Dietary Supplementation of Hericium erinaceus Increases Mossy Fiber-CA3 Hippocampal Neurotransmission and Recognition Memory in Wild-Type Mice

Hericium erinaceus (Bull.) Pers. is a medicinal mushroom capable of inducing a large number of modulatory effects on human physiology ranging from the strengthening of the immune system to the improvement of cognitive functions. In mice, dietary supplementation with H. erinaceus prevents the impairment of spatial short-term and visual recognition memory in an Alzheimer model. Intriguingly other neurobiological effects have recently been reported like the effect on neurite outgrowth and differentiation in PC12 cells. Until now no investigations have been conducted to assess the impact of this dietary supplementation on brain function in healthy subjects. Therefore, we have faced the problem by considering the effect on cognitive skills and on hippocampal neurotransmission in wild-type mice. In wild-type mice the oral supplementation with H. erinaceus induces, in behaviour test, a significant improvement in the recognition memory and, in hippocampal slices, an increase in spontaneous and evoked excitatory synaptic current in mossy fiber-CA3 synapse. In conclusion, we have produced a series of findings in support of the concept that H. erinaceus induces a boost effect onto neuronal functions also in nonpathological conditions

Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy

Cardiomyopathies have unresolved genotype–phenotype relationships and lack disease-specific treatments. Here we provide a framework to identify genotype-specific pathomechanisms and therapeutic targets to accelerate the development of precision medicine. We use human cardiac electromechanical in-silico modelling and simulation which we validate with experimental hiPSC-CM data and modelling in combination with clinical biomarkers. We select hypertrophic cardiomyopathy as a challenge for this approach and study genetic variations that mutate proteins of the thick (MYH7R403Q/+) and thin filaments (TNNT2R92Q/+, TNNI3R21C/+) of the cardiac sarcomere. Using in-silico techniques we show that the destabilisation of myosin super relaxation observed in hiPSC-CMs drives disease in virtual cells and ventricles carrying the MYH7R403Q/+ variant, and that secondary effects on thin filament activation are necessary to precipitate slowed relaxation of the cell and diastolic insufficiency in the chamber. In-silico modelling shows that Mavacamten corrects the MYH7R403Q/+ phenotype in agreement with hiPSC-CM experiments. Our in-silico model predicts that the thin filament variants TNNT2R92Q/+ and TNNI3R21C/+ display altered calcium regulation as central pathomechanism, for which Mavacamten provides incomplete salvage, which we have corroborated in TNNT2R92Q/+ and TNNI3R21C/+ hiPSC-CMs. We define the ideal characteristics of a novel thin filament-targeting compound and show its efficacy in-silico. We demonstrate that hybrid human-based hiPSC-CM and in-silico studies accelerate pathomechanism discovery and classification testing, improving clinical interpretation of genetic variants, and directing rational therapeutic targeting and design

Mental Health of Parents and Life Satisfaction of Children: A Within-Family Analysis of Intergenerational Transmission of Well-Being

This paper addresses the extent to which there is an intergenerational transmission of mental health and subjective well-being within families. Specifically it asks whether parents’ own mental distress influences their child’s life satisfaction, and vice versa. Whilst the evidence on daily contagion of stress and strain between members of the same family is substantial, the evidence on the transmission between parental distress and children’s well-being over a longer period of time is sparse. We tested this idea by examining the within-family transmission of mental distress from parent to child’s life satisfaction, and vice versa, using rich longitudinal data on 1,175 British youths. Results show that parental distress at year t-1 is an important determinant of child’s life satisfaction in the current year. This is true for boys and girls, although boys do not appear to be affected by maternal distress levels. The results also indicated that the child’s own life satisfaction is related with their father’s distress levels in the following year, regardless of the gender of the child. Finally, we examined whether the underlying transmission correlation is due to shared social environment, empathic reactions, or transmission via parent-child interaction

The LOFAR Two Meter Sky Survey: Deep Fields, I -- Direction-dependent calibration and imaging

The Low Frequency Array (LOFAR) is an ideal instrument to conduct deep extragalactic surveys. It has a large field of view and is sensitive to large-scale and compact emission. It is, however, very challenging to synthesize thermal noise limited maps at full resolution, mainly because of the complexity of the low-frequency sky and the direction dependent effects (phased array beams and ionosphere). In this first paper of a series, we present a new calibration and imaging pipeline that aims at producing high fidelity, high dynamic range images with LOFAR High Band Antenna data, while being computationally efficient and robust against the absorption of unmodeled radio emission. We apply this calibration and imaging strategy to synthesize deep images of the Boötes and Lockman Hole fields at ∼150 MHz, totaling ∼80 and ∼100 h of integration, respectively, and reaching unprecedented noise levels at these low frequencies of .30 and .23 µJy beam−1 in the inner ∼3 deg2 . This approach is also being used to reduce the LOTSS-wide data for the second data release

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. METHODS: We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias. RESULTS: Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM. CONCLUSIONS: Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM

Early Adversity and the Prospective Prediction of Depressive and Anxiety Disorders in Adolescents

The current study was a prospective exploration of the specificity of early childhood adversities as predictors of anxiety and depressive disorders in adolescents. Participants were 816 adolescents (414 males, 402 females) with diagnostic information collected at age 15; information on early adversities had been collected from the mothers during pregnancy, at birth, age 6 months, and age 5 years for a related study. Adolescents with "pure" anxiety disorders were compared with adolescents with "pure" depressive disorders (major depressive disorder, dysthymia), and these groups were compared to never-ill controls. Analyses controlled for gender and maternal depression and anxiety disorders. Results indicated that adolescents with anxiety disorders were more likely than depressed youth to have been exposed to various early stressors, such as maternal prenatal stress, multiple maternal partner changes, and more total adversities, whereas few early childhood variables predicted depressive disorders. Even when current family stressors at age 15 were controlled, early adversity variables again significantly predicted anxiety disorders. Results suggest that anxiety disorders may be more strongly related to early strees exposure, while depressive disorders may be related to more proximal stressors or to early stressors not assessed in the current study

Parental longevity correlates with offspring’s optimism in two cohorts of community-dwelling older subjects

Dispositional optimism and other positive personality traits have been associated with longevity. Using a familial approach, we investigated the relationship between parental longevity and offspring’s dispositional optimism among community-dwelling older subjects. Parental age of death was assessed using structured questionnaires in two different population-based samples: the Leiden Longevity Study (n = 1,252, 52.2% female, mean age 66 years, SD = 4) and the Alpha Omega Trial (n = 769, 22.8% female, mean age 69 years, SD = 6). Adult offspring’s dispositional optimism was assessed with the Life Orientation Test—Revised (LOT-R). The association between parental age of death and levels of optimism in the offspring was analysed using linear regression analysis within each sample and a meta-analysis for the overall effect. In both samples, the parental mean age of death was positively associated with optimism scores of the offspring. The association remained significant after adjustment for age, gender, living arrangement, body mass index, smoking status, education and self-rated health of the offspring. The pooled B coefficient (increase in LOT-R score per 10-year increase in parental mean age of death) was 0.30 (SE = 0.08, p < 0.001). In conclusion, parental longevity was positively associated with optimism in adult offspring, suggesting a partial linked heritability of longevity and optimism

ATLAS liquid argon calorimeter back end electronics

The Liquid Argon calorimeters play a central role in the ATLAS (A Toroidal LHC Apparatus) experiment. The environment at the Large Hadron Collider (LHC) imposes strong constraints on the detectors readout systems. In order to achieve very high precision measurements, the detector signals are processed at various stages before reaching the Data Acquisition system (DAQ). Signals from the calorimeter cells are received by on-detector Front End Boards (FEB), which sample the incoming pulse every 25ns and digitize it at a trigger rate of up to 75~kHz. Off-detector Read Out Driver (ROD) boards further process the data and send reconstructed quantities to the DAQ while also monitoring the data quality. In this paper, the ATLAS Liquid Argon electronics chain is described first, followed by a detailed description of the off-detector readout system. Finally, the tests performed on the system are summarized