Biology subjects

Lei, J.

Publications and source records attributed to Lei, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developing Drosophila brain

Glia derived secretory factors play diverse roles in supporting the development, physiology, and stress responses of the central nervous system (CNS). Through transcriptomics and imaging analyses, we have identified Obp44a as one of the most abundantly produced secretory proteins from Drosophila CNS glia. Protein structure homology modeling and Nuclear Magnetic Resonance (NMR) experiments reveal Obp44a as a fatty acid binding protein (FABP) with a high affinity towards long-chain fatty acids in both native and oxidized forms. Further analyses demonstrate that Obp44a effectively infiltrates the neuropil, traffics between neuron and glia, and is secreted into hemolymph, acting as a lipid chaperone and scavenger to regulate lipid and redox homeostasis in the developing brain. In agreement with this essential role, deficiency of Obp44a leads to anatomical and behavioral deficits in adult animals and elevated oxidized lipid levels. Collectively, our findings unveil the crucial involvement of a noncanonical lipid chaperone to shuttle fatty acids within and outside the brain, as needed to maintain a healthy brain lipid environment. These findings could inspire the design of novel approaches to restore lipid homeostasis that is dysregulated in CNS diseases.

developmental biology↗

bioRxiv2024

The subcommissural organ regulates brain development via secreted peptides

The subcommissural organ (SCO) is a gland located at the entrance of the aqueduct of Sylvius in the brain. It exists in species as distantly related as amphioxus and humans, but its function is largely unknown. To explore its function, we compared transcriptomes of SCO and non-SCO brain regions and found three genes, Sspo, Car3, and Spdef, that are highly expressed in the SCO. Mouse strains expressing Cre recombinase from endogenous promoter/enhancer elements of these genes were used to genetically ablate SCO cells during embryonic development, resulting in severe hydrocephalus and defects in neuronal migration and development of neuronal axons and dendrites. Unbiased peptidomic analysis revealed enrichment of three SCO-derived peptides, namely thymosin beta 4, thymosin beta 10, and NP24, and their reintroduction into SCO-ablated brain ventricles substantially rescued developmental defects. Together, these data identify a critical role for the SCO in brain development.

neuroscience↗

bioRxiv2024

Augmented Doubly Robust Post-Imputation Inference for Proteomic data

Quantitative measurements produced by mass spectrometry proteomics experiments offer a direct way to explore the role of proteins in molecular mechanisms. However, analysis of such data is challenging due to the large proportion of missing values. A common strategy to address this issue is to utilize an imputed dataset, which often introduces systematic bias into down-stream analyses if the imputation errors are ignored. In this paper, we propose a statistical framework inspired by doubly robust estimators that offers valid and efficient inference for proteomic data. Our framework combines powerful machine learning tools, such as variational autoencoders, to augment the imputation quality with high-dimensional peptide data, and a parametric model to estimate the propensity score for debiasing imputed outcomes. Our estimator is compatible with the double machine learning framework and has provable properties. Simulation studies verify its empirical superiority over other existing procedures. In application to both single-cell proteomic data and bulk-cell Alzheimers Disease data our method utilizes the imputed data to gain additional, meaningful discoveries and yet maintains good control of false positives.

bioinformatics↗

bioRxiv2024

Turnover of RNA-binding Proteins and MicroRNAs by intrinsically disordered region-directed ZSWIM8 ubiquitin ligase during brain development

Widely present in mammalian proteomes, intrinsically disordered regions (IDRs) in proteins play important biological functions by conferring structural flexibility and mediating biomolecular interactions. IDR-containing proteins, including many RNA-binding proteins (RBPs), are prone to misfolding and aggregation and must be constantly monitored. Here we show that the conserved ZSWIM8-type Cullin-RING ubiquitin ligase (CRLZSWIM8) is a master regulator of such proteins during brain development. ZSWIM8 selects its substrates via an IDR-dependent mechanism, and deletion of ZSWIM8 causes aberrant accumulation of numerous RBPs including AGO2 and ELAV1 in neonatal brains. Furthermore, AGO2 ubiquitination by ZSWIM8 is triggered by microRNA binding, leading to target-directed microRNA degradation (TDMD) of MiR7. Dysregulation of MiR7 in the absence of ZSWIM8 results in defects in oligodendrocyte maturation and functions. Together, our findings have demonstrated that, by utilizing variable target-recognition strategies, ZSWIM8 controls the abundance of conformationally flexible RBPs and miRNA metabolism that are essential for brain development. TeaserA conserved ubiquitin ligase controls the quality of disordered proteins to ensure brain development.

developmental biology↗

bioRxiv2023

Spatially resolved molecular and cellular atlas of the mouse brain

A comprehensive atlas of genes, cell types, and their spatial distribution across a whole mammalian brain is fundamental for understanding function of the brain. Here, using snRNA-seq and Stereo-seq techniques, we generated a mouse brain atlas with spatial information for 308 cell clusters with single-cell resolution involving over 6 million cells as well as for 29,655 genes. We have identified new astrocyte clusters, and demonstrated that distinct cell clusters exhibit preference for cortical subregions. In addition, we identified 155 genes exhibiting regional specificity in the brainstem, and 513 long non-coding RNA exhibited regional specificity in the adult brain. Parcellation of brain regions based on spatial transcriptomic information showed large overlap with that by traditional method. Furthermore, we have uncovered 411 transcription factor regulons with spatiotemporal specificity during development. Thus, our study has discovered genes and regulon with spatiotemporal specificity, and provided a high-resolution spatial transcriptomic atlas of the mouse brain.

neuroscience↗

bioRxiv2023

Berberine impairs spermatogenesis in mice by modulating ornithine metabolism via gut microbiota regulation

Berberine (BBR) is used to treat diarrhea clinically, its reproductive toxicity, however, is poorly documented. This study aims to investigate the impact of BBR on the male reproductive system. Gradient doses of BBR were administered orally to experimental mice for consecutive 14 days. The gut microbiota, sperm concentration of cauda epididymis, and serum testosterone levels were measured after the last dose for assessing the effects of BBR. Moreover, the metabolome and transcriptome of the mice and microbiota were also investigated. Intragastric BBR administration resulted in a significant decrease in serum testosterone levels and epididymal sperm concentration in mice, which was attributed to a dramatic decrease of Muribaculaceae abundance in the gut microbiota of mice. Both fecal microbiota transplantation (FMT) and polyethylene glycol (PEG) treatment experiments also demonstrated that Muribaculaceae is necessary for spermatogenesis. Metabolomic analysis revealed that BBR affected the arginine and proline metabolism pathways, of which ornithine levels were downregulated after BBR administration. Intragastric administration of M.intestinale and its metabolite ornithine to BBR-treated mice achieved a recovery of sperm concentration and testosterone levels. RNA sequencing of testes showed the genes related to the LDLR-mediated cholesterol-synthesis testosterone pathway were downregulated after BBR administration. The levels of testosterone increased and Ldlr gene became more transcriptionally active in TM3 cells cultured in media supplemented with ornithine. This study for the first time revealed an association between BBR-induced gut Muribaculaceae dysbiosis and defects in spermatogenesis via ornithine metabolism, which provided a candidate and strategy for the treatment of infertility caused by a decreased serum testosterone level-induced by gut microbiota dysbiosis.

pharmacology and toxicology↗

bioRxiv2023

M1 Macrophage-Related Genes Model for NSCLC Immunotherapy Response Prediction

2.Patients diagnosed with non-small cell lung cancer have a limited lifespan and exhibit poor immunotherapy outcomes. M1 macrophages have been found to be essential for anti-tumor immunity. This study aimed to develop an immunotherapy response evaluation model for NSCLC patients based on transcriptional expression. RNA sequencing profiles of 254 advanced-stage NSCLC patients treated with immunotherapy were downloaded from POPLAR and OAK projects. Immune cell infiltration in NSCLC patients has been examined, and thereafter different co-expressed genes were identified. Following that, the impact of M1 macrophage related genes on the prognosis of NSCLC patients was investigated. Six M1 macrophage co-expression genes, namely NKX2-1, CD8A, SFTA3, IL2RB, IDO1, and CXCL9, exhibited a strong association with the prognosis of NSCLC and served as effective predictors for immunotherapy response. A response model was constructed using Cox regression model and Lasso Cox regression analysis. The M1 genes were validated on our previous TD- FOREKNOW NSCLC clinical trial by RT-qPCR. The response model showed excellent immunotherapy response predicting and prognosis evaluating value in advanced stage of NSCLC. The model can effectively predict advanced NSCLC prognosis and aid in identifying patients who could benefit from customized immunotherapy as well as sensitive drugs.

immunology↗

bioRxiv2023

Suppression of progesterone by influenza A virus causes adverse maternal and fetal outcomes in mice

Influenza A virus infection during pregnancy can cause adverse maternal and fetal outcomes, but the mechanism responsible remains elusive. Infection of outbred mice with 2009 H1N1 at embryonic day (E) 10 resulted in significant maternal morbidity, placental tissue damage and inflammation, fetal growth restriction, and developmental delays that lasted through weaning. Restriction of pulmonary virus replication was not inhibited during pregnancy, but infected dams had suppressed circulating and placental progesterone (P4) concentrations that were caused by H1N1-induced upregulation of pulmonary cyclooxygenase (COX)-1, but not COX-2-, dependent synthesis and secretion of prostaglandin (PG) F2. Treatment with 17--hydroxyprogesterone caproate (17-OHPC), a synthetic progestin that is safe to use in pregnancy, ameliorated the adverse maternal and fetal outcomes from H1N1 infection and prevented placental cell death and inflammation. These findings highlight the therapeutic potential of progestin treatments for influenza during pregnancy. ImportancePregnant individuals are at risk of severe outcomes from both seasonal and pandemic influenza A viruses. Influenza infection during pregnancy is associated with adverse fetal outcomes at birth and adverse consequences for offspring into adulthood. We developed an outbred mouse model of 2009 H1N1 influenza virus infection during pregnancy, with semi-allogenic fetuses. When dams are infected with 2009 H1N1, in addition to pulmonary virus replication, tissue damage, and inflammation, the placenta shows evidence of transient damage and inflammation that is mediated by increased activity along the arachidonic acid pathway leading to suppression of circulating progesterone. Placental damage and suppressed progesterone are associated with long-term effects on perinatal growth and developmental delays in offspring. Treatment of H1N1-infected pregnant mice with 17-OHPC, a synthetic progestin treatment safe that is safe to use in pregnancy, prevents placental damage and inflammation and adverse fetal outcomes. This provided a novel therapeutic option for treatment of influenza during pregnancy that should be explored clinically.

microbiology↗

bioRxiv2023

Pan-cancer analysis reveals embryonic and hematopoietic stem cell signatures to distinguish different cancer subtypes

PurposeStem cells-like properties in cancer cells may confer cancer development and therapy resistance. With the advancement of multi-omics technology, the multi-omics-based exploration of cancer stemness has attracted certain interests. However, subtyping of cancer based on the combination of different types of stem cell signatures remains scarce. MethodsIn this study, 10,323 cancer specimens from 33 TCGA cancer types were clustered based on the enrichment scores of six stemness gene sets, representing two types of stem cell backgrounds: embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs). ResultsWe identified four subtypes of pan-cancer, termed StC1, StC2, StC3 and StC4, which displayed distinct molecular and clinical features, including stemness, genome integrity, intratumor heterogeneity, methylation levels, tumor microenvironment, tumor progression, chemotherapy and immunotherapy responses, and survival prognosis. This subtyping method for pan-cancer is reproducible at the protein level. ConclusionOur findings indicate that the ESC signature is an adverse prognostic factor, while the HSC signature and ratio of HSC/ESC signatures are positive prognostic factors in cancer. The ESC and HSC signatures-based subtyping of cancer may provide insights into cancer biology and clinical implications of cancer.

bioinformatics↗

bioRxiv2023

Zfp318 controls the recallability of memory B cells

Expression of the transcriptional regulator ZFP318 is induced in germinal center (GC)- exiting memory B cell precursors and memory B cells (MBCs). Using a conditional ZFP318 fluorescence reporter that also enables ablation of ZFP318-expressing cells, we found that ZFP318-expressing MBCs were highly enriched with GC-derived cells. Although ZFP318-expressing MBCs constituted only a minority of the antigen-specific MBC compartment, their ablation severely impaired recall responses. Deletion of Zfp318 did not alter the magnitude of primary responses but markedly reduced MBC participation in recall. CD40 ligation promoted Zfp318 expression, whereas B-cell receptor (BCR) signaling was inhibitory. Enforced ZFP318 expression enhanced recall performance of MBCs that otherwise responded poorly. ZFP318-deficient MBCs expressed less mitochondrial genes, had structurally compromised mitochondria, and were susceptible to reactivation-induced cell death. The abundance of ZFP318-expressing MBCs, instead of the number of antigen-specific MBCs, correlated with the potency of prime-boost vaccination. Therefore, ZFP318 controls the MBC recallability and represents a quality checkpoint of humoral immune memory.

immunology↗

bioRxiv2023

Lipid-anchored Proteasomes Control Membrane Protein Homeostasis

Protein degradation in eukaryotic cells is mainly carried out by the 26S proteasome, a macromolecular complex not only present in the cytosol and nucleus but also associated with various membranes. How proteasomes are anchored to the membrane and the biological meaning thereof have been largely unknown in higher organisms. Here we show that N-myristoylation of the Rpt2 subunit is a general mechanism for proteasome-membrane interaction. Loss of this modification in the Rpt2-G2A mutant cells leads to profound changes in the membrane-associated proteome, perturbs the endomembrane system and undermines critical cellular processes such as cell adhesion, endoplasmic reticulum-associated degradation (ERAD) and membrane protein trafficking. Rpt2G2A/G2A homozygous mutation is embryonic lethal in mice and is sufficient to abolish tumor growth in a nude mice xenograft model. These findings have defined an evolutionarily conserved mechanism for maintaining membrane protein homeostasis and underscored the significance of compartmentalized protein degradation by myristoyl-anchored proteasomes (MAPs) in health and disease.

biochemistry↗

bioRxiv2023

Dynamics of cell type transition mediated by epigenetic modifications

Maintaining tissue homeostasis requires appropriate regulation of stem cell differentiation. The Waddington landscape posits that gene circuits in a cell form a potential landscape of different cell types, wherein cells follow attractors of the probability landscape to develop into distinct cell types. However, how adult stem cells achieve a delicate balance between self-renewal and differentiation remains unclear. We propose that random inheritance of epigenetic states plays a pivotal role in stem cell differentiation and present a hybrid model of stem cell differentiation induced by epigenetic modifications. Our comprehensive model integrates gene regulation networks, epigenetic state inheritance, and cell regeneration, encompassing multi-scale dynamics ranging from transcription regulation to cell population. Through model simulations, we demonstrate that random inheritance of epigenetic states during cell divisions can spontaneously induce cell differentiation, dedifferentiation, and transdifferentiation. Further-more, we investigate the influences of interfering with epigenetic modifications and introducing additional transcription factors on the probabilities of dedifferentiation and transdifferentiation, revealing the underlying mechanism of cell reprogramming. This in silico model provides valuable insights into the intricate mechanism governing stem cell differentiation and cell reprogramming and offers a promising path to enhance the field of regenerative medicine.

systems biology↗

bioRxiv2023

Migratory herbivorous waterfowl couple the seed wave and the green wave during spring migration

East Asian herbivorous waterfowl intensively use farmland in spring, next to their natural habitat. Accordingly, they might have expanded their migration strategy from merely tracking the green wave of newly emerging vegetation to also incorporating the availability of post-harvest agricultural seeds (here dubbed the seed wave). However, if and how waterfowl use multiple food resources to time their seasonal migration is still unknown. We test this migration strategy using 167 spring migration tracks of five East Asian herbivorous waterfowl species and mixed-effect resource selection function models. We find all study species arrive at their core stopover sites in the Northeast China Plain after agricultural seeds become available, extend their stay after spring vegetation emerges, and arrive at breeding sites around the emergence of vegetation. Moreover, the cue used in exploiting the availability of both food resources varies in different regions and among species. At the core stopover sites, larger-bodied species use the seed wave and smaller-bodied ones adopt the green wave. At the breeding sites, the former follow the green wave, and the latter track the snow-free time. Our findings suggest that waterfowl track multiple resource waves to finetune their migration, highlighting new opportunities for conservation.

ecology↗

bioRxiv2023

Adverse outcomes in SARS-CoV-2 infected pregnant mice are gestational age-dependent and resolve with antiviral treatment

SARS-CoV-2 infection during pregnancy is associated with severe COVID-19 and adverse fetal outcomes, but the underlying mechanisms remain poorly understood. Moreover, clinical studies assessing therapeutics against SARS-CoV-2 in pregnancy are limited. To address these gaps, we developed a mouse model of SARS-CoV-2 infection during pregnancy. Outbred CD1 mice were infected at embryonic day (E) 6, E10, or E16 with a mouse adapted SARS-CoV-2 (maSCV2) virus. Outcomes were gestational age-dependent, with greater morbidity, reduced anti-viral immunity, greater viral titers, and more adverse fetal outcomes occurring with infection at E16 (3rd trimester-equivalent) than with infection at either E6 (1st trimester-equivalent) or E10 (2nd trimester-equivalent). To assess the efficacy of ritonavir-boosted nirmatrelvir (recommended for pregnant individuals with COVID-19), we treated E16-infected dams with mouse equivalent doses of nirmatrelvir and ritonavir. Treatment reduced pulmonary viral titers, decreased maternal morbidity, and prevented adverse offspring outcomes. Our results highlight that severe COVID-19 during pregnancy and adverse fetal outcomes are associated with heightened virus replication in maternal lungs. Ritonavir-boosted nirmatrelvir mitigated adverse maternal and fetal outcomes of SARS-CoV-2 infection. These findings prompt the need for further consideration of pregnancy in preclinical and clinical studies of therapeutics against viral infections.

microbiology↗

bioRxiv2023

Plasticity of the binding pocket in peptide transporters underpins promiscuous substrate recognition

Proton-coupled oligopeptide transporters (POTs) are promiscuous transporters of the Major Facilitator Superfamily, that constitute the main route of entry for a wide range of dietary peptides and orally administrated peptidomimetic drugs. Given their clinical and pathophysiological relevance, several bacterial and mammalian POT homologs have been extensively studied on a structural and molecular level. However, the molecular basis of recognition and transport of the wide range of peptide substrates has remained elusive. Here we present 14 X-ray structures of the bacterial POT DtpB in complex with chemically diverse di- and tripeptides, providing novel insights into the plasticity of the conserved central binding cavity. We analyzed binding affinities for more than 80 peptides and monitored uptake by a fluorescence-based transport assay. To probe if all natural 8400 di- and tripeptides can bind to DtpB, we employed state-of-the-art molecular docking and machine learning and conclude that peptides of a specific subset with compact hydrophobic residues are the best DtpB binders.

biophysics↗

bioRxiv2022

Soft and stretchable organic bioelectronics for continuous intra-operative neurophysiological monitoring during microsurgery

Continuous intra-operative neurophysiological monitoring (CINM) that provides precise mapping of neural anatomy through the entire microsurgery process is essential to preserve the structural and functional integrity of the nerve. However, bulky and rigid electrodes used currently in clinics are usually unable to reliably maintain continuous and stable contacts with the vulnerable and complex nerve networks, thus often resulting in detrimental post-operative complications, such as hemiplegia and sensory disturbances. Here, we describe a biomechanically compatible, suture-free, and individually reconfigurable CINM based on soft and stretchable organic electronic materials. Due to both low impedance and modulus of our conducting polymer electrodes, we achieved for the first time continuous recording of near-field action potential with high signal-to-noise ratio and minimal invasiveness during microsurgeries. Utilizing this unprecedented CINM modality, in conjunction with localized neurostimulation, we further demonstrated our approach in enabling optimal post-operative prognosis in preclinical animal models by preserving normal neural functions after a variety of tumor resection surgeries.

bioengineering↗

bioRxiv2022

An R-R-type MYB transcription factor promotes nonclimacteric pepper fruit ripening pigmentation

Carotenoids act as phytohormones and volatile compound precursors that influence plant development and confer characteristic colours, affecting both the aesthetic and nutritional value of fruits. Carotenoid pigmentation in ripening fruits is highly dependent on developmental trajectories. Transcription factors incorporate developmental and phytohormone signalling to regulate the biosynthesis process. In contrast to the well-established pathways regulating ripening-related carotenoid biosynthesis in climacteric fruit, carotenoid regulation in nonclimacteric fruit is poorly understood. Capsanthin is the primary carotenoid of nonclimacteric pepper (Capsicum) fruit; its biosynthesis is tightly associated with fruit ripening, and it confers red pigment to the ripening fruit. In this study, using a weighted gene coexpression network and expression analysis, we identified an R-R-type MYB transcription factor, DIVARICATA1, and demonstrated that it is tightly associated with the levels of carotenoid biosynthetic genes (CBGs) and capsanthin accumulation. DIVARICATA1 encodes a nucleus-localized protein that functions primarily as a transcriptional activator. Functional analyses demonstrated that DIVARICATA1 positively regulates CBG transcript levels and capsanthin contents by directly binding to and activating the CBG promoter transcription. Furthermore, the association analysis revealed a significant positive association between DIVARICATA1 transcription level and capsanthin content. Abscisic acid (ABA) promotes capsanthin biosynthesis in a DIVARICATA1-dependent manner. Comparative transcriptomic analysis of DIVARICATA1 in pepper and its orthologue in a climacteric fruit, tomato, suggests that its function might be subject to divergent evolution among the two species. This study illustrates the transcriptional regulation of capsanthin biosynthesis and offers a novel target for breeding peppers with high red colour intensity.

plant biology↗

bioRxiv2022

Mechanism of treatment-free remission in patients with chronic myeloid leukemia revealed by a computational model of CML evolution

In the past few years, international treatment guidelines for chronic myeloid leukemia (CML) have incorporated recommendations for attempting discontinuation of treatment with tyrosine kinase inhibitors (TKIs) outside of the setting of a clinical trial with the aim of treatment-free remission (TFR). Multiple clinical studies have shown consistent results that 40%-50% patients can achieve long-term TFR after TKI discontinuation, and most relapse patients undergo molecular recurrence within 6 months after TKI discontinuation, however the underling mechanisms remain unclear. To understand the mechanism of TFR in patients with CML, we consider the competition between leukemia stem cell and bone marrow microenvironment, and develop a mathematical model to investigate the CML progression dynamics. Model simulations are consistent with clinical observation of CML progression, and reveal a mechanism of dimorphic response after TKI discontinuation. Our model predicts that neoplasitic microenvironment is significant for CML occurrence and progression. We furthermore discuss the prediction of TFR based on the change rates of microenvironment index and leukemia stem cells ratio prior TKI discontinuation.

cancer biology↗