Smiling synchronization predicts interaction enjoyment in peer dyads of autistic and neurotypical youth.

LAY ABSTRACT: For autistic and neurotypical youth, having positive social interactions with other youth is an important part of well-being. Other researchers have found that one factor that can make people feel like social interactions have gone well is synchronization. Synchronization happens when peoples' body movements and facial expressions align while they're interacting. We focus on smiling synchronization here because other studies have found that when neurotypical individuals synchronize their smiles more in a social interaction, they say they enjoy that social interaction more. However, no studies have directly tested whether smiling synchrony influences social interaction enjoyment in autistic and neurotypical youth. We measured smiling synchrony in pairs of interacting autistic and neurotypical youth who were meeting each other for the first time. Some pairs were autistic youth interacting with other autistic youth (autistic with autistic participant pairs), some pairs were autistic youth interacting with neurotypical youth (autistic with neurotypical participant pairs), and other pairs were neurotypical youth interacting with neurotypical youth (neurotypical with neurotypical participant pairs). We found that autistic with neurotypical participant pairs had lower smiling synchrony than neurotypical with neurotypical participant pairs. Youth who were in dyads that had more smiling synchrony said they enjoyed interacting with their partner more and that they wanted to interact with their partner again. Our research shows that smiling synchrony is one part of interactions between autistic and neurotypical youth that influences how well youth say the interaction went. Identifying natural opportunities for autistic and neurotypical youth to share positive feelings could be one way to promote positive social interactions between autistic and neurotypical youth.

Co-Packaged PARP inhibitor and photosensitizer for targeted photo-chemotherapy of 3D ovarian cancer spheroids.

BACKGROUND: Within the last decade, poly(ADP-ribose) polymerase inhibitors (PARPi) have emerged in the clinic as an effective treatment for numerous malignancies. Preclinical data have demonstrated powerful combination effects of PARPi paired with photodynamic therapy (PDT), which involves light-activation of specialized dyes (photosensitizers) to stimulate cancer cell death through reactive oxygen species generation. RESULTS: In this report, the most potent clinical PARP inhibitor, talazoparib, is loaded into the core of a polymeric nanoparticle (NP-Tal), which is interfaced with antibody-photosensitizer conjugates (photoimmunoconjugates, PICs) to form PIC-NP-Tal. In parallel, a new 3D fluorescent coculture model is developed using the parental OVCAR-8-DsRed2 and the chemo-resistant subline, NCI/ADR-RES-EGFP. This model enables quantification of trends in the evolutionary dynamics of acquired chemoresistance in response to various treatment regimes. Results reveal that at a low dosage (0.01 µM), NP-Tal kills the parental cells while sparing the chemo-resistant subline, thereby driving chemoresistance. Next, PIC-NP-Tal and relevant controls are evaluated in the 3D coculture model at multiple irradiation doses to characterize effects on total spheroid ablation and relative changes in parental and subline cell population dynamics. Total spheroid ablation data shows potent combination effects when PIC and NP-Tal are co-administered, but decreased efficacy with the conjugated formulation (PIC-NP-Tal). Analysis of cell population dynamics reveals that PIC, BPD + NP-Tal, PIC + NP-Tal, and PIC-NP-Tal demonstrate selection pressures towards chemoresistance. CONCLUSIONS: This study provides key insights into manufacturing parameters for PARPi-loaded nanoparticles, as well as the potential role of PDT-based combination therapies in the context of acquired drug resistance.

Neural sensitivity to social reward predicts links between social behavior and loneliness in youth during the COVID-19 pandemic.

Neural reward network sensitivity in youth is proposed to differentially impact the effects of social environments on social outcomes. The COVID-19 pandemic provided an opportunity to test this hypothesis within a context of diminished in-person social interaction. We examined whether neural sensitivity to interactive social reward moderates the relationship between a frequency of interactive or passive social activity and social satisfaction. Survey reports of frequency of interactions with friends, passive social media use, and loneliness and social satisfaction were gathered in 2020 during mandated precautions limiting in-person contact. A subset of participants (age = 10-17) previously participated in a functional magnetic resonance imaging (fMRI) study examining social-interactive reward during a simulated peer interaction (survey n = 76; survey + fMRI n = 40). We found evidence of differential response to social context, such that youth with higher neural reward sensitivity showed a negative association between a frequency of interactive connections with friends and a combined loneliness and social dissatisfaction component (LSDC) score, whereas those with lower sensitivity showed the opposite effect. Further, high reward sensitivity was associated with greater LSDC as passive social media use increased, whereas low reward sensitivity showed the opposite. This indicates that youth with greater sensitivity to social-interactive reward may be more susceptible to negative effects of infrequent contact than their low reward-sensitive counterparts, who instead maintain social well-being through passive viewing of social content. These differential outcomes could have implications for supporting youth during times of major social disruption as well as ensuring mental health and well-being more broadly.

Transient fluid flow improves photoimmunoconjugate delivery and photoimmunotherapy efficacy.

Circulating drugs in the peritoneal cavity is an effective strategy for advanced ovarian cancer treatment. Photoimmunotherapy, an emerging modality with potential for the treatment of ovarian cancer, involves near-infrared light activation of antibody-photosensitizer conjugates (photoimmunoconjugates) to generate cytotoxic reactive oxygen species. Here, a microfluidic cell culture model is used to study how fluid flow-induced shear stress affects photoimmunoconjugate delivery to ovarian cancer cells. Photoimmunoconjugates are composed of the antibody, cetuximab, conjugated to the photosensitizer, and benzoporphyrin derivative. Longitudinal tracking of photoimmunoconjugate treatment under flow conditions reveals enhancements in subcellular photosensitizer accumulation. Compared to static conditions, fluid flow-induced shear stress at 0.5 and 1 dyn/cm2 doubled the cellular delivery of photoimmunoconjugates. Fluid flow-mediated treatment with three different photosensitizer formulations (benzoporphyrin derivative, photoimmunoconjugates, and photoimmunoconjugate-coated liposomes) led to enhanced phototoxicity compared to static conditions. This study confirms the fundamental role of fluid flow-induced shear stress in the anti-cancer effects of photoimmunotherapy.

Social reward network connectivity differs between autistic and neurotypical youth during social interaction.

A core feature of autism is difficulties with social interaction. Atypical social motivation is proposed to underlie these difficulties. However, prior work testing this hypothesis has shown mixed support and has been limited in its ability to understand real-world social-interactive processes in autism. We attempted to address these limitations by scanning neurotypical and autistic youth (n = 86) during a text-based reciprocal social interaction that mimics a "live" chat and elicits social reward processes. We focused on task-evoked functional connectivity (FC) of regions responsible for motivational-reward and mentalizing processes within the broader social reward circuitry. We found that task-evoked FC between these regions was significantly modulated by social interaction and receipt of social-interactive reward. Compared to neurotypical peers, autistic youth showed significantly greater task-evoked connectivity of core regions in the mentalizing network (e.g., posterior superior temporal sulcus) and the amygdala, a key node in the reward network. Furthermore, across groups, the connectivity strength between these mentalizing and reward regions was negatively correlated with self-reported social motivation and social reward during the scanner task. Our results highlight an important role of FC within the broader social reward circuitry for social-interactive reward. Specifically, greater context-dependent FC (i.e., differences between social engagement and non-social engagement) may indicate an increased "neural effort" during social reward and relate to differences in social motivation within autistic and neurotypical populations.

Social-interactive reward elicits similar neural response in autism and typical development and predicts future social experiences.

Challenges in initiating and responding to social-interactive exchanges are a key diagnostic feature of autism spectrum disorder, yet investigations into the underlying neural mechanisms of social interaction have been hampered by reliance on non-interactive approaches. Using an innovative social-interactive neuroscience approach, we investigated differences between youth with autism and youth with typical development in neural response to a chat-based social-interactive reward, as well as factors such as age and self-reported social enjoyment that may account for heterogeneity in that response. We found minimal group differences in neural and behavioral response to social-interactive reward, and variation within both groups was related to self-reported social enjoyment during the task. Furthermore, neural sensitivity to social-interactive reward predicted future enjoyment of a face-to-face social interaction with a novel peer. These findings have important implications for understanding the nature of social reward and peer interactions in typical development as well as for future research informing social interactions in individuals on the autism spectrum.

Effects of sex and pro-inflammatory cytokines on context discrimination memory.

In learning and memory tasks, immune overactivation is associated with impaired performance, while normal immune activation is associated with optimal performance. In one specific domain of memory, context discrimination memory, peripheral immune stimulation has been shown to impair performance on the context-object discrimination memory task in male rats. In order to evaluate potential sex differences in this task, as well as potential mechanisms for the memory impairment, we evaluated the ability of peripheral immune stimulation to impair task performance in both males and females. Next, we examined whether treatment with interleukin-1 receptor antagonist (IL-1ra), a receptor antagonist for the pro-inflammatory cytokine interleukin (IL)-1ß, was able to rescue the memory deficit. We examined microglial morphology in the hippocampus and cytokine mRNA and protein expression in the hippocampus and the periphery. Male rats displayed memory impairment in response to LPS, and this impairment was not rescued by IL-1ra. Female rats did not have significant memory impairments and IL-1ra administration improved memory following inflammation. A subset of cytokines and chemokines were increased only in LPS-treated males. Inflammation alone did not alter microglia morphology, but IL-1ra did in certain sub-regions of the hippocampus. Together, these results indicate that sex differences exist in the ability of a peripheral immune stimulus to influence context discrimination memory and specific cytokine signals may be altered in impaired males. This study highlights the importance of sex differences in response to inflammatory challenges, especially related to memory impairments in context discrimination memory.

Theory of mind in naturalistic conversations between autistic and typically developing children and adolescents.

LAY ABSTRACT: Conversation is a key part of everyday social interactions. Previous studies have suggested that conversational skills are related to theory of mind, the ability to think about other people's mental states, such as beliefs, knowledge, and emotions. Both theory of mind and conversation are common areas of difficulty for autistic people, yet few studies have investigated how people, including autistic people, use theory of mind during conversation. We developed a new way of measuring cToM using two rating scales: cToM Positive captures behaviors that show consideration of a conversation partner's mental states, such as referring to their thoughts or feelings, whereas cToM Negative captures behaviors that show a lack of theory of mind through violations of neurotypical conversational norms, such as providing too much, too little, or irrelevant information. We measured cToM in 50 pairs of autistic and typically developing children (ages 8-16 years) during 5-min "getting to know you" conversations. Compared to typically developing children, autistic children displayed more frequent cToM Negative behaviors but very similar rates of cToM Positive behaviors. Across both groups, cToM Negative (but not Positive) ratings were related to difficulties in recognizing emotions from facial expressions and a lower tendency to talk about others' mental states spontaneously (i.e., without being instructed to do so), which suggests that both abilities are important for theory of mind in conversation. Altogether, this study highlights both strengths and difficulties among autistic individuals, and it suggests possible avenues for further research and for improving conversational skills.

Interpersonal Synchrony in Autism.

PURPOSE OF REVIEW: We review evidence for the presence, quality, and correlates of interpersonal synchrony in autism spectrum disorder (ASD) across four domains: motor, conversational, physiological, and neural. We also propose cognitive and neural mechanisms for the disruption of interpersonal synchrony and investigate synchrony as a mechanism of intervention in ASD. RECENT FINDINGS: Across domains, synchrony is present but reduced or atypical in individuals with ASD during interactions with individuals with typical development (TD). Atypical synchrony may reflect the contribution of both intrapersonal mechanisms, such as atypical motor timing, and interpersonal mechanisms, such as atypical interindividual coupling. Research suggests evidence for synchrony interventions leading to improvements in some aspects of social behavior. Understanding synchrony in ASD has the potential to lead to biomarkers and interventions to support social functioning. However, further research should clarify mechanisms of atypical synchrony in ASD including taking features of the dyad into account.

Self-reported social impairments predict depressive disorder in adults with autism spectrum disorder.

In adults with autism spectrum disorder, co-occurring psychiatric conditions are prevalent, and depression is one of the most common co-occurring disorders. This study examined the relationship between depression and cognitive ability, autism symptom severity, and self-reported social impairments in autism spectrum disorder. A total of 33 adults with autism spectrum disorder and 28 adults with typical development completed a standardized psychiatric interview, cognitive test, measure of clinician-rated autism symptom severity, and self-report of social impairments. Nine participants with autism spectrum disorder (27%) met the criteria for a depressive disorder (autism spectrum disorder + depressive disorder). Relatively more females with autism spectrum disorder had a co-occurring depressive disorder. The typical development group had a higher intelligence quotient than the autism spectrum disorder group, but the autism spectrum disorder + depressive disorder group did not differ from the typical development or autism spectrum disorder group. While the autism spectrum disorder + depressive disorder group had lower clinician-rated autism symptom severity than the autism spectrum disorder group, the autism spectrum disorder + depressive disorder group reported more social impairments than the autism spectrum disorder group. Self-reported social impairments predicted depression in adults with autism spectrum disorder when accounting for symptom severity and cognitive ability. These findings suggest that more self-perceived social impairments are related to depressive disorders in autism spectrum disorder, and may help clinicians identify individuals who are vulnerable in developing a co-occurring depressive disorder. Future directions include follow-up studies with larger cohorts and longitudinal designs to support inferences regarding directionality of these relationships.

Systems genetics of sensation seeking.

Sensation seeking is a multifaceted, heritable trait which predicts the development of substance use and abuse in humans; similar phenomena have been observed in rodents. Genetic correlations among sensation seeking and substance use indicate shared biological mechanisms, but the genes and networks underlying these relationships remain elusive. Here, we used a systems genetics approach in the BXD recombinant inbred mouse panel to identify shared genetic mechanisms underlying substance use and preference for sensory stimuli, an intermediate phenotype of sensation seeking. Using the operant sensation seeking (OSS) paradigm, we quantified preference for sensory stimuli in 120 male and 127 female mice from 62 BXD strains and the C57BL/6J and DBA/2J founder strains. We used relative preference for the active and inactive levers to dissociate preference for sensory stimuli from locomotion and exploration phenotypes. We identified genomic regions on chromosome 4 (155.236-155.742 Mb) and chromosome 13 (72.969-89.423 Mb) associated with distinct behavioral components of OSS. Using publicly available behavioral data and mRNA expression data from brain regions involved in reward processing, we identified (a) genes within these behavioral QTL exhibiting genome-wide significant cis-eQTL and (b) genetic correlations among OSS phenotypes, ethanol phenotypes and mRNA expression. From these analyses, we nominated positional candidates for behavioral QTL associated with distinct OSS phenotypes including Gnb1 and Mef2c. Genetic covariation of Gnb1 expression, preference for sensory stimuli and multiple ethanol phenotypes suggest that heritable variation in Gnb1 expression in reward circuitry partially underlies the widely reported relationship between sensation seeking and substance use.

Sex and strain influence attribution of incentive salience to reward cues in mice.

The propensity to attribute incentive salience to reward cues, measured by Pavlovian sign-tracking, is strongly associated with addiction-related traits including cocaine self-administration, impulsivity, novelty reactivity, and novelty preference. Despite its critical role in addiction, the genetic underpinnings of incentive salience attribution and its relationship to drug addiction are unknown. Mouse genetics can be a powerful means to discover genetic mechanisms underlying this relationship. However, feasibility of genetic dissection of sign-tracking in mice is unknown as only a single study limited to male C57BL/6J mice has rigorously examined this behavior, and limited sign-tracking was observed. Highly diverse mouse populations such as the Collaborative Cross (CC) and Diversity Outbred population (DO) possess a greater range of behavioral and genetic variation than conventional laboratory strains. In the present study, we evaluated sign-tracking and the related phenotype goal-tracking in mice of both sexes from five inbred CC and DO founder strains. Male CAST/EiJ mice exhibited robust sign-tracking; male NOD, male C57BL/6J, and female A/J mice also exhibited significant sign-tracking. Male and female mice from all strains exhibited significant goal-tracking, and significant strain and sex differences were observed. Sign-tracking in males was genetically correlated with exploration of a novel environment, and heritability of sign-tracking and goal-tracking ranged from .32 to .41. These data highlight the importance of considering genetic diversity when evaluating the occurrence of specific behavioral traits in the laboratory mouse and demonstrate that the CC and DO mouse populations can be used to discover mechanisms underlying genetic relationships among sign-tracking and addiction-related behaviors.

Kangaroo mother care diminishes pain from heel lance in very preterm neonates: a crossover trial.

BACKGROUND: Skin-to-skin contact, or kangaroo mother care (KMC) has been shown to be efficacious in diminishing pain response to heel lance in full term and moderately preterm neonates. The purpose of this study was to determine if KMC would also be efficacious in very preterm neonates. METHODS: Preterm neonates (n = 61) between 28 0/7 and 31 6/7 weeks gestational age in three Level III NICU's in Canada comprised the sample. A single-blind randomized crossover design was employed. In the experimental condition, the infant was held in KMC for 15 minutes prior to and throughout heel lance procedure. In the control condition, the infant was in prone position swaddled in a blanket in the incubator. The primary outcome was the Premature Infant Pain Profile (PIPP), which is comprised of three facial actions, maximum heart rate, minimum oxygen saturation levels from baseline in 30-second blocks from heel lance. The secondary outcome was time to recover, defined as heart rate return to baseline. Continuous video, heart rate and oxygen saturation monitoring were recorded with event markers during the procedure and were subsequently analyzed. Repeated measures analysis-of-variance was employed to generate results. RESULTS: PIPP scores at 90 seconds post lance were significantly lower in the KMC condition (8.871 (95%CI 7.852-9.889) versus 10.677 (95%CI 9.563-11.792) p < .001) and non-significant mean differences ranging from 1.2 to1.8. favoring KMC condition at 30, 60 and 120 seconds. Time to recovery was significantly shorter, by a minute(123 seconds (95%CI 103-142) versus 193 seconds (95%CI 158-227). Facial actions were highly significantly lower across all points in time reaching a two-fold difference by 120 seconds post-lance and heart rate was significantly lower across the first 90 seconds in the KMC condition. CONCLUSION: Very preterm neonates appear to have endogenous mechanisms elicited through skin-to-skin maternal contact that decrease pain response, but not as powerfully as in older preterm neonates. The shorter recovery time in KMC is clinically important in helping maintain homeostasis. TRIAL REGISTRATION: (Current Controlled Trials) ISRCTN63551708.

Zinc-coordination oligomers of phenanthrolinylporphyrins.

[structure: see text] We report the synthesis of mono- and bisphenanthrolinylporphyrins 5-(9-carboxy-1,10-phenanthroline-2),15-(p-tolyl)-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin (MPPc) and 5,15-bis(9-carboxy-1,10-phenanthroline-2)-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin (BPPc), respectively. The formation of dimers and oligomers, with MPPc and BPPc, respectively, upon exposure to zinc acetate is described. Oligomerization of the porphyrins was monitored spectrophotometrically, and a kinetic study was performed to estimate the average oligomer chain length.