Shicheng Guo

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 🧪

A missense variant in ASCL5 is found in all 17 patients with lobodontia. The study involves Thai and Croatian families. PMID:41673016, Nat Commun 2026, @NatureComms @OTSociety @NAR_Open https://doi.org/10.1038/s41467-026-69323-1 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

A short-acting psychedelic intervention for major depressive disorder: a phase IIa randomized placebo-controlled trial | Nature Medicine Major depressive disorder (MDD) is a leading cause of disability worldwide, yet many patients have inadequate responses to current treatments. Dimethyltryptamine (DMT), a serotonergic psychedelic with rapid onset and short duration, shows promise as a potential antidepressant (AD), although clinical evidence in MDD remains limited. We conducted a phase IIa, double-blind, placebo-controlled, randomized clinical trial to evaluate the efficacy and safety of intravenous DMT (SPL026; DMT fumarate) in adults with moderate-to-severe MDD. Participants received a single 21.5-mg dose of DMT or placebo infused over 10 min, along with supportive psychotherapeutic support, followed by a 2-week assessment. A subsequent open-label phase offered all participants a second DMT dose. The primary outcome was the change in Montgomery–Åsberg Depression Rating Scale (MADRS) at 2 weeks. Secondary outcomes included response (≥50% reduction in MADRS score) and remission (MADRS ≤ 10). A total of 34 participants

Phase IIa study: 34% MDD patients improved with intravenous DMT (SPL026), highlighting potential rapid antidepressant effects. PMID:41699126, Nat Med 2026, @NatureMedicine https://doi.org/10.1038/s41591-025-04154-z #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Targeting excessive cholesterol deposition alleviates secondary lymphoedema | Nature Lymphoedema is a chronic debilitating disease caused by impaired lymphatic drainage and is characterized by tissue swelling, fat expansion, inflammation and fibrosis1,2. However, the exact mechanisms that drive lymphoedema are poorly understood. Although lymphatic vessels are known to transport cholesterol from peripheral tissues back to the systemic circulation3, the importance of impaired lymphatic drainage for cholesterol clearance in humans and its relevance to lymphoedema remain unknown. Here we show that lymphatic drainage insufficiency in human lymphoedema leads to excessive cholesterol accumulation in the lymphoedematous dermal tissue and around lymphatic vessels. Cholesterol deposition resulted in dermal adipose tissue remodelling, characterized by adipocyte hypertrophy and dysfunction, progressing to death and dermal fibrosis. Surgical intervention improved lymphatic drainage and reduced cholesterol deposition. Using two mouse models that reproduce features of human lymphoede

Study unveils that targeting cholesterol buildup can relieve secondary lymphoedema symptoms like swelling, fat gain, and inflammation. Discover new relief! PMID:41673147, Nature 2026, @Nature https://doi.org/10.1038/s41586-025-10016-y #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Innovative "Trikines" form 3-chain cytokine receptor complexes, activating unique pSTAT5 and pSTAT3 pathways unlike IL-2 or IL-10. PMID:41712697, Science 2026, @ScienceMagazine https://doi.org/10.1126/science.adx9954 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Exciting findings: Mutating a CUG codon blocks toxic DPR production, rescuing ALS/FTD phenotypes without affecting repeat RNAs. [74]-times! PMID:41643021, Science 2026, @ScienceMagazine https://doi.org/10.1126/science.adv2600 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Discover how DAMAGE (Death Manipulation Gene) innovatively fuses gasdermins with type III-E CRISPR, enhancing pyroptosis control. PMID:41667457, Nat Commun 2026, @NatureComms @OTSociety @NAR_Open https://doi.org/10.1038/s41467-026-69179-5 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Hearing loss related genes: ESPN, TRIOBP, MYO6, ANKRD24, ADGRV1, HOMER2, CLRN2, COL11A1, OTOR, ILDR1, MARVELD2, TMPRSS3, ATP6V0A4, LOXHD1, MSRB3, PJVK, STX4, EYA4, REST, CCDC2. Let's write an literature review paper to review each of them. Interested in, let's contact!

Innate antiviral and immune functions associated with the HIV reservoir decay after anti-PD-1 therapy | Nature Medicine Antiretroviral therapy (ART) suppresses HIV but does not eliminate the latent viral reservoir, which persists in programmed cell death protein 1 (PD-1)-expressing CD4+ T cells. Anti-PD-1 therapies have reduced the HIV reservoir in people living with HIV (PLWH) and cancer; however, the individuals who benefit and the mechanisms driving reservoir reduction remain unclear. We performed a prespecified exploratory, longitudinal multiomic profiling of 30 PLWH (29 males and one female) with cancer in the phase 1 CITN-12 clinical trial, in which pembrolizumab was evaluated for safety and preliminary antitumor activity. The therapy was generally well tolerated, with most adverse events graded 1–2 and objective antitumor response observed in five participants (one complete response and four partial responses). Within 24 hours of treatment, we observed an expansion of proliferating HIV-specific effector CD8+ T cells and a decline in plasma TGFβ. Furthermore, among the 14 participants tracked to t

Study: Anti-PD-1 therapy reduces HIV reservoirs in CD4+ T cells in 30 PLWH (29M, 1F); explores mechanisms behind this reduction. PMID:41680482, Nat Med 2026, @NatureMedicine https://doi.org/10.1038/s41591-025-04139-y #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

DNMT1 tracking shows its mobility dynamics change during the cell cycle. Only ~12% chromatin-binding in S phase sustains methylation. PMID:41641704, Nucleic Acids Res 2026, @NAR_Open https://doi.org/10.1093/nar/gkag089 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Discover the DBDIY array: a droplet-based, high-throughput immunoassay using patterned plasmonic chips. Max sensitivity, minimal costs, and user-friendly. PMID:41690928, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-69570-2 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Af-CUT&Tag: a sensitive and antibody-free chromatin profiling method using genetically encoded tags and high-affinity binders fused to Tn5 | Nature Communications Conventional chromatin profiling techniques are often limited by antibody availability and performance. Here, we introduce Af-CUT&Tag, a target antibody-free method that overcomes these limitations by using CRISPR-integrated peptide tags (HiBiT/ALFA-tag) recognized by engineered binders (LgBiT/NbALFA) fused to a Tn5 transposase. Af-CUT&Tag eliminates dependence on traditional target antibodies, achieving robust specificity and sensitivity with as few as 500 cells. It provides high-quality chromatin profiles, with improved signal-to-noise ratios and library quality compared with conventional antibody-based counterparts, while also enabling single-cell resolution (scAf-CUT&Tag). Applying Af-CUT&Tag to Hippo effectors (YAP1/TAZ) during liver regeneration reveals dynamic chromatin remodeling, including YAP1/TAZ-mediated control of lipid metabolism (e.g., Lpin1, Fasn) and heme clearance (Hpx, Trf). We further identify miR-122 as a critical regulator of these processes, impac

Discover Af-CUT&Tag: a breakthrough in chromatin profiling with CRISPR tags & engineered binders. High fidelity in just 500 cells! PMID:41547832, Nat Commun 2026, @NatureComms @OTSociety @NAR_Open https://doi.org/10.1038/s41467-026-68454-9 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Seq-Scope-X enhances spatial omics to submicrometer resolution. Enlarges tissues, reducing transcript diffusion effects for over 10x higher spatial detail! PMID:41667485, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-69346-8 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Next-generation therapeutics for diabetic kidney disease | Nature Reviews Nephrology Diabetes mellitus is the leading cause of chronic kidney disease and kidney failure worldwide, and diabetic kidney disease (DKD) is associated with excess cardiovascular and all-cause mortality. The pathophysiology of DKD is complex and multifactorial, characterized by physiologically redundant haemodynamic, metabolic and inflammatory pathways that promote maladaptive renal remodelling and accelerate disease progression. Current management of DKD centres around four key pillars of guideline-directed medical therapy (GDMT): renin–angiotensin–aldosterone system inhibitors, sodium-glucose cotransporter-2 inhibitors, non-steroidal mineralocorticoid receptor antagonists and glucagon-like peptide-1 receptor agonists. These therapies are increasingly used in combination for cardiorenal protection in DKD. However, substantial residual cardiorenal risk persists even among patients receiving optimal GDMT. Next-generation therapies for DKD that are currently in development include various increti

Diabetes leads to DKD as a top cause of kidney issues & death. DKD worsens via hemodynamic, metabolic & inflammatory paths. PMID:41526484, Nat Rev Nephrol 2026, @NatRevNeph https://doi.org/10.1038/s41581-025-01042-0 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Live-cell tracking reveals RNAPI/III PICs have longer chromatin interactions than RNAPII in yeast. Study quantifies kinetics of 58 proteins! PMID:41642946, Science 2026, @ScienceMagazine https://doi.org/10.1126/science.ads0960 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

In-network behavioral health access is limited: only 17% of adults get timely care, often facing 2-3x longer wait. PMID:41563784, JAMA Psychiatry 2026, @JAMAPsych https://doi.org/10.1001/jamapsychiatry.2025.4344 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Breakthrough in solar energy: Dewar pyrimidone stores sunlight as thermal energy at 1.6 MJ/kg, activated at 300 nm. A nod to DNA design! PMID:41678586, Science 2026, @ScienceMagazine https://doi.org/10.1126/science.aec6413 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Discover how single-molecule fluorescence reveals spatial-temporal dance of proteins in bacterial electron transfer, key to biotech and microbial life! PMID:41702934, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-69655-y #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

CRISPR knock-in: TCF1 pivotal for CD8+ T stem-like cells. However, TCF1 can't reverse exhaustion. Key insight in cancer therapy! PMID:41702943, Nat Commun 2026, @NatureComms @OTSociety @NAR_Open https://doi.org/10.1038/s41467-026-69671-y #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Dynamic signature of activity-stability tradeoff in lactamase evolution | Nature Communications Our ability to understand protein evolution hinges on understanding how evolutionary landscapes are shaped at the fundamental protein level. Using TEM-1 β-lactamase we show that molecular traits related to the statistical ensemble nature of protein structure contribute to broader substrate specificity, active site-scaffold communication, and the selection of stabilizing substitutions. During the evolution of cefotaxime resistance, the initial mutation reorganizes the active site, introducing a new function conformation. Secondary substitutions improve catalytic efficiency by redistributing the ensemble and restoring a significant population of the original conformation, rather than by stabilizing the new conformation. Stability defects associated with initial mutations are not evenly disseminated but are clustered at specific distal scaffold elements. The capacity of mutants to independently modulate the populations of individual active site walls and scaffold regions through narrow re

Explore how TEM-1 β-lactamase evolution reveals protein landscape intricacies! Initial mutations boost cefotaxime resistance by active site reorganization. PMID:41559101, Nat Commun 2026, @NatureComms https://doi.org/10.1038/s41467-026-68620-z #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Inhibitory probes for spatiotemporal analysis of Gαs protein signaling | Nature Chemical Biology Gαs serves as the prototypical signal transducer for G-protein-coupled receptors (GPCRs) and is the heterotrimeric G protein most frequently mutated in cancer. The classical view of the plasma membrane as the only cellular location where GPCR signal transduction occurs has been challenged by evidence suggesting that Gs also signals from intracellular compartments. However, progress on this topic has stalled because of insufficient approaches with adequate spatiotemporal resolution. Here we describe genetically encoded probes and cell-penetrating compounds that block the effector-binding site of active Gαs in cells to prevent signal propagation at discrete subcellular locations, at user-specified times and across diverse experimental conditions. Using these tools, we show direct evidence of Gαs-mediated signaling on intracellular organelles, unique spatiotemporal features of signaling by Gαs oncomutants and specific regulation of physiologically relevant responses in cardiac or immune c

Discover inhibitory probes for spatiotemporal control of Gα_s signaling, crucial in GPCRs and mutated in cancer. Stay tuned! 🔍✨ PMID:41634441, Nat Chem Biol 2026, @nchembio https://doi.org/10.1038/s41589-025-02138-1 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Microtubule depolymerization at kinetochores restricts anaphase spindle elongation | Nature Chemical Biology Anaphase chromosome segregation depends on forces exerted by spindle microtubules. Current models propose two force-generating mechanisms: kinetochore–microtubule (kMT) depolymerization pulls chromosomes toward spindle poles (anaphase A), while antiparallel microtubule sliding in the central spindle further separates sister chromosomes by elongating the spindle (anaphase B). Experimental evidence in cells supports the sliding mechanism but contributions of the depolymerization mechanism remain unclear. We show that kMT depolymerization limits spindle elongation rather than moving chromosomes apart. We developed a chemical optogenetic approach to recruit microtubule depolymerases to kinetochores at anaphase onset, thereby increasing kMT depolymerization rates without perturbing earlier stages of mitosis. We find that increased depolymerization slows the velocity at which spindle poles move apart without changing kinetochore separation velocities. Our findings support a model in which ki

Microtubule depolymerization at kinetochores limits anaphase spindle elongation, balancing forces for precise chromosome segregation. PMID:41617855, Nat Chem Biol 2026, @nchembio https://doi.org/10.1038/s41589-026-02143-y #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

Coomassie blue-derived lipidoids deliver CRISPR proteins efficiently to mouse retina. Breakthrough for inherited retinal diseases! PMID:41654520, Nat Commun 2026, @NatureComms @OTSociety @NAR_Open https://doi.org/10.1038/s41467-026-69077-w #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪