Biology subjects

Andrews, A.

Publications and source records attributed to Andrews, A..

11 recordsLinked to original sources

bioRxiv2026

Predicting the Risk of Avian Influenza Zoonosis using Viral Genome Sequencing Data

Avian Influenza viruses (AIVs) infect a broad host range despite having a natural reservoir in wild aquatic birds. Whilst most strains stay within their host species, some break the species barrier through genetic adaptations. We are most concerned about zoonotic cases, where a human becomes infected. Despite these events being rare, they are associated with high mortality and introduce the risk of onward human-to-human transmission of AIV. As a novel pathogen within the human population, this could have pandemic potential. Using genetic composition features for 8 AIV proteins drawn from viral sequence data, we employ machine-learning algorithms to classify AIV cases as zoonotic or not. These genetic features encode host 'signatures' which can indicate zoonosis and include frequency measures such as dipeptide composition and amino acid physiochemical properties. We consistently find XGBoost to outperform all other algorithms. We optimise parameters for ten classification models: one for each of the 8 proteins and two combined models. Following this, we show that a multi-model approach gives the best performing prediction for AIV zoonosis. We have identified all 8 proteins as having a role in predicting zoonotic transmission. Of particular importance is the PB2 and HA proteins, with specific amino acid physiochemical properties such as charge, secondary structure and hydrophobicity amongst the most indicative features in our combined models. Our alignment-free computational study can identify AIV cases still within avian hosts which are genetically closest to zoonotic AIV cases, thereby identifying the cases most likely to cross the species barrier. In a resource limited environment, our model could be used to quickly identify high priority cases for further investigation.

genomics↗

bioRxiv2026

Rapid spread of nutritional Wolbachia symbionts across and within solitary bee species

Maternally inherited, intracellular Bacteria of the genus Wolbachia are extremely widespread among arthropods. Their evolutionary success is owed to frequent host shifts and rapid subsequent spread within host populations, often facilitated by Wolbachia-induced reproductive manipulations. Theory suggests that carrying Wolbachia must also be beneficial for a successful spread, however the nature of such benefits remains unclear. Here, we demonstrate that Wolbachias success in many solitary bee species is strongly associated with the presence of a gene cassette enabling Wolbachia to synthesize Biotin (vitamin B7). This ability is absent from almost all other Wolbachia strains but common among bee associated strains. We show that Wolbachia occurs in up to 70% of all bee species and that strains carrying this rare genomic element have independently spread into numerous bee hosts recently. We further demonstrate that the presence of the biotin operon is associated with specialised diets in several bee species, suggesting a previously overlooked nutritional role of Wolbachia in this group of important pollinators. Overall, our results suggest that nutritional benefits provided by symbionts may represent a more widespread and important mechanism by which reproductive manipulators spread into new host species than previously appreciated.

evolutionary biology↗

bioRxiv2026

A de novo CO2 Reductase Featuring a Cysteine-Ligated Cobalt Porphyrin Cofactor

Modern protein design methods based on deep learning allow generation of customized protein scaffolds with diverse geometries and functionalities. Here, we capitalize on these recent advances to develop hyper-thermostable de novo CO2 reductases featuring a cobalt porphyrin IX cofactor (CoPPIX). CoPPIX containing enzymes were assembled in vivo through media supplementation with cobalt salts and assessed for photocatalytic CO2 reductase activity. We identified two cysteine-ligated designs that exhibit high activity (>1000 turnovers at rates of up to 25 min-1) while suppressing competing hydrogen evolution pathways. A 2.1 [A] crystal structure shows close agreement to the design model with the Co-Cys bond programmed as intended. This study showcases the power of computational protein design in developing artificial enzymes to activate challenging molecules such as CO2.

biochemistry↗

bioRxiv2025

Axon guidance deficits in a human sensory neuron model of Fabry disease

Fabry disease (FD) is a rare genetic galactosidase alpha (GLA) gene associated lysosomal disorder caused by alpha-galactosidase A (AGAL) deficiency, leading to sphingolipid (globotriaosylceramide, Gb3) accumulation in multiple tissues. Burning pain due to small fiber neuropathy is an early symptom with great impact on health- related quality of life. The pathophysiological role of Gb3 accumulations in sensory neurons of the dorsal root ganglia is incompletely understood. We have differentiated induced pluripotent stem cells of an isogenic GLA knockout line (p.S364del, hemizygous) and its healthy control into sensory neurons to model FD in vitro. We have compared both lines on transcriptional and proteomic level and investigated the effects of AGAL enzyme supplementation. FD sensory neurons showed dysregulation of disease-related pathways, including axon guidance at both RNA and protein level and microfluidic assays revealed shorter neurite length. While AGAL did not restore the transcriptomic state, it reduced Gb3 accumulation and lowered protein ephrin 5A and glycoprotein M6A level. These findings highlight axon guidance alterations in an isogenic human FD sensory model, with potential implications for early central and peripheral innervation in small fiber neuropathy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/673441v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@199cd19org.highwire.dtl.DTLVardef@682521org.highwire.dtl.DTLVardef@15da60borg.highwire.dtl.DTLVardef@1404c10_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Romiumeter: An Open-Source Inertial Measurement Unit-Based Goniometer for Range of Motion Measurements

Range of motion (ROM) serves as a crucial metric for assessing movement impairments. Traditionally, clinicians use goniometers to measure the ROM, but this method relies on the clinicians skill, in particular for difficult joints such as the shoulder and neck joints. Recent studies have explored the use of wearable inertial measurement units (IMUs) as an alternative. IMUs exhibit excellent agreement with goniometers, but the lack of affordable, accessible, and clinically validated tools remains an issue. This paper introduces the Romiumeter, a single IMU-based device designed to measure the ROM of the neck and shoulder movements. To validate its accuracy, the Romiumeter was tested on 34 asymptomatic individuals for shoulder and neck movements, using an optical motion capture system as the ground truth. The device demonstrated good accuracy, with a maximum absolute error of less than 5{degrees} with moderate to good reliable measurements(inter-rater reliability: 0.69 - 0.87 and intra-rater reliability: 0.76 - 0.87). Additionally, the Romiumeter underwent validation for different algorithms, including the complementary and Madgwick filters. Interestingly, no significant differences were found between the algorithms. Overall, the Romiumeter provides reliable measurements for assessing shoulder and neck ROM in asymptomatic individuals.

bioengineering↗

bioRxiv2022

The carnitine shuttle links mitochondrial metabolism to histone acetylation and lipogenesis

Acetyl-CoA is a central metabolite used for lipid synthesis in the cytosol and histone acetylation in the nucleus, among other pathways. The two major precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. While some evidence has suggested the existence of additional routes to nuclear-cytosolic acetyl-CoA, such pathways remain poorly defined. To investigate this, we generated cancer cell lines lacking both ACLY and ACSS2. Unexpectedly, and in contrast to observations in fibroblasts, ACLY and ACSS2 double knockout (DKO) cancer cells remain viable and proliferate, maintain pools of cytosolic acetyl-CoA, and are competent to acetylate proteins in both cytosolic and nuclear compartments. Using stable isotope tracing, we show that both glucose and fatty acids feed acetyl-CoA pools and histone acetylation in DKO cells. Moreover, we provide evidence for the carnitine shuttle and carnitine acetyltransferase (CrAT) as a substantial pathway to transfer two-carbon units from mitochondria to cytosol independent of ACLY. Indeed, in the absence of ACLY, glucose can feed fatty acid synthesis in a carnitine responsive and CrAT-dependent manner. This work defines a carnitine-facilitated route to produce nuclear-cytosolic acetyl-CoA, shedding light on the intricate regulation and compartmentalization of acetyl-CoA metabolism

cell biology↗

bioRxiv2021

Spatially distributed infection increases viral load in a computational model of SARS-CoV-2 lung infection

A key question in SARS-CoV-2 infection is why viral loads and patient outcomes vary dramatically across individuals. Because spatial-temporal dynamics of viral spread and immune response are challenging to study in vivo, we developed Spatial Immune Model of Coronavirus (SIMCoV), a scalable computational model that simulates hundreds of millions of lung cells, including respiratory epithelial cells and T cells. SIMCoV replicates viral growth dynamics observed in patients and shows how spatially dispersed infections can lead to increased viral loads. The model also shows how the timing and strength of the T cell response can affect viral persistence, oscillations, and control. By incorporating spatial interactions, SIMCoV provides a parsimonious explanation for the dramatically different viral load trajectories among patients by varying only the number of initial sites of infection, and the magnitude and timing of the T cell immune response. When the branching airway structure of the lung is explicitly represented, we find that virus spreads faster than in a 2D layer of epithelial cells, but much more slowly than in an undifferentiated 3D grid or in a well-mixed ODE model. These results illustrate how realistic spatially explicit computational models can improve understanding of within-host dynamics of SARS-CoV-2 infection. SummaryA key question in SARS-CoV-2 infection is why viral loads and patient outcomes are so different across individuals. Because its difficult to see how the virus spreads in the lungs of infected people, we developed Spatial Immune Model of Coronavirus (SIMCoV), a computational model that simulates hundreds of millions of cells, including lung cells and immune cells. SIMCoV simulates how virus grows and then declines, and the simulations match data observed in patients. SIMCoV shows that when there are more initial infection sites, the virus grows to a higher peak. The model also shows how the timing of the immune response, particularly the T cell response, can affect how long the virus persists and whether it is ultimately cleared from the lungs. SIMCoV shows that the different viral loads in different patients can be explained by how many different places the virus is initially seeded inside their lungs. We explicitly add the branching airway structure of the lung into the model and show that virus spreads slightly faster than it would in a two-dimensional layer of lung cells, but much slower than traditional mathematical models based on differential equations. These results illustrate how realistic spatial computational models can improve understanding of how SARS-CoV-2 infection spreads in the lung.

immunology↗

bioRxiv2019

Modulation of emotion perception and memory via sub-threshold amygdala stimulation in humans

A common human experience is noticing that emotional life events are more vividly remembered than dull ones. Studies show that the amygdala plays a central role in such emotionally driven enhancement of memory. With this in mind, we investigated the effect of electrical brain stimulation of the left human amygdala on performance on an emotional perception and emotional memory task. We randomly applied sub-threshold 50 Hz stimulation to the left amygdala in 10 patients (5 female and 5 male) with intracranial electrodes during the encoding portion of an emotional valence perception and emotional memory task. We found that amygdala stimulation did not affect reported valence for neutral stimuli (non-stimulated group average valence 5.34, stimulated 5.38, p=0.68) but it did affect positively (non-stimulated group average valence 7.31, stimulated 6.70, p=0.004) and negatively (non-stimulated group average valence 2.79, stimulated 3.55, p=0.0002) valenced stimuli in effect reporting both valence categories as more neutral. Furthermore, we found that stimulation did not significantly disrupt memory for neutral stimuli (68% vs. 61% correctly remembered p=0.48) or positive stimuli (87% vs. 70% correct, trend towards significant difference p=0.09) but did for negative stimuli (83% vs. 67% correct, p=0.03). These results suggest that electrical brain stimulation by our parameters likely reversibly inhibits amygdala function disrupting neural networks responsible for emotional perception and memory. This effect may have clinical implications in treatment of certain neuropsychiatric disorders, such as emotional dysregulation and post-traumatic stress disorder.\n\nStatement of significanceThe current study builds and expands on extensive prior research into the function of the human amygdala. It provides the first systematic description in humans of a cognitive change brought about by direct electrical stimulation of the amygdala on perception of emotional valence and emotional memory. The results provide further evidence on the importance of the amygdala in human cognition. Likewise, out method utilized to study the function of the amygdala can be extended to study the function of other brain regions in humans, such as the cingulate. While these results are preliminary and need to be duplicated, we aim to further study the effects of amygdala stimulation on emotional processing including possible therapeutic application for diverse group of neuropsychiatric conditions.

neuroscience↗

bioRxiv2018

Two factor authorization: Asf1 mediates crosstalk between H3 K14 and K56 acetylation

Acetylation of histones plays a critical role in maintaining the epigenetic state of the eukaryotic cell. One such acetylation site critical for DNA damage repair is H3K56ac. In Saccharomyces cerevisiae, H3K56ac is thought to be driven mainly by Rtt109, a lysine acetyltransferase (KAT) that associates with the histone chaperones Vps75 and Asf1. Both of these chaperones can increase the specificity of histone acetylation by Rtt109, but neither alter the selectivity. It has been shown that histones extracted from cells (Drosophila), presumably containing pre-acetylated histones, can incorporate higher amounts of H3K56ac relative to recombinant non-acetylated histones. We hypothesized that histone pre-acetylation and histone chaperones could function together to drive acetylation of H3K56. In the present study, we test this hypothesis using a series of singly acetylated histones to determine the impact of crosstalk on enzyme selectivity. Our data suggest that crosstalk between acetylation sites plays a major role in altering the selectivity of Rtt109-Vps75 and that the histone chaperone Asf1 mediates this crosstalk. Specifically, we show that H3K14ac/H4 functions with Asf1 to drive H3K56ac by Rtt109-Vps75. We identified an acidic patch in Asf1 that mediates this cross-talk and show that mutations to this region can alter the Asf1 mediated crosstalk that changes Rtt109-Vps75 selectivity. These data explain the genetic link between Gcn5, which acetylates H3K14 and Rtt109. More broadly these data demonstrate that acetylation sites can dictate site selectivity even in the absence of a bromodomain and helps to explain the limited complexity that has been observed of the histone post-translational modifications patterns by global proteomic studies.

biochemistry↗

bioRxiv2018

T Cell Activation Triggers Reversible Inosine-5'-Monophosphate Dehydrogenase Assembly

T cell-mediated adaptive immunity requires naive, unstimulated T cells to transition from a quiescent metabolic state into a highly proliferative state upon T cell receptor engagement. This complex process depends on transcriptional changes mediated by Ca2+-dependent NFAT signaling, mTOR-mediated signaling and increased activity of the guanine nucleotide biosynthetic enzyme inosine-5-monophosphate (IMP) dehydrogenase (IMPDH). Inhibitors of these pathways serve as potent immunosuppressants. Unexpectedly, we discovered that all three pathways converge to promote the assembly of IMPDH protein into micron-scale macromolecular filamentous structures in response to T cell activation. Assembly is post-transcriptionally controlled by mTOR and the Ca2+ influx regulator STIM1. Furthermore, IMPDH assembly and catalytic activity were negatively regulated by guanine nucleotide levels, suggesting a negative feedback loop that limits biosynthesis of guanine nucleotides. Filamentous IMPDH may be more resistant to this inhibition, facilitating accumulation of the higher GTP levels required for T cell proliferation.

immunology↗

bioRxiv2017

IMPDH polymers accommodate both catalytically active and inactive conformations

Several metabolic enzymes undergo reversible polymerization into macromolecular assemblies. The function of these assemblies is often unclear but in some cases they regulate enzyme activity and metabolic homeostasis. The guanine nucleotide biosynthetic enzyme inosine monophosphate dehydrogenase (IMPDH) forms octamers that polymerize into helical chains. In mammalian cells, IMPDH filaments can associate into micron-length assemblies. Polymerization and enzyme activity are regulated in part by binding of purine nucleotides to an allosteric regulatory domain. ATP promotes octamer polymerization, whereas GTP promotes a compact, inactive conformation whose ability to polymerize is unknown. An open question is whether polymerization directly alters IMPDH catalytic activity. To address this, we identified point mutants of human IMPDH2 that either prevent or promote polymerization. Unexpectedly, we found that polymerized and non-assembled forms of IMPDH have comparable catalytic activity, substrate affinity, and GTP sensitivity and validated this finding in cells. Electron microscopy revealed that substrates and allosteric nucleotides shift the equilibrium between active and inactive conformations in both the octamer and the filament. Unlike other metabolic filaments, which selectively stabilize active or inactive conformations, IMPDH filaments accommodate multiple states. Thus, although polymerization alone does not impact catalytic activity, substrate availability and purine balance dramatically affect IMPDH filament architecture.

biochemistry↗