Biology subjects

Hu, S.

Publications and source records attributed to Hu, S..

At least 91 records · Page 5Linked to original sources

bioRxiv2024

Target-aware Molecule Generation for Drug Design Using a Chemical Language Model

Generative drug design facilitates the creation of compounds effective against pathogenic target proteins. This opens up the potential to discover novel compounds within the vast chemical space and fosters the development of innovative therapeutic strategies. However, the practicality of generated molecules is often limited, as many designs focus on a narrow set of drug-related properties, failing to improve the success rate of subsequent drug discovery process. To overcome these challenges, we develop TamGen, a method that employs a GPT-like chemical language model and enables target-aware molecule generation and compound refinement. We demonstrate that the compounds generated by TamGen have improved molecular quality and viability. Additionally, we have integrated TamGen into a drug discovery pipeline and identified 7 compounds showing compelling inhibitory activity against the Tuberculosis ClpP protease, with the most effective compound exhibiting a half maximal inhibitory concentration (IC50) of 1.9 M. Our findings underscore the practical potential and real-world applicability of generative drug design approaches, paving the way for future advancements in the field.

biochemistry↗

bioRxiv2023

A direct estrogenic involvement in the expression of human hypocretin

BackgroundHypocretin-1 may play an important role in depression, which was increased in female depression in LHA in our previous study. Estrogen acts through its nuclear transcriptional receptors. MethodsWe studied the possibility of a direct action of estrogen receptors on the expression of human hypocretin. To explore the activation of ERs by hypocretin, we first investigated the potential presence of co-localization of the estrogen receptors (ERs) in hypocretin-immunoreactive neurons in the lateral hypothalamic area (LHA) in human and nuclear ERs in hypocretin immunoreactive neuroblastoma SK-N-SH cells. We investigated the relationship between E2 and hypocretin in female rats. After we explored the regulating role of exogenous estrogen on hypocretin gene expression via ERs through Chromatin immunoprecipitation, Electrophoretic mobility shift assay and Luciferase assay. ResultsWe found that hypocretin-1 plasma level was significantly higher in female depression. Estrogen receptors (ER and ER{beta}) and hypocretin are co-localized in female depression LHA, PC12 and SK-N-SH cell lines. The estrogen receptor response elements (EREs) existing in the hypocretin promoter region may directly regulate the expression of hypocretin, the synchronicity of change of hypocretin and estradiol both in hypothalamus and plasma was verified in female rats. With the presence of estradiol, there is specific binding between human ER and the Hypocretin-ERE. Expression of ER combined with estradiol repressed hypocretin promoter activity through the ERE. Conclusionswe defined that estradiol may affect hypocretin neurons in the human hypothalamus via ER binding to the Hypocretin-ERE directly, which may thus lead to the sex-specific pathogenesis of depression.

neuroscience↗

bioRxiv2023

Not dasycladalean alga, but an Odyssey of the earliest Phanerozoic animal reef-builders

The compacted macrofossil Protomelission? sp. from the early Cambrian Xiaoshiba Lagerstatte was recently ascribed to early dasycladalean green algae and used to disprove the bryozoan affinity of coeval phosphatized microfossils, which made the puzzling question whether the bryozoans originated in early Cambrian pending again. Our new analyses of multiple specimens which are conspecific with Protomelission? from the Chengjiang Lagerstatte indicate that they are not dasycladaleans but one of the three groups of archaeocyath-like sponges that atypically inhabited siliciclastic substrates. All the archaeocyath-like fossils share the same preservation mode and exhibit archaeocyath-type external skeletal features. Particularly, the Protomellision?-like fossils preserve structures indicative of archaeocyath aquiferous system and ontogeny. They represent the first recognized one-walled archaeocyath sponges in South China and evidence the niche expansion of archaeocyaths on their way of global radiation from Siberia, 518 million years ago. The origin of the bryozoans remains a mystery.

paleontology↗

bioRxiv2023

{xi}-π: a nonparametric model for neural powerspectra decomposition

The power spectra estimated from the brain recordings are the mixed representation of aperiodic transient activity and periodic oscillations, i.e., aperiodic component (AC) and periodic component (PC). Quantitative neurophysiology requires precise decomposition preceding parameterizing each component. However, the shape, statistical distribution, scale, and mixing mechanism of AC and PCs are unclear, challenging the effectiveness of current popular parametric models such as FOOOF, IRASA, BOSC, etc. Here,{xi} -{pi} was proposed to decompose the neural spectra by embedding the nonparametric spectra estimation with penalized Whittle likelihood and the shape language modeling into the expectation maximization frame-work.{xi} -{pi} was validated on the synthesized spectra with loss statistics and on the sleep EEG and the large sample iEEG with evaluation metrics and neurophysiological evidence. Compared to FOOOF, both the simulation presenting shape irregularities and the batch simulation with multiple isolated peaks indicated that{xi} -{pi} improved the fit of AC and PCs with less loss and higher F1-score in recognizing the centering frequencies and the number of peaks; the sleep EEG revealed that{xi} -{pi} produced more distinguishable AC exponents and improved the sleep state classification accuracy; the iEEG showed that{xi} -{pi} approached the clinical findings in peak discovery. Overall,{xi} -{pi} offered good performance in the spectra decomposition, which allows flexible parameterization using descriptive statistics or kernel functions.{xi} -{pi} may be a promising tool for brain signal decoding in fields such as cognitive neuroscience, brain-computer interface, neurofeedback, and brain diseases.

bioinformatics↗

bioRxiv2023

Cutaneous T cell lymphoma atlas reveals malignant Th2 cells supported by a B cell-rich microenvironment

Cutaneous T-cell lymphoma (CTCL) is a potentially fatal clonal malignancy of T cells primarily affecting the skin. The most common form of CTCL, mycosis fungoides (MF), can be difficult to diagnose resulting in treatment delay. The pathogenesis of CTCL is not fully understood due to limited data from patient studies. We performed single-cell RNA sequencing and spatial transcriptomics profiling of skin from patients with MF-type CTCL, and an integrated comparative analysis with human skin cell atlas datasets from healthy skin, atopic dermatitis and psoriasis. We reveal the co-optation of Th2-immune gene programmes by malignant CTCL cells and modelling of the tumour microenvironment to support their survival. We identify MHC-II+ fibroblast subsets reminiscent of lymph node T-zone reticular cells and monocyte-derived dendritic cells that can maintain Th2-like tumour cells. CTCL Th2-like tumour cells are spatially associated with B cells, forming aggregates reminiscent of tertiary lymphoid structures which are more prominent with progressive disease. Finally, we validated the enrichment of B cells in CTCL skin infiltrates and its association with disease progression across three independent patient cohorts. Our findings provide diagnostic aids, potential biomarkers for disease staging and therapeutic strategies for CTCL.

genomics↗

bioRxiv2023

Metabolic interactions of a minimal bacterial consortium drive robust nitritation at acidic pH

Microbial communities efficiently mediate aerobic ammonia oxidation even at acidic pH. However, little is known about the adaptations and interactions that allow these communities to withstand challenges such as acidic stress, reactive nitrogen species, and resource deprivation under such conditions. Here we combined metagenomic analysis and biogeochemical measurements to infer the composition, metabolic interactions, and stress adaptation mechanisms of microbial consortia in three acidic nitritation bioreactors, operating at pH 5 to 2. This resulted in the recovery of 70 high-quality and mostly novel metagenome-assembled genomes (MAGs). The dominant ammonia oxidiser across all three bioreactors was a novel proteobacterium, herein named Candidatus (Ca.) Nitrosoglobus kelleri, that we enriched to a relative abundance of 55%. Also present were several heterotrophic bacteria that are predicted to engage in metabolically cross-feeding with the Nitrosoglobus. Particularly abundant were mycobacteria, including the novel actinobacterium Ca. Mycobacterium cookii, which are predicted to use organic carbon, hydrogen, carbon monoxide, sulfide and possibly nitrite as energy sources to drive aerobic respiration and denitrification. Remarkably, we observed efficient conversion of ammonia to nitrate even at pH 2, by a minimalistic community comprising the Nitrosoglobus and Mycobacterium as its only core members. Genomic analysis suggests these bacteria each use multiple strategies to maintain intracellular pH homeostasis, detoxify reactive nitrogen species, and scavenge nutrients at this pH. Altogether, these findings reveal that minimal communities can drive a key biogeochemical process even at acidic pH, and have implications for understanding nitrogen cycling and enhancing wastewater treatment.

ecology↗

bioRxiv2023

Climate warming suppresses soil abundant fungal taxa and reduces soil carbon efflux in a semi-arid grassland

The abundance, diversity and activity of soil microorganisms critically control the fate of recent plant carbon (C) inputs as well as protecting soil organic C, regulating C-climate feedbacks. However, the effects of climate change drivers such as warming and precipitation change on soil microbial communities and C dynamics remain poorly understood. Utilizing a long-term field warming and precipitation manipulation in a semi-arid grassland on the Loess Plateau and a complementary incubation experiment, here we show that warming and rainfall reduction differentially affect the abundance and composition of bacteria and fungi, and soil C efflux. Warming significantly reduced the abundance of fungi but not bacteria, increasing the relative dominance of bacteria in the soil microbial community. In particular, warming shifted the community composition of abundant fungi in favor of oligotrophic Capnodiales and Hypocreales over potential saprotroph Archaeorhizomycetales. In contrast, precipitation reduction increased soil microbial biomass, but did not significantly affect either the abundance or diversity of bacteria. Furthermore, soil abundant, not rare, fungal community composition was significantly correlated with soil CO2 efflux. Our findings suggest that alterations in the fungal community composition, in response to changes in soil C and moisture, dominate the microbial responses to climate change and thus control soil C dynamics in semi-arid grasslands. Impact statementSemi-arid grasslands play a critical role in global carbon (C) cycle and potential feedbacks to climate change. Understanding the responses of soil microorganisms to warming and rainfall change is key to evaluating and predicting semi-arid grassland soil C dynamics under future climate change scenarios. Our study showed that warming induced a shift in the abundant fungal community, favoring oligotrophic fungi (i.e., Capnodiales and Hypocreales) over the potential saprotrophic Archaeorhizomycetales, and reduced C efflux. These findings advance our understanding of soil microbial and C responses to climate change drivers and may help predict and possibly manage soil C sequestration in semi-arid grasslands.

ecology↗

bioRxiv2023

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-{gamma} and TNF stimulated lung macrophages to chronically release IL-1{beta}, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-{gamma} and TNF, or IL-1{beta} after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.

immunology↗

bioRxiv2023

Preclinical evaluation of the efficacy and safety of AAV1-hOTOF in mice and non-human primates

Pathogenic mutations in the OTOF gene cause autosomal recessive hearing loss 9 (DFNB9), one of the most common forms of auditory neuropathy. There is no biological treatment for DFNB9. Here, we designed an OTOF gene therapy agent by dual AAV1 carrying human OTOF coding sequences with the expression driven by the hair cell-specific promoter Myo15, AAV1-hOTOF. To develop a clinical application of AAV1-hOTOF gene therapy, we evaluated its efficacy and safety in animal models by pharmacodynamics, behavior, and histopathology. AAV1-hOTOF inner ear delivery significantly improved hearing in Otof -/- mice without affecting normal hearing in wild-type mice. AAV1 was predominately distributed to the cochlea although it was detected in other organs such as the central nervous system and the liver, and no obvious toxic effects of AAV1-hOTOF were observed in mice. To further evaluate the safety of Myo15 promoter-driven AAV1-transgene, AAV1-GFP was delivered into the inner ear of Macaca fascicularis via the round window membrane. AAV1-GFP transduced 60-94% of the inner hair cells along the cochlear turns. AAV1-GFP was detected in isolated organs and no significant adverse effects were detected. These results suggest that AAV1-hOTOF is well tolerated and effective in animals, providing critical support for its clinical translation.

genetics↗

bioRxiv2023

Distinct mechanisms by which antioxidant transcription factors Nrf1 and Nrf2 as drug targets contribute to the anticancer efficacy of Cisplatin on hepatoma cells

Cisplatin (cis-Dichlorodiamineplatinum[II], CDDP) is generally accepted as a platinum-based alkylating agent type of the DNA-damaging anticancer drug, which is widely administrated in clinical treatment of many solid tumors. The pharmacological effect of CDDP is mainly achieved by replacing the chloride ion (Cl-) in its structure with H2O to form active substances with the strong electrophilic properties and then react with any nucleophilic molecules, primarily leading to genomic DNA damage and subsequent cell death. In this process, those target genes driven by the consensus electrophilic and/or antioxidant response elements (EpREs/AREs) in their promoter regions are also activated or repressed by CDDP. Thereby, we here examined the expression profiling of such genes regulated by two principal antioxidant transcription factors Nrf1 and Nrf2 (both encoded by Nfe2l1 and Nfe2l2, respectively) in diverse cellular signaling responses to this intervention. The results demonstrated distinct cellular metabolisms, molecular pathways and signaling response mechanisms by which Nrf1 and Nrf2 as the drug targets differentially contribute to the anticancer efficacy of CDDP on hepatoma cells and xenograft tumor mice. Interestingly, the role of Nrf1, rather than Nrf2, is required for the anticancer effect of CDDP, to suppress malignant behavior of HepG2 cells by differentially monitoring multi-hierarchical signaling to gene regulatory networks. To our surprise, it was found there exists a closer relationship of Nrf1 than Nrf2 with DNA repair, but the hyperactive Nrf2 in Nrf1-/-cells manifests a strong correlation with its resistance to CDDP, albeit their mechanistic details remain elusive.

cell biology↗

bioRxiv2023

Leveraging fine-scale population structure reveals conservation in genetic effect sizes between human populations across a range of human phenotypes

An understanding of genetic differences between populations is essential for avoiding confounding in genome-wide association studies (GWAS) and understanding the evolution of human traits. Polygenic risk scores constructed in one group perform poorly in highly genetically-differentiated populations, for reasons which remain controversial. We developed a statistical ancestry inference pipeline able to decompose ancestry both within and between countries, and applied it to the UK Biobank data. This identifies fine-scale patterns of genetic relatedness not captured by standard and widely used principal components (PCs), and allows fine-scale population stratification correction that removes both false positive and false negative associations for traits with geographic correlations. We also develop and apply ANCHOR, an approach leveraging segments of distinct ancestries within individuals to estimate similarity in underlying causal effect sizes between groups, using an existing PGS. Applying ANCHOR to >8000 people of mixed African and European ancestry, we demonstrate that estimated causal effect sizes are highly similar across these ancestries for 26 of 29 quantitative molecular and non-molecular phenotypes (mean correlation 0.98 +/-0.08), providing evidence that gene-environment and gene-gene interactions do not play major roles in the poor prediction of European-ancestry PRS scores in African populations for these traits, contradicting previous findings. Instead our results provide optimism that shared causal mutations operate similarly in different groups, focussing the challenge of improving GWAS "portability" between groups on joint fine-mapping.

genetics↗

bioRxiv2023

Recombinant Rotavirus Expressing the Glycosylated S1 Protein of SARS-CoV-2

Reverse genetic systems have been used to introduce heterologous sequences into the rotavirus segmented double-stranded (ds)RNA genome, enabling the generation of recombinant viruses that express foreign proteins and possibly serve as vaccine vectors. Notably, insertion of SARS-CoV-2 sequences into the segment 7 (NSP3) RNA of simian SA11 rotavirus was previously shown to result in the production of recombinant viruses that efficiently expressed the N-terminal domain (NTD) and the receptor-binding domain (RBD) of the S1 region of the SARS-CoV-2 spike protein. However, efforts to generate a similar recombinant (r) SA11 virus that efficiently expressed full-length S1 were less successful. In this study, we describe modifications to the S1-coding cassette inserted in the segment 7 RNA that allowed recovery of second-generation rSA11 viruses that efficiently expressed the [~]120-kDa S1 protein. The [~]120-kDa S1 products were shown to be glycosylated, based on treatment with endoglycosidase H, which reduced the protein to a size of [~]80 kDa. Co-pulldown assays demonstrated that the [~]120-kDa S1 proteins had affinity for the human ACE2 receptor. Although all the second-generation rSA11 viruses expressed glycosylated S1 with affinity for the ACE receptor, only the S1 product of one virus (rSA11/S1f) was appropriately recognized by anti-S1 antibody, suggesting the rSA11/S1f virus expressed an authentic form of S1. Probably due to the presence of FLAG tags on their S1 signal peptides, the S1 products of the other viruses (rSA11/3fS1 and rSA11/3fS1-His) may have undergone defective glycosylation, impeding antibody binding. In summary, these results indicate that recombinant rotaviruses can serve as expression vectors of foreign glycosylated proteins, raising the possibility of generating rotavirus-based vaccines that can induce protective immune responses against enteric and mucosal viruses with glycosylated capsid components, including SARS-CoV-2.

microbiology↗

bioRxiv2023

Prominent contributions of selective neuronal subtypes to pediatric drug-resistant focal dysplasia

About 75% cases of epilepsy begin during childhood, and 10 - 30% of pediatric epilepsy patients are resistant to drug treatment. The predominant seizure type in children is focal cortical dysplasia (FCD) which is highly associated with drug-resistant epilepsy, but its underlying cause is poorly understood. We performed single-cell RNA sequencing and patch-clamp recording on fresh brain tissues obtained from pediatric FCD patients shortly after surgery to reveal critical factors contributing to FCD. We report that known epilepsy genes or significant transcriptomic alterations occur in only a few neuronal subgroups, suggesting that epilepsy-associated neurons cluster into only a few neuronal subtypes. These epilepsy-subtypes displayed significant epilepsy-related transcriptomic alterations, especially in the genes associated with excitation/inhibition balance and neuron functional signal pathways. Among eight epilepsy-subtypes, L2_4_CUX2_YWHAH and PVALB_RGS5 subtypes showed the most prominent alterations in FCD patient tissues. Supporting PV-neurons being important, recording from fast-spiking/parvalbumin-containing neurons in acute FCD patient brain slices revealed reduced excitatory synaptic inputs, implicating lower activity in these neurons and fewer synaptic inputs onto them. A higher percentage of mitochondria genes, and likely higher activity in the pathways associated with oxidative phosphorylation and ATP biosynthetic process, was observed in the epilepsy-subtypes, suggesting a high energy expenditure in them. Interestingly, the activity of the above two pathways in most epilepsy-subtypes was lower in the FCD patients, suggesting these subtypes may be more vulnerable to energy deficit in epilepsy. Altogether, transcriptomics is significantly altered in only a few neuronal subtypes in pediatric FCD patient brains. These selective epilepsy-subtypes may play prominent roles in the genesis of pediatric drug-resistant seizure and targeting them may provide new treatment options.

bioinformatics↗

bioRxiv2023

Sorcin-STAT3-Serpin E1/CCL5 axis can be the trigger of pancreatic cancer-associated new-onset diabetes

A rise in blood glucose is the early warning signs of underlying pancreatic cancer (PC), which could be the externalization of genetic events in PC progression. But there is still a vacancy in the field of mechanism research on pancreatic cancer-associated new-onset diabetes (PCAND). Using siRNA-mediated gene knockdown in vitro, we made MIN6 cells incubated with conditioned media from transfected PC cells, and detected its response. Immunological techniques were used to explore the interaction between sorcin and STAT3. Human cytokine array was performed to explore the inflammatory cytokines downstream of sorcin. In the present study, we have identified a PCAND driver gene SRI. In PC cells, sorcin and STAT3 form a positive feedback loop to enhance the transcription of serpin E1 and CCL5, which can impair nearby islet {beta}-cells, likely by activating the p38 pathway. In 88 biopsies, expression of sorcin was elevated in PC tissues, especially so in PCAND patient samples. Furthermore, clinical-SRI gene combination model can better distinguish PCAND from T2DM, and serpin E1 level is higher in the peripheral blood samples from PCAND than T2DM. Thus, Sorcin could be the key driver in PCAND, and figuring out sorcin-STAT3-serpin E1/CCL5 signaling axis can help us better understand the pathogenesis of PCAND and identify potential biomarkers. Statement of significanceThis study mapped out a novel sorcin-STAT3-Serpin E1/CCL5 signaling axis in pancreatic cancer cells, which explains how early pre-symptomatic pancreatic cancer may coincide with new-onset diabetes in some patients.

cancer biology↗

bioRxiv2023

Rapid identification of key genes for the rod-shaped morphology in bacteria using multi-species genomes

Accurate identification of key genes is pivotal in biological research. Here, we introduce machine learning to the field of functional gene identification, enabling precise prediction of bacterial shape based on genomic information. Our machine learning model successfully predicts bacterial shape, and we determine the influence of various protein domains on shape using the model. This approach facilitates the identification of candidate genes involved in regulating bacterial shape. Through targeted knockout experiments on eight potential key regulatory genes (pal, yicC, mreB, tolQ, ftsX, amiC, yddB, and rpoZ) in Escherichia coli, we observe significant alterations in rod-shaped morphology upon individual knockout of pal and mreB genes. E. coli transitions from rod-shaped to spherical or cell wall-deficient protoplasmic states. Experimental validations validate the robustness of our newly developed method. This study establishes an innovative avenue for exploring functional genes, harnessing large-scale genomic information to promptly uncover key genes governing shared traits across species.

genetics↗

bioRxiv2023

Huntingtin loss in hepatocytes is associated with altered metabolism, adhesion, and liver zonation

Huntingtons disease arises from a toxic gain of function in the huntingtin (HTT) gene. As a result, many HTT-lowering therapies are being pursued in clinical studies, including those that reduce HTT RNA and protein expression in the liver. To investigate potential impacts, we characterized molecular, cellular, and metabolic impacts of chronic HTT lowering in mouse hepatocytes. Lifelong hepatocyte HTT loss is associated with multiple physiological changes, including increased circulating bile acids, cholesterol and urea, hypoglycemia, and impaired adhesion. HTT loss causes a clear shift in the normal zonal patterns of liver gene expression, such that pericentral gene expression is reduced. These alterations in liver zonation in livers lacking HTT are observed at the transcriptional, histological and plasma metabolite level. We have extended these phenotypes physiologically with a metabolic challenge of acetaminophen, for which the HTT loss results in toxicity resistance. Our data reveal an unexpected role for HTT in regulating hepatic zonation, and we find that loss of HTT in hepatocytes mimics the phenotypes caused by impaired hepatic {beta}-catenin function. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/546334v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1dd0f15org.highwire.dtl.DTLVardef@938f7org.highwire.dtl.DTLVardef@17ae025org.highwire.dtl.DTLVardef@11cd15_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Optimizing Cell Therapy by Sorting Cells with High Extracellular Vesicle Secretion

Critical challenges remain in clinical translation of extracellular vesicle (EV)-based therapeutics due to the absence of methods to enrich cells with high EV secretion. Current cell sorting methods are limited to surface markers that are uncorrelated to EV secretion or therapeutic potential. We developed a nanovial technology for enrichment of millions of single cells based on EV secretion. This approach was applied to select mesenchymal stem cells (MSCs) with high EV secretion as therapeutic cells for improving treatment. The selected MSCs exhibited distinct transcriptional profiles associated with EV biogenesis and vascular regeneration and maintained high levels of EV secretion after sorting and regrowth. In a mouse model of myocardial infarction, treatment with high-secreting MSCs improved heart functions compared to treatment with low-secreting MSCs. These findings highlight the therapeutic importance of EV secretion in regenerative cell therapies and suggest that selecting cells based on EV secretion could enhance therapeutic efficacy.

bioengineering↗

bioRxiv2023

The transcription factor OsbZIP48 governs rice responses to zinc deficiency

Zinc deficiency is the most prevalent micronutrient disorder in rice and leads to delayed development and decreased yield. Nevertheless, despite its primary importance, how rice responds to zinc deficiency remains poorly understood. Herein, we present genetic evidence that OsbZIP48 is essential for regulating rice responses to zinc deficiency. Using the reverse genetics approach, genetic inactivation of OsbZIP48 in rice seedlings caused a hyper sensitivity to zinc deficiency, associated with a significant decrease in the root-to-shoot translocation of zinc. Consistently, OsbZIP48 was constitutively expressed in roots, slightly induced by zinc deficiency in shoots, and localized into nuclei induced by Zn deficiency. Comparative transcriptome analysis of the wild-type plants and osbzip48 mutant grown under zinc deficiency enabled the identification of OsbZIP48 target genes, including key zinc transporter genes (OsZIP4 and OsZIP8). We demonstrated that OsbZIP48 controlled the expressions of these genes by directly binding to their promoters, specifically to the zinc deficiency response element (ZDRE) motif. Collectively, we showed that the OsbZIP48 gene encodes for a transcription factor in rice, and demonstrates its critical role in the response to zinc deficiency in this crop. This knowledge is crucial for the design of rice plants that are resilient to the globally prevalent zinc limitation through zinc bio-fortification programs.

plant biology↗