Biology subjects

Taylor, A. B.

Publications and source records attributed to Taylor, A. B..

8 recordsLinked to original sources

bioRxiv2026

Dietary specializations are captured by jaw muscle proportions in mammals

Mammalian diet and feeding ecology are often reflected by craniofacial skeleton specializations, but feeding requires skeletal actuation by a complex suite of muscles with varying sizes, lines of action, and mechanical function. While muscles play a critical role in feeding mechanics, and hence diet, it remains unclear how well variation in jaw muscle morphology predicts diet in mammals. We quantified the evolutionary interplay between mammalian muscle morphology and diet using a large and taxonomically broad sample. We measured the relative proportions and putative force production capacity, quantified as muscle physiological cross-sectional area (PCSA), for the major adductor complexes, along with a key jaw depressor, in 91 mammalian species (30 chiropterans, 33 primates, and 28 ungulates, carnivorans, rodents, and marsupials). We recovered clear dietary signals for several muscle complexes, with the medial pterygoid (larger in herbivores) and temporalis (larger in carnivores) performing best as dietary predictors. The medial pterygoid is particularly relevant for the mechanical innovation in mammals of moving the mandible along non-orthal, medio-lateral trajectories during mastication. Our findings underscore the intuitive, yet previously unquantified, importance of muscles in the evolution of mandibular roll, yaw, and lateral translation, all mammalian hallmarks of processing diverse types of food.

zoology↗

bioRxiv2026

BRD4 recruitment desilences transcription without erasure or depletion of repressive chromatin

How genes are desilenced within mesoscale repressive chromatin is a crucial yet poorly understood phenomenon. Prevailing models posit that methylation of lysine-9 of histone H3 (H3K9me3) engages heterochromatin protein 1 (HP1) to drive chromatin compaction and transcriptional silencing. The erasure of this repressive mark and its replacement with acetyl/acyl groups recruits positive factors such as BRD4/BET to elicit gene transcription. We report that in Friedreichs ataxia, a synthetic gene regulator (SynGR1) drives transcription across repressive chromatin without removal or replacement of H3K9me3 or HP1. By selectively recruiting BRD4/BET into repressive GAA-repeats in frataxin (FXN), SynGR1 creates a paradoxical state where gene transcription and repressive chromatin co-exist. Contrary to convention, we find that BRD4 readily partitions into phase separated HP1 condensates in vitro and into HP1 puncta in patient-derived cells, thus presenting a mechanistic explanation for desilencing transcription without the dispersal of mesoscale repressive chromatin. Epigenetic drugs that gate sequential steps in transcription, synergistically stimulate FXN expression while concomitantly increasing, rather than eliminating, repressive H3K9me3 and HP1 levels. More broadly, this study highlights the dynamic nature of repressive chromatin and the context-dependence of epigenetic marks in regulating gene expression.

cell biology↗

bioRxiv2024

Reconciling competing models on the roles of condensates and soluble complexes in transcription factor function

Phase separation explains the exquisite spatial and temporal regulation of many biological processes, but the role of transcription factor-mediated condensates in gene regulation is contentious, requiring head-to-head comparison of competing models. Here, we focused on the prototypical yeast transcription factor Gcn4 and assessed two models for gene transcription activation, i.e., mediated via soluble complexes or transcriptional condensates. Both models rely on the ability of transcription factors and coactivators to engage in multivalent interactions. Unexpectedly, we found that propensity to form homotypic Gcn4 condensates does not correlate well with transcriptional activity. Contrary to prevailing models, binding to DNA suppresses Gcn4 phase separation. Notably, the ability of Gcn4 to form soluble complexes with coactivator subunit Med15 closely mirrored the propensity to recruit Med15 into condensates, indicating that these properties are intertwined and cautioning against interpretation of mutational data without head-to-head comparisons. However, Gcn4 variants with the highest affinity for Med15 do not function as well as expected and instead have activities that reflect their abilities to phase separate with Med15. These variants therefore indeed form cellular condensates, and those attenuate activity. Our results show that transcription factors can function as soluble complexes as well as condensates, reconciling two seemingly opposing models, and have implications for other phase-separating systems. Highlights- Homotypic phase separation propensities of Gcn4 variants do not predict in vivo activities well. - DNA binding leads to solubilization of GCN4 condensates, which is reversed by Med15 association. - The abilities to co-phase separate and form soluble complexes with Med15 are highly intertwined. - Variants with high affinities for Med15 form condensates that attenuate function.

biophysics↗

bioRxiv2024

Structures of TGF-beta with betaglycan and the signaling receptors reveal the mechanism whereby betaglycan potentiates receptor complex assembly and signaling

Betaglycan (BG) is a transmembrane co-receptor of the transforming growth factor-{beta} (TGF-{beta}) family of signaling ligands. It is essential for embryonic development and tissue homeostasis and fertility in adults. It functions by enabling binding of the three TGF-{beta} isoforms to their signaling receptors and is additionally required for inhibin A (InhA) activity. Despite its requirement for the functions of TGF-{beta}s and InhA in vivo, structural information explaining BG ligand selectivity and its mechanism of action is lacking. Here, we determine the structure of TGF-{beta} bound both to BG and the signaling receptors, TGFBR1 and TGFBR2. We identify key regions responsible for ligand engagement, which has revealed novel binding interfaces that differ from those described for the closely related co-receptor of the TGF-{beta} family, endoglin, thus demonstrating remarkable evolutionary adaptation to enable ligand selectivity. Finally, we provide a structural explanation for the hand-off mechanism underlying TGF-{beta} signal potentiation.

biophysics↗

bioRxiv2023

Oxamniquine Derivatives Overcome Praziquantel Treatment Limitations for Schistosomiasis

Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies for schistosomiasis. Previous treatment of S. mansoni included the use of oxamniquine (OXA), a drug that is activated by a schistosome sulfotransferase (SULT). Guided by data from X-ray crystallography and Schistosoma killing assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150610 and CIDD-0150303 as potent derivatives in vitro that kill (100%) of all three Schistosoma species at a final concentration of 71.5 {micro}M. We evaluated the efficacy of the best OXA derivates in an in vivo model after treatment with a single dose of 100 mg/kg by oral gavage. The highest rate of worm burden reduction was achieved by CIDD-150303 (81.8%) against S. mansoni, CIDD-0149830 (80.2%) against S. haematobium and CIDD-066790 (86.7%) against S. japonicum. We have also evaluated the ability of the derivatives to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150303 demonstrated (100%) killing for all life stages at a final concentration of 143 {micro}M in vitro and effective reduction in worm burden in vivo against S. mansoni. To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150303 and CIDD-0150610 demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we fine tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg/kg by oral gavage with co-dose of PZQ + CIDD-0150303 reduced the worm burden of PZQ resistant parasites in an animal model by 90.8%. Therefore, we conclude that CIDD-0150303, CIDD-0149830 and CIDD-066790 are novel drugs that overcome some of PZQ limitations, and CIDD-0150303 can be used with PZQ in combination therapy. Author SummaryHuman schistosomiasis is a neglected tropical disease caused by parasitic worms in the genus Schistosoma. Human schistosomiasis is caused mainly by three major species: S. mansoni, S. haematobium, and S. japonicum. It affects some 229 million people in 78 countries. Currently, there is no effective vaccine against human schistosomiasis. Praziquantel is the method of choice for treatment and evidence for drug resistance has been reported. Our focus is drug discovery for schistosomiasis. Our project team is designing, synthesizing, and testing reengineered derivatives of oxamniquine against the three human species of Schistosoma. The aim is to develop a new drug for schistosomiasis to overcome developing resistance and improve efficacy. We developed and identified compounds that kill all three human Schistosoma species in addition to a PZQ-resistant strain in animal models. Additionally, animal studies demonstrate that combination treatment of reengineered oxamniquine drugs and praziquantel effectively reduced the infection with a praziquantel resistant strain in infected mice.

biochemistry↗

bioRxiv2022

The amino acid transporter pfaat1 modulates chloroquine resistance and fitness in malaria parasites

Malaria parasites break down host hemoglobin into peptides and amino acids in the digestive vacuole for export to the parasite cytoplasm for growth: interrupting this process is central to the mode of action of several antimalarial drugs. Mutations in the chloroquine (CQ) resistance transporter, pfcrt, located in the digestive vacuole membrane, confer CQ resistance in Plasmodium falciparum, but typically affect parasite fitness. However, the role of other parasite loci in the evolution of CQ resistance is unclear. Here we use a combination of population genomics, genetic crosses and gene editing to demonstrate that a second vacuolar transporter plays a key role in both resistance and compensatory evolution. Longitudinal genomic analyses of the Gambian parasites revealed temporal signatures of selection on an amino acid transporter (pfaat1) S258L variant which increased from 0-87% in frequency between 1984 and 2014 in parallel with pfcrt1 K76T. Parasite genetic crosses then identified a chromosome 6 quantitative trait locus containing pfaat1 that is selected by CQ treatment. Gene editing demonstrated that pfaat1 S258L potentiates CQ-resistance but at a cost of reduced fitness, while pfaat1 F313S, a common Southeast Asian polymorphism, reduces CQ-resistance while restoring fitness. Our analyses reveal hidden complexity in CQ-resistance evolution, suggesting that pfaat1 may underlie regional differences in the dynamics of resistance evolution, and modulate parasite resistance or fitness by manipulating the balance between both amino acid and drug transport.

genomics↗

bioRxiv2019

Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment

Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p.E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29 - 14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni.\n\nAUTHOR SUMMARYIt has been argued that drug resistance is unlikely to spread rapidly in helminth parasites infecting humans. This is based, at least in part, on the premise that resistance mutations are rare or absent within populations prior to treatment, and take a long time to reach appreciable frequencies because helminth parasite generation time is long. This argument is critically dependent on the starting frequency of resistance alleles - if high levels of \"standing variation\" for resistance are present prior to deployment of treatment, resistance may spread rapidly. We examined frequencies of oxamniquine resistance alleles present in Schistosoma mansoni from Africa and the Middle East where oxamniquine has seen minimal use. We found that oxamniquine resistance alleles are widespread in the Old World, ranging from 4.29% in the Middle East to 14.91% in East African parasite populations. Furthermore, we show that resistance alleles from West African and the Caribbean schistosomes share a common origin, suggesting that these alleles travelled to the New World with S. mansoni during the transatlantic slave trade. Together, these results demonstrate extensive standing variation for oxamniquine resistance. Our results have important implications for both drug treatment policies and drug development efforts, and demonstrate the power of molecular surveillance approaches for guiding helminth control.

evolutionary biology↗

bioRxiv2018

High affinity interactions of Pb2+ with Synaptotagmin I

Lead (Pb) is a potent neurotoxin that disrupts synaptic neurotransmission. We report that Synaptotagmin I (SytI), a key regulator of Ca2+-evoked neurotransmitter release, has two high-affinity Pb2+ binding sites that belong to its cytosolic C2A and C2B domains. The crystal structures of Pb2+-complexed C2 domains revealed that protein-bound Pb2+ ions have holodirected coordination geometries and all-oxygen coordination spheres. The on-rate constants of Pb2+ binding to the C2 domains of SytI are comparable to those of Ca2+ and are diffusion-limited. In contrast, the off-rate constants are at least two orders of magnitude smaller, indicating that Pb2+ can serve as both thermodynamic and kinetic trap for the C2 domains. We demonstrate, using NMR spectroscopy, that population of these sites by Pb2+ ions inhibits further Ca2+ binding despite the existing coordination vacancies. Our work offers a unique insight into the bioinorganic chemistry of Pb(II) and suggests a mechanism by which low concentrations of Pb2+ ions can interfere with the Ca2+-dependent function of SytI in the cell.

biophysics↗