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Ethnopharmacological Relevance: Euonymus alatus (Thunb.) Siebold. (EA), a traditional Chinese medicine, is widely used in the treatment of diabetes. Our group has previously found that EA could treat diabetic retinopathy (DR) and stigmast-4-en-3-one (Numbered E6) is the active substance responsible for inhibiting angiogenesis in vitro by EA. However, the effects and mechanisms of E6 in the treatment of DR is still unknown., Aim of the Study: The aim of this study was to investigate the effects and mechanisms of E6 in EA on DR. Additionally, a comparison was made between the effects of E6 and triamcinolone acetonide (TA), as well as the side effects of E6 and dexamethasone., Materials and Methods: Ocular affinity assessment and pharmacokinetic parameter prediction were conducted to evaluate the potential of E6 to treat DR. Retinal endothelial cells were used to investigate the in vitro inhibitory effect of E6 on vascular proliferation. Additionally, chicken embryos, zebrafish, and mice were used to investigate the in vivo anti-vascular proliferation effect of E6. Finally, diabetic mice were used to investigate whether E6 improves diabetic retinopathy and to compare its efficacy with that of TA. We then used network pharmacology to study the targets of E6 and performed molecular docking; followed by immunofluorescence experiments, ELISA, Western blot, and tube formation experiments to further investigate its mechanism. Finally, we compared the side effects of E6 with those of dexamethasone., Results: E6 was found to have an affinity for the eye and to inhibit vascular proliferation both in vivo and in vitro. Moreover, E6 was found to be more efficacious than TA in the treatment of DR. Molecular docking experiments predicted that the glucocorticoid receptor (GR) is a potential target of E6, and immunofluorescence analyses confirmed that E6 upregulated the expression of the GR in the retina of hyperglycemic mice. In addition, western blotting results and tube formation experiments showed that E6 also attenuated angiogenesis by inhibiting the Hippo and VEGF pathways. Finally, by comparing the effects of E6 and dexamethasone on glucose regulation and osteoporosis, E6 was found to have fewer side effects., Conclusions: E6 is a highly effective drug for the treatment of DR, superior to TA and with fewer side effects than dexamethasone. Its mechanism involves the activation of glucocorticoid receptor and inhibition of Hippo and VEGF pathways to alleviate angiogenesis and inflammation. This study is the first to investigate the role and mechanism of E6 in improving DR. The findings suggest that E6 has unique advantages in the treatment of DR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Secondary organic aerosol (SOA) accounts for a large fraction of fine particulate matter (PM 2.5 ), but the lack of vertical observations of SOA in the urban boundary layer (UBL) limits a comprehensive understanding of its sources and formation mechanisms. In this study, PM 2.5 samples were simultaneously collected at 3 m, 118 m, and 488 m on the Canton Tower in Guangzhou during winter. Typical SOA tracers, including oxidation products of isoprene (SOA I ), monoterpene (SOA M ), sesquiterpene (SOA S ), and toluene (ASOA), were investigated alongside meteorological parameters and gaseous/particulate pollutants. Total concentrations of SOA tracers showed an increasing trend with height, with daytime levels exceeding nighttime levels. C 5 -alkene triols and 2-methylglyceric acid displayed a significant increase with height, potentially affected by nighttime chemistry in the residual layer, determining the overall vertical trend of SOA I tracers. Concentrations of later-generation SOA M (SOA M_S ) tracers also increased with height, while those of first-generation SOA M (SOA M_F ) tracers decreased, indicating relatively aged SOA M in the upper layers. SOA S and ASOA tracers exhibited higher enhancement under polluted conditions, likely impacted by biomass burning and anthropogenic emissions. The yields of SOA I tracers varied with temperature in the vertical profile. The formation of SOA M_F tracers was negatively correlated with relative humidity, liquid water content, and pH, affecting their vertical distributions. The effect of O 3 on SOA formation enhanced significantly with height, influenced by air mass transport, and likely contributed to the higher yields of SOA in the upper layer. However, at ground level, SOA formation was primarily driven by high local emissions of both NO x and volatile organic compounds. We also observed the roles of SO 2 in SOA generation, particularly at 118 m. This study demonstrates the vertical diurnal characteristics of SOA tracers in the UBL, highlighting the varying effects of meteorological conditions and anthropogenic pollutants on SOA formation at different heights., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To rich the research for mannoproteins (MPs) suppressive effect on the bitterness of wine, this study distinguished bitterness into initial bitterness and bitter aftertaste. By utilizing the thermal alkali extraction method, MPs were extracted from three different yeast species: Saccharomyces cerevisiae (CECA), Lachancea thermotolerans (A38), and Torulaspora delbrueckii (2082). Their basic structures, addition concentrations, and correlation with bitter suppression ability were characterized. CECA exhibited stronger initial bitterness suppression ability, may attributed to its more branches and lack of a triple-helix structure. 2082 showed greater bitter aftertaste suppression and might due to smaller particle aggregation, fewer branches, and triple-helix structure. Additionally, it was noteworthy that due to the unique structure of 2082, it may bound more monomer and oligomeric proanthocyanidins (MOPC) on MPs surface, reducing its initial bitterness suppression ability. Concerning concentration, the increase in polysaccharide chain polymerization hindered further interaction with MOPC, leading to a decrease in its initial bitterness suppression ability. Bitter aftertaste exhibited different behaviors. As the concentration of CECA increased, there was an increase in oral adhesion instead., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The rapid industrial progress in today's world has led to an alarming increase in water pollution caused by various contaminants such as synthetic dyes. To address this issue, a new hydrogel sorbent, BC-r-Na-Alg-g-p(NIPAm-co-AAc), was developed by combining bentonite clay, sodium alginate, and poly(N-isopropyl acrylamide-co-acrylic acid) through one-pot free radical polymerization at 60 °C. The developed sorbent was characterized using several analytical techniques including SEM, FTIR, TGA, UTM, and swelling studies. The swelling capacity of the sorbent was observed to increase remarkably with an increase in pH, reaching a maximum of 9664 % at pH 11. In batch mode sorption experiments, the sorbent's performance toward methylene green (MG) was investigated by analysing the effects of contact time, pH, temperature, and concentration. The experimental data were fitted to pseudo-second-order kinetic and Langmuir isotherm models, indicating chemisorption as the dominant interaction mode between the anionic sorbent and cationic MG. However, physisorption may also occur to a lesser extent, indicated by the significant R 2 of the pseudo-first-order kinetic and Freundlich isotherm models. Additionally, the sorbent exhibited very little decrease (approximately 5 %) in sorptive performance for six sorption-desorption cycles. Overall, the facile fabrication, excellent swelling (9664 %), promising sorption performance (2573 mg.g -1 ), and good recyclability (6 cycles) make the developed sorbent a potential candidate for various industrial applications., Competing Interests: Declaration of competing interest I on the behalf of all the co-authors confirm that we have no conflict of interest in submission of this paper to the Journal of “International Journal of Biological Macromolecules” for possible publication., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Observational studies have established a connection between gut microbiota and ankylosing spondylitis (AS) risk; however, whether the observed associations are causal remains unclear. Therefore, we conducted a two-sample Mendelian randomization (MR) analysis to assess the potential causal associations of gut microbiota with AS risk., Methods: Instrumental variants of gut microbiota were obtained from the MiBioGen consortium (n = 18,340) and the Dutch Microbiome Project (n = 7738). The FinnGen consortium provided genetic association summary statistics for AS, encompassing 2860 cases and 270,964 controls. We used the inverse-variance weighted (IVW) method as the primary analysis, supplemented with the weighted median method, maximum likelihood-based method, MR pleiotropy residual sum and outlier test, and MR-Egger regression. In addition, we conducted a reverse MR analysis to assess the likelihood of reverse causality., Results: After the Bonferroni correction, species Bacteroides vulgatus remained statistically significantly associated with AS risk (odds ratio (OR) 1.55, 95% confidence interval (CI) 1.22-1.95, P = 2.55 × 10 -4 ). Suggestive evidence of associations of eleven bacterial traits with AS risk was also observed (P < 0.05 by IVW). Among them, eight were associated with an elevated AS risk (OR 1.37, 95% CI 1.07-1.74, P = 0.011 for phylum Verrucomicrobia; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for class Verrucomicrobiae; OR 1.17, 95% CI 1.01-1.36, P = 0.035 for order Bacillales; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for order Verrucomicrobiales; OR 1.43, 95% CI 1.13-1.82, P = 0.003 for family Alcaligenaceae; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for family Verrucomicrobiaceae; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for genus Akkermansia; OR 1.55, 95% CI 1.19-2.02, P = 0.001 for species Sutterella wadsworthensis). Three traits exhibited a negative association with AS risk (OR 0.68, 95% CI 0.53-0.88, P = 0.003 for genus Dialister; OR 0.84, 95% CI 0.72-0.97, P = 0.020 for genus Howardella; OR 0.75, 95% CI 0.59-0.97, P = 0.026 for genus Oscillospira). Consistent associations were observed when employing alternate MR methods. In the reverse MR, no statistically significant correlations were detected between AS and these bacterial traits., Conclusion: Our results revealed the associations of several gut bacterial traits with AS risk, suggesting a potential causal role of gut microbiota in AS development. Nevertheless, additional research is required to clarify the mechanisms by which these bacteria influence AS risk. Key Points • The association of gut microbiota with AS risk in observational studies is unclear. • This MR analysis revealed associations of 12 gut bacterial traits with AS risk., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Luminal Androgen Receptor (LAR) triple-negative breast cancers (TNBC) express androgen receptors (AR), exhibit high frequency of PIK3CA mutations and intact RB. Herein, we investigated combined blockade of the CDK4/6 and PI3K signaling with palbociclib, alpelisib, and capivasertib, which inhibit CDK4/6, PI3Kα, and AKT1-3, respectively. The combination of palbociclib/capivasertib, but not palbociclib/alpelisib, synergistically inhibited proliferation of MDA-MB-453 and MFM-223 LAR cells [synergy score 7.34 (p = 5.81x10 -11 ) and 4.78 (p = 0.012), respectively]. The AR antagonist enzalutamide was inactive against MDA-MB-453, MFM-223, and CAL148 cells and did not enhance the efficacy of either combination. Palbociclib/capivasertib inhibited growth of LAR patient-derived xenografts more potently than palbociclib/alpelisib. Treatment of LAR cells with palbociclib suppressed phosphorylated-RB and resulted in adaptive phosphorylation/activation of S473 pAKT and AKT substrates GSK3β, PRAS40, and FoxO3a. Capivasertib blocked palbociclib-induced phosphorylation of AKT substrates more potently than alpelisib. Treatment with PI3Kβ inhibitors did not block phosphorylation of AKT substrates, suggesting that PI3Kβ did not mediate the adaptive response to CDK4/6 inhibition. Phosphokinase arrays of MDA-MB-453 cells treated with palbociclib showed time-dependent upregulation of PDGFRβ, GSK3β, STAT3, and STAT6. RNA silencing of PDGFRβ in palbociclib-treated MDA-MB-453 and MFM-223 cells blocked the upregulation of S473 pAKT, suggesting that the adaptive response to CDK4/6 blockade involves PDGFRβ signaling. Finally, treatment with palbociclib and the PDGFR inhibitor CP637451 arrested growth of MDA-MB-453 and MFM-223 cells to the same degree as palbociclib/capivasertib. These findings support testing the combination of CDK4/6 and AKT inhibitors in patients with LAR TNBC, and further investigation of PDGFR antagonists in this breast cancer subtype., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ariella B. Hanker received or has received research grants from Takeda and Lilly and nonfinancial support from Puma Biotechnology, Daiichi Sankyo, and Tempus. Carlos L. Arteaga receives or has received research grants from Pfizer, Lilly, and Takeda; holds minor stock options in Provista; serves or has served in an advisory role to Novartis, Merck, Lilly, Daiichi Sankyo, Taiho Oncology, OrigiMed, Puma Biotechnology, Immunomedics, AstraZeneca, Arvinas, and Sanofi; and reports scientific advisory board remuneration from the Susan G. Komen Foundation., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Utilizing inexhaustible solar energy for water purification represents a green and sustainable solution to water scarcity. However, the developments of efficient, inexpensive, convenient and reliable photothermal materials remain a major challenge. Herein, a facile and versatile preparation strategy of sodium alginate (SA)-CuS composite coating with superior adhesion and stability has been proposed toward high-efficiency solar-driven interfacial evaporation. The fabrication process can be quickly completed in aqueous solution with cheap reagents. The SA-CuS coating can be firmly adhered on different substrates, which can withstand rinsing treatment, iterative freeze-thaw cycles as well as high and low pH environments. The SA-CuS coating can convert various substrates into photothermal materials with broad light absorption for desirable solar evaporation because of high CuS loading and rough surface. As a proof of concept, a wood evaporator covered with the SA-CuS coating can achieve a water evaporation rate of ∼2.2 kg m -2  h - 1 under one sun illumination, which is superior to most reported wood-based solar evaporators., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Reusable point-of-care biosensors offer a cost-effective solution for serial biomarker monitoring, addressing the critical demand for tumour treatments and recurrence diagnosis. However, their realization has been limited by the contradictory requirements of robust reusability and high sensing capability to multiple interactions among transducer surface, sensing probes and target analytes. Here we propose a drug-mediated organic electrochemical transistor as a robust, reusable epidermal growth factor receptor sensor with striking sensitivity and selectivity. By electrostatically adsorbing protonated gefitinib onto poly(3,4-ethylenedioxythiophene):polystyrene sulfonate and leveraging its strong binding to the epidermal growth factor receptor target, the device operates with a unique refresh-in-sensing mechanism. It not only yields an ultralow limit-of-detection concentration down to 5.74 fg ml -1 for epidermal growth factor receptor but, more importantly, also produces an unprecedented regeneration cycle exceeding 200. We further validate the potential of our devices for easy-to-use biomedical applications by creating an 8 × 12 diagnostic drug-mediated organic electrochemical transistor array with excellent uniformity to clinical blood samples., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Learning from a sequence of tasks for a lifetime is essential for an agent toward artificial general intelligence. Despite the explosion of this research field in recent years, most work focuses on the well-known catastrophic forgetting issue. In contrast, this work aims to explore knowledge-transferable lifelong learning without storing historical data and significant additional computational overhead. We demonstrate that existing data-free frameworks, including regularization-based single-network and structure-based multinetwork frameworks, face a fundamental issue of lifelong learning, named anterograde forgetting, i.e., preserving and transferring memory may inhibit the learning of new knowledge. We attribute it to the fact that the learning network capacity decreases while memorizing historical knowledge and conceptual confusion between the irrelevant old knowledge and the current task. Inspired by the complementary learning theory in neuroscience, we endow artificial neural networks with the ability to continuously learn without forgetting while recalling historical knowledge to facilitate learning new knowledge. Specifically, this work proposes a general framework named cycle memory networks (CMNs). The CMN consists of two individual memory networks to store short- and long-term memories separately to avoid capacity shrinkage and a transfer cell between them. It enables knowledge transfer from the long-term to the short-term memory network to mitigate conceptual confusion. In addition, the memory consolidation mechanism integrates short-term knowledge into the long-term memory network for knowledge accumulation. We demonstrate that the CMN can effectively address the anterograde forgetting on several task-related, task-conflict, class-incremental, and cross-domain benchmarks. Furthermore, we provide extensive ablation studies to verify each framework component. The source codes are available at: https://github.com/GeoX-Lab/CMN.

It has been reported that the self-assembly pattern of light levitating droplet clusters above the hot gas-liquid interface is dependent on the quantity of droplets. However, the already-reported theoretical explanation of the quantity-dependent self-assembly pattern cannot work well when the quantity of the light levitating droplet exceeds 15. Herein, we propose a new theoretical perspective to understand the self-assembly of a light levitating droplet cluster by referring to the classical densest packing problem of identical rigid circles in a larger circle with the introduction of the minimum total potential energy principle. Amazingly, the theoretical results obtained by this new approach agree well with experimental results, even though the quantity of the light levitating droplet is up to 142. This study deepens our understanding of the quantity-dependent self-assembly pattern of the light levitating droplet clusters and provides significant inspiration for other analogous self-assembly phenomena.

Objective: The objective of this study is to analyze the death characteristics and burden of disease (BOD) in diabetes mellitus (DM) patients in Weifang from 2010 to 2021. The findings will serve as a foundational data source and theoretical framework for public health administrative departments in the formulation of DM-related policies., Methods: The annual percent change (APC) and average annual percent change (AAPC) of the disability-adjusted life years (DALY), years of life lost (YLL), and years lived with disability (YLD) in DM residents from 2010 to 2021 were analyzed using the Joinpoint software to reflect the changing trend of the BOD in DM patients. Additionally, we conducted an analysis of the various causes of death among these patients and compared BOD in diabetic patients with different backgrounds., Results: From 2010 to 2021, the burden of disease, which includes DALY, YL, and YLD, has been increasing among patients with DM in Weifang. It is noteworthy that the burden of disease is particularly pronounced among male patients and those aged 75 or above. Additionally, it is observed that widowed and illiterate DM patients have comparatively longer survival times. Furthermore, among the DM patients who have unfortunately passed away, it has been identified that unspecified DM with ketoacidosis accounts for 10.03% of the deaths as a direct cause of death. In contrast, type 2 diabetes mellitus (T2DM) with kidney complications contributes to 10.23% of the deaths as the fundamental cause of death., Conclusion: The city is faced with a significant challenge of diabetes, which is influenced by factors such as gender, age, cultural background, and marital status. Unspecified diabetes mellitus (DM) with ketoacidosis (10.03%) and T2DM with renal complications (0.23%) are identified as the primary direct and underlying causes of death among diabetic patients, respectively. This study serves as a valuable reference for other regions in terms of diabetes prevention, control, and the management of chronic diseases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

T cell receptor (TCR) engagement causes a global cellular response that entrains signaling pathways, cell cycle regulation, and cell death. The molecular regulation of mRNA translation in these processes is poorly understood. Using a whole-genome CRISPR screen for regulators of CD95 (FAS/APO-1)-mediated T cell death, we identified AMBRA1, a protein previously studied for its roles in autophagy, E3 ubiquitin ligase activity, and cyclin regulation. T cells lacking AMBRA1 resisted FAS-mediated cell death by down-regulating FAS expression at the translational level. We show that AMBRA1 is a vital regulator of ribosome protein biosynthesis and ribosome loading on select mRNAs, whereby it plays a key role in balancing TCR signaling with cell cycle regulation pathways. We also found that AMBRA1 itself is translationally controlled by TCR stimulation via the CD28-PI3K-mTORC1-EIF4F pathway. Together, these findings shed light on the molecular control of translation after T cell activation and implicate AMBRA1 as a translational regulator governing TCR signaling, cell cycle progression, and T cell death., Competing Interests: Competing interests statement:The authors declare no competing interest.

Ethnopharmacological Relevance: The traditional medicinal formulation, Qifu-yin (QFY), has been widely prescribed for Alzheimer's disease (AD) treatment in China, yet the comprehensive mechanisms through which QFY mitigates AD pathology remain to be fully delineated., Aim of the Study: This study aimed to explore the therapeutic implications of QFY on the synaptic injury and oxidative stress in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice, with a concerted effort to elucidate the molecular mechanisms related to synaptic preservation and memory improvement., Materials and Methods: The components of QFY were identified by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The neuroprotective effects of QFY was evaluated using six-month-old male APP/PS1 mice. Subsequent to a 15 days of QFY regimen, spatial memory was assessed utilizing the Morris water maze (MWM) test. Amyloid-beta (Aβ) aggregation was detected via immunostaining, while the quantification of Aβ 1-40 and Aβ 1-42 was achieved through enzyme-linked immunosorbent assay (ELISA). Transmission electron microscopy (TEM) was used to investigate the synaptic structure and mitochondrial morphology. Golgi staining was applied to examine dendritic spine density. Reactive oxygen species (ROS), 3-nitrotyrosine (3-NT) and 4-hydroxy-nonenal (4-HNE) assays were employed to assess oxidative stress. The expression profiles of Aβ metabolism-associated enzymes and the Keap1/Nrf2/ARE signaling pathway were determined by Western blot., Results: A total of 20 principal compounds in QFY were identified. QFY mitigated memory deficits of APP/PS1 mice, including reducing escape latency and search distance and increasing the time and distance spent in the target quadrant. In addition, QFY increased platform crossings of APP/PS1 mice in the probe trial of MWM tests. TEM analysis showed that QFY increased synapse number in the CA1 region of APP/PS1 mice. Further studies indicated that QFY elevated the expression levels of Post synaptic density protein 95 (PSD95) and synaptophysin, and mitigated the loss of dendritic spine density in the hippocampus of APP/PS1 mice. QFY has been shown to ameliorated the structural abnormalities of mitochondria, including mitochondrial dissolution and degradation, up-regulate ATP synthesis and membrane potential in the hippocampus of APP/PS1 mice. Moreover, QFY activated the Keap1/Nrf2/ARE signaling pathway in the hippocampus of APP/PS1 mice, which might contribute to the neuroprotective effects of QFY., Conclusion: QFY activates the Keap1/Nrf2/ARE signaling, and protects against synaptic and mitochondrial dysfunction in APP/PS1 mice, proposing a potential alternative therapeutic strategy for AD management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Enzalutamide (Enz) resistance is a poor prognostic factor for patients with castration-resistant prostate cancer (CRPC), which often involves aberrant expression of the androgen receptor (AR). Myosin VI (MYO6), one member of the myosin family, plays an important role in regulating cell survival and is highly expressed in prostate cancer (PCa). However, whether MYO6 is involved in Enz resistance in CRPC and its mechanism remain unclear., Methods: Multiple open-access databases were utilized to examine the relationship between MYO6 expression and PCa progression, and to screen differentially expressed genes (DEGs) and potential signaling pathways associated with the MYO6-regulated Enz resistance. Both in vitro and in vivo tumorigenesis assays were employed to examine the impact of MYO6 on the growth and Enz resistance of PCa cells. Human PCa tissues and related clinical biochemical data were utilized to identify the role of MYO6 in promoting PCa progression and Enz resistance. The molecular mechanisms underlying the regulation of gene expression, PCa progression, and Enz resistance in CRPC by MYO6 were investigated., Results: MYO6 expression increases in patients with PCa and is positively correlated with AR expression in PCa cell lines and tissues. Overexpression of AR increases MYO6 expression to promote PCa cell proliferation, migration and invasion, and to inhibit PCa cell apoptosis; whereas knockdown of MYO6 expression reverses these outcomes and enhances Enz function in suppressing the proliferation of the Enz- sensitive and resistant PCa cells both in vitro and in vivo. Mechanistically, AR binds directly to the promoter region (residues - 503 to - 283 base pairs) of MYO6 gene and promotes its transcription. Furthermore, MYO6 activates focal adhesion kinase (FAK) phosphorylation at tyrosine-397 through integrin beta 8 (ITGB8) modulation to promote PCa progression and Enz resistance. Notably, inhibition of FAK activity by Y15, an inhibitor of FAK, can resensitize CRPC cells to Enz treatment in cell lines and mouse xenograft models., Conclusions: MYO6 has pro-tumor and Enz-resistant effects in CRPC, suggesting that targeting MYO6 may be beneficial for ENZ-resistant CRPC therapy through the AR/MYO6/FAK signaling pathway., (© 2024. The Author(s).)

Objective: This study aimed to evaluate the association between vegetable intake and major depressive disorder (MDD) through cross-sectional analysis and bidirectional two-sample Mendelian randomisation (MR)., Design: Cross-sectional analysis was conducted on National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2018 and the corresponding Food Patterns Equivalents Database (FPED). Genome-wide association study (GWAS) data were obtained from UK Biobank and Psychiatric Genomics Consortium (PGC) dataset. Logistic regression analysis was performed after calculating the weights of the samples. Inverse variance weighted, MR-Egger and weighted median methods were used to evaluate the causal effects., Setting: A Patient Health Questionnaire-9 score ≥ 10 was considered to indicate MDD. Low vegetable intake was defined as < 2 cups of vegetables per day., Participants: 30 861 U.S. adults from NHANES. The GWAS data sample size related to vegetable intake were comprised 448 651 and 435 435 cases respectively, while the GWAS data sample size associated with MDD encompassed 500 199 cases., Results: There were 23 249 (75·33 %) participants with low vegetable intake. The relationship between vegetable intake and MDD was nonlinear. In the multivariate model adjusted for sex, age, education, marital status, poverty income ratio, ethnicity and BMI, participants with low vegetable intake were associated with an increased risk of MDD (OR = 1·53, 95 % CI (1·32, 1·77), P < 0·001). Bidirectional MR showed no causal effects between vegetable intake and MDD., Conclusions: Cross-sectional analysis identified a significant relationship between vegetable intake and MDD, whereas the results from bidirectional two-sample MR did not support a causal role.

The catalytic activity of most epigenetic enzymes requires a metabolite produced by central carbon metabolism as a cofactor or (co-)substrate. The concentrations of these metabolites undergo dynamic changes in response to nutrient levels and environmental conditions, reprogramming metabolic processes and epigenetic landscapes. Abnormal accumulations of epigenetic modulatory metabolites resulting from mutations in metabolic enzymes contribute to tumorigenesis. In this review, we first present the concept that metabolite regulation of gene expression represents an evolutionarily conserved mechanism from prokaryotes to eukaryotes. We then review how individual metabolites affect epigenetic enzymes and cancer development. Lastly, we discuss the advancement of and opportunity for therapeutic targeting of metabolite-epigenetic regulation in cancer therapy., Competing Interests: Declaration of interests Y.X. is an employee of Cullgen, Inc., and equity holder of Cullgen, Inc., and Meton Biopharma., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Absent in melanoma 2 (AIM2) is a protein encoded by the AIM2 gene located on human chromosomes, AIM2 can recognize and bind to double stranded DNA (dsDNA), leading to the assembly of the AIM2 inflammasome. The AIM2 inflammasome plays important proinflammation role in many diseases, and can induce pyroptotic cell death. It has also been closely linked to the development and progression of metabolic diseases and can be activated in obesity, diabetes, nonalcoholic fatty liver disease, and atherosclerosis. In this article, we mainly review the role of AIM2 in glucose metabolism, especially in obesity-related disorders of glucose and lipid metabolism, and provide insights to better understand the role of AIM2 in the pathogenesis, and clinical treatment of metabolic disease., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Zhang et al.)

In order to prepare flexible thermal protection aerogel materials, using dimethyldimethoxysilane (DMDMS) and methyltrimethoxysilane (MTMS) as co-precursors, isocyanate-propyltrimethoxysilane (CFS-006) was added to the co-precursor as a coupling agent, and resorcinol and formaldehyde were added to the sol solution to prepare a phenolic silicone hybrid aerogel (FAS) by the sol-gel method. The prepared FAS aerogel had no phase separation problem, the density was only 0.118 g/cm 3 , the hydrophobic angle reached 155.3°, and it had certain flexibility. It could be compressed to 70% and still be restored to its original state. The FAS aerogel also had a low thermal conductivity of 0.0318 W/(m·K) and good high temperature insulation. The introduction of phenolic groups improved thermal stability; Tmax increased to 643.7 °C, and the residual carbon rate was 24.5%. This work has positive significance for the future combination of aerogels and textiles in the preparation of firefighting protective clothing.

In this investigation, we explored the molecular dynamics guiding the progression of castration-resistant prostate cancer (CRPC) influenced by Helicobacter pylori (H. pylori)-mediated M2 polarization of macrophages through the IL-17RA/CTSK/EMT axis. An 830-patient clinical trial categorized subjects into hormone-sensitive prostate cancer (HSPC) and CRPC groups. H. pylori infection, evaluated by ELISA, exhibited a higher incidence in CRPC patients, impacting overall survival (OS) and progression-free survival. In-depth in vitro and in vivo experiments, including 16S rDNA sequencing, immunohistochemical tests, and transcriptome analysis, unveiled that H. pylori promotes CRPC growth and metastasis by upregulating IL-17RA and CTSK, leading to enhanced EMT. Notably, M2 macrophages emerged as pivotal immune cells influencing CRPC progression. This study uncovers a novel pathway wherein H. pylori enrichment exacerbates CRPC by inducing macrophage M2 polarization, IL-17RA/CTSK expression, and EMT activation, shedding light on a previously unrecognized mechanism contributing to the growth and metastasis of CRPC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Wearable haptics serve as an enhanced media to connect humans and VR/robots. The inevitable sweating issue in all wearables creates a bottleneck for wearable haptics, as the sweat/moisture accumulated in the skin/device interface can substantially affect feedback accuracy, comfortability, and create hygienic problems. Nowadays, wearable haptics typically gain performance at the cost of sacrificing the breathability, comfort, and biocompatibility. Here, we developed a fully integrated breathable haptic textile (FIBHT) to solve these trade-off issues, where the FIBHT exhibits high-level integration of 128 pixels over the palm, great stretchability of 400%, and superior permeability of over 657 g/m 2 /day (moisture) and 40 mm/s (air). It is a stand-alone haptic system totally composed of stretchable, breathable, and bioadhesive materials, which empowers it with precise, sweating/movement-insensitive and dynamic feedback, and makes FIBHT powerful for virtual touching in broad scenarios.

Background: Clinical evidence of the potential influence of stress hyperglycemia ratio (SHR) for patients with large ischemic stroke whether or not receiving endovascular therapy is not clear., Methods: This study was a subanalysis of a prospective, multicenter registry, and included 745 patients with large ischemic stroke across 38 centers in China. A total of 427 patients were included in this study, with 285 received endovascular therapy (EVT) and 142 received standard medical therapy (SMT). SHR was defined as glucose (mmol/L)/(1.59 × HbA1C)-2.59. The primary outcome was a moderate neurological outcome (modified Rankin Scale (mRS) score ≤3) at 90 days., Results: A significant interaction was observed between SHR and whether received EVT (p=0.017). Among patients who received EVT (adjusted OR (aOR) 0.46; 95% CI 0.23 to 0.92; p=0.029), patients in the highest tertile of SHR were significantly less likely to achieve a moderate neurological outcome at 90 days compared with those in the lowest tertile. However, this association was not observed in patients receiving SMT (aOR 2.46; 95% CI 0.74 to 8.21; p=0.142). EVT patients with higher SHR had a significantly higher incidence of symptomatic intracranial hemorrhage compared with lower SHR (aOR 3.29; 95% CI 1.08 to 10.06; p=0.036), while such an association was not observed in the SMT group (aOR 1.52; 95% CI 0.56 to 4.12; p=0.410)., Conclusions: In patients with large ischemic stroke treated with EVT, SHR is associated with a reduced likelihood of achieving a moderate neurological outcome, as well as an increased risk of symptomatic intracranial hemorrhage., Trial Registration Number: ChiCTR2100051664., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The function and homeostasis of the mammalian ovary depend on complex paracrine interactions between multiple cell types. Using primary mouse tissues and isolated cells, we showed in vitro that ovarian follicles secrete a factor(s) that suppresses growth of ovarian epithelial cells in culture. Most of the growth suppressive activity was accounted for by Anti-Mullerian Hormone/Mullerian Inhibitory Substance (AMH/MIS) secreted by granulosa cells of the follicles, as determined by immune depletion experiments. Additionally, conditioned medium from granulosa cells from wild type control, but not AMH knockout, suppressed epithelial cell growth. Tracing of the AMH regulated cells using AMHR2 (AMH receptor 2)-Cre:ROSA26 mutant mice indicated the presence of populations of AMHR2-positive epithelial cells on the ovarian surface and oviduct epithelia. Cells isolated from the mutant mice indicated that a subpopulation of cells marked by AMHR2-Cre:ROSA26 accounted for most cell growth and expansion in ovarian surface epithelial cells, and the AMHR2 lineage derived cells were regulated by AMH in vitro; whereas, fewer AMHR2-Cre:ROSA26 marked cells accounted for oviduct epithelial cell outgrowth. The results reveal a paracrine pathway in maintaining follicle-epithelial homeostasis in ovary and support a subpopulation of AMHR2 lineage marked epithelial cells as ovarian epithelial stem/progenitor cells with higher proliferative potential regulatable by follicle secreted AMH., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Diffuse pleural mesothelioma (DPM) is a lethal cancer with a poor prognosis and limited treatment options. The Hippo signaling pathway genes, such as NF2 and LATS1/2, are frequently mutated in DPM, indicating a tumor suppressor role in the development of DPM. Here, we show that in DPM cell lines lacking NF2 and in mice with a conditional Nf2 knockout, downregulation of WWC proteins, another family of Hippo pathway regulators, accelerates DPM progression. Conversely, the expression of SuperHippo, a WWC-derived minigene, effectively enhances Hippo signaling and suppresses DPM development. Moreover, the adeno-associated virus serotype 6 (AAV6) has been engineered to deliver both NF2 and SuperHippo genes into mesothelial cells, which substantially impedes tumor growth in xenograft and genetic DPM models and prolongs the median survival of mice. These findings serve as a proof of concept for the potential use of gene therapy targeting the Hippo pathway to treat DPM., Competing Interests: Declaration of interests A patent application about mesothelioma gene therapy has been filed., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In situ immobilization is a widely used measure for passivating Cd-contaminated soils. Amendments need to be continuously applied to achieve stable remediation effects. However, few studies have evaluated the impact of consecutive application of amendments on soil health and the microecological environment. A field experiment was conducted in a Cd-contaminated paddy (available Cd concentration 0.40 mg kg -1 ) on the Chengdu Plain to investigate the changes in soil Cd availability and response characteristics of soil bacterial communities after consecutive application of rice straw biochar (SW), fly ash (FM) and marble powder (YH) amendments from 2018 to 2020. Compared with control treatment without amendments (CK), soil pH increased by 0.6, 0.5 and 1.5 under SW, FM and YH amendments, respectively, and the soil available Cd concentration decreased by 10.71%, 21.42% and 25.00%, respectively. The Cd concentration in rice grain was less than 0.2 mg kg -1 under YH amendment, which was within the Chinese Contaminant Limit in Food of National Food Safety Standards (GB2762-2022) in the second and third years. The three amendments had different effects on the transformation of Cd fractions in soil, which may be relevant to the specific bacterial communities shaped under different treatments. The proportion of Fe-Mn oxide-bound fraction Cd (OX-Cd) increased by 11% under YH treatment, which may be due to the promotion of Fe(III) and Cd binding by some enriched iron-oxidizing bacteria, such as Lysobacter, uncultured&#95;Pelobacter sp. and Sulfurifusis. Candidatus&#95;Tenderia and Sideroxydans were enriched under SW and FM amendments, respectively, and were likely beneficial for reducing Cd availability in soil through Cd immobilization. These results revealed the significance of the bacterial community in soil Cd immobilization after consecutive application of amendments and highlighted the potential of applying YH amendment to ensure the safe production of rice in Cd-contaminated soil., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: This exploratory analysis of the CHART trial (ClinicalTrials.gov: NCT03520478) investigated prostate-specific antigen (PSA) kinetics and the correlation between PSA and survival outcomes in high-volume, metastatic, hormone-sensitive prostate cancer (mHSPC)., Methods: A total of 654 patients were randomized 1:1 to receive either rezvilutamide plus androgen deprivation therapy (ADT; n = 326) or bicalutamide plus ADT (n = 328). PSA kinetics were evaluated, and the correlation between survival and the achievement of undetectable PSA (≤0.2 ng/mL) or ≥90% PSA reduction (PSA90) was assessed., Findings: The rezvilutamide group exhibited higher proportions of ≥50% PSA reduction (PSA50; 98.2% vs. 87.5%), PSA90 (88.7% vs. 63.1%), and undetectable PSA (38.3% vs. 17.7%) responses compared to the bicalutamide group by 3 months. The rezvilutamide group demonstrated superior efficacy in delaying PSA progression compared to the bicalutamide group (hazard ratio [HR] 0.21, 95% confidence interval 0.16-0.27). The achievement of undetectable PSA and PSA90 by 6 months in the rezvilutamide group was associated with prolonged overall survival (undetectable PSA, HR = 0.34; PSA90, HR = 0.22), radiographic progression-free survival (HR = 0.36, HR = 0.26), time to PSA progression (HR = 0.25, HR = 0.17), and time to castration resistance (HR = 0.34, HR = 0.23) compared to those who did not achieve these PSA milestones. Stratification by baseline PSA level revealed consistent survival improvements with rezvilutamide plus ADT across quartiles., Conclusions: PSA kinetics is a valuable prognostic factor in mHSPC treated with rezvilutamide plus ADT, and the achievement of undetectable PSA and PSA90 is associated with improved survival. These findings highlight the importance of monitoring PSA kinetics in the management of mHSPC., Funding: This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd., Competing Interests: Declaration of interests X.Y., J.L., and W.W. reported being employed by Jiangsu Hengrui Pharmaceuticals Co., Ltd., (Copyright © 2024. Published by Elsevier Inc.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported .CheckMate 274 is a phase III, randomized, double-blind trial of adjuvant nivolumab versus placebo for muscle-invasive urothelial carcinoma (MIUC) at high risk of recurrence after radical resection. The primary end points of disease-free survival (DFS) in intent-to-treat (ITT) and tumor PD-L1 expression ≥1% populations were met. We report results at an extended median follow-up of 36.1 months in the ITT population. In addition, we report interim overall survival (OS) data for the first time and an exploratory analysis among patients with bladder primary tumors (muscle-invasive bladder cancer [MIBC]). Consistent DFS benefit with nivolumab versus placebo was observed in both the ITT (hazard ratio [HR], 0.71 [95% CI, 0.58 to 0.86]) and PD-L1 ≥1% (HR, 0.52 [95% CI, 0.37 to 0.72]) patients. The HR for OS with nivolumab versus placebo was 0.76 (95% CI, 0.61 to 0.96) in the ITT population and 0.56 (95% CI, 0.36 to 0.86) in the PD-L1 ≥1 population. Continuous benefit in nonurothelial tract recurrence-free survival and distant metastasis-free survival was also observed in both patient populations. The exploratory analysis of patients with MIBC also showed continued efficacy benefits, irrespective of PD-L1 status. No new safety signals were reported. Overall, these results further support adjuvant nivolumab as a standard of care for high-risk MIUC after radical resection.

Background and Objective: Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024., Methods: Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists")., Key Findings and Limitations: Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis., Conclusions and Clinical Implications: The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Black carbon (BC), as a critical light-absorbing constituent within aerosols, exerts profound effects on atmospheric radiation balance, climate, air quality and human health, etc. And it is also a long-standing focus in rapidly developing megacities. So, this study primarily focuses on investigating the variation characteristics and underlying causes of BC in Chongqing (31,914,300 population), which is one of the municipalities directly under the central government of China, serving as a pivotal economic hub in southwest China. Utilizing MERRA-2 reanalysis data, we examined the long-term changes of atmospheric BC over Chongqing 20 years (from 2002 to 2021). Moreover, BC mass concentration observations were conducted using an Aethalometer (AE-33) from March 15 to June 14, 2021 in Liangping District, Chongqing. The statistical analysis over the last 20 years reveals an annual mean BC concentration in Chongqing of 3.42 ± 0.20 μg/m 3 , exhibiting growth from 2002 to 2008, followed by a decline from 2008 to 2021. Monthly concentration displays a "U-shaped" trend, with the lowest values occurring in summer and the highest in winter. Due to topographical and meteorological influences, local emissions primarily contribute to BC pollution, characterized by a spatial distribution pattern of high in the west and low in the east. Ground observation indicates a distinct dual-peaked pattern in the diurnal variation of BC, with peak concentrations aligning with periods of high traffic emissions. The variation in BC is significantly influenced by meteorological conditions (wind, temperature, atmospheric boundary layer) and local pollution sources (predominantly traffic). Furthermore, extreme events analysis suggests that local emissions and regional transport (with higher contributions from Chongqing and the Sichuan Basin) predominantly contributed to BC pollution. This study effectively makes up for the deficiency in analyzing the distribution and sources of BC pollution in Chongqing, providing valuable scientific insights for the atmospheric environment of megacities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lung cancer brain metastasis (LCBM) poses a significant clinical challenge due to acquired resistance to tyrosine kinase inhibitor (TKI) treatment. To elucidate its underlying mechanisms, we employed single-cell RNA sequencing analysis on surgically obtained LCBM samples with diverse genetic backgrounds and TKI treatment histories. Our study uncovers that TKI treatment elevates the immune checkpoint CTLA4 expression in T cells, promoting an immune-suppressive microenvironment. This immunomodulation is initiated by tumor-derived HMGB1 in response to TKIs. In LCBM syngeneic murine models with TKI-sensitive or TKI-resistant EGFR mutations, combining CTLA4 blockade with TKIs demonstrates enhanced efficacy over TKI monotherapy or TKIs with PD1 blockade. These findings provide insights into the TKI resistance mechanisms and highlight the potential of CTLA4 blockade in effectively overcoming TKI resistance in LCBM., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The improvement of hydrogen evolution reaction kinetics can be largely accelerated by introducing a well-designed hydrogen spillover pathway into the catalysts. However, the driving force and mechanism of hydrogen migration on the surface of catalysts are poorly understood and are rarely explored in depth. Here, inspired by the specific ferroelectric property of HfO 2 , Mn-O-Ca sites in Mn 4 CaO 5 , and Fe-Fe sites in hydrogenases, we constructed a bioinspired HfO 2 coupled with Ir catalysts (Ir/HfO 2 @C) with an alkaline hydrogen reverse spillover effect from HfO 2 to interface and acid hydrogen spillover effect from Ir to interface. Benefiting from the bidirectional hydrogen spillover pathways controlled by pH, Ir/HfO 2 @C displays a narrow overpotential difference between acidic and alkaline electrolytes. Remarkably, Ir/HfO 2 @C shows a remarkable mass current density and turnover frequency value, far exceeding the benchmark Ir/C by 20.6 times. More importantly, this Ir/HfO 2 @C achieves extraordinarily low overpotentials of 146 and 39 mV at 10 mV cm -2 in seawater and alkaline seawater, respectively. The anion-exchange membrane water electrolyzer equipped with Ir/HfO 2 @C as a cathode exhibits excellent and stable H 2 -evolution performance on 2.22 V at 1.0 A cm -2 . We expect that the bioinspired strategy will provide a new concept for designing catalytic materials for efficient and pH-universal electrochemical hydrogen production.

Protein acetylation is a common and reversible posttranslational modification tightly governed by protein acetyltransferases and deacetylases crucial for various biological processes in both eukaryotes and prokaryotes. Although recent studies have characterized many acetyltransferases in diverse bacterial species, only a few protein deacetylases have been identified in prokaryotes, perhaps in part due to their limited sequence homology. In this study, we identified YkuR, encoded by smu&#95;318 , as a unique protein deacetylase in Streptococcus mutans . Through protein acetylome analysis, we demonstrated that the deletion of ykuR significantly upregulated protein acetylation levels, affecting key enzymes in translation processes and metabolic pathways, including starch and sucrose metabolism, glycolysis/gluconeogenesis, and biofilm formation. In particular, YkuR modulated extracellular polysaccharide synthesis and biofilm formation through the direct deacetylation of glucosyltransferases (Gtfs) in the presence of NAD + . Intriguingly, YkuR can be acetylated in a nonenzymatic manner, which then negatively regulated its deacetylase activity, suggesting the presence of a self-regulatory mechanism. Moreover, in vivo studies further demonstrated that the deletion of ykuR attenuated the cariogenicity of S. mutans in the rat caries model, substantiating its involvement in the pathogenesis of dental caries. Therefore, our study revealed a unique regulatory mechanism mediated by YkuR through protein deacetylation that regulates the physiology and pathogenicity of S. mutans ., Competing Interests: Competing interests statement:The authors declare no competing interest.

Collective cell migration (CCM) is involved in multiple biological processes, including embryonic morphogenesis, angiogenesis, and cancer invasion. However, the molecular mechanisms underlying CCM, especially leader cell formation, are poorly understood. Here, we show that a signaling pathway regulating angiomotin (AMOT) cleavage plays a role in CCM, using mammalian epithelial cells and mouse models. In a confluent epithelial monolayer, full-length AMOT localizes at cell-cell junctions and limits cell motility. After cleavage, the C-terminal fragment of AMOT (AMOT-CT) translocates to the cell-matrix interface to promote the maturation of focal adhesions (FAs), generate traction force, and induce leader cell formation. Meanwhile, decreased full-length AMOT at cell-cell junctions leads to tissue fluidization and coherent migration of cell collectives. Hence, the cleavage of AMOT serves as a molecular switch to generate polarized contraction, promoting leader cell formation and CCM., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Recent clinical trials have shown that patients with large ischemic cores have better outcomes with endovascular thrombectomy (EVT) compared with standard medical treatment (SMT) alone.We aim to assess whether the relationship between EVT and improvements in clinical outcomes varies depending on the location of the occlusive sites., Methods: This study is a subgroup analysis conducted within a prospective, nationwide, multi-center registry. The cohort included patients with acute large vessel occlusion in the anterior circulation and an Alberta Stroke Program Early Computed Tomography Score of 0 to 5 within 24 hours from last known well. We utilized the adjusted common odds ratio for a shift toward better outcome on the modified Rankin Scale after EVT compared with SMT alone as the primary outcome. Safety outcomes included symptomatic intracranial hemorrhage (sICH)., Results: A total of 745 patients with large ischemic cores were included: 272(36.5%) with internal carotid artery occlusion, 392(52.6%) with M1 segment of the middle cerebral artery occlusion, and 81(11.0%) with M2 segment of the middle cerebral artery occlusion. The adjusted common odds ratios were as follows: 1.98 (95% CI, 1.01-3.89) for ICA occlusions, 2.09 (95% CI, 1.35-3.23) for M1 occlusions, and 1.13 (95% CI, 0.43-2.94) for M2 occlusions. There was no significant treatment-by-occlusion site interaction observed (P=0.69). However, the incidence of sICH was significantly greater in all groups receiving EVT than in those receiving SMT alone. Additionally, we observed that the secondary outcomes and subgroup analyses were generally consistent with the main outcomes., Conclusions: In this study, we found that patients with internal carotid artery and M1 occlusion demonstrated a better outcome with EVT, while the benefit for patients with M2 occlusion remains uncertain., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The emergent reconfigurable metasurfaces (RMs) have attracted a lot of attention due to their potential in broad applications. As a general platform, RMs are able to control the reflection (or refraction) of incident waves with predefined functionalities. Nevertheless, the operation of RMs is highly dependent on the arrival direction of incidence. The self-adaptive design of an RM, so that it can respond to varied incident waves automatically, is highly requested in practical implementation, which is actually challenging. This study reports the realization of an intelligent RM (IRM) system, which can detect the arrival direction of impinging waves and respond to the incidence with a predefined functionality accordingly. This IRM system is constructed by integrating a direction of the arrival estimation module, a frontend by the varactor-based metasurface, and a central control unit. In experiments, an IRM system designed for TM polarization is demonstrated to perform various functions, i.e., retroreflection, directional reflection, and fixed-point energy focusing, which are highly requested by edge communication and sensing. The measured results imply that this IRM system responds quite well within a wide incident range from -60° to 60° in a frequency range from 9 to 9.5 GHz. The proposed IRM can be a good candidate for boosting 5G communication and Internet of Things applications, including beam shaping/steering, RCS manipulation, object imaging, and sensor recharging.

We aimed to evaluate the relationship of dietary magnesium intake with all-cause and cause-specific mortality among patients with gout and hyperuricemia (HUA). We analyzed data of 1171 gout patients and 6707 HUA patients from the National Health and Nutrition Examination Survey (NHANES) 2007-2018 and 2001-2018, respectively. Dietary intake data were obtained from 24-h dietary recall interviews. Mortality status was determined using the NHANES public-use linked mortality fill. We used Cox regression model and restricted cubic spline analysis to probe the association of dietary magnesium intake and mortality among gout and HUA patients. During 7081 person-years of follow-up, 257 deaths were documented in gout patients, among which 74 died from cardiovascular disease (CVD) and 48 died from cancer. For HUA patients followed up for 58,216 person-years, 1315 all-cause deaths occurred, including 411 CVD deaths and 224 cancer deaths. After multifactorial adjustments, higher dietary magnesium intake was associated with lower risk of all-cause mortality. Nonlinear negative associations were found between dietary magnesium intake and CVD mortality among gout and HUA patients, with inflection points of 152.5 mg/day and 303 mg/day, respectively, and cancer mortality among HUA patients, with the inflection point of 232 mg/day. The results were robust in subgroup and sensitivity analyses. High dietary magnesium intake is linearly related to all-cause mortality, and nonlinearly associated with cause-specific mortality among gout and HUA patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Transcriptional factors (TFs) act as key determinants of cell death and survival by differentially modulating gene expression. Here, we identified many TFs, including TEAD4, that form condensates in stressed cells. In contrast to YAP-induced transcription-activating condensates of TEAD4, we found that co-factors such as VGLL4 and RFXANK alternatively induced repressive TEAD4 condensates to trigger cell death upon glucose starvation. Focusing on VGLL4, we demonstrated that heterotypic interactions between TEAD4 and VGLL4 favor the oligomerization and assembly of large TEAD4 condensates with a nonclassical inhibitory function, i.e., causing DNA/chromatin to be aggregated and entangled, which eventually impede gene expression. Based on these findings, we engineered a peptide derived from the TEAD4-binding motif of VGLL4 to selectively induce TEAD4 repressive condensation. This "glue" peptide displayed a strong antitumor effect in genetic and xenograft mouse models of gastric cancer via inhibition of TEAD4-related gene transcription. This new type of repressive TF phase separation exemplifies how cofactors can orchestrate opposite functions of a given TF, and offers potential new antitumor strategies via artificial induction of repressive condensation., (© 2024. The Author(s).)

The excessive use of chemical fertilizers in the Guanxi honey pomelo production area has led to severe soil acidification and magnesium (Mg) deficiency, adversely affecting pomelo fruit quality. To address this issue, an integrated nutrient optimization model crucial for ensuring the sustainable and environmentally friendly development of the Guanxi honey pomelo industry has been explored. In a three-year experiment, two fertilizer treatments were implemented: a farmer fertilizer practice (FP) and an NPK reduction plus foliar Mg fertilizer (OPT + fMg). We investigated the impact of this integrated optimized fertilization measure on pomelo fruit quality from three aspects: flavor (sugars and organic acids), nutrition (vitamin C and mineral elements), and antioxidant properties (phenolics, flavonoids, and phytic acid). The results revealed that the OPT + fMg treatment improved fruit flavor by reducing acidity (titratable acid, citric acid, and quinine), while having a minimal impact on sugar components (sucrose, fructose, and glucose). Additionally, the OPT + fMg treatment increased the total phenolics, total flavonoids, and phytic acid in the fruit peel, enhancing its potential antioxidant quality. However, the OPT + fMg treatment reduced the mineral nutrient quality (excluding calcium) in the fruit. As for the fruit developmental period, the OPT + fMg treatment significantly increased the total flavonoid concentration in the peel from the mid-expansion fruit stage, followed by notable increases in phytic acid in the peel during the mid-to-late expansion fruit stage. The total phenolic concentration in the peel significantly rose only during the late fruit development stage. The most pronounced effect was observed on phytic acid in both peel and pulp. The influence of the OPT + fMg treatment on the mineral nutrients (excluding calcium) primarily occurred during the mid-to-late expansion fruit stage. Overall, the OPT + fMg treatment significantly improved the comprehensive nutritional quality of pomelo fruit, providing valuable insights for scientifically reducing fertilizer application while enhancing fruit quality.

Protein quality control serves as the primary defense mechanism for cells against proteotoxicity induced by proteasome dysfunction. While cells can limit the build-up of ubiquitinated misfolded proteins during proteasome inhibition, the precise mechanism is unclear. Here, we find that protein kinase Ca 2+ /Calmodulin (CaM)-dependent protein kinase II (CaMKII) maintains proteostasis during proteasome inhibition. We show that proteasome inhibition activates CaMKII, which phosphorylates B-cell lymphoma 2 (Bcl-2)-associated athanogene 3 (BAG3) at residues S173, S377, and S386. Phosphorylated BAG3 activates the heme-regulated inhibitor (HRI)- eukaryotic initiation factor-2α (eIF2α) signaling pathway, suppressing protein synthesis and the production of aggregated ubiquitinated misfolded proteins, ultimately mitigating the proteotoxic crisis. Inhibition of CaMKII exacerbates the accumulation of aggregated misfolded proteins and paraptosis induced by proteasome inhibitors. Based on these findings, we validate that combined targeting of proteasome and CaMKII accelerates tumor cell death and enhances the efficacy of proteasome inhibitors in tumor treatment. Our data unveil a new proteasomal inhibition-induced misfolded protein quality control mechanism and propose a novel therapeutic intervention for proteasome inhibitor-mediated tumor treatment., (© 2024. The Author(s).)

Pharyngeal endoderm cells undergo convergence and extension (C&E), which is essential for endoderm pouch formation and craniofacial development. Our previous work implicates Gα13/RhoA-mediated signaling in regulating this process, but the underlying mechanisms remain unclear. Here, we have used endoderm-specific transgenic and Gα13 mutant zebrafish to demonstrate that Gα13 plays a crucial role in pharyngeal endoderm C&E by regulating RhoA activation and E-cadherin expression. We showed that during C&E, endodermal cells gradually establish stable cell-cell contacts, acquire apical-basal polarity and undergo actomyosin-driven apical constriction, which are processes that require Gα13. Additionally, we found that Gα13-deficient embryos exhibit reduced E-cadherin expression, partially contributing to endoderm C&E defects. Notably, interfering with RhoA function disrupts spatial actomyosin activation without affecting E-cadherin expression. Collectively, our findings identify crucial cellular processes for pharyngeal endoderm C&E and reveal that Gα13 controls this through two independent pathways - modulating RhoA activation and regulating E-cadherin expression - thus unveiling intricate mechanisms governing pharyngeal endoderm morphogenesis., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Liver metastases from prostate cancer are associated with an aggressive disease course and poor prognosis. Results from autopsy studies indicate a liver metastasis prevalence of up to 25% in patients with advanced prostate cancer. Population data estimate that ~3-10% of patients with metastatic castration-resistant prostate cancer harbour liver metastases at the baseline, rising to 20-30% in post-treatment cohorts, suggesting that selective pressure imposed by novel therapies might promote metastatic spread to the liver. Liver metastases are associated with more aggressive tumour biology than lung metastases. Molecular profiling of liver lesions showed an enrichment of low androgen receptor, neuroendocrine phenotypes and high genomic instability. Despite advancements in molecular imaging modalities such as prostate-specific membrane antigen PET-CT, and liquid biopsy markers such as circulating tumour DNA, early detection of liver metastases from prostate cancer remains challenging, as both approaches are hampered by false positive and false negative results, impeding the accurate identification of early liver lesions. Current therapeutic strategies showed limited efficacy in this patient population. Emerging targeted radionuclide therapies, metastasis-directed therapy, and novel systemic agents have shown preliminary activity against liver metastases, but require further validation. Treatment with various novel prostate cancer therapies might lead to an increase in the prevalence of liver metastasis, underscoring the urgent need for coordinated efforts across preclinical and clinical researchers to improve characterization, monitoring, and management of liver metastases from prostate cancer. Elucidating molecular drivers of liver tropism and interactions with the liver microenvironment might ultimately help to identify actionable targets to enhance survival in this high-risk patient group., (© 2024. Springer Nature Limited.)

The use of hydrogel-based interfacial solar evaporators for desalination is a green, sustainable, and extremely concerned freshwater acquisition strategy. However, developing evaporators that are easy to manufacture, cheap, and have excellent porous structures still remains a considerable challenge. This work proposes a novel strategy for preparing a self-assembling sponge-like poly(vinyl alcohol)/graphite composite hydrogel based on the Hofmeister effect for the first time. The sponge-like hydrogel interfacial solar evaporator (PGCNG) is successfully obtained after combining with graphite. The whole process is environmental-friendly and of low-carbon free of freezing process. The PGCNG can be conventionally dried and stored. PGCNG shows impressive water storage performance and water transmission capacity, excellent steam generation performance and salt resistance. PGCNG has a high evaporation rate of 3.5 kg m -2 h -1 under 1 kW m -2 h -1 solar irradiation and PGCNG demonstrates stable evaporation performance over both 10 h of continuous brine evaporation and 30 cycles of brine evaporation. Its excellent performance and simple, scalable preparation strategy make it a valuable material for practical interface solar seawater desalination devices., (© 2024 Wiley‐VCH GmbH.)

Background: Genetic testing for cardiac channelopathies is the standard of care. However, many rare genetic variants remain classified as variants of uncertain significance (VUS) due to lack of epidemiological and functional data. Whether deep protein language models may aid in VUS resolution remains unknown. Here, we set out to compare how 2 deep protein language models perform at VUS resolution in the 3 most common long-QT syndrome-causative genes compared with the gold-standard patch clamp., Methods: A total of 72 rare nonsynonymous VUS (9 KCNQ1, 19 KCNH2 , and 50 SCN5A ) were engineered by site-directed mutagenesis and expressed in either HEK293 cells or TSA201 cells. Whole-cell patch-clamp technique was used to functionally characterize these variants. The protein language models, evolutionary scale modeling, version 1b and AlphaMissense, were used to predict the variant effect of missense variants and compared with patch clamp., Results: Considering variants in all 3 genes, the evolutionary scale modeling, version 1b model had a receiver operating characteristic curve-area under the curve of 0.75 ( P =0.0003). It had a sensitivity of 88% and a specificity of 50%. AlphaMissense performed well compared with patch-clamp with an receiver operating characteristic curve-area under the curve of 0.85 ( P <0.0001), sensitivity of 80%, and specificity of 76%., Conclusions: Deep protein language models aid in VUS resolution with high sensitivity but lower specificity. Thus, these tools cannot fully replace functional characterization but can aid in reducing the number of variants that may require functional analysis., Competing Interests: Dr Ackerman is a consultant for Abbott, BioMarin Pharmaceutical, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Illumina, Invitae, Medtronic, Solid Biosciences, Tenaya Therapeutics, and UpToDate. Dr Ackerman and Mayo Clinic are involved in an equity/intellectual property/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. However, none of these entities have contributed to this study in any manner. The other authors report no conflicts.

Upon intravascular applications, i.e., cancer treatment, nanoparticles (NPs) are required to deliver through blood circulation, sustain serum protein interactions, before they penetrate the blood vessels and reach targeted sites for payload drug release. For a delivery process as such, it is elusive and difficult to comprehend the morphological change of NP surface and evaluate associated effects on its targeted delivery. Herein, we used silica NPs with different surface modifications to demonstrate the morphological impact of NPs during the application of the NP-blood protein interaction, vascular endothelial cell penetration, subsequent targeted delivery and photodynamic therapy efficacy, and pursue high drug-load NPs with surface designs. Compared to solid and mesoporous NPs, we found the spiky tubular NPs reserved the NPs' antifouling properties (or shedding of "protein corona"), promoted better endothelial penetration and less destruction in vitro and in vivo. Such effects could be attributed to their spiky surface structures, which can limit the NP-protein interaction area and promote the NP-protein steric hindrance. Further in molecular simulations, we determined that the spiky tubular morphological modification on NPs enhanced the interaction free energy and lowered the amino acids number and the subsequent frequency in contacting with VE-cadherin of vascular endothelia. As a result, the spiky tubular NPs demonstrated its advantages in mitigating damages to VE-cadherin stability and endothelial cell integrity. Exploiting such spiky tubular surface modification, we can improve the NP delivery efficiency and prohibit the leakiness of vascular endothelia, helping address challenges faced by tumor migration in nanomedicine applications for cancer therapy., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A key challenge of continual reinforcement learning (CRL) in dynamic environments is to promptly adapt the reinforcement learning (RL) agent's behavior as the environment changes over its lifetime while minimizing the catastrophic forgetting of the learned information. To address this challenge, in this article, we propose DaCoRL, that is, dynamics-adaptive continual RL. DaCoRL learns a context-conditioned policy using progressive contextualization, which incrementally clusters a stream of stationary tasks in the dynamic environment into a series of contexts and opts for an expandable multihead neural network to approximate the policy. Specifically, we define a set of tasks with similar dynamics as an environmental context and formalize context inference as a procedure of online Bayesian infinite Gaussian mixture clustering on environment features, resorting to online Bayesian inference to infer the posterior distribution over contexts. Under the assumption of a Chinese restaurant process (CRP) prior, this technique can accurately classify the current task as a previously seen context or instantiate a new context as needed without relying on any external indicator to signal environmental changes in advance. Furthermore, we employ an expandable multihead neural network whose output layer is synchronously expanded with the newly instantiated context and a knowledge distillation regularization term for retaining the performance on learned tasks. As a general framework that can be coupled with various deep RL algorithms, DaCoRL features consistent superiority over existing methods in terms of stability, overall performance, and generalization ability, as verified by extensive experiments on several robot navigation and MuJoCo locomotion tasks.

Background: The investigation of dietary micronutrient intakes and risk of alcoholic liver disease (ALD) based on observational studies was limited., Objectives: Our study aimed to explore the associations of 30 dietary micronutrients intakes with risk of ALD, interactions between dietary micronutrients and genetic variation, and mediation effects of blood and urinary biomarkers on the associations between dietary micronutrients and risk of ALD., Methods: A case-control study was conducted within the UK Biobank cohort, with 231 incident ALD cases and 1386 controls. Dietary data were collected using a dietary questionnaire that relied on a 24-h dietary recall of the previous day. Logistic regression models were employed to assess the associations of dietary micronutrient intakes with risk of ALD. We conducted stratified analyses on the associations between dietary micronutrient intakes and risk of ALD by PNPLA3 rs738409 and tested the interactions between dietary micronutrients and genetic variation. In addition, we conducted mediation analyses to investigate the mediating effects of biomarkers on the associations between dietary micronutrients and risk of ALD., Results: Our findings indicated significant inverse associations of thiamin, riboflavin, niacin equivalent, pantothenic acid, vitamin B-6, folate, vitamin E, calcium, magnesium, phosphorus, potassium, copper, iodine, and manganese with risk of ALD (all false discovery rate-P trend < 0.050). We also found a significant interaction between PNPLA3 rs738409 and magnesium (P interaction = 0.028). Creatinine (enzymatic) in urine, aspartate aminotransferase, and insulin-like growth factor 1 were the top 3 biomarkers with the highest number of significant mediation effects on the associations between the dietary micronutrients and risk of ALD., Conclusions: Dietary intakes of thiamin, riboflavin, niacin equivalent, pantothenic acid, vitamin B-6, folate, vitamin E, calcium, magnesium, phosphorus, potassium, copper, iodine, and manganese were inversely associated with risk of ALD., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment., (© 2024 John Wiley & Sons Ltd.)