Biology subjects

Cai, W.

Publications and source records attributed to Cai, W..

At least 19 recordsLinked to original sources

bioRxiv2026

The human circular Tau 12->7 RNA is translated in mouse neurons and promotes tau aggregation

In addition to numerous mRNA isoforms, the human microtubule associated protein tau (MAPT) gene generates circular RNAs that are not known to be expressed in rodents. Using adeno associated viruses, we expressed human circular Tau RNA generated from backsplicing of exon 12 to exon 7 (circTau 12->7) in mouse brain. We observed rolling circle translation of circTau 12->7, similar to cultured human HEK293 cells. Despite using a ubiquitously active promoter, circTau 12->7 protein and a control circEGFP protein were only observed in mouse neurons, indicating neuron-specific translation of these circular RNAs. CircTau 12->7 expression resulted in tau aggregates resembling neurofibrillary tangles in mouse brain that included endogenous mouse tau protein. Our data support a model where neuron-specific translation of circTau RNAs induces 'linear', mRNA-translated tau aggregation, which could contribute to tauopathies, including Alzheimer's disease. Thus, targeting circTau RNAs could be a therapeutic approach for Alzheimer's disease.

neuroscience↗

bioRxiv2026

NeuroPack: Advanced Learnable Packaging Toolkit Towards Ultra-High Compression Ratio for Volumetric Neuroimaging

High-throughput 3D microscopic imaging generates brain-volume datasets at terabyte to petabyte scale, posing significant storage challenges for large-scale neuroimaging data. In this study, we introduce NeuroPack, a hyperprior-driven 3D deep-learning-based packaging toolkit specifically designed for compressing 3D microscopic volumes at the mesoscale. NeuroPack encodes a compact hyperprior stream that conditions its entropy model on local voxel-wise variance, adaptively allocating bits to preserve mesoscale anatomical details for an optimal rate-distortion balance. To ensure reproducible deployment across heterogeneous microscopy datasets and computing environments, NeuroPack implements model integerization for the hyperprior side-information pathway, whose hyper-decoder predicts the Gaussian mean and scale parameters used by the arithmetic coder. By replacing platform-dependent floating-point hyper-decoding with deterministic fixed-point integer convolutions, NeuroPack produces bit-exact entropy models across CPUs, GPUs, local workstations, and cloud servers, thereby preventing decoding drift caused by floating-point rounding, fused-multiply-add ordering, or library-specific kernels. This integerized design preserves rate-distortion behavior while maintaining efficient encoding and decoding for large anisotropic 3D microscopy volumes. Our method enables high-fidelity microscopy reconstruction at 100- to 1000-fold compression across diverse modalities and species. Quantitatively, NeuroPack delivers the strongest overall rate-distortion performance in both BD-PSNR and BD-MSSSIM, with average relative gains of 73.4% and 50.8%, respectively, over the best competing codec. Importantly, NeuroPack preserves image fidelity required for downstream morphological reconstruction and analysis, as validated by simultaneous human annotation of original and decompressed confocal whole-brain zebrafish microscopy images. Together, NeuroPack provides a learning-based compression framework explicitly tailored for microscopy data, establishing a scalable storage solution for data-intensive neuroimaging and AI-empowered biological discovery.

bioengineering↗

bioRxiv2026

Forward reactivation in human hippocampal CA1 supports repetition learning and is preserved in the aging brain

Repetition is a fundamental mechanism for strengthening episodic memory, yet the neural computations engaged during re-exposure remain disputed. Competing accounts attribute repetition-related gains either to retrospective reinstatement of prior events or to the prospective use of learned structure to anticipate what comes next. Using high-resolution functional MRI and representational similarity analysis in a lifespan cohort (N = 418, ages 36 -100), we tracked hippocampal representations as participants twice encoded two fixed sequences of face-name pairs, resolving reactivation by direction, distance and sequence. During repeated encoding, CA1 and CA2/3/DG representations spontaneously anticipated immediate next states, unprompted by explicit task demands. Forward, but not backward, reactivation predicted repetition-related gains, and showed no detectable age dependence. Only CA1 forward reactivation predicted memory gains after accounting for reactivation in other medial temporal lobe regions. Repetition learning is thus an active, temporally local prospective computation with a distinctive CA1 contribution that appears preserved well into old age.

neuroscience↗

bioRxiv2026

Functional deficits of the inhibitory control system in children with ADHD: A task-based fMRI meta-analysis

Inhibitory control deficits have long been proposed as a central neurocognitive mechanism underlying childhood Attention Deficit/Hyperactivity Disorder (ADHD). However, neuroimaging findings remain heterogeneous, partly due to methodological variability across developmental samples and experimental paradigms. The present study aimed to characterize the neural architecture of motor response inhibition in typically developing (TD) children and identify reproducible functional abnormalities associated with pediatric ADHD using stringent, developmentally specific inclusion criteria. We conducted two coordinate-based meta-analyses using Activation Likelihood Estimation (ALE). Following a systematic literature search (up to August 2026), we identified 23 task-based fMRI studies reporting inhibitory-control-related activation in TD children (237 foci) and 17 studies comparing children with ADHD and TD peers (114 foci) during the Stop-Signal Task or Go/No-Go Task. All participants were younger than 18 years of age. Statistical significance was determined using cluster-level family-wise error (FWE) correction. In TD children, ALE revealed a robust inhibitory-control network encompassing the bilateral anterior insula (AI), inferior frontal gyrus (IFG), and the midline pre-supplementary motor area (preSMA) and anterior cingulate cortex (ACC). This spatial organization closely resembled the canonical inhibitory-control network consistently observed in adults, suggesting that the core neural architecture supporting motor inhibition is already detectably organized during development. In the between-group analysis, children with ADHD exhibited significant hypoactivation primarily within the preSMA. Notably, this region demonstrated striking spatial overlap with the preSMA cluster reliably recruited in TD children during motor inhibition. These findings provide convergent support for inhibitory-control models of ADHD and identify altered preSMA recruitment as one of the most consistent functional abnormalities associated with pediatric ADHD. While the neural infrastructure supporting inhibitory control is broadly established during childhood, children with ADHD exhibit reduced recruitment of a key cortical node within this network during motor inhibition demands.

neuroscience↗

bioRxiv2026

NexuST: A Hierarchical Foundation Model for Spatial Transcriptomics

Spatial transcriptomics captures molecular states within cells and their organisation in tissue. However, integrating fine-grained gene information with spatial context at scale remains challenging for existing foundation models. Here we present NexuST, a hierarchical foundation model that repeatedly interleaves gene-level molecular modelling with cell-level spatial modelling, allowing the two levels to refine one another during end-to-end pretraining. For pretraining, we curated HumanST-46M, comprising 45.7 million human cells from 72 datasets across 11 organs and three imaging-based platforms. Across four held-out datasets totalling approximately 2.6 million cells, NexuST achieved state-of-the-art or competitive performance in cell-type annotation, region prediction, gene recovery and neighbourhood-composition prediction. We find that cell-intrinsic expression remains informative even for spatial tasks, as shown by an expression-only PCA baseline, while NexuST shows particularly strong gains where spatial context is essential. Overall, NexuST establishes a hierarchical framework that can serve as a general backbone for future spatial transcriptomics foundation models.

bioinformatics↗

bioRxiv2026

Genome-wide association study and genetic differentiation analysis reveal the genetic basis of Vibrio harveyi resistance in blackspotted croaker (Protonibea diacanthus)

Vibrio harveyi is a primary causative agent of vibriosis, leading to catastrophic economic losses in the blackspotted croaker (Protonibea diacanthus) aquaculture. However, the genetic architecture underlying its resistance remains poorly understood. In this study, we conducted the first integrated genome-wide association study (GWAS) and genetic differentiation analysis (F_ST) to investigate the genetic basis of V. harveyi resistance. A total of 450 juveniles were challenged, and 300 individuals (comprising 150 resistant and 150 susceptible) were selected for whole-genome resequencing. Genomic heritability (h^2) was estimated at 0.374+/-0.29 for survival time (ST) and 0.237+/-0.185 for survival status (SS), indicating moderate genetic control. Notably, an exceptionally high genetic correlation (r_g = 0.999) was observed between ST and SS, while resistance traits were genetically independent of growth performance (r_g < 0.03). Through the convergence of GWAS and selection sweep signals, a major-effect QTL was identified on chromosome 4. Candidate gene prioritization identified high-confidence targets involved in post-transcriptional regulation and mRNA stability, specifically elavl4 (harboring a top-tier exon variant), rorb, cbpc6, and epn4. Functional enrichment analysis further revealed that resistance is significantly associated with "rRNA processing", "mRNA surveillance pathway", and "nucleocytoplasmic transport", suggesting that efficient RNA metabolic control is a critical determinant of host survival. These findings provide novel insights into the non-canonical immune mechanisms of P. diacanthus and offer robust molecular markers for marker-assisted selection and genomic selection, facilitating the development of disease-resistant strains in the sciaenid industry.

genomics↗

bioRxiv2026

Integrated Transcriptomics and Histological Analysis Reveals Gill Adaptation Mechanisms to Hypoxic Stress in Largemouth Bass (Micropterus salmoides)

Largemouth bass (Micropterus salmoides) is a globally significant freshwater aquaculture species known for its rapid growth, high-quality flesh, and excellent nutritional value. Given the increasing incidence of hypoxia in its aquaculture setting, understanding the molecular mechanisms underlying gill adaptation to hypoxic stress is critical for improving resilience in this species. To achieve this, we employed full-length transcript sequencing using PacBio Iso-Seq and high-throughput Illumina RNA-seq to construct a comprehensive transcriptome profile. Histological analyses revealed apparent structural alterations in gill tissues under hypoxic stress (dissolved oxygen: 2.0 +/- 0.5 mg/L, duration: 96 h), including curved and swollen gill filaments, apoptosis, and epithelial cell vacuolation. Comparative transcriptomic analysis revealed pronounced shifts in the expression of genes involved in energy metabolism, angiogenesis, immune responses, cell proliferation, and apoptosis. Notably, the down-regulation of genes associated with cell cycle and proliferation suggests that M. salmoides may conserve energy by suppressing cell division under hypoxic conditions. In contrast, the increased expression of apoptosis-related genes, including Caspase 7, indicates that apoptosis may play a protective role to maintain tissue homeostasis under hypoxia. Furthermore, the suppression of chemokine-mediated immune pathways implies that hypoxia redirects energy toward essential metabolic processes at the cost of local immune responses. GO and KEGG enrichment analyses identified TNF- and chemokine-mediated signaling pathways as key regulators for tissue homeostasis and adaptive responses to hypoxic stress. These findings enhance our understanding of the mechanisms underlying hypoxia adaptation and provide valuable genetic resources for breeding strategies aimed at enhancing hypoxia tolerance in M. salmoides.

genomics↗

bioRxiv2026

Unmasking genetic load: Genomic inbreeding drives growth depression in captive critically endangered Chinese Bahaba (Bahaba taipingensis)

Chinese bahaba (Bahaba taipingensis) is a critically endangered marine fish that has been commercially extinct in the wild. Conservation-oriented captive breeding has become an effective strategy for rescuing such endangered species, but concerns about inbreeding depression often remain. Here, after merely two generations of closed breeding from 18 wild founders, Chinese bahaba exhibited severe growth depression, with body length and weight diverging by more than three-fold. To further investigate the early genomic consequences of captive breeding, we analyzed whole-genome sequences from 348 F2 individuals together with 19 wild individuals from the same marine region. While genome-wide genetic diversity was overall preserved, closed breeding rapidly partitioned the F2 population into eight distinct genetic lineages. A significant elevation in genomic inbreeding was observed to facilitate the homozygous exposure of recessive deleterious mutations, which was strongly correlated with growth decline. An integrative framework combining GWAS, gene-level burden test, and ROH hotspots was applied to dissect the genetic architecture underlying growth decline, which converged predominantly on skeletal scaffolding and immune regulation. This was evidenced by candidate genes related to skeleton development and homeostasis (e.g. fam20b, c-fos, trpv5, and il23r), the GH/IGF axis (e.g. socs1a), and immune/inflammatory pathways (e.g. il23r, nlrp7, cd163, il12rb2), as well as calcium ion transport pathway. Together, our findings provide novel insights into the genomic consequences and genetic architecture of growth decline under captive conditions in Chinese bahaba, and offer critical guidance for genetic management in captive conservation programs of endangered species.

genetics↗

bioRxiv2026

From pelagic to reef: Genomic basis of morphological adaption during life-history transition in the orbicular batfish (Platax orbicularis)

Metamorphosis enables teleosts to transition between ecological niches, driving lineage-specific morphological innovations. The orbicular batfish (Platax orbicularis) exemplifies this, transforming from a pelagic larva into a reef-associated juvenile with extreme allometric fin elongation. Here, we generated a chromosome-level genome assembly of 715.46 Mb, with 99.4% completeness. Integrating comparative genomics with tissue-specific transcriptomics, we demonstrate that such transformation is a systemic process shaped by both long-term evolutionary adaptation and short-term developmental reprogramming. Comparative analyses revealed expansion of development-related gene families and significant evolution of immune- and sensory-related families, likely associated with ecological niche transition. Spatiotemporal clustering of metamorphosing fin transcriptomes identified rapid cell cycle activation accompanied by sustained suppression of basal metabolism, indicating developmental trade-offs during fin elongation. Several differentially expressed genes involved in cell cycle (ankfn1 and mcph1), ossification (cyp24a1 and sema4d), and extracellular matrix remodeling (sdc4 and serpine1) exhibited positive selection, suggesting coordinated regulatory and protein-level adaptation. Among an extensive repertoire of 49 hox genes, four (hoxb6b, hoxc8a, hoxd9b, hoxd10a) were differentially expressed, implicating developmental regulators in fin remodeling. Together, our findings offer new insights into the evolutionary context and molecular mechanisms of metamorphosis in orbicular batfish, and advance the understanding of adaptive evolution and metamorphosis innovations in teleosts.

genomics↗

bioRxiv2026

A pan-genomic and methylomic analysis reveals a distinct signature in Vibrio alginolyticus isolated from wild fish

Vibrio alginolyticus is a ubiquitous opportunistic pathogen in estuarine and marine ecosystems and a leading cause of vibriosis in humans and aquatic animals. Yet genomic and epigenomic landscapes of V. alginolyticus from wild fish remain poorly defined. Here, we present a pan-genomic and methylomic framework based on 89 high-quality V. alginolyticus genomes, including 46 newly sequenced isolates recovered from 105 wild marine fish representing 17 species in Hong Kong waters of the South China Sea, plus all publicly available complete genomes. We reported a 32.38% prevalence of V. alginolyticus in wild fish. Phylogenomic analysis resolved four distinct clades, with Clade IV dominated by wild-fish isolates and characterized by low virulence and low antimicrobial resistance. Pan-genomic analysis revealed a closed pan-genome with a substantially depleted accessory genome in Clade IV. We identified a total of 763 antimicrobial resistance (AMR) genes from 89 strains, which covered 32 gene types and spanned four resistance mechanisms, with efflux pumps as the most prevalent strategy. Critically, resistance genes were almost exclusively chromosomal rather than plasmid-borne. Virulence profiling confirmed the presence of tlh and T6SS genes but the absence of the high-risk human pathogenic factors tdh and ctxB. Methylomic analysis using nanopore sequencing uncovered 355 DNA methyltransferases and 140 strain-specific methylation motifs with dominance by 6mA. Notably, 71.90% of methyltransferases resided in the accessory genome and were disseminated by mobile genetic elements, especially plasmids. Motif combinations were highly strain-specific and largely decoupled from phylogeny, except for a shared motif signature defining Clade IV. The GATC motif was essential across all V. alginolyticus strains and showed significant enrichment in virulence gene regions but not in AMR gene loci, revealing differentiated epigenetic modification characteristics. This study nearly doubled the number of high-quality complete genomes available for V. alginolyticus and provides the first comprehensive methylomic characterization for this species. Our findings reveal a phylogenetically distinct, low-virulence, low-resistance V. alginolyticus clade widely shared among wild fish, with important implications for One Health surveillance and evolutionary adaptation of marine pathogens.

genomics↗

bioRxiv2026

Meta-analysis of gut microbiome in largemouth bass (Micropterus salmoides) under different aquaculture systems

The teleost gastrointestinal tract hosts metabolically active microbial assemblages that play critical roles in nutrient use, immune regulation, physiology, behavior, growth, reproduction, and health status. However, the extent to which aquaculture production systems restructure these communities remains poorly defined. In this study, metagenomic sequencing was applied to characterize gut microbiota in largemouth bass (Micropterus salmoides) reared under four representative farming conditions: industrial aquaculture (IA), captive pond-based farming (CA), ordinary pond aquaculture with healthy fish (PH), and ordinary pond aquaculture with diseased fish (PD). Results revealed that the four groups exhibited pronounced differences in microbial diversity, taxonomic composition, functional capacity, carbohydrate-active enzyme profiles, and antibiotic resistance genes (ARGs). Notably, bacterial taxa accounted for more than 95% of the gut microbial communities across all groups. IA fish showed greater microbial richness and diversity than CA and PH fish, consistent with a more complex and potentially more stable intestinal ecosystem under industrialized rearing conditions. Taxonomic profiling at both the phylum and genus levels identified production system-specific microbial signatures. In particular, opportunistic pathogens, including Aeromonas veronii and Aeromonas hydrophila, were disproportionately enriched in CA fish, suggesting a microbiota profile associated with increased disease vulnerability. Functional prediction analysis further indicated distinct metabolic states among groups, with purine and fatty acid metabolism enriched in PD fish, potentially reflecting disease-associated disruption of host-microbiota interactions. Carbohydrate-active enzyme analysis revealed substantial variation in microbial carbohydrate-processing potential, whereas ARG profiling indicated that farming conditions were linked to distinct gut resistome patterns. Collectively, these findings identify aquaculture regimes as a key ecological driver of intestinal microbiome structure in largemouth bass and provide a mechanistic basis for optimizing microbiome-informed health management in aquaculture systems. Keywords: Largemouth bass (Micropterus salmoides); gut microbiota; aquaculture modes

microbiology↗

bioRxiv2026

M.FcoHsdM-dependent DNA methylation coordinates secretion-associated gene expression, interbacterial competition, and virulence in Flavobacterium columnare

Flavobacterium columnare causes columnaris disease in freshwater fish, but the contribution of DNA methylation to its physiology and pathogenicity remains poorly understood. Here, we characterized M. FcoHsdM, a type I restriction-modification methyltransferase previously identified by nanopore methylome analysis. Deletion of the gene encoding M. FcoHsdM abolished methylation at its associated recognition motifs without affecting planktonic growth. The mutant exhibited impaired biofilm formation, gliding motility, colony spreading, and gelatinolytic activity, together with increased outer-membrane vesicle production and complete attenuation in a zebrafish infection model. Transcriptomic and extracellular proteomic analyses revealed broad changes in secretion and cell surface associated functions. In particular, genes encoding components of a putative type VI secretion system were coordinately downregulated, and the mutant showed reduced antagonistic activity against Aeromonas hydrophila. Several predicted type IX secretion system substrates and extracellular enzymes were also reduced, potentially contributing to the motility and virulence defects. Two such motifs were identified in tssP, which encodes a predicted Bacteroidota-specific type VI secretion system membrane-complex component. One motif overlapped a computationally predicted binding site for the leucine-responsive regulatory protein Lrp, raising the hypothesis that intragenic methylation may influence regulator occupancy at the tssP locus. Collectively, these findings identify M.FcoHsdM-dependent methylation as an important contributor to secretion-associated gene expression, interbacterial antagonism, and virulence in F. columnare.

microbiology↗

bioRxiv2026

Isolation, identification, and comparative genomic analysis of Vibrio harveyi as a causative agent for a skin ulcer disease of endangered fish Chinese bahaba (Bahaba taipingensis)

Chinese bahaba (Bahaba taipingensis) is a fish species endemic to China and listed as a Class I nationally protected wild animal. Although significant breakthroughs have been achieved in its artificial breeding, high mortality rates persist during cultivation. Beginning in August 2024, sustained mass mortalities occurred in artificially farmed Chinese bahaba at a farm in Guangdong Province. Diseased fish exhibited pronounced skin ulcers, ascites, gastroenteritis, and splenomegaly. Histopathological examination revealed severe necrotizing gastroenteritis, gill necrosis and edema, muscle congestion with inflammatory cell infiltration, hepatic congestion with marked vasculitis, renal interstitial necrosis with tubular atrophy, and abundant melanomacrophage centers in the spleen. Based on biochemical characterization and whole-genome phylogenomic analysis, the isolated strain HCY1 was identified as Vibrio harveyi. Artificial infection experiments with this strain resulted in 100% mortality and reproduced clinical signs similar to those in naturally infected fish. Antimicrobial susceptibility testing showed that HCY1 remained susceptible to florfenicol and trimethoprim-sulfamethoxazole, but was resistant to multiple antibiotics, including {beta}-lactams and tetracyclines. Comparative genomic analysis revealed that HCY1 carries various antimicrobial resistance genes primarily conferring resistance to {beta}-lactam and tetracycline antibiotics, consistent with the phenotypic resistance profile. The strain also harbored numerous virulence genes, including complete type III and type VI secretion systems (T3SS and T6SS), tlh, hap/vvp, and rtxB. Its plasmids encoded multiple virulence-enhancing genes, such as mcpA, pal, and esiB. To our knowledge, this is the first systematic investigation of a disease outbreak in cultured Chinese bahaba, and provides valuable insights for disease control and population conservation of this endangered species.

microbiology↗

bioRxiv2026

ApoE4 impairs astrocyte lipid droplet formation via endolysosomal dysfunction

An important component of neuron-glia coupling is the transport and delivery of neuron-derived lipids to glial lipid droplets. This pathway is important as failure to store incoming lipids in glial lipid droplets exacerbates neurodegeneration. ApoE4, a risk factor for Alzheimer's disease, impairs this transport pathway. But how ApoE4 affects lipid trafficking in glia and whether these alterations can be restored is poorly understood. Here, we demonstrate that ApoE4 particles impair endolysosomal function and promote lipofuscin formation in cultured primary astrocytes, thereby disrupting the trafficking of lipids for storage into lipid droplets. Lipid droplets, however, can be recovered by preventing lysosomal impairment with PCSK9, a secreted protein that prevents LDLR recycling and reduces ApoE4 internalization. Lipid droplets are similarly recovered in the presence of ApoE4 by repairing endolysosomal function. Our findings reveal new insight into how ApoE4 dysregulates lipid storage while uncovering new mechanisms to correct these defects.

neuroscience↗

bioRxiv2026

Whole-brain modeling of dynamic causal circuits in human cognition using amortized variational inference

Understanding dynamic mechanisms underlying cognition remains a major challenge in human neuroscience. Here, we develop, validate, and apply Multivariate Dynamical Systems Identification with Amortized Variational Inference (MDSI-AVI), a novel computational framework designed to address critical challenges in capturing asymmetric, context-dependent, whole-brain directed interactions while accounting for regional hemodynamic response variability in fMRI data. MDSI-AVI leverages simulation-based inference through forward and reverse variational inference to address the limitations of conventional variational methods in high-dimensional settings. By averaging over uncertainty in hemodynamic response parameters using forward simulation, MDSI-AVI provides well-calibrated posteriors of directed connectivity that scale efficiently to networks with hundreds of nodes. Applied to Human Connectome Project data (N=728), MDSI-AVI reveals new insights into working memory mechanisms, identifying the dorsal anterior insula as a critical hub influencing activity at the whole-brain level. We demonstrate task-dependent modulation of causal influences, where the salience network drives frontoparietal network activity, which differentially influences the default mode and sensorimotor networks depending on working memory load. These whole-brain causal interactions distinguish task conditions with high accuracy and predict working memory performance. Our framework demonstrates reproducible results across whole-brain parcellations, establishing MDSI-AVI as a robust tool for advancing our understanding of circuit dynamics in cognition and disease.

neuroscience↗

bioRxiv2026

BaiZe: A Multi-View Dynamic Framework for Simulating and Interpreting Cellular Responses Across Perturbation Contexts

Accurately predicting how cells respond to perturbations is important for understanding cellular regulation and prioritizing experimental interventions, yet existing models are often designed for specific perturbation types or biological contexts. Here we present BaiZe, a multi-view conditional state-transition framework that predicts the post-perturbation transcriptome from a control-state transcriptome together with genetic, chemical, temporal and optional chromatin-accessibility information. BaiZe models perturbation responses as context-dependent transitions between cellular states. BaiZe supports prediction across held-out cell states and genetic perturbations, unseen multi-gene combinations, chemical structures and doses, temporal stages and species contexts. Benchmarking across diverse perturbation settings demonstrates that BaiZe effectively recovers major transcriptional response programs under previously unseen conditions. Incorporating matched ATAC-seq context further improves selected state-transition predictions and enables model-based attribution of chromatin regions to response-associated genes and pathways. BaiZe also supports few-shot transfer of perturbation responses from human to mouse cellular systems and connects predicted transcriptomes to candidate morphology projections. To facilitate interpretation and use, BaiZe-Agent organizes response genes, pathways, chromatin evidence, cross-species predictions and projected phenotypes into traceable, queryable perturbation records. Together, BaiZe provides a broadly applicable framework for predicting and interpreting context-dependent cellular responses and for prioritizing hypotheses across diverse perturbation settings.

bioinformatics↗

bioRxiv2026

Protracted Maturation of Proactive and Reactive Systems Predicts Cognitive Stability and Psychopathology : A longitudinal multi-cohort study

Inhibitory control matures progressively from childhood to early adulthood, yet the neural mechanisms driving this development and their relevance to psychiatric risk remain poorly understood. Guided by the Dual Cognitive Control model, we leveraged longitudinal fMRI from two independent cohorts in the US (ABCD, ages 9-12) and Europe (IMAGEN, ages 14-22) to map the spatiotemporal dynamics of reactive and proactive control using novel single-trial modeling and representational similarity analysis. We found both reactive and proactive stopping networks stabilize after mid-adolescence, tracking the developmental patterns of inhibitory control and behavioral stability. By decoding trial-by-trial fluctuations along a speed-caution continuum, we demonstrate that brain-behavior coupling to a proactive "Safe state" tightens progressively with age. Furthermore, network-level representational coherence of this Safe state emerged as a scanner-invariant, trait-like biomarker that robustly predicted inhibitory control, behavioral stability, and transdiagnostic psychopathology across multiple developmental windows, providing a validated neural phenotype for precision psychiatry.

neuroscience↗

bioRxiv2026

RT-nested and interfering-Primer PCR reveal prevalent isoform-specific A-to-I RNA editing in neuronal genes

BackgroundMetazoan adenosine-to-inosine (A-to-I) mRNA editing temporospatially diversifies the neuronal transcriptome and proteome. The limited read length from next-generation sequencing (NGS) constrains the quantification of the potentially differential editing levels across different splicing isoforms, restricting our understanding of the extent to which RNA editing contributes to molecular diversity and its interplay with splicing. MethodsWe employed reverse transcription nested PCR (RT-nPCR) and developed a novel interfering-Primer PCR (iPrimer PCR) technique to distinguish different transcripts of any gene. We selected multiple essential genes exhibiting RNA editing in coding sequences (CDSs) or untranslated regions (UTRs) for isoform-specific amplification and Sanger sequencing. ResultsNine different Adar isoforms together with pre-mRNA had distinct editing levels at the S>G auto-recoding site, which was predicted to have isoform-specific effects on catalytic activities. Although pre-mRNA editing might exert isoform-dependent promotion/suppression of splicing, closely located editing sites, such as those in neuronal genes qvr and stj, still exhibited high correlation in editing levels due to co-editing. iPrimer strategy further discovered differential recoding levels between the long/short 3UTR isoforms of gene jef. ConclusionsWe provide the first comprehensive solution for isoform-specific PCR amplification of any gene, enabling quantification of RNA editing level of different isoforms. Our results offer insights into how RNA editing interplays with splicing, and highlight its complicated role in expanding molecular diversity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/725286v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@3c4e61org.highwire.dtl.DTLVardef@13def88org.highwire.dtl.DTLVardef@138fa91org.highwire.dtl.DTLVardef@1ca7460_HPS_FORMAT_FIGEXP M_FIG C_FIG We developed isoform-specific PCR followed by Sanger sequencing, and achieved the quantification of differential RNA editing levels in different transcripts of a gene.

molecular biology↗