología de TCA favoreciendo el grupo control. Otros componentes de la intervención no fueron asociados con resultados o abandonos de tratamiento. Discusión: Los resultados fueron discutidos en relación a las limitaciones de la escala utilizada para cuantificar las características de la intervención digital, así como la limitada diversidad y sofisticación tecnológica de las intervenciones digitales para TCA disponibles. Estos hallazgos indican la importancia de entender los componentes digitales que diferencían los programas terapéuticos en línea.

The Role of Regular Eating and Self-Monitoring in the Treatment of Bulimia Nervosa: A Pilot Study of an Online Guided Self-Help CBT Program.

Background: Despite cognitive behavioural therapy (CBT) being regarded as the first-line treatment option for bulimia nervosa (BN), barriers such as its time-consuming and expensive nature limit patient access. In order to broaden treatment availability and affordability, the efficacy and convenience of CBT could be improved through the use of online treatments and selective emphasis on its most 'potent' components of which behavioural techniques form the focus. Method: Twenty-six individuals with BN were enrolled in an online CBT-based self-help programme and 17 completed four weeks of regular eating and food-monitoring using the online Food Diary tool. Participants were contacted for a weekly check-in phone call and had their bulimic symptom severity assessed at five time points (baseline and weeks 1-4). Results: There was a significant decrease in the frequency of self-reported objective binge episodes, associated loss of control and objective binge days reported between pre- and post-treatment measures. Significant improvements were also observed in most subscales of the Eating Disorder Examination-Questionnaire. Conclusion: This study provides encouraging preliminary evidence of the potential of behavioural techniques of online CBT in the treatment of BN. Online therapy with this focus is potentially a viable and practical form of treatment delivery in this illness group. These preliminary findings support the need for larger studies using control groups.

Differential expression of stem cell-like proteins in normal, hyperplastic and dysplastic oral epithelium.

OBJECTIVE: The identification of stem cells (SC) remains challenging. In the human oral mucosal epithelium, these cells are believed to be in the basal layer (stem cell niche), but their exact location is unclear. The aim of this study was to examine the dysplastic oral epithelium for these SC-like proteins in order to assess their diagnostic value as biomarkers complementing the histological grading of dysplasia. MATERIAL AND METHODS: Thirty oral epithelial dysplasia (OED), 25 oral lichen planus (OLP), 10 oral hyperkeratosis and 5 normal oral epithelium (OE) were immunohistochemically examined for four SC markers [integrin ß1, neuron-glial-2 (NG2), notch 1 (N1) and keratin 15 (K15)]. RESULTS: Three of four SC markers were heterogeneously detected in all samples. K15 overexpression in the lower two-thirds of severe OED suggests an expanded SC niche. Integrin ß1 distribution pattern was not measurably different between OEDs and control. NG2 was almost negative to absent in all samples examined. N1 expression was weak and highly variable in normal and dysplastic epithelium, making it an unreliable epithelial stem cell marker. CONCLUSIONS: Present findings suggest that these markers were unable to identify individual epithelial stem cells. Instead, subpopulations of cells, most probably stem cells and transit amplifying cells with stem cell-like properties were identified in the dysplastic oral epithelium. The characteristic expressions of K15 might be of diagnostic value for oral dysplasia and should be investigated further.

Differential expression of stem cell-like proteins in normal, hyperplastic and dysplastic oral epithelium

Objective The identification of stem cells (SC) remains challenging. In the human oral mucosal epithelium, these cells are believed to be in the basal layer (stem cell niche), but their exact location is unclear. The aim of this study was to examine the dysplastic oral epithelium for these SC-like proteins in order to assess their diagnostic value as biomarkers complementing the histological grading of dysplasia. Material and Methods Thirty oral epithelial dysplasia (OED), 25 oral lichen planus (OLP), 10 oral hyperkeratosis and 5 normal oral epithelium (OE) were immunohistochemically examined for four SC markers [integrin β1, neuron-glial-2 (NG2), notch 1 (N1) and keratin 15 (K15)]. Results Three of four SC markers were heterogeneously detected in all samples. K15 overexpression in the lower two-thirds of severe OED suggests an expanded SC niche. Integrin β1 distribution pattern was not measurably different between OEDs and control. NG2 was almost negative to absent in all samples examined. N1 expression was weak and highly variable in normal and dysplastic epithelium, making it an unreliable epithelial stem cell marker. Conclusions Present findings suggest that these markers were unable to identify individual epithelial stem cells. Instead, subpopulations of cells, most probably stem cells and transit amplifying cells with stem cell-like properties were identified in the dysplastic oral epithelium. The characteristic expressions of K15 might be of diagnostic value for oral dysplasia and should be investigated further. .