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Epilepsia Open Mar 2021Drug-resistant epileptic patients make up approximately one-third of the global epilepsy population. The pathophysiology of drug resistance has not been fully... (Review)
Review
Drug-resistant epileptic patients make up approximately one-third of the global epilepsy population. The pathophysiology of drug resistance has not been fully elucidated; however, current evidence suggests intestinal dysbiosis, as a possible etiopathogenic factor. Ketogenic diet, whose effect is considered to be mediated by alteration of gut microbiota synthesis, has long been administered in patients with medically refractory seizures, with positive outcomes. In this review, we present data derived from clinical studies regarding alterations of gut microbiome profile in drug-resistant epileptic patients. We further attempt to describe the mechanisms through which the gut microbiome modification methods (including ketogenic diet, pre- or probiotic administration) improve drug-resistant epilepsy, by reporting findings from preclinical and clinical studies. A comprehensive search of the published literature on the PubMed, Embase, and Web of science databases was performed. Overall, the role of gut microbiome in drug-resistant epilepsy is an area which shows promise for the development of targeted therapeutic interventions. More research is required to confirm the results from preliminary studies, as well as safety and effectiveness of altering gut bacterial composition, through the above-mentioned methods.
Topics: Diet, Ketogenic; Drug Resistant Epilepsy; Dysbiosis; Gastrointestinal Microbiome; Humans; Probiotics
PubMed: 33681645
DOI: 10.1002/epi4.12461 -
MBio Feb 2021CsrA is a posttranscriptional global regulator in Although CsrA is critical for survival within the mammalian host, the regulatory targets of CsrA remain mostly...
CsrA is a posttranscriptional global regulator in Although CsrA is critical for survival within the mammalian host, the regulatory targets of CsrA remain mostly unknown. To identify pathways controlled by CsrA, RNA-seq transcriptome analysis was carried out by comparing the wild type and the mutant grown to early exponential, mid-exponential, and stationary phases of growth. This enabled us to identify the global effects of CsrA-mediated regulation throughout the growth cycle. We found that CsrA regulates 22% of the transcriptome, with significant regulation within the gene ontology (GO) processes that involve amino acid transport and metabolism, central carbon metabolism, lipid metabolism, iron uptake, and flagellum-dependent motility. Through CsrA-RNA coimmunoprecipitation experiments, we found that CsrA binds to multiple mRNAs that encode regulatory proteins. These include transcripts encoding the major sigma factors RpoS and RpoE, which may explain how CsrA regulation affects such a large proportion of the transcriptome. Other direct targets include , encoding a central regulator in flagellar gene expression, and , encoding the virulence gene transcription factor AphA. We found that CsrA binds to the mRNA both and , and CsrA significantly increases AphA protein synthesis. The increase in AphA was due to increased translation, not transcription, in the presence of CsrA, consistent with CsrA binding to the transcript and enhancing its translation. CsrA is required for the virulence of and this study illustrates the central role of CsrA in virulence gene regulation., a Gram-negative bacterium, is a natural inhabitant of the aqueous environment. However, once ingested, this bacterium can colonize the human host and cause the disease cholera. In order to successfully transition between its aqueous habitat and the human host, the bacterium must sense changes in its environment and rapidly alter gene expression. Global regulators, including CsrA, play an integral role in altering the expression of a large number of genes to promote adaptation and survival, which is required for intestinal colonization. We used transcriptomics and a directed CsrA-RNA coimmunoprecipitation to characterize the CsrA regulon and found that CsrA alters the expression of more than 800 transcripts in Processes regulated by CsrA include motility, the rugose phenotype, and virulence pathways. CsrA directly binds to the transcript and positively regulates the production of the virulence regulator AphA. Thus, CsrA regulates multiple processes that have been linked to pathogenesis.
Topics: Bacterial Proteins; Gene Expression Regulation, Bacterial; RNA-Binding Proteins; Regulon; Trans-Activators; Transcriptome; Vibrio cholerae; Virulence
PubMed: 33531387
DOI: 10.1128/mBio.03380-20 -
ELife Oct 2020Psychedelic drugs are potent modulators of conscious states and therefore powerful tools for investigating their neurobiology. N,N, Dimethyltryptamine (DMT) can rapidly...
Psychedelic drugs are potent modulators of conscious states and therefore powerful tools for investigating their neurobiology. N,N, Dimethyltryptamine (DMT) can rapidly induce an extremely immersive state of consciousness characterized by vivid and elaborate visual imagery. Here, we investigated the electrophysiological correlates of the DMT-induced altered state from a pool of participants receiving DMT and (separately) placebo (saline) while instructed to keep their eyes closed. Consistent with our hypotheses, results revealed a spatio-temporal pattern of cortical activation (i.e. travelling waves) similar to that elicited by visual stimulation. Moreover, the typical top-down alpha-band rhythms of closed-eyes rest were significantly decreased, while the bottom-up forward wave was significantly increased. These results support a recent model proposing that psychedelics reduce the 'precision-weighting of priors', thus altering the balance of top-down versus bottom-up information passing. The robust hypothesis-confirming nature of these findings imply the discovery of an important mechanistic principle underpinning psychedelic-induced altered states.
Topics: Adult; Alpha Rhythm; Brain; Consciousness; Female; Hallucinogens; Humans; Male; Middle Aged; N,N-Dimethyltryptamine; Young Adult
PubMed: 33043883
DOI: 10.7554/eLife.59784 -
Proceedings of the National Academy of... Oct 2022In the United States, systemic racism has had lasting effects on the structure of cities, specifically due to government-mandated redlining policies that produced...
In the United States, systemic racism has had lasting effects on the structure of cities, specifically due to government-mandated redlining policies that produced racially segregated neighborhoods that persist today. However, it is not known whether varying habitat structures and natural resource availability associated with racial segregation affect the demographics and evolution of urban wildlife populations. To address this question, we repurposed and reanalyzed publicly archived nuclear genetic data from 7,698 individuals spanning 39 terrestrial vertebrate species sampled in 268 urban locations throughout the United States. We found generally consistent patterns of reduced genetic diversity and decreased connectivity in neighborhoods with fewer White residents, likely because of environmental differences across these neighborhoods. The strength of relationships between the racial composition of neighborhoods, genetic diversity, and differentiation tended to be weak relative to other factors affecting genetic diversity, possibly in part due to the recency of environmental pressures on urban wildlife populations. However, the consistency of the direction of effects across disparate taxa suggest that systemic racism alters the demography of urban wildlife populations in ways that generally limit population sizes and negatively affect their chances of persistence. Our results thus support the idea that limited capacity to support large, well-connected wildlife populations reduces access to nature and builds on existing environmental inequities shouldered by predominantly non-White neighborhoods.
Topics: Humans; Animals; United States; Animals, Wild; Systemic Racism; Ecosystem; Urban Population; Residence Characteristics; Genetic Variation; Racism
PubMed: 36256811
DOI: 10.1073/pnas.2102860119 -
Frontiers in Synaptic Neuroscience 2023The synapse has consistently been considered a vulnerable and critical target within Alzheimer's disease, and synapse loss is, to date, one of the main biological... (Review)
Review
The synapse has consistently been considered a vulnerable and critical target within Alzheimer's disease, and synapse loss is, to date, one of the main biological correlates of cognitive decline within Alzheimer's disease. This occurs prior to neuronal loss with ample evidence that synaptic dysfunction precedes this, in support of the idea that synaptic failure is a crucial stage within disease pathogenesis. The two main pathological hallmarks of Alzheimer's disease, abnormal aggregates of amyloid or tau proteins, have had demonstrable effects on synaptic physiology in animal and cellular models of Alzheimer's disease. There is also growing evidence that these two proteins may have a synergistic effect on neurophysiological dysfunction. Here, we review some of the main findings of synaptic alterations in Alzheimer's disease, and what we know from Alzheimer's disease animal and cellular models. First, we briefly summarize some of the human evidence to suggest that synapses are altered, including how this relates to network activity. Subsequently, animal and cellular models of Alzheimer's disease are considered, highlighting mouse models of amyloid and tau pathology and the role these proteins may play in synaptic dysfunction, either in isolation or examining how the two pathologies may interact in dysfunction. This specifically focuses on neurophysiological function and dysfunction observed within these animal models, typically measured using electrophysiology or calcium imaging. Following synaptic dysfunction and loss, it would be impossible to imagine that this would not alter oscillatory activity within the brain. Therefore, this review also discusses how this may underpin some of the aberrant oscillatory patterns seen in animal models of Alzheimer's disease and human patients. Finally, an overview of some key directions and considerations in the field of synaptic dysfunction in Alzheimer's disease is covered. This includes current therapeutics that are targeted specifically at synaptic dysfunction, but also methods that modulate activity to rescue aberrant oscillatory patterns. Other important future avenues of note in this field include the role of non-neuronal cell types such as astrocytes and microglia, and mechanisms of dysfunction independent of amyloid and tau in Alzheimer's disease. The synapse will certainly continue to be an important target within Alzheimer's disease for the foreseeable future.
PubMed: 36970154
DOI: 10.3389/fnsyn.2023.1129036 -
Scientific Reports Apr 2023In contrast to long-term relationships, far less is known about the temporal evolution of transient relationships, although these constitute a substantial fraction of...
In contrast to long-term relationships, far less is known about the temporal evolution of transient relationships, although these constitute a substantial fraction of people's communication networks. Previous literature suggests that ratings of relationship emotional intensity decay gradually until the relationship ends. Using mobile phone data from three countries (US, UK, and Italy), we demonstrate that the volume of communication between ego and its transient alters does not display such a systematic decay, instead showing a lack of any dominant trends. This means that the communication volume of egos to groups of similar transient alters is stable. We show that alters with longer lifetimes in ego's network receive more calls, with the lifetime of the relationship being predictable from call volume within the first few weeks of first contact. This is observed across all three countries, which include samples of egos at different life stages. The relation between early call volume and lifetime is consistent with the suggestion that individuals initially engage with a new alter so as to evaluate their potential as a tie in terms of homophily.
Topics: Humans; Social Support; Emotions; Ego; Cell Phone; Italy
PubMed: 37059731
DOI: 10.1038/s41598-023-32206-2 -
European Journal of Applied Physiology Jan 2021To critically examine the research on novel supplements and strategies designed to enhance carbohydrate delivery and/or availability. (Review)
Review
PURPOSE
To critically examine the research on novel supplements and strategies designed to enhance carbohydrate delivery and/or availability.
METHODS
Narrative review.
RESULTS
Available data would suggest that there are varying levels of effectiveness based on the supplement/supplementation strategy in question and mechanism of action. Novel carbohydrate supplements including multiple transportable carbohydrate (MTC), modified carbohydrate (MC), and hydrogels (HGEL) have been generally effective at modifying gastric emptying and/or intestinal absorption. Moreover, these effects often correlate with altered fuel utilization patterns and/or glycogen storage. Nevertheless, performance effects differ widely based on supplement and study design. MTC consistently enhances performance, but the magnitude of the effect is yet to be fully elucidated. MC and HGEL seem unlikely to be beneficial when compared to supplementation strategies that align with current sport nutrition recommendations. Combining carbohydrate with other ergogenic substances may, in some cases, result in additive or synergistic effects on metabolism and/or performance; however, data are often lacking and results vary based on the quantity, timing, and inter-individual responses to different treatments. Altering dietary carbohydrate intake likely influences absorption, oxidation, and and/or storage of acutely ingested carbohydrate, but how this affects the ergogenicity of carbohydrate is still mostly unknown.
CONCLUSIONS
In conclusion, novel carbohydrate supplements and strategies alter carbohydrate delivery through various mechanisms. However, more research is needed to determine if/when interventions are ergogenic based on different contexts, populations, and applications.
Topics: Animals; Dietary Carbohydrates; Dietary Supplements; Humans; Nutritive Value; Sports Nutritional Physiological Phenomena
PubMed: 33106933
DOI: 10.1007/s00421-020-04534-y -
The Lancet. Psychiatry Apr 2023Immune system dysfunction is considered to play an aetiological role in schizophrenia spectrum disorders, with substantial alterations in the concentrations of specific... (Meta-Analysis)
Meta-Analysis
Alteration patterns of peripheral concentrations of cytokines and associated inflammatory proteins in acute and chronic stages of schizophrenia: a systematic review and network meta-analysis.
BACKGROUND
Immune system dysfunction is considered to play an aetiological role in schizophrenia spectrum disorders, with substantial alterations in the concentrations of specific peripheral inflammatory proteins, such as cytokines. However, there are inconsistencies in the literature over which inflammatory proteins are altered throughout the course of illness. Through conducting a systematic review and network meta-analysis, this study aimed to investigate the patterns of alteration that peripheral inflammatory proteins undergo in both acute and chronic stages of schizophrenia spectrum disorders, relative to a healthy control population.
METHODS
In this systematic review and meta-analysis, we searched PubMed, PsycINFO, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials from inception to March 31, 2022, for published studies reporting peripheral inflammatory protein concentrations in cases of people with schizophrenia-spectrum disorders and healthy controls. Inclusion criteria were: (1) observational or experimental design; (2) a population consisting of adults diagnosed with schizophrenia-spectrum disorders with a specified indicator of acute or chronic stage of illness; (3) a comparable healthy control population without mental illness; (4) a study outcome measuring the peripheral protein concentration of a cytokine, associated inflammatory marker, or C-reactive protein. We excluded studies that did not measure cytokine proteins or associated biomarkers in blood. Mean and SDs of inflammatory marker concentrations were extracted directly from full-text publshed articles; articles that did not report data as results or supplementary results were excluded (ie, authors were not contacted) and grey literature and unpublished studies were not sought. Pairwise and network meta-analyses were done to measure the standardised mean difference in peripheral protein concentrations between three groups: individuals with acute schizophrenia-spectrum disorder, individuals with chronic schizophrenia-spectrum disorder, and healthy controls. This protocol was registered on PROSPERO, CRD42022320305.
FINDINGS
Of 13 617 records identified in the database searches, 4492 duplicates were removed, 9125 were screened for eligibility, 8560 were excluded after title and abstract screening, and three were excluded due to limited access to the full-text article. 324 full-text articles were then excluded due to inappropriate outcomes, mixed or undefined schizophrenia cohorts, or duplicate study populations, five were removed due to concerns over data integrity, and 215 studies were included in the meta-analysis. 24 921 participants were included, with 13 952 adult cases of schizophrenia-spectrum disorder and 10 969 adult healthy controls (descriptive data for the entire cohort were not available for age, numbers of males and females, and ethnicity). Concentration of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), soluble interleukin-2 receptor (sIL-2R), IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, and C-reactive protein were consistently elevated in both individuals with acute schizophrenia-spectrum disorder and chronic schizophrenia-spectrum disorder, relative to healthy controls. IL-2 and interferon (IFN)-γ were significantly elevated in acute schizophrenia-spectrum disorder, while IL-4, IL-12, and IFN-γ were significantly decreased in chronic schizophrenia-spectrum disorder. Sensitivity and meta-regression analyses revealed that study quality and a majority of the evaluated methodological, demographic, and diagnostic factors had no significant impact on the observed results for most of the inflammatory markers. Specific exceptions to this included: methodological factors of assay source (for IL-2 and IL-8), assay validity (for IL-1β), and study quality (for transforming growth factor-β1); demographic factors of age (for IFN-γ, IL-4, and IL-12), sex (for IFN-γ and IL-12), smoking (for IL-4), and BMI (for IL-4); and diagnostic factors including diagnostic composition of schizophrenia-spectrum cohort (for IL-1β IL-2, IL-6, and TNF-α), antipsychotic-free cases (for IL-4 and IL-1RA), illness duration (for IL-4), symptom severity (for IL-4), and subgroup composition (for IL-4).
INTERPRETATION
Results suggest that people with schizophrenia-spectrum disorders have a baseline level of inflammatory protein alteration throughout the illness, as reflected by consistently elevated pro-inflammatory proteins, hypothesised here as trait markers (eg, IL-6), while those with acute psychotic illness might have superimposed immune activity with increased concentrations of hypothesised state markers (eg, IFN-γ). Further research is required to determine whether these peripheral alterations are reflected within the central nervous system. This research facilitates an entry point in understanding how clinically relevant inflammatory biomarkers might one day be useful to the diagnosis and prognostication of schizophrenia-spectrum disorders.
FUNDING
None.
Topics: Male; Adult; Female; Humans; Cytokines; Schizophrenia; Interleukin 1 Receptor Antagonist Protein; Network Meta-Analysis; Interleukin-6; C-Reactive Protein; Interleukin-2; Interleukin-4; Interleukin-8; Tumor Necrosis Factor-alpha; Interleukin-12; Biomarkers
PubMed: 36863384
DOI: 10.1016/S2215-0366(23)00025-1 -
Journal of Developmental Origins of... Apr 2015There has been a substantial body of evidence, which has shown that genetic variation is an important determinant of disease risk. However, there is now increasing... (Review)
Review
There has been a substantial body of evidence, which has shown that genetic variation is an important determinant of disease risk. However, there is now increasing evidence that alterations in epigenetic processes also play a role in determining susceptibility to disease. Epigenetic processes, which include DNA methylation, histone modifications and non-coding RNAs play a central role in regulating gene expression, determining when and where a gene is expressed as well as the level of gene expression. The epigenome is highly sensitive to a variety of environmental factors, especially in early life. One factor that has been shown consistently to alter the epigenome is maternal diet. This review will focus on how maternal diet can modify the epigenome of the offspring, producing different phenotypes and altered disease susceptibilities.
Topics: Animals; Diet; Disease Susceptibility; Epigenesis, Genetic; Female; Humans; Maternal Nutritional Physiological Phenomena
PubMed: 25857738
DOI: 10.1017/S2040174415000124 -
Personality Neuroscience 2020"Personality is an abstraction used to explain consistency and coherency in an individual's pattern of affects, cognitions, desires and behaviors [ABCDs]" (Revelle,... (Review)
Review
"Personality is an abstraction used to explain consistency and coherency in an individual's pattern of affects, cognitions, desires and behaviors [ABCDs]" (Revelle, 2007, p. 37). But personality research currently provides more a taxonomy of patterns than theories of fundamental causes. Psychiatric disorders can be viewed as involving extremes of personality but are diagnosed via symptom patterns not biological causes. Such surface-level taxonomic description is necessary for science, but consistent predictive explanation requires causal theory. Personality constructs, and especially their clinical extremes, should predict variation in ABCD patterns, with parsimony requiring the lowest effective causal level of explanation. But, even biologically inspired personality theories currently use an intuitive language-based approach for scale development that lacks biological anchors. I argue that teleonomic "purpose" explains the organisation and outputs of conserved brain emotion systems, where high activation is adaptive in specific situations but is otherwise maladaptive. Simple modulators of whole-system sensitivity evolved because the requisite adaptive level can vary across people and time. Sensitivity to a modulator is an abstract predictive personality factor that operates at the neural level but provides a causal explanation of both coherence and occasional apparent incoherence in ABCD variation. Neuromodulators impact all levels of the "personality hierarchy" from metatraits to aspects: stability appears altered by serotonergic drugs, neuroticism by ketamine and trait anxiety by simple anxiolytic drugs. Here, the tools of psychiatry transfer to personality research and imply both interaction between levels and oblique factor mappings to ABCD. On this view, much psychopathology reflects extremes of neural-level personality factors, and we can view much pharmacotherapy as temporarily altering personality. So, particularly for personality factors linked to basic emotions and their disorders, I think we should start with evolutionary biology and look directly at conserved neural-level modulators for our explanatory personality constructs and only invoke higher order, emergent, explanations when neural-level explanation fails.
PubMed: 32524065
DOI: 10.1017/pen.2020.5