Biology subjects

Dinh, L.

Publications and source records attributed to Dinh, L..

3 recordsLinked to original sources

bioRxiv2025

TOMM40 suppression promotes neuronal cholesterol imbalance and molecular and behavioral phenotypes of Alzheimer's disease

INTRODUCTIONWhile the APOE4 allele is a major risk factor for Alzheimers disease (AD), the role of TOMM40--an adjacent gene involved in mitochondrial protein import--is not known. METHODSMice, human iPSC-derived neurons (iNeurons), and human brain tissue were used for study of animal cognition, cholesterol metabolism, mitochondrial function, and gene expression. RESULTSTOMM40 knockdown (KD) impaired memory in mice and increased cholesterol and A{beta} 42 in mouse brains and human iNeurons. KD disrupted mitochondria-endoplasmic reticulum contact sites (MERCs), causing mitochondrial dysfunction and promoting reactive oxygen species that led to activation of LXRB (NR1H2), upregulation of APOE and LDLR. and increased cellular cholesterol and A{beta} 42 independent of APOE4. Human brain transcriptomics showed reduced TOMM40 expression that correlated with cholesterol regulatory gene expression, amyloid burden, and clinical AD diagnosis. DISCUSSIONTOMM40 is a novel mediator of AD pathology through dual effects on MERCs that regulate cholesterol homeostasis and mitochondrial function. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/685963v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@e3e3e2org.highwire.dtl.DTLVardef@1861f67org.highwire.dtl.DTLVardef@77a813org.highwire.dtl.DTLVardef@1bb9a83_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Dietary fiber content in clinical ketogenic diets modifies the gut microbiome and seizure resistance in mice

The gut microbiome is emerging as an important modulator of the anti-seizure effects of the classic ketogenic diet. However, many variations of the ketogenic diet are used clinically to treat refractory epilepsy, and how different dietary formulations differentially modify the gut microbiome in ways that impact seizure outcome is poorly understood. We find that clinically prescribed ketogenic infant formulas vary in macronutrient ratio, fat source, and fiber content and also in their ability to promote resistance to 6-Hz psychomotor seizures in mice. By screening specific dietary variables for their effects on a model human infant microbial community, we observe that dietary fiber, rather than fat ratio or source, drives substantial metagenomic shifts. Addition of dietary fiber to a fiber-deficient ketogenic formula restores seizure resistance, and supplementing protective ketogenic formulas with excess dietary fiber further potentiates seizure resistance. By screening 13 fiber sources and types, we identify distinct subsets of metagenomic responses in the model human infant microbial community that correspond with increased seizure resistance in mice. In particular, supplementation with seizure-protective fibers enriches microbial representation of genes related to queuosine biosynthesis and preQ0 biosynthesis and decreases representation of microbial genes related to sucrose degradation, which is also seen in seizure-protected mice that are fed fiber-containing ketogenic infant formulas. Overall, this study reveals that different formulations of clinical ketogenic diets, and dietary fiber content in particular, differentially impact seizure outcome in mice, likely through modification of the gut microbiome. Understanding interactions between dietary components of the ketogenic diet, the gut microbiome, and host susceptibility to seizures could inform novel microbiome-guided approaches to treat refractory epilepsy.

microbiology↗

bioRxiv2018

Differences in DNA methylation of white blood cell types at birth and in adulthood reflect postnatal immune maturation and influence accuracy of cell type prediction

BackgroundDNA methylation profiling of peripheral blood leukocytes has many research applications, and characterizing the changes in DNA methylation of specific white blood cell types between newborn and adult could add insight into the maturation of the immune system. As a consequence of developmental changes, DNA methylation profiles derived from adult white blood cells are poor references for prediction of cord blood cell types from DNA methylation data. We thus examined cell-type specific differences in DNA methylation in leukocyte subsets between cord and adult blood, and assessed the impact of these differences on prediction of cell types in cord blood.\n\nResultsThough all cell types showed differences between cord and adult blood, some specific patterns stood out that reflected how the immune system changes after birth. In cord blood, lymphoid cells showed less variability than in adult, potentially demonstrating their naive status. In fact, cord CD4 and CD8 T cells were so similar that genetic effects on DNA methylation were greater than cell type effects in our analysis, and CD8 T cell frequencies remained difficult to predict, even after optimizing the library used for cord blood composition estimation. Myeloid cells showed fewer changes between cord and adult and also less variability, with monocytes showing the fewest sites of DNA methylation change between cord and adult. Finally, including nucleated red blood cells in the reference library was necessary for accurate cell type predictions in cord blood.\n\nConclusionChanges in DNA methylation with age were highly cell type specific, and those differences paralleled what is known about the maturation of the postnatal immune system.

genetics↗