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Wu, J.

Publications and source records attributed to Wu, J..

At least 181 records · Page 10Linked to original sources

A Benchmark of Evo2 Genomic AI Models for Efficient and Practical Deployment

The rapid advancement of DNA foundation language models has brought about a transformative shift in genomics, allowing for the deciphering of intricate patterns and regulatory mechanisms embedded within DNA sequences. The genomic foundation model Evo2 demonstrates remarkable capabilities in decoding DNA functional patterns through cross-species pretraining. However, despite the great potential of Evo2 in basic genomics research, there is currently no clear and systematic guidance on its specific application scenarios, performance, and optimization directions in the field of tumor genomics, and its performance dependency on specialized hardware (such as FP8 precision on H800 GPUs) has not been empirically benchmarked. Here, we present a focused validation of Evo2 using two independent cancer genomic datasets (Bladder Urothelial Carcinoma and Ovarian Cancer), we tested the downstream tasks of Evo2, including the prediction of tumor pathogenic variants and the prediction of mutational effects, and compared its performance on A100 and H800 GPUs. The results show that critical importance of FP8 precision, enabling the H800 to achieve a 4x faster inference speed than the A100 with stable accuracy (AUC 0.88-0.95). The 7B-parameter model emerged as the top performer, whereas the 40B model experienced a severe performance drop (AUC to 0.48) on non-FP8 hardware like the A100. These findings empirically validated Evo2s hardware specifications and provided practical insights for researchers implementing the model with similar computational resources. Futhermore, our findings provide a framework for the application and optimization of downstream tasks of the DNA language model Evo2 in cancer, and can guide researchers in effectively applying it in genomic studies. Key PointsO_LIHardware Precision Impact: FP8 precision on H800 GPUs is critical for Evo 2s performance, enabling 4x faster inference than A100 (without FP8 support) while maintaining high accuracy (AUC 0.88-0.95). C_LIO_LIModel Scale Optimization: The 7B-parameter model outperformed larger variants (e.g., 40B), which suffered severe accuracy drops (AUC as low as 0.48) on non-FP8 hardware, highlighting a balance between efficiency and performance. C_LIO_LIPractical Guidelines: We provide a framework for deploying Evo 2 in cancer genomics, including hardware recommendations, dataset curation, and downstream task optimization--valuable for researchers with varied computational resources. C_LI

genomics↗

Synthesis and Characterization of ULK1/2 Kinase Inhibitors that Inhibit Autophagy and Upregulate Expression of Major Histocompatibility Complex I for the Treatment of Non-Small Cell Lung Cancer

Autophagy inhibition represents a promising therapeutic approach for the management of various cancers including non-small cell lung cancer (NSCLC). We previously reported SBP-7455, a dual inhibitor of unc-51-like kinase 1 (ULK1) and its homologue ULK2, and described its effects on triple-negative breast cancer (TNBC) cells. Herein we report the design, synthesis, and characterization of SBP-5147 and SBP-7501, two new dual ULK1/2 inhibitors that are cytotoxic against NSCLC cells, inhibit autophagic flux in A549 cells, and present greater oral exposure than SBP-7455 at a lower dose. In addition, SBP-5147 effectively modulates autophagy and increases the expression of major histocompatibility complex (MHC) class I in NSCLC cells, which may support the rationale for ULK1/2 inhibition as a strategy to overcome resistance to immunotherapy. Together these data support the use of ULK inhibitors as part of a cancer treatment strategy, both as a single agent as well as in combination with current therapies.

cancer biology↗

Tartrate-resistant acid phosphatase (TRAP/ACP5) sex-specifically regulates bone maintenance in old mice, but the anabolic effects of mechanical loading is regulated in a sex-independent way

Tartrate-resistant acid phosphatase (TRAP/ACP5), primarily known as an osteoclast marker, has emerged as a critical regulator of skeletal integrity, regulating sex-specific bone growth, and bones response to mechanical load in young adult male mice. In this study, we investigated the sex-specific roles of TRAP in bone structure and response to mechanical stimuli in old (19-month-old) wild-type (WT) and TRAP-deficient (TRAP-/-) mice using micro-computed tomography, serum bone turnover markers, in vivo axial mechanical loading, and in vitro mechanotransduction assays. Our findings revealed that TRAP-/- mice of both sexes maintained shorter tibiae than WT mice independent of sex. Notably, male, but not female, TRAP-/- mice have increased trabecular bone volume fraction and cortical bone area compared to WT, indicative of disrupted bone remodelling processes in male mice. Interestingly, TRAP-deficiency substantially impaired the anabolic bone response to mechanical loading, affecting both trabecular and cortical compartments in both sexes, indicating that when challenged, TRAP is important for bone formation also in female mice. Mechanical stimulation in vitro of hematopoietic progenitor cells from WT and TRAP-/- mice revealed that the increased ATP-release in response to mechanical stimulation was only disrupted in male mice, while mechanically induced increase in osteoclast formation was inhibited in TRAP-/- mice of both sexes. These results highlight the importance of TRAP in maintaining trabecular architecture and cortical bone in male mice and underscore its critical function in mediating adaptive responses to mechanical loading of both sexes, during aging. Future investigations should focus on elucidation of TRAP-dependent pathways as potential therapeutic targets to counteract age-related deficits in bone adaptation and remodelling.

developmental biology↗

Real-time in vivo imaging of rodent brain response to hypoperfusion enabled by remotely controlled elastomeric micro-balloons

Current preclinical models of ischemic stroke in mice do not permit simultaneous and continuous in vivo brain imaging during the peri-stroke period, therefore missing critical pathophysiological events that could be pivotal for stroke management at the early stage. Here we report remote control of the blood flow of cerebral arteries in live mice continuously at different states to induce stroke in a precise, reliable, and reversible manner. The sub-millimeter scale micro-balloons can expand more than four times their initial diameter, featuring a monolithic elastomeric wall with selectively stiffened regions for controlled inflation and elasticity depending on the target vessels. By allowing for the control of common carotid artery diameter through a cuff pressing against the artery, the micro-balloon recapitulates clinically relevant haemodynamics in a mouse model of global brain ischemia, evidenced by real-time imaging of the brain through intravital microscopy and magnetic resonance imaging. The presented micro-balloons hold significant potential to improve the treatment of stroke patients for minimally invasive intervention and in vivo imaging of the pathophysiological events in the peri-stroke phase.

bioengineering↗

Extracellular Vesicles of Salivary Mesenchymal Stem Cells Mitigate Acute Irradiation Injury: Use of an ex-vivo organotypic human slice tissue culture as a disease model

AbstractIonizing radiation (IR) therapy for cancer patients can damage surrounding healthy tissues, particularly the salivary glands (SGs), leading to oral and systemic health issues reducing the quality of life of the patients. The mechanisms behind IR damage in SGs are not fully understood, and current therapies often fail to meet patient needs adequately. Therefore, identifying targeted pathways and alternative treatments is essential. To address this, we developed an ex vivo model of SG damage using human salivary glands obtained from patients. Healthy submandibular glands were harvested, cultured, and exposed to IR. RNA sequencing revealed elevated markers for DNA damage, inflammation, and ferroptosis, with four specific genes--FDXR, MDM2, H2AX, and p21--showing increases in expression that correlated with the IR dose. Using them, we developed a high-throughput genetic screening method to evaluate stem cell therapies aimed at mitigating IR injury. Conditioned media from mesenchymal stem/stromal cells (MSC-CM) were found to reduce the expression of all four markers, maintain tissue viability, promote cell proliferation, and decrease oxidative stress. Further analysis involved separating MSC-CM into two fractions: Extracellular Vesicles (EV)-rich and EV-depleted. The EV-depleted fractions retained elevated levels of DNA damage response markers, indicating that EVs play a crucial role in mediating tissue repair. In contrast, the EV-rich fractions reduced the markers of DNA damage response and were readily absorbed by the tissue slices. In conclusion, we have developed a genetic screening method to evaluate treatments for acute IR injury, emphasizing the significant role that EVs play in the repair process.

molecular biology↗

Response-driven Serial Dependence: When Response Mode Consistency Matters More than Shared Memory Encoding

Serial dependence - the bias from recent experience on present response - is often linked to shared memory representations. Yet, it remains unclear whether this bias across tasks when stimulus features are shared but response modes differ. To test this, we interleaved temporal reproduction and bisection tasks using a post-cue design that held duration encoding constant while varying motor output across trials. Using structural equation modeling (SEM), we dissociated perceptual (stimulus-driven) and decisional (response-driven) components of serial dependence. With consecutive same tasks, we replicated repulsive perceptual serial dependence and attractive decisional carryover. Critically, these effects vanished across tasks, despite identical stimulus processing - suggesting that consistent motor responses, not shared memory alone, drive sequential biases. Moreover, SEM uncovered repulsive perceptual influences that standard regression missed, highlighting its power to isolate overlapping effects. Together, these findings reveal that response-specific reactivation underpins serial dependence, pointing to motor-context binding as a key factor in temporal decision-making.

neuroscience↗

Structural insights and engineering of deep-sea halophilic PET hydrolytic enzymes

Pervasive use of polyethylene terephthalate (PET) poses tremendous challenges for global waste management and environmental sustainability, fueling growing interests in enzymatic degradation as an eco-friendly solution. While PET hydrolases hold significant promise, their industrial deployment is hindered by insufficient performance, particularly under high-salinity conditions raised from high substrate loads. Building on our previous discovery of three deep-sea PET hydrolases (dsPETase01, dsPETase05 and dsPETase06) with exceptional halophilicity and PET-degrading activity, we here present their three-dimensional structures and mechanistic characterization. Structural comparison, site-directed mutagenesis, and domain swapping reveal key structural features and the essential role of C-terminal acidic residues in salt tolerance. Integrating semi-rational protein design, Transformer-based modeling, and disulfide bond engineering, we synergistically enhance the thermostability and catalytic efficiency of dsPETase05. These findings elucidate the unique structural features and salt adaptation mechanisms of deep-sea halophilic PET hydrolases, and inform the future engineering of biocatalysts for application in harsh industrial environments.

molecular biology↗

Acoustic Transparency Enabling Functional Ultrasound Imaging Through Mouse and Human Skulls

Ultrasound is one of the most widely used non-invasive imaging modalities for internal organs, yet its application to the brain has been hindered for decades by the skulls acoustic barrier. This same barrier has kept functional ultrasound imaging (fUSI)--an emerging technology capable of capturing brain-wide neural activity in real time at sub-100 m resolution--from reaching its transformative potential in neuroscience and clinical medicine. Here, we present an acoustic transparency strategy by modulating skull acoustic properties, to render the brain visible to ultrasound. A brief topical application of an FDA-approved chelating agent matches the skulls acoustic impedance and sound speed to those of soft tissue, enabling nearly complete ultrasound transmission (94.0 {+/-} 4.4%) with minimal energy loss or distortion. Leveraging this discovery, we developed an acoustic-transparent fUSI platform that maps brain activation across the full brain depth at [~]20 m spatial resolution without skull removal. This method enables safe, longitudinal brain imaging, is fully reversible, and is demonstrated to be applicable to the ex vivo human skull. This conceptually distinct paradigm--controlling acoustic wave propagation via acoustic property modulation--offers a practical and generalizable solution to one of the most persistent obstacles in transcranial ultrasound imaging, opening the door to broader clinical and research application of ultrasound neuroimaging.

bioengineering↗

Translation control by altered start codon usage as a means of modulating the general stress response and virulence in Listeria monocytogenes.

In the food-borne pathogen Listeria monocytogenes, SigB is the central regulator of general stress response (GSR) and it mediates host entry by promoting acid resistance and epithelial cell attachment. The post-translational regulation of SigB activity is complex and is controlled by multiple genes. There is significant evidence that mutations can readily arise in these regulatory genes, or in sigB itself, leading to reduced SigB activity, which suggests that there is considerable genetic plasticity In the GSR. To further investigate this, we defined the complete genome sequence of a clinical isolate with attenuated SigB activity and investigated how it adapts to lethal acidic challenge (mimicking the selective pressure encountered during entry into the host). Acid resistance developed rapidly and 6 acid resistant derivatives (ARDs) were selected for further investigation. All 6 ARDs restored SigB activity due to mutations acquired in rsbW, which encodes an antagonist of SigB. These mutations resulted in non-canonical start codons (rsbWATG to rsbWATA or rsbWATT) or premature translation termination (rsbW-). A translational reporter assay demonstrated distinct differences in translation efficiency between three start codons: ATG>ATA>ATT, suggesting that a perturbation of RsbW:SigB stoichiometry alters SigB activity. We then analysed start codon usage for all conserved genes in 60,692 L. monocytogenes genomes available in the NCBI database. This analysis revealed flexible usage of start codons associated with genetic clades in 39 conserved genes, 13 of which are involved in virulence and stress response. Further, we show that flexible use of canonical start codons (ATG and GTG) also mediates different levels of expression of virulence and stress response genes. Taken together, we show the genetic plasticity of GSR regulation in a model pathogen, and highlight the importance of translational control as a means of fine-tuning gene expression during short-term adaptation and long-term evolution for optimal fitness. Author SummaryThe general stress response (GSR) in foodborne pathogen Listeria monocytogenes is important for environmental stress response and for host entry, but GSR is also highly variable across wild isolates. In this study, we analysed the evolutionary trajectory of a clinical isolate with attenuated GSR and characterized the adaption by this strain to a host-mimicking stress (acidic condition). Under extreme selective pressure, mutations disabling a negative regulator of the GSR were enriched. Interestingly, several independently occurring mutations negatively affect the translation initiation by using non-canonical start codons. Prompted by this, we analysed the population-wide start codon usage by examining all available L. monocytogenes genomes available (n = 60,690). This analysis revealed differential start codon usage in 39 conserved genes that are associated with different genetic clades. Furthermore, we demonstrated differential translation efficiencies between the different canonical start codons. This work highlights the genetic plasticity of GSR in the important food-borne pathogen L. monocytogenes and shows that altered translational start codon can be used as means of regulatory control. Together the data suggest that genetic changes in the regulation of the GSR might confer niche-specific fitness advantages.

microbiology↗

GASPS: A Multi-Omics Framework for Defining Genomic Aberration-Driven Signatures and Predicting Patient Outcomes in Lung Cancer

Lung cancer is the most common cause of cancer-related death worldwide. Recent advancements in targeted therapies and immunotherapies have achieved remarkable success. However, patient responses to treatments with lung cancer vary substantially. The mutation status of driver genes can direct personalized treatment, but their prognostic value and treatment efficacy are limited. In this study, we developed a statistical framework named Genomic Aberration-Derived Signature for Patient Stratification (GASPS) to characterize the transcriptomic deregulation of driver genomic aberrations and stratify patients. By applying GASPS to The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) data, we developed gene signatures for 38 driver genomic aberrations, including gene mutations, amplifications, and deletions. These signatures were applied to independent lung cancer transcriptomic datasets containing a total of 2,226 patient samples. Our results indicated that these driver gene signatures are much more prognostic than their corresponding genomic mutations. Interestingly, the two EGFR-related signatures characterizing EGFR mutation and amplification, respectively, exhibited contrasting associations with prognosis, treatment response, and immune infiltration in the tumor microenvironment. Moreover, the STK11 mutation signature, rather than the mutation status, was found to be predictive of the response and long-term benefit of patients treated with immune checkpoint blockade therapy in lung cancer. This framework is readily applicable to most cancer types using existing data to improve prognostic risk assessment and treatment efficacy by guiding personalized therapies.

bioinformatics↗

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

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

neuroscience↗

Enhancer Placement Impacts Transcriptional Dynamics in Drosophila Embryos

The functional role of enhancer-promoter configurations in transcription regulation remains poorly understood, despite the wide range of linear genomic distance and relative enhancer positioning observed in endogenous contexts. While canonical models suggest that enhancers operate independently of genomic position, technical limitations have obscured insights on transcriptional kinetics. Here, we employ single-cell MS2/MCP-based live imaging in Drosophila embryos to systematically analyze transcriptional dynamics driven by sub-10kb enhancer-promoter arrangements. Kinetic analyses reveal that while linear enhancer-promoter distance moderately tunes transcriptional output, downstream enhancer positioning reduces mRNA output by 70%. Each configuration modulates distinct transcriptional parameters: linear distance governs initiation kinetics, while relative enhancer positioning dictates transcriptional stability. These effects are consistent across varied enhancer and reporter sequences, revealing configuration-dependent cis-regulatory element arrangement as an intrinsic mechanism for transcriptional fine-tuning. This work challenges the paradigm of configuration-independent enhancer function and establishes a framework to dissect the interplay between genome architecture and trans-acting factors.

molecular biology↗

A Reproducible Supermicrosurgical Model of Cervical Lymphatic-Venous Anastomosis in a Transgenic Alzheimer's Mouse: Technical Translation, Proficiency, and a Validated Learning Curve

BackgroundCervical Lymphatic-Venous Anastomosis(LVA) holds therapeutic potential for Alzheimer disease (AD). However, a validated AD animal model for preclinical investigation remains lacking. This study aimed to establish and standardize LNVA, as a form of lymphatic-venous Anastomosis, in a murine AD model; to quantitatively assess its surgical learning curve; and to create a platform for mechanistic exploration and translational research. MethodsWe established and standardized a deep cervical lymph node-to-vein anastomosis (DC-LNVA), a specific type of lymphatic-venous anastomosis (LVA), in rodents. A two-stage training program was applied to a junior surgeon: 60 DC-LNVA procedures were performed in 30 small Sprague-Dawley rats (50-60g), followed by 20 bilateral anastomoses in 10 male 5XFAD mice. Surgical proficiency was evaluated using procedure time, UWOMSA scoring, and CUSUM analysis. Anatomical parameters were assessed with ImageJ. Anastomotic patency was confirmed via ICG lymphangiography. Intranasal Evans Blue was used to trace cranial distribution pathways. ResultsSD rats had significantly larger external jugular veins (0.376 {+/-} 0.013 mm vs. 0.228 {+/-} 0.011 mm) and DCLNs (1.359 {+/-} 0.084 mm2 vs. 0.333 {+/-} 0.022 mm2) than mice (P < 0.0001). Proficiency was achieved after 27 anastomoses in rats and 10 in mice. ICG confirmed 100% patency in 9 surviving 5XFAD mice. Evans Blue suggested a nasal-cranial pathway for tracer distribution. ConclusionWe developed and validated a cervical lymphatic-venous bypass (LVA) in transgenic AD mice. This platform complements existing loss-of-function approaches and offers a foundation for mechanistic and translational research into brain lymphatic clearance.

animal behavior and cognition↗

Machine Learning Guided Structure Activity Discovery of Polymer Configurations in Lipid Nanoparticles for Kiss-and-Run Endosomal Escape

Endosomal escape remains a major barrier to effective nucleic acid delivery via lipid nanoparticles (LNPs). Here, we address this challenge by incorporating a pH-sensitive polymer, polyhistidine, into LNPs (pLNPs) to facilitate endosomal escape, with a focus on optimizing the polymers molecular weight (MW) and configuration--parameters that remain largely unexplored. Through systematic engineering, we designed linear and branched polyhistidine architectures with varied MWs and configurations. In vivo screening identified an optimized pLNP formulation incorporating a symmetrical bis-lysine histidine dendron with a MW of [~]1800 g/mol, which achieved a 266-fold increase in liver bioluminescence following intravenous delivery of luciferase mRNA compared to standard LNPs at an equivalent RNA dose. Mechanistic studies revealed that polymer configuration within pLNPs is critical for eliciting the proton sponge effect, leading to osmotic swelling and endosomal rupture. This configuration also promoted rapid endosomal membrane destabilization via a kiss-and-run mechanism, enabling efficient cytosolic release. When delivering base editor mRNA and single-guide RNA, the optimized pLNPs achieved 8% gene editing efficiency in the mouse liver at a low dose of 0.1 mg/kg, compared to 1% with standard LNPs. To accelerate discovery and address macromolecular design challenges, we developed a machine learning (ML) framework based on amino acid-level graph neural networks (GNNs). This approach identified branched, dendritic configurations with densely arranged histidine residues on a multivalent core as key determinants of delivery performance. The top ML-predicted candidate, NS535, achieved a 705-fold increase in liver bioluminescence over standard LNPs, validating our data-driven design strategy. Together, these findings establish a closed-loop platform integrating rational design, mechanistic validation, and ML-guided optimization to advance RNA delivery. By elucidating structure-activity relationships for polyhistidine carriers and demonstrating efficient, low-dose genome editing, this work provides a blueprint for next-generation nucleic acid therapeutics.

bioengineering↗

Bottlebrush Polymer Conjugates for Enhanced Antisense Oligonucleotide Therapy in Myotonic Dystrophy Type 1

Oligonucleotides are a promising genetic medicine for myotonic dystrophy type 1 (DM1), the most common adult-onset muscular dystrophy. However, poor muscle distribution of nucleic acid drugs after systemic administration has hindered drug development, and no curative treatment exists. Additionally, DM1 pathology requires drug localization to the nucleus, where pathogenic mutant RNA is trapped, posing challenges after endocytosis and endosomal escape. Here, we show that a locked nucleic acid oligonucleotide targeting mutant CUGexp RNA tracts, conjugated to a bottlebrush polymer, exhibited improved muscle distribution and potent correction of DM1-associated splicing at low nanomolar doses in a DM1 mouse model. Significant improvements in myotonia, body weight, and grip strength were observed. The conjugates were well tolerated after 12 weeks of weekly intravenous dosing. These results suggest that bottlebrush polymer bioconjugates may overcome key limitations of traditional antisense drugs for muscular dystrophies, with the potential as potent, durable, and cost-efficient DM1 therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/668589v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@e3961corg.highwire.dtl.DTLVardef@194225dorg.highwire.dtl.DTLVardef@5c470dorg.highwire.dtl.DTLVardef@3cc46a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

Modeling structural variations sequencing information to address missing heritability and enhance risk prediction

Missing heritability remains a significant challenge in genome-wide studies focused on single nucleotide polymorphisms (SNPs) when analyzing the genetic basis of complex traits. Structural variations (SVs), which span broader genomic regions and often exert larger functional impacts than SNPs, hold promise for capturing this heritability. Although graph-based pangenomes have advanced SV detection and association analysis, traditional SNP-centric frameworks typically overlook detailed SV sequence information, treating overlapping SVs as independent variants and leading to reduced statistical power. To overcome this limitation, we developed SVrefiner, an algorithm that aligns overlapping SVs and partitions them into non-overlapping refined SVs (rSVs) based on sequence congruence. By generating precise genotype matrices, SVrefiner enables more accurate association studies. When applied to human, tomato, and pig genomes, SVrefiner delineated 48,712 rSVs from 77,696 human SVs, 6,607 rSVs from 51,561 tomato SVs, and 5,237 rSVs from 142,784 pig SVs. Incorporating rSVs alongside SNPs, indels, and unrefined SVs enhanced heritability estimates by up to 24.47%. Further, refined analysis revealed that gene expression traits are often influenced by specific SV subregions rather than entire SVs. Notably, integration of rSVs in human datasets increased total eQTLs by 71.56%, with cis- and trans-eQTLs rising by 21.3% and 94.4%, respectively. Mean risk prediction accuracy across over 16,000 traits improved by as much as 16.8%. These findings deepen the understanding of complex trait heritability and demonstrate the utility of rSVs for genetic improvement and disease risk assessment.

genetics↗

TRPM7 Annexin A1 Mechanosensitive Pathway Drives Capillary Infiltration by Circulating Tumor Cells

Successful metastatic dissemination requires tumor cells to overcome significant physical barriers. When circulating tumor cells (CTCs) become lodged in capillary beds, studies reveal that only a small subset can adapt to fluid shear stress (FSS) within the constricted vasculature. These rare, mechanically resilient cells may subsequently extravasate and form metastatic lesions, but details on this adaptation of the physical environment and its molecular basis are not well understood. Utilizing a microfluidics platform that mimics microcirculatory dynamics, we discover that only breast cancer cells with high metastatic potential maintain directional migration under physiologically relevant FSS conditions. This highlights the mechanical selection process of metastatic precursors during hematogenous dissemination. We identify the TRPM7-Annexin A1-actin signaling pathway as essential for overcoming physical barriers and regulating cell motility under capillary FSS. FSS prompts cytoskeletal reorganization and actin disassembly, restricting cell movement. Cancer cells respond to this by increasing mechanical loading, activating TRPM7 and triggering calcium influx, which then activates Annexin A1. This calcium-dependent protein, Annexin A1, interacts with the actin cortex to prevent FSS-induced actin disassembly, thus aiding migration. Experiments conducted in mouse liver capillaries validate the critical role of this pathway in cancer cell motility. Additionally, we propose a mechano-pharmacological strategy using FTY720 to target the TRPM7 pathway, highlighting its therapeutic potential to modify CTC receptor specificity and inhibit distant metastasis.

cancer biology↗