Trajectories of cognitive development during adolescence among youth at-risk for schizophrenia.

BACKGROUND: Among adults with schizophrenia, evidence suggests that premorbid deficits in different cognitive domains follow distinct developmental courses during childhood and adolescence. The aim of this study was to delineate trajectories of adolescent cognitive functions prospectively among different groups of youth at-risk for schizophrenia, relative to their typically developing (TD) peers. METHOD: Using linear mixed models adjusted for sex, ethnicity, parental occupation and practice effects, cognitive development between ages 9 and 16 years was compared for youth characterised by a triad of well-replicated developmental antecedents of schizophrenia (ASz; N = 32) and youth with a least one affected relative with schizophrenia or schizoaffective disorder (FHx; N = 29), relative to TD youth (N = 45). Participants completed measures of IQ, scholastic achievement, memory and executive function at three time-points, separated by approximately 24-month intervals. RESULTS: Compared to TD youth, both ASz and FHx youth displayed stable developmental deficits in verbal working memory and inhibition/switching executive functions. ASz youth additionally presented with stable deficits in measures of vocabulary (IQ), word reading, numerical operations, and category fluency executive function, and a slower rate of growth (developmental lag) on spelling from 9 to 16 years than TD peers. Conversely, faster rates of growth relative to TD peers (developmental delay) were observed on visual and verbal memory, and on category fluency executive function (ASz youth only) and on matrix reasoning (IQ) and word reading (FHx youth only). CONCLUSIONS: These differential patterns of deviation from normative adolescent cognitive development among at-risk youth imply potential for cognitive rehabilitation targeting of specific cognitive deficits at different developmental phases.

The relationship between salivary C-reactive protein and cognitive function in children aged 11-14years: Does psychopathology have a moderating effect?

Elevated C-reactive protein (CRP), a non-specific biomarker of systemic bodily inflammation, has been associated with more pronounced cognitive impairments in adults with psychiatric disorders, particularly in the domains of memory and executive function. Whether this association is present in early life (i.e., the time at which the cognitive impairments that characterise these disorders become evident), and is specific to those with emerging psychiatric disorders, has yet to be investigated. To this end, we examined the association between salivary CRP and cognitive function in children aged 11-14years and explored the moderating effect of psychopathology. The study utilised data from an established longitudinal investigation of children recruited from the community (N=107) that had purposively over-sampled individuals experiencing psychopathology (determined using questionnaires). CRP was measured in saliva samples and participants completed assessments of cognition (memory and executive function) and psychopathology (internalising and externalising symptoms and psychotic-like experiences). Linear regression models indicated that higher salivary CRP was associated with poorer letter fluency (ß=-0.24, p=0.006) and scores on the inhibition (ß=-0.28, p=0.004) and inhibition/switching (ß=-0.36, p<0.001) subtests of the colour-word interference test, but not with performance on any of the memory tasks (working, visual, and verbal memory tasks). Results were largely unchanged after adjustment for psychopathology and no significant interactions between CRP and psychopathology were observed on any cognitive measure. Our findings provide preliminary evidence that elevated salivary CRP is associated with poorer cognitive function in early life, but that this association is not moderated by concurrent psychopathology. These findings have implications for early intervention strategies that attempt to ameliorate cognitive deficits associated with emerging psychiatric disorders. Further research is needed to determine whether salivary CRP levels can be used as a valid marker of peripheral inflammation among healthy adolescents.

Daily stressors and negative life events in children at elevated risk of developing schizophrenia.

BACKGROUND: Psychological stress is implicated in the development of schizophrenia, but little is known about experiences of stress among children at elevated risk for the disorder. AIMS: To examine stressor exposure and reactivity in children with different vulnerability profiles for schizophrenia: (a) children presenting multiple antecedents of schizophrenia (ASz group), (b) children with a family history of schizophrenia (FHx group) and (c) typically developing low-risk (TD) children. METHOD: Ninety-five children (ASz = 29; FHx = 19; ASz+FHx = 5; TD = 42), identified aged 9-12 years using a community-based screening procedure or as relatives of individuals with schizophrenia, completed questionnaires assessing environmental stressors and psychopathology at age 11-14 years. RESULTS: Relative to their typically developing peers, children in the FHx and ASz groups were exposed to a greater number of negative life events and a higher frequency of daily stressors, respectively; and were more distressed by these experiences. CONCLUSIONS: Stress exposure and reactivity may constitute useful targets of early intervention for psychosis.

Cortisol Levels in Childhood Associated With Emergence of Attenuated Psychotic Symptoms in Early Adulthood.

BACKGROUND: In individuals at clinical high-risk for psychosis, elevated cortisol levels predict subsequent onset of psychotic disorder. However, it is unclear whether cortisol alterations are evident at an earlier clinical stage and promote progression of psychosis expression. This study aimed to address this issue by investigating whether cortisol levels in childhood were associated with the emergence of attenuated psychotic symptoms in early adulthood. In exploratory analyses, we examined whether cortisol and psychosocial stress measures interacted in predicting attenuated psychotic symptoms. METHODS: A sample of children (N = 109) enriched for psychosis risk factors were recruited at age 9-12 years and assessed at age 11-14 years (T1) and 17-21 years (T2). Measures of psychopathology, psychosocial stressors, and salivary cortisol were obtained at T1. Attenuated psychotic symptoms were assessed at T2 using the Prodromal Questionnaire. RESULTS: Diurnal cortisol (ß = 0.915, 95% CI: 0.062-1.769) and daily stressors (ß = 0.379, 95% CI: 0.034-0.723) at T1 were independently associated with total Prodromal Questionnaire scores at T2 after accounting for demographic factors and T1 psychopathology. Exploratory analyses indicated a significant interaction between T1 diurnal cortisol and daily stressors (ß = 0.743, 95% CI: 0.081-1.405), with the highest predicted T2 total Prodromal Questionnaire scores occurring when both diurnal cortisol and daily stressors were increased. CONCLUSIONS: Our findings suggest that daily stressors and elevations in diurnal cortisol in late childhood/early adolescence increases risk for developing attenuated psychotic symptoms. These findings emphasize the importance of assessing environmental and biological risk factors for psychosis during neurodevelopmentally vulnerable time periods.

Trajectories of Mismatch Negativity and P3a Amplitude Development From Ages 9 to 16 Years in Children With Risk Factors for Schizophrenia.

BACKGROUND: Mismatch negativity (MMN) and P3a amplitude reductions are robust abnormalities of sensory information processing in schizophrenia, but they are variably present in different profiles of risk (family history vs. clinical high risk) for the disorder. This study aimed to determine whether these abnormalities characterize children presenting replicated risk factors for schizophrenia, using longitudinal assessment over the ages of 9-16 years in children with multiple replicated antecedents of schizophrenia (ASz) and with family history of schizophrenia (FHx), relative to typically developing (TD) peers. METHODS: A total of 105 children (52 female) sampled from the community were assessed at ages 9-12 years and approximately 2 and 4 years later. Linear mixed models were fitted to MMN and P3a peak amplitudes and latencies, with intercept and slope estimates from 32 ASz and 28 FHx children compared with those of 45 TD peers. RESULTS: In ASz relative to TD children, MMN amplitude initially increased and then prominently decreased during adolescence. Both ASz and FHx children had greater P3a amplitude than TD children at 11 years, which decreased with age, in contrast to P3a amplitude increasing during adolescence in TD youths. MMN abnormalities were specific to ASz children who continued to present symptoms during follow-up. CONCLUSIONS: Age-dependent MMN and P3a abnormalities demarcate adolescent development of ASz and FHx from TD children, with auditory change detection abnormalities specific to ASz children with continuing symptoms and attention-orienting abnormalities characterizing both ASz and FHx risk profiles. Follow-up is required to determine whether these abnormalities index vulnerability for schizophrenia or an illness nonspecific developmental delay.

Adolescent trajectories of fine motor and coordination skills and risk for schizophrenia.

Premorbid motor dysfunction is one of the earliest of developmental antecedents identified among individuals who develop schizophrenia in adulthood. However, among individuals with schizophrenia, premorbid motor dysfunction is not apparent at all stages of childhood development and may reduce with increasing age. Currently, little is known about the trajectories of motor development during adolescence among youth at-risk for the disorder. One hundred and one participants were assessed repeatedly, at approximately 24-month intervals (time 1, aged 9-12 years; time 2, 11-14 years; and time 3, 13-16 years), on the Purdue Pegboard assessment, comprising four subtests: Dominant Hand (DH), Non-Dominant Hand (NDH), Both Hands (BH), and Assembly. Fine motor and coordination skills development between ages 9-16 years was compared between youth characterised by a triad of developmental antecedents of schizophrenia (ASz, N = 32); youth with at least one affected relative with schizophrenia/schizoaffective disorder (FHx; N = 26); and typically developing youth without antecedents or family history (TD, N = 43). Longitudinal mixed models for repeated measures indicated significant motor skills improvements with age in TD youth on the Assembly subtest only. Relative to TD youth, we found evidence for developmental deficits (i.e., dysfunction that emerged early and remained stable) among ASz youth on DH and BH subtests, and among FHx youth on the Assembly subtest. ASz youth were characterised by a developmental delay on the Assembly subtest (i.e., initial performance decrement in middle childhood that caught up with peers' performance during adolescence). These divergences from normative motor development may reflect differences in structural and functional neural correlates.

DNA recognition by the Salmonella enterica serovar Typhimurium transcription factor SlyA.

The Salmonella regulatory protein SlyA is implicated in virulence, survival in macrophages and resistance to oxidative stress and anti-microbial peptides. SlyA is a member of the MarR family of winged-helix transcription factors. Systematic mutational analysis of the SlyA operator sequence and of the predicted DNA-binding region of SlyA shows that no single base pair in the palindromic SlyA operator sequence is essential for DNA binding, and identifies amino acid residues required to allow SlyA to recognise DNA. Combining the structure-function studies described here and elsewhere with the structures of MarR family proteins suggests a possible model for regulation of SlyA binding to DNA.

Mental health service use by young people: the role of caregiver characteristics.

AIMS: Many children and adolescents experiencing mental health problems do not receive appropriate care. Strategies to encourage appropriate access to services might be improved by a more detailed understanding of service use determinants within this group. In view of caregivers' key role in young people's pathways to care, this study aimed to advance understanding of caregiver-related characteristics that influence service use among young people. METHODS: We interviewed 407 primary caregivers of young people aged 9-18 years, recruited from a Greater London (United Kingdom) community sample. Caregivers reported on young people's service use in health care sector and/or education settings, and caregivers' intended stigmatising behaviours, help-seeking attitudes, and personal service use. Logistic regression analyses examined the relationship between these caregiver characteristics and young people's service use, controlling for young people's clinical and socio-demographic factors. RESULTS: Caregivers' intended stigmatising behaviours in particular exerted a strong influence on young people's service use within each service setting. The impact of this characteristic interacted with caregivers' service use in influencing young people's service use across health care and education settings and health care settings specifically. For young people's service use within education settings, caregivers' intended stigmatising behaviours score had a main effect. CONCLUSIONS: This study highlights the key role caregivers' attitudes and experiences hold in young people's service use. The findings indicate that strategies aiming to bridge the gap between young people's service needs and utilisation might be improved by targeting stigma amongst caregivers.

Screening for potential co-products in a Miscanthus sinensis mapping family by liquid chromatography with mass spectrometry detection.

Society is demanding more green chemicals from sustainable sources. Miscanthus is a potential source of platform chemicals and bioethanol through fermentation. Miscanthus sinensis (M. sinensis) has been found to contain particularly high levels of soluble phenols (hydroxycinnamates and flavonoids) which may have application in the nutraceutical, cosmetic and pharmaceutical industries. Here, we describe the first study on the identification and quantification of phenols from the leaf tissue of a bi-parental M. sinensis mapping family. Parents and progeny showed complex profiles of phenols with highly related structures which complicated characterisation of individual phenotypes. Separation of semi-purified extracts by reverse-phase liquid chromatography, coupled with detection by diode array and ESI-MS/MS, enabled distinction of different profiles of phenols. Ten hydroxycinnamates (O-cinnamoylquinic acids) and several flavones (one mono-O-glycosyl flavone, eight mono-C-glycosyl flavones, two di-C-glycosyl flavones, five O-glycosyl-C-glycosyl flavones and nine 2″-O-glycosyl-C-glycosyl flavones) were identified and quantified in leaf tissue of two hundred progeny and maternal and paternal plants during the seedling stage. Progeny exhibiting high, moderate and low amounts of hydroxycinnamates and flavonoids and both parents were selected and screened at seven months' growth to determine the abundance of these phenols at their highest biomass and compared with seedlings. Concentrations of phenols generally decreased as leaves matured. Several flavone-glycosides were identified. This technique can be used for rapid screening of plants in a mapping family to identify genotypes with high phenol content to add value in the biorefinery chain. This comparative study provides information on the content of potentially valuable compounds from readily renewable resources and possible biomarkers for identification in breeding programmes.

Cortisol awakening response and diurnal cortisol among children at elevated risk for schizophrenia: relationship to psychosocial stress and cognition.

Abnormal hypothalamic-pituitary-adrenal (HPA) axis function, as indexed by elevated diurnal cortisol levels and/or a blunted cortisol awakening response (CAR), has been observed among patients with first episode psychosis and associated with neurocognitive deficits in this population. However, the extent to which these features precede illness onset is unclear. The current study aimed to determine whether children who are at putatively elevated risk for psychosis because they present multiple antecedents of schizophrenia (ASz), and high-risk children with a family history of illness (FHx), are characterized by abnormal cortisol levels when compared with their typically developing (TD) peers. A further aim was to investigate the extent to which cortisol levels are associated with psychosocial stress and neurocognitive function. Thirty-three ASz children, 22 FHx children, and 40 TD children were identified at age 9-12 years using a novel community-based screening procedure or as relatives of individuals with schizophrenia. All participants were antipsychotic-naive and not currently seeking treatment for their symptoms. At age 11-14 years, participants provided salivary cortisol samples and completed psychosocial stress measures and tests of memory and executive function. Results indicated that FHx children, but not ASz children, were characterized by a blunted CAR relative to their TD peers (effect size=-0.73, p=0.01) that was not explained by psychosocial stress exposure or by distress relating to these experiences. Neither FHx nor ASz children were characterized by elevated diurnal cortisol. Among both FHx and ASz children, more pronounced HPA axis function abnormalities (i.e., higher diurnal cortisol levels and greater blunting of the CAR) were associated with poorer performance on tests of verbal memory and executive function. These findings support the notion that at least some HPA axis abnormalities described in psychosis precede illness onset, rather than being a subsequent epiphenomenon. We speculate that the blunted CAR may constitute an early (potentially genetically mediated) marker of psychosis vulnerability, whilst elevated diurnal cortisol levels may emerge only proximally to disease onset.

Characterization of the Escherichia coli K-12 ydhYVWXUT operon: regulation by FNR, NarL and NarP.

In Escherichia coli K-12 the expression of many genes is controlled by the oxygen-responsive transcription factor FNR and the nitrate- and nitrite-responsive two-component systems NarXL and NarPQ. Here, the ydhY gene is shown to be the first gene of a six-gene operon (ydhYVWXUT) that encodes proteins predicted to be components of an oxidoreductase. Mapping the ydhY-T transcript start and site-directed mutagenesis confirmed that the ydhY-T genes are transcribed from an FNR-dependent class II promoter and showed that the FNR site is centred at -42.5. In the presence of nitrate or nitrite, NarXL and NarPQ repressed ydhY-T expression. Analysis of the DNA sequence of the ydhY promoter region (PydhY) revealed the presence of four heptameric sequences similar to NarL/P binding sites centred at -42, -16, +6 and +15. The latter heptamers are arranged as a 7-2-7 inverted repeat, which is required for recognition by NarP. Accordingly, NarP protected the 7-2-7 region in DNase I footprints, and mutation of either heptamer +6 or heptamer +15 impaired nitrite-mediated repression, whereas mutation of heptamer -42 and heptamer -16 did not affect the response to nitrite. The NarL protein also protected the 7-2-7 region, but in contrast to NarP, the NarL footprint extended further upstream to encompass the -16 heptamer. The extended NarL footprint was consistent with the presence of multiple NarL-PydhY complexes in gel retardation assays. Mutation of heptamer -42, which is located within the FNR binding site, or heptamer +6 (but not heptamers -16 or +15) impaired nitrate-mediated repression. Thus, although the region of the ydhY-T promoter containing the -16 and +15 heptamers was recognized by NarL in vitro, mutation of these heptamers did not affect NarL-mediated repression in vivo.

Transition of Escherichia coli from aerobic to micro-aerobic conditions involves fast and slow reacting regulatory components.

Understanding life at a systems level is a major aim of biology. The bacterium Escherichia coli offers one of the best opportunities to achieve this goal. It is a metabolically versatile bacterium able to respond to changes in oxygen availability. This ability is a crucial component of its lifestyle, allowing it to thrive in aerobic external environments and under the oxygen-starved conditions of a host gut. The controlled growth conditions of chemostat culture were combined with transcript profiling to investigate transcriptome dynamics during the transition from aerobic to micro-aerobic conditions. In addition to predictable changes in transcripts encoding proteins of central metabolism, the abundances of transcripts involved in homeostasis of redox-reactive metals (Cu and Fe), and cell envelope stress were significantly altered. To gain further insight into the responses of the regulatory networks, the activities of key transcription factors during the transition to micro-aerobic conditions were inferred using a probabilistic modeling approach, which revealed that the response of the direct oxygen sensor FNR was rapid and overshot, whereas the indirect oxygen sensor ArcA reacted more slowly. Similarly, the cell envelope stress sensors RpoE and CpxR reacted rapidly and more slowly, respectively. Thus, it is suggested that combining rapid and slow reacting components in regulatory networks might be a feature of systems in which a signal is perceived by two or more functionally related transcription factors controlling overlapping regulons.

Regulation of Escherichia coli hemolysin E expression by H-NS and Salmonella SlyA.

The Escherichia coli hlyE gene (also known as clyA or sheA) codes for a novel pore-forming toxin. Previous work has shown that the global transcription factors FNR and CRP positively regulate hlyE expression by binding at the same site. Here in vivo transcription studies reveal that FNR occupies the hlyE promoter more frequently than CRP, providing a mechanism for the moderate upregulation of hlyE expression in response to two distinct environmental signals (oxygen and glucose starvation). It has been reported that H-NS interacts with two large regions of the hlyE promoter (PhlyE), one upstream of the -35 element and one downstream of the -10 element. Here we identify two high-affinity H-NS sites, H-NS I, located at the 3' end of the extended upstream footprint, and H-NS II, located at the 5' end of the extended downstream footprint. It is suggested that these high-affinity sites initiate the progressive formation of higher order complexes, allowing a range of H-NS-mediated regulatory effects at PhlyE. Finally, the identification of a SlyA binding site that overlaps the H-NS I site in PhlyE suggests a mechanism to explain how SlyA overproduction enhances hlyE expression by antagonizing the negative effects of H-NS.

Expression of the Escherichia coli yfiD gene responds to intracellular pH and reduces the accumulation of acidic metabolic end products.

The YfiD protein of Escherichia coli has been reported to be an acid-inducible protein. Here it is shown that expression of a yfiD::lac reporter fusion is enhanced up to 3 small middle dot5-fold during acidic growth. The anaerobic transcription factor FNR was confirmed as the major regulator of yfiD expression, and ArcA was found to enhance anaerobic yfiD expression, probably by displacing a repressing FNR dimer in the -93 small middle dot5 region of the promoter. Moreover, the pyruvate sensor PdhR was shown to act as a minor anaerobic repressor of yfiD expression. On the basis of its strong homology to the C-terminal region of pyruvate formate-lyase (PFL) it was predicted that YfiD would be a radical-containing enzyme. The YfiD radical was found to be introduced by the PFL-activase enzyme, but unlike PFL, AdhE did not deactivate radicalized YfiD. The extent of radical activation of YfiD was enhanced by low intracellular pH, and thus it was concluded that both yfiD expression and YfiD activity are affected by growth at low pH. The yfiD mutant strain JRG4033 excreted increased levels of organic acids compared to the parental strain when grown in chemostat culture under oxygen-starved conditions, consistent with the acid-inducibility of yfiD expression and the recently reported ability of YfiD to rescue the activity of oxygenolytically cleaved PFL.

Properties of haemolysin E (HlyE) from a pathogenic Escherichia coli avian isolate and studies of HlyE export.

Haemolysin E (HlyE) is a novel pore-forming toxin first identified in Escherichia coli K-12. Analysis of the 3-D structure of HlyE led to the proposal that a unique hydrophobic beta-hairpin structure (the beta-tongue, residues 177-203) interacts with the lipid bilayer in target membranes. In seeming contradiction to this, the hlyE sequence from a pathogenic E. coli strain (JM4660) that lacks all other haemolysins has been reported to encode an Arg residue at position 188 that was difficult to reconcile with the proposed role of the beta-tongue. Here it is shown that the JM4660 hlyE sequence encodes Gly, not Arg, at position 188 and that substitution of Gly188 by Arg in E. coli K-12 HlyE abolishes activity, emphasizing the importance of the head domain in HlyE function. Nevertheless, 76 other amino acid substitutions were confirmed compared to the HlyE protein of E. coli K-12. The JM4660 HlyE protein was dimeric, suggesting a mechanism for improving toxin solubility, and it lysed red blood cells from many species by forming 36-41 A diameter pores. However, the haemolytic phenotype of JM4660 was found to be unstable due to defects in HlyE export, indicating that export of active HlyE is not an intrinsic property of the protein but requires additional components. TnphoA mutagenesis of hlyE shows that secretion from the cytoplasm to the periplasm does not require the carboxyl-terminal region of HlyE. Finally, disruption of genes associated with cell envelope function, including tatC, impairs HlyE export, indicating that outer membrane integrity is important for effective HlyE secretion.

DNA recognition by the Salmonella enterica serovar Typhimurium transcription factor SlyA

The Salmonella regulatory protein SlyA is implicated in virulence, survival in macrophages and resistance to oxidative stress and anti-microbial peptides. SlyA is a member of the MarR family of winged-helix transcription factors. Systematic mutational analysis of the SlyA operator sequence and of the predicted DNA-binding region of SlyA shows that no single base pair in the palindromic SlyA operator sequence is essential for DNA binding, and identifies amino acid residues required to allow SlyA to recognise DNA. Combining the structure-function studies described here and elsewhere with the structures of MarR family proteins suggests a possible model for regulation of SlyA binding to DNA (AU)

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