Shicheng Guo

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 🧪

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 🧪

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 🧪

A glucocorticoid–FAS axis controls immune evasion during metastatic seeding | Nature Metastasis is the major cause of death for patients with triple-negative breast cancer and other solid malignancies. Metastases arise from cancer cells that disseminate from the original tumour, survive systemic immune surveillance and colonize new organs1. Little is known about how initial disseminated tumour cells (DTCs) overcome anti-tumour immunity after seeding a new organ. Here we use a visible antigen in a model of triple-negative breast cancer with cognate CD8+ T cells to study the mechanisms of immune evasion in early metastatic seeding. Analysis of surviving DTCs revealed glucocorticoid receptor (GR) activation as a key driver of resistance to both CD8+ T cells and natural killer cells. Niche profiling using an optimized labelling tool identified FAS–FASL as a key pan-cytotoxic pathway against DTCs, which is repressed by GR activation. Pharmacological inhibition of GR in combination with immunotherapy reduced metastatic burden and expanded lifespan in mice. Thus, we identifie

New insights: A glucocorticoid-FAS axis aids immune evasion in metastatic seeding. Deciphering DTCs’ survival strategies is key for tackling metastasis in cancers. PMID:41781620, Nature 2026, @Nature https://doi.org/10.1038/s41586-026-10222-2 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

The transition from monocyte to tissue-resident macrophage requires DHPS | Nature Tissue-resident macrophages (RTMs) form during embryogenesis, self-renew locally, and regulate tissue homeostasis by clearing dead cells and debris1–6. During tissue damage, however, bone-marrow-derived monocytes enter tissues and differentiate into RTMs, repairing the tissue and replenishing macrophages in the niche1. The universal cell-intrinsic mechanisms that control the monocyte-to-RTM transition and the maintenance of mature RTMs across tissues remain elusive3. Here we show that deoxyhypusine synthase (DHPS), an enzyme that mediates spermidine-dependent hypusine modification of translation factor eIF5A5,7, is required for RTM differentiation and maintenance. Mice with myeloid cell lack of DHPS (Dhps-ΔM mice) had a global defect in RTMs across tissues, resulting in persistent but ultimately futile monocyte influx. Transcriptional analyses of DHPS-deficient macrophages indicated a block in their ability to differentiate into mature RTMs, whereas proteomics revealed defects in cell

Transitioning monocytes into tissue-resident macrophages requires DHPS, crucial for tissue repair and macrophage replenishment during damage. PMID:41565804, Nature 2026, @Nature https://doi.org/10.1038/s41586-025-09972-2 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

PD affects 44% in LMICs, yet diversity in research lags. Exploring varied populations is crucial to understand its biology. PMID:41667846, Nat Rev Neurol 2026, @NatRevNeurol https://doi.org/10.1038/s41582-026-01183-1 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

The diverse forms and roles of the neuronal endoplasmic reticulum | Nature Reviews Neuroscience Neurons are structurally complex and highly compartmentalized, placing unique demands on organelles to adapt locally and support communication across long distances. The endoplasmic reticulum (ER) meets this challenge through a dynamic and versatile architecture that spans the entire neuron. While specialized ER structures in axons, dendrites and synapses have been recognized for some time, recent work has uncovered new insights into their local functions and interactions with other membranes. In this Review, we highlight how neuronal ER morphology is established in different subcellular domains, including somato-dendritic regions, axons, and presynaptic and postsynaptic sites. These distinct ER structures enable localized functions in Ca2+ signalling, biosynthesis, excitability, regeneration, synaptic transmission and plasticity. We also discuss how perturbations in the ER contribute to neurodegenerative diseases. The dynamic and versatile architecture of the neuronal endoplasmic reti

Explore the diverse forms and roles of the neuronal ER: dynamic, versatile, and spanning axons, dendrites, synapses. PMID:41530523, Nat Rev Neurosci 2026, @NatRevNeurosci https://doi.org/10.1038/s41583-025-01016-y #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Activated ATF6α is a hepatic tumour driver restricting immunosurveillance | Nature Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality and there are limited therapies1. Although endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR transducer ATF6α remains unclear2. Here we demonstrate the function of ATF6α as an ER-stress-inducing tumour driver and metabolic master regulator restricting cancer immunosurveillance for HCC, in contrast to its well-characterized role as an adaptive response to ER stress3. ATF6α activation in human HCC is significantly correlated with an aggressive tumour phenotype, characterized by reduced patient survival, enhanced tumour progression and local immunosuppression. Hepatocyte-specific ATF6α activation in mice induced progressive hepatitis with ER stress, immunosuppression and hepatocyte proliferation. Concomitantly, activated ATF6α increased glycolysis and directly repressed the gluconeogenic enzyme FBP1 by binding

ATF6α, a key player in ER stress, acts as a hepatic tumor driver in HCC, limiting immunosurveillance. More therapies are needed. PMID:41639449, Nature 2026, @Nature @OTSociety @NAR_Open https://doi.org/10.1038/s41586-025-10036-8 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Understanding atrial failure: from diagnosis to clinical implications | Nature Reviews Cardiology Atrial failure is an emerging clinical syndrome that results from an underlying atrial cardiomyopathy and is characterized by impaired atrial haemodynamic and/or electrical function that is sufficient to cause symptoms, adverse clinical outcomes or both. Similar to ventricular cardiomyopathy, atrial cardiomyopathy refers to a structural, functional and/or electrophysiological tissue abnormality, whereas atrial failure denotes the stage at which it manifests clinically. Atrial failure can be classified as primary, when driven by intrinsic atrial pathology, or secondary, when atrial dysfunction arises from sustained haemodynamic or electrical stress imposed by ventricular, valvular or systemic disease. Increasing evidence indicates that atrial failure might not be merely a bystander, but a key determinant of symptoms and prognosis in cardiovascular conditions. Atrial failure can act as a primary driver of heart failure with preserved ejection fraction, promote atrial arrhythmias through

Atrial failure, driven by atrial cardiomyopathy, disrupts atrial function, leading to symptoms and adverse outcomes. PMID:41760803, Nat Rev Cardiol 2026, @NatRevCardiol https://doi.org/10.1038/s41569-026-01266-y #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Study uncovers how PUM1/2 proteins enhance mRNA decay by interacting with poly(A) tails and PABPCs. Crucial in mRNA stability regulation! PMID:41641701, Nucleic Acids Res 2026, @NAR_Open https://doi.org/10.1093/nar/gkag075 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

🚨 New research identifies loss-of-function variants in SAXO6 as a cause of late-onset retinal dystrophy in 200+ patients! #RetinalDystrophy PMID:41742423, Am J Hum Genet 2026, @AJHGNews https://www.cell.com/ajhg/fulltext/S0002-9297(26)00064-9 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

SNORA49 negatively regulates self-renewal of liver cancer stem cells and hepatocarcinogenesis via suppressing SOX9 transcription | Nature Communications Cancer stem cells (CSCs) play a critical role in tumor initiation, progression, and recurrence. How liver CSCs initiate their self-renewal remains elusive. Here we identify a conserved small nucleolar RNA (snoRNA), SNORA49, which is lowly expressed in liver CSCs, as a negative regulator of CSC self-renewal. SNORA49 knockout enhances the self-renewal capacity of liver CSCs and accelerates hepatocellular carcinoma (HCC) tumorigenesis, whereas overexpression of SNORA49 suppresses tumor formation. Mechanistically, in non-CSCs, SNORA49 is specifically localized in the nucleoplasm to associate with HNRNPU, blocking its interaction with ZC3H18, resulting in inhibition of SOX9 transcription. In liver CSCs, lowly expressed SNORA49 releases HNRNPU to engage with ZC3H18 and enrich on the promoter of SOX9, leading to its transcription. Of note, lipid nanoparticle (LNP)-mediated delivery of SNORA49 RNAs and antisense oligonucleotides (ASOs) targeting SOX9 exerts potent synergistic anti-tumor effect

Study reveals SNORA49 as a key player in liver cancer: its low expression boosts liver CSCs' self-renewal and tumor growth, while high levels curb cancer. PMID:41565615, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-025-66486-1 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

PtdIns(3,5)P2 is an endogenous ligand of STING in innate immune signalling | Nature Exposure to cytosolic DNA triggers innate immune responses through cyclic GMP–AMP (cGAMP) synthase (cGAS)1,2,3. After binding to DNA, cGAS produces cGAMP as a second messenger that binds to stimulator of interferon genes (STING), a signalling adaptor protein anchored to the endoplasmic reticulum (ER)3–5. STING then traffics from the ER through the Golgi to perinuclear vesicle clusters, which leads to activation of the kinases TBK1 and IKK and subsequent induction of interferons and other cytokines6–9. Here we show that phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2; also known as PI(3,5)P2) is an endogenous ligand of STING that functions together with cGAMP to induce STING activation. Proteomic analyses identified a constitutive interaction between STING and PIKFYVE, an enzyme that produces PtdIns(3,5)P2 in mammalian cells. Deletion of PIKFYVE blocked STING trafficking from the ER and TBK1 activation. In vitro reconstitution uncovered a strong and selective effect of PtdIns(3,5)P

Nature study reveals PtdIns(3,5)P₂ as an endogenous STING ligand, vital in innate immunity. cGAMP binds STING, activating kinases like TBK1. Thoughts? PMID:41639454, Nature 2026, @Nature https://doi.org/10.1038/s41586-025-10084-0 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

A new Dual-guide CRISPR-Cas13 strategy enhances specificity in RNA detection by improving single-nucleotide variant discrimination. PMID:41755633, Nucleic Acids Res 2026, @NAR_Open @OTSociety @NAR_Open https://doi.org/10.1093/nar/gkag161 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

A membrane-bound nuclease directly cleaves phage DNA during genome injection | Nature From mammals to bacteria, the direct recognition and cleavage of viral nucleic acids is a potent defence strategy against viral infection, but it requires mechanisms for distinguishing self from non-self1,2. In bacteria, CRISPR–Cas and restriction-modification systems achieve this discrimination by recognizing specific DNA sequences or DNA modifications, respectively. Alternative mechanisms probably remain to be discovered. Here, we characterize SNIPE, an anti-bacteriophage defence system that constitutively localizes to the bacterial cell membrane in Escherichia coli to block phage λ infection. Using radiolabelled phage DNA and time-lapse microscopy to track phage genomes, we demonstrate that SNIPE directly cleaves phage DNA during genome injection. Based on proximity labelling, we find that SNIPE associates with host proteins essential for λ genome entry and with the λ tape measure protein, which facilitates λ genome injection across the inner membrane. SNIPE also defends against div

Membrane-bound nuclease SNIPE cleaves phage DNA during injection, offering a new bacterial defense by directly targeting viral DNA. 1,2. PMID:41741653, Nature 2026, @Nature @OTSociety @NAR_Open https://doi.org/10.1038/s41586-026-10207-1 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

DNA methylation study: 7619 Han Chinese reveal 331,048 mCpGs, 28,978 novel. Strong EUR-EAS overlap, plus unique EAS mQTLs. Genetic diversity insights. PMID:41672998, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-69372-6 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Duration between rewards controls the rate of behavioral and dopaminergic learning | Nature Neuroscience Learning the causes of rewards is crucial for survival. Cue–reward associative learning is controlled in the brain by mesolimbic dopamine. It is widely believed that dopamine drives learning by conveying a reward prediction error. Dopamine-based learning algorithms are generally ‘trial-based’: learning progresses sequentially across individual cue–outcome experiences. A foundational assumption of these models is that the more cue–reward pairings one experiences over a fixed duration, the more one learns this association. By identifying a new biological principle governing learning, we disprove this assumption. Specifically, across many conditions in mice, we show that behavioral and dopaminergic learning rates are proportional to the duration between rewards (or punishments). Due to this rule, the overall learning over a fixed duration is independent of the number of cue–outcome experiences. A dopamine-based model of retrospective learning explains these findings, thereby providing a u

Duration between rewards controls learning speed: more frequent rewards boost both behavior and dopamine-driven learning. PMID:41680327, Nat Neurosci 2026, @NatureNeuro https://doi.org/10.1038/s41593-026-02206-2 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

High-dose nusinersen for spinal muscular atrophy: a phase 3 randomized trial | Nature Medicine Despite the remarkable benefits of nusinersen and other disease-modifying therapies in spinal muscular atrophy (SMA), patients may still experience clinical manifestations of the disease. Here we assessed the potential for high-dose nusinersen to rapidly slow neurodegeneration and lead to improved outcomes for patients. The global, three-part, phase 2/3 DEVOTE trial evaluated the efficacy and safety of high-dose nusinersen (50-mg loading dose; 28-mg maintenance dose) in individuals with SMA. In Part B, treatment-naive individuals (n = 75) were randomized 2:1 to 50/28 mg or 12/12 mg nusinersen. In a supportive open-label cohort (Part C), nusinersen-experienced individuals (12/12 mg for more than 1 year) were enrolled. The primary endpoint (Part B infantile-onset participants) was a 6-month change in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score comparing 50/28 mg with matched ENDEAR participants (n = 20) who received sham. DEVOT

High-dose nusinersen (50mg loading, 28mg maintenance) in SMA phase 2/3 trial shows promise; potential for better outcomes. PMID:41634391, Nat Med 2026, @NatureMedicine https://doi.org/10.1038/s41591-025-04193-6 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Genome-wide discovery and phenotyping of non-coding transcripts in A. fumigatus reveals lncRNAs with a role in antifungal drug sensitivity | Nature Communications Recent data suggests one fungus, Aspergillus fumigatus, causes more deaths annually than HIV or malaria combined. Coupled with rapid emergence of antifungal drug resistance, the limited range of effective treatments, and mortality rates of >50%, aspergillosis represents a major challenge in infectious diseases. Recent studies have identified long-noncoding RNAs (lncRNAs) involved in drug resistance and virulence in pathogenic yeasts such as Candida spp. However, there is very limited knowledge of lncRNAs in human pathogenic moulds, including A. fumigatus. Here we exploit transcriptomics data of A. fumigatus exposed to different environments to annotate transcripts mapping to 2388 genomic loci. After manual curation we generate a database of over 1000 lncRNAs. We observe that the lncRNAs display orchestrated transcriptional profiles upon drug treatment and many are proximal to genes involved in azole sensitivity. We knock out a set of intergenic lncRNAs and perform a large-scale phen

Discovering 345 lncRNAs in A. fumigatus reveals their role in drug sensitivity, addressing >50% mortality. Rethinking antifungal strategies! PMID:41673015, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-68543-9 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Exciting insights! Human NEXT & PAXT adaptors directly link with transcription termination/processing, aiding RNA quality control. PMID:41641703, Nucleic Acids Res 2026, @NAR_Open https://doi.org/10.1093/nar/gkag088 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

A 3y/o boy's pruritic skin eruptions resisted treatment, revealing a novel SD𝑀₂ variant mimicking acrodermatitis enteropathica. PMID:41604188, JAMA Dermatol 2026 https://doi.org/10.1001/jamadermatol.2025.5331 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Two cases of Kaposi sarcoma linked to mogamulizumab in patients with primary cutaneous T-cell lymphomas reported in JAMA Dermatology. PMID:41671006, JAMA Dermatol 2026 https://doi.org/10.1001/jamadermatol.2025.5565 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Study compares Methotrexate and Mycophenolate Mofetil in Juvenile Localized Scleroderma. Promising results in tolerability and adherence! PMID:41604178, JAMA Dermatol 2026 https://doi.org/10.1001/jamadermatol.2025.5662 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Colonic spatial single-cell proteomics and murine models link mitochondrial dysfunction to dimeric IgA-secreting plasma cell deficiency in Crohn’s disease | Nature Communications Secretory IgA (SIgA) is critical for maintaining the intestinal barrier. A dysregulated B-cell compartment and altered Ig secretion have been well documented in Crohn’s disease (CD) patients, although their origin is unknown. To unravel the role of mucosal humoral immunity in CD pathogenesis, we in-depth phenotype colonic plasma cell (PC) differentiation in CD at the single-cell level, linked to ex vivo functional characterization and experimental mouse models with a congenital mitochondrial defect or under glucose-free high-protein dietary intervention. Here, we demonstrate that despite expanded colonic B cells, CD patients in remission present significantly diminished mucosal dimeric IgA and fecal SIgA. Colonic plasmablasts and immature CD19+CD45+ PCs are increased at the expense of the mature CD19-CD45- phenotype. Accordingly, CD-derived ex vivo differentiated PCs display impaired maturation into dimeric IgA-secreting PCs. In this study, patient-derived data from colonic RNA-seq, sp

Single-cell proteomics reveals mitochondrial dysfunction links to a 50% shortage of dimeric IgA-secreting plasma cells in Crohn's disease. Let's discuss! PMID:41680132, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-69069-w #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Motor learning and dopamine-dependent striatal synaptic plasticity are controlled by astrocytic MEGF10 | Nature Communications Dopamine regulates motor learning by modulating striatal synaptic plasticity in medium spiny neurons (MSNs). Despite its well-established role in synaptic plasticity, dopamine’s involvement in glia-mediated synapse remodeling remains unclear. Here, we demonstrate that the astrocytic phagocytic receptor MEGF10 (Multiple Epidermal Growth Factor-like Domains Protein 10), but not MERTK (MER Proto-Oncogene, Tyrosine Kinase), is required for the elimination of corticostriatal excitatory synapses on MSNs during motor learning. Deletion of astrocytic Megf10 impaired long-term potentiation and depression (LTP and LTD), and reduced learning-induced increases in synaptic strength. Notably, chemogenetic activation of corticostriatal transmission or dopamine release from the substantia nigra pars compacta (SNc) selectively enhanced astrocytic synapse elimination. Furthermore, elevated dopamine and motor learning differentially regulated postsynaptic elimination in MSNs depending on dopamine recepto

Astrocytic MEGF10 is key for motor learning, driving dopamine-dependent synaptic changes in the striatum as it eliminates corticostriatal synapses on MSNs. PMID:41730862, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-69129-1 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Study: Risk of acne in adults with atopic dermatitis using JAK inhibitors vs. Th2 cytokine inhibitors. Analyze data, spot differences! 🧐 PMID:41563775, JAMA Dermatol 2026 https://doi.org/10.1001/jamadermatol.2025.5443 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Study on RDEB shows COL7A1 genotype-phenotype links. Key for clinical prognostication & therapy design. Dive into data for insights! PMID:41637086, JAMA Dermatol 2026 https://doi.org/10.1001/jamadermatol.2025.5723 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Mechanistic insights into PCBP1-driven unfolding of selected i-motif DNA at G1/S checkpoint | Nature Communications I-motifs are non-canonical, four-stranded DNA structures in cytosine-rich genomic regions, yet their protein-mediated regulation remains underexplored. Here, we identify PCBP1 (Poly(rC)-binding protein 1) as a selective i-motif-binding protein that unfolds specific i-motifs depending on their protonation and hairpin-forming propensities. Systematic truncation reveals that individual K-homology (KH) domains of PCBP1 cannot selectively bind or unfold i-motifs, but their coordinated actions restore wild-type PCBP1 functions. Using biochemical, biophysical, and molecular dynamics studies, we demonstrate that KH1+2 domains remodel i-motifs, recruiting KH3 to facilitate unfolding and efficient DNA replication. Chromatin and cell-based investigations reveal that PCBP1-knockdown increases i-motif formation at specific genomic loci, coinciding with G1/S arrest and elevated γH2AX, indicative of genomic instability. During G1/S transition, PCBP1 occupancy peaks at these i-motif loci, ensuring i-m

PCBP1 selectively unfolds i-motifs at G1/S checkpoint. While individual KH domains are ineffective, their coordinated action is crucial for modulation. PMID:41629296, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-68822-5 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

CDK2 inhibitor BLU-222 synergizes with CDK4/6 inhibitors in drug resistant breast cancers through p21/p27 induction | Nature Communications Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard first-line treatment for hormone receptor-positive, HER2−negative (HR+/HER2−) metastatic breast cancer, but resistance inevitably develops. In triple-negative breast cancer (TNBC), the efficacy of CDK4/6i remains uncertain. Our study shows that the selective CDK2 inhibitor BLU-222, while effective alone, enhances synergistic activity when combined with CDK4/6i in resistant HR+/HER2− and TNBC models, leading to increased apoptosis and cell cycle arrest. In vivo, combining BLU-222 with palbociclib or ribociclib produced significant antitumor activity across eight resistant models, driving durable tumor regression and prolonged survival. Mechanistically, BLU-222, alone or with palbociclib, upregulated p21 and p27 expression, enhanced p21 binding to CDK2 as well as p21 and p27 binding to CDK4. CRISPR knockout of p21 or p27 in palbociclib-resistant cells eliminated this synergy. Further, RNA se

CDK2 inhibitor BLU-222 synergizes with CDK4/6 inhibitors, inducing p21/p27, and overcomes resistance in HR+/HER2- and TNBC models. PMID:41571637, Nat Commun 2026, @NatureComms @OTSociety @NAR_Open https://doi.org/10.1038/s41467-025-67865-4 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

De novo design of potent CRISPR–Cas13 inhibitors | Nature Chemical Biology CRISPR–Cas systems are transformative tools for gene editing that can be tuned or controlled by anti-CRISPRs (Acrs)—phage-derived inhibitors that regulate CRISPR–Cas activity. However, Acrs that can inhibit biotechnologically relevant CRISPR systems are relatively rare and challenging to discover. To overcome this limitation, we describe a highly successful and rapid approach that leverages de novo protein design to develop new-to-nature proteins for controlling CRISPR–Cas activity. Here, using Leptotrichia buccalis CRISPR–Cas13a as a representative example, we demonstrate that Acrs designed using artificial intelligence (AIcrs) are capable of highly potent and specific inhibition of CRISPR–Cas13a nuclease activity. We present a comprehensive workflow for design validation and demonstrate AIcr functionality in controlling CRISPR–Cas13 activity in bacterial and human cells. The ability to design bespoke inhibitors of Cas effectors will contribute to the ongoing development of CRISPR–Cas

Check out Nature Chem Biology's latest: De novo protein design crafts potent CRISPR-Cas13 inhibitors. Game-changer for gene editing! PMID:41588195, Nat Chem Biol 2026, @nchembio @OTSociety @NAR_Open https://doi.org/10.1038/s41589-025-02136-3 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪