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USP11 is a promising therapeutic target implicated in Alzheimer's disease and various cancers; however, no specific inhibitors are currently available, with the only known inhibitor being mitoxantrone, which primarily targets topoisomerase II. To identify novel chemical starting points, we conducted high-throughput virtual screening using a USP11 homology model. Screening over 600,000 compounds yielded five structurally distinct hits with significant inhibitory activity. Biochemical validation highlighted two promising scaffolds: benzoxadiazole derivatives and pyrrolo-phenylamidine analogues, both demonstrating structure-dependent inhibition and tractable SAR profiles. Docking studies further characterised their binding modes, supporting their potential for optimisation. Hydroxyphenyl hydrazone analogues raised PAINS-related concerns, while compounds such as squalamine were deprioritized due to weak binding affinity and structural complexity. Overall, this study provides valuable scaffolds and mechanistic insights that can inform future development of potent, selective USP11 inhibitors.

C-X-C motif chemokine ligand 12(CXCL12) is an essential chemokine for organ development and homeostasis in multiple tissues. Its receptor, C-X-C chemokine receptor type 4(CXCR4), is expressed on the surface of target cells. The chemokine and receptor are expressed almost ubiquitously in human tissues and cells throughout life, and abnormal expression of CXCL12 and CXCR4 is observed in pathological conditions, such as inflammation and cancer. CXCR4 is reportedly translated into five splicing variants of different lengths, which each have different amino acids in the N-terminus. As the N-terminus is the first recognition site for chemokines, CXCR4 variants may respond differently to CXCL12. Despite these differences, the molecular and functional properties of CXCR4 variants have not been thoroughly described or compared. Here, we explored the expression of CXCR4 variants in cell lines and analyzed their roles in cellular responses using biochemical approaches. RT-PCR revealed that most cell lines express more than one CXCR4 variant. When expressed in HEK293 cells, the CXCR4 variants differed in protein expression efficiency and cell surface localization. Although variant 2 demonstrated the strongest expression and cell surface localization, variants 1, 3, and 5 also mediated chemokine signaling and induced cellular responses. Our results demonstrate that the N-terminal sequences of each CXCR4 variant determine the expression of the receptor and affect ligand recognition. Functional analyses revealed that CXCR4 variants may also affect each other or interact during CXCL12-stimulated cellular responses. Altogether, our results suggest that CXCR4 variants may have distinct functional roles that warrant additional investigation and could contribute to future development of novel drug interventions.

The neurokinin-1 receptor (NK1R) has been investigated as a potential target for major depressive disorder owing to its role in stress regulation and neuroinflammation. However, clinical trials of NK1R antagonists have yielded inconsistent results, leaving it unclear whether these outcomes reflect limitations of NK1R as a therapeutic target or shortcomings inherent to the clinical candidates tested. The majority of previously developed NK1R antagonists contain a 3,5-bis-trifluoromethylphenyl moiety, which enhances receptor binding but may also influence drug metabolism, pharmacokinetics or receptor interactions, potentially affecting therapeutic efficacy. Whether structurally distinct NK1R antagonists exhibit different antidepressant potential remains an open question. Here we used computational approaches to identify NK1R antagonists lacking the 3,5-bis-trifluoromethylphenyl group and evaluated their effects in preclinical models of depression. Several compounds exhibited NK1R antagonistic activity and reduced depressive-like behaviors, with compound #15 demonstrating the most pronounced effects. Molecular docking and molecular dynamics simulations revealed a distinct binding mode for compound #15, characterized by a hydrogen bond interaction with Asn109 and π–π stacking with His197, suggesting structural differences that may influence NK1R modulation. These findings support the potential of structurally diverse NK1R antagonists to modulate behavior and neuroinflammatory responses in preclinical models. While the relevance of these structural differences to clinical outcomes remains to be determined, our results provide a preliminary framework for further investigation of chemically novel NK1R antagonists in the context of major depressive disorder.

Ubiquitin-specific protease 18 (USP18) is a multifunctional cysteine protease primarily responsible for deconjugating the interferon-inducible ubiquitin-like modifier ISG15 from protein substrates. Here, we report the design and synthesis of activity-based probes (ABPs) that incorporate unnatural amino acids into the C-terminal tail of ISG15, enabling the selective detection of USP18 activity over other ISG15 cross-reactive deubiquitinases (DUBs) such as USP5 and USP14. Combined with a ubiquitin-based DUB ABP, the USP18 ABP is employed in a chemoproteomics screening platform to identify and assess inhibitors of DUBs including USP18. We further demonstrate that USP18 ABPs can be utilized to profile differential activities of USP18 in lung cancer cell lines, providing a strategy that will help define the activity-related landscape of USP18 in different disease states and unravel important (de)ISGylation-dependent biological processes. USP18 is a multifunctional cysteine protease involved in IFN pathways. Here, the authors report chemical probes and chemoproteomics platforms that allow to detect and perturb USP18 activity in complex biological systems with the potential to unravel important (de)ISGylation-dependent processes.

Background Tachykinins and their cognate receptors, neurokinin receptors (NKs) including NK1, NK2, and NK3 play vital roles in regulating various physiological processes including neurotransmission, nociception, inflammation, smooth muscle contractility, and stimulation of endocrine and exocrine gland secretion. Their abnormal expression has been reported to be associated with neurological disorders, inflammation, and cancer. Even though NKs are expressed in the same cells with their expression being inversely correlated in some conditions, there is no direct evidence to prove their interaction. Understanding the functional crosstalk between NKs in mediated downstream signaling and cellular responses may elucidate the roles of each receptor in pathophysiology. Results In this study, we showed that NKs were co-expressed in some cells. However, different from NK3, which only forms homodimerization, we demonstrated a direct interaction between NK1 and NK2 at the protein level using co-immunoprecipitation and NanoBiT-based protein interaction analysis. Through heterodimerization, NK2 downregulated substance P-stimulated NK1 signals, such as intracellular Ca 2+ mobilization and ERK phosphorylation, by enhancing β-arrestin recruitment, even at the ligand concentration that could not activate NK2 itself or in the presence of NK1 specific antagonist, aprepitant. In A549 cells with receptors deleted and reconstituted, NK2 exerted a negative effect on substance P/NK1-mediated cell migration. Conclusion Our study has provided the first direct evidence of an interaction between NK1 and NK2, which highlights the functional relevance of their heterodimerization in cellular responses. Our findings demonstrated that through dimerization, NK2 exerts negative effects on downstream signaling and cellular response mediated by NK1. Moreover, this study has significant implications for understanding the complexity of GPCR dimerization and its effect on downstream signaling and cellular responses. Given the important roles of tachykinins and NKs in pathophysiology, these insights may provide clues for developing NKs-targeting drugs.

In this study, a donkey-specific primer pair and probe were designed from mitochondrial cytochrome b gene for the detection of raw donkey meat and different processed meat mixtures. The PCR product size for donkey DNA was 99 bp, and primer specificity was verified using 20 animal species. The limit of detection (LOD) was examined by serially diluting donkey DNA. Using real-time PCR, 0.001 ng of donkey DNA could be detected. In addition, binary meat mixtures with various percentages of donkey meat (0.001%, 0.01%, 0.1%, 1%, 10%, and 100%) in beef were analyzed to determine the sensitivity of this real-time PCR assay. At least 0.001% of donkey meat was detected in raw, boiled, roasted, dried, grinded, fried, and autoclaved meat mixtures. The developed real-time PCR method showed sufficient specificity and sensitivity in identification of donkey meat and could be a useful tool for the identification of donkey meat in processed products.

A one-step immunoassay is presented for the detection of ochratoxin A (OTA) using an antibody complex with switching peptides. Because the switching peptides (fluorescence-labeled) were able to bind the frame region of antibodies (IgGs), they were dissociated from antibodies immediately when target analytes were bound to the binding pockets of antibodies. From the fluorescence signal measurements of switching peptides, a quantitative analysis of target analytes, via a one-step immunoassay without any washing steps, could be performed. As the first step, the binding constant (KD) of OTA to the antibodies was estimated under the continuous flow conditions of a surface plasmon resonance biosensor. Then, the optimal switching peptide, among four types of switching peptides, and the reaction condition for complex formation with the switching peptide were determined for the one-step immunoassay for OTA analysis. Additionally, the selectivity test of one-step immunoassay for OTA was carried out in comparison with phenylalanine and zearalenone. For the application to the one-step immunoassay to detect OTA in wines, two types of sample pre-treatment methods were compared: (1) a liquid extraction was carried out using chloroform as a solvent with subsequent resuspension in phosphate-buffered saline (total analysis time < 1 h); (2) direct dilution of the wine sample (total analysis time < 0.5 h). Finally, the direct dilution method was found to be effective for the one-step immunoassay based on the switching peptide assay for OTA in wines with a markedly improved total analysis time (< 0.5 h). Additionally, the assay results were compared with commercial lateral flow immunoassay.

Plastic waste worldwide is becoming a serious pollution problem for the planet. Various physical and chemical methods have been tested in attempts to remove plastic dumps. However, these have usually resulted in secondary pollution issues. Recently, the biodegradation of plastic by fungal and bacterial strains has been spotlighted as a promising solution to remove plastic wastes without generating secondary pollution. We have previously reported that a Pseudomonas aeruginosa strain isolated from the gut of a superworm is capable of biodegrading polystyrene (PS) and polyphenylene sulfide (PPS). Herein, we demonstrate the extraordinary biodegradative power of P. aeruginosa in efficiently depolymerizing four different types of plastics: PS, PPS, polyethylene (PE) and polypropylene (PP). We further compared biodegradation rates for these four plastic types and found that PE was biodegraded fastest, whereas the biodegradation of PP was the slowest. Moreover, the growth rates of P. aeruginosa were not always proportional to biodegradation rates, suggesting that the rate of bacterial growth could be influenced by the composition and properties of intermediate molecules produced during plastic biodegradation, and these may supply useful cellular precursors and energy. In conclusion, an initial screening system to select the most suitable bacterial strain to biodegrade certain types of plastic is particularly important and may be necessary to solve plastic waste problems both presently and in the future.

Perovskites are semiconductor materials with the ABX3 structure, and they possess several attractive features, such as a tunable bandgap, high photoluminescence quantum yield (PLQY), charge mobility, and carrier lifetime. Hence, they are widely used in various applications, such as light-emitting devices, solar cells, and photosensors. However, the perovskite defects, including grain boundaries, vacancies, ion migration, and structural deformation, interfere with the effective performance of the perovskite-based devices. The intrinsic instability and trap states caused by the perovskite defects decrease the stability and performance of perovskite-based devices. Two methods of defect passivation are carried out to enhance the effectiveness of perovskite-based devices: (1) polymers and (2) chemical additives. Defect passivation protects the surface to increase stability and reduce trap states, thereby enhancing the performance of perovskite-based devices. This article reviews the technologies for defect passivation in perovskite-based devices. The effect of defect passivation has been analyzed using various methodologies: (1) surface analysis using atomic force microscopy (AFM) and scanning electron microscopy (SEM), (2) bandgap and charge carrier lifetime analysis using photoluminescence (PL) and time-resolved photoluminescence (TRPL) spectra, (3) the trap-state density calculations based on the I–V curve under dark conditions, and (4) comparison of the critical parameters of the perovskite-based devices. This review provides an overview of the defect passivation technologies available to enhance the stability and applicability of perovskite-based photosensors.

One-step homogeneous immunoassay was developed for detecting influenza viruses A and B (Inf-A and Inf-B) using the switching peptide H2. As the fluorescence-labeled switching peptide dissociated from the binding pocket of detection antibodies, the fluorescence signal could be directly generated by the binding of Inf-A and Inf-B without washing (i.e., one-step immunoassay). For the one-step homogeneous immunoassay with detection antibodies in solution, graphene was labeled with the antibodies as a fluorescence quencher. To test the feasibility of the homogeneous one-step immunoassay, the stability of the antibody complex with the switching peptide was evaluated under different pH and salt conditions. The one-step homogeneous immunoassay with switching peptide was conducted using influenza virus antigens in phosphate-buffered saline and real samples with inactivated Inf-A and Inf-B spiked in serum. Finally, the one-step homogeneous immunoassay results were compared with those of commercially available lateral flow immunoassays.