Shicheng Guo

NSD2 targeting reverses plasticity and drug resistance in prostate cancer | Nature Lineage plasticity is a cancer hallmark that drives disease progression and treatment resistance1,2. Plasticity is often mediated by epigenetic mechanisms that may be reversible; however, there are few examples of such reversibility. In castration-resistant prostate cancer (CRPC), plasticity mediates resistance to androgen receptor (AR) inhibitors and progression from adenocarcinoma to aggressive subtypes, including neuroendocrine prostate cancer (CRPC-NE)3–5. Here we show that plasticity-associated treatment resistance in CRPC can be reversed through the inhibition of NSD2, a histone methyltransferase6. NSD2 upregulation in CRPC-NE correlates with poor survival outcomes, and NSD2-mediated H3K36 dimethylation regulates enhancers of genes associated with neuroendocrine differentiation. In prostate tumour organoids established from genetically engineered mice7 that recapitulate the transdifferentiation to neuroendocrine states, and in human CRPC-NE organoids, CRISPR-mediated targeting of

NSD2 targeting reverses epigenetic plasticity and drug resistance in castration-resistant prostate cancer, offering new therapeutic hope. PMID:41299174, Nature 2025, @Nature @OTSociety @NAR_Open https://doi.org/10.1038/s41586-025-09727-z #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Lymphoid gene expression supports neuroprotective microglia function | Nature Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer’s disease (AD)1. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic2. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with plaques. Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation3,4. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1low microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1low CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD

Microglia protect the brain by attacking Alzheimer's plaques. The transcription factor PU.1, when reduced, decreases plaque impact. Vital for AD therapies. PMID:41193812, Nature 2025, @Nature https://doi.org/10.1038/s41586-025-09662-z #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Explore PPI networks with IID 2025! New features: co-purified sets, curated data, enhanced docking. Perfect for biological insights! PMID:41296544, Nucleic Acids Res 2025, @NAR_Open https://doi.org/10.1093/nar/gkaf1259 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Discover MetaNetX 2025! It updates chemical & reaction data, enabling better multi-omics integration with standardized IDs. PMID:41296556, Nucleic Acids Res 2025, @NAR_Open https://doi.org/10.1093/nar/gkaf1286 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

How do ARRB1 loss-of-function variants alter GLP-1R internalization and cAMP signaling, and do GLP1R Gly168Ser carriers show distinct weight-loss responses? Can polygenic models integrating GLP1R and ARRB1 predict long-term GLP-1RA efficacy across ancestries?

Looking for an AI that can take my entire to-do list and automatically build my schedule—no manual planning, full priority management. Basically a personal COO for my calendar. Motion claims to do this (paid), but I’m curious whether Microsoft or Google offer anything similar?

New study reveals the crucial role of the S2' site in SARS-CoV-2 spike protein fusion. Understanding S1/S2 processing provides insight into viral entry. PMID:41309650, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-66693-w #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

80+ nursing home residents with SBP <130 were randomized in France. Study: cut antihypertensives vs. usual care. Who gets benefits? Risks? PMID:40879421, N Engl J Med 2025, @NEJM https://doi.org/10.1056/NEJMoa2508157 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Secretome translation shaped by lysosomes and lunapark-marked ER junctions | Nature The endoplasmic reticulum (ER) is a highly interconnected membrane network that serves as a central site for protein synthesis and maturation1. A crucial subset of ER-associated transcripts, termed secretome mRNAs, encode secretory, lumenal and integral membrane proteins, representing nearly one-third of human protein-coding genes1. Unlike cytosolic mRNAs, secretome mRNAs undergo co-translational translocation, and thus require precise coordination between translation and protein insertion2,3. Disruption of this process, such as through altered elongation rates4, activates stress response pathways that impede cellular growth, raising the question of whether secretome translation is spatially organized to ensure fidelity. Here, using live-cell single-molecule imaging, we demonstrate that secretome mRNA translation is preferentially localized to ER junctions that are enriched with the structural protein lunapark and in close proximity to lysosomes. Lunapark depletion reduced ribosome den

Discover how secretome mRNA translation is influenced by lysosomes and lunapark-marked ER junctions. Pioneering insights into 1/3 of human genes! PMID:41193816, Nature 2025, @Nature https://doi.org/10.1038/s41586-025-09718-0 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Microglial phagocytosis in Alzheimer disease | Nature Reviews Neurology Accumulating evidence indicates that Alzheimer disease (AD) is caused by dysregulated microglial phagocytosis. The main risk factor for AD is age, and ageing reduces microglial phagocytosis of amyloid-β (Aβ) plaques, while increasing microglial phagocytosis of synapses and neurons. Most of the known genetic risk for AD can be linked to microglial phagocytosis, including ABCA1, ABI3, ACE, ADAM17, APOE, APP, BIN1, BLNK, CD2AP, CD33, CLU, CR1, CTSB, CTSH, EED, GRN, INPP5D, LILRB2, PICALM, PLCG2, PSEN1, PTK2B, SIGLEC11, SORL1, SPI1, TMEM106B and TREM2. Moreover, the only disease-modifying treatments for AD — anti-Aβ antibodies — work by increasing microglial phagocytosis of Aβ aggregates. Microglial phagocytosis of Aβ via TREM2, LRP1, CD33, TAM receptors and anti-Aβ antibodies appears to reduce AD pathology by pruning and compacting plaques, restricting subsequent tau pathology, whereas microglial phagocytosis of synapses and neurons seems detrimental in the later stages of AD, via complem

Age-related changes in microglial phagocytosis, linked to 20+ genes, contribute to Alzheimer’s by altering amyloid-β and neuron clearance. PMID:41315858, Nat Rev Neurol 2025, @NatRevNeurol https://doi.org/10.1038/s41582-025-01162-y #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Explore Genenames.org for info on 44.4k genes: 19.25k protein-coding, 14.5k pseudogenes, and 9.5k non-coding RNAs. PMID:41287213, Nucleic Acids Res 2025, @NAR_Open https://doi.org/10.1093/nar/gkaf1229 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Study: 5-year data (2017-2020) indicate sexual assault survivors have higher risk for FSD like CWP, IBS, CF. Danish cohort. PMID:41222960, JAMA Psychiatry 2025, @JAMAPsych https://doi.org/10.1001/jamapsychiatry.2025.3251 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Endothelial-to-hematopoietic transitions revealed: 3 distinct trajectories found in yolk sac & AGM via single-cell profiling. PMID:41219569, Nat Cardiovasc Res 2025 https://doi.org/10.1038/s44161-025-00740-z #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Polymorphisms in IGK and IGL loci shape antibody light chain diversity, impacting immune responses. Discoveries made using advanced genomic techniques. PMID:41315391, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-66759-9 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer | Nature Genetics The androgen receptor (AR) is a critical driver of prostate cancer (PCa). Here, to study regulators of AR protein levels and oncogenic activity, we developed a live-cell quantitative endogenous AR fluorescent reporter. Leveraging this AR reporter, we performed genome-scale CRISPRi flow cytometry sorting screens to systematically identify genes that modulate AR protein levels. We identified and validated known AR protein regulators, including HOXB13 and GATA2, and also unexpected top hits including PTGES3—a poorly characterized gene in PCa. PTGES3 repression resulted in loss of AR protein, cell-cycle arrest and cell death in AR-driven PCa models. Clinically, analysis of PCa data demonstrates that PTGES3 expression is associated with AR-directed therapy resistance. Mechanistically, we show PTGES3 binds directly to AR, regulates AR protein stability and is necessary for AR function in the nucleus at AR target genes. PTGES3 represents a potential therapeutic target for overcoming known mec

CRISPR screens reveal PTGES3 as a key modulator of androgen receptor in prostate cancer, identifying crucial AR regulators. PMID:41193657, Nat Genet 2025, @NatureGenet @OTSociety @NAR_Open https://doi.org/10.1038/s41588-025-02388-8 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer’s disease | Nature Neuroscience Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer’s disease (AD). In this study, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in individuals across the AD spectrum. We examined 101 individuals using positron emission tomography radiotracers to assess Aβ deposition ([18F]AZD4694), tau aggregation ([18F]MK-6240) and microglial activation ([11C]PBR28), along with plasma biomarkers for astrocyte reactivity (GFAP) and tau phosphorylation (p-tau217). We further evaluated 251 individuals with cerebrospinal fluid levels of the microglial marker sTREM2. We found that Aβ pathology was associated with astrocyte reactivity across cortical brain regions only in the presence of microglial activation. The microglia-dependent effects of Aβ on astrocyte reactivity were further related to cognitive impairment through tau phosphorylation and aggregation. Our r

101 individuals with AD were studied using PET radiotracers: [18F]AZD4694 for Aβ and [18F]MK-6240 for tau. Microglia impact astrocyte reactivity. PMID:41198899, Nat Neurosci 2025, @NatureNeuro https://doi.org/10.1038/s41593-025-02103-0 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Discover InsectBase 3.0: A one-stop platform with 1230+ insect genomes & multi-omics datasets, perfect for researching insect diversity & evolution! PMID:41263103, Nucleic Acids Res 2025, @NAR_Open https://doi.org/10.1093/nar/gkaf1248 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Discover GEAR: a cutting-edge atlas of gene expression in Arabidopsis thaliana, unlocking insights into plant circadian rhythms for agriculture! PMID:41188074, Nucleic Acids Res 2025, @NAR_Open https://doi.org/10.1093/nar/gkaf1056 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Discover the ANPDB: Explore 11,000+ African natural compounds with NMR/MS data integration and advanced search tools! PMID:41243981, Nucleic Acids Res 2025, @NAR_Open https://doi.org/10.1093/nar/gkaf1186 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

GPR1 structures with chemerin plus β-arrestins 1 & 2 reveal unexpected signaling patterns, shedding light on its unique internalization role. PMID:41264711, Science 2025, @ScienceMagazine https://doi.org/10.1126/science.adt8794 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

New study reveals very long-chain 1-deoxy-dihydroceramides, like m18:0/24:1 & m18:0/24:0, drive 1-deoxySphingolipid toxicity. PMID:41298489, Nat Commun 2025, @NatureComms @OTSociety @NAR_Open https://doi.org/10.1038/s41467-025-66687-8 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations | Nature Communications Expansion of RNA polymerase III (Pol III) activity in cancer can activate the transcription of typically silent small RNA genes, including snaR-A (small NF90-associated RNA isoform A), a hominid-specific noncoding RNA that promotes cell proliferation through unclear mechanisms. Here, we show that snaR-A interacts with mRNA splicing factors, including the U2 small nuclear ribonucleoprotein (snRNP) subunit SF3B2, and localizes near subnuclear foci enriched in splicing machinery. Overexpression of snaR-A increases intron retention, a hallmark of inefficient splicing, whereas its depletion enhances splicing of mRNAs characterized by high U2 snRNP occupancy and nuclear speckle proximity. These improvements in splicing coincide with reduced cell proliferation, consistent with tumor-level patterns linking snaR-A to growth in primary cancers. Together, these findings identify snaR-A as a molecular antagonist of splicing and potential disease driver in cancer. We propose that snaR-A-related spl

Cancer-associated snaR-A RNA activates silent Pol III RNA genes, disrupts mRNA splicing by interacting with U2 snRNP, and fosters cell proliferation. PMID:41290606, Nat Commun 2025, @NatureComms https://doi.org/10.1038/s41467-025-65448-x #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

A study links intermittent IV methylprednisolone pulse with mycophenolate mofetil to improved outcomes in juvenile dermatomyositis. PMID:41259047, JAMA Dermatol 2025 https://doi.org/10.1001/jamadermatol.2025.4483 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

iPEX enables micrometre-resolution deep spatial proteomics via tissue expansion | Nature The number of spatial omics technologies being developed is increasing1. However, a missing tool is one that can locate proteins in tissues in an untargeted manner at high spatial resolution and coverage. Here we present in situ imaging proteomics via expansion (iPEX), which integrates isotropic tissue magnification2 with matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging. iPEX provides scalable spatial resolution down to the micrometre scale and substantially increases the sensitivity of protein identification by 10–100-fold. Using the retina as a model, iPEX enabled the construction of spatial proteomic maps with high precision, the visualization of single-cell layers and extrasomatic structures and the identification of colocalized proteins. iPEX was readily applied to diverse tissues, including brain, intestine, liver and organoids, detecting 600–1,500 proteins at 1–5-µm effective pixel size. The application of iPEX to depict spatial proteomic maps in bra

Discover iPEX: a breakthrough in spatial proteomics revealing untargeted protein locations at micrometer resolution using tissue expansion and MALDI imaging. PMID:41224995, Nature 2025, @Nature https://doi.org/10.1038/s41586-025-09734-0 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

A skin-permeable polymer for non-invasive transdermal insulin delivery | Nature Non-invasive skin permeation is widely used for convenient transdermal delivery of small-molecule therapeutics (less than 500 Da) with appropriate hydrophobicities1. However, it has long been deemed infeasible for large molecules—particularly polymers, proteins and peptides2,3—due to the formidable barrier posed by the skin structure. Here we show that the fast skin-permeable polyzwitterion poly[2-(N-oxide-N,N-dimethylamino)ethyl methacrylate] (OP) can efficiently penetrate the stratum corneum, viable epidermis and dermis into circulation. OP is protonated to be cationic and is therefore enriched in the acidic sebum and paracellular stratum corneum lipids containing fatty acids, and subsequently diffuses through the intercorneocyte lipid lamella. Beneath the stratum corneum, at the normal physiological pH, OP becomes a neutral polyzwitterion, ‘hopping’ on cell membranes, enabling its efficient migration through the epidermis and dermis and ultimately entering dermal lymphatic vessels a

Transdermal insulin delivery breakthrough! A new polyzwitterion easily passes skin barrier, transporting large molecules effectively. Science redefined at 500 Da. PMID:41261125, Nature 2025, @Nature https://doi.org/10.1038/s41586-025-09729-x #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

New findings reveal that the Slurp1 gene adapts skin for land locomotion in tetrapods, with mutations linked to PPK creating thickened soles & palms. PMID:40763735, Cell 2025, @Cell https://www.cell.com/cell/fulltext/S0092-8674(25)00801-3 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

JAK₂ fusions linked to cytotoxic CTCL, found in indolent forms too. Study shows potential for better diagnosis and treatment. PMID:41296329, JAMA Dermatol 2025 https://doi.org/10.1001/jamadermatol.2025.4688 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Advances and continuing challenges in differentiation of stem cells to human kidney tissue | Nature Reviews Nephrology The capacity to generate a human model of the kidney via the directed differentiation of human pluripotent stem cells is a remarkable advance. Such three-dimensional multicellular tissues can accurately recapitulate certain kidney disease phenotypes in vitro, enabling the development of novel therapies for inherited kidney disease. These models also suggest the future possibility of engineering kidney tissue for kidney replacement therapy. Here, we focus on the latest advances in the field, including protocols for generating ureteric organoids and their combination with nephron-forming organoids to create integrated assembloid models, as well as examining the challenges in the application of these protocols. Although current protocols are modelled on differentiation in vivo, gaps in this knowledge remain, as well as challenges in recapitulating such complex events in vitro. The scale and complexity of the transcriptional analyses required to evaluate these models can also prove difficu

Breakthrough in kidney modeling: Stem cell-derived tissues replicate disease phenotypes, paving way for novel therapies & future kidney engineering. PMID:41214197, Nat Rev Nephrol 2025, @NatRevNeph https://doi.org/10.1038/s41581-025-01018-0 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Lupus-like symptoms in MDS/CMML are rare but increasing. Atypical features and refractory cases compared to idiopathic lupus. PMID:41259063, JAMA Dermatol 2025 https://doi.org/10.1001/jamadermatol.2025.4586 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Pig-to-human decedent kidney xenotransplant achieved 61 days of stability and dialysis independence with alpha-Gal KO pig organs. No CD40 blockade used! PMID:41233546, Nature 2025, @Nature https://doi.org/10.1038/s41586-025-09847-6 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪