Biology subjects

Larson, R.

Publications and source records attributed to Larson, R..

12 recordsLinked to original sources

bioRxiv2026

One-carbon metabolism sustains effector T cell function through cell-surface glycosylation

Folate is a driver of one-carbon metabolism that is essential in T cells. The cellular consequences of its deprivation in CD8+ T cells and impact on anti-tumor function are unknown. Single cell RNA-seq analysis of primary central nervous system lymphoma (PCNSL) patients' tumor samples revealed exhaustion in T cells with high folate metabolism gene expression signature. Functional genomics, metabolite profiling, and glycomics identified disrupted cell surface glycosylation as a major consequence of folate deprivation in CD8+ T cells. Mechanistically, folate deprivation reduced nucleotide sugar levels, perturbed glycosylation, and triggered the apoptotic unfolded protein response. Overexpressing folate transporters in adoptively transferred CD8+ T cells increased intratumoral T cell numbers and reduced exhaustion. Therefore, our data draw a mechanistic line between one-carbon metabolism, cell-surface glycosylation, and anti-tumor T cell function, and support a hypothesis that increased folate uptake can enhance CD8+ T cell function including ex vivo and in vivo CAR-T cells.

cell biology↗

bioRxiv2026

Systemic hypoxia drives glycogen-fueled progression of lung adenocarcinoma

In advanced stages, lung adenocarcinoma obstructs airways and disrupts ventilation-perfusion relationships in the lung, causing systemic hypoxemia and enabling a feed-forward loop that accelerates malignancy. Systemic hypoxemia is also experienced due to common respiratory comorbidities such as chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), potentially accelerating malignancy. In a statewide electronic health record network, pre-existing COPD (598 matched pairs) or sleep apnea (235 matched pairs) independently predicted worse survival following incident lung cancer diagnosis. Since the mechanistic basis of the link between malignancy and hypoxia is not well understood, we created systemic hypoxia in KrasLSL-G12D/+;Trp53fl/fl (KP) mice by delivering low inspired oxygen concentrations (8% inspired oxygen; 8 h daily). Hypoxia nearly doubled tumor multiplicity and selectively remodeled cancer central carbon metabolism. Spatially resolved metabolomics revealed marked tumor-compartment glycogen accumulation, elevated tricarboxylic-acid cycle intermediates, and depleted glycolytic pools. Quantitative proteomics across cellular models and autochthonous tumors demonstrated that systemic hypoxia drives glycogen mobilization selectively through the lysosomal enzyme acid -glucosidase (GAA). Tumor-cell-autonomous deletion of GAA eliminated the hypoxia-driven growth advantage and disrupted downstream anabolic biosynthetic pathways. Thus, systemic hypoxia drives lung adenocarcinoma expansion by mobilizing lysosomal glycogen reserves through GAA to sustain proliferative growth.

cancer biology↗

bioRxiv2026

A multi-organ spatial metabolomic atlas of exercising mice reveals neuronal Complex I as a convergent and sufficient axis for tau pathology reduction in PS19

We constructed a spatially resolved metabolomic atlas of long-term exercise across six major organs in wild-type mice: brain, heart, lung, liver, kidney, and skeletal muscle, cataloguing 224 metabolic features and revealing coordinated inter-organ remodeling. Surprisingly, the brain showed particularly pronounced region-specific adaptation. Because pathological tau associates with synaptic mitochondria from early stages of tauopathy, we extended this multi-organ spatial metabolomic approach to PS19 mice and found that exercise reduced over 70% of observable tau pathology in PS19 hippocampus and restored the mitochondrial-related metabolome. Integrated proteomic and spatial metabolomic analyses identified NADH dehydrogenase Complex I as the convergent node. To test this finding biologically, we expressed the yeast NADH dehydrogenase, Ndi1, in PS19 neurons in the absence of exercise. This increased cerebral antioxidants, restored shuttle-linked metabolites, and reduced tau pathology. Increasing NADH dehydrogenase activity through NDI1 reproduces the core anti-tau and metabolic effects of exercise. These findings provide a molecular mechanism for how exercise may prevent or slow tau pathology accumulation, complementing the human-cohort literature linking exercise to delayed cognitive decline.

neuroscience↗

bioRxiv2026

Metabolic Coherence of the Mouse Brain

The brains metabolic demands are well established, but how metabolism is coordinated across anatomically distinct regions remains poorly understood. Here, using matrix-assisted laser desorption/ionization (MALDI) imaging integrated with the Allen Brain Atlas and optimal transport-based computational analysis, we map the spatial metabolome across twelve major mouse brain divisions. We define an optimal-transport-derived inter-regional metabolite similarity metric and refer to it as metabolic coherence. This structure is largely preserved in an amyloid mouse model of Alzheimers disease despite widespread changes in individual metabolite and lipid levels. Individual metabolites and lipids shift in a coordinated manner across regions, sustaining inter-regional relationships even as absolute levels change in patterns indicative of mitochondrial dysfunction. To test whether the coherence metric is responsive to local intervention, we targeted the left hippocampus of mice from this model via lentiviral shHIF1 knockdown or neuronal AAV-mediated AOX expression. Both interventions were associated with metabolite normalization at the injection site. More importantly, normalization extended across distal regions sharing high metabolic similarity with the hippocampus and was accompanied by improved social memory in a single behavioral assay. Gene modulation and amyloid plaque reduction localized to the injection site.

neuroscience↗

bioRxiv2026

Chronic Paraventricular OX1R Overexpression Induces Oxidative Stress and Hypertension in Rats

BackgroundHyperactivity of the orexin system has been implicated in hypertension, yet the long-term impact of orexin 1 receptor (OX1R) overexpression in the paraventricular nucleus (PVN), a key brain region involved in arterial blood pressure (ABP) regulation, remains unclear. This study examined whether chronic OX1R overexpression in the PVN alters cardiovascular, neuroendocrine, and oxidative functions. MethodsAdult male Sprague-Dawley rats received bilateral PVN injections of AAV2-OX1R or control virus AAV2-GFP. Their ABP and heart rate (HR) were monitored for eight weeks via radiotelemetry. Renal sympathetic nerve activity (RSNA) and ABP responses to PVN orexin A administration were assessed using in vivo recordings. Reactive oxygen species (ROS) were quantified using MitoProbe, and gene expression was analyzed by qPCR. Primary neuronal cultures were used to explore underlying mechanism involved in increased ROS production and neuronal activity. ResultsPVN OX1R overexpression increased mean ABP ([~]10 mmHg), water intake, and ROS levels in both the PVN and peripheral organs. In addition, orexin A evoked exaggerated RSNA (155% vs. 73%) and pressor responses (27 vs. 16 mmHg) in PVN OX1R overexpression rats compared to control rats, these effects were attenuated by the OX1R antagonist SB408124. Plasma vasopressin levels were elevated, and brain sections confirmed increased ROS in OX1R-positive neurons. In vitro experiments further demonstrated that orexin A upregulated ROS-generating enzymes, suppressed antioxidant genes, and enhanced neuronal excitability. ConclusionChronic PVN OX1R overexpression induces oxidative stress, sympathetic overactivity, and increased plasma vasopressin, contributing to hypertension development. Targeting PVN OX1R signaling may provide therapeutic benefit for hypertension.

physiology↗

bioRxiv2024

Prevalence and environmental abundance of the elusive membrane trafficking complex TSET in five cosmopolitan eukaryotic groups

Eukaryotic cell biology is largely understood from paradigms established on few model organisms, largely from the animal and fungi (opisthokonts) and to a lesser extent plants. These organisms, however, constitute only a small proportion of eukaryotic diversity, and the principles of their cell biology may not be universal to other, understudied but globally impactful, organisms. Intriguingly, there are cellular components that are present in diverse eukaryotes, but are not in the animals and fungi on which the best developed models of cell biology are derived. Consequently, these components are not included in the generally adopted frameworks of cellular function that are meant to explain eukaryotic biology. The membrane complex TSET is the best studied such example, well established to play a role in cell division and endocytosis in plants. It is found across eukaryotes, but is highly reduced in opisthokonts. Its general prevalence, abundance, and relevance in eukaryotic cellular activity is unclear. Here we show that TSET is encoded in genomes of five cosmopolitan and critical groups of primarily photosynthetic eukaryotes (green algae, red algae, stramenopiles, haptophytes and cryptophytes), with particular prevalence in the green algae and some stramenopile groups. A meta-analysis of published gene expression data from the model diatom Phaeodactylum tricornutum shows that this complex is coregulated with components of the endomembrane trafficking machinery. Moreover, meta-transcriptomic data from Tara Oceans reveals that TSET genes are both present and expressed by diatoms in the wild. These data suggest that TSET may be playing an important and underrecognized role in cellular activities within marine ecosystems. More broadly, the results support the idea that use of systems-level data for non-model organisms can illuminate our understanding of core principles of eukaryotic cell function, and may reveal important and under-appreciated players that deserve to be integrated into the pervasive models of cellular capacity.

microbiology↗

bioRxiv2020

A versatile toolkit for CRISPR-Cas13-based RNA manipulation in Drosophila

Advances in CRISPR technology have immensely improved our ability to manipulate nucleic acids, and the recent discovery of the RNA-targeting endonuclease Cas13 adds even further functionality. Here, we show that Cas13 works efficiently in Drosophila, both ex vivo and in vivo. We tested 44 different Cas13 variants to identify enzymes with the best overall performance and showed that Cas13 could target endogenous Drosophila transcripts in vivo with high efficiency and specificity. We also developed Cas13 applications to edit mRNAs and target mitochondrial transcripts. Our vector collection represents a versatile tool collection to manipulate gene expression at the post-transcriptional level.

molecular biology↗

bioRxiv2020

Production of the Short Chain Fatty Acid, Acetic Acid/Acetate from Ethanol Metabolism Activates NMDAR

Binge alcohol consumption elicits robust sympathoexcitation and excitatory neuronal output. However, the central mechanism that mediates these effects remains elusive. We investigated the effects of ethanol metabolism within the central nucleus of the amygdala (CeA) on sympathoexcitation, and elucidated the role of acetate in these excitatory responses. In vivo arterial blood pressure, heart rate and sympathetic nerve activity responses to CeA microinjected ethanol or acetate with appropriate inhibitors/antagonists were tracked. In vitro whole-cell electrophysiology recording responses to acetate in CeA neurons with axon projecting to the rostral ventrolateral medulla (CeA-RVLM) were investigated, and cytosolic calcium responses in primary neuronal cultures were quantified. We demonstrate that in Sprague Dawley rats, local brain metabolism of ethanol in the CeA to acetic acid/acetate elicits sympathoexcitatory responses in vivo through activation of NMDA receptor (NMDAR). Alcohol dehydrogenase or aldehyde dehydrogenase inhibition using fomepizole or cyanamide and NMDAR antagonism using AP5 or memantine blunted these effects. Whole-cell patch-clamp recordings in brain slices containing autonomic CeA-RVLM neurons revealed a dose-dependent increase in neuronal excitability in response to acetate. NMDAR antagonists suppressed the acetate-induced increase in CeA-RVLM neuronal excitability, and memantine suppressed the direct activation of NMDAR-mediated inward currents by acetate in brain slices. We observed that acetate increased cytosolic Ca2+ in a time-dependent manner in primary neuronal cell cultures. The acetate enhancement of calcium signaling was abolished by memantine. These findings suggest that within the CeA, ethanol is sympathoexcitatory through local brain metabolism, which generates acetic acid/acetate leading to activation of NMDAR. NEW AND NOTEWORTHYBrain ethanol metabolism to acetic acid (vinegar)/acetate causes activation of N-methyl-D-aspartate receptors (NMDARs) in the central nucleus of the amygdala and elicits sympathoexcitatory responses. This excitatory mechanism is opposite to the inhibitory effects of ethanol at NMDAR. Understanding the active compounds that arise from ethanol metabolism, and the molecular mechanisms by which they influence alcohol reward and cardiovascular function, may be beneficial in developing targeted intervention strategies for both alcohol use disorder and its cardiovascular sequelae. Graphical Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/212597v4_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@18d8ec9org.highwire.dtl.DTLVardef@996b70org.highwire.dtl.DTLVardef@5cbecaorg.highwire.dtl.DTLVardef@f1cd4b_HPS_FORMAT_FIGEXP M_FIG Proposed mechanisms for ethanol and acetate induced increases in sympathoexcitation within the central nucleus of the amygdala (CeA). Abbreviations: Acetic acid (HOAc), acetate (-OAc), ADH (alcohol dehydrogenase), ALDH (aldehyde dehydrogenase), BBB (blood brain barrier), FOM (fomepizole), CYAN (cyanamide), CYP450 (cytochrome P450), IML (intermediolateral nucleus), RVLM (rostral ventrolateral medulla), SNA (sympathetic nerve activity). C_FIG

physiology↗

bioRxiv2020

Mapping Spatially Distributed Material Properties in Finite Element Models of Plant Tissue Using Computed Tomography

Plant tissues are often heterogeneous. To accurately investigate these tissues, we will need methods to spatially map these tissue stiffness values onto finite element models. The purpose of this research is to develop a method for using specimen-specific computed tomography data to inform the spatial mapping of Youngs modulus values on finite element models. The spatial mapping of Youngs modulus was calculated and then used to predict the response of specimen tests. Results indicated that this method can be used to obtain spatial distributions of material properties, thus enabling finite element models that account for material heterogeneity.

bioengineering↗

bioRxiv2019

Maize Stem Buckling Failure is Dominated by Morphological Factors

The maize (Zea mays) stem is a biological structure that must both balance biotic and structural load bearing duties. These competing requirements are particularly relevant in the design of new bioenergy crops. With the right balance between structural and biological activities, it may be possible to design crops that are high-yielding and have digestible biomass. But increased stem digestibility is typically associated with a lower structural strength and higher propensity for lodging. This study investigates the hypothesis that geometric factors are much more influential in determining structural strength than tissue properties. To study these influences, both physical and in silico experiments were used. First, maize stems were tested in three-point bending. Specimen-specific finite element models were created based on x-ray computed tomography scans. Models were validated by comparison with in vitro data. As hypothesized, geometry was found to have a much stronger influence on structural stability than material properties. This information reinforces the notion that deficiencies in tissue strength could be offset by manipulation of stalk morphology, thus allowing the creation of stalks with are both resilient and digestible. HighlightThis study utilized physical and in silico experiments to confirm that geometric parameters are far more influential in determining stalk strength than mechanical tissue stiffnesses.

bioengineering↗

bioRxiv2018

Prenatal exposure to household air pollution and adverse birth outcomes among newborns in Sri Lanka

BackgroundAbout 74% of the Sri Lankan population use biomass in the form of unprocessed wood as the primary cooking fuel. A growing body of evidence from meta-analyses and individual studies although limited by few prospective studies, report that prenatal exposure to particulate matter of size 2.5 {micro}m (PM2.5) emissions from biomass fuel burning may be associated with low birth weight (LBW) (<2500 grams). We present results examining the association between PM2.5 and LBW in context of a birth cohort study in Sri Lanka. MethodsWe followed 545 pregnant women from their first trimester until delivery and assessed outcomes at birth. Exposure to household air pollution (HAP) from biomass smoke was assessed using detailed questionnaire about fuel type, kitchen characteristics and cooking practices; two-hour measurements of kitchen PM2.5 were collected in a subset of households (n=304, 56%). Data from questionnaires and measured PM2.5 were used to estimate two-hour kitchen PM2.5 concentrations in unmeasured households. Data on covariates related to household characteristics, socio-demographic, maternal health and lifestyle factors were collected from baseline interviews. We performed linear and logistic regression analysis to evaluate the association between HAP exposure, and birth weight and LBW. ResultsOf the total, 78% of the households used wood as primary or secondary fuel (n=425); households using wood had four-fold higher PM2.5 levels compared to those using LPG. In linear regression models, we found an inverse association between a 10-unit increase in PM2.5 and birth weight ({beta},-0.03; SE, 0.02; p, 0.06) adjusted for covariates. Similarly, categorical HAP exposure (>50% wood use) was significantly associated with birth weight as compared to LPG users ({beta}, -0.13; SE, 0.06; p, 0.0331). In logistic regression models, a 10-unit increase in PM2.5 was associated with increased odds for LBW (OR, 1.26; 95%CI, 1.02-1.55; p, 0.0355), while the prevalence of LBW was highest among >50% wood users (OR, 2.82; 95%CI, 1.18-6.73; p, 0.0124), as compared to those using >50% LPG with wood and only LPG users. The association between HAP exposure and birth weight/LBW were consistent among term births (n=486). ConclusionsThe finding of a significant association between prenatal PM2.5 exposure and LBW in a low-middle income country (LMIC) setting where competing risk factors are minimal fills a gap in the body of evidence linking HAP from biomass smoke to LBW. These results underscore the crucial need to implement prevention and reduction of HAP exposure in LMICs where the HAP burden is high.

epidemiology↗

bioRxiv2018

Particulate Matter fractions and kitchen characteristics in Sri Lankan households using solid fuel and LPG

IntroductionUse of solid fuel for cooking is a major source of household air pollution in developing countries. Of the many pollutants emitted during solid fuel combustion, Particulate Matter (PM)is considered to be one of the most hazardous pollutants. We monitored PM fractions emitted during solid fuel and Liquefied Petroleum Gas(LPG) combustion in kitchens of Sri Lankan households.\n\nMethodsHouseholds of children in a longitudinal study in Ragama, Sri Lanka was the study population. At the age of 36 months of children, a sample of households were visited and different aerodynamic diameters of PM (PM1, PM2.5, PM10) were monitored during the main cooking session for 3 hours. Basic characteristics of kitchen (e.g., availability of chimney, functionality of chimney, etc.) were assessed by a questionnaire. Cooking energy, other sources of household air pollution, size of open spaces in the kitchen (e.g., windows), etc. were assessed at the time of PM monitoring.\n\nResultsQuestionnaire was administered for mothers in 426 households. Out of them, 245 (57.5%)and 116 (27.2%) households used LPG and wood as the primary cooking fuel respectively. During the cooking period, PM2.5 concentrations of households uses only wood fuel and cook inside the main housing building were 344.1 g/m3(Inter Quartile Range(IQR) = 173.2-878.0g/m3), 88.7 g/m3(54.8- 179.2 g/m3); 91.7 g/m3 (56.0- 184.9 g/m3) and 115.1 g/m3(83.4 - 247.9 g/m3) in kitchen, sleeping room, living room and immediate outdoor respectively. Immediate outdoor PM2.5 concentrations in wood burning households was higher among households not having chimney (n = 8)compare to those having a chimney (n = 8) (245.9g/m3 (IQR = 72.5 - 641.7g/m3)) VS. (105.7g/m3 (83.4- 195.8g/m3)).Fuel type and stove type, availability of a chimney and their functional status, ratio between open space and total space of kitchen, PM2.5 concentration at the non-cooking time (i.e., baseline PM2.5concentration) were the determinants of PM2.5 in wood using kitchens during cooking period.\n\nConclusionsPM concentrations were higher in kitchen and other microenvironments of the households use wood for cooking as compared to LPG use for cooking. Immediate outdoor PM concentration was higher than the sleeping and living room PM concentrations. Several factors determine the PM2.5concentrationsduring the cooking including the fuel type.

epidemiology↗