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Abstract Layered bismuth (Bi) has been focused on two Peierls distortion derivatives, i.e., bulk stable β-phase (A7 phase), black phosphorus-like α-phase (A17 phase), and their mutated structures. Metastable structures beyond Peierls distortion system are yet rarely accessible. Here, Bi in square symmetry ( $${C}_{4v}$$ C 4 v ), called s-Bi, was grown via physical vapor deposition. The co-existence of three 120°-associated s-Bi crystal grains was analyzed using transmission electron microscopy. 120°-oriented one-dimensional (1D) nuclei indicate s-Bi heteroepitaxy on six-fold symmetric ( $${C}_{6v}$$ C 6 v ) mica (001). A subsequent nanorod-like nuclei coalescing could promote a morphology evolution, resulting in triangular or hexagonal nanosheets with the unique triple s-Bi structure suitable for later β-Bi growth. Lattice misfit and strain calculations suggest a supercell match between $$4\times 7$$ 4 × 7 s-Bi and $$3\times 3$$ 3 × 3 mica (001). This work demonstrates the metastable s-Bi structure via anisotropic heteroepitaxy of $${C}_{4v}$$ C 4 v s-Bi on $${C}_{6v}$$ C 6 v mica.

Abstract Background Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive oral cancer with a poor prognosis. Its polygenic risk is likely influenced by complex transcriptional disorders involving networks of co-expressed and functionally related genes, though such investigations are limited in OSCC. Methods We analyzed the GSE37991 dataset, comprising 40 OSCC and 40 normal oral tissue samples from the Gene Expression Omnibus. Tumor-specific modules were identified using weighted correlation network analysis (WGCNA), leading to the selection of hub mRNAs and lncRNAs. These lncRNAs were used to construct lncRNA–mRNA and competing endogenous RNA networks. We further examined the expression profiles and survival data of these genes from the Cancer Genome Atlas. Prognostic markers were identified and validated through 5-year survival analysis and Cox proportional hazards modeling. RT-qPCR was used to validate the expression levels in clinical OSCC tissues. Results We identified 1847 differentially expressed genes in OSCC tissues. WGCNA revealed four OSCC-specific modules, screening 120 hub mRNAs and five hub lncRNAs. Two prognostic markers (AQP5, IL-26) from hub mRNAs and three (FRMD5, INHBB, GUCY1A3) from the lncRNA–mRNA network were associated with survival. Validation showed lower expression of AQP5 and GUCY1A3, and higher expression of FRMD5 and INHBB in OSCC compared to normal tissues. Conclusion This study enhances our understanding of transcriptional dysregulation in OSCC and may highlights AQP5, IL-26, FRMD5, INHBB, and GUCY1A3 as promising prognostic biomarkers.

Abstract Arterial endothelial cells (AECs) are the founder cells for intraembryonic haematopoiesis. Here, we report a method for the efficient generation of human haemogenic DLL4+ AECs from pluripotent stem cells (PSC). Time-series single-cell RNA-sequencing reveals the dynamic evolution of haematopoiesis and lymphopoiesis, generating cell types with counterparts present in early human embryos, including stages marked by the pre-haematopoietic stem cell genes MECOM/EVI1, MLLT3 and SPINK2. DLL4+ AECs robustly support lymphoid differentiation, without the requirement for exogenous NOTCH ligands. Using this system, we find IL7 acts as a morphogenic factor determining the fate choice between the T and innate lymphoid lineages and also plays a role in regulating the relative expression level of RAG1. Moreover, we document a developmental pathway by which human RAG1+ lymphoid precursors give rise to the natural killer cell lineage. Our study describes an efficient method for producing lymphoid progenitors, providing insights into their endothelial and haematopoietic ontogeny, and establishing a platform to investigate the development of the human blood system.

Abstract P2X receptors, a subfamily of ligand-gated ion channels activated by extracellular ATP, are implicated in various physiopathological processes, including inflammation, pain perception, and immune and respiratory regulations. Structural determinations using crystallography and cryo-EM have revealed that the extracellular three-dimensional architectures of different P2X subtypes across various species are remarkably identical, greatly advancing our understanding of P2X activation mechanisms. However, structural studies yield paradoxical architectures of the intracellular domain (ICD) of different subtypes (e.g., P2X3 and P2X7) at the apo state, and the role of the ICD in P2X functional regulation remains unclear. Here, we propose that the P2X3 receptor’s ICD has an apo state conformation similar to the open state but with a less tense architecture, containing allosteric sites that influence P2X3’s physiological and pathological roles. Using covalent occupancy, engineered disulfide bonds and voltage-clamp fluorometry, we suggested that the ICD can undergo coordinated motions with the transmembrane domain of P2X3, thereby facilitating channel activation. Additionally, we identified a novel P2X3 enhancer, PSFL77, and uncovered its potential allosteric site located in the 1α3β domain of the ICD. PSFL77 modulated pain perception in P2rx3 +/+, but not in P2rx3 −/−, mice, indicating that the 1α3β, a “tunable” region implicated in the regulation of P2X3 functions. Thus, when P2X3 is in its apo state, its ICD architecture is fairly ordered rather than an unstructured outward folding, enabling allosteric modulation of the signaling of P2X3 receptors.

Abstract Converting solar energy into fuels is pursued as an attractive route to reduce dependence on fossil fuel. In this context, photothermal catalysis is a very promising approach through converting photons into heat to drive catalytic reactions. There are mainly three key factors that govern the photothermal catalysis performance: maximized solar absorption, minimized thermal emission and excellent catalytic property of catalyst. However, the previous research has focused on improving solar absorption and catalytic performance of catalyst, largely neglected the optimization of thermal emission. Here, we demonstrate an optically selective catalyst based Ti3C2Tx Janus design, that enables minimized thermal emission, maximized solar absorption and good catalytic activity simultaneously, thereby achieving excellent photothermal catalytic performance. When applied to Sabatier reaction and reverse water-gas shift (RWGS) as demonstrations, we obtain an approximately 300% increase in catalytic yield through reducing the thermal emission of catalyst by ~70% under the same irradiation intensity. It is worth noting that the CO2 methanation yield reaches 3317.2 mmol gRu −1 h−1 at light power of 2 W cm−2, setting a performance record among catalysts without active supports. We expect that this design opens up a new pathway for the development of high-performance photothermal catalysts.

Abstract In this work we discuss the neutrino mass dependent nuclear matrix element (NME) of the neutrinoless double beta decay process and derive the limit on the parameter space of the minimal Type-I seesaw model from the current available experimental data as well as the future sensitivities from the next-generation experiments. Both the explicit many-body calculations and naive extrapolations of the mass dependent NME are employed in the current work. The uncertainties of the theoretical nuclear structure models are taken into account. By combining the latest experimental data from 76Ge-based experiments, GERDA and MAJORANA, the 130Te-based experiment, CUORE and the 136Xe-based experiments, KamLAND-Zen and EXO-200, the bounds on the parameter space of the minimal Type-I seesaw model are obtained and compared with the limits from other experimental probes. Sensitivities for future experiments utilizing 76Ge-based (LEGEND-1000), 82Se-based (SuperNEMO), 130Te based (SNO+II) and 136Xe-based (nEXO), with a ten-year exposure, are also derived.

Abstract Background A better understanding of the association between chronic kidney disease (CKD) and glaucoma is required to optimize clinical outcomes. Therefore, this study aimed to investigate the association of chronic kidney disease (CKD) with new diagnoses of glaucoma over time from January 2009 to December 2019. Method This retrospective propensity-matched cohort study utilizing Taiwanese electronic health records examined the incidence of newly diagnosed glaucoma in patients with and without chronic kidney disease (CKD). The exposure variable was the diagnosis of CKD, identified through diagnostic codes. The primary outcome was the incidence of new-onset glaucoma. Subgroup analyses on glaucoma risk included age, gender, comorbidities, glaucoma subtypes, and dialysis status. Statistical analyses included Kaplan–Meier analysis, Cox proportional hazards models, and Poisson regression models, with the associated hazard ratios and confidence intervals reported. Results Seven hundred twenty-three thousand two hundred sixteen patients with CKD (42.3% female; mean [SD] age at index, 66.3 [15.6] years) and 723,216 patients without CKD (42.3% female; mean [SD] age at index, 66.3 [15.7]) were recruited. We showed a significantly increased risk of glaucoma irrespective of subtypes in CKD patients compared to those without CKD (HR: 1.29 [CI: 1.26–1.32], p 80: aHR 1.29 [CI: 1.21–1.37]); all income brackets and all urbanization status were associated with significantly increased risk of glaucoma from among the CKD cohort when compared to their respective non-CKD cohort (p

Abstract Background Obesity is well-established as a significant contributor to the development of insulin resistance (IR) and diabetes, partially due to elevated plasma saturated free fatty acids like palmitic acid (PA). Grb10-interacting GYF Protein 2 (GIGYF2), an RNA-binding protein, is widely expressed in various tissues including the liver, and has been implicated in diabetes-induced cognitive impairment. Whereas, its role in obesity-related IR remains uninvestigated. Methods In this study, we employed palmitic acid (PA) exposure to establish an in vitro IR model in the human liver cancer cell line HepG2 with high-dose chronic PA treatment. The cells were stained with fluorescent dye 2-NBDG to evaluate cell glucose uptake. The mRNA expression levels of genes were determined by real-time qRT-PCR (RT-qPCR). Western blotting was employed to examine the protein expression levels. The RNA immunoprecipitation (RIP) was used to investigate the binding between protein and mRNA. Lentivirus-mediated gene knockdown and overexpression were employed for gene manipulation. In mice, an IR model induced by a high-fat diet (HFD) was established to validate the role and action mechanisms of GIGYF2 in the modulation of HFD-induced IR in vivo. Results In hepatocytes, high levels of PA exposure strongly trigger the occurrence of hepatic IR evidenced by reduced glucose uptake and elevated extracellular glucose content, which is remarkably accompanied by up-regulation of GIGYF2. Silencing GIGYF2 ameliorated PA-induced IR and enhanced glucose uptake. Conversely, GIGYF2 overexpression promoted IR, PTEN upregulation, and AKT inactivation. Additionally, PA-induced hepatic IR caused a notable increase in STAU1, which was prevented by depleting GIGYF2. Notably, silencing STAU1 prevented GIGYF2-induced PTEN upregulation, PI3K/AKT pathway inactivation, and IR. STAU1 was found to stabilize PTEN mRNA by binding to its 3’UTR. In liver cells, tocopherol treatment inhibits GIGYF2 expression and mitigates PA-induced IR. In the in vivo mice model, GIGYF2 knockdown and tocopherol administration alleviate high-fat diet (HFD)-induced glucose intolerance and IR, along with the suppression of STAU1/PTEN and restoration of PI3K/AKT signaling. Conclusions Our study discloses that GIGYF2 mediates obesity-related IR by disrupting the PI3K/AKT signaling axis through the up-regulation of STAU1/PTEN. Targeting GIGYF2 may offer a potential strategy for treating obesity-related metabolic diseases, including type 2 diabetes. Graphical Abstract

Abstract Delivering synthetic protein-coding RNA bypassing the DNA stage for ectopic protein functioning is a novel therapeutic strategy. Joining the linear RNA head-to-tail covalently could be a state-of-the-art strategy for functioning longer. Here we enroll a cis-acting ligase ribozyme (RzL) to generate circular RNA (circRNA) in vitro for ectopic protein expression. The RNA circularization is confirmed by masking the 5’ phosphate group, resisting exonuclease RNase R digestion, failing for further tailing, and sequencing the RT-PCR products of the joined region. Interestingly, one internal ribosome entry site (IRES) renders circRNA translation competent, but two IRES in cis, not trans, hamper the translation. The circRNA with highly potent in translation is conferred for antiviral functioning. Accompanying specific guided RNA, a circRNA expressing ribonuclease Cas13 shows excellent potential against the corresponding RNA virus, further extending circRNA functioning in its growing list of applications.

Increasing the proportion of bainite and martensite phases is one of the effective ways to enhance the toughness of medium-carbon low-alloy steel(42CrMo). In this paper, the surface heat treatment of 42CrMo steel is carried out by using a laser heat source to achieve complete austenitization, then with electromagnetic induction heating for several times to implement insulation, and eventually to promote bainite phase transformation. In conjunction with the temperature history curves, OM, SEM, and EBSD are used to characterize the bainite morphology and percentage of bainite via different parameters of the hybrid process. The results demonstrate that the hybrid process combined with twice electromagnetic induction heating can yield a considerable proportion of bainite phase in 42CrMo steel. The resulting duplex structure, consisting of bainite and a minor fraction of martensite, exhibits a significant increase (81.1%) in tensile strength, while maintaining similar impact toughness. The elongation after fracture only has a slight reduction of 5.5% compared to that of the substrate. This innovative process provides a practical alternative to traditional bainite isothermal treatment method which must perform in a heat treatment furnace. Therefore, it is presented as a promising solution for enhancing the mechanical properties of medium-carbon low-alloy high strength steels.

Microplastics are contaminants in marine ecosystems, posing great threats to biota and human health. In this work, we provide an overview of the progress made in understanding microplastic prevalence in tropical coastal environments, focusing on the Johor and the Singapore Straits as a case study. We examine the sources, distribution, transport, and ecological impact of microplastic pollution in this region through a systematic review. All papers relating to marine microplastics in Singapore’s sand and benthic sediments, seawater, and marine biota were used for analysis, from 2004 to 2023. In addition, we discuss the influence of envi-ronmental factors such as coastal morphology and anthropogenic activities on patterns of microplastic accumulation. We emphasize that microplastic pollution is more prevalent along the eutrophic Johor Strait compared to the Singapore Strait due to hydrological conditions. Rainfall is also a key factor that influences mi-croplastic abundance during the monsoon seasons. Furthermore, the bacterial and plankton assemblages of organisms on microplastic surfaces are diverse, with eutrophic waters enhancing the diversity of organisms on microplastic surfaces. Novel harmful cyanobacteria and bloom species of phytoplankton were also found on microplastic surfaces. By synthesizing existing research findings and highlighting regional characteristics, this paper contributes to ongoing efforts to mitigate microplastic pollution in tropical regions.

Abstract Background An impaired ocular surface presents substantial challenges in terms of planning for cataract surgery. As a multifactorial ocular disorder, dry eye disease (DED) is common in the general population and prevalent in patients scheduled for lens replacement surgery. Cataract surgery can exacerbate DED and worsen several ocular parameters. Timely diagnosis and appropriate treatment of DED are vital to ensuring positive ophthalmic surgical outcomes. This consensus report of the Taiwan Society of Cataract and Refractive Surgeons (TSCRS) regarding the management of DED before, during, and after cataract surgery highlights the gaps between clinical guidelines and several aspects of DED, including diagnostic testing, diagnostic criteria, and clinical practice treatment. Methods An expert panel of five specialists in the field of ophthalmology was recruited to develop consensus statements regarding the management of DED in both the general population and in patients undergoing cataract surgery in Taiwan. Two separate meetings of the five specialists, who were endorsed by the TSCRS, were convened for this purpose. A survey questionnaire consisting of binary or multiple-choice questions was developed through a consensus-driven formulation process. A percentage value was calculated for each statement, and a minimum of 60% agreement (equivalent to three out of five members) was required to achieve consensus. The second discussion meeting involved the presentation of the finalized consensus statements and concluded the consensus development process. Lastly, the finalized consensus statements were approved by all the experts, and the formulated recommendations for DED in the general population and prospective cataract surgery patients were accordingly presented. Results The optimal algorithm for managing DED in the general population and in patients scheduled for cataract surgery was developed to address the unmet needs of this cohort in Taiwan. Conclusion This report provides recommendations for managing dry eye disease. It is essential to screen and confirm DED through endorsed questionnaires and tests and then diagnose it. Treatment and management of DED should follow a stepwise approach. Screening and diagnosing DED is also recommended before cataract surgery. After cataract surgery, relatively aggressive treatment strategies are recommended to manage DED effectively.

Unique challenges have been elicited by climate change, demanding the utilisation of effective adaptation strategies that are both environmentally and economically sustainable. Regrettably, the agricultural sector has not been spared from the effects of climate change, but it is among the largest employers and the primary source of food security globally. The situation is worse in Pakistan, where poverty, hunger, and malnutrition are reported to be prevalent. The complexity of risks posed by climate change has called for climate-smart agriculture (CSA) technologies, which potentially could augment cost efficiency and yield in wheat production. Surprisingly, previous studies have largely overlooked this crucial aspect. Therefore, our research seeks to address two fundamental questions: What is the comparative cost efficiency between adopters and non-adopters of CSA practices in wheat production? And what are the yield effects associated with CSA adoption, particularly compared to non-adopters? To this end, a multi-stage sampling technique was employed to randomly select 400 farm households in a climate risk hotspot province in Pakistan, on which the stochastic frontier analysis (SFA) and endogenous switching regression (ESR) were applied. The results revealed that CSA adoption was associated with improved cost efficiency and yield. Interestingly, if non-adopters decided to adopt CSA, they would increase their wheat yield by about 20%. Given the importance of wheat for food security, this would contribute to poverty and hunger eradication. Therefore, our study conforms to the aspirations of the 2030 agenda by promoting rethinking food production through possible improvement in cost efficiency and yield in the face of a changing climate.

Abstract Corneal transplantation can restore visual function when visual impairment is caused by a corneal disease. However, this treatment is associated with the scarcity of cornea donors. The suitability of corneal donation from patients with glaucoma using ocular hypotensive agents (OHAs) is controversial. This study aimed to elucidate changes in corneal thickness, corneal endothelial cell density, and corneal endothelial cell hexagonality after OHA use in patients with primary open‐angle glaucoma. We retrospectively reviewed the data of 53 glaucoma suspect eyes without OHA use and 106 primary open‐angle glaucoma eyes under OHA use. All participants underwent corneal parameter assessment using SP‐3000P (Topcon Corp., Tokyo, Japan) at the time of diagnosis and the final visit. The OHA dose and timing of use were recorded. The ocular hypotensive agents score (OHAS) was determined based on the number, formula, frequency, and duration of OHA use. Baseline data showed no significant differences between the two groups with and without OHA use. At the final visit, the OHA‐treated group showed significantly lower corneal thickness and corneal endothelial cell density than those of the control group. A weak positive correlation between the OHAS and changes in corneal endothelial cell hexagonality was noted. However, no correlation was observed between the OHAS and changes in corneal thickness or endothelial cell density. In conclusion, patients with glaucoma and using OHAs should undergo the corneal structural properties examinations before donation to ensure the quality of donor cornea.

Enhancing the economic resilience of agriculture is essential for promoting sustainable and high-quality agricultural development. The emergence of digital technology has created new opportunities in this field. However, existing research predominantly focuses on traditional agricultural factors and technologies. Therefore, the impact of digital technology on agricultural economic resilience within the broader context of the “production–operation–industry” system in agriculture has not been comprehensively explored. To bridge this gap, this study analyzes panel data from 30 Chinese provinces from 2011 to 2020. It employs the static Van Dorn’s law and a dynamic spatial panel model to examine how digital technology empowers agricultural resilience. The findings indicate a continuous strengthening of digital technology development in China, albeit with significant polarization and spatial imbalances. Moreover, the resilience of the agricultural economy undergoes notable fluctuations, initially narrowing and subsequently displaying an upward trend. Digital technology clearly plays a pivotal role in empowering resilience through agricultural scale operation, industrial transformation, and technological progress. Its impact, particularly on the promotion of resilience in the eastern region and non-grain-producing areas and on high-level agricultural economies, also shows regional and technological variations.

Abstract Garnet oxide is one of the most promising solid electrolytes for solid-state lithium metal batteries. However, the traditional interface modification layers cannot completely block electron migrating from the current collector to the interior of the solid-state electrolyte, which promotes the penetration of lithium dendrites. In this work, a highly electron-blocking interlayer composed of potassium fluoride (KF) is deposited on garnet oxide Li6.4La3Zr1.4Ta0.6O12 (LLZTO). After reacting with melted lithium metal, KF in-situ transforms to KF/LiF interlayer, which can block the electron leakage and inhibit lithium dendrite growth. The Li symmetric cells using the interlayer show a long cycle life of ~3000 hours at 0.2 mA cm−2 and over 350 hours at 0.5 mA cm−2 respectively. Moreover, an ionic liquid of LiTFSI in C4mim-TFSI is screened to wet the LLZTO|LiNi0.8Co0.1Mn0.1O2 (NCM) positive electrode interfaces. The Li|KF-LLZTO | NCM cells present a specific capacity of 109.3 mAh g−1, long lifespan of 3500 cycles and capacity retention of 72.5% at 25 °C and 2 C (380 mA g−1) with an average coulombic efficiency of 99.99%. This work provides a simple and integrated strategy on high-performance quasi-solid-state lithium metal batteries.

[Introduction] Fusion energy has the characteristics of large energy released through reactions, safe and reliable operation, abundant fuel sources, and low environmental pollution. Therefore, it is expected to become a commercial energy source that can be supplied in the market on a large scale, providing stable energy output and power supply in the future. To popularize the development path of magnetic confined fusion energy in China, the article reviews the discovery and realization path of fusion energy. [Method] The article provided an overview of the early research and development process of magnetic confined fusion energy in China by the method of literature review. The paper took the development of magnetic confined fusion energy as an example to provide a preliminary overview of the construction of typical research devices in China, such as tokamak, stellarator, spherical tokamak, reversed field pinch, magnetic mirror field, linear plasma, and dipole magnetic field devices. [Result] Based on the construction and researches of these devices, China has cultivated a group of scientific and technological talents in the field of magnetic confined fusion research, achieving significant progress. In addition, the article provides an overview of international cooperation in fusion energy research, as well as the International Thermonuclear Experimental Reactor (ITER) project that China is participating in construction. [Conclusion] Although the current research on fusion energy still needs to overcome significant challenges from various aspects, such as fusion plasma physics, fusion reactor materials, and tritium self-sustaining technology, it is believed that the magnetic confined fusion energy in China will turn from a blueprint into a reality in the future thanks to the urgent need for energy structure transformation and the strong support for fusion researches in China.

Abstract Background The aim of this study was to assess the outcomes of the combination technique of strip free gingival grafts (SFGG) and xenogeneic collagen matrix (XCM) in augmenting the width of keratinized mucosa (KMW) around dental implants, and compare its efficacy with the historical control group (FGG). Methods Thirteen patients with at least one site with KMW ≤ 2 mm after implant surgery were included and received SFGG in combination with XCM. Another thirteen patients with the same inclusion and exclusion criteria from the previous trial received FGG alone. The same outcomes as the previous trial were evaluated. KMW, thickness of keratinized mucosa (KMT), gingival index (GI) and probing depth (PD) were measured at baseline, 2 and 6 months. Postoperative pain, patient satisfaction and aesthetic outcomes were also assessed. Results At 6 months after surgery, the combination technique could attain 3.3 ± 1.6 mm of KMW. No significant change could be detected in GI or PD at 6 months compared to those at 2 months (p > 0.05). The postoperative pain and patient satisfaction in VAS were 2.6 ± 1.2 and 9.5 ± 1.2. The total score of aesthetic outcomes was 3.8 ± 1.2. In the historical FGG group, 4.6 ± 1.6 mm of KMW was reported at 6 months, and the total score of aesthetic outcomes was higher than the combination technique (4.8 ± 0.7 vs. 3.8 ± 1.2, p

Background: The clinical presentations of abusive head trauma can abruptly worsen, so the occurrence of seizures and changes of EEG can be variable according to patients’ conditions. Since the changes of EEG background waves reflect the cortical function of children, we aimed to find out whether the timing of EEG background, epileptiform discharges and seizure patterns were associated with the outcomes of patients with AHT. Material and methods: Using seizure type and acute stage electroencephalographic (EEG) characteristics to assess adverse neurological outcomes in children with seizures secondary to abusive head trauma (AHT). Children who were hospitalized with AHT at a tertiary referral hospital from October 2000 to April 2010 were evaluated retrospectively. A total of 50 children below 6 years of age admitted due to AHT were included. KOSCHI outcome scale was used to evaluate the primary outcome and neurological impairment was used as secondary outcome after 6 months discharge. Results: Children with apnea, cardiac arrest, reverse blood flow and skull fracture in clinic had a higher mortality rate even in the no-seizure group (3/5 [60%] vs. 3/45 [6.7%], odds ratio [OR] = 11; 95% CI = 2.3–52; p = 0.025). Seizure occurrence reduced mostly at the second day after admission in seizure groups; but children with persistent seizures for 1 week showed poor neurological outcomes. The occurrence of initial seizure was frequency associated with younger age; focal seizure, diffuse cortical dysfunction in acute-stage EEG, and low Glasgow Coma Scale (GCS) score were significantly related to poor outcomes after 6 months. Diffuse cortical dysfunction was also associated with motor, speech, and cognitive dysfunction. Conclusions: Diffuse cortical dysfunction in acute-stage EEG combined with low GCS score and focal seizure may related to poor outcomes and neurological dysfunctions in children with AHT.

Abstract Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs. Methods We established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment. Results Betulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts. Conclusions BA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers. Graphical abstract

Abstract In the built heritage studies, the intricate web of social and selective processes that define heritage is evident. These processes are, in many cases, intertwined with the notion of scale, examplified through the production of heritage sites at the local, national, and transnational scales. While heritage and geography scholars have articulated the role played by scale in heritage-making and argue against a rigid, fixed, and hierarchical understanding of scale, they highlight the constant reproduction of scale. There is, so far, limited explanation of how the perception of scale gets reproduced and how crucial actors manipulate scalar power and resources for heritage making and the reproduction of scale. To fill this gap, this paper delves into mainland China’s heritage-making, using the southern Anhui historical villages as an example. Based on intensive 5-month field research, this paper has three findings: 1) The nomination process for a World Heritage Site is notably influenced by politics and selectivity; 2) Diverse stakeholders are pivotal in shaping heritage narratives; 3) Individual contributions to heritage creation directly interact with, and subsequently reshape, ‘scale’, an entity that is simultaneously discursive and tangible. By integrating the notion of ‘scale’ into heritage discussions, we illuminate two concurrent processes: creating hierarchies through rule assimilation by interpreting the UNESCO standard internally and evolving socio-spatial dynamics via the manifestation of individual agency with resource manipulation, scale jumping, and reproduction of scale. This approach aligns with the material orientation in human geography and repositions ‘scale’. Here, it’s not just an epistemological framework but also a tangible force that steers individual perceptions and actions and yields measurable material impacts.

Abstract Pulse shape discrimination (PSD) is widely used in particle and nuclear physics. Specifically in liquid scintillator detectors, PSD facilitates the classification of different particle types based on their energy deposition patterns. This technique is particularly valuable for studies of the diffuse supernova neutrino background (DSNB), nucleon decay, and dark matter searches. This paper presents a detailed investigation of the PSD technique, applied in the DSNB search performed with the Jiangmen Underground Neutrino Observatory (JUNO). Instead of using conventional cut-and-count methods, we employ methods based on boosted decision trees and neural networks and compare their capability to distinguish the DSNB signals from the atmospheric neutrino neutral-current background events. The two methods demonstrate comparable performance, resulting in a 50–80% improvement in signal efficiency compared to a previous study performed for JUNO (An et al. [JUNO] in J Phys G 43(3):030401, 2016). Moreover, we study the dependence of the PSD performance on the visible energy and final state composition of the events and find a significant dependence on the presence/absence of $$^{11}$$ 11 C. Finally, we evaluate the impact of the detector effects (photon propagation, PMT dark noise, and waveform reconstruction) on the PSD performance.