Health-related quality of life 90 days after stroke assessed by the International Consortium for Health Outcome Measurement standard set.

BACKGROUND AND PURPOSE: Stroke has detrimental effects in multiple health domains not captured by routine scales. The International Consortium for Health Outcome Measurement has developed a standardized set for self-reported assessment to overcome this limitation. The aim was to assess this set in acute stroke care. METHODS: Consecutive patients with acute ischaemic stroke, transient ischaemic attack or intracerebral hemorrhage were enrolled. Demographics, living situation and cardiovascular risk factors were collected from medical records and interviews. The Patient-reported Outcomes Measurement Information System 10-Question Short Form (PROMIS-10) and the Patient Health Questionnaire-4 (PHQ-4) were conducted 90 days after admission. Linear and logistic regression analyses were used to identify predictors of outcome. The study is registered at ClinicalTrials.gov, NCT03795948. RESULTS: In all, 1064 patients were enrolled; mean age was 71.6 years, 51% were female, and median National Institutes of Health Stroke Scale (NIHSS) on admission was 3. Diagnosis was acute ischaemic stroke in 74%, transient ischaemic attack in 20% and intracerebral hemorrhage in 6%. 673 patients were available for outcome evaluation at 90 days; of these 90 (13%) had died. In survivors, t scores of PROMIS-10 physical and mental health were 40.3 ± 6.17 and 44.3 ± 8.63, compared to 50 ± 10 in healthy populations. 16% reported symptoms indicating depression or anxiety on the PHQ-4. Higher NIHSS, prior stroke and requiring help pre-stroke predicted lower values in physical and mental health scores. Higher NIHSS and diabetes were associated with anxiety or depression. CONCLUSIONS: Integrated in the routine of acute stroke care, systematic assessment of patient-reported outcomes reveals impairments in physical and mental health. Main predictors are severity of stroke symptoms and comorbidities such as hypertension and diabetes.

Prevalence of problem drinking and associated factors in a representative German sample of adolescents and young adults.

BACKGROUND: Alcohol use in youth is regarded as an important public health concern and in a recent survey in 35 European countries, every third student reported heavy episodic drinking. While prevalence estimates for problem drinking in adults from representative population samples are available, corresponding numbers for adolescents in Germany are currently lacking. METHODS: A representative sample of 1531 12-25 years old in Germany was investigated with a standardized questionnaire concerning problem drinking (assessed with the AUDIT-C) and psychosocial aspects (anxiety with the GAD-2, depressive symptoms with the PHQ-2 and smoking behavior). Due to missing values, we could calculate prevalence estimates, chi-square tests and logistic regression analyses for 1490 cases. RESULTS: The 1-year prevalence of problem drinking in 12-25 years old in Germany was 18.2%. Overall, 5.0% of the adolescents (aged 12-17 years) and 27.7% of the young adults (aged 18-25 years) reported problem drinking in the last year. Young adult males more often showed problem drinking than females, while no gender differences in adolescents were observed. Problem drinking was associated with male gender, higher age, smoking behavior and depressive symptoms. CONCLUSIONS: According to the study findings, problem drinking is widespread in 12-25 years old in Germany.

Factors Influencing Confidence in Diagnostic Ratings and Retreatment Recommendations in Coiled Aneurysms.

BACKGROUND AND PURPOSE: Angiographic occlusion and retreatment of coiled aneurysms are commonly used as surrogate end points in clinical trials. We aimed to evaluate the influence of aneurysm, patient, and rater characteristics on the confidence of visual evaluation of aneurysm coiling and retreatment decisions. MATERIALS AND METHODS: Twenty-six participants of the Advanced Course in Endovascular Interventional Neuroradiology of the European Society of Neuroradiology were asked to evaluate digital subtraction angiography examinations of patients who had undergone endovascular coiling, by determining the grade of aneurysm occlusion, the change between immediate postprocedural and follow-up angiograms, their level of confidence, the technical difficulty of retreatment, and the best therapeutic approach. The experience, knowledge, and skills of each participant were assessed. The influence of rater and case characteristics on indicated confidence in diagnostic ratings and retreatment recommendations was analyzed. RESULTS: Interrater reliability was moderate regarding the assessment of aneurysm occlusion grade (intraclass correlation coefficient = 0.581) and substantial regarding change (intraclass correlation coefficient = 0.776). Overall confidence in the diagnostic rating was high (median, "very certain"). Confidence was statistically significantly higher in cases that were generally rated as "worse." The odds of recommending retreatment were significantly higher in cases that were generally rated with higher mean confidence. CONCLUSIONS: Although overall confidence in the diagnostic rating was high, our study confirms the suboptimal interrater reliability of visual assessment of aneurysm occlusion as well as retreatment recommendations, rendering both questionable as primary outcome measures. Besides recurrence status, recommendation of retreatment is significantly influenced by patient age, aneurysm neck width, and characteristics of the therapist.

[Psychotherapy of depressive disorders : Procedures, evidence and perspectives]. / Psychotherapie depressiver Störungen : Verfahren, Evidenz und Perspektiven.

BACKGROUND: Depressive disorders are associated with a high burden of suffering and significantly reduce the well-being and the self-esteem of affected patients. Psychotherapy is one of the main treatment options for depressive disorders. OBJECTIVE: The aim of this article is to present the current evidence for antidepressive psychotherapeutic treatments. MATERIAL AND METHODS: During the revision of the German S3- and National Disease Management Guideline (NDMG) on unipolar depression in 2015, a comprehensive and systematic evidence search was conducted. The results of this search along with a systematic update are summarized. RESULTS: The most intensively investigated psychotherapeutic method is cognitive behavioral therapy (CBT), which proved to be effective in many trials. Evidence also exists for psychodynamic psychotherapy and interpersonal therapy (IPT), followed by systemic therapy and client-centered psychotherapy; however, the evidence is less robust. CONCLUSION: Psychotherapy alone or in combination with pharmacotherapy was shown to be an effective treatment option. Psychotherapy represents a key element in the treatment of depressive disorders.

[Psychotherapy of depressive disorders: Evidence in chronic depression and comorbidities]. / Psychotherapie depressiver Störungen: Evidenz bei chronischer Depression und bei Komorbidität.

BACKGROUND: Psychotherapy has been shown to be an effective treatment option for depressive disorders; however, its effectiveness varies depending on patient and therapist characteristics and the individual form of the depressive disorder. OBJECTIVES: The aim of this article is to present the current evidence for psychotherapeutic antidepressive treatments for patients with chronic and treatment-resistant depression as well as for patients with mental and somatic comorbidities. MATERIAL AND METHODS: During the revision of the currently valid German S3- and National Disease Management Guideline (NDMG) on unipolar depression published in 2015, a comprehensive and systematic evidence search including psychotherapy for specific patient groups was conducted. The results of this search along with a systematic update are summarized. RESULTS: Psychotherapy has been shown to be effective in reducing depressive symptoms in patients suffering from chronic and treatment-resistant depression and in patients with mental and somatic comorbidities. The evidence is insufficient particularly for patients with mental comorbidities. CONCLUSION: Based on the current evidence and clinical expertise the NDMG recommends psychotherapy alone or in combination with pharmacotherapy to treat most of these depressive patient groups. Evidence gaps were identified, which highlight the need for further research.

The transformative potential of an integrative approach to pregnancy.

BACKGROUND: Complex traits typically involve diverse biological pathways and are shaped by numerous genetic and environmental factors. Pregnancy-associated traits and pathologies are further complicated by extensive communication across multiple tissues in two individuals, interactions between two genomes-maternal and fetal-that obscure causal variants and lead to genetic conflict, and rapid evolution of pregnancy-associated traits across mammals and in the human lineage. Given the multi-faceted complexity of human pregnancy, integrative approaches that synthesize diverse data types and analyses harbor tremendous promise to identify the genetic architecture and environmental influences underlying pregnancy-associated traits and pathologies. METHODS: We review current research that addresses the extreme complexities of traits and pathologies associated with human pregnancy. RESULTS: We find that successful efforts to address the many complexities of pregnancy-associated traits and pathologies often harness the power of many and diverse types of data, including genome-wide association studies, evolutionary analyses, multi-tissue transcriptomic profiles, and environmental conditions. CONCLUSION: We propose that understanding of pregnancy and its pathologies will be accelerated by computational platforms that provide easy access to integrated data and analyses. By simplifying the integration of diverse data, such platforms will provide a comprehensive synthesis that transcends many of the inherent challenges present in studies of pregnancy.

Internet gaming disorder in early adolescence: Associations with parental and adolescent mental health.

BACKGROUND: Internet gaming disorder (IGD) has been included in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Currently, associations between IGD in early adolescence and mental health are largely unexplained. In the present study, the relation of IGD with adolescent and parental mental health was investigated for the first time. METHODS: We surveyed 1095 family dyads (an adolescent aged 12-14 years and a related parent) with a standardized questionnaire for IGD as well as for adolescent and parental mental health. We conducted linear (dimensional approach) and logistic (categorical approach) regression analyses. RESULTS: Both with dimensional and categorical approaches, we observed statistically significant associations between IGD and male gender, a higher degree of adolescent antisocial behavior, anger control problems, emotional distress, self-esteem problems, hyperactivity/inattention and parental anxiety (linear regression model: corrected R2=0.41, logistic regression model: Nagelkerke's R2=0.41). CONCLUSIONS: IGD appears to be associated with internalizing and externalizing problems in adolescents. Moreover, the findings of the present study provide first evidence that not only adolescent but also parental mental health is relevant to IGD in early adolescence. Adolescent and parental mental health should be considered in prevention and intervention programs for IGD in adolescence.

Clinical instruments and methods for assessing physical oral health: A systematic review.

OBJECTIVE: This study aimed at exploring available clinical instruments and methods for assessing physical oral health, and at identifying those with sufficient diagnostic performance. METHODS: A systematic literature search was conducted in Embase and MEDLINE. Identified instruments and methods were critically appraised, and quality of diagnostic performance was rated by two independent reviewers as A (sufficient diagnostic performance), B (either sufficient reliability or validity) or C (insufficient quality, or empirical results unsatisfactory and/or inconsistent). For all A-rated instruments and methods, an in-depth literature search was conducted to supplement and verify their effectiveness and accuracy. RESULTS: A total of 141 instruments and methods were identified. Only 12 methods with sufficient diagnostic performance could be rated as A, 72 were rated as B, and 34 received a C-rating. Further 23 instruments and methods could not be rated due to lack of available information on diagnostic performance. Of all A-rated instruments, six were designed for tooth structure, two for periodontium, one for endodontium and three for temporomandibular joints and muscles. CONCLUSION: Even though some instruments and methods exhibited good to excellent reliability and validity and can be recommended for research and clinical practice, they do not allow assessing all components of physical oral health. There is a need to identify and define standard instruments, and for components of physical oral health where methods with sufficient diagnostic performance are lacking, further research is required.

GEneSTATION 1.0: a synthetic resource of diverse evolutionary and functional genomic data for studying the evolution of pregnancy-associated tissues and phenotypes.

Mammalian gestation and pregnancy are fast evolving processes that involve the interaction of the fetal, maternal and paternal genomes. Version 1.0 of the GEneSTATION database (http://genestation.org) integrates diverse types of omics data across mammals to advance understanding of the genetic basis of gestation and pregnancy-associated phenotypes and to accelerate the translation of discoveries from model organisms to humans. GEneSTATION is built using tools from the Generic Model Organism Database project, including the biology-aware database CHADO, new tools for rapid data integration, and algorithms that streamline synthesis and user access. GEneSTATION contains curated life history information on pregnancy and reproduction from 23 high-quality mammalian genomes. For every human gene, GEneSTATION contains diverse evolutionary (e.g. gene age, population genetic and molecular evolutionary statistics), organismal (e.g. tissue-specific gene and protein expression, differential gene expression, disease phenotype), and molecular data types (e.g. Gene Ontology Annotation, protein interactions), as well as links to many general (e.g. Entrez, PubMed) and pregnancy disease-specific (e.g. PTBgene, dbPTB) databases. By facilitating the synthesis of diverse functional and evolutionary data in pregnancy-associated tissues and phenotypes and enabling their quick, intuitive, accurate and customized meta-analysis, GEneSTATION provides a novel platform for comprehensive investigation of the function and evolution of mammalian pregnancy.

Gestational tissue transcriptomics in term and preterm human pregnancies: a systematic review and meta-analysis.

BACKGROUND: Preterm birth (PTB), or birth before 37 weeks of gestation, is the leading cause of newborn death worldwide. PTB is a critical area of scientific study not only due to its worldwide toll on human lives and economies, but also due to our limited understanding of its pathogenesis and, therefore, its prevention. This systematic review and meta-analysis synthesizes the landscape of PTB transcriptomics research to further our understanding of the genes and pathways involved in PTB subtypes. METHODS: We evaluated published genome-wide pregnancy studies across gestational tissues and pathologies, including those that focus on PTB, by performing a targeted PubMed MeSH search and systematically reviewing all relevant studies. RESULTS: Our search yielded 2,361 studies on gestational tissues including placenta, decidua, myometrium, maternal blood, cervix, fetal membranes (chorion and amnion), umbilical cord, fetal blood, and basal plate. Selecting only those original research studies that measured transcription on a genome-wide scale and reported lists of expressed genetic elements identified 93 gene expression, 21 microRNA, and 20 methylation studies. Although 30 % of all PTB cases are due to medical indications, 76 % of the preterm studies focused on them. In contrast, only 18 % of the preterm studies focused on spontaneous onset of labor, which is responsible for 45 % of all PTB cases. Furthermore, only 23 of the 10,993 unique genetic elements reported to be transcriptionally active were recovered 10 or more times in these 134 studies. Meta-analysis of the 93 gene expression studies across 9 distinct gestational tissues and 29 clinical phenotypes showed limited overlap of genes identified as differentially expressed across studies. CONCLUSIONS: Overall, profiles of differentially expressed genes were highly heterogeneous both between as well as within clinical subtypes and tissues as well as between studies of the same clinical subtype and tissue. These results suggest that large gaps still exist in the transcriptomic study of specific clinical subtypes as well in the generation of the transcriptional profile of well-studied clinical subtypes; understanding the complex landscape of prematurity will require large-scale, systematic genome-wide analyses of human gestational tissues on both understudied and well-studied subtypes alike.

[Transcultural prevention of alcohol-related disorders : effects of a culture- and migration-sensitive approach in elderly migrants with respect to attitudes and behavior: a cluster randomized controlled trial]. / Transkulturelle Prävention von Alkoholerkrankungen : Effekte eines kultur- und migrationssensitiven Ansatzes auf Einstellungen und Verhalten älterer Personen mit Migrationshintergrund - Eine Cluster-randomisierte kontrollierte Studie.

BACKGROUND: For migrants who are older than 50, alcohol frequently becomes a problem. Simultaneously alcohol-related prevention measures only reach this group insufficiently. Therefore, a transcultural concept for preventing alcohol-related disorders in elderly (≥ 45 years) migrants has been developed. METHOD: The transcultural concept, which consisted of a prevention event as well as a cultural and language-sensitive information booklet, was evaluated in a cluster-randomized controlled trial (n = 310 immigrants). As a control condition there was a prevention event with materials from Deutsche Hauptstelle für Suchtfragen (German Centre for Addiction Issues). Data were obtained before and after the event, as well as after 6 months. All materials were available both in German and in Russian, Italian, Spanish and Turkish. RESULTS: Directly after the event, as well as 6 months thereafter, the transcultural approach was rated significantly better than the general prevention event. 73.4 % of the participants read the cultural and migration-sensitive booklet, whereas only 21.2 % in the control condition (p = 0.0001). Furthermore, significantly more participants of the transcultural approach reported a reduced alcohol consumption (49.4 vs. 16.7 %; p = 0.004) after 6 months. CONCLUSION: The consideration of diversity with respect to cultural, migration-related, socio demographic und linguistic aspects improves the effectiveness of prevention measures.

[Psychometric Testing of a New Scale Assessing the Reasons for Non-Utilisation of Health Care Services by People with Migration Backgrounds]. / Psychometrische Überprüfung eines Fragebogens zur Erfassung der Barrieren der Inanspruchnahme von Gesundheitsleistungen durch Personen mit Migrationshintergrund.

BACKGROUND: In Germany live a lot of migrants. Cultural and migration specific aspects seem to have an effect on utilisation of health care. There are no instruments that measure such factors of influence. METHODS: A systematic literature research or article that identify the difficulties of the migrants in using the health care system, was made. The relevant aspects were explored during a health related opinion survey of migrants from former USSR, Turkey, Italy and Spain. The psychometric qualities of this questionnaire were investigated with factor and reliability analyses. RESULTS: There were 24 reasons identified for non-utilisation health care. They were combined in a questionnaire. The factor analysis showed 2-factor structure ("janguage und information related Reasons" Chronbach's α=0.928 and "experience with/attitude toward health care system", Chronbach's α=0.879). Furthermore, there was a total scale with Chronbach's α=0.945. The acceptance was between 80.0 and 96.3%. CONCLUSIONS: The results confirm the psychometric quality of this measuring instrument. For further generalisability more verification will be necessary.

Clustering of two genes putatively involved in cyanate detoxification evolved recently and independently in multiple fungal lineages.

Fungi that have the enzymes cyanase and carbonic anhydrase show a limited capacity to detoxify cyanate, a fungicide employed by both plants and humans. Here, we describe a novel two-gene cluster that comprises duplicated cyanase and carbonic anhydrase copies, which we name the CCA gene cluster, trace its evolution across Ascomycetes, and examine the evolutionary dynamics of its spread among lineages of the Fusarium oxysporum species complex (hereafter referred to as the FOSC), a cosmopolitan clade of purportedly clonal vascular wilt plant pathogens. Phylogenetic analysis of fungal cyanase and carbonic anhydrase genes reveals that the CCA gene cluster arose independently at least twice and is now present in three lineages, namely Cochliobolus lunatus, Oidiodendron maius, and the FOSC. Genome-wide surveys within the FOSC indicate that the CCA gene cluster varies in copy number across isolates, is always located on accessory chromosomes, and is absent in FOSC's closest relatives. Phylogenetic reconstruction of the CCA gene cluster in 163 FOSC strains from a wide variety of hosts suggests a recent history of rampant transfers between isolates. We hypothesize that the independent formation of the CCA gene cluster in different fungal lineages and its spread across FOSC strains may be associated with resistance to plant-produced cyanates or to use of cyanate fungicides in agriculture.

Shared Selective Pressures on Fungal and Human Metabolic Pathways Lead to Divergent yet Analogous Genetic Responses.

Reduced metabolic efficiency, toxic intermediate accumulation, and deficits of molecular building blocks, which all stem from disruptions of flux through metabolic pathways, reduce organismal fitness. Although these represent shared selection pressures across organisms, the genetic signatures of the responses to them may differ. In fungi, a frequently observed signature is the physical linkage of genes from the same metabolic pathway. In contrast, human metabolic genes are rarely tightly linked; rather, they tend to show tissue-specific coexpression. We hypothesized that the physical linkage of fungal metabolic genes and the tissue-specific coexpression of human metabolic genes are divergent yet analogous responses to the range of selective pressures imposed by disruptions of flux. To test this, we examined the degree to which the human homologs of physically linked metabolic genes in fungi (fungal linked homologs or FLOs) are coexpressed across six human tissues. We found that FLOs are significantly more correlated in their expression profiles across human tissues than other metabolic genes. We obtained similar results in analyses of the same six tissues from chimps, gorillas, orangutans, and macaques. We suggest that when selective pressures remain stable across large evolutionary distances, evidence of selection in a given evolutionary lineage can become a highly reliable predictor of the signature of selection in another, even though the specific adaptive response in each lineage is markedly different.

Verbal fluency in focal epilepsy: a systematic review and meta-analysis.

Testing of verbal fluency is currently part of standard presurgical neuropsychological assessment for patients with focal epilepsy. However, to date no systematic review has been conducted on semantic (SVF) and phonemic verbal fluency (PVF) in this patient group. The present review compares verbal fluency between healthy control subjects and subgroups of adult presurgical patients with focal epilepsy according to lateralisation and localisation of the dysfunction. PubMed was searched with a comprehensive search string. Abstracts of all studies and full-texts of potentially relevant studies were screened. Study quality was assessed by independent raters according to predefined criteria. 39 studies were included. Meta-analyses were performed to compare SVF and PVF across groups of patients with temporal (TLE) and frontal lobe epilepsy (FLE) as well as healthy controls (HC). Both patients with left- and right sided TLE were impaired on SVF and PVF compared to HC. Patients with left-sided TLE were slightly more impaired than patients with right-sided TLE. Patients with FLE showed a larger impairment in PVF than patients with TLE, whereas on SVF there was no difference between FLE and TLE. For TLE comparisons the study pool seems to have been sufficient, whereas more studies are needed to verify results for FLE. Semantic verbal fluency might not differentiate between FLE and TLE. While verbal fluency impairment was anticipated, especially in left-sided TLE and FLE patients, the impairment in patients with right-sided TLE was larger than expected. Results are discussed with regard to neuropsychological theory and practice.

Functional divergence for every paralog.

Because genes can be constrained by selection at more than one phenotypic level, the relaxation of constraints following gene duplication allows for functional divergence (FD) along multiple phenotypic axes. Many studies have generated individual measures of FD, but the profile of FD between paralogs across levels of phenotypic space remains largely uncharted. We evaluate paralog pairs that originated via the yeast whole-genome duplication (ohnolog pairs) at three distinct phenotypic levels (properties of proteins, gene expression, and overall organismal growth) using eight complementary measures of FD (protein: evolutionary rates, radical amino acid substitutions, and domain architecture; gene expression: expression differences in a single species and condition, across species in a single condition, and in a single species across conditions; and organismal: genetic interaction profiles and growth profiles in multiple conditions). We find that the majority of ohnolog pairs show FD by multiple phenotypic measures. Within each phenotypic level, measures of FD are strongly correlated but are generally weakly correlated between levels, suggesting that functional constraints exerted on genes from distinct phenotypic levels are largely decoupled. Our results suggest that redundancy is a rare functional fate for retained paralogs and that FD cannot be fully captured by measures at any single phenotypic level.

Ecology drives the distribution of specialized tyrosine metabolism modules in fungi.

Gene clusters encoding accessory or environmentally specialized metabolic pathways likely play a significant role in the evolution of fungal genomes. Two such gene clusters encoding enzymes associated with the tyrosine metabolism pathway (KEGG #00350) have been identified in the filamentous fungus Aspergillus fumigatus. The l-tyrosine degradation (TD) gene cluster encodes a functional module that facilitates breakdown of the phenolic amino acid, l-tyrosine through a homogentisate intermediate, but is also involved in the production of pyomelanin, a fungal pathogenicity factor. The gentisate catabolism (GC) gene cluster encodes a functional module likely involved in phenolic compound degradation, which may enable metabolism of biphenolic stilbenes in multiple lineages. Our investigation of the evolution of the TD and GC gene clusters in 214 fungal genomes revealed spotty distributions partially shaped by gene cluster loss and horizontal gene transfer (HGT). Specifically, a TD gene cluster shows evidence of HGT between the extremophilic, melanized fungi Exophiala dermatitidis and Baudoinia compniacensis, and a GC gene cluster shows evidence of HGT between Sordariomycete and Dothideomycete grass pathogens. These results suggest that the distribution of specialized tyrosine metabolism modules is influenced by both the ecology and phylogeny of fungal species.

[Length of hospitalization for inpatient treatment of depression. Results of a multicentre study on the effects of a new treatment model]. / Verweildauer in der stationären Depressionsbehandlung. Ergebnisse einer Multicenterstudie zum Effekt eines neuen Behandlungsmodells.

BACKGROUND: Patients with depression are treated for a relatively long period as inpatients in Germany. A new treatment model with symptom-orientated release management, post-hospitalization treatment and standardized referral to outpatient therapists could be suitable to specifically shorten the hospital stay of patients who have already profited sufficiently from treatment. MATERIALS AND METHODS: The aim of the present study was to investigate the effects of a new treatment method (intervention group) with hospitalized depressive patients in comparison to a standard protocol (treatment-as-usual control group) on the length of stay as part of a pragmatic randomized, controlled multicentre study. The evaluation was made using covariance analysis. RESULTS: Of the 202 randomized patients 184 could be included in the analysis. The estimated marginal mean of the length of stay (n = 83) was 57.3 days (range 1-305 days, SE = 3.8) in the intervention group and (n = 101) 57.6 days (range: 6-196 days, SE = 3.5) in the control group. There were no significant statistical differences between the groups (p = 0.966). CONCLUSIONS: An effect of the new treatment model on the inpatient length of hospital stay in depressive patients could not be demonstrated.

Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds.

Genomic analyses have proliferated without being tied to tangible phenotypes. For example, although coordination of both gene expression and genetic linkage have been offered as genetic mechanisms for the frequently observed clustering of genes participating in fungal metabolic pathways, elucidation of the phenotype(s) favored by selection, resulting in cluster formation and maintenance, has not been forthcoming. We noted that the cause of certain well-studied human metabolic disorders is the accumulation of toxic intermediate compounds (ICs), which occurs when the product of an enzyme is not used as a substrate by a downstream neighbor in the metabolic network. This raises the hypothesis that the phenotype favored by selection to drive gene clustering is the mitigation of IC toxicity. To test this, we examined 100 diverse fungal genomes for the simplest type of cluster, gene pairs that are both metabolic neighbors and chromosomal neighbors immediately adjacent to each other, which we refer to as "double neighbor gene pairs" (DNGPs). Examination of the toxicity of their corresponding ICs shows that, compared with chromosomally nonadjacent metabolic neighbors, DNGPs are enriched for ICs that have acutely toxic LD50 doses or reactive functional groups. Furthermore, DNGPs are significantly more likely to be divergently oriented on the chromosome; remarkably, ∼40% of these DNGPs have ICs known to be toxic. We submit that the structure of synteny in metabolic pathways of fungi is a signature of selection for protection against the accumulation of toxic metabolic intermediates.

Prediction of gene-phenotype associations in humans, mice, and plants using phenologs.

BACKGROUND: Phenotypes and diseases may be related to seemingly dissimilar phenotypes in other species by means of the orthology of underlying genes. Such "orthologous phenotypes," or "phenologs," are examples of deep homology, and may be used to predict additional candidate disease genes. RESULTS: In this work, we develop an unsupervised algorithm for ranking phenolog-based candidate disease genes through the integration of predictions from the k nearest neighbor phenologs, comparing classifiers and weighting functions by cross-validation. We also improve upon the original method by extending the theory to paralogous phenotypes. Our algorithm makes use of additional phenotype data--from chicken, zebrafish, and E. coli, as well as new datasets for C. elegans--establishing that several types of annotations may be treated as phenotypes. We demonstrate the use of our algorithm to predict novel candidate genes for human atrial fibrillation (such as HRH2, ATP4A, ATP4B, and HOPX) and epilepsy (e.g., PAX6 and NKX2-1). We suggest gene candidates for pharmacologically-induced seizures in mouse, solely based on orthologous phenotypes from E. coli. We also explore the prediction of plant gene-phenotype associations, as for the Arabidopsis response to vernalization phenotype. CONCLUSIONS: We are able to rank gene predictions for a significant portion of the diseases in the Online Mendelian Inheritance in Man database. Additionally, our method suggests candidate genes for mammalian seizures based only on bacterial phenotypes and gene orthology. We demonstrate that phenotype information may come from diverse sources, including drug sensitivities, gene ontology biological processes, and in situ hybridization annotations. Finally, we offer testable candidates for a variety of human diseases, plant traits, and other classes of phenotypes across a wide array of species.