Biology subjects

Gu, H.

Publications and source records attributed to Gu, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Exercise Conditioning Enhances Insulin Sensitivity with Metabolic and Glycemic Control Driven by Hepatic Silencing of HMGB1 in Type 2 Diabetic Mice

Type 2 Diabetes (T2D) is characterized by chronic insulin resistance and inflammation. Exercise induces hyperglycemia control in T2D more than pharmacologic therapies alone. High Mobility Group Box 1 (HMGB1) is a ubiquitous nuclear factor for T2D progression. We hypothesize that hepatic silencing of HMGB1 in T2D and exercise will increase insulin sensitivity and shift metabolic routes, decrease liver damage and improve metabolic health in T2D mice. MethodsLiver HMGB1 KO (HMGB1{Delta}) was induced with AAV8-TBG in HMGB1 flox mice (AAV8-EGFP was used as wildtype controls). T2D mice were induced with a low-dose STZ and a high-fat diet. T2D mice ran for four weeks (1hr daily). Dual Energy X-Ray Absorptiometry (DEXA), A1C, glycemia, HMGB1, metabolomics and metabolic cage analysis were performed pre- and post-exercise. RT-PCR, immunoblotting and immunohistochemistry for glucose metabolism markers were performed in tissue samples. ResultsT2D HMGB1{Delta} mice show 20% less hyperglycemia compared to controls with a strong correlation between reduced HMGB1 levels and lower A1C following exercise. Additionally, fat percentage, liver damage, and glycogen storage were significantly reduced. These findings highlight the high potential effect of exercise potentiated has via HMGB1 governed mechanisms and highlights HMGB1 as a therapeutic target for managing hyperglycemia in T2D. ARTICLE HIGHLIGHTSHMGB1 hepatic silencing in Type 2 Diabetic mice is a promising therapeutic target for enhancing Insulin sensitivity. Combination of hepatic HMGB1 silencing and exercise potentiates the metabolic benefits and liver protection in Type 2 Diabetic mice. Shift in metabolic routes and carbohydrate metabolism due to regulation of hepatic HMGB1 expression makes HMGB1 an ideal target for pharmacologic intervention. However, our study also underscores the value of exercise as the primary focus of diabetic glucose control aided by enhanced therapeutic targeting of HMGB1 for chronic inflammation and hyperglycemia.

molecular biology↗

bioRxiv2025

Cadmium-induced gut dysbiosis precedes the onset of hippocampus-dependent learning and memory deficits in mice

BackgroundCadmium (Cd) is a heavy metal recognized as a neurotoxicant. However, the mechanisms underlying its neurotoxicity remain poorly understood. The gut-brain axis, a bidirectional communication pathway between the central nervous system and the gut microbiome, has been linked to various neurological disorders. Because the gut microbiome is a known target of Cd, it is important to investigate whether the gut-brain axis mechanistically contributes to the Cd-induced neurotoxicity. ObjectiveIn our initial exploration of the role of the gut-brain axis in modulating Cd neurotoxicity on cognition, we investigated whether Cd exposure induces gut dysbiosis before the onset of cognitive deficits and explored the potential link between gut microbiome alterations and Cd-induced cognitive deficits. MethodsAdult male mice were exposed to 3 mg/L Cd via drinking water for nine weeks. Behavioral assessments were conducted throughout the exposure period to evaluate cognitive function. Fresh fecal pellets were collected weekly to monitor changes in the gut microbiome composition. The effects of Cd on the hippocampus and intestine were analyzed using transcriptomics and mass spectrometry (MS)-based metabolomics. ResultsCd exposure resulted in hippocampus-dependent learning and memory deficits, first observed at four weeks into exposure. RNA sequencing of the hippocampus at the terminal time point revealed reduced expression of genes involved in cognition and neuroinflammation in Cd exposed mice. Metagenomic shotgun sequencing showed that Cd-induced gut dysbiosis preceded the onset of cognitive impairments, with specific bacterial species associated with Cd-induced cognitive deficits. Furthermore, Cd exposure reduced the expression of genes involved in intestinal barrier integrity, increased inflammatory cytokines levels, and altered the levels of neuroactive microbial metabolites. ConclusionOur study is the first to show that Cd exposure triggers gut microbial shifts before the onset of cognitive deficits, accompanied by increased intestinal permeability and elevated proinflammatory biomarkers in both the intestine and brain at the terminal time point. These findings suggest a potential critical role of gut-brain axis in modulating Cd neurotoxicity and underscore the need for future research to elucidate the mechanistic involvement of gut microbiome as a potential target for mitigating Cd-induced cognitive decline.

systems biology↗

bioRxiv2025

Long non-coding RNA BCAR4 is required for efficient influenza A virus replication

Long non-coding RNAs (lncRNAs) regulate diverse biological processes, including influenza A virus (IAV) infection. However, the understanding of lncRNAs in IAV infection is limited. By using both bioinformatic analyses and virological assays, we showed that lncRNA BCAR4 expression can be highly induced by infection of multiple different IAV subtypes. BCAR4 was required for the propagation of IAV infection. Genetic inactivation of BCAR4 inhibited IAV growth. Investigation of the IAV infection cycle revealed a suppressed IAV viral RNA transcription and replication, and attenuated viral protein synthesis in the BCAR4-deficient cells. BCAR4 potentially interacted with cellular splicing-associated proteins and the activation of BCAR4 was associated with influenza viral NS segment. These findings suggest the important role of lncRNA BCAR4 in regulation of IAV infection. ImportanceLong non-coding RNAs (lncRNAs) serve as critical regulators in the biological processes of influenza A virus (IAV) infection. However, how lncRNAs engage IAV infection remains unclear. Here we show BCAR4 as highly universally induced lncRNA in infection of multiple different IAV subtypes. Deletion of BCAR4 reduced IAV multiplication. In the IAV infection cycle, BCAR4 deficiency decreased IAV viral RNA transcription, replication and viral protein biosynthesis. BCAR4 was potentially binding to the host RNA splicing associated protein, and the IAV viral NS segment is required for the activation of BCAR4. Our results highlight important regulation of BCAR4 in IAV infection.

microbiology↗

bioRxiv2024

A molecularly defined brain circuit module for regulating the panic-like defensive state

Panic is an episode of strong defensive state, characterized by intense fear and severe physical symptoms such as elevated cardiorespiratory activities. How the brain generates panic state remains poorly understood. Here, we developed a robot-based experimental paradigm to evoke panic-like defensive state in mice. When stimulated by the robot, the mice exhibited jumping escapes and elevated cardiorespiratory activities. With this paradigm, we identified Cbln2-expressing (Cbln2+) neurons in the posterior hypothalamic nucleus (PHN) as a key neuronal population essential for the induction of panic-like defensive state. Activation of Cbln2+ PHN neurons induced behavioral and physical symptoms of panic-like defensive state. These neurons were strongly activated by noxious mechanical stimuli and encode jumping escape vigor. They were synaptically innervated by anxiety-associated brain areas and provoked panic-like defensive state via their projection to the periaqueductal gray. Together, our results reveal a molecularly defined circuit module that regulates the panic-like defensive state in mice.

neuroscience↗

bioRxiv2024

Assessment of DNA methylation from a single genomic region of ELOV2 is sufficient to predict chronological age

Estimation of chronological age is particularly informative in forensic contexts. Assessment of DNA methylation status allows for the prediction of age, though the accuracy and ease of manipulation may vary across different models. In this study, we started with a carefully designed discovery cohort recruiting more elderly subjects than other age categories, to diminish the effect of epigenetic drifting. We analyzed DNA methylation from a single genomic region of ELOV2, which was sufficient to construct an age-prediction model comprising 15 CpG sites. This model is further validated by an independent cohort as well as a multi-center test using trace dried bloodstains. The nature of our analytical pipeline, when combined the assessment of a single genomic locus with high-throughput sequencing, can easily be scaled up with low cost. Taken together, we propose a new age-prediction model featuring accuracy, ease of manipulation, high-throughput, and low cost. This model can be readily applied in both classic and newly emergent forensic contexts that require age estimation.

genetics↗

bioRxiv2024

Biomass allocation of trees in response to mono- and heterospecific neighbourhoods

Carbon sequestration by trees is crucial to mitigate the effects of the current climate crisis. The extent to trees sequester and allocate carbon to above- or belowground structures in turn is mediated by neighbouring species. Although many studies have demonstrated positive effects of diverse neighbourhoods on a trees productivity, little is known about biomass allocation responses to mono-vs. heterospecific neighbourhoods. In the present study we quantified above- and belowground biomass production and root-to-shoot ratios (RSR) of trees grown in mono- and heterospecific neighbourhoods. To this end we analysed growth of mono- and heterospecific tree species pairs (TSPs) established in a greenhouse and a field experiment. In the greenhouse experiment response variables were measured after one year of growth after sapling harvest. In the field experiment, conducted in the context of a forest biodiversity experiment in subtropical China, we analysed biomass density and RSR over three years using terrestrial laser scanner and minirhizotrons. RSR of trees in heterospecific TSPs were significantly higher than in monospecific TSPs. In the greenhouse experiment, this was related to a stronger below-than aboveground overyielding in heterospecific TSPs. In the field experiment, trees in heterospecific TSPs showed a stronger increase in aboveground investments over time than in monospecific TSPs, indicating that positive diversity effects became stronger for aboveground structures with progressing tree development. Our findings are consistent with the optimal biomass partitioning theory and highlight the importance of tree-tree interactions on biomass allocation. Higher RSR in mixtures further suggest a higher resistance or resilience of tree saplings against environmental stressors related to climate change (drought, heat waves).

ecology↗

bioRxiv2024

Cell-type-specific striatal modulation of amygdalar acetylcholine in salience assignment

The salience assignment is pivotal for both natural and artificial intelligence. Pioneering studies established that basal forebrain cholinergic neurons process behaviorally relevant salient information. However, the neural circuit mechanism underlying salience assignment remains poorly understood. Here we show that the acetylcholine (ACh) level in the basolateral amygdala (BLA) dynamically represented behavioral salience. Distinct neuronal subpopulations in the nucleus accumbens (NAc), D1- and D2-expressing medium spiny neurons (MSNs), antagonistically and specifically promote and suppress ACh release in the BLA, but not the cortex and hippocampus. These striatal D1 and D2 MSNs regulate BLA ACh by disinhibiting and inhibiting cholinergic neurons in the basal forebrain subregion substantia innominata (SI), respectively. Optogenetic manipulations of the pathway from striatal D1 and D2 MSNs to the SI opposingly affect associative learning. Our findings uncover an unconventional role of striatal MSNs in salience assignment via regulating the salience-representing amygdalar ACh activity.

neuroscience↗

bioRxiv2024

Unlocking the Potential: FKK6 as a Microbial Mimicry Based Therapy for Chronic Inflammation-Associated Colorectal Cancer in a Murine Model

Chronic intestinal inflammation significantly contributes to the development of colorectal cancer (CRC) and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics FKK6, which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). FKK6 (2 mg/kg) displayed substantial anti-tumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, {beta}-catenin, Ki-67, cyclin D) in the colon. In addition, we carried out the chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and {gamma}-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in AOM/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC.

pharmacology and toxicology↗

bioRxiv2024

Joint exome and metabolome analysis in individuals with dyslexia: Evidence for associated dysregulations of olfactory perception and autoimmune functions

Dyslexia is a learning disability that negatively affects reading, writing, and spelling development at the word level in 5%-9% of children. The phenotype is variable and complex, involving several potential cognitive and physical concomitants such as sensory dysregulation and immunodeficiencies. The biological pathogenesis is not well-understood. Toward a better understanding of the biological drivers of dyslexia, we conducted the first joint exome and metabolome investigation in a pilot sample of 30 participants with dyslexia and 13 controls. In this analysis, eight metabolites of interest emerged (pyridoxine, kynurenic acid, citraconic acid, phosphocreatine, hippuric acid, xylitol, 2-deoxyuridine, and acetylcysteine). A metabolite-metabolite interaction analysis identified Krebs cycle intermediates that may be implicated in the development of dyslexia. Gene ontology analysis based on exome variants resulted in several pathways of interest, including the sensory perception of smell (olfactory) and immune system-related responses. In the joint exome and metabolite analysis, the olfactory transduction pathway emerged as the primary pathway of interest. Although the olfactory transduction and Krebs cycle pathways have not previously been described in dyslexia literature, these pathways have been implicated in other neurodevelopmental disorders including autism spectrum disorder and obsessive-compulsive disorder, suggesting the possibility of these pathways playing a role in dyslexia as well. Immune system response pathways, on the other hand, have been implicated in both dyslexia and other neurodevelopmental disorders.

bioinformatics↗

bioRxiv2024

Maternal dietary deficiencies in folic acid and choline change metabolites levels in offspring after ischemic stroke

Ischemic stroke is a debilitating disease, with nutrition being a modifiable risk factor. Changes in levels of metabolites can be used to measure the alterations in the gut, a significant marker for the etiology of diseases. This study utilized untargeted metabolomics to investigate changes in fecal samples of offspring in response to maternal dietary deficiencies and ischemic stroke. Female mice were placed on control (CD), folic acid- (FADD), or choline-deficient (ChDD) diets prior to, during pregnancy, and lactation. Offspring were weaned on to CD and at 2 months of age an ischemic stroke was induced. Fecal samples were collected prior to ischemic stroke, and at 1- and 4-weeks post-stroke for analysis. Sex and maternal dietary differences in metabolites were observed at both the 1- and 4-week post-stroke timepoints. At the 1-week post-stroke, female FADD offspring had more changes in metabolites than males. Comparatively, at the 4-week post-stroke timepoint, female offspring on either FADD or ChDD demonstrated metabolite changes. This study demonstrates a long-lasting impact of maternal dietary deficiencies on central nervous system and gut microbiome function after ischemic stroke. Summary StatementOur study investigated metabolite changes in female and male offspring fecal samples from mothers maintained on folic acid or choline deficient diet. We report that female offspring metabolite levels were impacted.

neuroscience↗

bioRxiv2024

Detection of Nontoxic BoNT/A Levels in Post-Facial Botox Injection Breastmilk using a Multi-technique Approach

BackgroundThe use of cosmetic Botox (Botulinum Neurotoxin Type A, BoNT/A ) has become increasingly prevalent. Particularly after pregnancy, postpartum depression represents one major factor motivating women to use Botox even during the lactation and breastfeeding period. Currently, there is limited understanding of the impact of Botox on lactation and the potential of its active component passing into breastmilk and affecting the infant. MethodsBreastmilk samples were acquired from five women aged between 28 - 45 through a clinic in Suzhou, Jiangsu, P.R. China. Three sample sets ranged from 1 hour to 1 year after facial Botox treatments (64 U), whereas the remaining two sample sets were from women who never received Botox treatment. BoNT/A concentrations in samples were detected using standard Enzyme-Linked Immunosorbent Assay (ELISA), unreduced and reduced Western Blotting, confocal micro-Raman Spectroscopy, and Mass Spectrometry(LC-MS). FindingsFrom ELISA, breastmilk BoNT/A concentrations peaked at 33.4 pg/mL 4 days after Botox injection. BoNT/A concentrations were highest overall in the first week and around two months after injection. While non-reducing polyacrylamide gel electrophoresis (PAGE) showed a protein band of 150 kDa peaking at 48 hours, reduced SDS-PAGE detected a 100 kDa protein first peaking at 72 hours, then re-emerging after 7 days, respectively, and in line with previous observations by others. Interestingly, micro-Raman spectroscopy indicated additional Raman peaks at 6 hours and 48 hours that were not present in other breastmilk samples which were evaluated in this study. However, no clear indication of BoNT/A was detected in Mass Spectrometry (LC-MS). InterpretationThe amount of BoNT/A in breastmilk peaks around 48 hours, and at 2 months after facial injection. Even over a year after injection, BoNT/A can be detected. However, all quantities of BoNT/A detected in this study are highly likely to be safe for infants. Additionally, our study suggests that alternative methods, besides ELISA, may be utilized for the rapid detection of low concentrations of BoNT/A in body fluid samples. FundingDuke Kunshan University Start-Up funds, Duke Kunshan University Undergraduate Studies Signature Work Research Grant, Synear and Wang-Cai Biochemistry grants, and Kunshan Municipal Government research funding. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/595434v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@fcdd11org.highwire.dtl.DTLVardef@11591daorg.highwire.dtl.DTLVardef@11ab30eorg.highwire.dtl.DTLVardef@1e19311_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBoNT/A was detected in the breastmilk of 3 women after facial Botox injections of 64 U. C_LIO_LIToxin levels peaked in the first week and at around 2 months after injection. C_LIO_LIAll detected levels (up to 33.40 pg/mL) were significantly below the lethal dose for newborns. C_LI

molecular biology↗

bioRxiv2024

Endothelial fatty acid-binding proteins contribute to the pathogenesis of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Single-cell RNA sequencing (scRNAseq) analysis found that both FABP4 and FABP5 were highly induced in endothelial cells (ECs) of Egln1Tie2Cre (CKO) mice, which was also observed in pulmonary arterial ECs (PAECs) from idiopathic PAH (IPAH) patients, and in whole lungs of pulmonary hypertension (PH) rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters using plasma proteome analysis. Genetic deletion of both Fabp4 and 5 in CKO mice (Egln1Tie2Cre/Fabp4-5-/-, TKO) caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure assessed by echocardiography, hemodynamic and histological analysis. Employing bulk RNA-seq and scRNA-seq, and spatial transcriptomic analysis, we showed that Fabp4/5 deletion also inhibited EC glycolysis and distal arterial programming, reduced ROS and HIF-2 expression in PH lungs. Thus, PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced ECs glycolysis and distal arterial programming, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.

molecular biology↗

bioRxiv2023

Role of Staphylococcus aureus Buoyant Density in the Development of Biofilm Associated Antibiotic Resistance

Bacterial biofilms are clusters of bacterial cells that form at various interfaces, including those between air and liquid or liquid and solid. Due to their roles in enhancing wastewater treatment processes, and their unfortunate propensity to cause persistent human infections through high antibiotic resistance, understanding and managing bacterial biofilms is of paramount importance. A pivotal stage in biofilm development is the initial bacterial attachment to these interfaces. However, the determinants of bacterial cell choice in colonizing an interface first and heterogeneity in bacterial adhesion remain elusive. Recent research has unveiled variations in the buoyant density of Staphylococcus aureus cells, irrespective of their growth phase. Cells with a low cell buoyant density, characterized by fewer cell contents, exhibited greater resistance to antibiotic treatments (100 g/mL vancomycin) and favored biofilm formation at air-liquid interfaces. In contrast, cells with higher buoyant cell density, which have richer cell contents, were more vulnerable to antibiotics and predominantly formed biofilms on liquid-solid interfaces when contained upright. In essence, S. aureus cells with higher buoyant cell density are more inclined to adhere to upright substrates.

microbiology↗

bioRxiv2023

Connecting single neuron transcriptomes to the projectome in mouse visual cortex

The mammalian brain is composed of diverse neuron types that play different functional roles. Recent single-cell RNA sequencing approaches have led to a whole brain taxonomy of transcriptomically-defined cell types, yet cell type definitions that include multiple cellular properties can offer additional insights into a neurons role in brain circuits. While the Patch-seq method can investigate how transcriptomic properties relate to the local morphological and electrophysiological properties of cell types, linking transcriptomic identities to long-range projections is a major unresolved challenge. To address this, we collected coordinated Patch-seq and whole brain morphology data sets of excitatory neurons in mouse visual cortex. From the Patch-seq data, we defined 16 integrated morphoelectric-transcriptomic (MET)-types; in parallel, we reconstructed the complete morphologies of 300 neurons. We unified the two data sets with a multi-step classifier, to integrate cell type assignments and interrogate cross-modality relationships. We find that transcriptomic variations within and across MET-types correspond with morphological and electrophysiological phenotypes. In addition, this variation, along with the anatomical location of the cell, can be used to predict the projection targets of individual neurons. We also shed new light on infragranular cell types and circuits, including cell-type-specific, interhemispheric projections. With this approach, we establish a comprehensive, integrated taxonomy of excitatory neuron types in mouse visual cortex and create a system for integrated, high-dimensional cell type classification that can be extended to the whole brain and potentially across species.

neuroscience↗

bioRxiv2023

Dual Ethanolamine Head Groups in Ionizable Lipids Facilitate Phospholipid-free Stable Nanoparticle Formulation for Augmented and Safer mRNA Delivery

The accelerated advent of mRNA-based therapeutics and vaccines, highlighted by the battle against SARS-CoV-2, underscores the urgency to refine lipid nanoparticles (LNPs) for efficient mRNA delivery. In this work, we introduce a novel series of ionizable lipids characterized by double ethanolamine head groups, significantly amplifying mRNA binding affinity. A succinct three-component formulation is subsequently delineated, obviating the conventional dependency on phospholipids inherent in traditional four-component LNPs. Intriguingly, this formulation enables particle formation under neutral pH conditions, a notable departure from the acidic milieu traditionally required, attributable to the enhanced nonionic interactions predominating in mRNA encapsulation. The resultant particles exhibit exceptional stability, superior mRNA encapsulation efficiency, and maintain robust delivery efficacy. When deployed as a vaccine platform, the formulation elicited pronounced humoral and T-cell immune responses, concurrently exhibiting a favorable toxicity profile with a reduced induction of pro-inflammatory cytokines such as IL-6. Our exploration suggests that by fine-tuning the non-electrostatic interactions between the ionizable lipid and mRNA, the dynamics of particle formation can be considerably divergent from the prevailing paradigms of mRNA-LNP formation, hinting at a broader horizon for lipid optimization within the realm of mRNA delivery systems.

bioengineering↗

bioRxiv2023

NEUROMETABOLOMIC IMPACTS OF MODELED WILDFIRE SMOKE AND PROTECTIVE BENEFITS OF ANTI-AGING THERAPEUTICS IN AGED FEMALE C57BL/6J MICE

Wildland fires have become progressively more extensive over the past 30 years in the US, and now routinely generate smoke that deteriorates air quality for most of the country. We explored the neurometabolomic impact that smoke derived from biomass has on older (18 months) female C57BL/6J mice, both acutely and after 10 weeks of recovery from exposures. Mice (N=6/group) were exposed to wood smoke (WS) 4 hours/day, every other day, for 2 weeks (7 exposures total) to an average concentration of 0.448mg/m3 per exposure. One group was euthanized 24 hours after the last exposure. Other groups were then placed on 1 of 4 treatment regimens for 10 weeks after wood smoke exposures: vehicle; resveratrol in chow plus nicotinamide mononucleotide in water (RNMN); senolytics via gavage (dasatanib+quercetin; DQ); or both RNMN with DQ (RNDQ). Among the findings, the aging from 18 months to 21 months was associated with the greatest metabolic shift, including changes in nicotinamide metabolism, with WS exposure effects that were relatively modest. WS caused a reduction in NAD+ within the prefrontal cortex immediately after exposure and a long-term reduction in serotonin that persisted for 10 weeks. The serotonin reductions were corroborated by forced swim tests, which revealed an increased immobility (reduction in motivation) immediately post-exposure and persisted for 10 weeks. RNMN had the most beneficial effects after WS exposure, while RNDQ caused markers of brain aging to be upregulated within WS-exposed mice. Findings highlight the persistent neurometabolomic and behavioral effects of woodsmoke exposure in an aged mouse model. Significance StatementNeurological impacts of wildfire smoke are largely underexplored but include neuroinflammation and metabolic changes. The present study highlights modulation of major metabolites in the prefrontal cortex and behavioral consequences in aged (18 month) female mice that persists 10 weeks after wood smoke exposure ended. Supplements derived from the anti-aging field were able to mitigate much of the woodsmoke effect, especially a combination of resveratrol and nicotinamide mononucleotide.

pharmacology and toxicology↗

bioRxiv2023

Decision-consistent bias mediated by drift dynamics of human visual working memory

Sensory evidence tends to be fleeting, often unavailable when we categorize or estimate world features. To overcome this, our brains sustain sensory information in working memory. Although keeping that information accurate while acting on it is vital, humans display two canonical biases: estimates are biased toward a few stimuli ("stimulus-specific bias") and prior decisions ("decision-consistent bias"). Integrative--especially neural mechanistic--accounts of these biases remain scarce. Here, we identify drift dynamics toward discrete attractors as a common source of both biases in orientation estimation, with decisions further steering memory states. Behavior and neuroimaging data reveal how these biases co-evolve through the decision-steered attractor dynamics. Task-optimized recurrent neural networks suggest neural mechanisms that enable categorical decisions to emerge from working memory for continuous stimuli while updating its trajectory, warping decision-consistent biases under stimulus-specific drift.

neuroscience↗

bioRxiv2023

Lysine vitcylation is a novel vitamin C-derived protein modification that enhances STAT1-mediated immune response

Vitamin C (vitC) is a vital nutrient for health and also used as a therapeutic agent in diseases such as cancer. However, the mechanisms underlying vitCs effects remain elusive. Here we report that vitC directly modifies lysine without enzymes to form vitcyl-lysine, termed "vitcylation", in a dose-, pH-, and sequence-dependent manner across diverse proteins in cells. We further discover that vitC vitcylates K298 site of STAT1, which impairs its interaction with the phosphatase PTPN2, preventing STAT1 Y701 dephosphorylation and leading to increased STAT1-mediated IFN pathway activation in tumor cells. As a result, these cells have increased MHC/HLA class-I expression and activate immune cells in co-cultures. Tumors collected from vitC-treated tumor-bearing mice have enhanced vitcylation, STAT1 phosphorylation and antigen presentation. The identification of vitcylation as a novel PTM and the characterization of its effect in tumor cells opens a new avenue for understanding vitC in cellular processes, disease mechanisms, and therapeutics.

biochemistry↗