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Quinn, K.

Publications and source records attributed to Quinn, K..

At least 19 recordsLinked to original sources

Scalable high-density tactile arenas for measuring ground-contact forces in freely moving animals

Understanding how animals physically interact with their environment is fundamental to studying movement, sensorimotor control, and neurological function. Yet most behavioral measurement systems primarily capture movement and posture, while direct measurements of contact forces often require specialized instrumentation or involve trade-offs among spatial coverage, resolution, and acquisition speed. Here, we introduce a scalable tactile sensing platform that transforms the surface beneath freely moving animals into a high-resolution contact-imaging instrument. By combining modular sensor arrays with adaptive compressive tactile sampling, the platform provides 16,384 tactile sensing elements at 2-mm pitch across a 512 x 128-mm runway, with nominal 1 kHz acquisition. Rather than exhaustively scanning the entire array, the system concentrates measurements around active contacts, enabling high-speed sensing across an extended behavioral surface. Synchronized overhead video and a camera-assisted analysis pipeline enable paw-resolved measurements of contact loading, stance dynamics, footprint morphology, interlimb weight redistribution, and center-of-pressure trajectories. In a longitudinal rat model of sciatic nerve injury, the platform detected reduced loading of the injured hindlimb and increased loading of the contralateral limb, including changes that conventional gait timing measures underestimated. The modular architecture, together with openly available hardware designs, software and data, provides an accessible framework for studying the mechanical interactions underlying freely moving behavior, with potential applications across neuroscience, injury, and motor recovery research.

bioengineering↗

D-Methionine Improves Spatial Navigation and Attenuates Oxidative Stress and Amyloid Pathology in a Sex-Specific Manner

BackgroundOxidative stress and maladaptive neuroimmune activation contribute to cognitive decline in Alzheimers disease (AD) and represent therapeutic targets beyond amyloid-centered approaches. ObjectiveTo determine whether oral D-methionine (D-Met), a redox-active amino acid, reduces amyloid pathology and lipid peroxidation and confers disease-modifying benefits in AD mouse models. MethodsMale and female APP/PS1 and APPNL-F mice with advanced AD pathology received oral D-Met or vehicle. Behavioral assessments included locomotor activity and hippocampal-dependent spatial learning and memory. Amyloid burden, lipid peroxidation, peripheral metabolic and inflammatory markers, and hippocampal microglial phenotypes were evaluated using biochemical and histological analyses. ResultsD-Met did not alter locomotor or exploratory behavior but improved spatial memory recall in both sexes of APP/PS1 mice and in female APPNL-F mice. APPNL-F males exhibited improved learning during Morris water maze (MWM) acquisition. Amyloid pathology was modestly and region-specifically reduced, including decreased hippocampal plaque size in male APPNL-F mice, reduced cortical plaque size in female APP/PS1 mice, and lower soluble amyloid-{beta} (A{beta})42 in male APP/PS1 mice. Lipid peroxidation, assessed by malondialdehyde, was reduced only in female APPNL-F mice. D-Met induced pronounced sex-dependent peripheral effects, increasing adiposity and pro-inflammatory adipose signaling in males, while reducing perigonadal white adipose tissue (pgWAT) IL-6 expression in female APPNL-F mice. In the hippocampus, D-Met remodeled microglial signatures, with female APPNL-F mice showing reduced Iba1 and disease-associated microglial (DAM) markers and increased Axl expression. ConclusionShort-term D-Met acts as a metabolic and redox modulator with modest amyloid-lowering effects mediated by improved microglial function. Therapeutic efficacy is strongly sex- and model-dependent, with the greatest benefit observed in female APPNL-F mice.

neuroscience↗

Characterizing the role of mitochondrial dynamics during Drosophila convergent extension using NADH fluorescence lifetime imaging

Mitochondria are dynamic organelles that can fragment or fuse to support different bioenergetic demands (e.g., glycolysis vs. oxidative phosphorylation) and distinct cell behaviors (e.g., mitosis or migration). While the role of mitochondrial dynamics in wound healing and metabolic disorders has received significant attention, the role of mitochondrial fission and fusion during normal embryonic development is less well understood--in part due to the difficulty of studying such processes in vivo. Combined with the depth-resolved imaging capabilities of multiphoton microscopy, fluorescence lifetime imaging (FLIM) of the mitochondrial cofactor NADH can be used to simultaneously visualize mitochondrial network morphology and infer certain aspects of cellular bioenergetics (e.g., glycolysis vs. oxidative phosphorylation) in a label-free, non-invasive manner. Here we demonstrate that NADH FLIM can be used to accurately track the subcellular localization and topology of mitochondrial networks in live Drosophila embryos. We used this technique to assess whether cells show changes in NADH lifetime during convergent extension (CE)--a conserved process of tissue remodeling in which thousands of germband cells undergo coordinated intercalation to drive elongation of the head-to-tail axis. Contrary to our expectations, we did not observe significant changes in NADH lifetime or network appearance during CE in wild-type embryos, suggesting that germband cells do not need to alter their baseline metabolism to fuel cell intercalation during normal development. To directly assess the role of mitochondrial fission and fusion during CE, we used RNA interference to disrupt the fission mediator Drp1 and the fusion mediator Opa1. Consistent with expectations, inhibiting mitochondrial fission in Drp1-knockdown embryos led to hyper-fused networks and significantly longer NADH lifetimes, indicating a shift towards oxidative phosphorylation. Conversely, inhibiting mitochondrial fusion in Opa1-knockdown embryos led to more hyper-fragmented networks and significantly shorter NADH lifetimes, indicating a shift towards glycolysis. Interestingly, inhibiting either fission or fusion altered tissue elongation and greatly increased the rate of cell intercalation errors, suggesting that a precise network topology is required for proper CE. We hypothesize that the CE defects in Drp1-knockdown embryos are primarily due to incorrect basal subcellular localization of mitochondria, whereas the CE defects in Opa1-knockdown embryos are due to deficient ATP and/or ROS production. These experiments demonstrate the utility of FLIM-based applications for characterizing the role of mitochondria during normal embryonic development, which could yield a better understanding of the metabolic underpinnings of various pathologies that involve epithelial remodeling, including spina bifida, defective wound healing, and cancer metastasis.

developmental biology↗

Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons

The end-stage pathology of Parkinsons disease (PD) involves the loss of dopamine-producing neurons in the substantia nigra pars compacta (SNc). However, synaptic deregulation of these neurons begins much earlier. Understanding the mechanisms behind synaptic deficits is crucial for early therapeutic intervention, yet these remain largely unknown. In the SNc, different dopamine neuron subtypes show varying susceptibility patterns to PD, complicating our understanding. This study uses intersectional genetic mouse models to uncover synaptic perturbations in vulnerable dopamine neurons, focusing on the LRRK2 kinase, a protein closely linked to PD. Through a combination of immunofluorescence and advanced proximity labeling methods, we found higher LRRK2 expression in the most vulnerable dopamine neuron subclusters. High-resolution imaging revealed that pathogenic LRRK2 disrupts release sites in vulnerable dopamine axons, leading to decreased in vivo spontaneous and evoked striatal dopamine release in mice with LRRK2 mutations. Proteomic and biochemical analyses indicate that mutant LRRK2 increases the phosphorylation of RAB3 proteins, reducing their interactions with RIM1and RIM2 effector proteins and impacting their synaptic functions. Overall, this research highlights the cell-autonomous dysfunctions caused by mutant LRRK2 in neurons, which are primarily affected by the disease. It also provides a framework for future therapeutic strategies for early nigrostriatal synaptic deficits in PD.

neuroscience↗

Surgical Removal of Visceral Adipose Tissue has Therapeutic Benefit in Male APPNL-F Mice

PurposeVisceral white adipose tissue (vWAT) accumulation causes systemic inflammation, insulin resistance, metabolic syndrome, and senescent cell accumulation that are risk factors for Alzheimers disease (AD). Visceral fat removal (VFR) improves metabolism and reduces pro-inflammatory cytokines. We hypothesized that VFR removal in AD mice would improve metabolism and cognition. MethodsMale and female APPNL-F mice underwent sham or vWAT surgical resection (periovarian or epididymal and perirenal) at 4 (pre-symptomatic) and 16 (symptomatic) months of age to understand interventional and therapeutic effects, respectively. At 18 months of age, glucose metabolism and novel object recognition (NOR) memory were assayed followed by assessment of body composition and tissue-specific markers of metabolism, cell senescence, inflammation, or amyloid accumulation. ResultsMale and female APPNL-F mice showed distinct VFR responses. In pre-symptomatic males, increased vWAT lipolysis and hepatic lipogenesis led to ectopic liver lipid accumulation, with reduced adiponectin and leptin, elevated visfatin, and impaired glucose metabolism. Symptomatic males showed reduced vWAT lipogenesis, enhanced hepatic lipolysis, glycolysis, and glycogenesis, lowering liver lipids and improving insulin sensitivity. Only symptomatic males improved NOR, linked to elevated hippocampal learning and memory markers. Female vWAT reaccumulation was due to increased lipogenesis and lower lipolysis. Pre-symptomatic females had lower hepatic lipogenesis, while glycolysis and glycogenesis declined with disease progression. Hippocampal senescence and inflammation were elevated early in the disease that persisted symptomatically. ConclusionsSex-specific differences in glucose and lipid metabolism and lipid accumulation underlie the divergent responses to VFR in APPNL-F mice, with symptomatic males showing the only beneficial outcomes in metabolism and cognition. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/669175v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@6ec644org.highwire.dtl.DTLVardef@9ad821org.highwire.dtl.DTLVardef@1e37775org.highwire.dtl.DTLVardef@b7a558_HPS_FORMAT_FIGEXP M_FIG C_FIG Male and female APPNL-F mice exhibited distinct VFR responses to AD progression. In males, early disease stages were marked by vWAT lipolysis and hepatic lipid accumulation with metabolic dysfunction, while symptomatic stages showed a metabolic shift that improved insulin sensitivity and NOR performance. In contrast, females displayed progressive vWAT reaccumulation, reduced hepatic metabolism, and persistent hippocampal senescence and inflammation from early stages onward.

neuroscience↗

Lifespan of male and female APP/PS1 and APPNL-F/NL-F mouse models of Alzheimer's disease

Alzheimers disease (AD) disproportionately affects women, yet most preclinical research studies are male-centric. We performed lifespan analyses of male and female AD mouse models (APP/PS1 and APPNL-F/NL-F) and their shared genetic background control (C57BL/6). Survival curves support significant sex differences between within genotypes. Minimal longevity revealed increased age in male APP/PS1, and decreased age in APPNL-F/NL-F mice. Maximal longevity revealed an increased average age in males. Furthermore, median lifespan differed between sex and genotype. This study supports sexual dimorphic survival in two mouse models of AD, emphasizing the need to examine mechanisms and treatments in both sexes.

physiology↗

Targeting an Olfactory Receptor Mitigates High Residual Platelet Reactivity and Arterial Thrombosis Through Actin Cytoskeleton Depolymerization

BackgroundDespite antiplatelet therapy, some patients remain at high risk for ischemic events due to medication non-responsiveness or High Residual Platelet Reactivity (HRPR). Our goal was to target an orphan G-Protein-Coupled Receptor (GPCR) on platelets belonging to the olfactory receptor family as a new antithrombotic strategy. MethodsUsing an engineered reporter cell line expressing Olfactory Receptor 2L13 (OR2L13) that was recently identified as an orphan GPCR to limit platelet reactivity, we performed a high-throughput screen (HST) of non-odorant bioactive compounds with counter-screen validation, followed by studies to determine changes in platelet function in healthy subjects and in patients with coronary artery disease and peripheral artery disease. Phospho-proteomics identified key signal transduction pathways, and a variety of ex vivo assays and in vivo functional studies examined the impact of an identified non-odorant compound on platelet signaling, platelet biomechanics, and thrombosis. ResultsWe identified 6 ligands specific for OR2L13 that function as receptor agonists, leading to the suppression of platelet aggregation and -granule exocytosis via P2Y12, PAR1, Thromboxane Receptor (TxR) and glycoprotein VI (GPVI) receptors, suggesting involvement of common downstream mediator. The lead OR2L13 agonist identified phosphorylates heat shock protein 27 (HSP27) and depolymerizes the platelet filamentous actin cytoskeleton which was further confirmed in a clot retraction assay (CCF0054500 clot area 70.6 vs. vehicle clot area 5.2, P<0.0001). This anti-thrombotic effect of the OR2L13 agonist was reversed by a HSP27 inhibitor (clot area 3.6, P<0.0001). In a murine cremaster arterial injury model, platelet accumulation at the injury site was reduced by 88.9% by the lead OR2L13 agonist compared to vehicle (P<0.0003) without altering fibrin generation in vivo, or interfering with the coagulation cascade, and without impairing the protective mechanism of platelet hemostasis. ConclusionWe describe and characterize the first non-olfactory tool to target an olfactory receptor for the purpose of inhibiting platelet activation and thrombosis through downstream HSP27 in a comprehensive investigation using a first-of-its kind platelet inhibitor targeting an orphan platelet GPCR.

physiology↗

PTPN11 Mutation Clonal Hierarchy in Acute Myeloid Leukemia

Mutations in protein tyrosine phosphatase non-receptor type 11 (PTPN11) have been considered late acquired mutations in acute myeloid leukemia (AML) development. To interrogate the ontogeny of PTPN11 mutations, we utilized single-cell DNA sequencing and identified that PTPN11 mutations can occur as initiating events in some AML patients when accompanied by strong oncogenic drivers, commonly NPM1 mutations. The co-driver role of PTPN11 mutations was confirmed in a novel murine model that exhibits an AML phenotype with early expansion of a diverse set of variably differentiated myeloid cells that engrafted into immunodeficient and immunocompetent mice. This immune diversity was reconstituted from early precursor cells when engrafted into immunodeficient mice. Moreover, immune diversity was also observed in the blast component of patient samples with NPM1 and PTPN11 mutations, providing novel antigen targets for immune based approaches in this subset of AML that is resistant to multiple targeted therapies.

cancer biology↗

Thermotherapy has Sexually Dimorphic Responses in APP/PS1 Mice

A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimers disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30{degrees}C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30{degrees}C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-{beta} (A{beta})42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy, but future studies are needed to determine therapeutic benefits for those with AD.

neuroscience↗

Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APPNL-F/NL-F Mice.

Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimers disease (AD). The APPNL-F/NL-F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APPNL-F/NL-F mice. Thus, four month old male and female APPNL-F/NL-F mice were treated monthly with vehicle, 5 mg/kg Dasatinib + 50 mg/kg Quercetin, or 100 mg/kg Fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + Quercetin treatment in female APPNL-F/NL-F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-{beta} (A{beta})42 and senescence associated-{beta}-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APPNL-F/NL-F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.

neuroscience↗

Altered Hippocampal Glutamatergic Neurotransmission and Cognitive Impairment in APP Knock-In Mice

BackgroundIt is well established that glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies indicate that glutamate dynamics shift with Alzheimers disease (AD) progression, contributing to negative cognitive outcomes. ObjectiveIn this study, we characterized hippocampal glutamatergic signaling with age and disease progression in a knock-in mouse model of AD (APPNL-F/NL-F). MethodsAt 2-4 and 18+ months old, male and female APPNL/NL, APPNL-F/NL-F, and C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR). Then, basal and 70 mM KCl stimulus-evoked glutamate release was measured in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus using a glutamate-selective microelectrode in anesthetized mice. ResultsGlutamate recordings support elevated stimulus-evoked glutamate release in the DG and CA3 of young APPNL-F/NL-F male mice that declined with age compared to age-matched control mice. Young female APPNL-F/NL-F mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APPNL-F/NL-F mice exhibited decreased CA1 basal glutamate levels, while males also showed depletion in the CA3. Cognitive assessment demonstrated impaired spatial cognition in aged male and female APPNL-F/NL-F mice, but only aged females displayed recognition memory deficits compared to age-matched control mice. ConclusionsThese findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APPNL-F/NL-F mice. Further, data illustrate a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL-F/NL-F mice than their male counterparts. Research outcomes mirror that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes.

neuroscience↗

Myomatrix arrays for high-definition muscle recording

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous systems actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ("Myomatrix arrays") that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a "motor unit", during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous systems motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and in identifying pathologies of the motor system.

neuroscience↗

Regulation of ATAD2B bromodomain binding activity by the histone code

The ATPase family AAA+ domain containing 2 (ATAD2) protein, and its paralog ATAD2B, have a C-terminal bromodomain that functions as a reader of acetylated lysine residues on histone proteins. Using a structure-function approach, we investigated the ability of the ATAD2 and ATAD2B bromodomains to select acetylated lysine among multiple histone post-translational modifications. Isothermal titration calorimetry experiments revealed that the ATAD2 and ATAD2B bromodomains selectively recognize distinct patterns of acetylated lysine residues on the N-terminal tails of histone proteins. Adjacent methylation or phosphorylation marks were found to either enhance or weaken the recognition of acetylated lysine by the ATAD2/B bromodomains. Complementary structural studies provide mechanistic insights into how residues within the bromodomain binding pocket coordinate the acetyllysine group in the context of adjacent post- translational modifications. Furthermore, we investigated how sequence changes in amino acids of the histone ligands, either as onco mutations or as histone variants, impact the recognition of an adjacent acetylated lysine residue. In summary, our study highlights how the interplay between multiple combinations of histone modifications influences the reader activity of the ATAD2 and ATAD2B bromodomains, resulting in distinct binding modes of the two bromodomains. KEY POINTSO_LIMultiple independent ATAD2 gene duplication events are evident during metazoan evolution, indicating expansion of functionality in the ATAD2 gene family and suggesting distinct functions for ATAD2 and ATAD2B. C_LIO_LIHigh-resolution structures of the ATAD2 and ATAD2B bromodomains in complex with their histone ligands demonstrate how multiple post-translational modifications are coordinated. C_LIO_LIRecognition of different subsets acetylated histone ligands by the ATAD2 and ATAD2B bromodomains is driven by unique features within the binding pockets of these paralogous proteins. C_LIO_LIOnco-histone mutations and histone variants that change the amino acid sequence of the histone tails modulate the ATAD2 and ATAD2B bromodomain activity. C_LIO_LIThis study demonstrates how the combinatorial activity of multiple post- translational modifications forms a histone code and influences the recognition of acetylated lysine by bromodomain-containing proteins. C_LI

biochemistry↗

Sexual dimorphic responses of C57BL/6 mice to Fisetin or Dasatinib and Quercetin cocktail oral treatment

Senolytic treatment in aged mice clears senescent cell burden leading to functional improvements. However, less is known regarding the effects of these compounds when administered prior to significant senescent cell accumulation. From 4-13 months of age, C57BL/6 male and female mice received monthly oral dosing of either 100 mg/kg Fisetin or a 5 mg/kg Dasatinib (D) plus 50 mg/kg Quercetin (Q) cocktail. During treatment, several aspects of healthy aging were assayed including glucose metabolism using an insulin and glucose tolerance test, cognitive performance using Morris water maze and novel object recognition, and energy metabolism using indirect calorimetry. Afterwards, mice were euthanized for plasma and tissue specific markers of senescence-associated secretory phenotype (SASP) and white adipose tissue accumulation (WAT). Sexually dimorphic treatment effects were observed. Fisetin treated male mice had reduced SASP, enhanced glucose and energy metabolism, improved cognitive performance, and increased mRNA expression of adiponectin receptor 1 and glucose transporter 4. D+Q treatment had minimal effects in male C57BL/6 mice, but was detrimental to females causing increased SASP expression along with accumulation of WAT depots. Reduced energy metabolism and cognitive performance were also noted. Fisetin treatment had no effect in female C57BL/6 mice potentially due to a slower rate of biological aging. In summary, the senolytic treatment in young adulthood, has beneficial, negligible, or detrimental effects in C57BL/6 mice dependent upon sex and treatment. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation. Graphical AbstractMale and female C57BL/6 mice were treated with once monthly oral doses of either Dasatinib (D) + Quercetin (Q) or Fisetin from 4-13 months of age. Females treated with D+Q had increased adiposity and SASP markers (red spheres) along with decreased metabolism (blue flame) and cognitive performance. Males treated with Fisetin had reduced SASP markers (blue spheres) as well as improved metabolism (red flame) and cognition. No effects were observed in females treated with Fisetin or males treated with D+Q. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/467509v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1d7f450org.highwire.dtl.DTLVardef@e8b32forg.highwire.dtl.DTLVardef@14be597org.highwire.dtl.DTLVardef@1ce31af_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

Systems analysis of gut microbiome influence on metabolic disease in HIV and high-risk populations

Poor metabolic health, characterized by insulin resistance and dyslipidemia, is higher in people living with HIV and has been linked with inflammation, anti-retroviral therapy (ART) drugs, and ART-associated lipodystrophy (LD). Metabolic disease is associated with gut microbiome composition outside the context of HIV but has not been deeply explored in HIV infection nor in high-risk men who have sex with men (HR-MSM), who have a highly altered gut microbiome composition. Furthermore, the contribution of increased bacterial translocation and associated systemic inflammation that has been described in HIV-positive and HR-MSM individuals has not been explored. We used a multi-omic approach to explore relationships between impaired metabolic health, defined using fasting blood markers, gut microbes, immune phenotypes and diet. Our cohort included ART-treated HIV positive MSM with and without LD, untreated HIV positive MSM, and HR-MSM. For HIV positive MSM on ART, we further explored associations with the plasma metabolome. We found that elevated plasma lipopolysaccharide binding protein (LBP) was the most important predictor of impaired metabolic health and network analysis showed that LBP formed a hub joining correlated microbial and immune predictors of metabolic disease. Taken together, our results suggest the role of inflammatory processes linked with bacterial translocation and interaction with the gut microbiome in metabolic disease among HIV positive and negative MSM. Importance StatementThe gut microbiome in people living with HIV (PLWH) is of interest as chronic infection often results in long term comorbidities. Metabolic disease is prevalent in PLWH even in well-controlled infection and has been linked with the gut microbiome in previous studies, but little attention has been given to PLWH. Furthermore, integrated analyses that consider gut microbiome together with diet, systemic immune activation, metabolites, and demographics have been lacking. In a systems-level analysis of predictors of metabolic disease in PLWH and men who are at high risk of acquiring HIV, we found that increased LBP, an inflammatory marker indicative of compromised intestinal barrier function, was associated with worse metabolic health. We also found impaired metabolic health associated with specific dietary components, gut microbes, and host and microbial metabolites. This work lays the framework for mechanistic studies aimed at targeting the microbiome to prevent or treat metabolic endotoxemia in HIV-infected individuals.

microbiology↗

Targeting the resolvin E1 - eicosapentaenoic acid axis improves hyperinsulinemia and hyperglycemia in a host genetic dependent manner

ObjectiveEicosapentaenoic acid (EPA) has recently garnered strong attention given the success of the REDUCE-IT trial, which overturned previous conclusions on EPA and led to its FDA approval for lowering cardiovascular disease risk. Therefore, there is a need to study EPA for cardiometabolic risk factors. Here we focused on EPAs preventative role on hyperglycemia and hyperinsulinemia. MethodsC57BL/6J male mice were fed a high fat diet in the absence or presence of pure EPA. Mass spectrometry was used to identify how EPA prevents hyperinsulinemia and hyperglycemia that drove subsequent experiments with resolvin E1 (RvE1) across inbred and outbred models. ResultsAdministration of EPA to C57BL/6J mice prevented obesity-induced glucose intolerance, hyperinsulinemia, and hyperglycemia. Supporting analyses of National Health and Nutrition Examination Survey data showed fasting glucose levels of obese adults were inversely related to EPA intake in a sex-specific manner. We next investigated how EPA improved murine hyperinsulinemia and hyperglycemia. Mass spectrometry revealed EPA overturned the obesity-driven decrement in the concentration of 18-hydroxyeicosapentaenoic acid (18-HEPE) in white adipose tissue and liver. Treatment of obese mice with RvE1, the immunoresolvant metabolite of 18-HEPE, reversed hyperinsulinemia and hyperglycemia through the G-protein coupled receptor ERV1/ChemR23. RvE1s effects were not mediated by macrophage enrichment in white adipose tissue. Finally, we determined if the metabolic effects of RvE1 were dependent on host genetics. RvE1s effects on hyperinsulinemia and hyperglycemia were divergent in diversity outbred mice that model human genetic variation. Secondary SNP analyses further revealed extensive genetic variation in human RvE1- and EPA- metabolizing genes. ConclusionsThe data suggest EPA prevents hyperinsulinemia and hyperglycemia through the endogenous bioactive metabolite RvE1 that activates ERV1/ChemR23. Importantly, the studies reveal host genetics are an overlooked but critical factor in the metabolic response to RvE1. These results underscore the need for personalized administration of EPA-derived RvE1 based on genetic/metabolic enzyme profiles.

biochemistry↗

Citizen-Centered, Auditable, and Privacy-Preserving Population Genomics

The growing number of health-data breaches, the use of genomic databases for law enforcement purposes and the lack of transparency of personal-genomics companies are raising unprecedented privacy concerns. To enable a secure exploration of genomic datasets with controlled and transparent data access, we propose a novel approach that combines cryptographic privacy-preserving technologies, such as homomorphic encryption and secure multi-party computation, with the auditability of blockchains. This approach provides strong security guarantees against realistic threat models by empowering individual citizens to decide who can query and access their genomic data and by ensuring end-to-end data confidentiality. Our open-source implementation supports queries on the encrypted genomic data of hundreds of thousands of individuals, with minimal overhead. Our work opens a path towards multi-functional, privacy-preserving genomic-data analysis.\n\nOne Sentence SummaryA citizen-centered open-source response to the privacy concerns that hinder population genomics, based on modern cryptography.

genomics↗

Circuit-Specific Early Impairment of Proprioceptive Sensory Neurons in the SOD1G93A Mouse Model for ALS

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which motor neurons degenerate resulting in muscle atrophy, paralysis and fatality. Studies using mouse models of ALS indicate a protracted period of disease development with progressive motor neuron pathology, evident as early as embryonic and postnatal stages. Key missing information includes concomitant alterations in the sensorimotor circuit essential for normal development and function of the neuromuscular system. Leveraging unique brainstem circuitry, we show in vitro evidence for reflex circuit-specific postnatal abnormalities in the jaw proprioceptive sensory neurons in the well-studied SOD1G93A mouse. These include impaired and arrhythmic action potential burst discharge associated with a deficit in Nav1.6 Na+ channels. However, the mechanoreceptive and nociceptive trigeminal ganglion neurons and the visual sensory retinal ganglion neurons were resistant to excitability changes in age matched SOD1G93A mice. Computational modeling of the observed disruption in sensory patterns predicted asynchronous self-sustained motor neuron discharge suggestive of imminent reflexive defects such as muscle fasciculations in ALS. These results demonstrate a novel reflex circuit-specific proprioceptive sensory abnormality in ALS.\n\nSignificance StatementNeurodegenerative diseases have prolonged periods of disease development and progression. Identifying early markers of vulnerability can therefore help devise better diagnostic and treatment strategies. In this study, we examined postnatal abnormalities in the electrical excitability of muscle spindle afferent proprioceptive neurons in the well-studied SOD1G93A mouse model for neurodegenerative motor neuron disease, ALS. Our findings suggest that these proprioceptive sensory neurons are exclusively afflicted early in the disease process relative to sensory neurons of other modalities. Moreover, they presented Nav1.6 Na+ channel deficiency which contributed to arrhythmic burst discharge. Such sensory arrhythmia could initiate reflexive defects such as muscle fasciculations in ALS as suggested by our computational model.

neuroscience↗