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Objective To investigate the effect of Shewanella algae （S.algae） on the occurrence and development of colorectal adenoma and its regulatory effect on the immune microenvironment in mice. Methods Twenty-four mice were divided into three groups： control group， azoxymethane （AOM）/ dextran sodium sulfate （DSS） group， AOM/DSS+S.algae group. The survival status and colorectal adenoma of mice were compared among three groups. Colorectal tissues in the AOM/DSS group and AOM/DSS+S.algae group were collected for high-throughput RNA-seq. Gene set enrichment analysis （GSEA）and cell-type identification by estimating relative subsets of RNA transcripts （CIBERSORT） were used to analyze the changes of immune-related pathways， immune cells and immune factors. Results Compared with the AOM/DSS group， the body weight （P < 0.05） and survival rate were decreased， the hematochezia was aggravated， the survival status was worsened，the colorectal length was shortened （all P < 0.05）， and the average number and size of adenomas were significantly increased （both P < 0.05） in the AOM/DSS+S.algae group. Compared with the AOM/DSS group， the inflammatory responses were significantly enhanced in AOM/DSS+S.algae group （P < 0.05）. The production of pro-inflammatory cytokines including interleukin （IL）-2， IL-6， IL-12， IL-17， interferon （IFN）， tumor necrosis factor （TNF） （all P < 0.05） and IL-1β showed an upward trend in the AOM/DSS+S.algae group， while the production of anti-inflammatory cytokines including IL-4， IL-10， IL-13 （all P < 0.05） and transforming growth factor β showed an inhibitory trend. Both naive B cells and plasma cells （both P < 0.05） were increased in AOM/DSS+S.algae group， and the nuclear factor -κB （NF-κB） signaling pathway was activated. Conclusion S.algae may form a tumor-promoting immune microenvironment by activating immune signals， such as activation of B cells and activation of the NF-κB pathway， and then promote the development of colorectal adenoma.

The global spread of viral respiratory infections continues to pose a substantial threat to human health, exacerbating the societal burden. Timely and precise detection of viruses is pivotal in mitigating pandemic transmission. Currently, the prevalent diagnostic techniques for viruses include real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and colloidal gold assays. However, intricate workflows and protracted processing times of RT-qPCR and ELISA preclude real-time diagnostics, despite their high accuracy. Colloidal gold assays offer rapid turnaround. However, their accuracy and sensitivity are limited, particularly in the context of emerging variants like SARS-CoV-2, which renders them suboptimal test tools. Mounting evidence suggests that surface-enhanced Raman spectroscopy (SERS), with its streamlined operation, rapid analysis, high specificity and sensitivity, holds significant potential as a superior alternative test tool. This review consolidates various SERS-based approaches for detecting respiratory infection virus (RIV) and delineates their characteristics. The unique strengths of SERS technology, including its exceptional sensitivity, robust specificity, and expedited turnaround times, earmark it as particularly well-suited for large-scale instant screening of viral infections within populations.

In advancing the practical application of photocatalytic degradation for pollutant removal, batch preparation of environmentally friendly photocatalysts plays a crucial role. Herein, we prepared C/P co-doped urchin-like TiO2 (C/P–TiO2) through a straightforward room temperature impregnation and atmospheric annealing process. Phytic acid served as the dopant precursor for introducing C and P onto the TiO2 surface. This doping process was verified through energy dispersive X-ray spectroscopy (EDX), electron spin resonance (ESR), and X-ray photoelectron spectroscopy (XPS) analysis. The C/P–TiO2 photocatalyst exhibited exceptional efficiency in degrading the target compound trimethoprim (TMP), achieving a degradation of 98% TMP within 60 min and a mineralization of 40% TMP within 120 min, which were respectively 2.4 and 1.6 times higher than that of pristine TiO2. The intermediate products of TMP were detected, and a plausible degradation pathway was proposed. Photoelectric characterization results also confirmed that C/P co-doping could effectively enhance the carrier separation efficiency of C/P–TiO2. The catalysts prepared using the scaled-up impregnation system and reusing the phytic acid solution consistently demonstrated stable catalytic performance, which confirmed the viability of the method for green and batch preparation of C/P co-doped TiO2. Notably, the obtained catalyst consistently exhibited high degradation efficacy in various real water bodies, highlighting its substantial potential for practical application. The green and batch preparation method of C/P–TiO2 introduces a novel approach to the practical application of photocatalysis technology in treatment of water contaminants.

Abstract Background While de novo cholesterol biosynthesis plays a crucial role in chemotherapy resistance of colorectal cancer (CRC), the underlying molecular mechanism remains poorly understood. Methods We conducted cell proliferation assays on CRC cells with or without depletion of squalene epoxidase (SQLE), with or without 5-fluorouracil (5-FU) treatment. Additionally, a xenograft mouse model was utilized to explore the impact of SQLE on the chemosensitivity of CRC to 5-FU. RNA-sequencing analysis and immunoblotting analysis were performed to clarify the mechanism. We further explore the effect of SQLE depletion on the ubiquitin of NF-κB inhibitor alpha (IκBα) and (S)-2,3-epoxysqualene on the binding of IκBα to beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) by using immunoprecipitation assay. In addition, a cohort of 272 CRC patients were selected for our clinical analyses. Results Mechanistically, (S)-2,3-epoxysqualene promotes IκBα degradation and subsequent NF-κB activation by enhancing the interaction between BTRC and IκBα. Activated NF-κB upregulates the expression of baculoviral IAP repeat containing 3 (BIRC3), sustains tumor cell survival after 5-FU treatment and promotes 5-FU resistance of CRC in vivo. Notably, the treatment of terbinafine, an inhibitor of SQLE commonly used as antifungal drug in clinic, enhances the sensitivity of CRC to 5-FU in vivo. Additionally, the expression of SQLE is associated with the prognosis of human CRC patients with 5-FU-based chemotherapy. Conclusions Thus, our finding not only demonstrates a new role of SQLE in chemoresistance of CRC, but also reveals a novel mechanism of (S)-2,3-epoxysqualene-dependent NF-κB activation, implicating the combined potential of terbinafine for 5-FU-based CRC treatment.

The power industry has been dedicated to applying virtual reality (VR) technology to build training systems in virtual environments, enabling personnel to complete skill training in real simulated environments while ensuring their safety. Conventional action scoring systems struggle to provide accurate scores for fine movements. Accurate scoring of fine movements can help workers identify their shortcomings during power operations, thus improving learning efficiency. This is of great significance for training on virtual environment-based power operation. This paper proposes a power operation-orientated VR action evaluation method based on the Gaussian distance-improved dynamic time warping (DTW) algorithm and the temporal convolutional network (TCN) model. First, the adaptive adapter is used to extract one-dimensional features from the three-dimensional data of the data gloves. Then, based on the TCN model, action data with significant discrepancies are filtered out. Finally, the obtained data are input into the Gaussian distance-improved DTW algorithm, where the path size is calculated. Corresponding scoring criteria are established on the basis of the path size to evaluate the actions. The results demonstrate that the VR action evaluation method based on the Gaussian distance-improved DTW algorithm and the TCN model significantly improves the accuracy of evaluating fine movements compared to traditional evaluation algorithms.

With the promotion of national “carbon neutral” and “green mine” strategies, pure electric mining vehicles are crucial in promoting energy conservation and emission reduction in the mining industry. However, “mileage anxiety” is the primary problem limiting their promotion and application. Regenerative braking is an essential technology for improving energy efficiency and reducing the life-cycle costs of pure electric vehicles. However, because of harsh driving conditions and substantial changes in load capacity and road slope, the scale and fluctuation characteristics of energy demand vary sharply during operation, affecting the feedback efficiency and battery life of an electric mining dump truck. Therefore, designing reasonable regenerative braking strategies for pure electric mining dump trucks is crucial. This paper uses a 50-ton pure electric mining truck as the research object and proposes a regenerative braking feedback strategy based on the deep reinforcement learning optimization algorithm. First, a mathematical model of a pure electric mining dump truck was established, which included a permanent magnet synchronous motor, power battery, four-speed automated mechanical transmission, and vehicle longitudinal dynamic model. Furthermore, power performance verification based on the Matlab/Simulink simulation platform was performed. Subsequently, an energy management strategy was proposed based on the soft actor–critic (SAC) algorithm and the deep deterministic strategy gradient (DDPG) deep reinforcement learning algorithm considering load and slope changes. In particular, the state variables include vehicle speed, acceleration, vehicle mass, road slope, battery state of charge (SOC), and battery charge–discharge rate. The transmission gear is selected as the action variable of the proposed strategy. Battery SOC and battery lifetime are used as reward functions. Furthermore, an automatic entropy adjustment mechanism is introduced to improve the adaptability of the proposed control strategy to different operating conditions. Simulation results show that compared to the rule-based control strategy, the energy efficiency of the control strategy based on dynamic programming and the proposed optimization control strategy based on the SAC and DDPG algorithms are improved by 18.15%, 17.18%, and 16.63%, respectively, and the battery lifetime is improved by 57.31%, 56.87%, and 57.38%, respect ively. Finally, the proposed energy management strategy is compared with the control strategy based on DDPG to further verify its superiority by comparing the reward curves. The results demonstrate the feasibility of the proposed control strategy based on the SAC algorithm, which has improved convergence speed by 166.7%.

Abstract The precise structural integration of single-atom and high-entropy-alloy features for energy electrocatalysis is highly appealing for energy conversion, yet remains a grand challenge. Herein, we report a class of single-atom Mo-tailored PdPtNiCuZn high-entropy-alloy nanosheets with dilute Pt-Pt ensembles and intrinsic tensile strain (Mo1-PdPtNiCuZn) as efficient electrocatalysts for enhancing the methanol oxidation reaction catalysis. The as-made Mo1-PdPtNiCuZn delivers an extraordinary mass activity of 24.55 A mgPt −1 and 11.62 A mgPd+Pt −1, along with impressive long-term durability. The planted oxophilic Mo single atoms as promoters modify the electronic structure of isolated Pt sites in the high-entropy-alloy host, suppressing the formation of CO adsorbates and steering the reaction towards the formate pathway. Meanwhile, Mo promoters and tensile strain synergistically optimize the adsorption behaviour of intermediates to achieve a more energetically favourable pathway and minimize the methanol oxidation reaction barrier. This work advances the design of atomically precise catalytic sites by creating a new paradigm of single atom-tailored high-entropy alloys, opening an encouraging pathway to the design of CO-tolerance electrocatalysts.

Ceftazidime-avibactam (CZA) is employed for the treatment of infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP). Resistance to CZA is frequently linked to point mutations in the blaKPC. We conducted in vitro simulations of in vivo blaKPC mutations using CZA. Four pre-therapy KPC-KP isolates (K1, K2, K3, and K4) were evaluated, all initially exhibited susceptibility to CZA and produced KPC-2. The crucial distinction was that following CZA treatment, the blaKPC-2 mutated in K1, K2, and K3, rendering them resistant to CZA, while K4 achieved microbiological clearance, and blaKPC-2 remained unaltered. The induction assay identified various blaKPC-2 variants, including blaKPC-25, blaKPC-127, blaKPC-100, blaKPC-128, blaKPC-137, blaKPC-138, blaKPC-144 and blaKPC-180. Our findings suggest that the resistance of KPC-KP to CZA primarily results from the emergence of KPC variants, complemented by increased blaKPC expression. A close correlation exists between avibactam concentration and the rate of increased CZA minimum Inhibitory concentration, as well as blaKPC mutation. Inadequate avibactam concentration is more likely to induce resistance in strains against CZA, there is also a higher likelihood of mutation in the blaKPC-2 and the optimal avibactam ratio remains to be determined. Simultaneously, we selected a blaKPC-33-producing K. pneumoniae strain (mutated from blaKPC-2) and induced it with imipenem and meropenem, respectively. The blaKPC-2 was detected during the process, indicating that the mutation is reversible. Clinical use of carbapenems to treat KPC variant strains increases the risk of infection, as the gene can mutate back to blaKPC-2, rendering the strain even more cross-resistant to carbapenems and CZA.

Objectives Calcium oxalate (CaOx) crystal deposition in acute kidney injury (AKI) patients is under recognized but impacts renal outcomes. This study investigates its determinants and effects.Methods We studied 814 AKI patients with native kidney biopsies from 2011 to 2020, identifying CaOx crystal deposition severity (mild: 10 crystals per section). We assessed factors like urinary oxalate, citrate, urate, electrolytes, pH, tubular calcification index, and SLC26A6 expression, comparing them with creatinine-matched AKI controls without oxalosis. We analyzed how these factors relate to CaOx severity and their impact on renal recovery (eGFR < 15 mL/min/1.73 m2 at 3-month follow-up). Results CaOx crystal deposition was found in 3.9% of the AKI cohort (32 cases), with 72% due to nephrotoxic medication-induced tubulointerstitial nephritis. Diuretic use, higher urinary oxalate-to-citrate ratio induced by hypocitraturia, and tubular calcification index were significant contributors to moderate and/or severe CaOx deposition. Poor baseline renal function, low urinary chloride, high uric acid and urea nitrogen, tubular SLC26A6 overexpression, and glomerular sclerosis were also associated with moderate-to-severe CaOx deposition. Kidney recovery was delayed, with 43.8%, 31.2%, and 18.8% of patients having eGFR < 15 mL/min/1.73 m2 at 4, 12, and 24-week post-injury. Poor outcomes were linked to high urinary α1-microglobulin-to-creatinine (α1-MG/C) ratios and active tubular injury scores. Univariate analysis showed a strong link between this ratio and poor renal outcomes, independent of oxalosis severity.Conclusions In AKI, CaOx deposition is common despite declining GFR. Factors worsening tubular injury, not just oxalate-to-citrate ratios, are key to understanding impaired renal recovery.

Abstract Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORγt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51, by pharmacological or genetic interventions, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel mechanism of cancer–immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.

The Earth's Free Core Nutation (FCN) causes Earth tides and forced nutation with frequencies close to the FCN that exhibit resonance effects. High-precision superconducting gravimeter (SG) and very long baseline interferometry (VLBI) provide good observation techniques for detecting the FCN parameters. However, some choices in data processing and solution procedures increase the uncertainty of the FCN parameters. In this study, we analyzed the differences and the effectiveness of weight function and ocean tide corrections in the FCN parameter detection using synthetic data, SG data from thirty-one stations, and the 10 celestial pole offset (CPO) series. The results show that significant discrepancies are caused by different computing options for a single SG station. The stacking method, which results in a variation of 0.24–5 sidereal days (SDs) in the FCN period (T) and 103-104 in the quality factor (Q) due to the selection of the weighting function and the ocean tide model (OTM), can effectively suppress this influence. The statistical analysis results of synthetic data shows that although different weight choices, while adjusting the proportion of diurnal tidal waves involved, do not significantly improve the accuracy of fitted FCN parameters from gravity observations. The study evaluated a series of OTMs using the loading correction efficiency. The fitting of FCN parameters can be improved by selecting the mean of appropriate OTMs based on the evaluation results. Through the estimation of the FCN parameters based on the forced nutation, it was found that the weight function P1 is more suitable than others, and different CPO series (after 2009) resulted in a difference of 0.4 SDs in the T and of 103 in the Q. We estimated the FCN parameters for SG (T = 430.4 ± 1.5 SDs and Q = 1.52 × 104 ± 2.5 × 103) and for VLBI (T = 429.8 ± 0.7 SDs, Q = 1.88 × 104 ± 2.1 × 103).

In this work, a comprehensive multi-physics electrochemical hybrid stack model is developed for a vanadium redox flow battery (VRFB) stack considering electrolyte flow, mass transport, electrochemical reactions, shunt currents, and as heat generation and transfer simultaneously. Compared with other VRFB stack models, this model is more comprehensive in considering the influence of multiple factors. Based on the established model, the electrolyte flow rate distribution across cells in the stack is investigated. The distribution and variation in shunt currents, single-cell current and single-cell voltage are analyzed. The distribution and variation in temperature and heat generation and heat transfer are also researched. It can be found that the VRFB stack temperature will exceed 40 °C when operating at 60 A and 100 mA cm−2 at an ambient temperature of 30 °C, which will lead to electrolyte ion precipitation, affecting the performance and safety of the battery. To control the stack temperature below 40 °C, a new tank cooling control strategy is proposed, and the suitable starting cooling point and the controlled temperature are specified. Compared with the common room cooling strategy, the new tank cooling strategy reduces energy consumption by 27.18% during 20 charge–discharge cycles.

The template matching method has been widely utilized in the defect detection of wafer surfaces. However, the traditional matching approaches are limited by illumination, noise, and deformation, which cannot meet the requirements of accuracy and robustness. In this paper, a novel multiple targets localization method, named Normalized Cross-correlation Adaptive Variable Step-Size Dynamic Template (NCC-AVSSDT) matching, is proposed to improve the accuracy and efficiency of image localization, which combines the advantages of NCC and AVSSDT. The AVSSDT method is utilized to dynamically adjust the scanning step size based on the NCC matching coefficients. This approach optimizes the scanning process, accelerating convergence toward the optimal matching position. Experimental results verify the accuracy and robustness of the proposed method under different conditions, especially when dealing with rotational variations and variations in noise textures. Therefore, NCC-AVSSDT can be used to perform multiple targets localization of chip image in nearly real-time. Three experiment types were used for comprehensive evaluations, including multiple targets, noise, and rotation angles. Experimental results show that NCC-AVSSDT is much better than the sequential similarity detection algorithm and mean absolute deviation methods in terms of multiple targets (0.667 vs 0.811 s, 0.832 s) and success rate (100% vs 35%, 20%).

Winged helix (wH) domains, also termed winged helix-turn-helix (wHTH) domains, are widespread in all kingdoms of life and have diverse roles. In the context of DNA binding and DNA modification sensing, some eukaryotic wH domains are known as sensors of non-methylated CpG. In contrast, the prokaryotic wH domains in DpnI and HhiV4I act as sensors of adenine methylation in the 6mApT (N6-methyladenine, 6mA, or N6mA) context. DNA-binding modes and interactions with the probed dinucleotide are vastly different in the two cases. Here, we show that the role of the wH domain as a sensor of adenine methylation is widespread in prokaryotes. We present previously uncharacterized examples of PD-(D/E)XK—wH (FcyTI, Psp4BI), PUA—wH—HNH (HtuIII), wH—GIY-YIG (Ahi29725I, Apa233I), and PLD—wH (Aba4572I, CbaI) fusion endonucleases that sense adenine methylation in the Dam+ Gm6ATC sequence contexts. Representatives of the wH domain endonuclease fusion families with the exception of the PLD—wH family could be purified, and an in vitro preference for adenine methylation in the Dam context could be demonstrated. Like most other modification-dependent restriction endonucleases (MDREs, also called type IV restriction systems), the new fusion endonucleases except those in the PD-(D/E)XK—wH family cleave close to but outside the recognition sequence. Taken together, our data illustrate the widespread combinatorial use of prokaryotic wH domains as adenine methylation readers. Other potential 6mA sensors in modified DNA are also discussed.

Introduction: Due to the cardiotoxicity of pirarubicin (THP), it is necessary to investigate new compounds for the treatment of THP-induced cardiotoxicity. Isoquercitrin (IQC) is a natural flavonoid with anti-oxidant and anti-apoptosis properties. Thus, the present study aimed to investigate the influence of IQC on preventing the THP-induced cardiotoxicity in vivo and in vitro.Methods: The optimal concentration and time required for IQC to prevent THP-induced cardiomyocyte damage were determined by an MTT assay. The protective effect was further verified in H9c2 and HCM cells using dichlorodihydrofluorescein diacetate fluorescent probes, MitoTracker Red probe, enzyme-linked immunosorbent assay, JC-1 probe, and real time-quantitative polymerase chain reaction (RT-qPCR). Rats were administered THP to establish cardiotoxicity. An electrocardiogram (ECG) was performed, and cardiac hemodynamics, myocardial enzymes, oxidative stress indicators, and hematoxylin-eosin staining were studied. Voltage-dependent anion channel 1 (VDAC1), adenine nucleotide translocase 1 (ANT1), and cyclophilin D (CYPD) were detected by qRT-PCR, and the Phlpp1/AKT/Bcl-2 axis proteins were detected by western blot, confirming that IQC markedly increased cell viability and superoxide dismutase (SOD) levels, diminished the levels of ROS and MDA, and elevated mitochondrial function and apoptosis in vivo and in vitro.Results: Results showed that IQC reduced THP-induced myocardial histopathological injury, electrocardiogram (ECG) abnormalities, and cardiac dysfunction in vivo. IQC also decreased serum levels of MDA, BNP, CK-MB, c-TnT, and LDH, while increasing levels of SOD and GSH. We also found that IQC significantly reduced VDAC1, ANT1, and CYPD mRNA expression. In addition, IQC controlled apoptosis by modulating Phlpp1/AKT/Bcl-2 signaling pathways. IQC markedly increased H9c2 and HCM cell viability and SOD levels, diminished the levels of ROS and MDA, and elevated mitochondrial function in H9c2 and HCM cells to defend against THP-induced cardiomyocyte apoptosis in vitro. The AKT inhibitor IMQ demonstrated that IQC lacked antioxidant and anti-apoptotic properties. Moreover, our data showed that IQC regulates Phlpp1 expression, thereby influencing the expression levels of p-AKT, cytochrome c, caspase-3, caspase-9, Bcl-2, and Bax.Discussion: In conclusion, our results indicate that IQC protects the changes in mitochondrial membrane permeability in cardiomyocytes by regulating the Phlpp1/AKT/Bcl-2 signaling pathway, inhibits the release of cytc from the mitochondrial inner membrane to the cytoplasm, forms apoptotic bodies, induces cell apoptosis, and reduces THP induced cardiotoxicity.

Exposure to benzo[a]pyrene (B[a]P) has been linked to lung injury and carcinogenesis. Airway epithelial cells express the B[a]P receptor AHR, so B[a]P is considered to mainly target airway epithelial cells, whereas its potential impact on alveolar cells remains inadequately explored. Metformin, a first-line drug for diabetes, has been shown to exert anti-inflammatory and tissue repair-promoting effects under various injurious conditions. Here, we explored the effect of chronic B[a]P exposure on alveolar cells and the impact of metformin on B[a]P-induced lung injury by examining the various parameters including lung histopathology, inflammation, fibrosis, and related signal pathway activation. MLKL knockout (Mlkl-/-) and AT2-lineage tracing mice (SftpcCre-ERT2;LSL-tdTomatoflox+/-) were used to delineate the role of necroptosis in B[a]P-induced alveolar epithelial injury and repair. Mice receiving weekly administration of B[a]P for 6 weeks developed a significant alveolar damaging phenotype associated with pulmonary inflammation, fibrosis, and activation of the necroptotic cell death pathway. These effects were significantly relieved in MLKL null mice. Furthermore, metformin treatment, which were found to promote AMPK phosphorylation and inhibit RIPK3, as well as MLKL phosphorylation, also significantly alleviated B[a]P-induced necroptosis and lung injury phenotype. However, the protective efficacy of metformin was rendered much less effective in Mlkl null mice or by blocking the necroptotic pathway with RIPK3 inhibitor. Our findings unravel a potential protective efficacy of metformin in mitigating the detrimental effects of B[a]P exposure on lung health by inhibiting necroptosis and protecting AT2 cells.

Summary: Locomotion through spatially confining spaces is an important in vivo migration mode. Here, we present a protocol for in situ visualization of mitochondrial reactive oxygen species and apoptosis in cancer cells during confined migration. We then detail sample preparation of confined cells for transcriptome and immunoblotting analysis by using transwell chambers. This approach allows in situ evaluation of a variety of cellular functions during confined migration and preparation of the samples of confined cells for further biochemical analysis.For complete details on the use and execution of this protocol, please refer to Cai et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

The scale of tourism has continued to expand in recent years, and many associated activities cause damage to the natural environment. The tourism, economy and natural environment constitute a system: destruction of the natural environment reduces the value of tourism and a lack of tourism affects the development of the economy. To explore the relationship between the tourism, economy and natural environment, and to explore possibilities for sustainable development, this paper takes Hangzhou, a tourist city in China, as a research object. An analysis of time series data is carried out. First, the tourism, economy and natural environment subsystems are constructed by extracting time series data acquired between 2010 and 2020. Second, a tourism evaluation model with coupled economic and natural environment data is constructed and the coupling degree and coupling coordination level in Hangzhou are evaluated. Third, the time series of each subsystem and the coupling coordination level of the whole system are analyzed. Finally, an optimization strategy is proposed for the coupled coordinated development of the tourism, economy and natural environment in Hangzhou. A key result is that the tertiary industry represented by tourism has become the main source of local income. Hangzhou's tourism coupling coordination level has changed from slight disorder in 2010 to good in 2020. It is also found that the COVID-19 pandemic has become a major factor restricting the development of tourism. Before the outbreak of COVID-19, Hangzhou's tourism industry and economy were synchronized. After the outbreak of COVID-19, both the number of tourists and tourism revenue in Hangzhou fell by nearly 15%.

Under the action of waves, a small unmanned surface vehicle (USV) will experience continuous oscillation, significantly impacting its photovoltaic power generation system. This paper proposes a USV photovoltaic power generation simulation model, and the efficiency of photovoltaic MPPT control under wave action is studied. A simulation model for solar irradiance on solar panels of USV under wave action is established based on CFD and solar irradiation models. The dynamic changes in irradiance of USV solar panels under typical wave conditions are analyzed. The MPPT efficiency of USV photovoltaic power generation devices under continuously changing irradiance conditions is studied on this basis. The simulation research results indicate that waves and solar altitude angles significantly impact the instantaneous irradiation energy of USV photovoltaic devices. However, the impact of waves on the average irradiance is relatively tiny. The sustained oscillation of irradiance poses certain requirements for the Maximum Power Point Tracking (MPPT) control frequency of USV photovoltaic systems; a disturbance control frequency of no less than 50 Hz is proposed.

Background: This meta-analysis explores alterations in the gut microbiota of patients with Multiple Sclerosis (MS) using 16S ribosomal RNA (rRNA) gene sequencing. Methods: Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, our comprehensive review spanned major databases, including PubMed, Web of Science, Embase, Cochrane, and Ovid, targeting observational studies that implemented 16S rRNA gene sequencing on fecal specimens. The quality of these studies was meticulously evaluated using the Newcastle-Ottawa scale. Results: Our search yielded 26 relevant studies conducted between 2015-2022, encompassing 2885 participants. No significant differences were observed in alpha diversity indices (Shannon, Chao1, Operational Taxonomic Units (OTU), and Simpson) between MS patients and controls in general. Nonetheless, subgroup analyses according to disease activity using the Shannon index highlighted a significant decrease in microbial diversity during MS’s active phase. Similarly, an evaluation focusing on MS phenotype revealed diminished diversity in individuals with relapsing-remitting MS (RRMS). Microbial composition analysis revealed no consistent increase in pro-inflammatory Bacteroidetes or decrease in anti-inflammatory Firmicutes within the MS cohort. Conclusion: The gut microbiome’s role in MS presents a complex panorama, where alterations in microbial composition might hold greater significance to disease mechanisms than diversity changes. The impact of clinical factors such as disease activity and phenotype are moderately significant, underscoring the need for further research to elucidate these relationships. Prospective research should employ longitudinal methodologies to elucidate the chronological interplay among gut microbiota, disease evolution, and therapeutic strategies.

To ensure the conservation of waterlogged archaeological wood, sustainable, safe, and effective methods must be implemented, with consolidation and dehydration being crucial for long-term preservation to maintain dimensional stability and structural integrity. This study compares the permeability of 45% methyltrimethoxysilane (MTMS) and 45% trehalose solutions to evaluate the dimensional changes, hygroscopicity, and mechanical properties of treated wood. Since the collected samples (from an ancient ship, Luoyang Canal No. 1) were mildly degraded, the drying method had a slight impact on the properties of archaeological wood. Consolidated with trehalose and MTMS agents, the longitudinal compressive strength of the waterlogged wood’s cell walls increased by 66.8% and 23.5%, respectively. Trehalose proved to be more advantageous in filling pores and reducing overall shrinkage, while MTMS significantly reduced the hygroscopicity and surface hydrophilicity of the wood substance. Overall, the MTMS treatment has a smaller effect on the appearance of samples, making it more suitable for the consolidation of mildly degraded waterlogged archaeological wood.

Abstract Recent advancements have been made in the development of cell-based in-vitro neuronal networks, or organoids. In order to better understand the network structure of these organoids, a super-selective algorithm has been proposed for inferring the effective connectivity networks from multi-electrode array data. In this paper, we apply a novel statistical method called spectral mirror estimation to the time series of inferred effective connectivity organoid networks. This method produces a one-dimensional iso-mirror representation of the dynamics of the time series of the networks which exhibits a piecewise linear structure. A classical change point algorithm is then applied to this representation, which successfully detects a change point coinciding with the neuroscientifically significant time inhibitory neurons start appearing and the percentage of astrocytes increases dramatically. This finding demonstrates the potential utility of applying the iso-mirror dynamic structure discovery method to inferred effective connectivity time series of organoid networks.

Abstract Background Knee Osteoarthritis (KOA) is one of the main causes of disability in the elderly and with limited treatment options. Swimming was considered as an ideal form of non-surgical management of KOA. Nevertheless, the mechanism of swimming intervene OA remains unclear. ACLT induced OA model was often used to study the pathogenesis and treatment of OA. Thus, we evaluated the protective effect of swimming on KOA mouse and tried to explore the underlying mechanism. Methods Forty C57BL/6 mice were randomly divided into five groups: Blank group, ACLT group, ACLT + Swim group, Sham group and Sham + Swim group (n = 8). OA model was established by Anterior Cruciate Ligament Transection surgery (ACLT). After modeling, mice in ACLT + Swim and Sham + Swim groups were trained with a moderate swimming program, 5 d/week, for 6 weeks. HE and Safranin-O/fast staining, Immunohistochemistry, TUNEL assay and Western blot were used to detect the effect of swimming on pathological changes, cell death and the mechanism in KOA mouse. Results Swimming significantly enhanced CoII expression and suppressed ADAMTS5 expression in cartilage of KOA mouse, thus ameliorated KOA development. Apoptotic and autophagic processes were enhanced in OA cartilage, which might be caused by down-regulation of PI3K/AKT pathway; swimming could activate PI3K/AKT pathway and thus regulate apoptosis and autophagy processes of chondrocytes. Conclusion Swimming could prevent cell death of chondrocytes via PI3K/AKT pathways, thus delayed the progression of KOA in an experimental model.

Evaluation of the ecological carrying capacity of marine ranching is a prerequisite and guarantee for ensuring the sustainable development of aquaculture activities, protecting and maintaining the stability and security of marine ecosystems. Based on high-resolution satellite remote sensing data and survey data of Wailingding marine ranching in Zhuhai from 2006 to 2021, this study constructed a marine ecological carrying capacity (MECC) index system with three levels: resources, environment, and ecology. A combination of the analytic hierarchy process (AHP) method and entropy method was applied to assign values to indexes, and then, the MECC of marine ranching was evaluated based on the state-space model and the weighted Bonferroni mean (WBM) model. Results showed that the MECC of Wailingding marine ranching increased from 0.49 (2006) before the marine ranching construction to 0.79 (2021) after the marine ranching construction. Marine ranching had elevated MECC from a loadable state to a fully loaded state. The intertidal subsystem, with a weight of 52.51%, dominates the MECC of marine ranching, in which resource and environmental factors are the major influencing factors. The increased rate of the state-space model (61.73%) was higher than that of the WBM model (44.34%), indicating that the state-space model is more feasible for the MECC assessment of Wailingding marine ranching.

Summary: Loss of Protocadherin 9 (PCDH9) is associated with the metastasis and the prognosis of gastric cancer patients, while the molecular mechanism of PCDH9-impaired gastric cancer metastasis remains unclear. Here we show that PCDH9 is cleaved in gastric cancer cells. Intracellular domain of PCDH9 translocates into nucleus, where it interacts with DNA methyltransferase 1 (DNMT1) and increases DNMT1 activity. Activated DNMT1 downregulates cadherin 2 (CDH2) expression by increasing DNA methylation at its promoter, thereby dampening the migration and in vivo metastasis of gastric cancer cells. In addition, the levels of nuclear PCDH9 correlate with CDH2 expression, lymph node metastasis, and the prognosis of gastric cancer patients. Our finding demonstrates a unique mechanism of nuclear PCDH9-impaired gastric cancer metastasis by promoting DNA methylation of CDH2 promoter.

ObjectiveInvestigating the causal relationship between Lachnospiraceae and Appendicular lean mass (ALM) and identifying and quantifying the role of Aminopeptidase O Protein (AOPEP) as a potential mediator.MethodsThe summary statistics data of gut microbiota composition from the largest available genome-wide association study (GWAS) meta-analysis conducted by the MiBioGen Consortium (n = 13,266). Appendicular lean mass data were obtained from the UK-Biobank (n = 450,243). We conducted bidirectional two-sample Mendelian randomization (MR) analysis using summary-level data from GWAS to investigate the causal relationship between Lachnospiraceae and ALM. Additionally, we employed a drug-targeted MR approach to assess the causal relationship between AOPEP and ALM. Finally, a two-step MR was employed to quantitatively estimate the proportion of the effect of Lachnospiraceae on ALM that is mediated by AOPEP. Cochran's Q statistic was used to quantify heterogeneity among instrumental variable estimates.ResultsIn the MR analysis, it was found that an increase in genetically predicted Lachnospiraceae [OR = 1.031, 95% CI (1.011–1.051), P = 0.002] is associated with an increase in ALM. There is no strong evidence to suggest that genetically predicted ALM has an impact on Lachnospiraceae genus [OR = 1.437, 95% CI (0.785–2.269), P = 0.239]. The proportion of genetically predicted Lachnospiraceae mediated by AOPEP was 34.2% [95% CI (1.3%−67.1%)].ConclusionOur research reveals that increasing Lachnospiraceae abundance in the gut can directly enhance limb muscle mass and concurrently suppress AOPEP, consequently mitigating limb muscle loss. This supports the potential therapeutic modulation of gut microbiota for sarcopenia. Interventions such as drug treatments or microbiota transplantation, aimed at elevating Lachnospiraceae abundance and AOPEP inhibition, synergistically improve sarcopenia in the elderly, thereby enhancing the overall quality of life for older individuals.

PurposeOlecranon fracture is considered intra-articular when there is obvious displacement or an irregular articular surface. Such fractures should be reduced and fixed via surgery. No clear indications regarding the surgical technique to be adopted exist. Therefore, this study aimed to compare the outcomes of tension band wiring (TBW) and Herbert screw fixations for olecranon fractures.MethodsWe retrospectively analyzed the clinical data of 29 children with olecranon fractures. They were divided into the tension band wiring and Herbert screw groups. We assessed early epiphyseal closure and maximum length of the ulna using radiography. Patients were clinically evaluated using the average QuickDASH score.ResultsBoth groups had good radiological outcomes. Herbert screws demonstrated advantages in terms of bleeding, operative time, intraoperative blood loss, surgery duration, and particularly the QuickDASH score (1.57 vs. 4.18, p

It has been recognized that depth of invasion (DOI) is closely associated with patient survival for most types of cancer. The purpose of this study was to determine the DOI optimal cutoff value and its prognostic value in laryngeal squamous carcinoma (LSCC). Most importantly, we evaluated the prognostic performance of five candidate modified T-classification models in patients with LSCC. LSCC patients from Harbin Medical University Cancer Hospital and Chinese Academy of Medical Sciences Cancer Hospital were divided into training group (n = 412) and validation group (n = 147). The primary outcomes were overall survival (OS) and relapse-free survival (RFS), and the effect of DOI on prognosis was analyzed using a multivariable regression model. We identified the optimal model based on its simplicity, goodness of fit and Harrell’s consistency index. Further independent testing was performed on the external validation queue. The nomograms was constructed to predict an individual’s OS rate at one, three, and five years. In multivariate analysis, we found significant associations between DOI and OS (Depth of Medium-risk invasion HR, 2.631; P

The aim of this study was to identify the high-risk factors for caesarean scar pregnancy (CSP) and establish a nomogram to predict the risk of caesarean scar pregnancy in pregnant women with a history of caesarean section. Among 1273 pregnant women with a history of caesarean section, 70% of the patients (892 patients, training sample) were randomly selected for analysis, and a prediction model was generated. The remaining patients (381 patients, validation sample) were validated for the model. Four high-risk factors for CSP were established, including: parity, number of previous abortions, uterus position, and early vaginal bleeding. The area under the curve of the nomogram for the training set was 0.867 and that for the validation set was 0.881, indicating good performance. Calibration curves for predicting CSP showed good calibrations. Decision curve analyses showed good application prospects for the model. Our results show that our nomogram for predicting CSP risks can be a practical tool to help in the early identification of CSP.Impact Statement What is already known on this subject? The high-risk factors for "caesarean scar pregnancy", An simple nomogram could be constructed to predict the risk of the disease through these high-risk factors. What do the results of this study add? This study can quickly predict whether the patient is a high-risk group for uterine scar pregnancy based on the patient’s previous pregnancy, early vaginal bleeding and uterine position. What are the implications of these findings for clinical practice and/or further research? Caesarean scar pregnancy was secondary Long-term complications after caesarean section that with a high risk of pregnancy. In this study, we established a nomogram based on the number of cases of CSP and a control group with a history of caesarean section delivery at term, The high-risk factors were assigned a certain risk value in the early stage, if the woman contains more high-risk factors, the higher the risk of developing CSP, it should be highly valued in the early stage, and the rate of visiting a doctor should be increased.

ABSTRACTThe rapid growth of local SOEs in China largely depends on high leverage, thus local governments and their SOEs will face harder budget constraints when the central bank implements tight credit policies. Using a sample of listed local SOEs in the Chinese A-share market, this paper attempts to investigate the relationship between financial deleveraging and privatization of local SOEs. We find that privatization of the Chinese local SOEs increases significantly during financial deleveraging, and this effect is more pronounced among SOEs with less tax contribution, fewer employees and that cause greater financial burden to the local governments. This paper broadens the research on environmental factors that drive politicians to privatize.

Highlights A hybrid co-catalysts system comprising Au nanoparticles (NPs) and PtSAs with different functions was constructed on the polymeric carbon nitride (PCN) surface by double-solvent method. For the dual co-catalysts, the Au NPs absorb relatively long-wavelength light to produce plasmonic hot-electrons, and the adjacent Pt single atoms (PtSAs) can trap the plasmonic hot-electrons effectively for H2 evolution. The PtSAs–Au2.5/PCN exhibits excellent broad-spectrum photocatalytic H2 evolution activity with the H2 evolution rate of 8.8 mmol g− 1 h− 1 at 420 nm and 264 μmol g− 1 h− 1 at 550 nm, respectively.

Abstract Background Paediatric orthopaedics is a significant and difficult for undergraduate students to master. During the COVID-19 pandemic, we used the WeChat platform to combine the advantages offered by problem-based learning (PBL), case-based learning (CBL) and paper review teaching methods to establish a new blended online teaching model and demonstrated its feasibility and effectiveness. Objective This study aims to demonstrate the feasibility and effectiveness of a new blended pedagogical method that uses the WeChat platform and combines PBL, CBL and paper review. Methods We enrolled 22 students participating in the Department of Paediatric Orthopaedics. They participated in the WeChat blended pedagogy mode. Their departmental rotation examination scores were compared with those of 23 students who participated in the traditional teaching method. Moreover, an anonymous questionnaire was used to evaluate students’ perceptions and experiences. Results The total average scores of students who participated in the WeChat blended pedagogy mode and the traditional teaching method were 47.27 and 44.52, respectively. There were no statistically significant differences between the online teaching mode and the traditional teaching method in terms of possessing professional accomplishment, gaining knowledge and promoting interpersonal skills (P = 0.07, P = 0.12 and P = 0.65, respectively). In terms of independent clinical thinking, self-improving capability and improving clinical skills, the scores associated with the WeChat blended pedagogy mode were 8.00, 8.00 and 6.00, whereas those associated with the traditional teaching method were 6.70, 6.87 and 7.48. The overall satisfaction with the WeChat blended pedagogy mode reached 100%. A total of 64%, 86%, 68%, 64% and 59% of students chose very large or large in response to the items concerning professional accomplishment, knowledge absorption, independent clinical thinking skills, English reading and literature exploring capacity, as well as interpersonal skills, respectively. Fifteen participants claimed that the WeChat blended pedagogy mode was less helpful to them with regard to promoting the improvement of their clinical skills. Nine students claimed that the WeChat blended pedagogy mode was time-consuming. Conclusions Our study verified the feasibility and effectiveness of the WeChat blended pedagogy mode for undergraduate paediatric orthopaedics internships. Trial Registration Retrospectively registered.

Different modified atmosphere packaging bags combined with low temperature treatment were used to store and preserve freshness of Chimonabambusa quadrangularis shoots to investigate the optimal preservation process of freshness of Chimonabambusa quadrangularis shoots. The freshness of Chimonabambusa quadrangularis shoots were stored in four different modified atmosphere packaging bags (WK, PE20, PE30, PE40) for 50 d in a cool storage facility at (1.0±0.3) ℃. The respiration intensity, hardness, browning index, polyphenols, soluble protein, PAL and POD of freshness of Chimonabambusa quadrangularis shoots were measured by sampling every 10 d during storage. And the effect of preservation of freshness of Chimonabambusa quadrangularis shoots by different modified atmosphere packaging bags was analyzed by combining with principal component analysis. The results showed that: PE20 could effectively reduce the respiration intensity of freshness of Chimonabambusa quadrangularis shoots, inhibit the rise of hardness, delay the change of total color difference value of fresh bamboo shoots, and inhibit the rise of decay rate, browning index, POD activity and PAL activity during storage of fresh bamboo shoots. The nutrients (VC, soluble protein) of freshness of Chimonabambusa quadrangularis shoots were maintained at a high level. Principal component analysis showed that respiration intensity, medium hardness, and decay rate were the key indicators affecting the freshness of Chimonabambusa quadrangularis shoots. The results of the analysis were subjected to a composite evaluation score, and the composite evaluation score of PE20 packaging at 50 d was higher than that of the other three modified atmosphere packages. The combined index determination and principal component analysis concluded that the treatment with modified atmosphere packaging bags of PE20 was the most effective in preserving freshness of Chimonabambusa quadrangularis shoots.

Local electric-field around multitype pores (dielectric pore, interface pore, electrode pore) in multilayer ceramic capacitors (MLCCs) was investigated using Kelvin probe force microscopy combined with the finite element simulation to understand the effect of pores on the electric reliability of MLCCs. Electric-field is found to be concentrated significantly in the vicinity of these pores and the strength of the local electric-field is 1.5–5.0 times of the nominal strength. Unexpectedly, the concentration degree of the pores in the inner electrode is much higher than that in the dielectrics and dielectric-electrode interfaces. Meanwhile, geometry orientations are found to have a remarkable influence on the local electric field strength. The pores act as an insulation degradation precursor via local electric, thermal center, and oxygen vacancies accumulation center. Such unusual local electric field concentration of multitype pores can provide new insights into the understanding of insulation degradation evolution, processing tailoring and design optimization for MLCCs.

This study provides a detailed investigation of archaeological wood samples from the Luoyang Canal No. 1 site, focusing on wood species identification, physical properties, mechanical property analyses, and morphological examination. The identified wood species, belonging to the Ulmus genus, exhibited a 43% decline in compressive strength in waterlogged environments. Further, the wood exhibited increased moisture content, higher porosity, reduced basic density, and elevated shrinkage rates, indicating a mild level of degradation. X-ray diffraction was employed for the observation of cellulose structure, and Fourier transform infrared spectroscopy (FT-IR) demonstrated significant removal of cellulose and hemicellulose components. These findings emphasize the importance of understanding wood degradation mechanisms to evaluate structural integrity and durability in guiding the development of effective preservation strategies for archaeological wood artifacts. Continued research and conservation are crucial to deepen our knowledge of wood deterioration processes and enhance the implementation of preservation techniques.

Effluent discharged from urban wastewater treatment plants (WWTPs) is a major source of emerging contaminants (ECs) requiring effective regulation. To this end, we collected discharge datasets of pharmaceuticals (PHACs) and endocrine-disrupting chemicals (EDCs), representing two primary categories of ECs, from Chinese WWTP effluent from 2012 to 2022 to establish an exposure database. Moreover, high-risk ECs’ long-term water quality criteria (LWQC) were derived using the species sensitivity distribution (SSD) method. A total of 140 ECs (124 PHACs and 16 EDCs) were identified, with concentrations ranging from N.D. (not detected) to 706 μg/L. Most data were concentrated in coastal regions and Gansu, with high ecological risk observed in Gansu, Hebei, Shandong, Guangdong, and Hong Kong. Using the assessment factor (AF) method, 18 high-risk ECs requiring regulation were identified. However, only three of them, namely carbamazepine, ibuprofen, and bisphenol-A, met the derivation requirements of the SSD method. The LWQC for these three ECs were determined as 96.4, 1010, and 288 ng/L, respectively. Exposure data for carbamazepine and bisphenol-A surpassed their derived LWQC, indicating a need for heightened attention to these contaminants. This study elucidates the occurrence and risks of ECs in Chinese WWTPs and provides theoretical and data foundations for EC management in urban sewage facilities.

An abnormal level of dopamine (DA), a kind of neurotransmitter, correlates with a series of diseases, including Parkinson’s disease, Willis-Ekbom disease, attention deficit hyperactivity disorder, and schizophrenia. Hence, it is imperative to achieve a precise, rapid detection method in clinical medicine. In this study, we synthesized nanocomposite carbon aerogels (CAs) doped with iron and iron carbide, based on algae residue-derived biomass materials, using Fe(NO3)3 as the iron source. The modified glassy carbon electrode (GCE) for DA detection, denoted as CAs-Fe/GCE, was prepared through surface modification with this composite material. X-ray photoelectron spectroscopy and X-ray diffraction characterization confirmed the successful doping of iron into the as-prepared CAs. Additionally, the electrochemical behavior of DA on the modified electrode surface was investigated and the results demonstrate that the addition of the CAs-Fe promoted the electron transfer rate, thereby enhancing their sensing performance. The fabricated electrochemical DA biosensor exhibits an accurate detection of DA in the concentration within the range of 0.01~200 µM, with a detection limit of 0.0033 µM. Furthermore, the proposed biosensor is validated in real samples, showing its high applicability for the detection of DA in beverages.

The bonding of cement mortar to the concrete substrate is crucial in buildings. In this study, cement mortar was prepared using manufactured sand (MS) instead of river sand (RS). The bonding strength between manufactured sand mortar (MSM) and concrete substrate was evaluated and the effects of curing age, water-to-cement ratio (w/c) and thermal cycling on the bonding strength were discussed and compared with those of the river sand mortar (RSM). The compressive strength of the MSM was consistently higher than that of the RSM, while the bonding strength of RSM was consistently higher than that of MSM, indicating that the bonding strength does not depend on the compressive strength of the mortar. As the number of thermal cycles increased, the pull-off strengths at the interface between the concrete and MSM or RSM at different w/c ratios all decreased, and the RSM experienced a larger reduction. After 400 cycles, the percentage decrease in bonding strength of MSM sample ranged from 18.62% to 30.86%.

Metabolic reprogramming has emerged as a prominent hallmark of cancer, characterized by substantial alterations in nutrient uptake and intracellular metabolic pathways. Consequently, intracellular metabolite concentrations undergo significant changes which can contribute to tumorigenesis through diverse mechanisms. Beyond their classical roles in regulating metabolic pathway flux, metabolites exhibit noncanonical functions that play a crucial role in tumor progression. In this review, we delve into the nonclassical functions of metabolites in the context of tumor progression, with a particular focus on their capacity to modulate gene expression and cell signaling. Furthermore, we discuss the potential exploitation of these nonclassical functions in the enhancement of cancer therapy.

We propose and study a data-driven method that can interpolate between a classical and a modern approach to classification for a class of linear models. The class is the convex combinations of an average of the source task classifiers and a classifier trained on the limited data available for the target task. We derive the expected loss of an element in the class with respect to the target distribution for a specific generative model, propose a computable approximation of the loss, and demonstrate that the element of the proposed class that minimizes the approximated risk is able to exploit a natural bias–variance trade-off in task space in both simulated and real-data settings. We conclude by discussing further applications, limitations, and potential future research directions.