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 🧪

1/18 Wang collected the optic glands from #octopuses at each phase and sequenced the #RNA transcriptome of each.

RNA carries instructions from #DNA about how to produce proteins, so sequencing it is a good way to understand the activity of genes and what’s going on inside cells at a given time.

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 🧪

Eterna Town Hall soon
March 14, 2026 16:00 UTC

Anthony Stohr (University of Delaware) will discuss the incorporation of highly efficient Eterna switches into a metabolite-responsive scaffold RNA (MR-scRNA) for conditional control of CRISPR activation.

Come join us!
#RNA #citizenscience

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 🧪

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 🧪

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 🧪

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 🧪

🧪 Tiny molecular differences can rewrite big origin-of-life questions!
HFSP-supported research shows simple coacervate droplets could have supported early RNA chemistry, reshaping ideas about the transition from #RNA to #DNA worlds.

#OriginOfLife #sts #HFSP
🔗 zurl.co/ZMFM3

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 🧪

Great talk by Phillip Yesley from the group of Wim Velema at #Lunteren2026.

He discussed the use of mutational profiling to find covalent ligands for structured #RNA using acyl imidazoles as the reactive group.

onlinelibrary.wiley.com/doi/10.1002/...
#ChemSky #ChemBio #Covalent #CovalentInhibitor

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 🧪

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 🧪

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 🧪

New work @jem.org from Duan, Fairbrother et al. @brown.edu reveals how intronic Alu repeats and #RNA metabolism shape endogenous #dsRNA levels and cell-intrinsic immunity. rupress.org/jem/article/...

#InnateImmunity #Inflammation

New work from Duan, Fairbrother et al. @brown.edu reveals how intronic Alu repeats and #RNA metabolism shape endogenous #dsRNA levels and cell-intrinsic immunity. rupress.org/jem/article/...

#InnateImmunity #Inflammation

The newly discovered tiny QT45 ribozyme, shown here in an artist’s depiction, helped researchers explore the origins of life. Image credit: Elfy Chiang, microscopy image by James Attwater.

Short strands of #RNA nearly self-replicate, recreating a possible step in the dawn of #life. In PNAS Journal Club: https://ow.ly/XjtL50YsUIS

#OriginsofLife #ribozyme #RNAWorldHypothesis

Hot off the press from the RTI: Conjugated Antisense Oligonucleotides for Skipping of Duchenne Muscular Dystrophy Exon 53: A Cautionary Study

buff.ly/AMsTrGa #RNA #RNATherapeutics @UMassChan

Conjugated Antisense Oligonucleotides for Skipping of Duchenne Muscular Dystrophy Exon 53: A Cautionary Study - PubMed Exon skipping antisense oligonucleotides (AONs) have been extensively studied as a promising method of treating Duchenne muscular dystrophy (DMD), yet the clinical efficacy of the conditionally approved...

Hot off the press from the RTI: Conjugated Antisense Oligonucleotides for Skipping of Duchenne Muscular Dystrophy Exon 53: A Cautionary Study
pubmed.ncbi.nlm.nih.gov/41814159/?ut... #RNA #RNATherapeutics

First group lunch of the year! We had a good start to the year; 4 PhD Theses recently submitted, several papers, 2 new Honours students joining, and our Honours student from last year returning to do a PhD with a University Medal in tow. So we celebrated with a delicious Thai lunch! #ozchem #RNA

Bacteriophage-Encoded Small RNAs: Emerging Tools for Phage Therapy and Antibacterial Intervention - Aviezer Silverman, Sahar Melamed, 2026 Bacteriophages (phages) are viruses that specifically infect bacteria and play a central role in shaping microbial communities and bacterial evolution. Beyond t...

🚨Happy to share our new mini-review on phage-encoded small RNAs and their potential for phage therapy and antibacterial strategies, written with Aviezer Silverman!
journals.sagepub.com/doi/10.1177/...
#RNA
#phage
@journals.sagepub.com
@hebrewuniversity.bsky.social
@phagedirectory.bsky.social

I'm going to start exploring this in a somewhat naive style, to see where I get. In this case, it's about a new gene therapy based on viral RNA against hepatitis A, for DIANA.
#illustration #health #illustration #DIANA #RNA #hepatitisA #naive #digitalillustration #virus #therapy #treatment

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 🧪

ML for RNA secondary structure: Review of field's evolution from classical methods to DL and foundation models. Explores data evolution, the generalization crisis, struggles, and perspectives #RNA #DeepLearning bit.ly/4az24YW

Congratulations to our National Cancer Institute scholarship awardees: Anamica Das, Natalia Pinello Gini, Eleni Liapi, Benedetta Ricci, Fu Xu & Kohki Yamada.

The future of RNA biology and epitranscriptomics looks bright! ✨

#RNA #RNAModifications #Epitranscriptomics #CancerResearch

Tiny, 45 base long RNA can make copies of itself Self-copying RNAs may have been a key stop along the pathway to life.

🔄 Tiny, 45 base long RNA can make copies of itself

arstechnica.com/science/2026...

#rna #molecules #replication #molbio

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 🧪

NCN @ncn.gov.pl project spotlight 🔬
We investigate how mRNA folds in vivo, how its structure changes across the cell, and how RNA structure regulates gene expression in yeast. #RNA #mRNA #RNAstructure #GeneExpression #Yeast

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 🧪

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 🧪