Browse Articles

Dissecting spatial patterning and signaling with directional diffusion in spatial multi-omics

Spatial multi-omics sequencing enables the simultaneous profiling of transcriptomics, proteomics, and epigenomics at a spatial resolution, offering insights into complex tissue organization and molecular regulation. However, the effective integration of multiple omics modalities in a spatial context remains a major challenge. Here, we present SpaDDM, a spatial multi-omics integration framework based on directional diffusion models (DDMs), which supports spatial pattern identification, cross-omics alignment, and inter-and intracellular signaling flow analysis. SpaDDM employs DDM-based graph networks to learn omics-specific representations by jointly incorporating spatial coordinates and molecular measurements within each modality, followed by an attention mechanism to align features across modalities. We benchmarked SpaDDM on diverse spatial multi-omics datasets, including transcriptomics-epigenomics and transcriptomics-proteomics combinations across multiple tissues and species. SpaDDM consistently outperformed existing methods by more accurately deciphering spatial tissue patterns and effectively reducing the boundary noise between spatial regions. Moreover, the learned low-dimensional coembedded representations of individual cells serve as integral mediators for inferring the signaling flows that underlie spatial patterning. Finally, we demonstrated that SpaDDM alignment of complementary information across multi-omics layers facilitates cross-omics translation and significantly improves the prediction of cell state alignments.

Nonlinear association of residual cholesterol to high-density lipoprotein cholesterol ratio with diabetes mellitus: a retrospective cohort study

Fear extinction induces maladaptive generalization via noradrenergic and GABAergic systems

Exposure therapy for anxiety disorders relies on fear extinction to reduce pathological fear responses. Here, we show that while effective at diminishing conditioned fear, extinction training paradoxically enhances fear generalization to safe stimuli through activation of the locus coeruleus–dentate gyrus (LC-DG) noradrenergic circuit. Specifically, LC norepinephrine release during extinction stimulates DG GABAergic neurons via β1-adrenergic receptors, engaging a PKA/CREB-dependent signaling cascade that ultimately leads to α4-GABA A R-mediated inhibition of granule cells and impaired threat discrimination. Genetic ablation of α4-GABA A R confirms their essential role. Crucially, this generalization can be prevented by targeting the pathway at distinct points: β1-AR blockade immediately after extinction or pharmacological inhibition of the PKA/CREB signal during the same postextinction window. These findings reveal that extinction produces competing neural consequences—adaptive fear suppression coupled with LC-DG-mediated maladaptive generalization. The identified molecular targets and their critical timing windows provide a neurobiological framework for improving exposure-based therapies.

Effects of ultrasound-guided posterior quadratus lumborum block on atelectasis in pediatric patients undergoing inguinal hernia repair and orchiopexy surgeries: A randomized controlled study

Wild vegetables contribute to improving the diversity and sustainability of vegetable diets in China

Vegetables are vital to human diets, supplying essential micronutrients critical to overall health. Despite this, it remains unclear whether current supply systems effectively ensure equitable access to cultivated vegetables across regions or fully leverage the potential of wild vegetables to diversify diets. Here, we analyzed data from 2,983 supermarkets across 330 cities for cultivated vegetables, alongside a comprehensive database of 2,461 species of wild vegetables, to evaluate the current state of vegetable supply and the potential of wild vegetables to enhance dietary diversity in China. Our analysis revealed that the species richness of cultivated vegetables is relatively low, with markets predominantly offering 52 common species. Wealthier regions exhibited greater diversity in cultivated vegetable offerings, while the availability of common cultivated vegetables was equitable and consistently distributed across vast areas of the country. However, overreliance on a few dominant species has led to a homogenization of vegetable diets across the country. Conversely, wild vegetables demonstrated a significantly richer species pool with notable regional variations. These wild vegetables serve as an important supplemental food source, particularly in regions with limited diversity of cultivated vegetables. They contribute to food security and nutrition, especially during shortages, and align with traditional food preferences in local communities. The broad distribution and rich diversity of wild vegetables present valuable opportunities for germplasm and essential micronutrient sources for humans. Our findings provide a comprehensive overview of the current state and limitations of cultivated vegetable supply, emphasizing the untapped potential of wild vegetables in diversifying and enriching human diets.

Prediction, syntax and semantic grounding in the brain and large language models

Abstract Language comprehension involves continuous anticipation of upcoming linguistic input, requiring the rapid integration of syntactic structure and semantic information. To capture the spatio-temporal dynamics of such anticipatory processes during naturalistic language comprehension, we combined electroencephalography (EEG) and magnetoencephalography (MEG), leveraging their complementary sensitivities and high temporal resolution. Using this combined EEG-MEG approach, we investigated word-class-specific neural responses during continuous speech perception and related these findings to word class-level predictability and representational structure in a large language model. Twenty-nine healthy participants listened to a German audio book while their neural responses were recorded. Event-related fields and event-related potentials for different word classes showed highly reproducible, characteristic spatio-temporal signatures, including significant pre-onset activity for nouns, suggesting enhanced anticipatory processing of this word class. Source-space analyses revealed activity patterns extending beyond temporal regions into areas compatible with sensorimotor cortices, suggesting a deeper semantic grounding of nouns in e.g. sensory experiences than verbs. By analyzing word class-specific predictability and representational structure in the transformer-based language model Llama, we provide a computational reference frame that complements the neural findings at the level of word classes. These findings highlight the power of simultaneous MEG-EEG recordings in unraveling the predictive, syntactic, and semantic mechanisms that underlie language comprehension.

HPV16 E6 oncoprotein promotes microhomology-mediated viral integration by increasing PolΘ protein expression

Integration of the high-risk human papillomavirus 16 (HPV16) genome into the host chromosome, frequently driven by microhomology-mediated end joining (MMEJ), is a critical step in the carcinogenesis of HPV-associated tumors. However, the mechanisms by which viral oncoproteins manipulate the error-prone MMEJ pathway remain poorly defined. Here, we demonstrate that the HPV16 E6 oncoprotein upregulates MMEJ to facilitate viral genome integration. This heightened MMEJ activity is driven by a marked increase in the protein levels of DNA polymerase theta (PolΘ), a central enzyme of the MMEJ pathway. Mechanistically, we show that the elevation of PolΘ levels in response to HPV16 E6 expression is dependent on the host E3 ubiquitin ligase UBE3A/E6AP but is independent of p53 degradation. E6 redirects UBE3A to enhance the ubiquitination and degradation of RAD23A, a shuttle protein required for delivering polyubiquitinated PolΘ to the proteasome. Consequently, the loss of functional RAD23A phenocopies the effect of HPV16 E6, leading to PolΘ protein stabilization and increased MMEJ activity. By elucidating the E6-UBE3A-RAD23A-PolΘ axis, our findings reveal a mechanism through which HPV manipulates the host DNA repair machinery to promote its integration and oncogenic potential.

La-Ni-MOF(BDC) composite with graphene oxide for enhanced bifunctional electrocatalysis in electrochemical water splitting

ABCC1 protects skin dendritic cells from FITC-induced toxicity by efflux and extracellular glutathione buffering

Dendritic cell (DC) migration is critical for initiating adaptive immune responses. Previous work suggested a role for ATP-binding cassette transporter C1 (ABCC1) in skin DC migration following cutaneous fluorescein isothiocyanate (FITC) exposure, but the precise mechanism involved was unclear. Here, we establish that the primary contribution of ABCC1 to skin DC function following FITC exposure is not modulation of migration, but enhancement of survival. Our findings demonstrate that ABCC1 operates on a dual level: Intracellularly, by transporting toxic FITC and fluorescein out of DCs, and extracellularly, by contributing to a glutathione (GSH) buffer zone that protects surrounding cells. DCs are particularly susceptible to FITC-mediated toxicity, possibly due to their high endocytic activity. This study elucidates the critical dependence of DCs on ABCC1 and extracellular GSH for resistance to toxic organic molecules and thereby identifies potential therapeutic avenues targeting ABCC1 to modulate immune responses.

Integrated spatio-temporal modeling with hybrid graph convolutions and the graph fourier neural operator for traffic prediction

A theoretical index for understanding distinct land relative humidity trends in observations, reanalyses, and models

Land surface relative humidity (RH) is a key variable in the coupled land–atmosphere system that profoundly influences terrestrial hydroclimate and ecosystems. Yet historical changes in land RH are not well understood due to limited observations, biased reanalyses, and the lack of a framework for interpreting RH changes under multiple influencing factors. Here, we show that the spatiotemporal variability of land RH and its distinct historical trends among observations, reanalyses, and Earth system models are captured by a simple index based on the ratio of precipitation (P) to a modified potential evapotranspiration formulated independently of RH ( P E T o ). The index provides a physical calibration of biased land RH in reanalyses and a quantitative framework for interpreting land RH changes. Over 1973–2024, land RH has decreased substantially, owing to the intrinsic rise in P E T o with temperature and little increase in land precipitation. Reanalyses overestimate the observed RH decrease, consistent with exaggerated surface warming and precipitation decline. The index captures this coherent bias and enables a calibration using observed precipitation and temperature. Models simulate a wide range of land RH trends, but nearly all runs underrepresent the historical drying. The index captures the model spread and discrepancy and attributes them to contributions of precipitation and P E T o . Weaker land RH decreases in models arise mainly from weaker subtropical precipitation declines, linked to muted intensification of subtropical highs and biased subtropical climatology. The model–observation discrepancy is unlikely explained by internal variability, implying model underestimation of forced RH decrease and a drier land future than current projections.

HIF3A-mediated aberrant activation of TXNIP promotes Alzheimer’s disease progression

Loss of function of the chromatin remodeling gene <i>INO80D</i> leads to neurogenic features of schizophrenia

Schizophrenia has been linked to severely damaging de novo mutations in synaptic junction proteins, neurotransmitter receptors, transcription factors, and chromatin remodeling proteins. In a patient with schizophrenia in the absence of a family history of severe mental illness, we identified de novo nonsense mutation, INO80D p.Q568X, associated with both a truncated protein and partial nonsense-mediated decay. Three experiments were undertaken to evaluate the consequences of the mutation. 1) In neural stem cells (iNSCs) differentiated from WTC11 iPSCs, CRISPRi knockdown of INO80D led to downregulation of three subunits of the AMPA-glutamate receptor, of multiple genes mutant in schizophrenia, and of genes of synaptic function. 2) INO80D p.Q568X iNSCs and neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) had significantly lower expression of neurogenesis genes compared to patient-derived cells with the mutation corrected by CRISPR-Cas9 gene editing. Patient-derived INO80D p.Q568X neurons had significantly higher expression of cell division genes compared to lines with the mutation corrected, consistent with the possibility that some of these cells may be undergoing mitosis, which is not normal for neurons. 3) Finally, on microelectrode array (MEA) plates, WTC11-derived glutamatergic neurons with reduced expression of INO80D had more rapid firing rate and increased average network burst duration, both features of neurons derived from patients with neurodevelopmental disorders. Overall, these findings suggest that partial loss of INO80D function due to de novo mutation may have disrupted normal neurodevelopment and contributed to the schizophrenia of this patient.

Distilling population specific expertise into a unified model for generalizable brain tumor segmentation

Direct evidence of acid-driven protein desolvation

Water and its ability to modulate the protonation states of biomolecules govern the physical chemistry of life, dictating their metabolic functions. However, how amino acid protonation alters protein hydration and solubility is an open question since Kuntz and Kauzmann proposed p H -driven protein desolvation in 1974. Here, in a series of high-resolution cryoelectron microscopy structures of a protein complex at different p H values (from p H 9.0 to 3.5), we examined thousands of observable hydration sites. Cryoelectron microscopy data, in agreement with constant-p H molecular dynamics simulations, show that nearly half of protein-bound waters exchanged with the bulk solvent upon acidification, with ~100 waters lost per p H unit per molecule. The loss of waters was most significant around the side chains of glutamate and aspartate residues while specific polar residues, mostly asparagine, anchored persistent waters. A positionally conserved hydration layer was observed across all p H conditions, accounting for 40% of resolved waters. Those waters displayed denser packing than less persistent waters, forming a p H -independent solvation shell. Acid-induced water exchange also displaced bound iron, providing a mechanistic link between solvation and metal release. Our findings demonstrate the core principles of acid-driven protein desolvation, resolving a 50-y-old biochemical hypothesis.

A lightweight CNN for enhanced non-small cell lung cancer classification using CT scan image

Disruption of a selective vesicle pool upon retrograde amnesia dissociates memory at presynaptic terminals

A single learning episode induces both labile and consolidated forms of aversive olfactory memory in Drosophila melanogaster . Retrograde amnesia triggered by post-learning perturbations specifically impairs the labile memory. However, synaptic mechanisms for this selectivity remain elusive. Here, we show that diverse amnestic treatments, such as concussion, commonly disrupt the presynaptic clustering of Synapsin, which is required for anesthesia-sensitive memory. Consistently, targeted knockout of synaptojanin , a key regulator of the endocytic pathway, selectively impaired labile memory and the Synapsin-associated vesicles. In contrast, we identified Rab3, a small GTPase that regulates the late steps of vesicle exocytosis at the active zone, as selectively required for anesthesia-resistant memory. Rab3 hyperactivation enhanced its association with vesicles while displacing Synapsin. Strikingly, this manipulation biased memory toward stabilization at the cost of the labile component. We thus propose distinct vesicle pools at the presynaptic terminal underlie the formation of labile and consolidated memories. Thus, our work offers a molecular framework for controlling memory stability through targeted manipulation of vesicle dynamics.

A photovoltaic maximum power point tracking strategy based on the IRBMO-VP&amp;O algorithm

Reactivation of the silenced <i>BASP1</i> gene suppresses oncogenic WNT signaling in human colorectal cancer cells

Starting from human colon cancer cells showing aberrant WNT/β-catenin/TCF signaling, hyperactivated MYC, and silenced BASP1 , we generated stable cell lines overexpressing BASP1 , either ectopically, or by reactivating the dormant BASP1 promoter using a lentiviral CRISPR-based system. BASP1 encodes a neuronal signaling protein and transcriptional corepressor, from which tumor-suppressive functions have been described in avian cell systems and in multiple human cancer cell types. Proteome and transcriptome analyses revealed activation of several tumor and metastasis suppressors in BASP1-expressing cells, which also show strong repression of the transformed phenotype in terms of contact inhibition, anchorage-independent growth, and tumor formation. Cells with reactivated BASP1 display a flat and differentiated morphology with enhanced migratory potential, accompanied by expression of multiple genes implicated in actin polymerization, focal adhesion, and neuronal migration. Furthermore, MYC protein expression is substantially repressed due to BASP1-mediated transcriptional MYC downregulation involving BASP1 interaction with β-catenin and binding to the MYC promoter. Upon BASP1 activation, multiple key proteins of the canonical WNT signaling pathway become suppressed. One of these BASP1 targets is the protein kinase TNIK catalyzing phosphorylation of TCF7L2, the latter required for transcriptional MYC activation. Results obtained with a preclinical TNIK inhibitor in human colorectal cancer cells show efficient abrogation of MYC expression and consequently impaired dimerization with its interaction partner MAX. The antagonistic BASP1 effect on MYC and the MYC dependency on TNIK could enhance the development of strategies to interfere with oncogenic functions of the cancer driver MYC.

Label-free multiphoton microscopy and machine learning for recognition of hepatocellular carcinoma

Abstract Complete tumor resection is crucial in oncological liver surgery, and the evaluation of intraoperative resection margins is essential to prove R0 resection. This can be challenging for hepatocellular carcinoma (HCC) due to the heterogeneity of both the tumor and background liver tissue. Label-free multiphoton microscopy (MPM) enables tissue analysis based on endogenous optical signals, and has the potential for intraoperative real-time assessment of resection planes. Matched samples of human HCC and background liver tissue from 76 patients were imaged using a multimodal approach, including coherent anti-Stokes Raman scattering, two-photon autofluorescence, and second harmonic generation. The morphological information contained in each channel was reduced to 17 texture parameters that were used for classification. A neural network model was trained on approximately 25,000 images (35 patients) and used to classify a test set of approximately 27,000 images (38 patients) as well as create maps showing the tumor border (3 patients). Label-free MPM revealed HCC growth patterns as well as steatotic and desmoplastic features. Accurate tumor recognition was achieved on low-lateral-resolution MPM images, mimicking the use of endoscopes. The model achieved a test set correct rate of 97.3% (98.2% for liver and 96.5% for tumor). Analysis of the contribution of the different nonlinear signals to the classification showed that autofluorescence plays a key role in discriminating between neoplastic and non-neoplastic tissue. In conclusion, label-free intraoperative optical histopathology of HCC has the potential to improve tumor resection margins. By implementation in endoscopes, MPM may enable on-site tissue analysis for optimization of tumor identification or characterization of liver tissue.