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1.
Nature ; 575(7783): 494-499, 2019 11.
Article in English | MEDLINE | ID: mdl-31723263

ABSTRACT

In rapidly adapting asexual populations, including many microbial pathogens and viruses, numerous mutant lineages often compete for dominance within the population1-5. These complex evolutionary dynamics determine the outcomes of adaptation, but have been difficult to observe directly. Previous studies have used whole-genome sequencing to follow molecular adaptation6-10; however, these methods have limited resolution in microbial populations. Here we introduce a renewable barcoding system to observe evolutionary dynamics at high resolution in laboratory budding yeast. We find nested patterns of interference and hitchhiking even at low frequencies. These events are driven by the continuous appearance of new mutations that modify the fates of existing lineages before they reach substantial frequencies. We observe how the distribution of fitness within the population changes over time, and find a travelling wave of adaptation that has been predicted by theory11-17. We show that clonal competition creates a dynamical 'rich-get-richer' effect: fitness advantages that are acquired early in evolution drive clonal expansions, which increase the chances of acquiring future mutations. However, less-fit lineages also routinely leapfrog over strains of higher fitness. Our results demonstrate that this combination of factors, which is not accounted for in existing models of evolutionary dynamics, is critical in determining the rate, predictability and molecular basis of adaptation.


Subject(s)
Adaptation, Physiological/genetics , Cell Lineage , Evolution, Molecular , Laboratories , Mutation , Saccharomyces cerevisiae/cytology , Saccharomyces cerevisiae/genetics , Clone Cells/cytology , Clone Cells/metabolism , DNA Barcoding, Taxonomic , Genetic Fitness/genetics
2.
Hum Brain Mapp ; 44(2): 535-548, 2023 02 01.
Article in English | MEDLINE | ID: mdl-36177528

ABSTRACT

Sex differences in white matter microstructure have been robustly demonstrated in the adult brain using both conventional and advanced diffusion-weighted magnetic resonance imaging approaches. However, sex differences in white matter microstructure prior to adulthood remain poorly understood; previous developmental work focused on conventional microstructure metrics and yielded mixed results. Here, we rigorously characterized sex differences in white matter microstructure among over 6000 children from the Adolescent Brain Cognitive Development study who were between 9 and 10 years old. Microstructure was quantified using both the conventional model-diffusion tensor imaging (DTI)-and an advanced model, restriction spectrum imaging (RSI). DTI metrics included fractional anisotropy (FA) and mean, axial, and radial diffusivity (MD, AD, RD). RSI metrics included normalized isotropic, directional, and total intracellular diffusion (N0, ND, NT). We found significant and replicable sex differences in DTI or RSI microstructure metrics in every white matter region examined across the brain. Sex differences in FA were regionally specific. Across white matter regions, boys exhibited greater MD, AD, and RD than girls, on average. Girls displayed increased N0, ND, and NT compared to boys, on average, suggesting greater cell and neurite density in girls. Together, these robust and replicable findings provide an important foundation for understanding sex differences in health and disease.


Subject(s)
White Matter , Adult , Adolescent , Humans , Child , Male , Female , White Matter/pathology , Diffusion Tensor Imaging/methods , Sex Characteristics , Brain/pathology , Diffusion Magnetic Resonance Imaging , Anisotropy
3.
Brain ; 145(1): 378-387, 2022 03 29.
Article in English | MEDLINE | ID: mdl-34050743

ABSTRACT

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Adolescent , Autism Spectrum Disorder/genetics , Autistic Disorder/genetics , Brain , Brain Mapping , Child , Female , Humans , Magnetic Resonance Imaging , Male
4.
Aust N Z J Psychiatry ; 56(6): 695-708, 2022 06.
Article in English | MEDLINE | ID: mdl-34231423

ABSTRACT

OBJECTIVE: This study aimed to evaluate whether the Therapist-assisted Online Parenting Strategies programme increased parenting behaviours known to be supportive of adolescents experiencing anxiety and/or depression. Secondary parenting outcomes of parental self-efficacy, parental accommodation, carer burden, parent-adolescent attachment, family functioning and parent distress were also examined, along with adolescent outcomes of anxiety and depression symptoms, suicidal ideation and sleep. METHOD: Seventy-one parents (94.4% females) and their adolescents (73.2% females) aged 12-18 years (Mean = 15.02, SD = 1.56) being treated for depression and/or anxiety in Australia were recruited into a single-arm double-baseline open-label trial. Parents received Therapist-assisted Online Parenting Strategies, which comprised up to nine web-based modules each supplemented with coaching sessions via videoconferencing. Outcomes were analysed using latent growth curve modelling to determine if changes to outcomes at post-intervention (4 month post-second baseline) exceeded changes between two baselines measured 1 month apart. RESULTS: Sixty-five parents (91.6%) completed at least one module of the online parenting intervention and on average received nine coaching sessions (SD = 2). Parenting behaviours targeted by Therapist-assisted Online Parenting Strategies improved at post-intervention (Cohen's d = 1.16, 95% confidence interval [0.78, 1.51]). Parent-reported parental self-efficacy and parent-adolescent attachment increased (Cohen's d = 1.44 [1.05, 1.82] and 0.39 [0.05, 0.74], respectively), while impairments to family functioning and parent distress decreased (Cohen's d = -0.51 [-0.86, -0.16] and -0.84 [-1.23, -0.44], respectively). Changes to adolescent anxiety, depression and sleep were not significant. CONCLUSION: The Therapist-assisted Online Parenting Strategies intervention improved self-reported parenting behaviours, parental self-efficacy, parent levels of distress, parent-adolescent attachment, and family functioning in parents with adolescents being treated for anxiety and/or depression. However, significant changes in adolescent mental health and sleep outcomes at post-intervention were not observed. The usefulness of a therapist-supported online parenting programme in addressing a service gap for parents seeking professional help is indicated. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Number (ACTRN) 12618000290291, prospectively registered on 26 February 2018; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368031.


Subject(s)
Depression , Parenting , Adolescent , Anxiety/psychology , Anxiety/therapy , Australia , Child , Depression/psychology , Depression/therapy , Female , Humans , Male , Parenting/psychology , Parents/psychology
5.
Infect Immun ; 89(12): e0022521, 2021 11 16.
Article in English | MEDLINE | ID: mdl-34460289

ABSTRACT

Heligmosomoides polygyrus is a helminth which naturally infects mice and is widely used as a laboratory model of chronic small intestinal helminth infection. While it is known that infection with H. polygyrus alters the composition of the host's bacterial microbiota, the functional implications of this alteration are unclear. We investigated the impact of H. polygyrus infection on short-chain fatty acid (SCFA) levels in the mouse intestine and sera. We found that helminth infection resulted in significantly upregulated levels of the branched SCFA isovaleric acid, exclusively in the proximal small intestine, which is the site of H. polygyrus colonization. We next set out to test the hypothesis that elevating local levels of isovaleric acid was a strategy used by H. polygyrus to promote its own fitness within the mammalian host. To test this, we supplemented the drinking water of mice with isovalerate during H. polygyrus infection and examined whether this affected helminth fecundity or chronicity. We did not find that isovaleric acid supplementation affected helminth chronicity; however, we found that it did promote helminth fecundity, as measured by helminth egg output in the feces of mice. Through antibiotic treatment of helminth-infected mice, we found that the bacterial microbiota was required in order to support elevated levels of isovaleric acid in the proximal small intestine during helminth infection. Overall, our data reveal that during H. polygyrus infection there is a microbiota-dependent localized increase in the production of isovaleric acid in the proximal small intestine and that this supports helminth fecundity in the murine host.


Subject(s)
Fatty Acids, Volatile/metabolism , Host-Parasite Interactions , Intestinal Mucosa/metabolism , Intestinal Mucosa/parasitology , Nematospiroides dubius/physiology , Strongylida Infections/metabolism , Strongylida Infections/parasitology , Animals , Disease Models, Animal , Lipid Metabolism , Mice
6.
Cereb Cortex ; 30(9): 5107-5120, 2020 07 30.
Article in English | MEDLINE | ID: mdl-32350530

ABSTRACT

Autism spectrum disorder (ASD) is associated with the altered functional connectivity of 3 neurocognitive networks that are hypothesized to be central to the symptomatology of ASD: the salience network (SN), default mode network (DMN), and central executive network (CEN). Due to the considerably higher prevalence of ASD in males, however, previous studies examining these networks in ASD have used primarily male samples. It is thus unknown how these networks may be differentially impacted among females with ASD compared to males with ASD, and how such differences may compare to those observed in neurotypical individuals. Here, we investigated the functional connectivity of the SN, DMN, and CEN in a large, well-matched sample of girls and boys with and without ASD (169 youth, ages 8-17). Girls with ASD displayed greater functional connectivity between the DMN and CEN than boys with ASD, whereas typically developing girls and boys differed in SN functional connectivity only. Together, these results demonstrate that youth with ASD exhibit altered sex differences in these networks relative to what is observed in typical development, and highlight the importance of considering sex-related biological factors and participant sex when characterizing the neural mechanisms underlying ASD.


Subject(s)
Autism Spectrum Disorder/physiopathology , Brain/physiopathology , Neural Pathways/physiopathology , Sex Characteristics , Adolescent , Brain Mapping/methods , Child , Female , Humans , Magnetic Resonance Imaging , Male
7.
PLoS Genet ; 14(11): e1007701, 2018 11.
Article in English | MEDLINE | ID: mdl-30383767

ABSTRACT

Breast cancer susceptibility gene 1 (BRCA1) and binding partner BRCA1-associated RING domain protein 1 (BARD1) form an essential E3 ubiquitin ligase important for DNA damage repair and homologous recombination. The Caenorhabditis elegans orthologs, BRC-1 and BRD-1, also function in DNA damage repair, homologous recombination, as well as in meiosis. Using functional GFP fusions we show that in mitotically-dividing germ cells BRC-1 and BRD-1 are nucleoplasmic with enrichment at foci that partially overlap with the recombinase RAD-51. Co-localization with RAD-51 is enhanced under replication stress. As cells enter meiosis, BRC-1-BRD-1 remains nucleoplasmic and in foci, and beginning in mid-pachytene the complex co-localizes with the synaptonemal complex. Following establishment of the single asymmetrically positioned crossover on each chromosome pair, BRC-1-BRD-1 concentrates to the short arm of the bivalent. Localization dependencies reveal that BRC-1 and BRD-1 are interdependent and the complex fails to properly localize in both meiotic recombination and chromosome synapsis mutants. Consistent with a role for BRC-1-BRD-1 in meiotic recombination in the context of the synaptonemal complex, inactivation of BRC-1 or BRD-1 enhances the embryonic lethality of mutants defective in chromosome synapsis. Our data suggest that under meiotic dysfunction, BRC-1-BRD-1 stabilizes the RAD-51 filament and alters the recombination landscape; these two functions can be genetically separated from BRC-1-BRD-1's role in the DNA damage response. Together, we propose that BRC-1-BRD-1 serves a checkpoint function at the synaptonemal complex where it monitors and modulates meiotic recombination.


Subject(s)
BRCA1 Protein/metabolism , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Meiosis/genetics , Recombination, Genetic , Synaptonemal Complex/metabolism , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Alleles , Animals , BRCA1 Protein/genetics , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , DNA Replication , Embryo, Nonmammalian , Genes, Reporter , Germ Cells , Protein Transport , Rad51 Recombinase/genetics , Rad51 Recombinase/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Tumor Suppressor Proteins/genetics , Ubiquitin-Protein Ligases/genetics
8.
J Res Adolesc ; 30(1): 249-265, 2020 03.
Article in English | MEDLINE | ID: mdl-31246378

ABSTRACT

Burgeoning research suggests that parents can reduce the risk of anxiety and depression in their adolescents and that parental self-efficacy (PSE) may be related to parental risk and protective factors for these disorders. As there are currently no measures available to assess PSE in relation to parenting behaviors that may reduce adolescent risk for depression and anxiety, we developed and validated a measure of PSE, the Parental Self-Efficacy Scale (PSES). Using a sample of 359 parents and 332 adolescents (aged 12-15), the PSES was found to have high reliability, confirmatory factor analysis supported its validity, and most of the hypothesized relationships between the PSES and other measures of parenting practices and adolescent depressive and anxiety symptoms were supported.


Subject(s)
Anxiety/prevention & control , Depression/prevention & control , Parenting/psychology , Self Efficacy , Adolescent , Child , Female , Humans , Male , Parent-Child Relations , Protective Factors , Reproducibility of Results , Surveys and Questionnaires/standards
10.
J Med Internet Res ; 21(8): e13628, 2019 08 15.
Article in English | MEDLINE | ID: mdl-31418422

ABSTRACT

BACKGROUND: Prevention of depression and anxiety disorders early in life is a global health priority. Evidence on risk and protective factors for youth internalizing disorders indicates that the family represents a strategic setting to target preventive efforts. Despite this evidence base, there is a lack of accessible, cost-effective preventive programs for parents of adolescents. To address this gap, we recently developed the Partners in Parenting (PiP) program-an individually tailored Web-based parenting program targeting evidence-based parenting risk and protective factors for adolescent depression and anxiety disorders. We previously reported the postintervention outcomes of a single-blinded parallel-group superiority randomized controlled trial (RCT) in which PiP was found to significantly improve self-reported parenting compared with an active-control condition (educational factsheets). OBJECTIVE: This study aimed to evaluate the effects of the PiP program on parenting risk and protective factors and symptoms of adolescent depression and anxiety using data from the final assessment time point (12-month follow-up) of this RCT. METHODS: Parents (n=359) and adolescents (n=332) were recruited primarily from secondary schools and completed Web-based assessments of parenting and adolescent depression and anxiety symptoms at baseline, postintervention (3 months later), and 12-month follow-up (317 parents, 287 adolescents). Parents in the PiP intervention condition received personalized feedback about their parenting and were recommended a series of up to 9 interactive modules. Control group parents received access to 5 educational factsheets about adolescent development and mental health. Both groups received a weekly 5-min phone call to encourage progress through their program. RESULTS: Intervention group parents completed an average of 73.7% of their intended program. For the primary outcome of parent-reported parenting, the intervention group showed significantly greater improvement from baseline to 12-month follow-up compared with controls, with a medium effect size (Cohen d=0.51; 95% CI 0.30 to 0.72). When transformed data were used, greater reduction in parent-reported adolescent depressive symptoms was observed in the intervention group (Cohen d=-0.21; 95% CI -0.42 to -0.01). Mediation analyses revealed that these effects were mediated by improvements in parenting (indirect effect b=-0.08; 95% CI -0.16 to -0.01). No other significant intervention effects were found for adolescent-reported parenting or adolescent depression or anxiety symptoms. Both groups showed significant reductions in anxiety (both reporters) and depressive (parent reported) symptoms. CONCLUSIONS: PiP improved self-reported parenting for up to 9 months postintervention, but its effects on adolescent symptoms were less conclusive, and parent-reported changes were not perceived by adolescents. Nonetheless, given its scalability, PiP may be a useful low-cost, sustainable program to empower parents of adolescents. TRIAL REGISTRATION: Australian Clinical Trials Registration Number (ACTRN): 12615000328572; http://www.anzctr.org.au/ACTRN12615000328572.aspx (Archived by WebCite at http://www.webcitation.org/6qgsZ3Aqj).


Subject(s)
Adolescent Behavior , Anxiety Disorders/prevention & control , Cognitive Behavioral Therapy , Depressive Disorder/prevention & control , Internet , Parenting , Psychometrics , Adolescent , Adult , Anxiety Disorders/psychology , Australia , Child , Depressive Disorder/psychology , Female , Humans , Male , Middle Aged , Surveys and Questionnaires , Treatment Outcome
11.
J Trop Pediatr ; 65(4): 380-388, 2019 08 01.
Article in English | MEDLINE | ID: mdl-30476332

ABSTRACT

AIM: The aim of this article was to determine off-label (OL) use in paediatric ambulatory clinics in a South African central hospital. PATIENTS AND METHODS: OL medicine events were documented in three paediatric clinics (general, highly specialized and dedicated HIV paediatric clinics) at Tygerberg Hospital, South Africa, and analysed according to South African medicine registration information. RESULTS: There were 2167 medicine events for 658 children. Mean age was 5.6 years (interquartile range 1.8-8.8). There were 123 OL medicine events (6%). Extemporaneous OL use was most common (n = 58, 47%), followed by weight (n = 45, 37%) and lack of paediatric data (n = 38, 31%). Of note was OL use for weight for general paediatrics (n = 32, 78%, p < 0.001), lack of appropriate paediatric data for highly specialized paediatrics (n = 26, 61%, p = 0.004) and extemporaneous use for HIV-infected children (n = 34, 87%, p < 0.001), with significant less OL use for HIV-infected children (p = 0.009). CONCLUSIONS: Of note is significant extemporaneous OL use in HIV-infected children.


Subject(s)
Drug Prescriptions/statistics & numerical data , Off-Label Use/statistics & numerical data , Practice Patterns, Physicians'/statistics & numerical data , Adolescent , Ambulatory Care Facilities , Child , Child, Preschool , Cohort Studies , Female , HIV Infections/drug therapy , Hospital Units , Humans , Infant , Male , Prospective Studies
12.
Australas Psychiatry ; 27(1): 56-59, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30226078

ABSTRACT

OBJECTIVES:: A lack of compassion for oneself, or harsh self-criticism, is associated with a range of psychiatric disorders including borderline personality disorder (BPD). Personal recovery in the context of a mental illness such as BPD involves building a life that is subjectively meaningful and satisfying. Limited self-compassion or harsh self-criticism may be an impediment to recovery from BPD. The association between self-compassion and recovery and self- criticism and recovery were examined. METHOD:: Nineteen individuals diagnosed with BPD completed the Neff Self-Compassion Scale, the Forms of Self-Criticising/Attacking and Self-Reassuring Scale and the Recovery Assessment Scale at a single time point. RESULTS:: There was a strong positive correlation between self-compassion and recovery ( r = 0.75) and a strong negative correlation ( rho = -0.67) between self- criticism and recovery. CONCLUSIONS:: Although preliminary in nature, these results suggest the importance of fostering self-compassion and working to address self-criticism within clinical interventions supporting recovery from BPD.


Subject(s)
Borderline Personality Disorder/physiopathology , Borderline Personality Disorder/rehabilitation , Empathy/physiology , Outcome Assessment, Health Care , Self Concept , Adult , Female , Humans , Male , Middle Aged , Young Adult
13.
J Pathol ; 243(1): 26-36, 2017 09.
Article in English | MEDLINE | ID: mdl-28678427

ABSTRACT

Endometrial epithelium is the presumed tissue of origin for both eutopic and endometriosis-derived clear cell and endometrioid carcinomas. We had previously hypothesized that the morphological, biological and clinical differences between these carcinomas are due to histotype-specific mutations. Although some mutations and genomic landscape features are more likely to be found in one of these histotypes, we were not able to identify a single class of mutations that was exclusively present in one histotype and not the other. This lack of genomic differences led us to an alternative hypothesis that these cancers could arise from distinct cells of origin within endometrial tissue, and that it is the cellular context that accounts for their differences. In a proteomic screen, we identified cystathionine γ-lyase (CTH) as a marker for clear cell carcinoma, as it is expressed at high levels in clear cell carcinomas of the ovary and endometrium. In the current study, we analysed normal Müllerian tissues, and found that CTH is expressed in ciliated cells of endometrium (both eutopic endometrium and endometriosis) and fallopian tubes. We then demonstrated that other ciliated cell markers are expressed in clear cell carcinomas, whereas endometrial secretory cell markers are expressed in endometrioid carcinomas. The same differential staining of secretory and ciliated cells was demonstrable in a three-dimensional organoid culture system, in which stem cells were stimulated to differentiate into an admixture of secretory and ciliated cells. These data suggest that endometrioid carcinomas are derived from cells of the secretory cell lineage, whereas clear cell carcinomas are derived from, or have similarities to, cells of the ciliated cell lineage. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Endometrioid/metabolism , Cell Differentiation , Cell Lineage , Cystathionine gamma-Lyase/metabolism , Endometrial Neoplasms/metabolism , Epithelial Cells/metabolism , Stem Cells/metabolism , Carcinoma, Endometrioid/pathology , Cells, Cultured , Cilia/metabolism , Cilia/pathology , Endometrial Neoplasms/pathology , Epithelial Cells/pathology , Female , Fluorescent Antibody Technique , Humans , Immunophenotyping/methods , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Stem Cells/pathology , Tissue Array Analysis
14.
Compr Psychiatry ; 84: 68-74, 2018 07.
Article in English | MEDLINE | ID: mdl-29694935

ABSTRACT

BACKGROUND: Childhood trauma has been linked to the presence of delusions and hallucinations in psychosis, although the mechanisms underlying this relationship require elucidation. Dissociation, characterized by disruptions to the integrative functioning of several core mental domains, has emerged as a potential mechanism. There is a paucity of research using a clinician-rated measure of dissociation to test the indirect effect of dissociation on the relationship between childhood trauma and psychotic symptoms. This study aimed to investigate whether dissociation mediated both the relationships between childhood trauma and hallucinations, and childhood trauma and delusions utilizing a clinician-administered measure of dissociation, namely the Structured Clinical Interview for DSM-IV Dissociative Disorders - Revised (SCID-D-R). METHOD: Sixty-six first-episode psychosis (FEP) participants completed a research interview and questionnaires. Information about experiences of childhood trauma, psychosis, dissociation, general psychopathology and demographics were collected. RESULTS: When using the SCID-D-R, childhood trauma positively correlated with dissociation. Further, dissociation mediated the relationship between childhood trauma and delusions. Contrary to previous findings, we found no relationship between dissociation and hallucinations and no mediating effect of dissociation on the association between childhood trauma and hallucinations. The results of the SCID-D-R differed significantly from those of the Dissociative Experiences Scale-II (DES-II) which were consistent with previous research. CONCLUSIONS: Our findings are the first to use a clinician-rated measure to test the mediating effect of dissociation on the relationship between childhood trauma and positive symptoms (i.e., hallucinations and delusions). Given the discrepancies in results between the SCID-D-R and DES-II, how dissociation is measured in future research is an important consideration. The results add to a body of work that increasingly recognizes the importance of dissociative symptoms on the relationship between childhood trauma and psychosis. The results suggest that dissociative symptoms should be part of routine assessment in those with a history of trauma and present to FEP services.


Subject(s)
Adverse Childhood Experiences/trends , Delusions/psychology , Dissociative Disorders/psychology , Hallucinations/psychology , Psychotic Disorders/psychology , Adolescent , Adult , Child , Cross-Sectional Studies , Delusions/diagnosis , Delusions/epidemiology , Dissociative Disorders/diagnosis , Dissociative Disorders/epidemiology , Female , Hallucinations/diagnosis , Hallucinations/epidemiology , Humans , Male , Psychotic Disorders/diagnosis , Psychotic Disorders/epidemiology , Retrospective Studies , Surveys and Questionnaires , Victoria/epidemiology , Young Adult
15.
PLoS Genet ; 11(4): e1005150, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25898113

ABSTRACT

Errors in replication or segregation lead to DNA damage, mutations, and aneuploidies. Consequently, cells monitor these events and delay progression through the cell cycle so repair precedes division. The DNA damage response (DDR), which monitors DNA integrity, and the spindle assembly checkpoint (SAC), which responds to defects in spindle attachment/tension during metaphase of mitosis and meiosis, are critical for preventing genome instability. Here we show that the DDR and SAC function together throughout the cell cycle to ensure genome integrity in C. elegans germ cells. Metaphase defects result in enrichment of SAC and DDR components to chromatin, and both SAC and DDR are required for metaphase delays. During persistent metaphase arrest following establishment of bi-oriented chromosomes, stability of the metaphase plate is compromised in the absence of DDR kinases ATR or CHK1 or SAC components, MAD1/MAD2, suggesting SAC functions in metaphase beyond its interactions with APC activator CDC20. In response to DNA damage, MAD2 and the histone variant CENPA become enriched at the nuclear periphery in a DDR-dependent manner. Further, depletion of either MAD1 or CENPA results in loss of peripherally associated damaged DNA. In contrast to a SAC-insensitive CDC20 mutant, germ cells deficient for SAC or CENPA cannot efficiently repair DNA damage, suggesting that SAC mediates DNA repair through CENPA interactions with the nuclear periphery. We also show that replication perturbations result in relocalization of MAD1/MAD2 in human cells, suggesting that the role of SAC in DNA repair is conserved.


Subject(s)
DNA Damage/genetics , Genomic Instability/genetics , M Phase Cell Cycle Checkpoints/genetics , Mad2 Proteins/genetics , Animals , Autoantigens/genetics , Caenorhabditis elegans/genetics , Centromere Protein A , Chromatin/genetics , Chromosomal Proteins, Non-Histone/genetics , Chromosomes/genetics , DNA Repair/genetics , Humans , Metaphase/genetics
16.
J Med Internet Res ; 20(1): e17, 2018 01 19.
Article in English | MEDLINE | ID: mdl-29351895

ABSTRACT

BACKGROUND: Depression and anxiety disorders in young people are a global health concern. Parents have an important role in reducing the risk of these disorders, but cost-effective, evidence-based interventions for parents that can be widely disseminated are lacking. OBJECTIVE: This study aimed to examine the postintervention effects of the Partners in Parenting (PiP) program on parenting risk and protective factors for adolescent depression and anxiety, and on adolescent depression and anxiety symptoms. METHODS: A two-arm randomized controlled trial was conducted with 359 parent-adolescent dyads, recruited primarily through schools across Australia. Parents and adolescents were assessed at baseline and 3 months later (postintervention). Parents in the intervention condition received PiP, a tailored Web-based parenting intervention designed following Persuasive Systems Design (PSD) principles to target parenting factors associated with adolescents' risk for depression and anxiety problems. PiP comprises a tailored feedback report highlighting each parent's strengths and areas for improvement, followed by a set of interactive modules (up to nine) that is specifically recommended for the parent based on individually identified areas for improvement. Parents in the active-control condition received a standardized package of five Web-based factsheets about adolescent development and well-being. Parents in both conditions received a 5-min weekly call to encourage progress through their allocated program to completion. Both programs were delivered weekly via the trial website. The primary outcome measure at postintervention was parent-reported changes in parenting risk and protective factors, which were measured using the Parenting to Reduce Adolescent Depression and Anxiety Scale (PRADAS). Secondary outcome measures were the adolescent-report PRADAS, the parent- and child-report Short Mood and Feelings Questionnaire (depressive symptoms), and parent- and child-report Spence Children's Anxiety Scale (anxiety symptoms). RESULTS: Parents in the intervention condition completed a mean of 73.7% of their intended personalized PiP program. A total of 318 parents (88.6%, 318/359) and 308 adolescents (92.8%, 308/332) completed the postintervention assessment. Attrition was handled using mixed model of repeated measures analysis of variance. As hypothesized, we found a significant condition-by-time interaction on the PRADAS, with a medium effect size, Cohen d=0.57, 95% CI 0.34-0.79. No significant differences between conditions were found at postintervention on any of the secondary outcome measures, with adolescent depressive (parent-report only) and anxiety (both parent- and adolescent-report) symptoms decreasing significantly from baseline to postintervention in both conditions. CONCLUSIONS: The fully automated PiP intervention showed promising short-term effects on parenting behaviors that are associated with adolescents' risk for depression and anxiety. Long-term follow-up is required to ascertain whether these effects translate into reduced adolescent depression and anxiety problems. The intervention may be useful as a low-cost universal public health program to increase parenting practices believed to benefit adolescents' mental health. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry: ACTRN12615000328572; https://www.anzctr.org.au/ Trial/Registration/TrialReview.aspx? id=368274 (Archived by WebCite at http://www.webcitation.org/6qgsZ3Aqj).


Subject(s)
Anxiety/psychology , Delivery of Health Care/methods , Depression/psychology , Internet/instrumentation , Parenting/psychology , Adolescent , Child , Female , Humans , Male , Middle Aged , Protective Factors , Surveys and Questionnaires
17.
J Med Internet Res ; 20(4): e148, 2018 04 26.
Article in English | MEDLINE | ID: mdl-29699964

ABSTRACT

BACKGROUND: Depression and anxiety disorders are significant contributors to burden of disease in young people, highlighting the need to focus preventive efforts early in life. Despite substantial evidence for the role of parents in the prevention of adolescent depression and anxiety disorders, there remains a need for translation of this evidence into preventive parenting interventions. To address this gap, we developed a single-session, Web-based, tailored psychoeducation intervention that aims to improve parenting practices known to influence the development of adolescent depression and anxiety disorders. OBJECTIVE: The aim of this study was to evaluate the short-term effects of the intervention on parenting risk and protective factors and symptoms of depression and anxiety in adolescent participants. METHODS: We conducted a single-blind, parallel group, superiority randomized controlled trial comparing the intervention with a 3-month waitlist control. The intervention is fully automated and consists of two components: (1) completion of an online self-assessment of current parenting practices against evidence-based parenting recommendations for the prevention of adolescent depression and anxiety disorders and (2) an individually tailored feedback report highlighting each parent's strengths and areas for improvement based on responses to the self-assessment. A community sample of 349 parents, together with 327 adolescents (aged 12-15 years), were randomized to either the intervention or waitlist control condition. Parents and adolescents completed online self-reported assessments of parenting and adolescent symptoms of depression and anxiety at baseline, 1-month (parent-report of parenting only), and 3-month follow-up. RESULTS: Compared with controls, intervention group parents showed significantly greater improvement in parenting risk and protective factors from baseline to 1-month and 3-month follow-up (F2,331.22=16.36, P<.001), with a small to medium effect size at 3-month follow-up (d=0.33). There were no significant effects of the intervention on adolescent-report of parenting or symptoms of depression or anxiety in the adolescents (all P>.05). CONCLUSIONS: Findings suggest that a single-session, individually tailored, Web-based parenting intervention can improve parenting factors that are known to influence the development of depression and anxiety in adolescents. However, our results do not support the effectiveness of the intervention in improving adolescent depression or anxiety symptoms in the short-term. Long-term studies are required to adequately assess the relationship between improving parenting factors and adolescent depression and anxiety outcomes. Nonetheless, this is a promising avenue for the translation of research into a low-cost, sustainable, universal prevention approach. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12615000247572; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12615000247572 (Archived by WebCite at http://www.webcitation.org/6v1ha19XG)


Subject(s)
Anxiety/prevention & control , Depression/prevention & control , Parenting/psychology , Parents/education , Adolescent , Anxiety/psychology , Child , Depression/psychology , Female , Humans , Internet , Male , Middle Aged , Parents/psychology
18.
Phys Rev Lett ; 116(23): 235301, 2016 Jun 10.
Article in English | MEDLINE | ID: mdl-27341242

ABSTRACT

We report on the site-resolved observation of characteristic states of the two-dimensional repulsive Fermi-Hubbard model, using ultracold ^{40}K atoms in an optical lattice. By varying the tunneling, interaction strength, and external confinement, we realize metallic, Mott-insulating, and band-insulating states. We directly measure the local moment, which quantifies the degree of on-site magnetization, as a function of temperature and chemical potential. Entropies per particle as low as 0.99(6)k_{B} indicate that nearest-neighbor antiferromagnetic correlations should be detectable using spin-sensitive imaging.

19.
J Clin Psychol ; 71(5): 439-50, 2015 May.
Article in English | MEDLINE | ID: mdl-25809713

ABSTRACT

Between-session interventions, or homework, are crucial to a range of psychological therapies, including cognitive behavior therapy (CBT). Therapeutic interventions often involve experiencing emotions and situations, or examining strongly held views about their problems, that clients can find distressing. Hence, the clinician faces a particular challenge in collaborating with the client to carry out these interventions between sessions. In this article, we convey how this process in CBT requires not only a consideration of the theoretically meaningful determinants of adherence behavior but also a sophisticated cognitive case conceptualization. Using case material, we illustrate the interplay between in-session design, planning, and review of between-session interventions and the conceptualization. We also include a distinction between generic elements of the therapeutic relationship and CBT-specific elements. The case material also attends to the person of the therapist, and his or her own cognitive and emotional reactions occurring throughout the process of discussing between-session interventions.


Subject(s)
Cognitive Behavioral Therapy/methods , Professional-Patient Relations , Adult , Concept Formation , Female , Humans
20.
Langmuir ; 30(39): 11746-52, 2014 Oct 07.
Article in English | MEDLINE | ID: mdl-24621350

ABSTRACT

A novel two-photon-fluorescent N,O-heteroatom-rich carbon nanomaterial has been synthesized and characterized. The new carbon nanoparticles were produced by hydrothermal conversion from a one-photon-fluorescent poly(4-vinylpyridine) precursor (P4VP). The carbonized particles (cP4VP dots) with nonuniform particle diameter (ranging from sub-6 to 20 nm with some aggregates up to 200 nm) exhibit strong fluorescence properties in different solvents and have also been investigated for applications in cell culture media. The cP4VP dots retain their intrinsic fluorescence in a cellular environment and exhibit an average excited-state lifetime of 2.0 ± 0.9 ns in the cell. The cP4VP dots enter HeLa cells and do not cause significant damage to outer cell membranes. They provide one-photon or two-photon fluorescent synthetic scaffolds for imaging applications and/or drug delivery.


Subject(s)
Carbon/chemistry , Fluorescent Dyes/chemistry , Microscopy, Fluorescence, Multiphoton , Nanoparticles/chemistry , Photons , Polyvinyls/chemistry , Temperature , Biological Transport , Fluorescent Dyes/metabolism , HeLa Cells , Humans , Polyvinyls/metabolism
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