Individual Variation in Contagious Yawning Susceptibility Is Highly Stable and Largely Unexplained by Empathy or Other Known Factors

The contagious aspect of yawning is a well-known phenomenon that exhibits variation in the human population. Despite the observed variation, few studies have addressed its intra-individual reliability or the factors modulating differences in the susceptibility of healthy volunteers. Due to its obvious biological basis and impairment in diseases like autism and schizophrenia, a better understanding of this trait could lead to novel insights into these conditions and the general biological functioning of humans. We administered 328 participants a 3-minute yawning video stimulus, a cognitive battery, and a comprehensive questionnaire that included measures of empathy, emotional contagion, circadian energy rhythms, and sleepiness. Individual contagious yawning measurements were found to be highly stable across testing sessions, both in a lab setting and if administered remotely online, confirming that certain healthy individuals are less susceptible to contagious yawns than are others. Additionally, most individuals who failed to contagiously yawn in our study were not simply suppressing their reaction, as they reported not even feeling like yawning in response to the stimulus. In contrast to previous studies indicating that empathy, time of day, or intelligence may influence contagious yawning susceptibility, we found no influence of these variables once accounting for the age of the participant. Participants were less likely to show contagious yawning as their age increased, even when restricting to ages of less than 40 years. However, age was only able to explain 8% of the variability in the contagious yawn response. The vast majority of the variability in this extremely stable trait remained unexplained, suggesting that studies of its inheritance are warranted

Sex-Specific Effects of Prenatal Stress on Bdnf Expression in Response to an Acute Challenge in Rats : a Role for Gadd45β

Exposure to early adversities represents a major risk factor for psychiatric disorders. We have previously shown that exposure to prenatal stress (PNS) in rats alters the developmental expression of brain-derived neurotrophic factor (Bdnf) with a specific temporal profile. However, exposure to early-life stress is known to alter the ability to cope with challenging events later in life, which may contribute to the enhanced vulnerability to stress-related disorders. Since Bdnf is also an important player for activity-dependent plasticity, we investigated whether the exposure to PNS in rats could alter Bdnf responsiveness to an acute challenge at adulthood. We found that exposure to PNS produces significant changes in Bdnf responsiveness with brain region- and gender-specific selectivity. Indeed, exposure to an acute stress upregulates Bdnf expression in the prefrontal cortex, but not in the hippocampus, of control animals. Moreover, such modulatory activity is selectively impaired in PNS female rats, an effect that was associated with changes in the modulation of the DNA demethylase Gadd45\u3b2. Our results suggest that exposure to PNS may reprogram gene transcription through epigenetic mechanisms reducing the ability to cope under adverse conditions, a trait that is disrupted in psychiatric diseases

Do hospital mergers reduce waiting times? Theory and evidence from the english NHS

We analyse - theoretically and empirically- the effect of hospital mergers on waiting times in healthcare markets where prices are fixed. Using a spatial modelling framework where patients choose provider based on travelling distance and waiting times, we show that the effect is theoretically ambiguous. In the presence of cost synergies, the scope for lower waiting times as a result of the merger is larger if the hospitals are more profit- oriented. This result is arguably confirmed by our empirical analysis, which is based on a conditional flexible difference-in-differences methodology applied to a long panel of data on hospital merger in the English NHS, where we find that the effects of a merger on waiting times crucially rely on a legal status that can reasonably be linked to the degree of profit-orientation. Whereas hospital mergers involving Foundation Trusts tend to reduce waiting times, the corresponding effect of mergers involving hospitals without this legal status tends to go in the opposite direction

Mimicking human skin constructs using norbornene-pullulan-based hydrogels

There has been a huge demand for engineered skin tissues in the realms of both in vitro and in vivo applications. Selecting the right material scaffold is a critical consideration in making engineered skin tissues, since it should possess a good balance between elasticity and mechanical stability while promoting an adequate cell microenvironment to support both the dermal and the epidermal compartments of skin tissue. In this study, 3D-bioprinted norbornene-pullulan photocrosslinkable hydrogels were utilized as alternative scaffolds to produce epithelized dermal skin models. By employing visible light, 2.5 mm3 cell-laden hydrogels could be printed in 10 s. The thiol-ene photocrosslinking chemistry employed in this work enabled the formation of a well-defined extracellular matrix with orthogonal crosslinks, where encapsulated fibroblasts maintained high cellular viability rates. Through this method, an epidermal layer could be grown on top of the fibroblasts. The coexistence and interaction of human fibroblasts and keratinocytes were visualized by determining the expression of specific markers. This approach represents a promising starting point for the development of photocrosslinkable hydrogel-based human skin constructs by using thiol-ene norbornene chemistry, paving the way toward manufacture of complex in vitro models of human tissues

Natural products improve healthspan in aged mice and rats: a systematic review and meta-analysis

Over the last decades a decrease in mortality has paved the way for late onset pathologies such as cardiovascular, metabolic or neurodegenerative diseases. This evidence has led many researchers to shift their focus from researching ways to extend lifespan to finding ways to increase the number of years spent in good health; “healthspan” is indeed the emerging concept of such quest for ageing without chronic or disabling diseases and dysfunctions. Regular consumption of natural products might improve healthspan, although the mechanisms of action are still poorly understood. Since preclinical studies aimed to assess the efficacy and safety of these compounds are growing, we performed a systematic review and meta-analysis on the effects of natural products on healthspan in mouse and rat models of physiological ageing. Results indicate that natural compounds show robust effects improving stress resistance and cognitive abilities. These promising data call for further studies investigating the underlying mechanisms in more depth

Anchored phosphatases modulate glucose homeostasis.

Endocrine release of insulin principally controls glucose homeostasis. Nutrient-induced exocytosis of insulin granules from pancreatic β-cells involves ion channels and mobilization of Ca(2+) and cyclic AMP (cAMP) signalling pathways. Whole-animal physiology, islet studies and live-β-cell imaging approaches reveal that ablation of the kinase/phosphatase anchoring protein AKAP150 impairs insulin secretion in mice. Loss of AKAP150 impacts L-type Ca(2+) currents, and attenuates cytoplasmic accumulation of Ca(2+) and cAMP in β-cells. Yet surprisingly AKAP150 null animals display improved glucose handling and heightened insulin sensitivity in skeletal muscle. More refined analyses of AKAP150 knock-in mice unable to anchor protein kinase A or protein phosphatase 2B uncover an unexpected observation that tethering of phosphatases to a seven-residue sequence of the anchoring protein is the predominant molecular event underlying these metabolic phenotypes. Thus anchored signalling events that facilitate insulin secretion and glucose homeostasis may be set by AKAP150 associated phosphatase activity

Morc1 knockout evokes a depression-like phenotype in mice

Morc1 gene has recently been identified by a DNA methylation and genome-wide association study as a candidate gene for major depressive disorder related to early life stress in rodents, primates and humans. So far, no transgenic animal model has been established to validate these findings on a behavioral level. In the present study, we examined the effects of a Morc1 loss of function mutation in female C57BL/6N mice on behavioral correlates of mood disorders like the Forced Swim Test, the Learned Helplessness Paradigm, O-Maze and Dark-Light-Box. We could show that Morc1(-/-) mice display increased depressive-like behavior whereas no behavioral abnormalities regarding locomotor activity or anxiety-like behavior were detectable. CORT plasma levels did not differ significantly between Morc1(-/-) mice and their wildtype littermates, yet - surprisingly - total Bdnf mRNA-levels in the hippocampus were up-regulated in Morc1(-/-) animals. Although further work would be clarifying, Morc1(-/-) mice seem to be a promising epigenetically validated mouse model for depression associated with early life stress

Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia.

Schizophrenia is a severe psychiatric disorder with strong heritability and marked heterogeneity in symptoms, course, and treatment response. There is strong interest in identifying genetic risk factors that can help to elucidate the pathophysiology and that might result in the development of improved treatments. Linkage and genome-wide association studies (GWASs) suggest that the genetic basis of schizophrenia is heterogeneous. However, it remains unclear whether the underlying genetic variants are mostly moderately rare and can be identified by the genotyping of variants observed in sequenced cases in large follow-up cohorts or whether they will typically be much rarer and therefore more effectively identified by gene-based methods that seek to combine candidate variants. Here, we consider 166 persons who have schizophrenia or schizoaffective disorder and who have had either their genomes or their exomes sequenced to high coverage. From these data, we selected 5,155 variants that were further evaluated in an independent cohort of 2,617 cases and 1,800 controls. No single variant showed a study-wide significant association in the initial or follow-up cohorts. However, we identified a number of case-specific variants, some of which might be real risk factors for schizophrenia, and these can be readily interrogated in other data sets. Our results indicate that schizophrenia risk is unlikely to be predominantly influenced by variants just outside the range detectable by GWASs. Rather, multiple rarer genetic variants must contribute substantially to the predisposition to schizophrenia, suggesting that both very large sample sizes and gene-based association tests will be required for securely identifying genetic risk factors. © 2012 The American Society of Human Genetics

Safety and efficacy of apremilast through 104 weeks in patients with moderate to severe psoriasis who continued on apremilast or switched from etanercept treatment: findings from the LIBERATE study

Background Apremilast, an oral phosphodiesterase‐4 inhibitor, has demonstrated efficacy in patients with moderate to severe psoriasis. Objective To evaluate long‐term efficacy and safety of apremilast in biologic‐naive patients with moderate to severe plaque psoriasis and safety of switching from etanercept to apremilast in the phase 3b LIBERATE trial. Methods Two hundred fifty patients were randomized to placebo, apremilast 30 mg BID or etanercept 50 mg QW through Week 16; thereafter, all patients continued or switched to apremilast through Week 104 (extension phase). Skin, scalp and nail involvement at Weeks 16, 52 and 104 were assessed using the Psoriasis Area and Severity Index (PASI; 0–72), Scalp Physician Global Assessment (ScPGA; 0–5) and Nail Psoriasis Severity Index (NAPSI; 0–8); patient‐reported outcomes (PROs) were assessed using the Dermatology Life Quality Index (DLQI; 0–32) and pruritus visual analog scale (VAS; 0–100 mm). Results The apremilast‐extension phase (Weeks 16–104) included 226 patients in the placebo/apremilast (n = 73), apremilast/apremilast (n = 74) and etanercept/apremilast (n = 79) groups, and at Week 104, 50.7%, 45.9% and 51.9% of these patients, respectively, maintained ≥75% reduction from baseline in PASI score (based on last‐observation‐carried‐forward analysis). Across treatment groups, ScPGA 0 (clear) or 1 (minimal) was achieved by 50.0%–59.2% of patients; NAPSI mean change from baseline was −48.1% to −51.1%; DLQI score ≤5 was achieved by 66.0%–72.5% of patients; and pruritus VAS mean change from baseline was −24.4 to −32.3. AEs in ≥5% of patients (diarrhoea, nausea, nasopharyngitis, upper respiratory tract infection and headache) did not increase with prolonged apremilast exposure. Conclusions Apremilast demonstrated significant and sustained improvements in skin, scalp, nails and PROs (pruritus and quality of life) over 104 weeks in patients with moderate to severe plaque psoriasis. Safety was consistent with the known safety profile of apremilast

Identification of multiple rare variants associated with a disease

Identifying rare variants that are responsible for complex disease has been promoted by advances in sequencing technologies. However, statistical methods that can handle the vast amount of data generated and that can interpret the complicated relationship between disease and these variants have lagged. We apply a zero-inflated Poisson regression model to take into account the excess of zeros caused by the extremely low frequency of the 24,487 exonic variants in the Genetic Analysis Workshop 17 data. We grouped the 697 subjects in the data set as Europeans, Asians, and Africans based on principal components analysis and found the total number of rare variants per gene for each individual. We then analyzed these collapsed variants based on the assumption that rare variants are enriched in a group of people affected by a disease compared to a group of unaffected people. We also tested the hypothesis with quantitative traits Q1, Q2, and Q4. Analyses performed on the combined 697 individuals and on each ethnic group yielded different results. For the combined population analysis, we found that UGT1A1, which was not part of the simulation model, was associated with disease liability and that FLT1, which was a causal locus in the simulation model, was associated with Q1. Of the causal loci in the simulation models, FLT1 and KDR were associated with Q1 and VNN1 was correlated with Q2. No significant genes were associated with Q4. These results show the feasibility and capability of our new statistical model to detect multiple rare variants influencing disease risk