Background: Elevated APOBEC3B expression in tumours correlates with a kataegic pattern of localised hypermutation. We assessed the cellular phenotypes associated with high-level APOBEC3B expression and the influence of p53 status on these phenotypes using an isogenic system.Methods: We used RNA interference of p53 in cells with inducible APOBEC3B and assessed DNA damage response (DDR) biomarkers. The mutational effects of APOBEC3B were assessed using whole-genome sequencing. In vitro small-molecule inhibitor sensitivity profiling was used to identify candidate therapeutic vulnerabilities.Results: Although APOBEC3B expression increased the incorporation of genomic uracil, invoked DDR biomarkers and caused cell cycle arrest, inactivation of p53 circumvented APOBEC3B-induced cell cycle arrest without reversing the increase in genomic uracil or DDR biomarkers. The continued expression of APOBEC3B in p53-defective cells not only caused a kataegic mutational signature but also caused hypersensitivity to small-molecule DDR inhibitors (ATR, CHEK1, CHEK2, PARP, WEE1 inhibitors) as well as cisplatin/ATR inhibitor and ATR/PARP inhibitor combinations.Conclusions: Although loss of p53 might allow tumour cells to tolerate elevated APOBEC3B expression, continued expression of this enzyme might impart a number of therapeutic vulnerabilities upon tumour cells.
Short linear motifs (SLiMs) are the most ubiquitous protein interaction motifs within unstructured regions of the human proteome, yet their contribution to cellular homeostasis remains poorly understood. Here, to systematically assess SLiM function, we applied base editing to mutate all reported and a set of computationally predicted SLiMs defined by SLiM-like evolutionary patterns. By screening 7,293 SLiM-containing regions with 80,473 mutations in HAP1 cells, we define a SLiM dependency map identifying 450 reported and 264 predicted SLiMs required for normal cell proliferation. Mutational consequences were highly reproducible in RPE1 cells, with differences attributed to cell-line-specific gene essentiality. We show that many predicted SLiMs affecting proliferation do not belong to existing classes and identify binding partners for several of these, providing mechanistic insight into a disease-associated ANKRD17 mutation. Our study provides a proteome-wide resource on SLiM essentiality uncovering numerous uncharacterized essential SLiMs.
We rigorously analyse global tripartite entanglement in a mixed-spin ( (1,1/2,1 (1,1/2,1) Heisenberg trimer under varying exchange couplings, magnetic fields, and temperatures. Entanglement is quantified using the geometric mean of all three bipartite negativities, enabling us to map precisely the regions of spontaneous global entanglement and to classify the tripartite states according to the distribution of reduced bipartite correlations. We further investigate the thermal stability of entanglement across the full parameter space, with particular focus on the experimentally realised trimer [Ni(bapa)(H2O)]2Cu(pba)(ClO4)2 (bapa = bis(3-aminopropyl)amine; pba = 1, 3-propylenebis(oxamato)), where global entanglement is predicted to persist up to similar to 100 K and magnetic fields approaching 210 T. Notably, we observe a thermally induced activation of robust entanglement in regions with a biseparable ground state, reaching values close to 1/2-a phenomenon not previously reported. Finally, we propose a connection between the theoretically predicted tripartite entanglement and experimentally measurable quantities.
Organic-inorganic hybrid materials have attracted considerable attention in terms of integrated opto-electronic devices, most of which are focused on the lead-free light absorbers. Recently, Bi-based organic inorganic semiconductors proved their fascinating properties as solid state visible light absorber for solar cells (SCs) as well as photoluminescent materials. In this work, a new quasi-three-dimensional molecular crystal (HTZP)4[Bi6I22]·2NO2·4H2O, (HTZP = [C5H5N4]+ = 1 H-1,2,3-Triazolo[4,5-b]pyridinium), abbreviated (HTZP)BiI, has been successfully synthesized. (HTZP)BiI structure was characterized by single-crystal X-ray diffraction. The optical and electronic behavior of (HTZP)BiI were studied by UV/Vis/NIR diffuse-reflectance and steady-state photoluminescence spectroscopies, energy-resolved electrochemical impedance spectroscopy (ER-EIS) and density functional theory. The obtained results demonstrate the semiconducting behavior of the material with a direct experimental band gap energy of 1.35 eV obtained by ER-EIS. Experimental and theoretical density of state studies reveal an unusual involvement of the organic electronic states near the band edges making this material a promising candidate for photovoltaic SC applications. The recorded photoluminescence spectra display an emission band in the 450–550 nm range, resulting from fast organic fluorescence of the HTZP + cations revealing the suitability of the synthesized (HTZP)BiI for light-emitting diodes.
Social disconnection, consisting of loneliness and social isolation, is increasingly recognized as a significant public health problem. This cross-sectional population study aims to investigate the prevalence of social disconnection in the general adult population of the Slovak Republic and its associations to socio – demographic/economic and health indicators. A representative sample of 3006 adults from the Slovak Republic was recruited for this study. Data were collected through standardized questionnaires via face-to-face interviews during November 2024. Chi-square tests and logistic regressions were used to examine the associations between covariates and social disconnection. The prevalence of social disconnection was found to be 25.3
