Perera J et al., R., Thadke S. A., Thrikawala S. W., Wilson W. D., Tan K. W. R., Chand N. Z. W., Phan A. T., Ly D. H., et al. A pothole-filling strategy for selective targeting of rCUG-repeats associated with myotonic dystrophy type 1. Proc. Natl. Acad. Sci. U.S.A - Gamma-PNA triplet ligands with Janus bases selectively bind expanded rCUG repeats, displace MBNL1, and show length-dependent cooperativity with partial splicing rescue.

Study Highlights:
The authors designed compact three-unit bifacial nucleic acid ligands (Janus bases on a γPNA backbone) and evaluated them against rCUG repeat duplexes and DM1 patient-derived myotubes using molecular dynamics, EMSA, SPR, AFM, and cellular splicing assays. MD and EMSA/SPR show cooperative, length-dependent binding with Kd values decreasing to ~0.56 µM for rCUG98 and Hill coefficients rising to ~5, driven by enhanced hydrogen-bonding and π–π stacking between adjacent ligands. AFM revealed a 0.348 nm increase in RNA helix contour height on binding, consistent with a pothole-filling insertion mechanism that selectively recognizes hairpin duplexes over single-stranded RNA. Functionally, a cell-permeable LG2c analog reduced nuclear foci and partially restored mis-splicing of Serca1, cTNT, and IR in DM1 myotubes, though cellular uptake remains limiting.

Conclusion:
Short bifacial γPNA triplet ligands selectively recognize pathogenic rCUG hairpins via a pothole-filling mechanism, displace MBNL1, and can partially restore splicing in DM1 myotubes while cellular delivery requires further optimization.

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Reference:
Perera J. D. R., Thadke S. A., Thrikawala S. W., Wilson W. D., Tan K. W. R., Chand N. Z. W., Phan A. T., Ly D. H., et al. A pothole-filling strategy for selective targeting of rCUG-repeats associated with myotonic dystrophy type 1. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2507065123. https://doi.org/10.1073/pnas.2507065123

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Strobl et al., & Stary, G. Human epidermal Langerhans cells induce tolerance and hamper T cell function upon tick-borne pathogen transmission. Nature Communications - Human epidermal Langerhans cells exposed to Ixodes ricinus tick saliva and Borrelia burgdorferi adopt a tolerogenic state with CXCR4/CCR7-driven emigration that impairs T cell priming.

Study Highlights:
The study uses clinical human tick bite biopsies, an ex vivo human skin tick bite model, in vitro monocyte- and CD34-derived Langerhans cells, immune spheroid cultures and single-cell RNA-sequencing of erythema migrans lesions, employing imaging, migration assays, co-cultures and scRNA-seq. Tick salivary gland extract (SGE) up-regulates CXCR4 and CCR7 on LCs, promotes emigration from the epidermis into dermis and lymphatic vessels, and reduces keratinocyte TGF-β consistent with migration. SGE and Borrelia burgdorferi drive up-regulation of tolerogenic transcription factors IDO1 and IRF4 while blunting immunogenic IRF1/NFκB programs, and SGE-primed LCs induce Treg and Th2 bias with reduced Tfh, Th17 and Th9 induction. Functionally, these changes dampen protective adaptive responses in lymphoid models and in patient lesions, which may reduce bacterial clearance and memory formation.

Conclusion:
Tick saliva reprograms human epidermal Langerhans cells to migrate to lymphatics and adopt a tolerogenic program that impairs protective T cell responses and may facilitate Borrelia transmission.

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Reference:
Strobl, J., Kleissl, L., Eder, J., Conolly, S., Frey, T., Gail, L. M., Kopf, A., Weninger, S., Markowicz, M., Bartíková, P., Freystätter, C., Schmetterer, K., Strobl, H., Stockinger, H., Wijnveld, M. & Stary, G. Human epidermal Langerhans cells induce tolerance and hamper T cell function upon tick-borne pathogen transmission. Nature Communications. 2025. https://doi.org/10.1038/s41467-025-66821-6

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Girelli et al., Coherent X-rays reveal anomalous molecular diffusion and cage effects in crowded protein solutions. Nat Commun ( - MHz-XPCS of ferritin solutions at EuXFEL shows anomalous, cage-trapped protein diffusion with reduced long-time transport and ~1.2 nm rattling at high concentration.

Study Highlights:
The study probes crowded ferritin solutions using megahertz X-ray Photon Correlation Spectroscopy (MHz-XPCS) at EuXFEL combined with SAXS and δγ-theory modeling. Intensity autocorrelation functions g2(q,t) become non-exponential at high concentrations, and double-exponential analysis yields short- and long-time diffusion components with Dlong/Dshort ≈ 0.12 ± 0.04 at 730 mg/ml and an interaction time estimated near 4.25 µs. δγ-theory of hydrodynamically interacting spheres reproduces the q-dependent hydrodynamic function only when a scaling factor tied to direct protein interactions is included, indicating hydrodynamics set the q-dependence while direct forces reduce overall self-diffusion. Cage analysis finds an average rattling displacement δ ≈ 1.0 ± 0.3 nm for ≈89% of proteins, implying cage-trapping substantially slows molecular transport with consequences for ferritin-based drug delivery.

Conclusion:
MHz-XPCS measurements and δγ-theory modeling demonstrate that crowded ferritin solutions exhibit anomalous, cage-trapped diffusion with separate short- and long-time components and markedly reduced self-diffusion, indicating slower molecular transport under crowding.

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Reference:
Girelli, A., Bin, M., Filianina, M. et al. Coherent X-rays reveal anomalous molecular diffusion and cage effects in crowded protein solutions. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66972-6

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