Biology subjects

Maes, M.

Publications and source records attributed to Maes, M..

18 recordsLinked to original sources

bioRxiv2026

Chronic Unpredictable Stress Drives Non-pathological, Adaptive Metabolic Hormone Reprogramming with Reduced Insulin Resistance Linked to Depressive-like Behaviors

Major Depressive Disorder (MDD) is increasingly conceptualized as a neuroimmune-metabolic-oxidative stress (NIMETOX) condition, partly driven by environmental stressors. While new antidepressant strategies have emerged to target NIMETOX pathways, the mechanism by which chronic stress reshapes metabolic regulation-particularly in the absence of clinically overt metabolic disease-remain poorly understood. Using a 6-week chronic unpredictable mild stress (CUMS) paradigm in metabolically healthy male and female mice, we evaluated depressive-like behaviors alongside circulating glucose and metabolic hormones, including insulin, resistin, Glucose-dependent Insulinotropic Polypeptide (GIP), Glucagon-like Peptide-1 (GLP-1), glucagon, ghrelin, leptin, and Plasminogen Activator Inhibitor-1 (PAI-1). We further assessed whether simvastatin, curcumin, S-adenosyl methionine (SAMe), or pyrrolidine dithiocarbamate (PDTC), an NF-{kappa}B inhibitor, normalize CUMS-induced metabolic and behavioral alterations, using fluoxetine as a reference antidepressant. CUMS induced a hypoinsulinemic state accompanied by enhanced basal insulin sensitivity and reduced insulin resistance, while central appetite regulation and adipose inflammatory profiles remained preserved. Indices of lower insulin resistance were strongly associated with sucrose preference and immobility time. Glucagon and PAI-1 showed positive associations with novel object recognition performance, whereas GIP and leptin were inversely related to open-field activity. Glucose levels correlated positively with rearing behavior. Despite significant improvements in depressive-like behaviors, none of the pharmacological interventions normalized the stress-induced metabolic hormone profile. Marked sex differences were observed, with females displaying a catabolic, immune-ready phenotype and males showing a relative anabolic bias. These findings indicate that CUMS induces a non-pathological, adaptive metabolic hormone reprogramming rather than metabolic dysfunction, supporting the interpretation of stress-related metabolic changes as resilient adaptations within the NIMETOX framework.

neuroscience↗

bioRxiv2025

Effects of basalt amendment and mycorrhizal inoculation on soil chemical properties and maize growth

AbstractEnhanced weathering (EW) of silicate minerals has emerged as a promising carbon dioxide removal (CDR) strategy, with potential benefits for soil fertility and crop performance. However, the soil processes that determine these co-benefits remain poorly constrained. In particular, interactions between basalt amendments and soil biota such as arbuscular mycorrhizal fungi (AMF) may influence nutrient mobilization and plant uptake, but these effects have rarely been quantified. In a 113-day mesocosm experiment with Zea mays using a Belgian, sandy loam soil, we investigated the effect of basalt and AMF inoculation on soil properties, nutrient and heavy metal availability, and crop yield and quality. We also assessed potential AMF-driven bio-weathering via cation mass balance and pore water dissolved inorganic carbon (DIC), pH, and alkalinity measurements. Basalt application, but not AMF, improved soil pH, cation exchange capacity, base saturation, and generally increased exchangeable Ca and Mg, whereas most other nutrients in the pore water remained unaffected. Crop yield and quality were largely unaltered by basalt or AMF, except for an increase in plant Mg with basalt application. Moreover, heavy metal availability and plant uptake were also generally unaffected, with the notable exception of soil pore water and corn Ni, which increased with basalt. These results suggest that risk for heavy metal contamination is not generic but may arise under specific environmental conditions. Finally, despite a synergistic effect of basalt and AMF on pore water DIC, we found no indication that AMF enhanced basalt weathering rates. Overall, AMF had limited influence on soil fertility indicators and crop performance. Basalt application improved key soil chemical indicators and increased the exchangeable fractions of Ca and Mg, demonstrating its role as a soil improver. Unlike several studies conducted in more acidic soils, these chemical enhancements did not increase maize growth here, indicating that the agronomic benefits of basalt are context-dependent.

bioengineering↗

bioRxiv2025

Molecular Mimicry Between Epstein-Barr Virus and Human Herpesvirus-6 Proteins and Central Nervous System Proteins: Implications for T and B Cell Immunogenicity in an In Silico Study.

BackgroundThe Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) are frequently linked to neuropsychiatric illnesses such as multiple sclerosis, depression, and chronic fatigue syndrome/myalgic encephalomyelitis. These viruses may induce autoimmune reactions by molecular mimicry, leading to damage to self-epitopes in the central nervous system (CNS). ObjectiveThis study seeks to explore the common pentapeptides present in EBV and HHV-6 viral antigens alongside various CNS-related proteins via molecular mimicry. Additionally, it will assess the immunogenicity of these shared pentapeptides in T and B cells. MethodSequence alignment was conducted to assess molecular mimicry between 32 EBV and HHV-6 antigens and 10 CNS autoantigens. Protein sequences were obtained from UniProt, structural homology was analyzed using AlphaFold and PyMol, and shared pentapeptides were identified with Alignmentaj. Immunogenicity was assessed via the Immune Epitope Database (IEDB) for potential T- and B-cell activation. ResultsA total of 91 mimicry pentapeptides were identified between viral antigens (EBV and human HHV-6), and CNS proteins. Notably, synapsin (SYN)1 exhibited the highest mimicry, sharing multiple pentapeptides with EBV nuclear antigen (EBNA)1, EBNA6, latent membrane protein (LMP)1, and early antigen diffused (EA-D) and 6 different HHV-6 antigens. Myelin proteins including myelin basic protein, myelin-associated glycoprotein, and myelin-oligodendrocyte glycoprotein also displayed shared pentapeptides with EBV/HHV-6 antigens, indicating potential immune cross-reactivity. EBNA1, EBNA2, EBNA6, LMP1, LMP2, EA-D, and BLLF1 structurally resemble CNS autoantigens and act as immunoreactive epitopes for human T and B cells. Except for EBNA2 and protein U94, all share immunogenic pentapeptide sequences with SYN1. ConclusionEBV and HHV-6 antigens mimic CNS proteins, potentially triggering autoimmune responses via T and B cell activation. Shared pentapeptides suggest a link between viral infections and CNS autoimmunity. Further research is needed to clarify molecular mechanisms and explore targeted therapies to mitigate virus-induced neuroinflammation.

bioinformatics↗

bioRxiv2025

Regulatory T and activated T cells in the chronic unpredictable mild stress mice: sex differences and effects of treatments

Background: Major depressive disorder (MDD) is associated with immune dysregulation, including T-cell activation and reduced regulatory T cells. Pharmacological treatments like fluoxetine, simvastatin, curcumin, and S-adenosylmethionine (SAMe) show promise in alleviating depressive symptoms, but their effects on immune responses are not fully understood. Methods: This study explored immune status in MDD using the chronic unpredictable mild stress (CUMS) mouse model. It examined how fluoxetine, simvastatin, curcumin, and SAMe affected immune responses and depressive behaviors. The study also investigated sex differences. Six groups, each with 12 mice (6 males and 6 females), were included: control, CUMS, and drug treatments. Male and female mice were housed separately in sex-specific cages throughout the experiment, with three mice per cage. Behavioral tests included sucrose preference, forced swimming, open field, and active avoidance. Immune cell markers were analyzed by flow cytometry. Results: CUMS mice showed immune imbalance, with Treg depletion (p = 0.047) and a higher CD154/CD152 ratio (p = 0.006). All treatments improved depressive-like behaviors (all p < 0.05), with SAMe normalizing the CD154/CD152 ratio (p = 0.009). Furthermore, female mice exhibited lower levels of Treg-related immune regulation and T-cell activation compared to males (both p < 0.001), along with a higher CD154/CD152 ratio (p = 0.008). Conclusion: This study highlights that curcumin, simvastatin, fluoxetine, and SAMe alleviate depressive-like behaviors, while SAMe also reduces the CD154/CD152 ratio. These findings reveal marked sex differences in T-cell activation and immune regulation, highlighting the importance of considering sex as a biological variable in CUMS research.

immunology↗

bioRxiv2024

FTO (fat-mass and obesity-associated protein) deficiency aggravates age-dependent depression-like behaviors and cognitive impairment

AbstractO_ST_ABSBackgroundC_ST_ABSThe demethylase fat mass and obesity-related protein (FTO) is strongly associated with depression. Aging is a risk factor for synaptic plasticity damage in the brain and leads to neurocognitive dysfunctions. However, whether FTO is associated with susceptibility to depression in different age groups remains unknown. MethodsWe subjected 3-and 12-month-old C57BL/6J male mice to 6 weeks of chronic unpredictable mild stress (CUMS) and 3 weeks of hippocampal injection of FTO knockdown adeno-associated virus 9 shRNA (FTO-KD AAV9). Finally, 36 male mice in each 3-month-old and 12-month-old groups were divided into three groups (n=12): Sham, CUMS, and FTO-KD. After 6 weeks, we assessed behavioral deficits (depressive and anxiety-like behaviors and cognitive impairment) by behavioral tests and hippocampal neuronal damage (dendritic spine density, neuronal atrophy, and expression of proteins associated with synaptic plasticity) by molecular biochemical experiments. ResultsThe results showed that 12-month-old C57BL/6J mice were more likely to develop depression-like behavior and spatial learning and memory impairment induced by CUMS than 3-month-old mice. Chronic stress-induced depression-like behavior and cognitive impairment worsened after the FTO-KD intervention. In the hippocampus of 3-and 12-month-old mice, CUMS induced the downregulation of FTO, nerve growth factor (NGF), reelin, and synaptic plasticity-related proteins. It also caused abnormal BDNF-TrkB signaling, reduced density of dendritic spines, and an increased number of neuronal pyknotic nuclei, leading to neuronal disarray, which was more significant in 12-month-old animals. FTO deficiency accelerated neuronal damage in the hippocampus of 12-month-old CUMS mice. ConclusionsThis study provides rodent evidence that FTO deficiency may increase the susceptibility to depression in older adults by impairing hippocampal neuronal function and neuronal synaptic plasticity in an age-dependent manner. This suggests that the development of FTO activators may be an effective treatment for depression in older adults.

neuroscience↗

bioRxiv2024

Preventing Inappropriate Signals Pre- and Post-Ligand Perception by a Toggle-Switch Mechanism of ERECTA

Dynamic control of signaling events requires swift regulation of receptors at an active state. By focusing on Arabidopsis ERECTA (ER) receptor kinase, which perceives peptide ligands to control multiple developmental processes, we report a mechanism preventing inappropriate receptor activity. The ER C-terminal tail (ER_CT) functions as an autoinhibitory domain: its removal confers higher kinase activity and hyperactivity during inflorescence and stomatal development. ER_CT is required for the binding of a receptor kinase inhibitor, BKI1, and two U-box E3 ligases PUB30 and PUB31 that inactivate activated ER. We further identify ER_CT as a phosphodomain trans-phosphorylated by the co-receptor BAK1. The phosphorylation impacts the tail structure, likely releasing from autoinhibition. The phosphonull version enhances BKI1 association, whereas the phosphomimetic version promotes PUB30/31 association. Thus, ER_CT acts as an off-on-off toggle switch, facilitating the release of BKI1 inhibition, enabling signal activation, and swiftly turning over the receptors afterwards. Our results elucidate a mechanism fine-tuning receptor signaling via a phosphoswitch module, keeping the receptor at a low basal state and ensuring the robust yet transient activation upon ligand perception. SignificanceCells perceive and process external signals through their cell-surface receptors, whose activity must be tightly maintained to prevent the spread of misinformation. How do plant cells prevent the inappropriate receptor activity? We identify a structural module within the C-terminal tail of the ERECTA (ER_CT), that inhibits the receptor pre- and post-signal activation. The ER_CT comprises of a linker and an -helix. Before activation, ER_CT is autoinhibitory and associates with an inhibitory protein. Ligand perception triggers the transphosphorylation of ER_CT by the co-receptor, which then recruits a degradation machinery to swiftly turn over the activated receptor. Thus, we reveal an off-on-off toggle switch mechanism that finely adjusts the activity of the plant receptor, enabling the precise control over cell signaling.

plant biology↗

bioRxiv2023

Vacuum Insulated Probe Heated ElectroSpray Ionization source (VIP-HESI) enhances micro flow rate chromatography signals in the Bruker timsTOF mass spectrometer

By far the largest contribution to ion detectability in liquid chromatography-driven mass spectrometry-based proteomics is the efficient generation of peptide ions by the electrospray source. To maximize the transfer of peptides from liquid to a gaseous phase to allow molecular ions to enter the mass spectrometer at micro-spray flow rates, an efficient electrospray process is required. Here we describe superior performance of new Vacuum-Insulated-Probe-Heated-ElectroSpray-Ionization source (VIP-HESI) coupled with micro-spray flow rate chromatography and Bruker timsTOF PRO mass spectrometer. VIP-HESI significantly improves chromatography signals in comparison to nano-spray ionization using the CaptiveSpray source and provides increased protein detection with higher quantitative precision, enhancing reproducibility of sample injection amounts. Protein quantitation of human K562 lymphoblast samples displayed excellent chromatographic retention time reproducibility (<10% coefficient-of-variation (CV)) with no signal degradation over extended periods of time, and a mouse plasma proteome analysis identified 12% more plasma protein groups allowing large-scale analysis to proceed with confidence (1,267 proteins at 0.4% CV). We show that Slice-PASEF mode with VIP-HESI setup is sensitive in identifying low amounts of peptide without losing quantitative precision. We demonstrate that VIP-HESI coupled with micro-flow-rate chromatography achieves higher depth of coverage and run-to-run reproducibility for a broad range of proteomic applications.

biochemistry↗

bioRxiv2022

Obesity associated with attenuated tissue immune cell responses in COVID-19

Obesity is common and associated with more severe COVID-19, proposed to be in part related to an adipokine-driven pro-inflammatory state. Here we analysed single cell transcriptomes from bronchiolar lavage in three adult cohorts, comparing obese (Ob, body mass index (BMI) >30m2) and non-obese (N-Ob, BMI <30m2). Surprisingly, we found that Ob subjects had attenuated lung immune/inflammatory responses in SARS-CoV-2 infection, with decreased expression of interferon (IFN), IFN{gamma} and tumour necrosis factor (TNF) alpha response gene signatures in almost all lung epithelial and immune cell subsets, and lower expression of IFNG and TNF in specific lung immune cells. Analysis of peripheral blood immune cells in an independent adult cohort showed a similar, but less marked, reduction in type I IFN and IFN{gamma} response genes, as well as decreased serum IFN, in Ob patients with SARS-CoV-2. Nasal immune cells from Ob children with COVID-19 also showed reduced enrichment of IFN and IFN{gamma} response genes. Altogether, these findings show blunted tissue immune responses in Ob COVID-19 patients, with clinical implications.

immunology↗

bioRxiv2021

FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome

Prevention of SARS-CoV-2 entry in cells through the modulation of viral host receptors, such as ACE2, could represent a new therapeutic approach complementing vaccination. However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We demonstrate that FXR antagonists, including the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA), downregulate ACE2 levels, and reduce susceptibility to SARS-CoV-2 infection in lung, cholangiocyte and gut organoids. We then show that therapeutic levels of UDCA downregulate ACE2 in human organs perfused ex situ and reduce SARS-CoV-2 infection ex vivo. Finally, we perform a retrospective study using registry data and identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection, including hospitalisation, ICU admission and death. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that this approach could be beneficial for reducing SARS-CoV-2 infection, thereby paving the road for future clinical trials.

microbiology↗

bioRxiv2021

High-content imaging to phenotype antimicrobial effects on individual bacteria at scale

High-content imaging (HCI) is technique for screening multiple cells in high resolution to detect subtle morphological and phenotypic variation. The method has been commonly deployed on model eukaryotic cellular systems, often for screening new drugs and targets. HCI is not commonly utilised for studying bacterial populations but may be powerful tool in understanding and combatting antimicrobial resistance. Consequently, we developed a high-throughput method for phenotyping bacteria under antimicrobial exposure at the scale of individual bacterial cells. Imaging conditions were optimised on an Opera Phenix confocal microscope (Perkin-Elmer) and novel analysis pipelines were established for both Gram-negative bacilli and Gram-positive cocci. The potential of this approach was illustrated using isolates of Klebsiella pneumoniae, Salmonella enterica serovar Typhimurium, and Staphylococcus aureus. HCI enabled the detection and assessment of subtle morphological characteristics, undetectable through conventional phenotypical methods, that could reproducibly distinguish between bacteria exposed to different classes of antimicrobials with distinct modes of action (MOA). In addition, distinctive responses were observed between susceptible and resistant isolates. By phenotyping single bacterial cells, we observed intra-population differences, which may be critical in identifying persistence or emerging resistance during antimicrobial treatment. The work presented here outlines a comprehensive method for investigating morphological changes at scale in bacterial populations under specific perturbation. ImportanceHigh-content imaging (HCI) is a microscopy technique that permits the screening of multiple cells simultaneously in high resolution to detect subtle morphological and phenotypic variation. The power of this methodology is that is can generate large datasets comprised of multiple parameters taken from individual cells subjected to range of different conditions. We aimed to develop novel methods for using HCI to study bacterial cells exposed to a range of different antibiotic classes. Using an Opera Phenix confocal microscope (Perkin-Elmer) and novel analysis pipelines we created a method to study the morphological characteristics of Klebsiella pneumoniae, Salmonella enterica serovar Typhimurium, and Staphylococcus aureus when exposed to antibacterial drugs with differing modes of action. By imaging individual bacterial cells at high resolution and scale, we observed intra-population differences associated with different antibiotics. The outlined methods are highly relevant for how we begin to better understand and combat antimicrobial resistance.

microbiology↗

bioRxiv2020

Spontaneous emergence of azithromycin resistance in independent lineages of Salmonella Typhi in Northern India

BackgroundThe emergence and spread of antimicrobial resistance (AMR) pose a major threat to the effective treatment and control of typhoid fever. The ongoing outbreak of extensively drug resistant (XDR) Salmonella Typhi (S. Typhi) in Pakistan has left azithromycin as the only remaining broadly efficacious oral antimicrobial for typhoid in South Asia. Ominously, azithromycin resistant S. Typhi organisms have been subsequently reported in Bangladesh, Pakistan, and Nepal. MethodsHere, we aimed to understand the molecular basis of AMR in 66 S. Typhi isolated in a cross-sectional study performed in a suburb of Chandigarh in Northern India using whole genome sequencing (WGS) and phylogenetic analysis. ResultsWe identified seven S. Typhi organisms with the R717Q mutation in the acrB gene that was recently found to confer resistance to azithromycin in Bangladesh. Six out of the azithromycin-resistant S. Typhi isolates also exhibited triple mutations in gyrA (S83F and D87N) and parC (S80I) genes and were resistant to ciprofloxacin. These contemporary ciprofloxacin/azithromycin-resistant isolates were phylogenetically distinct from each other and from those reported from Bangladesh, Pakistan, and Nepal. ConclusionsThe independent emergence of azithromycin resistant typhoid in Northern India reflects an emerging broader problem across South Asia and illustrates the urgent need for the introduction of typhoid conjugate vaccines (TCVs) in the region. Key pointsWe identified ciprofloxacin/azithromycin-resistant Salmonella Typhi (S. Typhi) in Chandigarh in Northern India. The independent emergence of ciprofloxacin/azithromycin-resistant typhoid in Bangladesh, Pakistan, Nepal, and India and the continued spread of extensively-drug resistant (XDR) typhoid in Pakistan highlight the limitations of licensed oral treatments for typhoid fever in South Asia.

genomics↗

bioRxiv2020

A novel therapeutic antibody screening method using bacterial high-content imaging reveals functional antibody binding phenotypes of Escherichia coli ST131

The increase of antimicrobial resistance (AMR), and lack of new classes of licensed antimicrobials, have made alternative treatment options for AMR pathogens increasingly attractive. Recent studies have demonstrated anti-bacterial efficacy of a humanised monoclonal antibody (mAb) targeting the O25b O-antigen of Escherichia coli ST131. To evaluate the phenotypic effects of antibody binding to diverse clinical E. coli ST131 O25b bacterial isolates in high-throughput, we designed a novel mAb screening method using high-content imaging (HCI) and image-based morphological profiling to screen a mAb targeting the O25b O-antigen. Screening the antibody against a panel of 86 clinical E. coli ST131 O25:H4 isolates revealed 4 binding phenotypes: no binding (18.60%), weak binding (4.65%), strong binding (69.77%) and strong agglutinating binding (6.98%). Impaired antibody binding could be explained by the presence of insertion sequences or mutations in O-antigen or lipopolysaccharide core biosynthesis genes, affecting the amount, structure or chain length of the O-antigen. The agglutinating binding phenotype was linked with lower O-antigen density, enhanced antibody-mediated phagocytosis and increased serum susceptibly. This study highlights the need to screen candidate mAbs against large panels of clinically relevant isolates, and that HCI can be used to evaluate mAb binding affinity and potential functional efficacy against AMR bacteria.

microbiology↗

bioRxiv2020

A blueprint for the implementation of a validated approach for the detection of SARS-Cov2 in clinical samples in academic facilities

The COVID-19 pandemic is expanding at an unprecedented rate. As a result, diagnostic services are stretched to their limit, and there is a clear need for the provision of additional diagnostic capacity. Academic laboratories, many of which are closed due to governmental lockdowns, may be in a position to support local screening capacity by adapting their current laboratory practices. Here, we describe the process of developing a SARS-Cov2 diagnostic workflow in a conventional academic Containment Level 2 (CL2) laboratory. Our outline includes simple SARS-Cov2 deactivation upon contact, the methods for a quantitative real-time reverse transcriptase PCR (qRT-PCR) detecting SARS-Cov2, a description of process establishment and validation, and some considerations for establishing a similar workflow elsewhere. This was achieved under challenging circumstances through the collaborative efforts of scientists, clinical staff, and diagnostic staff to mitigate to the ongoing crisis. Within 14 days, we created a validated COVID-19 diagnostics service for healthcare workers in our local hospital. The described methods are not exhaustive, but we hope may offer support to other academic groups aiming to set up something comparable in a short time frame.

molecular biology↗

bioRxiv2019

The Manifold Actions of Signaling Peptides on Subcellular Dynamics of a Receptor Specify Stomatal Cell Fate

Receptor endocytosis is important for signal activation and transduction. However, how a receptor interprets conflicting signals to adjust cellular output is not clearly understood. During plant development, the family of EPIDERMAL PATTERNING FACTOR (EPF) peptides fine-tunes stomatal patterning through ERECTA-family receptor kinases. Using genetic, cell biological, and pharmacological approaches, we report here that ERECTA-LIKE1 (ERL1), the major receptor restricting stomatal differentiation, undergoes dynamic subcellular behaviors in response to different signal inputs. ERL1 is constitutively recycled, whereas its activation by EPF1 peptide induces rapid internalization to multivesicular bodies (MVB). In contrast, the dominant-negative ERL1 resides predominantly in plasma membrane. The co-receptor, TOO MANY MOUTHS (TMM), is essential for EPF1-induced ERL1 internalization but dispensable for EPFL6-induced ERL1 internalization. The peptide antagonist of EPF1, Stomagen/EPFL9, triggers retention of ERL1 in the endoplasmic reticulum. Our study elucidates that multiple related yet unique peptides specify cell fate by deploying the differential subcellular dynamics of a single receptor.

plant biology↗

bioRxiv2018

Paranoid schizophrenia and methamphetamine-induced paranoia are both characterized by a similar LINE-1 partial methylation profile, which is more pronounced in paranoid schizophrenia.

BackgroundThere is evidence that schizophrenia is a neuro-immune disorder. Genes linked to intragenic LINE-1 methylation show a strong association with immune-associated disorders including psychosis. The aim of this study was to examine LINE-1 methylation patterns in paranoid schizophrenia and methamphetamine-induced paranoia, a model for schizophrenia.\n\nMethodsThis study recruited 31 patients with paranoid schizophrenia, 94 with methamphetamine-induced paranoia (MIP) and 163 normal controls. LINE-1 methylation patterns were assayed in peripheral blood mononuclear cells and a combined bisulphite restriction analysis and COBRA were used to estimate global methylation (mC) and LINE-1 CpG dinucleotide methylation patterns, namely 2 methylated (mCmC) and 2 unmethylated (uCuC) CpGs and the partially methylated loci mCuC (5m with 3u) and uCmC (5u with 3m).\n\nResultsPatients with paranoid schizophrenia show highly significant changes in LINE-1 partial methylation patterns, namely a higher % mCuC and lower % uCmC as compared with controls and MIP patients, while the latter show higher % mCuC but lower % uCmC as compared with controls. Higher % mCuC significantly predicts paranoid schizophrenia with a sensitivity of 51.6%, specificity of 97.5% and an area under the ROC curve of 0.895.\n\nConclusionsThe results indicate that a common dysfunction in LINE-1 partial methylation may underpin both paranoid schizophrenia and MIP and that this methylation pattern is significantly more expressed in paranoid schizophrenia than MIP. Reciprocal links between impairments in LINE-1 methylation and neuro-immune and neuro-oxidative pathways may underpin the pathophysiology of both MIP and paranoid schizophrenia.

neuroscience↗

bioRxiv2018

Early Life Trauma Predicts Affective Phenomenology and the Effects are Partly Mediated by Staging Coupled with Lowered Lipid-Associated Antioxidant Defences.

BackgroundEarly life trauma (ELT) may drive mood disorder phenomenology, neuro-oxidative and neuro-immune pathways and impairments in semantic memory. Nevertheless, there are no data regarding the impact of ELT on affective phenomenology and whether these pathways are mediated by staging or lowered lipid-associated antioxidant defences.\n\nMethodsThis study examined healthy controls (n=54) and patients with affective disorders including major depression, bipolar disorder and anxiety disorders (n=118). ELT was assessed using the Child Trauma Questionnaire. In addition, we measured affective phenomenology and assayed advanced oxidation protein products; malondialdehyde, paraoxonase 1 (CMPAase) activity, high-sensitivity C-reactive protein (hsCRP), and high-density lipoprotein (HDL) cholesterol.\n\nResultsELT was associated with increased risk for mood and comorbid anxiety disorders and a more severe phenomenology, including staging characteristics (number of mood episodes), severity of depression and anxiety, suicide attempts, suicidal ideation, type of treatments received, disabilities, body mass index, smoking behaviour and hsCRP, as well as lowered health-related quality of life, socio-economic status, antioxidant defences and semantic memory. The number of mood episodes and CMPAase/HDL-cholesterol levels could be reliably combined into a new vulnerability staging-biomarker index, which mediates in part the effects of ELT on affective phenomenology, while lowered antioxidant defences are associated with increased oxidative stress. Moreover, the effects of female sex on mood disorders and affective phenomenology are mediated by ELT.\n\nDiscussionThe cumulative effects of different types of ELT drive many aspects of affective phenomenology either directly or indirectly through effects of staging and/or lipid-associated antioxidant defences. The results show that children, especially girls, with ELT are at great risk to develop mood disorders and more severe phenotypes of affective disorders.

neuroscience↗

bioRxiv2018

Supervised machine learning to decipher the complex associations between neuro-immune biomarkers and quality of life in schizophrenia

Stable phase schizophrenia is characterized by altered patterning in tryptophan catabolites (TRYCATs) and memory impairments, which are associated with PHEMN (psychosis, hostility, excitation, mannerism and negative) and DAPS (depression, anxiety and physio-somatic) symptoms. This study was carried out to examine the association between TRYCAT patterning, memory impairments, psychopathological features and health-related quality of life (HR-QoL) in schizophrenia.\n\nThe World Health Organization (WHO) QoL instrument-Abbreviated version (WHO-QoL-BREF), IgA/IgM responses to TRYCATs, cognitive tests, Scale for the Assessment of Negative Symptoms (SANS), Hamilton and Depression (HAMD) and Anxiety (HAMA) Rating Scales and the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale (FF) were measured in 80 schizophrenia patients and 40 controls.\n\nNeural Network analysis shows that the total HR-Qol score is best predicted by (in descending order) FF, HAMA and SANS scores, Mini Mental State examination, hostility, ratio noxious/protective TRYCATs and HAMD score. Partial least Squares (PLS) analysis shows that 55.1% of the variance in Domain1 (physical) is predicted by PHEMN and DAPS latent vector (LV) scores, while 57.9% of domain2 (psychological), 32.7% of domain3 (social) and 55.0% of domain4 (environment) are explained by DAPS LV scores. TRYCATs and episodic/semantic memory impairments have specific indirect effects on domains 2, 3 and 4, which are mediated by DAPS symptoms, while the effects of TRYCATs on domain1 are mediated by PHEMN and DAPS symptoms. Picolinic acid, xanthurenic acid and 3-hydroxy-kynurenine decrease WHO-QoL scores, whilst anthranilic acid is protective.\n\nThe results show that lowered HR-Qol in schizophrenia is strongly predicted by noxious TRYCATs, impairments in episodic and semantic memory and DAPS symptoms, especially physio-somatic symptoms and anxiety. Neuro-immune pathways and the consequent cognitive impairments determine to a great extent lowered HR-QoL in schizophrenia.

neuroscience↗

bioRxiv2018

A new schizophrenia model: immune activation is associated with induction of thetryptophan catabolite pathway and increased eotaxin levels which together determinememory impairments and schizophrenia symptom dimensions.

AbstractO_ST_ABSObjectiveC_ST_ABSRecently, we reported that stable-phase schizophrenia is characterized by two interrelated symptom dimensions: PHEMN (psychotic, hostility, excitation, mannerism and negative symptoms); and DAPS (depressive, anxiety and physio-somatic symptoms) and that Major Neuro-Cognitive psychosis (MNP) is the full blown phenotype of schizophrenia (largely overlapping with deficit schizophrenia). Herein we examined the effects of immune activation in association with tryptophan catabolite (TRYCAT) patterning and memory disorders on PHEMN/DAPS dimensions and MNP.\n\nMethodSerum levels of macrophage inflammatory protein-1 (MIP-1), soluble interleukin (IL)-1 receptor antagonist (sIL-1RA), IL-10, eotaxin, IgA/IgM responses to TRYCATs, and Consortium to Establish a Registry for Alzheimers disease (CERAD) tests were assessed in 40 controls and 80 schizophrenia patients.\n\nResultsSchizophrenia and MNP were predicted by significantly increased levels of IL-10, eotaxin and TRYCATs. A large part of the variance in both PHEMN/DAPS symptom dimensions (42.8%) was explained by cytokine levels and TRYCATs combined. The MTP+sTL-1R A+IL-10 composite score and eotaxin explained each around 19% of the variance in symptom dimensions, and approximately 18% of memory deficits. Moreover, MIP+sIL-1RA+IL-10 was significantly associated with elevations in picolinic acid, xanthurenic acid and 3-OH-kynurenine. Partial Least Squares path modeling shows that the highly significant effects of MIP+sIL-1RA+IL-10 on symptomatology are mediated by the effects of noxious TRYCATs on memory deficits.\n\nConclusionsCurrent findings indicate that in schizophrenia, immune activation may underpin activation of indoleamine-2,3-dioxygenase and kynurenine monooxygenase, while impairments in episodic and semantic memory may be caused by the neurotoxic effects of TRYCATs and eotaxin. The combined effects of immune activation, eotaxin and memory defects determine to a large extent PHEMN/DAPS symptoms and the MNP phenotype. These findings indicate that schizophrenia phenomenology is largely mediated by multiple neuro-immune pathways and that immune activation, increased production of eotaxin and neurotoxic TRYCATs (picolinic acid, xanthurenic acid and 3-HO-kynurenine) are new drug targets in schizophrenia and MNP.

neuroscience↗