Biology subjects

Campbell, T.

Publications and source records attributed to Campbell, T..

12 recordsLinked to original sources

bioRxiv2026

ALDH2 Knockout Induces Dysregulation of Arginine biosynthesis in SKBR-3 Breast Cancer Cells

Background/Objectives: Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, mitigates cellular stress by detoxifying reactive aldehydes produced during alcohol exposure and endogenous metabolic processes. ALDH2*2 polymorphism, which results in deficient catalytic activity, is prevalent in East Asian populations and is associated with an increased risk of cancer and other diseases. While the effects of ALDH2 deficiency on cellular stress responses are well documented, the specific metabolic dysregulations arising from this deficiency require further investigation. Methods; An ALDH2 knockout subline of SKBR-3 cells was established using CRISPR/Cas9 strategy. The metabolomic profiles of control (SKBR-3/C) and ALDH2 knockout (SKBR-3/ADKO) cells were evaluated via ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Results: ALDH2 knockout in SKBR-3 cells resulted in increased cellular stress, evidenced by elevated levels of 8-OHdG, reactive oxygen species (ROS), and malondialdehyde (MDA). Metabolomic analysis of the paired cell lines assigned a total of 5,033 signals, of which 281 were significantly different (fold change [≥] 2, p-value <0.05) between the two groups. Pathway analysis with MetaboAnalyst identified significant metabolic pathways associated with ALDH2 deficiency, particularly those involving arginine biosynthesis, and arginine and proline metabolism. ALDH2 deficiency reprogramed arginine metabolism toward polyamine pathways while suppressing the urea cycle. Network analysis further revealed alterations in amino acid and lipid metabolism in ALDH2-deficient cells. Conclusions; This study provides a novel insight into the role of ALDH2 in cancer metabolism and may have broader implication for cancer biology.

cell biology↗

bioRxiv2026

Follistatin improves vascular function by inhibiting oxidative stress and inducing browning of perivascular adipose tissue in essential hypertension

BackgroundEssential hypertension, characterized by vascular dysfunction, remains a leading modifiable cause of death globally. Perivascular adipose tissue (PVAT), which normally reduces vasoconstriction, becomes less anticontractile in hypertension due at least in part to increased reactive oxygen species (ROS). Brown PVAT has emerged as a protective regulator of vascular tone. Follistatin, an activin antagonist, induces browning of peripheral adipose tissue depots via AMPK. We recently reported improved blood pressure, vascular function and reduced vascular ROS by follistatin in the spontaneously hypertensive rat (SHR) model of essential hypertension. Here, we investigate whether follistatin reduces ROS and induces browning in SHR PVAT to restore PVAT function. MethodsSHR were treated with vehicle, follistatin or hydralazine for 8 weeks. Mesenteric white and thoracic brown PVAT from SHR and normotensive Wistar-Kyoto were utilized, with wire myography used to assess vascular function. Nitric oxide (NO) and nitrite were measured in PVAT using DAF-2 FM fluorescence or Griess reagent, respectively. PVAT ROS and browning markers were assessed biochemically and via immunohistochemistry. PVAT was treated ex vivo for 3 days to assess mechanisms of browning. Unbiased proteomic analysis of PVAT was performed using liquid chromatography-mass spectrometry. ResultsSHR PVAT dysfunction, manifest as a pro-contractile effect, was inhibited by follistatin through reducing ROS, enhancing NO bioavailability and inducing browning. Activin neutralization and AMPK phosphorylation mediated the beneficial effect of follistatin on SHR PVAT. Hydralazine-induced blood pressure reduction did not replicate follistatin effects, suggesting vascular benefits of follistatin are mediated by direct PVAT modulation. Proteomic analysis showed that follistatin shifts PVAT proteome towards normal state, upregulating processes associated with adipose tissue browning. ConclusionFollistatin restores PVAT-mediated vascular relaxation via ROS reduction, activin neutralization and AMPK-dependent browning, positioning the potential for PVAT as a therapeutic target for vascular dysfunction in essential hypertension.

physiology↗

bioRxiv2025

The impact of western versus agrarian diet consumption on gut microbiome composition and immune dysfunction in people living with HIV in rural and urban Zimbabwe

BackgroundPeople living with HIV (PLWH) suffer from chronic inflammation even with effective antiretroviral therapy (ART). A high-fat, low-fiber western-type diet has been linked with inflammation, in part through gut microbiome changes. In sub-Saharan Africa (SSA), a region with high HIV burden, urbanization has been linked with a shift from traditional agrarian towards westernized diets, and with changes in food security. To explore the relationship between diet, inflammation, and the gut microbiome in PLWH, we enrolled 1) ART Naive PLWH who provided samples before and after 24 weeks of ART, 2) PLWH on ART at both timepoints and 3) HIV-seronegative controls. Individuals were evenly recruited from rural and urban Zimbabwe (locations were 145 kilometers/90 miles apart). Using a food frequency survey designed to measure intake of agrarian versus western-type food items in Zimbabwe, we determined how diet differs with urbanization, HIV-infection and treatment, and is related to inflammation and the gut microbiome. ResultsIndividuals residing in a rural area of Zimbabwe less frequently consumed high-fat, low-fiber western type food items and had lower consumption of diverse food items overall, except for sadza-a subsistence staple-processed from home-grown grains. Consumption of a more western-type diet correlated with lower CD4+ T cell percentage in untreated and treated PLWH and with increased T cell exhaustion in PLWH on ART. PLWH on ART at time of enrollment also consumed diverse food items at a lower frequency and more often were underweight. Low food consumption correlated with muted improvements in T cell exhaustion after 24 weeks of ART. Individuals residing in the rural area had more Prevotella-rich/Bacteroides-poor microbiomes, but this did was not significantly mediated by diet. western diet consumption reduced the diversity of carbohydrate substrate degradation capabilities in the microbiome, based on predictions made using metagenomic polysaccharide utilization loci. ConclusionsTaken together, this work supports that consumption of more high-fat/low-fiber type food items has the potential to exacerbate HIV pathogenesis in a sub-Saharan setting where HIV burden is high and reinforces the importance of nutritional support for promoting immunologic response to ART in PLWH in SSA.

microbiology↗

bioRxiv2025

Synaptotoxic effects of extracellular tau are mediated by its microtubule-binding region

Immunotherapies targeting extracellular tau share the premise that interrupting cell-to-cell spread of tau pathology in Alzheimers disease (AD) will slow dementia pathogenesis. How these interventions affect the actions of synaptotoxic, extracellular tau species that may help mediate cognitive impairment is relatively unknown. Here, we assayed synaptic plasticity disruption in anaesthetised live rats caused by intracerebral injection of synaptotoxic tau present either in (a) secretomes of induced pluripotent stem cell-derived neurons (iNs) from people with Trisomy 21, the most common genetic cause of AD, or (b) aqueous extracts of human AD brain. Extracellular tau in iN secretomes was found to include fragments that contain the extended microtubule binding regions of tau, MTBR/R and adjacent C-terminal peptides. Immunodepletion or co-injection with antibodies targeting epitopes within these fragments prevented the acute disruption of synaptic plasticity by these patient-derived synaptotoxic tau preparations. Conversely, a recombinant human tau fragment encompassing the core MTBR/R- region present in tau fibrils, tau297-391 potently mimicked this deleterious action of patient-derived tau. MTBR/R-directed antibodies also rapidly reversed a very persistent synaptotoxic effect of soluble brain tau. Our findings reveal a hitherto relatively unexplored potential benefit of targeting MTBR/R.

neuroscience↗

bioRxiv2024

Targeting the acetyltransferase NAT10 corrects pathologies in human frontotemporal neurons and extends lifespan in an in vivo Drosophila tauopathy model

Disruption of the neuronal nuclear membrane and perturbation of nucleocytoplasmic transport are features of neurodegenerative diseases, including Alzheimers disease, that involve the microtubule-associated protein tau (MAPT). We previously identified that missense and splicing mutations in the MAPT gene, causal for frontotemporal dementia, result in nuclear envelope deformation and disrupted nucleocytoplasmic transport in human neurons. This is most likely due to microtubule mechanical stress, similar to that observed in Hutchinson-Gilford Progeria Syndrome (HGPS). A small molecule inhibitor of the acetyltransferase NAT10 has been shown to correct nuclear membrane defects in HGPS by modulating microtubule dynamics. We report here that NAT10 inhibition alters microtubule dynamics and corrects nuclear lamina defects and aberrant nucleocytoplasmic transport in human iPSC-derived FTD-MAPT neurons. Similarly, NAT10 inhibition and haploinsufficiency correct neuronal nuclear shape defects and extend lifespan in vivo in a Drosophila model of tauopathy. Our results show that NAT10 mediates neuronal pathologies in tauopathies and is a promising new therapeutic target in these diseases.

neuroscience↗

bioRxiv2024

Skin-associated Corynebacterium amycolatum shares cobamides

The underlying interactions that occur to maintain skin microbiome composition, function, and overall skin health are largely unknown. Often, these types of interactions are mediated by microbial metabolites. Cobamides, the vitamin B12 family of cofactors, are essential for metabolism in many bacteria, but are only synthesized by a small fraction of prokaryotes, including certain skin-associated species. Therefore, we hypothesize that cobamide sharing mediates skin community dynamics. Preliminary work predicts that several skin-associated Corynebacterium species encode de novo cobamide biosynthesis and that their abundance is associated with skin microbiome diversity. Here, we show that commensal Corynebacterium amycolatum produces cobamides and that this synthesis can be tuned by cobalt limitation. To demonstrate cobamide sharing by C. amycolatum, we employed a co-culture assay using an E. coli cobamide auxotroph and show that C. amycolatum produces sufficient cobamides to support E. coli growth, both in liquid co-culture and when separated spatially on solid medium. We also generated a C. amycolatum non-cobamide-producing strain (cob-) using UV mutagenesis that contains mutated cobamide biosynthesis genes cobK and cobO and confirm that disruption of cobamide biosynthesis abolishes support of E. coli growth through cobamide sharing. Our study provides a unique model to study metabolite sharing by microorganisms, which will be critical for understanding the fundamental interactions that occur within complex microbiomes and for developing approaches to target the human microbiota for health advances.

microbiology↗

bioRxiv2024

Cellular mechanisms underlying beneficial versus detrimental effects of bacterial antitumor immunotherapy

Bacteria engineered to express tumor antigens as a cancer vaccine have yielded mixed results. Here, we utilized an attenuated strain of Listeria monocytogenes ({Delta}actA, Lm) that does not express tumor antigen to explore the immunological response to Listeria itself in the context of intravenous (IV), intratumoral (IT), or a combination of IV+IT administration into tumor-bearing mice. Unexpectedly, we found that Lm persisted in tumors of immune competent mice, regardless of the administration route. While IT Lm alone led to the recruitment of immunosuppressive immune cells that promoted tumor growth, IV Lm followed by IT Lm controlled tumor growth. IV Lm vaccination generated a pool of anti-Lm cytotoxic CD8 T cells that killed Lm-infected non-tumor cells to control tumor growth both indirectly, by limiting cancer cell proliferation, and directly, by enhancing tumor-specific T cell responses. Our findings reveal a differential impact of IT Lm administration on tumor progression that depends on the presence of anti-Lm CD8 T cells, which alone are sufficient to promote therapeutic efficacy.

immunology↗

bioRxiv2022

Population Structure and Migration in the Eastern Highlands of Papua New Guinea; a Region Impacted by the kuru Epidemic

Populations of the Eastern Highlands of Papua New Guinea (EHPNG, area 11,157 km2) lived in relative isolation from the rest of the world until the mid-20th century, and the region contains a wealth of linguistic and cultural diversity. Notably, several populations of EHPNG were devastated by an epidemic prion disease, kuru, which at its peak in the mid-twentieth century led to some villages being almost depleted of adult women. Until now, population genetic analyses to learn about genetic diversity, migration, admixture and the impact of the kuru epidemic have been restricted to a small number of variants or samples. Here, we present a population genetic analysis of the region based on genome-wide genotype data of 943 individuals from 21 linguistic groups and 68 villages in EHPNG, including 34 villages in the South Fore linguistic group, which the group most affected by kuru. We find a striking degree of genetic population structure in the relatively small region (average FST between linguistic groups 0.024; area similar to Jamaica). The genetic population structure correlates well with linguistic grouping, with some noticeable exceptions. Also, we find evidence of a series of discrete admixture events that appear to coincide with previously expected introduction dates and movement of the sweet potato in the region. Finally, we find signatures of more recent migration within the EHPNG region and observe a substantial excess of female migration into the heavily kuru-affected South Fore linguistic group (p=0.0017, Chi Squared Test), likely reflecting the sex-bias in incidence of kuru. These data provide an in-depth look at the population genetics of a region devastated by a prion disease epidemic and which was until recently relatively isolated from the rest of the world.

genetics↗

bioRxiv2022

Cellular Heterogeneity of Pluripotent Stem Cell Derived Cardiomyocyte Grafts is Mechanistically Linked to Treatable Arrhythmias

BackgroundExciting pre-clinical data have confirmed that human pluripotent stem cell derived cardiomyocytes (PSC-CMs) can remuscularise the injured or diseased heart, with several clinical trials now in planning or recruitment stages worldwide. However, ventricular arrhythmias are a predictable complication following engraftment of intramyocardially injected PSC-CMs. Therefore, there is an urgent unmet need to gain mechanistic insights and treatment strategies to control or prevent these engraftment arrhythmias (EAs). MethodsWe used a porcine model of myocardial infarction and PSC-CM transplantation to investigate efficacy of pharmacologic and catheter based anti-arrhythmic strategies in mitigating EAs. Furthermore, cell doses were robustly phenotyped using single cell ribonucleic acid sequencing and high parameter flow cytometry to identify cellular characteristics predictive of arrhythmogenesis. ResultsCombination therapy with amiodarone and ivabradine significantly reduced EA rate and burden following PSC-CM transplantation. Catheter ablation was also a feasible and effective treatment strategy which could be considered in the case of pharmacologically refractory arrhythmias. In addition, we show that EAs are mechanistically linked to cellular heterogeneity in the input PSC-CM and resultant graft. Specifically, we identify atrial and pacemaker-like cardiomyocytes as culprit arrhythmogenic subpopulations. We further describe two unique surface marker signatures, SIRPA+/CD90-/CD200+ and SIRPA+/CD90-/CD200-, which identify arrhythmogenic and non-arrhythmogenic cardiomyocytes respectively. ConclusionOur data deepens mechanistic understanding of EAs and suggests that modifications to current PSC-CM production and/or selection protocols could ameliorate this problem. We further show that current clinical pharmacologic and interventional anti-arrhythmic strategies can control and potentially abolish these arrhythmias, an important safety consideration given several impending clinical trials.

cell biology↗

bioRxiv2022

SARS-CoV-2-specific T cells associate with reduced lung function and inflammation in pulmonary post-acute sequalae of SARS-CoV-2

As of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC). Compared to RC, participants with respiratory PASC had up to 34-fold higher frequencies of IFN-{gamma}- and TNF--producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood and elevated levels of plasma CRP and IL-6. Importantly, in PASC participants the frequency of TNF--producing SARS-CoV-2-specific CD4+ and CD8+ T cells, which exhibited the highest levels of Ki67 indicating they were activity dividing, correlated positively with plasma IL-6 and negatively with measures of lung function, including forced expiratory volume in one second (FEV1), while increased frequencies of IFN-{gamma}-producing SARS-CoV-2-specific T cells associated with prolonged dyspnea. Statistical analyses stratified by age, number of comorbidities and hospitalization status demonstrated that none of these factors affect differences in the frequency of SARS-CoV-2 T cells and plasma IL-6 levels measured between PASC and RC cohorts. Taken together, these findings demonstrate elevated frequencies of SARS-CoV-2-specific T cells in individuals with pulmonary PASC are associated with increased systemic inflammation and decreased lung function, suggesting that SARS-CoV-2-specific T cells contribute to lingering pulmonary symptoms. These findings also provide mechanistic insight on the pathophysiology of PASC that can inform development of potential treatments to reduce symptom burden. Author SummaryLong COVID-19 or post-acute sequelae of SARS-CoV-2 (PASC) impacts 20-30% of those infected with SARS-CoV-2 and is characterized by COVID-19 symptoms exceeding 4 weeks from symptom onset. While those with PASC experience a wide variety of persistent symptoms including shortness of breath, cough, chest pain, irregular heartbeat, brain fog, fatigue, and intermittent fever, lung-related conditions are the most common. Although, infection with SARS-CoV-2 is clearly the inciting factor for PASC, the mechanisms responsible for long-term lung dysfunction are unclear and current treatments are ineffective at resolving pulmonary symptoms. Generalized PASC has been associated with SARS-CoV-2-specific T cells, a component of adaptive immunity, suggesting that residual virus may persist. Here, we investigated the frequency and function of virus-specific T cells in the blood of individuals with pulmonary PASC and correlated their presence with systemic inflammation and lung function. Our findings demonstrated that T cells specific for SARS-CoV-2 are elevated in the blood of those with pulmonary PASC and are associated with increased IL-6, a cytokine strongly associated with COVID-19 severity, and decreased lung function. These findings provide mechanistic insight into the pathophysiology of pulmonary PASC needed for the development of new treatments to improve quality of life for those affected.

immunology↗

bioRxiv2020

Secondhand homes: Woodpecker cavity location and structure influences secondary nester's success.

O_LIUnderstanding how ecosystem engineers influence other organisms has long been a goal of ecologists. Woodpeckers select nesting sites with high food availability and will excavate and then abandon multiple cavities through their lifetime. These cavities are crucial to secondary cavity nesting birds (SCB) that are otherwise limited by the availability of naturally occurring cavities. C_LIO_LIOur study examined the role food resources have on the nest site location and home range size of woodpeckers, and the respective influence woodpeckers and the construction of cavities have on the nesting success of SCB. C_LIO_LIUsing five years of avian point count data to locate golden-fronted woodpeckers (GFWO: Melanerpes aurifrons), we correlated insect availability with GFWO home range size and determined differences in insect availability between GFWO occupied and unoccupied sites, while recording nesting success (success: [≥] 1 fledgling) for the GFWO and common SCB in south Texas: Black-crested Titmouse (Baeolophus atricristatus), Ash-throated Flycatcher (Myiarchus cinerascens), Brown-crested Flycatcher (Myiarchus tyrannulus), and Bewicks Wren (Thryomanes bewickii). We used model averaging to fit species-specific logistic regression models to predict nest success based on cavity metrics across all species. C_LIO_LISites occupied by GFWO had a higher biomass of insects in orders Coleoptera, Hymenoptera, and Orthoptera than unoccupied sites, and there was a negative correlation between the availability of these insect orders and home-range size. GFWO had increased nest success in trees with increased vegetation cover and lower levels of decay, while SCB had higher levels of nesting success in abandoned GFWO cavities opposed to naturally occurring ones, and in trees with low decay. C_LIO_LIOur results suggest that SCB may be drawn to nest in abandoned woodpecker cavities where they have higher rates of nest success compared to natural cavities. Additionally, the prevalence for GFWO to excavate cavities in trees with lower levels of decay contradicts previous literature and may indicate a novel temperature trade-off, with live trees requiring more energy to excavate, but providing more protection from high breeding season temperatures in arid and semi-arid areas. C_LI

ecology↗

bioRxiv2018

An exploration of Prevotella-rich microbiomes in HIV and men who have sex with men

BackgroundGut microbiome characteristics associated with HIV infection are of intense research interest but a deep understanding has been challenged by confounding factors across studied populations. Notably, a Prevotella-rich microbiome described in HIV-infected populations is now understood to be common in men who have sex with men (MSM) regardless of HIV status, but driving factors and potential health implications are unknown.\n\nResultsHere we further define the MSM-associated gut microbiome and describe compositional differences between the fecal microbiomes of Prevotella-rich MSM and non-MSM that may underlie observed pro-inflammatory properties. Furthermore, we show relatively subtle gut microbiome changes in HIV infection in MSM and women that include an increase in potential pathogens that is ameliorated with antiretroviral therapy (ART). Lastly, using a longitudinal cohort, we describe microbiome changes that happen after ART initiation.\n\nConclusionsThis study provides an in-depth characterization of microbiome differences that occur in a US population infected with HIV and demonstrates the degree to which these differences may be driven by lifestyle factors, ART and HIV infection itself. Understanding microbiome compositions that occur with sexual behaviors that are high-risk for acquiring HIV and untreated and ART-treated HIV infection will guide the investigation of immune and metabolic functional implications to ultimately target the microbiome therapeutically.

microbiology↗