Metabolic control by the Bithorax Complex-Wnt signaling crosstalk in Drosophila.

Adipocytes distributed throughout the body play crucial roles in lipid metabolism and energy homeostasis. Regional differences among adipocytes influence normal function and disease susceptibility, but the mechanisms driving this regional heterogeneity remain poorly understood. Here, we report a genetic crosstalk between the Bithorax Complex ( BX-C ) genes and Wnt/Wingless signaling that orchestrates regional differences among adipocytes in Drosophila larvae. Abdominal adipocytes, characterized by the exclusive expression of abdominal A ( abd-A ) and Abdominal B ( Abd-B ), exhibit distinct features compared to thoracic adipocytes, with Wnt signaling further amplifying these disparities. Depletion of BX-C genes in adipocytes reduces fat accumulation, delays larval-pupal transition, and eventually leads to pupal lethality. Depleting Abd-A or Abd-B reduces Wnt target gene expression, thereby attenuating Wnt signaling-induced lipid mobilization. Conversely, Wnt signaling stimulated abd-A transcription, suggesting a feedforward loop that amplifies the interplay between Wnt signaling and BX-C in adipocytes. These findings elucidate how the crosstalk between cell-autonomous BX-C gene expression and Wnt signaling define unique metabolic behaviors in adipocytes in different anatomical regions of fat body, delineating larval adipose tissue domains.

Distinct effects of CDK8 module subunits on cellular growth and proliferation in Drosophila.

The Mediator complex, composed of about 30 conserved subunits, plays a pivotal role in facilitating RNA polymerase II-dependent transcription in eukaryotes. Within this complex, the CDK8 kinase module (CKM), comprising Med12, Med13, CDK8, and CycC (Cyclin C), serves as a dissociable subcomplex that modulates the activity of the small Mediator complex. Genetic studies in Drosophila have revealed distinct phenotypes of CDK8-CycC and Med12-Med13 mutations, yet the underlying mechanism has remained unknown. Here, using Drosophila as a model organism, we show that depleting CDK8-CycC enhances E2F1 target gene expression and promotes cell-cycle progression. Conversely, depletion of Med12-Med13 affects the expression of ribosomal protein genes and fibrillarin, indicating a more severe reduction in ribosome biogenesis and cellular growth compared to the loss of CDK8-CycC. Moreover, we found that the stability of CDK8 and CycC relies on Med12 and Med13, with a mutually interdependent relationship between Med12 and Med13. Furthermore, CycC stability depends on the other three CKM subunits. These findings reveal distinct roles for CKM subunits in vivo , with Med12-Med13 disruption exerting a more pronounced impact on ribosome biogenesis and cellular growth compared to the loss of CDK8-CycC. Significance: The CDK8 kinase module (CKM), comprising CDK8, CycC, Med12, and Med13, is essential in the Mediator complex for RNA polymerase II-dependent transcription in eukaryotes. While expected to function jointly, CKM subunit mutations result in distinct phenotypes in Drosophila . This study investigates the mechanisms driving these differing effects. Our analysis reveals the role of Med12-Med13 pair in regulating ribosomal biogenesis and cellular growth, contrasting with the involvement of CDK8-CycC in E2F1-dependent cell-cycle progression. Additionally, an asymmetric interdependence in the stability of CDK8-CycC and Med12-Med13 was observed. CKM mutations or overexpression are associated with cancers and cardiovascular diseases. Our findings underscore the distinct impacts of CKM mutations on cellular growth and proliferation, advancing our understanding of their diverse consequences in vivo .

Decoding working memory information from neurons with and without persistent activity in the primate prefrontal cortex.

Persistent activity of neurons in the prefrontal cortex has been thought to represent the information maintained in working memory, though alternative models have challenged this idea. Theories that depend on the dynamic representation of information posit that stimulus information may be maintained by the activity pattern of neurons whose firing rate is not significantly elevated above their baseline during the delay period of working memory tasks. We thus tested the ability of neurons that do and do not generate persistent activity in the prefrontal cortex of monkeys to represent spatial and object information in working memory. Neurons that generated persistent activity represented more information about the stimuli in both spatial and object working memory tasks. The amount of information that could be decoded from neural activity depended on the choice of decoder and parameters used but neurons with persistent activity outperformed non-persistent neurons consistently. Averaged across all neurons and stimuli, the firing rate did not appear clearly elevated above baseline during the maintenance of neural activity particularly for object working memory; however, this grand average masked neurons that generated persistent activity selective for their preferred stimuli, which carried the majority of stimulus information. These results reveal that prefrontal neurons that generate persistent activity maintain information more reliably during working memory.NEW & NOTEWORTHY Competing theories suggest that neurons that generate persistent activity or do not are primarily responsible for the maintenance of information, particularly regarding object working memory. Although the two models have been debated on theoretical terms, direct comparison of empirical results has been lacking. Analysis of neural activity in a large database of prefrontal recordings revealed that neurons that generate persistent activity were primarily responsible for the maintenance of both spatial and object working memory.

Transcriptional coupling of telomeric retrotransposons with the cell cycle.

Instead of employing telomerases to safeguard chromosome ends, dipteran species maintain their telomeres by transposition of telomeric-specific retrotransposons (TRs): in Drosophila , these are HeT-A , TART , and TAHRE . Previous studies have shown how these TRs create tandem repeats at chromosome ends, but the exact mechanism controlling TR transcription has remained unclear. Here we report the identification of multiple subunits of the transcription cofactor Mediator complex and transcriptional factors Scalloped (Sd, the TEAD homolog in flies) and E2F1-Dp as novel regulators of TR transcription and telomere length in Drosophila . Depletion of multiple Mediator subunits, Dp, or Sd increased TR expression and telomere length, while over-expressing E2F1-Dp or knocking down the E2F1 regulator Rbf1 (Retinoblastoma-family protein 1) stimulated TR transcription, with Mediator and Sd affecting TR expression through E2F1-Dp. The CUT&RUN analysis revealed direct binding of CDK8, Dp, and Sd to telomeric repeats. These findings highlight the essential role of the Mediator complex in maintaining telomere homeostasis by regulating TR transcription through E2F1-Dp and Sd, revealing the intricate coupling of TR transcription with the host cell-cycle machinery, thereby ensuring chromosome end protection and genomic stability during cell division.

Decoding working memory information from persistent and activity-silent neurons in the primate prefrontal cortex.

Persistent activity of neurons in the prefrontal cortex has been thought to represent the information maintained in working memory, though alternative models have recently challenged this idea. Activity-silent theories posit that stimulus information may be maintained by the activity pattern of neurons that do not produce firing rate significantly elevated about their baseline during the delay period of working memory tasks. We thus tested the ability of neurons that do and do not generate persistent activity in the prefrontal cortex of monkeys to represent spatial and object information in working memory. Neurons that generated persistent activity represented more information about the stimuli in both spatial and object working memory tasks. The amount of information that could be decoded from neural activity depended on the choice of decoder and parameters used but neurons with persistent activity outperformed non-persistent neurons consistently. Although averaged across all neurons and stimuli, firing rate did not appear clearly elevated above baseline during the maintenance of neural activity particularly for object working memory, this grant average masked neurons that generated persistent activity selective for their preferred stimuli, which carried the majority of information about the stimulus identity. These results reveal that prefrontal neurons with generate persistent activity constitute the primary mechanism of working memory maintenance in the cortex. NEW AND NOTEWORTHY: Competing theories suggest that neurons that generate persistent activity or do not are primarily responsible for the maintenance of information, particularly regarding object working memory. While the two models have been debated on theoretical terms, direct comparison of empirical results have been lacking. Analysis of neural activity in a large database of prefrontal recordings revealed that neurons that generate persistent activity were primarily responsible for the maintenance of both spatial and object working memory.

Developmentally programmed early-age skin localization of iNKT cells supports local tissue development and homeostasis.

Skin is exposed to various environmental assaults and undergoes morphological changes immediately after birth. Proper localization and function of immune cells in the skin is crucial for protection and establishment of skin tissue homeostasis. Here we report the discovery of a developmentally programmed process that directs preferential localization of invariant natural killer T (iNKT) cells to the skin for early local homeostatic regulation. We show that iNKT cells are programmed predominantly with a CCR10+ skin-homing phenotype during thymic development in infant and young mice. Early skin localization of iNKT cells is critical for proper commensal bacterial colonization and tissue development. Mechanistically, skin iNKT cells provide a local source of transferrin that regulates iron metabolism in hair follicle progenitor cells and helps hair follicle development. These findings provide molecular insights into the establishment and physiological functions of iNKT cells in the skin during early life.

Detecting pathological exercise in college men: An investigation using latent profile analysis.

OBJECTIVE: Pathological exercise is a dangerous behavior often observed in eating disorders. Data investigating associated characteristics of pathological exercise in men are lacking, despite college men and women being at equally elevated risk for developing eating disorders. PARTICIPANTS: Two hundred and twenty-four college men who exercise regularly completed a series of self-report questionnaires. METHODS: Latent profile analysis was used to identify empirically-derived homogenous subgroups of regular exercisers based on severity of other eating disorder attitudes and behaviors. Profiles were also compared on differences in exercise motivation and general psychopathology (i.e., depression, anxiety). RESULTS: Fit indices indicated a three-profile solution. Profiles described an eating psychopathology group, a low psychopathology group, and a high exercise frequency group without eating disorder features. CONCLUSIONS: Pathological exercise cannot be identified using exercise frequency alone. Other features like body dissatisfaction and exercise motivation style are relevant in identifying pathological exercise behavior in college men.

Gamification and neurotraining to engage men in behavioral weight loss: Protocol for a factorial randomized controlled trial.

Over 70% of men are overweight, and most desire weight loss; however, men are profoundly underrepresented in weight loss programs. Gamification represents a novel approach to engaging men and may enhance efficacy through two means: (1) game-based elements (e.g., streaks, badges, team-based competition) to motivate weight control behaviors and (2) arcade-style "neurotraining" to enhance neurocognitive capacities to resist the temptation of unhealthy foods and more automatically select healthy foods. This study will use a 2 × 2 factorial design to examine the independent and combinatory efficacy of gamification and inhibitory control training (ICT). Men with overweight/obesity (N = 228) will receive a 12-month mobile weight loss program that incorporates behavioral weight loss strategies (e.g., self-monitoring, goal setting, stimulus control). Men will be randomly assigned to a non-gamified or gamified version, and an active or sham ICT. A game design company will create the program, with input from a male advisory panel. Aims of the project are to test whether a gamified (versus non-gamified) weight loss program and/or ICT (versus sham) promotes greater improvements in weight, diet, and physical activity; whether these treatment factors have combinatory or synergistic effects; to test whether postulated mechanisms of action (increased engagement, for gamification, and inhibitory control, for ICT) mediate treatment effects; and whether baseline gameplay frequency and implicit preferences for ICT-targeted foods moderate effects. It is hoped this study will contribute to improved mHealth programs for men and enhance our understanding of the impact of gamified elements and neurocognitive training on weight control.

Associations between behaviour change technique clusters and weight loss outcomes of automated digital interventions: a systematic review and meta-regression.

Automated digital interventions for weight loss represent a highly scalable and potentially cost-effective approach to treat obesity. However, current understanding of the active components of automated digital interventions is limited, hindering efforts to improve efficacy. Thus, the current systematic review and meta-analysis (preregistration: PROSPERO 2021-CRD42021238878) examined relationships between utilisation of behaviour change techniques (BCTs) and the efficacy of automated digital interventions for producing weight loss. Electronic database searches (December 2020 to March 2021) were used to identify trials of automated digital interventions reporting weight loss as an outcome. BCT clusters were coded using Michie's 93-item BCT taxonomy. Mixed-effects meta-regression was used to examine moderating effects of BCT clusters and techniques on both within-group and between-group measures of weight change. One hundred and eight conditions across sixty-six trials met inclusion criteria (13,672 participants). Random-effects meta-analysis revealed a small mean post-intervention weight loss of -1.37 kg (95% CI, -1.75 to -1.00) relative to control groups. Interventions utilised a median of five BCT clusters, with goal-setting, feedback and providing instruction on behaviour being most common. Use of Reward and Threat techniques, and specifically social incentive/reward BCTs, was associated with a higher between-group difference in efficacy, although results were not robust to sensitivity analyses.

Comparison of the Iowa Reference Algorithm to the Heidelberg Spectralis optical coherence tomography segmentation algorithm.

For spectral-domain optical coherence tomography (SD-OCT) studies of neurodegeneration, it is important to understand how segmentation algorithms differ in retinal layer thickness measurements, segmentation error locations and the impact of manual correction. Using macular SD-OCT images of frontotemporal degeneration patients and controls, we compare the individual and aggregate retinal layer thickness measurements provided by two commonly used algorithms, the Iowa Reference Algorithm and Heidelberg Spectralis, with manual correction of significant segmentation errors. We demonstrate small differences of most retinal layer thickness measurements between these algorithms. Outer sectors of the Early Treatment Diabetic Retinopathy Study grid require a greater percent of eyes to be corrected than inner sectors of the retinal nerve fiber layer (RNFL). Manual corrections affect thickness measurements mildly, resulting in at most a 5% change in RNFL thickness. Our findings can inform researchers how to best use different segmentation algorithms when comparing retinal layer thicknesses.

Fitting NTCP models to bladder doses and acute urinary symptoms during post-prostatectomy radiotherapy.

BACKGROUND: To estimate the radiobiological parameters of three popular normal tissue complication probability (NTCP) models, which describe the dose-response relations of bladder regarding different acute urinary symptoms during post-prostatectomy radiotherapy (RT). To evaluate the goodness-of-fit and the correlation of those models with those symptoms. METHODS: Ninety-three consecutive patients treated from 2010 to 2015 with post-prostatectomy image-guided intensity modulated radiotherapy (IMRT) were included in this study. Patient-reported urinary symptoms were collected pre-RT and weekly during treatment using the validated Prostate Cancer Symptom Indices (PCSI). The assessed symptoms were flow, dysuria, urgency, incontinence, frequency and nocturia using a Likert scale of 1 to 4 or 5. For this analysis, an increase by ≥2 levels in a symptom at any time during treatment compared to baseline was considered clinically significant. The dose volume histograms of the bladder were calculated. The Lyman-Kutcher-Burman (LKB), Relative Seriality (RS) and Logit NTCP models were used to fit the clinical data. The fitting of the different models was assessed through the area under the receiver operating characteristic curve (AUC), Akaike information criterion (AIC) and Odds Ratio methods. RESULTS: For the symptoms of urinary urgency, leakage, frequency and nocturia, the derived LKB model parameters were: 1) D50 = 64.2Gy, m = 0.50, n = 1.0; 2) D50 = 95.0Gy, m = 0.45, n = 0.50; 3) D50 = 83.1Gy, m = 0.56, n = 1.00; and 4) D50 = 85.4Gy, m = 0.60, n = 1.00, respectively. The AUC values for those symptoms were 0.66, 0.58, 0.64 and 0.64, respectively. The differences in AIC between the different models were less than 2 and ranged within 0.1 and 1.3. CONCLUSIONS: Different dose metrics were correlated with the symptoms of urgency, incontinence, frequency and nocturia. The symptoms of urinary flow and dysuria were poorly associated with dose. The values of the parameters of three NTCP models were determined for bladder regarding four acute urinary symptoms. All the models could fit the clinical data equally well. The NTCP predictions of urgency showed the best correlation with the patient reported outcomes.