Shicheng Guo

The A-C linker controls centriole structural integrity and duplication | Nature Communications Centrioles are evolutionarily conserved barrel-shaped organelles playing crucial roles in cell division and ciliogenesis. These functions are underpinned by specific structural sub-elements whose functions have been under investigation since many years. The A-C linker structure, connecting adjacent microtubule triplets in the proximal region, has remained unexplored due to its unknown composition. Here, using ultrastructure expansion microscopy, we characterized two recently identified A-C linker proteins, CCDC77 and WDR67, and discovered MIIP as an additional A-C linker protein. Our findings reveal that these proteins localize between microtubule triplets at the A-C linker, forming a complex. Depletion of A-C linker components disrupt microtubule triplet cohesion, leading to breakage at the proximal end. Co-removal of the A-C linker and the inner scaffold demonstrates their joint role in maintaining centriole architecture. Moreover, we uncover an unexpected function of the A-C li

Exploring centriole integrity: Ultrastructure expansion microscopy reveals the A-C linker’s crucial role in structural integrity and duplication. PMID:40707486, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-62154-6 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Visceral adiposity increases in middle-aged mice due to active adipogenesis driven by distinct APCs, as shown through lineage tracing. PMID:40273250, Science 2025, @ScienceMagazine https://doi.org/10.1126/science.adj0430 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Discovering key mRNA roles in pre-implantation! Polysome profiling reveals translational dynamics in oocytes & early embryos. PMID:40985772, Nucleic Acids Res 2025, @NAR_Open https://doi.org/10.1093/nar/gkaf956 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

New research shows CRISPR-Cas9 can fend off phages by rapidly nicking target-strands, lowering DNA abundance. Key: Mg2+ levels! 🧬✨ PMID:40985777, Nucleic Acids Res 2025, @NAR_Open https://doi.org/10.1093/nar/gkaf900 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Reversal of cerebrovascular anomalies in a zebrafish model of vein of Galen aneurysm | Nature Cardiovascular Research Congenital vascular malformations result from abnormal development of the vascular tree, with the aneurysmal malformation of the vein of Galen (VGAM) being the most prevalent neurovascular malformation in neonates, associated with poor outcomes. This condition is linked to germline mutations in the RASA1 and EPHB4 genes, although the underlying developmental mechanisms remain unclear. Here we generate zebrafish models lacking rasa1a and ephb4a that replicate the genetic and structural features of VGAMs. Our findings connect the development of malformations to insufficient fusion of precursor blood vessels, a process regulated by blood flow and the responses of endothelial cells. RASA1 deficiency destabilizes the homeostatic response to blood flow and contributes to impaired flow-mediated activation of MAPK and phosphatidylinositol-3-kinase signaling. By pharmacologically targeting these signaling pathways in mutant models, we restore normal fusion in existing malformations, offering po

Zebrafish lacking rasa1a & ephb4a reveal insights into vein of Galen aneurysm, boosting understanding of neurovascular defects. PMID:40506481, Nat Cardiovasc Res 2025 https://doi.org/10.1038/s44161-025-00659-5 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Exploring how the oral cavity’s unique immunity, with herpesviruses and HPV threats, remains pivotal yet underexplored. PMID:39533045, Nat Rev Immunol 2025, @NatRevImmunol https://doi.org/10.1038/s41577-024-01100-x #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

A genetically encoded biosensor for point-of-care and live-cell detection of d-2-hydroxyglutarate | Nature Communications d-2-Hydroxyglutarate (d-2-HG) is a functional endogenous metabolite in various domains of life. Its abnormal accumulation promotes human tumorigenesis. Convenient d-2-HG testing for diagnosis and prognosis of d-2-HG-related diseases remains technically challenging, and there is no analytical method to directly detect d-2-HG in living cells. Here, we identify a d-2-HG-specific transcriptional activator, HgcR, and develop a d-2-HG sensor (DHOR) using HgcR as a sensing moiety. Then, we build a portable device adaptive with DHOR for rapid and low-cost point-of-care d-2-HG testing in serum, urine, and glioma tissue samples. DHOR also allow spatiotemporal resolution of d-2-HG in living bacteria and human cells. We use DHOR to identify d-2-HG transporters from Escherichia coli and human solute carrier 22 family. Overall, DHOR provides a powerful and versatile tool for in vitro and live-cell detection of d-2-HG, offering the opportunity to deepen our understanding about physiological and patho

Discover a new biosensor DHOR for detecting D-2-Hydroxyglutarate. Engineered from HgcR, it enables direct live-cell analysis, advancing cancer diagnostics. PMID:40715112, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-62225-8 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Oral semaglutide 25 mg offers an alternative to injectable 2.4 mg & 50 mg oral for overweight/obesity. 71-week study across 4 countries, 22 sites. PMID:40934115, N Engl J Med 2025, @NEJM https://doi.org/10.1056/NEJMoa2500969 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Two cases of amivantamab-induced scalp and facial necrosis showed remarkable improvement using topical β-blocker wet wrap therapy. PMID:40928786, JAMA Dermatol 2025 https://doi.org/10.1001/jamadermatol.2025.3122 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

The human RIF1-Long isoform interacts with BRCA1 to promote recombinational fork repair under DNA replication stress | Nature Communications RIF1 is a multifunctional protein that regulates DNA replication and repair. RIF1-deficient cells are hypersensitive to DNA replication stress. Of the two alternatively spliced RIF1 isoforms, called RIF1-Short and RIF1-Long, the RIF1-Long isoform is more capable than RIF1-Short in supporting cell recovery from replication stress. Examining replication stress resistance mechanisms specific to RIF1-Long, we find that prolonged replication stress unexpectedly induces interaction of RIF1-Long with BRCA1. Mechanistically, a phosphorylated SPKF motif unique to the RIF1-Long isoform binds the tandem BRCT domain of BRCA1. BRCA1–RIF1-Long interaction is strongly down-regulated through dephosphorylation by RIF1-associated Protein Phosphatase 1. BRCA1–RIF1-Long interaction requires ATR signaling, and occurs predominantly during S phase. Loss of RIF1-Long impairs the formation of RAD51 foci, and reduces the efficiency of homology-mediated repair at broken replication forks. In summary, our investi

RIF1-Long teams up with BRCA1 to tackle DNA replication stress, supporting cell recovery. RIF1-Long has a special role in boosting fork repair efficiency! PMID:40595496, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-60817-y #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Early IVIG treatment in anti-IgLON5 may lower disability/death risk. Study: 2014-2024, median 66 months follow-up. PMID:40758377, JAMA Neurol 2025, @JAMANeuro https://doi.org/10.1001/jamaneurol.2025.2574 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

The subordinate role of pseudogenization to recombinative deletion following polyploidization in angiosperms | Nature Communications Extensive gene loss is a hallmark of rediploidization following polyploidization, but its molecular basis remains unclear: whether it occurs primarily through pseudogenization or DNA deletion. Here, we examine pseudogenization in collinear segments from ancient whole-genome multiplications (WGMs) across 12 angiosperms. Although total pseudogenes are abundant, we find far fewer WGM-derived pseudogenes than expected if pseudogenization and DNA deletion contribute equally to gene loss. Simulations of neutrally evolving pseudogenes indicate that, if DNA deletion is absent, pseudogenes should be detectable for far longer than observed in the paleo-polyploid genomes, suggesting gene loss driven by DNA deletion. Analyses of three neo-autopolyploid genomes confirm this pattern: among substantial gene loss, DNA deletions occur on average 1.5 times more frequently than pseudogenization. Our findings imply that gene loss post-polyploidization primarily takes place via DNA deletion, enabled by a g

Study of 12 angiosperms shows fewer WGM-derived pseudogenes than expected, revealing DNA deletion as a major force in gene loss post-polyploidization. PMID:40634370, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-61676-3 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study | Nature Medicine We investigated the potential role of the opioid system in modulating glutamatergic effects of ketamine administration in major depressive disorder. Twenty-six adults with major depressive disorder participated in a double-blind crossover study, receiving oral placebo or 50 mg naltrexone before an intravenous infusion of 0.5 mg per kg ketamine. Brain glutamatergic activity in the anterior cingulate cortex was measured using functional magnetic resonance spectroscopy and depressive symptoms were assessed with the Montgomery–Åsberg Depression Rating Scale. Naltrexone attenuated the increase in glutamate + glutamine to total N-acetylaspartate ratio during ketamine infusion compared to placebo (F1,253 = 4.83, P = 0.029) and also attenuated the reduction in Montgomery–Åsberg Depression Rating Scale scores on day 1 (condition-by-time interaction, F1,74 = 5.39, P = 0.023). These findings demonstrate that the opioid system modulates the acute response to ketamine and subsequent antidepressant

Naltrexone (50mg) pretreatment before ketamine (0.5mg/kg) infusion in 26 adults with major depression shows opioid role in glutamate modulation. PMID:40707608, Nat Med 2025, @NatureMedicine https://doi.org/10.1038/s41591-025-03800-w #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

DNA pol κ is key in translesion synthesis of aldehyde ICLs. Disruptions link to Fanconi anaemia and flawed repair processes. PMID:40985768, Nucleic Acids Res 2025, @NAR_Open https://doi.org/10.1093/nar/gkaf875 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Sotatercept trial shows promise! In patients with PAH diagnosed within 1 year, significant reductions in morbidity & mortality observed. PMID:41025556, N Engl J Med 2025, @NEJM https://doi.org/10.1056/NEJMoa2508170 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Production of live monkeys and their genetically matched embryonic stem cells from single embryos | Nature Communications Immune rejection poses a challenge in stem cell therapy, especially with allogeneic embryonic stem cells (ESCs). Non-human primates offer a promising avenue for developing genetically matched ESCs for regenerative medicine. Here, we successfully derive three live monkeys and their genetically matched autologous ESCs (aESCs) using embryo splitting. Additionally, from fibroblasts of one of these monkeys, we generate induced pluripotent stem cells (iPSCs) and nuclear transfer embryonic stem cells (ntESCs), creating a set of genetically matched aESCs, iPSCs, and ntESCs. Single-cell RNA-seq analysis reveals that aESCs potentially exhibit reduced heterogeneity, lower transcriptional noise, and enhanced genomic stability compared to iPSCs and ntESCs. Furthermore, we successfully derive ESCs from human split embryos, highlighting the potential for obtaining human aESCs. Collectively, our study offers an avenue for establishing autologous pluripotent stem cells and provides the theoretical basi

Three live monkeys and their genetically matched ESCs derived from single embryos! Autologous ESCs pave way for better regenerative solutions. PMID:40593544, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-60694-5 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Integrated single-cell atlas of human atherosclerotic plaques | Nature Communications Atherosclerosis, a major cause of cardiovascular diseases, is characterized by the buildup of lipids and chronic inflammation in the arteries, leading to plaque formation and potential rupture. Despite recent advances in single-cell transcriptomics (scRNA-seq), the underlying immune mechanisms and transformations in structural cells driving plaque progression remain incompletely defined. Existing datasets often lack comprehensive coverage and consistent annotations, limiting the utility of downstream analyses. Here, we present an integrated single-cell atlas of human atherosclerotic plaques, covering roughly 250k high-quality annotated cells. We achieve robust cell type annotations validated by expert consensus and surface protein measurements. Using this atlas, we introduce distinct markers for plaque neutrophils, identify a proangiogenic endothelial cell cluster enriched in advanced lesions, and specialized macrophage subsets. We also establish that fibromyocytes are exclusive to vas

Explore insights from 211,000 cells: a single-cell atlas reveals the complex immune and structural transformations in human atherosclerotic plaques. PMID:40931012, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-63202-x #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

LRP8 is a receptor for tick-borne encephalitis virus | Nature Tick-borne encephalitis virus (TBEV) causes tick-borne encephalitis (TBE), a severe and sometimes life-threatening disease characterized by viral invasion of the central nervous system with symptoms of neuroinflammation1,2. As with other orthoflaviviruses—enveloped, arthropod-borne RNA viruses—host factors required for TBEV entry remain poorly defined. Here we used a genome-scale CRISPR–Cas9-based screen to identify LRP8, an apolipoprotein E and reelin receptor with high expression in the brain, as a TBEV receptor. LRP8 downregulation reduced TBEV infection in human cells, and its overexpression enhanced infection. LRP8 bound directly to the TBEV E glycoprotein and mediated viral attachment and internalization into cells. An LRP8-based soluble decoy blocked infection of human cell lines and neuronal cells and protected mice from lethal TBEV challenge. LRP8’s role as a TBEV receptor has implications for TBEV neuropathogenesis and the development of antiviral countermeasures. LRP8, an ap

Discovery: LRP8 identified as a receptor for TBEV, crucial for viral CNS invasion causing severe tick-borne encephalitis. Study utilized CRISPR-Cas9. PMID:40993380, Nature 2025, @Nature https://doi.org/10.1038/s41586-025-09500-2 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Author reflects on disparities in emergency care in Italy as a 1st-hand observer, highlighting triage privilege in a vacation ER. PMID:40824650, JAMA Neurol 2025, @JAMANeuro https://doi.org/10.1001/jamaneurol.2025.2878 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

A neuronal architecture underlying autonomic dysreflexia | Nature Autonomic dysreflexia is a life-threatening medical condition characterized by episodes of uncontrolled hypertension that occur in response to sensory stimuli after spinal cord injury (SCI)1. The fragmented understanding of the mechanisms underlying autonomic dysreflexia hampers the development of therapeutic strategies to manage this condition, leaving people with SCI at daily risk of heart attack and stroke2–5. Here we expose the neuronal architecture that develops after SCI and causes autonomic dysreflexia. In parallel, we uncover a competing, yet overlapping neuronal architecture activated by epidural electrical stimulation of the spinal cord that safely regulates blood pressure after SCI. The discovery that these adversarial neuronal architectures converge onto a single neuronal subpopulation provided a blueprint for the design of a mechanism-based intervention that reversed autonomic dysreflexia in mice, rats and humans with SCI. These results establish a path towards essential p

A breakthrough in understanding autonomic dysreflexia: revealing neuronal changes post-SCI could pave the way for new treatments. Science at its best! PMID:40963010, Nature 2025, @Nature https://doi.org/10.1038/s41586-025-09487-w #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

ExIGS tech shows that in progeria fibroblasts, lamin defects connect to chromatin regulation hotspots at subnuclear levels. PMID:40440430, Science 2025, @ScienceMagazine https://doi.org/10.1126/science.adt2781 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Consider offering psychedelic treatments to those with psychiatric conditions before physician-assisted dying as life-preserving care. PMID:40560567, JAMA Psychiatry 2025, @JAMAPsych https://doi.org/10.1001/jamapsychiatry.2025.1457 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Higher education linked to faster tau buildup in Alzheimer’s. Data from ADNI (2015-22, 3.0 yr) and A4 (2014-22, 4.7 yr) analyzed. PMID:40622710, JAMA Neurol 2025, @JAMANeuro https://doi.org/10.1001/jamaneurol.2025.1801 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Child with lesions that started as vesicles, spreading to form concentric, spiraled rings. A unique bullous tinea manuum case! PMID:40960847, JAMA Dermatol 2025 https://doi.org/10.1001/jamadermatol.2025.3261 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

CellNavi predicts genes directing cellular transitions by learning a gene graph-enhanced cell state manifold | Nature Cell Biology A select few genes act as pivotal drivers in the process of cell state transitions. However, finding key genes involved in different transitions is challenging. Here, to address this problem, we present CellNavi, a deep learning-based framework designed to predict genes that drive cell state transitions. CellNavi builds a driver gene predictor upon a cell state manifold, which captures the intrinsic features of cells by learning from large-scale, high-dimensional transcriptomics data and integrating gene graphs with directional connections. Our analysis shows that CellNavi can accurately predict driver genes for transitions induced by genetic, chemical and cytokine perturbations across diverse cell types, conditions and studies. By leveraging a biologically meaningful cell state manifold, it is proficient in tasks involving critical transitions such as cellular differentiation, disease progression and drug response. CellNavi represents a substantial advancement in driver gene predictio

CellNavi unveils crucial genes in cell transitions using deep learning on vast transcriptomics data. Surely a game-changer! PMID:41044372, Nat Cell Biol 2025, @NatureCellBio https://doi.org/10.1038/s41556-025-01755-1 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Circular RNA-based protein replacement therapy mitigates osteoarthritis in male mice | Nature Communications In vitro-transcribed and circularized RNAs (ivcRNAs) represent a robust platform for sustained protein translation, offering promising potential for localized therapeutic delivery in joint diseases. Osteoarthritis (OA), the most prevalent degenerative joint disorder, remains a major clinical challenge due to its progressive nature and the lack of disease-modifying treatments. In this study, we identify Musashi2 (Msi2) deficiency in articular chondrocytes as a key contributor to OA pathogenesis. To evaluate the efficacy of ivcRNA-mediated protein replacement therapy, we developed a localized delivery strategy that enables high-yield and prolonged protein expression in chondrocytes. Using a destabilization of the medial meniscus (DMM) mouse model, we demonstrate that intra-articular delivery of ivcRNA encoding MSI2 effectively mitigates OA progression in male mice. Furthermore, therapeutic supplementation of SOX5, a downstream effector of MSI2, via ivcRNA delivery further validates this

Circular RNA-based therapy using ivcRNAs restores Msi2 in mice, reducing osteoarthritis progression. Promising findings for targeting joint diseases. PMID:41006212, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-63343-z #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Study links parental mental disorders to higher offspring mortality risk up to middle age. Analyzed 1973-2014 Swedish data. PMID:40991263, JAMA Psychiatry 2025, @JAMAPsych https://doi.org/10.1001/jamapsychiatry.2025.2572 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Inhibiting heme piracy by pathogenic Escherichia coli using de novo-designed proteins | Nature Communications Iron is an essential nutrient for most bacteria and is often growth-limiting during infection, due to the host sequestering free iron as part of the innate immune response. To obtain the iron required for growth, many bacterial pathogens encode transporters capable of extracting the iron-containing cofactor heme directly from host proteins. Pathogenic E. coli and Shigella spp. produce the outer membrane transporter ChuA, which binds host hemoglobin and extracts its heme cofactor, before importing heme into the cell. Heme extraction by ChuA is a dynamic process, with the transporter capable of rapidly extracting heme from hemoglobin in the absence of an external energy source, without forming a stable ChuA-hemoglobin complex. In this work, we utilise a combination of structural modelling, Cryo-EM, X-ray crystallography, mutagenesis, and phenotypic analysis to understand the mechanistic detail of this process. Based on this understanding we utilise artificial intelligence-based protein d

Exciting new study! Blocking heme theft by pathogenic E. coli with innovative de novo proteins. Promising step towards combating bacterial infections. PMID:40634285, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-60612-9 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α | Nature Cardiovascular Research Endurance exercise promotes adaptive growth and improved function of myocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are in part transcriptionally coordinated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise training and instead leads to heart failure after just 6 weeks of training. Consistent with this, in humans, rare genetic variants in PPARGC1A, which encodes PGC-1α, are associated with increased risk of heart failure. In this model, we identify growth differentiation factor 15 (GDF15) as a key heart-secreted mediator that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyt

Endurance exercise boosts heart health via PGC-1α, suppressing GDF15. Without PGC-1α in heart cells, benefits drop! #CardiacScience PMID:40993371, Nat Cardiovasc Res 2025 @broadinstitute https://doi.org/10.1038/s44161-025-00712-3 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Preclinical mouse models of immune checkpoint inhibitor-associated myocarditis | Nature Cardiovascular Research In this Review, we present a comprehensive analysis of preclinical models used to study immune checkpoint inhibitor-associated myocarditis (hereafter ICI-myocarditis), a potentially lethal immune-related adverse event. We begin by providing an overview of immune checkpoint inhibitors, highlighting how their efficacy in cancer treatment is counterbalanced by their predisposition to cause immune-related adverse events. Next, we draw from human data to identify disease features that an effective mouse model should ideally mimic. After that, we present a critical evaluation of a wide variety of existing mouse models including genetic, pharmacological and humanized models. We summarize insights gathered about the underlying mechanisms of ICI-myocarditis and the role of mouse models in these discoveries. We conclude with a perspective on the future of preclinical models, highlighting potential model improvements and research directions that could strengthen our understanding of ICI-myocardit

Explore models for ICI-myocarditis, a deadly immune side effect of cancer drugs. Details: efficacy vs. risk. 📄❤️ #ResearchMatters PMID:40335724, Nat Cardiovasc Res 2025 https://doi.org/10.1038/s44161-025-00640-2 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪