Disrupting Smad3 potentiates immunostimulatory function of NK cells against lung carcinoma by promoting GM-CSF production.

Through Smad3-dependent signalings, transforming growth factor-ß (TGF-ß) suppresses the development, maturation, cytokine productions and cytolytic functions of NK cells in cancer. Silencing Smad3 remarkably restores the cytotoxicity of NK-92 against cancer in TGF-ß-rich microenvironment, but its effects on the immunoregulatory functions of NK cells remain obscure. In this study, we identified Smad3 functioned as a transcriptional repressor for CSF2 (GM-CSF) in NK cells. Therefore, disrupting Smad3 largely mitigated TGF-ß-mediated suppression on GM-CSF production by NK cells. Furthermore, silencing GM-CSF in Smad3 knockout NK cells substantially impaired their anti-lung carcinoma effects. In-depth study demonstrated that NK-derived GM-CSF strengthened T cell immune responses by stimulating dendritic cell differentiation and M1 macrophage polarization. Meanwhile, NK-derived GM-CSF promoted the survival of neutrophils, which in turn facilitated the terminal maturation of NK cells, and subsequently boosted NK-cell mediated cytotoxicity against lung carcinoma. Thus, Smad3-silenced NK-92 (NK-92-S3KD) may serve as a promising immunoadjuvant therapy with clinical translational value given its robust cytotoxicity against malignant cells and immunostimulatory functions to reinforce the therapeutic effects of other immunotherapies.

Quantum spin driven Yu-Shiba-Rusinov multiplets and fermion-parity-preserving phase transition in K3C60.

Magnetic impurities in superconductors are of increasing interest due to emergent Yu-Shiba-Rusinov (YSR) states and Majorana zero modes for fault-tolerant quantum computation. However, a direct relationship between the YSR multiple states and magnetic anisotropy splitting of quantum impurity spins remains poorly characterized. By using scanning tunneling microscopy, we systematically resolve individual transition-metal (Fe, Cr, and Ni) impurities induced YSR multiplets as well as their Zeeman effects in the K3C60 superconductor. The YSR multiplets show identical d orbital-like wave functions that are symmetry-mismatched to the threefold K3C60(1 1 1) host surface, breaking point-group symmetries of the spatial distribution of YSR bound states in real space. Remarkably, we identify an unprecedented fermion-parity-preserving quantum phase transition between ground states with opposite signs of the uniaxial magnetic anisotropy that can be manipulated by an external magnetic field. These findings can be readily understood in terms of anisotropy splitting of quantum impurity spins, and thus elucidate the intricate interplay between the magnetic anisotropy and YSR multiplets.

A pedigree with retinitis pigmentosa and its concomitant ophthalmic diseases.

AIM: To characterize the ophthalmic clinical phenotype of a family with retinitis pigmentosa (RP) and closed-angle glaucoma and to detect pathogenic genes and mutation sites causing RP in this family. METHODS: Ophthalmic clinic performance was examined in detail in 8 enrolled family members. Genomic DNA was extracted from the peripheral blood of 4 family members for whole-exome sequencing (WES) to select potential genetic mutations whose structures were identified by bioinformatics analysis. Then, Sanger sequencing was used in 12 family members and control group members to validate and confirm the disease-causing mutation loci, and we analyzed the genotype-phenotype relationships. RESULTS: The known c.512C>T (p.P171L) mutation in the rhodopsin (RHO) gene was only found in afflicted family members and was confirmed by WES and Sanger sequencing as the pathogenic mutation in this family. In addition to being diagnosed with RP, family member III:4 was found to have bilateral closed-angle glaucoma, high myopia, and concurrent cataracts, and family members II:2 and II:4 had pathological changes of anterior chamber angle narrowing. Family members IV:3 and IV:4 were found to have retinoschisis. CONCLUSION: Glaucoma and related pathological changes, such as retinoschisis, in family members are preliminarily considered RP complications caused by RHO mutation.