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Inhibitors of enzymes that inactivate amine neurotransmitters (dopamine, serotonin), such as catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), are thought to increase neurotransmitter levels and are widely used to treat Parkinson's disease and psychiatric disorders, yet the role of these enzymes in regulating behavior remains unclear. Here, we investigated the genetic loss of a similar enzyme in the model organism Drosophila melanogaster . Because the enzyme Ebony modifies and inactivates amine neurotransmitters, its loss is assumed to increase neurotransmitter levels, increasing behaviors such as aggression and courtship and decreasing sleep. Indeed, ebony mutants have been described since 1960 as \"aggressive mutants,\" though this behavior has not been quantified. Using automated machine learning-based analyses, we quantitatively confirmed that ebony mutants exhibited increased aggressive behaviors such as boxing but also decreased courtship behaviors and increased sleep. Through tissue-specific knockdown, we found that ebony ’s role in these behaviors was specific to glia. Unexpectedly, direct measurement of amine neurotransmitters in ebony brains revealed that their levels were not increased but reduced. Thus, increased aggression is the anomalous behavior for this neurotransmitter profile. We further found that ebony mutants exhibited increased aggression only when fighting each other, not when fighting wild-type controls. Moreover, fights between ebony mutants were less likely to end with a clear winner than fights between controls or fights between ebony mutants and controls. In ebony vs. control fights, ebony mutants were more likely to win. Together, these results suggest that ebony mutants exhibit prolonged aggressive behavior only in a specific context, with an equally dominant opponent.

Mutations in Cullin-3 ( Cul3 ), a conserved gene encoding a ubiquitin ligase, are strongly associated with autism spectrum disorder (ASD). Here, we characterize ASD-related pathologies caused by neuron-specific Cul3 knockdown in Drosophila . We confirmed that neuronal Cul3 knockdown causes short sleep, paralleling sleep disturbances in ASD. Because sleep defects and ASD are linked to metabolic dysregulation, we tested the starvation response of neuronal Cul3 knockdown flies; they starved faster and had lower triacylglyceride levels than controls, suggesting defects in metabolic homeostasis. ASD is also characterized by increased biomarkers of oxidative stress; we found that neuronal Cul3 knockdown increased sensitivity to hyperoxia, an exogenous oxidative stress. Additional hallmarks of ASD are deficits in social interactions and learning. Using a courtship suppression assay that measures social interactions and memory of prior courtship, we found that neuronal Cul3 knockdown reduced courtship and learning compared to controls. Finally, we found that neuronal Cul3 depletion alters the anatomy of the mushroom body, a brain region required for memory and sleep. Taken together, the ASD-related phenotypes of neuronal Cul3 knockdown flies establish these flies as a genetic model to study molecular and cellular mechanisms underlying ASD pathology, including metabolic and oxidative stress dysregulation and neurodevelopment.

Natural aerosol components such as particulate methanesulfonic acid (MSAp) play an important role in the Arctic climate. However, numerical models struggle to reproduce MSAp concentrations and seasonality. Here we present an alternative data-driven methodology for modeling MSAp at four High Arctic stations (Alert, Gruvebadet, Pituffik (formerly Thule), and Utqiaġvik (formerly Barrow)). In our approach, we create input features that consider the ambient conditions experienced during atmospheric transport (e.g., dimethyl sulfide (DMS) emission, temperature, radiation, cloud cover, precipitation) for use in two data-driven models: a random forest (RF) regressor and an additive model (AM). The most important features were selected through automatic selection procedures, and their relationships with MSAp model output was investigated. Although the overall performance of our data-driven models on test data is modest (max. R2=0.29), the models can capture variability in the data well (max. Pearson correlation coefficient = 0.77), outperform the current numerical models and reanalysis products, and produce physically interpretable results. The data-driven models selected features which can be grouped into three categories, the sources, chemical processing, and removal of MSAp, with specific differences between stations. The seasonal cycles and selected features suggest gas-phase oxidation is relatively more important during peak concentration months at Alert, Gruvebadet, and Pituffik (Thule), while aqueous-phase oxidation is relatively more important at Utqiaġvik (Barrow). Alert and Pituffik (Thule) appear to be more influenced by processes aloft than in the boundary layer. Our models usually selected chemical-processing-related features as the main factors influencing MSAp predictions, highlighting the importance of properly simulating oxidation-related processes in numerical models.

Most molecular hallmarks of cellular senescence have been identified in studies of cells aged in vitro by driving them into replicative or stress-induced senescence. Comparatively, less is known about the characteristic features of cells that have aged in vivo. Here we provide a systematic molecular analysis of normal human dermal fibroblasts (NHDFs) that were isolated from intrinsically aged human skin of young versus middle aged versus old donors. Intrinsically aged NHDFs in culture exhibited more frequently nuclear foci positive for p53 binding protein 1 and promyelocytic leukemia protein reminiscent of ‘DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS)’. Formation of such foci was neither accompanied by increased DNA double strand breaks, nor decreased cell viability, nor telomere shortening. However, it was associated with the development of a secretory phenotype, indicating incipient cell senescence. By quantitative analysis of the entire secretome present in conditioned cell culture supernatant, combined with a multiplex cytokine determination, we identified 998 proteins secreted by intrinsically aged NHDFs in culture. Seventy of these proteins exhibited an age-dependent secretion pattern and were accordingly denoted ‘skin aging–associated secreted proteins (SAASP)’. Systematic comparison of SAASP with the classical senescence-associated secretory phenotype (SASP) revealed that matrix degradation as well as proinflammatory processes are common aspects of both conditions. However, secretion of 27 proteins involved in the biological processes of ‘metabolism’ and ‘adherens junction interactions’ was unique for NHDFs isolated from intrinsically aged skin. In conclusion, fibroblasts isolated from intrinsically aged skin exhibit some, but not all, molecular hallmarks of cellular senescence. Most importantly, they secrete a unique pattern of proteins that is distinct from the canonical SASP and might reflect specific processes of skin aging.

Aims/hypotheses Obesity is associated with decreased insulin sensitivity (IS) and elevated plasma branched-chain amino acids (BCAAs). The purpose of this study was to investigate the relationship between BCAA metabolism and IS in overweight (OW) individuals during exercise intervention. Methods Whole-body leucine turnover, IS by hyperinsulinaemic–euglycaemic clamp, and circulating and skeletal muscle amino acids, branched-chain α-keto acids and acylcarnitines were measured in ten healthy controls (Control) and nine OW, untrained, insulin-resistant individuals (OW-Untrained). OW-Untrained then underwent a 6 month aerobic and resistance exercise programme and repeated testing (OW-Trained). Results IS was higher in Control vs OW-Untrained and increased significantly following exercise. IS was lower in OW-Trained vs Control expressed relative to body mass, but was not different from Control when normalised to fat-free mass (FFM). Plasma BCAAs and leucine turnover (relative to FFM) were higher in OW-Untrained vs Control, but did not change on average with exercise. Despite this, within individuals, the decrease in molar sum of circulating BCAAs was the best metabolic predictor of improvement in IS. Circulating glycine levels were higher in Control and OW-Trained vs OW-Untrained, and urinary metabolic profiling suggests that exercise induces more efficient elimination of excess acyl groups derived from BCAA and aromatic amino acid (AA) metabolism via formation of urinary glycine adducts. Conclusions/interpretation A mechanism involving more efficient elimination of excess acyl groups derived from BCAA and aromatic AA metabolism via glycine conjugation in the liver, rather than increased BCAA disposal through oxidation and turnover, may mediate interactions between exercise, BCAA metabolism and IS. Trial registration: Clinicaltrials.gov NCT01786941

ObjectiveThis study aimed to describe the epidemiology, outcomes and costs of four immune-mediated inflammatory rheumatic diseases (IMIRDs)—systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS)—in Brazil’s public and private healthcare systems from 2018 to 2022.DesignRetrospective observational study.SettingThe study was conducted across hospital and outpatient levels of care in Brazil, based on nationwide data representing the public (Department of Informatics of the Unified Health System—DATASUS) and private (National Supplementary Health Agency—ANS) healthcare sectors.ParticipantsThe study analysed data from four distinct systems: 609 427 patients from the public Outpatient Information System (SIA), 32 119 patients from the public Hospital Information System (SIH), 19 083 deaths from the public Mortality Information System (SIM) and 11 846 hospitalisations from the private healthcare system (ANS).ResultsRA had the highest incidence, ranging from 19.9 to 24.9 per 100 000, while SLE remained stable (6.3–6.7 per 100 000). Prevalence increased for all diseases: RA rose from 95.7 to 136.8, SLE from 23.4 to 38.9, AS from 15.0 to 23.6 and PsA from 10.8 to 17.4 per 100 000. SLE had the highest hospitalisation (7.2%) and lethality rates (8.7%), along with the highest average outpatient cost (US$440.9 per patient). In the private system, RA and SLE accounted for the most hospitalisations (36.3% each). SLE had the highest proportion of emergency hospitalisations (70.5%), while PsA had the highest proportion of elective hospitalisations (61.8%).ConclusionsRA had the highest prevalence and incidence rates among the studied IMIRDs, while SLE was associated with the highest lethality, outpatient costs and emergency hospitalisations. The rising prevalence of these diseases highlights their growing burden on Brazil’s healthcare systems.Trial registration numberNCT06698900.

The assessment of cardiac autonomic regulation (CAR) with non-invasive techniques, such as heart rate variability (HRV), might be of practical interest in elite sports, considering its importance in determining training. We studied 117 soccer players (74 male and 43 female) from three First Division European soccer teams. We used a ranked Autonomic Nervous System Index (ANSI, resulting from the combination of multivariate statistical methodologies applied to HRV-derived indices) to assess CAR. We hypothesized that ANSI might differentiate playing positions, considering goalkeepers, defenders, midfielders, and forwards. We also assessed the perception of somatic symptoms and stress. We observed in male athletes that ANSI was significantly greater in males as compared to females (p < 0.001), being higher in midfielders and defenders (p = 0.035), who usually sustain the greatest external load. Interestingly, this result was not observed in female athletes, who, instead, reported a significantly higher perception of somatic symptoms (p = 0.018) and stress (p = 0.049), the latter being particularly high in midfielders and forwards (p = 0.045). This approach might represent a convenient model to study the effects of long-term physical exercise on CAR in soccer, even to unveil possible differences due to sex, different playing positions characterized by distinct exercise routines, or stress perception.

Introduction Three out of 10 older adults are admitted for acute care in U.S. hospitals where they are at risk for a rapid decline in physical function due to deconditioning. Identifying factors, such as sleep quality, that may be related to recovery of physical functioning is a key step in facilitating independence following hospital discharge. Thus, this study aimed to examine the association between sleep quality and functional recovery after an acute hospitalization in community dwelling older adults. Methods Participants (n=52; age 71.3 ± 6.8y, 75% female, 94.2% white), were recruited during an acute hospitalization. Participants completed sleep questionnaires including PROMIS Sleep-Related Impairment and Sleep Disturbance, as well as physical function testing and questionnaires, Short Physical Performance Battery (SPPB) and PROMIS Physical Function prior to hospital discharge (baseline) and at 4-weeks post-discharge (follow-up). Separate multivariate regression models were conducted to determine whether baseline sleep predicted physical functioning at follow-up as well as if pre-post hospital changes in sleep predicted pre-post changes in physical functioning. Results The PROMIS Sleep-Related Impairment score at baseline was inversely associated with SPPB Gait (0.02±0.009, p=0.04), SPPB Balance (0.02±0.008, p=0.02), SPPB Chair Stand (0.05±0.02, p=0.006) and Total SPPB (0.19±0.04, p<.0001) at follow-up. Similarly, baseline PROMIS Sleep Disturbance score was inversely associated with PROMIS Physical Function at follow-up (0.19±0.07, p=0.008). The change in PROMIS Sleep-Related Impairment was inversely associated with the change in Total SPPB (0.05±0.03, p=0.03), SPPB Balance (0.05±0.02, p=0.01) and PROMIS Physical Function (0.15±0.06, p=0.012) from baseline to follow-up. The change in PROMIS Sleep Disturbance was inversely correlated with the change in PROMIS Physical Function (0.11±0.05, p=0.04) from baseline to follow-up. Conclusion Together, these results demonstrated that self-reported sleep disturbance and daytime sleep-related impairments during and following hospitalization predicted physical functioning at 4-weeks post-discharge. Improving sleep during hospitalization may reduce hospital deconditioning and improve functional recovery. Support (if any) This work is supported by NIH Grant #s R01NR018342 (PI: Nowakowski), P30AG024832, UTMB Pepper OAIC, (PI: Volpi), UL1TR001439, (UTMB ITS); and the National Dairy Council (1229, PI: Volpi) Additional support was provided by the Center for Innovations in Quality, Effectiveness and Safety (CIN 13-413).

Introduction Three out of 10 older adults are admitted for acute care in U.S. hospitals where they are at risk for a rapid decline in physical function due to deconditioning. Identifying factors, such as sleep continuity, that may be related to recovery of physical functioning is a key step in facilitating independence following hospital discharge. Thus, this study aimed to examine the association between actigraphy-assessed sleep parameters and physical functioning after an acute hospitalization in community dwelling older adults. Methods Participants (n=24; age 68.9±5.5y, 71% female, 96% white), were recruited during an acute hospitalization. Participants completed physical performance testing using the Short Physical Performance Battery (SPPB) during acute hospitalization (baseline) and at 4-weeks post-discharge (follow-up). At the time of discharge, participants were given Philips Actiwatch-2® device to record sleep continuity for four weeks following hospital discharge. Actigraphy parameters included total sleep time (TST), sleep efficiency (SE), sleep onset latency (SOL) and wake after sleep onset (WASO). We conducted multivariate regression analyses using Poisson distribution to determine whether actigraphy-derived sleep parameters predicted of physical function. Results Increase in actigraphy-derived SE was associated with greater SPPB Balance (0.05±0.02, p=0.04) at the 4-week follow-up assessment. Increased TST was associated with improvements in SPPB total score (0.004±0.002, p=0.05) change score from baseline to 4-week follow-up. SE (0.11±0.04, p=0.01) and TST (0.004±0.002, p=0.005) were positively associated, whereas WASO (0.03±0.01, p=0.05) and SOL (0.15±0.07, p=0.03) were inversely associated with improvement in SPPB Balance change score from baseline to 4-week follow-up. Conclusion Together, these results demonstrated that improvements in actigraphy-derived sleep parameters (increased sleep efficiency and total sleep time; and decreased wake after sleep onset and sleep onset latency) were associated with improvements in physical functioning from hospital to 4-week follow up. Improving sleep during hospitalization may reduce hospital deconditioning and improve functional recovery. Support (if any) This work is supported by NIH Grant #s R01NR018342 (PI: Nowakowski), P30AG024832, UTMB Pepper OAIC, (PI: Volpi), UL1TR001439, (UTMB ITS); and the National Dairy Council (1229, PI: Volpi) Additional support was provided by the Center for Innovations in Quality, Effectiveness and Safety (CIN 13-413).

Natural aerosols are an important, yet understudied, part of the Arctic climate system. Natural marine biogenic aerosol components (e.g., methanesulfonic acid, MSA) are becoming increasingly important due to changing environmental conditions. In this study, we combine in situ aerosol observations with atmospheric transport modeling and meteorological reanalysis data in a data-driven framework with the aim to (1) identify the seasonal cycles and source regions of MSA, (2) elucidate the relationships between MSA and atmospheric variables, and (3) project the response of MSA based on trends extrapolated from reanalysis variables and determine which variables are contributing to these projected changes. We have identified the main source areas of MSA to be the Atlantic and Pacific sectors of the Arctic. Using gradient-boosted trees, we were able to explain 84% of the variance and find that the most important variables for MSA are indirectly related to either the gas- or aqueous-phase oxidation of dimethyl sulfide (DMS): shortwave and longwave downwelling radiation, temperature, and low cloud cover. We project MSA to undergo a seasonal shift, with non-monotonic decreases in April/May and increases in June-September, over the next 50 years. Different variables in different months are driving these changes, highlighting the complexity of influences on this natural aerosol component. Although the response of MSA due to changing oceanic variables (sea surface temperature, DMS emissions, and sea ice) and precipitation remains to be seen, here we are able to show that MSA will likely undergo a seasonal shift solely due to changes in atmospheric variables.