Biology subjects

Bell, J. A.

Publications and source records attributed to Bell, J. A..

5 recordsLinked to original sources

bioRxiv2026

Single-Cell RNA Sequencing Reveals Distinct Cellular and Molecular Features of Steroid-Induced Osteonecrosis of the Femoral Head Compared to Alcohol-Induced Osteonecrosis and Hip Osteoarthritis

Osteonecrosis of the femoral head (ONFH) remains a devastating complication of glucocorticoid therapy and alcohol abuse, yet the pathophysiology is poorly understood. Using single-cell RNA sequencing, we analyzed femoral head specimens from patients undergoing total hip arthroplasty due to steroid-induced ONFH, alcohol-induced ONFH, or hip osteoarthritis (OA). Our comprehensive analysis across conditions revealed etiology-specific cellular compositions and transcriptional profiles. Steroid-induced ONFH demonstrated a distinctive immunological signature characterized by a neutrophil-predominant, elevated innate-to-adaptive immune cell ratio compared to alcohol-induced ONFH or OA. T cell analysis revealed impaired maturation in steroid-induced ONFH, with abundant naive T cells but reduced mature CD4+ T cells and CD4+ memory T cells compared to both alcohol-induced ONFH and OA. In addition, compared to alcohol-induced ONFH, steroid-induced ONFH was associated with an increase in exhausted/dysfunctional CD8+ T cells which suggests an impaired response to stress and reflects chronic immune dysfunction. Within stromal cell populations, steroid-induced ONFH demonstrated an increase in pericytes, endothelial cells, and mesenchymal cell with osteogenic features as compared to both alcohol-induced ONFH or OA. These findings collectively reveal novel cellular mechanisms underlying steroid-induced ONFH which may contribute to further investigation of etiology-specific pathogenesis and treatment strategies.

genomics↗

bioRxiv2024

Mild neonatal hypoxia disrupts adult hippocampal learning and memory and is associated with CK2-mediated dysregulation of synaptic calcium-activated potassium channel KCNN2

ObjectiveAlthough nearly half of preterm survivors display persistent neurobehavioral dysfunction including memory impairment without overt gray matter injury, the underlying mechanisms of neuronal or glial dysfunction, and their relationship to commonly observed cerebral white matter injury are unclear. We developed a mouse model to test the hypothesis that mild hypoxia during preterm equivalence is sufficient to persistently disrupt hippocampal neuronal maturation related to adult cellular mechanisms of learning and memory. Methods: Neonatal (P2) mice were exposed to mild hypoxia (8%O2) for 30 min and evaluated for acute injury responses or survived until adulthood for assessment of learning and memory and hippocampal neurodevelopment. ResultsNeonatal mild hypoxia resulted in clinically relevant oxygen desaturation and tachycardia without bradycardia and was not accompanied by cerebral gray or white matter injury. Neonatal hypoxia exposure was sufficient to cause hippocampal learning and memory deficits and abnormal maturation of CA1 neurons that persisted into adulthood. This was accompanied by reduced hippocampal CA3-CA1 synaptic strength and LTP and reduced synaptic activity of calcium-sensitive SK2 channels, key regulators of spike timing dependent neuroplasticity, including LTP. Structural illumination microscopy revealed reduced synaptic density, but intact SK2 localization at the synapse. Persistent loss of SK2 activity was mediated by altered casein kinase 2 (CK2) signaling. InterpretationClinically relevant mild hypoxic exposure in the neonatal mouse is sufficient to produce morphometric and functional disturbances in hippocampal neuronal maturation independently of white matter injury. Additionally, we describe a novel persistent mechanism of potassium channel dysregulation after neonatal hypoxia. Collectively our findings suggest an unexplored explanation for the broad spectrum of neurobehavioral, cognitive and learning disabilities that paradoxically persist into adulthood without overt gray matter injury after preterm birth.

neuroscience↗

bioRxiv2021

Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis

Extracellular matrix (ECM) stiffening with downstream activation of mechanosensitive pathways is strongly implicated in fibrosis. We previously reported that altered collagen nanoarchitecture is a key determinant of pathogenetic ECM structure-function in human fibrosis (Jones et al., 2018). Here, through human tissue, bioinformatic and ex vivo studies we show that hypoxia-inducible factor (HIF) pathway activation is a critical pathway for this process regardless of oxygen status (pseudohypoxia). Whilst TGF{beta} increased rate of fibrillar collagen synthesis, HIF pathway activation was required to dysregulate post-translational modification of fibrillar collagen, promoting bone-type cross-linking, altering collagen nanostructure, and increasing tissue stiffness. In vitro, knock down of Factor Inhibiting HIF (FIH) or oxidative stress caused pseudohypoxic HIF activation in normal fibroblasts. In contrast, endogenous FIH activity was reduced in fibroblasts from patients with lung fibrosis in association with significantly increased normoxic HIF pathway activation. In human lung fibrosis tissue, HIF mediated signalling was increased at sites of active fibrogenesis whilst subpopulations of IPF lung mesenchymal cells had increases in both HIF and oxidative stress scores. Our data demonstrate that oxidative stress can drive pseudohypoxic HIF pathway activation which is a critical regulator of pathogenetic collagen structure-function in fibrosis.

cell biology↗

bioRxiv2019

Early metabolic features of genetic liability to type 2 diabetes: cohort study with repeated metabolomics across early life

BackgroundType 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterising liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to detailed metabolic traits across early life.\n\nMethods and FindingsData were from up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children cohort. Linear models were used to examine effects of a genetic risk score (GRS, including 162 variants) for adult type 2 diabetes on 4 repeated measures of 229 traits from targeted nuclear magnetic resonance (NMR) metabolomics. These traits included lipoprotein subclass-specific cholesterol and triglyceride content, amino and fatty acids, inflammatory glycoprotein acetyls, and others, and were measured in childhood (age 8y), adolescence (age 16y), young-adulthood (age 18y), and adulthood (age 25y). For replication, two-sample Mendelian randomization (MR) was conducted using summary data from genome-wide association studies of metabolic traits from NMR in an independent sample of adults (N range 13,476 to 24,925; mean (SD) age range 23.9y (2.1y) to 61.3y (2.9y)). Among ALSPAC participants (49.7% male), the prevalence of type 2 diabetes was very low across time points (< 5 cases when first assessed at age 16y; 7 cases (0.4%) when assessed at age 25y). At age 8y, type 2 diabetes liability (per SD-higher GRS) was associated with lower lipids in high-density lipoprotein (HDL) particle subtypes - e.g. -0.03 SD (95% CI = -0.06, -0.003; P = 0.03) for total lipids in very-large HDL. At age 16y, associations remained strongest with lower lipids in HDL and became stronger with pre-glycemic traits including citrate (-0.06 SD, 95% CI = -0.09, -0.02; P = 1.41x10-03) and with glycoprotein acetyls (0.05 SD, 95% CI = 0.01, 0.08; P = 0.01). At age 18y, associations were stronger with branched chain amino acids including valine (0.06 SD; 95% CI = 0.02, 0.09; P = 1.24x10-03), while at age 25y, associations had strengthened with VLDL lipids and remained consistent with previously altered traits including HDL lipids. Results of two-sample MR in an independent sample of adults indicated persistent patterns of effect of type 2 diabetes liability, with higher type 2 diabetes liability positively associated with VLDL lipids and branched chain amino acid levels, and inversely associated with HDL lipids - again for large and very large HDL particularly (-0.004 SD (95% CI = -0.007, -0.002; P = 8.45x10-04) per 1 log odds of type 2 diabetes for total lipids in large HDL). Study limitations include modest sample sizes for ALSPAC analyses and limited coverage of protein and hormonal traits; insulin was absent as it is not quantified by NMR and not consistently available at each time point. Analyses were restricted to white-Europeans which reduced confounding by population structure but limited inference to other ethnic groups.\n\nConclusionsOur results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability which precedes higher branched chain amino acid and inflammatory glycoprotein acetyl levels. This feature is apparent in childhood as early as age 8y, decades before the clinical onset of disease.\n\nAuthor summaryO_ST_ABSWhy was this study done?C_ST_ABSO_LIType 2 diabetes develops for many years before diagnosis. Clinical disease is characterised by numerous metabolic perturbations that are detectable in circulation, but which of these reflect the developmental stages of type 2 diabetes - as opposed to independent causes of type 2 diabetes or markers of other disease processes - is unknown. Revealing traits specific to type 2 diabetes development could inform the targeting of key pathways to prevent the clinical onset of disease and its complications.\nC_LIO_LIGenetic liability to type 2 diabetes is less prone to confounding than measured type 2 diabetes or blood glucose and may help reveal early perturbations in the blood that arise in response to type 2 diabetes liability itself.\nC_LI\n\nWhat did the researchers do and find?O_LIWe examined effects of genetic liability to adult type 2 diabetes, based on a genetic risk score including 162 variants, on detailed metabolic traits measured on the same individuals across four stages of early life - childhood (age 8y), adolescence (age 16y), young-adulthood (age 18y), and adulthood (age 25y).\nC_LIO_LIWe found that higher type 2 diabetes liability was associated most consistently across ages with lower lipid content in certain subtypes of HDL particles. Effects were more gradual on higher lipid content in VLDL particles and on higher branched chain amino acid and inflammatory glycoprotein acetyl levels.\nC_LI\n\nWhat do these findings mean?O_LISigns of type 2 diabetes liability are detectable in the blood in childhood, decades before the disease becomes noticeable. These signs, taken to reflect the early features of, or coincident with, disease, likely involve lower lipid content in HDL particles, followed by higher levels of branched chain amino acids and inflammation.\nC_LIO_LIGenetic risk scores for adult diseases can be integrated with metabolic measurements taken earlier in life to help to reveal the timing at which signs of disease liability become visible and the traits most central to its development.\nC_LI

genetics↗

bioRxiv2019

Puberty timing and adiposity change across childhood and adolescence: disentangling cause and consequence

ObjectiveTo better understand if earlier puberty is more likely a result of adiposity gain in childhood than a cause of adiposity gain in adulthood.\n\nDesignProspective birth cohort study.\n\nSettingPopulation based study of children born in 1991/1992 in Bristol UK (Avon Longitudinal Study of Parents and Children (ALSPAC)).\n\nParticipants4,186 participants (2,176 female and 1,990 male) of predominantly White ethnicity with 18,232 repeated measures throughout follow-up.\n\nExposures & outcomesRepeated measures of height from 5y to 20y to identify puberty timing (age at peak height velocity) and repeated measures of dual-energy X-ray absorptiometry-derived fat mass from age 9y to 18y, modelled separately in females and males using models based on chronological age and time before and after puberty onset.\n\nResultsMean age at peak height velocity was 11.7y (standard deviation (SD)=0.8y) for females and 13.6y (SD=0.9y) for males. In adjusted models of fat mass by chronological age, a one-year later age at peak height velocity was associated with 20.4% (95% Confidence Interval (CI): 18.5% to 22.3%) and 22.8% (95% (CI): 20.7% to 24.8%) lower fat mass in females and males respectively at 9y. These differences were smaller at age 18y: 7.8% (95% (CI):5.9% to 9.6%) and 11.9% (95% (CI): 9.1%, to 14.7%) lower fat mass in females and males respectively per year later age at peak height velocity. Trajectories of fat mass by time before and after puberty onset provided strong evidence for an association of pre-pubertal fat mass with puberty timing, and little evidence of an association of puberty timing with post-pubertal changes in fat mass in females. In males, findings were less clear before puberty though there was some evidence for an association of earlier puberty timing with great post-pubertal gain in fat mass.\n\nConclusionsEarlier puberty is more likely a result of adiposity gain in childhood than a cause of adiposity gain in adulthood in females. In males early to puberty, differences in fat mass after puberty are driven partially by tracking of adiposity from early childhood but also greater gains in post-pubertal adiposity. Reducing levels of childhood adiposity may help prevent both earlier puberty, later life adiposity and their associated adverse social, mental and physical health sequelae.

epidemiology↗