Metal organic framework (MOF) have gained considerable attention in the field of energy storage and supercapacitors applications. Herein, we synthesized copper oxide (CuO) through the precipitation method and concurrently derived from the solvothermal prepared copper-benzene dicarboxylate (Cu-BDC) by calcination. The integration of MOF-derived nanostructures with traditional CuO to form a hybrid electrode material, has not been extensively explored. The synthesized materials were characterized using XRD, FTIR, XPS, BET and morphological analysis was conducted using SEM, affirming the composite\'s nature. Electrochemical impedance spectroscopy, galvanostatic charge-discharge, and cyclic voltammetry were used to evaluate the electrochemical properties of electrode material. With a specific capacitance of 691 F g-1 for CuO obtained from Cu-BDC (benzene dicarboxylic acid) and 236 Fg-1 for CuO via the precipitation method, measured at a scan rate of 5 mV/s in 6 M KOH was found to be the optimal performance solution for the electrode material. The mesoporous structures are crucial for their absorption ability and improved ion transport, resulting in optimized electrochemical performance. Finally, we demonstrate significant improvements in specific capacitance and cycling stability compared to pure CuO-based electrodes, highlighting the potential of this composite structure for advanced supercapacitor applications.

The purpose of this article is to analyze a sequence of independent bets by modeling it with a convective-diffusion equation (CDE). The approach follows the derivation of the Kelly Criterion (i.e., with a binomial distribution for the numbers of wins and losses in a sequence of bets) and reframes it as a CDE in the limit of many bets. The use of the CDE clarifies the role of steady growth (characterized by a velocity U) and random fluctuations (characterized by a diffusion coefficient D) to predict a probability distribution for the remaining bankroll as a function of time. Whereas the Kelly Criterion selects the investment fraction that maximizes the median bankroll (0.50 quantile), we show that the CDE formulation can readily find an optimum betting fraction f for any quantile. We also consider the effects of \"ruin\" using an absorbing boundary condition, which describes the termination of the betting sequence when the bankroll becomes too small. We show that the probability of ruin can be expressed by a dimensionless Péclet number characterizing the relative rates of convection and diffusion. Finally, the fractional Kelly heuristic is analyzed to show how it impacts returns and ruin. The reframing of the Kelly approach with the CDE opens new possibilities to use known results from the chemico-physical literature to address sequential betting problems.

PARP inhibitors (PARPi) hold substantial promise in treating glioblastoma (GBM). However, the adverse effects have restricted their broad application. Through unbiased transcriptomic and proteomic sequencing, it is discovered that the BET inhibitor (BETi) Birabresib profoundly alters the processes of DNA replication and cell cycle progression in GBM cells, beyond the previously reported impact of BET inhibition on homologous recombination repair. Through in vitro experiments using established GBM cell lines and patient-derived primary GBM cells, as well as in vivo orthotopic transplantation tumor experiments in zebrafish and nude mice, it is demonstrated that the concurrent administration of PARPi and BETi can synergistically inhibit GBM. Intriguingly, it is observed that DNA damage lingers after discontinuation of PARPi monotherapy, implying that sequential administration of PARPi followed by BETi can maintain antitumor efficacy while reducing toxicity. In GBM cells with elevated baseline replication stress, the sequential regimen exhibits comparable efficacy to concurrent treatment, protecting normal glial cells with lower baseline replication stress from DNA toxicity and subsequent death. This study provides compelling preclinical evidence supporting the development of innovative drug administration strategies focusing on PARPi for GBM therapy.

OBJECTIVE: This study aims to find whether the proliferation and migration of triple negative breast cancer (TNBC) cell lines can be reduced by treatment with bromodomain and extra-terminal domain (BET) inhibitor JQ1 and BET protein targeting chimeras (PROTACs) ARV-771 and MZ1.
METHODS: Cytotoxicity tests, scratch migration assays and western blot proteome profiler arrays for protein expression of cancer-related proteins were used to evaluate the impact of a BET-inhibitor and two BET-directed PROTACs on cell viability, migration and on protein expression.
RESULTS: JQ1 and the PROTACs MZ1 and ARV-771 significantly inhibited the growth and migration of the KRAS G13D-mutated MDA-MB-231 cells. In this cell line, the PROTACs suppressed the residual expression of ERBB2/HER2, 3 and 4 that are essential for the proliferation of breast cancer cells and this cell line proved sensitive to HER2 inhibitors. In contrast, the effects of the PROTACs on the protein expression of MDA-MB-436 cells mostly affected cytokines and their cognate receptors.
CONCLUSIONS: The degradation of BET-protein by PROTACs demonstrated significant anti-proliferative effects. The KRAS-mutated MDA-MB-231 cells belong to the low-HER2 expressing tumors that have a poorer prognosis compared to HER2-null patients. Since first oral PROTACs against tumor hormone receptors are in clinical trials, this mode of tumor therapy is expected to become an important therapeutic strategy in the future treatment of TNBC.

Epigenetics is the study of heritable changes to the genome and gene expression patterns that are not caused by direct changes to the DNA sequence. Examples of these changes include posttranslational modifications to DNA-bound histone proteins, DNA methylation, and remodeling of nuclear architecture. Collectively, epigenetic changes provide a layer of regulation that affects transcriptional activity of genes while leaving DNA sequences unaltered. Sequence variants or mutations affecting enzymes responsible for modifying or sensing epigenetic marks have been identified in patients with congenital heart disease (CHD), and small-molecule inhibitors of epigenetic complexes have shown promise as therapies for adult heart diseases. Additionally, transgenic mice harboring mutations or deletions of genes encoding epigenetic enzymes recapitulate aspects of human cardiac disease. Taken together, these findings suggest that the evolving field of epigenetics will inform our understanding of congenital and adult cardiac disease and offer new therapeutic opportunities.

Loss of PTEN tumor suppressor is an important event during colorectal cancer (CRC) development and is a target for therapeutic exploitation. This study reports that bromodomain and extra-terminal motif (BET) is a synthetic lethal partner of PTEN in CRC. BET inhibition (BETi) selectively induced G1 cell cycle arrest and apoptosis in PTEN-/- CRC. Further, BETi selectively and dose-dependently suppressed the growth of PTEN-/- CRC tumor xenografts in mice and patient-derived organoids. Mechanistically, PTEN-deficient CRC cells elevated the level of cytoplasmic p21CIP1/WAF1 that is hyper-phosphorylated at Thr145 by AKT. BETi suppressed AKT activation in PTEN-deficient CRC cells, followed by the reduction in p21 phosphorylation at Thr145, thereby promoting its nuclear translocation. In addition, BETi suppressed MYC level and this in turn increased the total p21 level in the nuclei. Over-expression of a phospho-mimetic p21 mutant (T145D) significantly rescued the BETi effect on PTEN-deficient CRC. These results suggest that BETi has a dual action on p21: elevating the level of p21 by inhibiting MYC and converting the oncogenic (cytoplasmic) p21 into the tumor-suppressive (nuclear) p21 by inhibiting AKT. Taken together, this study identified the synthetic lethal interaction between PTEN and BET, and provides a potential actionable target for CRC with PTEN loss.

Identifying the interactome for a protein of interest is challenging due to the large number of possible binders. High-throughput experimental approaches narrow down possible binding partners but often include false positives. Furthermore, they provide no information about what the binding region is (e.g., the binding epitope). We introduce a novel computational pipeline based on an AlphaFold2 (AF) Competitive Binding Assay (AF-CBA) to identify proteins that bind a target of interest from a pull-down experiment and the binding epitope. Our focus is on proteins that bind the Extraterminal (ET) domain of Bromo and Extraterminal domain (BET) proteins, but we also introduce nine additional systems to show transferability to other peptide-protein systems. We describe a series of limitations to the methodology based on intrinsic deficiencies of AF and AF-CBA to help users identify scenarios where the approach will be most useful. Given the method\'s speed and accuracy, we anticipate its broad applicability to identify binding epitope regions among potential partners, setting the stage for experimental verification.

UNASSIGNED: Bromodomain and ExtraTerminal (BET) domain proteins are transcriptional cofactors that, recognizing acetylated lysines of histone and non-histone proteins, can modulate gene expression. The BET family consists of four members, each of which contains two bromodomains (BD1 and BD2) able to recognize the acetylated mark. Pan-BET inhibitors (BETi) have shown a promising anticancer potential in many clinical trials; however, their further development has been in part hampered by the side effects due to their lack of selectivity. Mounting evidence suggests that BD1 is primarily involved in cancer and that its selective inhibition can phenocopy the anticancer effects of pan-BETi with increased tolerability. Therefore, the development of BD1 selective inhibitors is highly pursed in both academia and industry.
UNASSIGNED: This review aims at giving an overview of the patent literature of BD1-selective BETi between 2014 and 2023. WIPO, USPTO, EPO, and SciFinder® databases were used for the search of patents.
UNASSIGNED: The development of BD1-selective BETi, despite challenging, is highly desirable as it could have a great impact on the development of new safer anticancer therapeutics. Several strategies could be applied to discover potent and selective compounds with limited side effects.

The molecular electron density theory (MEDT) was employed to examine the [4 + 2] cycloaddition reaction between (E)-N-((dimethylamino)methylene)benzothioamide (1) and (S)-3-acryloyl-4-phenyloxazolidin-2-one (2) at the B3LYP/6-311++G(d,p) design level. Parr functions and energy studies clearly show that this reaction is regio- and stereoselective, in perfect agreement with experimental results. By evaluating the chemical mechanism in terms of bond evolution theory (BET) and electron localization function (ELF), which divulges a variety of variations in the electron density along the reaction path, a single-step mechanism with highly asynchronous transition states structures was revealed. Additionally, we conducted a docking study on compounds P1, P2, P3, and P4 in the SARS-CoV-2 main protease (6LU7) in comparison to Nirmatrelvir. Our findings provide confirmation that product P4 may serve as a potent antiviral drug.

Identifying the interactome for a protein of interest is challenging due to the large number of possible binders. High-throughput experimental approaches narrow down possible binding partners, but often include false positives. Furthermore, they provide no information about what the binding region is (e.g. the binding epitope). We introduce a novel computational pipeline based on an AlphaFold2 (AF) Competition Assay (AF-CBA) to identify proteins that bind a target of interest from a pull-down experiment, along with the binding epitope. Our focus is on proteins that bind the Extraterminal (ET) domain of Bromo and Extraterminal domain (BET) proteins, but we also introduce nine additional systems to show transferability to other peptide-protein systems. We describe a series of limitations to the methodology based on intrinsic deficiencies to AF and AF-CBA, to help users identify scenarios where the approach will be most useful. Given the speed and accuracy of the methodology, we expect it to be generally applicable to facilitate target selection for experimental verification starting from high-throughput protein libraries.