Biology subjects

Hawkins, T.

Publications and source records attributed to Hawkins, T..

3 recordsLinked to original sources

bioRxiv2025

An Evolutionary Distinct Nipah G Glycosylation Site Provides Stability for Receptor Engagement

Nipah virus is a deadly paramyxovirus with 40-75% mortality and >750 cases since 1998. Currently there are no clinically approved vaccines or therapeutics to target infection. Nipah is an enveloped virus with two surface glycoproteins, the trimeric fusion (F) and tetrameric attachment glycoprotein (G). G is responsible for cellular attachment via binding to ephrin B2/B3. Glycosylation of Nipah G and its effects on receptor engagement has not previously been studied but is important as glycosylation impacts immunogenicity, receptor binding and structural conformations for other enveloped virus glycoproteins. Our phylogenetic and mass spectrometry analysis of site-specific N-glycans of the Nipah G Malaysia strain revealed how N-glycosylation has evolved since the appearance of the virus in 1998. We discovered that the N481 N-glycosite is not conserved and although the glycan does not directly contribute to receptor binding, the threonine/serine in the glycosylation sequon is critical for maintaining long-range stability of individual G subunits that facilitates ephrin B2 binding affinity. Together, these data reveal plasticity of N-glycosylation sites across Nipah species and the presence of hydrogen bonding networks that contribute to G stability and host engagement, which is valuable information for understanding virus attachment/entry mechanisms as well as the rationale design of structure-based vaccines. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/646399v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@15960a8org.highwire.dtl.DTLVardef@d8cacdorg.highwire.dtl.DTLVardef@ea6eb4org.highwire.dtl.DTLVardef@10a2c84_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Subsets of extraocular motoneurons produce kinematically distinct saccades during hunting and exploration.

Animals construct diverse behavioural repertoires by moving a limited number of body parts with varied kinematics and patterns of coordination. There is evidence that distinct movements can be generated by changes in activity dynamics within a common pool of motoneurons, or by selectively engaging specific subsets of motoneurons in a task-dependent manner. However, in most cases we have an incomplete understanding of the patterns of motoneuron activity that generate distinct actions and how upstream premotor circuits select and assemble such motor programmes. In this study, we used two closely related but kinematically distinct types of saccadic eye movement in larval zebrafish as a model to examine circuit control of movement diversity. In contrast to the prevailing view of a final common pathway, we found that in oculomotor nucleus, distinct subsets of motoneurons were engaged for each saccade type. This type-specific recruitment was topographically organised and aligned with ultrastructural differ-ences in motoneuron morphology and afferent synaptic innervation. Medially located motoneu-rons were active for both saccade types and circuit tracing revealed a type-agnostic premotor pathway that appears to control their recruitment. By contrast, a laterally located subset of motoneurons was specifically active for hunting-associated saccades and received premotor in-put from pretectal hunting command neurons. Our data support a model in which generalist and action-specific premotor pathways engage distinct subsets of motoneurons to elicit varied movements of the same body part that subserve distinct behavioural functions.

neuroscience↗

bioRxiv2020

Preventive efficacy of a tenofovir alafenamide fumarate nanofluidic implant in SHIV-challenged nonhuman primates

Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing HIV transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here we show that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers partial protection from HIV transmission. We demonstrate that sustained subcutaneous delivery through nTAF in rhesus macaques maintained tenofovir diphosphate concentration at a median of 390.00 fmol/106 peripheral blood mononuclear cells, 9 times above clinically protective levels. In a non-blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal SHIVSF162P3 challenge, the nTAF cohort had a 62.50% reduction (95% CI: 1.72% to 85.69%; p=0.068) in risk of infection per exposure compared to the control. Our finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, where 60.00% protective efficacy was observed in macaques, and clinically, 67.00% reduction in risk with 86.00% preventive efficacy in individuals with detectable drug in the plasma. Overall, our nanofluidic technology shows potential as a subcutaneous delivery platform for long-term PrEP and provides insights for clinical implementation of LA TAF for HIV prevention.

bioengineering↗