Differential susceptibility to plasticity: a 'missing link' between gene-culture co-evolution and neuropsychiatric spectrum disorders?

Brüne's proposal that erstwhile 'vulnerability' genes need to be reconsidered as 'plasticity' genes, given the potential for certain environments to yield increased positive function in the same domain as potential dysfunction, has implications for psychiatric nosology as well as a more dynamic understanding of the relationship between genes and culture. In addition to validating neuropsychiatric spectrum disorder nosologies by calling for similar methodological shifts in gene-environment-interaction studies, Brüne's position elevates the importance of environmental contexts - inclusive of socio-cultural variables - as mechanisms that contribute to clinical presentation. We assert that when models of susceptibility to plasticity and neuropsychiatric spectrum disorders are concomitantly considered, a new line of inquiry emerges into the co-evolution and co-determination of socio-cultural contexts and endophenotypes. This presents potentially unique opportunities, benefits, challenges, and responsibilities for research and practice in psychiatry

Sexual Health and Well-being Among Older Men and Women in England: Findings from the English Longitudinal Study of Ageing

We describe levels of sexual activity, problems with sexual functioning, and concerns about sexual health among older adults in the English Longitudinal Study of Ageing (ELSA), and associations with age, health, and partnership factors. Specifically, a total of 6,201 core ELSA participants (56 % women) aged 50 to >90 completed a comprehensive Sexual Relationships and Activities questionnaire (SRA-Q) included in ELSA Wave 6 (2012/13). The prevalence of reporting any sexual activity in the last year declined with age, with women less likely than men at all ages to report being sexually active. Poorer health was associated with lower levels of sexual activity and a higher prevalence of problems with sexual functioning, particularly among men. Difficulties most frequently reported by sexually active women related to becoming sexually aroused (32 %) and achieving orgasm (27 %), while for men it was erectile function (39 %). Sexual health concerns most commonly reported by women related to their level of sexual desire (11 %) and frequency of sexual activities (8 %). Among men it was level of sexual desire (15 %) and erectile difficulties (14 %). While the likelihood of reporting sexual health concerns tended to decrease with age in women, the opposite was seen in men. Poor sexual functioning and disagreements with a partner about initiating and/or feeling obligated to have sex were associated with greater concerns about and dissatisfaction with overall sex life. Levels of sexual activity decline with increasing age, although a sizable minority of men and women remain sexually active until the eighth and ninth decades of life. Problems with sexual functioning were relatively common, but overall levels of sexual health concerns were much lower. Sexually active men reported higher levels of concern with their sexual health and sexual dissatisfaction than women at all ages. Older peoples’ sexual health should be managed, not just in the context of their age, gender, and general health, but also within their existing sexual relationship

The Evolution of Bat Vestibular Systems in the Face of Potential Antagonistic Selection Pressures for Flight and Echolocation

PMCID: PMC3634842This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Optimization of Concurrent Deployments of the Juvenile Salmon Acoustic Telemetry System and Other Hydroacoustic Equipment at John Day Dam

The purpose of this report is to document the results of the acoustic optimization study conducted at John Day Dam during January and February 2008. The goal of the study was to optimize performance of the Juvenile Salmon Acoustic Telemetry System (JSATS) by determining deployment and data acquisition methods to minimize electrical and acoustic interference from various other acoustic sampling devices. Thereby, this would allow concurrent sampling by active and passive acoustic methods during the formal evaluations of the prototype surface flow outlets at the dam during spring and summer outmigration seasons for juvenile salmonids. The objectives for the optimization study at John Day Dam were to: 1. Design and test prototypes and provide a total needs list of pipes and trolleys to deploy JSATS hydrophones on the forebay face of the powerhouse and spillway. 2. Assess the effect on mean percentage decoded of JSATS transmissions from tags arrayed in the forebay and detected on the hydrophones by comparing: turbine unit OFF vs. ON; spill bay OPEN vs. CLOSED; dual frequency identification sonar (DIDSON) and acoustic Doppler current profiler (ADCP) both OFF vs. ON at a spill bay; and, fixed-aspect hydroacoustic system OFF vs. ON at a turbine unit and a spill bay. 3. Determine the relationship between fixed-aspect hydroacoustic transmit level and mean percentage of JSATS transmissions decoded. The general approach was to use hydrophones to listen for transmissions from JSATS tags deployed in vertical arrays in a series perpendicular to the face of the dam. We used acoustic telemetry equipment manufactured by Technologic and Sonic Concepts. In addition, we assessed old and new JSATS signal detectors and decoders and two different types of hydrophone baffling. The optimization study consisted of a suite of off/on tests. The primary response variable was mean percentage of tag transmissions decoded. We found that there was no appreciable adverse effect on mean percentage decoded for JSATS transmitters from: turbine operations; spillway operations; DIDSON/ADCP acoustic energy; and PAS hydroacoustic systems at transmit level of -12 dB, although there was a significant impact at all higher transmit levels (-11 to -6 dB). The main conclusion from this optimization study is that valid JSATS telemetry data can be collected simultaneously with a DIDSON/ADCP and a PAS hydroacoustic system at transmit level -12 dB. Multiple evaluation tools should be considered to increase the robustness and thoroughness of future fish passage evaluations at John Day and other dams

miR-16 and miR-21 Expression in the Placenta Is Associated with Fetal Growth

BACKGROUND: Novel research has suggested that altered miRNA expression in the placenta is associated with adverse pregnancy outcomes and with potentially harmful xenobiotic exposures. We hypothesized that aberrant expression of miRNA in the placenta is associated with fetal growth, a measurable phenotype resulting from a number of intrauterine factors, and one which is significantly predictive of later life outcomes. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed 107 primary, term, human placentas for expression of 6 miRNA reported to be expressed in the placenta and to regulate cell growth and development pathways: miR-16, miR-21, miR-93, miR-135b, miR-146a, and miR-182. The expression of miR-16 and miR-21 was markedly reduced in infants with the lowest birthweights (p<0.05). Logistic regression models suggested that low expression of miR-16 in the placenta predicts an over 4-fold increased odds of small for gestational age (SGA) status (p = 0.009, 95% CI = 1.42, 12.05). Moreover, having both low miR-16 and low miR-21 expression in the placenta predicts a greater increase in odds for SGA than having just low miR-16 or miR-21 expression (p<0.02), suggesting an additive effect of both of these miRNA. CONCLUSIONS/SIGNIFICANCE: Our study is one of the first to investigate placental miRNA expression profiles associated with birthweight and SGA status. Future research on miRNA whose expression is associated with in utero exposures and markers of fetal growth is essential for better understanding the epigenetic mechanisms underlying the developmental origins of health and disease

A Potential Role for Bat Tail Membranes in Flight Control

Wind tunnel tests conducted on a model based on the long-eared bat Plecotus auritus indicated that the positioning of the tail membrane (uropatagium) can significantly influence flight control. Adjusting tail position by increasing the angle of the legs ventrally relative to the body has a two-fold effect; increasing leg-induced wing camber (i.e., locally increased camber of the inner wing surface) and increasing the angle of attack of the tail membrane. We also used our model to examine the effects of flying with and without a tail membrane. For the bat model with a tail membrane increasing leg angle increased the lift, drag and pitching moment (nose-down) produced. However, removing the tail membrane significantly reduced the change in pitching moment with increasing leg angle, but it had no significant effect on the level of lift produced. The drag on the model also significantly increased with the removal of the tail membrane. The tail membrane, therefore, is potentially important for controlling the level of pitching moment produced by bats and an aid to flight control, specifically improving agility and manoeuvrability. Although the tail of bats is different from that of birds, in that it is only divided from the wings by the legs, it nonetheless, may, in addition to its prey capturing function, fulfil a similar role in aiding flight control

Assessing Susceptibility from Early-Life Exposure to Carcinogens

Cancer risk assessment methods currently assume that children and adults are equally susceptible to exposure to chemicals. We reviewed available scientific literature to determine whether this was scientifically supported. We identified more than 50 chemicals causing cancer after perinatal exposure. Human data are extremely limited, with radiation exposures showing increased early susceptibility at some tumor sites. Twenty-seven rodent studies for 18 chemicals had sufficient data after postnatal and adult exposures to quantitatively estimate potential increased susceptibility from early-life exposure, calculated as the ratio of juvenile to adult cancer potencies for three study types: acute dosing, repeated dosing, and lifetime dosing. Twelve of the chemicals act through a mutagenic mode of action. For these, the geometric mean ratio was 11 for lifetime exposures and 8.7 for repeat exposures, with a ratio of 10 for these studies combined. The geometric mean ratio for acute studies is 1.5, which was influenced by tissue-specific results [geometric mean ratios for kidney, leukemia, liver, lymph, mammary, nerve, reticular tissue, thymic lymphoma, and uterus/vagina > 1 (range, 1.6–8.1); forestomach, harderian gland, ovaries, and thyroid < 1 (range, 0.033–0.45)]. Chemicals causing cancer through other modes of action indicate some increased susceptibility from postnatal exposure (geometric mean ratio is 3.4 for lifetime exposure, 2.2 for repeat exposure). Early exposures to compounds with endocrine activity sometimes produce different tumors after exposures at different ages. These analyses suggest increased susceptibility to cancer from early-life exposure, particularly for chemicals acting through a mutagenic mode of action

Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM (-/-) patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors