Biology subjects

Towers, D.

Publications and source records attributed to Towers, D..

7 recordsLinked to original sources

bioRxiv2026

Genetically restricted human antibodies recognize a conserved β-hairpin in postfusion influenza hemagglutinin

A public class of broadly protective, human antibodies (Abs) binds a conserved {beta}-hairpin exposed in the postfusion conformation of influenza virus hemagglutinin (HA). We here describe use of in vitro immunoassays and high-resolution cryogenic electron microscopy analysis of Ab:HA complexes to explain the apparent genetic restriction of these Abs and the wide range of influenza A and B subtypes they recognize. We show that recognition of the {beta}-hairpin epitope requires 1) germline-encoded residues unique to certain alleles of the human immunoglobulin heavy chain gene IGHV1-2, 2) a short (<14-residue) HCDR3 to avoid steric clash with HA, and 3) several Ab light chain residues that are germline-encoded by various IGLV2-family genes or IGLV7-46. Despite the genetic restrictions, the capacity to make {beta}-hairpin Abs is widespread among humans. We recovered examples of these Abs from 14 genetically unrelated donors, and a previously reported analysis of the IGHV genotypes of ~2,500 individuals sampled from major ethnic populations estimates that >75% of people have the necessary IGHV1-2 alleles to make these Abs. We conclude that an immunogen that displays the {beta}-hairpin epitope might reliably elicit broadly protective influenza antibodies in most humans.

immunology↗

bioRxiv2025

The N-terminal region of malaria vaccine candidate Plasmodium falciparum asparagine-rich merozoite antigen is immunodominant and targeted by polyreactive antibodies

The development of malaria blood-stage vaccines has been hampered by sequence variation in many Plasmodium falciparum proteins involved in erythrocyte invasion. In the past few years, asparagine-rich merozoite antigen (PfARMA) has emerged as a potential vaccine candidate due to its low amino acid sequence diversity and the association between anti-PfARMA antibody levels and protection to malaria. Here, we used samples from P. falciparum-exposed individuals to study naturally acquired B cell and antibody responses to PfARMA. B cell responses to PfARMA were dominated by IgM+ B cells that recognized the N-terminal intrinsically disordered region 1 (IDR1) of PfARMA. A human monoclonal antibody (hmAb) to IDR1 was non-neutralizing, while a second hmAb binding to the folded domain showed weak neutralizing activity. Both PfARMA-specific plasma IgM and IgG responses predominately targeted IDR1 and their levels increased with P. falciparum exposure. However, in contrast to previous reports, these antibody responses did not correlate with protection in age and exposure-matched children. Interestingly, approximately 30% of unexposed individuals had IgG that also targeted IDR1 and was polyreactive, binding to regions with high asparagine content. Finally, we determined that PfARMA is located in or near PfEBA-175+ micronemes. These data suggest that while IgG to the folded domain of PfARMA may inhibit parasite growth, antibody responses to PfARMA are primarily directed to IDR1 and may not directly contribute to protection against malaria.

immunology↗

bioRxiv2025

Machine Learning Reveals Immediate Disruption in Mosquito Flight when exposed to Olyset Nets

Insecticide-treated nets (ITNs) remain a critical intervention in controlling malaria transmission, yet the behavioural adaptations of mosquitoes in response to these interventions are not fully understood. This study examined the flight behaviour of insecticide-resistant (IR) and insecticide-susceptible (IS) Anopheles gambiae strains around an Olyset net (OL), a permethrin-impregnated ITN, versus an untreated net (UT). Using machine learning (ML) models, we classified mosquito flight trajectories with high accuracy (0.838) and ROC AUC (0.925). Contrary to assumptions that behavioural changes at OL would intensify over time, our findings show an immediate onset of convoluted, erratic flight paths for both IR and IS mosquitoes around the treated net. SHAP analysis identified three key predictive features of OL exposure: frequency of zero-crossings in flight angle change, first quartile of flight angle change, and zero-crossings in horizontal velocity. These suggest disruptive flight patterns, indicating insecticidal irritancy. While IS mosquitoes displayed rapid, disordered trajectories and mostly died within 30 minutes, IR mosquitoes persisted throughout the 2-hour experiments but exhibited similarly disturbed behaviour, suggesting resistance does not fully mitigate disruption. Our findings challenge literature suggesting permethrins repellency in solution form, instead supporting an irritant or contactdriven effect when incorporated into net fibres. This study highlights the value of ML-based trajectory analysis for understanding mosquito behaviour, refining ITN configurations and evaluating novel active ingredients aimed at disrupting mosquito flight behaviour. Future work should extend these methods to other ITNs to further illuminate the complex interplay between mosquito behaviour and insecticidal intervention.

animal behavior and cognition↗

bioRxiv2024

Discrimination of inherent characteristics of susceptible and resistant strains of Anopheles gambiae by explainable Artificial Intelligence Analysis of Flight Trajectories

Understanding mosquito behaviours is vital for development of insecticide-treated bednets (ITNs), which have been successfully deployed in sub-Saharan Africa to reduce disease transmission, particularly malaria. However, rising insecticide resistance (IR) among mosquito populations, owing to genetic and behavioural changes, poses a significant challenge. We present a machine learning pipeline that successfully distinguishes between IR and insecticide-susceptible (IS) mosquito behaviours by analysing trajectory data. Data driven methods are introduced to accommodate common tracking system shortcomings that occur due to mosquito positions being occluded by the bednet or other objects. Trajectories, obtained from room-scale tracking of two IR and two IS strains around a human-baited, untreated bednet, were analysed using features such as velocity, acceleration, and geometric descriptors. Using these features, an XGBoost model achieved a balanced accuracy of 0.743 and a ROC AUC of 0.813 in classifying IR from IS mosquitoes. SHAP analysis helped decipher that IR mosquitoes tend to fly slower with more directed flight paths and lower variability than IS--traits that are likely a fitness advantage by enhancing their ability to respond more quickly to bloodmeal cues. This approach provides valuable insights based on flight behaviour that can reveal the action of interventions and insecticides on mosquito physiology.

animal behavior and cognition↗

bioRxiv2023

Insecticidal roof barriers mounted on untreated bednets can be as effective against Anopheles gambiae s.l. as insecticidal bednets

Barrier bednets (BBnets), regular bednets with a vertical insecticidal panel to target mosquitoes above the bednet roof, where activity is highest, have the potential to improve existing Insecticidal Treated Bednets (ITNs), by reducing quantity of insecticide required per net, reducing the toxic risks to those using the net, thus increasing the range of insecticides to choose from. We evaluated performance of different BBnet variants based on the PermaNet 3 (i.e., P3 BBnets with pyrethroid and piperonyl butoxide (PBO) on the roof or barrier; pyrethroid alone on the side walls) in room-scale bioassays, simultaneously video-recorded to track mosquitoes. Experimental results showed the longitudinal P3 barrier (P3L) to be highly effective: P3+P3L were consistently though not significantly more effective than the reference P3 bednet while performance of Ut+P3L was comparable to the reference P3. Comparing contact duration at the treated sections of each variant, the Ut+P3L accumulated 1273 contacts with 1374 seconds duration, all on the barrier, greatly exceeding the 792 seconds duration, from 8049 contacts, accumulated across the entire surface of the PermaNet 3 reference bednet. The BBnets potential to augment existing bednets and enhance their performance is considered.

animal behavior and cognition↗

bioRxiv2022

Behaviour of pyrethroid-resistant Anopheles gambiae at the interface of two dual active-ingredient bed nets, assessed by room-scale infrared video tracking

BackgroundThe success of Insecticide Treated Bednets (ITNs) for malaria vector control in Africa relies on the behaviour of the major malaria vectors, Anopheles species. Research into mosquito behavioural traits influencing the performance of ITNs has focused largely on time or location of biting. Here we investigated less tractable behaviours including timings of net contact, willingness to refeed and longevity post exposure to two next-generation nets, PermaNet(R) 3.0 (P3) and Interceptor(R) G2 (IG2) in comparison with a standard pyrethroid only net (Olyset (OL)) and an untreated net. MethodsSusceptible and resistant Anopheles gambiae mosquitoes were exposed to the nets with a human volunteer host in a room scale assay. Mosquito movements were tracked for two hours using an infrared video system, collecting flight trajectory, spatial position and net contact data. Post-assay, mosquitoes were monitored for a range of sublethal insecticide effects. ResultsOL, P3 and IG2 all killed over 90% of susceptible mosquitoes 24 hours after exposure, but this effect was not seen with resistant mosquitoes where mortality ranged from 16% to 72%. Total mosquito activity was higher around untreated nets than ITNs. There was no difference in total activity, the number, or duration, of net contact, between any mosquito strain, with similar behaviours recorded in susceptible and resistant strains at all ITNs. Net contact was focussed predominantly on the roof for all bednets. We observed a steep decay in activity for both susceptible strains when P3 and OL were present and with IG2 for one of the two susceptible strains. All treated nets reduced the willingness of resistant strains to re-feed when offered blood one-hour post-exposure, with a more pronounced effect seen with P3 and OL than IG2. ConclusionResults indicate that the effects of ITNs on mosquito behaviour are consistent, with no major differences in responses between strains of different pyrethroid susceptibility.

animal behavior and cognition↗

bioRxiv2019

A flexible quantitative phase imaging microscope for label-free imaging of thick biological specimens using aperture masks

A flexible quantitative phase imaging microscope is reported that offers new capabilities in terms of phase measurement from both thin and thick biological specimens. The method utilises Zernikes phase contrast approach for label-free imaging with a Twymann-Green based phase shifting module in the back focal plane. The interfering wave fronts are manipulated by laser cut apertures to form the scattered and non-scattered fields. The design is flexible and low-cost. It is shown that the bandwidth of the optical source can be optimised to enable larger optical path differences to be measured whilst giving essentially speckle free imaging. Phase maps of the cell membrane, nucleus and nucleolus of transparent epidermis cells of Allium cepa have been examined as proof of concept. Measurements from a range of glass beads confirm the optical path difference capability. The implementation of the phase shifting module is < 10% of the cost of that using a spatial light modulator whilst delivering equivalent phase resolution.

biophysics↗