Behavioral Responses in Mice Selectively Bred for High and Low Levels of Open-Field Thigmotaxis

In animal psychology, the open-field (OF) test is a traditional method for studying different aspects of rodent behavior, with thigmotaxis (i.e., wallseeking behavior) being one of the best validated OF parameters employed to measure emotionality. The main purpose of the present study was to investigate the selection response in mice selectively bred for high and low levels of OF thigmotaxis (the HOFT and LOFT lines, respectively). The mice (N = 2048) were selected for 23 generations, resulting in bidirectional phenotypic divergence between the two lines; that is, the HOFT mice were more thigmotactic (i.e., more emotional) than the LOFT mice across the different generations. The origin of the line difference in thigmotaxis was further investigated by using the crossfostering paradigm, with the results suggesting that the divergence between the two lines was primarily innate in origin and not influenced by differing maternal behavior. The stability of the selection trait was examined by testing the animals at different ages as well as in varying conditions. The results indicated that the line difference in thigmotaxis was not affected by age at the time of testing, and it also persisted in the different OF testing situations as well as during pregnancy and lactation. The examination of a possible coselection of other characteristics revealed that the more thigmotactic HOFT mice lived longer than the less thigmotactic LOFT mice. In addition, the HOFT mice tended to rear and explore less than the LOFT mice, supporting the general assumption that emotionality and exploration are inversely related. The two lines did not generally differ in ambulation and defecation, that is, in the traditional OF indexes of emotionality, conforming to the suggestion that emotionality is a multidimensional construct. The effects of sex on different OF parameters were also assessed, with the results suggesting that among the HOFT and LOFT lines, the female mice were more emotional than the male mice. The examination of the temporal changes in the HOFT and LOFT lines’ OF behavior revealed some contradictory findings that also partially conflicted with general assumptions. Although this study did not show prominent differences in maternal responsiveness between the HOFT and LOFT mothers, the results suggested that the line divergence in emotionality was more pronounced in the presence of a pup after parturition than during pregnancy. The present study clearly demonstrates that OF thigmotaxis is a strong characteristic for producing two diverging lines of mice. The difference in thigmotaxis between the selectively bred HOFT and LOFT mice seemed to be a stable and robust feature of these animals, and it appeared to stem from a genetic background.Siirretty Doriast

Pre-pregnancy overweight or obesity and gestational diabetes as predictors of body composition in offspring twenty years later : evidence from two birth cohort studies

Background. Global prevalence of overweight/obesity and gestational diabetes (GDM) is increasing. In pregnant women both conditions affect offspring's later health. Overweight/obesity is a risk factor of GDM; to what extent maternal overweight/obesity explains long-term effects of GDM in offspring is unknown. Objective. To evaluate effects of maternal pre-pregnancy overweight/obesity (BMI ⩾25 kg/m2) and GDM, occurring together or separately, on body composition among adult offspring. Methods. Participants include 891 individuals aged 24.1 years (s.d. 1.4) from two longitudinal cohort studies (ESTER and AYLS). Adult offspring of normoglycemic mothers with overweight/obesity (ONOO, n=153), offspring of mothers with GDM (OGDM; n=191) and controls (n=547) underwent anthropometric measurements and bioimpedance analysis. GDM was diagnosed by oral glucose tolerance test. Data were analyzed by linear regression models adjusted for confounders. Results. Compared with controls, ONOO-participants showed higher BMI [men 1.64 kg/m2 (95% confidence interval 0.57, 2.72); women 1.41 kg/m2 (0.20, 2.63)] and fat percentage [men 2.70% (0.99, 4.41); women 2.98% (0.87, 5.09)] with larger waist circumferences [men 3.34 cm (0.68, 5.99); women 3.09 cm (0.35, 5.83)]. Likewise, OGDM-participants showed higher fat percentage [men 1.97% (0.32, 3.61); women 2.32% (0.24, 4.41)]. BMI was non-significantly different between OGDM-participants and controls [men 0.88kg/m2 (-0.17, 1.92); women 0.82 kg/m2 (-0.39, 2.04)]. Also waist circumferences were larger [men 2.63 cm (-0.01, 5.28); women 3.39 cm (0.60, 6.18)], this difference was statistically significant in OGDM-women only. Differences in body composition measures were stronger among offspring of women with both GDM and overweight/obesity. For instance, fat mass was higher among OGDM-participants of overweight mothers [men 4.24 kg (1.36, 7.11) vs controls; women 5.22 kg (1.33, 9.11)] than OGDM participants of normal weight mothers [men 1.50 kg (-2.11, 5.11) higher vs controls; women 1.57 kg (-3.27, 6.42)]. Conclusions. Maternal pre-pregnancy overweight and GDM are associated with unhealthy body size and composition in offspring over 20 years later. Effects of maternal pre-pregnancy overweight appear more pronounced

Investigation on the role of biallelic variants in VEGF-C found in a patient affected by Milroy-like lymphedema

Background Milroy-like disease is the diagnostic definition used for patients with phenotypes that resemble classic Milroy disease (MD) but are negative to genetic testing forFLT4. In this study, we aimed at performing a genetic characterization and biochemical analysis of VEGF-C variations found in a female proband born with congenital edema consistent with Milroy-like disease. Methods The proband underwent next-generation sequencing-based genetic testing for a panel of genes associated with known forms of hereditary lymphedema. Segregation analysis was performed on family members by direct sequencing. In vitro studies were performed to evaluate the role of a novel identified variant. Results TwoVEGF-Cvariations were found in the proband, a novel p.(Ser65Arg) and a pathogenic c.148-3_148-2delCA, of paternal and maternal origin, respectively. Functional characterization of the p.(Ser65Arg) variation in vitro showed alterations in VEGF-C processing. Conclusions Our findings reveal an interesting case in which biallelic variants inVEGF-Care found in a patient with Milroy-like lymphedema. These data expand our understanding of the etiology of congenital Milroy-like lymphedema.Peer reviewe

Genetic Variants of VEGFA and FLT4 Are Determinants of Survival in Renal Cell Carcinoma Patients Treated with Sorafenib

Molecular markers of sorafenib efficacy in patients with metastatic renal cell carcinoma (mRCC) are not available. The purpose of this study was to discover genetic markers of survival in patients with mRCC treated with sorafenib. Germline variants from 56 genes were genotyped in 295 patients with mRCC. Variant-overall survival (OS) associations were tested in multivariate regression models. Mechanistic studies were conducted to validate clinical associations. VEGFA rs1885657, ITGAV rs3816375, and WWOX rs8047917 (sorafenib arm), and FLT4 rs307826 and VEGFA rs3024987 (sorafenib and placebo arms combined) were associated with shorter OS. FLT4 rs307826 increased VEGFR-3 phosphorylation, membrane trafficking, and receptor activation. VEGFA rs1885657 and rs58159269 increased transcriptional activity of the constructs containing these variants in endothelial and RCC cell lines, and VEGFA rs58159269 increased endothelial cell proliferation and tube formation. FLT4 rs307826 and VEGFA rs58159269 led to reduced sorafenib cytotoxicity. Genetic variation in VEGFA and FLT4 could affect survival in sorafenib-treated patients with mRCC. These markers should be examined in additional malignancies treated with sorafenib and in other angiogenesis inhibitors used in mRCC. Significance: Clinical and mechanistic data identify germline genetic variants in VEGFA and FLT4 as markers of survival in patients with metastatic renal cell carcinoma.Peer reviewe

Early development of attention to threat-related facial expressions

Infants from an early age have a bias to attend more to faces than non-faces and after 5 months are particularly attentive to fearful faces. We examined the specificity of this “fear bias” in 5-, 7-, and 12-month-old infants (N = 269) and 36-month-old children (N = 191) and whether its development is associated with features of the early rearing environment, specifically maternal anxiety and depression symptoms. Attention dwell times were assessed by measuring the latencies of gaze shifts from a stimulus at fixation to a new stimulus in the visual periphery. In infancy, dwell times were shorter for non-face control stimuli vs. happy faces at all ages, and happy vs. fearful, but not angry, faces at 7 and 12 months. At 36 months, dwell times were shorter for non-faces and happy faces compared to fearful and angry faces. Individual variations in attention dwell times were not associated with mothers’ self-reported depression or anxiety symptoms at either age. The results suggest that sensitivity to fearful faces precedes a more general bias for threat-alerting stimuli in early development. We did not find evidence that the initial manifestation of these biases is related to moderate variations in maternal depression or anxiety symptoms

Performance of HPGe Detectors in High Magnetic Fields

A new generation of high-resolution hypernuclear gamma$-spectroscopy experiments with high-purity germanium detectors (HPGe) are presently designed at the FINUDA spectrometer at DAPhiNE, the Frascati phi-factory, and at PANDA, the antiproton proton hadron spectrometer at the future FAIR facility. Both, the FINUDA and PANDA spectrometers are built around the target region covering a large solid angle. To maximise the detection efficiency the HPGe detectors have to be located near the target, and therefore they have to be operated in strong magnetic fields B ~ 1 T. The performance of HPGe detectors in such an environment has not been well investigated so far. In the present work VEGA and EUROBALL Cluster HPGe detectors were tested in the field provided by the ALADiN magnet at GSI. No significant degradation of the energy resolution was found, and a change in the rise time distribution of the pulses from preamplifiers was observed. A correlation between rise time and pulse height was observed and is used to correct the measured energy, recovering the energy resolution almost completely. Moreover, no problems in the electronics due to the magnetic field were observed.Comment: submitted to Nucl. Instrum. Meth. Phys. Res. A, LaTeX, 19 pages, 9 figure

Understanding developmental language disorder -The Helsinki longitudinal SLI study (HelSLI) : A study protocol

Background: Developmental language disorder (DLD, also called specific language impairment, SLI) is a common developmental disorder comprising the largest disability group in pre-school-aged children. Approximately 7% of the population is expected to have developmental language difficulties. However, the specific etiological factors leading to DLD are not yet known and even the typical linguistic features appear to vary by language. We present here a project that investigates DLD at multiple levels of analysis and aims to make the reliable prediction and early identification of the difficulties possible. Following the multiple deficit model of developmental disorders, we investigate the DLD phenomenon at the etiological, neural, cognitive, behavioral, and psychosocial levels, in a longitudinal study of preschool children. Methods: In January 2013, we launched the Helsinki Longitudinal SLI study (HelSLI) at the Helsinki University Hospital ( http://tiny.cc/HelSLI ). We will study 227 children aged 3-6 years with suspected DLD and their 160 typically developing peers. Five subprojects will determine how the child's psychological characteristics and environment correlate with DLD and how the child's well-being relates to DLD, the characteristics of DLD in monolingual versus bilingual children, nonlinguistic cognitive correlates of DLD, electrophysiological underpinnings of DLD, and the role of genetic risk factors. Methods include saliva samples, EEG, computerized cognitive tasks, neuropsychological and speech and language assessments, video-observations, and questionnaires. Discussion: The project aims to increase our understanding of the multiple interactive risk and protective factors that affect the developing heterogeneous cognitive and behavioral profile of DLD, including factors affecting literacy development. This accumulated knowledge will form a heuristic basis for the development of new interventions targeting linguistic and non-linguistic aspects of DLD. © 2018 The Author(s).Non peer reviewe

Association of screen time with long-term stress and temperament in preschoolers: results from the DAGIS study

Screen time is increasing rapidly in young children. The aim of this study was to examine associations of long-term stress and temperament with screen time in Finnish preschool children and the moderating role of socioeconomic status. Cross-sectional DAGIS data were utilized. Long-term stress was assessed using hair cortisol concentration, indicating values of the past 2 months. Temperament was reported by the parents using the Children’s Behavior Questionnaire (the Very Short Form), and three broad temperament dimensions were constructed: surgency, negative affectivity, and effortful control. Screen time was reported by the parents over 7 days. The highest education level in the household was used as an indicator of socioeconomic status. In total, 779 children (mean age, 4.7 ± 0.9 years, 52% boys) were included in the study. Of the temperament dimensions, a higher effortful control was associated with less screen time (B = − 6.70, p = 0.002). There was no evidence for an association between hair cortisol concentration and screen time nor a moderating role of socioeconomic status in the associations (p > 0.05).Conclusion: Our findings indicate that preschool children with a higher score in effortful control had less screen time. Because effortful control reflects general self-regulatory abilities, promoting these skills may be effective in reducing screen time in young children.</p