Predictors of Depressive Symptoms in Autistic Youth-A Longitudinal Study From the Province of Ontario Neurodevelopmental Disorders (POND) Network: Prédicteurs des symptômes dépressifs chez les jeunes autistes-une étude longitudinale du Réseau des troubles neurodéveloppementaux de la province de l'Ontario (réseau POND).

OBJECTIVE: The objective of this study was to identify longitudinal predictors of depressive symptoms in autistic children and youth. METHODS: Participants were youth with a diagnosis of autism who were part of the Province of Ontario Neurodevelopmental Disorders Network longitudinal substudy. Depressive symptoms were assessed using the child behaviour checklist (CBCL) affective problems subscale. Univariate and multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between clinical and demographic characteristics at baseline (T1) and clinically elevated depressive symptoms (CEDS) approximately 4 years later (T2). RESULTS: The mean age of participants (n = 75) at T1 was 9.8 years (SD = 2.7) and at T2 was 14.1 years (SD = 2.8). A total of 37% and 35% of participants had CEDS at T1 and T2, respectively. Additionally, 24% of participants had CEDS at both T1 and T2. T1 characteristics associated with T2 CEDS were: loneliness (OR = 3.0, 95% CI, 1.1 to 8.8), self-harm (OR = 4.0, 95% CI, 1.1 to 16.9), suicidal ideation (OR = 3.9, 95% CI, 1.0 to 16.5), more social and adaptive skills (OR = 0.3, 95% CI, 0.1 to 0.9), elevated restricted and repetitive behaviours (OR = 3.8, 95% CI, 1.3 to 11.6), psychotropic medication use (OR = 3.0, 95% CI, 1.1 to 8.4), attention-deficient/hyperactivity disorder (OR = 2.8, 95% CI, 1.1 to 7.8), and T1 CEDS (OR = 8.8, 95% CI, 3.1 to 27.0) (uncorrected for multiple comparisons). Associations persisted after adjusting for age and intelligence quotient (IQ) differences. Age, sex, IQ, teasing/bullying on the CBCL, family psychiatric history and family income were not associated with T2 CEDS. CONCLUSION: Our results highlight both high prevalence and high potential for the persistence of depressive symptoms in autism and emphasize the importance of early support to address loneliness and social participation.

Study assessing risk factors for depression in autistic youthPlain Language SummaryObjectiveThe goal of this study was to find risk factors for depression in autistic youth.MethodsThe study included autistic youth who were part of the Province of Ontario Neurodevelopmental Disorders Network. Symptoms of depression were identified using mental health surveys and screening tools completed by parents. We studied 75 youth over two time points, to understand what factors might predict greater depression risk.ResultsThe average age of our study population at the first visit was 10 years old, and 14 years old at the second visit. Our study found that 37% of participants had elevated symptoms of depression at the first visit, and 35% at the second visit. Factors associated with future depressive symptoms included: loneliness, self-harm, suicidal ideation, high levels of restrictive/repetitive behaviours, depressive symptoms at the first visit, and ADHD. Factors that protected against depressive symptoms included high levels of social skills.ConclusionOur results show high levels of depressive symptoms among autistic youth, and the potential for this to persist over time in this population. Our findings emphasize the importance of early supports to address loneliness and social participation.

Effect of Micellar Morphology on the Temperature-Induced Structural Evolution of ABC Polypeptoid Triblock Terpolymers into Two-Compartment Hydrogel Network.

We investigated the temperature-dependent structural evolution of thermoreversible triblock terpolypeptoid hydrogels, namely poly(N-allyl glycine)-b-poly(N-methyl glycine)-b-poly(N-decyl glycine) (AMD), using small-angle neutron scattering (SANS) with contrast matching in conjunction with X-ray scattering and cryogenic transmission electron microscopy (cryo-TEM) techniques. At room temperature, A100M101D10 triblock terpolypeptoids self-assemble into core-corona-type spherical micelles in aqueous solution. Upon heating above the critical gelation temperature (T gel), SANS analysis revealed the formation of a two-compartment hydrogel network comprising distinct micellar cores composed of dehydrated A blocks and hydrophobic D blocks. At T ≳ T gel, the temperature-dependent dehydration of A block further leads to the gradual rearrangement of both A and D domains, forming well-ordered micellar network at higher temperatures. For AMD polymers with either longer D block or shorter A block, such as A101M111D21 and A43M92D9, elongated nonspherical micelles with a crystalline D core were observed at T < T gel. Although these enlarged crystalline micelles still undergo a sharp sol-to-gel transition upon heating, the higher aggregation number of chains results in the immediate association of the micelles into ordered aggregates at the initial stage, followed by a disruption of the spatial ordering as the temperature further increases. On the other hand, fiber-like structures were also observed for AMD with longer A block, such as A153M127D10, due to the crystallization of A domains. This also influences the assembly pathway of the two-compartment network. Our findings emphasize the critical impact of initial micellar morphology on the structural evolution of AMD hydrogels during the sol-to-gel transition, providing valuable insights for the rational design of thermoresponsive hydrogels with tunable network structures at the nanometer scale.

The trajectory of depression and anxiety among children and adolescents over two years of the COVID-19 pandemic.

Longitudinal research examining children's mental health (MH) over the course of the COVID-19 pandemic is scarce. We examined trajectories of depression and anxiety over two pandemic years among children with and without MH disorders. Parents and children 2-18 years completed surveys at seven timepoints (April 2020 to June 2022). Parents completed validated measures of depression and anxiety for children 8-18 years, and validated measures of emotional/behavioural symptoms for children 2-7 years old; children ≥10 years completed validated measures of depression and anxiety. Latent growth curve analysis determined depression and anxiety trajectories, accounting for demographics, child and parent MH. Data were available on 1315 unique children (1259 parent-reports; 550 child-reports). Trajectories were stable across the study period, however individual variation in trajectories was statistically significant. Of included covariates, only initial symptom level predicted symptom trajectories. Among participants with pre-COVID data, a significant increase in depression symptoms relative to pre-pandemic levels was observed; children and adolescents experienced elevated and sustained levels of depression and anxiety during the two-year period. Findings have direct policy implications in the prioritization and of maintenance of educational, recreational, and social activities with added MH supports in the face of future events.

Sex and intelligence quotient differences in age of diagnosis among youth with attention-deficit hyperactivity disorder.

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental condition and is characterized by inattention, hyperactivity, and impulsivity. Research suggests that some populations, such as females and individuals with high intelligence quotients may be a risk for late ADHD diagnosis and subsequent treatment. Our goal is to advance our understanding of ADHD diagnosis, by examining (1) how child sex and cognitive abilities together are related to the age of diagnosis and (2) whether symptom presentation, current internalizing and externalizing symptoms, and demographic factors are related to age of diagnosis. METHODS: Our analyses contained children who completed the required tests (N = 568) from a pre-existing dataset of 1380 children with ADHD from the Province of Ontario Neurodevelopmental Disorders (POND) Network (pond-network.ca). First, we conducted a moderation analysis with sex as the predictor, cognitive abilities as the moderator, and age of diagnosis as the outcome. Second, we conducted correlation analyses examining how symptom presentation, current internalizing and externalizing symptoms, and demographic factors are related to age of diagnosis. RESULTS: Higher IQ was related to a later age of diagnosis. Higher hyperactive-impulsive symptoms and externalizing symptoms were related to an earlier age of diagnosis. Internalizing symptoms were trend associated with a later age of diagnosis in girls. Higher socioeconomic status and non-White maternal ethnicity were related to later age of diagnosis. CONCLUSIONS: IQ, sex, ADHD symptomology, internalizing symptoms, externalizing symptoms, and socio-demographic factors affect the age of diagnosis.

Inactivation of Desiccation-Resistant Salmonella on Apple Slices Following Treatment with ε-Polylysine, Sodium Bisulfate, or Peracetic Acid and Subsequent Dehydration.

Salmonella is capable of surviving dehydration within various foods, such as dried fruit. Dried fruit, including apple slices, have been the subject of product recalls due to contamination with Salmonella. A study was conducted to determine the fate of Salmonella on apple slices, following immersion in three antimicrobial solutions (viz., ε-polylysine [epsilon-polylysine or EP], sodium bisulfate [SBS], or peracetic acid [PAA]), and subsequent hot air dehydration. Gala apples were aseptically cored and sliced into 0.4 cm thick rings, bisected, and inoculated with a five-strain composite of desiccation-resistant Salmonella, to a population of 8.28 log CFU/slice. Slices were then immersed for 2 min in various concentrations of antimicrobial solutions, including EP (0.005, 0.02, 0.05, and 0.1%), SBS (0.05, 0.1, 0.2, and 0.3%), PAA (18 or 42 ppm), or varying concentrations of PAA + EP, and then dehydrated at 60°C for 5 h. Salmonella populations in positive control samples (inoculated apple slices washed in sterile water) declined by 2.64 log after drying. In the present study, the inactivation of Salmonella, following EP and SBS treatments, increased with increasing concentrations, with maximum reductions of 3.87 and 6.20 log (with 0.1 and 0.3% of the two compounds, respectively). Based on preliminary studies, EP concentrations greater than 0.1% did not result in lower populations of Salmonella. Pretreatment washes with either 18 or 42 ppm of PAA inactivated Salmonella populations by 4.62 and 5.63 log, respectively, following desiccation. Combining PAA with up to 0.1% EP induced no greater population reductions of Salmonella than washing with PAA alone. The addition of EP to PAA solutions appeared to destabilize PAA concentrations, reducing its biocidal efficacy. These results may provide antimicrobial predrying treatment alternatives to promote the reduction of Salmonella during commercial or consumer hot air drying of apple slices.

The Pediatric Autism Research Cohort (PARC) Study: protocol for a patient-oriented prospective study examining trajectories of functioning in children with autism.

INTRODUCTION: The developmentally variable nature of autism poses challenges in providing timely services tailored to a child's needs. Despite a recent focus on longitudinal research, priority-setting initiatives with stakeholders highlighted the importance of studying a child's day-to-day functioning and social determinants of health to inform clinical care. To address this, we are conducting a pragmatic multi-site, patient-oriented longitudinal investigation: the Pediatric Autism Research Cohort (PARC) Study. In young children (<7 years of age) newly diagnosed with autism, we will: (1) examine variability in trajectories of adaptive functioning from the point of diagnosis into transition to school; and (2) identify factors associated with trajectories of adaptive functioning. METHODS AND ANALYSIS: We aim to recruit 1300 children under 7 years of age with a recent (within 12 months) diagnosis of autism from seven sites: six in Canada; one in Israel. Participants will be followed prospectively from diagnosis to age 8 years, with assessments at 6-month intervals. Parents/caregivers will complete questionnaires administered via a customized online research portal. Following each assessment timepoint, families will receive a research summary report describing their child's progress on adaptive functioning and related domains. Analysis of the longitudinal data will map trajectories and examine child, family and service characteristics associated with chronogeneity (interindividual and intraindividual heterogeneity over time) and possible trajectory turning points around sensitive periods like the transition to school. ETHICS AND DISSEMINATION: Ethics approvals have been received by all sites. All parents/respondents will provide informed consent when enrolling in the study. Using an integrated knowledge translation approach, where stakeholders are directly engaged in the research process, the PARC Study will identify factors associated with trajectories of functioning in children with autism. Resulting evidence will be shared with government policy makers to inform provincial and national programs. Findings will be disseminated at conferences and published in peer-reviewed journals.

Behaviour-correlated profiles of cerebellar-cerebral functional connectivity observed in independent neurodevelopmental disorder cohorts.

The cerebellum, through its connectivity with the cerebral cortex, plays an integral role in regulating cognitive and affective processes, and its dysregulation can result in neurodevelopmental disorder (NDD)-related behavioural deficits. Identifying cerebellar-cerebral functional connectivity (FC) profiles in children with NDDs can provide insight into common connectivity profiles and their correlation to NDD-related behaviours. 479 participants from the Province of Ontario Neurodevelopmental Disorders (POND) network (typically developing = 93, Autism Spectrum Disorder = 172, Attention Deficit/Hyperactivity Disorder = 161, Obsessive-Compulsive Disorder = 53, mean age = 12.2) underwent resting-state functional magnetic resonance imaging and behaviour testing (Social Communication Questionnaire, Toronto Obsessive-Compulsive Scale, and Child Behaviour Checklist - Attentional Problems Subscale). FC components maximally correlated to behaviour were identified using canonical correlation analysis. Results were then validated by repeating the investigation in 556 participants from an independent NDD cohort provided from a separate consortium (Healthy Brain Network (HBN)). Replication of canonical components was quantified by correlating the feature vectors between the two cohorts. The two cerebellar-cerebral FC components that replicated to the greatest extent were correlated to, respectively, obsessive-compulsive behaviour (behaviour feature vectors, rPOND-HBN = -0.97; FC feature vectors, rPOND-HBN = -0.68) and social communication deficit contrasted against attention deficit behaviour (behaviour feature vectors, rPOND-HBN = -0.99; FC feature vectors, rPOND-HBN = -0.78). The statistically stable (|z| > 1.96) features of the FC feature vectors, measured via bootstrap re-sampling, predominantly comprised of correlations between cerebellar attentional and control network regions and cerebral attentional, default mode, and control network regions. In both cohorts, spectral clustering on FC loading values resulted in subject clusters mixed across diagnostic categories, but no cluster was significantly enriched for any given diagnosis as measured via chi-squared test (p > 0.05). Overall, two behaviour-correlated components of cerebellar-cerebral functional connectivity were observed in two independent cohorts. This suggests the existence of generalizable cerebellar network differences that span across NDD diagnostic boundaries.

Predictors of health-related quality of life for children with neurodevelopmental conditions.

Neurodevelopmental conditions can be associated with decreased health-related quality of life; however, the predictors of these outcomes remain largely unknown. We characterized the predictors of health-related quality of life (HRQoL) in a sample of neurodiverse children and youth. We used a cross-sectional subsample from the Province of Ontario Neurodevelopmental Disorders Network (POND) consisting of those children and young people in the POND dataset with complete study data (total n = 615; 31% female; age: 11.28 years ± 2.84 years). Using a structural equation model, we investigated the effects of demographics (age, sex, socioeconomic status), core features (Social Communication Questionnaire, Toronto Obsessive Compulsive Scale, Strengths and Weaknesses of attention deficit/hyperactivity disorder (ADHD)-symptoms and Normal Behavior), co-occurring symptoms (Child Behaviour Checklist), and adaptive functioning (Adaptive Behaviour Assessment System) on HRQoL (KINDL). A total of 615 participants had complete data for this study (autism = 135, ADHD = 273, subthreshold ADHD = 7, obsessive-compulsive disorder (OCD) = 38, sub-threshold OCD = 1, neurotypical = 161). Of these participants, 190 (31%) identified as female, and 425 (69%) identified as male. The mean age was 11.28 years ± 2.84 years. Health-related quality of life was negatively associated with co-occurring symptoms (B = - 0.6, SE = 0.20, CI (- 0.95, - 0.19), p = 0.004)) and age (B = - 0.1, SE = 0.04, CI (- 0.19, - 0.01), p = 0.037). Fewer co-occurring symptoms were associated with higher socioeconomic status (B = - 0.5, SE = - 0.05, CI (- 0.58, - 0.37), p < 0.001). This study used a cross-sectional design. Given that one's experiences, needs, supports, and environment and thus HrQoL may change significantly over the lifespan and a longitudinal analysis of predictors is needed to capture these changes. Future studies with more diverse participant groups are needed. These results demonstrate the importance of behavioural and sociodemographic characteristics on health-related quality of life across neurodevelopmental conditions.

Gender diversity is correlated with dimensional neurodivergent traits but not categorical neurodevelopmental diagnoses in children.

BACKGROUND: Gender clinic and single-item questionnaire-based data report increased co-occurrence of gender diversity and neurodevelopmental conditions. The nuances of these associations are under-studied. We used a transdiagnostic approach, combining categorical and dimensional characterization of neurodiversity, to further the understanding of its associations with gender diversity in identity and expression in children. METHODS: Data from 291 children (Autism N = 104, ADHD N = 104, Autism + ADHD N = 17, neurotypical N = 66) aged 4-12 years enrolled in the Province of Ontario Neurodevelopmental Network were analyzed. Gender diversity was measured multi-dimensionally using a well-validated parent-report instrument, the Gender Identity Questionnaire for Children (GIQC). We used gamma regression models to determine the significant correlates of gender diversity among age, puberty, sex-assigned-at-birth, categorical neurodevelopmental diagnoses, and dimensional neurodivergent traits (using the Social Communication Questionnaire and the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scales). Internalizing and externalizing problems were included as covariates. RESULTS: Neither a categorical diagnosis of autism nor ADHD significantly correlated with current GIQC-derived scores. Instead, higher early-childhood dimensional autistic social-communication traits correlated with higher current overall gender incongruence (as defined by GIQC-14 score). This correlation was potentially moderated by sex-assigned-at-birth: greater early-childhood autistic social-communication traits were associated with higher current overall gender incongruence in assigned-males-at-birth, but not assigned-females-at-birth. For fine-grained gender diversity domains, greater autistic restricted-repetitive behavior traits were associated with greater diversity in gender identity across sexes-assigned-at-birth; greater autistic social-communication traits were associated with lower stereotypical male expression across sexes-assigned-at-birth. CONCLUSIONS: Dimensional autistic traits, rather than ADHD traits or categorical neurodevelopmental diagnoses, were associated with gender diversity domains across neurodivergent and neurotypical children. The association between early-childhood autistic social-communication traits and overall current gender diversity was most evident in assigned-males-at-birth. Nuanced interrelationships between neurodivergence and gender diversity should be better understood to clarify developmental links and to offer tailored support for neurodivergent and gender-diverse populations.

Dynamic structure factor of undulating vesicles: finite-size and spherical geometry effects with application to neutron spin echo experiments.

We consider the dynamic structure factor (DSF) of quasi-spherical vesicles and present a generalization of an expression that was originally formulated by Zilman and Granek (ZG) for scattering from isotropically oriented quasi-flat membrane plaquettes. The expression is obtained in the form of a multi-dimensional integral over the undulating membrane surface. The new expression reduces to the original stretched exponential form in the limit of sufficiently large vesicles, i.e., in the micron range or larger. For much smaller unilamellar vesicles, deviations from the asymptotic, stretched exponential equation are noticeable even if one assumes that the Seifert-Langer leaflet density mode is completely relaxed and membrane viscosity is neglected. To avoid the need for an exhaustive numerical integration while fitting to neutron spin echo (NSE) data, we provide a useful approximation for polydisperse systems that tests well against the numerical integration of the complete expression. To validate the new expression, we performed NSE experiments on variable-size vesicles made of a POPC/POPS lipid mixture and demonstrate an advantage over the original stretched exponential form or other manipulations of the original ZG expression that have been deployed over the years to fit the NSE data. In particular, values of the membrane bending rigidity extracted from the NSE data using the new approximations were insensitive to the vesicle radii and scattering wavenumber and compared very well with expected values of the effective bending modulus ([Formula: see text]) calculated from results in the literature. Moreover, the generalized scattering theory presented here for an undulating quasi-spherical shell can be easily extended to other models for the membrane undulation dynamics beyond the Helfrich Hamiltonian and thereby provides the foundation for the study of the nanoscale dynamics in more complex and biologically relevant model membrane systems.

Dorsal Striatal Functional Connectivity and Repetitive Behavior Dimensions in Children and Youths With Neurodevelopmental Disorders.

BACKGROUND: Impairing repetitive behaviors are one of the core diagnostic symptoms in autism spectrum disorder and obsessive-compulsive disorder, but they also manifest in attention-deficit/hyperactivity disorder. Although the dorsal striatal circuit has been implicated in repetitive behaviors, extensive heterogeneity in and cross-diagnostic manifestations of these behaviors have suggested phenotypic and likely neurobiological heterogeneity across neurodevelopmental disorders (NDDs). METHODS: Intrinsic dorsal striatal functional connectivity was examined in 3 NDDs (autism spectrum disorder, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder) and typically developing control participants in a large single-cohort sample (N = 412). To learn how diagnostic labels and overlapping behaviors manifest in dorsal striatal functional connectivity measured with functional magnetic resonance imaging, the main and interaction effects of diagnosis and behavior were examined in 8 models (2 seed functional connectivity [caudate and putamen] × 4 sub-behavioral domains [sameness/ritualistic, self-injury, stereotypy, and compulsions]). RESULTS: The obsessive-compulsive disorder group demonstrated distinctive patterns in visual and visuomotor coordination regions compared with the other diagnostic groups. Lower-order repetitive behaviors (self-injury and stereotypy) manifesting across all participants were implicated in regions involved in motor and cognitive control, although the findings did not survive effects of multiple comparisons, suggesting heterogeneity in these behavioral domains. An interaction between self-injurious behavior and an attention-deficit/hyperactivity disorder diagnosis were observed on caudate-cerebellum functional connectivity. CONCLUSIONS: These findings confirmed high heterogeneity and overlapping behavioral manifestations in NDDs and their complex underlying neural mechanisms. A call for diagnosis-free symptom measures that can capture not only observable symptoms and severity across NDDs but also the underlying functions and motivations of such behaviors across diagnoses is needed.

Brain-charting autism and attention deficit hyperactivity disorder reveals distinct and overlapping neurobiology.

Background: Autism and attention deficit hyperactivity disorder (ADHD) are heterogeneous neurodevelopmental conditions with complex underlying neurobiology. Despite overlapping presentation and sex-biased prevalence, autism and ADHD are rarely studied together, and sex differences are often overlooked. Normative modelling provides a unified framework for studying age-specific and sex-specific divergences in neurodivergent brain development. Methods: Here we use normative modelling and a large, multi-site neuroimaging dataset to characterise cortical anatomy associated with autism and ADHD, benchmarked against models of typical brain development based on a sample of over 75,000 individuals. We also examined sex and age differences, relationship with autistic traits, and explored the co-occurrence of autism and ADHD (autism+ADHD). Results: We observed robust neuroanatomical signatures of both autism and ADHD. Overall, autistic individuals showed greater cortical thickness and volume localised to the superior temporal cortex, whereas individuals with ADHD showed more global effects of cortical thickness increases but lower cortical volume and surface area across much of the cortex. The autism+ADHD group displayed a unique pattern of widespread increases in cortical thickness, and certain decreases in surface area. We also found evidence that sex modulates the neuroanatomy of autism but not ADHD, and an age-by-diagnosis interaction for ADHD only. Conclusions: These results indicate distinct cortical differences in autism and ADHD that are differentially impacted by age, sex, and potentially unique patterns related to their co-occurrence.

The Distinction Between Social Connectedness and Support When Examining Depressive Symptoms Among Children and Adolescents During the COVID-19 Pandemic.

Childhood depression is associated with significant social and functional impairment, suicide risk, and persistence throughout adulthood. Recent evidence demonstrates that social connectedness and social support may serve as protective factors against the development of depression. The current study aimed to examine the effect of change in social connectedness and social support on depressive symptoms among children and adolescents during the COVID-19 pandemic. Hierarchical regression was performed. Results indicated that parent-reported measures of change in social connectedness were inversely associated with depressive symptom severity, and could significantly predict future depressive symptom severity. In contrast, parent-reported measures of social support (i.e., from family and friends) did not significantly predict future depressive symptom severity. The presence of a pre-COVID psychiatric and/or neurodevelopmental diagnosis and baseline depressive symptom severity were also important factors associated with future depressive symptom severity. The findings suggest that an awareness of the presence of social supports (i.e., family or friends) is not sufficient for children to feel connected, but rather the mechanisms of social relationships are crucial. As our approach to public health restrictions evolves, the risk transmission of COVID-19 should be carefully balanced with the risks associated with decreased connectedness among youth.

A thermodynamic analysis of CLC transporter dimerization in lipid bilayers.

The CLC-ec1 chloride/proton antiporter is a membrane-embedded homodimer with subunits that can dissociate and associate, but the thermodynamic driving forces favor the assembled dimer at biological densities. Yet, the physical reasons for this stability are confounding as dimerization occurs via the burial of hydrophobic interfaces away from the lipid solvent. For binding of nonpolar surfaces in aqueous solution, the driving force is often attributed to the hydrophobic effect, but this should not apply in the membrane since there is very little water. To investigate this further, we quantified the thermodynamic changes associated with CLC dimerization in membranes by carrying out a van 't Hoff analysis of the temperature dependency of the free energy of dimerization, ΔG°. To ensure that the reaction reached equilibrium at different temperatures, we utilized a Förster resonance energy transfer assay to report on relaxation kinetics of subunit exchange as a function of temperature. Equilibration times were then applied to measure CLC-ec1 dimerization isotherms at different temperatures using the single-molecule subunit-capture photobleaching analysis approach. The results demonstrate that the dimerization free energy of CLC in Escherichia coli-like membranes exhibits a nonlinear temperature dependency corresponding to a large, negative change in heat capacity, a signature of solvent ordering effects such as the hydrophobic effect. Consolidating this with our previous molecular analyses suggests that the nonbilayer defect required to solvate the monomeric state is one source of the observed change in heat capacity and indicates the existence of a generalizable driving force for protein association in membranes.

SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment.

The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in a wide range of malignancies. Intriguingly, SHP2 has also been described as a critical regulator of the tumor microenvironment. Based on this evidence SHP2 is considered a multifaceted target in cancer, spurring the notion that the development of direct inhibitors of SHP2 would provide the twofold benefit of tumor intrinsic and extrinsic inhibition. In this review, we will discuss the role of SHP2 in cancer and the tumor microenvironment, and the clinical strategies in which SHP2 inhibitors are leveraged as combination agents to improve therapeutic response. SIGNIFICANCE: The SHP2 phosphatase functions as a pleiotropic factor, and its inhibition not only hinders tumor growth but also reshapes the tumor microenvironment. Although their single-agent activity may be limited, SHP2 inhibitors hold the potential of being key combination agents to enhance the depth and the durability of tumor response to therapy.

Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors.

Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest in oncology, both for treating with a single agent and in combination with a KRAS inhibitor. We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of GDC-1971 (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation.

Linkage of whole genome sequencing and administrative health data in autism: A proof of concept study.

Whether genetic testing in autism can help understand longitudinal health outcomes and health service needs is unclear. The objective of this study was to determine whether carrying an autism-associated rare genetic variant is associated with differences in health system utilization by autistic children and youth. This retrospective cohort study examined 415 autistic children/youth who underwent genome sequencing and data collection through a translational neuroscience program (Province of Ontario Neurodevelopmental Disorders Network). Participant data were linked to provincial health administrative databases to identify historical health service utilization, health care costs, and complex chronic medical conditions during a 3-year period. Health administrative data were compared between participants with and without a rare genetic variant in at least 1 of 74 genes associated with autism. Participants with a rare variant impacting an autism-associated gene (n = 83, 20%) were less likely to have received psychiatric care (at least one psychiatrist visit: 19.3% vs. 34.3%, p = 0.01; outpatient mental health visit: 66% vs. 77%, p = 0.04). Health care costs were similar between groups (median: $5589 vs. $4938, p = 0.4) and genetic status was not associated with odds of being a high-cost participant (top 20%) in this cohort. There were no differences in the proportion with complex chronic medical conditions between those with and without an autism-associated genetic variant. Our study highlights the feasibility and potential value of genomic and health system data linkage to understand health service needs, disparities, and health trajectories in individuals with neurodevelopmental conditions.

The role of parenting practices in parent and child mental health over time.

BACKGROUND: Parent and child mental health has suffered during the pandemic and transition phase. Structured and shared parenting may be intervention targets beneficial to families who are struggling with parent or child mental health challenges. AIMS: First, we investigated associations between structured and shared parenting and parent depression symptoms. Second, we investigated associations between structured and shared parenting and depression, hyperactivity/inattention and irritability symptoms in children. METHOD: A total of 1027 parents in two-parent households (4797 observations total; 85.1% mothers) completed online surveys about themselves and their children (aged 2-18 years) from April 2020 to July 2022. Structured parenting and shared parenting responsibilities were assessed from April 2020 to November 2021. Symptoms of parent depression, child depression, child hyperactivity and inattention, child irritability, and child emotional and conduct problems were assessed repeatedly (one to 14 times; median of four times) from April 2020 to July 2022. RESULTS: Parents who reported higher levels of shared parenting responsibilities had lower depression symptoms (ß = -0.09 to -0.32, all P < 0.01) longitudinally. Parents who reported higher levels of shared parenting responsibilities had children with fewer emotional problems (ages 2-5 years; ß = -0.07, P < 0.05), fewer conduct problems (ages 2-5 years; ß = -0.09, P < 0.01) and less irritability (ages 13-18 years; ß = -0.27, P < 0.001) longitudinally. Structured parenting was associated with fewer conduct problems (ages 2-5 years; ß = -0.05, P < 0.05). CONCLUSIONS: Shared parenting is beneficial for parent and child mental health, even under chaotic or inflexible life conditions. Structured parenting is beneficial for younger children.

Exploring the association between social skills struggles and social communication difficulties and depression in youth with autism spectrum disorder.

Autism spectrum disorder is characterized by social communication difficulties and social skills abilities that are significantly differ from neurotypical populations as well as restricted and repetitive behaviors and interests. Furthermore, many autistic youth experience co-occurring conditions, with one of the most common being depression. This depression is suggested to be, in part, the result of the relative social isolation experienced by autistic youth. Therefore, it is important to examine social functioning differences in autistic youth and their association with depression. There has been limited research investigating the association between social communication difficulties and depression, or the association between social skills struggles and depression, and no research investigating both of these in the same population. We found that social communicative symptoms of autism (as measured by the Autism Diagnostic Observation Schedule) were not associated with depression scores (as measured by the Revised Checklist for Anxiety and Depression) after controlling for age, sex, and IQ. In contrast, we did find a significant association between social skills struggles (as measured by the Adaptive Behavior Assessment System-2) and depression in the same sample. Higher social skills struggles were associated with higher depression scores after controlling for age, sex, and IQ. Reasons for the potential discrepancy between these findings are discussed, and clinical implications of these findings are explored.