Biology subjects

Tu, J.

Publications and source records attributed to Tu, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Context-dependent regulatory networks connect Alzheimer's disease genetics to microglial inflammatory responses

Inflammation is central to Alzheimer's disease (AD) pathogenesis. Microglia, the resident innate immune cells of the brain, exhibit diverse inflammatory states and are enriched for AD-associated genetic variants within active cis-regulatory elements (CREs). However, the interplay among genetic variants, transcription factor (TF)-CRE-gene programs, and microglial responses across inflammatory and disease contexts remain poorly understood. Here, we develop context-dependent epigenomic networks (cEpiNets), integrating bulk and single-nucleus assay for transposase-accessible chromatin using sequencing (ATAC-seq) to reconstruct regulatory programs across inflammatory, genetic perturbation, and disease contexts. Leveraging TF footprinting and graph embedding, cEpiNets identifies shared and context-specific programs and predicts regulatory circuits in unseen biological contexts. In a SORL1-marked inflammatory microglial state that expands during AD progression, cEpiNets annotates AD risk variants at the SORL1 locus and identifies variants associated with cellular state abundance across donors. Cross-context analysis further identifies ZBTB14, whose inflammation-associated program connects AD risk variant-harboring CREs to target genes and widespread TF remodeling in AD. Donor-level ZBTB14 footprint activity is negatively associated with AD pathology, while combined IFN{gamma}/TNF stimulation represses ZBTB14 and activates a subset of inferred targets. Collectively, cEpiNets bridges genetic variation, regulatory programs, and disease-associated cellular phenotypes to facilitate mechanistic interpretation of complex disease genetics.

bioinformatics↗

bioRxiv2026

Environmental complexity reveals memory-guided search as the locus of learning in prey capture

Ethological behavior requires the integration of perception, memory, and decision-making, yet standard laboratory tasks are often too simplified to recruit these processes jointly. Here, mice that were expert hunters in a bare arena were challenged to capture live insect prey among objects that occlude vision and afford opportunities to hide. This revealed an axis of learning absent in an empty arena: mice improved not by refining pursuit but by reorganizing how they searched for concealed prey. An agent-based model showed that short-term memory and learning of object-specific values are sufficient to account for the behavior demonstrated by mice. A compact ethogram of object-directed actions revealed that animals selectively acquired the interactions most likely to expose prey. These results show that environmental complexity recruits memory- and value-guided search strategies. Reproducible with inexpensive materials, the paradigm and its open-source analyses offer a sensitive read-out of cognitive processes largely unobservable in conventional assays.

neuroscience↗

bioRxiv2026

Peri-Locus Coeruleus Controls Endothelial Cell Heterogeneity in Enriched Environments via Region-Specific Norepinephrine Signaling

The brain acts as a central integrator that enables organisms to interpret environmental stimuli and coordinate adaptive responses across the body. While enriched environments are known to enhance neural plasticity and cognitive function, their impact on peripheral organ systems remains less understood. Here, we show that enriched environmental conditions activate a peri-locus coeruleus (peri-LC) neuronal ensemble that preserves CD31hiEMCNhi type H endothelium, a specialized bone-associated endothelial subtype, against age-associated decline, thereby enhancing femoral bone density. Chemogenetic activation and ablation experiments further revealed that this peri-LC ensemble is functionally distinct from other sympathetic regulatory brain regions in its control of bone endothelial heterogeneity and skeletal mass. Three-dimensional bone clearing and spatial analyses showed that CD31hiEMCNhi endothelium is closely associated with sympathetic nerve terminals. The peri-LC mediates this process through sympathetic signaling and {beta}2-adrenergic receptors on bone vascular endothelial cells. In vivo imaging further demonstrated that norepinephrine release is spatially restricted, with sprouting endothelial cells near the growth plate exhibiting the highest sensitivity. Together, these findings reveal a refined brain-periphery regulatory logic in which distinct sympathetic brain circuits engage spatially restricted norepinephrine signaling to coordinate organ-specific vascular and skeletal adaptations.

neuroscience↗

bioRxiv2026

Sex-specific Genetic Regulatory Effects in Chickens

Sexual dimorphism is a defining vertebrate feature, yet its sex-specific molecular architecture remains poorly understood. Here we established a sex-balanced, uniformly reared chicken cohort to map this landscape, integrating individual whole-genome sequencing with 7,969 bulk and 779,380 single nucleus transcriptomes across 32 tissues from 280 birds. We identified 495,098 independent expression quantitative trait loci for 20,194 genes, including 10,937 loci modulated by cell-type composition. Notably, 340 genes were regulated by 449 loci in a sex-dependent manner, significantly enrichment in endocrine tissues like adipose and the adrenal gland. Furthermore, we fine-mapped 1,219 structural variants, demonstrating their unique roles to tissue- and sex-specific expression beyond SNPs. Ultimately, we showed the utility of these regulatory effects in elucidating the molecular basis of metabolism and complex traits in both chickens and humans. This comprehensive atlas of regulatory effects provides profound insights into the genomic and molecular basis of sexual dimorphism in vertebrates.

genomics↗

bioRxiv2025

Comparative Evaluation of Assumption Lean Community Detection Methods for Human Connectome Networks

Community detection on resting-state functional connectivity provides a principled lens on mesoscale organization in functional brain networks. Currently, the choice of community count K, lacks a standardized or principled guideline. We conducted a systematic benchmark of three assumption-lean approaches on weighted functional connectivity matrices: the Weighted Stochastic Block Model, Spectral Clustering, and K-means Clustering. Performance was assessed on synthetic networks with known ground truth and on three neuroimaging cohorts which included adult and infant datasets. We compared several strategies for selecting K, including the silhouette index and other approaches commonly used in the existing literature. These were evaluated alongside a likelihood-based criterion for the weighted stochastic block model that employs bootstrap confidence intervals for differences in log-likelihood between successive values of K. For the synthetic networks, WSBM and Spectral Clustering correctly identified the true number of communities, whereas K-means Clustering did not. In adult datasets, most indices did not yield a unique optimum, whereas the likelihood-based criterion selected K = 11, which is consistent with established sensory and association systems. In infants and toddlers, the same procedure supports a larger K around 15 and reveals developmentally distinct mesoscale architecture, including anterior and posterior subdivisions within default mode and fronto parietal systems.

neuroscience↗

bioRxiv2025

Enduring Autism-like Phenotypes and Deregulated Hypothalamic Prosocial Peptides After Early-Life Exposure to Indoor Flame Retardants in Male C57BL/6 Mice

BackgroundPolybrominated diphenyl ethers (PBDEs) are neuroendocrine disrupting chemicals that produce adverse neurodevelopmental effects. PBDEs have been implicated as risk factors for autism spectrum disorder (ASD), which is characterized by abnormal psychosocial functioning and is commonly accompanied by co-morbidities such as cognitive and attentional deficits. Here, we used a mouse model with translationally relevant exposure to establish direct causal evidence that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in male offspring. MethodsC57Bl6/N mouse dams were exposed to a commercial PBDE mixture, DE-71, via oral administration of 0 (vehicle control, VEH/CON), 0.1 (L-DE-71), or 0.4 (H-DE-71) mg/kg bw/d for 10 weeks, spanning three weeks prior to gestation through the end of lactation at postnatal day (PND) 21. ResultsMass spectrometric analysis indicated dose-dependent transfer of PBDEs (in ppb) to brains of F1 male offspring at PND 30, with reduction in levels by PND 110. Adult F1 male offspring displayed ASD-relevant neurobehavioral phenotypes, including impaired short- and long-term social recognition memory (SRM), despite intact general sociability, and exaggerated repetitive behavior. Exposed mice also displayed altered olfactory discrimination of social odors, impaired novel object recognition memory, and reduced open field habituation. However, no changes were observed in anxiety-like, sensorimotor, or depressive-like behaviors relative to VEH/CON. At the molecular level, DE-71 exposed males displayed deregulated gene markers of prosocial neuropeptides. Oxt was upregulated in the paraventricular nucleus (PVN); Avp was upregulated in the PVN and bed nucleus of the stria terminalis (BNST) but downregulated in the lateral septum (LS); Avp1ar and Adcyap1 were upregulated in the BNST; and Adcyap1r1 was upregulated in the PVN, supraoptic nucleus (SON), and BNST. ConclusionsThese findings demonstrate that developmental PBDE exposure produces enduring behavioral and neurochemical phenotypes that resemble core domains of ASD, which may result from early neurodevelopmental reprogramming within central social and memory networks.

neuroscience↗

bioRxiv2025

Claustrum-cortical reciprocal connections orchestrate allostatic responses following stress

Anxiety is an evolutionarily conserved response that supports threat detection and survival, yet dysregulated stress responses can drive its progression into pathological states. Here, we identify the claustrum (CLA) as a central hub that links acute stress responses to chronic affective dysfunction through cell-type-specific circuit dynamics. Acute social defeat stress robustly activated the CLA and induced anxiety-like behaviors in mice. Multimodal profiling revealed transcriptional and functional plasticity within CLA neurons, with Egr2-expressing excitatory and Gad2-expressing inhibitory populations exhibiting distinct adaptations to acute versus chronic stress. We further delineate a reciprocal CLA-anterior cingulate cortex (ACC) circuit that bidirectionally regulates stress responses in which glutamatergic CLAEgr2 [->] ACC projections promoted anxiety-like behaviors, whereas top-down ACC [->] CLAGad2inhibitory inputs constrained claustral output. Chronic stress induced hyperactivity in CLAGad2 inhibitory neurons and reshaped excitatory neuron dynamics, leading to increased intrinsic excitability, local circuit imbalance, and ultimately, depression-like phenotypes. These findings define a dynamic claustrum-centered circuit that governs the transition from adaptive anxiety to maladaptive affective states through balanced Egr2-Gad2 activity, and show that chronic-stress driven disruption of this excitatory-inhibitory equilibrium impairs stress coping and drives pathological behavioral outcomes. Graphic summaryAcute stress engages a claustrum (CLA)-centered network with activation of Egr2 excitatory neurons, promoting anxiety-like behaviors. Chronic stress drives CLAG142 neurons into a hyperactive state, enhancing local inhibition and suppressing excitatory output to induce depressive-like behaviors. A reciprocal CLAE7182[->]ACC feedforward and ACC[->]CLAG142 feedback circuit forms a state-dependent regulatory hub governing stress adaptation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/673892v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@75d664org.highwire.dtl.DTLVardef@4e5c31org.highwire.dtl.DTLVardef@86b5f2org.highwire.dtl.DTLVardef@135045_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

The Social Switchboard: Context and Rank Shapes Behavioural and Neural Responses During Macaque Decision-Making

Key PointsO_LISociality influences ethologically important decisions and demand a high level of cognitive sophistication C_LIO_LIWe used a novel decision making task with 6 macaques where social hierarchy could be tested across social audience, coaction, envy, altruism, cooperation & competition contexts. C_LIO_LISubjects decision making performance was significantly modulated by context and social rank, reflected by their social eye gaze patterns. C_LIO_LIThere were significant differences in fronto-parietal brain regions as the social context changed C_LI Social interactions shape many of our most ethologically relevant decisions and require considerable cognitive sophistication. Factors such as immediate needs, social bonds, hierarchical status, and reciprocity norms impact decision-making. Yet most laboratory paradigms examine individuals in isolation. We developed a face-to-face cognitive testing platform using a transparent touchscreen that allowed pairs of adult male Macaca fascicularis (n = 6) with established dominance relationships to perform a decision-making task across six social contexts: audience, co-action, envy, cooperation, competition, and altruism. We recorded eye movements simultaneously from both subjects (gaze position and pupil diameter), synchronised behavioural video, and task performance. Across social contexts, macaques performed better in the presence of a conspecific than when tested alone, but performance declined under altruistic and competitive conditions. Dominance substantially modulated motivation: dominant subjects were less willing to engage when rewards were shared (envy), when only the partner was rewarded (altruism), or when contingent action with a subordinate was required (cooperation). Eye-tracking revealed greater pre-choice arousal and social attention during social sessions, indexed by larger pupils, longer fixations on the partners face, and more saccades before--but not during or after--choices. Pupil dilation was larger in dyads where both individuals were dominant than in dyads where one was subordinate. Finally, noninvasive functional near-infrared spectroscopy (fNIRS) showed increased cortical engagement relative to baseline in audience, altruism, competition, and cooperation conditions. These findings demonstrate that social context and hierarchical dominance systematically shape choices, attentional allocation, autonomic arousal, and cortical engagement in macaques, and provide a tractable platform for further dissecting the neural bases of contextual social decisionmaking.

neuroscience↗

bioRxiv2025

CIAdex: Single-Cell FTIR Spectral Fingerprinting for Cell Identity Verification and Aging Quantification in Therapeutic Cell Manufacturing

Ensuring the identity and optimal aging state of cell products is critical for the efficacy and safety of cell therapies. Despite rapid iterations, there remains an urgent need for robust and easy-to-implement tests to characterize cell products. Here, we present CIAdex (Cell Identification and Aging Index), an analytical framework that utilizes single-cell Fourier-transform infrared (FTIR) spectral fingerprints and machine learning to achieve precise label-free cell identity assessment and aging quantification. CIAdex employs a Feature Extraction Processor to automatically extract FTIR spectral variables corresponding to distinct cellular biomolecular features, enabling reliable distinction of lineage-, donor-, and batch-specific cell populations using linear discriminant analysis. Through application of the XGBoost algorithm, a quantitative aging index (trPDL/trPN) was further generated for tracking cellular aging dynamics along culture expansion. Notably, trPDL/trPN quantitatively represent subtle age-related shifts among different batches and drug-induced senescence or rejuvenation effects which are unmeasurable by existing methods. Together, our work demonstrates that CIAdex, by simultaneous label-free identity verification and aging quantification of cell populations, offers a transformative approach to interpret single-cell FTIR spectral fingerprints and provides novel metrics for quality control in cell manufacturing with significant potential for optimization and assurance of cell therapies safety and efficacy.

cell biology↗

bioRxiv2025

Metabolic Cage Analysis of Surgically Catheterized C57Bl/6J Mice (Mus musculus) Treated with Carprofen and Sustained-release Buprenorphine

Federal regulations require that appropriate analgesia be provided for laboratory animals for pain control. Carprofen and buprenorphine are two common analgesics used for laboratory mice (Mus musculus). However, given the potential gastrointestinal side effects that these analgesics have in various species, the impact of these analgesics on mice used in metabolic studies could be concerning. To investigate the impact of carprofen and sustained-release buprenorphine on food consumption, activity level, and whole-body metabolism, we administered carprofen alone or in combination with sustained-release buprenorphine to mice that underwent jugular vein and carotid artery catheterization, or a sham surgery. The mice were individually housed in instrumented metabolic cages to continuously quantify food consumption, activity levels, and energy expenditure by indirect calorimetry. We hypothesized that catheterized mice receiving both carprofen and sustained-release buprenorphine would have decreased food consumption and increased activity level compared to mice that received sham surgery and carprofen, and catheterized mice treated with carprofen only would have similar food consumption and activity level as sham mice that received carprofen. Our results demonstrate that during the initial 12h after surgery, catheterized mice that received both carprofen and sustained-release buprenorphine were more active than sham mice that received carprofen, and were more active and consumed more food than catheterized mice that received carprofen only. Our study demonstrated how analgesia regimen can affect metabolic parameters. Therefore, researchers should carefully consider the effects that analgesic drugs can have on mice when designing metabolic or behavioral experiments.

animal behavior and cognition↗

bioRxiv2025

RSPO2-based peptibodies conjugated with pyrrolobenzodiazepine dimer or camptothecin analogs demonstrate potent anti-tumor activity by targeting the three receptors LGR4/5/6

Leucine-rich repeat containing, G protein-coupled receptor 4, 5, and 6 (LGR4/5/6) are three homologous receptors that are co-expressed or alternately expressed at high levels in tumor cells of colorectal cancer (CRC) and high-risk neuroblastoma (NB). Simultaneous targeting of all three receptors may provide increased efficacy or overcome drug resistance due to tumor heterogeneity and cancer cell plasticity. LGR4/5/6 all bind to R-spondins (RSPOs) with high affinity and potentiate Wnt/{beta}-catenin signaling in response. Previously, we showed that a peptibody based on a mutant RSPO4 furin domain that bound to LGR4/5/6 without potentiating Wnt/{beta}-catenin signaling was able to deliver cytotoxins into cancer cells that express any of the three receptors. We have now generated a mutant RSPO2 furin domain that retains high affinity binding to LGR4/5/6 without signaling activity. Peptibodies based on this RSPO2 furin mutant were conjugated with either pyrrolobenzodiazepine dimer (PBD) or camptothecin derivative (CPT2), and the resulting peptibody-drug conjugates (PDCs) showed potent and specific cytotoxic activity in NB and CRC cell lines expressing any of LGR4/5/6 in vitro and robust anti-tumor activity in vivo. The results support the potential of RSPO2-based PDCs for the treatment of CRC, high-risk NB, and other cancers that express any of LGR4/5/6.

pharmacology and toxicology↗

bioRxiv2025

Deep-learning based Embedding of Functional Connectivity Profiles for Precision Functional Mapping

Spatial correlation of functional connectivity profiles across matching anatomical locations in individuals is often calculated to delineate individual differences in functional networks. Likewise, spatial correlation is assessed across average functional connectivity profiles of groups to evaluate the maturity of functional networks during development. Despite its widespread use, spatial correlation is limited to comparing two samples at a time. In this study, we employed a variational autoencoder to embed functional connectivity profiles from various anatomical locations, individuals, and group averages for simultaneous comparison. We demonstrate that our variational autoencoder, with pre-trained weights, can project new functional connectivity profiles from the vertex space to a latent space with as few as two dimensions, yet still retain meaningful global and local structures in the data. Functional connectivity profiles from various functional networks occupy distinct compartments of the latent space. Moreover, the variability of functional connectivity profiles from the same anatomical location is readily captured in the latent space. We believe that this approach could be useful for visualization and exploratory analyses in precision functional mapping.

neuroscience↗

bioRxiv2024

Gene Conversion Directed Successive Engineering of Modular Polyketide Synthases

Modular polyketide synthases (PKSs) can produce various secondary metabolites in a collinearity fashion. Although rational engineering of modular PKS can ultimately create a diverse array of novel compounds, de novo generation of defined structures usually results in the loss or remarkable decline of productivity due primarily to the incompatibility of different elements. Here, we present a modular PKS engineering strategy driven by an evolutionary event of gene conversion to accomplish successive engineering of the modular PKS in cinnamomycin biosynthetic gene cluster (cmm BGC). By simulating the gene conversion process, cmm BGC is consecutively reprogrammed to generate a novel macrolide with predicted structural features. Moreover, in contrast to previous notion, the intra-module KS domain is demonstrated to associate with the selectivity of extender units. Collectively, the coordination between evolutionary consequence and functional manipulation of assembly line may shed a new light on modular PKS engineering. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/630704v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@11bd249org.highwire.dtl.DTLVardef@18af1a9org.highwire.dtl.DTLVardef@ffa287org.highwire.dtl.DTLVardef@10756cf_HPS_FORMAT_FIGEXP M_FIG Gene conversion process, typically occurred in KS (purple squares) and AT (blue squares), plays an integral role of structural diversity of polyketides. In this study, an unusual gene conversion was observed in cmm BGC. Subsequently, a homologous BGC was obtained through genome mining by a gene conversion-associated KS domain. Under the direction of gene conversion, the modular PKS in cmm BGC was successively reprogrammed, resulting in de novo biosynthesis of a new-to-nature polyketide. C_FIG

bioengineering↗

bioRxiv2024

L-Asparaginase treatment induces reversible immunoregulatory and immunosuppressive effects in non-malignant B cells in a model of T-cell dependent B cell activation

Metabolic reprogramming is critical for immune cell adaptation upon activation to exert full functionality with amino acids being a key metabolic factor. While L-asparagine is a non- essential amino acid it turns out to be conditionally essential in malignant B cells due to defective asparagine synthetase making L-asparaginase a commonly used chemotherapeutic agent. Off-target enzymatic activity including glutaminolysis impacting crucial immune function. However, its effects on healthy B cells remain unclear, therefore in this study, we explored how L-asparaginase modulates the biology and function of CD40-activated B cells, using an in-vitro model. B cells from healthy donors were treated with increasing L- asparaginase concentrations and analyzed for proliferation, immune phenotype, and metabolic changes. Results showed L-asparaginase reduced B cell proliferation and homotypic clustering without inducing apoptosis, instead impairing metabolic pathways, lowering glycolysis and oxidative phosphorylation, and reducing surface markers associated with antigen-presenting cell (APC) function. Functional assays confirmed that L-asparaginase- treated B cells had diminished ability to activate T cells. Supplementing with asparagine or glutamine restored B cell proliferation and function, with glutamine slightly more effective than asparagine. Interestingly, L-asparaginase induced a regulatory B cell phenotype, marked by CD24+CD38+CD27+ expression and increased interleukin-10 and TGF-beta, suggesting a potential immunosuppressive mechanism. These findings indicate that L-asparaginase not only affects malignant cells but also impacts the function of non-malignant B cells, proposing potential therapeutic applications in B cell-driven autoimmune disorders. Further studies are needed to explore its effects at lower, clinically relevant concentrations. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/625617v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@1ae8d10org.highwire.dtl.DTLVardef@af405borg.highwire.dtl.DTLVardef@1aa4c0eorg.highwire.dtl.DTLVardef@16750ea_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Anti-tumor activity of camptothecin analog conjugate of a RSPO4-based peptibody targeting LGR4/5/6 in preclinical models of colorectal cancer.

Antibody-drug conjugates (ADCs) have emerged as a major modality of targeted cancer therapy, yet no ADC has been approved specifically for colorectal cancer (CRC). LGR4/5/6 (leucine-rich repeat containing, G protein-coupled receptor 4, 5, 6) are three related receptors that are expressed at high levels together or alternately in nearly all cases of CRC. ADCs targeting LGR5 have been shown to have robust anti-tumor potency, but not all CRC cells express LGR5 and LGR5-positive tumor cells may lose LGR5 expression due to cancer cell plasticity. R-spondin 4 (RSPO4) is a natural protein ligand of LGR4/5/6 with high affinity for all three receptors. We fused a mutant form of RSPO4 furin domain that retains high affinity binding to LGR4/5/6 to human IgG1 Fc to create a peptibody designated R462. Conjugation of R462 with a camptothecin analog designated CPT2 at eight drugs per peptibody led to the generation of R462-CPT2 that showed highly potent cytotoxic activity in vitro in CRC cell lines expressing any of LG4/5/6. In cell line xenograft and PDX models of CRC, R462-CPT2 demonstrated robust anti-tumor effect. Importantly, R462-CPT2 showed no major adverse effect at therapeutically effective dose levels. These results strongly support the use of RSPO ligand drug-conjugates that target LGR4/5/6 simultaneously for the treatment of CRC.

pharmacology and toxicology↗

bioRxiv2024

Loss of PMR4 callose synthase results in salicylic acid-independent and broad-spectrum resistance to clubroot in Arabidopsis and Brassica napus

The clubroot disease caused by protist Plasmodiophora brassicae is one of the most important diseases of Brassica crops. Growing clubroot-resistant cultivars remains the most effective and practical approach to managing clubroot disease. However, resistance gene-mediated immunity is rapidly overcome in the field when new pathotypes arise. In this study, we identified PMR4 as a potential gene target for creating a novel clubroot-resistant source. Recessive PMR4 mutations in Arabidopsis thaliana conferred broad-spectrum resistance to multiple P. brassicae pathotypes, independent of salicylic acid-mediated plant immunity. CRISPR/Cas9-mediated gene-editing was employed to create mutations in two PMR4 orthologs in the B. napus genome, and resulting homozygous mutants exhibited dual resistance to powdery mildew and clubroot. PMR4 is required for the callose deposition at wound and powdery mildew infection sites in leaves. This study reveals that callose deposition in roots is induced by P. brassicae infection and requires PMR4. It appears that the clubroot disease progression is arrested at the primary-to-secondary infection phase in pmr4-1 mutants. Together, this study demonstrates that PMR4-encoded callose synthase is a host susceptibility factor required for P. brassicae to complete its life cycle, and that PMR4 can be targeted against both powdery mildew and clubroot diseases in Brassica crops.

plant biology↗

bioRxiv2024

Early Life Neuroimaging: The Generalizability of Cortical Area Parcellations Across Development

The cerebral cortex consists of distinct areas that develop through intrinsic embryonic patterning and postnatal experiences. Accurate parcellation of these areas in neuroimaging studies improves statistical power and cross-study comparability. Given significant brain changes in volume, microstructure, and connectivity during early life, we hypothesized that cortical areas in 1- to 3-year-olds would differ markedly from neonates and increasingly resemble adult patterns as development progresses. Here, we parcellated the cerebral cortex into putative areas using local functional connectivity gradients in 92 toddlers at 2 years old. We demonstrate high reproducibility of these cortical regions across 1- to 3-year-olds in two independent datasets. The area boundaries in 1- to 3-year-olds were more similar to those in adults than those in neonates. While the age-specific group area parcellation better fit the underlying functional connectivity in individuals during the first 3 years, adult area parcellations might still have some utility in developmental studies, especially in children older than 6 years. Additionally, we provide connectivity-based community assignments of the parcels, showing fragmented anterior and posterior components based on the strongest connectivity, yet alignment with adult systems when weaker connectivity was included.

neuroscience↗

bioRxiv2024

Programmable Editing of Primary MicroRNA Switches Stem Cell Differentiation and Improves Tissue Regeneration

Programmable RNA editing is harnessed for modifying mRNA. Besides mRNA, miRNA also regulates numerous biological activities, but current RNA editors have yet to be exploited for miRNA manipulation. To engineer primary miRNA (pri-miRNA), the miRNA precursor, we present a customizable editor REPRESS (RNA Editing of Pri-miRNA for Efficient Suppression of miRNA) and characterize critical parameters. The optimized REPRESS is distinct from other mRNA editing tools in design rationale, hence enabling editing of pri-miRNAs that are not editable by other RNA editing systems. We edited various pri-miRNAs in different cells including adipose-derived stem cells (ASCs), hence attenuating mature miRNA levels without disturbing host gene expression. We further developed an improved REPRESS (iREPRESS) that enhances and prolongs pri-miR-21 editing for at least 10 days, with minimal perturbation of transcriptome and miRNAome. iREPRESS reprograms ASCs differentiation, promotes in vitro cartilage formation and augments calvarial bone regeneration in rats, thus implicating its potentials for engineering miRNA for many applications such as stem cell engineering and tissue regeneration.

bioengineering↗