Biology subjects

Hartley, A.

Publications and source records attributed to Hartley, A..

7 recordsLinked to original sources

bioRxiv2026

Preserved Barrier Integrity and Altered Immune Profiles in Chronic Cannabis Users: Potential Roles of Δ9-Tetrahydrocannabinol

Although cannabinoids such as delta-9-tetrahydrocannabinol (THC) are generally immunosuppressive in preclinical models, chronic cannabis use in humans is paradoxically associated with increased infection risk and systemic inflammation. In this study, we demonstrate that THC directly strengthens intestinal epithelial barrier function in vitro by increasing trans-epithelial electrical resistance in a concentration-dependent manner in Caco-2 monolayers. In a cross-sectional study of chronic cannabis users via smoking or snorting compared with non-using controls, plasma lipopolysaccharide (LPS), and microbial translocation-driven inflammatory cytokines (IL-23, MCP-1, IL-8) were significantly reduced, while some cytokines (IL-6, IL-1{beta}, TNF-, IL-10) remained unchanged. Concurrently, users exhibited elevated macrophage-derived chemokine (MDC) and homeostatic cytokines IL-15 and IL-21, markedly suppressed IL-7 and IL-4. Plasma IL-15 and MDC levels correlated with consumption intensity, and IL-23, IL-7, and IP-10 correlated with age of first use or during heaviest use. These findings suggest that habitual cannabis use may protect gut barrier integrity and reduce microbial translocation and associated inflammation, while simultaneously disrupting systemic immune homeostasis through selective cytokine dysregulation. This dual, dose-dependent immunomodulatory profile highlights the complex balance between potential benefits and risks in both recreational and therapeutic cannabis use.

immunology↗

bioRxiv2025

Female-predominant anti-CD4 IgG autoantibody production and its correlations with plasma levels of progesterone, microbial translocation, and blunted immune reconstitution in HIV-infected patients on suppressive ART

Autoimmunity contributes to HIV immunopathogenesis even in the absence of overt autoimmune disease. We previously showed that anti-CD4 autoantibodies from people with HIV (PWH) on suppressive antiretroviral therapy (ART) can mediate cytotoxicity against CD4+ T cells, implicating a role in impaired immune reconstitution. Despite viral suppression, many PWH with poor CD4 recovery exhibit chronic immune activation, microbial translocation, and dysregulated humoral immunity. Here, we identify a female-predominant elevation of plasma anti-CD4 IgG autoantibodies in aviremic PWH receiving ART. Across two independent cohorts, HIV-positive females, but not males, displayed significantly higher anti-CD4 IgG, predominantly IgG1, compared with HIV-negative controls, without parallel increases in anti-CD4 IgA or IgM. This sex-specific pattern was unique to anti-CD4 IgG and was not observed for anti-CD8 IgG, anti-double-stranded DNA IgG, or anti-nuclear antigen IgG; these control autoantibodies correlated with one another but not with anti-CD4 IgG. Elevated anti-CD4 IgG levels were associated with lower plasma progesterone levels and reduced absolute CD4+ T-cell counts. Markers of microbial translocation, soluble CD14 (sCD14), lipopolysaccharide-binding protein (LBP), and lipopolysaccharide (LPS), were also selectively increased in HIV-positive females, with sCD14 and LBP showing significant or borderline associations with anti-CD4 IgG. Together, these findings identify anti-CD4 IgG as a sex-dimorphic autoimmune signature in treated HIV infection, linked to progesterone levels, persistent microbial translocation, and incomplete immune recovery. This work highlights an under-recognized intersection of sex, mucosal barrier dysfunction, and autoimmunity in HIV pathogenesis and suggests potential therapeutic targets to improve immune reconstitution in women.

pathology↗

bioRxiv2025

Characterize Oral-to-Blood Microbial DNA Translocation in Individuals with Cocaine Use Disorder

BackgroundCocaine disrupts gut barriers in animal models, potentially enabling microbial translocation and inflammation in the periphery and central nervous system (CNS), but its direct role in inducing inflammation remains controversial. This study aimed to determine if the oral cavity is a source of circulating microbial DNA translocation in individuals with current cocaine use disorder (CUD). ResultsA cross-sectional case-control study was conducted, comparing CUD and demographically matched non-drug controls. Ten CUD (via smoking or vaping) and 24 controls provided paired saliva and blood samples. Microbial 16S rRNA V4 region was sequenced in isolated microbial DNA from saliva and plasma. Single-cell RNA sequencing (scRNAseq) was analyzed in human peripheral blood mononuclear cells. Saliva from CUD, but not plasma, exhibited reduced alpha diversity and altered beta diversity, characterized by enriched Streptococcus and depleted Fusobacterium, Neisseria, and other taxa relative to controls. Controls exhibited low to undetectable microbial translocation in plasma. By contrast, plasma displayed CUD-specific oral enrichment of several Streptococcal species and evidence of translocation into the bloodstream. S. parasanguinis, but not cocaine alone, induced IL-1{beta} and TNF- production in human primary monocytes in vitro. scRNAseq further revealed innate immune activation, impaired T cell function, and heightened susceptibility to infection in CUD. ConclusionsThis pilot study demonstrating that CUD via smoking or snorting exhibited oral microbial dysbiosis and selective oral-to-blood microbial translocation in vivo. These findings suggest that a compromised oral-to-blood barrier, rather than cocaine itself, promotes immune perturbations in CUD.

microbiology↗

bioRxiv2024

Loss of ARID1A accelerates prostate tumourigenesis with a proliferative collagen-poor phenotype through co-operation with AP1 subunit cFos

Prostate cancer (PC) is the most common male visceral cancer, and second leading cause of cancer mortality in men in the Western world. Using a forward-mutagenesis Sleeping Beauty (SB) transposon-based screen in a Probasin Cre-Recombinase (Pb-Cre) Pten-deficient mouse model of PC, we identified Arid1a loss as a driver in the development of metastatic disease. The insertion of transposon in the Arid1a gene resulted in a 60% reduction of Arid1a expression, and reduced tumour free survival (SB:Ptenfl/fl Arid1aINT median 226 days vs SB:Ptenfl/fl Arid1aWT293 days, p=0.02),with elevated rates of metastasis (SB:Ptenfl/fl Arid1aINT 75% lung metastasis rate vs 17% SB:Ptenfl/fl Arid1aWT, p<0.001 ). We further generated a Pb-Cre Pten- and Arid1a-deficient mouse model, in which loss of Arid1a demonstrated a profound acceleration in tumorigenesis in Ptenfl/fl mice compared to Pten loss alone (Pb-Cre Ptenfl/flArid1a+/+median survival of 267 days vs Pb-Cre Ptenfl/fl Arid1afl/fl103 days, p<0.0001). Our data revealed homozygous Arid1a loss is required to dramatically accelerate prostate tumourigenesis, resulting in tumours with a less differentiated phenotype and a disorganised stroma. Furthermore, Arid1a loss mediated tumour formation in the mouse involved both the anterior and dorsolateral lobes, a unique feature from Pten-loss and other reported PC GEMM where tumour formation tends to be limited to the anterior lobes. Analysis of RNA and ChIP -Sequencing data suggests Arid1a loss enhanced the function of AP-1 subunit cFos. In clinical PC cohort, ARID1A and cFos levels stratified an aggressive subset of PC with a poor survival outcome with a median of only 30 months.

cancer biology↗

bioRxiv2022

First superferromagnetic remanence characterization and scan optimization for super-resolution Magnetic Particle Imaging

Magnetic particle imaging (MPI) is a sensitive, high contrast tracer modality that images superparamagnetic iron oxide nanoparticles (SPIOs), enabling radiation-free theranostic imaging. MPI resolution is currently limited by scanner and particle constraints. Recent tracers have experimentally shown 10x resolution and signal improvements, with dramatically sharper M-H curves. Experiments suggest that this results from interparticle interactions, conforming to literature definitions of superferromagnetism. We thus call our tracers superferromagnetic iron oxide nanoparticles (SFMIOs). While SFMIOs provide excellent signal and resolution, they exhibit hysteresis, with non-negligible remanence and coercivity. We provide the first report on MPI scanning with remanence and coercivity, including the first quantitative measurements of SFMIO remanence decay and reformation using a novel multi-echo pulse sequence. We also describe an SNR-optimized pulse sequence for SFMIOs under human electromagnetic safety limitations. The resolution from SFMIOs could enable clinical MPI with 10x reduced scanner selection fields, reducing hardware costs by up to 100x.

bioengineering↗

bioRxiv2019

Older age at Initiation of Antiretroviral Therapy Predicts Low Bone Mineral Density in Children with perinatally-infected HIV in Zimbabwe

BackgroundPerinatally-acquired HIV infection commonly causes stunting in children, but how this affects bone and muscle development is unclear. We investigated differences in bone and muscle mass and muscle function between children with HIV (CWH) and uninfected children.\n\nSettingCross-sectional study of CWH (6-16 years) receiving antiretroviral therapy (ART) for >6 months and children in the same age-group testing HIV-negative at primary health clinics in Zimbabwe.\n\nMethodsFrom Dual-energy X-ray Absorptiometry (DXA) we calculated total-body less-head (TBLH) Bone Mineral Content (BMC) for lean mass adjusted-for-height (TBLH-BMCLBM) Z-scores, and lumbar spine (LS) Bone Mineral Apparent Density (BMAD) Z-scores.\n\nResultsThe 97 CWH were older (mean age 12.7 vs. 10.0 years) and therefore taller (mean height 142cm vs. 134cm) than those 77 uninfected. However, stunting (height-for-age Z-score[≤]-2) was more prevalent in CWH (35% vs. 5%, p<0.001). Amongst CWH, 15% had low LS-BMAD (Z-score [≤]-2) and 13% had low TBLH-BMCLBM, vs. 1% and 3% respectively in those uninfected (both p[≤]0.02). After age, sex, height and puberty adjustment, LS-BMAD was 0.33 SDs (95%CI -0.01, 0.67; p=0.06) lower in CWH, with no differences in TBLH-BMCLBM, lean mass or grip strength by HIV status. However, there was a strong relationship between age at ART initiation and both LS-BMAD Z-score (r=-0.33, p=0.001) and TBLH-BMCLBM Z-score (r=-0.23, p=0.027); for each year ART initiation was delayed a 0.13 SD reduction in LS-BMAD was seen.\n\nConclusionSize-adjusted low bone density is common in CWH. Delay in initiating ART adversely affects bone density. Findings support immediate ART initiation at HIV diagnosis.

epidemiology↗

bioRxiv2019

A rare SMAD9 mutation identifies the BMP signalling pathway as a potential osteoanabolic target

To identify targets for novel anabolic medicines for osteoporosis, we recruited a large cohort with unexplained high bone mass (HBM). Exome sequencing identified a rare (minor allele frequency 0.0014) missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in an autosomal dominant family. The same mutation was identified in another two unrelated individuals with HBM. In-silico protein modelling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density [BMD] Z-Scores +3 to +5, with increased volumetric cortical and trabecular BMD, increased cortical thickness, and low/normal bone turnover. Fractures and nerve compressions are not seen. Both genome-wide, and gene-based association testing of heel estimated-BMD in >362,924 UK-Biobank British subjects showed strong associations with SMAD9 (PGWAS=6x10-16; PGENE =8x10-17). Smad9 is highly expressed in murine osteocytes and zebrafish bone tissue. Our findings support SMAD9 as a novel HBM gene, and a potential novel osteoanabolic target.

genetics↗