Shicheng Guo

Shicheng Guo

@shihcheng.bsky.social

Senior Director, Translational Genetics and Data Science, Translational Medicine | Data Science | Computational Biology | Drug Discovery. Opinions are my own! Linkedin: https://www.linkedin.com/in/shg047/

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Shicheng Guo
@shihcheng.bsky.social

We are seeking for a 𝗦𝗲𝗻𝗶𝗼𝗿 𝗦𝗰𝗶𝗲𝗻𝘁𝗶𝘀𝘁 (𝗧𝗿𝗮𝗻𝘀𝗹𝗮𝘁𝗶𝗼𝗻𝗮𝗹 𝗚𝗲𝗻𝗲𝘁𝗶𝗰𝘀 & 𝗥𝗲𝗮𝗹-𝗪𝗼𝗿𝗹𝗱 𝗘𝘃𝗶𝗱𝗲𝗻𝗰𝗲) at 𝗔𝗿𝗿𝗼𝘄𝗵𝗲𝗮𝗱 𝗣𝗵𝗮𝗿𝗺𝗮𝗰𝗲𝘂𝘁𝗶𝗰𝗮𝗹𝘀, our 𝗧𝗿𝗮𝗻𝘀𝗹𝗮𝘁𝗶𝗼𝗻𝗮𝗹 𝗚𝗲𝗻𝗲𝘁𝗶𝗰𝘀 & 𝗗𝗮𝘁𝗮 𝗦𝗰𝗶𝗲𝗻𝗰𝗲 team. www.linkedin.com/posts/shg047...

Shicheng Guo
@shihcheng.bsky.social

Fibronectin overactivation of αVβ3-PI3K-PIP3-PDK1-ILK signaling boosts AKT-NOS2, driving aortic disease in Marfan syndrome. Time for a treatment breakthrough! PMID:42409814, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-74707-4 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

doi.orgFibronectin-induced overactivation of αVβ3-PI3K-PIP3-PDK1-ILK signaling drives aortic disease in Marfan syndrome | Nature CommunicationsThoracic aortic aneurysms and dissections (TAAD), a life-threatening complication of Marfan syndrome (MFS), lack curative therapies. Our previous studies revealed that versican accumulation drives MFS aortopathy through AKT-NO pathway overactivation, but the upstream mechanisms remained unclear. Here, we show that versican-driven fibronectin (FN) accumulation activates an αVβ3-PI3K-PIP3-PDK1-ILK signaling cascade leading to AKT-NOS2 upregulation and aortic disease. FN accumulates in aortas of MFS patients and mice of both sexes and correlates with increased αVβ3 integrin and ILK expression. Disrupting FN assembly or inhibiting αVβ3, PI3K, PIP3, PDK1 or ILK prevents FN-induced AKT activation and NOS2 upregulation, restores vascular contractility, and limits aortic dilation in MFS mice. Inhibition of ILK or PDK1, aortic silencing of Ilk, or smooth muscle-specific deletion of Ilk reverses or prevents aortic growth. Together, these findings define a mechanistically integrated FN-αVβ3-PI3K-
Shicheng Guo
@shihcheng.bsky.social

Explore how the MLH1 C-terminal domain uniquely interacts with FAN1's MIP and MIM motifs. Crystal structures reveal key insights into Huntington's regulation. PMID:42409804, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-74991-0 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

doi.orgStructural insights into the MLH1–FAN1 interaction reveal an uncharacterized binding interface on MLH1 | Nature CommunicationsHuntington’s disease is driven by CAG repeat expansion in the mutant huntingtin gene. Nuclease FAN1 and mismatch repair protein MLH1 regulate repeat expansion through direct interaction, but the underlying structural basis remains unclear. Here, we show that the MLH1 C-terminal domain binds to FAN1-derived peptides containing either the MIP or MIM motif with comparable affinities. Crystal structures of this domain bound to each motif provide structural insights into human MLH1–FAN1 interaction, revealing a conserved mechanism for FAN1-MIP recognition and a previously unrecognized binding site on MLH1, termed the S3 site, for FAN1-MIM engagement. Co-immunoprecipitation assays confirmed that mutation of key MLH1 residues disrupts FAN1 binding in cells. These findings establish the molecular basis of MLH1–FAN1 recognition and provide a structural framework for understanding the regulation of CAG repeat expansion in Huntington’s disease. CAG repeat expansion in the huntingtin gene drives H
Shicheng Guo
@shihcheng.bsky.social

Nearly 3,000 abstracts from ACR Convergence 2026 are now online! A rich resource for exploring emerging targets, disease mechanisms, and clinical advances in rheumatology ahead of the November 6–11 meeting in Orlando. #ACR26 #Rheumatology

Shicheng Guo
@shihcheng.bsky.social

Explore advanced 3D organoid models from iPSCs revealing cell-autonomous and non-cell-autonomous mechanisms in motor neuron diseases, crucial for new therapies. PMID:42410005, Nat Rev Neurosci 2026, @NatRevNeurosci https://doi.org/10.1038/s41583-026-01057-x #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

doi.orgUsing human 3D organoid models to gain mechanistic insight in motor neuron diseases | Nature Reviews NeuroscienceMotor neuron diseases (MNDs) are caused by the progressive loss of motor neurons and eventually lead to paralysis and death. Once viewed as primarily neurocentric, MNDs are now recognized to be driven by intertwined cell-autonomous and non-cell-autonomous mechanisms. Dissecting these interactions is essential for developing effective therapies. Here, we describe induced pluripotent stem cell-derived 3D models that can be used to capture distinct aspects of MND pathology. We show that spinal cord organoids can be used to investigate cell-autonomous mechanisms and motor neuron–glia interactions (with axially elongated spinal cord organoids being particularly useful to study developmental vulnerability) as well as in 3D muscle and combined neuromuscular models to dissect muscle pathology and neuromuscular junction dismantling. In parallel, we discuss advances in bioengineering, machine learning and human trunk-like models, which together can begin to reproduce the coordinated co-deve
Shicheng Guo
@shihcheng.bsky.social

Discover FLOWR.ROOT: a model merging 3D ligand creation and binding predictions (pIC50, pKi, pKd, pEC50) with high-confidence estimation in one. Fascinating, right? PMID:42409794, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-74130-9 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

doi.orgFLOWR.ROOT – A flow matching-based foundation model for joint multi-purpose structure-aware 3D ligand generation and affinity prediction | Nature CommunicationsWe present FLOWR.ROOT, an SE(3)-equivariant flow-matching foundation model that unifies pocket-aware 3D ligand generation with multi-endpoint binding affinity prediction (pIC50, pKi, pKd, pEC50) and pLDDT-based confidence estimation in a single backbone. One trained model supports de novo pocket-conditional generation, interaction- and pharmacophore-conditional sampling, scaffold hopping and elaboration, and fragment growing or replacement, enabled by a mixed isotropic–anisotropic prior placement strategy. Training proceeds in three stages: large-scale pre-training on billions of ligand conformations and millions of mixed-fidelity protein–ligand complexes, refinement on curated co-crystal data, and project-specific adaptation via parameter-efficient LoRA finetuning. Joint structure–affinity modelling enables inference-time importance-sampling guidance for single- and multi-objective design without external scoring functions. Case studies on kinase selectivity (CK2α/CLK3) and scaffold e
Shicheng Guo
@shihcheng.bsky.social

New research reveals that parvalbumin-expressing (BF-PV) inhibitory neurons in the basal forebrain enhance sustained attention, challenging traditional views on cholinergic roles in focus! PMID:42349384, Cell 2026, @Cell https://www.cell.com/cell/fulltext/S009286742600646X #Medsky #Pharmsky #RNA 🧪

cell.comA disinhibitory basal forebrain-to-cortex projection supports sustained attentionCell Press article: A disinhibitory basal forebrain-to-cortex projection supports sustained attention
Shicheng Guo
@shihcheng.bsky.social

Allelic variants of the LRIP1 gene in Arabidopsis provide dual resistance to different pathogens. One variant, found in arid regions, showcases its protective power! 🌱✨ PMID:42409812, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-75012-w #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

doi.orgAllelic variation of an LRR only protein confers dual pathogen resistance in Arabidopsis | Nature CommunicationsPlants utilize versatile leucine-rich repeat (LRR) proteins to perceive diverse pathogen-derived signals, thereby activating or suppressing defense responses. However, the specific roles of LRR-only proteins in pathogen-specific resistance remain largely unclear. Here, we show that allelic variations in an Arabidopsis thaliana LRR-only gene, LEUCINE-RICH REPEAT IMMUNE PROTEIN 1 (LRIP1), underlies dual functions in combating distinct pathogens. An allele common in arid regions confers resistance to Pseudomonas syringae pv. tomato (Pst) bacteria via salicylic acid (SA) signaling pathway, whereas an allele enriched in high-precipitation regions protects against Botrytis cinerea fungus via camalexin biosynthesis. Divergence in promoter and coding sequences between the two alleles modulates gene expression and elicitor-associated immune responses, thereby promoting pathogen-specific complex formation with BRASSINOSTEROID INSENSITIVE 1 (BRI1)-ASSOCIATED RECEPTOR KINASE 1 (BAK1). Globally dis
Shicheng Guo
@shihcheng.bsky.social

Discover how cephalotaxinone enzymes unveil a complete plant model for homoharringtonine biosynthesis! Explore the CET/HHT pathway in Cephalotaxus. 🌿 #Biosynthesis PMID:42410025, Nat Chem Biol 2026, @nchembio @Stanford https://doi.org/10.1038/s41589-026-02260-8 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

doi.orgCephalotaxinone enzymes reveal a whole plant model for homoharringtonine biosynthesis | Nature Chemical BiologyHomoharringtonine (HHT) is a plant-derived protein translation inhibitor used widely in ribosomal profiling and as a treatment for chronic myeloid leukemia approved by the US Food and Drug Administration. HHT is commercially semisynthesized from the alkaloid core cephalotaxine (CET) extracted from endangered Cephalotaxus species. Despite its importance, the CET/HHT biosynthetic pathway remains unresolved. Here, we use paired untargeted metabolomics (stable-isotope precursor feeding) and transcriptomics to elucidate a near-complete CET biosynthesis. We show that, while CET is biosynthesized only in growing root tips, CET and HHT accumulate throughout the plant. We identify seven pathway intermediates and six enzymes—including cytochrome P450s, an atypical short-chain dehydrogenase and a 2-oxoglutarate-dependent dioxygenase—that enable carbon excision and CET/HHT pentacyclic backbone formation to produce cephalotaxinone, the likely direct precursor of CET. This study establishes a metabo
Shicheng Guo
@shihcheng.bsky.social

Bclaf1 is up in HFrEF hearts and mice models. Overexpressing it leads to hypertrophy and dysfunction. Splicing partner Srsf2 enhances these effects. PMID:42409820, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-75125-2 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

doi.orgBclaf1 drives heart failure by recruiting Srsf2 to enhance Hand2 pre-mRNA splicing and pathological hypertrophy | Nature CommunicationsHeart failure with reduced ejection fraction (HFrEF) remains a major therapeutic challenge. B-cell lymphoma 2-associated transcription factor 1 (Bclaf1) is implicated in RNA splicing and cardiac disease, but its role in HFrEF pathogenesis is unknown. Here, we demonstrate that Bclaf1 expression is elevated in human HFrEF myocardium and in male murine pressure-overload models. Cardiac-specific Bclaf1 overexpression drives pathological hypertrophy and systolic dysfunction, whereas its genetic knockout or adeno-associated virus serotype 9 (AAV9)-mediated knockdown attenuates these phenotypes. Mechanistically, Bclaf1 interacts with the splicing factor serine/arginine-rich splicing factor 2 (Srsf2) to bind to heart and neural crest derivatives expressed 2 (Hand2) pre-mRNA and enhance its splicing efficiency, leading to increased mature Hand2 levels and maladaptive remodeling. Inhibition of either Bclaf1 or Hand2 rescues cardiac function and structure in experimental HFrEF. Our work defines a
Shicheng Guo
@shihcheng.bsky.social

Discover cell states in tumors effectively with Statescope! This Bayesian tool uses DNA data for precision, outperforming others in cell fraction and state estimation. 📊 PMID:42409797, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-74997-8 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

doi.orgStatescope: an integrative deconvolution framework for discovering cell states in tumors | Nature CommunicationsAccurate deconvolution of cell states from bulk tumor RNA-seq is hindered by heterogeneous malignant cells specifically in cancer applications. We present Statescope, a Bayesian framework that incorporates DNA-derived malignant cell purity to overcome this heterogeneity and explicitly models inter-sample variation to accurately identify cell states. Comprehensive benchmarking shows Statescope outperforms existing methods in both cell fraction and state estimation, and is unique in its ability to identify states entirely absent from single-cell references. In real-data applications, Statescope successfully recapitulates established cell states, including multiple states in neutrophils, a cell type often missed by single-cell methods in lung cancer. Critically, in the POPLAR/OAK clinical trials, Statescope identifies a combinatorial signature of effector CD8 + T cells and conventional dendritic cell states that together predict a striking survival benefit from immunotherapy. Collectively
Shicheng Guo
@shihcheng.bsky.social

Unlocking insights with Imaging-Derived Phenotypes (IDPs): From MRI, CT, X-rays, these heritable traits reveal genotype-phenotype ties. #GenomicsRevolution PMID:42409965, Nat Rev Genet 2026, @NatureRevGenet @Princeton https://doi.org/10.1038/s41576-026-00989-5 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

doi.orgGenetic analysis of imaging-derived phenotypes | Nature Reviews GeneticsImaging-derived phenotypes (IDPs) developed from medical imaging data, such as magnetic resonance imaging, computed tomography and X-ray scans, are traits that provide quantitative information on anatomical and functional properties of organs and tissues. IDPs are powerful tools for identifying biomarkers and studying disease mechanisms. When coupled with genetic data, IDPs can be analysed as heritable phenotypes using modern gene mapping methods to uncover genotype–phenotype relationships. The field of imaging genomics is rapidly maturing, with the emergence of high-quality imaging datasets collected in biobank-scale cohorts and sophisticated computational methods for extracting IDPs from imaging data, including tools that leverage machine learning. Here we review common imaging modalities and analytical approaches for developing IDPs, discuss biological insights gleaned from the large-scale genetic analysis of imaging traits and highlight emerging areas and remaining challenges that
Shicheng Guo
@shihcheng.bsky.social

New study: Integrin-α8⁺ mesenchymal stem cells in the bone marrow play key roles in maintaining hematopoietic stem cell function. Depleting these cells decreases HSC numbers and activity. PMID:42409817, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-75276-2 #Medsky #Pharmsky #RNA 🧪

doi.orgEndosteal integrin-α8⁺ mesenchymal stem cells maintain haematopoietic stem cell function via extracellular matrix-mediated interactions | Nature CommunicationsThe stem cell niche is a specialised microenvironment essential for maintaining haematopoietic stem cells (HSCs). Here we identify a distinct subset of mesenchymal stem cells (MSCs) expressing integrin α8 (Itga8⁺ MSCs) within the bone marrow (BM) endosteum. These cells exhibit distinct MSC properties and higher haematopoietic supportive activity than other MSC subsets. Depletion of Itga8⁺ MSCs decreased HSC numbers, reduced quiescence of endosteal HSCs and diminished BM repopulating capacity. Itga8⁺ MSCs support haematopoiesis through cell adhesion-related mechanisms. Single-cell RNA sequencing further identified Itga8⁺ MSCs as a distinct subpopulation within bone-lining cells. Moreover, we identified Mfap4 as a candidate factor expressed in Itga8⁺ MSCs, and Mfap4 supported the BM reconstitution capacity of HSCs. These results suggest that Itga8⁺ MSCs represent a distinct niche cell population for HSC maintenance. This work provides new insights into HSC regulation and strategies to op
Shicheng Guo
@shihcheng.bsky.social

Discover 103 human proteins with SFMs crucial in actin-binding. New research uncovers key roles via cryo-EM; unmissable insights! PMID:42410114, Nat Cell Biol 2026, @NatureCellBio https://doi.org/10.1038/s41556-026-01979-9 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

doi.orgEvolutionarily conserved short linear motifs drive actin filament binding | Nature Cell BiologyRegulation of the actin cytoskeleton by actin-binding proteins is essential for cellular homeostasis, and the mode of actin binding determines the activity of actin-binding proteins. Here we identify a ‘short linear actin filament-binding motif’ (SFM) based on the cryo-electron microscopy structure of the ITPKA–actin filament complex. Using the computational pipeline SLiMFold, we discovered 103 human proteins containing SFMs with diverse cellular roles. Phylogenetic analysis suggests that SFMs arose de novo and are conserved across eukaryotes, exhibiting actin filament-binding affinities of 2–12 µM. Critical residues mediating binding and modulating affinity were defined, and the cryo-electron microscopy structures of two SFM–actin filament complexes revealed that SFM binding decreases actin-filament stiffness. These findings indicate that SFMs regulate actin-filament conformation and serve as anchoring modules that connect actin dynamics to a broad variety of cellular functions, provi