Biology subjects

Liu, G. Y.

Publications and source records attributed to Liu, G. Y..

11 recordsLinked to original sources

bioRxiv2025

Effect of Perinatal Ampicillin or Amoxicillin/Clavulanate Exposure on Maternal and Infant Gut Microbiome, Metabolome, and Infant Responses to the 20-valent Pneumococcal Conjugate Vaccine

Emerging studies suggest that antibiotics can disrupt the gut microbiome and alter vaccine-induced immune responses, but the specific consequences of early-life exposure on neonatal immune development remains poorly understood. Here, we examined how two antibiotics frequently used in perinatal care, broad-spectrum ampicillin (AMP) and the extended-spectrum combination amoxicillin/clavulanate (AMOX/CLAV), administered during gestation and lactation, influence neonatal gut microbiome composition, fecal metabolome profiles, and responses to the 20-valent pneumococcal conjugate vaccine (PCV20). Maternal treatment with AMOX/CLAV, but not AMP, significantly reduced PCV-specific IgG titers at 4-and 6-weeks post-prime immunization compared to untreated controls. Exclusive exposure to AMOX/CLAV also impaired neutrophil-mediated opsonophagocytic killing, indicating diminished antibody functionality. These effects were transient, with immune parameters normalizing by week 8 post-prime immunization. Metabolomic and microbiome profiling revealed that maternal AMP and AMOX/CLAV differentially perturbed specific metabolite classes including bile acids, N-acyl lipids, and indole-derivatives, as well as key commensal taxa including Bacteroidales and Coriobacteriales within the gut microbiota. Together, these findings reveal a previously underappreciated maternal-offspring route of antibiotic influence that transiently disrupts neonatal vaccine responsiveness through microbiome and metabolome alterations. These results highlight maternal antibiotic exposure as a modifiable factor shaping early-life immunity.

microbiology↗

bioRxiv2025

Atlas of Lysosomal Aging Reveals a Molecular Clock of Storage Disorder-Associated Metabolites

Lysosomal dysfunction is a well-recognized feature of aging, yet its systematic molecular investigation remains limited. Here, we employ a suite of tools for rapid lysosomal isolation to construct a multi-tissue atlas of the metabolite changes that murine lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle and adipose accumulate glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders like Batten disease. Levels of these metabolites increase linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigates these changes in the heart but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction, uncover a metabolic lysosomal "aging clock," and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases. One-Sentence SummaryAging in mice is tracked by a lysosomal "clock", where glycerophosphodiesters and cystine - metabolites causally linked to juvenile lysosomal storage disorders - gradually accumulate in lysosomes of the brain, heart, skeletal muscle and adipose tissue.

cell biology↗

bioRxiv2025

Reduced efficacy of an anti-toxin vaccine from senescence-driven attenuation of toxin virulence

It remains unclear why vaccines targeting prominent microbial virulence factors often fail in clinical trials. Because microbial virulence depends on interaction with the host immune system, we investigated how changes in host immune function alter vaccine efficacy. Using a vaccine against Staphylococcus aureus alpha toxin (Hla), which targets host metalloprotease ADAM10 on myeloid cells, we show that Hla virulence is reduced in aged mice due to diminished ADAM10 activity and impaired myeloid cell function. Depletion of myeloid cells with cyclophosphamide in young mice similarly reduced toxin virulence. Immunization against Hla conferred strong protection against Staphylococcus aureus infection in young but not aged mice. These findings indicate that pathogenic functions of microbial factors characterized in immunocompetent young animals may not predict virulence or vaccine efficacy in immunocompromised hosts. These findings underscore the need to account for host immune status in the development and evaluation of vaccines targeting microbial virulence factors.

microbiology↗

bioRxiv2025

Influence of perinatal ampicillin exposure on maternal fecal microbial and metabolic profiles

Indirect exposure to antibiotics during early life, via maternal intrapartum antibiotic prophylaxis (IAP) or postpartum maternal antibiotic usage, is increasingly common and has been epidemiologically linked to altered growth and immune developmental trajectories in offspring. Nevertheless, the underlying mechanisms remain poorly understood. Here, we explored the effects of antepartum and postpartum maternal ampicillin administration on the dams fecal microbiome and metabolic profiles in vivo. Ampicillin caused a reproducible depletion of beneficial bacterial species belonging to the Muribaculaceae family, including Muribaculum intestinale and Duncaniella dubosii, and led to cohort-dependent enrichments of Enterococcus and Prevotella species. These microbial alterations were accompanied by substantial metabolic remodeling, characterized by elevated fecal acylcarnitines and dysregulation of the bile acids profile. Intriguingly, we identified two previously uncharacterized trihydroxylated bile acids conjugated to a hexose moiety, which appeared to be associated with antibiotic exposure across public metabolomics repositories. These alterations in the fecal maternal microbiome and metabolome coincided with increased weight gain in offspring, suggesting a possible role for maternal antibiotic exposure in shaping early developmental trajectories. Further studies are warranted to elucidate the long-term implications of these changes in infant health. IMPORTANCEPerinatal antibiotic administration is a critical intervention to reduce maternal and neonatal infections, including early-onset group B Streptococcus (GBS) disease, a major cause of neonatal mortality. Nevertheless, mounting evidence suggests that the use of broad-spectrum antibiotics during the perinatal period in mothers can affect infant gut microbiome development, with potential consequences for immune maturation and early development. Understanding how maternal antibiotic exposure affects the gut microbiome and metabolome is essential for uncovering the potential pathways by which maternal intervention may influence offspring outcomes and for guiding strategies that balance infection control with long-term infant health.

microbiology↗

bioRxiv2023

Nephron progenitors rhythmically alternate between renewal and differentiation in synchrony with kidney branching morphogenesis

The developing mammalian kidney exponentially duplicates nephron-forming stem cell niches at the tips of the urinary collecting duct tree to achieve massively parallel function. Nephron formation rate has a clinically meaningful effect on person-to-person variability in nephron endowment1-5, while exerting in vitro control could enable sustained waves of nephrogenesis in organoid-derived synthetic kidney tissues6,7. However, how the kidney arrives at an appropriate number and ratio of nephrons to collecting ducts is unclear. Here we show that nephron formation is rhythmic and synchronized with branching of the ureteric bud tree (the future urinary collecting ducts). We correlate human and mouse spatial transcriptomics data with the branching life-cycle to uncover rhythmically alternating signatures of nephron progenitor differentiation and renewal. The nephron progenitor rhythm parallels rhythmic nuclear elongation and other hallmarks of mechanical tension in surrounding stromal cells that we attribute to branching-induced deformation. Stroma-specific knockdown of actomyosin activity leads to a striking loss of synchronization between nephron formation and ureteric bud branching without blocking either. These results suggest that the stroma acts as a mechanically entrained pacemaker for nephron formation. Together, our findings uncover a feedback mechanism for clock-like coordination of organ composition during exponential growth.

developmental biology↗

bioRxiv2023

Glycan-specific IgM is critical for human immunity to Staphylococcus aureus

Staphylococcus aureus is a major human pathogen but the immune factors that protect against it remain elusive. In particular, high opsonic IgG titers achieved in preclinical S. aureus animal immunization studies have consistently failed to translate to protection in human clinical trials. Here, we investigated the antibody responses to a conserved surface glycan, Wall Teichoic Acid (WTA). IgM and IgG antibodies specific to WTA were universally present in plasma from healthy individuals. Functionally, WTA-specific IgM outperformed IgG in opsonophagocytic killing of S. aureus and conferred passive protection against S. aureus infection in vivo. In the clinical setting, WTA-specific IgM responses, but not IgG responses, were significantly lower in S. aureus bacteremia patients compared to healthy individuals, correlated with mortality risk and showed impaired bacterial opsonization. Our findings can guide risk stratification of hospitalized patients and inform future design of antibody-based therapies and vaccines against serious S. aureus infection.

microbiology↗

bioRxiv2023

An evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway

Animals must sense and respond to nutrient availability in their local niche. This task is coordinated in part by the mTOR complex 1 (mTORC1) pathway, which regulates growth and metabolism in response to nutrients1-5. In mammals, mTORC1 senses specific amino acids through specialized sensors that act through the upstream GATOR1/2 signaling hub6-8. To reconcile the conserved architecture of the mTORC1 pathway with the diversity of environments that animals can occupy, we hypothesized that the pathway might maintain plasticity by evolving distinct nutrient sensors in different metazoan phyla1,9,10. Whether such customization occurs-- and how the mTORC1 pathway might capture new nutrient inputs--is not known. Here, we identify the Drosophila melanogaster protein Unmet expectations (Unmet, formerly CG11596) as a species-restricted nutrient sensor and trace its incorporation into the mTORC1 pathway. Upon methionine starvation, Unmet binds to the fly GATOR2 complex to inhibit dTORC1. S-adenosylmethionine (SAM), a proxy for methionine availability, directly relieves this inhibition. Unmet expression is elevated in the ovary, a methionine-sensitive niche11, and flies lacking Unmet fail to maintain the integrity of the female germline under methionine restriction. By monitoring the evolutionary history of the Unmet-GATOR2 interaction, we show that the GATOR2 complex evolved rapidly in Dipterans to recruit and repurpose an independent methyltransferase as a SAM sensor. Thus, the modular architecture of the mTORC1 pathway allows it to co-opt preexisting enzymes and expand its nutrient sensing capabilities, revealing a mechanism for conferring evolvability on an otherwise highly conserved system.

cell biology↗

bioRxiv2021

Precise control of microtubule disassembly in living cells

Microtubules (MTs) are components of the evolutionarily conserved cytoskeleton, which tightly regulates various cellular activities. Our understanding of MTs is largely based on MT-targeting agents, which, however, are insufficient to dissect the dynamic mechanisms of specific MT populations due to their slow effects on the entire pool of MTs in cells. To address this limitation, we have used chemogenetics and optogenetics to disassemble specific MT subtypes by rapid recruitment of engineered MT-cleaving enzymes. Acute MT disassembly swiftly halted vesicular trafficking and lysosome dynamics. We also used this approach to disassemble MTs specifically modified by tyrosination and several MT-based structures including primary cilia, mitotic spindles, and intercellular bridges. These effects were rapidly reversed by inhibiting the activity or MT association of the cleaving enzymes. The disassembly of targeted MTs with spatial and temporal accuracy enables to uncover new insights of how MTs precisely regulate cellular architectures and functions.

cell biology↗

bioRxiv2021

Photoinactivation of Catalase Sensitizes Wide-Ranging Bacteria to ROS-Producing Agents and Immune Cells

Bacteria have evolved to cope with the detrimental effects of reactive oxygen species (ROS) using their essential molecular components. Catalase, a heme-containing tetramer protein expressed universally in most of the aerobic bacteria, plays an indispensable role in scavenging excess hydrogen peroxide (H2O2). Here, through utilization of wild-type and catalase-deficient mutants, we identified catalase as an endogenous therapeutic target of 400-420 nm blue light. Catalase residing in bacteria could be effectively inactivated by blue light, subsequently rendering the pathogens extremely vulnerable to H2O2 and H2O2-producing agents. As a result, photoinactivation of catalase and H2O2 synergistically eliminate a wide range of catalase-positive planktonic bacteria and P. aeruginosa inside biofilms. In addition, photoinactivation of catalase is shown to facilitate macrophages to defend against intracellular pathogens. The antimicrobial efficacy of catalase photoinactivation is further validated using a Pseudomonas aeruginosa-induced mice abrasion model. Taken together, our findings offer a catalase-targeting phototherapy against multidrug-resistant bacterial infections.

microbiology↗

bioRxiv2020

Granadaene Photobleaching Reduces the Virulence and Increases Antimicrobial Susceptibility of Streptococcus agalactiae

Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is increasingly recognized as a major cause of soft tissue and invasive diseases in the elderly and diabetic populations. Antibiotics like penicillin are used with great frequency to treat these infections, although antimicrobial resistance is increasing among GBS strains and underlines a need for alternative methods not reliant on traditional antibiotics. GBS hemolysin/cytolysin and granadaene pigment are two major linked virulence factors that contribute to GBS pathogenicity. Here we show that photobleaching of the antioxidant granadaene renders the pathogen more susceptible to killing by mouse macrophages and to hydrogen peroxide killing. Photo-treatment also leads to loss of activity of the linked hemolysin/cytolysin although photobleaching disproportionally affected the activity of the two factors. Treatment with light also affected GBS membrane permeability and contribute to increased susceptibility to the cell membrane active antibiotic daptomycin and to penicillin. Overall our study demonstrates a dual effect of photobleaching on the virulence and antimicrobial susceptibility of GBS and suggests a novel approach for the treatment of GBS infection. Our findings further provide new insight on the relationship between GBS hemolysin and the granadaene pigment. ImportanceFor elderly individuals or those with chronic underlying conditions (such as diabetes), skin infections caused by Streptococcus agalactiae represent a significant risk for the development of invasive disease. S. agalactiae strains are becoming increasingly resistant to antibiotics. By utilizing blue light to neutralize the granadaene pigment present in S. agalactiae, this paper presents a non-invasive and non-antibiotic reliant process capable of reducing GBS virulence while increasing the antimicrobial susceptibility of the bacterium. The differential effect of blue light on the linked GBS hemolysin/cytolysin and granadene pigment further provides new insight on the relationship between the two virulence factors. Overall photo-treatment represents a novel strategy for the treatment of S. agalactiae infections.

microbiology↗

bioRxiv2019

Photo-Disassembly of Membrane Microdomains Revives Conventional Antibiotics against MRSA

Confronted with the rapid evolution and dissemination of antibiotic resistance, there is an urgent need to develop alternative treatment strategies for drug-resistant pathogens. Here, we present an unconventional approach to restore the susceptibility of methicillin-resistant S. aureus (MRSA) to a broad spectrum of conventional antibiotics via photo-disassembly of functional membrane microdomains. The photo-disassembly of microdomains is based on effective photolysis of staphyloxanthin, the golden carotenoid pigment that gives its name. Upon pulsed laser treatment, cell membranes are found severely disorganized and malfunctioned to defense antibiotics, as unveiled by membrane permeabilization, membrane fluidification, and detachment of membrane protein, PBP2a. Consequently, our photolysis approach increases susceptibility and inhibits development of resistance to a broad spectrum of antibiotics including penicillins, quinolones, tetracyclines, aminoglycosides, lipopeptides, and oxazolidinones.\n\nOne Sentence SummaryUsing photons to crash S. aureus cell membrane and its formidable defense against a broad spectrum of antibiotics.

microbiology↗