Biology subjects

Andrews, L.

Publications and source records attributed to Andrews, L..

6 recordsLinked to original sources

bioRxiv2026

Distinct nigral and brainstem pathology markers map onto separable subthalamic electrophysiological signatures in Parkinson's disease

Subthalamic local field potentials (LFPs) are increasingly used as physiomarkers of the symptomatic state in Parkinsons disease, but their relationship to the underlying neurodegenerative pathology remains unclear. Here, we combined OFF-medication subthalamic LFP recordings with quantitative MRI markers of nigral and brainstem pathology in 33 people with Parkinsons disease. Distinct pathological markers mapped onto dissociable electrophysiological components. Substantia nigra pars compacta susceptibility was associated with increased occupancy, duration and rate of low-{beta} bursts, whereas nigral free water was associated with greater low-frequency aperiodic offset and a steeper slope. Pedunculopontine nucleus free-water- corrected axial diffusivity was selectively associated with high-frequency aperiodic activity, and this relationship strengthened with increasing nigral susceptibility, consistent with dopaminergic-state- dependent influences of extranigral pathology on subthalamic physiology. Only low-frequency aperiodic offset was also associated with contralateral bradykinesia. These findings indicate that the subthalamic LFP is not a unitary readout of dopamine loss or motor state, but an integrated physiological signal in which pathology across interconnected systems is expressed through separable oscillatory and aperiodic components. Chronically implanted devices may therefore provide physiological readouts of underlying disease biology alongside control signals for adaptive therapy.

neuroscience↗

bioRxiv2023

Identifying LasR quorum sensors with improved signal specificity by mapping the sequence-function landscape

Programmable intercellular signaling using components of naturally-occurring quorum sensing can allow for coordinated functions to be engineered in microbial consortia. LuxR-type transcriptional regulators are widely used for this purpose and are activated by homoserine lactone (HSL) signals. However, they often suffer from imperfect molecular discrimination of structurally similar HSLs, causing misregulation within engineered consortia containing multiple HSL signals. Here, we studied one such example, the regulator LasR from Pseudomonas aeruginosa. We elucidated its sequence-function relationship for ligand specificity using targeted protein engineering and multiplexed high-throughput biosensor screening. A pooled combinatorial saturation mutagenesis library (9,486 LasR DNA sequences) was created by mutating six residues in LasRs {beta}5 sheet with single, double, or triple amino acid substitutions. Sort-seq assays were performed in parallel using cognate and non-cognate HSLs to quantify each corresponding sensors response to each HSL signal, which identified hundreds of highly specific variants. Sensor variants identified were individually assayed and exhibited up to 60.6-fold (p = 0.0013) improved relative activation by the cognate signal compared to the wildtype. Interestingly, we uncovered prevalent mutational epistasis and previously unidentified residues contributing to signal specificity. The resulting sensors with negligible signal crosstalk could be broadly applied to engineer bacteria consortia.

synthetic biology↗

bioRxiv2023

Synthetic Homoserine Lactone Sensors for Gram-Positive Bacillus subtilis using LuxR-type Regulators

A universal biochemical signal for bacterial cell-cell communication could facilitate programming dynamic responses in diverse bacterial consortia. However, the classical quorum sensing paradigm is that gram-negative and gram-positive bacteria generally communicate via homoserine lactones (HSL) or oligopeptide molecular signals, respectively, to elicit population responses. Here, we create synthetic HSL sensors for gram-positive Bacillus subtilis 168 using allosteric LuxR-type regulators (RpaR, LuxR, RhlR, and CinR) and synthetic promoters. Promoters were combinatorially designed from different sequence elements (-35, -16, -10, and transcriptional start regions). We quantified the effects of these combinatorial promoters on sensor activity and determined how regulator expression affects its activation, achieving up to 293-fold activation. Using statistical design of experiments, we identified significant effects of promoter regions and pairwise interactions on sensor activity, which helped to understand the sequence-function relationships for synthetic promoter design. We present the first known set of functional HSL sensors ([≥] 20-fold dynamic range) in B. subtilis for four different HSL chemical signals: p-coumaroyl-HSL, 3-oxohexanoyl-HSL, n-butyryl-HSL, and n-(3-hydroxytetradecanoyl)-HSL. This set of synthetic HSL sensors for a gram-positive bacterium can pave the way for designable interspecies communication within microbial consortia.

synthetic biology↗

bioRxiv2023

Stochastic population models to identify optimal and cost-effective harvest strategies for feral pig eradication

Eradicating feral pigs from island ecosystems can assist in restoring damaged biodiversity values and protect commercial industries such as agriculture. Although many feral pig eradications have been attempted, management decisions are often led by practitioner experience rather than empirical evidence. Few interventions have been guided by population models to identify harvest rates necessary to achieve eradication within a specified time frame, nor have they applied data on control effort and cost to evaluate the relative cost-effectiveness of proposed control strategies. We used effort and cost data from a feral pig-control program on Kangaroo Island, South Australia over 17 months to derive functional-response relationships between control effort (hours pig-1) and pig abundance for four control methods: (i) ground-based shooting, (ii) trapping with remote triggers, (iii) poison baiting, and (iv) thermal-assisted aerial culling. We developed a stochastic Leslie matrix with compensatory density feedback on survival and fertility to project population trajectories from an initial population (N0) of 250 female pigs with an estimated island-wide carrying capacity (K) of 2500 over 3 and 10 years for populations subjected to an annual harvest of 35% to 95%. We built functional-response models to calculate annual effort and cost for six cull scenarios across all harvest rates. We derived total cost and effort over 3- and 10-year projections from the sum of annual cost and effort within the projection intervals. Pig populations were reduced to < 10% N0 based on harvest rates > 70% and 50% for culls of 3- and 10-year duration, respectively. In all scenarios except trapping only, the total cost to reduce population to [≤] 10% of N0 decreased with increasing harvest proportion, with lower total costs incurred over 3 years compared to 10 years. The simulations suggest that the most cost-effective approach for most scenarios is to maximise annual harvest and complete eradication effort over the shortest periods.

ecology↗

bioRxiv2021

Bifurcated monocyte states are predictive of mortality in severe COVID-19

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection presents with varied clinical manifestations1, ranging from mild symptoms to acute respiratory distress syndrome (ARDS) with high mortality2,3. Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in severe COVID-19. We performed high-dimensional cellular and molecular profiling of blood and respiratory samples from critically ill COVID-19 patients to define immune cell genomic states that are predictive of outcome in severe COVID-19 disease. Critically ill patients admitted to the intensive care unit (ICU) manifested increased frequencies of inflammatory monocytes and plasmablasts that were also associated with ARDS not due to COVID-19. Single-cell RNAseq (scRNAseq)-based deconvolution of genomic states of peripheral immune cells revealed distinct gene modules that were associated with COVID-19 outcome. Notably, monocytes exhibited bifurcated genomic states, with expression of a cytokine gene module exemplified by CCL4 (MIP-1{beta}) associated with survival and an interferon signaling module associated with death. These gene modules were correlated with higher levels of MIP-1{beta} and CXCL10 levels in plasma, respectively. Monocytes expressing genes reflective of these divergent modules were also detectable in endotracheal aspirates. Machine learning algorithms identified the distinctive monocyte modules as part of a multivariate peripheral immune system state that was predictive of COVID-19 mortality. Follow-up analysis of the monocyte modules on ICU day 5 was consistent with bifurcated states that correlated with distinct inflammatory cytokines. Our data suggests a pivotal role for monocytes and their specific inflammatory genomic states in contributing to mortality in life-threatening COVID-19 disease and may facilitate discovery of new diagnostics and therapeutics.

immunology↗

bioRxiv2018

Effect of Infection with, and Treatment of, Sensitive and Resistant Strains of Teladorsagia Circumcincta on the Ovine Intestinal Microbiota

Nematodes are one of the main impactors on health, welfare and productivity of farmed animals. Teladorsagia circumcincta is arguably one of the most globally important nematode species in sheep. Control of these nematode infections is essential and heavily reliant on chemotherapy (anthelmintics), but this has been complicated by the development of anthelmintic resistance. In mammals the composition of the intestinal microbiota has been shown to have a significant effect on overall health. The interactions between host, microbiota and pathogens are complex and influenced by numerous factors. In this study, the interactions between T. circumcincta infections and microbial composition and abundance were investigated. In a preliminary study the intra-and inter-individual diversity and composition of the microbiota of grazing sheep was assessed in two distinct regions of the ovine intestinal tract, the terminal ileum (TI) and rectal contents. Additionally, the effects of experimental infection of sheep with two strains of T. circumcincta (anthelmintic resistant or sensitive) on the microbiota were assessed with and without anthelmintic (monepantel) administration. The inter-animal variability was greater in the TI compared to the rectal samples. However, the alpha-diversity (species richness) was significantly lower in the TI samples. In the experimental study, clear differences were observed between successfully treated animals and those sheep that were left untreated and/or those carrying resistant nematodes. Differences in microbiota between the four different experimental conditions were observed and potential predictive biomarkers were identified. In particular, a restoration of potentially beneficial Bifidobacteria sp. in successfully-treated animals was observed.

microbiology↗