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Huang, C.

Publications and source records attributed to Huang, C..

At least 109 records · Page 6Linked to original sources

PVN-mPFC OT projections modulates pup-directed pup care or attacking in virgin mandarin voles

In many species, adult animals may exhibit caregiving or aggression towards conspecific offspring. The neural mechanisms underlying the infanticide and pup care remain poorly understood. Here, using monogamous virgin mandarin voles (Microtus mandarinus) that may exhibit pup care or infanticide, we found that more oxytocin (OT) neurons in the paraventricular nucleus (PVN) were activated during pup caring than infanticide. Optogenetic activation of OT neurons in the PVN facilitated pup-caring in male and female mandarin voles. In infanticide voles, optogenetic activation of PVN OT cells prolonged latency to approach and attack pups, whereas inhibition of these OT neurons facilitated approach and infanticide. In addition, OT release in the medial prefrontal cortex (mPFC) in pup-care voles increased upon approaching and retrieving pups, and decreased in infanticide voles upon attacking pups. Optogenetic activation of PVN OT neuron projections to the mPFC shortened the latency to approach and retrieve pups and facilitated the initiation of pup care, whereas inhibition of these projections had little effect. For pup-care females, neither activation nor inhibition of the fibers affected their behavior towards pups. In infanticide male and female voles, optogenetic activation of PVN-mPFC OT projection fibers prolonged the latency to approach and attack pups and suppressed the initiation of infanticide, whereas inhibition of these projections promoted approach and infanticide. Finally, we found that intraperitoneal injection of OT promoted pup care and inhibited infanticide behavior. It is suggested that the OT system, especially PVN OT neurons projecting to mPFC, modulates pup-directed behaviors and OT can be used to treat abnormal behavioral responses associated with some psychological diseases such as depression and psychosis.

neuroscience↗

PI3K/HSCB axis facilitates FOG1 nuclear translocation to promote erythropoiesis and megakaryopoiesis

Erythropoiesis and megakaryopoiesis are stringently regulated by signaling pathways. However, the precise molecular mechanisms through which signaling pathways regulate key transcription factors controlling erythropoiesis and megakaryopoiesis remain partially understood. Herein, we identified heat shock cognate B (HSCB), which is well known for its iron-sulfur cluster delivery function, as an indispensable protein for friend of GATA 1 (FOG1) nuclear translocation during erythropoiesis of K562 human erythroleukemia cells and cord-blood-derived human CD34+CD90+ hematopoietic stem cells (HSCs), as well as during megakaryopoiesis of the CD34+CD90+ HSCs. Mechanistically, HSCB could be phosphorylated by phosphoinositol-3-kinase (PI3K) to bind with and mediate the proteasomal degradation of transforming acidic coiled-coil containing protein 3 (TACC3), which otherwise detained FOG1 in the cytoplasm, thereby facilitating FOG1 nuclear translocation. Given that PI3K is activated during both erythropoiesis and megakaryopoiesis, and that FOG1 is a key transcription factor for these processes, our findings elucidate an important, previously unrecognized iron-sulfur cluster delivery independent function of HSCB in erythropoiesis and megakaryopoiesis.

molecular biology↗

Beta-cell adaptation to metabolic stresses requires prolactin receptor signaling

The role of prolactin receptor (PRLR) signaling in {beta}-cell adaptation to maternal insulin resistance of pregnancy has been well demonstrated. Using transgenic mice with an inducible {beta}-cell-specific Prlr deletion ({beta}Prlr-/-), we found that intact PRLR, as found in {beta}Prlr+/+ mice, were protected from developing glucose intolerance during pregnancy, and the main mechanism responsible for this PRLR-mediated effect is the up regulation of {beta}-cell proliferation and insulin synthesis. Interestingly, studies in male mice and humans have found a link between diminished PRLR signaling and abnormal {beta}-cell function. We aimed to determine whether PRLR has a role in regulating {beta}-cell function outside of pregnancy, protecting {beta}-cell against exposure to metabolic stressors. In this study, we found that {beta}-cell-specific PRLR reduction resulted in impaired glucose tolerance in multiparous female mice challenged with a 12-week course of high-fat diet (HFD). Unlike in pregnancy, where PRLR signaling up regulates {beta}-cell proliferation resulting in a greater {beta}-cell mass, we observed no difference in {beta}-cell mass between the wild type ({beta}Prlr+/+) and mutant ({beta}Prlr-/-) mice. In vitro glucose-stimulated insulin secretion using isolated islets from wild type ({beta}Prlr+/+) and mutant ({beta}Prlr-/-) mice showed comparable insulin response, but {beta}Prlr-/- mice showed blunted first-phase insulin release in vivo, although only when challenged with glucose orally and not intraperitoneally, suggesting an impairment of the incretin effect. In support of the observed defect in incretin action, we found a reduction in expression of both incretin hormone receptors, Gipr and Glp-1r, and several of their upstream regulators, such as E2f1, Nkx6.1, Pax6, Ppar{gamma}, and Tcf7l2. Islets from the mutant mice also have a lower insulin content and reduced levels of genes that regulate glucose metabolism. Together, these results suggested that PRLR signaling plays an important role in preserving {beta}-cell function in mice exposed to metabolic stress by maintaining incretin receptor expression and insulin secretory capacity in {beta} cells.

physiology↗

A split-GAL4 driver line resource for Drosophila CNS cell types

Techniques that enable precise manipulations of subsets of neurons in the fly central nervous system have greatly facilitated our understanding of the neural basis of behavior. Split-GAL4 driver lines allow specific targeting of cell types in Drosophila melanogaster and other species. We describe here a collection of 3060 lines targeting a range of cell types in the adult Drosophila central nervous system and 1373 lines characterized in third-instar larvae. These tools enable functional, transcriptomic, and proteomic studies based on precise anatomical targeting. NeuronBridge and other search tools relate light microscopy images of these split-GAL4 lines to connectomes reconstructed from electron microscopy images. The collections are the result of screening over 77,000 split hemidriver combinations. Previously published and new lines are included, all validated for driver expression and curated for optimal cell type specificity across diverse cell types. In addition to images and fly stocks for these well-characterized lines, we make available 300,000 new 3D images of other split-GAL4 lines.

neuroscience↗

Principles of visual cortex excitatory microcircuit organization

Microcircuit function is determined by patterns of connectivity and short-term plasticity that vary with synapse type. Elucidating microcircuit function therefore requires synapse-specific investigation. The state of the art for synapse-specific measurements has long been paired recordings. Although powerful, this method is slow, leading to a throughput problem. To improve yield, we therefore created optomapping -- an approximately 100-fold faster 2-photon optogenetic method -- which we validated with paired-recording data. Using optomapping, we tested 15,433 candidate excitatory inputs to find 1,184 connections onto pyramidal, basket, and Martinotti cells in mouse primary visual cortex, V1. We measured connectivity, synaptic weight, and short-term dynamics across the V1 layers. We found log-normal synaptic strength distributions, even in individual inhibitory cells, which was previously not known. We reproduced the canonical circuit for pyramidal cells but found surprising and differential microcircuit structures, with excitation of basket cells concentrated to layer 5, and excitation of Martinotti cells dominating in layer 2/3. Excitation of inhibitory cells was denser, stronger, and farther-reaching than excitation of excitatory cells, which promotes stability and difference-of-Gaussian connectivity. We gathered an excitatory short-term plasticitome, which revealed that short-term plasticity is simultaneously target-cell specific and dependent on presynaptic cortical layer. Peak depolarization latency in pyramidal cells also emerged as more heterogeneous, suggesting heightened sensitivity to redistribution of synaptic efficacy. Optomapping additionally revealed high-order connectivity patterns including shared-input surplus for interconnected pyramidal cells in layer 6. Optomapping thus offered both resolution to the throughput problem and novel insights into the principles of neocortical excitatory fine structure. HIGHLIGHTSO_LI2-photon optomapping of microcircuits is verified as fast, accurate, and reliable C_LIO_LISynaptic weights distribute log-normally even for individual inhibitory neurons C_LIO_LIMaximal excitation of basket and Martinotti cells in layer 5 and 2/3, respectively C_LIO_LIShort-term plasticity depends on layer in addition to target cell C_LI

neuroscience↗

Glycodiversification of gentamicins through in vivo glycosyltransferase swapping enabled the creation of novel hybrid aminoglycoside antibiotics with potent activity and low ototoxicity

Aminoglycosides (AGs) are a class of potent antibiotics with a broad spectrum of activity. However, their use is limited by safety concerns associated with nephrotoxicity and ototoxicity, as well as drug resistance. To address these issues, semi-synthetic approaches for modifying natural AGs have successfully generated new generations of AGs, however, with limited types of modification due to significant challenges in synthesis. This study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid AGs, installing extensive natural modifications from gentamicins onto kanamycins. This was achieved by glycodiversification of gentamicins via swapping the glycosyltransferase (GT) in their producer with the GT from kanamycins biosynthetic pathway and resulted in the creation of a series of novel AGs with combined structural features of two, therefore referred to as genkamicins (GKs). The manipulation of the hybrid metabolic pathway enabled the target accumulation of different GK species and the successful isolation and characterization of six GK components. These compounds display retained antimicrobial activity against a panel of World Health Organization (WHO) critical priority pathogens, and GK-C2a, in particular, demonstrates low ototoxicity compared to clinical drugs in zebrafish embryos. This study provides a new strategy for diversifying the structure of AGs and a potential avenue for developing less toxic AG drugs to combat infectious diseases.

synthetic biology↗

UDP-glucosyltransferase 71C4 regulates seed development by redistributing phenylpropanoid metabolism in cotton

Seeds are important for plant reproduction, and hence it is important to identify genes regulating seed development. Here, we focused on a member of the glycosyltransferase (GT) family, UDP-glucosyltransferase 71C4 (UGT71C4), which influences the seed width, seed length, and yield traits (lint percentage and seed index) by regulating the lignin and flavonoid pathways of phenylpropane metabolism, affects the oil and protein contents of mature seeds, and controls the seed size by regulating cell proliferation. Overexpression of UGT71C4 leads to seed enlargement by activating expression of peroxiredoxins and the flavonoid metabolism pathway; induces accumulation of ROS, which promotes cell proliferation; and significantly improves yield traits, with the seed index increasing from 10.66 to 11.91 and protein increasing by 5.34%, but oil content decreasing 8.98%. Conversely, knockout of UGT71C4 causes seeds to become smaller; the lignin metabolism pathway to be activated, especially enzymes relating to lignin synthesis leading to increased ectopic deposition of lignin in the ovule and constrained ovule growth and development; and significant improvement of yield traits, with lint percentage increasing from 39.62% to 41.94%, seed index decreasing from 10.66 to 8.60, protein content decreasing 4.28%, and no significant change in oil content. Our research provides new insights into seed size regulation through UDP-glucosyltransferase, providing potential methods for improving plant yield.

plant biology↗

Distinct and interdependent functions of three RING proteins regulate recombination during mammalian meiosis

During meiosis, each pair of homologous chromosomes becomes connected by at least one crossover, as required for accurate segregation at the first division, and adjacent crossovers are widely separated thereby limiting total numbers. In coarsening models, crossover patterning results from nascent recombination sites competing to accrue a limiting pro-crossover RING-domain protein (COR) that diffuses between synapsed chromosomes. Here we delineate the localization dynamics of three mammalian CORs in mouse and determine their interdependencies. RNF212, HEI10 and a new member RNF212B show divergent spatiotemporal dynamics along synapsed chromosomes, including profound differences in spermatocytes and oocytes, that are not easily reconciled by elementary coarsening models. Contrasting mutant phenotypes and genetic requirements indicate that RNF212B, RNF212, and HEI10 play distinct but interdependent functions in regulating meiotic recombination and coordinating the events of meiotic prophase-I by integrating signals from DNA breaks, homolog synapsis, the cell-cycle, and incipient crossover sites. SIGNIFICANCEMeiosis produces haploid gametes by precisely halving the chromosome complement. Crossing over between homologous chromosomes (homologs) is essential for their accurate segregation and defects are associated with infertility, miscarriage, and congenital disease. Factors that ensure crossing over between each pair of homologs include mammalian RING-domain proteins RNF212, HEI10, and RNF212B, alleles of which are linked to infertility and heritable variation in crossover rate. This study focuses on understanding the functions and relationships between pro-crossover RING proteins (CORs) in mouse, providing important insights into their roles in regulating recombination, the DNA repair process that gives rise to crossovers. Notably, chromosomal localization dynamics of the three CORs are distinct and show striking sexual dimorphism with important implications for models of crossover control.

genetics↗

Non-modular Fatty Acid Synthases Yield Unique Acylation in Ribosomal Peptides

Recent efforts in genome mining of ribosomally synthesized and post-translationally modified peptides (RiPPs) have expanded the diversity of post-translational modification chemistries1, 2. However, RiPPs are rarely reported as hybrid molecules incorporating biosynthetic machineries from other natural product families3-8. Here, we report lipoavitides, a class of RiPP/fatty acid hybrid lipopeptides that display a unique, membrane-targeting 4-hydroxy-2,4-dimethylpentanoyl (HMP)-modified N-terminus. The HMP is formed via condensation of isobutyryl-CoA and methylmalonyl-CoA catalyzed by a 3-ketoacyl-ACP synthase III enzyme, followed by successive tailoring reactions in the fatty acid biosynthetic pathway. The HMP and RiPP substructures are then connected by an acyltransferase exhibiting promiscuous activity towards the fatty acyl and RiPP substrates. Overall, the discovery of lipoavitides contributes a prototype of RiPP/fatty acid hybrids and provides possible enzymatic tools for lipopeptide bioengineering.

biochemistry↗

Automated, self-resistance gene-guided, and high-throughput genome mining of bioactive natural products from Streptomyces

Natural products (NPs) produced by bacteria, fungi and plants are a major source of drug leads. Streptomyces species are particularly important in this regard as they produce numerous natural products with prominent bioactivities. Here we report a fully automated, scalable and high-throughput platform for discovery of bioactive natural products in Streptomyces (FAST-NPS). This platform comprises computational prediction and prioritization of target biosynthetic gene clusters (BGCs) guided by self-resistance genes, highly efficient and automated direct cloning and heterologous expression of BGCs, followed by high-throughput fermentation and product extraction from Streptomyces strains. As a proof of concept, we applied this platform to clone 105 BGCs ranging from 10 to 100 kb that contain potential self-resistance genes from 11 Streptomyces strains with a success rate of 95%. Heterologous expression of all successfully cloned BGCs in Streptomyces lividans TK24 led to the discovery of 23 natural products from 12 BGCs. We selected 5 of these 12 BGCs for further characterization and found each of them could produce at least one natural product with antibacterial and/or anti-tumor activity, which resulted in a total of 8 bioactive natural products. Overall, this work would greatly accelerate the discovery of bioactive natural products for biomedical and biotechnological applications. Graphic Abstracts O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/564101v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@11068c9org.highwire.dtl.DTLVardef@4f68c5org.highwire.dtl.DTLVardef@16767edorg.highwire.dtl.DTLVardef@1d82eab_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

The Interferon-inducible NAMPT acts as a protein phosphoribosylase to restrict viral infection

As obligate intracellular pathogens, viruses often activate host metabolic enzymes to supply intermediates that support progeny production. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the salvage NAD+ synthesis, is an interferon-inducible protein that inhibits the replication of several RNA and DNA viruses with unknown mechanism. Here we report that NAMPT restricts herpes simplex virus 1 (HSV-1) replication via phosphoribosyl-hydrolase activity toward key viral structural proteins, independent of NAD+ synthesis. Deep mining of enriched phosphopeptides of HSV-1-infected cells identified phosphoribosylated viral structural proteins, particularly glycoproteins and tegument proteins. Indeed, NAMPT de-phosphoribosylates viral proteins in vitro and in cells. Chimeric and recombinant HSV-1 carrying phosphoribosylation-resistant mutations show that phosphoribosylation promotes the incorporation of structural proteins into HSV-1 virions and subsequent virus entry. Moreover, loss of NAMPT renders mice highly susceptible to HSV-1 infection. The work describes a hidden enzyme activity of a metabolic enzyme in viral infection and host defense, offering a system to interrogate roles of phosphoribosylation in metazoans.

molecular biology↗

Automated customization of large-scale spiking network models to neuronal population activity

Understanding brain function is facilitated by constructing computational models that accurately reproduce aspects of brain activity. Networks of spiking neurons capture the underlying biophysics of neuronal circuits, yet the dependence of their activity on model parameters is notoriously complex. As a result, heuristic methods have been used to configure spiking network models, which can lead to an inability to discover activity regimes complex enough to match large-scale neuronal recordings. Here we propose an automatic procedure, Spiking Network Optimization using Population Statistics (SNOPS), to customize spiking network models that reproduce the population-wide covariability of large-scale neuronal recordings. We first confirmed that SNOPS accurately recovers simulated neural activity statistics. Then, we applied SNOPS to recordings in macaque visual and prefrontal cortices and discovered previously unknown limitations of spiking network models. Taken together, SNOPS can guide the development of network models and thereby enable deeper insight into how networks of neurons give rise to brain function.

neuroscience↗

Exploiting Substrate Specificities of 6-O-Sulfotransferases to Enzymatically Synthesize Keratan Sulfate Oligosaccharides

Keratan sulfate (KS) is a glycosaminoglycan that is widely expressed in the extracellular matrix of various tissue types where it is involved in many biological processes. Herein, we describe a chemo-enzymatic approach to prepare well-defined KS oligosaccharides by exploiting known and newly discovered substrate specificities of relevant sulfotransferases. The premise of the approach is that recombinant GlcNAc-6-O-sulfotransferases (CHST2) only sulfates terminal GlcNAc moieties to give GlcNAc6S that can be galactosylated by B4GalT4. Furthermore, CHST1 can modify internal galactosides of a poly-LacNAc chain, however, it was found that a GlcNAc6S residue greatly increases the reactivity of CHST1 of a neighboring and internal galactoside. The presence of a 2,3-linked sialoside further modulates the site of modification by CHST1, and a galactoside flanked by 2,3-Neu5Ac and GlcNAc6S is preferentially sulfated over other Gal residues. The substrate specificities of CHST1 and 2 were exploited to prepare a panel of KS oligosaccharides including selectively sulfated N-glycans. The compounds and several other reference derivatives were used to construct a microarray that was probed for binding by several plant lectins, Siglec proteins and hemagglutinins of influenza viruses. It was found that not only the sulfation pattern but also presentation of epitopes as part of an O- or N-glycan determines binding properties.

biochemistry↗

PSTPIP2 ameliorates aristolochic acid nephropathy by suppressing interleukin-19-mediated neutrophil extracellular trap formation

Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by herbal medicines. Previously, we found that proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2) and neutrophil extracellular traps (NETs) play important roles in kidney injury and immune defense, respectively; however, the mechanism of AAN regulation by PSTPIP2 and NETs remains unclear. We found that renal tubular epithelial cell (RTEC) apoptosis, neutrophil infiltration, and inflammatory factor and NET production were increased in a mouse model of AAN, while PSTPIP2 expression was low. Conditional knock-in of PSTPIP2 in mouse kidneys inhibited cell apoptosis, reduced neutrophil infiltration, suppressed the production of inflammatory factors and NETs, and ameliorated renal dysfunction. In contrast, restoring normal PSTPIP2 expression promoted kidney injury. In vivo, the use of Ly6G-neutralizing antibody to remove neutrophils and peptidyl arginine deiminase 4 (PAD4) inhibitors to prevent NET formation reduced apoptosis, thereby alleviating kidney injury. In vitro, damaged RTECs released interleukin-19 (IL-19) via the PSTPIP2/nuclear factor (NF)-{kappa}B pathway and induced NET formation via the IL-20R{beta} receptor. Concurrently, NETs promoted the apoptosis of damaged RTECs. PSTPIP2 affected NET formation by regulating IL-19 expression via inhibition of NF-{kappa}B pathway activation in RTECs, inhibiting their apoptosis and reducing kidney damage.

pharmacology and toxicology↗

Seed size control via phloem end by callose deposition/degradation of β-1,3-glucanase

Seed formation is crucial for lives of plants as well as humans; however, the mechanisms governing seed size require further investigation. Here, we present a new mechanism to modify the seed size by the newly identified phloem end that support nutrient transport, at the chalazal end of the ovule, however, blocked by callose deposition. Callose is removed after central cell fertilization (open state), allowing nutrients to be transported to the seed. However, if fertilization fails, callose deposition persists (closed state), preventing the phloem end from transporting nutrients. {beta}-1,3-glucanase genes, including putative plasmodesmata-associated proteins (AtBG_ppap), were identified as regulators of callose removal. The Atbg_ppap mutant had the phloem end in the closed state and produced smaller seeds due to incomplete callose degradation. In contrast, the AtBG_ppap overexpression line produced larger seeds than the wild type due to continuous callose degradation, indicating that the phloem end regulates substance flow via callose deposition/degradation.

plant biology↗

Identification of five characteristic ferroptosis-related genes as novel biomarkers for ischemic stroke using bioinformatic and machine learning strategies

Ferroptosis is crucial in neuronal cell death, associated with various neurological disorders. However, the role of ferroptosis-related genes (FRGs) in ischaemic stroke (IS) has yet to be well elucidated. We downloaded IS-related gene information and FRGs from the Gene Expression Omnibus (GEO) and Ferritin databases (FerrDb). 22 IS-related DE-FRGs were obtained. Functional enrichment analysis showed that these genes involve multiple regulatory pathways related to IS pathogenesis, including redox, amino acid metabolism, and cell cycle. Subsequently, DUOX2, MDM2, EGFR, MAP3K14, and TRIM46 were identified as core marker genes among the 22 DE-FRGs by lasso and SVM-RFE algorithms. The construction of the nomogram using the five marker genes had excellent diagnostic value. In addition, CIBERSORT analysis showed that changes in the immune microenvironment of IS patients might be associated with TRIM46, MDM2, and DUOX2. In addition, a total of 66 drugs targeting two characteristic FRGs were obtained. The ceRNA networks revealed complex regulatory relationships based on characteristic FRGs. These findings provide new insights into the diagnosis and treatment of IS.

bioinformatics↗

Exogenous Methylglyoxal Improves Maize Yield by Alleviating Plant Diabetes and leaf senescence under Drought

Drought-induced leaf senescence is related to high sugar levels in leaves, photosynthesis inhibition, and ultimate yield loss. This physiological phenomenon in leaves bears resemblance to the symptom of diabetes in human disease. However, the underlying mechanisms of plant diabetes on carbon imbalance in maize leaf and corresponding detoxification strategy have not been well understood. In this study, we demonstrated that foliar application of exogenous methylglyoxal (MG) delayed leaf senescence and promoted photoassimilation, retrieved 14% yield loss induced by drought stress during grain filling stage. Transcriptome and metabolite analysis revealed that drought increased sugar accumulation in leaf with inhibition of sugar transporters facilitating phloem loading. This further lead to disequilibrium of glycolysis and over-accumulation of endogenous MG. Contrarily, exogenous MG significantly upregulated glycolytic flux and glyoxalase system catabolizing endogenous MG and advanced glycation end products toxicity, ultimately alleviating plant diabetes. Besides, the genes facilitating anabolism and catabolism of trehalose- 6-phosphate were promoted and suppressed by drought, respectively, whereas exogenous MG reversed the effect. Moreover, exogenous MG activated phenylpropanoid biosynthetic pathway, likely promoting cell structural integrity. Collectively, these results suggest that exogenous MG alleviates the toxic effect from drought-induced sugar accumulation and activates the defense-related pathway, thereby maintaining leaf function and yield production. HighlightExogenous methylglyoxal stimulates glycolytic flux and glyoxalase system, providing a potential insight to alleviate plant diabetes under drought condition.

physiology↗

Reprogramming human B cells with custom heavy chain antibodies

We describe a genome editing strategy to reprogram the immunoglobulin heavy chain (IgH) locus of human B cells to express custom molecules that respond to immunization. These heavy chain antibodies (HCAbs) comprise a custom antigen-recognition domain linked to an Fc domain derived from the IgH locus and can be differentially spliced to express either B cell receptor (BCR) or secreted antibody isoforms. The HCAb editing platform is highly flexible, supporting antigen-binding domains based on both antibody and non-antibody components, and also allowing alterations in the Fc domain. Using HIV Env protein as a model antigen, we show that B cells edited to express anti-Env HCAbs support the regulated expression of both BCRs and antibodies, and respond to Env antigen in a tonsil organoid model of immunization. In this way, human B cells can be reprogrammed to produce customized therapeutic molecules with the potential for in vivo amplification.

immunology↗