Biology subjects

Haldenby, S.

Publications and source records attributed to Haldenby, S..

5 recordsLinked to original sources

bioRxiv2025

Cytokines of the Interleukin-1 superfamily and Interleukin-6 are associated with neuroinflammation and brain injury in Herpes Simplex Virus Encephalitis

Herpes simplex virus (HSV) is the leading cause of encephalitis, with high rates of morbidity and mortality. Dysregulated immune responses have been associated with poor outcomes in small series, driving interest in immunotherapies. However, the key mediators of neuropathology, their cellular sources, and responsiveness to corticosteroid treatment remain unknown. We present findings from an RCT of dexamethasone in 55 adults with HSV encephalitis, alongside a representative murine model. Clinical severity and adverse outcomes were associated with neuroglial injury biomarkers (GFAP, tau, UCH-L1), increased cerebral oedema on MRI, and higher IL-1RA, IL-18, and IL-6. These mediators were more abundant in matched CSF than serum, and were not reduced by dexamethasone. In the model, neurons, astrocytes and microglia robustly expressed IL-1 and IL-6, supporting their CNS origin. These findings identify IL-1 and IL-6 signalling as key drivers of immunopathology in HSV encephalitis and potential therapeutic targets to mitigate neuroinflammation and improve outcomes. FundingNational Institute for Health and Care Research (grant number 12/205/28).

neuroscience↗

bioRxiv2025

Characterising the effect of age and sex on post-transcriptional regulation in synovial joint tissues

Age and sex are major risk factors for joint degeneration and disease susceptibility. While epigenetic and post-transcriptional mechanisms are known to be influenced by these factors, their effects on mRNA kinetics and configuration in musculoskeletal tissues remain poorly defined. To address this gap, we used an equine model to examine how age and sex impact mRNA stability in joint tissues. We measured global transcript half-life in primary chondrocytes from young and old female and young male horses using SLAM-seq. Polyadenylation patterns were additionally analysed in cartilage and synovium across age groups. Our findings demonstrated that age and sex exert distinct regulatory influences on post-transcriptional gene expression in joint tissues. Specifically, ageing alters polyadenylation site usage and transcript turnover in cartilage, even in absence of overt pathology, suggesting that molecular ageing may precede and predispose to joint degeneration. We also found that mean RNA half-life differed significantly between young females and males, with male chondrocytes showing greater transcript stability. This difference suggests that sex-specific regulatory mechanisms may influence RNA stability, which could contribute to differential susceptibility to joint degeneration. Together, these results point to age and sex as key drivers of post-transcriptional regulation with potential roles in shaping joint health trajectories. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/677035v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@99310borg.highwire.dtl.DTLVardef@162ee69org.highwire.dtl.DTLVardef@125108org.highwire.dtl.DTLVardef@860828_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

MUTE drives asymmetric divisions to form stomatal subsidiary cells in Crassulaceae succulents

Amongst the evolutionary innovations of many succulents is a photosynthetic lifestyle, where stomatal gas exchange is decoupled from light-dependent carbon fixation. Stomatal complexes in the emerging succulent model Kalanchoe laxiflora consist of two guard cells surrounded by three anisocytic subsidiary cells (SCs). Here, we show that these SCs shuttle ions and thus likely support stomatal movements. Furthermore, gene editing, reporter lines and protein overexpression implicate the stomatal transcription factor MUTE in facilitating additional rounds of asymmetric divisions that form SCs in succulents. This is opposite to the role of MUTE in Arabidopsis thaliana, where it stops rather than induces asymmetric divisions, but reminiscent of MUTEs SC-related function in grasses. Together, our work deciphers an intricate genetic mechanism that generates innovative stomatal morphology in Crassulaceae succulents.

plant biology↗

bioRxiv2023

Genotypic and Phenotypic Analyses of Two Distinct Sets of Pseudomonas aeruginosa Urinary Tract Isolates

Urinary tract infections (UTIs) are associated with a high burden of morbidity, mortality, and cost. Pseudomonas aeruginosa employs a myriad of virulence factors, including biofilm formation and motility mechanisms, to cause infections including persistent UTIs. P. aeruginosa is highly resistant to antibiotics and the World Health Organization has identified it as a pathogen for which novel antimicrobials are urgently required. Genotypic and phenotypic characterization of P. aeruginosa from UTIs are underreported. In addition, the rise of antimicrobial resistance (AMR) is a cause for concern, particularly in many countries where surveillance is severely lacking. 22 P. aeruginosa UTI isolates were sourced from the United Kingdom (UK) and Kuwait. To establish the phenotypes of UK isolates, growth analysis, biofilm formation assays, motility assays, and antibiotic disc diffusion assays were performed. Whole genome sequencing, antimicrobial susceptibility assays, and in silico detection of AMR-associated genes were conducted on both sets of isolates. In terms of their phenotypic characteristics and genomic composition, the UTI isolates varied. Multiple resistance genes associated with resistance to various classes of antibiotics, such as aminoglycosides, fluoroquinolones, and {beta}-lactams, particularly in isolates from Kuwait. Extreme antibiotic resistance was detected in the isolates obtained from Kuwait, indicating that the country may be an antibiotic resistance hotspot. This study highlights that isolates from UTIs are diverse and can display extremely high resistance. Surveillance in countries such as Kuwait are currently limited and this study suggest the need for greater surveillance.

microbiology↗

bioRxiv2019

Trimester-specific Zika virus infection affects placental responses in women

Zika virus (ZIKV) infection during pregnancy is associated with neurologic birth defects, but the effects on placental development are unclear. Full-term placentas from three women, each infected with ZIKV during specific pregnancy trimesters, were harvested for anatomic, immunologic and transcriptomic analysis. In this study, each woman exhibited a unique immune response, but they collectively diverged from healthy controls with raised IL-1RA, IP-10, EGF and RANTES expression, and neutrophil numbers during the acute infection phase. Although ZIKV NS3 antigens co-localized to placental Hofbauer cells, the placentas showed no anatomical defects. Transcriptomic analysis of samples from the placentas revealed that infection during trimester 1 caused a disparate cellular response centered on differential eIF2 signaling, mitochondrial dysfunction and oxidative phosphorylation. These findings should translate to improve clinical prenatal screening procedures for virus-infected pregnant patients.

immunology↗