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Abstract Until recently, understanding developmental conservation and change has relied on embryological comparisons and analyses of single genes. Several studies, including one recently published in BMC Biology, have now taken a genomic approach to this classical problem, providing insights into how selection operates differentially across the life cycle.

Wound healing in response to acute injury is mediated by the coordinated and transient activation of parenchymal, stromal, and immune cells that resolves to homeostasis. Environmental, genetic, and epigenetic factors associated with inflammation and aging can lead to persistent activation of the microenvironment and fibrosis. Here, we identify opposing roles of interleukin-4 (IL-4) cytokine signaling in interstitial macrophages and type II alveolar epithelial cells (ATIIs). We show that IL4Ra signaling in macrophages promotes regeneration of the alveolar epithelium after bleomycin-induced lung injury. Using organoids and mouse models, we show that IL-4 directly acts on a subset of ATIIs to induce the expression of the transcription factor SOX9 and reprograms them toward a progenitor-like state with both airway and alveolar lineage potential. In the contexts of aging and bleomycin-induced lung injury, this leads to aberrant epithelial cell differentiation and bronchiolization, consistent with cellular and histological changes observed in interstitial lung disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Precise patterns of gene expression are driven by interactions between transcription factors, regulatory DNA sequences, and chromatin. How DNA mutations affecting any one of these regulatory "layers" are buffered or propagated to gene expression remains unclear. To address this, we quantified allele-specific changes in chromatin accessibility, histone modifications, and gene expression in F1 embryos generated from eight Drosophila crosses at three embryonic stages, yielding a comprehensive data set of 240 samples spanning multiple regulatory layers. Genetic variation (allelic imbalance) impacts gene expression more frequently than chromatin features, with metabolic and environmental response genes being most often affected. Allelic imbalance in cis -regulatory elements (enhancers) is common and highly heritable, yet its functional impact does not generally propagate to gene expression. When it does, genetic variation impacts RNA levels through two alternative mechanisms involving either H3K4me3 or chromatin accessibility and H3K27ac. Changes in RNA are more predictive of variation in H3K4me3 than vice versa, suggesting a role for H3K4me3 downstream from transcription. The impact of a substantial proportion of genetic variation is consistent across embryonic stages, with 50% of allelic imbalanced features at one stage being also imbalanced at subsequent developmental stages. Crucially, buffering, as well as the magnitude and evolutionary impact of genetic variants, is influenced by regulatory complexity (i.e., number of enhancers regulating a gene), with transcription factors being most robust to cis -acting, but most influenced by trans -acting, variation., (© 2021 Floc'hlay et al.; Published by Cold Spring Harbor Laboratory Press.)

Enhancers are essential drivers of cell states, yet the relationship between accessibility, regulatory activity, and in vivo lineage commitment during embryogenesis remains poorly understood. Here, we measure chromatin accessibility in isolated neural and mesodermal lineages across a time course of Drosophila embryogenesis. Promoters, including tissue-specific genes, are often constitutively open, even in contexts where the gene is not expressed. In contrast, the majority of distal elements have dynamic, tissue-specific accessibility. Enhancer priming appears rarely within a lineage, perhaps reflecting the speed of Drosophila embryogenesis. However, many tissue-specific enhancers are accessible in other lineages early on and become progressively closed as embryogenesis proceeds. We demonstrate the usefulness of this tissue- and time-resolved resource to definitively identify single-cell clusters, to uncover predictive motifs, and to identify many regulators of tissue development. For one such predicted neural regulator, l(3)neo38, we generate a loss-of-function mutant and uncover an essential role for neuromuscular junction and brain development., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Transcription factor (TF) binding is determined by sequence as well as chromatin accessibility. Although the role of accessibility in shaping TF-binding landscapes is well recorded, its role in evolutionary divergence of TF binding, which in turn can alter cis-regulatory activities, is not well understood. In this work, we studied the evolution of genome-wide binding landscapes of five major TFs in the core network of mesoderm specification, between Drosophila melanogaster and Drosophila virilis, and examined its relationship to accessibility and sequence-level changes. We generated chromatin accessibility data from three important stages of embryogenesis in both Drosophila melanogaster and Drosophila virilis and recorded conservation and divergence patterns. We then used multivariable models to correlate accessibility and sequence changes to TF-binding divergence. We found that accessibility changes can in some cases, for example, for the master regulator Twist and for earlier developmental stages, more accurately predict binding change than is possible using TF-binding motif changes between orthologous enhancers. Accessibility changes also explain a significant portion of the codivergence of TF pairs. We noted that accessibility and motif changes offer complementary views of the evolution of TF binding and developed a combined model that captures the evolutionary data much more accurately than either view alone. Finally, we trained machine learning models to predict enhancer activity from TF binding and used these functional models to argue that motif and accessibility-based predictors of TF-binding change can substitute for experimentally measured binding change, for the purpose of predicting evolutionary changes in enhancer activity., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Understanding how gene regulatory networks control the progressive restriction of cell fates is a long-standing challenge. Recent advances in measuring gene expression in single cells are providing new insights into lineage commitment. However, the regulatory events underlying these changes remain unclear. Here we investigate the dynamics of chromatin regulatory landscapes during embryogenesis at single-cell resolution. Using single-cell combinatorial indexing assay for transposase accessible chromatin with sequencing (sci-ATAC-seq), we profiled chromatin accessibility in over 20,000 single nuclei from fixed Drosophila melanogaster embryos spanning three landmark embryonic stages: 2-4 h after egg laying (predominantly stage 5 blastoderm nuclei), when each embryo comprises around 6,000 multipotent cells; 6-8 h after egg laying (predominantly stage 10-11), to capture a midpoint in embryonic development when major lineages in the mesoderm and ectoderm are specified; and 10-12 h after egg laying (predominantly stage 13), when each of the embryo's more than 20,000 cells are undergoing terminal differentiation. Our results show that there is spatial heterogeneity in the accessibility of the regulatory genome before gastrulation, a feature that aligns with future cell fate, and that nuclei can be temporally ordered along developmental trajectories. During mid-embryogenesis, tissue granularity emerges such that individual cell types can be inferred by their chromatin accessibility while maintaining a signature of their germ layer of origin. Analysis of the data reveals overlapping usage of regulatory elements between cells of the endoderm and non-myogenic mesoderm, suggesting a common developmental program that is reminiscent of the mesendoderm lineage in other species. We identify 30,075 distal regulatory elements that exhibit tissue-specific accessibility. We validated the germ-layer specificity of a subset of these predicted enhancers in transgenic embryos, achieving an accuracy of 90%. Overall, our results demonstrate the power of shotgun single-cell profiling of embryos to resolve dynamic changes in the chromatin landscape during development, and to uncover the cis-regulatory programs of metazoan germ layers and cell types.

Animal promoters initiate transcription either at precise positions (narrow promoters) or dispersed regions (broad promoters), a distinction referred to as promoter shape. Although highly conserved, the functional properties of promoters with different shapes and the genetic basis of their evolution remain unclear. Here we used natural genetic variation across a panel of 81 Drosophila lines to measure changes in transcriptional start site (TSS) usage, identifying thousands of genetic variants affecting transcript levels (strength) or the distribution of TSSs within a promoter (shape). Our results identify promoter shape as a molecular trait that can evolve independently of promoter strength. Broad promoters typically harbor shape-associated variants, with signatures of adaptive selection. Single-cell measurements demonstrate that variants modulating promoter shape often increase expression noise, whereas heteroallelic interactions with other promoter variants alleviate these effects. These results uncover new functional properties of natural promoters and suggest the minimization of expression noise as an important factor in promoter evolution.

Ocean acidification (OA) is increasing due to anthropogenic CO2 emissions and poses a threat to marine species and communities worldwide. To better project the effects of acidification on organisms' health and persistence, an understanding is needed of the 1) mechanisms underlying developmental and physiological tolerance and 2) potential populations have for rapid evolutionary adaptation. This is especially challenging in nonmodel species where targeted assays of metabolism and stress physiology may not be available or economical for large-scale assessments of genetic constraints. We used mRNA sequencing and a quantitative genetics breeding design to study mechanisms underlying genetic variability and tolerance to decreased seawater pH (-0.4 pH units) in larvae of the sea urchin Strongylocentrotus droebachiensis. We used a gene ontology-based approach to integrate expression profiles into indirect measures of cellular and biochemical traits underlying variation in larval performance (i.e., growth rates). Molecular responses to OA were complex, involving changes to several functions such as growth rates, cell division, metabolism, and immune activities. Surprisingly, the magnitude of pH effects on molecular traits tended to be small relative to variation attributable to segregating functional genetic variation in this species. We discuss how the application of transcriptomics and quantitative genetics approaches across diverse species can enrich our understanding of the biological impacts of climate change., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Background: While active LINE-1 (L1) elements possess the ability to mobilize flanking sequences to different genomic loci through a process termed transduction influencing genomic content and structure, an approach for detecting polymorphic germline non-reference transductions in massively-parallel sequencing data has been lacking., Results: Here we present the computational approach TIGER (Transduction Inference in GERmline genomes), enabling the discovery of non-reference L1-mediated transductions by combining L1 discovery with detection of unique insertion sequences and detailed characterization of insertion sites. We employed TIGER to characterize polymorphic transductions in fifteen genomes from non-human primate species (chimpanzee, orangutan and rhesus macaque), as well as in a human genome. We achieved high accuracy as confirmed by PCR and two single molecule DNA sequencing techniques, and uncovered differences in relative rates of transduction between primate species., Conclusions: By enabling detection of polymorphic transductions, TIGER makes this form of relevant structural variation amenable for population and personal genome analysis.

Embryogenesis is remarkably robust to segregating mutations and environmental variation; under a range of conditions, embryos of a given species develop into stereotypically patterned organisms. Such robustness is thought to be conferred, in part, through elements within regulatory networks that perform similar, redundant tasks. Redundant enhancers (or "shadow" enhancers), for example, can confer precision and robustness to gene expression, at least at individual, well-studied loci. However, the extent to which enhancer redundancy exists and can thereby have a major impact on developmental robustness remains unknown. Here, we systematically assessed this, identifying over 1,000 predicted shadow enhancers during Drosophila mesoderm development. The activity of 23 elements, associated with five genes, was examined in transgenic embryos, while natural structural variation among individuals was used to assess their ability to buffer against genetic variation. Our results reveal three clear properties of enhancer redundancy within developmental systems. First, it is much more pervasive than previously anticipated, with 64% of loci examined having shadow enhancers. Their spatial redundancy is often partial in nature, while the non-overlapping function may explain why these enhancers are maintained within a population. Second, over 70% of loci do not follow the simple situation of having only two shadow enhancers-often there are three (rols), four (CadN and ade5), or five (Traf1), at least one of which can be deleted with no obvious phenotypic effects. Third, although shadow enhancers can buffer variation, patterns of segregating variation suggest that they play a more complex role in development than generally considered., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In order to obtain a systems-level understanding of a complex biological system, detailed proteome information is essential. Despite great progress in proteomics technologies, thorough interrogation of the proteome from quantity-limited biological samples is hampered by inefficiencies during processing. To address these challenges, here we introduce a novel protocol using paramagnetic beads, termed Single-Pot Solid-Phase-enhanced Sample Preparation (SP3). SP3 provides a rapid and unbiased means of proteomic sample preparation in a single tube that facilitates ultrasensitive analysis by outperforming existing protocols in terms of efficiency, scalability, speed, throughput, and flexibility. To illustrate these benefits, characterization of 1,000 HeLa cells and single Drosophila embryos is used to establish that SP3 provides an enhanced platform for profiling proteomes derived from sub-microgram amounts of material. These data present a first view of developmental stage-specific proteome dynamics in Drosophila at a single-embryo resolution, permitting characterization of inter-individual expression variation. Together, the findings of this work position SP3 as a superior protocol that facilitates exciting new directions in multiple areas of proteomics ranging from developmental biology to clinical applications., (© 2014 The Authors. Published under the terms of the CC BY 4.0 license.)

Regulatory interactions buffer development against genetic and environmental perturbations, but adaptation requires phenotypes to change. We investigated the relationship between robustness and evolvability within the gene regulatory network underlying development of the larval skeleton in the sea urchin Strongylocentrotus purpuratus. We find extensive variation in gene expression in this network throughout development in a natural population, some of which has a heritable genetic basis. Switch-like regulatory interactions predominate during early development, buffer expression variation, and may promote the accumulation of cryptic genetic variation affecting early stages. Regulatory interactions during later development are typically more sensitive (linear), allowing variation in expression to affect downstream target genes. Variation in skeletal morphology is associated primarily with expression variation of a few, primarily structural, genes at terminal positions within the network. These results indicate that the position and properties of gene interactions within a network can have important evolutionary consequences independent of their immediate regulatory role., Competing Interests: The authors have declared that no competing interests exist.

Genomic structural variation (SV) is a major determinant for phenotypic variation. Although it has been extensively studied in humans, the nucleotide resolution structure of SVs within the widely used model organism Drosophila remains unknown. We report a highly accurate, densely validated map of unbalanced SVs comprising 8962 deletions and 916 tandem duplications in 39 lines derived from short-read DNA sequencing in a natural population (the "Drosophila melanogaster Genetic Reference Panel," DGRP). Most SVs (>90%) were inferred at nucleotide resolution, and a large fraction was genotyped across all samples. Comprehensive analyses of SV formation mechanisms using the short-read data revealed an abundance of SVs formed by mobile element and nonhomologous end-joining-mediated rearrangements, and clustering of variants into SV hotspots. We further observed a strong depletion of SVs overlapping genes, which, along with population genetics analyses, suggests that these SVs are often deleterious. We inferred several gene fusion events also highlighting the potential role of SVs in the generation of novel protein products. Expression quantitative trait locus (eQTL) mapping revealed the functional impact of our high-resolution SV map, with quantifiable effects at >100 genic loci. Our map represents a resource for population-level studies of SVs in an important model organism.

Stress responses play an important role in shaping species distributions and robustness to climate change. We investigated how stress responses alter the contribution of additive genetic variation to gene expression during development of the purple sea urchin, Strongylocentrotus purpuratus, under increased temperatures that model realistic climate change scenarios. We first measured gene expression responses in the embryos by RNA-seq to characterize molecular signatures of mild, chronic temperature stress in an unbiased manner. We found that an increase from 12 to 18 °C caused widespread alterations in gene expression including in genes involved in protein folding, RNA processing and development. To understand the quantitative genetic architecture of this response, we then focused on a well-characterized gene network involved in endomesoderm and ectoderm specification. Using a breeding design with wild-caught individuals, we measured genetic and gene-environment interaction effects on 72 genes within this network. We found genetic or maternal effects in 33 of these genes and that the genetic effects were correlated in the network. Fourteen network genes also responded to higher temperatures, but we found no significant genotype-environment interactions in any of the genes. This absence may be owing to an effective buffering of the temperature perturbations within the network. In support of this hypothesis, perturbations to regulatory genes did not affect the expression of the genes that they regulate. Together, these results provide novel insights into the relationship between environmental change and developmental evolution and suggest that climate change may not expose large amounts of cryptic genetic variation to selection in this species., (© 2012 Blackwell Publishing Ltd.)

Natural selection can act on all the expressed genes of an individual, leaving signatures of genetic differentiation or diversity at many loci across the genome. New power to assay these genome-wide effects of selection comes from associating multi-locus patterns of polymorphism with gene expression and function. Here, we performed one of the first genome-wide surveys in a marine species, comparing purple sea urchins, Strongylocentrotus purpuratus, from two distant locations along the species' wide latitudinal range. We examined 9112 polymorphic loci from upstream non-coding and coding regions of genes for signatures of selection with respect to gene function and tissue- and ontogenetic gene expression. We found that genetic differentiation (F(ST)) varied significantly across functional gene classes. The strongest enrichment occurred in the upstream regions of E3 ligase genes, enzymes known to regulate protein abundance during development and environmental stress. We found enrichment for high heterozygosity in genes directly involved in immune response, particularly NALP genes, which mediate pro-inflammatory signals during bacterial infection. We also found higher heterozygosity in immune genes in the southern population, where disease incidence and pathogen diversity are greater. Similar to the major histocompatibility complex in mammals, balancing selection may enhance genetic diversity in the innate immune system genes of this invertebrate. Overall, our results show that how genome-wide polymorphism data coupled with growing databases on gene function and expression can combine to detect otherwise hidden signals of selection in natural populations.

The need to establish the efficacy of psychoanalytic long-term treatments has promoted efforts to operationalize psychic structure and structural change as key elements of psychoanalytic treatments and their outcomes. Current, promising measures of structural change, however, require extensive interviews and rater training. The purpose of this paper is to present the theory and measurement of Levels of Emotional Awareness (LEA) and to illustrate its use based on clinical case vignettes. The LEA model lays out a developmental trajectory of affective processing, akin to Piaget's theory of sensory-cognitive development, from implicit to explicit processing. Unlike other current assessments of psychic structure (Scales of Psychological Capacities, Reflective Functioning, Operationalized Psychodynamic Diagnostics) requiring intensive rater and interviewer training, it is easily assessed based on a self-report performance test. The LEA model conceptualizes a basic psychological capacity, affect processing. As we will illustrate using two case vignettes, by operationalizing implicit and explicit modes of affect processing, it provides a clinical measure of emotional awareness that is highly pertinent to the ongoing psychoanalytic debate on the nature and mechanisms of structural change., (Copyright © 2011 Institute of Psychoanalysis.)

Comparisons of genomic sequence between divergent species can provide insight into the action of natural selection across many distinct classes of proteins. Here, we examine the extent of positive selection as a function of tissue-specific and stage-specific gene expression in two closely-related sea urchins, the shallow-water Strongylocentrotus purpuratus and the deep-sea Allocentrotus fragilis, which have diverged greatly in their adult but not larval habitats. Genes that are expressed specifically in adult somatic tissue have significantly higher dN/dS ratios than the genome-wide average, whereas those in larvae are indistinguishable from the genome-wide average. Testis-specific genes have the highest dN/dS values, whereas ovary-specific have the lowest. Branch-site models involving the outgroup S. franciscanus indicate greater selection (ω(FG)) along the A. fragilis branch than along the S. purpuratus branch. The A. fragilis branch also shows a higher proportion of genes under positive selection, including those involved in skeletal development, endocytosis, and sulfur metabolism. Both lineages are approximately equal in enrichment for positive selection of genes involved in immunity, development, and cell-cell communication. The branch-site models further suggest that adult-specific genes have experienced greater positive selection than those expressed in larvae and that ovary-specific genes are more conserved (i.e., experienced greater negative selection) than those expressed specifically in adult somatic tissues and testis. Our results chart the patterns of protein change that have occurred after habitat divergence in these two species and show that the developmental or functional context in which a gene acts can play an important role in how divergent species adapt to new environments.

The process and consequences of hybridization are of interest to evolutionary biologists because of the importance of hybridization in understanding reproductive isolation, speciation, and the influence of introgression on population genetic structure. Recent studies of hybridization have been enhanced by the advent of sensitive, genetic marker-based techniques for inferring the degree of admixture occurring within individuals. Here we present a genetic marker-based analysis of hybridization in a large-bodied, long-lived mammal over multiple generations. We analysed patterns of hybridization between yellow baboons (Papio cynocephalus) and anubis baboons (Papio anubis) in a well-studied natural population in Amboseli National Park, Kenya, using genetic samples from 450 individuals born over the last 36 years. We assigned genetic hybrid scores based on genotypes at 14 microsatellite loci using the clustering algorithm implemented in STRUCTURE 2.0, and assessed the robustness of these scores by comparison to pedigree information and through simulation. The genetic hybrid scores showed generally good agreement with previous morphological assessments of hybridity, but suggest that genetic methods may be more sensitive for identification of low levels of hybridity. The results of our analysis indicate that the proportion of hybrids in the Amboseli population has grown over time, but that the average proportion of anubis ancestry within hybrids is gradually decreasing. We argue that these patterns are probably a result of both selective and nonselective processes, including differences in the timing of life-history events for hybrid males relative to yellow baboon males, and stochasticity in long-distance dispersal from the source anubis population into Amboseli.

Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.

As whole-genome sequence assemblies accumulate, a challenge is to determine how these can be used to address fundamental evolutionary questions, such as inferring the process of speciation. Here, we use the sequence assemblies of Drosophila pseudoobscura and D. persimilis to test hypotheses regarding divergence with gene flow. We observe low differentiation between the two genome sequences in pericentromeric and peritelomeric regions. We interpret this result as primarily a remnant of the correlation between levels of variation and local recombination rate observed within populations. However, we also observe lower differentiation far from the fixed chromosomal inversions distinguishing these species and greater differentiation within and near these inversions. This finding is consistent with models suggesting that chromosomal inversions facilitate species divergence despite interspecies gene flow. We also document heterogeneity among the inverted regions in their degree of differentiation, suggesting temporal differences in the origin of each inverted region consistent with the inversions arising during a process of divergence with gene flow. While this study provides insights into the speciation process using two single-genome sequences, it was informed by lower throughput but more rigorous examinations of polymorphism and divergence. This reliance highlights the need for complementary genomic and population genetic approaches for tackling fundamental evolutionary questions such as speciation.

The theory of bugs and bowls," as outlined by Javanbakht (2005), is, in essence a psychobiological metaphor for understanding psychotic processes. It attempts to bridge psychological and biological explanations for psychotic phenomena by using the metaphor of "bugs and bowls." In this metaphor, the bowl represents the organism's capacity to contain its own inner experience. The bowl is described psychologically, in analytic terms, vis-à-vis traditional ego function and its action of repression. Interestingly, the superego is left out in this discussion. Inner experience, in this regard, corresponds to the wishes and fears of the unconscious. Repressed pathological memories are included in this explanation as well. On the biological side, neuroanatomic, neurochemical, and cortical-subcortical circuits and neural networks are reviewed and folded into the metaphor. The author cites a variety of different literatures to beef up his proposal that "bugs and bowls" is a utilitarian model for the modern clinician. Although we are quite fond of the analogy, there are a few things about it that "bug" us.

The authors examined the reliability and validity of American Board of Psychiatry and Neurology-style oral exams (ASOs) given jointly by two schools. ASOs were given to 80 psychiatry residents from all four postgraduate years during the study period. Interrater reliability was near perfect for two years at one university, but it was much weaker at the second site. Test-retest reliability could not be demonstrated at either institution. Concurrent validity was demonstrated one year but was inconsistently demonstrated the second year. Likewise, predictive and construct validity were variable. International medical graduates were more apt to fail than American medical graduates. Although resident and faculty satisfaction with the examination was high, site-to-site variability in reliability and validity indicates the need to improve this ASO before using it for high-stakes evaluations.

Fourteen combat veterans completed a 9-week open trial of nefazodone for treatment of posttraumatic stress disorder (PTSD). Overall PTSD symptoms as measured by the Clinician-Administered PTSD Scale (CAPS) showed a modest but statistically significant decrease with nefazodone treatment. Decreases in CAPS reexperiencing and avoidance, but not hyperarousal symptoms, approached statistical significance. Anxiety decreased significantly, and there were trends toward decreased depression and anger on structured assessments. This study adds to the clinical evidence that nefazodone may be helpful for the management of PTSD symptoms.

Background: Gonadotropins and sex hormones are intimately related to the stability of affective states. Patients with affective disorders may demonstrate abnormal levels of sex hormones and gonadotropins. It is therefore possible that affective disorder patients may experience mood dysregulation by synthetic sex hormones and gonadotropins like lupron., Methods: A case report of a young woman with a history of endometriosis and a past history of irritability and depression is described. Treatment of the endometriosis with lupron induced a manic episode., Results: The lupron-induced mania was successfully treated with a mood-stabilizing agent, lithium carbonate., Conclusions: Patients with a history of affective disorder may develop manic episodes when treated with Lupron. Mood-stabilizing agents are helpful in ameliorating this unwanted effect.

This essay discusses an overlooked ingredient in the psychotherapy of psychosis which is termed the "curative audience." Central to the equation of psychological selfhood is the evocation of a sense of self by experiences that the patient has with objects in the environment. This essay calls attention to an essential function of this environment, namely, that it provides an audience that makes it possible for these "selfobject" transferences, transference interpretations or new, helpful relational experiences to become significant. In essence, it is argued that a "private experience" without an internal or external audience is not therapeutic in the reassembly of self, especially when the power and intensity to overcome psychotic disintegration is required. The idea that the psychotic patient recompensates not only with the help of a therapist but under the auspices of a third entity, has not been previously discussed. Interestingly, all the schools of psychoanalysis have touched on the role of audience in the healing of patients with both neurosis and psychosis, yet this thread has not been followed into its binding together of subjectivity. Three forms of curative audience can be identified corresponding to the beginning, middle, and end phases of treatment. The role of audience in the reassembly of the self is taking its first form in the initial contact or initial relationship with the other and over time develops into the second form, the therapeutic alliance. In the third form of the curative audience, the establishment of an external selfobject milieu that performs the functions of the curative audience is seen as essential to continued cohesion in the recovery from psychosis. Performative statements exert self-cohering effects and can be seen to have their source in the curative audience. Two clinical vignettes were presented to illustrate these ideas.

Psychoanalysts and psychotherapists who work with psychotic patients often encounter unusual clinical phenomena. In this article, a certain kind of phenomena is described, wherein the patient refers to a body part of the therapist as being owned by the patient. This "body part borrowing" or "merger" can be explained by the classical and object relations schools in terms of part and transitional object concepts. These diagnostic formulations will then guide therapeutic intervention. Newer concepts, from the psychoanalytic school of self psychology, particularly that of the twinship selfobject experience, provide for a more effective intervention in these complex clinical situations. Certain psychotic responses, in these cases, delusional misperceptions, can be viewed as the patient's attempt to stave off empathic rupture and fragmentation. "Body-part borrowing" in the treatment setting thus serves as a twinship selfobject compensation; it attenuates the unbearable affects generated by empathic failure. In this article, we offered clinical vignettes to illustrate these processes in two patients with psychosis and one with neurosis. We then offered various suggestions for clinical intervention based on a selfobject understanding of these phenomena.

In recent years, residency programs have neglected to teach psychotherapy for psychotic patients to their trainees. This training has value in teaching residents how to more fully understand psychopathology, to understand the concept of the unconscious, and to work more effectively in using combined pharmacopsychotherapy with psychotic patients. The author suggests that an "affect-centered" psychotherapy approach is both clinically appropriate and educationally useful with psychotic patients. Recommendations for teaching this approach are given.

Artificial intelligence computer simulation methods can be used to investigate psychotic or "crazy" speech. Here, symbolic reasoning algorithms establish semantic networks that schematize speech. These semantic networks consist of two main structures: case frames and object taxonomies. Node-based reasoning rules apply to object taxonomies and pathway-based reasoning rules apply to case frames. Normal listeners may recognize speech as "crazy talk" based on violations of node- and pathway-based reasoning rules. In this article, three separate segments of schizophrenic speech illustrate violations of these rules. This artificial intelligence approach is compared and contrasted with other neurolinguistic approaches and is discussed as a conceptual link between neurobiological and psychodynamic understandings of psychopathology.

The two main problems of patients suffering from paranoid phenomena are discussed from a treatment perspective. These two problems arising from "having trusted too much" and having lost "ownership of the self" result in the classic projections and loss of initiative commonly seen in paranoid psychopathology. Clinicians must first ward off the patients' projections and help patients work toward a position of "healthy skepticism." This article shows: (1) the specific role of narcissism, its structures and processes, as they contribute to the internal changes needed to achieve this goal; (2) how clinicians can rekindle important sources of initiative and aspiration within the patient. Selfobject relationships, the agency of the ego ideal and the role of the affects of hope and affection, along with such specific interventions as "performative statements," have been offered as helpful tools for clinicians who work with paranoid patients.

The potential benefit of artificial intelligence (AI) technology as a tool of psychiatry has not been well defined. In this essay, the technology of natural language processing and its position with regard to the two main schools of AI is clearly outlined. Past experiments utilizing AI techniques in understanding psychopathology are reviewed. Natural language processing can automate the analysis of transcripts and can be used in modeling theories of language comprehension. In these ways, it can serve as a tool in testing psychological theories of psychopathology and can be used as an effective tool in empirical research on verbal behavior in psychopathology.

Since Freud's (1911) explication of the nature of paranoia, much has been written concerning the dynamic underpinnings of the illness but less have been detailed regarding its manifestations structurally. This essay, with its case illustration, attempts to detail the relationship between paranoia and the ego-ideal. Both Blos' (1974) ideas on the negative Oedipus complex and Kohut's (1966) ideas on the developmental line of narcissism prove to be useful ways of linking the clinical picture of paranoia to the psychic structure of the ego-ideal. Both technical aspects of treatment as well as theoretical understandings are explored.

Multiple sclerosis and affective disorder are both diseases that wax and wane as well as have variable clinical symptomatology. Their common co-occurrence has given rise to intense speculation about their etiological and clinical connection. In this paper, 2 case reports and discussions are presented, and a pertinent review of the literature is included concerning the question whether affective symptomatology is the direct result of, a reaction to, or coexistent with, the neurological disease process. The specific cataloguing of affective symptoms with multiple sclerosis is suggested as possibly being helpful in warning clinicians as to the presence of multiple sclerosis. The rhythmicity of both illnesses is briefly discussed in the light of recent literature on circadian rhythms.

Fifteen male schizophrenic patients between the ages of 18 and 40 were compared with 15 matched control subjects on their performance on the Facial Affect Recognition Task and on the O'Brien-Epstein Sources of Self-Esteem Inventory. As has been previously reported, schizophrenic subjects score significantly lower than normals in the recognition of emotion in the human face, particularly on the 'negative' emotions of anger, fear and disgust. Significant differences were found between groups on self-esteem domains of 'competence' and 'personal power', with normal subjects scoring higher. However, on the self-esteem scale of 'defensive self-enhancement', schizophrenic patients scored higher than the control group. Thus, the schizophrenic patients do not have uniformly lower self-esteem than normals but, rather, specific domains of self-esteem are affected. In addition, a significant negative correlation was found between affect recognition and defensive self-enhancement. The clinical-theoretical implications of working with schizophrenia are discussed in the light of these findings.

Analysis of schizophrenic thought disorder reveals structures and regulatory processes that govern its phenotypic expressions. In particular, the three primary variants of this thought disorder--combinative thinking, drive-dominated thinking, and loss of reality testing--can be viewed in terms of thematic structures. Schizophrenic communication is characterized by an affective rule-governing process that channels information into case-grammar thematic structures. The author elaborates an earlier proposal that transformational grammar subunits should be identified and modeled to schizophrenic thought and explicates the use of these specific structures and processes. He then suggests clinical interventions and future research applications.