The structural biology of patellamide biosynthesis

This work was supported by grants from the ERC339367 (JHN and MJ) and BBSRCBB/K015508/1 (JHN and MJ).The biosynthetic pathways for patellamide and related natural products have recently been studied by structural biology. These pathways produce molecules that have a complex framework and exhibit a diverse array of activity due to the variability of the amino acids that are found in them. As these molecules are difficult to synthesize chemically, exploitation of their properties has been modest. The patellamide pathway involves amino acid heterocyclization, peptide cleavage, peptide macrocyclization, heterocycle oxidation and epimerization; closely related products are also prenylated. Enzyme activities have been identified for all these transformations except epimerization, which may be spontaneous. This review highlights the recent structural and mechanistic work on amino acid heterocyclization, peptide cleavage and peptide macrocyclization. This work should help in using the enzymes to produce novel analogs of the natural products enabling an exploitation of their properties.Peer reviewe

Nucleotide Sequence Variation within the PI3K p85 Alpha Gene Associates with Alcohol Risk Drinking Behaviour in Adolescents

While the phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway is typically known to regulate cell growth and survival, emerging evidence suggest a role for this pathway in regulating the behavioural responses to addictive drugs.To investigate whether PI3K contributes to patterns of risky alcohol drinking in human, we investigated genetic variations in PIK3R1, encoding the 85 kD regulatory subunit of PIK, in 145 family trios consisting of 15-16 year old adolescents and their parents. Screening for mutations in exons, exon-intron boundaries and regulatory sequences, we identified 14 single nucleotide polymorphisms (SNPs) in the PIK3R1 gene region from exon 1 to the beginning of the 3' untranslated region (UTR). These SNPs defined haplotypes for the respective PIK3R1 region. Four haplotype tagging (ht)SNPs (rs706713, rs2302975, rs171649 and rs1043526), discriminating all haplotypes with a frequency >or=4.5% were identified. These htSNPs were used to genotype adolescents from the "Mannheim Study of Risk Children" (MARC). Transmission disequilibrium tests in these adolescents and their parents demonstrated sex-specific association of two SNPs, rs2302975 and rs1043526, with patterns of risky alcohol consumption in male adolescents, including lifetime prevalence of drunkenness (p = 0.0019 and 0.0379, respectively) and elevated maximum amount of drinking (p = 0.0020 and 0.0494, respectively), as a measure for binge drinking pattern.Our findings highlight a previously unknown relevance of PIK3R1 genotypes for alcohol use disorders and might help discriminate individuals at risk for alcoholism

Consumer-orientated development of hybrid beef burger and sausage analogues

Hybrid meat analogues, whereby a proportion of meat has been partially replaced by more sustainable protein sources, have been proposed to provide a means for more sustainable diets in the future. Consumer testing was conducted to determine consumer acceptability of different formulations of Hybrid beef burgers and pork sausages in comparison to both meat and meat free commercial products. Acceptability data was generated using the 9-point hedonic scale. Check-all-that-apply (CATA) questioning was used to determine the sensory attributes perceived in each product as well as information on the attributes of consumers’ ideal products. It was identified that Hybrid products were generally well liked among consumers and no significant differences in consumer acceptability (p < 0.05) was identified between Hybrid and full meat products whereas meat free products were found to be less accepted. However, hybrid sausages received higher acceptability scores (6.00 to 6.51) than Hybrid burgers (5.84 to 5.92) suggesting format may have a large impact on consumer acceptability of Hybrid products. Correspondence Analysis (CA) indicated that Hybrid products were grouped with meat products in their sensory attributes. Penalty analysis found that a ‘meaty flavour’ was the largest factor driving consumer acceptability in both burgers and sausages. Cluster analysis of consumer acceptability data identified key differences in overall acceptability between different consumer groups (consumers that only eat meat products and consumers who eat both meat and meat free). The Hybrid concept was found to bridge the acceptability gap between meat and meat free, however further product reformulation is required to optimise consumer acceptability

Inferring neutral winds in the ionospheric transition region from atmospheric-gravity-wave traveling-ionospheric-disturbance (AGW-TID) observations with the EISCAT VHF radar and the Nordic Meteor Radar Cluster

Atmospheric gravity waves and traveling ionospheric disturbances can be observed in the neutral atmosphere and the ionosphere at a wide range of spatial and temporal scales. Especially at medium scales, these oscillations are often not resolved in general circulation models and are parameterized. We show that ionospheric disturbances forced by upward-propagating atmospheric gravity waves can be simultaneously observed with the EISCAT very high frequency incoherent scatter radar and the Nordic Meteor Radar Cluster. From combined multi-static measurements, both vertical and horizontal wave parameters can be determined by applying a specially developed Fourier filter analysis method. This method is demonstrated using the example of a strongly pronounced wave mode that occurred during the EISCAT experiment on 7 July 2020. Leveraging the developed technique, we show that the wave characteristics of traveling ionospheric disturbances are notably impacted by the fall transition of the mesosphere and lower thermosphere. We also demonstrate the application of using the determined wave parameters to infer the thermospheric neutral wind velocities. Applying the dissipative anelastic gravity wave dispersion relation, we obtain vertical wind profiles in the lower thermosphere.</p

Personality, attentional biases towards emotional faces and symptoms of mental disorders in an adolescent sample

Objective To investigate the role of personality factors and attentional biases towards emotional faces, in establishing concurrent and prospective risk for mental disorder diagnosis in adolescence. Method Data were obtained as part of the IMAGEN study, conducted across 8 European sites, with a community sample of 2257 adolescents. At 14 years, participants completed an emotional variant of the dot-probe task, as well two personality measures, namely the Substance Use Risk Profile Scale and the revised NEO Personality Inventory. At 14 and 16 years, participants and their parents were interviewed to determine symptoms of mental disorders. Results Personality traits were general and specific risk indicators for mental disorders at 14 years. Increased specificity was obtained when investigating the likelihood of mental disorders over a 2-year period, with the Substance Use Risk Profile Scale showing incremental validity over the NEO Personality Inventory. Attentional biases to emotional faces did not characterise or predict mental disorders examined in the current sample. Discussion Personality traits can indicate concurrent and prospective risk for mental disorders in a community youth sample, and identify at-risk youth beyond the impact of baseline symptoms. This study does not support the hypothesis that attentional biases mediate the relationship between personality and psychopathology in a community sample. Task and sample characteristics that contribute to differing results among studies are discussed

Blunted ventral striatal responses to anticipated rewards foreshadow problematic drug use in novelty-seeking adolescents.

Novelty-seeking tendencies in adolescents may promote innovation as well as problematic impulsive behaviour, including drug abuse. Previous research has not clarified whether neural hyper- or hypo-responsiveness to anticipated rewards promotes vulnerability in these individuals. Here we use a longitudinal design to track 144 novelty-seeking adolescents at age 14 and 16 to determine whether neural activity in response to anticipated rewards predicts problematic drug use. We find that diminished BOLD activity in mesolimbic (ventral striatal and midbrain) and prefrontal cortical (dorsolateral prefrontal cortex) regions during reward anticipation at age 14 predicts problematic drug use at age 16. Lower psychometric conscientiousness and steeper discounting of future rewards at age 14 also predicts problematic drug use at age 16, but the neural responses independently predict more variance than psychometric measures. Together, these findings suggest that diminished neural responses to anticipated rewards in novelty-seeking adolescents may increase vulnerability to future problematic drug use

Neural correlates of three types of negative life events during angry face processing in adolescents.

Negative life events (NLE) contribute to anxiety and depression disorders, but their relationship with brain functioning in adolescence has rarely been studied. We hypothesized that neural response to social threat would relate to NLE in the frontal-limbic emotional regions. Participants (N = 685) were drawn from the Imagen database of 14-year-old community adolescents recruited in schools. They underwent functional MRI while viewing angry and neutral faces, as a probe to neural response to social threat. Lifetime NLEs were assessed using the 'distress', 'family' and 'accident' subscales from a life event dimensional questionnaire. Relationships between NLE subscale scores and neural response were investigated. Links of NLE subscales scores with anxiety or depression outcomes at the age of 16 years were also investigated. Lifetime 'distress' positively correlated with ventral-lateral orbitofrontal and temporal cortex activations during angry face processing. 'Distress' scores correlated with the probabilities of meeting criteria for Generalized Anxiety Disorder or Major Depressive Disorder at the age of 16 years. Lifetime 'family' and 'accident' scores did not relate with neural response or follow-up conditions, however. Thus, different types of NLEs differentially predicted neural responses to threat during adolescence, and differentially predicted a de novo internalizing condition 2 years later. The deleterious effect of self-referential NLEs is suggested

Oxytocin Receptor Genotype Modulates Ventral Striatal Activity to Social Cues and Response to Stressful Life Events

Background Common variants in the oxytocin receptor gene (OXTR) have been shown to influence social and affective behavior and to moderate the effect of adverse experiences on risk for social-affective problems. However, the intermediate neurobiological mechanisms are not fully understood. Although human functional neuroimaging studies have reported that oxytocin effects on social behavior and emotional states are mediated by amygdala function, animal models indicate that oxytocin receptors in the ventral striatum (VS) modulate sensitivity to social reinforcers. This study aimed to comprehensively investigate OXTR-dependent brain mechanisms associated with social-affective problems. Methods In a sample of 1445 adolescents we tested the effect of 23-tagging single nucleotide polymorphisms across the OXTR region and stressful life events (SLEs) on functional magnetic resonance imaging blood oxygen level-dependent activity in the VS and amygdala to animated angry faces. Single nucleotide polymorphisms for which gene-wide significant effects on brain function were found were then carried forward to examine associations with social-affective problems. Results A gene-wide significant effect of rs237915 showed that adolescents with minor CC-genotype had significantly lower VS activity than CT/TT-carriers. Significant or nominally significant gene × environment effects on emotional problems (in girls) and peer problems (in boys) revealed a strong increase in clinical symptoms as a function of SLEs in CT/TT-carriers but not CC-homozygotes. However, in low-SLE environments, CC-homozygotes had more emotional problems (girls) and peer problems (boys). Moreover, among CC-homozygotes, reduced VS activity was related to more peer problems. Conclusions These findings suggest that a common OXTR-variant affects brain responsiveness to negative social cues and that in "risk- carriers" reduced sensitivity is simultaneously associated with more social-affective problems in "favorable environments" and greater resilience against stressful experiences. © 2014 Society of Biological Psychiatry