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Ubiquitination, a pivotal posttranslational modification of proteins, plays a fundamental role in regulating protein stability. The dysregulation of ubiquitinating and deubiquitinating enzymes is a common feature in various cancers, underscoring the imperative to investigate ubiquitin ligases and deubiquitinases (DUBs) for insights into oncogenic processes and the development of therapeutic interventions. In this review, we discuss the contributions of the ubiquitin–proteasome system (UPS) in all hallmarks of cancer and progress in drug discovery. We delve into the multiple functions of the UPS in oncology, including its regulation of multiple cancer-associated pathways, its role in metabolic reprogramming, its engagement with tumor immune responses, its function in phenotypic plasticity and polymorphic microbiomes, and other essential cellular functions. Furthermore, we provide a comprehensive overview of novel anticancer strategies that leverage the UPS, including the development and application of proteolysis targeting chimeras (PROTACs) and molecular glues.

The assembly of constitutive heterochromatin is a prerequisite for maintaining genome stability. However, the mechanism of heterochromatin formation has yet to be completely understood. Here, we demonstrate a crucial role of the nuclear poly(A)-binding protein (PABP) Pab2/PABPN1 in promoting constitutive heterochromatin formation in the fission yeast Schizosaccharomyces japonicus . Histone H3 Lys 9 di- and tri-methylation, hallmarks of heterochromatin, are significantly reduced at centromeres in the absence of Pab2. Pab2 forms nuclear condensates through its RNA-recognition motif (RRM) and the intrinsically disordered domain (IDR), both of which bind to centromeric non-coding RNAs. Intriguingly, two key heterochromatin factors, the histone H3 Lys9 methyltransferase Clr4 and the Mi2-type chromatin remodeler Mit1, associate with centromeres in a Pab2-dependent manner. Pab2 interacts with two putative RNA-binding proteins, the ZC3H3 ortholog Red5 and the RBM26·27 ortholog Rmn1, both essential for heterochromatin formation. Deletion of the Pab2 N-terminal region, which disrupts this interaction, largely abolishes Pab2 function, underscoring the importance of this complex. Pab2 also associates and colocalizes with Ppn1 (a PPP1R10 ortholog), a component of the cleavage and polyadenylation specificity factor (CPSF) complex, and ppn1 mutations disrupt constitutive heterochromatin. Notably, both Ppn1 and Rmn1 are able to interact with Clr4. Our findings reveal that Pab2 plays a pivotal role in heterochromatin assembly by forming nuclear condensates through its RRM/IDR, and Pab2 condensates facilitate the recruitment of Clr4 and Mit1 to centromeres, potentially through its binding proteins, Ppn1 and Rmn1. This study provides new insights into the mechanisms underlying heterochromatin formation and highlights the importance of RNA-binding proteins and phase separation in this process.

Significant progress has been made in the field of two-dimensional WS 2 , yet the precise control of the doping process to achieve desired properties and the interpretation of complex physical phenomena in these novel materials necessitate thorough research. In this study, Nb-doped WS 2 is synthesized using chemical vapor deposition technology, leading to triangular flakes with a side length of 12–20 μm. The X-ray photoelectron spectroscopy analysis indicates that the Nb W substitution defect functions as an electron acceptor. The interlayer and transverse forces of the Nb-doped WS 2 flake approach 1 nN and 150 pN, respectively. As the doping concentration increases, the valence band maximum energy of Nb-doped WS 2 ranges from 4.06 eV to 4.3 eV. Furthermore, the performance of the photodetector is discussed.

The iron-catalyzed hydroarylation of alkenes with indoles is a sustainable, effective synthetic transformation towards the construction of functionalized indoles - crucial motifs for various bioactive molecules and drug candidates. However, such transformations have proven challenging for unactivated alkenes, and the requirement for (super)stoichiometric amounts of reactive Grignard reagents has limited broader applications. Herein, we address these major challenges by integrating iron/ N -heterocyclic carbene-catalyzed C–H activation with mechanochemistry techniques. This approach enables mechanochemical iron-catalyzed anti -Markovnikov hydroarylations of unactivated alkenes using a bis( N -heterocyclic carbene) ligand, as well as regiodivergent hydroarylation of aryl alkenes by varying the N -heterocyclic carbene ligand. To this end, magnesium metal serves as a convenient reductant to form catalytically active iron(0) species by mechanochemistry, thereby improving the sustainability and functional group compatibility. Experimental and computational studies elucidate the possible catalytic mode of action, and a data science analysis captured the key features of the N -heterocyclic carbene ligands in controlling regiodivergent selectivity. While iron catalysis holds immense promise in organic synthesis due to the comparatively wide availability and low toxicity of the metal, modulation of the catalyst’s oxidation state still typically relies on conventional and wasteful approaches. Here, the authors integrate mechanochemistry into iron-catalyzed regiodivergent hydroarylation of alkenes with indoles, leading to an efficient generation of alkylated indoles.

To assess resistance situation and evolutionary risks, 510 Echinochloa populations from 13 rice-growing regions in Jiangsu Province (2018–2022) were tested against seven herbicides (penoxsulam, quinclorac, cyhalofop-butyl, bispyribac-sodium, pretilachlor, metamifop, and florpyrauxifen-benzyl), with cross- and multiple-resistance patterns analyzed. Penoxsulam resistance increased ninefold over five years, while quinclorac resistance consistently exceeded 40% annually for four years. Cyhalofop-butyl and bispyribac-sodium resistance frequencies also rose annually, with the strongest resistance to penoxsulam and bispyribac-sodium observed in southern Jiangsu, particularly in Suzhou, Wuxi, Changzhou, and Zhenjiang. In northern Jiangsu, Huaian showed the highest resistance to multiple herbicides, while quinclorac resistance was widespread across all regions. Pretilachlor and metamifop resistance remained low, with only sporadic outbreaks, indicating that they continued to be used. However, prolonged use of single-site herbicides, particularly ALS inhibitors and ACCase inhibitors, has led to cross-resistance evolution. Multiple-resistance analysis indicated that quinclorac, penoxsulam, and cyhalofop-butyl should not be used in binary or ternary mixtures to control resistant Echinochloa . Notably, 14 populations exhibited florpyrauxifen-benzyl resistance, with 13 also showing quinclorac resistance, suggesting a potential link between prior quinclorac resistance and florpyrauxifen-benzyl resistance evolution, which warrants further investigation. This study clarifies herbicide resistance patterns in  Echinochloa  in Jiangsu Province, offering critical insights for resistance management strategies.

As both L- and D-BAIBA are increased with exercise, we sought to determine if circulating levels would be associated with physical performance. Serum levels of L- and D-BAIBA were quantified in 120 individuals (50% female) aged 20–85 years and categorized as either a “low” (LP), “average” (AP) or “high” performing (HP). Association analysis was performed using Spearman (S) and Pearson (P) correlation. Using Spearman correlation, L-BAIBA positively associated with (1) body mass index BMI (0.23) and total fat mass (0.19) in the 120 participants, (2) total fat mass in the 60 males (0.26), and (3) bone mineral density, BMD, (0.28) in addition to BMI (0.26) in the 60 females. In HP females, L-BAIBA positively associated with BMD (0.50) and lean mass (0.47). D-BAIBA was positively associated with (1) age (P 0.20) in the 120 participants, (2) age (P 0.49) in the LP females and (3) with gait speed (S 0.20) in the 120 participants. However, in HP males, this enantiomer had a negative association with appendicular lean/height (S − 0.52) and in the AP males a negative correlation with BMD (S − 0.47). No associations were observed in HP or AP females, whereas, in LP females, a positive association was observed with grip strength (S 0.45), but a negative with BMD (P − 0.52, S − 0.63) and chair stands (P − 0.47, S − 0.51). L-BAIBA may play a role in BMI and BMD in females, not males, whereas D-BAIBA may be a marker for aging and physical performance. The association of L-BAIBA with BMI and fat mass may reveal novel, not previously described functions for this enantiomer.

Declining physical performance with age and disease is an important indicator of declining health. Biomarkers that identify declining physical performance would be useful in predicting treatment outcomes and identifying potential therapeutics. γ-aminobutyric acid (GABA), a muscle autocrine factor, is a potent inhibitor of muscle function and works as a muscle relaxant. L -α-aminobutyric acid ( L -AABA) is a biomarker for malnutrition, liver damage, and depression. We sought to determine if GABA and L -AABA may be useful for predicting physical performance. Serum levels of GABA and L- AABA were quantified in 120 individuals divided by age, sex, and physical capacity into low, average, and high performer groups. Analyses explored correlations between serum levels and physical performance. Both GABA and the ratio of GABA/AABA (G/A), but not AABA, were highly positively associated with age (Pearson correlations r  = 0.35, p  = 0.0001 for GABA, r  = 0.31, p  = 0.0007 for G/A, n = 120). GABA showed negative associations in the whole cohort with physical performance [fast gait speed, 6 min walk test (6MWT), PROMIS score, and SF36PFS raw score] and with subtotal and femoral neck bone mineral density. L -AABA was positively associated with usual gait speed, 6MWT, total SPPB score, and SF36PFS raw score in the total cohort of 120 human subjects, also with 6MWT and SF36PFS raw score in the 60 male subjects, but no associations were observed in the 60 females. As both GABA and L -AABA appear to be indicative of physical performance, but in opposite directions, we examined the G/A ratio. Unlike GABA, the G/A ratio showed a more distinct association with mobility tests such as total SPPB score, usual and fast gait speed, 6MWT, and SF36PFS raw score in the males, regardless of age and metabolic status. Serum G/A ratio could be potentially linked to physical performance in the male population. Our findings strongly suggest that GABA, L -AABA, and the G/A ratio in human serum may be useful markers for both age and physical function. These new biomarkers may significantly enhance the goal of identifying universal biomarkers to accurately predict physical performance and the beneficial effects of exercise training for older adults.

Haemodynamic management in critical care typically relies on static, population-based targets that overlook patient-specific physiology and the evolving nature of illness. We develop and validate a framework for real-time, personalised haemodynamic management using a time-dependent Cox model that integrates static and dynamic clinical data to predict survival probabilities and derive optimal heart rate and systolic blood pressure targets over time. Trained on the electronic Intensive Care Unit dataset and externally validated with Medical Information Mart for Intensive Care IV and Indiana University Health cohorts, the model demonstrates high predictive accuracy (c-index up to 0.931) and generalisability across diverse populations. Patients with heart rate and systolic blood pressure values closer to model-predicted targets exhibit significantly lower intensive care unit mortality than those aligned with fixed, population-based thresholds. Exploratory dose-response and propensity score–matched analyses confirm outcome relevance, while case studies illustrate feasibility in critical care settings. This personalised, dynamic approach—termed Haemodynamic Management by Time-Adaptive, Risk-Guided Estimation of Targets (HM-TARGET)—offers a scalable framework for precision haemodynamic management in critically ill patients. Prospective trials are warranted to evaluate clinical impact. Hemodynamic management is essential in critical care, but optimal targets for heart rate and blood pressure remain unclear. Here, the authors show that a time-dependent Cox model can derive personalized, real-time targets associated with reduced mortality.

Mesenchymal stem cells (MSCs) have shown great potential in the treatment of several inflammatory diseases due to their immunomodulatory ability, which is mediated by exosomes secreted by MSCs (MSC-Exs). The incidence of inflammatory bowel disease (IBD) is increasing globally, but there is currently no long-term effective treatment. As an emerging therapy, MSC-Exs have proven to be effective in alleviating IBD experimentally, and the specific mechanism continues to be explored. The gut microbiota plays an important role in the occurrence and development of IBD, and MSCs and MSC-Exs can effectively regulate gut microbiota in animal models of IBD, but the mechanism involved and whether the outcome can relieve the characteristic dysbiosis necessary to alleviate IBD still needs to be studied. This review provides current evidence on the effective modulation of the gut microbiota by MSC-Exs, offering a basis for further research on the pathogenic mechanism of IBD and MSC-Ex treatments through the improvement of gut microbiota.

Vehicle logo detection plays a crucial role in various computer vision applications, such as vehicle classification and detection. In this research, we propose an improved vehicle logo detection method leveraging the self-attention mechanism. Our feature-sampling structure integrates multiple attention mechanisms and bidirectional feature aggregation to enhance the discriminative power of the detection model. Specifically, we introduce the multi-head attention for multi-scale feature fusion module to capture multi-scale contextual information effectively. Moreover, we incorporate the bidirectional aggregation mechanism to facilitate information exchange between different layers of the detection network. Experimental results on a benchmark dataset (VLD-45 dataset) demonstrate that our proposed method outperforms baseline models in terms of both detection accuracy and efficiency. Our experimental evaluation using the VLD-45 dataset achieves a state-of-the-art result of 90.3% mAP. Our method has also improved AP by 10% for difficult samples, such as HAVAL and LAND ROVER. Our method provides a new detection framework for small-size objects, with potential applications in various fields.