Biology subjects

Yin, N.

Publications and source records attributed to Yin, N..

14 recordsLinked to original sources

bioRxiv2024

Targeted protein degradation via CAR endocytosis of antigen in T cells

Targeted protein degradation (TPD) relies on molecules engaging host protein degradation machinery. Here, we developed a novel TPD platform based on antigen endocytosis and degradation by chimeric antigen receptor (CAR) T cells. T cells expressing a CAR with TNFR1 as the antigen-binding domain (TNFR1T) were able to bind, endocytose, and degrade TNF in vitro. To enhance in vivo expansion and persistence of TNFR1T cells, BCOR and ZC3H12A were depleted, generating TNFR1TIF cells. In a human TNF transgenic mouse model of rheumatoid arthritis, a single infusion of TNFR1TIF cells sustainably reduced serum hTNF to near wild-type levels, leading to long-term disease remission. This approach extends CAR T cell targets from cells to extracellular proteins, enabling long-term degradation of inflammatory cytokines and durable remission in chronic inflammatory diseases.

immunology↗

bioRxiv2024

Multi-omics analysis reveals the mechanism of BnC07MYB3a is involved in seed coat color in Brassica napus L.

In rapeseed (Brassica napus), yellow-seeded varieties accumulate less flavonoid pigments (anthocyanins/proanthocyanidins) in their seed coats compared with black-seeded varieties. The yellow-seeded trait is associated with greatly improved seed oil yield, quality, and commercial value. Many R2R3 MYB activators have been characterized in rapeseed, but how MYB-type repressors affect pigment biosynthesis is not yet fully understood. In this study, we performed transcriptome sequencing and metabolomic analysis of B. napus varieties with extreme differences in seed coat color, combined with weighted gene co-expression network analysis. This analysis identified an R2R3-MYB-type transcription factor, BnC07MYB3a (BnaC07G0178800ZS), as a candidate regulator of the yellow-seeded trait in B. napus. Overexpressing BnC07MYB3a in Arabidopsis thaliana and B. napus downregulated the expression of flavonoid biosynthetic genes, resulting in significantly lower anthocyanin and proanthocyanidin accumulation than in the wild-type and a lighter seed coat color in transgenic plants. BnC07MYB3a directly binds to the promoter of the TRANSPARENT TESTA (TT) gene BnTT6 and represses its expression. BnC07MYB3a also physically interacts with BnA06bHLH92a and the WD40 transcription factor TRANSPARENT TESTA GLABRA1 (BnTTG1), suggesting that they might form a previously unidentified MYB-bHLH-WD40 transcription factor complex. Our results reveal the molecular mechanism and regulatory network of BnC07MYB3a in determining seed coat color in B. napus and provide a genetic resource for breeding yellow-seeded cultivars of B. napus.

molecular biology↗

bioRxiv2024

Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex: Implications for renal dysfunction

Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia and hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on the role of oxidized low-density lipoprotein (oxLDL) and angiotensin II (Ang II) in renal injury via G protein q subunit (Gq) signaling. We hypothesized that oxLDL enhances Ang II-induced Gq signaling via the AT1 (Ang II type 1 receptor)-LOX1 (lectin-like oxLDL receptor) complex. Based on CHO and renal cell model experiments, oxLDL alone did not activate Gq signaling. However, when combined with Ang II, it significantly potentiated Gq-mediated inositol phosphate 1 production and calcium influx in cells expressing both LOX-1 and AT1 but not in AT1-expressing cells. This suggests a critical synergistic interaction between oxLDL and Ang II in the AT1-LOX1 complex. Conformational studies using AT1 biosensors have indicated a unique receptor conformational change due to the oxLDL-Ang II combination. In vivo, wild-type mice fed a high-fat diet with Ang II infusion presented exacerbated renal dysfunction, whereas LOX-1 knockout mice did not, underscoring the pathophysiological relevance of the AT1-LOX1 interaction in renal damage. These findings highlight a novel mechanism of renal dysfunction in CKD driven by dyslipidemia and hypertension and suggest the therapeutic potential of AT1-LOX1 receptor complex in patients with these comorbidities.

molecular biology↗

bioRxiv2024

5-HT Neurons Integrate GABA and Dopamine Inputs to Regulate Meal Initiation

Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRN{lozenge}arcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.

neuroscience↗

bioRxiv2024

A single-cell 3D spatiotemporal multi-omics atlas from Drosophila embryogenesis to metamorphosis

The development of a multicellular organism is a highly intricate process tightly regulated by numerous genes and pathways in both spatial and temporal manners. Here, we present Flysta3D, a comprehensive multi-omics atlas of the model organism Drosophila, spanning its developmental lifespan from embryo to pupa. Our datasets encompass 3D single-cell spatial transcriptomic, single-cell transcriptomic, and single-cell chromatin accessibility information. By integrating these multi-dimensional data, we constructed cell state trajectories that uncover the detailed profiles of tissue development. With a focus on the central nervous system (CNS) and midgut, we dissected the spatiotemporal dynamics of gene regulatory networks, cell type diversity, and morphological changes from a multi-omics perspective. This extensive atlas provides an unprecedentedly rich resource and serves as a systematic platform for studying Drosophila development with integrated single-cell data at an ultra-high spatiotemporal resolution.

developmental biology↗

bioRxiv2023

EfNST: A composite scaling network of EfficientNet for improving spatial domain identification performance

Spatial Transcriptomics (ST) leverages Gene Expression Profiling while preserving Spatial Location and Histological Images, enabling it to provide new insights into tissue structure, tumor microenvironment, and biological development. The identification of spatial domains serves as not only the foundation for ST research but also a crucial step in various downstream analyses. However, accurately identifying spatial domains using computational methods remains a tremendous challenge due to the poor computational performance of many existing algorithms. Here, we propose EfNST, a deep learning algorithm based on a composite scaling network of the EfficientNet Network, designed specifically for the analysis of 10X Visium spatial transcriptomics data. We applied EfNST to three different datasets: human Dorsolateral Prefrontal Cortex, human breast cancer and mouse brain anterior. EfNST outperforms five advanced competing algorithms, achieving the best Adjusted Rand Index (ARI) scores of 0.554, 0.607, and 0.466, respectively. Notably, EfNST demonstrated high accuracy in identifying fine tissue structure and discovering corresponding marker genes with an improved running speed. In conclusion, EfNST offers a novel approach for inferring spatial organization of cells from discrete datapoints, facilitating the exploration of new insights in this field.

bioinformatics↗

bioRxiv2023

One infusion of engineered long-lasting and multifunctional T cells cures asthma in mice

The majority of common chronic human diseases are incurable, which affect a large portion of population and require life-long treatments that impose huge disease, economic and social burden. For example, asthma is the most common respiratory disease affecting over 300 million people and accounts for > 250,000 death annually, for which there is no cure. Unlike traditional therapyies, engineered T cells, such as chimeric antigen receptor CAR T (CAR-T) cells, function as living drugs and can cure some hematological malignancies, but whether engineered T cells can cure common diseases beyond cancer remains elusive. Here, we develop a curative therapy for asthma based on enginerred T cell. With IL-5 as the targeting domain and depletion of BCOR and ZC3H12A, we produce long-lasting CAR-T cells eradicating IL-5R+ eosinophils, termed Immortal-like and Functional IL-5 CAR-T cells (5TIF) cells. We further enginerred 5TIF cells to secrete an IL-4 mutein that blocks the singaling of both IL-4 and IL-13, two driver inflammatory cytokines in asthma, named as 5TIF4 cells. In multiple models of asthma, one infusion of 5TIF4 cells in fully immunocompetent mice, in the absence of any conditioning regimen, confers long-term depletion of pathological eosinophils and blockade of IL-4/IL-13 actions, resulting in sustained repression of type 2 inflammation and asthmatic symptoms. Furthurmore, 5TIF4 cells can also be induced in human T cells in NSG mice. Our data demonstrate that asthma, a common noncancerous disease, can be cured by a single infusion of engineered long-lasting and multifunctional T cells, which paves the way for curing common chronic diseases by engineered long-lived T cells.

immunology↗

bioRxiv2023

Induction of immortal-like and functional CAR-T cells by defined factors

Long-term antitumor efficacy of chimeric antigen receptor (CAR)-T cells depends on their functional persistence in vivo. T cells with stem-like property show better persistence, but factors conferring T cells bona fide stemness remain to be determined. Here, we demonstrate the induction of CAR-T cells into an immortal-like and functional state, termed TIF. The induction of CAR-TIF cells depends on repression of two factors: BCOR and ZC3H12A, and requires antigen or CAR tonic signaling. The reprogrammed CAR-TIF cells possess almost infinite stemness resembling induced pluripotent stem cells but retain functionality of mature T cells, which exhibit superior antitumor effect. CAR-TIF cells enter a metabolically dormant state after elimination of target cells, which persist in vivo with a saturable niche and mediate memory protection. CAR-TIF cells represent a novel state of T cells with unprecedented stemness conferring long-term functional persistence of CAR-T cells in vivo, which have broad potentials in T cell therapies.

immunology↗

bioRxiv2021

The rs1421085 variant within FTO promotes but not inhibits thermogenesis and is potentially associated with human migration

Disease-associated GWAS loci are predominantly scattered among noncoding regions of the human genome, which impedes causality estimation. One lead risk signal of obesity-rs1421085 T>C within the FTO gene-is reported to functional in vitro but lack of organismal evidence. Here, we established global and the brown-adipocyte specific locus-knock-in mice to recapitulate this homologous variant in humans, and discovered the minor allele (C-allele) as one candidate thermogenic locus. Mice carrying the C-alleles showed increased thermogenic capacity and a resistance to high-fat diet-induced adiposity. In terms of mechanism, the knock-in models showed enhanced FTO expression, while FTO knockdown or inhibition effectively eliminated the increased thermogenic ability of brown adipocytes. In humans, the C-allele was associated with lower birthweight, and its allele frequency increases following the environmental temperature decreases. Cumulatively, these findings demonstrated rs1421085 T>C as a functional variant regulating whole-body thermogenesis, and this variation was possibly related to early human migration from hot to cold environments.

genetics↗

bioRxiv2021

Hypothalamic perineuronal nets are regulated by sex and dietary interventions

Perineuronal nets (PNNs) are widely present in the hypothalamus, and are thought to provide physical protection and ion buffering for neurons, and regulate their synaptic plasticity and intracellular signaling. Recent evidence indicates that PNNs in the mediobasal hypothalamus plays an important role in the regulation of glucose homeostasis. However, whether and how hypothalamic PNNs are regulated are not fully understood. In the present study, we examined whether PNNs in various hypothalamic regions in mice can be regulated by sex, gonadal hormones, dietary interventions, or their interactions. We demonstrated that gonadal hormones are required to maintain normal PNNs in the arcuate nucleus of hypothalamus in both male and female mice. In addition, PNNs in the terete hypothalamic nucleus display a sexual dimorphism with females higher than males, and high-fat diet feeding increases terete PNNs only in female mice but not in male mice. On the other hand, PNNs in other hypothalamic regions are not influenced by sex, gonadal hormones or dietary interventions. In summary, we demonstrated that hypothalamic PNNs are regulated in a region-specific manner and these results provide a framework to further investigate the potential functions of PNNs in regulating energy/glucose homeostasis at the interplay of sex, gonadal hormones and diets.

neuroscience↗

bioRxiv2021

Cinnamoyl-CoA Reductase 1 (CCR1) and CCR2 Function Divergently in Tissue Lignification, Flux Control and Cross-talk with Glucosinolate Pathway in Brassica napus

Cinnamoyl-CoA reductase (CCR) is the entry point of lignin pathway and a crucial locus in dissection and manipulation of associated traits, but its functional dissection in Brassicaceae plants is largely lagged behind though Arabidopsis thaliana CCR1 has been characterized to certain extent. Here, 16 CCR genes are identified from Brassica napus and its parental species B. rapa and B. oleracea. Brassicaceae CCR genes are divided into CCR1 subfamily and CCR2 subfamily with divergent organ-specificity, yellow-seed trait participation and stresses responsiveness. CCR1 is preferential in G- and H-lignins biosynthesis and vascular development, while CCR2 has a deviation to S-lignin biosynthesis and interfascicular fiber development. CCR1 has stronger effects on lignification-related development, lodging resistance, phenylpropanoid flux control and seed coat pigmentation, whereas CCR2 controls sinapates levels. CCR1 upregulation could delay bolting and flowering time, while CCR2 upregulation weakens vascular system in leaf due to suppressed G lignin accumulation. Besides, CCR1 and CCR2 are deeply but almost oppositely linked with glucosinolates metabolism through inter-pathway crosstalk. Strangely, upregulation of both CCR1 and CCR2 could not enhance resistance to UV-B and S. sclerotiorum though CCR2 is sharply induced by them. These results provide systemic dissection on Brassica CCRs and CCR1-CCR2 divergence in Brassicaceae. HighlightBrassicaceae contains two types of Cinnamoyl-CoA reductase. As revealed in Brassica napus, they are divergently involved in lignin monomer biosynthesis, tissue lignification, phenylpropanoid flux control, and inter-pathway crosstalk with glucosinolates.

plant biology↗

bioRxiv2021

The influence of positive emotion and negative emotion on false memory based on EEG signals analysis

Analyzing the influence of emotion on false memory through electroencephalogram is helpful to further explore the cognition function of brain. In this study, we improved the Deese-Roediger-McDermott paradigm experiment to study the false memory. The memory materials are combined with mixed emotions, which are closer to real life. Twenty-eight participants were randomly divided into positive group and negative group. We used music to induce the participants in the positive group and the negative group to generate corresponding emotions. Finally, we analyzed the difference between the positive group and the negative group from the behavior data, source location and cortex functional network of event related potential. The results of behavioral data analysis show that the false memory rate of positive group (85%) is significantly higher than that of negative group (72%). The results of source localization show that the brain of the positive group is more active than that of the negative group, and the difference of brain activation location between the two groups is mainly manifested in the BA24 and BA45 brain regions. The results of cortex functional network show that the node degree, clustering coefficient, global efficiency and small-world property of the positive group are significantly higher than those of the negative group. It can be found from the three aspects that participants emotional state and brains understanding of semantic are the main reasons for the difference in the incidence of false memory between the two groups.

animal behavior and cognition↗

bioRxiv2020

Glycolysis Fuels Phosphoinositide 3-Kinase Signaling to Bolster T Cell Immunity

Infection triggers clonal expansion and effector differentiation of microbial antigen-specific T cells in association with metabolic reprograming. Here, we show that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+ T effector cells via phosphoinositide 3-kinase (PI3K)-dependent mechanisms. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes glycolytic adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes with glycolytic ATP serving as a rheostat to gauge PI3K/Akt/Foxo1 signaling in T cell immunity control. Such a bioenergetics mechanism of signaling regulation implies a root cause for the century-old phenomenon of Warburg effect, and could guide development of novel therapeutics for infectious diseases and cancer. One Sentence SummaryA PI3K and LDHA circuit enables T cell immunity

immunology↗

bioRxiv2019

Engineering of membrane complex sphingolipids improves osmotic tolerance of Saccharomyces cerevisiae

In order to enhance the growth performance of S. cerevisiae under harsh environmental conditions, mutant XCG001, which tolerates up to 1.5M NaCl, was isolated via adaptive laboratory evolution (ALE). Comparisons made via transcriptome data of XCG001 and the wild-type strain identified ELO2 as being associated with osmotic tolerance. Overexpression of ELO2 increased the contents of inositol phosphorylceramide (IPC, t18:0/26:0), mannosylinositol phosphorylceramide (MIPC, t18:0/22:0(2OH)), MIPC (d18:0/22:0), MIPC (d20:0/24:0), mannosyldiinositol phosphorylceramide (M(IP)2C, d20:0/26:0), M(IP)2C (t18:0/26:0(2OH)) and M(IP)2C (d20:0/26:0(2OH)) by 88.3-, 166.9-, 63.3-, 23.9-, 27.9-, 113.8- and 208.1-fold at 1.0 M NaCl, respectively, compared those of strain XCG002. As a result, membrane integrity, cell growth and cell survival of the ELO2 overexpression strain (XCG010) increased by 24.4%, 29% and 22.1% at 1.0 M NaCl, respectively, compared those of strain XCG002. The findings provided a novel strategy for engineering complex sphingolipids to enhance osmotic tolerance.\n\nIMPORTANCEThis study demonstrated a novel strategy for manipulation membrane complex sphingolipids to enhance S. cerevisiae tolerance to osmotic stress. Osmotic tolerance was related to sphingolipid acyl chain elongase, Elo2, via transcriptome analysis of the wild-type strain and an osmotic tolerant strain generated from ALE. Overexpression of ELO2 increased complex sphingolipid with longer acyl chain, thus improved membrane integrity and osmotic tolerance.

bioengineering↗