Biology subjects

Yuan, C.

Publications and source records attributed to Yuan, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Epilepsy-Associated SCN2A-L1342P Mutation Drives Network Hyperexcitability and Widespread Transcriptomic Changes in Human Cortical Organoids

ObjectiveSCN2A pathogenic mutations, such as the recurrent heterozygous Nav1.2-L1342P, are monogenic causes of epilepsy. In this human-induced pluripotent stem cell model system, we aim to investigate the molecular and cellular mechanisms underlying the SCN2A-L1342P-associated pathology. MethodsUsing a human male iPSC reference line (KOLF) carrying the Nav1.2-L1342P mutation, we generated 3D cortical organoids for functional studies. Patch clamp and multi-electrode array (MEA) recordings, immunocytochemistry, and RNA sequencing were used to characterize the disease phenotypes. ResultsNav1.2-L1342P organoid neurons displayed increased intrinsic excitability, and amplified excitatory post-synaptic currents, which are consistent with an increase in excitatory synapse formation revealed by PSD95/SYN1 immunostaining. Moreover, elevated network firing activity, as demonstrated by MEA, indicates a pronounced network hyperexcitability. Transcriptomic profiling of organoids carrying the Nav1.2-L1342P mutation further revealed significant alterations in synaptic, glutamatergic, and developmental pathways. SignificanceOur findings demonstrate that the Nav1.2-L1342P mutation drives a multifaceted disease phenotype, including network hyperexcitability and disruption of pathways related to neuronal and synaptic functions. These results advance our understanding of SCN2A-related Developmental and Epileptic Encephalopathy (DEE), laying a foundation for personalized interventions. Key PointsO_LIKey Point 1: Human neurons carrying epilepsy-causing SCN2A-L1342P display intrinsic hyperexcitability in cortical organoids. C_LIO_LIKey Point 2: Synaptic transmission is enhanced in organoids carrying the SCN2A-L1324P mutation, consistent with the presence of elevated excitatory synapses, which leads to increased network hyperexcitability. C_LIO_LIKey Point 3: Transcriptomics analysis reveals that the SCN2A-L1342P mutation causes significant differential changes in forebrain developmental genes, synaptic and glutamatergic signaling pathways, and enhances cellular senescence and apoptosis. C_LI

neuroscience↗

bioRxiv2025

Construction of a genome-wide pooled CRISPRi library as a resource for exploring the acid tolerance mechanism in Streptococcus mutans

Streptococcus mutans is recognized as the primary etiological agent of dental caries, one of the most prevalent infectious diseases globally. Its remarkable acid tolerance enables survival and proliferation in the low-pH biofilm microenvironment, establishing S. mutans as the dominant species in dental plaque and a key contributor to cariogenesis. Although numerous studies have identified genes linked to acid tolerance mechanisms, the full set of essential acid tolerance genes within its genome remains incompletely characterized, largely due to the lack of systematic, genome-scale investigations. To address this knowledge gap, we constructed a genome-wide pooled CRISPR interference (CRISPRi) library targeting 95% of the predicted S. mutans genes and employed next-generation sequencing to identify acid tolerance determinants systematically. Our screen revealed 95 acid tolerance-associated genes, a subset of which were functionally validated through gene knockout studies. Functional enrichment analysis demonstrated significant associations with metabolic pathways (including cofactor biosynthesis and amino/nucleotide sugar metabolism), tRNA modification, and transcriptional regulation. Protein-protein interaction (PPI) network analysis identified critical interactors (ComYC, SMU_1979c, DeoC, AcpP, NadD, and SMU_1988c) and two functionally cohesive modules. These findings provide novel mechanistic insights into the acid adaptation strategies of S. mutans and highlight potential therapeutic targets for caries prevention.

microbiology↗

bioRxiv2025

Composition of Carotid Plaques Differs Between Chinese and United States Patients: A Histology Study

BackgroundThe clinical manifestations of cerebrovascular disease are known to differ between the Chinese and United States (U.S.) populations as do the plaque features on imaging. ObjectivesThe aim of this study was to investigate and compare the histological features of excised carotid plaques from Chinese and U.S. patients. MethodsCarotid endarterectomy specimens collected from two prospective studies were included. The entire plaque was serially sectioned (10 {micro}m thickness) at 0.5-1 mm intervals. Hematoxylin and eosin staining and Mallorys trichrome staining were performed. The morphology and components of the plaques were measured and compared between the two groups. ResultsA total of 1,152 histological sections from 75 Chinese patients and 1,843 sections from 111 U.S. patients were analyzed. The Chinese group had significantly smaller minimum lumen diameters (median: 1.1 vs. 1.3 mm, p=0.046) and a larger percent wall volume (median: 74% vs. 70%, p=0.018) than the U.S. group. After adjusting for confounding factors, carotid plaques in the Chinese population were more likely to have more lipid pools ({beta}=10.0%, 95%CI: 4.9 to 15.9%), more recent intraplaque hemorrhage (IPH; {beta}=8.4%, 95%CI: 4.5 to 12.7%), and less late IPH ({beta}=-8.2%, 95%CI: -11.3 to -5.4), and fewer fibrous cap disruptions (45% vs. 67%, p=0.061). Chinese plaques were more homogeneous and had a higher percentage of plaques with features of xanthomas than did U.S. plaques (20% vs 2.7%, p<0.001). ConclusionsThe histology of Chinese plaques differs significantly from that of U.S. plaques, suggesting substantial differences in the pathophysiology of atherosclerotic cerebrovascular disease between Chinese and North American populations, which could enhance the gap in racial pathology comparison, indicating a need for a different management approach. Central illustration O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/658993v1_ufig1.gif" ALT="Figure 1"> View larger version (83K): org.highwire.dtl.DTLVardef@14f16corg.highwire.dtl.DTLVardef@f60d66org.highwire.dtl.DTLVardef@1e9a822org.highwire.dtl.DTLVardef@11d7a31_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2025

Gene therapies alleviate absence epilepsy associated with Scn2a deficiency in DBA/2J mice

Mutations in the voltage-gated sodium channel gene SCN2A, which encodes the NaV1.2 channel, cause severe epileptic seizures. Patients with SCN2A loss-of-function (LoF) mutations, such as protein-truncating mutations, often experience later-onset and drug-resistant epilepsy, highlighting an urgent unmet clinical need for new therapies. We previously developed a gene-trap Scn2a (Scn2agt/gt) mouse model with a global NaV1.2 reduction in the widely used C57BL/6N (B6) strain. Although these mice display multiple behavioral abnormalities, EEG recordings indicated only mild epileptiform discharges, possibly attributable to the seizure-resistant characteristics associated with the B6 strain. To enhance the epileptic phenotype, we derived congenic Scn2agt/gt mice in the seizure-susceptible DBA/2J (D2J) strain. Notably, we found that these mice exhibit prominent spontaneous absence seizures, marked by both short and long spike-wave discharges (SWDs). Restoring NaV1.2 expression in adult mice substantially reduced their SWDs, suggesting the possibility of SCN2A gene replacement therapy during adulthood. RNA sequencing revealed significant alterations in gene expression in the Scn2agt/gt mice, in particular a broad downregulation of voltage-gated potassium channel (KV) genes, including KV1.1. The reduction of KV1.1 expression was further validated in human cerebral organoids with SCN2A deficiency, highlighting KV1.1 as a promising therapeutic target for refractory seizures associated with SCN2A dysfunction. Importantly, delivery of exogenous human KV1.1 expression via adeno-associated virus (AAV) in D2J Scn2agt/gt mice substantially reduced absence seizures. Together, these findings underscore the influence of mouse strain on seizure severity and highlight the potential of targeted gene therapies for treating SCN2A deficiency-related epilepsies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=91 SRC="FIGDIR/small/657652v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@35374eorg.highwire.dtl.DTLVardef@1c22197org.highwire.dtl.DTLVardef@2b4582org.highwire.dtl.DTLVardef@e06e68_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefScn2a deficiency leads to absence seizures in D2J mice and neuronal hyperexcitability with compensatory KV reduction; restoring NaV1.2 or introducing human KV1.1 reduces seizure burden. HighlightsO_LIScn2a deficiency induces robust absence seizures in the DBA/2J but not the C57BL/6N strain. C_LIO_LICortical neurons in adult DBA/2J mice with Scn2a deficiency exhibit intrinsic hyperexcitability. C_LIO_LISevere Scn2a deficiency leads to downregulation of multiple potassium channel genes. C_LIO_LIGenetic restoration of NaV1.2 expression alleviates spike-wave discharges (SWDs). C_LIO_LIAAV-mediated human KV1.1 delivery substantially reduced absence seizures, demonstrating the therapeutic potential of targeted gene therapy. C_LI

neuroscience↗

bioRxiv2025

Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carrying SCN2A mutation

Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABAB receptor gene within striatal organoids. To investigate the contributions of microglia to neural circuitry, we created microglia-incorporated midbrain-striatal assembloids, modeling a core circuit node for many neuropsychiatric disorders including autism. Using chemogenetics to activate this midbrain-striatal circuit, we observed increased calcium signaling in microglia involving GABAB receptors. Leveraging this model, we examined microglial responses within neural circuits harboring an SCN2A nonsense (C959X) mutation associated with profound autism. Remarkably, microglia displayed heightened calcium responses to SCN2A mutation-mediated neuronal hyperactivity, and engaged in excessive synaptic pruning. These pathological effects were reversed by pharmacological inhibition of microglial GABAB receptors. Collectively, our findings establish an advanced platform to dissect human neuroimmune interactions in sub-cortical regions, highlighting the important role of microglia in shaping critical circuitry related to neuropsychiatric disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/657874v1_ufig1.gif" ALT="Figure 1"> View larger version (72K): org.highwire.dtl.DTLVardef@125b36eorg.highwire.dtl.DTLVardef@270079org.highwire.dtl.DTLVardef@903525org.highwire.dtl.DTLVardef@19145c4_HPS_FORMAT_FIGEXP M_FIG C_FIG TeaserModeling regional microglial diversity in sub-cortical regions is challenging. We generated human organoid and assembloid models containing microglia that acquire region-specific heterogeneity. Our work shows dynamic responses of microglia when exposed to hyperexcitable midbrain-striatal circuits, providing an exciting platform to study neuroimmune interactions in human brain development and neuropsychiatric disorders, including SCN2A mutation-mediated monogenic autism. HighlightsO_LI* Single-cell RNA sequencing analyses reveal six distinct microglial subtypes that spontaneously attain unique specialization in human cortical, striatal, and midbrain organoids. C_LIO_LI* Microglia facilitate axonal projections across regional organoids, promoting assembloid formation. C_LIO_LI* Microglia respond to hyperexcitable neurons via calcium signaling and exhibit excessive pruning of neuronal synapses. C_LIO_LI* Blocking microglial GABAB receptors normalizes calcium activity and reduces synaptic pruning, suggesting a potential targeting strategy for synaptic deficits. C_LI

neuroscience↗

bioRxiv2025

Autism-associated SCN2A deficiency disrupts cortico-striatal circuitry in human brain assembloids

Profound autism spectrum disorder (ASD) is frequently attributable to single-gene mutations, with SCN2A (voltage-gated sodium channel NaV1.2) protein-truncating variants (PTVs) being one of the most penetrant. Although cortico-striatal circuitry is implicated as a key node in ASD, the impact of SCN2A deficiency on human neural circuits is unknown. Using the human cortico-striatal assembloid model, we show that the autism-causing PTV SCN2A-C959X impairs long-range cortical axonal projections, reduces striatal spine density, and attenuates excitatory cortical-striatal synaptic transmission. Surprisingly, these assembloids carrying the heterozygous SCN2A nonsense mutation exhibited pronounced network hyperexcitability, a human cell-specific phenotype not observed in Scn2a+/- mice, highlighting a human-specific circuit vulnerability. Collectively, our study unveils human circuit-specific dysfunctions of SCN2A deficiency and SCN2A-mediated ASD. HighlightsO_LIAxonal projections facilitate synapse formation and functional connectivity in human brain assembloids. C_LIO_LINaV1.2 is expressed along neuronal axons, extending to soma and dendrites in human brain assembloids. C_LIO_LISCN2A-C959X disrupts axonal projection patterns, impairs excitatory synaptic transmission, reduces spine density, and results in elevated neuronal excitability. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/657036v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@6d5b1forg.highwire.dtl.DTLVardef@1795ecdorg.highwire.dtl.DTLVardef@13f0d7eorg.highwire.dtl.DTLVardef@8ee059_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefO_ST_ABSSCN2A haploinsufficiency impairs cortico-striatal circuitry.C_ST_ABSSCN2A haploinsufficiency disrupts axon initial segment (AIS) integrity, leading to hyperexcitability (red arrow), reduced axon projections, and impaired synaptic transmission (decreased sEPSCs and altered network firing). These deficits result in dysfunction within the cortico-striatal circuitry.

neuroscience↗

bioRxiv2025

The China Brain Multi-omics Atlas Project (CBMAP)

The China Brain Multi-omics Atlas Project (CBMAP) aims to generate a comprehensive molecular reference map of over 1,000 human brains (Phase I), spanning a broad age range and multiple regions in China, to address the underrepresentation of East Asian populations in brain research. By integrating genome, epigenome, transcriptome, proteome (including multiple post-translational modifications), and metabolome data, CBMAP is set to provide a rich and invaluable resource for investigating the molecular underpinnings of aging-related brain phenotypes and neuropsychiatric disorders. Leveraging high-throughput omics data and advanced technologies, such as spatial transcriptomics, proteomics, and single-nucleus 3D chromatin structure analysis, this atlas will serve as a crucial resource for the brain science community, illuminating disease mechanisms and enhancing the utility of data from genome-wide association studies (GWAS). CBMAP is also poised to accelerate drug discovery and precision medicine for brain disorders.

neuroscience↗

bioRxiv2025

LncMamba: A Deep Learning Model for lncRNA Localization Prediction Based on the Mamba Model

Accurate prediction of long non-coding RNA (lncRNA) subcellular localization is crucial for understanding its biological functions. In this study, we propose a novel deep learning framework, LncMamba, which utilizes a two-layer FPN network for multi-scale feature extraction and introduces the Mamba network to lncRNA localization prediction tasks for the first time. Based on this, we improved the localization-specific attention mechanism, allowing the model to more effectively focus on key sequence motifs related to localization. Additionally, through statistical analysis of localization motifs, we revealed the potential relationship between nucleotide motifs and lncRNA subcellular localization.The code is available at: https://anonymous.4open.science/r/lncMamba-731F.

bioinformatics↗

bioRxiv2025

mcDETECT: Decoding 3D Spatial Synaptic Transcriptomes with Subcellular-Resolution Spatial Transcriptomics

Spatial transcriptomics (ST) is a powerful tool for studying the molecular basis of brain diseases. However, most current analyses focus only on nuclear or somatic expression, overlooking distally localized mRNAs, known as the "dark transcriptome." These transcripts, which make up nearly 40% of the brain transcriptome, are packaged into RNA granules and transported to polarized neuronal structures critical for neuronal function. Here, we present mcDETECT, a machine learning framework that leverages in situ ST (iST) data to detect RNA granules and resolve their RNA composition. Applying mcDETECT to simulated and real datasets from multiple iST platforms, we demonstrate robust granule detection and molecular subtyping. Granule-informed downstream analysis further revealed functionally distinct neuronal substates not captured by somatic expression alone. In an Alzheimers disease (AD) mouse model, mcDETECT uncovered alterations in RNA granule distributions and associated neuronal substates prior to measurable neuronal loss, highlighting potential therapeutic targets for early AD pathology.

bioinformatics↗

bioRxiv2025

Inwardly rectifying potassium channels regulate membrane potential polarization and direction sensing during neutrophil chemotaxis

Potassium channels regulate membrane potential and diverse physiological processes, including cell migration. However, the specific function of the inwardly rectifying potassium channels in immune cell chemotaxis is unknown. Here, we identified that the inwardly rectifying potassium channel Kir7.1 (KCNJ13) maintains the resting membrane potential and is required for directional sensing during neutrophil chemotaxis. Pharmacological or genetic inhibition of Kir7.1 in neutrophils impaired direction sensing toward various chemoattractants without affecting cell polarization in multiple neutrophil models. Using genetically encoded voltage indicators, we observed oscillating depolarization of the membrane potential in protrusions in zebrafish neutrophils, and Kir7.1 is required for polarized depolarization towards the chemokine source. Focal depolarization with optogenetic tools biases pseudopod selection and induces de novo protrusions. Global hyperpolarizing neutrophils stalled cell migration. Furthermore, Kir7.1 regulates GPCR signaling activation. This work adds membrane potential to the intricate feedforward mechanism, coupling the adaptive and excitable network required to steer immune cells in complex tissue environments.

cell biology↗

bioRxiv2025

Lethal streptococcal infection is associated with widened lymph node bottlenecks

Streptococcus suis serotype 2 (SS2) infection causes streptococcal toxic shock-like syndrome (STSLS), which can be lethal in both pigs and humans. In mouse models, relatively subtle differences in the inoculum size result in drastically different infection outcomes, from clearance to acute death. Here, we leveraged barcoded SS2 in a murine model to define the bacterial population dynamics associated with death. Barcode sequencing analysis demonstrated that a 10-fold increase in inoculum size led to a 100-1,000-fold increase in the number of bacteria that initiated infection in certain lymph nodes, ultimately driving lethality. This lethal dose threshold was in part driven by suilysin (SLY), the major SS2 virulence factor. At higher doses, the clearance and replication kinetics of bacteria lacking SLY mimicked WT SS2 at sub-lethal doses. Our findings suggest that acute death in SS2 infection is caused by a wholesale failure of the immune system, enabling a large number of bacteria to initiate infection. These results demonstrate how subtle changes in inoculum size can have dramatic consequences for infection outcome and how lethal infection is driven by widened infection bottlenecks. Author SummaryLethal infections are often associated with a specific dose threshold, where increasing inoculum size is associated with an increased likelihood of death. However, a quantitative explanation how this numeric threshold is established is lacking. For example, lethal dose thresholds may reflect a dose where at least one microbe can pass through host-imposed barriers to infection. Alternatively, lethal dose thresholds may reflect a failure of the host immune system, leading to numerous microbes initiating infection. Here, using barcoded Streptococcus suis serotype 2 (SS2), we compare the within-host population dynamics associated between lethal and non-lethal infections. We find that lethal doses are associated with dramatic widening of infection bottlenecks, leading to a large number of bacteria that initiate infection. Lethal infection is also driven by suilysin, the major SS2 virulence factor. These observations demonstrate how lethal doses are quantitatively established by the relationship between host bottlenecks and bacterial virulence factors.

microbiology↗

bioRxiv2025

Voluntary Running Sustains the Correction of Inflammation-Related Gene Expression Conferred by AAV Gene Therapy in Mdx Mice

Duchenne Muscular Dystrophy is a fatal disease characterized by persistent skeletal muscle degeneration, inflammation, and fibrosis. Gene therapy using an adeno-associated virus derived vector and a microdystrophin transgene is currently under investigation in patients but the impact of physical activity on long-term therapeutic outcome remains poorly understood. Recently, we reported 21-weeks of voluntary wheel running complemented the positive endurance and muscle function outcomes of gene therapy in mdx mice. In the present study, we performed a transcriptomic analysis of the gene expression changes associated with functional recovery in the diaphragm. RNA-Sequencing and bioinformatic analysis revealed 2881 dysregulated genes in untreated and unexercised mdx mice including inflammatory and fibrotic signaling pathways frequently affected in Duchenne Muscular Dystrophy patients. Among the dysregulated genes, 774 were rescued towards WT after adeno-associated virus microdystrophin injection. Importantly, 93% of the rescued genes were maintained by voluntary running, which indicates that physical exercise has no significant impact on the outcome of gene therapy in the mdx diaphragm. Our study provides vital information that could help guide DMD patient follow-up protocols after treatment with gene therapy.

pathology↗

bioRxiv2025

Wnt/LRP6 signaling imbalance impairs ciliogenesis in human retina epithelial cells

The primary cilium is a microtubule-based organelle essential for various cellular functions, particularly signal transduction. While the role of cilia in regulating signaling pathways has been extensively studied, the impact of signaling pathways on cilia formation remains less well understood. Wnt signals are critical modulators of cell fate. In this study, we investigate how modulating Wnt signaling affects cilia formation in human retinal epithelial cells. Our findings show that enhancement of Wnt/LRP6 signaling before serum starvation impairs ciliogenesis. Cells with high baseline Wnt activity exhibited defective distal appendage formation, failure to remove CP110/CEP97 from mother centrioles, and reduced Rab8-vesicular docking, which are critical events for cilia membrane establishment and axoneme extension. Additionally, these cells displayed reduced autophagic flux, increased mTOR kinase activity, and elevated OFD1 levels at centriolar satellites. Importantly, mTOR inhibition rescued ciliogenesis in cells with elevated Wnt activity, underscoring the interplay between these signaling pathways. Our data also indicate that insufficient Wnt signaling activation disrupts ciliogenesis, emphasizing the need for precisely regulated Wnt levels. SummaryThis study investigates how modulating Wnt signaling affects ciliogenesis in human retinal epithelial cells, revealing that both excessive and insufficient Wnt activity disrupt cilia formation and highlighting the interplay between Wnt and mTOR signaling in this process.

cell biology↗

bioRxiv2024

Genomic Insights into Hybridization and Speciation of Mitten Crabs in the Eriocheir Genus

Hybridization is a prominent and influential phenomenon with significant implications for adaptive evolution, species distribution and biodiversity. However, the intricacies of how hybridization influences genomic structure and facilitates adaptive evolution still elude our full understanding. Analyzing whole genome data from seven populations within Eriocheir genus across diverse geographic regions, we have validated a complex hybridization history between Chinese and Japanese mitten crabs. This hybridization gave rise to two distinct ecological species: Hepu and Russian mitten crabs with unique genomic architectures and adaptations. Genes related to reproduction, development, and temperature adaptation exhibit divergent selection signals, potentially contributing to their phenotypic diversity and ecological niches. Meanwhile, genes associated with reproduction, namely Birc6, Bap31, and Poxn, displayed robust evidence of selective sweeps in Hepu mitten crab. Notably, the favored alleles for these genes originated from the parental lineages during the hybridization process. Furthermore, Hepu mitten crab is a homoploid hybrid species that originated from an ancient hybridization event, resolving its longstanding taxonomic controversy. Our study sheds light on the evolutionary history of mitten crabs and highlights the crucial role of hybridization in driving adaptation, range expansion, and diversification within the Eriochier genus.

genomics↗

bioRxiv2024

Does domestication trade-off stress tolerance for leaf growth? A search for evidence across eight Pooideae grass species

Plant domestication is thought to create trade-offs between high yield and stress tolerance, raising concerns about yield stability in future climates. Previous studies have found limited direct evidence for such trade-offs, often focusing on weakened defenses associated with higher growth rates. However, trade-offs can also occur when traits (such as yield in agriculture) optimized for favorable conditions perform less efficiently in stressful conditions. Deciphering the mechanisms driving these trade-offs is crucial for maintaining yield in changing environments. We examine leaf growth, a key trait influencing carbon assimilation, in eight species of grasses. We use a machine learning pipeline to automatically extract cell dimensions and positions from leaf microscope images to study cell kinematics, finding that domesticated plants generally have longer leaves, larger division zones and higher cell production rates. We found no clear evidence of trade-off between domestication and drought response in final leaf length. However, a trade-off is observed in development as wild species exhibited a smaller decrease in elongation zone size under drought than their domesticated counterparts. These nuanced trade-offs associated with domestication highlight the importance of examining physiological traits and mechanisms in greater detail, possibly informing breeding strategies to enhance crop resilience in the face of climate change. HighlightThis study uses a high throughput pipeline to characterize leaf elongation responding to drought stress across eight species including barley, wheat, oat and wild relatives.

plant biology↗

bioRxiv2024

Alzheimer's Disease Patient Brain Extracts Induce Multiple Pathologies in Vascularized Neuroimmune Organoids for Disease Modeling and Drug Discovery

Alzheimers Disease (AD) is the most common cause of dementia afflicting 55 million individuals worldwide, with limited treatment available. Current AD models mainly focus on familial AD (fAD), which is due to genetic mutations. However, models for studying sporadic AD (sAD), which represents over 95% of AD cases without specific genetic mutations, are severely limited. Moreover, the fundamental species differences between humans and animals might significantly contribute to clinical failures for AD therapeutics that have shown success in animal models, highlighting the urgency to develop more translational human models for studying AD, particularly sAD. In this study, we developed a complex human pluripotent stem cell (hPSC)-based vascularized neuroimmune organoid model, which contains multiple cell types affected in human AD brains, including human neurons, microglia, astrocytes, and blood vessels. Importantly, we demonstrated that brain extracts from individuals with sAD can effectively induce multiple AD pathologies in organoids four weeks post-exposure, including amyloid beta (A{beta}) plaques-like aggregates, tau tangles-like aggregates, neuroinflammation, elevated microglial synaptic pruning, synapse/neuronal loss, and impaired neural network. Furthermore, after treatment with Lecanemab, an FDA-approved drug targeting A{beta}, AD brain extract exposed organoids showed a significant reduction of amyloid burden. Thus, the neuroimmune organoid model provides a unique opportunity to study AD, particularly sAD under a pathophysiological relevant three-dimensional (3D) human cell environment. It also holds great promise to facilitate AD drug development, particularly for immunotherapies.

neuroscience↗

bioRxiv2024

Cancer-associated adipocytes mediate CD8+T cell dysfunction via FGF21-driven lipolysis

Cancer-associated adipocytes (CAAs) reprogram metabolic status of tumor microenvironment (TME). The metabolic crosstalk between CAAs and CD8+T cells in TME remains unclear. Here we report that CAAs undergo lipolysis, releasing free fatty acids that promote lipid peroxidation and disturb mitochondrial homeostasis in CD8+T cells, leading to their functional exhaustion. Importantly, we uncover that fibroblast growth factor 21 (FGF21) autocrinally drives CAA lipolysis through upregulating adipose triglyceride lipase (ATGL) via FGFR1/KLB-p38 signaling. FGF21 deletion in adipose tissue or ATGL inhibition impedes CAA lipolysis, mitigates lipid peroxidation, normalizes mitochondrial dynamics of CD8+T cells, and restores their effector function, consequently blunting tumor growth. Moreover, combining ATGL inhibitor with anti-PD-1 therapy synergistically enhances the antitumor activity of CD8+T cells, yielding greater therapeutic efficacy. Our findings highlight the pivotal role of CAA lipol ysis in CD8+T cell dysfunction within TME, suggesting that targeting CAA lipolysis represents a valuable avenue for improving cancer immunotherapy.

cancer biology↗

bioRxiv2024

Discovery and Biosynthesis of Sulfenicin and Its New-to-Nature Acylsulfenic Acid Functional Group

Lifes organic molecules are built with diverse functional groups that enable biology by fine tuning intimate connections through time and space. As such, the discovery of new-to-nature functional groups can expand our understanding of the natural world and motivate new applications in biotechnology and biomedicine. Herein we report the genome-aided discovery of sulfenicin, a novel polyketide-nonribosomal peptide hybrid natural product from a marine Streptomyces bacterium bearing a unique acylsulfenic acid functionality. Through a series of heterologous biosynthesis, functional genetics, and enzymatic reconstitution experiments, we show that this previously described synthetic functional group is biologically assembled by a set of enzymes from both primary and secondary metabolism, including a novel flavin-dependent S-hydroxylase that hydroxylates a thiocarboxylic acids sulfur atom. While the sulfenicin biosynthetic gene cluster is presently without parallel in public databases, acylsulfenic acid-encoding enzymes are widely distributed in bacterial genomes, implying that this labile functional group may similarly have a broad distribution among specialized metabolites.

biochemistry↗