Biology subjects

Roe, A.

Publications and source records attributed to Roe, A..

5 recordsLinked to original sources

bioRxiv2025

C-reactive protein and the menstrual cycle in females with sickle cell disease

There are notable sex disparities in the frequency and severity of vaso-occlusive pain episodes (VOEs) in sickle cell disease (SCD), with females experiencing more frequent and severe episodes during the reproductive years. Many individuals report a temporal link between VOEs and the menstrual cycle, suggesting that sex hormones may play a role in modulating inflammation and pain. This study explores the relationship between inflammatory markers and the menstrual cycle in females with SCD. Plasma samples from 13 female and 18 male individuals with confirmed SCD were analyzed for C-reactive protein (CRP) and other inflammatory biomarkers. In female patients, sex hormones were measured to determine the menstrual cycle phase. While no overall difference in CRP levels was observed between males and females, CRP levels fluctuated significantly across the menstrual cycle in females, with higher levels in the follicular phase compared to the luteal phase. Additionally, platelet counts were significantly elevated in females during the follicular phase compared to males. These findings suggest that cyclic inflammation may contribute to the increased frequency and severity of VOEs in females, particularly during the perimenstrual period. Further research is needed to explore whether hormonal interventions can reduce perimenstrual VOEs in SCD.

immunology↗

bioRxiv2024

Major changes in gene expression between strains of diapausing and non-diapause spruce budworm despite little evidence of genetic divergence

To survive harsh winter conditions, many insects enter a state of dormancy called diapause which allows them to withstand extreme temperatures and lack of food. When diapause is induced, insects enter a state of arrested development and low metabolic rate. Because diapause and environmental conditions are closely linked, variation within and between species in diapause induction, depth, and duration is extremely common. Studies investigating the genetic underpinnings of diapause tend to focus on either different populations and/or environmental variation, which runs the risk of confounding the genetic signal either due to isolation-by-distance or variation in environmental conditions. We use the eastern spruce budworm (Choristoneura fumiferana) to circumvent these issues and investigate within-population variation in diapause. C. fumiferana usually diapauses as second instar larvae, but a small subset of individuals does not diapause and instead continues through development. This non-diapause phenotype can be selected to create a non-diapause strain. Here, we present a chromosome-level assembly of such a non-diapause strain, and compare it to an earlier published genome assembly of the diapause strain. We did not find evidence of major chromosome rearrangements, indicating that the genetic variation between strains is likely small and multi-genic. Gene expression comparisons between the strains indicate major gene expression changes, where genes associated with glycolysis and environmental signaling processing increase in expression in the diapause strain. Lastly, we found that gene expression diverges halfway through the first instar, and not before, indicating that the signal to induce diapause happens early in the first instar. Significance statementThe ability to enter diapause is a crucial adaptation for many insects to survive cold winters. The genetic underpinnings of the diapause phenotype has been the target of many investigations. However, many of these studies focus on variation in diapause on between geographic regions or changes in environmental conditions, which can lead to confounding factors. Here, we focus on within-population variation in diapause in the eastern spruce budworm, with two strains established from the same source population that vary in their ability to induce diapause. We present a chromosome level assembly of the non-diapause strain, and report that genetic changes between the diapause and the non-diapause line are likely small and involve multiple loci. Gene expression differences were extensive, and mostly associated with mechanisms to avoid freezing. This work sets the stage to further investigate how minimal genetic changes can lead to large-scale phenotypic changes as impactful as diapause.

genetics↗

bioRxiv2024

Plasticity in cryoprotectant synthesis involves coordinated shunting away from pyruvate production

Insects living in temperate regions often accumulate a large amount of glycerol during winter to avoid freezing. This seasonal accrual of glycerol is generally produced from glycogen reserves through the pentose phosphate pathway. An alternative pathway to produce glycerol is through glycolysis, normally used for pyruvate production for eventual ATP synthesis. Aside from seasonal accumulation, some insects will also rapidly increase glycerol production as a short-term response to a sudden cold event, thereby increasing cold hardiness when necessary. In the eastern spruce budworm Choristoneura fumiferana, this plasticity in cold hardiness is locally adapted, where northern populations produce more glycerol upon cold shock. Here we investigate how glycerol is produced during the rapid plastic response to fluctuating cold conditions, and whether this pathway could be a target of local adaptation. After a period of repeated cold exposure, we found evidence of increased enzyme activity and increased mRNA abundance of several proteins associated with glycolysis, and a downregulation in expression of glucose-6-phosphate dehydrogenase, associated with pentose phosphate. Pyruvate production is prevented through downregulation of glyceraldehyde-3-phosphate dehydrogenase. We found higher overall enzyme activity and glycerol accumulation in a northern population from Alberta, although there was no evidence of an interaction effect between population and cold shock treatment. This is one the first studies to show a mechanistic basis of such plasticity in cold hardiness.

physiology↗

bioRxiv2024

Mitochondrial metabolism is a key determinant of chemotherapy sensitivity in Colorectal Cancer

Therapy resistance is attributed to over 80% of cancer deaths per year emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. Here, we investigate the transcriptional responses of CRC cells to 5FU treatment, revealing significant metabolic reprogramming towards heightened mitochondrial activity. Utilizing CRC models, we demonstrate sustained enhancement of mitochondrial biogenesis and function following 5FU treatment, leading to resistance in both in vitro and in vivo settings. Furthermore, we show that targeting mitochondrial metabolism, specifically by inhibiting Complex I (CI), sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, our analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.

cancer biology↗

bioRxiv2022

VelcroVax: a bolt-on vaccine platform technology improves antibody titres against a viral glycoprotein in mice

Having varied approaches to the design and manufacture of vaccines is critical in being able to respond to worldwide needs and to newly emerging pathogens. Virus-like particle (VLP) vaccines form the basis of two of the most successful licensed vaccines (against hepatitis B virus (HBV) and human papillomavirus). They are produced by recombinant expression of viral structural proteins, which self-assemble into immunogenic nanoparticles. VLPs can also be modified to present unrelated antigens, and here we describe a universal bolt-on vaccine platform (termed VelcroVax) where the capturing VLP and the target antigen (hapten) are produced separately. We utilise a modified HBV core (HBcAg) VLP, with surface expression of a high-affinity binding sequence (Affimer) directed against a SUMO tag and use this to capture SUMO-tagged gp1 glycoprotein from the arenavirus, Junin virus (JUNV). Using this model system, we have solved high-resolution structures of VelcroVax VLPs, and shown that the VelcroVax-JUNV gp1 complex induces superior humoral immune responses compared to the non-complexed viral protein. We propose that this system could be modified to present a range of haptens and therefore form the foundation of future rapid-response vaccination strategies.

immunology↗