Biology subjects

Skelton, M.

Publications and source records attributed to Skelton, M..

8 recordsLinked to original sources

bioRxiv2023

Network-based integrative multi-omics approach reveals biosignatures specific to COVID-19 disease phases.

BackgroundCOVID-19 disease is characterized by a spectrum of disease phases (mild, moderate, and severe). Each disease phase is marked by changes in omics profiles with corresponding changes in the expression of features (biosignatures). However, integrative analysis of multiple omics data from different experiments across studies to investigate biosignatures at various disease phases is limited. Exploring an integrative multi-omics profile analysis through a network approach could be used to determine biosignatures associated with specific disease phases and enable the examination of the relationships between the biosignatures. AimTo identify and characterize biosignatures underlying various COVID-19 disease phases in an integrative multi-omics data analysis. MethodWe leveraged the correlation network approach to integrate transcriptomics, metabolomics, proteomics, and lipidomics data. The World Health Organization (WHO) Ordinal Scale (WOS) was used as a disease severity reference to harmonize COVID-19 patient metadata across two studies with independent data. A unified COVID-19 knowledge graph was constructed by assembling a disease-specific interactome from the literature and databases. Disease-state omics-specific graphs were constructed by integrating multi-omics data with the unified COVID-19 knowledge graph. We expanded on the network layers of multiXrank, a random walk with restart on multilayer network algorithm, to explore disease state omics-specific graphs and perform enrichment analysis. ResultsNetwork analysis revealed the biosignatures involved in inducing chemokines and inflammatory responses as hubs in the severe and moderate disease phases. We observed more shared biosignatures between severe and moderate disease phases as compared to mild-moderate and mild-severe disease phases. We further identified both biosignatures that discriminate between the disease states and interactions between biosignatures that are either common between or associated with COVID-19 disease phases. Interestingly, cross-layer interactions between different omics profiles increased with disease severity. ConclusionThis study identified both biosignatures of different omics types enriched in disease-related pathways and their associated interactions that are either common between or unique to mild, moderate, and severe COVID-19. These biosignatures include molecular features that underlie the observed clinical heterogeneity of COVID-19 and emphasize the need for disease-phase-specific treatment strategies. In addition, the approach implemented here can be used for other diseases. Key findings Integrative multi-omics analysis revealed biosignatures and biosignature interactions associated with COVID-19 disease states. Disease severity increases with biosignature interactions across different multi-omics data. The harmonization approach proposed and implemented here can be applied to other diseases

bioinformatics↗

bioRxiv2023

MacaqueNet: big-team research into the biological drivers of social relationships

O_LIFor many animals, social relationships are a key determinant of fitness. However, major gaps remain in our understanding of the adaptive function, ontogeny, evolution, and mechanistic underpinnings of social relationships. There is a vast and ever-accumulating amount of social behavioural data on individually recognised animals, an incredible resource to shed light onto the biological basis of social relationships. Yet, the full potential of such data lies in comparative research across taxa with distinct life histories and ecologies. Substantial challenges impede systematic comparisons, one of which is the lack of persistent, accessible, and standardised databases. C_LIO_LIHere, we advocate for the creation of big-team collaborations and comparative databases to unlock the wealth of behavioural data for research on social relationships by introducing MacaqueNet (https://macaquenet.github.io/). C_LIO_LIAs a global collaboration of over 100 researchers, the MacaqueNet database encompasses data from 1981 to the present on 14 species and is the first publicly searchable and standardised database on affiliative and agonistic animal social networks. With substantial inter-specific variation in ecology and social structure and the first published record on macaque behaviour dating back to 1956, macaque research has already contributed to answering fundamental questions on the biological bases and evolution of social relationships. Building on these strong foundations, we believe that MacaqueNet can further promote collaborative and comparative research on social behaviour. C_LIO_LIWe believe that big-team approaches to building standardised databases, bringing together data contributors and researchers, will aid much-needed large-scale comparative research in behavioural ecology and beyond. We describe the establishment of MacaqueNet, from starting a large-scale collective to the creation of a cross-species collaborative database and the implementation of data entry and retrieval protocols. As such, we hope to provide a functional example for future endeavours of large-scale collaborative research into the biology of social behaviour. C_LI

animal behavior and cognition↗

bioRxiv2023

Deciphering Neuronal Deficit and Protein Profile Changes in Human Brain Organoids from Patients with Creatine Transporter Deficiency

Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human brain organoids from induced pluripotent stem cells of healthy subjects and CTD patients. Brain organoids from CTD donors had reduced creatine uptake compared with those from healthy donors. The expression of neural progenitor cell markers SOX2 and PAX6 was reduced in CTD derived organoids, while GSK3{beta}, a key regulator of neurogenesis, was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical analysis identified changes in abundance of proteins associated with intellectual disability, epilepsy, and autism. Re-establishment of the expression a functional SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression of SOX2, GSK3{beta} and other key proteins associated with clinical features of CTD patients. Our brain organoid model opens new avenues for further characterizing the CTD pathophysiology and supports the concept that reinstating creatine levels in patients with CTD could result in therapeutic efficacy. Summary HeadingTherapeutic targets associated with Creatine Transporter Deficiency

neuroscience↗

bioRxiv2022

Dodecyl Creatine Ester Improves Cognitive Function and Identifies Drivers of Creatine Deficiency.

Creatine transporter deficiency prevents creatine uptake into the brain, leading to mental retardation. To better understand the pathophysiology, this study focuses on the identification of biomarkers related to cognitive improvement in a Slc6a8 knockout mouse model (Slc6a8/y) engineered to mimic the clinical features of CTD patients which have low brain creatine content. Shotgun proteomics analysis of 4,035 proteins in four different brain regions; the cerebellum, cortex, hippocampus (associated with cognitive functions) and brain stem, and muscle as a control, was performed in 24 mice. Comparisons of the protein abundance in the four brain regions between DCE-treated intranasally Slc6a8-/y mice and wild type and DCE-treated Slc6a8-/y and vehicle group identified 14 biomarkers, shedding light on the mechanism of action of DCE. Integrative bioinformatics and statistical modeling identified key proteins associated with CTD, including KIF1A and PLCB1. The abundance of these proteins in the four brain regions was significantly correlated with both the object recognition and the Y-maze tests. Functional analysis confirmed their key roles and associated molecules in CTD pathogenesis.

neuroscience↗

bioRxiv2022

Creatine transporter (Slc6a8) knockout mice show an inattentive-like phenotype in the 5-choice serial reaction time test

Disorders of creatine (Cr) synthesis and transport cause moderate to severe intellectual disability, epilepsy, and a lack of speech development. Mutations of the X-linked Cr transporter (CrT; SLC6A8) gene are the most frequent cause of Cr deficiency and one of the leading causes of X-linked intellectual disability. There are no treatments for CrT deficiency (CTD) and there are many unanswered questions related to this disorder. Rodent models of CTD have deficits in spatial learning and memory, object recognition memory, fear conditioning, and working memory, making them high-fidelity models of CTD. While these cognitive deficits provide important information related to CTD, they lack some translational relevance and do not address important aspects of executive function like attention and impulsivity. To address this gap in knowledge, we tested brain specific Slc6a8 knockout (bKO) mice in the 5-choice serial reaction time test (5CSRTT), a correlate of the continuous performance task in humans. Following 5CSRTT training, mice were then tested for 3 sessions using trials with a variable stimulus duration followed by 3 sessions using a fixed stimulus duration and variable intertrial interval. During both the testing phases the bKO mice had reduced accuracy along with increased omissions and correct latencies compared with controls. There were no increases in premature responses during the vITI, suggesting that these mice do not have an impulsive phenotype. The results of this study expand the known phenotype of Slc6a8 deficient mice and add a translationally relevant behavioral output to test potential therapies. SynopsisThis study shows that a mouse model of human creatine transporter deficiency, a devastating human condition, has an attention-deficit disorder-like phenotype without an increase in impulsivity.

neuroscience↗

bioRxiv2019

Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness

Approximately 20% of adults in the U.S. will experience an affective disorder during their life. While it is well established that serotonin (5-HT) is a crucial factor in mood, impaired cellular bioenergetics are also implicated. Creatine (Cr), through the Cr/Phospho-Cr (PCr) shuttle, maintains high ATP concentrations in the neuron. This system may be implicated in the etiology of affective disorders, as reduced Cr, PCr, and ATP are often seen in the brains of affected patients. To address this issue, Cr transporter (Crt) deficient male mice (Slc6a8-/y) and female mice heterozygous for Crt expression (Slc6a8+/-) were used to evaluate how a Cr deficient system would alter affective-like behaviors. Slc6a8-/y and Slc6a8+/- mice had more escapes and faster escape latencies in learned helplessness, indicating a potential resilience to behavioral despair. Elevated zero maze and tail-suspension test performance matched that of wildtype mice, however. Slc6a8-/y mice have increased 5-hydroxyindoleacetic acid content in the hippocampus and striatum and increased monoamine oxidase protein and tryptophan hydroxylase-2 protein content in the hippocampus, while serotonin levels are unchanged. This indicates an increase in 5-HT turnover. Our results indicate that Cr plays a complex role in affective disorders and 5-HT neurotransmission, warranting further investigation.

animal behavior and cognition↗

bioRxiv2019

Deletion of the creatine transporter gene in neonatal, but not adult, mice lead to cognitive deficits.

Creatine (Cr) is a guanidino compound that provides readily-available phosphate pools for the regeneration of spent ATP. The lack of brain Cr causes moderate to severe intellectual disability, language impairment, and epilepsy. The most prevalent cause of Cr deficiency are mutations in the X-linked SLC6A8 (Creatine transporter; CrT) gene, known as CrT deficiency (CTD). There are no current treatments for CTD and the mechanisms that underlie the cognitive deficits are poorly understood. One of the most critical areas that need to be addressed is if Cr is necessary for brain development. To address this concern, the Slc6a8 gene was knocked out in either neonatal (postnatal day (P)5) or adult (P60) mice. The P5 knockout mice showed deficits in the Morris water maze and novel object recognition, while there were no deficits in P60 knockout mice. Interestingly, the P5 knockout mice showed hyperactivity during the dark phase; however, when examining control mice, the effect was due to the administration of tamoxifen from P5-10. Taken together, the results of this study show that Cr is necessary during periods of brain development involved in spatial and object learning. This study also highlights the continued importance of using proper control groups for behavioral testing.\n\nTake-home messageThe learning and memory deficits seen in Slc6a8-deficient mice are likely due to the developmental loss of Cr.

neuroscience↗

bioRxiv2018

Deletion of the Creatine Transporter in dopaminergic neurons leads to hyperactivity in mice.

Creatine (Cr) is required for proper neuronal function, as evidenced by the intellectual disability and epileptic phenotype seen in patients with cerebral Cr deficiency syndromes (CCDS). In addition, attention-deficit hyperactivity disorder (ADHD) is a frequent co-morbidity of Cr transporter (Crt) deficiency, the leading cause of CCDS. While the effects of the loss of Cr in the whole brain is clear, it is unknown if Cr is required for the proper function of all neurons. Of particular interest are dopaminergic neurons, as many CCDS patients have ADHD and Cr has been implicated in dopamine-associated neurodegenerative disorders, such as Parkinsons and Huntingtons diseases. The purpose of this study was to examine the effect of a loss of the Slc6a8 (Cr transporter; Crt) gene in cells expressing the dopamine transporter (Slc6a3; DAT) on activity levels and motor function as the animals age. DAT-specific Crt-knockout (DAT-Crt) mice were tested along with control (Crt-FLOX) mice monthly from 3 to 12 months of age in locomotor activity, the challenging beam test, and spontaneous activity. DAT-Crt mice were hyperactive compared with controls and this finding persisted throughout the lifetime of the mice. No changes were observed in errors to cross a narrow bridge in the challenging beam test. In a measurement of spontaneous activity, DAT-Crt mice showed increased rearing and hind limb steps, suggesting the hyperactivity carried over to this task. Taken together, these data suggest that the lack of Cr in dopaminergic neurons causes hyperactivity while sparing motor function.\n\nAbbreviations

neuroscience↗