Biology subjects

Marks, N.

Publications and source records attributed to Marks, N..

8 recordsLinked to original sources

bioRxiv2026

Trophoblast ferroptosis restricts SARS-CoV-2 spread in the placenta

Prenatal SARS-CoV-2 infection is associated with adverse pregnancy outcomes, but placental mechanisms that restrict viral spread remain unclear. Here we show that SARS-CoV-2 exposure induces ferroptosis-linked iron dysregulation in the placenta as a host defense. Human placentas from early gestation SARS-CoV-2-exposed pregnancies exhibited persistent viral protein expression at term, iron accumulation, disrupted localization of iron transport proteins, and reduced expression of the ferroptosis inhibitor, GPX4. In trophoblast cells and newly generated stem cell-derived trophoblast organoids (SC-TOs) with physiological apical-out polarity, infection with live SARS-CoV-2 Delta variant suppressed expression of iron efflux transporter, ferroportin and ferroptosis inhibitors, GPX4 and PLA2G6, promoting lipid peroxidation and ferroptotic signaling. Sub-lethal pharmacological activation of ferroptosis reduced viral titers in trophoblasts, indicating an antiviral function. Together, these results uncover a new mechanism through which the placenta attempts to restrict SARS-CoV-2 replication. However, this protective response is accompanied by placental iron sequestration, which may compromise maternal-fetal iron transfer and help explain iron deficiency and anemia reported in infants born after prenatal SARS-CoV-2 exposure, highlighting a delicate balance between iron and ferroptosis-mediated protection and damage with implications for pregnancy outcomes.

cell biology↗

bioRxiv2023

Discovery of long non-coding RNAs in the liver fluke, Fasciola hepatica

Long non-coding (lnc)RNAs are a class of eukaryotic RNA that do not code for protein and are linked with transcriptional regulation, amongst a myriad of other functions. Using a custom in silico pipeline we have identified 6,436 putative lncRNA transcripts in the liver fluke parasite, Fasciola hepatica; none of which are conserved with those previously described from Schistosoma mansoni. F. hepatica lncRNAs were distinct from F. hepatica mRNAs in transcript length, coding probability, exon/intron composition, expression patterns, and genome distribution. RNA-Seq and digital droplet PCR measurements demonstrated developmentally regulated expression of lncRNAs between intra-mammalian life stages; a similar proportion of lncRNAs (14.2 %) and mRNAs (12.8 %) were differentially expressed (p<0.001), supporting a functional role for lncRNAs in F. hepatica life stages. While most lncRNAs (81%) were intergenic, we identified some that overlapped protein coding loci in antisense (13%) or intronic (6%) configurations. We found no unequivocal evidence for correlated developmental expression within positionally correlated lncRNA:mRNA pairs, but global co-expression analysis identified five lncRNA that were inversely co-regulated with 89 mRNAs, including a large number of functionally essential proteases. The presence of micro (mi)RNA binding sites in 3135 lncRNAs indicates the potential for miRNA-based post-transcriptional regulation of lncRNA, and/or their function as competing endogenous (ce)RNAs. This first description of lncRNAs in F. hepatica provides an avenue to future functional and comparative genomics studies that will provide a new perspective on a poorly understood aspect of parasite biology.

genomics↗

bioRxiv2022

Pan-phylum In Silico Analyses of Nematode Endocannabinoid Signalling Systems Highlight Novel Opportunities for Parasite Drug Target Discovery

The endocannabinoid signalling (ECS) system is a complex lipid signalling pathway that modulates diverse physiological processes in both vertebrate and invertebrate systems. In nematodes, knowledge of endocannabinoid (EC) biology is derived primarily from the free-living model species Caenorhabditis elegans, where ECS has been linked to key aspects of nematode biology. The conservation and complexity of nematode ECS beyond C. elegans is largely uncharacterised, undermining the understanding of ECS biology in nematodes including species with key importance to human, veterinary and plant health. In this study we exploited publicly available omics datasets, in silico bioinformatics and phylogenetic analyses to examine the presence, conservation and life-stage expression profiles of EC-effectors across phylum Nematoda. Our data demonstrate that: (i) ECS is broadly conserved across phylum Nematoda, including in therapeutically and agriculturally relevant species; (ii) EC-effectors appear to display clade and lifestyle-specific conservation patterns; (iii) filarial species possess a reduced EC-effector complement; (iv) there are key differences between nematode and vertebrate EC-effectors; (v) life stage-, tissue- and sex-specific EC-effector expression profiles suggest a role for ECS in therapeutically relevant parasitic nematodes. These data also highlight putative novel targets for anthelmintic therapies. To our knowledge, this study represents the most comprehensive characterisation of ECS pathways in phylum Nematoda and inform our understanding of nematode ECS complexity. Fundamental knowledge of nematode ECS systems will seed follow-on functional studies in key nematode parasites to underpin novel drug target discovery efforts. CONTRIBUTION TO THE FIELDThis manuscript reports the in silico characterisation of endocannabinoid (EC) signalling pathways across the nematode phylum. The physiological relevance and therapeutic potential of EC signalling in higher organisms has received significant attention. In contrast much of our knowledge on EC signalling in nematodes has been derived from the free-living nematode Caenorhabditis elegans where the EC signalling system appears to play key roles in nematode biology and features GPCRs distinct from vertebrate cannabinoid receptors. Unfortunately, the configuration and broader biological significance of EC signalling pathways across the nematode phylum, including in parasites of agricultural, veterinary and medical significance, remains unknown. The in silico exploration of the nematode EC signalling system reported here will provide baseline data on novel neuronal signalling pathways to seed future drug target discovery pipelines for parasites.

neuroscience↗

bioRxiv2022

Transcriptomic analysis reveals a role for the nervous system in regulating growth and development of Fasciola hepatica juveniles

Fasciola spp. liver fluke have significant impacts in veterinary and human medicine. The absence of a vaccine and increasing anthelmintic resistance threaten sustainable control and underscore the need for novel flukicides. Functional genomic approaches underpinned by in vitro culture of juvenile Fasciola hepatica facilitate control target validation in the most pathogenic life stage. Comparative transcriptomics of in vitro and in vivo maintained 21 day old F. hepatica finds that 86% of genes are expressed at similar levels across maintenance treatments suggesting commonality in core biological functioning within these juveniles. Phenotypic comparisons revealed higher cell proliferation and growth rates in the in vivo juveniles compared to their in vitro counterparts. These phenotypic differences were consistent with the upregulation of neoblast-like stem cell and cell-cycle associated genes in in vivo maintained worms. The more rapid growth/development of in vivo juveniles was further evidenced by a switch in cathepsin protease expression profiles, dominated by cathepsin B in in vitro juveniles and then by cathepsin L in in vivo juveniles. Coincident with more rapid growth/development was the marked downregulation of both classical and peptidergic neuronal signalling components in in vivo maintained juveniles, supporting a role for the nervous system in regulating liver fluke growth and development. Differences in the miRNA complements of in vivo and in vitro juveniles identified 31 differentially expressed miRNAs, notably fhe-let-7a-5p, fhe-mir-124-3p and, miRNAs predicted to target Wnt-signalling, supporting a key role for miRNAs in driving the growth/developmental differences in the in vitro and in vivo maintained juvenile liver fluke. Widespread differences in the expression of neuronal genes in juvenile fluke grown in vitro and in vivo expose significant interplay between neuronal signalling and the rate of growth/development, encouraging consideration of neuronal targets in efforts to dysregulate growth/development for parasite control. Author SummaryParasitic worms are notoriously difficult to study outside of a host organism. However, recent developments in culture methods for Fasciola hepatica liver fluke juveniles support growth and development of these parasites in the laboratory (in vitro) towards adult parasites. Having the ability to grow pathogenic juvenile stages in vitro enables functional studies to validate potential drug and vaccine targets. However, comparison of in vitro grown juveniles to juveniles retrieved from infected hosts (in vivo) shows considerable size differences suggesting at least some differences in biology that could undermine the relevance of data generated from in vitro maintained parasites. This study examines gene expression differences between in vitro and in vivo maintained F. hepatica juveniles via transcriptomic analysis to identify similarities and differences in their biology which may help explain differences in the rate of growth and development. 86% of genes were shown to be expressed at similar levels across treatment groups suggesting a high level of biological similarity between in vitro and in vivo juveniles. However, the genes that are expressed differently between these juveniles will help improve current culture methods and provide a new group of potential drug targets that impact on juvenile growth and development.

molecular biology↗

bioRxiv2021

Animal lifestyle changes acceptable mass limits for attached tags

O_LIAnimal-attached devices have transformed our understanding of vertebrate ecology. To minimize tag-related harm for these studies, researchers have long advocated that tag masses should not exceed 3% of the animals body mass. However, this proposition ignores tag forces generated as a result of animal movement. C_LIO_LIUsing data from collar-attached accelerometers on diverse free-ranging terrestrial animals, we detail a tag-based acceleration method (TbAM) in which we quantify animal athleticism in terms of fractions of animal movement time devoted to different collar-recorded accelerations. The varying accelerations are converted to forces imposed on the animals based on the acceleration and tag mass and allow derivation of defined force limits, including those amounting to 3% of the animals mass, for specified fractions of any animals active time. C_LIO_LIWe demonstrate how species athleticism is the principal determinant of tag forces, whereas body mass is of little importance. Forces exerted by 3% tags were mostly equivalent to 4-19% of the animals masses during moving, with a maximum of 54% in a hunting cheetah. Cumulative frequency curves of tag acceleration for periods when animals were active, all showed a characteristic sigmoid pattern, which was displaced further to the right as higher acceleration activities accounted for an increasing proportion of any animals time. Specifying that tags should exert forces that are less than 3% of the animals body mass for 95% of the time led to corrected tag masses constituting between 1.6% and 2.98% of our study animals masses, with values depending on animal athleticism. C_LIO_LIRecognition that animal athleticism affects tag forces of their carriers fundamentally changes how acceptable tag mass limits should be determined by ethics bodies. In order to have a scientifically robust acceptable threshold to limit the forces experienced by an animal carrier, we suggest practitioners derive a similar cumulative acceleration profile for their study species and use a minimum of the 95% limits on the plot (although higher limits may be more appropriate). C_LI

zoology↗

bioRxiv2020

Forces experienced by instrumented animals depend on lifestyle

Animal-attached devices have transformed our understanding of vertebrate ecology. However, to be acceptable, researchers must minimize tag-related harm. The long-standing recommendation that tag masses should not exceed 3% of the animals body mass ignores tag forces generated by movement. We used collar-attached accelerometers on four free-ranging carnivores, spanning two orders of magnitude in mass, to reveal that during movement, forces exerted by 3% tags were generally equivalent to 4-19% of the animals masses, with a record of 54% in a hunting cheetah. Controlled studies on domestic dogs revealed how the tag forces are dictated by animal gait and speed but appear largely invariant of body mass. This fundamentally changes how acceptable tag mass limits should be determined, requiring cognizance of animal athleticism. One Sentence SummaryThere can be no universal rule for collar-tag masses as a percentage of carrier mass since tag forces depend on lifestyle.

ecology↗

bioRxiv2020

Path tortuosity changes the transport cost paradigm in terrestrial animals

Animal movement paths are variously tortuous, with high turn rates predicted to be energetically costly, especially at high speeds. Animals travel most efficiently at the speed that gives the lowest cost of transport (COT), a well-defined point for movement in fluid media. However, theoretically, land animals should travel at their maximum speed to minimize COT, which they do not, instead travelling at walking pace. We measured oxygen consumption in humans to demonstrate that the energetic costs of turning increase disproportionately with both speed and angular velocity. This resulted in the minimum COT speed occurring at very low speeds, which reduced with increased path tortuosity. Data on turn rates from six free-ranging terrestrial species underpinned this because all individuals turned faster at the slowest speeds across the full speed range. The optimum movement speed for minimum COT in land animals thus depends on the environment and behavior since both affect track tortuosity.

ecology↗

bioRxiv2020

Cholinergic basal forebrain degeneration due to obstructive sleep apnoeaincreases Alzheimer's pathology in mice

Epidemiological studies indicate that obstructive sleep apnoea is a strong risk factor for the development of Alzheimers disease but the mechanisms of the risk remain unclear. We developed a method of modelling obstructive sleep apnoea in mice that replicates key features of human obstructive sleep apnoea: altered breathing during sleep, sleep disruption, moderate intermittent hypoxemia and cognitive impairment. When we induced obstructive sleep apnoea in a familial Alzheimers disease model, the mice displayed exacerbation of cognitive impairment and pathological features of Alzheimers disease, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons. These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the neurodegeneration was mediated by the oxygen-sensitive p75 neurotrophin receptor and hypoxia inducible factor 1 alpha activity. Furthermore, restoring blood oxygen levels during sleep to prevent intermittent hypoxia prevented the pathological changes induced by the OSA. These findings provide a signalling mechanism by which obstructive sleep apnoea induces cholinergic basal forebrain degeneration and could thereby increase the risk of developing Alzheimers disease, as well as providing a rationale for testing a range of possible prophylactic treatment options for people with obstructive sleep apnoea and hypoxia including increased compliance of continuous positive airway pressure therapy.

neuroscience↗