Developmental exposure to 17-α-hydroxyprogesterone caproate disrupts decision-making in adult female rats: A potential role for a dopaminergic mechanism.

The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals at risk for preterm birth and is likely transferred from mother to fetus. Yet, there is little information regarding the potential effects of 17-OHPC administration on behavioral and neural development in offspring. In rats, neonatal 17-OHPC exposure altered dopaminergic fiber distribution and density in the prelimbic medial prefrontal cortex (mPFC) in neonates and adolescents, respectively. Additionally, neonatal 17-OHPC exposure in male rats increased response omissions in a delay discounting task of impulsive decision-making. Because developmental 17-OHPC exposure has differential effects in males and females, investigating the effects of 17-OHPC on impulsive decision-making in female rats is necessary. The present study tested the effects of developmental 17-OHPC exposure (P1-P14) in a delay discounting task in which female rats chose between a small immediate reward and a larger delayed (0, 15 30, or 45 s) reward. 17-OHPC-exposed females made more omissions than controls. There was no effect of 17-OHPC on large reward preference nor on response time, and omissions were similar during both free- and forced-choice trials. The present study also aimed to investigate the neural mechanisms underlying omissions in 17-OHPC-exposed female rats. The dopamine transporter inhibitor, methylphenidate (MPH), was administered prior to delay discounting testing. MPH treatment did not reduce omissions in 17-OHPC-exposed females. If anything, MPH increased omissions in control females nearly fourfold during the longest delays. These results suggest that developmental 17-OHPC exposure increased omissions without affecting impulsivity or slowing decision-making. Furthermore, omissions may be regulated, at least in part, by dopaminergic mechanisms.

Glycogen phase separation drives macromolecular rearrangement and asymmetric division in E. coli.

Bacteria often experience nutrient limitation in nature and the laboratory. While exponential and stationary growth phases are well characterized in the model bacterium Escherichia coli, little is known about what transpires inside individual cells during the transition between these two phases. Through quantitative cell imaging, we found that the position of nucleoids and cell division sites becomes increasingly asymmetric during transition phase. These asymmetries were coupled with spatial reorganization of proteins, ribosomes, and RNAs to nucleoid-centric localizations. Results from live-cell imaging experiments, complemented with genetic and 13C whole-cell nuclear magnetic resonance spectroscopy studies, show that preferential accumulation of the storage polymer glycogen at the old cell pole leads to the observed rearrangements and asymmetric divisions. In vitro experiments suggest that these phenotypes are likely due to the propensity of glycogen to phase separate in crowded environments, as glycogen condensates exclude fluorescent proteins under physiological crowding conditions. Glycogen-associated differences in cell sizes between strains and future daughter cells suggest that glycogen phase separation allows cells to store large glucose reserves without counting them as cytoplasmic space.

An evaluation of the German version of the Sensory Perception Quotient from an expert by experience perspective.

Sensory processing is often altered in individuals with autism; thus, it is essential to develop reliable measurement tools to assess sensory perception. The Sensory Perception Quotient (SPQ) quantifies basic sensory sensitivities in adults via self-report. Adopting an expert by experience perspective, this study aimed to evaluate a German translation of the SPQ for its use in clinical and research applications, especially for autistic adults. 108 adults (n = 54 autistic) completed the German SPQ in an online assessment. A 92-item and a 35-item version of the German SPQ were analyzed for group differences and internal consistency. Our results show that adults with autism reported greater sensory sensitivity compared to non-autistic adults. Results further suggest good to excellent internal consistency for the 95-item and 35-item SPQ translations. This finding was supported by the correlative relationship between sensory sensitivity and autistic traits. These findings confirm the reliability of our SPQ translation, making it a suitable German assessment tool for basic sensory sensitivity in autistic adults.

Reduced stereotypicality and spared use of facial expression predictions for social evaluation in autism.

Background/Objective: Autism has been investigated through traditional emotion recognition paradigms, merely investigating accuracy, thereby constraining how potential differences across autistic and control individuals may be observed, identified, and described. Moreover, the use of emotional facial expression information for social functioning in autism is of relevance to provide a deeper understanding of the condition. Method: Adult autistic individuals (n = 34) and adult control individuals (n = 34) were assessed with a social perception behavioral paradigm exploring facial expression predictions and their impact on social evaluation. Results: Autistic individuals held less stereotypical predictions than controls. Importantly, despite such differences in predictions, the use of such predictions for social evaluation did not differ significantly between groups, as autistic individuals relied on their predictions to evaluate others to the same extent as controls. Conclusions: These results help to understand how autistic individuals perceive social stimuli and evaluate others, revealing a deviation from stereotypicality beyond which social evaluation strategies may be intact.

Classifying autism in a clinical population based on motion synchrony: a proof-of-concept study using real-life diagnostic interviews.

Predictive modeling strategies are increasingly studied as a means to overcome clinical bottlenecks in the diagnostic classification of autism spectrum disorder. However, while some findings are promising in the light of diagnostic marker research, many of these approaches lack the scalability for adequate and effective translation to everyday clinical practice. In this study, our aim was to explore the use of objective computer vision video analysis of real-world autism diagnostic interviews in a clinical sample of children and young individuals in the transition to adulthood to predict diagnosis. Specifically, we trained a support vector machine learning model on interpersonal synchrony data recorded in Autism Diagnostic Observation Schedule (ADOS-2) interviews of patient-clinician dyads. Our model was able to classify dyads involving an autistic patient (n = 56) with a balanced accuracy of 63.4% against dyads including a patient with other psychiatric diagnoses (n = 38). Further analyses revealed no significant associations between our classification metrics with clinical ratings. We argue that, given the above-chance performance of our classifier in a highly heterogeneous sample both in age and diagnosis, with few adjustments this highly scalable approach presents a viable route for future diagnostic marker research in autism.

Machine learning classification of autism spectrum disorder based on reciprocity in naturalistic social interactions.

Autism spectrum disorder is characterized by impaired social communication and interaction. As a neurodevelopmental disorder typically diagnosed during childhood, diagnosis in adulthood is preceded by a resource-heavy clinical assessment period. The ongoing developments in digital phenotyping give rise to novel opportunities within the screening and diagnostic process. Our aim was to quantify multiple non-verbal social interaction characteristics in autism and build diagnostic classification models independent of clinical ratings. We analyzed videos of naturalistic social interactions in a sample including 28 autistic and 60 non-autistic adults paired in dyads and engaging in two conversational tasks. We used existing open-source computer vision algorithms for objective annotation to extract information based on the synchrony of movement and facial expression. These were subsequently used as features in a support vector machine learning model to predict whether an individual was part of an autistic or non-autistic interaction dyad. The two prediction models based on reciprocal adaptation in facial movements, as well as individual amounts of head and body motion and facial expressiveness showed the highest precision (balanced accuracies: 79.5% and 68.8%, respectively), followed by models based on reciprocal coordination of head (balanced accuracy: 62.1%) and body (balanced accuracy: 56.7%) motion, as well as intrapersonal coordination processes (balanced accuracy: 44.2%). Combinations of these models did not increase overall predictive performance. Our work highlights the distinctive nature of non-verbal behavior in autism and its utility for digital phenotyping-based classification. Future research needs to both explore the performance of different prediction algorithms to reveal underlying mechanisms and interactions, as well as investigate the prospective generalizability and robustness of these algorithms in routine clinical care.

Interacting with autistic virtual characters: intrapersonal synchrony of nonverbal behavior affects participants' perception.

Temporal coordination of communicative behavior is not only located between but also within interaction partners (e.g., gaze and gestures). This intrapersonal synchrony (IaPS) is assumed to constitute interpersonal alignment. Studies show systematic variations in IaPS in individuals with autism, which may affect the degree of interpersonal temporal coordination. In the current study, we reversed the approach and mapped the measured nonverbal behavior of interactants with and without ASD from a previous study onto virtual characters to study the effects of the differential IaPS on observers (N = 68), both with and without ASD (crossed design). During a communication task with both characters, who indicated targets with gaze and delayed pointing gestures, we measured response times, gaze behavior, and post hoc impression formation. Results show that character behavior indicative of ASD resulted in overall enlarged decoding times in observers and this effect was even pronounced in observers with ASD. A classification of observer's gaze types indicated differentiated decoding strategies. Whereas non-autistic observers presented with a rather consistent eyes-focused strategy associated with efficient and fast responses, observers with ASD presented with highly variable decoding strategies. In contrast to communication efficiency, impression formation was not influenced by IaPS. The results underline the importance of timing differences in both production and perception processes during multimodal nonverbal communication in interactants with and without ASD. In essence, the current findings locate the manifestation of reduced reciprocity in autism not merely in the person, but in the interactional dynamics of dyads.

Through the looking glass: An adventure into the metastable world of the bacterial cytoplasm.

This personal story recounts the accidental observation, the struggles, the breakthroughs, and the collaborative spirit of a few individuals that led to the discovery that bacterial cells expend energy to effectively fluidize their otherwise "glass-like" cytoplasm and promote the dispersal of large cytoplasmic components. This adventure, which led us into an uncharted world at the intersection of cell biology and condensed matter physics about ten years ago, forever transformed the way I view cells and conduct research.

Individual and Community level Developmental Adversities: Associations with Marijuana and Alcohol Use in Late-Adolescents and Young Adults.

Exposure to community and individual level stressors during adolescence has been reported to be associated with increased substance use. However, it remains unclear what the relative contribution of different community- and individual-level factors play when alcohol and marijuana use become more prevalent during late adolescence. The present study uses a large longitudinal sample of adolescents (Wave 1: N = 2017; 55% Female; 54.5% White, 22.3% Black, 8% Hispanic, 15% other) to evaluate the association and potential interactions between community- and individual-level factors and substance use from adolescence to young adulthood (Wave 1 to Wave 3 Age Mean [SD]: 16.7 [1.1], 18.3 [1.2], 19.3 [1.2]). Across three waves of data, multilevel modeling (MLM) is used to evaluate the association between community affluence and disadvantage, individual household socioeconomic status (SES, measured as parental level of education and self-reported public assistance) and self-reported childhood maltreatment with self-reported 12-month alcohol and 12-month marijuana use occasions. Sample-selection weights and attrition-adjusted weights are accounted for in the models to evaluate the robustness of the estimated effects. Across the MLMs, there is a significant positive association between community affluence and parental education with self-reported alcohol use but not self-reported marijuana use. In post hoc analyses, higher neighborhood affluence in older adolescents is associated with higher alcohol use and lower use in younger adolescents; the opposite association is found for neighborhood disadvantage. Consistent with past literature, there is a significant positive association between self-reported childhood maltreatment and self-reported 12-month alcohol and 12-month marijuana use. Results are largely consistent across weighted and unweighted analyses, however, in weighted analyses there is a significant negative association between community disadvantage and self-reported 12-month alcohol use. This study demonstrates a nuanced relationship between community- and individual-level factors and substance use during the transitional window of adolescence which should be considered when contextualizing and interpreting normative substance use during adolescence.

Targeting Borrelia burgdorferi HtpG with a berserker molecule, a strategy for anti-microbial development.

Conventional antimicrobial discovery relies on targeting essential enzymes in pathogenic organisms, contributing to a paucity of new antibiotics to address resistant strains. Here, by targeting a non-essential enzyme, Borrelia burgdorferi HtpG, to deliver lethal payloads, we expand what can be considered druggable within any pathogen. We synthesized HS-291, an HtpG inhibitor tethered to the photoactive toxin verteporfin. Reactive oxygen species, generated by light, enables HS-291 to sterilize Borrelia cultures by causing oxidation of HtpG, and a discrete subset of proteins in proximity to the chaperone. This caused irreversible nucleoid collapse and membrane blebbing. Tethering verteporfin to the HtpG inhibitor was essential, since free verteporfin was not retained by Borrelia in contrast to HS-291. For this reason, we liken HS-291 to a berserker, wreaking havoc upon the pathogen's biology once selectively absorbed and activated. This strategy expands the druggable pathogenic genome and offsets antibiotic resistance by targeting non-essential proteins.

Apparent simplicity and emergent robustness in the control of the Escherichia coli cell cycle.

To examine how bacteria achieve robust cell proliferation across diverse conditions, we developed a method that quantifies 77 cell morphological, cell cycle, and growth phenotypes of a fluorescently labeled Escherichia coli strain and >800 gene deletion derivatives under multiple nutrient conditions. This approach revealed extensive phenotypic plasticity and deviating mutant phenotypes were often nutrient dependent. From this broad phenotypic landscape emerged simple and robust unifying rules (laws) that connect DNA replication initiation, nucleoid segregation, FtsZ ring formation, and cell constriction to specific aspects of cell size (volume, length, or added length) at the population level. Furthermore, completion of cell division followed the initiation of cell constriction after a constant time delay across strains and nutrient conditions, identifying cell constriction as a key control point for cell size determination. Our work provides a population-level description of the governing principles by which E. coli integrates cell cycle processes and growth rate with cell size to achieve its robust proliferative capability. A record of this paper's transparent peer review process is included in the supplemental information.

[Autism spectrum disorder in adulthood]. / Autismus-Spektrum-Störung im Erwachsenenalter.

Autism is a neurodevelopmental disorder that starts in early childhood and persists over the lifespan. A combination of genetic factors and environmental factors around birth contribute to its etiology. Autistic individuals show differences and difficulties in social interaction and communication as well as repetitive, stereotypical behavior and interests. The diagnostic procedure is complex and should be carried out in a specialized assessment unit. Diagnostic assessment is based on behavioral observation and a careful evaluation of developmental history. A wide range of potential differential diagnoses should be considered. Autistic adults have a higher risk of developing psychiatric disorders such as anxiety and depression. Psychotherapeutic treatment that is adapted to autism-related difficulties can be helpful. Co-occurring conditions should be treated in accordance with disorder-specific guidelines. Psychopharmacological treatment of co-occurring conditions is, in most cases, only recommended as an addition to behavioral interventions. Autistic people often experience difficulties in social participation, which can be targeted with sociotherapeutic interventions.

A conserved isoleucine in the binding pocket of RIG-I controls immune tolerance to mitochondrial RNA.

RIG-I is a cytosolic receptor of viral RNA essential for the immune response to numerous RNA viruses. Accordingly, RIG-I must sensitively detect viral RNA yet tolerate abundant self-RNA species. The basic binding cleft and an aromatic amino acid of the RIG-I C-terminal domain(CTD) mediate high-affinity recognition of 5'triphosphorylated and 5'base-paired RNA(dsRNA). Here, we found that, while 5'unmodified hydroxyl(OH)-dsRNA demonstrated residual activation potential, 5'-monophosphate(5'p)-termini, present on most cellular RNAs, prevented RIG-I activation. Determination of CTD/dsRNA co-crystal structures and mutant activation studies revealed that the evolutionarily conserved I875 within the CTD sterically inhibits 5'p-dsRNA binding. RIG-I(I875A) was activated by both synthetic 5'p-dsRNA and endogenous long dsRNA within the polyA-rich fraction of total cellular RNA. RIG-I(I875A) specifically interacted with long, polyA-bearing, mitochondrial(mt) RNA, and depletion of mtRNA from total RNA abolished its activation. Altogether, our study demonstrates that avoidance of 5'p-RNA recognition is crucial to prevent mtRNA-triggered RIG-I-mediated autoinflammation.

Differentiated, rather than shared, strategies for time-coordinated action in social and non-social domains in autistic individuals.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a highly heterogeneous adult phenotype that includes social and non-social behavioral characteristics. The link between the characteristics assignable to the different domains remains unresolved. One possibility is that social and non-social behaviors in autism are modulated by a common underlying deficit. However, here we report evidence supporting an alternative concept that is individual-centered rather than deficit-centered. Individuals are assumed to have a distinctive style in the strategies they adopt to perform social and non-social tasks with these styles presumably being structured differently between autistic individuals and typically-developed (TD) individuals. We tested this hypothesis for the execution of time-coordinated (synchronized) actions. Participants performed (i) a social task that required synchronized gaze and pointing actions to interact with another person, and (ii) a non-social task that required finger-tapping actions synchronized to periodic stimuli at different time-scales and sensory modalities. In both tasks, synchronization behavior differed between ASD and TD groups. However, a principal component analysis of individual behaviors across tasks revealed associations between social and non-social features for the TD persons but such cross-domain associations were strikingly absent for autistic individuals. The highly differentiated strategies between domains in ASD are inconsistent with a general synchronization deficit and instead highlight the individualized developmental heterogeneity in the acquisition of domain-specific behaviors. We propose a cognitive model to help disentangle individual-centered from deficit-centered effects in other domains. Our findings reinforce the importance to identify individually differentiated phenotypes to personalize autism therapies.

Organization and replicon interactions within the highly segmented genome of Borrelia burgdorferi.

Borrelia burgdorferi, a causative agent of Lyme disease, contains the most segmented bacterial genome known to date, with one linear chromosome and over twenty plasmids. How this unusually complex genome is organized, and whether and how the different replicons interact are unclear. We recently demonstrated that B. burgdorferi is polyploid and that the copies of the chromosome and plasmids are regularly spaced in each cell, which is critical for faithful segregation of the genome to daughter cells. Regular spacing of the chromosome is controlled by two separate partitioning systems that involve the protein pairs ParA/ParZ and ParB/Smc. Here, using chromosome conformation capture (Hi-C), we characterized the organization of the B. burgdorferi genome and the interactions between the replicons. We uncovered that although the linear chromosome lacks contacts between the two replication arms, the two telomeres are in frequent contact. Moreover, several plasmids specifically interact with the chromosome oriC region, and a subset of plasmids interact with each other more than with others. We found that Smc and the Smc-like MksB protein mediate long-range interactions on the chromosome, but they minimally affect plasmid-chromosome or plasmid-plasmid interactions. Finally, we found that disruption of the two partition systems leads to chromosome restructuring, correlating with the mis-positioning of chromosome oriC. Altogether, this study revealed the conformation of a complex genome and analyzed the contribution of the partition systems and SMC family proteins to this organization. This work expands the understanding of the organization and maintenance of multipartite bacterial genomes.

Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment.

Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/ß2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.

Synchrony in psychotherapy: High physiological positive concordance predicts symptom reduction and negative concordance predicts symptom aggravation.

OBJECTIVE: Therapeutic alliance is often considered as a predictor for therapeutic success. This study explored dyadic synchrony of skin conductance response (SCR) during naturalistic therapeutic interactions and investigated its potential as an objective biomarker for predicting therapy effectiveness. METHODS: In this proof-of-concept study, skin conductance from both dyad members was continuously measured via wristbands during psychotherapy. Patients and therapists completed post-session reports capturing their subjective appraisal of therapeutic alliance. Additionally, patients completed symptom questionnaires. Each therapeutic dyad was recorded twice in a follow-up design. The first session of the follow-up group was assessed for physiological synchrony (Single Session Index (SSI)). Therapy outcome was captured by the difference between symptom severity scores over time. RESULTS: SCR synchrony significantly predicted the outcome variable of change in patients' global severity index (GSI). High positive SCR concordance was linked to a reduction in patients' GSI, while negative or small positive SSI values were linked to an increase in patients' GSI. CONCLUSION: The results demonstrate the presence of SCR synchrony in clinical interactions. Skin conductance response synchrony was a significant predictor for change in patients' symptom severity index, emphasizing its potential as an objective biomarker in the context of evidence-based psychotherapy.

What is specific about employment status, workplace experiences and requirements in individuals with autism in Germany?

The challenge of sustainably integrating highly educated individuals with ASD without intellectual disabilities in the first labor market is repeatedly described in literature. In a retrospective study, a group of 197 clinically late-diagnosed adults with ASD without intellectual disabilities was compared to a closely matched group of 501 individuals who did not meet the criteria for the diagnosis of ASD within a utilization population of the Cologne Autism Outpatient Clinic. Results indicated that the pronounced demand for reduction of social and interpersonal requirements at the workplace (including planned or limited contact with colleagues and customers) as well as the experience of difficulties following unexpected changes in the daily routine were specific for ASD. In addition, individuals with ASD reported greater difficulties in finding a suitable job and being able to live on their wages, taking age and educational qualification into account. Supported employment measures were provided significantly more frequently to individuals in the ASD group. In conclusion, impairments in social skills emerged as one of the main obstacles of workplace performance for individuals with ASD emphasizing the necessity to develop and apply ASD-specific support services.