Biology subjects

Ng, E.

Publications and source records attributed to Ng, E..

18 recordsLinked to original sources

bioRxiv2026

Extracellular membrane vesicles - previously unrecognized components of Staphylococcus aureus biofilms

Staphylococcus aureus is a leading cause of biofilm-associated infections, in which communities of bacterial cells are encased in an extracellular matrix composed of polysaccharides, proteins, and extracellular DNA (eDNA) that protect bacteria from host immune defense and antibiotics. Despite their importance, the mechanisms by which matrix components are released from bacterial cells and incorporated into the biofilm matrix remain poorly understood. Using a drip-flow biofilm system, we showed that MVs were associated with the biofilm matrix formed by S. aureus clinical isolate MN8. Proteomic analysis of biofilm matrix proteins and purified MVs showed that biofilm-derived MVs carried cytoplasmic, membrane, and extracellular proteins that closely resembled the protein composition of the biofilm matrix but differed significantly from MVs produced by planktonic cultures. Biofilm-derived MVs carried significantly higher levels of DNA than MVs from planktonic cultures, and MV-associated DNA was resistant to DNase treatment. Although strain MN8 is known to form polysaccharide-dependent biofilms, exogenously added DNase or proteinase K significantly impaired biofilm formation and integrity. Notably, these inhibitory effects were reversed by the addition of biofilm-derived MVs, which significantly restored biofilm formation in enzyme-treated cultures. Together, these findings provide evidence that S. aureus MVs are generated within biofilms, and that these MVs serve as an important resource of matrix components and contribute to biofilm formation. ImportanceExtracellular membrane vesicles (MVs) are important mediators of intercellular communication and have been implicated in the physiology and pathogenesis of bacterial infections. While MV production in S. aureus planktonic cultures has been recognized for over one decade, their presence and function in S. aureus biofilm formation have remained unexplored. Here, we report for the first time the purification and characterization of MVs derived from S. aureus biofilms. Our studies demonstrate that S. aureus MVs are important components of the biofilm matrix that contribute to biofilm formation by serving as key carriers of matrix proteins and eDNA. This work advances our limited understanding of MVs in Gram-positive bacteria and reveal a previously unrecognized mechanism underlying S. aureus biofilm formation.

microbiology↗

bioRxiv2025

Hippocampal Cdk5 is regulated by distinct stress paradigms in male and female mice

Anxiety and mood disorders have been rising since the COVID-19 pandemic, marked by social isolation and stress. Women are disproportionately affected by stress-related disorders, yet the interaction between social isolation and stress remains understudied in females. Cyclin-dependent kinase 5 (Cdk5) is an atypical kinase that exhibits sex-specific regulation following various stressors but is studied almost exclusively in males. To complement these findings, we examined sex differences in mouse hippocampal Cdk5 mRNA and protein following short and long restraint stress with or without concomitant social isolation stress. While short restraint stress was sufficient to promote anxiety-like in both male and female mice, it did not alter Cdk5. Rather, hippocampal Cdk5 mRNA increased only after a longer restraint stress duration followed by social isolation, and only in male mice. Hippocampal Cdk5 protein also shifted from the cytosolic to the nuclear compartment only in male hippocampus. Surprisingly, repeated restraint stress promoted exploratory behavior in both group-housed and socially isolated male and female mice. Social isolation alone increased Cdk5 protein in females only. Finally, under all conditions, female mice were less immobile and more exploratory than male mice. Together, these results provide new insight into the sex-specific regulation of hippocampal Cdk5 by the combination of psychological and environmental stressors. HighlightsO_LIShort 10-minute restraint stress induced anxiety-like behavior in both sexes without altering hippocampal Cdk5 expression. C_LIO_LILong 1-hour restraint stress with post-stress social isolation elicited male-specific hippocampal Cdk5 transcription and Cdk5 cytosolic-to-nuclear protein redistribution. C_LIO_LIRepeated restraint stress increased exploratory behavior in both sexes, suggesting altered stress responsiveness. C_LIO_LISocial isolation interacted with repeated restraint to alter hippocampal Cdk5 protein levels selectively in females. C_LI

neuroscience↗

bioRxiv2025

DINOcell: Learning Generalizable Perturbation Effects through Self-Distillation

AO_SCPLOWBSTRACTC_SCPLOWPredicting cellular responses to therapeutics is a promising approach for novel target discovery. However, state-of-the-art computational models designed to predict perturbation effects struggle to generalize and outperform simple baselines. We present DINOcell, a weakly supervised framework that adapts self-distillation to single-cell transcriptomics for predicting perturbation effects. We demonstrate that DINOcell outperforms baselines in predicting the effects of single gene perturbations. Furthermore, DINOcell accurately predicts non-additive effects of combination perturbations, indicating its capacity to model complex genetic interactions. Finally, we show that DINOcell learns representations that capture biological signals and is a promising, generalizable approach for in silico perturbation modeling, providing a valuable tool for accelerating therapeutic target discovery.

bioinformatics↗

bioRxiv2025

Application of spatial transcriptomics across organoids: a high-resolution spatial whole-transcriptome benchmarking dataset

Stem cell-derived organoids hold promise to model tissue-specific disease. To enable this, it is crucial to assess how transcriptional signatures, cellular organisation and composition of organoids compare to in vivo counterparts. However, technologies which elucidate regional molecular identity, like spatial transcriptomics, have been challenging to apply to organoids. This study presents the first systematic profiling of multiple stem cell derived organoid models (brain, heart muscle, heart valve, kidney, lung, cartilage, and haematopoietic) with Stereo-seq, a full transcriptome, spatial transcriptomics assay using on-chip in situ RNA capture at subcellular resolution. It describes optimisation of this assay to characterise organoids, use of multiple organoid samples on a single chip, assess differences in RNA capture efficiency compared to reference tissues and its limitations. This study introduces a bespoke analysis method that partitions samples into regions and further characterises them. These findings inform future works to characterise organoids using spatial transcriptomics, providing insights in optimising RNA capture of multiple organoids across a chip and novel methods for regional analysis.

bioinformatics↗

bioRxiv2025

Macrophages Mediate Antiviral Immunity and Repair of Type 2 Alveolar Epithelial Cells in a Human Stem Cell Model

The lung alveoli are constantly exposed to inhaled pathogens and inorganic hazards, relying on robust defence mechanisms to maintain homeostasis. Alveolar macrophages and type 2 alveolar epithelial cells (AT2s) collaborate to orchestrate protection. Compromised defence can dysregulate immunity and repair, leading to acute and chronic respiratory diseases. To better understand these processes and drive therapeutic discovery, human model systems that capture key cell interactions are essential. Here, we develop the first induced pluripotent stem cell (iPSC)-derived platform that integrates AT2 cells and macrophages in an air-liquid interface culture. Coculture enhanced AT2-specific gene expression and lipid synthesis, while macrophages actively phagocytosed AT2-derived surfactant. iPSC-derived AT2s supported macrophage survival by producing M-CSF and coculture promoted an alveolar macrophage-like phenotype. Additionally, during respiratory infection macrophages played a crucial role in modulating proinflammatory signalling, enhancing antiviral immunity, and restricting viral replication. Furthermore, we identify a role for iPSC-derived macrophages in epithelial repair, with VEGF signalling to macrophages increasing epithelial permeability. We present an iPSC-derived air-interface platform to study AT2-macrophage interactions in homeostasis, infection, and repair, providing insights into their potential roles in the initiation and progression of respiratory diseases.

cell biology↗

bioRxiv2024

Defining the genetic determinants of CD8+ T cell receptor repertoire in the context of immune checkpoint blockade

CD8+ T cells play a central role in the cancer response to immune checkpoint blockade (ICB) treatment, with activity predicated upon antigen recognition by the associated T cell receptor (TCR) repertoire. The contribution of genetic variation to this in cancer treatment is under-explored. We have conducted a genome-wide and human leukocyte antigen (HLA)-focused analysis of CD8+ T cell TCR repertoire to identify genetic determinants of variable gene (V-gene) and CDR3 K-mer usage from samples taken prior to and after ICB treatment (n=250). We find 11 genome-wide significant cis associations and 10 trans associations, primarily to the HLA, with V-gene usage meeting permuted P-value thresholds. Notably, TCR clones containing V-genes associated with HLA were less likely to be persistent across treatment. In a single-cell experiment, we find cells with HLA-matched TCR clones have increased tumor reactivity expression profiles and patients with HLA-matched TCR clones have improved overall survival. Our work indicates a complex relationship between genotype and TCR repertoire in the context of treatment with ICB, which has novel implications for understanding determinants of treatment response and patient outcomes. One Sentence SummaryTCR repertoire is strongly associated with specific HLA alleles in cancer patients, but immune checkpoint blockade influences this association.

genetics↗

bioRxiv2024

Sinorhizobium meliloti BR-bodies promote fitness during host colonization

Biomolecular condensates, such as the nucleoli or P-bodies, are non-membrane-bound assemblies of proteins and nucleic acids that facilitate specific cellular processes. Like eukaryotic P-bodies, the recently discovered bacterial ribonucleoprotein bodies (BR-bodies) organize the mRNA decay machinery, yet the similarities in molecular and cellular functions across species have been poorly explored. Here, we examine the functions of BR-bodies in the nitrogen-fixing endosymbiont Sinorhizobium meliloti, which colonizes the roots of compatible legume plants. Assembly of BR-bodies into visible foci in S. meliloti cells requires the C-terminal intrinsically disordered region (IDR) of RNase E, and foci fusion is readily observed in vivo, suggesting they are liquid-like condensates that form via mRNA sequestration. Using Rif-seq to measure mRNA lifetimes, we found a global slowdown in mRNA decay in a mutant deficient in BR-bodies, indicating that compartmentalization of the degradation machinery promotes efficient mRNA turnover. While BR-bodies are constitutively present during exponential growth, the abundance of BR-bodies increases upon cell stress, whereby they promote stress resistance. Finally, using Medicago truncatula as host, we show that BR-bodies enhance competitiveness during colonization and appear to be required for effective symbiosis, as mutants without BR-bodies failed to stimulate plant growth. These results suggest that BR-bodies provide a fitness advantage for bacteria during infection, perhaps by enabling better resistance against the host immune response. SignificanceWhile eukaryotes often organize their biochemical pathways in membrane-bound organelles, bacteria generally lack such subcellular structures. Instead, membraneless compartments called biomolecular condensates have recently been found in bacteria to enhance biochemical activities. Bacterial ribonucleoprotein bodies (BR-bodies), as one of the most widespread biomolecular condensates identified to date, assemble the mRNA decay machinery via the intrinsically disordered regions (IDRs) of proteins. However, the implications of such assemblies are unclear. Using a plant-associated symbiont, we show that the IDR of its mRNA degradation protein is necessary for condensate formation. Absence of BR-bodies results in slower mRNA decay and ineffective symbiosis, suggesting that BR-bodies play critical roles in regulating biochemical pathways and promoting fitness during host colonization.

microbiology↗

bioRxiv2023

Partitioning heritability using single-cell multi-omics identifies a novel macrophage subpopulation conveying genetic risks of coronary artery disease.

BackgroundCoronary artery disease (CAD), the leading cause of death worldwide, is influenced by both environmental and genetic factors. While over 250 genetic risk loci have been identified through genome-wide association studies, the specific causal variants and their regulatory mechanisms are still largely unknown, particularly in disease-relevant cell types like macrophages. MethodsWe utilized single-cell RNA-seq (scRNA-seq) and single-cell multi-omics approaches in primary human monocyte-derived macrophages to explore the transcriptional regulatory network involved in a critical pathogenic event of coronary atherosclerosis--the formation of lipid-laden foam cells. Meta-analysis of scRNA-seq datasets from 26 human plaque samples was undertaken to provide a comprehensive atlas of lesional macrophages and to correlate subpopulations in vivo and ex vivo. The genetic risk levels of CAD were assessed by partitioning disease heritability across different macrophage subpopulations. ResultsWe identified a novel macrophage subpopulation, termed lipid-handling macrophages, both ex vivo and in vivo, and identified associated marker genes, transcription regulators, and functional pathways. 18,782 cis-regulatory elements were identified by jointly profiling the gene expression and chromatin accessibility of >5000 macrophages. Integration with CAD GWAS data prioritized 121 CAD-related genetic variants and 56 candidate causal genes. We showed that CAD heritability was not uniformly distributed and was particularly enriched in the gene programs of lipid-handling macrophages. We investigated the cis-regulatory effect of a risk variant rs10488763 on FDX1, implicating the recruitment of AP-1 and C/EBP-beta in the causal mechanisms at this locus. ConclusionsOur results provide genetic evidence of the divergent roles of macrophage subsets in atherogenesis and highlight lipid-handling macrophages as a key sub-population through which genetic variants actively influence disease. These findings provide an unbiased framework for functional fine-mapping of GWAS results using single-cell multi-omics and offer new insights into the genotype-environment interactions underlying atherosclerotic disease.

genetics↗

bioRxiv2023

Dysregulation of Neuroprotective Lipoxin Pathway in Astrocytes in Response to Cytokines and Ocular Hypertension

Glaucoma leads to vision loss due to retinal ganglion cell death. Astrocyte reactivity contributes to neurodegeneration. Our recent study found that lipoxin B4 (LXB4), produced by retinal astrocytes, has direct neuroprotective actions on retinal ganglion cells. In this study, we aimed to investigate how the autacoid LXB4 influences astrocyte activity in the retina under inflammatory cytokine-induced activation and during ocular hypertension. The protective activity of LXB4 was investigated in vivo using the mouse silicone-oil model of chronic ocular hypertension (n=40). By employing a range of analytical techniques, including bulk RNA-seq, RNAscope in-situ hybridization, qPCR, and lipidomic analyses, we discovered the formation of lipoxins and expression of the lipoxin pathway in rodents (including the retina and optic nerve), primates (optic nerve), and human brain astrocytes, indicating the presence of this neuroprotective pathway across various species. Findings in the mouse retina identified significant dysregulation of the lipoxin pathway in response to chronic ocular hypertension, leading to an increase in 5- lipoxygenase (5-LOX) activity and a decrease in 15-LOX activity. This dysregulation was coincident with a marked upregulation of astrocyte reactivity. Reactive human brain astrocytes also showed a significant increase in 5-LOX. Treatment with LXB4 amplified the lipoxin biosynthetic pathway by restoring and amplifying the generation of another member of the lipoxin family, LXA4, and mitigated astrocyte reactivity in mouse retinas and human brain astrocytes. In conclusion, the lipoxin pathway is functionally expressed in rodents, primates, and human astrocytes, and is a resident neuroprotective pathway that is downregulated in reactive astrocytes. Novel cellular targets for LXB4s neuroprotective action are inhibition of astrocyte reactivity and restoration of lipoxin generation. Amplifying the lipoxin pathway is a potential target to disrupt or prevent astrocyte reactivity in neurodegenerative diseases, including retinal ganglion cell death in glaucoma.

neuroscience↗

bioRxiv2023

Characterisation of the genetic determinants of context specific DNA methylation in primary monocytes

DNA methylation (DNAm) has pervasive effects on gene expression and associations with ageing-related traits. Here we describe monocyte DNAm responses to inflammatory stimuli across 192 individuals. We find that, unlike the similarly widespread changes in gene expression elicited by LPS and IFN{gamma}, DNAm is markedly more sensitive to LPS. Exposure to LPS caused differential methylation at 20,858 immune-modulated CpGs (imCpGs) which display distinct genomic localisation and transcription factor usage, dependent upon whether methylation is lost or gained. Demethylated imCpGs are profoundly enriched for enhancers, and are over-represented by genes implicated in human diseases, most notably cancer. We find LPS-induced demethylation follows hydroxymethylation and for most sites the degree of demethylation correlates with baseline signal. Notably, we find LPS exposure triggers gain in epigenetic age by approximately 6 months, identifying a potential cause of accelerated epigentic aging which has diverse negative health associations. Finally, we explore the effect of genetic variation on LPS-induced changes in DNAm, identifying 209 imCpGs under genetic control. Exploring shared causal loci between LPS-induced DNAm responses and human disease traits highlights examples of human disease associated loci that also modulate imCpG formation. In summary, our findings suggest innate immune activity continually remodels DNAm in a highly punctate, enhancerenriched fashion that is under tight genetic control and predominantly involves genes commonly mutated in cancer.

genetics↗

bioRxiv2022

The coordination between penicillin-binding protein 1a (PBP1a) and the hydrolytic peptidase DacB determines the integrity of bacterial cell poles

Peptidoglycan (PG) defines cell shape and protects bacteria against osmotic stress. The growth and integrity of PG require coordinated actions between synthases that insert new PG strands and hydrolases that generate openings to allow the insertion. However, the mechanisms of their coordination remain elusive. Here we show that moenomycin that inhibits a family of PG synthases known as Class-A penicillin-binding proteins (aPBPs), triggers cell lysis despite aPBPs being non-essential for cell integrity. We demonstrate that inhibited PBP1a2, an aPBP, accelerates the degradation of cell poles by DacB, a hydrolytic PG peptidase, in the bacterium Myxococcus xanthus. Moenomycin reduces the mobility of DacB molecules through PBP1a2, potentially promoting the binding between DacB and PG. Conversely, DacB also regulates the distribution and dynamics of aPBPs. These findings reveal the lethal action of moenomycin and suggest that disrupting the coordination between PG synthases and hydrolases could be more lethal than eliminating individual enzymes.

microbiology↗

bioRxiv2021

Structure-Activity Relationships in the Design of Mitochondria-Targeted Peptide Therapeutics

Mitochondria play a central role in metabolic homeostasis; hence, dysfunction of this organelle underpins the etiology of many heritable and aging-related diseases. Mitochondria-targeted tetrapeptides with alternating cationic and aromatic residues, such as SS-31 (Elamipretide), show promise as therapeutic compounds. In this study, we conducted a quantitative structure-activity analysis of three alternative tetrapeptide analogs that differed with respect to aromatic side chain composition and sequence register, benchmarked against SS-31. Using NMR and molecular dynamics approaches, we obtained the first structural models for this class of compounds, showing that all analogs except for SS-31 form compact reverse turn conformations in the membrane-bound state. All peptide analogs bound cardiolipin-containing membranes, yet they had significant differences in equilibrium binding behavior and membrane interactions. Notably, the analogs had markedly different effects on membrane surface charge, supporting a mechanism in which modulation of membrane electrostatics is a key feature of their mechanism of action. All peptide analogs preserved survival and energy metabolism more effectively than SS-31 in cell stress models. Within our peptide set, the analog containing tryptophan side chains, SPN10, had the strongest impact on most membrane properties and showed greatest efficacy in cell culture studies. Taken together, these results show that side chain composition and register strongly influence the activity of these mitochondria-targeted peptides. Furthermore, this work helps provide a framework for the rational design of next-generation therapeutics with enhanced potency.

biochemistry↗

bioRxiv2021

Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity

Natural Killer (NK) cells are innate lymphocytes with central roles in immunosurveillance and are implicated in autoimmune pathogenesis. The degree to which regulatory variants affect NK gene expression is poorly understood. We performed expression quantitative trait locus (eQTL) mapping of negatively selected NK cells from a population of healthy Europeans (n=245). We find a significant subset of genes demonstrate eQTL specific to NK cells and these are highly informative of human disease, in particular autoimmunity. An NK cell transcriptome-wide association study (TWAS) across five common autoimmune diseases identified further novel associations at 27 genes. In addition to these cis observations, we find novel master-regulatory regions impacting expression of trans gene networks at regions including 19q13.4, the Killer cell Immunoglobulin-like Receptor (KIR) Region, GNLY and MC1R. Our findings provide new insights into the unique biology of NK cells, demonstrating markedly different eQTL from other immune cells, with implications for disease mechanisms.

genetics↗

bioRxiv2020

Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

microbiology↗

bioRxiv2020

Poxvirus-encoded TNF receptor homolog dampens inflammation and protects the host from uncontrolled lung pathology and death during respiratory infection

Ectromelia virus (ECTV) causes mousepox, a surrogate mouse model for smallpox caused by variola virus in humans. Both viruses encode tumor necrosis factor receptor (TNFR) homologs termed cytokine response modifier (Crm) proteins, containing a TNF-binding domain and a chemokine-binding domain termed smallpox virus-encoded chemokine receptor (SECRET) domain. Infection of ECTV-resistant C57BL/6 mice with an ECTV CrmD deletion mutant resulted in uniform mortality due to excessive TNF secretion and dysregulated inflammatory cytokine production but viral load was not affected. CrmD dampened lung pathology, leukocyte recruitment and inflammatory cytokines including TNF, IL-6, IL-10 and IFN-{gamma}. Blockade of IL-6, IL-10R or TNF function with monoclonal antibodies reduced lung pathology and provided 60-100% protection from an otherwise lethal infection. IFN-{gamma} caused lung pathology only when both the TNF-binding and SECRET domains were deleted but it was neither necessary nor sufficient to cause pathology when only the CrmD SECRET domain was expressed by virus.

immunology↗

bioRxiv2019

TNF deficiency dysregulates inflammatory cytokine production leading to lung pathology and death during respiratory poxvirus infection

Excessive tumor necrosis factor (TNF) is known to cause significant pathology. Paradoxically, deficiency in TNF (TNF-/-) also caused significant pathology during respiratory ectromelia virus (ECTV) infection, a surrogate mouse model for smallpox. TNF-/- mice succumbed to fulminant disease whereas wild-type mice, and those expressing only transmembrane TNF, recovered. TNF deficiency did not affect viral load or leukocyte recruitment but caused severe lung pathology and excessive production of the cytokines IL-6, IL-10, TGF-{beta}, and IFN-{gamma}. Blockade of these cytokines reduced lung pathology concomitant with induction of protein inhibitor of activated STAT3 (PIAS3) and/or suppressor of cytokine signaling 3 (SOCS3), factors that inhibit STAT3 activation. Short-term inhibition of STAT3 activation in ECTV-infected TNF-/- mice with an inhibitor reduced lung pathology. TNF is essential for regulating inflammation and its deficiency exacerbates ECTV infection as a consequence of significant lung pathology caused by dysregulation of inflammatory cytokine production, in part via overactivation of STAT3.

immunology↗

bioRxiv2019

RUNX1-ETO induction rapidly alters chromatin landscape and growth of a specific sub-population of hESC-derived myeloid precursor cells by interfering with RUNX1 regulation

Acute myeloid leukemia is a hematopoietic malignancy caused by recurrent mutations in genes encoding transcriptional, epigenetic and/or signaling regulators. The t(8;21) translocation generates the aberrant transcription factor RUNX1-ETO whose expression can be detected in utero but is insufficient to cause overt disease. Although patients harboring cells with the t(8;21) translocation have acquired additional mutations and show extensive epigenetic reprogramming, the effects directly attributable to RUNX1-ETO expression are unclear. To address this question, we used a human embryonic stem cell differentiation system capable of forming definitive human myeloid progenitor cells to express RUNX1-ETO in an inducible fashion. Induction of RUNX1-ETO causes extensive chromatin reprogramming by interfering with RUNX1 binding, blocks differentiation and arrests cellular growth, whereby growth arrest is reversible following RUNX1-ETO removal. Single cell gene expression analyses show that RUNX1-ETO induction alters the differentiation of a defined sub-population of progenitors, indicating that oncoprotein-mediated transcriptional reprogramming is highly target cell specific.

cancer biology↗

bioRxiv2019

Using background noise to improve sound localization following simulated hearing loss

Many listening abilities become more difficult in noisy environments, particularly following hearing loss. Sound localization can be disrupted even if target sounds are clearly audible and distinct from background noise. Since subjects locate sounds by comparing the input to the two ears, sound localization is also considerably impaired by unilateral hearing loss. Currently, however, it is unclear whether the effects of unilateral hearing loss are worsened by background noise. To address this, we measured sound localization abilities in the presence or absence of broadband background noise. Adult human subjects of either sex were tested with normal hearing or with a simulated hearing loss in one ear (earplug). To isolate the role of binaural processing, we tested subjects with narrowband target sounds. Surprisingly, we found that continuous background noise improved narrowband sound localization following simulated unilateral hearing loss. By contrast, we found the opposite effect under normal hearing conditions, with background noise producing illusory shifts in sound localization. Previous attempts to model these shifts are inconsistent with behavioural and neurophysiological data. However, here we found that a simple hemispheric model of sound localization provides an explanation for our results, and provides key hypotheses for future neurophysiological studies. Overall, our results suggest that continuous background noise may be used to improve sound localization under the right circumstances. This has important implications for real-world hearing, both in normal-hearing subjects and the hearing-impaired.\n\nSignificance StatementIn noisy environments, many listening abilities become more difficult, even if target sounds are clearly audible. For example, background noise can produce illusory shifts in the perceived direction of target sounds. Because sound localization relies on the two ears working together, it is also distorted by a hearing loss in one ear. We might therefore expect background noise to worsen the effects of unilateral hearing loss. Surprisingly, we found the opposite, with background noise improving sound localization when we simulated a hearing loss in one ear. A simple hemispheric model of sound localization also helped explain the negative effects of background noise under normal hearing conditions. Overall, our results highlight the potential for using background noise to improve sound localization.

neuroscience↗