Biology subjects

Hui, M.

Publications and source records attributed to Hui, M..

10 recordsLinked to original sources

bioRxiv2026

Functional and evolutionary insights into the emerging tet(X4)-carrying non-O1/O139 Vibrio cholerae from retail pork

The tigecycline resistance gene tet(X4) is prevalent in Enterobacteriaceae, particularly in Escherichia coli. To our knowledge, no study has reported the dissemination dynamics of tet(X4) in Vibrio spp. Herein, we isolated and characterized a first tet(X4)-positive non-O1/O139 Vibrio cholerae isolate from retail pork. Genomic sequencing identified a novel tet(X4) variant in the V. cholerae chromosome, harboring a G568A nucleotide substitution that resulted in an Ala190Thr (A190T) amino acid substitution in Tet(X4). While this Tet(X4)-A190T variant conferred lower phenotypic resistance to tetracyclines (including tigecycline) than the wild-type Tet(X4), its overall catalytic efficiency against these antibiotics was paradoxically enhanced despite a reduced substrate affinity. Genomic comparisons revealed that two copies of ISCR2 flanked the variant gene, and the structure was ISCR2-hp-hp-abh-tet(X4)G568A -ISCR2, which is highly homologous to the reported E. coli plasmids carrying tet(X4). In addition, it confirmed the presence of an ISCR2-mediated circular intermediate, proving this modules capacity for horizontal transfer of the tet(X4)G568A variant. Furthermore, the ISCR2-tet(X4) genetic structure carrying the G568A substitution was integrated within a chimeric SXT/R391-like integrative and conjugative element (ICE), which is also serving as a vehicle for genetic dissemination. As per our knowledge, this is the first report on the emergence of SXT/R391-like ICE carrying tet(X4) in Vibrio strains. Our finding demonstrates that the clinically relevant tigecycline resistance gene tet(X4), previously confined mainly to Enterobacterales from humans and livestock, is now actively spreading into environmental Vibrio populations. This cross-species transfer highlights a previously underappreciated ecological and public health concern in aquatic ecosystems.

microbiology↗

bioRxiv2024

Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit, receiving strong input from the indirect pathway and regulating a variety of functions, including locomotor output and habit formation. We recently showed that it also acts as a gatekeeper of cocaine-induced behavioral plasticity, as inhibition of parvalbumin-positive cells in the GPe (GPePV) prevents the development of cocaine-induced reward and sensitization. However, the molecular and circuit mechanisms underlying this function are unknown. Here we show that GPePV cells control cocaine reward and sensitization by inhibiting GABAergic neurons in the substantia nigra pars reticulata (SNrGABA), and ultimately, selectively modulating the activity of ventral tegmental area dopamine (VTADA) cells projecting to the lateral shell of the nucleus accumbens (NAcLat). A major input to GPePV cells is the indirect pathway of the dorsomedial striatum (DMSD2), which receives DAergic innervation from collaterals of VTADA[->]NAcLat cells, making this a closed-loop circuit. Cocaine likely facilitates reward and sensitization not directly through actions in the GPe, but rather in the upstream DMS, where the cocaine-induced elevation of DA triggers a depression in DMSD2 cell activity. This cocaine-induced elevation in DA levels can be blocked by inhibition of GPePV cells, closing the loop. Interestingly, the level of GPePV cell activity prior to cocaine administration is correlated with the extent of reward and sensitization that animals experience in response to future administration of cocaine, indicating that GPePV cell activity is a key predictor of future behavioral responses to cocaine. Single nucleus RNA-sequencing of GPe cells indicated that genes encoding voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability are downregulated in GPePV cells following a single cocaine exposure, contributing to the elevation in GPePV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPePV cell excitability and also impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its potential as a therapeutic to counteract psychostimulant use disorder. Our findings illuminate the molecular and circuit mechanisms by which the GPe orchestrates brain-wide changes in response to cocaine that are required for reward, sensitization, and self-administration behaviors.

neuroscience↗

bioRxiv2024

Analysis of changes in inter-cellular communications during Alzheimer's Disease pathogenesis reveals conserved changes in glutamatergic transmission in mice and humans

Analysis of system-wide cellular communication changes in Alzheimers disease (AD) has recently been enabled by single nucleus RNA sequencing (snRNA-seq) and new computational methods. Here, we combined these to analyze data from postmortem human tissue from the entorhinal cortex of AD patients and compared our findings to those from multiomic data from the 5xFAD amyloidogenic mouse model at two different time points. Using the cellular communication inference tool CellChat we found that disease-related changes were largely related to neuronal excitability as well as synaptic communication, with specific signaling pathways including BMP, EGF, and EPHA, and relatively poor conservation of glial-related changes during disease. Further analysis using the neuron-specific NeuronChat revealed changes relating to metabotropic glutamate receptors as well as neuronal adhesion molecules including neurexins and neuroligins. Our results that cellular processes relating to excitotoxicity are the best conserved between 5xFAD mice and AD suggest that excitotoxicity is the main common feature between pathogenesis in 5xFAD mice and AD patients.

neuroscience↗

bioRxiv2023

Features that matter: evolutionary signatures that predict viral transmission routes

Routes of virus transmission between hosts are key to understanding viral epidemiology. Different routes have large effects on viral ecology, and likelihood and rate of transmission. For example, respiratory and vector-borne viruses together encompass the majority of high-consequence animal and plant outbreaks. However, the specific transmission route(s) can take months to years to determine, undermining the efficiency of mitigation efforts. Here, we identify the vial features and evolutionary signatures which are predictive of viral transmission routes, and use them to predict potential routes for fully-sequenced viruses - we perform this for both viruses with no observed routes, as well as viruses with missing routes. This was achieved by compiling a dataset of 24,953 virus-host associations with 81 defined transmission routes, constructing a hierarchy of virus transmission encompassing those routes and 42 higher-order modes, and engineering 446 predictive features from three complementary perspectives. We integrated those data and features, to train 98 independent ensembles of LightGBM classifiers, each incorporating five different class-balancing approaches. Using our trained ensembles, we demonstrated that all features contributed to the prediction for at least one of routes and/or modes of transmission, demonstrating the utility of our multi-perspective approach. Our approach achieved ROC-AUC=0.991, and F1-score=0.855 across all modelled transmission mechanisms; and was able to achieve high levels of predictive performance for high-consequence respiratory (ROC-AUC=0.990, and F1-score=0.864) and vector-borne transmission (ROC-AUC=0.997, and F1-score=0.921). Our framework ranks the viral features in order of their contribution to prediction, per transmission route, and hence identifies the genomic evolutionary signatures associated with each route. Together with the more matured field of viral host-range prediction, our predictive framework could: provide early insights into the potential for, and pattern of viral spread; facilitate rapid response with appropriate measures; and significantly triage the time-consuming investigations to confirm the likely routes of transmission. Moreover, the performance of our approach in high-consequence transmission routes showcases that our methodology has direct utility to pandemic preparedness. AUTHORS SUMMARYRoutes of virus transmission - the mechanism(s) by which a virus physically gets from an infected to an uninfected host, are crucial to understanding how viral diseases spread among animals and plants. Here, we uncover the evolutionary signatures which can predict the transmission routes a virus uses to move from one host to another, enabling us to identify any unobserved routes for known viruses and even predict potential routes of newly emerged viruses. We first compile a comprehensive dataset of virus-host associations. Leveraging this dataset, we employ a multi-perspective machine learning approach to achieve high predictive performance. Our framework ranks viral features by their significance in prediction, revealing genomic evolutionary signatures linked to each route. Our approach could provide early insights into viral spread patterns, facilitating prompt response efforts to new outbreaks and epidemics, and streamline laboratory investigations. Overall, our study represents a step forward in our ability to anticipate and mitigate the impact of emerging infectious diseases on human, animal, and plant health.

ecology↗

bioRxiv2022

Mapping long-term changes in inputs to the ventral tegmental area after a single drug exposure

Addictive drugs cause long-lasting changes in connectivity from inputs onto ventral tegmental area dopamine cells (VTADA) that contribute to drug-induced behavioral adaptations. However, it is not known which inputs are altered. Here we used a rabies virus (RABV)-based mapping strategy to quantify RABV-labeled inputs to VTA cells after a single exposure to one of a variety of misused drugs - cocaine, amphetamine, methamphetamine, morphine, and nicotine - and compared the relative global input labeling across conditions. We observed that all tested addictive drugs elicited similar input changes onto VTADA cells, in particular onto DA cells projecting to the lateral shell of the nucleus accumbens and amygdala. In addition, repeated administration of ketamine/xylazine to induce anesthesia induces a change in inputs to VTADA cells that is similar to but different from those elicited by a single exposure to addictive drugs, suggesting that caution should be taken when using ketamine/xylazine-based anesthesia in rodents when assessing motivated behaviors. Furthermore, comparison of viral tracing data to an atlas of gene expression in the adult mouse brain showed that the basal expression patterns of several gene classes, especially calcium channels, were highly correlated with the extent of both addictive drug- or ketamine/xylazine-induced changes in RABV-labeled inputs to VTADA cells. Reducing expression levels of the voltage-gated calcium channel Cacna1e in cells in the nucleus accumbens lateral shell reduced RABV-mediated input labeling of these cells into VTADA cells. These results directly link genes controlling cellular excitability and the extent of input labeling by RABV.

neuroscience↗

bioRxiv2022

Inhibitory effect of lactobacilli supernatants on biofilm and filamentation of C. albicans, C. tropicalis, and C. parapsilosis

Probiotic Lactobacillus strains had been investigated for the potential to protect against infection caused by the major fungal pathogen of human, Candida albicans. Besides antifungal activity, lactobacilli demonstrated a promising inhibitory effect on biofilm formation and filamentation of C. albicans. On the other hand, two commonly isolated non-albicans Candida species, C. tropicalis and C. parapsilosis, have similar characteristics in filamentation and biofilm formation with C. albicans. However, there is scant information of the effect of lactobacilli on the two species. In this study, biofilm inhibitory effects of L. rhamnosus ATCC 53103, L. plantarum ATCC 8014, and L. acidophilus ATCC 4356 were tested on the reference strain C. albicans SC5314 and six bloodstream isolated clinical strains, two each of C. albicans, C. tropicalis, and C. parapsilosis. Cell-free culture supernatants (CFSs) of L. rhamnosus and L. plantarum significantly inhibited in vitro biofilm growth of C. albicans and C. tropicalis. L. acidophilus, conversely, had little effect on C. albicans and C. tropicalis but was more effective on inhibiting C. parapsilosis biofilms. Neutralized L. rhamnosus CFS at pH 7 retained the inhibitory effect, suggesting that exometabolites other than lactic acid produced by the Lactobacillus strain might be accounted for the effect. Furthermore, we evaluated the inhibitory effects of L. rhamnosus and L. plantarum CFSs on the filamentation of C. albicans and C. tropicalis strains. Significantly less Candida filaments were observed after co-incubating with CFSs under hyphae-inducing conditions. Expressions of six biofilm-related genes (ALS1, ALS3, BCR1, EFG1, TEC1, and UME6 in C. albicans and corresponding orthologs in C. tropicalis) in biofilms co-incubated with CFSs were analyzed using quantitative real-time PCR. When compared to untreated control, the expressions of ALS1, ALS3, EFG1, and TEC1 genes were downregulated in C. albicans biofilm. In C. tropicalis biofilms, ALS3 and UME6 were downregulated while TEC1 was upregulated. Taken together, the L. rhamnosus and L. plantarum strains demonstrated an inhibitory effect, which is likely mediated by the metabolites secreted into culture medium, on filamentation and biofilm formation of C. albicans and C. tropicalis. Our finding suggested an alternative to antifungals for controlling Candida biofilm.

microbiology↗

bioRxiv2022

Monkeypox virus shows potential to infect a diverse range of native animal species across Europe, indicating high risk of becoming endemic in the region

BackgroundMonkeypox is a zoonotic virus which persists in animal reservoirs and periodically spills over into humans, causing outbreaks. During the current 2022 outbreak, monkeypox virus has persisted via human-human transmission, across all major continents and for longer than any previous record. This unprecedented spread creates the potential for the virus to spillback into local susceptible animal populations. Persistent transmission amongst such animals raises the prospect of monkeypox virus becoming enzootic in new regions. However, the full and specific range of potential animal hosts and reservoirs of monkeypox remains unknown, especially in newly at-risk non-endemic areas. MethodsHere, utilising ensembles of classifiers comprising different class balancing techniques and incorporating instance weights, we identify which animal species are potentially susceptible to monkeypox virus. Subsequently, we generate spatial distribution maps to highlight high-risk geographic areas at high resolution. FindingsWe show that the number of potentially susceptible species is currently underestimated by 2.4 to 4.3-fold, and that a high density of wild susceptible species are native to Europe. We provide lists of these species, and highlight high-risk hosts for spillback and potential long-term reservoirs, which may enable monkeypox virus to become endemic. InterpretationWe highlight the European red fox and brown rat, as they have established interactions with potentially contaminated urban waste and sewage, which provides a mechanism for potential spillback. We anticipate that our results will enable targeted active surveillance of potential spillback event, to minimise risk of the virus becoming endemic in these regions. Our results also indicate the potential of domesticated cats and dogs (latter now confirmed) being susceptible to monkeypox virus, and hence support many health organisations advice for infected humans to avoid physical interaction with pets.

ecology↗

bioRxiv2021

An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement

While midbrain dopamine (DA) neuronal circuits are central to motivated behaviors, much remains unknown about our knowledge of how these circuits are modified over time by experience to facilitate selective aspects of experience-dependent plasticity. Most studies of the DA system in drug addiction focus on the role of the mesolimbic DA pathway from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) in facilitating drug-associated reward. In contrast, less is known about how midbrain DA cells and associated circuits contribute to negative affective states including anxiety that emerge during protracted withdrawal from drug administration. Here, we demonstrate the selective role of a midbrain DA projection to the amygdala (VTADA[->]Amygdala) for anxiety that develops during protracted withdrawal from cocaine administration but does not participate in cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach revealed a persistent elevation in spontaneous and task-related activity of GABAergic cells from the bed nucleus of the stria terminals (BNST) and downstream VTADA[->]Amygdala cells that could be detected even after a single cocaine exposure. Activity in BNSTGABA cells was related to cocaine-induced anxiety but not reward or sensitization, and silencing the projection from these cells to the midbrain was sufficient to prevent the development of anxiety during protracted withdrawal following cocaine administration. We observed that VTADA[->]Amygdala cells, but not other midbrain DA cells, were strongly activated after a challenge exposure to cocaine, and found that activity in these cells was necessary for the expression of reinstatement of cocaine place preference. Lastly, the importance of activity in VTADA[->]Amygdala cells extends beyond cocaine, as these cells mediate the development of anxiety states triggered by morphine and a predator odor. Our results provide an exemplar for how to identify key circuit substrates that contribute to behavioral adaptations and reveal a critical role for BNSTGABA[->]VTADA[->]Amygdala pathway in anxiety states induced by drugs of abuse or natural experiences as well as cocaine-primed reinstatement of conditioned place preference.

neuroscience↗

bioRxiv2020

The Mouse Action Recognition System (MARS): a software pipeline for automated analysis of social behaviors in mice

The study of naturalistic social behavior requires quantification of animals interactions. This is generally done through manual annotation--a highly time consuming and tedious process. Recent advances in computer vision enable tracking the pose (posture) of freely-behaving animals. However, automatically and accurately classifying complex social behaviors remains technically challenging. We introduce the Mouse Action Recognition System (MARS), an automated pipeline for pose estimation and behavior quantification in pairs of freely interacting mice. We compare MARSs annotations to human annotations and find that MARSs pose estimation and behavior classification achieve human-level performance. We also release the pose and annotation datasets used to train MARS, to serve as community benchmarks and resources. Finally, we introduce the Behavior Ensemble and Neural Trajectory Observatory (BENTO), a graphical user interface for analysis of multimodal neuroscience datasets. Together, MARS and BENTO provide an end-to-end pipeline for behavior data extraction and analysis, in a package that is user-friendly and easily modifiable.

neuroscience↗

bioRxiv2018

Genetic determinants of resistance and virulence among carbapenemase-producing Klebsiella pneumoniae from Sri Lanka.

Whole genome sequencing of carbapenem-resistant Enterobacteriaceae from the intensive care units of a Sri Lankan teaching hospital revealed the presence of carbapenemase gene, blaOXA-181 among isolates of carbapenase-producing Klebsiella pneumoniae belonging to ST437 (2 strains) and ST147 (8 strains) in 2015. blaOXA-181 genes were carried in three variants of ColE-type plasmids. Elevated carbapemen resistance were observed in ompK36 mutant strains. ESBL genes, plasmid-mediated quinolone resistance (PMQR) determinants (qnr, aac(6)-Ib-cr, oqxAB) and mutations on chromosomal quinolone resistance-determining regions (QRDRs) with substitutions at ser83[->]I of gyrA and ser80[->]I of parC were observed. All strains possessed yersiniabactin on the mobile element ICEkp and other virulence determinants. Strict infection control and judicious use of antibiotics are warranted to prevent further spread of multidrug-resistant Klebsiella pneumoniae in the intensive care units.

microbiology↗