Differentiating neural sensitivity and bias during face-emotion processing in youth: a computational approach.

The ability to interpret face-emotion displays is critical for the development of adaptive social interactions. Using a novel variant of a computational model and fMRI data, we examined behavioral and neural associations between two metrics of face-emotion labeling (sensitivity and bias) and age in youth. Youth and adults (n = 44, M age = 20.02, s.d. = 7.44, range = 8-36) completed an explicit face-emotion labeling fMRI task including happy to angry morphed face emotions. A drift-diffusion model was applied to choice and reaction time distributions to examine sensitivity and bias in interpreting face emotions. Model fit and reliability of parameters were assessed on adult data (n = 42). Linear and quadratic slopes modeled brain activity associated with dimensions of face-emotion valence and ambiguity during interpretation. Behaviorally, age was associated with sensitivity. The bilateral anterior insula exhibited a more pronounced neural response to ambiguity with older age. Associations between sensitivity and bias metrics and activation patterns indicated that systems encoding face-emotion valence and ambiguity both contribute to the ability to discriminate face emotions. The current study provides evidence for age-related improvement in perceptual sensitivity to facial affect across adolescence and young adulthood.

White matter microstructure organization across the transition to fatherhood.

The transition to parenthood remains an understudied window of potential neuroplasticity in the adult brain. White matter microstructural (WMM) organization, which reflects structural connectivity in the brain, has shown plasticity across the lifespan. No studies have examined how WMM organization changes from the prenatal to postpartum period in men becoming fathers. This study investigates WMM organization in men transitioning to first-time fatherhood. We performed diffusion-weighted imaging to identify differences in WMM organization, as indexed by fractional anisotropy (FA). We also investigated whether FA changes were associated with fathers' postpartum mental health. Associations between mental health and WMM organization have not been rarely examined in parents, who may be vulnerable to mental health problems. Fathers exhibited reduced FA at the whole-brain level, especially in the cingulum, a tract associated with emotional regulation. Fathers also displayed reduced FA in the corpus callosum, especially in the forceps minor, which is implicated in cognitive functioning. Postpartum depressive symptoms were linked with increases and decreases in FA, but FA was not correlated with perceived or parenting stress. Findings provide novel insight into fathers' WMM organization during the transition to parenthood and suggest postpartum depression may be linked with fathers' neuroplasticity during the transition to parenthood.

Neural correlates of inhibitory control in the context of infant cry and paternal postpartum mental health.

BACKGROUND: Inhibitory control, a form of self-regulation, may support sensitive parenting, but has been understudied in new fathers despite their pronounced risk for stress and mental health challenges. METHODS: This study probed the neural correlates of inhibitory control and its associations to first-time fathers' postpartum mental health, focusing on depressive symptoms, state anxiety, and perceived stress. Six months after their child's birth, 38 fathers self-reported on their mood, anxiety, and stress, and performed a Go/No-Go fMRI task while listening to three sets of sounds (infant cry, pink noise, and silence). RESULTS: Fathers' behavioral inhibition accuracy was consistent across the sound conditions, but their patterns of neural activation varied. Compared to the pink noise condition, fathers showed heightened engagement in prefrontal regulatory regions when self-regulating during the infant cry and silent conditions. When examining correct trials only, results in visual motor area and primary somatosensory cortex emerged only for infant cry and not for pink noise and silence. Moreover, fathers reporting higher levels of postpartum depression, state anxiety, and perceived stress showed greater activation in prefrontal regions when inhibiting during infant cry or silence. CONCLUSION: This study is the first to underscore the complex interplay between the neural mechanisms related to inhibitory control and postpartum mental health and stress across varied auditory context, laying the groundwork for future research.

Prenatal testosterone synchrony in first-time parents predicts fathers' postpartum relationship quality.

There is evidence that men's testosterone levels decline across the transition to fatherhood and that this decline may reflect fathers' investment in the new family. There is also emerging evidence that cohabiting couples show synchrony or within-couple associations in testosterone levels during the perinatal period. Hormonal synchrony may act as a mechanism that supports fathers' biological preparation for parenthood, perhaps by facilitating perinatal declines in paternal testosterone. However, few studies have examined testosterone synchrony and change within couples. A sample of 97 U.S. couples expecting their first child provided testosterone samples during pregnancy, and of those couples, 78 couples also provided testosterone at seven months postpartum. Couples reported on relationship satisfaction both at prenatal and postpartum visits. Bayesian multilevel modeling revealed within-couple testosterone synchrony both during pregnancy and postpartum. Testosterone synchrony during pregnancy predicted a greater drop in fathers' testosterone levels from prenatal to postpartum and higher paternal postpartum relationship quality. Fathers' lower prenatal testosterone levels also subsequently predicted higher self-reported postpartum relationship quality for both parents. In sum, this study finds that couples' testosterone levels show synchrony across the transition to parenthood in ways that are associated with couple relationship quality and men's neuroendocrine preparation for fatherhood.

Prenatal prolactin predicts postnatal parenting attitudes and brain structure remodeling in first-time fathers.

Despite the important contributions that fathers make to parenting, the neurobiological underpinnings of men's adaptation to parenthood are still not well understood. The current study focuses on prolactin, a hormone that has been extensively linked with reproduction, lactation, and parental behavior in mothers. There is preliminary evidence that prolactin may also reflect the transition to sensitive fatherhood. We sampled prolactin in 91 first-time expectant fathers who participated in a laboratory visit along with their pregnant partners. Fathers' prolactin levels were correlated with their partners' prolactin levels. Men's prolactin levels during their partner's pregnancy were associated with their self-reported antenatal bonding to the unborn infant. Prenatal prolactin levels in fathers also predicted more positive attitudes toward fatherhood at three months postpartum, including lower parenting stress, greater enjoyment of the infant, and a more attunement-oriented parenting style. Within a smaller sample of 32 men who participated in MRI scanning before and after their child's birth, prenatal prolactin also predicted greater reductions in grey matter volume in the left posterior cingulate, left insula, and left nucleus accumbens. In conclusion, men's prenatal prolactin may reflect their perceptions of fatherhood and changes to their perinatal brain structure.

Changes in left hippocampal volume in first-time fathers: Associations with oxytocin, testosterone, and adaptation to parenthood.

The parenting brain may undergo remodeling that supports the adjustment to new parenthood. Prior work on human mothers has found gray matter volume decreases from preconception to early postpartum in multiple structures, including the left hippocampus, which was the only structure to show gray matter volume recovery at 2 years postpartum. This is consistent with evidence from animal models that the hippocampus is unusually plastic across reproductive transitions. However, no studies have focused specifically on hippocampal volume changes in human fathers. Among 38 men who were scanned by magnetic resonance imaging (MRI) before and after having their first child, individual differences in left hippocampal volume changes were associated with men's prenatal oxytocin, postpartum testosterone, and postpartum adaptation to parenthood. Across the whole sample, hippocampal volumes did not change significantly from prenatal to postpartum. However, men who showed larger increases in left hippocampal volume from prenatal to postpartum reported stronger parent-child bonding and affectionate attachment and lower parenting stress. Fathers with higher levels of prenatal oxytocin showed larger left hippocampal volume increases across the transition to parenthood. In turn, greater increases in left hippocampal volume predicted lower postpartum testosterone after adjusting for prenatal testosterone. These findings did not extend to the right hippocampus. In conclusion, remodeling of the left hippocampus across the transition to new fatherhood may reflect adaptation to parenthood in human males.

First-time fathers show longitudinal gray matter cortical volume reductions: evidence from two international samples.

Emerging evidence points to the transition to parenthood as a critical window for adult neural plasticity. Studying fathers offers a unique opportunity to explore how parenting experience can shape the human brain when pregnancy is not directly experienced. Yet very few studies have examined the neuroanatomic adaptations of men transitioning into fatherhood. The present study reports on an international collaboration between two laboratories, one in Spain and the other in California (United States), that have prospectively collected structural neuroimaging data in 20 expectant fathers before and after the birth of their first child. The Spanish sample also included a control group of 17 childless men. We tested whether the transition into fatherhood entailed anatomical changes in brain cortical volume, thickness, and area, and subcortical volumes. We found overlapping trends of cortical volume reductions within the default mode network and visual networks and preservation of subcortical structures across both samples of first-time fathers, which persisted after controlling for fathers' and children's age at the postnatal scan. This study provides convergent evidence for cortical structural changes in fathers, supporting the possibility that the transition to fatherhood may represent a meaningful window of experience-induced structural neuroplasticity in males.

20-HETE/GPR75 pairing modulates the expression and transcriptional activity of the androgen receptor in androgen-sensitive prostate cancer cells.

The androgen receptor (AR) and AR-driven genes are crucial in normal and neoplastic prostate tissue. Previous results showed a link between 20-hydroxyeicosatetraenoic acid (20-HETE) production and AR-driven prostate cancer (PCa) progression. This study aims to describe the contribution of GPR75, 20-HETE membrane receptor, in 20-HETE-mediated expression and transcriptional activity of AR in PCa. In LNCaP cells, 20-HETE increased AR expression, nuclear localization, and its transcriptional activity. Also, 20-HETE enhanced dihydrotestosterone (DHT) induced effects. All was abrogated by chemical antagonism of GPR75 (19-HEDE) or its transient knockdown. In human PCa, the expression of AR-driven genes correlated with GPR75. In LNCaP xenografts, tumors from castrated animals expressed higher levels of AR, this was impaired by inhibition of 20-HETE synthesis. These data suggest that 20-HETE, through the GPR75 receptor, regulates transcriptionally active AR in PCa cells, thus making 20-HETE/GRP75 potential targets to limit the expression of AR-driven phenotype in PCa cells.

Recent Neuroscience Advances in Human Parenting.

The transition to parenthood entails brain adaptations to the demands of caring for a newborn. This chapter reviews recent neuroscience findings on human parenting, focusing on neuroimaging studies. First, we describe the brain circuits underlying human maternal behavior, which comprise ancient subcortical circuits and more sophisticated cortical regions. Then, we present the short-term and long-term functional and structural brain adaptations that characterize the transition to motherhood, discuss the long-term effects of parenthood on the brain, and propose several underlying neural mechanisms. We also review neuroimaging findings in biological fathers and alloparents (such as other relatives or adoptive parents), who engage in parenting without directly experiencing pregnancy or childbirth. Finally, we describe perinatal mental illnesses and discuss the neural responses associated with such disorders. To date, studies indicate that parenthood is a period of enhanced brain plasticity within brain areas critical for cognitive and social processing and that both parenting experience and gestational-related factors can prime such plasticity.

Reliability of task-evoked neural activation during face-emotion paradigms: Effects of scanner and psychological processes.

Assessing and improving test-retest reliability is critical to efforts to address concerns about replicability of task-based functional magnetic resonance imaging. The current study uses two statistical approaches to examine how scanner and task-related factors influence reliability of neural response to face-emotion viewing. Forty healthy adult participants completed two face-emotion paradigms at up to three scanning sessions across two scanners of the same build over approximately 2 months. We examined reliability across the main task contrasts using Bayesian linear mixed-effects models performed voxel-wise across the brain. We also used a novel Bayesian hierarchical model across a predefined whole-brain parcellation scheme and subcortical anatomical regions. Scanner differences accounted for minimal variance in temporal signal-to-noise ratio and task contrast maps. Regions activated during task at the group level showed higher reliability relative to regions not activated significantly at the group level. Greater reliability was found for contrasts involving conditions with clearly distinct visual stimuli and associated cognitive demands (e.g., face vs. nonface discrimination) compared to conditions with more similar demands (e.g., angry vs. happy face discrimination). Voxel-wise reliability estimates tended to be higher than those based on predefined anatomical regions. This work informs attempts to improve reliability in the context of task activation patterns and specific task contrasts. Our study provides a new method to estimate reliability across a large number of regions of interest and can inform researchers' selection of task conditions and analytic contrasts.

Stronger mentalizing network connectivity in expectant fathers predicts postpartum father-infant bonding and parenting behavior.

Fathers play a critical role in parenting and in shaping child outcomes. However, the neurobiological underpinnings of successful adjustment to fatherhood have not been well-specified. Empathy and mentalizing abilities may characterize more effective fathering. These abilities may be supported by the functional connectivity (FC) of brain regions associated with social cognition and executive control. We used a seed-region-based approach to assess resting-state FC (rsFC) of the medial prefrontal cortex (mPFC) in 40 expectant fathers. We tested associations between mPFC whole-brain rsFC and fathers' self-report measures of empathy during pregnancy, as well as their ratings of father-infant bonding and fathering behaviors at six months postpartum. Stronger prenatal rsFC between the mPFC and precuneus, frontal pole, planum polare, and orbitofrontal cortex (OFC) was negatively associated with self-reported empathic concern and perspective-taking, whereas mPFC rsFC with the lateral occipital cortex (LOC) was positively associated with self-reported perspective-taking. Additionally, stronger prenatal connectivity between the mPFC rsFC and the superior parietal lobule and LOC regions predicted father reports of postpartum bonding with infants, and stronger prenatal mPFC rsFC with the LOC predicted more effective postpartum parenting. This study is the first to measure rsFC in expectant fathers as a predictor of subsequent adjustment to fathering.

The Bur1 cyclin-dependent kinase regulates telomere length in Saccharomyces cerevisiae.

Telomere length regulation is essential for cell viability in eukaryotes. While many pathways that affect telomere length are known, we do not yet have a complete understanding of the mechanism of length regulation. To identify new pathways that might regulate telomere length, we carried out a genetic screen in yeast and identified the cyclin-dependent kinase complex Bur1/2 as a regulator of telomere length. Mutations in either BUR1 cyclin-dependent kinase or the associated BUR2 cyclin resulted in short telomeres. This regulation did not function through the known role of BUR1 in regulating histone modification as bur1∆ set2∆ and bur2∆ set2∆ double mutants rescued cell growth but did not rescue the telomere shortening effects. We found that both bur1∆ and bur2∆ set2∆ were also defective in de novo telomere addition, and deletion of SET2 did also not rescue this elongation defect. The Bur1/2 cyclin-dependent kinase regulates transcription of many genes. We found that TLC1 RNA levels were reduced in bur2∆ set2∆ mutants; however, overexpression of TLC1 restored the transcript levels but did not restore de novo telomere elongation or telomere length. These data suggest that the Bur1/2 kinase plays a role in telomere elongation separate from its role in transcription of telomerase components. Dissecting the role of the Bur1/2 kinase pathway at telomeres will help complete our understanding of the complex network of telomere length regulation.

Fertility and Iron Bioaccumulation in Drosophila melanogaster Fed with Magnetite Nanoparticles Using a Validated Method.

Research on nanomaterial exposure-related health risks is still quite limited; this includes standardizing methods for measuring metals in living organisms. Thus, this study validated an atomic absorption spectrophotometry method to determine fertility and bioaccumulated iron content in Drosophila melanogaster flies after feeding them magnetite nanoparticles (Fe3O4NPs) dosed in a culture medium (100, 250, 500, and 1000 mg kg-1). Some NPs were also coated with chitosan to compare iron assimilation. Considering both accuracy and precision, results showed the method was optimal for concentrations greater than 20 mg L-1. Recovery values were considered optimum within the 95-105% range. Regarding fertility, offspring for each coated and non-coated NPs concentration decreased in relation to the control group. Flies exposed to 100 mg L-1 of coated NPs presented the lowest fertility level and highest bioaccumulation factor. Despite an association between iron bioaccumulation and NPs concentration, the 500 mg L-1 dose of coated and non-coated NPs showed similar iron concentrations to those of the control group. Thus, Drosophila flies' fertility decreased after NPs exposure, while iron bioaccumulation was related to NPs concentration and coating. We determined this method can overcome sample limitations and biological matrix-associated heterogeneity, thus allowing for bioaccumulated iron detection regardless of exposure to coated or non-coated magnetite NPs, meaning this protocol could be applicable with any type of iron NPs.

Theory of mind processing in expectant fathers: Associations with prenatal oxytocin and parental attunement.

Social cognition may facilitate fathers' sensitive caregiving behavior. We administered the Why-How Task, an fMRI task that elicits theory of mind processing, to expectant fathers (n = 39) who also visited the laboratory during their partner's pregnancy and provided a plasma sample for oxytocin assay. Three months postpartum, fathers reported their beliefs about parenting. When rating "Why" an action was being performed versus "How" the action was being performed (Why > How contrast), participants showed activation in regions theorized to support theory of mind, including the dorsomedial prefrontal cortex and superior temporal sulcus. Fathers' prenatal oxytocin levels predicted greater signal change during the Why > How contrast in the inferior parietal lobule. Both prenatal oxytocin and attunement parenting beliefs were associated with Why > How activation in the dorsolateral prefrontal cortex, a theory of mind region implicated in emotion regulation. Posterior parahippocampal gyrus and dorsolateral prefrontal cortex activation during the Why > How contrast predicted fathers' attunement parenting beliefs. In conclusion, fathers' neural activation when engaging in a theory of mind task was associated with their prenatal oxytocin levels and their postpartum attunement parenting beliefs. Results suggest biological and cognitive components of fathering may track with the theory of mind processing.

How do expectant fathers respond to infant cry? Examining brain and behavioral responses and the moderating role of testosterone.

Expectant parents' responses to infant cry may indicate future risk and resiliency in the parent-child relationship. Most studies of parental reactivity to infant cry have focused on mothers, and few studies have focused on expectant fathers, although fathers make important contributions to parenting. Additionally, although different responses to infant cry (behavioral, psychological and neural) are hypothesized to track together, few studies have analyzed them concurrently. The current investigation aimed to address these gaps by characterizing multimodal responses to infant cry within expectant fathers and testing whether prenatal testosterone moderates these responses. Expectant fathers responded to infant cry vs frequency-matched white noise with increased activation in bilateral areas of the temporal lobe involved in processing speech sounds and social and emotional stimuli. Handgrip force, which has been used to measure parents' reactivity to cry sounds in previous studies, did not differentiate cry from white noise within this sample. Expectant fathers with higher prenatal testosterone showed greater activation in the supramarginal gyrus, left occipital lobe and precuneus cortex to cry sounds. Expectant fathers appear to interpret and process infant cry as a meaningful speech sound and social cue, and testosterone may play a role in expectant fathers' response to infant cry.

The Clinician Affective Reactivity Index: Validity and Reliability of a Clinician-Rated Assessment of Irritability.

Irritability is impairing in youth and is the core feature of disruptive mood dysregulation disorder (DMDD). Currently, there are no established clinician-rated instruments to assess irritability in pediatric research and clinical settings. Clinician-rated measures ensure consistency of assessment across patients and are important specifically for treatment research. Here, we present data on the psychometric properties of the Clinician Affective Reactivity Index (CL-ARI), the first semistructured interview focused on pediatric irritability. The CL-ARI was administered to a transdiagnostic sample of 98 youth (M age = 12.66, SD = 2.47; 41% female). With respect to convergent validity, CL-ARI scores were (a) significantly higher for youth with DMDD than for any other diagnostic group, and (b) showed uniquely strong associations with other clinician-, parent-, and youth-report measures of irritability compared to measures of related constructs, such as anxiety. The three subscales of the CL-ARI (temper outbursts, irritable mood, impairment) showed excellent internal consistency. Test-retest reliability of the CL-ARI was adequate. These data support that irritability can be feasibly, validly, and reliably assessed by clinicians using the CL-ARI. A validated, gold-standard assessment of pediatric irritability is critical in advancing research and treatment efforts.

Cytochrome 450 metabolites of arachidonic acid (20-HETE, 11,12-EET and 14,15-EET) promote pheochromocytoma cell growth and tumor associated angiogenesis.

The importance of cytochrome P450 (CYP)-derived arachidonic acid (AA) metabolites, 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) as tumor growth promotors has already been described in several cancer types. The aim of this study was to evaluate the role of these compounds in the biology of pheochromocytoma/paraganglioma. These tumors originate from chromaffin cells derived from adrenal medulla (pheochromocytomas) or extra-adrenal autonomic paraganglia (paragangliomas), and they represent the most common hereditary endocrine neoplasia. According to mutations in the driver genes, these tumors are divided in two clusters: pseudo-hypoxic and kinase-signaling EETs, but not 20-HETE, exhibited a potent ability to sustain growth in a murine pheochromocytoma cell line (MPC) in vitro, EETs promoted an increase in cell proliferation and a decrease in cell apoptosis. In a mouse model of pheochromocytoma, the inhibition of CYP-mediated AA metabolism using 1-aminobenzotriazol resulted in slower tumor growth, a decreased vascularization, and a lower final volume. Also, the expression of AA-metabolizing CYP monooxygenases was detected in tumor samples from human origin, being their apparent abundance and the production of both metabolites higher in tumors from the kinase-signaling cluster. This is the first evidence of the importance of CYP- derived AA metabolites in the biology and development of pheochromocytoma/paraganglioma tumors.

GPR75 receptor mediates 20-HETE-signaling and metastatic features of androgen-insensitive prostate cancer cells.

PURPOSE: Recent studies have shown that 20-hydroxyeicosatetraenoic acid (20-HETE) is a key molecule in sustaining androgen-mediated prostate cancer cell survival. Thus, the aim of this study was to determine whether 20-HETE can affect the metastatic potential of androgen-insensitive prostate cancer cells, and the implication of the newly described 20-HETE receptor, GPR75, in mediating these effects. METHODS: The expression of GPR75, protein phosphorylation, actin polymerization and protein distribution were assessed by western blot and/or fluorescence microscopy. Additionally, in vitro assays including epithelial-mesenchymal transition (EMT), metalloproteinase-2 (MMP-2) activity, scratch wound healing, transwell invasion and soft agar colony formation were used to evaluate the effects of 20-HETE agonists/antagonists or GPR75 gene silencing on the aggressive features of PC-3 cells. RESULTS: 20-HETE (0.1 nM) promoted the acquisition of a mesenchymal phenotype by increasing EMT, the release of MMP-2, cell migration and invasion, actin stress fiber formation and anchorage-independent growth. Also, 20-HETE augmented the expression of HIC-5, the phosphorylation of EGFR, NF-κB, AKT and p-38 and the intracellular redistribution of p-AKT and PKCα. These effects were impaired by GPR75 antagonism and/or silencing. Accordingly, the inhibition of 20-HETE formation with N-hydroxy-N'-(4-n-butyl-2-methylphenyl) formamidine (HET0016) elicited the opposite effects. CONCLUSIONS: The present results show for the first time the involvement of the 20-HETE-GPR75 receptor in the activation of intracellular signaling known to be stimulated in cell malignant transformations leading to the differentiation of PC-3 cells towards a more aggressive phenotype. Targeting the 20-HETE/GPR75 pathway is a promising and novel approach to interfere with prostate tumor cell malignant progression.

TGF-ß Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia.

Fanconi anemia (FA) is an inherited DNA repair disorder characterized by progressive bone marrow failure (BMF) from hematopoietic stem and progenitor cell (HSPC) attrition. A greater understanding of the pathogenesis of BMF could improve the therapeutic options for FA patients. Using a genome-wide shRNA screen in human FA fibroblasts, we identify transforming growth factor-ß (TGF-ß) pathway-mediated growth suppression as a cause of BMF in FA. Blocking the TGF-ß pathway improves the survival of FA cells and rescues the proliferative and functional defects of HSPCs derived from FA mice and FA patients. Inhibition of TGF-ß signaling in FA HSPCs results in elevated homologous recombination (HR) repair with a concomitant decrease in non-homologous end-joining (NHEJ), accounting for the improvement in cellular growth. Together, our results suggest that elevated TGF-ß signaling contributes to BMF in FA by impairing HSPC function and may be a potential therapeutic target for the treatment of FA.

FANCD2 activates transcription of TAp63 and suppresses tumorigenesis.

Fanconi anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras-oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population.