Biology subjects

Wei, B.

Publications and source records attributed to Wei, B..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

The stability of lower genital tract microbiota correlates with reproductive system function and in vitro fertilization and frozen embryo transfer outcomes in women with polycystic ovarian syndrome

We previously found that the lower genital tract (LGT) microbiota of polycystic ovarian syndrome (PCOS) women has altered when compared to healthy reproductive-aged women, however whether this alternation will have an impact on the reproductive system function and pregnancy outcomes of PCOS patients have not yet been identified. Between 2018 and 2021, we totally enrolled 191 reproductive-aged women in three independent case-control studies, 209 vaginal and 209 cervical swabs, and 9 cervical epithelial cells samples were collected from the study subjects. Firstly, we analyzed the correlation between LGT flora and clinical characteristics of 97 women (containing 47 PCOS patients and 50 control reproductive-aged women), canonical correspondence analysis (CCA) showed that LH/FSH ratio was the most relevant factor that was related to the dominant genera in women with PCOS (r2=0.233, p=0.001), and menstrual cycle frequency was also strongly related to the LGT organisms (r2=0.116, p=0.005). Next, through analysis of 72 PCOS patients who were underwent IVF-FET therapy, the FET outcome in PNB group (PCOS with relative abundance of Lactobacillus [≥]50%, n=57) was significant better than PDB group(PCOS patients with relative abundance of Lactobacillus<50%, n=15). Further, we randomly selected nine reproductive-aged PCOS patients (approximately half of them had altered LGT microbiota: Lactobacillus spp. [≤]50%, n=5) and simultaneously collected both LGT swabs and cervical epithelial cells from them. By synchronization analysis of RNA sequencing of the cervical epithelial cells and 16S rRNA sequencing of the microbes, we found that the gene expression profiles of the cells significantly differed between the PDB (PCOS patients with relative abundance of Lactobacillus<50%, n=4) and PNB (PCOS with relative abundance of Lactobacillus [≥]50%, n=5) groups. Above all, we systematically elucidate the potential relationship between LGT microbiota with the reproductive system function and IVF-FET outcomes in PCOS patients. Importancepolycystic ovarian syndrome (PCOS) women always suffered from poor pregnancy outcome: high incidence of abortion, preterm-birth, and premature rupture of membranes. Although some patients have improved their reproductive outcomes through assisted reproductive technology, the risk of early clinical pregnancy loss for PCOS patients after IVF treatment still ranges from 12% to 48%. As we previously found that the LGT flora of PCOS women had significant altered when compared with healthy parallel group, and more evidence showed that the genital tract microbiota may have a critical role in the process of embryo implantation and development, here we used multiple study groups to explore the potential relationship between LGT microbiota with reproductive system function and FET outcome in PCOS patients in this study. Our findings provide a new perspective for exploring novel therapy to improve the reproductive outcomes of PCOS patients.

physiology↗

bioRxiv2023

Caspase-1 activates gasdermin A in all non-mammals

Gasdermins oligomerize to form pores in the cell membrane, causing regulated lytic cell death called pyroptosis. Mammals encode five gasdermins that can trigger pyroptosis: GSDMA, B, C, D, and E. Caspase and granzyme proteases cleave the linker regions of and activate GSDMB, C, D, and E, but no endogenous activation pathways are yet known for GSDMA. Here, we perform a comprehensive evolutionary analysis of the gasdermin family. A gene duplication of GSDMA in the common ancestor of caecilian amphibians, reptiles and birds gave rise to GSDMA-D in mammals. Uniquely in our tree, amphibian, reptile and bird GSDMA group in a separate clade than mammal GSDMA. Remarkably, GSDMA in numerous bird species contain caspase-1 cleavage sites like YVAD or FASD in the linker. We show that GSDMA from birds, amphibians, and reptiles are all cleaved by caspase-1. Thus, GSDMA was originally cleaved by the host-encoded protease caspase-1. In mammals the caspase-1 cleavage site in GSDMA is disrupted; instead, a new protein, GSDMD, is the target of caspase-1. Mammal caspase-1 uses exosite interactions with the GSDMD C-terminal domain to confer the specificity of this interaction, whereas we show that bird caspase-1 uses a stereotypical tetrapeptide sequence to confer specificity for bird GSDMA. Our results reveal an evolutionarily stable association between caspase-1 and the gasdermin family, albeit a shifting one. Caspase-1 repeatedly changes its target gasdermin over evolutionary time at speciation junctures, initially cleaving GSDME in fish, then GSDMA in amphibians/reptiles/birds, and finally GSDMD in mammals. One Sentence SummaryWe demonstrate that amphibians, reptiles and birds engage pyroptosis using caspase-1 and GS-DMA, filling an evolutionary gap in which caspase-1 cleaves GSDME in fish and GSDMD in mammals.

immunology↗

bioRxiv2023

PVN microglia via P2Y12 transmit hemodynamic signal to promote sympathetic excitation in hypertension

Hypertension is usually accompanied with an elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not fully understood. Recent advances reveal that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels, and found that microglia in the hypothalamic paraventricular nucleus (PVN) were early responders to hypertensive challenges. PVN is the central hub for maintaining cardiovascular function via regulation of fluid balance and sympathetic outflow. Comprehensive vasculature analyses unveiled that PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology among brain regions. As such, PVN is susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. ATP ligation to microglial P2Y12 receptor is responsible for the microglial accumulation and activation in the PVN. Furthermore, either pharmacological blockade or genetic ablation of microglial P2Y12 could substantially restrain blood pressure increase under hypertensive challenge. Together, these findings disclose that a unique vasculature pattern results in the vulnerability of PVN pre-sympathetic neurons to hypertension-associated insults, which is mediated by microglia.

neuroscience↗

bioRxiv2023

Cool temperature acclimation in toxigenic Microcystis aeruginosa PCC 7806 and its non-toxigenic mutant

For Microcystis aeruginosa PCC 7806, temperature decreases from 26{degrees} C to 19{degrees} C double the microcystin quota per cell during growth in continuous culture. Here we tested whether this increase in microcystin provided M. aeruginosa PCC 7806 with a fitness advantage during colder-temperature growth by comparing cell concentration, cellular physiology, and the transcriptomics-inferred metabolism to a non-toxigenic mutant strain M. aeruginosa PCC 7806 {Delta}mcyB. Photo-physiological data combined with transcriptomic data revealed metabolic changes in the mutant strain during growth at 19{degrees} C, which included increased electron sinks and non-photochemical quenching. Increased gene expression was observed for a glutathione-dependent peroxiredoxin during cold treatment, suggesting compensatory mechanisms to defend against reactive oxygen species are employed in the absence of microcystin in the mutant. Our observations highlight the potential selective advantages of a longer-term defensive strategy in management of oxidative stress (i.e., making microcystin) vs the shorter-term proactive strategy of producing cellular components to actively dissipate or degrade oxidative stress agents. ImportanceThrough comparisons of a microcystin-producing wildtype strain M. aeruginosa PCC 7806 and a non microcystin-producing mutant, M. aeruginosa PCC 7806{Delta} mcyB, our observations highlight defensive (microcystin production) vs active (production of degradation enzymes and increased electron sinks) strategies for dealing with cold-temperature induced oxidative stress as well as associated physiological changes. This work increases our understanding of microcystins intracellular function, and the role it may play in bloom ecology. In combination with other studies, this work begins to experimentally establish a mechanistic foundation to better understand cold-to-warm seasonal transitions from toxigenic to non-toxigenic strains frequently observed in situ.

microbiology↗

bioRxiv2023

Human Immune Cell Epigenomic Signatures in Response to Infectious Diseases and Chemical Exposures

The epigenomic landscape of human immune cells is dynamically shaped by both genetic factors and environmental exposures. However, the relative contributions of these elements are still not fully understood. In this study, we employed single-nucleus methylation sequencing and ATAC-seq to systematically explore how pathogen and chemical exposures, along with genetic variation, influence the immune cell epigenome. We identified distinct exposure-associated differentially methylated regions (eDMRs) corresponding to each exposure, revealing how environmental factors remodel the methylome, alter immune cell states, and affect transcription factor binding. Furthermore, we observed a significant correlation between changes in DNA methylation and chromatin accessibility, underscoring the coordinated response of the epigenome. We also uncovered genotype-associated DMRs (gDMRs), demonstrating that while eDMRs are enriched in regulatory regions, gDMRs are preferentially located in gene body marks, suggesting that exposures and genetic factors exert differential regulatory control. Notably, disease-associated SNPs were frequently colocalized with meQTLs, providing new cell-type-specific insights into the genetic basis of disease. Our findings underscore the intricate interplay between genetic and environmental factors in sculpting the immune cell epigenome, offering a deeper understanding of how immune cell function is regulated in health and disease.

genomics↗

bioRxiv2022

Identification of cancer-keeping genes as therapeutic targets by finding network control hubs

Finding cancer-driver genes - the genes whose mutations may transform normal cells into cancerous ones - remains a central theme of cancer research. We took a different perspective; instead of considering normal cells, we focused on cancerous cells and genes that maintained abnormal cell growth which we named cancer-keeping genes (CKGs). Intervention in CKGs may rectify aberrant cell growth so that they can be adopted as therapeutic targets for cancer treatment. We developed a novel approach to identifying CKGs by extending the well-established theory of network structural controllability, which aims at finding a control scheme (i.e., a minimal set of non-overlapping control paths covering all nodes) and control nodes (driver genes) that can steer the cell from any state to the designated state. Going beyond driver genes defined by one control scheme, we introduced control-hub genes located in the middle of a control path of every control scheme. Control hubs are essential for maintaining cancerous states and thus can be taken as CKGs. We applied our CKG-based approach to bladder cancer (BLCA) as a case study. All the genes on the cell cycle and p53 pathways in BLCA were identified as CKGs, showing the importance of these genes in cancer and demonstrating the power of our new method. Furthermore, sensitive CKGs that could be easily changed by structural perturbation were better suited as therapeutic targets. Six sensitive CKGs (RPS6KA3, FGFR3, N-cadherin (CDH2), EP300, caspase-1, and FN1) were subjected to small-interferencing-RNA knockdown in two BLCA cell lines to validate their cancer-suppressing effects. Knocking down RPS6KA3 in a mouse model of BLCA significantly inhibited the growth of tumor xenografts in mice. Combined, our results demonstrated the value of CKGs as therapeutic targets for cancer therapy. Key pointsO_LIFocus on genes that maintain aberrant cell growth, named cancer-keeping genes (CKGs). C_LIO_LIDevelop a novel approach for finding CKGs by extending the well-estabilished theory of network structural controllability to total network controllability. C_LIO_LIApply the new method to bladder cancer and experimentally validated the cancer-suppressing function of six CKGs in two bladder cancer cell lines and that of one CKG in bladder cancer mice. C_LI

bioinformatics↗

bioRxiv2022

S100A4 exerts robust mucosal adjuvant activity for co-administered antigens in mice

The lack of clinically applicable mucosal adjuvants is a major hurdle in designing effective mucosal vaccines. We hereby report that the calcium-binding protein S100A4, which regulates a wide range of biological functions, is a potent mucosal adjuvant in mice for co-administered antigens, including the SARS-CoV-2 spike protein, with comparable or even superior efficacy as cholera toxin but without causing any adverse reactions. Intranasal immunization with recombinant S100A4 elicited antigen-specific antibody and pulmonary cytotoxic T cell responses, and these responses were remarkably sustained for longer than six months. As a self-protein, S100A4 did not stimulate antibody responses against itself, a quality desired of adjuvants. S100A4 prolonged nasal residence of intranasally delivered antigens and promoted migration of antigen-presenting cells. S100A4-pulsed dendritic cells potently activated cognate T cells. Furthermore, S100A4 induced strong germinal center responses revealed by both microscopy and mass spectrometry, a novel technique for measuring germinal center activity. In conclusion, S100A4 may be a promising adjuvant in formulating mucosal vaccines, including vaccines against pathogens that infect via the respiratory tract, such as SARS-CoV-2.

immunology↗

bioRxiv2021

DeepPLA: a novel deep learning-based model for protein-ligand binding affinity prediction

The substantial cost of new drug research and development has consistently posed a huge burden for both pharmaceutical companies and patients. In order to lower the expenditure and development failure rate, repurposing existing and approved drugs by identifying interactions between drug molecules and target proteins based on computational methods have gained growing attention. Here, we propose the DeepLPI, a novel deep learning-based model that mainly consists of ResNet-based 1-dimensional convolutional neural network (1D CNN) and bi-directional long short term memory network (biLSTM), to establish an end-to-end framework for protein-ligand interaction prediction. We first encode the raw drug molecular sequences and target protein sequences into dense vector representations, which go through two ResNet-based 1D CNN modules to derive features, respectively. The extracted feature vectors are concatenated and further fed into the biLSTM network, followed by the MLP module to finally predict protein-ligand interaction. We downloaded the well-known BindingDB and Davis dataset for training and testing our DeepLPI model. We also applied DeepLPI on a COVID-19 dataset for externally evaluating the prediction ability of DeepLPI. To benchmark our model, we compared our DeepLPI with the state-of-the-art methods of DeepCDA and DeepDTA, and observed that our DeepLPI outperformed these methods, suggesting the high accuracy of the DeepLPI towards protein-ligand interaction prediction. The high prediction performance of DeepLPI on the different datasets displayed its high capability of protein-ligand interaction in generalization, demonstrating that the DeepLPI has the potential to pinpoint new drug-target interactions and to find better destinations for proven drugs.

bioinformatics↗

bioRxiv2021

Modeling the SARS-CoV-2 mutation based on geographical regions and time

The Coronavirus Disease 2019 (COVID-19) epidemic was first detected in late-December 2019. So far, it has caused 203,815,431 confirmed cases and 4,310,623 deaths in the world. We collected sequences from 150,659 COVID-19 patients. Based on the previous phylogenomic analysis, we found three major branches of the virus RNA genomic mutation located in Asia, America, and Europe which is consistent with other studies. We selected sites with high mutation frequencies from Asia, America, and Europe. There are only 13 common mutation sites in these three regions. It infers that the viral mutations are highly dependent on their location and different locations have specific mutations. Most mutations can lead to amino acid substitutions, which occurred in 3/5UTR, S/N/M protein, and ORF1ab/3a/8/10. Thus, the mutations may affect the pathogenesis of the virus. In addition, we applied an ARIMA model to predict the short-term frequency change of these top mutation sites during the spread of the disease. We tested a variety of settings of the ARIMA model to optimize the prediction effect of three patterns. This model can provide good help for predicting short-term mutation frequency changes.

bioinformatics↗

bioRxiv2021

High resolution ultrasonic neural modulation observedvia in vivo two-photon calcium imaging

Neural modulation plays a major role in delineating the circuit mechanisms and serves as the cornerstone of neural interface technologies. Among the various modulation mechanisms, ultrasound enables noninvasive label-free deep access to mammalian brain tissue. To date, most if not all ultrasonic neural modulation implementations are based on [~]1 MHz carrier frequency. The long acoustic wavelength results in a spatially coarse modulation zone, often spanning over multiple function regions. The modulation of one brain region is inevitably linked with the modulation of its neighboring regions. To significantly increase the spatial resolution, we explored the application of high-frequency ultrasound. To investigate the neuronal response at cellular resolutions, we developed a dual-modality system combining in vivo two-photon calcium imaging and focused ultrasound modulation. The studies show that the [~]30 MHz ultrasound can suppress the neuronal activity in awake mice at 100-micron scale spatial resolutions, paving the way for high-resolution ultrasonic neural modulation.

bioengineering↗

bioRxiv2021

Sequence determinants of human gene regulatory elements

DNA determines where and when genes are expressed, but the full set of sequence determinants that control gene expression is not known. To obtain a global and unbiased view of the relative importance of different sequence determinants in gene expression, we measured transcriptional activity of DNA sequences that are in aggregate [~]100 times longer than the human genome in three different cell types. We show that enhancers can be classified to three main types: classical enhancers1, closed chromatin enhancers and chromatin-dependent enhancers, which act via different mechanisms and differ in motif content. Transcription factors (TFs) act generally in an additive manner with weak grammar, with classical enhancers increasing expression from promoters by a mechanism that does not involve specific TF-TF interactions. Few TFs are strongly active in a cell, with most activities similar between cell types. Chromatin-dependent enhancers are enriched in forkhead motifs, whereas classical enhancers contain motifs for TFs with strong transactivator domains such as ETS and bZIP; these motifs are also found at transcription start site (TSS)-proximal positions. However, some TFs, such as NRF1 only activate transcription when placed close to the TSS, and others such as YY1 display positional preference with respect to the TSS. TFs can thus be classified into four non-exclusive subtypes based on their transcriptional activity: chromatin opening, enhancing, promoting and TSS determining factors - consistent with the view that the binding motif is the only atomic unit of gene expression.

genomics↗

bioRxiv2020

Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19

Our understanding of protective vs. pathologic immune responses to SARS-CoV-2, the virus that causes Coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses reveal widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, with the most profound disturbances including a prominent neutrophil hyperactivation signature and monocytes with anti-inflammatory features. We further demonstrate that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention. One Sentence SummarySingle-cell profiling demonstrates multifarious dysregulation of innate immune phenotype associated with COVID-19 severity.

immunology↗

bioRxiv2020

Clear optically matched panoramic access channel technique (COMPACT) for large-volume deep brain imaging

To understand neural circuit mechanisms underlying behavior, it is crucial to observe the dynamics of neuronal structure and function in different parts of the brain. Current imaging technologies allow cellular resolution imaging of neurons within ~1 millimeter below the cortical surface. Even for mice, the majority of brain tissue remains inaccessible. Although miniature optical imaging probes allow the access of deep brain regions, the cellular-resolution imaging is restricted to a small tissue volume. To drastically increase the tissue access volume and enable a high-throughput neurophotonic interface, we developed a clear optically matched panoramic access channel technique (COMPACT). With comparable probe dimension, COMPACT enables a two to three orders of magnitude greater tissue access volume for structural and function imaging. Leveraging the large-volume imaging capability of COMPACT, we demonstrated multiregional calcium imaging of deep brain functions associated with sleep for the first time. The compatibility of COMPACT for longitudinal large-volume in vivo imaging will be highly valuable to a variety of deep tissue imaging applications.

bioengineering↗

bioRxiv2020

Probing neuronal functions with precise and targeted laser ablation in the living cortex

Targeted cell ablation is an important strategy for dissecting the function of individual cells within biological tissues. Here we developed an amplified femtosecond laser-coupled two-photon microscopy (AFL-TPM) system that allows instantaneous and targeted ablation of individual cells and real-time monitoring of neuronal network changes in the living mouse cortex. Through precise and iterative control of the laser power and position, individual cells could be ablated by a single femtosecond light pulse with minimum collateral damage. We further show that ablation of individual somatostatin-expressing interneuron increases the activity of nearby neurons in the primary motor cortex during motor learning. Through precise dendrotomy, we reveal that different dendritic branches of layer 5 pyramidal neurons are structurally and functionally independent. By ablating individual cells and their processes in a spatiotemporally specific manner, the AFL-TPM system could serve as an important means for understanding the functions of cells within the complicated neuronal network.

neuroscience↗

bioRxiv2020

Tracing the origin of a new organ by inferring the genetic basis of rumen evolution

The rumen is the hallmark organ of ruminants and hosts a diverse ecosystem of microorganisms that facilitates efficient digestion of plant fibers. We used 897 transcriptomes from three Cetartiodactyla lineages: ruminants, camels and cetaceans, as well as data from ruminant comparative genomics and functional assays to explore the genetic basis of rumen origin and evolution. Comparative analyses reveal that the rumen and the first-chamber stomachs of camels and cetaceans shared a common tissue origin from the esophagus. The rumen recruited genes from other tissues/organs and up-regulated many esophagus genes to aquire functional innovations involving epithelium absorption, improvement of the ketone body metabolism and regulation of microbial community. These innovations involve such genetic changes as ruminant-specific conserved elements, newly evolved genes and positively selected genes. Our in vitro experiements validate the functions of one enhancer, one positively selected gene and two newly evolved antibacterial genes. Our study provides novel insights into the origin and evolution of a complex organ.

evolutionary biology↗

bioRxiv2020

Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer.

Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have improved for a number of solid tumors. Unfortunately, ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB) with reported low patient response rates. Using IHC staining, we find that PD-L2 is highly expressed in ovarian cancers and other malignancies with sub-optimal response to ICB, and is expressed at low levels in cancers responsive to ICB. Based on this observation, we hypothesized that the elevated expression of PD-L2 produced by both tumor and surrounding stromal cells contributes to immune-suppression. Since PD-L2 has been reported to have a 6- to10-fold higher native binding affinity to PD-1 compared with PD-L1, we hypothesized that high levels of PD-L2 can lead to insufficient blockade of the PD-1 signaling pathway. To overcome the immune repressive activity of PD-L2, we engineered a soluble PD-1 decoy molecule (sPD-1 mutant) that binds and neutralizes both PD-L1 and PD-L2 with a 10,000- and 200- fold improvement in binding affinity, respectively, when compared to wild-type binding to these same molecules. Such enhancement in binding affinity is facilitated by amino acid mutations both within and outside of the binding interface. Furthermore, this high affinity sPD-1 mutant molecule demonstrates superior in vivo efficacy in multiple cancer models including ovarian cancer where PD-L2 is highly expressed on the cell surface. One Sentence SummaryDual Inhibition of PD-L1 and PD-L2 using an affinity enhanced sPD-1 decoy molecule delivers superior antitumor activity when compared with PD-1 and PD-L1 antibodies in ovarian cancer.

cancer biology↗

bioRxiv2019

Suppression of membranous LRP5 recycling, WNT/β-catenin signaling, and colorectal tumorigenesis by 15-LOX-1 peroxidation of PI3P_linoleic acid

Aberrant Wnt/{beta}-catenin activation is a major driver of colorectal cancer (CRC), which is typically initiated by APC mutations. Additional modifiable factors beyond APC mutations have been recognized to be important for further potentiation of aberrant {beta}-catenin activation to promote colorectal tumorigenesis. These factors have yet to be clearly identified. Western-type diets are increasingly enriched in linoleic acid (LA). LA-enriched diet however promotes chemically-induced colorectal tumorigenesis in rodent models. Furthermore, the main metabolizing enzyme of LA, 15-lipoxygenase-1 (15-LOX-1), is transcriptionally silenced in CRC. Whether LA and 15-LOX-1 affect Wnt/{beta}-catenin signaling to modulate colorectal tumorigenesis is poorly understood. Herein, we report that high dietary LA promoted colorectal tumorigenesis in mice with intestinally targeted APC mutation (Apc{Delta}580) by upregulating a Wnt receptor, LRP5 expression, and {beta}-catenin activation. 15-LOX-1 transgenic expression in intestinal epithelial cells suppressed LRP5 expression, {beta}-catenin activation and subsequently CRC in these mice. In particular, 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) into PI3P_13-HODE decreased PI3P binding to SNX17and LRP5, which inhibited LRP5 recycling from endosomes to the plasma membrane, thereby leading to an increase of LRP5 lysosomal degradation. Our findings demonstrate for the first time that 15-LOX-1 metabolism of LA in PI3P to regulate LRP5 membrane abundance is a modifiable factor of Wnt/{beta}-catenin aberrant signaling that could be potentially therapeutically targeted to suppress colorectal tumorigenesis and progression.

cancer biology↗

bioRxiv2019

Recombinant Expression of Aldehyde Dehydrogenase 2 (ALDH2) in Escherichia coli Nissle 1917 for Oral Delivery in ALDH2-Deficient Individuals

Turning red after consuming alcohol may seem like a mere social inconvenience. Yet, this flushing response is caused by an accumulation of acetaldehyde, a carcinogenic intermediate of alcohol metabolism. Aldehyde dehydrogenase 2 (ALDH2) deficiency, the result of a point mutation, produces a less efficient ALDH2. The resulting accumulation of acetaldehyde greatly increases the risk of developing esophageal and head and neck cancers. In this study, we produced recombinant ALDH2 in the probiotic E. coli Nissle 1917, which successfully reduces acetaldehyde levels in simulated oral conditions. Packaged in a hard candy, the ALDH2-probiotic would remain in the mouth to specifically target salivary acetaldehyde. Using mathematical modeling, we also determined how much recombinant ALDH2 is needed to reduce elevated acetaldehyde levels.\n\nFinancial DisclosureThis work was funded by Taipei American School. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nCompeting InterestsThe authors have declared that no competing interests exist.\n\nEthics StatementN/A\n\nData AvailabilityYes - all data are fully available without restriction. Sequences for the plasmids used in this study are available through the Registry of Standard Biological Parts. Links to raw data are included in Supplementary Information.

synthetic biology↗