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Highlights The NiFeLa catalyst with 3d-5d orbital coupling exhibits remarkable oxygen evolution reaction (OER) activity and stability, enabling an anion-exchange membrane water electrolyzers device to achieve a cell voltage of only 1.58 V at 1 A cm−2 as well as long-term stability over 600 h. The introduction of La disrupts the symmetry of Ni-Fe units and optimize d band center, which affects the d-p orbital hybridization between the metal sites on the surface of the catalyst and oxygen-containing intermediates during the OER process. The 5d-introduced NiFeLa has enhanced adsorption strength of oxygen intermediates, which can reduce the rate-determining step energy barrier and prevent catalyst dissolution.

Since the beginning of the 21st century, the field of cancer drug development has undergone significant changes. Kinase inhibitors are the product category with the highest number of approved drugs and indications. However, despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product categories. In the year of 2023, the FDA’s Center for Drug Evaluation and Research (CDER) has approved 13 new cancer therapeutic drugs. In the past five years, a slight increase in drug approvals targeting biomarker-defined populations as well as emerging approvals that are agnostic to tumor anatomy has been recorded. Currently, new treatment approaches and technologies, such as the development of Artificial Intelligence (AI), have increasingly profound progress on cancer drug development.

Abstract A dose-escalation and expansion, phase 1/2 study (ClinicalTrials.gov, NCT04818333) was conducted to assess the novel antibody-drug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer (NSCLC). Here, we report results from the phase 1 portion. Patients who had previously failed or were intolerant to platinum-based chemotherapy were enrolled and received SHR-A1811 intravenously at doses of 3.2 to 8.0 mg/kg every 3 weeks. Dose escalation followed a Bayesian logistic regression model that included overdose control, with subsequent selection of tolerable levels for dose expansion. Overall, 63 patients were enrolled, including 43 receiving a recommended dose for expansion of 4.8 mg/kg. All patients had HER2-mutant disease. Dose-limiting toxicity occurred in one patient in the 8.0 mg/kg dose cohort. Grade ≥ 3 treatment-related adverse events occurred in 29 (46.0%) patients. One patient in the 6.4 mg/kg cohort died due to interstitial lung disease. As of April 11, 2023, the 4.8 mg/kg cohort showed an objective response rate of 41.9% (95% CI 27.0–57.9), and a disease control rate of 95.3% (95% CI 84.2–99.4). The median duration of response was 13.7 months, with 13 of 18 responses ongoing. The median progression-free survival was 8.4 months (95% CI 7.1–15.0). SHR-A1811 demonstrated favourable safety and clinically meaningful efficacy in pretreated advanced HER2-mutant NSCLC.

Due to the numerous and interconnected quality influencing parameters, the production process propagation and evolution of abnormal factors are complex, which can affect the stability of quality characteristics from multiple perspectives. This paper addresses the problem of identifying the quality fluctuations sources and proposes a variable-weighted reconstruction analysis-based method for identifying abnormal sources of quality fluctuations in the spinning process. The method monitors the degree of quality fluctuations by constructing information entropy statistics and reconstructs the weighted parameters of abnormal quality processes. On this basis, abnormal contribution ranking is performed based on the degree of change in quality characteristics before and after weight reconstruction, which achieves the identification of the abnormal source. The proposed method is validated using a spinning process dataset. It reveals that the method could accurately identify the quality fluctuation abnormal source, which indicates its practicability and feasibility and will provide a theoretical basis for the quality stability control.

Petrocodon liboensis Sheng H.Tang & Jia W.Yang is a new species of Gesneriaceae from Guizhou, southwestern China. The new taxon has a pale-yellow corolla and is most similar to P. luteoflorus. However, it differs from the latter by having a urceolate (vs. cannulate) corolla tube, an abaxial corolla lip 0.8–1.1 mm (vs. 2–2.2 mm) long, and filaments 1.5–1.7 mm (vs. ca. 7 mm) long that are straight (vs. S-shaped or geniculate near the middle). The new taxon is assessed as “Data Deficient” (DD) according to the IUCN standards.

The emergence of metacommunity theory has provided a framework for studying the spatial structure of biological communities. To unravel the underlying driving mechanisms of macroinvertebrate metacommunity structure and diversity, this paper evaluates macroinvertebrate data from a water body in eastern China using variance decomposition and stratified partitioning. The results suggest that spatial processes dominate macroinvertebrate metacommunity structure, while the combined effects of spatial processes, aquatic environment, and geoclimatic factors also explain part of the macroinvertebrate community structure. Spatial processes, aquatic environment, and geoclimatic factors significantly influenced macroinvertebrate alpha diversity and indirectly influenced beta diversity through alpha diversity. Therefore, the significant effects of spatial processes and geoclimatic variables cannot be ignored in biological assessments, especially biodiversity assessments. Our findings elucidate the metacommunity dynamics in the region and provide crucial information for conservation planning in riverine ecosystems.

The estimation of postmortem interval (PMI) has long been a focal point in the field of forensic science. Following the death of an organism, microorganisms exhibit a clock-like proliferation pattern during the course of cadaver decomposition, forming the foundation for utilizing microbiology in PMI estimation. The establishment of PMI estimation models based on datasets from different seasons is of great practical significance. In this experiment, we conducted microbiota sequencing and analysis on gravesoil and mouse intestinal contents collected during both the winter and summer seasons and constructed a PMI estimation model using the Random Forest algorithm. The results showed that the MAE of the gut microbiota model in summer was 0.47 ± 0.26 d, R2 = 0.991, and the MAE of the gravesoil model in winter was 1.04 ± 0.22 d, R2 = 0.998. We propose that, in practical applications, it is advantageous to selectively build PMI estimation models based on seasonal variations. Additionally, through a combination of morphological observations, gravesoil microbiota sequencing results, and soil physicochemical data, we identified the time of cadaveric rupture for mouse cadavers, occurring at around days 24–27 in winter and days 6–9 in summer. This study not only confirms previous research findings but also introduces novel insights, contributing to the foundational knowledge necessary to advance the utilization of microbiota for PMI estimation.

Abstract Different turbulent entrainment‐mixing mechanisms between clouds and environment are essential to cloud‐related processes; however, accurate representation of entrainment‐mixing in weather/climate models still poses a challenge. This study exploits the use of machine learning (ML) to address this challenge. Four ML (Light Gradient Boosting Machine [LGB], eXtreme Gradient Boosting, Random Forest, and Support Vector Regression) are examined and compared. It is found that LGB performs best, and thus is selected to understand the impact of entrainment‐mixing on microphysics using simulation data from Explicit Mixing Parcel Model. Compared with traditional parameterizations, the trained LGB provides more accurate microphysical properties (number concentration and cloud droplet spectral dispersion). The partial dependences of predicted microphysics on features exhibit a strong alignment with physical mechanisms and expectations, as determined by the interpreting method, thus overcoming the limitations of the “black box” scheme. The underlying mechanisms are that the smaller number concentration and larger spectral dispersion correspond to more inhomogeneous entrainment‐mixing. Specifically, number concentration after entrainment‐mixing is positively correlated with adiabatic number concentration and liquid water content affected by entrainment‐mixing, and inversely correlated with adiabatic volume mean radius. Spectral dispersion after entrainment‐mixing is negatively correlated with liquid water content affected by entrainment‐mixing, turbulent dissipation rate and relative humidity of entrained air. Sensitivity analysis further suggests that number concentration is mainly determined by cloud microphysical properties whereas spectral dispersion is influenced by both cloud microphysical properties and environmental variables. The results indicate that the LGB scheme has the potential to enhance the representation of entrainment‐mixing in weather/climate models.

Key Clinical Message A comprehensive diagnostic approach, including immunohistochemistry, is crucial for confirming pulmonary Langerhans cell histiocytosis in adults. Individualized treatment with dynamically adjusted chemotherapy based on therapeutic response leads to significant absorption of lesions and symptom alleviation. Regular follow‐up and timely treatment adjustments according to the patient's condition are essential in managing this rare disease.

Introduction: Polymyxin B is widely used to treat infections caused by multidrug-resistant Gram-negative bacteria. However, the pharmacokinetic study data of PB in the elderly are scarce. Herein, a simple method to measure the concentration of PB in human plasma was developed and validated by high performance liquid chromatography—tandem mass spectrometry, and it was applied to a PK study in the elderly.Methods: PB was extracted from human plasma by a rapid protein-precipitation method using 0.1% formic acid in methanol and then separated on an ultimate AQ-C18 column using linear gradient elution with a 0.5-mL/min flow rate. Subsequently, PB was detected using a mass spectrometer operated in positive-ion and multiple-reaction-monitoring modes.Results: The lower limits of quantification of the method for Polymyxin B1 and Polymyxin B2 were 1.00 and 0.10 μg/mL, respectively. The linear ranges for PB1 and PB2 were 1.00–20.02 and 0.10–2.04 μg/mL, respectively. Patients receiving a 75-mg maintenance dose every 12h had AUCss, 24 h, and Css, av values of 117.70 ± 37.03 μg h/mL and 4.14 ± 1.74 μg/mL, respectively. For patients receiving a 100 mg maintenance dose, these values were 152.73 ± 70.09 μg h/mL and 5.43 ± 2.85 μg/mL, respectively.Conclusion: The validated HPLC–MS/MS method was successfully applied to a study on the pharmacokinetics of PB in elderly patients infected with multidrug-resistant Gram-negative bacteria. Both two dose strategies in this study would have a excessive PB exposure in the elderly patients then the therapeutic window recommended by guidelines.

Background: Orthostatic intolerance (OI) is the inability to tolerate orthostatic stress during any postural change. The etiology of OI varies, and methods to obtain a specific diagnosis and plan appropriate treatment are important. The tools available within the Chinese context to swiftly identify orthostatic intolerance syndrome (OIS) are currently limited. Methods: Patients with OI symptoms were included in this study and categorized into two groups based on the results of the supine-to-stand test. Those with abnormal test results were assigned to the OIS group, while those with normal test results were placed in the non-OIS group. We evaluated the internal consistency and predictive value of the Chinese Orthostatic Discriminant and Severity Scale (ODSS) by comparing patients’ scores with their physiological measurements collected during orthostatic stress tests and the results of other available questionnaires, including the orthostatic Symptom Questionnaire and Orthostatic Grading Scale (OGS). Results: Patients with OIS scored significantly higher on all three questionnaires and showed significant differences in autonomic responses during orthostatic stress tests compared with non-OIS patients. Receiver operating characteristic curve analysis showed that the orthostatic score from the ODSS had moderate predictive value for the supine test (area under the curve [AUC] = 0.754). Further subgroup analysis revealed that the orthostatic score from the ODSS had uniquely high specificity and sensitivity for identifying patients with orthostatic hypotension with abnormal cerebral blood flow (OH–U, AUC = 0.919). Conclusions: We conclude that the Chinese version of the ODSS has sufficient reliability and validity to distinguish patients with OIS and could possibly be used as a diagnostic tool for OH–U patients. Thus, the Chinese ODSS offers a beneficial screening tool for quickly assessing whether patients have OIS that requires further clinical assessment.

Background: The immunomodulatory imide drugs (IMiDs) thalidomide, lenalidomide and pomalidomide may exhibit therapeutic efficacy in the prostate. In lower urinary tract symptoms (LUTS), voiding and storage disorders may arise from benign prostate hyperplasia, or overactive bladder. While current therapeutic options target smooth muscle contraction or cell proliferation, side effects are mostly cardiovascular. Therefore, we investigated effects of IMiDs on human detrusor and porcine artery smooth muscle contraction, and growth-related functions in detrusor smooth muscle cells (HBdSMC). Methods: Cell viability was assessed by CCK8, and apoptosis and cell death by flow cytometry in cultured HBdSMC. Contractions of human detrusor tissues and porcine interlobar and coronary arteries were induced by contractile agonists, or electric field stimulation (EFS) in the presence or absence of an IMID using an organ bath. Proliferation was assessed by EdU assay and colony formation, cytoskeletal organization by phalloidin staining, Results: Depending on tissue type, IMiDs inhibited cholinergic contractions with varying degree, up to 50 %, while non-cholinergic contractions were inhibited up to 80 % and 60 % for U46619 and endothelin-1, respectively, and EFS-induced contractions up to 75 %. IMiDs reduced viable HBdSM cells in a time-dependent manner. Correspondingly, proliferation was reduced, without showing pro-apoptotic effects. In parallel, IMiDs induced cytoskeletal disorganization. Conclusions: IMiDs exhibit regulatory functions in various smooth muscle-rich tissues, and of cell proliferation in the lower urinary tract. This points to a novel drug class effect for IMiDs, in which the molecular mechanisms of action of IMiDs merit further consideration for the application in LUTS.

Abstract Background Gastrointestinal dysfunction is one of the common complaints for patient post-surgery. Acupuncture has been employed to improve gastrointestinal function and sleeping quality and has confirmed clinical efficacy for emotional problems. This study aims to evaluate the clinical effect of electroacupuncture for postoperative rapid recovery. Methods This study design is a two-arm, parallel, double-blinded randomized controlled trial. 104 subjects, aged from 40 to 89 years old, diagnosed with gastrointestinal cancer undergoing laparoscopic surgery, will be divided into Interventional Group and Control Group. Patients of both groups receive perioperative care under the guidance of ERAS guidance. The Interventional Group receives electroacupuncture treatment starting from the first day post-surgery for a consecutive 5 days, whereas the Control Group receives placebo electroacupuncture treatment. The primary outcome will be the first flatus time whereas the secondary outcomes will be the first sign of borborygmus, recovery of defecation, laboratory tests and questionnaires including Self-rating anxiety scale, Ford Insomnia Response to Stress Test, TCM rating scale of Gastrointestinal symptoms and Gastrointestinal Symptoms Rating Scales. Discussion This study aims to provide timely intervention for post-laparoscopic patients with gastrointestinal tumour using the ERAS concept combined with electroacupuncture, observe the efficacy of this therapy in treating PGID, and contribute reliable scientific evidence for postoperative rapid recovery. Trial registration Chictr.org.cn Identifier: ChiCTR2300078710. Registered on 15th December 2023.

Abstract The oncogenic role of circRNA in cancers including esophageal cancer (EC) has been well studied. However, whether and how circRNAs are involved in cancer cell metabolic processes remains largely unknown. Here, we reported that circRNA, circHIPK3, is highly expressed in ESCC cell lines and tissues. Knockdown of circHIPK3 significantly restrained cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, circHIPK3 was found to act as a ceRNA by sponging miR-637 to regulate FASN expression and fatty acid metabolism in ESCC cells. Anti-sense oligonucleotide (ASO) targeting circHIPK3 substantially inhibited ESCC both in vitro and in vivo. Therefore, these results uncover a modulatory axis constituting of circHIPK3/miR-637/FASN may be a potential biomarker and therapeutic target for ESCC in the clinic.

Intelligent textile equipment can discover potential patterns in the production process through data mining, and utilize these patterns through intelligent optimization, ultimately achieving intelligent and automated textile production. This paper focuses on the spinning process parameters optimization under changing spinning conditions and proposes a dynamic non-dominant ranking parameter quality adaptive optimization algorithm. The factors of spinning process condition changes are transformed into mathematical dynamic constraints and constructing an adaptive optimization model for spinning parameter quality. Based on this, the response mechanism of spinning environment is established to readjust the optimization direction according to the change of spinning conditions, and the DNSGA-II is used to solve the quality adaptive optimization model. A case study is designed to validate the effectiveness, results show that for different usage periods of wire rings, the optimal breaking strength is 5.6, and the number of details is 33.3, 31.1, and 41.6 respectively. In some degree, the proposed algorithm can effectively adapt to the quality optimization problem of spinning process parameters under different spinning conditions, which could provide corresponding parameter optimization combinations for different spinning conditions.

AbstractImaging adult zebrafish’s cardiac organ is often hampered by the limited volume of the internal cavity. This research study aims to design, manufacture and apply a miniature illumination probe amended with an aluminum-coated polydimethylsiloxane (PDMS) concave cylindrical mirrors as well as 3D-printed casings for probe assembly in a light-sheet fluorescence microscopy to explore its applicability of visualizing adult zebrafish’s ventricle. The system was calibrated and characterized. The experimental results successfully demonstrated the tracking of the ventricular regeneration in female adult zebrafish at multiple time points and can be conducive to other heart-related research in in vivo settings.

Slope shape as a consequence of erosional landform development plays a prominent role in soil erosion. Clarifying the distribution of soil erosion and deposition patterns on different shaped slopes is crucial for soil erosion control. The aim of this study was to decipher the effects of slope shape on soil erosion and deposition patterns under natural rainfall conditions based on high-resolution unmanned aerial vehicle (UAV) data and geographic information system technology. Structure from motion (SfM)-UAV photogrammetry was carried out in four runoff plots with various slope shapes during the rainy season in 2021. Digital elevation models (DEMs) were developed for each slope shape before and after the rainy season. In addition to collecting runoff and sediment, the DEMs of difference were analyzed to quantify soil erosion and deposition patterns on various slope shapes in the rainy season. Results showed that the runoff volumes and sediment yields induced by rainfall were markedly different among various slope shapes. The mean runoff volume and sediment yield from the concave-convex slope were 1.09 ∼ 2.69 and 1.33 ∼ 27.16 times those of the other three slopes, respectively, with less sediment loss from the convex-concave slope and its combination slope. Slope shape exhibited a notable effect on the type of slope erosion and deposition. All four slopes showed considerable changes in surface elevation after the rainy season. The increase and decrease in surface elevation were concentrated in the range of –0.02 to –0.007 m and 0.007 to 0.02 m, respectively, with a low proportion of changes less than –0.03 m and greater than 0.03 m. The effectiveness of SfM-UAV in monitoring the microgeomorphic changes of slopes was verified by the consistency of soil erosion amounts based on sediment collection and SfM-UAV measurements. Reference values were provided to solve the threshold problem of slope length cutoff in soil erosion prediction models based on runoff plot experiments. Findings of this study could be useful for decision-making in soil erosion control and slope reconstruction.

With the increasing impact of global climate change, the frequency of extreme arid climates worldwide is rising. These extreme arid conditions can have adverse effects on expansive soil embankments. In this study, the digital image technology is used to study the crack development characteristics of expansive soil embankments. The findings indicate that the crack development process in expansive soil can be divided into three stages: slow development, rapid development, and stable development. During the drying process, cracks develop differently on the waterward side, the top of the embankment, and the backwater side of the embankment. Initially, cracks appear on the top of the embankment, and their degree of development is the highest in this area. The crack degree on the top of the embankment is approximately 2 to 3 times greater than that on the waterward and backwater sides. Furthermore, longitudinal cracks on the top of the embankment have been analyzed from both macro and micro perspectives. This study is expected to help analyze the underlying formation mechanisms of desiccation cracking-inducing geohazards and access the long-term performance of expansive soil embankments in arid climates.

BackgroundClear cell renal cell carcinoma (ccRCC) is a metabolic disorder characterized by abnormal lipid accumulation in the cytoplasm. Lipid metabolism-related genes may have important clinical significance for prognosis prediction and individualized treatment.MethodsWe collected bulk and single-cell transcriptomic data of ccRCC and normal samples to identify key lipid metabolism-related prognostic signatures. qPCR was used to confirm the expression of signatures in cancer cell lines. Based on the identified signatures, we developed a lipid metabolism risk score (LMRS) as a risk index. We explored the potential application value of prognostic signatures and LMRS in precise treatment from multiple perspectives.ResultsThrough comprehensive analysis, we identified five lipid metabolism-related prognostic signatures (ACADM, ACAT1, ECHS1, HPGD, DGKZ). We developed a risk index LMRS, which was significantly associated with poor prognosis in patients. There was a significant correlation between LMRS and the infiltration levels of multiple immune cells. Patients with high LMRS may be more likely to respond to immunotherapy. The different LMRS groups were suitable for different anticancer drug treatment regimens.ConclusionPrognostic signatures and LMRS we developed may be applied to the risk assessment of ccRCC patients, which may have potential guiding significance in the diagnosis and precise treatment of ccRCC patients.

Summary: Microorganisms are critical to the stability of aquatic environments, and understanding the ecological mechanisms of microbial community is essential. However, the distinctions and linkages across biogeographic patterns, ecological processes, and formation mechanisms of microbes in rivers and lakes remain unknown. Accordingly, microbiome-centric analysis was conducted in rivers and lakes in the Yangtze River watershed. Results revealed significant differences in the structure and diversity of microbial communities between rivers and lakes, with rivers showing higher diversity. Lakes exhibited lower community stability, despite higher species interactions. Although deterministic processes dominated microbial community assembly both in rivers and lakes, higher stochastic processes of rare and abundant taxa exhibited in rivers. Spatial factors influenced river microbial community, while environmental factors drove differences in the lake bacterial community. This study deepened the understanding of microbial biogeography and formation mechanisms in large watershed rivers and lakes, highlighting distinct community aggregation patterns between river and lake microorganisms.

Objectiveγ-aminobutyric acid (GABA) is a neurotransmitter inhibitor that has beneficial effects on various health conditions such as hypertension, cognitive dysfunction, and anxiety. In this study, we investigated a novel yogurt naturally enriched with GABA using a Levilactobacillus brevis strain isolated in our laboratory; the specific optimum yogurt production conditions for this strain were determined.MethodsWe isolated an L. brevis strain and used it to produce yogurt naturally enriched with GABA. We explored the optimal conditions to enhance GABA yield, including fermentation temperature, inoculation amount, L-monosodium glutamate (L-MSG) concentration, fermentation time, and sucrose content. We also performed mixed fermentation with Streptococcus thermophilus and evaluated the quality of the yogurt.ResultsFollowing optimization (43°C, 8% inoculation amount, 1.5 g/L L-MSG, and 8% sucrose for 40 h of fermentation), the GABA yield of the yogurt increased by 2.2 times, reaching 75.3 mg/100 g. Mixed fermentation with S. thermophilus demonstrated favorable results, achieving a GABA yield akin to that found in some commercially available functional foods. Moreover, the viable microbe count in the GABA-enriched yogurt exceeded 1 × 108 cfu/mL, which is higher than that of commercial standards. The yogurt also exhibited a suitable water-holding capacity, viscosity, 3-week storage time, and favorable sensory test results.ConclusionThis study highlights the potential of naturally enriched GABA yogurt as a competitive commercial yogurt with beneficial health effects.

Chimeric antigen receptor (CAR)-modified T cell therapy has achieved remarkable efficacy in treating hematological malignancies, but it confronts many challenges in treating solid tumors, such as the immunosuppressive microenvironment of the solid tumors. These factors reduce the antitumor activity of CAR-T cells in clinical trials. Therefore, we used the immunocytokine interleukin-12 (IL-12) to enhance the efficacy of CAR-T cell therapy. In this study, we engineered CAR-IL12R54 T cells that targeted mesothelin (MSLN) and secreted a single-chain IL-12 fused to a scFv fragment R54 that recognized a different epitope on mesothelin. The evaluation of the anti-tumor activity of the CAR-IL12R54 T cells alone or in combination with anti-PD-1 antibody in vitro and in vivo was followed by the exploration of the functional mechanism by which the immunocytokine IL-12 enhanced the antitumor activity. CAR-IL12R54 T cells had potency to lyse mesothelin positive tumor cells in vitro. In vivo studies demonstrated that CAR-IL12R54 T cells were effective in controlling the growth of established tumors in a xenograft mouse model with fewer side effects than CAR-T cells that secreted naked IL-12. Furthermore, combination of PD-1 blockade antibody with CAR-IL12R54 T cells elicited durable anti-tumor responses. Mechanistic studies showed that IL12R54 enhanced Interferon-γ (IFN-γ) production and dampened the activity of regulatory T cells (Tregs). IL12R54 also upregulated CXCR6 expression in the T cells through the NF-κB pathway, which facilitated T cell infiltration and persistence in the tumor tissues. In summary, the studies provide a good therapeutic option for the clinical treatment of solid tumors.

Abstract Prostate cancer (PCa) is a significant health concern affecting men worldwide. Previous studies have shown that nimotuzumab, a drug targeting the epidermal growth factor receptor (EGFR), can effectively inhibit cancer progression. Here, we aimed to explore the role of miR‐199a/214 cluster in mediating the inhibitory effect of nimotuzumab on the development of PCa. In this study, we conducted an MTT assay to assess cell proliferation and utilized flow cytometry to evaluate cell apoptosis and cell cycle arrest. To investigate the molecular mechanisms underlying the effects of nimotuzumab on prostate cancer development, we focused on the miR‐199a‐5p and miR‐214‐3p miRNA clusters. The TargetScan Human database was used to predict the binding sites between miR‐199a‐5p or miR‐214‐3p and the 3'‐UTR of the transducin (β)‐like 1 X‐linked receptor 1 (TBL1XR1) mRNA. To confirm the direct interaction and binding between miR‐199a‐5p or miR‐214‐3p and the 3'‐UTR of TBL1XR1 mRNA, we performed luciferase reporter assays. Our findings demonstrated that nimotuzumab exerted a significant dosage‐dependent suppression of PCa cell proliferation and facilitated PCa cell apoptosis and cell cycle arrest. Concurrently, nimotuzumab obviously impeded the activity of Wnt/β‐catenin and EGFR signaling pathways in PCa cells. We also observed downregulation of miR‐199a‐5p and miR‐214‐3p in PCa cells. Overexpression of miR‐199a/214 cluster inhibited PCa cell viability and enhanced cell apoptosis. Furthermore, we found that miR‐199a/214 cluster augmented the inhibitory effect of nimotuzumab on PCa cell proliferation and promoted its ability to induce apoptosis and cell cycle arrest. This effect was reversed upon TBL1XR1 overexpression, indicating that TBL1XR1 is involved in the regulatory pathway of miR‐199a/214 and nimotuzumab in PCa cells. We further revealed that TBL1XR1 was overexpressed in PCa and was identified as a downstream target of the miR‐199a/214 cluster. In nimotuzumab‐treated PCa cells, the overexpression of miR‐199a/214 markedly inhibited Wnt/β‐catenin and EGFR signaling, and this effect was also rescued by TBL1XR1 overexpression. In summary, our data indicated that miR‐199a/214 cluster play a crucial role in enhancing the inhibitory effect of nimotuzumab on PCa development by downregulating TBL1XR1 and modulating Wnt/β‐catenin and EGFR signaling pathways. These findings offer a novel therapeutic approach for the treatment of prostate cancer.

Changes in wetland ecosystems have a critical impact on the local ecology and species diversity. Different development scenarios and policies are key factors influencing their changes. Therefore, we studied changes of wetlands in the middle Yangtze River basin (MYRB) in 2001–2020, and a patch-generated land use simulation (PLUS) model and random forest (RF) method were applied to predict and analyze the changes under different scenarios in the MYRB in the future (i.e.2035–2095). The results indicated that: (1) The regions with high wetland proportions were concentrated in the central and eastern MYRB in 2001–2020, with a 1.5% decrease in overall wetland area; (2) The RF could simulate the future ecological quality with training and testing accuracies of 0.98 and 0.92, respectively; (3) Remote Sensing Ecological Index (RSEI) less than 0.5 in the central and eastern regions and 13.3% reduction in the northwest in the SSP245 scenario. In general, the study provides a basis for future regional studies of ecosystem quality and provides data to support wetland conservation and management.

Abstract Developing efficient (co-)catalysts with optimized interfacial mass and charge transport properties is essential for enhanced oxygen evolution reaction (OER) via electrochemical water splitting. Here we report one-atom-thick hexagonal boron nitride (hBN) as an attractive co-catalyst with enhanced OER efficiency. Various electrocatalytic electrodes are encapsulated with centimeter-sized hBN films which are dense and impermeable so that only the hBN surfaces are directly exposed to reactive species. For example, hBN covered Ni-Fe (oxy)hydroxide anodes show an ultralow Tafel slope of ~30 mV dec−1 with improved reaction current by about 10 times, reaching ~2000 mA cm−2 (at an overpotential of ~490 mV) for over 150 h. The mass activity of hBN co-catalyst is found exceeding that of commercialized catalysts by up to five orders of magnitude. Using isotope experiments and simulations, we attribute the results to the adsorption of oxygen-containing intermediates at the insulating co-catalyst, where localized electrons facilitate the deprotonation processes at electrodes. Little impedance to electron transfer is observed from hBN film encapsulation due to its ultimate thickness. Therefore, our work also offers insights into mechanisms of interfacial reactions at the very first atomic layer of electrodes.

Abstract ISGylation is a well-established antiviral mechanism, but its specific function in immune and tissue homeostasis regulation remains elusive. Here, we reveal that the RNA-binding protein RBM47 undergoes phosphorylation-dependent ISGylation at lysine 329 to regulate immune activation and maintain lung homeostasis. K329R knockin (KI) mice with defective RBM47-ISGylation display heightened susceptibility to LPS-induced acute lung injury and lung tumorigenesis, accompanied with multifaceted immunosuppression characterized by elevated pro-inflammatory factors, reduced IFNs/related chemokines, increased myeloid-derived suppressor cells, and impaired tertiary lymphoid structures. Mechanistically, RBM47-ISGylation regulation of the expression of TSC22D3 mRNA, a glucocorticoid-inducible transcription factor, partially accounts for the effects of RBM47-ISGylation deficiency due to its broad immunosuppressive activity. We further demonstrate the direct inhibitory effect of RBM47-ISGylation on TSC22D3 expression in human cells using a nanobody-targeted E3 ligase to induce site-specific ISGylation. Furthermore, epinephrine-induced S309 phosphorylation primes RBM47-ISGylation, with epinephrine treatment exacerbating dysregulated cytokine expression and ALI induction in K329R KI mice. Our findings provide mechanistic insights into the dynamic regulation of RBM47-ISGylation in supporting immune activation and maintaining lung homeostasis.

Amine transaminases (ATAs) catalyze the asymmetric amination of prochiral ketones or aldehydes to their corresponding chiral amines. However, the trade-off between activity and stability in enzyme engineering represents a major obstacle to the practical application of ATAs. Overcoming this trade-off is important for developing robustly engineered enzymes and a universal approach for ATAs. Herein, we modified the binding pocket of ω-ATA from Aspergillus terreus (AtATA) to identify the key amino acid residues controlling the activity and stability of AtATA toward 1-acetonaphthone. We discovered a structural switch comprising four key amino acid sites (R128, V149, L182, and L187), as well as the “best” mutant (AtATA_D224K/V149A/L182F/L187F; termed M4). Compared to the parent enzyme AtATA_D224K (AtATA-Pa), M4 increased the catalytic efficiency (kcat/Km1-acetonaphthone, where kcat is the constant of catalytic activities and is 10.1 min−1, Km1-acetonaphthone is Michaelis-Menten constant and is 1.7 mmol·L–1) and half-life (t1/2) by 59-fold to 5.9 L·min−1·mmol−1 and by 1.6-fold to 46.9 min, respectively. Moreover, using M4 as the biocatalyst, we converted a 20 mmol·L–1 aliquot of 1-acetonaphthone in a 50 mL scaled-up system to the desired product, (R)-(+)-1(1-naphthyl)ethylamine ((R)-NEA), with 78% yield and high enantiomeric purity (R > 99.5%) within 10 h. M4 also displayed significantly enhanced activity toward various 1-acetonaphthone analogs. The related structural properties derived by analyzing structure and sequence information of robust ATAs illustrated their enhanced activity and thermostability. Strengthening of intramolecular interactions and expansion of the angle between the substrate-binding pocket and the pyridoxal 5′-phosphate (PLP)-binding pocket contributed to synchronous enhancement of ATA thermostability and activity. Moreover, this pocket engineering strategy successfully transferred enhanced activity and thermostability to three other ATAs, which exhibited 8%–22% sequence similarity with AtATA. This research has important implications for overcoming the trade-off between ATA activity and thermostability.

Abstract Rechargeable batteries are highly in demand to power various electronic devices and future smart electric grid energy storage. The electrode–electrolyte interphases play a crucial role in influencing the electrochemical performance of batteries, with the solvation chemistries of the electrolyte being particularly significant in regulating these interfacial reactions. However, the reaction mechanisms of electrolyte solvation and their specific functions in batteries are not yet fully understood. In this review, we embark on an exploration of the fundamental principles governing solvation and present a comprehensive overview of how solvation structures impact interfacial reactions at the electrode–electrolyte interface. We underscore the significance of interactions among cations, anions, and solvents in shaping electrolyte solvation structures. The primary strategies for controlling solvation structures are also discussed, including the optimization of salt concentrations, solvent interactions, and the introduction of functional cosolvents. Furthermore, we elucidate the oxidation/reduction reaction mechanisms of electrolyte components in different solvation structures and the new understanding of electrolyte additives in modulating interfacial chemistries in batteries. Additionally, we emphasize the importance of incorporating new characterization techniques and theoretical simulations to attain a deeper understanding of the intricate processes taking place within batteries. This review provides an in‐depth understanding in solvations and interphasial properties and new ideas for designing advanced functional electrolytes for rechargeable batteries.

Abstract Background Lymph node (LN) metastasis is crucial in non‐small cell lung cancer (NSCLC) prognosis and treatment, but the TNM system lacks LN quantity consideration. Our goal is to investigate the role of positive LNs (nPLN) and positive LN rate (LNR) in overall survival (OS) and assess whether they offer higher value in prognostic assessment of NSCLC than N‐stage. Methods Patients were stratified into four subgroups using X‐Tile software. Statistical analysis was conducted using the Kaplan–Meier method, univariate analysis, and multivariate Cox regression analysis. Model performance was evaluated using the Harrell consistency index (C‐index), Akaike information criterion (AIC), and Bayesian information criterion (BIC). The prognostic performance of the nodal classification was validated using overall survival as the endpoint. Results The survival curves demonstrate distinct disparities between each nPLN and LNR category. A pronounced trend toward deteriorating overall survival from N‐PLN 1 to N‐PLN 2+ was observed across all tumor size categories. However, the differences between each LNR category were only significant for tumors ≤3 cm and 5–7 cm. Notably, both nPLN and LNR classifications displayed a higher C‐index, lower AIC, and lower BIC compared with the N staging. Furthermore, the LNR classification provided superior prognostic stratification when compared with the nPLN classification. Conclusions Our results demonstrate that nPLN and LNR classifications may offer improved prognostic performance compared with the current N classification for LN‐positive NSCLC patients. Nonetheless, more studies are needed to assess the feasibility of incorporating these classifications into the next TNM staging system.

Acid value (AV) serves as an important indicator to assess the quality of oil, which can be used to judge the deterioration of edible oil. In order to realize the quantitative prediction of the AV of camellia seed oil, which was made from camellia oleifolia, hyperspectral data of 168 camellia seed oil samples were collected using a hyperspectral imaging system, which were related to their AV content measured via classical chemical titration. On the basis of hyperspectral full wavelengths, characteristic wavelengths, and fusing spectral and image features, the quantitative prediction AV models for camellia seed oil were established. The results demonstrating the 2Der-SPA-GLCM-PLSR model fusing spectral and image features stood out as the optimal choices for the AV prediction of camellia seed oil, with the correlation coefficient of calibration set (Rc2) and the correlation coefficient of prediction set (Rp2) at 0.9698 and 0.9581, respectively. Compared with those of 2Der-SPA-PLSR, the Rc2 and Rp2 were improved by 2.11% and 2.57%, respectively. Compared with those of 2Der-PLSR, the Rc2 and Rp2 were improved by 5.02% and 5.31%, respectively. Compared with the model based on original spectrum, the Rc2 and Rp2 were improved by 32.63% and 40.11%, respectively. After spectral preprocessing, characteristic wavelength selection, and fusing spectral and image features, the correlation coefficient of the optimal AV prediction model was continuously improved, while the root mean square error was continuously decreased. The research demonstrated that hyperspectral imaging technology could precisely and quantitatively predict the AV of camellia seed oil and also provide a new environmental method for detecting the AV of other edible oils, which is conducive to sustainable development.

To achieve the rapid grade classification of camellia seed oil, hyperspectral imaging technology was used to acquire hyperspectral images of three distinct grades of camellia seed oil. The spectral and image information collected by the hyperspectral imaging technology was preprocessed by different methods. The characteristic wavelength selection in this study included the continuous projections algorithm (SPA) and competitive adaptive reweighted sampling (CARS), and the gray-level co-occurrence matrix (GLCM) algorithm was used to extract the texture features of camellia seed oil at the characteristic wavelength. Combined with genetic algorithm (GA) and support vector machine algorithm (SVM), different grade classification models for camellia seed oil were developed using full wavelengths (GA-SVM), characteristic wavelengths (CARS-GA-SVM), and fusing spectral and image features (CARS-GLCM-GA-SVM). The results show that the CARS-GLCM-GA-SVM model, which combined spectral and image information, had the best classification effect, and the accuracy of the calibration set and prediction set of the CARS-GLCM-GA-SVM model were 98.30% and 96.61%, respectively. Compared with the CARS-GA-SVM model, the accuracy of the calibration set and prediction set were improved by 10.75% and 12.04%, respectively. Compared with the GA-SVM model, the accuracy of the calibration set and prediction set were improved by 18.28% and 18.15%, respectively. The research showed that hyperspectral imaging technology can rapidly classify camellia seed oil grades.

Background: Prostate cancer (PCa) is one of the leading causes of cancer death in men. About 30% of PCa will develop a biochemical recurrence (BCR) following initial treatment, which significantly contributes to prostate cancer-related deaths. In clinical practice, accurate prediction of PCa recurrence is crucial for making informed treatment decisions. However, the development of reliable models and biomarkers for predicting PCa recurrence remains a challenge. In this study, the aim is to establish an effective and reliable tool for predicting the recurrence of PCa. Methods: We systematically screened and analyzed potential datasets to predict PCa recurrence. Through quality control analysis, low-quality datasets were removed. Using meta-analysis, differential expression analysis, and feature selection, we identified key genes associated with recurrence. We also evaluated 22 previously published signatures for PCa recurrence prediction. To assess prediction performance, we employed nine machine learning algorithms. We compared the predictive capabilities of models constructed using clinical variables, expression data, and their combinations. Subsequently, we implemented these machine learning models into a user-friendly web server freely accessible to all researchers. Results: Based on transcriptomic data derived from eight multicenter studies consisting of 733 PCa patients, we screened 23 highly influential genes for predicting prostate cancer recurrence. These genes were used to construct the Prostate Cancer Recurrence Prediction Signature (PCRPS). By comparing with 22 published signatures and four important clinicopathological features, the PCRPS exhibited a robust and significantly improved predictive capability. Among the tested algorithms, Random Forest demonstrated the highest AUC value of 0.72 in predicting PCa recurrence in the testing dataset. To facilitate access and usage of these machine learning models by all researchers and clinicians, we also developed an online web server (https://urology1926.shinyapps.io/PCRPS/) where the PCRPS model can be freely utilized. The tool can also be used to (1) predict the PCa recurrence by clinical information or expression data with high accuracy. (2) provide the possibility of PCa recurrence by nine machine learning algorithms. Furthermore, using the PCRPS scores, we predicted the sensitivity of 22 drugs from GDSC2 and 95 drugs from CTRP2 to the samples. These predictions provide valuable insights into potential drug sensitivities related to the PCRPS score groups. Conclusion: Overall, our study provides an attractive tool to further guide the clinical management and individualized treatment for PCa.

Summary: Tumor-derived small extracellular vesicles (TEVs) play a pivotal role in cancer progression by transferring functional biomolecules between the parental and recipient cells. Here, we present a protocol to isolate TEVs directly from murine primary mammary tumor using differential centrifugation. We describe steps for tissue dissociation, enzymatic digestion, and centrifugation. We then detail procedures for characterization of TEVs through transmission electron microscopy, immunoblotting, and nano-flow cytometry. This protocol can be used to extract EVs from other solid tumor types.For complete details on the use and execution of this protocol, please refer to Li, Mei-Xin et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Background The combination of immune-checkpoint inhibitors and antiangiogenic agents can synergistically modulate the tumor microenvironment and represents a promising treatment option. Here, we evaluated the efficacy and safety of camrelizumab plus famitinib (a receptor tyrosine kinase inhibitor) as a first-line treatment for advanced or metastatic NSCLC patients with a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥1%, in an open-label, multicenter, phase 2 basket trial.Methods Eligible patients received camrelizumab (200 mg once every 3 weeks via intravenous infusion) plus oral famitinib at an initial dose of 20 mg once daily. The primary endpoint was the objective response rate (ORR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors V.1.1. Key secondary endpoints included disease control rate (DCR), duration of respons, progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety profile.Results Of the enrolled 41 patients, 21 (51.2%) had a PD-L1 TPS of 1–49%. As of the cut-off date on June 22, 2022, the combination regimen of camrelizumab and famitinib achieved an ORR of 53.7% (95% CI 37.4% to 69.3%) and a DCR of 92.7% (95% CI 80.1% to 98.5%). The median PFS was 16.6 months (95% CI 8.3 to not reached), and OS data were not yet mature, with an estimated 12-month OS rate of 76.8% (95% CI 60.0% to 87.3%). The most common treatment-related adverse events of grade 3 or higher included hypertension (22.0%), increased alanine aminotransferase (12.2%), decreased neutrophil count (9.8%), proteinuria (7.3%), decrease platelet count (7.3%), and hypokalemia (7.3%). One (2.4%) patient died from grade 5 hemoptysis, which was considered possibly related to the study treatment by the investigator.Conclusion Camrelizumab plus famitinib demonstrated promising antitumor activity in advanced or metastatic NSCLC patients and had an acceptable safety profile. These findings suggest that this combination regimen could be an alternative therapeutic option and warrant further investigation.Trial registration number NCT04346381.

Background: Application of individualized positive end-expiratory pressure (PEEP) based on minimum driving pressure facilitates to prevent from postoperative pulmonary complications (PPCs). Whether lung protective ventilation strategy can reduce the risk of PPCs in COVID-19 patients remains unclear. In this study, we compared the effects of driving pressure-guided ventilation with conventional mechanical ventilation on PPCs in patients with COVID-19. Methods: Patients infected COVID-19 within 30-day before surgery were retrospectively enrolled consecutively. Patients were divided into two group: driving pressure-guided lung protective ventilation strategy group (LPVS group) and conventional mechanical ventilation group (Control group). Propensity score matching for variables selected was used by logistic regression with the nearest-neighbor method. The outcomes were the incidence of PPCs and hypoxemia in post-anesthesia care unit. Results: There was no significant difference in the baseline data between both groups (P > 0.05). The incidence of PPCs (12.73 % vs 36.36 %, χ2 = 7.068, P = 0.008) and hypoxemia [18.18 % vs 38.18 %, χ2 = 4.492, P = 0.034], and lung ultrasound scores [4.68 ± 1.60 vs 8.39 ± 1.87, t = 8.383, P

Abstract Genomic abnormalities are strongly associated with cancer and infertility. In this study, we develop a simple and efficient method — multiple genetic abnormality sequencing (MGA-Seq) — to simultaneously detect structural variation, copy number variation, single-nucleotide polymorphism, homogeneously staining regions, and extrachromosomal DNA (ecDNA) from a single tube. MGA-Seq directly sequences proximity-ligated genomic fragments, yielding a dataset with concurrent genome three-dimensional and whole-genome sequencing information, enabling approximate localization of genomic structural variations and facilitating breakpoint identification. Additionally, by utilizing MGA-Seq, we map focal amplification and oncogene coamplification, thus facilitating the exploration of ecDNA’s transcriptional regulatory function.

ABSTRACTThe unprecedented urbanization in China has dramatically changed the urban spatial structure of cities. With the proliferation of individual-level geospatial big data, previous studies have widely used the network abstraction model to reveal the underlying urban spatial structure. However, the construction of network abstraction models primarily focuses on the topology of the road network without considering individual travel flows along with the road networks. Individual travel flows reflect the urban dynamics, which can further help understand the underlying spatial structure. This study therefore aims to reveal the intra-urban hierarchical spatial structure by integrating the road network abstraction model and individual travel flows. To achieve this goal, we 1) quantify the spatial interaction relatedness of road segments based on the Word2Vec model using large volumes of taxi trip data, then 2) characterize the road abstraction network model according to the identified spatial interaction relatedness, and 3) implement a community detection algorithm to reveal sub-regions of a city. Our results reveal three levels of hierarchical spatial structures in the Wuhan metropolitan area. This study provides a data-driven approach to the investigation of urban spatial structure via identifying traffic interaction patterns on the road network, offering insights to urban planning practice and transportation management.