Biology subjects

Nitschke, P.

Publications and source records attributed to Nitschke, P..

4 recordsLinked to original sources

bioRxiv2023

Clinical prediction of wound re-epithelisation outcomes in non-severe burn injury using the plasma lipidome

Whilst wound repair in severe burns has received substantial research attention, non-severe burns (<20% total body surface area) remain relatively understudied, despite causing considerable physiological impact and constituting most of the hospital admissions for burns. Early prediction of healing outcomes would decrease financial and patient burden, and aid in preventing long-term complications from poor wound healing. Lipids have been implicated in inflammation and tissue repair and may play essential roles in burn wound healing. In this study, plasma samples were collected from 20 non-severe burn patients over 6 weeks from admission, including surgery, and analysed by liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy to detect 850 lipids and 112 lipoproteins. Orthogonal projections to latent structures-discriminant analysis was performed to identify changes associated with re-epithelialisation and delayed re-epithelisation. We demonstrated that the lipid and lipoprotein profiles at admission could predict re-epithelisation outcomes at 2 weeks post-surgery, and that these discriminatory profiles were maintained up to 6 weeks post-burn. Inflammatory markers GlycB and C-reactive protein indicated divergent systemic responses to the burn injury at admission. Triacylglycerols, diacylglycerols and low-density lipoprotein subfractions were associated with delayed wound closure (p-value <0.02, Cliffs delta >0.7), whilst high-density lipoprotein subfractions, phosphatidylinositols, phosphatidylcholines, and phosphatidylserines were associated with re-epithelisation at 2 weeks post-surgery (p-value <0.01, Cliffs delta <-0.7). Further model validation will potentially lead to personalised intervention strategies to reduce the risk of chronic complications post-burn injury.

systems biology↗

bioRxiv2023

Metabolic consequences of non-severe burn injury are associated with increased plasma markers of inflammation and cardiovascular disease risk.

Globally, burns are a significant cause of injury that can cause substantial acute trauma as well as lead to increased incidence of chronic co-morbidity and disease. To date, research has primarily focused on the systemic response to severe injury, with little in the literature reported on impact of non-severe injuries (<15% total burn surface area; TBSA). To elucidate the metabolic consequences of non-severe burn injury, longitudinal plasma was collected from adults (n=35) who presented at hospital with a non-severe burn injury at admission, and at 6 week follow up. A cross-sectional baseline sample was also collected from non-burn control participants (n=14). Samples underwent multiplatform metabolic phenotyping using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry to quantify 112 lipoprotein and glycoproteins signatures and 852 lipid species from across 20 subclasses. Multivariate data modelling (Orthogonal projection to latent structures-discriminate analysis) revealed alterations in lipoprotein and lipid metabolism when comparing baseline control to hospital admission samples, with the phenotypic signature found to be sustained at follow up. Univariate (Mann-Whitney U) testing and OPLS-DA indicated specific increases in GlycB (p-value <1.0e-4), low density lipoprotein-2 subfractions (Variable importance in projection score; VIP >6.83e-1) and monoacyglyceride (20:4)(p-value <1.0e-4) and decreases in circulating anti-inflammatory high-density lipoprotein-4 subfractions (VIP >7.75e-1), phosphatidylcholines, phosphatidylglycerols, phosphatidylinositols and phosphatidylserines. The results indicate a persistent systemic metabolic phenotype that occurs even in cases of non-severe burn injury. The phenotype is indicative of an acute inflammatory profile which continues to be sustained post-injury, suggesting an impact on systems health beyond the site of injury. The phenotypes contained metabolic signatures consistent with chronic inflammatory states reported to have elevated incidence post-burn injury. Such phenotypic signatures may provide patient stratification opportunities, to identify individual responses to injury, personalise intervention strategies and improve acute care, reducing risk of chronic co-morbidity.

systems biology↗

bioRxiv2020

MINPP1 prevents intracellular accumulation of the cation chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol polyphosphate phosphatase 1 gene (MINPP1). Patients were found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We found that patient-derived and genome edited MINPP1-/- induced pluripotent stem cells (iPSCs) are not able to differentiate efficiently into neurons. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakiphosphate (IP6), detected in HEK293, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis.

genetics↗

bioRxiv2019

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

Autism Spectrum Disorders (ASDs) are a heterogeneous collection of neurodevelopmental disorders with a strong genetic basis. Recent studies identified that a single hit of either a de novo or transmitted gene-disrupting, or likely gene-disrupting, mutation in a subset of 65 strongly associated genes can be sufficient to generate an ASD phenotype. We took advantage of consanguineous families with an ASD proband to evaluate this model. By a genome-wide homozygosity mapping of ten families with eleven children displaying ASD, we identified a linkage region of 133 kb in five families at the 3p14.2 locus that includes FEZF2 with a LOD score of 5.8 suggesting a founder effect. Sequencing FEZF2 revealed a common deletion of four codons. However, the damaging FEZF2 mutation did not appear to be sufficient to induce the disease as non-affected parents also carry the mutation and, similarly, Fezf2 knockout mouse embryos electroporated with the mutant human FEZF2 construct did not display any obvious defects in the corticospinal tract, a pathway whose development depends on FEZF2. We extended the genetic analysis of these five FEZF2-linked families versus five FEZF2 non-linked families by studying de novo and transmitted copy number variation (CNV) and performing Whole Exome Sequencing (WES). We identified damaging mutations in the subset of 65 genes strongly associated with ASD whose co-expression analysis suggests an impact on the prefrontal cortex during the mid-fetal periods. From these results, we propose that both FEZF2 deletion and multiple hits in the repertoire of these 65 genes are necessary to generate an ASD phenotype.\n\nSignificance StatementThe human neocortex is a highly organized laminar structure with neuron positioning and identity of deep-layer cortical neurons that depend on key transcription factors, such as FEZF2, SATB2, TSHZ3 and TBR1. These genes have a specific spatio-temporal pattern of expression in human midfetal deep cortical projection neurons and display mutations in patients with Autism Spectrum Disorder (ASD). Here, we identified a linkage region involving FEZF2 gene in five consanguineous families with an ASD proband. For these FEZF2-allele linked probands, we identified a four-codon deletion in FEZF2 and damaging mutations in other high-risk ASD genes, that exhibit regional and cell type-specific convergence in neocortical deep-layer excitatory neurons, suggesting a multi-hit genomic architecture of ASD in these consanguineous families.

neuroscience↗