Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment.

During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch-activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus 'poising' function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b expression, these inputs act in a stage-specific manner, providing a multitiered mechanism for developmental gene regulation.

NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness.

Adoptive transfer of T cells expressing chimeric antigen receptors (CAR-T) effectively treats refractory hematologic malignancies in a subset of patients but can be limited by poor T-cell expansion and persistence in vivo. Less differentiated T-cell states correlate with the capacity of CAR-T to proliferate and mediate antitumor responses, and interventions that limit tumor-specific T-cell differentiation during ex vivo manufacturing enhance efficacy. NOTCH signaling is involved in fate decisions across diverse cell lineages and in memory CD8+ T cells was reported to upregulate the transcription factor FOXM1, attenuate differentiation, and enhance proliferation and antitumor efficacy in vivo. Here, we used a cell-free culture system to provide an agonistic NOTCH1 signal during naïve CD4+ T-cell activation and CAR-T production and studied the effects on differentiation, transcription factor expression, cytokine production, and responses to tumor. NOTCH1 agonism efficiently induced a stem cell memory phenotype in CAR-T derived from naïve but not memory CD4+ T cells and upregulated expression of AhR and c-MAF, driving heightened production of interleukin-22, interleukin-10, and granzyme B. NOTCH1-agonized CD4+ CAR-T demonstrated enhanced antigen responsiveness and proliferated to strikingly higher frequencies in mice bearing human lymphoma xenografts. NOTCH1-agonized CD4+ CAR-T also provided superior help to cotransferred CD8+ CAR-T, driving improved expansion and curative antitumor responses in vivo at low CAR-T doses. Our data expand the mechanisms by which NOTCH can shape CD4+ T-cell behavior and demonstrate that activating NOTCH1 signaling during genetic modification ex vivo is a potential strategy for enhancing the function of T cells engineered with tumor-targeting receptors.

Dimensional and transdiagnostic phenotypes in psychiatric genome-wide association studies.

Genome-wide association studies (GWAS) provide biological insights into disease onset and progression and have potential to produce clinically useful biomarkers. A growing body of GWAS focuses on quantitative and transdiagnostic phenotypic targets, such as symptom severity or biological markers, to enhance gene discovery and the translational utility of genetic findings. The current review discusses such phenotypic approaches in GWAS across major psychiatric disorders. We identify themes and recommendations that emerge from the literature to date, including issues of sample size, reliability, convergent validity, sources of phenotypic information, phenotypes based on biological and behavioral markers such as neuroimaging and chronotype, and longitudinal phenotypes. We also discuss insights from multi-trait methods such as genomic structural equation modelling. These provide insight into how hierarchical 'splitting' and 'lumping' approaches can be applied to both diagnostic and dimensional phenotypes to model clinical heterogeneity and comorbidity. Overall, dimensional and transdiagnostic phenotypes have enhanced gene discovery in many psychiatric conditions and promises to yield fruitful GWAS targets in the years to come.

Guidelines for Evaluating the Comparability of Down-Sampled GWAS Summary Statistics.

Proprietary genetic datasets are valuable for boosting the statistical power of genome-wide association studies (GWASs), but their use can restrict investigators from publicly sharing the resulting summary statistics. Although researchers can resort to sharing down-sampled versions that exclude restricted data, down-sampling reduces power and might change the genetic etiology of the phenotype being studied. These problems are further complicated when using multivariate GWAS methods, such as genomic structural equation modeling (Genomic SEM), that model genetic correlations across multiple traits. Here, we propose a systematic approach to assess the comparability of GWAS summary statistics that include versus exclude restricted data. Illustrating this approach with a multivariate GWAS of an externalizing factor, we assessed the impact of down-sampling on (1) the strength of the genetic signal in univariate GWASs, (2) the factor loadings and model fit in multivariate Genomic SEM, (3) the strength of the genetic signal at the factor level, (4) insights from gene-property analyses, (5) the pattern of genetic correlations with other traits, and (6) polygenic score analyses in independent samples. For the externalizing GWAS, although down-sampling resulted in a loss of genetic signal and fewer genome-wide significant loci; the factor loadings and model fit, gene-property analyses, genetic correlations, and polygenic score analyses were found robust. Given the importance of data sharing for the advancement of open science, we recommend that investigators who generate and share down-sampled summary statistics report these analyses as accompanying documentation to support other researchers' use of the summary statistics.

A multivariate approach to understanding the genetic overlap between externalizing phenotypes and substance use disorders.

Substance use disorders (SUDs) are phenotypically and genetically correlated with each other and with other psychological traits characterized by behavioural under-control, termed externalizing phenotypes. In this study, we used genomic structural equation modelling to explore the shared genetic architecture among six externalizing phenotypes and four SUDs used in two previous multivariate genome-wide association studies of an externalizing and an addiction risk factor, respectively. We first evaluated five confirmatory factor analytic models, including a common factor model, alternative parameterizations of two-factor structures and a bifactor model. We next explored the genetic correlations between factors identified in these models and other relevant psychological traits. Finally, we quantified the degree of polygenic overlap between externalizing and addiction risk using MiXeR. We found that the common and two-factor structures provided the best fit to the data, evidenced by high factor loadings, good factor reliability and no evidence of concerning model characteristics. The two-factor models yielded high genetic correlations between factors (rg s ≥ 0.87), and between the effect sizes of genetic correlations with external traits (rg  ≥ 0.95). Nevertheless, 21 of the 84 correlations with external criteria showed small, significant differences between externalizing and addiction risk factors. MiXer results showed that approximately 81% of influential externalizing variants were shared with addiction risk, whereas addiction risk shared 56% of its influential variants with externalizing. These results suggest that externalizing and addiction genetic risk are largely shared, though both constructs also retain meaningful unshared genetic variance. These results can inform future efforts to identify specific genetic influences on externalizing and SUDs.

The Hierarchical Taxonomy of Psychopathology (HiTOP) in psychiatric practice and research.

The Hierarchical Taxonomy of Psychopathology (HiTOP) has emerged out of the quantitative approach to psychiatric nosology. This approach identifies psychopathology constructs based on patterns of co-variation among signs and symptoms. The initial HiTOP model, which was published in 2017, is based on a large literature that spans decades of research. HiTOP is a living model that undergoes revision as new data become available. Here we discuss advantages and practical considerations of using this system in psychiatric practice and research. We especially highlight limitations of HiTOP and ongoing efforts to address them. We describe differences and similarities between HiTOP and existing diagnostic systems. Next, we review the types of evidence that informed development of HiTOP, including populations in which it has been studied and data on its validity. The paper also describes how HiTOP can facilitate research on genetic and environmental causes of psychopathology as well as the search for neurobiologic mechanisms and novel treatments. Furthermore, we consider implications for public health programs and prevention of mental disorders. We also review data on clinical utility and illustrate clinical application of HiTOP. Importantly, the model is based on measures and practices that are already used widely in clinical settings. HiTOP offers a way to organize and formalize these techniques. This model already can contribute to progress in psychiatry and complement traditional nosologies. Moreover, HiTOP seeks to facilitate research on linkages between phenotypes and biological processes, which may enable construction of a system that encompasses both biomarkers and precise clinical description.

External validation of a bifactor model of oppositional defiant disorder.

Dimensions of irritability and defiant behavior, though correlated within the structure of ODD, convey separable developmental risks through adolescence and adulthood. Irritability predicts depression and anxiety, whereas defiant behavior is a precursor to antisocial outcomes. Previously we demonstrated that a bifactor model comprising irritability and defiant behavior dimensions, in addition to a general factor, provided the best-fitting structure of ODD symptoms in five large datasets. Herein we extend our previous work by externally validating the bifactor model of ODD using multiple regression and multivariate behavior genetic analyses. We used parent ratings of DSM IV ODD symptoms, and symptom dimensions for ADHD (i.e., inattention and hyperactivity-impulsivity), conduct disorder (CD), depression/dysthymia, and generalized anxiety disorder (GAD) from 846 6-18-year-old twin pairs. We found that the ODD irritability factor was associated only with depression/dysthymia and GAD and the ODD defiant behavior factor was associated only with inattention, hyperactivity-impulsivity, and CD, whereas the ODD general factor was associated with all five symptom dimensions. Multivariate behavior genetic analyses found all five symptom dimensions shared genetic influences in common with the ODD general, irritability, and defiant behavior factors. In contrast, the defiant behavior factor shared genetic influences uniquely with inattention and hyperactivity-impulsivity, whereas the irritability factor shared genetic influences uniquely with depression/dysthymia and GAD, but not vice versa. This suggests that genes that influence irritability in early childhood also predispose to depression and anxiety in adolescence and adulthood. These multivariate genetic findings also support the external validity of the three ODD dimensions at the etiological level. Our study provides additional support for subtyping ODD based on these symptom dimensions, as in the revisions in the ICD-11, and suggests potential mechanisms underlying the development from ODD to behavioral or affective disorders.

The Hierarchical Taxonomy of Psychopathology (HiTOP): A Quantitative Nosology Based on Consensus of Evidence.

Traditional diagnostic systems went beyond empirical evidence on the structure of mental health. Consequently, these diagnoses do not depict psychopathology accurately, and their validity in research and utility in clinicalpractice are therefore limited. The Hierarchical Taxonomy of Psychopathology (HiTOP) consortium proposed a model based on structural evidence. It addresses problems of diagnostic heterogeneity, comorbidity, and unreliability. We review the HiTOP model, supporting evidence, and conceptualization of psychopathology in this hierarchical dimensional framework. The system is not yet comprehensive, and we describe the processes for improving and expanding it. We summarize data on the ability of HiTOP to predict and explain etiology (genetic, environmental, and neurobiological), risk factors, outcomes, and treatment response. We describe progress in the development of HiTOP-based measures and in clinical implementation of the system. Finally, we review outstanding challenges and the research agenda. HiTOP is of practical utility already, and its ongoing development will produce a transformative map of psychopathology.

Development of a 19-plex short tandem repeat typing system for individual identification and parentage testing of horses (Equus caballus).

Individual identification of horses for pedigree verification and registration is important for the sustainable development of the horse industry. Horse individual identification and parentage tests commonly use the 17 short tandem repeats (STRs) recommended by the International Society for Animal Genetics (ISAG) and the locus LEX33. While many multiplex STR typing systems have been established for the horse, a sex determining marker is usually absent, and none of them can simultaneously detect all 17 ISAG recommended loci and the locus LEX33. Here, we present a 19-plex STR typing system that contains the 17 ISAG recommend loci, the locus LEX33 and amelogenin as sex determining loci. The results of our sensitivity, species specificity, stutter analysis and population data analysis, indicate that this system is a specific, sensitive, and robust tool for the identification of individuals, parentage testing and genetic research in the horse.

Les progrès dans la réalisation de la classification quantitative de la psychopathologie.

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is generally more dimensional than categorical. When the discreteness versus continuity of psychopathology is treated as a research question, as opposed to being decided as a matter of tradition, the evidence clearly supports the hypothesis of continuity. In addition, a related body of literature shows how psychopathology dimensions can be arranged in a hierarchy, ranging from very broad "spectrum level" dimensions, to specific and narrow clusters of symptoms. In this way, a quantitative approach solves the "problem of comorbidity" by explicitly modeling patterns of co-occurrence among signs and symptoms within a detailed and variegated hierarchy of dimensional concepts with direct clinical utility. Indeed, extensive evidence pertaining to the dimensional and hierarchical structure of psychopathology has led to the formation of the Hierarchical Taxonomy of Psychopathology (HiTOP) Consortium. This is a group of 70 investigators working together to study empirical classification of psychopathology. In this paper, we describe the aims and current foci of the HiTOP Consortium. These aims pertain to continued research on the empirical organization of psychopathology; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic; and the development of novel and comprehensive models and corresponding assessment instruments for psychopathology constructs derived from an empirical approach.

Hippocampal subfield pathologic burden in Lewy body diseases vs. Alzheimer's disease.

AIMS: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aß) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS: Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aß. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS: LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aß severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009). CONCLUSIONS: Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.

Correction to: The Association of Oxytocin Receptor Gene (OXTR) Polymorphisms with Antisocial Behavior: A Meta-analysis.

The original version of this article inadvertently omitted the word "with" between "Polymorphisms" and "Antisocial" from the title. The title "The Association of Oxytocin Receptor Gene (OXTR) Polymorphisms Antisocial Behavior: A Meta-Analysis" should be "The Association of Oxytocin Receptor Gene (OXTR) Polymorphisms with Antisocial Behavior: A Meta-Analysis." as presented above.

The Association of Oxytocin Receptor Gene (OXTR) Polymorphisms with Antisocial Behavior: A Meta-analysis.

Evidence suggests that the Oxytocin Receptor Gene (OXTR) influences human social cognition and behavior. OXTR has been investigated in relation to antisocial behavior, but studies examining this association have produced varying results in terms of the magnitude and significance of the association as well as which SNPs are implicated. This meta-analysis, based on 15 samples in 12 studies with a total sample of 12,236 individuals, examined the overall effects and consistency of associations between eight SNPs in OXTR and antisocial behavior. Random effects models identified a significant association between rs237887 and antisocial behavior (r = 0.06, p = 0.002) based on six studies that included a total of 6278 individuals. Sensitivity analyses suggest that these results were robust to exclusion of any individual study and publication bias. Nevertheless, the high levels of heterogeneity and quality control concerns with the original publications lead us to interpret this one significant finding with caution. We conclude that the available literature does not rule out, nor strongly support, an effect of OXTR on antisocial behavior.

Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Gemtuzumab ozogamicin for acute myeloid leukemia.

On 1 September 2017, the US Food and Drug Administration (FDA) approved gemtuzumab ozogamicin (GO) for the treatment of adults with newly diagnosed CD33+ acute myeloid leukemia and for patients aged ≥2 years with CD33+ acute myeloid leukemia who have experienced a relapse or who have not responded to initial treatment. This signals a new chapter in the long and unusual story of GO, which was the first antibody-drug conjugate approved for human use by the FDA.

Prospective test of the developmental propensity model of antisocial behavior: from childhood and adolescence into early adulthood.

BACKGROUND: The developmental propensity model of antisocial behavior posits that several dispositional characteristics of children transact with the environment to influence the likelihood of learning antisocial behavior across development. Specifically, greater dispositional negative emotionality, greater daring, and lower prosociality-operationally, the inverse of callousness- and lower cognitive abilities are each predicted to increase risk for developing antisocial behavior. METHODS: Prospective tests of key predictions derived from the model were conducted in a high-risk sample of 499 twins who were assessed on dispositions at 10-17 years of age and assessed for antisocial personality disorder (APD) symptoms at 22-31 years of age. Predictions were tested separately for parent and youth informants on the dispositions using multiple regressions that adjusted for oversampling, nonresponse, and clustering within twin pairs, controlling demographic factors and time since the first assessment. RESULTS: Consistent with predictions, greater numbers of APD symptoms in adulthood were independently predicted over a 10-15 year span by higher youth ratings on negative emotionality and daring and lower youth ratings on prosociality, and by parent ratings of greater negative emotionality and lower prosociality. A measure of working memory did not predict APD symptoms. CONCLUSIONS: These findings support future research on the role of these dispositions in the development of antisocial behavior.

Progression of alpha-synuclein pathology in multiple system atrophy of the cerebellar type.

AIMS: The aim of this study was to identify early foci of α-synuclein (α-syn pathology) accumulation, subsequent progression and neurodegeneration in multiple system atrophy of the cerebellar type (MSA-C). METHODS: We analysed 70-µm-thick sections of 10 cases with MSA-C and 24 normal controls. RESULTS: MSA-C cases with the lowest burden of pathology showed α-syn glial cytoplasmic inclusions (GCIs) in the cerebellum as well as in medullary and pontine cerebellar projections. Cerebellar pathology was highly selective and severely involved subcortical white matter, whereas deep white matter and granular layer were only mildly affected and the molecular layer was spared. Loss of Purkinje cells increased with disease duration and was associated with neuronal and axonal abnormalities. Neocortex, basal ganglia and spinal cord became consecutively involved with the increasing burden of α-syn pathology, followed by hippocampus, amygdala, and, finally, the visual cortex. GCIs were associated with myelinated axons, and the severity of GCIs correlated with demyelination. CONCLUSIONS: Our findings indicate that cerebellar subcortical white matter and cerebellar brainstem projections are likely the earliest foci of α-syn pathology in MSA-C, followed by involvement of more widespread regions of the central nervous system and neurodegeneration with disease progression.

Cultural isolation is greater than genetic isolation across an avian hybrid zone.

Elucidating the relationship between genetic and cultural evolution is important in understanding speciation, as learned premating barriers might be involved in maintaining species differences. Here, we test this relationship by examining a widely recognized premating barrier, bird song, in a hybrid zone between black-throated green (Setophaga virens) and Townsend's warblers (S. townsendi). We use song analysis, genomic techniques and playback experiments to characterize the cultural and genetic backgrounds of individuals in this region, expecting that if song is an important reproductive barrier between these species, there should be a strong relationship between song and genotype. We show that songs in the hybrid zone correspond to the distinctly different songs found in allopatry but that song and genotype are not tightly coupled in sympatry. Allopatric individuals responded only to local songs, indicating that individuals may have learned to respond to songs they commonly hear. We observed discordance between song and genotype clines; a narrower cline suggests that cultural selection on song is stronger than natural selection on genotype. These findings indicate that song is unlikely to play a role in reproductive isolation between these species, and we suggest that spatial variation in song may nonetheless be maintained by frequency-dependent cultural selection. This decoupling of genes and culture may contribute to hybridization in this region.

Parallel Interactive Processing as a Way to Understand Complex Information Processing: The Conjunction Fallacy and Other Examples.

Parallel interactive processing (PIP) represents an approach in which specific context generates interactive relationships between general attributes. This article summarizes previous research that demonstrates how such relationships influence inference making in categorization. This is followed by evidence that the approach can be extended to other areas of cognition, including probability judgments. PIP was successful in fitting data that revealed the prevalence of the conjunction fallacy as well as other probability estimation data. PIP provided better fits overall than the signed summation model and the configural weighted average model. The quantum probability model provided good fits for the conjunction fallacy data but not for other probability judgments.