Evidence for distinct genetic and environmental influences on fear acquisition and extinction.

BACKGROUND: Anxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction. METHODS: In total, 1937 twins aged 22-25 years, including 538 complete pairs from the Twins Early Development Study took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app. In the fear acquisition phase, participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase, the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase. RESULTS: Twin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15, 30 and 15%, respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations 0.4-0.5). CONCLUSIONS: Fear acquisition and extinction are heritable, and share some, but not all of the same genetic influences.

Depression, anxiety and PTSD symptoms before and during the COVID-19 pandemic in the UK.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors. METHOD: Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change. RESULTS: Prospective symptom analyses showed small decreases in depression (PHQ-9: -0.43 points) and anxiety [generalised anxiety disorder scale - 7 items (GAD)-7: -0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status. CONCLUSIONS: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

Introducing the Fear Learning and Anxiety Response (FLARe) app and web portal for the remote delivery of fear conditioning experiments.

Experimental paradigms measuring key psychological constructs can enhance our understanding of mechanisms underlying human psychological well-being and mental health. Delivering such paradigms remotely affords opportunities to reach larger, more representative samples than is typically possible with in-person research. The efficiency gained from remote delivery makes it easier to test replication of previously established effects in well-powered samples. There are several challenges to the successful development and delivery of remote experimental paradigms, including use of an appropriate delivery platform, identifying feasible outcome measures, and metrics of participant compliance. In this paper, we present FLARe (Fear Learning and Anxiety Response), open-source software in the form of a smartphone app and web portal for the creation and delivery of remote fear conditioning experiments. We describe the benefits and challenges associated with the creation of a remote delivery platform for fear conditioning, before presenting in detail the resultant software suite, and one instance of deploying this using the FLARe Research infrastructure. We provide examples of the application of FLARe to several research questions which illustrate the benefits of the remote approach to experiment delivery. The FLARe smartphone app and web portal are available for use by other researchers and have been designed to be user-friendly and intuitive. We hope that FLARe will be a useful tool for those interested in conducting well-powered fear conditioning studies to inform our understanding of the development and treatment of anxiety disorders.

Targeting Unique Ligand Binding Domain Structural Features Downregulates DKK1 in Y537S ESR1 Mutant Breast Cancer Cells.

Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Mutations to estrogen receptor alpha (ERα) arise after continued therapeutic pressure. Next generation selective estrogen receptor modulators and degraders/downregulators (SERMs and SERDs) show clinical efficacy, but responses are often non-durable. A tyrosine to serine point mutation at position 537 in the ERα ligand binding domain (LBD) is among the most common and most pathogenic alteration in this setting. It enables endocrine therapy resistance by superceding intrinsic structural-energetic gatekeepers of ER hormone-dependence, it enhances metastatic burden by enabling neomorphic ER-dependent transcriptional programs, and it resists SERM and SERD inhibiton by reducing their binding affinities and abilities to antagonize transcriptional coregulator binding. However, a subset of SERMs and SERDs can achieve efficacy by adopting poses that force the mutation to engage in a new interaction that favors the therapeutic receptor antagonist conformation. We previously described a chemically unconventional SERM, T6I-29, that demonstrates significant anti-proliferative activities in Y537S ERα breast cancer cells. Here, we use a comprehensive suite of structural-biochemical, in vitro, and in vivo approaches to better T6I-29's activities in breast cancer cells harboring Y537S ERα. RNA sequencing in cells treated with T6I-29 reveals a neomorphic downregulation of DKK1, a secreted glycoprotein known to play oncogenic roles in other cancers. Importantly, we find that DKK1 is significantly enriched in ER+ breast cancer plasma compared to healthy controls. This study shows how new SERMs and SERDs can identify new therapeutic pathways in endocrine-resistant ER+ breast cancers.

Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells.

Estrogen receptor alpha (ERα) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ERα conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer and other hormone-responsive tissues. By affecting disparate ligand binding domain structural features, unconventional ligand scaffolds can redirect ERα genomic binding patterns to engage novel therapeutic transcriptional programs. To improve our understanding of these ERα structure-transcriptional relationships, we develop a series of chemically unconventional antagonists based on the antiestrogens elacestrant and lasofoxifene. High-resolution x-ray co-crystal structures show that these molecules affect both classical and unique structural motifs within the ERα ligand binding pocket. They show moderately reduced antagonistic potencies on ERα genomic activities but are effective anti-proliferative agents in luminal breast cancer cells. Interestingly, they favor a 4-hydroxytamoxifen-like accumulation of ERα in breast cancer cells but lack uterotrophic activities in an endometrial cell line. Importantly, RNA sequencing shows that the lead molecules engage transcriptional pathways similar to the selective estrogen receptor degrader fulvestrant. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ERα accumulation in breast cancer cells.

Adenovirus E1A-mediated negative control of genes activated during F9 differentiation.

The phenotype of a differentiated cell results from the expression of a unique set of genes in that cell. The differentiation of F9 teratocarcinoma cells in response to retinoic acid and cyclic AMP is an excellent example of this process, as the appearance of several gene products during the course of the differentiation process has been documented. In principle, the activation of gene expression could be due to the appearance of positive-acting factors, the loss of negative-acting factors, or a combination of both. Since F9 cells have been shown to express a cellular E1A analog whereas differentiated F9 cells do not, and it is known that the viral E1A gene exerts a negative effect on transcription of both viral and cellular genes, we determined whether the cellular genes activated during F9 cell differentiation are subject to E1A negative control. We found that infection of differentiated F9 cells with wild-type adenovirus resulted in a decline in the levels of collagen type IV mRNA and plasminogen activator mRNA, both of which are induced by differentiation. At least for the collagen gene, this phenomenon appears to involve a transcriptional repression.

Predictive values of species' identifications from the Vitek Gram-Positive Identification Card using clinical isolates of coagulase-negative staphylococci.

The Gram-Positive Identification Card (GPI, bioMerieux Vitek) was compared to conventional tests for identification of 616 clinical isolates of coagulase-negative staphylococci. All tests were inoculated with subcultures from single isolated colonies. The predictive values of GPI species' identifications (the number of the system's correct calls divided by the total number of calls for each species) were 100% (12 of 12) for Staphylococcus capitis, 100% (79 of 79) for S saprophyticus, 98.4% (246 of 250) for S epidermidis and 96.0% (120 of 125) for S haemolyticus, but only 64.5% (69 of 107) for the other species analyzed. When an infrequently encountered Staphylococcus species is named using the GPI, the identification should be confirmed using additional tests.

Psychology of computer use: XL. Addictive use of the Internet: a case that breaks the stereotype.

This case involves a homemaker 43 years of age who is addicted to using the Internet. This case was selected as it demonstrates that a nontechnologically oriented woman with a reportedly content home life and no prior addiction or psychiatric history abused the Internet which resulted in significant impairment to her family life. This paper defines addictive use of the Internet, outlines the subject's progression of addictive on-line use, and discusses the implications of such addictive behavior on the new market of Internet consumers.

The functional neuroanatomy of the evolving parent-infant relationship.

Infant survival and the development of secure and cooperative relationships are central to the future of the species. In humans, this relies heavily on the evolving early parent-infant social and affective relationship. While much is known about the behavioural and psychological components of this relationship, relatively little is known about the underlying functional neuroanatomy. Affective and social neuroscience has helped to describe the main adult brain networks involved, but has so far engaged very little with developmental findings. In this review, we seek to highlight future avenues for research by providing a coherent framework for describing the parent-infant relationship over the first 18 months. We provide an outline of the evolving nature of the relationship, starting with basic orienting and recognition processes, and culminating in the infant's attainment of higher socio-emotional and cognitive capacities. Key social and affective interactions, such as communication, cooperative play and the establishment of specific attachments propel the development of the parent-infant relationship. We summarise our current knowledge of the developing infant brain in terms of structure and function, and how these relate to the emergent abilities necessary for the formation of a secure and cooperative relationship with parents or other caregivers. Important roles have been found for brain regions including the orbitofrontal, cingulate, and insular cortices in parent-infant interactions, but it has become clear that much more information is needed about the developmental time course and connectivity of these regions.

The molecular biology of CML: a review.

The t(9;22) generating the Ph1 chromosome in CML creates a new fusion gene (bcr/abl), which combines bcr sequence from chromosome 22 with abl sequence from chromosome 9. This gene generates a new fusion protein which has a much greater protein tyrosine kinase activity than the normal abl protein, and it is this ptk activity which has been shown to be essential for the transforming activity of the v-abl gene and for other related oncogenes which contain the homologous ptk region. The fusion gene is present in almost all patients with CML, including a sizable fraction of the patients with Ph1(-) CML. The Ph1 chromosome and CML have provided one of the most exciting stories of oncogene activation in human malignancy, and much more information, at both the level of basic and of clinical science, will result from the investigations currently underway in a number of laboratories.