Biology subjects

Zimmerman, K.

Publications and source records attributed to Zimmerman, K..

7 recordsLinked to original sources

bioRxiv2026

ARID3a-Expressing Naive B Cells in SLE have an Activated Phenotype and Transiently Express Surface CD68

Numbers of ARID3a (AT-Rich Interaction Domain 3a) -expressing B lymphocytes from patients with systemic lupus erythematosus (SLE) are associated with increased disease activity. Normally, ARID3a-expressing circulating naive B cells are rare, but in SLE naive B cells dramatically increase ARID3a expression. We found that in vitro stimulation of B lymphocytes from healthy individuals with a cocktail of cytokines and agonists induced ARID3a in a subset of activated naive B cells and in IgD-CD27- double negative B cells previously associated with autoimmunity. Single cell RNA-seq of isolated naive B cells from ten SLE patients, with varying frequencies of ARID3a-expressing cells, revealed that ARID3a-associated genes included activation markers. Moreover, our data revealed the unexpected co-expression of the scavenger receptor CD68 with ARID3a, at both the transcript and protein level, in activated subsets of naive B cells. Inhibition of ARID3a in stimulated B cell cultures blocked naive B cell activation and CD68 expression. Together, these data identify ARID3a and CD68 as markers of naive B cell precursors associated with autoimmunity in SLE.

immunology↗

bioRxiv2024

Spatial Transcriptomics and Single-Nucleus Multi-omics Analysis Revealing the Impact of High Maternal Folic Acid Supplementation on Offspring Brain Development

Folate, an essential vitamin B9, is crucial for diverse biological processes including neurogenesis. Folic acid (FA) supplementation during pregnancy is a standard practice for preventing neural tube defects (NTDs). However, concerns are growing over the potential risks of excessive maternal FA intake. Here, we employed mouse model and spatial transcriptomics and single-nucleus multi-omics approaches to investigate the impact of high maternal FA supplementation during the periconceptional period on offspring brain development. Maternal high FA supplementation affected gene pathways linked to neurogenesis and neuronal axon myelination across multiple brain regions, as well as gene expression alterations related to learning and memory in thalamic and ventricular regions. Single-nucleus multi-omics analysis revealed that maturing excitatory neurons in the dentate gyrus (DG) are particularly vulnerable to high maternal FA intake, leading to aberrant gene expressions and chromatin accessibility in pathways governing ribosomal biogenesis critical for synaptic formation. Our findings provide new insights into specific brain regions, cell types, gene expressions and pathways that can be affected by maternal high FA supplementation.

neuroscience↗

bioRxiv2022

Integrated Multi-Omics Analysis of Brain Aging in Female Nonhuman Primates Reveals Altered Signaling Pathways Relevant to Age-Related Disorders

The prefrontal cortex (PFC) has been implicated as a key brain region responsible for age-related cognitive decline. Little is known about aging-related molecular changes in PFC that may mediate these effects. To date, no studies have used untargeted discovery methods with integrated analyses to determine PFC molecular changes in healthy female primates. We quantified PFC changes associated with healthy aging in female baboons by integrating multiple omics data types (transcriptomics, proteomics, metabolomics) from samples across the adult age span. Our integrated omics approach using unbiased weighted gene co-expression network analysis (WGCNA) to integrate data and treat age as a continuous variable, revealed highly interconnected known and novel pathways associated with PFC aging. We found GABA tissue content associated with these signaling pathways, providing one potential biomarker to assess PFC changes with age. These highly coordinated pathway changes during aging may represent early steps for aging-related decline in PFC functions, such as learning and memory, and provide potential biomarkers to assess cognitive status in humans.

systems biology↗

bioRxiv2021

Cardiac Specific Overexpression of Transcription Factor EB (TFEB) in Normal Hearts Induces Pathologic Cardiac Hypertrophy and Lethal Cardiomyopathy

TFEB promotes lysosomal biogenesis, autophagy, and lysosomal exocytosis. The present study characterized the consequence of inducible TFEB overexpression in cardiomyocytes in vivo. We generated cardiomyocyte-specific doxycycline inducible (Tet off) mice to achieve spatial and temporal control of TFEB overexpression, by crossing TFEB transgenic mice with mice harboring the tTA transgene (TFEB/tTA). Two weeks after doxycycline removal, an 8-fold increase in TFEB protein expression was observed in transgenic hearts. Heart weight normalized to tibia length was increased by 2.5-fold following TFEB overexpression (TFEB/tTA), characterized by induction of markers of pathological hypertrophy, such as Nppa, Nppb and Acta1, progressive contractile dysfunction and cardiac dilatation. Overexpression of TFEB resulted in premature death, associated with high degree AV block. Reversal of TFEB overexpression normalized cardiac structure and function. Mitochondrial respiration and ATP levels were preserved after 2-weeks of TFEB induction, despite reduced mitochondrial (OXPHOS) protein expression, mtDNA content, and altered mitochondrial morphology. Signaling through mTOR was induced in TFEB/tTA mice, and when inhibited by rapamycin treatment for 4 weeks, partially offset left ventricular dysfunction. Transcriptome analysis revealed early suppression of mitochondrial metabolic pathways, induction of fibrosis and altered calcium signaling. MCOLN1, a lysosomal calcium release channel, the calcineurin target RCAN1.4, and the mitochondrial calcium uniporter (MCU) were strikingly induced in TFEB/tTA mice. In summary, persistent overexpression of TFEB at high levels (8-fold protein upregulation) in cardiomyocytes promotes pathologic cardiac hypertrophy via suppression of mitochondrial bioenergetic pathways and activation of pro-fibrotic and calcium regulatory pathways.

cell biology↗

bioRxiv2020

Investigating the interaction between white matter and brain state on tDCS-induced changes in brain network activity

BackgroundTranscranial direct current stimulation (tDCS) is a form of noninvasive brain stimulation whose potential as a cognitive therapy is hindered by our limited understanding of how participant and experimental factors influence its effects. Using functional MRI to study brain networks, we have previously shown in healthy controls that the physiological effects of tDCS are strongly influenced by brain state. We have additionally shown, in both healthy and traumatic brain injury (TBI) populations, that the behavioral effects of tDCS are positively correlated with white matter (WM) structure. ObjectivesIn this study we investigate how these two factors, WM structure and brain state, interact to shape the effect of tDCS on brain network activity. MethodsWe applied anodal, cathodal and sham tDCS to the right inferior frontal gyrus (rIFG) of healthy (n=22) and TBI participants (n=34). We used the Choice Reaction Task (CRT) performance to manipulate brain state during tDCS. We acquired simultaneous fMRI to assess activity of cognitive brain networks and used Fractional Anisotropy (FA) as a measure of WM structure. ResultsWe find that the effects of tDCS on brain network activity in TBI participants are highly dependent on brain state, replicating findings from our previous healthy control study in a separate, patient cohort. We then show that WM structure further modulates the brain-state dependent effects of tDCS on brain network activity. These effects are not unidirectional - in the absence of task with anodal and cathodal tDCS, FA is positively correlated with brain activity in several regions of the default mode network. Conversely, with cathodal tDCS during CRT performance, FA is negatively correlated with brain activity in a salience network region. ConclusionsOur results show that experimental and participant factors interact to have unexpected effects on brain network activity, and that these effects are not fully predictable by studying the factors in isolation.

neuroscience↗

bioRxiv2019

Paradoxical Aortic Stiffening and Subsequent Cardiac Dysfunction in Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare disorder with devastating sequelae resulting in early death, presently believed to stem primarily from heart failure secondary to central arterial stiffening. We analyze novel longitudinal cardiovascular data from a mouse model of HGPS (LmnaG609G/G609G) using allometric scaling and advanced computational modelling and show that a late-stage increase in pulse wave velocity, with associated diastolic dysfunction but preserved systolic function, emerges with a loss of aortic function, independent of sex. Specifically, there is a dramatic late-stage loss of smooth muscle function and cells and an excessive accumulation of proteoglycans along the entire aorta, which result in a loss of biomechanical function (contractility and elastic energy storage) and marked structural stiffening despite a distinctly low intrinsic material stiffness that is consistent with the lack of functional lamin A. Importantly, vascular function appears to be normal within the low stress environment of development, only to succumb progressively to pressure-related effects of the lamin A mutation and become extreme in the peri-morbid period. Because the dramatic life-threatening aortic phenotype manifests during the last quarter of life there may be a therapeutic window in maturity that could alleviate concerns with therapies administered during early periods of arterial development.\n\nDisclosuresD.T.B is an equity holder in, and receives research and consulting support from, Inozyme Pharma, Inc. for therapeutics for ENPP1 deficiency. None of the other authors declare any conflict, financial or otherwise.

bioengineering↗

bioRxiv2019

Fungal seed pathogens of wild chili peppers possess multiple mechanisms to tolerate capsaicinoids

The wild chili pepper Capsicum chacoense produces the spicy defense compounds known as capsaicinoids, including capsaicin and dihydrocapsaicin, antagonistic to the growth of fungal pathogens. Compared to other microbes, fungi isolated from infected seeds of C. chacoense possess much higher tolerance to these spicy compounds, having their growth slowed, but not entirely inhibited. Previous research has shown capsaicinoids inhibit microbes by disrupting ATP production via the binding of NADH dehydrogenase in the Electron Transport Chain (ETC), throttling Oxidative Phosphorylation (OXPHOS). Capsaicinoids may also disrupt cell membranes. Here, we investigated capsaicinoid tolerance in fungal seed pathogens isolated from C. chacoense. We selected 16 fungal isolates from four Ascomycete genera (Alternaria, Colletotrichum, Fusarium and Phomopsis). Using relative growth rate as a readout for tolerance, fungi were challenged with ETC inhibitors to infer if fungi possess alternative respiratory enzymes, and if effects on the ETC fully explained inhibition by capsaicinoids. In all isolates, we found evidence for at least one alternative NADH dehydrogenase. In many isolates we also found evidence for an alternative oxidase. These data suggest wild plant pathogens may be a rich source of alternative respiratory enzymes. We further demonstrate these fungal isolates are capable of the breakdown of capsaicinoids. Lastly, we determine the OXPHOS theory weakly explains the primary mechanism by which dihydrocapsaicin slows fungal growth, but not capsaicin. Our findings suggest capsaicinoids likely disrupt membranes in addition to energy poisoning, with implications for microbiology and human health.\n\nImportancePlants make chemical compounds to protect themselves. For example, chili peppers produce the spicy compound capsaicin to inhibit animal feeding and pathogen damage. In humans, capsaicin binds to a membrane channel protein, creating the sensation of heat, while in microbes, capsaicin limits energy production by binding respiratory enzymes. However, some data suggest capsaicin also disrupts membranes. Here we studied fungal pathogens (Alternaria, Colletotrichum, Fusarium, and Phomopsis) isolated from a wild chili pepper, Capsicum chacoense. By measuring growth rate in the presence of antibiotics with known respiratory targets, we infer wild plant pathogens may be rich with alternative respiratory enzymes. A zone of clearance around the colonies, as well as LCMS data, further indicate these fungi can break down capsaicin. Lastly, the total inhibitory effect of capsaicin was not fully explained by its effect on respiratory enzymes. Our findings lend credence to studies proposing capsaicin may disrupt cell membranes, with implications for microbiology as well as human health.

microbiology↗