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Wang, L.

Publications and source records attributed to Wang, L..

At least 91 records · Page 5Linked to original sources

LTBP isoforms differentially encode TGF-β spatial localization and activation

TGF-{beta} signals through a conserved pathway yet produces diverse outcomes, pointing to regulatory mechanisms upstream of receptor engagement. A family of four latent TGF-{beta} binding proteins (LTBPs) tether pro-TGF-{beta}s and control their localization and activation, but how distinct LTBPs contribute to this regulation is unclear. Here we combine cryo-electron microscopy with functional assays to dissect LTBP-pro-TGF-{beta} interactions. We resolve the LTBP-1/pro-TGF-{beta}1 and LTBP-3/pro-TGF-{beta}3 complex structures, revealing a conserved yet plastic hydrophobic binding interface, and systematically map key residues across all four LTBP and three pro-TGF-{beta} subtypes that determine binding specificity and affinity. Unexpectedly, LTBP-2, previously thought incapable of TGF-{beta} binding, engages pro-TGF-{beta}1 through a covalent linkage via its 16th EGF-like domain, providing a mechanistic link between LTBP-2 function and TGF-{beta} signaling. Beyond tethering, LTBP-3 shifts pro-TGF-{beta}3 from spontaneous activation toward integrin dependence, establishing LTPBs as dynamic modulators that dictate not only where but also how TGF-{beta} is unleashed. Collectively, these findings establish that LTBPs are not redundant ECM scaffolds but a family of functionally distinct regulators that differentially encode TGF-{beta} spatial localization and activation, with implications for isoform-selective therapeutic strategies.

biochemistry↗

A single-cell and multi-platform spatial atlas of the human pancreas resolves a transformation-associated epithelial axis and a recurrent boundary-organized tumour microenvironment

Most pancreatic ductal adenocarcinoma (PDAC) single-cell and spatial studies analyze one cohort or platform, obscuring recurrent biology. We assembled a human pancreas single-cell and single-nucleus reference of 1,186,130 cells from 19 studies and interpreted 176 Visium sections comprising 458,877 spots across non-diseased pancreas, chronic pancreatitis, PanIN, IPMN, primary PDAC and metastasis. Marker-supported labels were used after two RNA-based copy- number callers failed known-diploid controls. BANKSY domains, two reference-mapping methods and sample-level analyses resolved a cross-sectional epithelial axis extending from acinar-rich to malignant tissue. Five trajectory algorithms recovered similar ordering on a shared embedding; their consensus was interpreted as transformation-associated, not temporal or clonal. Malignant regions were globally segregated from fibroblast and myeloid compartments. Signed- distance analysis refined this pattern into a malignant core, a CAF/myeloid surround beginning at the tumour boundary and a more distal lymphoid compartment. Candidate extracellular-matrix communication, led by COLLAGEN, LAMININ and FN1, concentrated at the interface. Changes were reproduced in six patient-matched Normal-tumour pairs using exact patient-level tests. Visium HD resolved the same organization at single-cell resolution and showed that 8-um bins distorted immune-adjacency estimates. Xenium also revealed recurrent neighbourhoods but sample-specific stromal boundaries. We provide a confound-aware framework for identifying recurrent epithelial and microenvironmental organization in PDAC.

cancer biology↗

SBE1 drives the circumferential growth of the starch sheath around the Chlamydomonas reinhardtii pyrenoid

Pyrenoids are CO2-fixing organelles responsible for approximately one-third of global CO2 fixation. The pyrenoids of many algae are surrounded by a starch sheath proposed to perform the critical function of slowing leakage of concentrated CO2 out of the pyrenoid. How the cell shapes starch granules into curved starch plates that encase the pyrenoid to enable efficient CO2 fixation is currently unknown. Here, we elucidate how starch transitions from granules into a fully formed pyrenoid starch sheath using confocal microscopy of the model green alga Chlamydomonas reinhardtii. We observe that after initiation, starch granules grow circumferentially along the surface of the pyrenoid matrix to encapsulate it. We show that the starch branching enzyme SBE1 localizes to the pyrenoid and is essential for this circumferential starch granule growth. Our data suggest that SBE1 promotes the circumferential growth of pyrenoid-associated starch granules by branching starch at the matrix-granule-stroma interface. Our findings advance the understanding of pyrenoid starch sheath assembly and, more broadly, starch-shaping mechanisms. Significance StatementThe shape of the starch granules that surround the pyrenoid is critical for efficient carbon fixation, but how these granules are shaped into curved plates is currently not understood. We find that starch granules spread along the pyrenoid surface rather than growing equally in all directions, and that this bias requires SBE1, a branching enzyme localized to the surface of the spherical pyrenoid matrix condensate. The findings support a model in which localizing a metabolic enzyme directs polymer growth to create curvature. This mechanism connects branching enzyme placement to starch granule geometry and contributes to the understanding of how cells convert local biosynthetic activity into large-scale organelle architecture.

molecular biology↗

The Capillary endothelial cell-governed niche sustains angiogenesis in proliferating infantile hemangioma via multilayer stromal support

Infantile hemangioma (IH), the most common benign vascular tumor in infants, is characterized by the aberrant proliferation of hemangioma endothelial cells (HemECs) and excessive angiogenesis. However, it is unclear how the tumor microenvironment sustains these active angiogenic signals. We performed single-cell RNA sequencing and spatial transcriptomic to profile 30 samples from proliferating IH, involuting IH, and normal skin. The results indicated that HemECs comprised distinct subpopulations. Among them, capillary endothelial cells (Cap.ECs) had an immature phenotype and functioned as the core drivers of IH. The endothelial-to-mesenchymal transition endothelial cells (endoMT-ECs) secreted collagen and engaged in CD44-mediated crosstalk with Cap.ECs to construct the angiogenesis-active niche in the tumor microenvironment (TME) of proliferating IH. Blockade of CD44-mediated intercellular communication effectively suppresses the angiogenesis of HemECs and promotes tumor regression. Beyond the endothelial layer, pericytes tightly enveloped Cap.ECs, with SERPINE2+ subtypes sustaining their angiogenic activity via ANGPT signaling. Pseudotime trajectory analysis revealed that the mesenchymal stem cells (MSCs)-enriched niche serves as a progenitor pool for Cap.ECs in proliferating IH. Our findings thus revealed that IH progression relies on CD44-mediated endoMT-EC-Cap.EC crosstalk and on both pericyte and MSC niches to sustain angiogenesis. HIGHLIGHTSO_LICapillary endothelial cells drive infantile hemangioma progression, with pericytes tightly ensheathing them. C_LIO_LICD44-mediated capillary and endoMT-derived endothelial cells crosstalk construct the angiogenic-active niche in the tumor microenvironment of proliferating infantile hemangioma. C_LIO_LIThe MSC-enriched niche provides a progenitor pool for the capillary endothelial cells in proliferating infantile hemangioma. C_LI

cancer biology↗

Targeting the NuRD Component, CHD4, Impairs Foxp3+ Treg Cell Production and Function and Promotes Anti-Tumor Immunity

Little is known about why Foxp3 regulatory T (Treg) cells require at least three HDAC1/HDAC2-containing chromatin-remodeling complexes (NuRD, Sin3 and CoREST), or whether selective disruption of these complexes can be exploited to enhance antitumor immunity. Here, we investigated the role of chromodomain helicase DNA- binding protein 4 (CHD4), the ATP-dependent remodeling subunit of the NuRD complex, in Treg biology. Conditional deletion of Chd4 in Foxp3 Tregs resulted in severe systemic autoimmunity and early lethality, accompanied by reduced Foxp3 expression, impaired Treg suppressive function, and loss of Treg lineage stability. Transcriptomic analyses demonstrated that CHD4 deficiency closely phenocopied Hdac2 deletion, whereas quantitative proteomic analyses revealed that CHD4 assembles into highly conserved NuRD complexes in both Treg and conventional CD4 T cells. These findings indicate that the selective dependence of Tregs on CHD4 does not arise from the formation of lineage-specific protein complexes but rather from the unique epigenetic program maintained by CHD4-containing chromatin-remodeling complexes that is required for Treg differentiation and stability. Using a novel cellular target-engagement platform, we identified CH41, a potent small-molecule inhibitor of CHD4 that recapitulated the effects of genetic CHD4 ablation on Treg function. Pharmacological inhibition of CHD4 impaired intratumoral Treg accumulation and function and significantly inhibited the growth of lung and hepatocellular carcinomas in immunocompetent, but not immunodeficient, mice, without inducing systemic autoimmunity. Collectively, our findings identify CHD4 as a critical epigenetic regulator of Treg lineage stability and establish pharmacological targeting of the CHD4/NuRD axis as a promising strategy to selectively disrupt tumor-associated Tregs and enhance antitumor immunity.

cancer biology↗

Single-cell lineage tracing of human neuromesoderm organoids reveals TBX6-mediated posterior mesoderm fate diversification

Neuromesodermal progenitors (NMPs) drive vertebrate posterior axis elongation, but the lineage hierarchy of human NMP derivatives remains poorly defined. Here, we integrated a CRISPR/Cas9-based single-cell lineage tracing system with paired multiomics profiling--including scRNA-seq and scATAC-seq--in human pluripotent stem cell-derived neuromesodermal organoids (NMOs) to reconstruct high-resolution lineage relationships spanning 50 days of differentiation. Our data analysis reveal that intermediate mesoderm (IM) and paraxial mesoderm (PM) originate from a shared presomitic mesoderm (PSM) progenitor downstream of NMPs, whereas lateral plate mesoderm (LPM) segregates early from committed mesodermal progenitors. Notably, TBX6 ablation disrupts both IM and somite development, demonstrating that TBX6 functions as an upstream regulator of these two lineages. Mechanistically, TBX6 loss arrests PSM at the progenitor stage and abolishes activation of development programs required for IM maturation. We further delineate neural crest differentiation pathways from NMPs, identifying pre-bifurcation molecular signatures that predict neural crest fate. This work provides a clonal-resolution lineage map of human NMP differentiation and advances our understanding of human posterior trunk development and the etiology of TBX6-associated congenital disorders affecting both the spine and the kidney.

developmental biology↗

A hierarchical activation threshold shapes RSV F antibody repertoires from toddler vulnerability to adult protection

Respiratory syncytial virus (RSV) causes severe infant morbidity, yet the mechanisms underlying their suboptimal immunity and the failure of prefusion F-stabilized adult vaccines in infants remain unclear. Here we integrate deep mutational scanning of 761 preF-binding antibodies, repertoire profiling of 102 repeatedly exposed pediatricians and 61 RSV-experienced toddlers, structural analysis, and >40,000 viral genomes to decode RSV F immunity. We resolved 12 immunologically distinct functional antibody subclasses and uncovered a hierarchical activation threshold: apical epitope-targeting antibodies with superior neutralizing potency demand extensive somatic hypermutation and cooperative CDR networks, whereas central-to-basal epitope-directed, marginal or non-neutralizing antibodies engage germline-encoded antibodies through minimal mutations (e.g., S31G). Toddler repertoires are confined to low-threshold, non-productive sites; adult repertoires enrich for apical elite neutralizers whose immune pressure drives contemporary RSV-B evolution. These reframe pediatric RSV vulnerability as a threshold-gated repertoire deficit and prescribe vaccine strategies that actively redirect immunodominance from permissive epitopes toward high-barrier apical targets.

immunology↗

A mobile optical coherence microscope for studying aquatic organisms in- and outside the laboratory

High-resolution, three-dimensional imaging of live organisms has largely depended on laboratory-bound microscopes, limiting quantitative analysis of morphology and dynamics to species that survive transport and thrive under lab-controlled conditions. Here we present a mobile optical coherence microscopy (OCM) platform that overcomes this constraint, delivering [~]2.5 {micro}m axial resolution, label-free, volumetric imaging of live aquatic organisms in both laboratory and remote field environments. We demonstrate the platform across a broad range of aquatic organisms from the lab and field, spanning multiple phyla - including cnidarians, poriferans, annelids, arthropods and echinoderms - resolving internal anatomy, tissue boundaries and organismal morphology at micrometer scale without fixation, fluorescent labeling, or specialized sample preparation. High-speed acquisition, with up to 250 kHz A-line rate and 7.7 Hz volume rate, further enabled morphodynamic imaging of live biological processes, including cellular aggregate motility, embryonic cell division, and organ-level peristaltic dynamics in intact, living animals. To demonstrate field deployability, the platform was operated during the EMBL TREC pan-European expedition, enabling on-site, label-free imaging of marine organisms and plankton immediately upon collection. By decoupling high-resolution volumetric imaging from fixed laboratory settings, mobile OCM opens a path toward field-ready quantitative morphological and dynamic phenotyping of aquatic life.

bioengineering↗

Spaceland: Histology-Guided Reconstruction of High-Resolution Whole-Organ 3D Molecular Atlases from Sparse Spatial Transcriptomics

Reconstructing whole organs in three-dimensional molecular detail is a key step toward building virtual organs for modeling tissue organization, disease progression and drug perturbation responses. However, high-resolution whole-organ spatial transcriptomic profiling remains impractical, forcing a trade-off between reconstruction fidelity and sampling density. Here, we introduce Spaceland, a morphology-guided framework that reconstructs continuous, high-resolution 3D molecular landscapes from sparsely sampled spatial transcriptomic sections and serial H&E histology. Spaceland formulates this task as learning continuous gene-expression fields within a morphology-informed histological space. It constructs a dense 3D morphological scaffold by optical-flow interpolation of foundation model-derived H&E representations and decodes sparse spot-level transcriptomic measurements onto an 8 m histology-aligned grid. Across mouse olfactory bulb, mouse hemibrain and spatiotemporal planarian regeneration, Spaceland generalized across platforms, tissue scales and biological contexts. In mouse benchmarks, Spaceland bridged 400 m molecular gaps, resolved sub-spot organization, outperformed ST-based interpolation and 2D H&E-based prediction methods, and remained robust with 160-320 m H&E intervals. In planarian regeneration, it enabled time-resolved whole-organism analysis from only four Visium sections per stage, revealing dynamic neoblast-neural spatial remodeling. Together, Spaceland shifts 3D molecular atlas construction from exhaustive experimental sampling toward data-driven virtual tissue and organ modeling, providing a scalable route to whole-organ molecular reconstruction.

bioinformatics↗

Transcriptome Profiling Identifies a Natural Antisense Transcript of IRF4 Associated with EBV Latency

Epstein-Barr virus (EBV) establishes distinct latency programs that drive B-cell transformation through coordinated viral and host gene regulation. However, the contribution of host long noncoding RNAs (lncRNAs) to EBV-mediated pathogenesis remains poorly understood. Here, we performed transcriptome-wide lncRNA profiling comparing Type I and Type III EBV latency and identified differentially expressed host lncRNAs, among which we characterized a previously unannotated natural antisense transcript (NAT) of IRF4, designated IRF4-AS1. IRF4-AS1 is markedly upregulated in Type III latency and positively correlates with IRF4 expression across EBV-transformed lymphoblastoid cell lines (LCLs) established from diverse clinical backgrounds. Functional studies indicate a context-dependent positive regulatory relationship between IRF4-AS1 and IRF4. While overexpression of IRF4-AS1 increased IRF4 expression and IRF4 overexpression increased IRF4-AS1 levels, loss-of-function analyses suggest that this relationship is modulated by additional regulatory inputs in established transformed cells. In contrast to IRF4, IRF4-AS1 transcription is not regulated by the LMP1- NF{kappa}B signaling, indicating that the two transcripts are regulated through partially distinct mechanisms. In addition, we identified MIR3142HG as a highly induced latency-associated lncRNA and found that its embedded miRNAs, miR-146a and miR-3142, exhibited divergent expression patterns, suggesting differential post-transcriptional regulation. Together, these findings identify IRF4-AS1 as a NAT lncRNA for IRF4 and reveal extensive remodeling of host lncRNA networks during EBV latency, providing a foundation for future studies of lncRNA- mediated host-virus interactions in EBV pathogenesis. ImportanceEBV drives B-cell transformation through extensive reprogramming of host transcriptional networks, yet the contribution of host long noncoding RNAs (lncRNAs) to this process remains poorly defined. Transcriptome-wide lncRNA profiling, together with functional analysis, identified IRF4-AS1 as a previously unannotated natural antisense transcript of IRF4. IRF4- AS1 is upregulated in Type III latency and positively correlates with IRF4 expression across EBV-transformed cells. Together, this study provides a foundation for future mechanistic studies of lncRNA-mediated host-virus interactions in EBV pathogenesis.

microbiology↗

Perturb-seq resolves physiologic programs and bidirectional regulation of non-canonical NF-κB signaling in epidermal organoids

Regulated keratinocyte differentiation is required for formation of the stratified epidermis and a functional barrier. Understanding genetic drivers of keratinocyte differentiation is crucial for understanding several skin diseases. Perturb-seq is a single-cell CRISPR screen that measures transcriptomic responses to perturbations. To date, Perturb-seq experiments have principally focused on 2-dimensional cell culture models lacking hallmarks of skin development - physiological desmosome formation and barrier function. Here, we leverage Perturb-seq in an epidermal organoid model that recapitulates physiologically relevant differentiation programs. We demonstrate that our perturbations significantly impact diverse differentiation programs and reveal bidirectional function of non-canonical NF-{kappa}B signaling in late keratinocyte differentiation.

genomics↗

Glomerulus-Targeted Nanotherapy via Collagen IV-α3 Binding Enhances Renal Immunoregulation in Lupus Nephritis

Lupus nephritis requires long-term immunosuppressive therapy, which is often associated with severe systemic side effects. Therefore, new therapeutic strategies that maintain high efficacy while minimizing adverse effects is essential. Although nanomedicine has advanced systemic and kidney-targeted drug delivery, a reliable method for glomerulus-specific delivery is lacking. Collagen IV (Col4)-alpha 3, located in the glomerular basement membrane (GBM) at the blood-tissue interface through fenestrated capillary endothelium, represents an ideal target for glomeruli delivery. Herein, we developed a novel liposomal nanoparticle conjugated with a Col4-alpha 3 binding peptide (Col4-3-NPs) for selective glomerular targeting. Prednisolone-loaded Col4-3-NPs were administered to lupus-prone mice twice weekly for 8 weeks. Kidney injury and function were evaluated biweekly, and renal immune cell populations were analyzed by flow cytometry at study completion. The results show that rhodamine-labeled NPs predominantly accumulate in kidney glomeruli 48 hours after intravenous injection. The Col4-NP system demonstrated stable and prolonged release of the encapsulated drug for over 48 hours. Lupus-prone mice treated with prednisolone-loaded Col4-NPs showed significantly improved renal function and histology, including a 30% increase in glomerular filtration rate (GFR), a 56% reduction in proteinuria, and decreased IgG deposition and fibrosis. Notably, treatment also enhanced renal regulatory T cell (Treg) populations. These findings suggest that glomerulus-targeted Col4-3-NPs hold significant translational promise. This platform may offer an effective, site-specific treatment for lupus nephritis while minimizing systemic side effects and could be adapted for other glomerular diseases requiring targeted therapy.

physiology↗

Quantifying Cross-Modal Shared Information Between Histomorphology and Spatial Transcriptomics via Spatiotemporal Trajectory Correlation

Histopathological imaging and spatial transcriptomics (ST) provide synergistic morphological and molecular insights into tissue architecture. While conventional downstream analyses predominantly adopt a discrete paradigm, such as segmenting histological images or identifying spatial domains, emerging trajectory reconstruction methods offer a continuous perspective for analyzing these modalities. However, most current studies are confined to single-modality or single-organ analyses, lacking systematic integration across modalities and multiple organs. To address this limitation, we performed trajectory reconstruction on ST-derived gene expression data and on histopathological morphological features extracted using ten widely used pathology pretrained models across multiple cancer samples from six organs. The results demonstrate that trajectory reconstruction, as a continuous analytical framework, effectively bridges spatial transcriptomics and histopathological imaging. More importantly, we propose an innovative framework that uses trajectory pseudotime as a mediating variable to quantify the extent of information sharing between molecular and morphological features. This framework not only provides a new perspective for understanding the intrinsic links between modalities but also establishes a solid theoretical and methodological foundation for future cross-modal translation studies.

pathology↗

Assembling and annotating the Tainung 67 rice genome to trace its japonica and indica ancestries

Here we reported the 409.0 Mb assembly of the Tainung 67 (TNG67) genome, an early hybrid of japonica and indica cultivars. We used different platforms to sequence the TNG67 genome with a total coverage of 209.8x, from a combination of Illumina paired-end reads, Illumina mate-pair reads, and Oxford Nanopore Technology long reads. The assembly has an N50 of 32.3 Mb with the longest scaffold = 45.2 Mb. We have annotated 38,938 genes where 28,376 (72.9%) finished with the Blast2GO annotation stage. There were 4,821 genes, (98.4%) of the total gene count that have complete BUSCOs. 48.33% (197.5Mb) of the TNG67 genome is composed of repeats. We predicted a total of 527 blast-resistant genes in TNG67. We also analyzed a total of 20 grain size genes and 38 photoperiod-related genes of TNG67, Nipponbare and TN1, and grouped them in terms of whether the TNG67 genes are more similar to Nipponbare, more similar to TN1, hybrid, same, or unique. We also determined whether the sequences of the TNG67 genome were derived from its japonica or indica ancestors. This TNG67 genome may help rice researchers improve yield, develop resistance against biotic and abiotic stress, and understand the evolution of a hybrid cultivar of japonica and indica.

genomics↗

A consensus atlas of human brain development defines cell type-specific maturation trajectories across the lifespan

Human neurodevelopment is a continuous process that begins prenatally and extends into postnatal life. Current transcriptomic datasets are limited, fragmented across analytical frameworks, precluding comprehensive reconstruction of cellular trajectories linking developmental states to mature cell types. Here we present a consolidated cellular-resolution transcriptomic atlas of human brain development from the onset of neurogenesis to adulthood, covering [~]2.2 million cells from 156 donors across nine studies. All data were reprocessed from raw sequencing reads and annotated within a unified cell-type taxonomy, enabling reliable mapping across the lifespan. Cell types were highly replicable across heterogeneous datasets, enabling us to chart their maturation and cortical layer localization over time. We identify dynamic gene programs predictive of cell-type maturation, validate gene modules tracking known fate transitions, and leverage our atlas scale to characterize rare populations, including microglia. This resource establishes a standardized reference of human brain development and maturation gene modules for future comparisons across model systems, species, and disease states.

neuroscience↗

Biological Continued Pretraining Reshapes the Capability Profile of a Foundation Model Without Catastrophic Forgetting

It is widely assumed that continued pretraining (CPT) on a narrow, out-of-distribution corpus such as raw biological sequence must trade away a general-purpose models broad competence -- the "alignment tax" or catastrophic-forgetting intuition. We test this directly, without any new training, by re-analyzing three checkpoints from a single lineage of a 26B-parameter Mixture-of-Experts model (Gemma-4-26B-A4B): the instruction-tuned base, the same model after biological CPT (8.7B tokens of DNA, protein, and biomedical text), and after subsequent supervised fine-tuning (SFT). Across three independent capability axes -- general knowledge/reasoning (MMLU, ARC, HellaSwag), code generation (MBPP), and biomedical knowledge (BixBench) -- we find that biological CPT does not degrade the model; it lifts it: MMLU +13 points, MBPP pass@1 nearly doubles (0.33 [->]0.63), and BixBench discrimination rises sharply (MCC 0.23 [->] 0.92). The single measured regression is truthfulness (TruthfulQA 8.8 points), a small and interpretable domain drift. A clean vocabulary-expansion ablation (< 0.4 pt on every general metric) confirms the gains are attributable to CPT, not tokenizer changes. Crucially, subsequent SFT narrows the model back: all three axes fall to near-base levels, revealing a consistent division of labor -- CPT re-organizes and lifts the shared capability substrate; SFT cashes it out onto target tasks. We argue this reframes biological sequence not as a competitor for a foundation models capacity but as a form of structured scientific data that reshapes its capability profile, and that CPT and SFT should be budgeted as complementary rather than substitutable stages. All checkpoints, evaluation code, and per-example outputs are public. HighlightsO_LIA training-free re-analysis of one 26B MoE lineage isolates the effect of biological continued pretraining (CPT) from tokenizer changes and from fine-tuning. C_LIO_LIBiological CPT does not cause catastrophic forgetting; it raises general knowledge (MMLU +13 pts) and code generation (MBPP pass@1 0.33[->] 0.63). C_LIO_LICPT also makes chain-of-thought reasoning 41% shorter and near-backtrack-free while pre-serving accuracy -- an effect invisible to accuracy metrics. C_LIO_LIA consistent CPT-lifts / SFT-narrows division of labor recurs across four axes, reframing biological sequence as structured scientific data that reshapes a models capability profile. C_LI The Bigger PictureAdapting a general-purpose AI model to a specialized domain -- here, the language of DNA and proteins -- is usually assumed to come at a cost: teach it biology and it forgets how to reason about everything else. This "no free lunch" intuition shapes how practitioners budget compute and whether they attempt domain adaptation at all. We test the assumption directly, and without running any new training, by comparing three snapshots of the same model taken before and after biological training. The result overturns the intuition: feeding the model raw biological sequence made it better at general knowledge, at writing code, and even changed how it reasons -- producing shorter, more decisive chains of thought without losing accuracy. The gains appear during the sequence-pretraining stage and are partly given back during task-specific fine-tuning, revealing that the two stages play complementary rather than interchangeable roles. This suggests a broader principle for data-centric AI: structured scientific data -- biological sequence today, and by extension code, mathematics, and chemistry -- is not merely knowledge to be absorbed but a lever that reshapes what a foundation model can do.

bioinformatics↗

Assessing Microcirculation Impairment in Ischemic Stroke Mice Using Arteriovenous Co-fluctuation Analysis

Accurate assessment of cerebral hemodynamics impairment traditionally relies on arterial metrics, yet often overlooks venous drainage and arteriovenous dynamics, thereby limiting the evaluation of ischemia-induced microvascular dysfunction. To address this limitation, we implemented a signal-averaging framework, combined with co-fluctuation analysis, to extract predominantly arterial and venous hemodynamic signals and construct a dynamic arteriovenous co-fluctuation index that quantifies frame-by-frame coordination between arterial inflow and venous outflow activity. This time-resolved index enables spatial characterization of large-scale cortical arteriovenous coordination beyond conventional static correlation-based analyses. Comparative analyses between healthy controls and acute ischemic stroke mice demonstrated that the arteriovenous co-fluctuation index sensitively detects disruption of vascular coordination, revealing a slower state transition that occurs alongside distinct temporal abnormalities and regional heterogeneity between ischemic core and penumbral regions. These findings underscore the utility of arteriovenous coordination as a sensitive indicator of microcirculatory dysfunction, offering a practical analytical tool for assessing stroke-induced microvascular impairment.

neuroscience↗

Asymmetric Structural Transfer Between Natural Language and Biological Foundation Models

Cross-domain transfer is a defining property of foundation models, yet whether such transfer is symmetric across domains remains unknown. Prior work has reported a striking transfer from natural language to biological sequences: language models fine-tuned only on English structural tasks acquire zero-shot protein-homology discrimination. Here we ask the converse and general question--is structural transfer between language and biology directional? --and answer it systematically. We first reproduce forward transfer (language [->]biology) under controlled conditions, then evaluate the reverse direction (biology [->]language) across fine-tuning, iso-token continued pretraining, model scaling, multiple biological foundation-model families (ESM-2, ProtBERT), and adversarial synthetic structure tasks. Reverse transfer is consistently weak: it does not exceed matched-token controls, does not scale, and does not generalize. In an architecture-matched 2 x 2 analysis on models with known training data--which eliminates the pretraining-contamination confound that clouds large-model studies--a language model retains far more competence when moved to biology (off-domain drop 0.08) than a biological model retains when moved to language (drop 0.36). Scaling widens rather than closes this gap: language [->]biology transfer strengthens with size while biology [->]language transfer decays toward chance, a pattern shared by two independent protein-model families. Our findings establish that shared structural regularities between natural language and biological sequences do not imply symmetric representational transfer, revealing an intrinsic directionality in cross-domain foundation-model learning.

bioinformatics↗