Mechanisms of fear extinction MYERS, K. M; DAVIS, M
Molecular psychiatry,
02/2007, Volume:
12, Issue:
2
Journal Article
Peer reviewed
Open access
Excessive fear and anxiety are hallmarks of a variety of disabling anxiety disorders that affect millions of people throughout the world. Hence, a greater understanding of the brain mechanisms ...involved in the inhibition of fear and anxiety is attracting increasing interest in the research community. In the laboratory, fear inhibition most often is studied through a procedure in which a previously fear conditioned organism is exposed to a fear-eliciting cue in the absence of any aversive event. This procedure results in a decline in conditioned fear responses that is attributed to a process called fear extinction. Extensive empirical work by behavioral psychologists has revealed basic behavioral characteristics of extinction, and theoretical accounts have emphasized extinction as a form of inhibitory learning as opposed to an erasure of acquired fear. Guided by this work, neuroscientists have begun to dissect the neural mechanisms involved, including the regions in which extinction-related plasticity occurs and the cellular and molecular processes that are engaged. The present paper will cover behavioral, theoretical and neurobiological work, and will conclude with a discussion of clinical implications.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
As studies of DNA methylation increase in scope, it has become evident that methylation has a complex relationship with gene expression, plays an important role in defining cell types, and is ...disrupted in many diseases. We describe large-scale single-base resolution DNA methylation profiling on a diverse collection of 82 human cell lines and tissues using reduced representation bisulfite sequencing (RRBS). Analysis integrating RNA-seq and ChIP-seq data illuminates the functional role of this dynamic mark. Loci that are hypermethylated across cancer types are enriched for sites bound by NANOG in embryonic stem cells, which supports and expands the model of a stem/progenitor cell signature in cancer. CpGs that are hypomethylated across cancer types are concentrated in megabase-scale domains that occur near the telomeres and centromeres of chromosomes, are depleted of genes, and are enriched for cancer-specific EZH2 binding and H3K27me3 (repressive chromatin). In noncancer samples, there are cell-type specific methylation signatures preserved in primary cell lines and tissues as well as methylation differences induced by cell culture. The relationship between methylation and expression is context-dependent, and we find that CpG-rich enhancers bound by EP300 in the bodies of expressed genes are unmethylated despite the dense gene-body methylation surrounding them. Non-CpG cytosine methylation occurs in human somatic tissue, is particularly prevalent in brain tissue, and is reproducible across many individuals. This study provides an atlas of DNA methylation across diverse and well-characterized samples and enables new discoveries about DNA methylation and its role in gene regulation and disease.
This inaugural volume in the Graphic Medicine series establishes the principles of graphic medicine and begins to map the field. The volume combines scholarly essays by members of the editorial team ...with previously unpublished visual narratives by Ian Williams and MK Czerwiec, and it includes arresting visual work from a wide range of graphic medicine practitioners. The book’s first section, featuring essays by Scott Smith and Susan Squier, argues that as a new area of scholarship, research on graphic medicine has the potential to challenge the conventional boundaries of academic disciplines, raise questions about their foundations, and reinvigorate literary scholarship—and the notion of the literary text—for a broader audience. The second section, incorporating essays by Michael Green and Kimberly Myers, demonstrates that graphic medicine narratives can engage members of the health professions with literary and visual representations and symbolic practices that offer patients, family members, physicians, and other caregivers new ways to experience and work with the complex challenges of the medical experience. The final section, by Ian Williams and MK Czerwiec, focuses on the practice of creating graphic narratives, iconography, drawing as a social practice, and the nature of comics as visual rhetoric. A conclusion (in comics form) testifies to the diverse and growing graphic medicine community. Two valuable bibliographies guide readers to comics and scholarly works relevant to the field.
Small cell lung cancer (SCLC) is an aggressive lung cancer subtype with extremely poor prognosis. No targetable genetic driver events have been identified, and the treatment landscape for this ...disease has remained nearly unchanged for over 30 years. Here, we have taken a CRISPR-based screening approach to identify genetic vulnerabilities in SCLC that may serve as potential therapeutic targets. We used a single-guide RNA (sgRNA) library targeting ~5000 genes deemed to encode "druggable" proteins to perform loss-of-function genetic screens in a panel of cell lines derived from autochthonous genetically engineered mouse models (GEMMs) of SCLC, lung adenocarcinoma (LUAD), and pancreatic ductal adenocarcinoma (PDAC). Cross-cancer analyses allowed us to identify SCLC-selective vulnerabilities. In particular, we observed enhanced sensitivity of SCLC cells toward disruption of the pyrimidine biosynthesis pathway. Pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in this pathway, reduced the viability of SCLC cells in vitro and strongly suppressed SCLC tumor growth in human patient-derived xenograft (PDX) models and in an autochthonous mouse model. These results indicate that DHODH inhibition may be an approach to treat SCLC.
Patients with immunosuppression have a higher incidence of cutaneous squamous cell carcinoma (cSCC) and often present with more aggressive, multifocal disease.
To determine the risks for mortality in ...patients with cSCC and immunosuppression compared with nonimmunosuppression and to compare the difference in mortality risk based on the cause of immunocompromise.
This retrospective cohort study of patients with cSCC of the head and neck recruited participants from a tertiary cancer care center. Patients who underwent no treatment, wide local excision, or biopsy of the lesions were eligible for inclusion from January 1, 1995, to September 30, 2015. Data were analyzed from March 21, 2018, to April 4, 2019.
Immunocompromise, defined as having solid organ transplant, stem cell transplant, hematopoetic malignant disease, autoimmune disease requiring treatment with immunosuppressive therapy, type 1 or 2 diabetes treated with insulin, HIV or AIDS, or other hematoproliferative disorder.
Patients were divided into 2 groups according to their immune status (immunosuppression vs no immunosuppression). The primary outcome measure was disease-specific survival. A Cox proportional hazards regression model was used to determine the association of immune status with disease outcome.
A total of 796 patients (680 men 85.4%; median age, 69 range, 27-98 years), including 147 with and 649 without immunosuppression (IS and non-IS groups, respectively), constituted the final cohort. In the IS group, 77 (52.4%) had diabetes, 39 (26.5%) had lymphoma or leukemia, 25 (17.0%) had an organ or stem cell transplant, and 3 (2.0%) had HIV. Five-year disease-specific survival was 68.2% in the IS group compared with 84.1% in the non-IS group (difference, 15.9%; 95% CI, 3.5%-27.4%). Immunosuppression was independently associated with worse disease-specific survival (hazard ratio, 2.32; 95% CI, 1.53-3.50).
This study's findings suggest that immunosuppression is independently associated with a worse outcome in cSCC, with a 2.32 times increased risk of disease-specific death after adjusting for age, history of skin cancer, recurrent or persistent disease status, disease stage, and treatment.
In this letter, we present both the 1/f noise and phase noise performance of top-gated epitaxial graphene field-effect transistors (FETs) in nonlinear circuit applications for the first time. In the ...case of frequency doublers, the fundamental signal is suppressed by 25 dB below the second harmonic signal. With a phase noise of -110 dBc/Hz measured at a 10-kHz offset, a carrier-to-noise degradation (ΔCNR) of 6 dB was measured for the frequency doubler. This implies noiseless frequency multiplication without additional 1/f noise upconversion during the nonlinear process. The frequency multiplication was demonstrated above the gigahertz range. The 1/f noise of top-gated epitaxial graphene FETs is comparable or lower than that of exfoliated graphene FETs.
Abstract
We present HST spectroscopy for 45 cataclysmic variables (CVs), observed with HST/COS and HST/STIS. For 36 CVs, the white dwarf is recognisable through its broad Ly α absorption profile and ...we measure the white dwarf effective temperatures (T
eff) by fitting the HST data assuming log g = 8.35, which corresponds to the average mass for CV white dwarfs (≃0.8 M⊙). Our results nearly double the number of CV white dwarfs with an accurate temperature measurement. We find that CVs above the period gap have, on average, higher temperatures (〈T
eff〉 ≃ 23 000 K) and exhibit much more scatter compared to those below the gap (〈T
eff〉 ≃ 15 000 K). While this behaviour broadly agrees with theoretical predictions, some discrepancies are present: (i) all our new measurements above the gap are characterized by lower temperatures (T
eff ≃ 16 000–26 000 K) than predicted by the present-day CV population models (T
eff ≃ 38 000–43 000 K); (ii) our results below the gap are not clustered in the predicted narrow track and exhibit in particular a relatively large spread near the period minimum, which may point to some shortcomings in the CV evolutionary models. Finally, in the standard model of CV evolution, reaching the minimum period, CVs are expected to evolve back towards longer periods with mean accretion rates
$\dot{M}\lesssim 2 \times 10^{-11}\,\mathrm{M}_{\odot }\,\mathrm{yr}^{-1}$
, corresponding to T
eff ≲ 11 500 K. We do not unambiguously identify any such system in our survey, suggesting that this major component of the predicted CV population still remains elusive to observations.
The composite physiologic index (CPI) was derived to represent the extent of fibrosis on high-resolution computed tomography (HRCT), adjusting for emphysema in patients with idiopathic pulmonary ...fibrosis (IPF). We hypothesised that longitudinal change in CPI would better predict mortality than forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide (D(L,CO)) in all patients with IPF, and especially in those with combined pulmonary fibrosis and emphysema (CPFE). Cox proportional hazard models were performed on pulmonary function data from IPF patients at baseline (n = 321), 6 months (n = 211) and 12 months (n = 144). Presence of CPFE was determined by HRCT. A five-point increase in CPI over 12 months predicted subsequent mortality (HR 2.1, p = 0.004). At 12 months, a 10% relative decline in FVC, a 15% relative decline in D(L,CO) or an absolute increase in CPI of five points all discriminated median survival by 2.1 to 2.2 yrs versus patients with lesser change. Half our cohort had CPFE. In patients with moderate/severe emphysema, only a 10% decline in FEV(1) predicted mortality (HR 3.7, p = 0.046). In IPF, a five-point increase in CPI over 12 months predicts mortality similarly to relative declines of 10% in FVC or 15% in D(L,CO). For CPFE patients, change in FEV(1) was the best predictor of mortality.
The neural mechanisms by which fear is inhibited are poorly understood at the present time. Behaviorally, a conditioned fear response may be reduced in intensity through a number of means. Among the ...simplest of these is extinction, a form of learning characterized by a decrease in the amplitude and frequency of a conditioned response when the conditioned stimulus that elicits it is repeatedly nonreinforced. Because clinical interventions for patients suffering from fear dysregulation seek to inhibit abnormal, presumably learned fear responses, an understanding of fear extinction is likely to inform and increase the efficacy of these forms of treatment. This review considers the behavioral, cellular, and molecular literatures on extinction and presents the most recent advances in our understanding while identifying issues that require considerable further research.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
