Human Cytomegalovirus Dysregulates Cellular Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases and Sonic Hedgehog Pathway Proteins in Neural Astrocyte and Placental Models.

Human cytomegalovirus (CMV) infection is the leading non-genetic cause of congenital malformation in developed countries, causing significant fetal injury, and in some cases fetal death. The pathogenetic mechanisms through which this host-specific virus infects then damages both the placenta and the fetal brain are currently ill-defined. We investigated the CMV modulation of key signaling pathway proteins for these organs including dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) and Sonic Hedgehog (SHH) pathway proteins using human first trimester placental trophoblast (TEV-1) cells, primary human astrocyte (NHA) brain cells, and CMV-infected human placental tissue. Immunofluorescence demonstrated the accumulation and re-localization of SHH proteins in CMV-infected TEV-1 cells with Gli2, Ulk3, and Shh re-localizing to the CMV cytoplasmic virion assembly complex (VAC). In CMV-infected NHA cells, DYRK1A re-localized to the VAC and DYRK1B re-localized to the CMV nuclear replication compartments, and the SHH proteins re-localized with a similar pattern as was observed in TEV-1 cells. Western blot analysis in CMV-infected TEV-1 cells showed the upregulated expression of Rb, Ulk3, and Shh, but not Gli2. In CMV-infected NHA cells, there was an upregulation of DYRK1A, DYRK1B, Gli2, Rb, Ulk3, and Shh. These in vitro monoculture findings are consistent with patterns of protein upregulation and re-localization observed in naturally infected placental tissue and CMV-infected ex vivo placental explant histocultures. This study reveals CMV-induced changes in proteins critical for fetal development, and identifies new potential targets for CMV therapeutic development.

Developmental pathways of repetitive non-suicidal self-injury: predictors in adolescence and psychological outcomes in young adulthood.

BACKGROUND: Much longitudinal research has been carried out on non-suicidal self-injury (NSSI) during the last decades, but there still is a lack of studies of the individual developmental pathways of NSSI from adolescence into young adulthood. The aim of the present study was to investigate individual developmental pathways of repetitive non-suicidal self-injury (repNSSI) from adolescence into young adulthood, including adolescent predictors and psychological outcomes in young adulthood. Three developmental pathways were targeted: stable adolescence-limited repNSSI; repNSSI prolonged into young adulthood; and late-onset repNSSI; with no repNSSI as comparison. METHODS: Data were taken from a cohort of compulsory school students (N = 1064) in grades 7-8 in a Swedish municipality. The cohort was followed longitudinally, and this study included all individuals (n = 475) with NSSI data from three waves: T1 (when they were 13-15 years old); T2 (one year later); and T3 (ten years later). RepNSSI was operationalized as self-reports of at least 5 instances of NSSI during the past six/twelve months. RESULTS: The two pathways that involved stable repNSSI were observed significantly more often than expected by chance, with the strongest overrepresentation for the Prolonged RepNSSI pathway. Still, most adolescents who engaged in stable repNSSI stopped this before reaching young adulthood. Those who stopped did not, however, show a significantly better psychological adjustment in young adulthood than those who continued. Compared to participants with no repNSSI, participants who had stopped still reported significantly more stress, anxiety, and emotional dysregulation. As to the prediction of late onset NSSI, the findings were less robust, but sporadic NSSI at T1 and poor sleep at T2 were significant predictors, whereas depressive symptoms fell just short of significance at both timepoints. CONCLUSIONS: The present results indicate that among adolescents who engage in stable adolescent repNSSI (1) significantly more individuals than expected by chance still engage in repNSSI ten years later, and (2) those who stop engaging in repNSSI do not show significantly better psychological adjustment than those who still engage in it. The present findings also indicate that late onset of repNSSI as reported in young adulthood to some extent is predictable from symptom measures ten years earlier.

Demographics and gender-related measures in younger and older adolescents presenting to a gender service.

Transgender adolescents may present to gender identity specialty services earlier or later in adolescence. The aim of this study was to examine whether, 'younger' and 'older' presenters could be identified in a large cohort of transgender adolescents and if differences exist between the two groups. The study sample consisted of 1487 adolescents (506 birth-assigned males, 981 birth-assigned females) referred between 2000 and 2018. The distribution of age at intake was evaluated. Demographic, diagnostic, and treatment characteristics, the Recalled Childhood Gender Identity/Gender Role Questionnaire (RCGI) to measure childhood gender nonconformity and the Body Image Scale (BIS) to measure body image were collected. Based on a stem-and-leaf plot and a histogram, two groups were identified: adolescents presenting at ≤ 13.9 years ('younger presenters') and adolescents presenting at 14 years or older ('older presenters'). The sex ratio was more extreme in the group of older presenters favoring birth-assigned females (Χ2(1, N = 1487) = 19.69, p < 0.001). Furthermore, more adolescents from the younger presenting group lived with both biological parents (Χ2(1, N = 1427) = 24.78, p < 0.001), were diagnosed with gender dysphoria and started with medical gender-affirming treatment (Χ2(1, N = 1404) = 4.60, p = 0.032 and Χ2(1, N = 1487) = 29.16, p < 0.001). Younger presenters showed more gender nonconformity in childhood (ß 0.315, p < 0.001, 95% CI 0.224-0.407). Older presenters were more dissatisfied with various aspects of their bodies (p < 0.001). The differences between older and younger presenting adolescents suggest that there may be different developmental pathways in adolescents that lead to seeking gender-affirming medical care and argues for more tailored care.

Negative emotionality as a candidate mediating mechanism linking prenatal maternal mood problems and offspring internalizing behaviour.

Negative emotionality (NE) was evaluated as a candidate mechanism linking prenatal maternal affective symptoms and offspring internalizing problems during the preschool/early school age period. The participants were 335 mother-infant dyads from the Maternal Adversity, Vulnerability and Neurodevelopment project. A Confirmatory Bifactor Analysis (CFA) based on self-report measures of prenatal depression and pregnancy-specific anxiety generated a general factor representing overlapping symptoms of prenatal maternal psychopathology and four distinct symptom factors representing pregnancy-specific anxiety, negative affect, anhedonia and somatization. NE was rated by the mother at 18 and 36 months. CFA based on measures of father, mother, child-rated measures and a semistructured interview generated a general internalizing factor representing overlapping symptoms of child internalizing psychopathology accounting for the unique contribution of each informant. Path analyses revealed significant relationships among the general maternal affective psychopathology, the pregnancy- specific anxiety, and the child internalizing factors. Child NE mediated only the relationship between pregnancy-specific anxiety and the child internalizing factors. We highlighted the conditions in which prenatal maternal affective symptoms predicts child internalizing problems emerging early in development, including consideration of different mechanistic pathways for different maternal prenatal symptom presentations and child temperament.

Temperature-mediated developmental plasticity in winter and summer larvae of Palaemon serratus.

In a seasonal environment, variation in larval phenotype and developmental plasticity allow crustacean larvae to maximise survival by lengthening or shortening their development. The aim of this study is to investigate the effects of temperature, laying season and their interaction on larval developmental pathways (larval instars and larval stages). We monitored the different larval stages and calculated the number of larval instars reached during the development of winter and summer larvae of Palaemon serratus incubated at 12, 16 or 20 °C. We observed a great variability in the larval development (6-13 larval instars and 6 to 11 larval stages). A higher temperature decreases the development time and the number of larval instars. At a given temperature, the development time of winter and summer larvae was not different. Two larval stages were considered supernumerary (zoea 4 and 6), as they were more frequent at low temperatures. At higher temperatures, some larvae started to develop pleopods as early as the third instar, larval stage which had never been described (named here zoea 3'). This phenomenon was more common in winter larvae than in summer larvae. These results provide new insights into the expression of developmental plasticity in decapod larvae.

Head turning is an effective cue for gaze following: Evidence from newly sighted individuals, school children and adults.

In referential communication, gaze is often interpreted as a social cue that facilitates comprehension and enables word learning. Here we investigated the degree to which head turning facilitates gaze following. We presented participants with static pictures of a man looking at a target object in a first and third block of trials (pre- and post-intervention), while they saw short videos of the same man turning towards the target in the second block of trials (intervention). In Experiment 1, newly sighted individuals (treated for congenital cataracts; N = 8) benefited from the motion cues, both when comparing their initial performance with static gaze cues to their performance with dynamic head turning, and their performance with static cues before and after the videos. In Experiment 2, neurotypical school children (ages 5-10 years; N = 90) and adults (N = 30) also revealed improved performance with motion cues, although most participants had started to follow the static gaze cues before they saw the videos. Our results confirm that head turning is an effective social cue when interpreting new words, offering new insights for a pathways approach to development.

Examination of developmental pathways from preschool temperament to early adolescent ADHD symptoms through initial responsiveness to reward.

To identify sources of phenotypic heterogeneity in attention-deficit/hyperactivity disorder (ADHD) accounting for diversity in developmental/ pathogenic pathways, we examined, in a large sample of youth (N = 354), (a) associations between observed temperamental emotionality at age 3, an electrocortical index (i.e., reward positivity [RewP]) of initial responsiveness to reward at age 9, and ADHD symptoms at age 12, and (b) whether the association between emotionality and ADHD symptoms is mediated by initial responsiveness to reward. Bivariate analyses indicated greater positive emotionality (PE) was associated with enhanced RewP, lower age-9ADHD and lower age-12 inattention (IA). Negative emotionality (NE) was not associated with RewP or ADHD. Mediation analyses revealed the association between PE and hyperactivity/impulsivity (H/I) was mediated by RewP; enhanced RewP was associated with greater H/I. Greater PE was associated with enhanced RewP at a trend level. These effects held accounting for age-9 ADHD, age-12 IA and age-12 oppositional defiant and conduct disorder symptoms. As such, preschool emotionality is associated with adolescent ADHD-H/I symptoms through late childhood initial responsiveness to reward. These relations indicate that individual differences in emotionality and reward responsiveness may be informative for personalizing ADHD interventions.

Single-cell transcriptomics identifies master regulators of neurodegeneration in SOD1 ALS iPSC-derived motor neurons.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by the loss of motor neurons. We utilized single-cell transcriptomics to uncover dysfunctional pathways in degenerating motor neurons differentiated from SOD1 E100G ALS patient-derived induced pluripotent stem cells (iPSCs) and respective isogenic controls. Differential gene expression and network analysis identified activation of developmental pathways and core transcriptional factors driving the ALS motor neuron gene dysregulation. Specifically, we identified activation of SMAD2, a downstream mediator of the transforming growth factor ß (TGF-ß) signaling pathway as a key driver of SOD1 iPSC-derived motor neuron degeneration. Importantly, our analysis indicates that activation of TGFß signaling may be a common mechanism shared between SOD1, FUS, C9ORF72, VCP, and sporadic ALS motor neurons. Our results demonstrate the utility of single-cell transcriptomics in mapping disease-relevant gene regulatory networks driving neurodegeneration in ALS motor neurons. We find that ALS-associated mutant SOD1 targets transcriptional networks that perturb motor neuron homeostasis.

Reward-Related Dysfunctions in Children Developing Attention Deficit Hyperactivity Disorder-Roles of Oppositional and Callous-Unemotional Symptoms.

Objectives: Neurocognitive functions might indicate specific pathways in developing attention deficit hyperactivity disorder (ADHD). We focus on reward-related dysfunctions and analyze whether reward-related inhibitory control (RRIC), approach motivation, and autonomic reactivity to reward-related stimuli are linked to developing ADHD, while accounting for comorbid symptoms of oppositional defiant disorder (ODD), and callous-unemotional (CU) traits. Methods: A sample of 198 preschool children (115 boys; age: m = 58, s = 6 months) was re-assessed at age 8 years (m = 101.4, s = 3.6 months). ADHD diagnosis was made by clinical interviews. We measured ODD symptoms and CU traits using a multi-informant approach, RRIC (Snack-Delay task, Gift-Bag task) and approach tendency using neuropsychological tasks, and autonomic reactivity via indices of electrodermal activity (EDA). Results: Low RRIC and low autonomic reactivity were uniquely associated with ADHD, while longitudinal and cross-sectional links between approach motivation and ADHD were completely explained by comorbid ODD and CU symptoms. Conclusion: High approach motivation indicated developing ADHD with ODD and CU problems, while low RRIC and low reward-related autonomic reactivity were linked to developing pure ADHD. The results are in line with models on neurocognitive subtypes in externalizing disorders.

Patterns of Child Maltreatment and the Development of Conflictual Emerging Adult Romantic Relationships: An Examination of Mechanisms and Gender Moderation.

Individuals who experienced child maltreatment are at heightened risk for involvement in conflictual romantic relationships. The aim of this study was to examine the effect of patterns of child maltreatment on the development of maladaptive romantic relationships in emerging adulthood (EA), as well as to determine whether childhood physical aggression and disinhibition mediate this risk. Utilizing a longitudinal sample of emerging adult participants (N = 398 emerging adults; Mage = 19.67 years) who took part in a summer research camp as children (Mage = 11.27 years), we employed a combination of person-centered and variable-centered methods to test study aims. Significant differences in child behavior and developmental pathways emerged not only between those who experienced maltreatment and those who did not, but also among maltreated individuals with different constellations of maltreatment experiences. Specifically, childhood aggression was a robust mechanism underlying the risk associated with chronic/multi-subtype maltreatment, and the risk associated with neglect only, for involvement in dysfunctional EA romantic relationships. Together, these findings highlight the utility of person-centered methods for conceptualizing maltreatment, identify childhood aggression as a pathway of risk, and the underscore the criticality of prevention and early intervention to interrupt the intergenerational transmission of high conflict and aggression within families.

Regenerative Medicine and the Hope for a Cure.

Current therapeutic strategies have succeeded in slowing down the progression of idiopathic pulmonary fibrosis (IPF). Emerging evidence highlights IPF as a disease of aging and impaired regeneration. Novel antiaging and regenerative medicine approaches hold promise to be able to reverse disease and might present hope for a cure. Research focusing on a deeper understanding of lung stem cell populations and how these are regulated and altered in fibrotic disease continues to drive the field, and accompanied by earlier diagnosis, the adaptation of clinically relevant models and readouts for regeneration of diseased lung, ultimately paves the way for translation into clinics.

Social Functioning as a Mediator between Developmental Language Disorder (DLD) and Emotional Problems in Adolescents.

Adolescents with Developmental Language Disorder (DLD) are at risk for increased feelings of anxiety and depression compared to their typically developing (TD) peers. However, the underlying pathways involved in this relationship are unclear. In this initial study of the 'social mediation hypothesis', we examine social functioning as a mediator of emotional problems in a cross-sectional sample of adolescents with DLD and age- and sex-matched controls. Preliminary data from twenty-six participants with DLD and 27 participants with typical language development (TLD, 11-17 years) were compared on self- and parent-reported measures of social functioning and emotional outcomes. There was little evidence of group differences in self-reported social functioning and emotional outcomes, but parent-report of SDQ Peer Problems and Emotional Problems in the DLD group was significantly higher than in the TLD group. Parent-reported peer problems mediated parent-reported emotional problems, accounting for 69% of the relationship between DLD status and emotional problems. Parents of adolescents with DLD, but not adolescents themselves, report significantly higher peer and emotional problems compared to TLD peers. The hypotheses generated from these novel data suggest further investigation into adolescents' perceptions of socioemotional difficulties and friendships should be examined.

An Index Approach to Early Specialization Measurement: An Exploratory Study.

The methodological underpinnings of studies into early specialization have recently been critiqued. Previous researchers have commented on the variety of, and over-simplified, methods used to capture early specialization. This exploratory study, therefore, suggests a new direction for how early specialization can be conceptualized and measured. We aim to create an index approach whereby early specialization is measured as a continuous variable, in line with commonly used definitions. The continuous variable for degrees of early specialization is calculated from a questionnaire which captures the four key components of early specialization; (1) intensity, (2) year-round training, (3) single sport, and (4) commencing age 12 or younger. The proposed index approach is illustrated in a sample of 290 Swedish aesthetic performers aged 12-20 years (M = 15.88), whose descriptive statistics are used to discuss the suitability and usability of the measure. The proposed index approach functions as a guideline to future researchers. We hope that introducing a new index approach we will encourage further discussion around the measurement of early specialization. Additionally, we hope to pave the way for future research to explore more complex research questions.

Two Sides of the Same Coin: The Role of Developmental pathways and pluripotency factors in normal mammary stem cells and breast cancer metastasis.

Breast cancer initiation and progression are often observed as the result of dysregulation of normal developmental processes and pathways. Studies focused on normal mammary stem/progenitor cell activity have led to an understanding of how breast cancer cells acquire stemness-associated properties including tumor initiation, survival and multi-lineage differentiation into heterogeneous tumors that become difficult to target therapeutically. Importantly, more recent investigations have provided valuable insight into how key developmental regulators can impact multiple phases of metastasis, where they are repurposed to not only promote metastatic phenotypes such as migration, invasion and EMT at the primary site, but also to regulate the survival, initiation and maintenance of metastatic lesions at secondary organs. Herein, we discuss findings that have led to a better understanding of how embryonic and pluripotency factors contribute not only to normal mammary development, but also to metastatic progression. We further examine the therapeutic potential of targeting these developmental pathways, and discuss how a better understanding of compensatory mechanisms, crosstalk between pathways, and novel experimental models could provide critical insight into how we might exploit embryonic and pluripotency regulators to inhibit tumor progression and metastasis.

Developmental pathways to social anxiety and irritability: The role of the ERN.

Early behaviors that differentiate later biomarkers for psychopathology can guide preventive efforts while also facilitating pathophysiological research. We tested whether error-related negativity (ERN) moderates the link between early behavior and later psychopathology in two early childhood phenotypes: behavioral inhibition and irritability. From ages 2 to 7 years, children (n = 291) were assessed longitudinally for behavioral inhibition (BI) and irritability. Behavioral inhibition was assessed via maternal report and behavioral responses to novelty. Childhood irritability was assessed using the Child Behavior Checklist. At age 12, an electroencephalogram (EEG) was recorded while children performed a flanker task to measure ERN, a neural indicator of error monitoring. Clinical assessments of anxiety and irritability were conducted using questionnaires (i.e., Screen for Child Anxiety Related Disorders and Affective Reactivity Index) and clinical interviews. Error monitoring interacted with early BI and early irritability to predict later psychopathology. Among children with high BI, an enhanced ERN predicted greater social anxiety at age 12. In contrast, children with high childhood irritability and blunted ERN predicted greater irritability at age 12. This converges with previous work and provides novel insight into the specificity of pathways associated with psychopathology.

Gene ontology analysis of arthrogryposis (multiple congenital contractures).

In 2016, we published an article applying Gene Ontology Analysis to the genes that had been reported to be associated with arthrogryposis (multiple congenital contractures) (Hall & Kiefer, 2016). At that time, 320 genes had been reported to have mutations associated with arthrogryposis. All were associated with decreased fetal movement. These 320 genes were analyzed by biological process and cellular component categories, and yielded 22 distinct groupings. Since that time, another 82 additional genes have been reported, now totaling 402 genes, which when mutated, are associated with arthrogryposis (arthrogryposis multiplex congenita). So, we decided to update the analysis in order to stimulate further research and possible treatment. Now, 29 groupings can be identified, but only 19 groups have more than one gene.