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Due to their spatial and spectral information, hyperspectral images are frequently used in various scientific and industrial fields. Recent developments in hyperspectral image classification have revolved around the use of convolutional neural networks and transformers, which are capable of modeling local and global data. However, most of the backbone networks of existing methods are based on 3-D convolution, which has high complexity in network structure. Moreover, local information and global information are extracted through different modules, and the coupling relationship between the two types of information is weak. To address the above-mentioned issues, we propose a method named main–sub transformer network with spectral–spatial separable convolution method (MST-SSSNet), which includes two key modules: the spectral–spatial separable convolution (SSSC) module and the main–sub transformer encoder (MST) module. The SSSC module uses the proposed spectral–spatial separable convolution, reducing network parameters and efficiently extracting local features. The MST module adds the designed subtransformer in front of the conventional transformer encoder (main transformer). It assists the main-transformer encoder to establish global correlation by learning local information. The WHU-Hi dataset can be used as a benchmark dataset for precise crop classification and hyperspectral image classification research. MST-SSSNet is shown to deliver better classification performance than current state-of-the-art methods on the datasets.

Abstract Background The authors sought to determine if resident operative time in cataract extraction and intraocular lens insertion (CE/IOL) affects early visual outcomes and post-operative recovery. They further sought to investigate if attending surgeons can reduce resident operative time. Methods This retrospective, chart-review, case series at single Veterans Affairs Hospital (VA Tennessee Valley Healthcare System) studied resident cataract surgeries between March 1, 2018 and March 31, 2020. Following power analysis, 420 eyes of 400 patients from all resident cataract surgeries were included. Eyes with attending as primary surgeon, laser-assisted cataract surgery, or concurrent secondary procedures were excluded. Linear mixed effect models were used to study the association between operative time and visual outcomes while adjusting for covariates including cumulative dissipated energy, preoperative factors, and intraoperative complications. Results Longer operative time was statistically associated with worse post-operative-day 1 (POD1) pinhole visual acuity (PH-VA) adjusting for cumulative dissipated energy and other operative factors (p = 0.049). Although resident physicians were the primary surgeons, the operative times were different between the ten supervising attending surgeons in the study (p

Abstract Background Age-related hearing loss (ARHL) signifies the bilateral, symmetrical, sensorineural hearing loss that commonly occurs in elderly individuals. Several studies have suggested a higher risk of dementia among patients diagnosed with ARHL. Although the precise causal association between ARHL and cognitive decline remains unclear, ARHL has been recognized as one of the most significant factors that can be modified to reduce the risk of developing dementia potentially. Mild cognitive impairment (MCI) typically serves as the initial stage in the transition from normal cognitive function to dementia. Consequently, the objective of our randomized controlled trial (RCT) is to further investigate whether the use of hearing aids can enhance cognitive function in older adults diagnosed with ARHL and MCI. Methods and design This study is a parallel-arm, randomized controlled trial conducted at multiple centers in Shanghai, China. We aim to enlist a total of 688 older adults (age ≥ 60) diagnosed with moderate-to-severe ARHL and MCI from our four research centers. Participants will be assigned randomly to either the hearing aid fitting group or the health education group using block randomization with varying block sizes. Audiometry, cognitive function assessments, and other relevant data will be collected at baseline, as well as at 6, 12, and 24 months post-intervention by audiologists and trained researchers. The primary outcome of our study is the rate of progression to dementia among the two groups of participants. Additionally, various evaluations will be conducted to measure hearing improvement and changes in cognitive function. Apart from the final study results, we also plan to conduct an interim analysis using data from 12-month follow-up. Discussion In recent years, there has been a notable lack of randomized controlled trials (RCTs) investigating the possible causal relationship between hearing fitting and the improvement of cognitive function. Our findings may demonstrate that hearing rehabilitation can be a valuable tool in managing ARHL and preventing cognitive decline, which will contribute to the development of a comprehensive framework for the prevention and control of cognitive decline. Trial registration Chinese Clinical Trial Registry chictr.org.cn ChiCTR2000036139. Registered on 21 August 2020.

The rapid advancement of remote sensing technology has given rise to numerous global- and regional-scale medium- to high-resolution land cover (LC) datasets, making significant contributions to the exploration of worldwide environmental shifts and the sustainable governance of natural resources. Nonetheless, owing to the inherent uncertainties embedded within remote sensing imagery, LC datasets inevitably exhibit inaccuracies. In this study, a local accuracy assessment of LC datasets in Southwest China was conducted. The datasets utilized in our analysis include ESA WorldCover, CLCD, Esri Land Cover, CRLC, FROM-GLC10, GLC_FCS30, GlobeLand30, and SinoLC-1. This study employed a sampling approach that combines proportional allocation and stratified random sampling (SRS) to gather sample points and compute confusion matrices to validate eight LC products. The local accuracy of the eight LC maps differs significantly from the overall accuracy provided by the original authors in Southwest China. ESA WorldCover and CLCD demonstrate higher local accuracy than other products in Southwest China, with their overall accuracy (OA) values being 87.1% and 85.48%, respectively. Simultaneously, we computed the area for each LC map based on categories, quantifying uncertainty through the reporting of confidence intervals for both accuracy and area parameters. This study aims to validate and compare eight LC datasets and assess precision and area of diverse spatial resolution datasets for mapping and monitoring across Southwest China.

Purpose This article compares applicants' perceptions of and experiences with virtual and in-person interviews for surgical retina fellowship.

Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Clinical aggressiveness, resistance to traditional therapy, and a high mortality rate are all features of this disease. Our previous studies have shown that co-activation of AKT and c-Met induces HCC development, which is the malignant biological feature of human HCC. Cucurbitacin B (CuB), a naturally occurring tetracyclic triterpenoid compound with potential antitumor activity. However, the metabolic mechanism of AKT/c-Met-induced Hepatocellular Carcinogenesis and CuB in HCC remains unclear. In this study, we established an HCC mouse model by hydrodynamically transfecting active AKT and c-Met proto-oncogenes. Based on the results of hematoxylin-eosin (H&E), oil red O (ORO) staining, and immunohistochemistry (IHC), HCC progression was divided into two stages: the early stage of HCC (3 weeks after AKT/c-Met injection) and the formative stage of HCC (6 weeks after AKT/c-Met injection), and the therapeutic effect of CuB was evaluated. Through UPLC-Q-TOF-MS/MS metabolomics, a total of 26 distinct metabolites were found in the early stage of HCC for serum samples, while in the formative stage of HCC, 36 distinct metabolites were found in serum samples, and 13 different metabolites were detected in liver samples. 33 metabolites in serum samples and 11 in live samples were affected by CuB administration. Additionally, metabolic pathways and western blotting analysis revealed that CuB influences lipid metabolism, amino acid metabolism, and glucose metabolism by altering the AKT/mTORC1 signaling pathway, hence decreasing tumor progression. This study provides a metabolic basis for the early diagnosis, therapy, and prognosis of HCC and the clinical application of CuB in HCC.

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignant liver tumor after hepatocellular carcinoma (HCC). It poses a significant risk to human health as it is highly malignant, insidious, and prone to recurrence after surgery. However, current diagnostic techniques and treatments for ICC are limited. Therefore, it is critical to investigate biomarkers of ICC for the discovery of novel drugs that can effectively treat ICC. In a previous study on the molecular mechanisms of ICC, proto-oncogenes AKT and Yap were found to often be overexpressed or activated in ICC, and the co-expression of AKT/YapS127A could promote the formation of ICC in mice. In this study, co-expression of AKT/YapS127A in an ICC mouse model was established via hydrodynamic transfection. To identify ICC biomarkers, we investigated the inhibitory effect of Osthole on the formation of ICC in mice induced with the co-expression of AKT/YapS127A. Furthermore, we preliminarily established the pathogenesis of ICC and the mechanism of Osthole. The metabolomic profiles for different stages in ICC formation process and Osthole treatment were examined via UHPLC-Q-TOF-MS/MS. The morphology (hematoxylin and eosin and Sirius red staining) and immunohistochemistry (CK19, Ki67, Vimentin, and α-SMA) results demonstrated that the ICC mouse model was useful. The ICC formation process was divided into three stages: early (1–2 weeks), formative (3–4 weeks), and late (5–7 weeks) stages. For the metabolomic profiles of ICC formation process, 11 differential metabolite species were identified at the early stage, 14 at the formative stage, and 20 at the late stage. The model group mice mainly showed dysregulation of amino acids and lipid metabolism compared with the control group mice. For the metabolomic profiles of Osthole treatment, 14 potential biomarkers with reduced levels were preliminarily identified, which were also linked to the dysregulation of amino acids and lipid metabolism. Combined with the results of Western Blotting experiments, it was found that Osthole can stop tumors from progressing by altering the AKT/mTOR signaling pathway with changes in amino acid and lipid metabolism. This study can provide a potentially valuable metabolic basis for the early detection, treatment, and prognosis of ICC, as well as the clinical application of Osthole in ICC.

Abstract Background Acute kidney injury (AKI) is a major complication following liver resection. The aim of this study was to determine the risk factors for AKI after hepatic resection and whether intraoperative hypotension (IOH) was related to AKI. Methods Adult patients (≥ 18 years) undergoing liver resection between November 2017 and November 2019 at our hospital were retrospectively reviewed. AKI was defined as ≥50% increase in serum creatinine from baseline value within 48 h after surgery. IOH was defined as the lowest absolute mean arterial pressure (MAP)

New materials for electrochemical energy storage and conversion are the key to the electrification and sustainable development of our modern societies. Molecular modelling based on the principles of quantum mechanics and statistical mechanics as well as empowered by machine learning techniques can help us to understand, control and design electrochemical energy materials at atomistic precision. Therefore, this roadmap, which is a collection of authoritative opinions, serves as a gateway for both the experts and the beginners to have a quick overview of the current status and corresponding challenges in molecular modelling of electrochemical energy materials for batteries, supercapacitors, CO _2 reduction reaction, and fuel cell applications.

Pipe to elbow welds are usually identified as the weakest parts in the pipeline system of ultra-supercritical boilers due to the structural induced stress arising from internal steam pressure, and the constraint of supports and hangers. The finite element (FE) method has been applied to investigate the effect of structural induced stress on creep evolution in pipe to elbow welds. The results show that compressive axial structural induced stress can significantly increase the creep strain near the pipe’s outer surface. In contrast, the creep strain near the pipe’s inner surface is clearly accelerated by tensile axial structural induced stress. Compared with free deformation conditions in the pipe ends, when subject to a compressive axial structural induced stress under −30 MPa, the equivalent creep strain in the fine-grained heat affected zone (FGHAZ) at the 12:00 position on the outer surface increases by about 13.7 times. In the case of a 30 MPa tensile axial structural induced stress, the equivalent creep strain increases by about 83.3% in the FGHAZ at the 12:00 position on the inner surface. The maximum creep strain of the pipe to elbow weld in the ultra-supercritical boiler after creep for 5000 h is 1.9% and located at the 10:30 position in the FGHAZ on the pipe’s outer surface, which makes it the weakest part of the welded joint. The location of a crack in a pipe to elbow weld after running for 20,000 h is in agreement with the simulation results.

Shengmai injection (SMI), a traditional Chinese medicine formula with the nature of multicomponent and multi-target, has been widely used in clinic for treating cardiovascular diseases in China; however, its comprehensive mechanism of action remains unclear. In this study, a TMT-based quantitative serum proteomics was performed to explore SMI’s global mechanism and help identify serum biomarkers of its effect on isoproterenol (ISO)-induced myocardial ischemia rats. The results of TMT-based proteomic analysis identified 227, 100, and 228 differentially expressed proteins (DEPs) for the model compared to the control group, SMI pretreatment + model compared to the model group, and SMI pretreatment + model compared to the control group, respectively. Based on bioinformatics analyses of gene ontology (GO), KEGG pathways, and the protein-protein interaction (PPI) networks for the DEPs, it is concluded that the comprehensive mechanism of SMI’s effect on ISO-induced myocardial ischemia injury includes regulation of energy metabolism, reducing endothelial cell permeability, regulation of vessel and cardiac contractility, anti-inflammation, and prevention of cell apoptosis. Furthermore, 10 common DEPs were found, and six of them were regulated in model vs. control group, while back-regulated in SMI pretreatment + model vs. model group. Among them, three functional proteins of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Fas apoptotic inhibitory molecule 3 (FAIM3), and uncharacterized protein (M0R5J4), which were verified by the PRM analysis, might be the potential serum biomarkers on SMI’s effects. Overall, this serum proteomics of SMI not only provides insights into the comprehensive mechanism underlying SMI’s effects on ischemic heart disease but also helps identify serum biomarkers for directing SMI’s cardioprotective effects.

CRISPR-based enzymes have offered a unique capability to the design of genetic switches, with advantages in designability, modularity and orthogonality. CRISPR-based genetic switches operate on multiple levels of life, including transcription and translation. In both prokaryotic and eukaryotic cells, deactivated CRISPR endonuclease and endoribonuclease have served in genetic switches for activating or repressing gene expression, at both transcriptional and translational levels. With these genetic switches, more complex circuits have been assembled to achieve sophisticated functions including inducible switches, non-linear response and logical biocomputation. As more CRISPR enzymes continue to be excavated, CRISPR-based genetic switches will be used in a much wider range of applications.

Unwanted interactions between cellular components can complicate rational engineering of biological systems. Here the authors design insulated minimal promoters and operators that enable biophysical modeling of bacterial transcription without free parameters for precise circuit design.

The Magnoliaceae shows strong phylogenetic niche conservatism, in which temporal petal closure has been extensively reported. However, it is yet elusive whether temporal petal closure is an idle floral character inherited from their ancestors or an adaptive trait to their habitats. Here, we monitored the process of temporal floral closure and re-opening in a thermogenic plant, Magnolia denudata (Magnoliaceae). Furthermore, we artificially interrupted temporal petal closure and investigated its effects on development of female and male gametophytes. Intriguingly, we found considerable anatomical changes in the anthers shortly after temporal closure of petals: disintegration of tapeta, crack of anther walls, and release of matured pollens. In comparison with normal flowers, artificially interrupted flowers (no petal closure) showed delayed anther development and slower pollen germination on stigmas, while little difference in embryo morphology was observed during the early stage of embryo development. Moreover, seed set and quality were significantly decreased when petal closure was prevented. In addition, we found pollination accelerated floral closure in M. denudata. Taken together, temporal floral closure benefits reproduction of M. denudata in early spring by promoting anther development and pollen function, which suggests that it is an adaptive floral trait to its specific habitat.

Abstract Aberrant activation of NLRP3 inflammasome is associated with a variety of inflammatory diseases. Advances in understanding the molecular mechanisms of NLRP3 inflammasome have revealed that NEK7 is an essential component for its activation, but the development of drugs specifically targeting NEK7 remains challenging. Here we identify rociletinib (ROC), an anticancer drug in phase III clinical trial with high safety profile, as a highly potent and specific small-molecule antagonists of NEK7. Mechanistically, ROC covalent binds to the cysteine 79 of NEK7 through its reactive α, β-unsaturated carbonyl group, thereby inhibiting the interaction between NLRP3 and NEK7, and the subsequent assembly and activation of NLRP3 inflammasome. Furthermore, ROC alleviates the pathological features of metainflammation on the mouse model of type 2 diabetes (T2D). In summary, our results identify ROC as a covalent inhibitor of NEK7 and demonstrates that targeting NEK7 provides a potential and promising strategy for the treatment of NLRP3 inflammasome-driven T2D.

Abstract Background and purpose Neurodevelopmental disorders (NDDs) are characterized by abnormalities in brain development and neurobehaviors, including autism. The maternal–fetal interface (MFI) is a highly specialized tissue through which maternal factors affect fetal brain development. However, limited research exists on restoring and maintaining MFI homeostasis and its potential impact on NDDs. This study explores the role of placental indoleamine 2,3-dioxygenase (IDO-1) in MFI homeostasis and fetal brain development. Experimental Approach The maternal-fetal barrier was disrupted by sodium valproate (VPA) in pregnant mice, whose offspring show typical autism-like behaviors. Ultrastructural analysis and flow cytometric analysis were conducted to observe the morphological and immune system changes. Behavioral tests and immunofluorescence staining was used to investigate the ability and mechanism of taprenepag to alleviate the abnormal behaviors of VPA-exposed offspring and normalize the development of serotonergic neurons. Key results In VPA-exposed pregnant mice, the downregulation of IDO-1 led to maternal immune overactivation and disruption of maternal-fetal barrier, resulting in excessive 5-HT synthesis in the placenta. This process disrupted the development of the serotonergic neuronal system in the offspring, resulting in impaired development of serotonergic neurons, thalamocortical axons, and NDDs in the progeny. However, a single injection of taprenepag at E13.5 ultimately upregulated placental IDO-1 through amplifying the positive feedback loop COX-2/PGE2/PTGER-2/IDO-1 and abolished these alterations. Conclusion Taprenepag improved autism-like behaviors in the offspring of VPA-exposed mice by addressing placental IDO-1 downregulation. This study highlights the potential of targeting IDO-1 to mitigate MFI disruption and NDD development.

Abstract Arising from the extreme/saddle point in electronic bands, Van Hove singularity (VHS) manifests divergent density of states (DOS) and induces various new states of matter such as unconventional superconductivity. VHS is believed to exist in one and two dimensions, but rarely found in three dimension (3D). Here, we report the discovery of 3D VHS in a topological magnet EuCd2As2 by magneto-infrared spectroscopy. External magnetic fields effectively control the exchange interaction in EuCd2As2, and shift 3D Weyl bands continuously, leading to the modification of Fermi velocity and energy dispersion. Above the critical field, the 3D VHS forms and is evidenced by the abrupt emergence of inter-band transitions, which can be quantitatively described by the minimal model of Weyl semimetals. Three additional optical transitions are further predicted theoretically and verified in magneto-near-infrared spectra. Our results pave the way to exploring VHS in 3D systems and uncovering the coordination between electronic correlation and the topological phase.

Abstract While significant advances have been made in predicting static protein structures, the inherent dynamics of proteins, modulated by ligands, are crucial for understanding protein function and facilitating drug discovery. Traditional docking methods, frequently used in studying protein-ligand interactions, typically treat proteins as rigid. While molecular dynamics simulations can propose appropriate protein conformations, they’re computationally demanding due to rare transitions between biologically relevant equilibrium states. In this study, we present DynamicBind, a deep learning method that employs equivariant geometric diffusion networks to construct a smooth energy landscape, promoting efficient transitions between different equilibrium states. DynamicBind accurately recovers ligand-specific conformations from unbound protein structures without the need for holo-structures or extensive sampling. Remarkably, it demonstrates state-of-the-art performance in docking and virtual screening benchmarks. Our experiments reveal that DynamicBind can accommodate a wide range of large protein conformational changes and identify cryptic pockets in unseen protein targets. As a result, DynamicBind shows potential in accelerating the development of small molecules for previously undruggable targets and expanding the horizons of computational drug discovery.

Developing switchable and multifunctional metasurfaces is essential for high-integration photonics. However, most previous studies encountered challenges such as limited degrees of freedom, simple tuning of predefined functionality, and complicated control systems. Here, we develop a general strategy to construct switchable and multifunctional metasurfaces. Two spin-modulated wave-controls are enabled by the proposed high-efficiency metasurface, which is designed using both resonant and geometric phases. Furthermore, the switchable wavefront tailoring can also be achieved by flexibly altering the lattice constant and reforming the phase retardation of the metasurfaces based on the “rotating square” (RS) kirigami technique. As a proof of concept, a kirigami metasurface is designed that successfully demonstrates dynamic controls of three-channel beam steering. In addition, another kirigami metasurface is built for realizing tri-channel complex wavefront engineering, including straight beam focusing, tilted beam focusing, and anomalous reflection. By altering the polarization of input waves as well as transformation states, the functionality of the metadevice can be switched flexibly among three different channels. Microwave experiments show good agreement with full-wave simulations, clearly demonstrating the performance of the metadevices. This strategy exhibits advantages such as flexible control, low cost, and multiple and switchable functionalities, providing a new pathway for achieving switchable wavefront engineering.

Abstract Blank holder force (BHF) is a crucial parameter in deep drawing, having close relation with the forming quality of sheet metal. However, there are different BHFs maintaining the best forming effect in different stages of deep drawing. The variable blank holder force (VBHF) varying with the drawing stage can overcome this problem at an extent. The optimization of VBHF is to determine the optimal BHF in every deep drawing stage. In this paper, a new heuristic optimization algorithm named Jaya is introduced to solve the optimization efficiently. An improved “Quasi-oppositional” strategy is added to Jaya algorithm for improving population diversity. Meanwhile, an innovated stop criterion is added for better convergence. Firstly, the quality evaluation criteria for wrinkling and tearing are built. Secondly, the Kriging models are developed to approximate and quantify the relation between VBHF and forming defects under random sampling. Finally, the optimization models are established and solved by the improved QO-Jaya algorithm. A VBHF optimization example of component with complicated shape and thin wall is studied to prove the effectiveness of the improved Jaya algorithm. The optimization results are compared with that obtained by other algorithms based on the TOPSIS method.

Abstract Background Fragile X syndrome (FXS) is a leading cause of autism spectrum disorder (ASD) and resulted from a loss of the FMR1-encoded fragile X messenger ribonucleoprotein 1 (FMRP) protein due to large CGG repeat expansions in the promoter region of the FMR1 gene. The microtubule-associated protein Tau is a promising target for Tauopathic diseases and our preliminary study found that Tau protein levels were increased in the brain of Fmr1 knockout (KO) mice, a model of FXS. However, whether Tau reduction can prevent autism-like features in Fmr1 KO mice and become a novel strategy for FXS treatment remain unknown. Methods Tau was genetically reduced in Fmr1 KO mice through crossing Fmr1 ± female mice with Mapt ± male mice. The male offspring with different genotypes were subjected to various autism-related behavioral tests, RNA sequencing, and biochemical analysis. Fmr1 KO male mice were treated with Tau-targeting antisense oligonucleotide (ASO) and then subjected to behavioral tests and biochemical analysis. Results Tau expression was increased in the cortex of Fmr1 KO mice. Genetically reducing Tau prevented social defects, stereotyped and repetitive behavior, and spine abnormality in Fmr1 KO mice. Tau reduction also reversed increased periodic activity and partially rescued Per1 expression reduction in Fmr1 KO mice. Moreover, Tau reduction reversed compromised P38/MAPK signaling in Fmr1 KO mice. Finally, Tau-targeting ASO also effectively alleviated autism-like phenotypes and promoted P38/MAPK signaling in Fmr1 KO mice. Limitations Our study is limited to male mice, in agreement with the higher incidence of FXS in males than females. Whether Tau reduction also exerts protection in females deserves further scrutiny. Moreover, although Tau reduction rescues impaired P38/MAPK signaling in Fmr1 KO mice, whether this is the responsible molecular mechanism requires further determination. Conclusion Our data indicate that Tau reduction prevents autism-like phenotypes in Fmr1 KO mice. Tau may become a new target for FXS treatment.

Delaying an electromagnetic (EM) wave pulse on a thin screen for a significant time before releasing it is highly desired in many applications, such as optical camouflage, information storage, and wave–matter interaction boosting. However, available approaches to achieve this goal either require thick and complex systems or suffer from low efficiencies and a short delay time. This paper proposes an ultra-thin meta-platform that can significantly delay an EM-wave pulse after reflection. Specifically, our meta-platform consists of three meta-surfaces integrated together, of which two are responsible for efficiently coupling incident EM-wave pulse into surface waves (SWs) and vice versa, and the third one supports SWs exhibiting significantly reduced group velocity. We employ theoretical model analyses, full-wave simulations, and microwave experiments to validate the proposed concept. Our experiments demonstrate a 13 ns delay of an EM pulse centered at 12.975 GHz, enabled by a λ/8-thick and 38-λ-long meta-device with an efficiency of 32% (or 70%) with (or without) material loss taken into account. A larger delay time can be enabled by devices with larger sizes considering that the SWs group velocity of our device can be further reduced via dispersion engineering. These findings establish a new road for delaying an EM-wave pulse with ultra-thin screens, which may lead to many promising applications in integration optics.

We characterize the multiphase circumgalactic medium (CGM) and galaxy properties at z = 6.0–6.5 in four quasar fields from the James Webb Space Telescope A SPectroscopic survey of biased halos In the Reionization Era (ASPIRE) program. We use the Very Large Telescope/X-shooter spectra of quasar J0305–3150 to identify one new metal absorber at z = 6.2713 with multiple transitions (O i , Mg ii , Fe ii, and C ii ). They are combined with the published absorbing systems in Davies et al. at the same redshift range to form a sample of nine metal absorbers at z = 6.03–6.49. We identify eight galaxies within 1000 km s ^−1 and 350 kpc around the absorbing gas from the ASPIRE spectroscopic data, with their redshifts secured by [O iii ] ( λ λ 4959, 5007) doublets and H β emission lines. Our spectral energy distribution fitting indicates that the absorbing galaxies have stellar masses ranging from 10 ^7.2 to 10 ^8.8 M _⊙ and metallicity between 0.02 and 0.4 solar. Notably, the z = 6.2713 system in the J0305–3150 field resides in a galaxy overdensity region, which contains two (tentatively) merging galaxies within 350 kpc and seven galaxies within 1 Mpc. We measure the relative abundances of α elements to iron ([ α /Fe]) and find that the CGM gas in the most overdense region exhibits a lower [ α /Fe] ratio. Our modeling of the galaxy’s chemical abundance favors a top-heavy stellar initial mass function and hints that we may be witnessing the contribution of the first generation of Population III stars to the CGM at the end of the reionization epoch.

The topology optimization design of complex products can significantly improve material and power savings, and reduce inertial forces and mechanical vibrations effectively. In this study, a large-tonnage hydraulic press was chosen as a typically complex product to present the optimization method. We propose a new reliability topology optimization method based on the reliability-and-optimization decoupled model and teaching–learning-based optimization (TLBO) algorithm. The supports formed by the plate structure are considered as topology optimization objects, characterized by light weight and stability. The reliability optimization under certain uncertainties and structural topology optimization are processed collaboratively. First, the uncertain parameters in the optimization problem are modified into deterministic parameters using the finite difference method. Then, the complex nesting of the uncertainty reliability analysis and topology optimization are decoupled. Finally, the decoupled model is solved using the TLBO algorithm, which is characterized by few parameters and a fast solution. The TLBO algorithm is improved with an adaptive teaching factor for faster convergence rates in the initial stage and performing finer searches in the later stages. A numerical example of the hydraulic press base plate structure is presented to underline the effectiveness of the proposed method.

Abstract Background Activated Cdc42-associated kinase 1 (ACK1) is a promising druggable target for cancer, but its inhibitors only showed moderate effects in clinical trials. The study aimed to investigate the underlying mechanisms and improve the antitumor efficacy of ACK1 inhibitors. Methods RNA-seq was performed to determine the downstream pathways of ACK. Using Lasso Cox regression analysis, we built a risk signature with ACK1-related autophagy genes in the lung adenocarcinoma (LUAD) patients from The Cancer Genome Atlas (TCGA) project. The performance of the signature in predicting the tumor immune environment and response to immunotherapy and chemotherapy were assessed in LUAD. CCK8, mRFP-GFP-LC3 assay, western blot, colony formation, wound healing, and transwell migration assays were conducted to evaluate the effects of the ACK1 inhibitor on lung cancer cells. A subcutaneous NSCLC xenograft model was used for in vivo study. Results RNA-seq revealed the regulatory role of ACK1 in autophagy. Furthermore, the risk signature separated LUAD patients into low- and high-risk groups with significantly different prognoses. The two groups displayed different tumor immune environments regarding 28 immune cell subsets. The low-risk groups showed high immune scores, high CTLA4 expression levels, high immunophenoscore, and low DNA mismatch repair capacity, suggesting a better response to immunotherapy. This signature also predicted sensitivity to commonly used chemotherapy and targeted drugs. In vitro, the ACK1 inhibitors (AIM-100 and Dasatinib) appeared to trigger adaptive autophagy-like response to protect lung cancer cells from apoptosis and activated the AMPK/mTOR signaling pathway, partially explaining its moderate antitumor efficacy. However, blocking lysosomal degradation with chloroquine/Bafilamycine A1 or inhibiting AMPK signaling with compound C/shPRKAA1 enhanced the ACK1 inhibitor’s cytotoxic effects on lung cancer cells. The efficacy of the combined therapy was also verified using a mouse xenograft model. Conclusions The resulting signature from ACK1-related autophagy genes robustly predicted survival and drug sensitivity in LUAD. The lysosomal degradation inhibition improved the therapeutic effects of the ACK1 inhibitor, suggesting a potential role for autophagy in therapy evasion.

Abstract Background Ubiquitin-conjugating enzyme E2 T (UBE2T) is a potential oncogene. However, Pan-cancer analyses of the functional, prognostic and predictive implications of this gene are lacking. Methods We first analyzed UBE2T across 33 tumor types in The Cancer Genome Atlas (TCGA) project. We investigated the expression level of UBE2T and its effect on prognosis using the TCGA database. The correlation between UBE2T and cell cycle in pan-cancer was investigated using the single-cell sequencing data in Cancer Single-cell State Atlas (CancerSEA) database. The Weighted Gene Co-expression Network analysis (WGCNA), Univariate Cox and Least absolute shrinkage and selection operator (LASSO) Cox regression models, and receiver operating characteristic (ROC) were applied to assess the prognostic impact of UBE2T-related cell cycle genes (UrCCGs). Furthermore, the consensus clustering (CC) method was adopted to divide TCGA-lung adenocarcinoma (LUAD) patients into subgroups based on UrCCGs. Prognosis, molecular characteristics, and the immune panorama of subgroups were analyzed using Single-sample Gene Set Enrichment Analysis (ssGSEA). Results derived from TCGA-LUAD patients were validated in International Cancer Genome Consortium (ICGC)-LUAD data. Results UBE2T is highly expressed and is a prognostic risk factor in most tumors. CancerSEA database analysis revealed that UBE2T was positively associated with the cell cycle in various cancers(r > 0.60, p