Associations of four biological age markers with child development: a multi-omic analysis in the European HELIX cohort

Background: While biological age in adults is often understood as representing general health and resilience, the conceptual interpretation of accelerated biological age in children and its relationship to development remains unclear. We aimed to clarify the relationship of accelerated biological age, assessed through two established biological age indicators, telomere length and DNA methylation age, and two novel candidate biological age indicators , to child developmental outcomes, including growth and adiposity, cognition, behaviour, lung function and onset of puberty, among European school-age children participating in the HELIX exposome cohort. Methods: The study population included up to 1,173 children, aged between 5 and 12 years, from study centres in the UK, France, Spain, Norway, Lithuania, and Greece. Telomere length was measured through qPCR, blood DNA methylation and gene expression was measured using microarray, and proteins and metabolites were measured by a range of targeted assays. DNA methylation age was assessed using Horvath's skin and blood clock, while novel blood transcriptome and 'immunometabolic' (based on plasma protein and urinary and serum metabolite data) clocks were derived and tested in a subset of children assessed six months after the main follow-up visit. Associations between biological age indicators with child developmental measures as well as health risk factors were estimated using linear regression, adjusted for chronological age, sex, ethnicity and study centre. The clock derived markers were expressed as Δ age (i.e., predicted minus chronological age). Results: Transcriptome and immunometabolic clocks predicted chronological age well in the test set (r= 0.93 and r= 0.84 respectively). Generally, weak correlations were observed, after adjustment for chronological age, between the biological age indicators. Among associations with health risk factors, higher birthweight was associated with greater immunometabolic Δ age, smoke exposure with greater DNA methylation Δ age and high family affluence with longer telomere length. Among associations with child developmental measures, all biological age markers were associated with greater BMI and fat mass, and all markers except telomere length were associated with greater height, at least at nominal significance (p<0.05). Immunometabolic Δ age was associated with better working memory (p = 4e -3) and reduced inattentiveness (p= 4e -4), while DNA methylation Δ age was associated with greater inattentiveness (p=0.03) and poorer externalizing behaviours (p= 0.01). Shorter telomere length was also associated with poorer externalizing behaviours (p=0.03). Conclusions: In children, as in adults, biological ageing appears to be a multi-faceted process and adiposity is an important correlate of accelerated biological ageing. Patterns of associations suggested that accelerated immunometabolic age may be beneficial for some aspects of child development while accelerated DNA methylation age and telomere attrition may reflect early detrimental aspects of biological ageing, apparent even in children. Funding: UK Research and Innovation (MR/S03532X/1); European Commission (grant agreement numbers: 308333; 874583)

Equal versus equivalent access to the scientific literature

<p>Abstract</p

Using Neural Networks for Relation Extraction from Biomedical Literature

Using different sources of information to support automated extracting of relations between biomedical concepts contributes to the development of our understanding of biological systems. The primary comprehensive source of these relations is biomedical literature. Several relation extraction approaches have been proposed to identify relations between concepts in biomedical literature, namely, using neural networks algorithms. The use of multichannel architectures composed of multiple data representations, as in deep neural networks, is leading to state-of-the-art results. The right combination of data representations can eventually lead us to even higher evaluation scores in relation extraction tasks. Thus, biomedical ontologies play a fundamental role by providing semantic and ancestry information about an entity. The incorporation of biomedical ontologies has already been proved to enhance previous state-of-the-art results.Comment: Artificial Neural Networks book (Springer) - Chapter 1

PCSK9, apolipoprotein E and lipoviral particles in chronic hepatitis C genotype 3: evidence for genotype-specific regulation of lipoprotein metabolism.

BACKGROUND & AIMS: Hepatitis C virus (HCV) associates with lipoproteins to form "lipoviral particles" (LVPs) that can facilitate viral entry into hepatocytes. Initial attachment occurs via heparan sulphate proteoglycans and low-density lipoprotein receptor (LDLR); CD81 then mediates a post-attachment event. Proprotein convertase subtilisin kexin type 9 (PCSK9) enhances the degradation of the LDLR and modulates liver CD81 levels. We measured LVP and PCSK9 in patients chronically infected with HCV genotype (G)3. PCSK9 concentrations were also measured in HCV-G1 to indirectly examine the role of LDLR in LVP clearance. METHODS: HCV RNA, LVP (d1.07g/ml) fractions, were quantified in patients with HCV-G3 (n=39) by real time RT-PCR and LVP ratios (LVPr; LVP/(LVP+non-LVP)) were calculated. Insulin resistance (IR) was assessed using the homeostasis model assessment of IR (HOMA-IR). Plasma PCSK9 concentrations were measured by ELISA in HCV-G3 and HCV-G1 (n=51). RESULTS: In HCV-G3 LVP load correlated inversely with HDL-C (r=-0.421; p=0.008), and apoE (r=-0.428; p=0.013). The LVPr varied more than 35-fold (median 0.286; range 0.027 to 0.969); PCSK9 was the strongest negative predictor of LVPr (R(2)=16.2%; p=0.012). HOMA-IR was not associated with LVP load or LVPr. PCSK9 concentrations were significantly lower in HCV-G3 compared to HCV-G1 (p<0.001). PCSK9 did not correlate with LDL-C in HCV-G3 or G1. CONCLUSIONS: The inverse correlation of LVP with apoE in HCV-G3, compared to the reverse in HCV-G1 suggests HCV genotype-specific differences in apoE mediated viral entry. Lower PCSK9 and LDL concentrations imply upregulated LDLR activity in HCV-G3

Pelvic girdle pain - associations between risk factors in early pregnancy and disability or pain intensity in late pregnancy: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Recent studies have shown high prevalence rates for pelvic girdle pain (PGP) in pregnancy. Some risk factors for developing PGP have been suggested, but the evidence is weak. Furthermore there is almost no data on how findings from clinical examinations are related to subsequent PGP. The main purpose for this study was to study the associations between socio-demographical, psychological and clinical factors measured at inclusion in early pregnancy and disability or pain intensity in gestation week 30.</p> <p>Methods</p> <p>This is a prospective cohort study following women from early to late pregnancy. Eligible women were recruited at their first attendance at the maternity care unit. 268 pregnant women answered questionnaires and underwent clinical examinations in early pregnancy and in gestation week 30. We used scores on disability and pain intensity in gestation week 30 as outcome measures to capture the affliction level of PGP. Multiple linear regression analysis was used to study the associations between potential risk factors measured in early pregnancy and disability or pain intensity in gestation week 30.</p> <p>Results</p> <p>Self-reported pain locations in the pelvis, positive posterior pelvic pain provocation (P4) test and a sum of pain provocation tests in early pregnancy were significantly associated with disability and pain intensity in gestation week 30 in a multivariable statistic model. In addition, distress was significantly associated with disability. The functional active straight leg raise (ASLR) test, fear avoidance beliefs and the number of pain sites were not significantly associated with either disability or pain intensity.</p> <p>Conclusions</p> <p>The results suggest that a clinical examination, including a few tests, performed in early pregnancy may identify women at risk of a more severe PGP late in pregnancy. The identification of clinical risk factors may provide a foundation for development of targeted prevention strategies.</p

Effects of ecstasy/polydrug use on memory for associative information

Rationale Associative learning underpins behaviours that are fundamental to the everyday functioning of the individual. Evidence pointing to learning deficits in recreational drug users merits further examination. Objectives A word pair learning task was administered to examine associative learning processes in ecstasy/polydrug users. Methods After assignment to either single or divided attention conditions, 44 ecstasy/polydrug users and 48 non-users were presented with 80 word pairs at encoding. Following this, four types of stimuli were presented at the recognition phase: the words as originally paired (old pairs), previously presented words in different pairings (conjunction pairs), old words paired with new words, and pairs of new words (not presented previously). The task was to identify which of the stimuli were intact old pairs. Results Ecstasy/ploydrug users produced significantly more false-positive responses overall compared to non-users. Increased long-term frequency of ecstasy use was positively associated with the propensity to produce false-positive responses. It was also associated with a more liberal signal detection theory decision criterion value. Measures of long term and recent cannabis use were also associated with these same word pair learning outcome measures. Conjunction word pairs, irrespective of drug use, generated the highest level of false-positive responses and significantly more false-positive responses were made in the divided attention condition compared to the single attention condition. Conclusions Overall, the results suggest that long-term ecstasy exposure may induce a deficit in associative learning and this may be in part a consequence of users adopting a more liberal decision criterion value

Measurement and Computation of Movement of Bromide Ions and Carbofuran in Ridged Humic-Sandy Soil

Water flow and pesticide transport in the soil of fields with ridges and furrows may be more complex than in the soil of more level fields. Prior to crop emergence, the tracer bromide ion and the insecticide carbofuran were sprayed on the humic-sandy soil of a potato field with ridges and furrows. Rainfall was supplemented by sprinkler irrigation. The distribution of the substances in the soil profile of the ridges and furrows was measured on three dates in the potato growing season. Separate ridge and furrow systems were simulated by using the pesticide emission assessment at regional and local scales (PEARL) model for pesticide behavior in soil–plant systems. The substances travelled deeper in the furrow soil than in the ridge soil, because of runoff from the ridges to the furrows. At 19 days after application, the peak of the bromide distribution was measured to be in the 0.1–0.2 m layer of the ridges, while it was in the 0.3–0.5 m layer of the furrows. After 65 days, the peak of the carbofuran distribution in the ridge soil was still in the 0.1 m top layer, while the pesticide was rather evenly distributed in the top 0.6 m of the furrow soil. The wide ranges in concentration measured with depth showed that preferential water flow and substance transport occurred in the sandy soil. Part of the bromide ion distribution was measured to move faster in soil than the computed wave. The runoff of water and pesticide from the ridges to the furrows, and the thinner root zone in the furrows, are expected to increase the risk of leaching to groundwater in ridged fields, in comparison with more level fields

Electrophysiological Heterogeneity of Fast-Spiking Interneurons: Chandelier versus Basket Cells

In the prefrontal cortex, parvalbumin-positive inhibitory neurons play a prominent role in the neural circuitry that subserves working memory, and alterations in these neurons contribute to the pathophysiology of schizophrenia. Two morphologically distinct classes of parvalbumin neurons that target the perisomatic region of pyramidal neurons, chandelier cells (ChCs) and basket cells (BCs), are generally thought to have the same "fast-spiking" phenotype, which is characterized by a short action potential and high frequency firing without adaptation. However, findings from studies in different species suggest that certain electrophysiological membrane properties might differ between these two cell classes. In this study, we assessed the physiological heterogeneity of fast-spiking interneurons as a function of two factors: species (macaque monkey vs. rat) and morphology (chandelier vs. basket). We showed previously that electrophysiological membrane properties of BCs differ between these two species. Here, for the first time, we report differences in ChCs membrane properties between monkey and rat. We also found that a number of membrane properties differentiate ChCs from BCs. Some of these differences were species-independent (e.g., fast and medium afterhyperpolarization, firing frequency, and depolarizing sag), whereas the differences in the first spike latency between ChCs and BCs were species-specific. Our findings indicate that different combinations of electrophysiological membrane properties distinguish ChCs from BCs in rodents and primates. Such electrophysiological differences between ChCs and BCs likely contribute to their distinctive roles in cortical circuitry in each species. © 2013 Povysheva et al

Deletion of the GABAA α2-subunit does not alter self dministration of cocaine or reinstatement of cocaine seeking

Rationale GABAA receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine. Objective We investigated the reinforcing properties of cocaine in GABAA α2-subunit knockout (KO) mice using an intravenous self-administration procedure. Methods α2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg). Results No differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not. Conclusions Despite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the α2-subunit may be involved in modulating the “energising” aspect of cocaine’s effects on reward-seeking