Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetics methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN-Lx/Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular diseases and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival on Chromosome 16: 62.1-66.3 Mb. We subsequently fine-mapped the key phenotype to a locus that includes the Telo2-interacting protein 2 gene (Tti2)-a chaperone that modulates the activity and stability of PIKK kinases. To verify the hypothesis that differences in neurogenesis and glucose levels are caused by a polymorphism in Tti2, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia.

• MeSH
• fenotyp MeSH
• glukosa * genetika   metabolismus   MeSH
• hipokampus metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• neurogeneze * genetika   MeSH
• potkani inbrední BN MeSH
• potkani inbrední SHR MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Experience of early-life socioeconomic deprivation (ELSD) may increase the risk of mental disorders in young adulthood. This association may be mediated by structural and functional alterations of the hippocampus. METHODS: We conducted a prospective cohort study on 122 participants of the European Longitudinal Study of Pregnancy and Childhood. Information about ELSD was collected via questionnaire from mothers during the first 18 months of participants' lives. At age 23-24, participants underwent examination by structural magnetic resonance imaging, resting-state functional connectivity and assessment of depressive symptoms (Mood and Feelings Questionnaire) and anxiety (Spielberger State-Trait Anxiety Inventory). The association of ELSD with brain outcomes in young adulthood was assessed with correlations, linear regression (adjusting for sex, socioeconomic position and mother's mental health) and moderated mediation analysis. RESULTS: Higher ELSD was associated with greater depressive symptoms (B = 0.22; p = 0.001), trait anxiety (B = 0.07; p = 0.02) and lower global connectivity of the right hippocampus (B = -0.01; p = 0.02). These associations persisted when adjusted for covariates. In women, lower global connectivity of the right hippocampus was associated with stronger trait anxiety (B = -4.14; p = 0.01). Global connectivity of the right hippocampus as well as connectivity between the right hippocampus and the left middle temporal gyrus mediated the association between ELSD and trait anxiety in women. Higher ELSD correlated with a lower volume of the right hippocampus in men, but the volume of the right hippocampus was not related to mental health. CONCLUSIONS: Early preventive strategies targeted at children from socioeconomically deprived families may yield long-lasting benefits for the mental health of the population.

• MeSH
• deprese * MeSH
• dítě MeSH
• dospělí MeSH
• hipokampus MeSH
• lidé MeSH
• longitudinální studie MeSH
• magnetická rezonanční tomografie MeSH
• mladý dospělý MeSH
• prospektivní studie MeSH
• socioekonomické faktory MeSH
• těhotenství MeSH
• úzkost * MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: We tested predictions about the structure and magnitude of method biases in single-source personality trait assessments. We expected a large number of distinct biases that would parallel the observed structure of traits, at both facet and item levels. METHOD: We analyzed multimethod ratings on the Estonian NEO Personality Inventory-3 in a sample of 3,214 adults. By subtracting informant ratings from self-reports, we eliminated true score variance and analyzed the size and structure of the residual method biases. We replicated analyses using data (N = 709) from the Czech Revised NEO Personality Inventory. RESULTS: The magnitude of method biases was consistent with predictions by McCrae (2018, Psychological Assessment). Factor analyses at the facet level showed a clear replication of the normative Five-Factor Model structure in both samples. Item factor analyses within domains showed that facet-level method biases mimicked the facet structure of the instrument. CONCLUSIONS: Method biases apparently reflect implicit personality theory (IPT)-beliefs about how traits and trait indicators covary. We discuss the (collective) accuracy and possible origins of IPT. Because method biases limit the accuracy of single-source assessments, we recommend assessments that combine information from two or more informants.

• MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• osobnost * MeSH
• osobnostní dotazník normy   MeSH
• psychologická teorie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• srovnání kultur MeSH
• testování osobnosti normy   MeSH
• zpráva o sobě normy   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Estonsko MeSH

Ratios often lead to biased conclusions concerning the actual relationships between examined traits and comparisons of the relative size of traits among groups. Therefore, the use of ratios has been abandoned in most comparative studies. However, ratios such as body mass index and waist-to-hip ratio are widely used in evolutionary biology and medicine. One such, the ratio of the 2nd to the 4th finger (2D : 4D), has been the subject of much recent interest in both humans and animals. Most studies agree that 2D : 4D is sexually dimorphic. In men, the 2nd digit tends to be shorter than the 4th, while in women the 2nd digit tends to be of the same size or slightly longer than the 4th. Nevertheless, here we demonstrate that the sexes do not greatly differ in the scaling between the 2nd and 4th digit. Sexual differences in 2D : 4D are mainly caused by the shift along the common allometric line with non-zero intercept, which means 2D : 4D necessarily decreases with increasing finger length, and the fact that men have longer fingers than women. We conclude that previously published results on the 2D : 4D ratio are biased by its covariation with finger length. We strongly recommend regression-based approaches for comparisons of hand shape among different groups.

• MeSH
• lidé MeSH
• pohlavní dimorfismus MeSH
• prsty ruky anatomie a histologie   MeSH
• toxoplazmóza epidemiologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Bolest je signál ohrožení organizmu. Váže pozornost, narušuje probíhající psychické procesy a vyvolává strach, který neuropsychicky zesiluje bolest, působí hyperestézii a negativní nabuzení (arousal). Kognitivní hodnocení bolesti jako ohrožení vyvolá také strach. Výsledný strach je tedy generovaný neuropsychicky („reflexně“) i kognitivně. Strach, vyvolaný oběma mechanizmy, narušuje zvládání bolesti (coping). Selháváním procesu zvládání vzniká úzkost, zlost a deprese a dále nepříznivé hodnocení vlastní schopnosti zvládat bolest a spokojeně žít. Na předpokladu těchto procesů, jejichž podstatné segmenty byly testované strukturálním modelem EQS, je založen Dynamický model psychologických procesů při chronické bolesti (DM). Původní DM, podobně jako další současné modely chronické bolesti lze považovat za modely lokálně nezávislé (tedy vysvětlené „ze sebe sama“). V této práci jsou analyzovány „spouštějící“ procesy DM, pocit bolesti a kognitivní zpracovávání bolesti, a oběma procesy vyvolaný strach. Protože tyto procesy probíhají v rámci osobnosti jako vyššího psychologického celku, autoři rozšiřují původní předpoklad DM o rys úzkosti, jako další podmínku toho, jak silný bude strach, vyvolaný bolestí a jejím kognitivním zpracováním. Na souboru 272 pacientů s nemaligní bolestí, věk M = 47,93 (SD = 10,73) roků, trvání bolesti v letech = 11,06 (SD = 9,57), byl postupně testován odpovídající regresní model: K původním nezávisle proměnným, faktorům Bolest (Intenzita bolesti, Nepříjemnost bolesti) a Kognitivní zpracovávání bolesti (Očekávání bolesti v budoucnu, Vina druhých aj.), byla nově zavedena „vnější“ proměnná, Rys úzkosti, a vypočítána lineární regrese na Strach z bolesti. Po redukci modelu s 8 měřenými hodnotami (CFI = 0,81) na 5 měřených hodnot (CFI = 0,84) přistoupili autoři k zařazení další proměnné (tj. mimo původní DM), kovariancí mezi (reziduální variancí) Přetrváváním bolesti a Rysem úzkosti. Tento model se dobře shoduje s daty (CFI = 0,95). Předpoklad přímého vztahu mezi Přetrváváním bolesti a Rysem úzkosti tak významně zvyšuje shodu modelu s daty. Strach z bolesti je tedy nejvíce podmíněn kognitivně, a to očekáváním, že bolest potrvá, a přisuzováním viny za bolest druhým. Efekt dispoziční úzkosti je dvojí: a) Strach z bolesti je specifický projev dispoziční úzkosti při bolestivém stavu, b) dispoziční úzkost ovlivňuje nastavení kognitivních procesů a vede k očekávání bolesti v budoucnosti, a tím ke strachu z bolesti. Pocit bolesti, atribut bolestivého stavu, tyto procesy spouští. Efekt intenzity a nepříjemnosti bolesti na strach z bolesti je malý.

Pain represents a signal that an organism is in danger. It attracts attention, it disturbs ongoing mental processes and it brings about fear. In addition, cognitive appraisal of the pain brings about fear as well. The resulting fear triggers coping. If the coping fails, it is followed by anxiety, anger, depression and negative evaluation of one‘s ability to cope with the pain and to live well. Assumption of the processes forms the basis of the Dynamic Model of Psychological Processes in Chronic Pain (DM). The original DM, similarly to other recent models of chronic pain, may be considered a locally independent model (i.e., explained “by itself”). The present paper contains an analysis of “triggering” processes of the DM, the feeling and cognitive processing of the pain, as well as the fear caused by both processes. In addition, the DM assumption is expanded by an “external” variable – Trait Anxiety – representing another condition of the fear. In a group of 272 patients with non-malignant pain (age: M=47.9, SD=10.7 years; duration of pain: M=11.1, SD=9.6 years), the authors gradually tested the regression model: together with the original DM factors of Pain (Pain Intensity, Pain Unpleasantness, and Cognitive Processing of Pain) a new “external“ variable Trait Anxiety was entered and the linear regression on the Fear of Pain was calculated. After reducing the model containing 8 measured values (CFI=0.81) to a model having 5 measured values (CFI=0.84), additional variables were included and covariance between Permanence of Pain and Trait Anxiety was computed. Resulting model fits the data very well (CFI=0.95). The assumption of a direct relationship between the Permanence of Pain and Trait Anxiety significantly increases correspondence of the model with the data. The results show that the fear of pain is primarily cognitively dependent on expectation that pain will last in future and that pain is blamed on the others. Two effects of Trait Anxiety in the Fear of Pain were found: a) the Fear of Pain represents specific manifestation of Trait Anxiety under pain conditions, b) Trait Anxiety influences cognitive setting, which leads to expectation that pain will last and it thus creates Fear of Pain. The effect of Pain Intensity and Pain Unpleasantness on the Fear of Pain is small.

• MeSH
• chronická bolest * diagnóza   epidemiologie   psychologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• měření bolesti metody   MeSH
• percepce bolesti * MeSH
• psychologické jevy a procesy klasifikace   MeSH
• regresní analýza MeSH
• strach * psychologie   MeSH
• úzkost diagnóza   psychologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10-12, R2 = 1.9%) and continuous (P = 6.4 × 10-9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10-4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

• MeSH
• acetylcholin metabolismus   MeSH
• antimanika terapeutické užití   farmakologie   MeSH
• Bayesova věta MeSH
• bipolární porucha * farmakoterapie   genetika   MeSH
• celogenomová asociační studie metody   MeSH
• dospělí MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• kohortové studie MeSH
• kyselina glutamová metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lithium * terapeutické užití   farmakologie   MeSH
• multifaktoriální dědičnost * genetika   MeSH
• sloučeniny lithia terapeutické užití   farmakologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Human kinesin 14 (KIF14) is one of the 70 prognostic marker genes (so-called Amsterdam profile) previously identified by the microarray of breast carcinomas, and its high transcript expression in tumor specimens indicates a poor prognosis for patients. We performed a pilot study to explore the prognostic and predictive meaning of KIF14 germline genetic variability in breast cancer patients. METHODS: KIF14 coding sequence, including 5' and 3' untranslated regions and overlaps to introns for identification of splicing sites, was analyzed using next-generation sequencing in the testing set of blood DNA samples from 105 breast cancer patients with clinical follow-up. After rigorous evaluation of major allele frequency, haplotype blocks, in silico predicted functional aspects, expression quantitative trait loci, and clinical associations, eight single nucleotide variants were subsequently validated in the evaluation set of 808 patients. RESULTS: Carriers of minor alleles G (rs17448931) or T (rs3806362) had significantly shorter overall survival than wild type homozygotes (p = 0.010 and p = 0.023, respectively) thus successfully replicating the results of the testing set. Both associations remained significant in the multivariate Cox regression analysis, including molecular subtype and stage as covariates (hazard ratio, HR = 1.7, 95% confidence interval (CI) = 1.1-2.8 for rs17448931 and HR = 1.9, CI 1.2-3.0 for rs3806362). DISCUSSION: In conclusion, our preliminary data suggest that minor alleles in rs17448931 and rs3806362 of KIF14 represent candidate biomarkers of poor prognosis of breast cancer patients. After pending validation in independent populations and eventual functional characterization, these candidates might become useful biomarkers in the clinics.

• MeSH
• kineziny * MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory prsu * patologie   MeSH
• nukleotidy MeSH
• onkogenní proteiny genetika   metabolismus   MeSH
• pilotní projekty MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Subtle, prognostically important ECG features may not be apparent to physicians. In the course of supervised machine learning, thousands of ECG features are identified. These are not limited to conventional ECG parameters and morphology. We aimed to investigate whether neural network-derived ECG features could be used to predict future cardiovascular disease and mortality and have phenotypic and genotypic associations. METHODS: We extracted 5120 neural network-derived ECG features from an artificial intelligence-enabled ECG model trained for 6 simple diagnoses and applied unsupervised machine learning to identify 3 phenogroups. Using the identified phenogroups, we externally validated our findings in 5 diverse cohorts from the United States, Brazil, and the United Kingdom. Data were collected between 2000 and 2023. RESULTS: In total, 1 808 584 patients were included in this study. In the derivation cohort, the 3 phenogroups had significantly different mortality profiles. After adjusting for known covariates, phenogroup B had a 20% increase in long-term mortality compared with phenogroup A (hazard ratio, 1.20 [95% CI, 1.17-1.23]; P<0.0001; phenogroup A mortality, 2.2%; phenogroup B mortality, 6.1%). In univariate analyses, we found phenogroup B had a significantly greater risk of mortality in all cohorts (log-rank P<0.01 in all 5 cohorts). Phenome-wide association study showed phenogroup B had a higher rate of future atrial fibrillation (odds ratio, 2.89; P<0.00001), ventricular tachycardia (odds ratio, 2.00; P<0.00001), ischemic heart disease (odds ratio, 1.44; P<0.00001), and cardiomyopathy (odds ratio, 2.04; P<0.00001). A single-trait genome-wide association study yielded 4 loci. SCN10A, SCN5A, and CAV1 have roles in cardiac conduction and arrhythmia. ARHGAP24 does not have a clear cardiac role and may be a novel target. CONCLUSIONS: Neural network-derived ECG features can be used to predict all-cause mortality and future cardiovascular diseases. We have identified biologically plausible and novel phenotypic and genotypic associations that describe mechanisms for the increased risk identified.

• MeSH
• časové faktory MeSH
• elektrokardiografie * MeSH
• fenotyp * MeSH
• hodnocení rizik MeSH
• kardiovaskulární nemoci diagnóza   mortalita   genetika   patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• neuronové sítě * MeSH
• prediktivní hodnota testů * MeSH
• prognóza MeSH
• reprodukovatelnost výsledků MeSH
• rizikové faktory MeSH
• senioři MeSH
• srdeční frekvence MeSH
• strojové učení bez učitele MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Spojené státy americké MeSH

BACKGROUND: The etiology of Parkinson's disease (PD) remains unclear, and environmental risk-factors such as occupation have attracted interest. OBJECTIVE: The goal was to investigate occupational complexity in relation to PD. METHODS: We conducted a population-based cohort study based on the Swedish Twin Registry that included 28,778 twins born between 1886 and 1950. We identified 433 PD cases during the study period. Data on occupation were collected from either the 1970 or 1980 Swedish census, and occupational complexity was assessed via a job exposure matrix. Cox proportional hazard regression analyses with age as the underlying time scale were used to assess PD risk as a function of the three domains of occupational complexity: data, people, and things. Sex and smoking were included as covariates. Analyses stratified by twin pair were conducted to test for confounding by familial factors. RESULTS: High occupational complexity with data and people was associated with increased risk overall (Hazard Ratio [HR]  = 1.07, 95% confidence interval [CI] 1.02-1.14, and HR = 1.10, 95% CI 1.01-1.21, respectively), and in men (HR = 1.08, 95% CI 1.01-1.16, and HR = 1.15, 95% CI 1.03-1.28, respectively). Complexity with things was not associated with risk of PD. When the analyses were stratified by twin pair, the HRs for occupational complexity with data and people were attenuated in men. CONCLUSIONS: High complexity of work with data and people is related to increased risk of PD, particularly in men. The attenuation of risk observed in the twin pair-stratified analyses suggests that the association may partly be explained by familial factors, such as inherited traits contributing to occupational selection or other factors shared by twins.

• MeSH
• kohortové studie MeSH
• lidé MeSH
• Parkinsonova nemoc epidemiologie   etiologie   MeSH
• pracovní expozice * MeSH
• registrace MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Švédsko MeSH