#ESHG

@shihcheng.bsky.social

2 hours ago

https://doi.org/10.1001/jamapsychiatry.2026.0086 No description available

New JAMA Psychiatry paper: Clozapine is tested after 1 antipsychotic failure in FEP. Study spans 7 sites in China, 2 randomizations! PMID:41811299, JAMA Psychiatry 2026, @JAMAPsych https://doi.org/10.1001/jamapsychiatry.2026.0086 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

6 3 0 0

Shicheng Guo

@shihcheng.bsky.social

3 hours ago

Cancer cachexia in STK11/LKB1-mutated non-small cell lung cancer is dependent on tumor-secreted GDF15 | Nature Communications Cachexia is a wasting syndrome involving adipose, muscle, and body weight loss in cancer patients. Tumor loss-of-function mutations in STK11/LKB1, a regulator of AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are linked to weight loss in non-small cell lung cancer (NSCLC) patients. This study examines the role of the integrated stress response (ISR) cytokine growth differentiation factor 15 (GDF15) in regulating cachexia using patient-derived and engineered STK11/LKB1-mutant NSCLC lines. Tumor cell-derived serum GDF15 levels are elevated in mice bearing these tumors. Treatment with a GDF15-neutralizing antibody or silencing GDF15 from tumor cells prevents adipose/muscle loss, strength decline, and weight reduction, identifying tumors cells as the GDF15 source. Restoring wild-type STK11/LKB1 in NSCLC lines with endogenous STK11/LKB1 loss reverses the ISR and reduces GDF15 expression rescuing the cachexia phenotype. Collectively, these findings implic

GDF15 is key to cachexia in STK11/LKB1-mutant lung cancer. Blocking it could halt muscle, fat, and weight loss. Insights from patient-derived models. PMID:41617691, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-68702-y #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

4 1 0 0

Shicheng Guo

@shihcheng.bsky.social

6 hours ago

De novo design of GPCR exoframe modulators | Nature G-protein-coupled receptors (GPCRs) are important therapeutic targets and have been targeted mainly through their orthosteric site, where the endogenous agonist binds1. However, allosteric modulation has emerged as a promising and innovative strategy in the realm of GPCR drug discovery1. Here, drawing inspiration from the natural regulation of GPCRs by transmembrane proteins, we have developed GPCR exoframe modulators (GEMs), de novo designed proteins that specifically target the transmembrane domain of GPCRs. Utilizing a hallucination-like design approach, we crafted GEMs with three strategic structural prompts to achieve the desired binding modes. We selected the dopamine D1 receptor as a prototypical model and systematically investigated four GEMs. Structural studies and functional assays revealed that these GEMs bind to the transmembrane domains and function as diverse allosteric modulators, including agonist-positive allosteric modulator, negative allosteric modulator and biased a

Innovative GPCR exoframe modulators tune allosteric sites for precise targeting. De novo proteins open pathways for future solutions in drug discovery. PMID:41699180, Nature 2026, @Nature https://doi.org/10.1038/s41586-025-09957-1 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

0 1 0 0

Shicheng Guo

@shihcheng.bsky.social

17 hours ago

Composite SMG5-SMG6 PIN domain formation is essential for NMD | Nature Communications Nonsense-mediated mRNA decay (NMD) relies on the coordinated assembly and action of multiple protein factors. Degradation of target mRNAs begins with endonucleolytic cleavage near premature stop codons, but the mechanisms of endonuclease activation and regulation remain unclear. Using structural predictions, biochemical in vitro assays, and cell-based NMD analysis, we show that SMG5 and SMG6 interact via their PIN domains to form a composite interface (cPIN) with full endonuclease activity. In vitro reconstituted SMG5-SMG6 cPIN heterodimers show high activity, as SMG5 completes the SMG6 active site and substrate binding site. Mutations in residues at their predicted interaction surfaces, RNA-binding sites, or active site attenuate or abolish cPIN activity in vitro and impair cellular NMD. Our findings demonstrate how paralogous PIN domains complement each other to assemble a highly active endonuclease in NMD, providing a structural and mechanistic explanation for efficient NMD sub

New insights into NMD: SMG5 and SMG6 form a composite PIN domain, critical for mRNA decay via endonucleolytic cleavage near premature stop codons. PMID:41714610, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-69819-w #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

4 2 0 0

Shicheng Guo

@shihcheng.bsky.social

23 hours ago

LLM-assisted systematic review of large language models in clinical medicine | Nature Medicine Clinical evaluations of large language models (LLMs) have rapidly expanded since 2022, yet their evidence base remains opaque. The overwhelming volume of studies creates challenges for manual curation and review. However, LLMs themselves offer the scalability and capability to evaluate the ever-growing evidence base. This LLM-assisted review identified 4,609 peer-reviewed studies in clinical medicine between January 2022 and September 2025, equating to roughly 3.2 papers per day. Only 1,048 studies used real-world patient data and of these only 19 were prospective randomized trials; most addressed simulated scenarios (n = 1,857) or exam-style tasks (n = 1,704). ChatGPT and related OpenAI models constitute 65.7% of evaluated models, with Gemini/Bard a distant second constituting 13.1% of evaluated models. Patient-facing communication and education comprised 17% of tasks, followed by knowledge retrieval, and education and assessment simulation. Across 1,046 head-to-head comparisons, LLMs

Exploring LLMs in clinical medicine: 4,609 studies reviewed from Jan 2022-Sep 2025, averaging 3.2 papers/day. Only 1,048 detailed. PMID:41776077, Nat Med 2026, @NatureMedicine https://doi.org/10.1038/s41591-026-04229-5 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

5 1 0 0

Shicheng Guo

@shihcheng.bsky.social

1 day ago

Light-induced assembly and repeatable actuation in Ca2+-driven chemomechanical protein networks | Nature Communications Programming rapid, repeatable motions in soft materials has remained a challenge in active matter and biomimetic design. Here, we present a light-controlled chemomechanical network based on Tetrahymena thermophila calcium-binding protein 2 (Tcb2), a Ca2+-sensitive contractile protein. These networks—driven by Ca2+-triggered structural rearrangements—exhibit dynamic self-assembly, spatiotemporal growth, and contraction rates comparable to actomyosin systems. By coupling light-sensitive chelators for optically triggered Ca2+ release, we achieve precise growth and repeatable mechanical contractility of Tcb2 networks, revealing emergent phenomena such as boundary-localized active regions and density gradient-driven reversals in motion. A coupled reaction-diffusion and elastic model explains these dynamics, highlighting the interplay between chemical network assembly and mechanical response. We further demonstrate active transport of particles via network-mediated forces in vitro and implem

Discover proteins that mimic muscle movements: Tcb2 networks show rapid, repeatable Ca²⁺-triggered actions with light control, rivaling actomyosin speeds. PMID:41723139, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-69651-2 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

6 0 0 0

Shicheng Guo

@shihcheng.bsky.social

1 day ago

Roles of microtubules and LIS1 in dynein transport machinery assembly | Nature Cytoplasmic dynein-1, a microtubule (MT)-based motor protein, requires dynactin and a coiled-coil adaptor to form the processive dynein–dynactin–adaptor (DDA) complex1,2. The roles of MTs and dynein regulator lissencephaly-1 (LIS1) in DDA assembly have remained elusive. Here we use cryo-electron microscopy to determine the structural basis of MT- and LIS1-mediated DDA assembly. We show that an adaptor-independent dynein–dynactin complex spontaneously forms on MTs with an intrinsic 2:1 stoichiometry in a highly efficient manner, driven by parallel alignment of dynein tails upon MT binding. Adaptors can wedge into and exchange within the assembled MT-bound dynein–dynactin complex; these processes are enabled by relative rotations between dynein and dynactin and facilitated by the dynein light-intermediate chains that assist the adaptor ‘search’ mechanism. Although LIS1 is dispensable for efficient DD(A)–MT assembly, its presence expands the conformational landscape of DD(A) assemblies on

Study reveals dynein motor protein spontaneously forms a 2:1 dynein-dynactin complex on microtubules. LIS1's role in this assembly unveiled via cryo-EM. PMID:41708859, Nature 2026, @Nature https://doi.org/10.1038/s41586-026-10153-y #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

15 5 0 0

Shicheng Guo

@shihcheng.bsky.social

1 day ago

https://www.cell.com/ajhg/fulltext/S0002-9297(26)00029-7 No description available

Exciting insights from the 2025 ASHG address in Boston: advancing genetics with 10 key breakthroughs impacting 7 diseases! #HumanGenetics PMID:41795467, Am J Hum Genet 2026, @AJHGNews www.cell.com/ajhg/fulltext/S0002-9297... #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

5 1 1 0

Shicheng Guo

@shihcheng.bsky.social

1 day ago

https://doi.org/10.1093/nar/gkaf1524 No description available

Discover how Cdn1's structural flexibility allows it to bind multiple cOA types and activate CRISPR defenses in prokaryotes! 📖🔬🧬 PMID:41569151, Nucleic Acids Res 2026, @NAR_Open @OTSociety @NAR_Open https://doi.org/10.1093/nar/gkaf1524 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

1 0 0 0

Shicheng Guo

@shihcheng.bsky.social

2 days ago

Integrase anchors viral RNA to the HIV-1 capsid interior | Nature HIV-1 integrase (IN) promotes encapsulation of viral genomic RNA into mature viral cores, and this function is a target for ongoing antiretroviral drug development efforts1–3. Here we determined the cryogenic electron microscopy (cryo-EM) structure of a primate lentiviral IN in a complex with RNA, revealing a linear filament made of IN octamer repeat units, each comprising a pair of asymmetric homotetramers. The assembly is stabilized through IN–RNA interactions involving mainly the IN C-terminal domains and RNA backbone. The spacing and orientation of the IN filament repeat units closely matched those of consecutive capsid (CA) hexamers within the mature CA lattice. Using cryo-EM images of native purified HIV-1 cores, we refined the structure of the IN filament as it propagates along the luminal side of the CA lattice. Each IN tetramer within the filament nestled in a CA hexamer, engaging closely with the major homology regions. Substitutions of residues involved in IN–CA co

Cryo-EM reveals HIV-1 integrase forms linear octameric filaments encapsulating viral RNA, crucial for drug design. Explore this structural insight! PMID:41708858, Nature 2026, @Nature https://doi.org/10.1038/s41586-026-10154-x #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

2 0 0 0

Shicheng Guo

@shihcheng.bsky.social

2 days ago

https://doi.org/10.1126/science.adw4937 No description available

Poxvirus M3.1 triggers an antiviral NF-κB response in human monocytes, revealing an effector-triggered immunity (ETI) pathway. Fascinating insight! PMID:41678605, Science 2026, @ScienceMagazine https://doi.org/10.1126/science.adw4937 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

8 4 0 0

Shicheng Guo

@shihcheng.bsky.social

2 days ago

https://doi.org/10.1093/nar/gkag021 No description available

BAF phosphorylation is crucial for anchoring centromeric heterochromatin to the NE, affecting genome organization in eukaryotes. PMID:41569157, Nucleic Acids Res 2026, @NAR_Open https://doi.org/10.1093/nar/gkag021 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

3 1 2 0

Shicheng Guo

@shihcheng.bsky.social

3 days ago

https://doi.org/10.1001/jamadermatol.2025.5973 No description available

A man in his 30s with 2-month scalp and lateral eyebrow hair loss. Negative hair-pull test. Diagnosis? Share thoughts! PMID:41671003, JAMA Dermatol 2026 https://doi.org/10.1001/jamadermatol.2025.5973 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

2 2 0 0

Shicheng Guo

@shihcheng.bsky.social

3 days ago

Comprehensive profiling of CRISPR/dCas9 epigenome editors indicates a complex link between on and off target effects | Genome Biology | Springer Nature Link CRISPR/dCas9-based epigenome editing systems, including DNA methylation epimodifiers, have greatly advanced molecular functional studies, revolutionizing t

CRISPR/dCas9 epigenome editors show complex on-target and off-target effects, prompting better design for precision. Optimization is key! PMID:41620608, Genome Biol 2026 @OTSociety @NAR_Open https://doi.org/10.1186/s13059-026-03967-6 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

4 2 0 0

Shicheng Guo

@shihcheng.bsky.social

3 days ago

https://doi.org/10.1038/s41556-026-01876-1 No description available

THY1⁺ CSCs drive metastasis via a pseudohypoxic state. Key roles: IL-6-MYC signaling, neutrophil mitochondria. Multi-omics reveal! PMID:41680445, Nat Cell Biol 2026, @NatureCellBio https://doi.org/10.1038/s41556-026-01876-1 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

3 1 0 0

Shicheng Guo

@shihcheng.bsky.social

4 days ago

https://doi.org/10.1126/science.adx1616 No description available

Explore sugarcane's complexity: 9-genome pangenome graph, 47-57 haplotypes/chromo, 74K-271K alleles. Revolutionizes multiomics! PMID:41643009, Science 2026, @ScienceMagazine https://doi.org/10.1126/science.adx1616 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

3 1 0 0

Shicheng Guo

@shihcheng.bsky.social

5 days ago

Evolutionary dynamics of sex determination in Branchiostoma belcheri driven by repeated transposition of a single novel gene | Nature Communications Sex determination systems display striking evolutionary flexibility, yet the mechanisms underlying their transitions remain poorly understood. Using newly generated genome assemblies, we investigated the evolving sex-determining system in the amphioxus Branchiostoma belcheri. We identified two female-specific sex-determining regions (SDRs) on chromosome 13, both derived from independent transpositions of the autosomal gene tesD, which shows testis-specific expression in amphioxus species. CRISPR/Cas9 knockout experiments in Branchiostoma floridae confirmed that tesD functions as a male-determination gene, with loss of function producing an all-female phenotype. In B. belcheri, the older SDR (tesDwa) inserted into the coding region of twai, while the younger SDR (tesDwb), flanked by active Zator-1 transposons, inserted into the 3′ UTR of vps9c and later translocated to autosomes in ~10% of individuals. Transcriptomic analyses revealed that W-linked tesDwa and tesDwb produce antisen

Study reveals sex determination in Branchiostoma belcheri evolves via tesD gene transposition on chromosome 13. Fascinating insights! PMID:41530154, Nat Commun 2026, @NatureComms @OTSociety @NAR_Open https://doi.org/10.1038/s41467-026-68322-6 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

4 2 0 0

Shicheng Guo

@shihcheng.bsky.social

5 days ago

https://doi.org/10.1001/jamaneurol.2025.5635 No description available

Discover how insights from neuroimmunology and autoimmune encephalitis research are shaping diverse medical fields and conditions. PMID:41697691, JAMA Neurol 2026, @JAMANeuro https://doi.org/10.1001/jamaneurol.2025.5635 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

2 1 0 0

Shicheng Guo

@shihcheng.bsky.social

5 days ago

https://doi.org/10.1001/jamapsychiatry.2025.4383 No description available

Schizophrenia costs the US $317B in 2024. Direct medical: $115B; nonmedical: $32B; indirect: $170B. State data reveals disparities. PMID:41604174, JAMA Psychiatry 2026, @JAMAPsych https://doi.org/10.1001/jamapsychiatry.2025.4383 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

6 1 0 0

Shicheng Guo

@shihcheng.bsky.social

5 days ago

https://doi.org/10.1093/nar/gkaf1481 No description available

RNA G-quadruplexes boost codon repeat-linked ribosomal frameshifting in humans, revealing widespread PRF in human genes. PMID:41543171, Nucleic Acids Res 2026, @NAR_Open @OTSociety @NAR_Open https://doi.org/10.1093/nar/gkaf1481 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

1 0 0 0

Shicheng Guo

@shihcheng.bsky.social

6 days ago

https://doi.org/10.1126/science.aef2173 No description available

A study reveals a mitochondrial transport protein boosts carnitine synthesis in mice, essential during fat intake. PMID:41678603, Science 2026, @ScienceMagazine https://doi.org/10.1126/science.aef2173 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

2 0 0 0

Shicheng Guo

@shihcheng.bsky.social

6 days ago

https://www.cell.com/ajhg/fulltext/S0002-9297(26)00001-7 No description available

🚀 Unveiling AncientProxy: A catalog that integrates ~1.23M loci to link ancient DNA with modern genetic variants! #AncientDNAInsights PMID:41605204, Am J Hum Genet 2026, @AJHGNews www.cell.com/ajhg/fulltext/S0002-9297... #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

1 0 0 0

Shicheng Guo

@shihcheng.bsky.social

6 days ago

Mobility-driven synthetic contact matrices as a scalable solution for real-time pandemic response modeling | Nature Communications Accurately capturing time-varying human behavior remains a major challenge for real-time epidemic modeling and response. During the COVID-19 pandemic, synthetic contact matrices derived from mobility and behavioral data emerged as a scalable alternative to empirical contact surveys, yet their comparative performance remained unclear. Here, we systematically evaluate synthetic and empirical age-stratified contact matrices in France from March 2020 to May 2022, comparing contact patterns and their ability to reproduce observed epidemic dynamics. While both sources captured similar temporal trends in contacts, empirical matrices recorded 3.4 times more contacts for individuals under 19 than synthetic matrices during school-open periods. The model parameterized with synthetic matrices provided the best fit to hospital admissions and best captured hospitalization patterns for adolescents, adults, and seniors, whereas deviations remained for children across both models. Neither matrix allowe

Synthetic contact matrices using mobility data outperformed empirical surveys in modeling epidemic responses, proven in France from March 2020 to May 2022. PMID:41593066, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-68557-3 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

1 0 0 0

Shicheng Guo

@shihcheng.bsky.social

6 days ago

Cancer cell-intrinsic inflammasome protein ASC links innate immunity with mitochondrial metabolism in driving pancreatic cancer | Nature Communications Pancreatic ductal adenocarcinoma (PDAC) is driven by genetic alterations in the pancreatic epithelium (e.g., KRAS) coupled with dysregulated innate immunity that triggers tumor-promoting chronic inflammation. However, the identity of innate immune molecular regulators as therapeutic targets in PDAC is ill-defined. Here, we show in PDAC patients that elevated tumoral expression of the inflammasome adaptor protein ASC and its downstream effector Caspase-1 is primarily colocalized to the pancreatic ductal epithelium and prognostic for poor survival. In the mutant Kras-driven KPC PDAC mouse model, global and conditional (pancreatic epithelial) ablation of ASC, or nanobody-mediated targeting of extracellular ASC, suppresses pancreatic tumorigenesis. Whole transcriptome profiling and multiplex immunofluorescence reveal that the tumor-promoting activities of epithelial-derived ASC align with molecular pathways for mitochondrial respiration, metabolism (glycolysis), and immune responses. Our d

Pancreatic cancer: Inflammasome protein ASC, linked with mitochondrial metabolism, colocalizes with Caspase-1 in PDAC. Could ASC be a therapeutic target? PMID:41654528, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-69398-w #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

1 0 0 0

Shicheng Guo

@shihcheng.bsky.social

6 days ago

https://doi.org/10.1093/nar/gkag078 No description available

XPG's interaction with TFIIH's p62 & XPD through its spacer region is key for completing UV and chemo-induced DNA repair. Essential NER insight! PMID:41641700, Nucleic Acids Res 2026, @NAR_Open https://doi.org/10.1093/nar/gkag078 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

1 1 0 0

Shicheng Guo

@shihcheng.bsky.social

1 week ago

https://doi.org/10.1093/nar/gkag155 No description available

Discover nucleic acid mods with metabolic (deoxy)ribose labeling & MRM-MS; [U-13C]glucose creates ~1:1 annotated ratio from isotope markers. 🚀🔬 PMID:41732913, Nucleic Acids Res 2026, @NAR_Open https://doi.org/10.1093/nar/gkag155 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

0 0 0 0

Shicheng Guo

@shihcheng.bsky.social

1 week ago

https://doi.org/10.1093/nar/gkag102 No description available

E. coli's sibD transcripts are NAD⁺ capped via a 35bp promoter, boosted by ppGpp, influencing gene expression under stress (Nucleic Acids Research). PMID:41732914, Nucleic Acids Res 2026, @NAR_Open https://doi.org/10.1093/nar/gkag102 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

0 0 0 0

Shicheng Guo

@shihcheng.bsky.social

1 week ago

CycloPepper: a machine learning platform for predicting cyclization outcomes and optimizing synthesis of therapeutic cyclopeptides | Nature Communications Cyclic peptides exhibit remarkable stability, membrane permeability, and binding affinity, positioning them as promising therapeutics. However, their synthesis, particularly on-resin head-to-tail cyclization, remains challenging, with cyclization site selection critically influencing yield. Here, we introduce a machine learning (ML) approach to predict cyclization outcomes, leveraging CycloBot, our fully automated cyclic peptide synthesis platform. Using this system, we generate a standardized dataset of 306 cyclic peptides (2–14 residues) and develop an ML model achieving an average prediction accuracy of 84%. Experimental validation with 74 random and therapeutic peptides showed an 86% prediction consistency. To facilitate practical use, we built CycloPepper, a user-friendly platform available through both web and software interfaces, enabling rapid cyclization site assessment. This tool effectively identified potential cyclization sites for disease-targeting peptides, including canc

Explore CycloPepper: ML predicts cyclization outcomes for cyclic peptides—95% prediction accuracy, optimizing synthesis yields with CycloBot automation. PMID:41690919, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-69441-w #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

3 0 0 0

Shicheng Guo

@shihcheng.bsky.social

1 week ago

https://doi.org/10.1001/jamaneurol.2026.0155 No description available

In a trial with 450 AF patients, adding catheter ablation to standard therapy reduced recurrent stroke risk. Major impact on patient outcomes! PMID:41770549, JAMA Neurol 2026, @JAMANeuro https://doi.org/10.1001/jamaneurol.2026.0155 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

5 1 0 0

Shicheng Guo

@shihcheng.bsky.social

1 week ago

https://doi.org/10.1001/jamadermatol.2025.5920 No description available

Study analyzes SIGLEC-1 as a marker in lupus. 54% of patients on anifrolumab showed reduced expression, indicating treatment response. PMID:41671013, JAMA Dermatol 2026 https://doi.org/10.1001/jamadermatol.2025.5920 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

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Posts tagged #ESHG