RNA-binding properties orchestrate TDP-43 homeostasis through condensate formation in vivo.

Insoluble cytoplasmic aggregate formation of the RNA-binding protein TDP-43 is a major hallmark of neurodegenerative diseases including Amyotrophic Lateral Sclerosis. TDP-43 localizes predominantly in the nucleus, arranging itself into dynamic condensates through liquid-liquid phase separation (LLPS). Mutations and post-translational modifications can alter the condensation properties of TDP-43, contributing to the transition of liquid-like biomolecular condensates into solid-like aggregates. However, to date it has been a challenge to study the dynamics of this process in vivo. We demonstrate through live imaging that human TDP-43 undergoes nuclear condensation in spinal motor neurons in a living animal. RNA-binding deficiencies as well as post-translational modifications can lead to aberrant condensation and altered TDP-43 compartmentalization. Single-molecule tracking revealed an altered mobility profile for RNA-binding deficient TDP-43. Overall, these results provide a critically needed in vivo characterization of TDP-43 condensation, demonstrate phase separation as an important regulatory mechanism of TDP-43 accessibility, and identify a molecular mechanism of how functional TDP-43 can be regulated.

Dynamic relationships among feeling fat, fear of weight gain, and eating disorder symptoms in an eating disorder sample.

Feeling fat and fear of weight gain are key cognitive-affective symptoms that are theorized to maintain eating disorders (EDs). Little research has examined the dynamic relationships among feeling fat, fear of weight gain, emotions, cognitions, and ED behaviors. Furthermore, it is unknown if these relations vary by ED diagnosis (e.g., anorexia nervosa (AN) vs other ED). The current study (N = 94 ED participants; AN n = 64) utilized ecological momentary assessments collected four times a day for 18 days (72 timepoints) asking about feeling fat, fear of weight gain, emotions (i.e., anxiety, guilt), cognitions (i.e., feelings of having overeaten, thoughts about dieting), and ED behaviors (i.e., vomiting, diuretic/laxative use, excessive exercise, body checking, self-weighing, binge-eating, restriction) at stressful timepoints (contemporaneous [mealtime], and prospective/temporal [next-meal]). Multilevel modeling was used to test for between and within-person associations. Higher feeling fat and fear of weight gain independently predicted higher next-meal emotions (i.e., anxiety, guilt), cognitions (i.e., feelings of having overeaten, thoughts about dieting, fear of weight gain, feeling fat), and ED behaviors (i.e., body checking, self-weighing [feeling fat]). There were relationships in the opposite direction, such that some emotions, cognitions, and ED behaviors prospectively predicted feeling fat and fear of weight gain, suggesting existence of a reciprocal cycle. Some differences were found via diagnosis. Findings pinpoint specific dynamic and cyclical relationships among feeling fat, fear of weight gain, and specific ED symptoms, and suggest the need for more research on how feeling fat, fear of weight gain and cognitive-affective-behavioral aspects of ED operate. Future research can test if treatment interventions targeted at feeling fat and fear of weight gain may disrupt these cycles.

Paternal environment effects are driven by female reproductive fluid but not sperm age in an external fertilizer.

Sperm ageing after ejaculation can generate paternal environment effects that impact offspring fitness. In many species, female reproductive fluids (FRFs), i.e. ancillary fluids released by eggs or within the female reproductive tract, may protect sperm from ageing and can additionally interact with sperm to influence offspring viability. This raises the intriguing prospect that FRFs may alleviate paternal effects associated with sperm ageing. Here, we test this novel hypothesis using the broadcast spawning mussel, Mytilus galloprovincialis. We show that incubating sperm in FRF prior to fertilization increases offspring viability, and that these effects occur independently of sperm age. Our results provide novel evidence that FRFs allow females to selectively bias fertilization toward higher quality sperm within an ejaculate, which in turn yields more viable offspring. We consider this FRF-mediated paternal effect in the context of female physiological control over fertilization and the transgenerational effects of female-regulated haploid selection.

The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation.

Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by ceramide synthases (CerS) in the de novo pathway. Despite their critical function, mechanisms regulating CerS remain largely unknown. Using an unbiased proteomics approach, we find that the small heat shock protein 27 (Hsp27) interacts specifically with CerS1 but not other CerS. Functionally, our data show that Hsp27 acts as an endogenous inhibitor of CerS1. Wild-type Hsp27, but not a mutant deficient in CerS1 binding, inhibits CerS1 activity. Additionally, silencing of Hsp27 enhances CerS1-generated ceramide accumulation in cells. Moreover, phosphorylation of Hsp27 modulates Hsp27-CerS1 interaction and CerS1 activity in acute stress-response conditions. Biologically, we show that Hsp27 knockdown impedes mitochondrial function and induces lethal mitophagy in a CerS1-dependent manner. Overall, we identify an important mode of CerS1 regulation and CerS1-mediated mitophagy through protein-protein interaction with Hsp27.

Testing for age-dependent effects of dietary restriction on the strength of condition dependence in ejaculate traits in the guppy (Poecilia reticulata).

Ejaculates can be costly to produce and depend on an individual's condition, defined as the pool of resources allocated to fitness. A method for assessing condition dependence is to manipulate resource availability and test for a reduction in trait expression. Here, we assess the effects of dietary restriction on two determinants of reproductive fitness in the guppy Poecilia reticulata-sperm production and sperm motility. Importantly, we administered dietary restriction at distinct developmental stages to test: (1) whether dietary restriction, when applied exclusively to juveniles, compromised the ejaculates of newly mature males; (2) whether any observed effects of dietary restriction seen in (1) were reversible when fish returned to an unrestricted diet; and (3) whether dietary restriction applied exclusively to adults influenced ejaculates. We found detrimental effects of resource limitation on both traits, and these were consistent across the three developmental stages tested. Furthermore, dietary restriction reduced male body weight, but this was partially reversed when diet-stressed juveniles (i.e. group 2) returned to unrestricted diets. This latter result suggests that diet-stressed males may sacrifice growth in order to maintain their investment in ejaculates. Together these findings underscore the importance of resource acquisition in determining the expression of ejaculate traits.

Appetitive and Aversive Motivation in Dysregulated Behaviors: A Meta-Analysis.

Appetitive and aversive motivation are prominent in theories of dysregulated behaviors. The authors conducted a meta-analysis of the association between individual differences in appetitive and aversive motivation and several dysregulated behaviors (i.e., alcohol use, marijuana use, tobacco use, binge eating, aggression, gambling, and nonsuicidal self-injury). Alcohol use (r = .17, k = 141), marijuana use (r = .13, k = 23), aggression (r = .22, k = 52), and gambling (r = .08, k = 55) were all significantly positively related to appetitive motivation. Binge eating (r = .28, k = 34) and self-injury (r = .17, k = 10) were significantly positively related to aversive motivation. Effect sizes were similar to the median effect size in personality research. Together, these results provide some evidence that some dysregulated behaviors are more correlated with approach motivation, whereas others are more correlated with aversive motivation, which may indicate distinct etiological pathways.

Female reproductive fluids 'rescue' sperm from phenotypic ageing in an external fertilizer.

Female reproductive fluids (FRFs) serve key reproductive functions in sexually reproducing animals, including modifying the way sperm swim and detect eggs, and influencing sperm lifespan. Despite the central role of FRF during fertilization, we know surprisingly little about sperm-FRF interactions under different environmental conditions. Theory suggests that in external fertilizers FRF may 'rescue' sperm from ageing effects as they search to fertilize eggs. Here, we test the interaction between these two fundamental properties of the fertilization environment, ejaculate age (i.e. time since ejaculation) and FRF, on a range of functional sperm phenotypes in a broadcast spawning mussel, Mytilus galloprovincialis. We found that the effects of ejaculate age on multivariate sperm motility traits and total sperm motility were altered by FRF, and that longer-lived sperm exhibit stronger, likely more advantageous, responses to FRF after periods of ageing. We also detected significant among-male variation in the relationship between sperm motility traits and ejaculate age; notably, these patterns were only revealed when sperm encountered FRF. Collectively these findings underscore the importance of considering female reproductive physiology when interpreting ageing-related declines in sperm motility, as doing so may expose importance sources of variation in sperm phenotypic plasticity among males and environments.

A Pilot, Time-Series Investigation of Depression, Anxiety, and Eating Disorder Symptoms in Adults Experiencing Major Depressive Symptoms: The Need for Eating Disorder Assessment and Research in Depression.

Major Depressive Disorder (MDD) is a prevalent psychiatric disorder impacting 10-16% of Americans in their lifetime. Approximately 60% of individuals with MDD have comorbid anxiety disorders. Additionally, although scarce research has examined eating disorders (EDs) in depression, a bidirectional association exists between ED and MDD symptoms. The current pilot study (N = 31 individuals with moderate to severe depression) modeled networks of depressive, anxiety, and ED symptoms using intensive time-series data. This study also tested if temporal central symptoms predicted six-month clinical outcomes. The most central symptoms were guilt, self-dislike, lack of energy, and difficulty concentrating. Several anxiety and ED symptoms were also central, including physical anxiety, social anxiety, body dissatisfaction, and desire for thinness. The central symptom crying predicted six-month depression with a medium effect size. These findings suggest anxiety and ED symptoms may influence the day-to-day course of depression in some individuals with comorbid diagnoses, but predictors of symptoms across hours may differ from predictors across longer time scales (i.e., months). Time scale should be considered when conducting and interpreting research on MDD. Research, assessment, and treatment for MDD should continue to explore transdiagnostic approaches including anxiety and ED symptoms to optimize care for individuals with complex presentations.

Binge Eating, Purging, and Restriction Symptoms: Increasing Accuracy of Prediction Using Machine Learning.

Eating disorders are severe mental illnesses characterized by the hallmark behaviors of binge eating, restriction, and purging. These disordered eating behaviors carry extreme impairment and medical complications, regardless of eating disorder diagnosis. Despite the importance of these disordered behaviors to every eating disorder diagnosis, our current models are not able to accurately predict behavior occurrence. The current study utilized machine learning to develop longitudinal predictive models of binge eating, purging, and restriction in an eating disorder sample (N = 60) using real-time intensive longitudinal data. Participants completed four daily assessments of eating disorder symptoms and emotions for 25 days on a smartphone (total data points per participant = 100). Using data, we were able to compute highly accurate prediction models for binge eating, restriction, and purging (.76-.96 accuracy). The ability to accurately predict the occurrence of binge eating, restriction, and purging has crucial implications for the development of preventative interventions for the eating disorders. Machine learning models may be able to accurately predict onset of problematic psychiatric behaviors leading to preventative interventions designed to disrupt engagement in such behaviors.

Corrigendum: Modification of plant cell walls with hydroxycinnamic acids by BAHD acyltransferases.

[This corrects the article DOI: 10.3389/fpls.2022.1088879.].

Personalizing eating disorder treatment using idiographic models: An open series trial.

OBJECTIVE: Treatments for adults with eating disorders (EDs) only work in about 50% of individuals, and for some diagnoses (e.g., anorexia nervosa; atypical anorexia nervosa), there are no existing evidence-based treatments. Part of the reason that treatments may only work in a subset of individuals is because of the high heterogeneity present in the EDs, even within diagnoses. Manualized treatments delivered in a standard format may not always address the most relevant symptoms for a specific individual. METHOD: The current open series trial recruited participants with transdiagnostic ED diagnoses (N = 79) to investigate the feasibility, acceptability, and initial clinical efficacy of a 10-session network-informed personalized treatment for eating disorders. This treatment uses idiographic (i.e., one-person) network models of ecological momentary assessment symptom data to match participants to evidence-based modules of treatment. RESULTS: We found that network-informed personalized treatment was highly feasible with low dropout rates, was rated as highly acceptable, and had strong initial clinical efficacy. ED severity decreased from pre- to posttreatment and at 1-year follow-up with a large effect size. ED cognitions, behaviors, clinical impairment, worry, and depression also decreased from pre- to posttreatment. CONCLUSIONS: These data suggest that network-informed personalized treatment has high acceptability and feasibility and can decrease ED and related pathology, possibly serving as a feasible alternative to existing treatments. Future randomized controlled trials comparing network-informed personalized treatment for ED to existing gold standard treatments are needed. Additionally, more research is needed on this type of personalized treatment both in the EDs, as well as in additional forms of psychopathology, such as depression. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Identification of phosphorylated tau protein interactors in progressive supranuclear palsy (PSP) reveals networks involved in protein degradation, stress response, cytoskeletal dynamics, metabolic processes, and neurotransmission.

Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease defined pathologically by the presence of insoluble phosphorylated-Tau (p-Tau) in neurons and glia. Identifying co-aggregating proteins within p-Tau inclusions may reveal important insights into processes affected by the aggregation of Tau. We used a proteomic approach, which combines antibody-mediated biotinylation and mass spectrometry (MS) to identify proteins proximal to p-Tau in PSP. Using this proof-of-concept workflow for identifying interacting proteins of interest, we characterized proteins proximal to p-Tau in PSP cases, identifying >84% of previously identified interaction partners of Tau and known modifiers of Tau aggregation, while 19 novel proteins not previously found associated with Tau were identified. Furthermore, our data also identified confidently assigned phosphorylation sites that have been previously reported on p-Tau. Additionally, using ingenuity pathway analysis (IPA) and human RNA-seq datasets, we identified proteins previously associated with neurological disorders and pathways involved in protein degradation, stress responses, cytoskeletal dynamics, metabolism, and neurotransmission. Together, our study demonstrates the utility of biotinylation by antibody recognition (BAR) approach to answer a fundamental question to rapidly identify proteins in proximity to p-Tau from post-mortem tissue. The application of this workflow opens up the opportunity to identify novel protein targets to give us insight into the biological process at the onset and progression of tauopathies.

The downside of being openminded: The positive relation between openness to experience and nonsuicidal self-injury.

BACKGROUND: Sensation seeking and openness are two distinct, but related, individual differences that lead individuals to seek out intense sensations. As a result, these traits may also predispose individuals toward engaging in non-suicidal self-injury (NSSI); however, to date, no models have examined the relation between openness and NSSI after accounting for the influence of sensation. METHOD: The goals of this study were to (1) examine the relation between openness and NSSI while accounting for sensation seeking in a sample of racially diverse undergraduates (N = 340) and (2) conduct a meta-analysis of the existing research on the association between NSSI and openness. RESULTS: A negative binomial regression model demonstrated a significant positive association between NSSI and openness when accounting for sensation seeking; however, NSSI was not significantly related to sensation seeking. Moreover, multivariate meta-analysis with robust variance revealed a small, but significant, association between NSSI and openness across 15 studies. CONCLUSION: Together, these results suggest a positive association between openness and NSSI, highlighting an area for future research in what role openness to experience might play in the development of NSSI.

Identifying Central Symptoms and Bridge Pathways Between Autism Spectrum Disorder Traits and Suicidality Within an Active Duty Sample.

OBJECTIVE: This study employed network analysis to characterize central autism spectrum disorder (ASD) traits and suicide symptoms within an active duty military sample as well as to identify symptoms that may bridge between ASD traits and suicidality (i.e., suicidal ideation and behaviors). METHOD: Participants were active duty U.S. military service members (N = 287). Autism spectrum traits, suicidality, depression, and suicide related constructs were assessed online via self-report. RESULTS: Within the combined ASD trait-suicidality network, suicide rumination, suicide behaviors, and depression had the highest strength centrality. The most central bridge symptoms between ASD and suicidality were thwarted belongingness, social skills deficits, and depressive symptoms. CONCLUSIONS: Social skills deficits and thwarted belongingness may function as a meaningful bridge between ASD symptoms and suicidality within active duty members. Individuals with ASD symptoms who additionally present with high levels of thwarted belongingness and/or considerable social skills deficits may be at increased risk for suicidality.HIGHLIGHTSWithin an ASD-suicidality network, social skills deficits, low belonging, and depression had the greatest bridge strength.Although low belonging emerged as a bridge symptom, perceived burdensomeness did not.Suicide rumination, suicide behaviors, and depression were the most central symptom in an ASD-suicidality network.Symptoms related to social skills deficits may connect ASD traits and suicidality.

Complex polyploid and hybrid species in an apomictic and sexual tropical forage grass group: genomic composition and evolution in Urochloa (Brachiaria) species.

BACKGROUND AND AIMS: Diploid and polyploid Urochloa (including Brachiaria, Panicum and Megathyrsus species) C4 tropical forage grasses originating from Africa are important for food security and the environment, often being planted in marginal lands worldwide. We aimed to characterize the nature of their genomes, the repetitive DNA and the genome composition of polyploids, leading to a model of the evolutionary pathways within the group including many apomictic species. METHODS: Some 362 forage grass accessions from international germplasm collections were studied, and ploidy was determined using an optimized flow cytometry method. Whole-genome survey sequencing and molecular cytogenetic analysis were used to identify chromosomes and genomes in Urochloa accessions belonging to the 'brizantha' and 'humidicola' agamic complexes and U. maxima. KEY RESULTS: Genome structures are complex and variable, with multiple ploidies and genome compositions within the species, and no clear geographical patterns. Sequence analysis of nine diploid and polyploid accessions enabled identification of abundant genome-specific repetitive DNA motifs. In situ hybridization with a combination of repetitive DNA and genomic DNA probes identified evolutionary divergence and allowed us to discriminate the different genomes present in polyploids. CONCLUSIONS: We suggest a new coherent nomenclature for the genomes present. We develop a model of evolution at the whole-genome level in diploid and polyploid accessions showing processes of grass evolution. We support the retention of narrow species concepts for Urochloa brizantha, U. decumbens and U. ruziziensis, and do not consider diploids and polyploids of single species as cytotypes. The results and model will be valuable in making rational choices of parents for new hybrids, assist in use of the germplasm for breeding and selection of Urochloa with improved sustainability and agronomic potential, and assist in measuring and conserving biodiversity in grasslands.

Weight status is associated with clinical characteristics among individuals with bulimia nervosa.

Recent studies have found increasing rates of overweight and obesity in bulimia nervosa (BN). However, the relationships between body mass index (BMI) and BN symptoms and other clinically relevant constructs are unknown. Participants (N = 152 adults with BN) were assigned to three groups by BMI: group with no overweight or obesity (NOW-BN; BMI <25; N = 32), group with overweight (OW-BN; BMI ≥25 and <30; N = 66), and group with obesity (O-BN; BMI ≥30; N = 54). We compared the groups on demographics, diet and weight histories, body esteem, BN symptoms, and depression using chi square, analysis of variance, analysis of covariance, and Poisson regression models. The O-BN group was older (d = 0.57) and OW-BN and O-BN groups had greater proportions of race/ethnic minorities than NOW-BN group. The O-BN group was significantly younger at first diet (d = 0.41) and demonstrated significantly higher cognitive dietary restraint (d = 0.31). Compared to NOW-BN, O-BN participants had lower incidence of objective binge eating (incidence rate ratio [IRR] = 4.86) and driven exercise (IRR = 7.13), and greater incidence of vomiting (IRR = 9.30), laxative misuse (IRR = 4.01), and diuretic misuse (d = 2.08). O-BN participants also experienced higher shape (d = 0.41) and weight (d = 0.42) concerns than NOW-BN and OW-BN, although NOW-BN experienced higher shape (d = 0.44) and weight (d = 0.39) concerns than OW-BN. Groups did not differ on depression scores. These results were replicated when examining BMI as a continuous predictor across the full sample, with the exception of objective binge eating and driven exercise, which were not significantly associated with BMI. Individuals with BN and comorbid obesity have distinct clinical characteristics. Existing interventions may need to be adapted to meet clinical needs of these individuals.

Uniaxial strain tuning of organic molecule single photon sources.

Organic fluorophores are excellent single photon sources, combining high brightness, lifetime-limited linewidths and useful emission wavelengths. A key factor in their performance as photon emitters is their dynamic frequency tunability, which can be used to render the emission from multiple molecules indistinguishable. In this work we demonstrate dynamic tuning of dibenzoterrylene molecules embedded in anthracene crystals through the application of uniaxial strain fields. By bending a piezoelectric strip in two opposite directions in linear steps, we impose an escalating compressive or tensile strain on the molecular crystals, resulting in two opposite dynamic detunings of the dopant dibenzoterrylene emission wavelength. To validate that the tuning mechanism is strain, we performed a similar measurement using an identical strip that was depolarised by annealing in which the tuning was absent. Finally, we simulated the effect of strain on the dopant dibenzoterrylene emission wavelength by combining molecular dynamics and density functional theory techniques to determine the strain tuning rate which matched well with that found experimentally.

Microglia morphophysiological diversity and its implications for the CNS.

Microglia are mononuclear phagocytes of mesodermal origin that migrate to the central nervous system (CNS) during the early stages of embryonic development. After colonizing the CNS, they proliferate and remain able to self-renew throughout life, maintaining the number of microglia around 5-12% of the cells in the CNS parenchyma. They are considered to play key roles in development, homeostasis and innate immunity of the CNS. Microglia are exceptionally diverse in their morphological characteristics, actively modifying the shape of their processes and soma in response to different stimuli. This broad morphological spectrum of microglia responses is considered to be closely correlated to their diverse range of functions in health and disease. However, the morphophysiological attributes of microglia, and the structural and functional features of microglia-neuron interactions, remain largely unknown. Here, we assess the current knowledge of the diverse microglial morphologies, with a focus on the correlation between microglial shape and function. We also outline some of the current challenges, opportunities, and future directions that will help us to tackle unanswered questions about microglia, and to continue unravelling the mysteries of microglia, in all its shapes.