The Role of Spatial Location in Threat Memory: Modulation of Learning and Discrimination

Learning about dangers in our environment is a vital adaptive behavior, and many have studied the association of environmental cues with danger or safety. However, the outcome associated with a specific environmental cue can depend on where it is encountered, and relatively little is known about the neural mechanisms behind location-specific threat learning within a single environment. Through a series of experiments, I developed a novel virtual reality task comprised of safe and dangerous zones within a single environment. Healthy volunteers explored this environment while ‘picking flowers’, which they were told might contain bees. On contacting a flower, participants were frozen for a short period of time and, if ‘stung,’ received a mild electric shock at the end of this period. Participants had the opportunity to learn that bees only inhabited flowers in one ‘dangerous’ half of the environment. Participants were able to discriminate zones that predict safety and threat within a single environment, with galvanic skin responses and subjective reports increasing as they approached and picked flowers in the dangerous half of the environment. Using functional magnetic resonance imaging, I found posterior medial temporal lobe structures (parahippocampus, posterior hippocampus) to be involved in memory for object locations. In contrast, anterior hippocampus, amygdala, and ventromedial prefrontal cortex showed greater activity when approaching flowers, but this activity did not differentiate between safe and dangerous zones. However, once participants reached a flower in the dangerous zone, increased activity was seen in areas associated with imminent threat, such as the midbrain/periaqueductal gray, dorsal anterior cingulate, and insula cortices. These results are the first to reveal mechanisms of location-specific threat learning in humans, in the absence of obvious boundaries delineating safety and danger zones. In the future, I hope this new paradigm will be used to understand the overgeneralization of threat in anxiety disorders and post-traumatic stress disorder

Location-dependent threat and associated neural abnormalities in clinical anxiety

Anxiety disorders are characterized by maladaptive defensive responses to distal or uncertain threats. Elucidating neural mechanisms of anxiety is essential to understand the development and maintenance of anxiety disorders. In fMRI, patients with pathological anxiety (ANX, n = 23) and healthy controls (HC, n = 28) completed a contextual threat learning paradigm in which they picked flowers in a virtual environment comprising a danger zone in which flowers were paired with shock and a safe zone (no shock). ANX compared with HC showed 1) decreased ventromedial prefrontal cortex and anterior hippocampus activation during the task, particularly in the safe zone, 2) increased insula and dorsomedial prefrontal cortex activation during the task, particularly in the danger zone, and 3) increased amygdala and midbrain/periaqueductal gray activation in the danger zone prior to potential shock delivery. Findings suggest that ANX engage brain areas differently to modulate context-appropriate emotional responses when learning to discriminate cues within an environment

Inconsistent analytic strategies reduce robustness in fear extinction via skin conductance response

Robustness of fear conditioning and extinction paradigms has become increasingly important for many researchers interested in improving the study of anxiety and trauma disorders. We recently illustrated the wide variability in data analysis techniques in this paradigm, which we argued may result in lack of robustness. In the current study, we resampled data from six of our own fear acquisition and extinction datasets, with skin conductance as the outcome. In the resampled and original datasets, we found that effect sizes that were calculated using discrepant statistical strategies, sourced from a non-exhaustive search of high-impact articles, were often poorly correlated. The main contributors to poor correlations were selection of trials from different stages of each experimental phase and use of averaged compared to trial-by-trial analysis. These findings reinforce the importance of focusing on robustness in psychophysiological measurement of fear acquisition and extinction in the laboratory and may guide prospective researchers in which decisions may most impact the robustness of their results

Probing the Mutational Interplay between Primary and Promiscuous Protein Functions: A Computational-Experimental Approach

Protein promiscuity is of considerable interest due its role in adaptive metabolic plasticity, its fundamental connection with molecular evolution and also because of its biotechnological applications. Current views on the relation between primary and promiscuous protein activities stem largely from laboratory evolution experiments aimed at increasing promiscuous activity levels. Here, on the other hand, we attempt to assess the main features of the simultaneous modulation of the primary and promiscuous functions during the course of natural evolution. The computational/experimental approach we propose for this task involves the following steps: a function-targeted, statistical coupling analysis of evolutionary data is used to determine a set of positions likely linked to the recruitment of a promiscuous activity for a new function; a combinatorial library of mutations on this set of positions is prepared and screened for both, the primary and the promiscuous activities; a partial-least-squares reconstruction of the full combinatorial space is carried out; finally, an approximation to the Pareto set of variants with optimal primary/promiscuous activities is derived. Application of the approach to the emergence of folding catalysis in thioredoxin scaffolds reveals an unanticipated scenario: diverse patterns of primary/promiscuous activity modulation are possible, including a moderate (but likely significant in a biological context) simultaneous enhancement of both activities. We show that this scenario can be most simply explained on the basis of the conformational diversity hypothesis, although alternative interpretations cannot be ruled out. Overall, the results reported may help clarify the mechanisms of the evolution of new functions. From a different viewpoint, the partial-least-squares-reconstruction/Pareto-set-prediction approach we have introduced provides the computational basis for an efficient directed-evolution protocol aimed at the simultaneous enhancement of several protein features and should therefore open new possibilities in the engineering of multi-functional enzymes

CCS and NH3 emission associated with low-mass young stellar objects

In this work we present a sensitive and systematic single-dish survey of CCS emission (complemented with ammonia observations) at 1 cm, toward a sample of low- and intermediate-mass young star forming regions known to harbor water maser emission, made with NASA's 70 m antenna at Robledo de Chavela, Spain. Out of the 40 star forming regions surveyed in the CCS(2_{1}-1_{0}) line, only 6 low-mass sources show CCS emission: one transitional object between pre-stellar and protostellar Class 0 phase (GF9-2), three Class 0 protostars (L1448-IRS3, L1448C, and B1-IRS), a Class I source (L1251A), and a young T Tauri star (NGC2071-North). Since CCS is considered an ``early-time'' (<10E+5 yr) molecule, we explain these results by either proposing a revision of the classification of the age of NGC2071-North and L1251A, or suggesting the possibility that the particular physical conditions and processes of each source affect the destruction/production of the CCS. No statistically significant relationship was found between the presence of CCS and parameters of the molecular outflows and their driving sources. Nevertheless, we found a significant relationship between the detectability of CCS and the ammonia peak intensity (higher in regions with CCS), but not with its integrated intensity. This tendency found may suggest that the narrower ammonia line widths in the less turbulent medium associated with younger cores may compensate for the differences in ammonia peak intensity, rendering differences in integrated intensity negligible. From the CCS detection rate we derive a lifetime of this molecule of ~(0.7-3) x 10E+4 yr in low-mass star forming regions.Comment: 28 pages, 1 figure, 3 tables, to appear in the 2006 May 1 issue of the Astrophysical Journa

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Evolutionary Genomics Reveals Lineage-Specific Gene Loss and Rapid Evolution of a Sperm-Specific Ion Channel Complex: CatSpers and CatSperβ

The mammalian CatSper ion channel family consists of four sperm-specific voltage-gated Ca2+ channels that are crucial for sperm hyperactivation and male fertility. All four CatSper subunits are believed to assemble into a heteromultimeric channel complex, together with an auxiliary subunit, CatSperβ. Here, we report a comprehensive comparative genomics study and evolutionary analysis of CatSpers and CatSperβ, with important correlation to physiological significance of molecular evolution of the CatSper channel complex. The development of the CatSper channel complex with four CatSpers and CatSperβ originated as early as primitive metazoans such as the Cnidarian Nematostella vectensis. Comparative genomics revealed extensive lineage-specific gene loss of all four CatSpers and CatSperβ through metazoan evolution, especially in vertebrates. The CatSper channel complex underwent rapid evolution and functional divergence, while distinct evolutionary constraints appear to have acted on different domains and specific sites of the four CatSper genes. These results reveal unique evolutionary characteristics of sperm-specific Ca2+ channels and their adaptation to sperm biology through metazoan evolution

Changes in individual and contextual socio-economic level influence on reproductive behavior in Spanish women in the MCC-Spain study

Background The association between socioeconomic level and reproductive factors has been widely studied. For example, it is well known that women with lower socioeconomic status (SES) tend to have more children, the age at first-born being earlier. However, less is known about to what extent the great socioeconomic changes occurred in a country (Spain) could modify women reproductive factors. The main purpose of this article is to analyze the influence of individual and contextual socioeconomic levels on reproductive factors in Spanish women, and to explore whether this influence has changed over the last decades. Methods We performed a cross-sectional design using data from 2038 women recruited as population-based controls in an MCC-Spain case-control study. Results Higher parent’s economic level, education level, occupational level and lower urban vulnerability were associated with higher age at first delivery and lower number of pregnancies. These associations were stronger for women born after 1950: women with unfinished primary education had their first delivery 6 years before women with high education if they were born after 1950 (23.4 vs. 29.8 years) but only 3 years before if they were born before 1950 (25.7 vs. 28.0 years). For women born after 1950, the number of pregnancies dropped from 2.1 (unfinished primary school) to 1.7 (high education), whereas it remained almost unchanged in women born before 1950. Conclusions Reproductive behavior was associated with both individual and area-level socio-economic indicators. Such association was stronger for women born after 1950 regarding age at first delivery and number of pregnancies and for women born before 1950 regarding consumption of hormonal contraceptives or postmenopausal therapy

Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. METHOD: Adult subjects (N = 2229; 56.2% male) aged 18-69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age - chronological age) controlling for chronological age, sex, and scan site. RESULTS: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. DISCUSSION: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan