Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia.

Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽ 1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P = 1.5 × 10(-)(4)). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽ 0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P = 0.018) and de novo mutations (P = 0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N = 614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios.

Physician weight loss advice and patient weight loss behavior change: a literature review and meta-analysis of survey data.

Primary care providers (PCPs) can empower their patients to make health-promoting behavior changes. Many guidelines recommend that PCPs counsel overweight and obese patients about weight loss, yet few studies examine the impact of provider weight loss counseling on actual changes in patient behavior. We performed a systematic review and meta-analysis of published studies of survey data examining provider weight loss counseling and its association with changes in patient weight loss behavior. We reviewed the published literature using keywords related to weight loss advice. We used meta-analytic techniques to compute and aggregate effect sizes for the meta-analysis. We also tested variables that had the potential to moderate the responses. A total of 32 studies met criteria for the literature review. Of these, 12 were appropriate for the meta-analysis. Most studies demonstrated a positive effect of provider weight loss advice on patient weight loss behavior. In random effects meta-analysis, the overall mean weighted effect size for patient weight loss efforts was odds ratio (OR)=3.85 (95% confidence interval (CI) 2.71, 5.49; P<0.01), indicating a statistically significant impact of weight loss advice. There was no significant difference in the effectiveness of advice in studies using obese patients alone versus mixed samples (obese alone OR=3.44, 95% CI 2.37, 5.00; mixed sample OR=3.98, 95% CI 2.53, 6.26, P=0.63). PCP advice on weight loss appears to have a significant impact on patient attempts to change behaviors related to their weight. Providers should address weight loss with their overweight and obese patients.

Education eclipses ethnicity in predicting the development of the metabolic syndrome in different ethnic groups in midlife: the Study of Women's Health Across the Nation (SWAN).

OBJECTIVE: To determine the respective roles of socio-economic status (SES) and ethnicity in the risk of incident metabolic syndrome in middle-aged women. DESIGN AND PARTICIPANTS: A total of 3302 pre- and peri-menopausal women, not receiving hormone therapy at baseline, took part in the Study of Women's Health Across the Nation, a multi-site, community-based, longitudinal study of the menopausal transition. The main outcome measures were to ascertain the prevalence of the metabolic syndrome and the incidence of the metabolic syndrome over 5 years of follow-up. RESULTS: At baseline, the prevalence of the metabolic syndrome was 21% (n = 673). Among 2512 women without metabolic syndrome at baseline, 12.8% (n = 321) developed the metabolic syndrome during 5 years of follow-up. Both ethnicity and SES were significant univariate predictors of incident metabolic syndrome. In multivariate logistic regression models that included age at baseline, menopausal status and site, baseline smoking and alcohol consumption at follow-up visit 1, as well as baseline values of each of the components of the metabolic syndrome, only education was an independent predictor of incident metabolic syndrome. CONCLUSION: Approximately 13% of peri-menopausal women developed the metabolic syndrome during the 5-year follow-up period. Education, but not ethnicity, was an independent predictor of incident metabolic syndrome risk.

Socioeconomic characteristics of the community in childhood and cognition in old age.

We examined the relation of early life socioeconomic circumstances to cognition in older residents of a biracial urban community. Participants had brief cognitive testing three times at approximately 3-year intervals. At baseline, information about early life household and county socioeconomic level was collected. In mixed-effects models adjusted for age, sex, race, and education, both early life household and county socioeconomic levels were positively associated with baseline level of cognition but unrelated to cognitive decline. The results suggest that socioeconomic conditions in early life are associated with level of cognitive function in old age but not with rate of cognitive decline.

A population-based longitudinal study of cognitive functioning in the menopausal transition.

BACKGROUND: No longitudinal studies have tracked cognitive performance through the menopausal transition and thus the impact of the transition on cognition, independent of aging, is not known. The authors hypothesized that a decline in cognitive functioning occurs as women progress through the menopausal transition, independent of age, educational level, family income, ethnicity, and baseline self-perceived health. METHOD: The authors began a population-based, longitudinal study in January 1996 with yearly follow-up interviews. This report includes follow-up through November 2001. The authors randomly selected African American and white women from a census of two contiguous Chicago communities. After screening for eligibility (age 42 to 52 years, premenopausal or early perimenopausal, no exogenous hormone use in the past 3 months, and no hysterectomy), 868 agreed to participate. Women who became pregnant, had a hysterectomy, or began using hormones were censored from that time onward. This study reports on 803 women for whom cognitive assessments were available. The authors assessed working memory (Digit Span Backward) and perceptual speed (Symbol Digit Modalities Test). RESULTS: Contrary to the hypothesis, the authors found small but significant increases over time during the premenopausal and perimenopausal phases. This trend was not accounted for by chronological age, education, family income, ethnicity, or baseline self-perceived health. CONCLUSIONS: Transition through menopause is not accompanied by a decline in working memory and perceptual speed.

Visual short-term memory in the first year of life: capacity and recency effects.

A span task was developed to assess the amount of information infants could hold in short-term memory. In this task, infants were presented with up to 4 items in succession and then tested for recognition by successively pairing each item with a novel one. A large sample of full-terms and low-birth-weight preterms (< 1,750 g) was tested longitudinally, at 5, 7, and 12 months of age. Results were similar for both groups: (a) Longer spans were more difficult, especially at the 2 younger ages; (b) memory capacity increased over the 1st year of life--whereas less than 25% of the sample could hold as many as 3-4 items in mind at once at the younger ages, nearly half could do so by 12 months of age; (c) there was a marked recency effect (greater memory for the final item) for spans of 3 and 4 at all ages; and (d) there were modest cross-age correlations, indicating that individual differences in memory capacity showed some stability from age to age.

Modifying the distribution of attention in infants.

In three experiments, the distribution and malleability of infant visual attention were studied in 5-month-olds (N = 72) while they inspected large geometric designs. In Experiment 1, we established that infants maintained their distribution of attention from a pretest to a familiarization phase. We also replicated and extended our previous findings that infants who examined targets with briefer, more numerous looks and shifts-short lookers-had novelty scores above chance, whereas long lookers demonstrated chance responding. In Experiment 2, different portions of the display were successively illuminated with red light. This manipulation induced long lookers to scan like short lookers during familiarization; they then showed novelty scores well above chance. A third experiment ruled out the simple presence of a red light as the source of this effect. In sum, then, these results suggest that the distribution of attention is malleable, and that a broader distribution of attention, as reflected in briefer and more numerous looks and shifts, can improve processing.

Features of the parkin/ariadne-like ubiquitin ligase, HHARI, that regulate its interaction with the ubiquitin-conjugating enzyme, Ubch7.

We recently reported the identification of a RING finger-containing protein, HHARI (human homologue of Drosophila ariadne), which binds to the human ubiquitin-conjugating enzyme UbcH7 in vitro. We now demonstrate that HHARI interacts and co-localizes with UbcH7 in mammalian cells, particularly in the perinuclear region. We have further defined a minimal interaction region of HHARI comprising residues 186-254, identified individual amino acid residues essential for the interaction, and determined that the distance between the RING1 finger and IBR (in between RING fingers) domains is critical to maintaining binding. We have also established that the RING1 finger of HHARI cannot be substituted for by the highly homologous RING finger domains of either of the ubiquitin-protein ligase components c-CBL or Parkin, despite their similarity in structure and their independent capabilities to bind UbcH7. Furthermore, mutation of the RING1 finger domain of HHARI from a RING-HC to a RING-H2 type abolishes interaction with UbcH7. These studies demonstrate that very subtle changes to the domains that regulate recognition between highly conserved components of the ubiquitin pathway can dramatically affect their ability to interact.

Attention and recognition memory in the 1st year of life: a longitudinal study of preterm and full-term infants.

Several aspects of visual attention and their implications for recognition memory were examined in a longitudinal sample of full-term and preterm (birth weight < 1,750 g) infants seen at 5, 7, and 12 months of age. At all 3 ages, full-terms had shorter look durations, faster shift rates, less off-task behavior, and higher novelty scores than preterms. Both groups followed similar developmental trajectories, with older infants having shorter looks and more shifts. Infants were consistent in attentional style across problems of the same type, across problems that used different types of stimuli (faces and patterns), and across the familiarization and test phases of this paired-comparison design; there was also modest cross-age stability. Shorter looks and higher shift rates during familiarization were related to better recognition memory, with shift rate adding to prediction independently of either peak or mean look. These findings underscore the importance of attention to infant information processing.

Characterisation of the human and mouse orthologues of the Drosophila ariadne gene.

The specificity of the ubiquitin degradation system is regulated through interaction between individual ubiquitin-conjugating enzymes (E2s) and multiple ubiquitin-protein ligases (E3s). Here we describe the characterisation of a novel gene (ARIH1) that encodes the human homologue of Drosophila ariadne which interacts with the E2s, UbcH7 and UbcH8 and represents a component of an E3 complex. Three PACs (189N19, 142P17 and 179H7) were isolated that contain this gene. Using these PACs as probes, we mapped ARIH1 to human chromosome 15q24 by fluorescence in situ hybridisation (FISH). Sequencing of the ARIH1 PACs showed that the gene has 13 introns. In addition, we isolated two PACs (345D8 and 571P19) containing the mouse orthologue (Arih1) of ARIH1. The intron-exon structure of Arih1 was identical to ARIH1 and the proteins demonstrated a 98% identity at the amino acid level. Furthermore, comparison of Drosophila ariadne with ARIH1 indicates an identity at the amino acid level of 70% and introns at 3/7 identical sites. The high degree of homology demonstrated by the mouse and human orthologues of Drosophila ariadne indicates an important, conserved biological function, consistent with a putative role in ubiquitylation.

Genomic organization of the human ubiquitin-conjugating enzyme gene, UBE2L6 on chromosome 11q12.

The human UBE2L6 gene encodes UbcH8(Kumar), a ubiquitin-conjugating enzyme (E2) highly simliar in primary structure to UbcH7 which is encoded by UBE2L3. Like UBC4 and UBC5 in yeast, these proteins demonstrate functional redundancy. Herein we report the intron/exon structure of UBE2L6. Comparison of the genomic organization of UBE2L6 with UBE2L3 demonstrates that these genes remain highly conserved at the genomic as well as at the protein level. We also describe the chromosomal localization of UBE2L6, which maps to chromosome 11q12.

The ubiquitin-conjugating enzymes UbcH7 and UbcH8 interact with RING finger/IBR motif-containing domains of HHARI and H7-AP1.

Ubiquitinylation of proteins appears to be mediated by the specific interplay between ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s). However, cognate E3s and/or substrate proteins have been identified for only a few E2s. To identify proteins that can interact with the human E2 UbcH7, a yeast two-hybrid screen was performed. Two proteins were identified and termed human homologue of Drosophila ariadne (HHARI) and UbcH7-associated protein (H7-AP1). Both proteins, which are widely expressed, are characterized by the presence of RING finger and in between RING fingers (IBR) domains. No other overt structural similarity was observed between the two proteins. In vitro binding studies revealed that an N-terminal RING finger motif (HHARI) and the IBR domain (HHARI and H7-AP1) are involved in the interaction of these proteins with UbcH7. Furthermore, binding of these two proteins to UbcH7 is specific insofar that both HHARI and H7-AP1 can bind to the closely related E2, UbcH8, but not to the unrelated E2s UbcH5 and UbcH1. Although it is not clear at present whether HHARI and H7-AP1 serve, for instance, as substrates for UbcH7 or represent proteins with E3 activity, our data suggests that a subset of RING finger/IBR proteins are functionally linked to the ubiquitin/proteasome pathway.

Characterization of the mouse ubiquitin-conjugating enzyme gene UbcM4.

The ubiquitination pathway targets not only normal (short-lived) intracellular eukaryotic proteins for degradation when appropriate, but also serves to eliminate mutant/misfolded proteins from the cell. An understanding of the molecular basis of the interaction between the ubiquitin-conjugating enzymes (E2s), ubiquitin protein ligases (E3s), and target proteins is essential to explain the process in normal cellular function and in disease. UbcM4 is the mouse ortholog of the human E2, UbcH7, which can participate in the in vitro degradation of many proteins including p53. We describe the characterization of the mouse UbcM4 gene and the identification of a UbcM4 pseudogene. Four UbcM4 transcripts of approximately 0.7, 1.5, 2.1, and 2.6 kb, observed on Northern blots, are differentiated by their utilization of alternative UbcM4 polyadenylation sites. A single alternative splice variant cDNA, termed UbcM4Deltaex2, was also identified. The polypeptide encoded by UbcM4Deltaex2 is incapable of forming an ubiquitin-thioester in contrast to UbcM4, despite retaining the key cysteine residue essential for ubiquitin thioester formation and the active site consensus sequence that defines the ubiquitin-conjugating enzyme class. These observations are of particular relevance for analysis of UbcM4 function in vivo as our studies indicate that the targeted deletion of the coding exon absent in UbcM4Deltaex2 would produce an inactive UbcM4 protein and presents an alternative to disruption of its transcriptional initiation site/promoter region. Furthermore, it suggests that a similar strategy may be applicable to disrupt the function of other ubiquitin-conjugating enzymes in vivo.

The relation of affect to attention and learning in infancy.

The relation of positive affect to attention and learning was examined in 5-, 7-, and 9-month-olds (N = 84). Affect and attention were assessed while the infants inspected a photograph. Affect was rated globally, for overall mood, and specifically, for amount of time smiling. Attention was indexed by the duration of the infant's longest (or peak) look, a measure previously linked to differential cognitive performance. At all ages, positive affect (shown by approximately half the infants) was associated with long look durations and slower learning, as assessed on a task in which infants learned to distinguish a familiar face from a series of novel faces. By contrast, neutral affect was associated with short looks and faster learning. Affect and look duration had synergistic effects, in that learning was faster than expected for infants who displayed both short looks and neutral affect. These findings are compatible with adult research that links positive affect to less analytical processing, and provide the first evidence that affect may be associated with the speed of processing differences implicated in short and long looking.

Visual and auditory temporal processing, cross-modal transfer, and reading.

The present study reexamined the relevance of auditory and visual cross-modal matching to reading ability, an issue first addressed in a seminal study by Birch and Belmont (1964). By presenting all patterns to be matched as temporal sequences of tones and lights, including intramodal as well as cross-modal conditions, and covarying memory, three problems with the Birch and Belmont design were corrected. Results showed that poor readers had difficulty in perceiving temporal patterns generally: They did worse than good readers not only on cross-modal conditions but also on intramodal ones. These results were replicated in two tasks. Nonetheless, hierarchical regressions provided some indication that cross-modal abilities themselves are relevant to reading. For one of the two tasks, cross-modal performance contributed to the prediction of reading ability over and above intramodal performance. Poor readers also showed slower response times--a factor that contributed marginally to the prediction of reading independent of temporal processing.

Continuity in tactual-visual cross-modal transfer: infancy to 11 years.

The present study demonstrated that individual differences in cross-modal transfer showed continuity over a 10-year span. Tactual-visual tasks, requiring visual recognition of shapes that had previously been felt but not seen, were given to full-term and preterm children at 2 ages, 1 and 11 years. Cross-modal performance showed a left-hand advantage at 11 years and, for both groups, cross-age correlations were significant when tactual exploration at 11 years was done with the left hand (r = .34-.36). The continuity showed some specificity in that the infant measure did not relate to other types of cross-modal performance at 11 years and was not dependent on aspects of spatial ability involving form perception. This continuity accounted for most of the previously reported relation of infant cross-modal ability to 11-year IQ.

Memory and speed: their role in the relation of infant information processing to later IQ.

This study examined the extent to which memory and processing speed accounted for relations we had found earlier between infant information processing and childhood IQ. The measures of speed and memory were obtained when the children were 11 years of age using paper-and-pencil tasks and an extensive battery of computer-administered tasks. The relations of 7 months visual recognition memory and 1 year cross-modal transfer to 11 year IQ were both substantially reduced with statistical control of factors derived from these measures. These results suggest that speed and memory underlie some of the infant-childhood continuities in cognition. Path and structural equation modeling indicated that the significant pathways from 7 month visual recognition memory to 11 year IQ were both direct and indirect, the indirect paths going through memory and speed.

Infants' recognition of contour-deleted figures.

Infants' recognition of contour-deleted figures was investigated in four experiments using a habituation procedure. The results indicate that 12-month-old infants could recognize line drawings of figures that were missing 33%, 50%, or even as much as 66% of their contour. This was so whether the contour-deleted versions were used on habituation or on test: Intact figures were recognized after habituation to contour-deleted exemplars, and in most cases contour-deleted ones were recognized after habituation to the intact figure. The single failure appeared to be due to difficulty in discriminating between two extremely impoverished test stimuli. Findings from the final experiment, in which infants recognized complements of contour-deleted stimuli but not scrambled versions, suggested that they fill in the gaps of the contour-deleted figures so as to create a figural whole.