Biology subjects

Xia, A.

Publications and source records attributed to Xia, A..

17 recordsLinked to original sources

bioRxiv2026

Proteomic Remodeling of the Cochlea During Chronic Suppurative Otitis Media Reveals Immune-Driven Injury Pathways

Chronic suppurative otitis media (CSOM) is a persistent middle ear infection in which chronic inflammation drives irreversible sensorineural hearing loss (SNHL), yet the molecular mechanisms linking middle ear chronic infection to cochlear injury remain poorly defined. Using a murine model of CSOM induced by Pseudomonas aeruginosa (PA) persisters, a quantitative proteomic profiling of cochlear tissue was performed at seven days post-infection. Mass spectrometry revealed over 250 proteins that were significantly altered, indicating broad immune activation, oxidative stress, and disruption of ion homeostasis. Among the top candidates, HSPA5, MPO, and ATP2A2 were strongly associated with inflammatory stress and cellular injury pathways. These findings identify immunometabolic remodeling and macrophage-driven inflammation as central mechanisms linking chronic middle ear infection to cochlear injury.

immunology↗

bioRxiv2025

Medial temporal lobe encodes cognitive maps of real-world social networks

People routinely navigate their complex social networks1: From gossiping strategically with others2-4 to brokering connections between siloed groups5,6, our ability to make adaptive social choices hinges on whether we can construct useful mental representations of the social ties within our communities7. While decades of neuroscience research have shown that the medial temporal lobe encodes cognitive maps of physical8-10 or conceptual space11, how the brain represents our social networks in the wild to solve social problems remains unknown. By combining computational models with functional neuroimaging and longitudinal measurement of an evolving and densely interconnected real-world human network (N=187), we show that the entorhinal cortex encodes a cognitive map of the long-range connectivity between pairs of network members. This social map reflects the particular demands of social navigation and is specifically formatted to encode the simultaneous connectivity between network members, which critically enables tracking how information diffuses across the network. Moreover, the strength of its encoding in the entorhinal cortex aids in brokering connections that improve cohesion within peoples social communities. Our results illuminate how a domain-general neural mechanism12,13 is tailored to prioritize the natural dynamics of social phenomena in order to support adaptive navigation through these highly complex environments.

neuroscience↗

bioRxiv2024

Induction of a Muller glial-specific protective pathway safeguards the retina from diabetes induced damage

Diabetes can lead to cell-type-specific responses in the retina, including vascular lesions, glial dysfunction and neurodegeneration, all of which contribute to retinopathy. However, the molecular mechanisms underlying these cell type-specific responses, and the cell types that are sensitive to diabetes have not been fully elucidated. Employing single cell transcriptomic analyses, we profiled the transcriptional changes induced by diabetes in different retinal cell types in diabetic rat models as the disease progressed. Rod photoreceptors, a subtype of amacrine interneurons, and Muller glial cells exhibited rapid responses to diabetes at the transcript levels. Genes associated with ion regulation were upregulated in all three cell types, suggesting a common response to diabetes. Furthermore, focused studies revealed that while Muller glial cells initially increased the expression of genes playing protective roles, they cannot sustain this beneficial effect as the disease progressed. We explored one of the candidate protective genes, Zinc finger protein 36 homolog (Zfp36), and observed that depleting Zfp36 in rat Muller glial cells in vivo using AAV-based tools exacerbated early diabetes-induced phenotypes, including gliosis, neurodegeneration, and vascular defects. Notably, the over-expression of Zfp36 slowed the development of phenotypes associated with diabetic retinopathy. In summary, this work unveiled retinal cell types that are sensitive to diabetes and demonstrated that Muller glial cells can mount protective responses through Zfp36. The failure to maintain Zfp36 levels contributes to the development of diabetic retinopathy.

neuroscience↗

bioRxiv2023

High-throughput, microscopy-based screening, and quantification of genetic elements

Synthetic biology relies on the screening and quantification of genetic components to assemble sophisticated gene circuits with specific functions. Microscopy is powerful tool for characterizing complex cellular phenotypes with increasing spatial and temporal resolution to library screening of genetic elements. Microscopy-based assays are powerful tools for characterizing cellular phenotypes with spatial and temporal resolution, and can be applied to large-scale samples for library screening of genetic elements. However, strategies for high-throughput microscopy experiments remain limited. Here, we present a high-throughput, microscopy-based platform that can simultaneously complete the preparation of an 8x12-well agarose pads plate, allowing for the screening of 96 independent strains or experimental conditions in a single experiment. Using this platform, we screened a library of natural intrinsic promoters from Pseudomonas aeruginosa and identified a small subset of robust promoters that drives stable levels of gene expression under varying growth conditions. Additionally, the platform allowed for single-cell measurement of genetic elements over time, enabling the identification of complex and dynamic phenotypes to map genotype in high-throughput. We expected that the platform could be employed to accelerate the identification and characterization of genetic elements in various biological systems, as well as to understand the relationship between cellular phenotypes and internal states, including genotypes and gene expression programs. Impact statementThe high-throughput microscopy-based platform, presented in this study, enables efficient screening of 96 independent strains or experimental conditions in a single experiment, facilitating the rapid identification of genetic elements with desirable features, thereby advancing synthetic biology. The robust promoters identified through this platform, which provide predictable and consistent control over gene expression under varying growth conditions, can be utilized as reliable tools to regulate gene expression in various biological applications, including synthetic biology, metabolic engineering, and gene therapy, where consistent system performance is required.

molecular biology↗

bioRxiv2023

Plant immunity activated and suppressed by a conserved effector protein family in mirid bug Riptortus pedestris

Riptortus pedestris (Fabricius) a major soybean pest migrates into soybean fields during pod filling stage resulting in a leaf and stem staygreen while pods without beans syndrome. Given the agricultural importance of this species and the lack of characterized HAMP from piercing-sucking insects we performed a large scale of screening by expression of 87 R. pedestris salivary proteins with signal peptides in Nicotiana benthamiana obtaining a candidate HAMP RPH1. RPH1 activated a series of PTI responses including ROS burst upregulation of defense marker genes such as PR1 WRKY7 WRKY8 Acre31 and CYP71D20 MAPK activation and biosynthesis of phytohormones in plants. RPH1 significantly enhances soybean resistance against R. pedestris feeding. PRR coreceptors BAK1 and SOBIR1 were required for RPH1-induced PTI responses. Remarkably RPH1 homologs were widely distributed in herbivorous insects and majority of homologs from selected species induced cell death or ROS. Thus our results demonstrated that RPH1 is a conserved HAMP within chewing and piercing-sucking insects. We also discovered that R. pedestris evolved four paralogs to overcome the plant immunity triggered by RPH1. This study filled a major gap of HAMP identification from piercing-sucking insect and also deciphered a novel evasion strategy of plant immunity exploited by herbivorous insects. One sentence summaryRiptortus pedestris RPH1, a conserved HAMP in herbivores, activates a variety of PTI responses in plants. To couterdefense, R. pedestris evolved four paralogs to suppress RPH1-induced PTI responses. The author(s) responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (https://academic.oup.com/plcell/pages/General-Instructions) is: Ai Xia (xia@njau.edu.edu).

plant biology↗

bioRxiv2023

Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training and sex on its molecular landscape has not been fully established. Utilizing an integrative multi-omics approach with data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we identified profound sexual dimorphism in the dynamic response of rat scWAT to endurance exercise training. Despite similar cardiorespiratory improvements, only male rats reduced whole-body adiposity, scWAT adipocyte size, and total scWAT triglyceride abundance with training. Multi-omic analyses of adipose tissue integrated with phenotypic measures identified sex-specific training responses including enrichment of mTOR signaling in females, while males displayed enhanced mitochondrial ribosome biogenesis and oxidative metabolism. Overall, this study reinforces our understanding that sex impacts scWAT biology and provides a rich resource to interrogate responses of scWAT to endurance training.

molecular biology↗

bioRxiv2023

The mitochondrial multi-omic response to exercise training across tissues

Mitochondria are adaptable organelles with diverse cellular functions critical to whole-body metabolic homeostasis. While chronic endurance exercise training is known to alter mitochondrial activity, these adaptations have not yet been systematically characterized. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) mapped the longitudinal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats endurance trained for 1, 2, 4 or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart and skeletal muscle, while we detected mild responses in the brain, lung, small intestine and testes. The colon response was characterized by non-linear dynamics that resulted in upregulation of mitochondrial function that was more prominent in females. Brown adipose and adrenal tissues were characterized by substantial downregulation of mitochondrial pathways. Training induced a previously unrecognized robust upregulation of mitochondrial protein abundance and acetylation in the liver, and a concomitant shift in lipid metabolism. The striated muscles demonstrated a highly coordinated response to increase oxidative capacity, with the majority of changes occurring in protein abundance and post-translational modifications. We identified exercise upregulated networks that are downregulated in human type 2 diabetes and liver cirrhosis. In both cases HSD17B10, a central dehydrogenase in multiple metabolic pathways and mitochondrial tRNA maturation, was the main hub. In summary, we provide a multi-omic, cross-tissue atlas of the mitochondrial response to training and identify candidates for prevention of disease-associated mitochondrial dysfunction.

molecular biology↗

bioRxiv2022

Fortuitous Somatic Mutations during Antibody Evolution Endow Broad Neutralization against SARS-CoV-2 Omicron Variants

Striking antibody evasion by emerging circulating SARS-CoV-2 variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identified a clonally-related antibody family from a convalescent individual. One of the members, XG005, exhibited potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members showed significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface revealed how crucial somatic mutations endowed XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality, exhibited a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provided a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.

immunology↗

bioRxiv2022

Programming the lifestyles of engineered bacteria for cancer therapy

Bacteria can be genetically engineered to act as therapeutic delivery vehicles in the treatment of tumors, killing cancer cells or activating the immune system. This is known as Bacteria-Mediated Cancer Therapy (BMCT). Tumor invasion, colonization and tumor regression are major biological events, which are directly associated with antitumor effects and are uncontrollable due to the influence of tumor microenvironments during the BMCT process. Here, we developed a genetic circuit for dynamically programming bacterial lifestyles (planktonic, biofilm or lysis), to precisely manipulate the process of bacterial adhesion, colonization and drug release in BMCT process, via hierarchical modulation of the lighting power density (LPD) of near-infrared (NIR) light. The deep tissue penetration of NIR offers us a modality for spatiotemporal and noninvasive control of bacterial genetic circuits in vivo. By combining computational modeling with high throughput characterization device, we optimized the genetic circuits in engineered bacteria to program the process of bacterial lifestyle transitions by altering the illumination scheme of NIR. Our results showed that programming intratumoral bacterial lifestyle transitions allows precise control of multiple key steps throughout the BMCT process, and therapeutic efficacy can be greatly improved by controlling the localization and dosage of therapeutic agents via optimizing the illumination scheme.

synthetic biology↗

bioRxiv2022

Topical Delivery of Elastic Liposomal Vesicles for Treatment of Middle and Inner Ear Disease

We present a topical drug delivery mechanism through the ear canal to the middle and inner ear using liposomal nanoparticles without disrupting the integrity of the tympanic membrane. The current delivery method provides a non-invasive,and safer alternative to trans-tympanic membrane injections, ear tubes followed by ear drops administration and systemic drug formulations. We investigate the capability of liposomal NPs, particularly transfersomes (TLipo), used as drug delivery vesicles to penetrate the tympanic membrane (TM) and round window membrane (RWM) with high affinity, specificity, and retention time. The TLipo is applied to the ear canal and found to pass through tympanic membrane quickly in 3 hours post drug administration. They are identified in the middle ear cavity 6 hours and in the inner ear 24 hours after drug administration. We performed cytotoxicity in vitro and ototoxicity in vivo studies. Cell viability shows no significant difference between the applied TLipo concentration and control. Furthermore, auditory brainstem response (ABR) reveals no hearing loss in 1 week and 1 month post administration. Immunohistochemistry results demonstrates no evidence of hair cell loss in the cochlea at 1 month following TLipo administration. Together, the data suggested that TLipo can be used as a vehicle for topical drug delivery to the middle ear and inner ear.

bioengineering↗

bioRxiv2022

Disruption of anterior temporal lobe reduces distortions in memory from category knowledge

Memory retrieval does not provide a perfect recapitulation of past events, but instead an imperfect reconstruction of event-specific details and general knowledge. However, it remains unclear whether this reconstruction relies on mixtures of signals from different memory systems, including one supporting general knowledge. Here, we investigate whether the anterior temporal lobe (ATL) distorts new memories due to prior category knowledge. In this experiment (N=36), participants encoded and retrieved image-location associations. Most images locations were clustered according to their category, but some were in random locations. With this protocol, we previously demonstrated that randomly located images were retrieved closer to their category cluster relative to their encoded locations, suggesting an influence of category knowledge. We combined this procedure with transcranial magnetic stimulation (TMS) delivered to the left ATL before retrieval. We separately examined event-specific details (error) and category knowledge (bias) to identify distinct signals attributable to different memory systems. We found that TMS to ATL attenuated bias in location memory, but only for atypical category members. The magnitude of error was not impacted, suggesting that a memorys fidelity can be decoupled from its distortion by category knowledge. This raises the intriguing possibility that retrieval is jointly supported by separable memory systems.

neuroscience↗

bioRxiv2020

Optogenetical control of infection signaling cascade of bacteria by an engineered light-responsive protein

Bacterial pathogens operate by tightly controlling the pathogenicity to facilitate invasion and survival in host. While small molecule inducers can be designed to modulate pathogenicity to perform studies of pathogen-host interaction, these approaches, due to the diffusion property of chemicals, may have unintended, or pleiotropic effects that can impose limitations on their use. By contrast, light provides superior spatial and temporal resolution. Here, using optogenetics we reengineered GacS of the opportunistic pathogen Pseudomonas aeruginosa, signal transduction protein of the global Gac/Rsm cascade which is of central importance for regulation of infection factors. The resultant protein YGS24 displayed significant light-dependent activity of GacS kinases in Pseudomonas aeruginosa. When introduced in Caenorhabditis elegans host systems, YGS24 stimulated the pathogenicity of PAO1 in BHI and of PA14 in SK medium progressively upon blue-light exposure. This optogenetic system provides an accessible way to spatiotemporally control bacterial pathogenicity in defined host even specific tissues to develop new pathogenesis systems, which may in turn expedite development of innovative therapeutics.

synthetic biology↗

bioRxiv2019

Prediction and Characterization of RXLR Effectors in Pythium Species

Being widely existed in oomycetes, the RXLR effector features conserved RXLR-dEER motifs in its N terminal. Every known Phytophthora or Hyaloperonospora pathogen harbors hundreds of RXLRs. In Pythium species, however, none of the RXLR effectors has been characterized yet. Here, we developed a stringent method for de novo identification of RXLRs and characterized 359 putative RXLR effectors from nine tested Pythium species. Phylogenetic analysis revealed a single superfamily formed by all oomycetous RXLRs, suggesting they descent from a common ancestor. RXLR effectors from Pythium and Phytophthora species exhibited similar sequence features, protein structures and genome locations. In particular, the mosquito biological agent P. guiyangense contains a significantly larger RXLR repertoire than the other eight Pythium species examined, which may result from gene duplication and genome rearrangement events as indicated by synteny analysis. Expression pattern analysis of RXLR-encoding genes in the plant pathogen P. ultimum detected transcripts from the vast majority of predicted RXLRs with some of them being induced at infection stages. One such RXLRs showed necrosis-inducing activity. Furthermore, all predicted RXLRs were cloned from two biocontrol agents P. oligandrum and P. periplocum. Three of them were found to encode effectors inducing defense response in Nicotiana benthamiana. Taken together, our findings represent the first complete synopsis of Pythium RXLR effectors, which provides critical clues on their evolutionary patterns as well as the mechanisms of their interactions with diverse hosts. Author summaryPathogens from the Pythium genus are widespread across multiple ecological niches. Most of them are soilborne plant pathogens whereas others cause infectious diseases in mammals. Some Pythium species can be used as biocontrol agents for plant diseases or mosquito management. Despite that phylogenetically close oomycete pathogens secrete RXLR effectors to enable infection, no RXLR protein was previously characterized in any Pythium species. Here we developed a stringent method to predict Pythium RXLR effectors and compared them with known RXLRs from other species. All oomycetous RXLRs form a huge superfamily, which indicates they may share a common ancestor. Our sequence analysis results suggest that the expansion of RXLR repertoire results from gene duplication and genome recombination events. We further demonstrated that most predicted Pythium RXLRs can be transcribed and some of them encode effectors exhibiting pathogenic or defense-inducing activities. This work expands our understanding of RXLR evolution in oomycetes in general, and provides novel insights into the molecular interactions between Pythium pathogens and their diverse hosts.

microbiology↗

bioRxiv2019

Carbon starvation induces the expression of PprB-regulated genes in Pesudomonas aeruginosa

Pseudomonas aeruginosa can cause severe infections in humans. This bacteria often adopt a biofilm lifestyle that is hard to treat. In several previous studies, the PprA-PprB two-component system (TCS), which controls the expression of type IVb pili, BapA adhesin, and CupE fimbriae, was shown to be involved in biofilm formation. However, signals or environmental conditions that can trigger the PprA-PprB TCS are still unknown, and the molecular mechanisms of PprB-mediated biofilm formation are poorly characterized. Here we report that carbon starvation stress (CCS) can induce the expression of pprB and genes in the PprB regulon. The stress response sigma factor RpoS, rather than the two-component sensor PprA, was determined to mediate the induction of pprB transcription. We also observed a strong negative regulation of PprB to the transcription of itself. Further experiments showed that PprB overexpression greatly enhanced cell-cell adhesion (CCA) and cell-surface adhesion (CSA) in P. aeruginosa. Specially, under the background of PprB overexpression, both of the BapA adhesin and CupE fimbriae displayed positive effect on CCA and CSA, while the type IVb pili showed an unexpected negative effect on CCA and no effect on CSA. In addition, expression of the PprB regulon genes displayed significant increases in 3-day colony biofilms, indicating a possible carbon limitation state in these biofilms. The CSS-RpoS-PprB-Bap/Flp/CupE/Tad pathway identified in this study provides a new perspective on the process of biofilm formation under carbon-limited environments.\n\nIMPORTANCETypically, determining the external signals that can trigger a regulatory system is crucial to understand the regulatory logic and inward function of that system. The PprA-PprB two-component system was reported to be involved in biofilm formation in Pseudomonas aeruginosa, but the signals that can trigger this system are unknown. In this study, we found that carbon starvation stress (CSS) can induce the transcription of pprB and genes in PprB regulon, through an RpoS dependent pathway. Increase of PprB expression leads to enhanced cell-cell and cell-surface adhesions in P. aeruginosa, both of which are dependent mainly on the Bap adhesin secretion system and partially on the CupE fimbriae. Our findings suggest that PprB reinforces the structure of biofilms under carbon-limited conditions, and the Bap secretion system and CupE fimbriae are two potential targets for biofilm treatment.

microbiology↗

bioRxiv2019

Heterogeneity in surface sensing produces a division of labor in Pseudomonas aeruginosa populations

The second messenger signaling molecule cyclic diguanylate monophosphate (c-di-GMP) drives the transition from planktonic to biofilm growth in many bacterial species. Pseudomonas aeruginosa has two surface sensing systems that produce c-di-GMP in response to surface adherence. The current thinking in the field is that once cells attach to a surface, they uniformly respond with elevated c-di-GMP. Here, we describe how the Wsp system generates heterogeneity in surface sensing, resulting in two physiologically distinct subpopulations of cells. One subpopulation has elevated c-di-GMP and produces biofilm matrix, serving as the founders of initial microcolonies. The other subpopulation has low c-di-GMP and engages in surface motility, allowing for exploration of the surface. We also show that this heterogeneity strongly correlates to surface behavior for descendent cells. Together, our results suggest that after surface attachment, P. aeruginosa engages in a division of labor that persists across generations, accelerating early biofilm formation and surface exploration.

microbiology↗

bioRxiv2018

Elimination of peripheral auditory pathway activation does not affect motor responses from ultrasound neuromodulation

Recent studies in a variety of animal models including rodents, monkeys, and humans suggest that transcranial focused ultrasound (tFUS) has considerable promise for non-invasively modulating neural activity with the ability to target deep brain structures. However, concerns have been raised that motor responses evoked by tFUS may be due to indirect activation of the auditory pathway rather than direct activation of motor circuits. In this study, tFUS-induced electromyography (EMG) signals were recorded and analyzed in wild-type (WT) normal hearing mice and two strains of genetically deaf mice to examine the involvement of the peripheral auditory system in tFUS-stimulated motor responses. In addition, auditory brainstem responses (ABRs) were measured to elucidate the effect of the tFUS stimulus envelope on auditory and motor responses. We also varied the tFUS stimulation duration to measure its effect on motor response duration. We show, first, that the sharp edges in a tFUS rectangular envelope stimulus activate the peripheral afferent auditory pathway and, second, that smoothing these edges eliminates the auditory responses without affecting the motor responses in normal hearing WT mice. We further show that by eliminating peripheral auditory activity using two different strains of deaf knockout mice, motor responses are the same as in normal hearing WT mice. Finally, we demonstrate a high correlation between tFUS pulse duration and EMG response duration. These results support the concept that tFUS-evoked motor responses are not a result of stimulation of the peripheral auditory system.

neuroscience↗

bioRxiv2017

Optogenetics reprogramming of planktonic cells for biofilm formation

Single-cell behaviors play essential roles during early-stage biofilms formation. In this study, we evaluated whether biofilm formation could be guided by precisely manipulating single cells behaviors. Thus, we established an illumination method to precisely manipulate the type IV pili (TFP) mediated motility and microcolony formation of Pseudomonas aeruginosa by using a combination of a high-throughput bacterial tracking algorithm, optogenetic manipulation and adaptive microscopy. We termed this method as Adaptive Tracking Illumination (ATI). We reported that ATI enables the precise manipulation of TFP mediated motility and microcolony formation during biofilm formation by manipulating bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) levels in single cells. Moreover, we showed that the spatial organization of single cells in mature biofilms can be controlled using ATI. Thus, the established method (i.e., ATI) can markedly promote ongoing studies of biofilms.

microbiology↗