Explore the vast range of titles available.

Canonically, EZH2 serves as the catalytic subunit of PRC2, which mediates H3K27me3 deposition and transcriptional repression. Here, we report that in acute leukaemias, EZH2 has additional noncanonical functions by binding cMyc at non-PRC2 targets and uses a hidden transactivation domain (TAD) for (co)activator recruitment and gene activation. Both canonical (EZH2–PRC2) and noncanonical (EZH2-TAD–cMyc–coactivators) activities of EZH2 promote oncogenesis, which explains the slow and ineffective antitumour effect of inhibitors of the catalytic function of EZH2. To suppress the multifaceted activities of EZH2, we used proteolysis-targeting chimera (PROTAC) to develop a degrader, MS177, which achieved effective, on-target depletion of EZH2 and interacting partners (that is, both canonical EZH2–PRC2 and noncanonical EZH2–cMyc complexes). Compared with inhibitors of the enzymatic function of EZH2, MS177 is fast-acting and more potent in suppressing cancer growth. This study reveals noncanonical oncogenic roles of EZH2, reports a PROTAC for targeting the multifaceted tumorigenic functions of EZH2 and presents an attractive strategy for treating EZH2-dependent cancers. Wang et al. reveal a noncanonical mechanism for EZH2 in binding the oncoprotein cMyc to promote tumorigenesis, and develop a small-molecule degrader, MS177, to target both canonical and noncanonical functions of EZH2 to suppress tumour growth.

The importance of a low-viscosity asthenosphere underlying mobile plates has been highlighted since the earliest days of the plate tectonics revolution. However, absolute asthenospheric viscosities are still poorly constrained, with estimates spanning up to 3 orders of magnitude. Here we follow a new approach using analytic solutions for Poiseuille-Couette channel flow to compute asthenospheric viscosities under the Caribbean. We estimate Caribbean dynamic topography and the associated pressure gradient, which, combined with flow velocities estimated from geologic markers and tomographic structure, yield our best-estimate asthenospheric viscosity of (3.0 ± 1.5)*10 18 Pa s. This value is consistent with independent estimates for non-cratonic and oceanic regions, and challenges the hypothesis that higher-viscosity asthenosphere inferred from postglacial rebound is globally-representative. The active flow driven by Galapagos plume overpressure shown here contradicts the traditional view that the asthenosphere is only a passive lubricating layer for Earth’s tectonic plates. Here, the authors follow a new approach using analytic solutions for Poiseuille-Couette channel flow to compute asthenospheric viscosities under the Caribbean. Active asthenospheric flow observed under the Caribbean contradicts the traditional view that the asthenosphere is only a passive lubricating layer for Earth’s tectonic plates.

The treatment for stage III non-small cell lung cancer (NSCLC) often involves multi-modality treatment. This retrospective study aimed to evaluate whether multidisciplinary team (MDT) discussion results in better patient survival. MDT discussion was optional before February 2016 and was actively encouraged by the MDT committee beginning February 2016. We reviewed the medical charts and computer records of patients with stage III NSCLC between January 2013 and December 2018. A total of 515 patients were included. The median survival of all the patients was 33.9 months (M). The median survival of patients who were treated after MDT discussion was 41.2 M and that of patients treated without MDT discussion was 25.7 M (p = 0.018). The median survival of patients treated before February 2016 was 25.7 M and that of patients treated after February 2016 was 33.9 M (p = 0.003). The median survival of patients with stage IIIA tumors and those with stage IIIB tumors was 39.4 M and 25.7 M, respectively (p = 0.141). Multivariate analysis showed that MDT or not (p<0.001), T staging (p = 0.009), performance status (p<0.001), and surgery (p = 0.016) to be significant prognostic factors. The results of the study show that MDT discussion results in survival benefit in patients with stage III NSCLC. The MDT discussion, performance status, and if surgery was performed were independent prognostic factors for patients with stage III NSCLC.

Fusobacterium nucleatum is a key commensal anaerobe of the human oral cavity that plays a significant role in oral biofilm development and contributes to additional pathologies at extraoral sites, such as promoting preterm birth and colorectal cancer. Although F. nucleatum is known as a major producer of hydrogen sulfide (H 2 S), its genetic determinants and physiological functions are not well understood. The Gram-negative anaerobe Fusobacterium nucleatum is a major producer of hydrogen sulfide (H 2 S), a volatile sulfur compound that causes halitosis. Here, we dissected the genetic determinants of H 2 S production and its role in bacterial fitness and virulence in this important member of the oral microbiome. F. nucleatum possesses four enzymes, CysK1, CysK2, Hly, and MegL, that presumably metabolize l -cysteine to H 2 S, and CysK1 was previously shown to account for most H 2 S production in vitro , based on correlations of enzymatic activities with gene expression at mid-log phase. Our molecular studies showed that cysK1 and megL were highly expressed at the late exponential growth phase, concomitant with high-level H 2 S production, while the expression levels of the other genes remained substantially lower during all growth phases. Although the genetic deletion of cysK1 without supplementation with a CysK1-catalyzed product, lanthionine, caused cell death, the conditional Δ cysK1 mutant and a mutant lacking hly were highly proficient in H 2 S production. In contrast, a mutant devoid of megL showed drastically reduced H 2 S production, and a cysK2 mutant showed only minor deficiencies. Intriguingly, the exposure of these mutants to various antibiotics revealed that only the megL mutant displayed altered susceptibility compared to the parental strain: partial sensitivity to nalidixic acid and resistance to kanamycin. Most significantly, the megL mutant was attenuated in virulence in a mouse model of preterm birth, with considerable defects in the spread to amniotic fluid and the colonization of the placenta and fetus. Evidently, the l -methionine γ-lyase MegL is a major H 2 S-producing enzyme in fusobacterial cells that significantly contributes to fusobacterial virulence and antibiotic susceptibility. IMPORTANCE Fusobacterium nucleatum is a key commensal anaerobe of the human oral cavity that plays a significant role in oral biofilm development and contributes to additional pathologies at extraoral sites, such as promoting preterm birth and colorectal cancer. Although F. nucleatum is known as a major producer of hydrogen sulfide (H 2 S), its genetic determinants and physiological functions are not well understood. By a combination of bacterial genetics, biochemical methods, and in vivo models of infection, here, we demonstrate that the l -methionine γ-lyase MegL not only is a major H 2 S-producing enzyme of F. nucleatum but also significantly contributes to the antibiotic susceptibility and virulence of this organism.

The engagement of target-interceptor is an extremely complicated and nonlinear problem. Most literatures of developed guidance algorithms are hard to work in real-time missile guidance systems because of the complicated design of controllers, restriction in specific condition or excess computing loading. In this paper, the proposed guidance algorithm computes the predicted interception point of target-interceptor and applies particle swarm optimization to optimize the lateral acceleration control commands of missile where the definition of fitness function can guide the missile toward the predicted interception point when the computed fitness value is the minimum. According to the results of simulation experiments, the proposed method has the satisfied target-kill performance to the superior aircraft with high agility. The missile can greatly revise the flight route toward the computed collision course at the initial pursuit stage and the course curve of missile is flatter than the other two guidance laws. Besides, the proposed method can reduce the occurrence of big lateral acceleration control commands acting on the missile to avoid unlocking the evasive target at the terminal stage. As a result, the proposed guidance algorithm based on particle swarm optimization is very effective without using the complicated nonlinear control methods and excess storage burden of computer. It is a simple and feasible missile guidance algorithm due to the advantages of simplicity and effectiveness just like the proportional navigation guidance law but the performance of proposed guidance algorithm is better than proportional navigation guidance law and the other guidance algorithm designed by particle swarm optimization.

Mental health resources are an important basis for coping with mental health services. The equity is an important index of a reasonable allocation of health resources. This study aims to evaluate the mental health resources and its equity allocation in Hunan Province, which is one of the typical central south areas of China, so as to provide reference for the development of mental health in China and other areas. Data related to mental health resources was obtained from the Project of Mental Health Resources in Hunan Province, which was conducted by the Department of Hunan Mental Health Center in 2019. The Gini coefficient, the Theil index and other indicators were employed to quantitatively evaluate the equity of mental health resources' allocation. By the end of 2018, there were a total of 141 mental health institutions in Hunan Province of China, the bed density was 5.31 beds per 10,000 people, the ratio of doctors to nurses was 2.20, the number of outpatients of mental health institutions was 1288,047 per year. The mental health resources' allocation in terms of demographic dimension were in a preferred status with the Gini values all less than 0.3, and the Gini values for mental health resources`allocation in terms of geographical dimension ranged from 0.24 to 0.35. The Theil index for mental health allocation in terms of demographic dimension was lower than 0.05, and the Theil index for mental health allocation in terms of geographical dimension ranged from 0.04 to 0.11. The shortage of mental health resources is still the priority issue to be increased and optimized by policy-makers in Hunan in the future, especially the human resources. Moreover, the utilization of mental health resources was low though its equity was fair. Policy-makers need to consider the high utilization and geographical accessibility of health resources among different regions to ensure people in different regions could get access to available health services.

The Gram-negative oral pathobiont Fusobacterium nucleatum can traverse to extra-oral sites such as placenta and colon, promoting adverse pregnancy outcomes and colorectal cancer, respectively. How this anaerobe sustains many metabolically changing environments enabling its virulence potential remains unclear. Informed by our genome-wide transposon mutagenesis, we report here that the highly conserved R hodobacter n itrogen- f ixation (Rnf) complex, encoded by the rnfCDGEAB gene cluster, is key to fusobacterial metabolic adaptation and virulence. Genetic disruption of the Rnf complex via non-polar, in-frame deletion of rnfC (Δ rnfC ) abrogates polymicrobial interaction (or coaggregation) associated with adhesin RadD and biofilm formation. The defect in coaggregation is not due to reduced cell surface of RadD, but rather an increased level of extracellular lysine, which binds RadD and inhibits coaggregation. Indeed, removal of extracellular lysine via washing Δ rnfC cells restores coaggregation, while addition of lysine inhibits this process. These phenotypes mirror that of a mutant (Δ kamA ) that fails to metabolize extracellular lysine. Strikingly, the Δ rnfC mutant is defective in ATP production, cell growth, cell morphology, and expression of the enzyme MegL that produces hydrogen sulfide (H 2 S) from cysteine. Targeted metabolic profiling demonstrated that catabolism of many amino acids, including histidine and lysine, is altered in Δ rnfC cells, thereby reducing production of ATP and metabolites including H 2 S and butyrate. Most importantly, we show that the Δ rnfC mutant is severely attenuated in a mouse model of preterm birth. The indispensable function of Rnf complex in fusobacterial pathogenesis via modulation of bacterial metabolism makes it an attractive target for developing therapeutic intervention. This paper illuminates the significant question of how the oral commensal Fusobacterium nucleatum adapts to the metabolically changing environments of several extra-oral sites such as placenta and colon to promote various diseases as an opportunistic pathogen. We demonstrate here that the highly conserved R hodobacter n itrogen- f ixation complex, commonly known as Rnf complex, is key to fusobacterial metabolic adaptation and virulence. Genetic disruption of this Rnf complex causes global defects in polymicrobial interaction, biofilm formation, cell growth and morphology, hydrogen sulfide production, and ATP synthesis. Targeted metabolomic profiling demonstrates that the loss of this respiratory enzyme significantly diminishes catabolism of numerous amino acids, which negatively impacts fusobacterial virulence as tested in a preterm birth model in mice.

Stem cell pluripotency gene Sox2 stimulates expression of proneural basic-helix-loop-helix transcription factor Atoh1 . Sox2 is necessary for the development of cochlear hair cells and binds to the Atoh1 3’ enhancer to stimulate Atoh1 expression. We show here that Sox2 deletion in late embryogenesis results in the formation of extra hair cells, in contrast to the absence of hair cell development obtained after Sox2 knockout early in gestation. Sox2 overexpression decreased the level of Atoh1 protein despite an increase in Atoh1 mRNA. Sox2 upregulated E3 ubiquitin ligase, Huwe1 , by direct binding to the Huwe1 gene. By upregulating its cognate E3 ligase, Sox2 disrupts the positive feedback loop through which Atoh1 protein increases the expression of Atoh1 . We conclude that Sox2 initiates expression, while also limiting continued activity of bHLH transcription factor, Atoh1, and this inhibition represents a new mechanism for regulating the activity of this powerful initiator of hair cell development.

Intratumoural hypoxia induces HIF-1α and promotes tumour progression, metastasis and treatment resistance. HIF-1α stability is regulated by VHL-E3 ligase-mediated ubiquitin-dependent degradation; however, the hypoxia-regulated deubiquitinase that stabilizes HIF-1α has not been identified. Here we report that HAUSP (USP7) deubiquitinase deubiquitinates HIF-1α to increase its stability, induce epithelial-mesenchymal transition and promote metastasis. Hypoxia induces K63-linked polyubiquitinated HAUSP at lysine 443 to enhance its functions. Knockdown of HAUSP decreases acetylation of histone 3 lysine 56 (H3K56Ac). K63-polyubiquitinated HAUSP interacts with a ubiquitin receptor CBP to specifically mediate H3K56 acetylation. ChIP-seq analysis of HAUSP and HIF-1α binding reveals two motifs responsive to hypoxia. HectH9 is the E3 ligase for HAUSP and a prognostic marker together with HIF-1α. This report demonstrates that hypoxia-induced K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and causes CBP-mediated H3K56 acetylation on HIF-1α target gene promoters to promote EMT/metastasis, further defining HAUSP as a therapeutic target in hypoxia-induced tumour progression. Hypoxia-induced transcriptional responses mediated by HIF-1a are regulated through the ubiquitin-dependent pathway to control HIF-1a stability. Here the authors show that the deubiquitinase HAUSP modulates the stability of HIF-1a and K63-polyubiquitinated HAUSP serves as an anchor for HIF-1a-induced gene transcription.

Human activity recognition (HAR) using Wi-Fi-based sensing has emerged as a powerful, non-intrusive solution for monitoring human behavior in smart environments. Unlike wearable sensor systems that require user compliance, Wi-Fi channel state information (CSI) enables device-free recognition by capturing variations in signal propagation caused by human motion. This makes Wi-Fi sensing highly attractive for ambient healthcare, security, and elderly care applications. However, real-world deployment faces two major challenges: (1) significant cross-subject signal variability due to physical and behavioral differences among individuals, and (2) limited labeled data, which restricts model generalization. To address these sensor-related challenges, we propose TCN-MAML, a novel framework that integrates temporal convolutional networks (TCN) with model-agnostic meta-learning (MAML) for efficient cross-subject adaptation in data-scarce conditions. We evaluate our approach on a public Wi-Fi CSI dataset using a strict cross-subject protocol, where training and testing subjects do not overlap. The proposed TCN-MAML achieves 99.6% accuracy, demonstrating superior generalization and efficiency over baseline methods. Experimental results confirm the framework’s suitability for low-power, real-time HAR systems embedded in IoT sensor networks.