Biology subjects

Campbell, N.

Publications and source records attributed to Campbell, N..

9 recordsLinked to original sources

bioRxiv2026

Bioenergetic profiling of fresh human kidney tissue reveals compensatory metabolic adaptation and intrinsic mitochondrial dysfunction in diabetes

The kidney is a highly energetic organ, requiring substantial ATP production through mitochondrial oxidative phosphorylation to support tubular reabsorption. Metabolic reprogramming and impaired mitochondrial function are implicated in diabetic kidney disease, yet direct assessment of mitochondrial respiratory flux in the human kidney has been constrained by limited access to freshly obtained tissue. Consequently, much of the evidence supporting altered renal mitochondrial function in diabetes derives from animal models that do not fully recapitulate the human condition. We established a workflow for real-time bioenergetic profiling of fresh kidney cortex obtained during nephrectomy from living individuals with diabetes and preserved kidney function. Mitochondrial respiration, electron transport system activity and tubular mitochondrial morphology were compared with age- and sex-matched, histopathologically normal non-diabetic controls. High-resolution respirometry revealed increased mitochondrial respiratory flux in permeabilised diabetic kidney cortex. In contrast, mitochondria isolated from the same tissue exhibited reduced respiratory capacity and impaired complex I activity. Quantitative analysis of tubular cells demonstrated increased mitochondrial volume density together with greater mitochondrial fragmentation in diabetes. These findings reveal that the human kidney undergoes substantial metabolic adaptation early in diabetes, before measurable loss of kidney function. Increased tissue-level respiratory flux despite intrinsic mitochondrial impairment suggests that expansion and remodelling of the mitochondrial network may initially compensate for reduced organelle efficiency and sustain the kidneys high energetic demands. This compensatory state may, however, increase metabolic stress and vulnerability to subsequent kidney injury. To our knowledge, this study provides the first direct tissue-level functional evidence that mitochondrial metabolism is reprogrammed in the human kidney in diabetes before measurable kidney dysfunction develops. It defines an early bioenergetic signature characterised by tissue hypermetabolism despite impaired mitochondria-specific respiratory capacity, challenging the concept that diabetes produces a uniform decline in renal mitochondrial function. Failure to sustain this adaptive state may represent a critical transition towards diabetic kidney disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/740003v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@101eb51org.highwire.dtl.DTLVardef@100187corg.highwire.dtl.DTLVardef@1478af2org.highwire.dtl.DTLVardef@1f31fc1_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryDiabetes drives early metabolic reprogramming of the human kidney before measurable kidney dysfunction

pathology↗

bioRxiv2026

Using atorvastatin-induced vascular weakness to model brain haemorrhage in vascularised cerebral organoids

Intracerebral haemorrhage is the most severe subtype of stroke; however, pre-clinical investigation often fails to translate to the clinic. Cerebral organoids offer an adaptable, in vitro model of human brain tissue for pre-clinical investigation of disease. We recently demonstrated that the tissue can be successfully vascularised to mimic the cerebrovasculature. Cerebrovascular weakness was induced with atorvastatin to mimic damage observed in intracerebral haemorrhage and to replicate the diseases pathological features. We used atorvastatin to disrupt functional morphology in human brain microvascular endothelial cells in 2D and 3D model systems. Whole human blood was added to initiate damage to cerebral tissues. Vascularised cerebral organoids exhibited loss of vascular integrity when treated with atorvastatin. Tissue was vulnerable to injury from human whole blood, and an innate immune response was initiated, resulting in increased cell death. Here we show that vascularised cerebral organoids demonstrate a novel model platform for investigating pathology associated with human whole blood insult in intracerebral haemorrhage.

neuroscience↗

bioRxiv2025

Genome-wide SNP diversity in natural and cultivated populations informs restoration ecology with three Calamagrostis species from the Northwest Territories of Canada

There is growing demand for data-driven frameworks to guide robust plant restoration strategies in response to anthropogenic disturbances. Several seed-sourcing (i.e., provenancing) strategies have been proposed, which balance the use of locally adapted genotypes against mixed genotypes to reduce mutation load or assistant migration to anticipate future climate scenarios. However, taxonomic uncertainty and lack of data characterizing genetic differentiation and gene flow have hindered provenancing strategies for many ecologically important non-model plant species--especially those in remote but vulnerable regions like the boreal forests of northern Canada. To guide provenancing strategies following anthropogenic disturbance in Canadas Northwest Territories, we characterize species-specific markers, population structure, and hybridization among three Calamagrostis species. Double digest RAD sequencing (ddRAD) resulted in 2,951 polymorphic loci across 27 individuals, which we used to design loci for genotyping in thousands by sequencing (GT-seq), a cost-efficient target loci approach resulting in 256 polymorphic loci across 93 individuals from wild C. canadensis, C. stricta ssp. inexpansa and C. purpurascens populations. To help define the scale of local populations for seed sourcing, we characterized geographic variation and population structure among 57 wild collection sites. We also assessed genetic relationships of wild C. canadensis to 69 individuals across eight commercially maintained populations used in restoration projects. We found that GT-seq yields similar genetic differentiation patterns as common neutral molecular marker approaches like ddRAD-seq. Specifically, we resolve morphologically misidentified individuals, identify genetic hybrids, and characterize the scale of genetic isolation-by-distance. Finally, we determined that three cultivar seed sources were genetically similar to southern wild populations, whereas five cultivars aligned with northern wild populations of C. canadensis in the Northwest Territories of Canada. Overall, our results highlight the benefits of cost-effective methods for genome-wide multi-locus genotyping to inform provenancing best-practices and support more effective and sustainable restoration efforts.

genomics↗

bioRxiv2025

Closed-loop sonothermogenetic control of CAR T cells for metronomic brain cancer therapy

Achieving durable CAR T cell responses against primary brain tumors and metastases requires strategies that enable intracranial control of therapy to overcome the barriers of solid tumor treatment without compromising safety. Here, we show that closed-loop sonothermogenetics enables remote regulation of CAR T cell therapeutic activity through the intact skull. Using MR-guided focused ultrasound with closed-loop temperature feedback, we modulate CAR T cells engineered with a genetically encoded thermal bioswitch to achieve metronomic activation in the brain without lasting adverse effects on healthy brain tissue. In murine models of brain cancer, metronomic production of NKG2D T cell engagers by intratumoral CAR T cells overcomes antigen heterogeneity in breast cancer brain metastasis and myeloid-derived immunosuppression in glioblastoma to drive antitumor responses. Our findings support the use of closed-loop sonothermogenetics for spatial and temporal control of CAR T cell therapies targeting solid brain tumors.

bioengineering↗

bioRxiv2023

Genome-wide analysis of promoter contacts identifies novel regulators of late-stage adipogenesis

Adipogenesis is a multi-stage process essential for healthy fat storage and metabolic regulation. While early regulatory mechanisms are well characterized, the control of late-stage adipocyte differentiation remains poorly understood. Integrating CAGE-seq, promoter capture Hi-C, and a high-throughput siRNA screen of druggable genes, we report here that chromatin architecture rewiring promotes gene regulation changes essential for terminal adipogenesis. We identified nine clusters of dynamic promoter-anchored chromosomal interactions, many involving distal enhancers. Functional screening of genes engaged in these interactions revealed 19 novel regulators of late adipogenesis, including proteins with peptidase and ubiquitin ligase activity. Human genetic variant-to-gene mapping, coupled with cross-species chromatin interaction and synteny analyses, highlighted new gene-trait associations relevant to lipid traits (FXYD5, LAP3, SGPP1) and type 2 diabetes (FBXO17, FN3KRP, ZFAND6, TTC3). Our findings define the 3D gene regulatory landscape of late adipogenesis. The molecular links uncovered here provide mechanistic insight into metabolic disease risk and potential interventions.

genetics↗

bioRxiv2022

Molecular diversity and connectivity of accessory olfactory system neurons

Olfaction is the primary sensory modality by which most vertebrate species interpret environmental cues for appropriate behavioral outputs. The olfactory system is subdivided into main (MOS) and accessory (AOS) components which process volatile and non-volatile cues. While much is known regarding the molecular diversity of neurons that comprise the MOS, less is known about the AOS. Here, focusing on the AOS which is largely comprised of the peripheral vomeronasal organ (VNO), the accessory olfactory bulb (AOB) and the medial subnucleus of the amygdala (MeA), we studied the molecular diversity and neuronal subtype connectivity of this interconnected circuit. We show that populations of neurons of the AOS can be molecularly subdivided based on their current or prior expression of the transcription factors Foxp2 or Dbx1. We show that the majority of AOB neurons that project directly to the MeA are of the Foxp2-lineage. Using single cell patch clamp electrophysiology, we further reveal that in addition to sex-specific differences across lineage, the relative contributions of excitatory and inhibitory inputs to MeA Foxp2-lineage neurons differ between sexes. Together, this work uncovers a novel molecular diversity of AOS neurons and lineage- and sex-differences in patterns of connectivity.

neuroscience↗

bioRxiv2022

The imprinted Mir483 is a growth suppressor and metabolic regulator functioning through IGF1

Mir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Here, we uncover the control mechanisms and physiological functions of Mir483 in vivo, by generating constitutive loss-of-function and over-expressing mice. Mir483 expression is imprinted and dependent on the Igf2 promoters and Igf2/H19 imprinting control region. Over-expression of Mir483 causes severe mid-gestation fetal, but not placental, growth restriction, and late lethality. Fetal death is prevented by restoring Mir483 to endogenous levels using an inducible transgenic system. Continuous postnatal Mir483 over-expression induces growth stunting, elevated hepatic lipid content, increased adiposity, reduced local and systemic IGF1 levels and increased GH. The growth phenotypes are rescued by IGF1 infusion. Our findings provide evidence for a novel functional antagonism between a growth-suppressor microRNA and its growth-promoter host gene, and suggest that Mir483 evolved to limit excessive tissue growth through repression of IGF ligand signalling.

developmental biology↗

bioRxiv2022

A baseline for the genetic stock identification of Atlantic herring, Clupea harengus, in ICES Divisions 6.a, 7.b-c

Atlantic herring in ICES Divisions 6.a, 7.b-c comprises at least three populations, distinguished by temporal and spatial differences in spawning, which have until recently been managed as two stocks defined by geographic delineators. Outside of spawning the populations form mixed aggregations, which are the subject of acoustic surveys. The inability to distinguish the populations has prevented the development of separate survey indices and separate stock assessments. A panel of 45 SNPs, derived from whole genome sequencing, were used to genotype 3,480 baseline spawning samples (2014-2021). A temporally stable baseline comprising 2,316 herring from populations known to inhabit Division 6.a was used to develop a genetic assignment method, with a self-assignment accuracy >90%. The long-term temporal stability of the assignment model was validated by assigning archive (2003-2004) baseline samples (270 individuals) with a high level of accuracy. Assignment of non-baseline samples (1,514 individuals) from Division 6.a, 7.b-c indicated previously unrecognised levels of mixing of populations outside of the spawning season. The genetic markers and assignment models presented constitute a toolbox that can be used for the assignment of herring caught in mixed survey and commercial catches in Division 6.a into their population of origin with a high level of accuracy.

zoology↗

bioRxiv2021

PD-1 expression on NK cells can be related to cytokine stimulation and tissue residency

Although PD-1 was shown to be a hallmark of T cells exhaustion, controversial studies have been reported on the role of PD-1 on NK cells. Here, we found by flow cytometry and single cell RNA sequencing analysis that PD-1 can be expressed on MHC class I-deficient tumor-infiltrating NK cells in vivo. We also demonstrate distinct alterations in the phenotype of PD-1-deficient NK cells which in part could be attributed to a decrease in tumor-infiltrating NK cells in PD-1-deficient mice. NK cells from PD-1-deficient mice exhibited a more mature phenotype which might reduce their capacity to migrate and kill in vivo. Finally, our results demonstrate that PD-L1 molecules in membranes of PD-1-deficient NK cells migrate faster than in NK cells from wildtype mice, suggesting that PD-1 and PD-L1 form cis interactions with each other on NK cells.

immunology↗