UBR7 in concert with EZH2 inhibits the TGF-ß signaling leading to extracellular matrix remodeling.

The intricate interplay between resident cells and the extracellular matrix (ECM) profoundly influences cancer progression. In triple-negative breast cancer (TNBC), ECM architecture evolves due to the enrichment of lysyl oxidase, fibronectin, and collagen, promoting distant metastasis. Here we uncover a pivotal transcription regulatory mechanism involving the epigenetic regulator UBR7 and histone methyltransferase EZH2 in regulating transforming growth factor (TGF)-ß/Smad signaling, affecting the expression of ECM genes. UBR7 loss leads to a dramatic reduction in facultative heterochromatin mark H3K27me3, activating ECM genes. UBR7 plays a crucial role in matrix deposition in adherent cancer cells and spheroids, altering collagen content and lysyl oxidase activity, directly affecting matrix stiffness and invasiveness. These findings are further validated in vivo in mice models and TNBC patients, where reduced UBR7 levels are accompanied by increased ECM component expression and activity, leading to fibrosis-mediated matrix stiffness. Thus, UBR7 is a master regulator of matrix stiffening, influencing the metastatic potential of TNBC.

E-Protein Protonation Titration-Induced Single-Particle Chemical Force Spectroscopy for Microscopic Understanding and pI Estimation of Infectious DENV.

The ionization state of amino acids on the outer surface of a virus regulates its physicochemical properties toward the sorbent surface. Serologically different strains of the dengue virus (DENV) show different extents of infectivity depending upon their interactions with a receptor on the host cell. To understand the structural dependence of E-protein protonation over its sequence dependence, we have followed E-protein titration kinetics both experimentally and theoretically for two differentially infected dengue serotypes, namely, DENV-2 and DENV-4. We have performed E-protein protonation titration-induced single-particle chemical force spectroscopy using an atomic force microscope (AFM) to measure the surface chemistry of DENV in physiological aqueous solutions not only to understand the charge distribution dynamics on the virus surface but also to estimate the isoelectric point (pI) accurately for infectious dengue viruses. Cryo-EM structure-based theoretical pI calculations of the DENV-2 surface protein were shown to be consistent with the evaluated pI value from force spectroscopy measurements. We also highlighted here the role of the microenvironment around the titrable residues (in the 3D-folded structure of the protein) in altering the pKa. This is a comprehensive study to understand how the cumulative charge distribution on the outer surface of a specific serotype of DENV regulates a prominent role of infectivity over minute changes at the genetic level.

Green to deep-red emissive carbon dot formation by C+ion implantation on nitrogen beam created self-masked nano-template.

We report the formation of green to red emissive arrays of carbon dot on silicon-nitride nano-templates by successive implantation of nitrogen and carbon broad ion beams. The patterned nano-templates are formed by 14 keV N2+ion-bombardment at grazing incident (70°) on Si. Subsequently, 5 keV C+ions are implanted at the selective sites of the pyramidal nano-template by taking advantage of the self-masking effect. The nano-pyramidal pattern and the implanted carbon dots at the specific sites are confirmed by atomic force microscopy and cross sectional transmission electron microscopy measurements. The developed carbon dots (CDs) are mostly amorphous and consists of SiC and graphitic nitrogen (CN). G-band and D-band carbons are identified by Raman spectroscopy, while the presence of SiC and CN are detected by XPS measurements. A change of band-gap is observed for C-implanted templates by the UV-vis spectroscopy. Excitation wavelength-dependent photoemission from the dots is found in the green to red region. Maximum intense PL is observed in the green-orange region for excitation wavelength of 425 nm and a redshift of PL with decreasing intensity is observed with the increase of excitation wavelength. The observed photoluminescence is described in terms of the combined effects of quantum confinement, graphitic nitrogen and defect induced additional states formation in the carbon dots. The potential applications of CDs are also addressed.

A Mechanoelastic Glimpse on Hyaluronan-Coated Extracellular Vesicles.

Cancer cells secrete extracellular vesicles (EVs) covered with a carbohydrate polymer, hyaluronan (HA), linked to tumor malignancy. Herein, we have unravelled the contour lengths of HA on a single cancer cell-derived EV surface using single-molecule force spectroscopy (SMFS), which divulges the presence of low molecular weight HA (LMW-HA < 200 kDa). We also discovered that these LMW-HA-EVs are significantly more elastic than the normal cell-derived EVs. This intrinsic elasticity of cancer EVs could be directly allied to the LMW-HA abundance and associated labile water network on EV surface as revealed by correlative SMFS, hydration dynamics with fluorescence spectroscopy, and molecular dynamics simulations. This method emerges as a molecular biosensor of the cancer microenvironment.

Impact of porous nanomaterials on inhibiting protein aggregation behaviour.

Aggregation of intrinsically disordered as well as the ordered proteins under certain premises or physiological conditions leads to pathological disorder. Here we have presented a detailed investigation on the effect of a porous metallic (Au) and a non-metallic (Si) nanomaterial on the formation of ordered (fiber-like/amyloid) and disordered (amorphous) aggregates of proteins. Porous nanogold (PNG) was found to reduce the amyloid aggregation of insulin but does not have much impact on the lag phase in the aggregation kinetics, whereas porous nano-silica (PNS) was found both to decrease the amount of aggregation as well as prolong the lag phase of amyloid fiber formation from insulin. On the other hand, both the porous nanoparticles are found to decrease the extent of amorphous aggregation (with slight improvement for PNS) of pathogenic huntingtin (Htt) protein in Huntington's disease cell model. This is a noted direct observation in controlling and understanding protein aggregation diseases which may help us to formulate nanotherapeutic drugs for future clinical applications.