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HOMO JANUS 3rd edition Final August 2018

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Sex differences in the structures of human hypothalamus and adjacent brain structures have been observed that seem to be related to gender, to gender problems such as transsexuality, and to sexual orientation, that is, heterosexuality and homosexuality. Although these observations have yet to be confirmed, and their exact functional implications are far from clear, they open up a whole new field of structural-functional relationships in human brain research.
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Previous neuroimaging studies demonstrated sex and also sexual orientation related structural and functional differences in the human brain. Genetic information and effects of sex hormones are assumed to contribute to the male/female differentiation of the brain, and similar effects could play a role in processes influencing human's sexual orientation. However, questions about the origin and development of a person's sexual orientation remain unanswered, and research on sexual orientation related neurobiological characteristics is still very limited. To contribute to a better understanding of the neurobiology of sexual orientation, we used magnetic resonance imaging (MRI) in order to compare regional cortical thickness (Cth) and subcortical volumes of homosexual men (hoM), heterosexual men (heM) and heterosexual women (heW). hoM (and heW) had thinner cortices primarily in visual areas and smaller thalamus volumes than heM, in which hoM and heW did not differ. Our results support previous studies, which suggest cerebral differences between hoM and heM in regions, where sex differences have been reported, which are frequently proposed to underlie biological mechanisms. Thus, our results contribute to a better understanding of the neurobiology of sexual orientation.
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Our interest in healthy aging and in evolutionarily conserved mechanisms of lifespan extension prompted us to investigate whether features of age-related decline in the honey bee could be attenuated with resveratrol. Resveratrol is regarded as a caloric restriction mimetic known to extend lifespan in some but not all model species. The current, prevailing view is that resveratrol works largely by activating signaling pathways. It has also been suggested that resveratrol may act as an antioxidant and confer protection against nervous system impairment and oxidative stress. To test whether honey bee lifespan, learning performance, and food perception could be altered by resveratrol, we supplemented the diets of honey bees and measured lifespan, olfactory learning, and gustatory responsiveness to sucrose. Furthermore, to test the effects of resveratrol under metabolic challenge, we used hyperoxic environments to generate oxidative stress. Under normal oxygen conditions, two resveratrol treatments-30 and 130 μM-lengthened average lifespan in wild-type honey bees by 38% and 33%, respectively. Both resveratrol treatments also lengthened maximum and median lifespan. In contrast, hyperoxic stress abolished the resveratrol life-extension response. Furthermore, resveratrol did not affect learning performance, but did alter gustation. Honey bees that were not fed resveratrol exhibited greater responsiveness to sugar, while those supplemented with resveratrol were less responsive to sugar. We also discovered that individuals fed a high dose of resveratrol-compared to controls-ingested fewer quantities of food under ad libitum feeding conditions.
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Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery. Here, we report that the metabolic effects of resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca(2+) levels and activates the CamKKβ-AMPK pathway via phospholipase C and the ryanodine receptor Ca(2+)-release channel. As a consequence, resveratrol increases NAD(+) and the activity of Sirt1. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging.
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Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations. • gene • insulin • healthy aging • disease • disability
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Background/Introduction The gut microflora-dependent metabolite trimethylamine-N-oxide (TMAO) has emerged as a dietary-associated risk factor for incident cardiovascular events. Chronic obstructive pulmonary disease (COPD) is a prevalent disease worldwide with high associated risk for cardiovascular disease and death due to an infectious cause. Whether TMAO is predictive for adverse clinical outcomes in exacerbated COPD is unknown. Methods A total of 189 patients with COPD exacerbation were prospectively followed for a median of 6.1 years. TMAO plasma levels at emergency department admission were measured by liquid chromatography coupled with tandem mass spectrometry. Cox regression models and linear regression models were used to investigate associations of TMAO with all-cause mortality and different comorbidities. Results All-cause mortality was 55.6% after six years. Deceased showed significantly higher median admission TMAO (μmol L⁻¹) levels compared to survivors (3.9 [interquartile range (IQR), 2.3-7.1] vs. 2.9 [IQR, 1.8-4.7]; p=0.01) resulting in an unadjusted hazard ratio (HR) of 1.8 ([95% confidence interval, 1.2-3.0], p=0.01). This association was no longer significant after multivariate adjustment. Median TMAO levels were similar in non-pneumonic and pneumonic COPD exacerbation. Higher age, higher body mass index, diabetes mellitus and, chronic kidney disease were predictors for increased plasma TMAO levels in linear regression analysis. Conclusion Increased circulating TMAO levels per se were associated with long-term all-cause mortality in patients with COPD independent of type of exacerbation. This association, however, was largely explained by comorbidities and age. Whether TMAO levels can additionally be influenced by nutritional interventions should be addressed in future studies.
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Neurodevelopment is a complex process governed by both intrinsic and extrinsic signals. While historically studied by researching the brain, inputs from the periphery impact many neurological conditions. Indeed, emerging data suggest communication between the gut and the brain in anxiety, depression, cognition, and autism spectrum disorder (ASD). The development of a healthy, functional brain depends on key pre- and post-natal events that integrate environmental cues, such as molecular signals from the gut. These cues largely originate from the microbiome, the consortium of symbiotic bacteria that reside within all animals. Research over the past few years reveals that the gut microbiome plays a role in basic neurogenerative processes such as the formation of the blood-brain barrier, myelination, neurogenesis, and microglia maturation and also modulates many aspects of animal behavior. Herein, we discuss the biological intersection of neurodevelopment and the microbiome and explore the hypothesis that gut bacteria are integral contributors to development and function of the nervous system and to the balance between mental health and disease.
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Synapses are specialized cell-cell contacts that mediate communication between neurons. Most excitatory synapses in the brain are housed on dendritic spines, small actin-rich protrusions extending from dendrites. During development and in response to environmental stimuli, spines undergo marked changes in shape and number thought to underlie processes like learning and memory. Improper spine development, in contrast, likely impedes information processing in the brain, since spine abnormalities are associated with numerous brain disorders. Elucidating the mechanisms that regulate the formation and plasticity of spines and their resident synapses is therefore crucial to our understanding of cognition and disease. Rho-family GTPases, key regulators of the actin cytoskeleton, play essential roles in orchestrating the development and remodeling of spines and synapses. Precise spatio-temporal regulation of Rho GTPase activity is critical for their function, since aberrant Rho GTPase signaling can cause spine and synapse defects as well as cognitive impairments. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs). We propose that Rho-family GEFs and GAPs provide the spatiotemporal regulation and signaling specificity necessary for proper Rho GTPase function based on the following features they possess: (i) existence of multiple GEFs and GAPs per Rho GTPase, (ii) developmentally regulated expression, (iii) discrete localization, (iv) ability to bind to and organize specific signaling networks, and (v) tightly regulated activity, perhaps involving GEF/GAP interactions. Recent studies describe several Rho-family GEFs and GAPs that uniquely contribute to spinogenesis and synaptogenesis. Here, we highlight several of these proteins and discuss how they occupy distinct biochemical niches critical for synaptic development.
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Unlike most mammalian species, the prairie vole is highly affiliative, forms enduring social bonds between mates and displays biparental behavior. Over two decades of research on this species has enhanced our understanding of the neurobiological basis not only of monogamy, social attachment and nurturing behaviors but also other aspects of social cognition. Because social cognitive deficits are hallmarks of many psychiatric disorders, discoveries made in prairie voles can direct novel treatment strategies for disorders such as autism spectrum disorder and schizophrenia. With the ongoing development of molecular, genetic and genomic tools for this species, prairie voles will likely maintain their current trajectory becoming an unprecedented model organism for basic and translational research focusing on the biology of the social brain.