Project description:Oxidative metabolism is fine-tuned machinery that combines two tightly coupled fluxes of glucose and glutamine-derived carbons. Hypoxia interrupts the coordination between the metabolism of these two nutrients and leads to a decrease of the system efficacy and may eventually cause cell death. The subterranean blind mole rat, Spalax, is an underexplored, underground, hypoxia-tolerant mammalian group which spends its life under sharply fluctuating oxygen levels. Primary Spalax cells are an exceptional model to study the metabolic strategies that have evolved in mammals inhabiting low-oxygen niches. In this study we explored the metabolic frame of glutamine (Gln) homeostasis in Spalax skin cells under normoxic and hypoxic conditions and their impacts on the metabolism of rat cells. Targeted metabolomics employing liquid chromatography and mass spectrometry (LC-MS) was used to track the fate of heavy glutamine carbons (13C5 Gln) after 24 h under normoxia or hypoxia (1% O2). Our results indicated that large amounts of glutamine-originated carbons were detected as proline (Pro) and hydroxyproline (HPro) in normoxic Spalax cells with a further increase under hypoxia, suggesting a strategy for reduced Gln carbons storage in proteins. The intensity of the flux and the presence of HPro suggests collagen as a candidate protein that is most abundant in animals, and as the primary source of HPro. An increased conversion of αKG to 2 HG that was indicated in hypoxic Spalax cells prevents the degradation of hypoxia-inducible factor 1α (HIF-1α) and, consequently, maintains cytosolic and mitochondrial carbons fluxes that were uncoupled via inhibition of the pyruvate dehydrogenase complex. A strong antioxidant defense in Spalax cells can be attributed, at least in part, to the massive usage of glutamine-derived glutamate for glutathione (GSH) production. The present study uncovers additional strategies that have evolved in this unique mammal to support its hypoxia tolerance, and probably contribute to its cancer resistance, longevity, and healthy aging.

Project description:IntroductionChronic pain (CP) is one of the most frequently presenting conditions in health care and many patients with CP report mental fatigue and a decline in cognitive functioning. However, the underlying mechanisms are still unknown.Methods and analysisThis study protocol describes a cross-sectional study aimed at investigating the presence of self-rated mental fatigue, objectively measured cognitive fatigability and executive functions and their relation to other cognitive functions, inflammatory biomarkers and brain connectivity in patients with CP. We will control for pain-related factors such as pain intensity and secondary factors such as sleep disturbances and psychological well-being. Two hundred patients 18-50 years with CP will be recruited for a neuropsychological investigation at two outpatient study centres in Sweden. The patients are compared with 36 healthy controls. Of these, 36 patients and 36 controls will undergo blood sampling for inflammatory markers, and of these, 24 female patients and 22 female controls, between 18 and 45 years, will undergo an functional MRI investigation. Primary outcomes are cognitive fatigability, executive inhibition, imaging and inflammatory markers. Secondary outcomes include self-rated fatigue, verbal fluency and working memory. The study provides an approach to study fatigue and cognitive functions in CP with objective measurements and may demonstrate new models of fatigue and cognition in CP.Ethics and disseminationThe study has been approved by the Swedish Ethics Review Board (Dnr 2018/424-31; 2018/1235-32; 2018/2395-32; 2019-66148; 2022-02838-02). All patients gave written informed consent to participate in the study. The study findings will be disseminated through publications in journals within the fields of pain, neuropsychology and rehabilitation. Results will be spread at relevant national and international conferences, meetings and expert forums. The results will be shared with user organisations and their members as well as relevant policymakers.Trial registration numberNCT05452915.

Project description:This review focuses on the role of prenatal hypoxia in the development of brain functions in the postnatal period and subsequent increased risk of neurodegenerative disorders in later life. Accumulating evidence suggests that prenatal hypoxia in critical periods of brain formation results in significant changes in development of cognitive functions at various stages of postnatal life which correlate with morphological changes in brain structures involved in learning and memory. Prenatal hypoxia also leads to a decrease in brain adaptive potential and plasticity due to the disturbance in the process of formation of new contacts between cells and propagation of neuronal stimuli, especially in the cortex and hippocampus. On the other hand, prenatal hypoxia has a significant impact on expression and processing of a variety of genes involved in normal brain function and their epigenetic regulation. This results in changes in the patterns of mRNA and protein expression and their post-translational modifications, including protein misfolding and clearance. Among proteins affected by prenatal hypoxia are a key enzyme of the cholinergic system-acetylcholinesterase, and the amyloid precursor protein (APP), both of which have important roles in brain function. Disruption of their expression and metabolism caused by prenatal hypoxia can also result, apart from early cognitive dysfunctions, in development of neurodegeneration in later life. Another group of enzymes affected by prenatal hypoxia are peptidases involved in catabolism of neuropeptides, including amyloid-β peptide (Aβ). The decrease in the activity of neprilysin and other amyloid-degrading enzymes observed after prenatal hypoxia could result over the years in an Aβ clearance deficit and accumulation of its toxic species which cause neuronal cell death and development of neurodegeneration. Applying various approaches to restore expression of neuronal genes disrupted by prenatal hypoxia during postnatal development opens an avenue for therapeutic compensation of cognitive dysfunctions and prevention of Aβ accumulation in the aging brain and the model of prenatal hypoxia in rodents can be used as a reliable tool for assessment of their efficacy.

Project description:The links between emotions, bio-regulatory processes, and economic decision-making are well-established in the context of age-related changes in fluid, real-time, decision competency. The objective of the research reported here is to assess the relative contributions, interactions, and impacts of affective and cognitive intelligence in economic, value-based decision-making amongst older adults. Additionally, we explored this decision-making competency in the context of the neurobiology of aging by examining the neuroanatomical correlates of intelligence and decision-making in an aging cohort. Thirty-nine, healthy, community dwelling older adults were administered the Iowa Gambling Task (IGT), an ecologically valid laboratory measure of complex, economic decision-making; along with standardized, performance-based measures of cognitive and emotional intelligence (EI). A smaller subset of this group underwent structural brain scans from which thicknesses of the frontal, parietal, temporal, occipital, cingulate cortices and their sub-sections, were computed. Fluid (online processing) aspects of Perceptual Reasoning cognitive intelligence predicted superior choices on the IGT. However, older adults with higher overall emotional intelligence (EI) and higher Experiential EI area/sub-scores learned faster to make better choices on the IGT, even after controlling for cognitive intelligence and its area scores. Thickness of the left rostral anterior cingulate (associated with fluid affective, processing) mediated the relationship between age and Experiential EI. Thickness of the right transverse temporal gyrus moderated the rate of learning on the IGT. In conclusion, our data suggest that fluid processing, which involves "online," bottom-up, cognitive processing, predicts value-based decision-making amongst older adults, while crystallized intelligence, which relies on "offline" previously acquired knowledge, does not. However, only emotional intelligence, especially its fluid "online" aspects of affective processing predicts the rate of learning in situations of complex choice, especially when there is a paucity of cues/information available to guide decision-making. Age-related effects on these cognitive, affective and decision mechanisms may have neuroanatomical correlates, especially in regions that form a subset of the human mirror-neuron and mentalizing systems. While superior decision-making may be stereotypically associated with "smarter people" (i.e., higher cognitive intelligence), our data indicate that emotional intelligence has a significant role to play in the economic decisions of older adults.

Project description:Vaccine hesitation is a topic of utmost importance, with the COVID-19 pandemic serving as a clear reminder of its timeliness. Besides evaluating COVID-19 vaccine acceptance in a sample of Portuguese people, this study aims at understanding cognitive and emotional representations related to vaccination, and their influence on vaccination hesitation. A cross-sectional online survey was conducted between 27 December 2020 and 27 January 2021. It assessed cognitive and emotional COVID-19 representations; vaccination status; cognitive and emotional representations of vaccination and perceived necessity and concerns about vaccines. Of 31 × 58 participants, 91% accepted taking a COVID-19 vaccine. Among several other significant findings, women (71.3%) more often considered that the pandemic affected their lives (p < 0.001) and were more often concerned with being infected (p < 0.001). Likewise, there were significantly more female participants concerned about taking a COVID-19 vaccine and its possible effects, when compared to the number of male participants (p < 0.001). The number of participants with a higher education level that were more worried about becoming infected was greater (p = 0.001), when compared with those less educated. Regarding age groups, people aged 18 to 24 had fewer concerned participants (9.6%), while the number of individuals aged 55 to 64 had the most (p < 0.001). Somewhat surprisingly, perceiving oneself as extremely informed about COVID-19 was not associated with greater vaccine acceptance (OR = 1.534 [1.160-2.029]; (p = 0.003)). Moreover, people aged 25 to 64 years old and with lower education level were more likely not to accept vaccination (OR = 2.799 [1.085-7.221]; (p = 0.033)). Finally, being more concerned about taking a vaccine lowers its acceptance (OR = 4.001 [2.518-6.356]; (p < 0.001)). Cognitive and emotional representations have a great impact and are reliable predictors of vaccine acceptance. Thus, it is of extreme importance that public health messages be adapted to the different characteristics of the population.

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The Role of Glutamine Homeostasis in Emotional and Cognitive Functions

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