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PubMed1989

Extreme chromosomal heterogeneity in a small-island population of Rumex acetosa.

Chromosome analyses of 227 mature plants of the dioecious species Rumex acetosa collected on the small island of Skomer have revealed an extremely high level of unique and polymorphic variation. The three common polymorphisms in this species--supernumerary segments on chromosomes 1 and 6, and B-chromosomes--are widespread on the island and the frequency of supernumerary segment 1 is higher than in all 37 mainland populations previously studied. Novel variants, unknown elsewhere, occur in each polymorphism. Fourteen different chromosome rearrangements are unique to the island, and eleven of these were detected in 67 plants from a small area which had undergone a population crash in 1977. It is argued that the genome of R. acetosa is undergoing rapid reorganisation on this small island which may be associated with an enforced shift towards inbreeding in this dioecious species.

Chromosomes↗

PubMed2003

Polymorphisms in the 5'-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression.

We present evidence of complex balancing regulation of HTR1B transcription by common polymorphisms in its promoter. Computational analysis of the HTR1B gene predicted that a 5' segment, spanning common DNA sequence variations, T-261G, A-161T, and -182INS/DEL-181, contained a putative functional promoter. Using a secreted alkaline phosphatase (SEAP) reporter gene system, we found that the haplotype -261G_-182INS-181_A-161 enhanced transcriptional activity 2.3-fold compared with the haplotype T-261_-182INS-181_A-161. Conversely, -161T reversed this, and the net effect when -261G and -161T were in the same haplotype (-261G_-182INS-181_-161T) was equivalent to the major haplotype (T-261_-182INS-181_A-161). Electrophoretic mobility shift experiments showed that -261G and -161T modify the binding of transcription factors (TFs): -261G generates a new AP2 binding site, while alleles A-161 and -161T exhibit different binding characteristics to AP1. T-261G and A-161T were found to be in linkage disequilibrium (LD) with G861C in a European ancestry population. Interestingly, G861C has been reported to be associated with several psychiatric disorders. Our results indicate that HTR1B is the target of substantial transcriptional genetic regulation by common haplotypes, which are in LD with the HTR1B single-nucleotide polymorphism (SNP) most commonly used in association studies.

5' Untranslated Regions↗

PubMed2006

ROC and confusion analysis of structure comparison methods identify the main causes of divergence from manual protein classification.

BACKGROUND: Current classification of protein folds are based, ultimately, on visual inspection of similarities. Previous attempts to use computerized structure comparison methods show only partial agreement with curated databases, but have failed to provide detailed statistical and structural analysis of the causes of these divergences. RESULTS: We construct a map of similarities/dissimilarities among manually defined protein folds, using a score cutoff value determined by means of the Receiver Operating Characteristics curve. It identifies folds which appear to overlap or to be "confused" with each other by two distinct similarity measures. It also identifies folds which appear inhomogeneous in that they contain apparently dissimilar domains, as measured by both similarity measures. At a low (1%) false positive rate, 25 to 38% of domain pairs in the same SCOP folds do not appear similar. Our results suggest either that some of these folds are defined using criteria other than purely structural consideration or that the similarity measures used do not recognize some relevant aspects of structural similarity in certain cases. Specifically, variations of the "common core" of some folds are severe enough to defeat attempts to automatically detect structural similarity and/or to lead to false detection of similarity between domains in distinct folds. Structures in some folds vary greatly in size because they contain varying numbers of a repeating unit, while similarity scores are quite sensitive to size differences. Structures in different folds may contain similar substructures, which produce false positives. Finally, the common core within a structure may be too small relative to the entire structure, to be recognized as the basis of similarity to another. CONCLUSION: A detailed analysis of the entire available protein fold space by two automated similarity methods reveals the extent and the nature of the divergence between the automatically determined similarity/dissimilarity and the manual fold type classifications. Some of the observed divergences can probably be addressed with better structure comparison methods and better automatic, intelligent classification procedures. Others may be intrinsic to the problem, suggesting a continuous rather than discrete protein fold space.

Algorithms↗

PubMed2005

Phenotypic and genetic differentiation between native and introduced plant populations.

Plant invasions often involve rapid evolutionary change. Founder effects, hybridization, and adaptation to novel environments cause genetic differentiation between native and introduced populations and may contribute to the success of invaders. An influential idea in this context has been the Evolution of Increased Competitive Ability (EICA) hypothesis. It proposes that after enemy release plants rapidly evolve to be less defended but more competitive, thereby increasing plant vigour in introduced populations. To detect evolutionary change in invaders, comparative studies of native versus introduced populations are needed. Here, we review the current empirical evidence from: (1) comparisons of phenotypic variation in natural populations; (2) comparisons of molecular variation with neutral genetic markers; (3) comparisons of quantitative genetic variation in a common environment; and (4) comparisons of phenotypic plasticity across different environments. Field data suggest that increased vigour and reduced herbivory are common in introduced plant populations. In molecular studies, the genetic diversity of introduced populations was not consistently different from that of native populations. Multiple introductions of invasive plants appear to be the rule rather than the exception. In tests of the EICA hypothesis in a common environment, several found increased growth or decreased resistance in introduced populations. However, few provided a full test of the EICA hypothesis by addressing growth and defence in the same species. Overall, there is reasonable empirical evidence to suggest that genetic differentiation through rapid evolutionary change is important in plant invasions. We discuss conceptual and methodological issues associated with cross-continental comparisons and make recommendations for future research. When testing for EICA, greater emphasis should be put on competitive ability and plant tolerance. Moreover, it is important to address evolutionary change in characteristics other than defence and growth that could play a role in plant invasions.

Adaptation, Physiological↗

PubMed2004

The diversity within an expanded and redefined repertoire of phase-variable genes in Helicobacter pylori.

Phase variation is a common mechanism used by pathogenic bacteria to generate intra-strain diversity that is important in niche adaptation and is strongly associated with virulence determinants. Previous analyses of the complete sequences of the Helicobacter pylori strains 26695 and J99 have identified 36 putative phase-variable genes among the two genomes through their association with homopolymeric tracts and dinucleotide repeats. Here a comparative analysis of the two genomes is reported and an updated and expanded list of 46 candidate phase-variable genes in H. pylori is described. These have been systematically investigated by PCR and sequencing for the presence of the genes, and the presence and variability in length of the repeats in strains 26695 and J99 and in a collection of unrelated H. pylori strains representative of the main global subdivisions recently suggested. This provides supportive evidence for the phase variability of 30 of the 46 candidates. Other differences in this subset of genes were observed (i) in the repeats, which can be present or absent among the strains, or stabilized in different strains and (ii) in the gene-complements of the strains. Differences between genes were not consistently correlated with the geographic population distribution of the strains. This study extends and provides new evidence for variation of this type in H. pylori, and of the high degree of diversity of the repertoire of genes which display phase-variable switching within individual strains.

Animals↗

PubMed2007

Pharmacogenomics and nutrigenomics: synergies and differences.

The success of the Human Genome Project and the spectacular development of broad genomics tools have catalyzed a new era in both medicine and nutrition. The terms pharmacogenomics and nutrigenomics are relatively new. Both have grown out of their genetic forbears as large-scale genomics technologies have been developed in the last decade. The aim of both disciplines is to individualize or personalize medicine and food and nutrition, and ultimately health, by tailoring the drug or the food to the individual genotype. This review article provides an overview of synergies and differences between these two potentially powerful science areas. Individual genetic variation is the common factor on which both pharmacogenomics and nutrigenomics are based. Each human is genetically (including epigenetics) unique and phenotypically distinct. One of the expectations of both technologies is that a wide range of gene variants and related single-nucleotide polymorphism will be identified as to their importance in health status, validated and incorporated into genotype based strategies for the optimization of health and the prevention of disease. Pharmacogenomics requires rigorous genomic testing that will be regulated and analyzed by professionals and acted on by medical practitioners. As further information is obtained on the importance of the interaction of food and the human genotype in disease prevention and health, pharmacogenomics can provide an opportunity driver for nutrigenomics. As we move from disease treatment to disease prevention, the two disciplines will become more closely aligned.

Food, Organic↗

PubMed2004

No evidence for an association between common nonsynonymous polymorphisms in delta and bristle number variation in natural and laboratory populations of Drosophila melanogaster.

We test the hypothesis that naturally occurring nonsynonymous variants in the Delta ligand of the Notch signaling pathway contribute to standing variation in sternopleural and/or abdominal bristle number in Drosophila melanogaster, for both a large cohort of wild-caught flies and previously described laboratory lines. We sequenced the transcribed region of Delta for 16 naturally occurring chromosomes and 65 SNPs, including 7 nonsynonymous SNPs (nsSNPs), were observed. Identified nsSNPs and 6 additional common SNPs, all located in exon 6 and the 3' UTR, were genotyped in 2060 wild-caught flies using an OLA-based methodology and genotyped in 38 additional natural chromosomes via DNA sequencing. None of the genotyped nsSNPs were significantly associated with natural variation in bristle number as assessed by a permutation test. A 95% upper bound on the additive genetic variance attributable to each genotyped SNP in the large natural cohort is <2% of the total phenotypic variation. Results suggest that two previously detected genotype/phenotype associations between bristle number and variants in the introns of Delta cannot be explained by linkage disequilibrium between these variants and nearby nonsynonymous variants. Unidentified regulatory variants more parsimoniously explain previous observations.

3' Untranslated Regions↗

PubMed2005

Do variations in disease prevalence limit the usefulness of population-based hospitalization rates for studying variations in hospital admissions?

BACKGROUND: Studies of geographic variation in hospitalizations commonly examine age- and gender-adjusted population-based hospitalization rates (ie, the numbers of persons hospitalized relative to what is expected given the age/gender distributions in the area population). OBJECTIVE: To determine whether areas identified as extreme using population-based hospitalization rates remain extreme when ranked by disease-based hospitalization rates (the numbers of persons hospitalized relative to what is expected given the amount of disease in the area). DESIGN: The authors examined 1997 Medicare data on both inpatient admissions and outpatient visits of patients 65 years and older in each of 71 small areas in Massachusetts for 15 medical conditions. For each area, the number of people having each condition was calculated as the sum of those hospitalized plus those treated as outpatients only. The authors used hierarchical Bayesian modeling to estimate area-specific population-based hospitalization rates, disease-based hospitalization rates (DHRs), and disease prevalence. MAIN OUTCOME MEASURE: The extent to which the same areas were identified as extreme based on population-based hospitalization rates versus DHRs. RESULTS: Area-specific population-based hospitalization rates, DHRs, and disease prevalence varied substantially. Areas identified as extreme using population-based hospitalization rates often were not extreme when ranked by DHRs. For 11 of the 15 conditions, 5 or more of the 14 areas ranked in top and bottom deciles by population-based hospitalization rates were more likely than not (ie, with probability > or = 0.50) to be at least 2 deciles less extreme when ranked by DHRs. CONCLUSION: Differences in disease prevalence can limit the usefulness of population-based hospitalization rates for studying variations in hospital admissions.

Aged↗

PubMed2002

Fatty acid binding protein-2 gene variants and insulin resistance: gene and gene-environment interaction effects.

The intestinal fatty acid binding protein (FABP2) gene is proposed as a candidate gene for diabetes because the protein it codes is involved in fatty acid (FA) absorption and metabolism and may, therefore, affect insulin sensitivity and glucose metabolism. Numerous studies have assessed FABP2 gene variants and their association with insulin resistance and type 2 diabetes. Some weak evidence indicates that the silent variants and those in the noncoding regions of the gene (codon 118, 3' noncoding region, intron 2 trinucleotide repeat) might be associated with insulin resistance/type 2 diabetes. The most extensively studied variant is the missense Ala54Thr variation, which is common in diverse populations and results in increased FA absorption in vivo. Some evidence indicates that this variant may be associated with insulin sensitivity/type 2 diabetes. However, the large majority of studies assessing the potential association between the Ala54Thr FABP2 variant and insulin resistance/type 2 diabetes did not account for the independent and substantial effects of body composition, habitual physical activity (PA) levels, and diet on insulin resistance. We recently reported that there was an association between Ala54Thr FABP2 genotypes and insulin sensitivity after accounting for the independent effects of body composition and habitual PA levels on insulin sensitivity. Furthermore, others have demonstrated that Ala54Thr FABP2 may associate with insulin sensitivity, but only if individuals are consuming a high-fat diet. These results highlight the importance of including behavioral and environmental factors in the design of studies seeking to assess the impact of genes on physiological and clinical outcome phenotypes.

Amino Acid Substitution↗

PubMed1990

Binaural interaction in high-frequency neurons in inferior colliculus of the cat: effects of variations in sound pressure level on sensitivity to interaural intensity differences.

1. Development of models of the manner in which interaural intensity differences (IIDs), the major binaural cue for the azimuthal location of high-frequency sounds, are coded by populations of neurons requires knowledge of the extent to which the IID sensitivity of individual neurons is invariant with changes in sound pressure level (SPL) and other stimulus parameters. To examine this tissue, recordings were obtained from a large sample (n = 458) of neurons with characteristic frequency (CF) greater than 3 kHz in the central nucleus of the inferior colliculus (ICC) of anesthetized cats. The sensitivity to IIDs and the effects of changes in SPL on this sensitivity were examined in neurons receiving excitatory contralateral input and inhibitory or mixed inhibitory/facilitatory ipsilateral input (EI neurons). 2. The form of an EI neuron's IID sensitivity and the effects of changes in SPL on that sensitivity were found to be determined in part by the characteristics of the neuron's rate-intensity function for monaural contralateral stimulation, and detailed rate-intensity functions were therefore obtained for 91 neurons. Many ICC neurons have nonmonotonic rate-intensity functions, the proportion so classified depending on the criterion of nonmonotonicity employed. 3. IID sensitivity functions for CF tonal stimuli were obtained at one or more intensities for 90 neurons, using a method of generating IIDs that kept the average binaural intensity (ABI) of the stimuli at the two ears constant. In the standard ABI range in which a function was obtained for each unit, the majority of EI neurons (72%) had monotonic (sigmoidal) or near-monotonic IID sensitivity functions. The remainder had nonmonotonic (peaked) IID sensitivity functions, which were attributable either to mixed inhibitory and facilitatory ipsilateral influences or to the fact that the effects of ipsilateral stimulation were superimposed on nonmonotonic effects of changes in intensity at the excitatory ear. 4. IID sensitivity was examined at two or more ABIs (3-5 in most cases) for 40 neurons classified as having monotonic or near-monotonic functions in the standard ABI range and for 7 neurons classified as nonmonotonic. For a small proportion of neurons with monotonic IID sensitivity functions, the form of the function was relatively invariant with changes in ABI. In those monotonic neurons in which the form of the IID sensitivity function varied with changes in ABI, the most common type of variation was that the position of the sloping portion of the function shifted systematically in the direction of larger IIDs favoring the ipsilateral ear as ABI increased.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed2002

Environmental conditions and host genotype direct genetic diversity of Venturia ditricha, a fungal endophyte of birch trees.

We investigated whether genetic variation of a common foliar endophyte of birch trees, Venturia ditricha, is affected by environmental conditions or host genotype. Fungal samples were collected from 10 half-sibling families of mountain birch (Betula pubescens ssp. czerepanovii) grown in two environmental conditions with different daily average temperatures: a forested river valley and an adjacent open tundra (altitudinal difference 180 m). Genetic analysis of V. ditricha isolates was done using random amplified microsatellite polymerase chain reaction. We found that host genotypes, along with prevailing environmental conditions, influence the probability of infection by particular endophyte genotypes. The most susceptible host genotypes were highly infected with genetically similar endophyte genotypes, whereas the most resistant trees were poorly infected and they were infected by genetically dissimilar endophytes. Our results also showed environment-host genotype interactions, suggesting that the susceptibility of the host to a particular endophyte genotype may change in natural environments when environmental conditions are changed. It appears that a particular endophyte genotype needs to find the right host genotype for a successful infection. There are many host genotypes in natural stands; this means, from the point of view of the fungus, the environment is heterogeneous. Thus, under the influence of birch tree genotypes, genetically differentiated subgroups of the endophytic fungus may be formed in different environments.

Ascomycota↗

PubMed1997

Molecular biology of S-layers.

In this chapter we report on the molecular biology of crystalline surface layers of different bacterial groups. The limited information indicates that there are many variations on a common theme. Sequence variety, antigenic diversity, gene expression, rearrangements, influence of environmental factors and applied aspects are addressed. There is considerable variety in the S-layer composition, which was elucidated by sequence analysis of the corresponding genes. In Corynebacterium glutamicum one major cell wall protein is responsible for the formation of a highly ordered, hexagonal array. In contrast, two abundant surface proteins from the S-layer of Bacillus anthracis. Each protein possesses three S-layer homology motifs and one protein could be a virulence factor. The antigenic diversity and ABC transporters are important features, which have been studied in methanogenic archaea. The expression of the S-layer components is controlled by three genes in the case of Thermus thermophilus. One has repressor activity on the S-layer gene promoter, the second codes for the S-layer protein. The rearrangement by reciprocal recombination was investigated in Campylobacter fetus. 7-8 S-layer proteins with a high degree of homology at the 5' and 3' ends were found. Environmental changes influence the surface properties of Bacillus stearothermophilus. Depending on oxygen supply, this species produces different S-layer proteins. Finally, the molecular bases for some applications are discussed. Recombinant S-layer fusion proteins have been designed for biotechnology.

ATP-Binding Cassette Transporters↗

PubMed2003

A potentially useful distribution model for dietary intake data.

BACKGROUND: Conventional mixed models for the analysis of diet diary data have introduced several simplifying assumptions, such as that of a single standard deviation for within-person day-to-day variation which is common to all individuals. OBJECTIVE: We developed a model in which the within-person standard deviation was allowed to differ from person to person. DESIGN: The model was demonstrated using data on daily retinol intake from the Dietary and Nutritional Survey of British Adults. The data were from 7-day weighed dietary diaries. Estimation was performed by Markov chain Monte Carlo. Reliability of the model was assessed from the accuracy of estimation of the percentage of days on which various intakes were exceeded. For levels above the median retinol intake, estimation of percentages of days with excessive intakes was most accurate using the model with varying within-person standard deviation. SETTING: A survey of British adults aged 16-64 years. SUBJECTS: In total 2197 adults living in the UK, 1087 males and 1110 females. RESULTS: Under the traditional model, estimated daily intake ranged from 716.4 to 1421.8 microg depending on age and sex, with a within-person standard deviation of 4298.9 microg. Under the new model, estimated average daily intake ranged from 388.9 to 518.3 microg depending on age and sex, but with a within-person standard deviation varying between subjects with a 95% range of 29 to 8384 microg. The new model was shown to predict the percentage of days of exceeding large intakes more successfully than the traditional model. For example, the percentage of days of exceeding the maximum recommended intake (9000 microg for men and 7500 microg for women) was 2.4%. The traditional model predicted no excessive intakes, whereas the new model predicted 2.9%. CONCLUSIONS: This model is potentially useful in dietary research in general and for analysis of data on chemical contaminants in foods, in particular.

Adolescent↗

PubMed2007

Variation in left atrial transmural wall thickness at sites commonly targeted for ablation of atrial fibrillation.

BACKGROUND: The number of catheter ablations performed for atrial fibrillation (AF) has increased dramatically over the past several years. Regional variation in left atrial (LA) wall thickness is known to exist but have not been described in detail. AF ablation success and complication rates may be related to regional differences in LA wall thickness. OBJECTIVE: To evaluate differences in transmural wall thickness in five pre-defined anatomic areas within the LA which are commonly targeted for AF ablation. MATERIALS AND METHODS: We measured LA wall transmural thickness in 34 human heart specimens using calipers in five anatomic areas frequently targeted during AF ablation (anterior wall, septum, mitral isthmus, posterior wall and roof). RESULTS: The autopsied individuals were 53% female, 67.7% had CAD, 14.7% had atrial fibrillation, 61.8% had hypertension, and 21.6% had congestive heart failure. The roof was the thinnest region with mean thickness measuring significantly less than each other area (p 0.005 for the posterior wall and <0.001 for all other areas). The septum was the thickest region with mean thickness measuring significantly greater than each other area (p = 0.05, 0.001, <0.001, <0.001 measured against the anterior wall, isthmus, posterior wall and roof, respectively). CONCLUSIONS: Significant regional differences exist for mean left atrial wall thickness among the different anatomic areas within the left atrium which are often targeted during catheter ablation of AF. These differences may have significant implications in determining the ideal intensity and total duration of radiofrequency energy required to achieve a safe and successful ablation.

Adult↗

PubMed2005

Sensitivity of test for overdispersion in Poisson regression.

Overdispersion or extra-Poisson variation is very common for count data. This phenomenon arises when the variability of the counts greatly exceeds the mean under the Poisson assumption, resulting in substantial bias for the parameter estimates. To detect whether count data are overdispersed in the Poisson regression setting, various tests have been proposed and among them, the score tests derived by Dean (1992) are popular and easy to implement. However, such tests can be sensitive to anomalous or extreme observations. In this paper, diagnostic measures are proposed for assessing the sensitivity of Dean's score test for overdispersion in Poisson regression. Applications to the well-known fabric faults and Ames salmonella assay data sets illustrate the usefulness of the diagnostics in analyzing overdispersed count data.

Bias↗

PubMed1990

Karyotypic instability and viral integration in polyoma virus-induced mouse salivary gland tumors.

Stable integration of polyoma viral DNA into the host-cell genome is a prerequisite for continuous expression of the transformed phenotype. In this study we have mapped the chromosomal location of integrated viral DNA sequences in a polyoma-induced mouse salivary gland adenocarcinoma. By in situ hybridization, a major integration site was assigned to chromosome 14, band B. The combined results from in situ hybridizations to metaphase chromosomes, primary tumors, and cultured tumor cells indicate the presence of both integrated and free polyoma viral DNA in the tumors. Cytogenetically, the tumors were characterized by a pronounced karyotypic instability. No abnormal cells with the same karyotype were observed in any of the tumors. Nevertheless, it was possible to recognize a preferential pattern of chromosomes variation with certain common recurrent and sporadic deviations. Clonal gains and/or losses of single chromosomes were seen in all tumors. It is concluded from these results that karyotypic instability may play an important role in the genesis and progression of polyoma virus-induced salivary gland tumors.

Adenocarcinoma↗

PubMed2004

Safety of anthrax vaccine: an expanded review and evaluation of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS).

PURPOSE: To assess the safety of a licensed anthrax vaccine (AVA) given to more than 500,000 US military personnel, through review and medical evaluation of adverse events (AEs) reported to the Vaccine Adverse Event Reporting System (VAERS). METHODS: AEs were summarized by person, vaccine lot, type, frequency and impact. A Delphic approach was used to tentatively assess causality in an effort to detect serious AEs (SAEs) or other medically important AEs (OMIAEs) possibly attributable to AVA. RESULTS: The Anthrax Vaccine Expert Committee (AVEC) reviewed 1841 reports describing 3991 AEs (9.4 reports/10,000 doses of AVA) that were submitted to VAERS from 1Q1998 through 4Q2001. One hundred forty-seven reports described an SAE or OMIAE, of which 26 were tentatively rated as possible, probable or certain consequences of vaccination (injection-site reaction [12], 'anaphylactic-like reaction' [5] and eight other systemic AEs [1-2 each]). CONCLUSIONS: This review produced no evidence for an unusual rate of any SAE or OMIAE attributable to AVA. It supported an earlier impression that AVA may cause significant local inflammation and should be administered over the deltoid rather than the triceps to avoid direct or compression injury to the ulnar nerve. The subjects of VAERS reports tended to be older than all recipients of AVA. Females generally had and/or reported AEs more often than males, but transient articular reactions were surprisingly more common in males. Variations in the frequency or severity (as judged by hospitalization and/or loss of duty) of reported AEs did not suggest a significant problem with (1) a particular lot of AVA, (2) recurrent AEs after multiple doses or (3) vaccination of persons with a concomitant illness or those given other vaccines or medications.

Adult↗

PubMed2004

Application of DNA pooling to large studies of disease.

Large collections of individuals are required to investigate the association of commonly occurring genetic variation with disease. The laboratory assessment of one form of variation, single nucleotide polymorphisms, is costly in time and DNA. Robust statistical approaches are developed to allow the successful implementation of a recently described laboratory method for rapidly estimating allele frequency using pools of DNA. A substantial reduction in Type I error is demonstrated using simulation, through the incorporation of measurement error into confidence limits for a case-control study, illustrated on a case-control study of acute leukaemia in adults. A method for creating multiple sub-pools is described which will allow large studies, such as the proposed U.K. Biobank, to take advantage of this method. Furthermore, a set-based logistic regression is presented which allows the investigation of joint effects and interactions with other genes or environmental factors.

Adult↗