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Abstract Background L-DOPA has been considered the first-line therapy for treating Parkinson’s disease (PD) via restoring striatal dopamine (DA) to normalize the activity of local spiny projection neurons (SPNs) in the direct (dSPNs) pathway and the indirect (iSPNs) pathway. While the changes in striatal acetylcholine (ACh) induced by increasing DA have been extensively discussed, their validity remains controversial. Inhibition of striatal cholinergic signaling attenuates PD motor deficits. Interestingly, enhancing striatal ACh triggers local DA release, suggesting the pro-kinetic effects of ACh in movement control. Here, we investigated the in-vivo dynamics of ACh in the dorsolateral striatum (DLS) of the 6-OHDA-lesioned mouse model after L-DOPA administration, as well as its underlying mechanism, and to explore its modulatory role and mechanism in parkinsonian symptoms. Results Using in vivo fiber photometry recordings with genetically encoded fluorescent DA or ACh indicator, we found L-DOPA selectively decreased DLS ACh levels in parkinsonian conditions. DA inhibited ACh release via dopamine D2 receptors and dSPNs-mediated activation of type-A γ-aminobutyric acid receptors on cholinergic interneurons. Restoring DLS ACh levels during L-DOPA treatment induced additional DA release by activating nicotinic acetylcholine receptors, thereby promoting the activity of dSPNs and iSPNs. Enhancing DLS ACh facilitated L-DOPA-induced turning behavior but not dyskinesia in parkinsonian mice. Conclusions Our results demonstrated that enhancing striatal ACh facilitated the effect of L-DOPA by modulating DA tone. It may challenge the classical hypothesis of a purely competitive interaction between dopaminergic and cholinergic neuromodulation in improving PD motor deficits. Modulating ACh levels within the dopaminergic system may improve striatal DA availability in PD patients.

When constructing some buildings on the surface of mine goaf, the additional foundation stress may cause the activation of the stable structure in goaf, and in turn the residual movement and deformation of surface may affect the safety of buildings. In view of the few and imperfect models for calculating the additional stress and the depth of load effect on thin topsoil layer area, it is necessary to further investigate the additional stress transfer model of double layer elastic medium foundation from the perspective of simple calculation process, fewer parameters and easy access. Firstly, the foundation of thin topsoil area is regarded as the upper layer with thin thickness and weak mechanical strength, and the lower layer is the rock layer with larger thickness and high mechanical strength. Secondly, based on the Boussinesp elastic solution, it is assumed that each layer of the double-layered foundation is a transversely isotropic elastomer and there is no change of kinetic energy during the propagation of additional stress in the foundation. Thirdly, based on the conservation of elastic strain energy and the balance condition of vertical additional stress between the micro cell topsoil layer and bedrock layer on the interface of rock and soil layer, the balance equation is established, and each component of the balance equation is solved and simplified in its integral domain with help of Matlab. The equation for solving the additional stress under the center point of foundation with rectangular uniform load and circular uniform load in thin surface soil layer is derived. Then, according to the stability analysis method of goaf under the influence of additional stress of building foundation, an analysis software of the influence of proposed construction project on the stability of goaf is written using the C# language, which realizes the scientific and efficient calculation of the additional stress of foundation and the stability evaluation of goaf. The model for solving additional stress of double layer medium foundation is verified and the calculation results are compared with those of the widely used homogeneous medium model. Finally, the effect of parameters E1, μ1 and E2, μ2 on additional stress and depth of foundation are analyzed. Results show that the additional stress transfer model of double layer medium foundation with thin topsoil area is simple to be solved and can be used to guide the comprehensive utilization of mining subsidence area. For the coal mining subsidence area with thin topsoil layer, the vertical additional stress of foundation attenuates to a certain extent in the process of propagation in topsoil layer. Compared with homogeneous medium, the depth of additional stress on the foundation of double layer medium decreases by 5.3%−10.3%. The higher ratio of elastic modulus E2/E1 between bedrock and topsoil layer is, the more obvious attenuation of additional stress along the depth direction in bedrock is, and the smaller transfer depth is. Additional stress is less sensitive to the Poisson's ratio of topsoil and bedrock, but the smaller μ1/μ2 ratio, the smaller additional stress and the smaller the transfer depth in bedrock.

Abstract GH 3230 superalloy is a solution strengthening nickel-based superalloy and it is commonly used for fabricating hot components with the service temperature of above 900 ℃. In order to further improve high-temperature performance, nickel-based alloy matrix composites (NMCs) were proposed. Meanwhile, it is known that laser additive manufacturing is an optional method for fabricating nickel-based composites. However, the research on ceramic-reinforced GH 3230 fabricated by laser metal deposition (LMD) are highly lacking. The aim of this study is to develop TiC ceramic particle reinforced GH 3230 composites using laser metal deposition (LMD) method and study the effect of TiC content on their microstructure and tensile properties. The results showed that TiC particles not only changed the intensity and position of the X-ray diffraction peaks of the alloy matrix but also had a significant effect on the refinement of the cellular dendrites. Meanwhile, it was found that an interfacial layer with sub-micrometer thickness was formed between the TiC ceramic particle and the superalloy matrix, which was identified to be (W, Ti)C1-x phase by the TEM. In terms of the as-built composites, the ultimate tensile strength (UTS) and yield strength (YS) gradually increased, but elongation (EL) decreased with the increase of TiC content. For the as-LMDed 10 vol.% TiC/GH3230 composites, UTS and EL reached 1077.0 MPa and 12.4%, respectively. The enhancement of the tensile strength for composites was attributed to the combined effect of grain refinement strengthening, Orowan strengthening, dislocation strengthening and loading-bearing strengthening.

Abstract Wireless local area network (WLAN) has gained widespread application as a convenient network access method, demanding higher network efficiency, stability, and responsiveness. High-performance filters are crucial components to meet these needs. Film bulk acoustic resonators (FBARs) are ideal for constructing these filters due to their high-quality factor (Q) and low loss. In conventional air-gap type FBAR, aluminum nitride (AlN) is deposited on the sacrificial layer with poor crystallinity. Additionally, FBARs with single-crystal AlN have high internal stress and complicated fabrication process. These limit the development of FBARs to higher frequencies above 5 GHz. This paper presents the design and fabrication of FBARs and filters for WLAN applications, combining the high electromechanical coupling coefficient ( $${K}_{{\rm{t}}}^{2}$$ K t 2 ) of Al0.8Sc0.2N film with the advantages of the thin film transfer process. An AlN seed layer and 280 nm-thick Al0.8Sc0.2N are deposited on a Si substrate via physical vapor deposition (PVD), achieving a full width at half maximum (FWHM) of 2.1°. The ultra-thin film is then transferred to another Si substrate by wafer bonding, flipping, and Si removal. Integrating conventional manufacturing processes, an FBAR with a resonant frequency reaching 5.5 GHz is fabricated, demonstrating a large effective electromechanical coupling coefficient ( $${{k}}_{{\rm{eff}}}^{2}$$ k eff 2 ) of 13.8% and an excellent figure of merit (FOM) of 85. A lattice-type filter based on these FBARs is then developed for the Wi-Fi UNII-2 band, featuring a center frequency of 5.5 GHz and a −3 dB bandwidth of 306 MHz, supporting high data rates and large throughputs in WLAN applications.

Abstract Abundant residual heat from industrial emissions may provide energy resource for CO2 conversion, which relies on H2 gas and cannot be accomplished at low temperatures. Here, we report an approach to store electrons and hydrogen atoms in catalysts using sunlight and water, which can be released for CO2 reduction in dark at relatively low temperatures (150−300 °C), enabling on-demand CO2 conversion. As a proof of concept, a model catalyst is developed by loading single Cu sites on hexagonal tungsten trioxide (Cu/WO3). Under light illumination, hydrogen atoms are generated through photocatalytic water splitting and stored together with electrons in Cu/WO3, forming a metastable intermediate (Cu/HxWO3). Subsequent activation of Cu/HxWO3 through low-temperature heating releases the stored electrons and hydrogen atoms, reducing CO2 into valuable products. Furthermore, we demonstrate the practical feasibility of utilizing natural sunlight to drive the process, opening an avenue for harnessing intermittent solar energy for CO2 utilization.

Abstract Background Acetate is an important chemical feedstock widely applied in the food, chemical and textile industries. It is now mainly produced from petrochemical materials through chemical processes. Conversion of lignocellulose biomass to acetate by biotechnological pathways is both environmentally beneficial and cost-effective. However, acetate production from carbohydrate in lignocellulose hydrolysate via glycolytic pathways involving pyruvate decarboxylation often suffers from the carbon loss and results in low acetate yield. Results Escherichia coli BL21 (DE3) was confirmed to have high tolerance to acetate in this work. Thus, it was selected from seven laboratory E. coli strains for acetate production from lignocellulose hydrolysate. The byproduct-producing genes frdA, ldhA, and adhE in E. coli BL21 (DE3) were firstly knocked out to decrease the generation of succinate, lactate, and ethanol. Then, the genes pfkA and edd were also deleted and bifunctional phosphoketolase and fructose-1,6-bisphosphatase were overexpressed to construct an EP-bifido pathway in E. coli BL21 (DE3) to increase the generation of acetate from glucose. The obtained strain E. coli 5K/pFF can produce 22.89 g/L acetate from 37.5 g/L glucose with a yield of 0.61 g/g glucose. Finally, the ptsG gene in E. coli 5K/pFF was also deleted to make the engineered strain E. coli 6K/pFF to simultaneously utilize glucose and xylose in lignocellulosic hydrolysates. E. coli 6K/pFF can produce 20.09 g/L acetate from corn stover hydrolysate with a yield of 0.52 g/g sugar. Conclusion The results presented here provide a promising alternative for acetate production with low cost substrate. Besides acetate production, other biotechnological processes might also be developed for other acetyl-CoA derivatives production with lignocellulose hydrolysate through further metabolic engineering of E. coli 6K/pFF.

Abstract Background Whey, which has high biochemical oxygen demand and chemical oxygen demand, is mass-produced as a major by-product of the dairying industry. Microbial fermentation using whey as the carbon source may convert this potential pollutant into value-added products. This study investigated the potential of using whey powder to produce α-ketoisovalerate, an important platform chemical. Results Klebsiella oxytoca VKO-9, an efficient L-valine producing strain belonging to Risk Group 1 organism, was selected for the production of α-ketoisovalerate. The leucine dehydrogenase and branched-chain α-keto acid dehydrogenase, which catalyzed the reductive amination and oxidative decarboxylation of α-ketoisovalerate, respectively, were inactivated to enhance the accumulation of α-ketoisovalerate. The production of α-ketoisovalerate was also improved through overexpressing α-acetolactate synthase responsible for pyruvate polymerization and mutant acetohydroxyacid isomeroreductase related to α-acetolactate reduction. The obtained strain K. oxytoca KIV-7 produced 37.3 g/L of α-ketoisovalerate from lactose, the major utilizable carbohydrate in whey. In addition, K. oxytoca KIV-7 also produced α-ketoisovalerate from whey powder with a concentration of 40.7 g/L and a yield of 0.418 g/g. Conclusion The process introduced in this study enabled efficient α-ketoisovalerate production from low-cost substrate whey powder. Since the key genes for α-ketoisovalerate generation were integrated in genome of K. oxytoca KIV-7 and constitutively expressed, this strain is promising in stable α-ketoisovalerate fermentation and can be used as a chassis strain for α-ketoisovalerate derivatives production.

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by massive neuronal loss in the brain. Both cortical glutamatergic neurons and basal forebrain cholinergic neurons (BFCNs) in the AD brain are selectively vulnerable. The degeneration and dysfunction of these two subtypes of neurons are closely associated with the cognitive decline of AD patients. The determination of cellular and molecular mechanisms involved in AD pathogenesis, especially in the early stage, will largely facilitate the understanding of this disease and the development of proper intervention strategies. However, due to the inaccessibility of living neurons in the brains of patients, it remains unclear how cortical glutamatergic neurons and BFCNs respond to pathological stress in the early stage of AD. In this study, we established in vitro differentiation systems that can efficiently differentiate patient-derived iPSCs into BFCNs. We found that AD-BFCNs secreted less Aβ peptide than cortical glutamatergic neurons did, even though the Aβ42/Aβ40 ratio was comparable to that of cortical glutamatergic neurons. To further mimic the neurotoxic niche in AD brain, we treated iPSC-derived neurons with Aβ42 oligomer (AβO). BFCNs are less sensitive to AβO induced tau phosphorylation and expression than cortical glutamatergic neurons. However, AβO could trigger apoptosis in both AD-cortical glutamatergic neurons and AD-BFCNs. In addition, AD iPSC-derived BFCNs and cortical glutamatergic neurons exhibited distinct electrophysiological firing patterns and elicited different responses to AβO treatment. These observations revealed that subtype-specific neurons display distinct neuropathological changes during the progression of AD, which might help to understand AD pathogenesis at the cellular level.

Abstract Casuarina equisetifolia trees are used as windbreaks in subtropical and tropical coastal zones, while C. equisetifolia windbreak forests can be degraded by seawater atomization (SA) and seawater encroachment (SE). To investigate the mechanisms underlying the response of C. equisetifolia to SA and SE stress, the transcriptome and metabolome of C. equisetifolia seedlings treated with control, SA, and SE treatments were analyzed. We identified 737, 3232, 3138, and 3899 differentially expressed genes (SA and SE for 2 and 24 h), and 46, 66, 62, and 65 differentially accumulated metabolites (SA and SE for 12 and 24 h). The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that SA and SE stress significantly altered the expression of genes related to plant hormone signal transduction, plant–pathogen interaction, and starch and sucrose metabolism pathways. The accumulation of metabolites associated with the biosynthetic pathways of phenylpropanoid and amino acids, as well as starch and sucrose metabolism, and glycolysis/gluconeogenesis were significantly altered in C. equisetifolia subjected to SA and SE stress. In conclusion, C. equisetifolia responds to SA and SE stress by regulating plant hormone signal transduction, plant–pathogen interaction, biosynthesis of phenylpropanoid and amino acids, starch and sucrose metabolism, and glycolysis/gluconeogenesis pathways. Compared with SA stress, C. equisetifolia had a stronger perception and response to SE stress, which required more genes and metabolites to be regulated. This study enhances our understandings of how C. equisetifolia responds to two types of seawater stresses at transcriptional and metabolic levels. It also offers a theoretical framework for effective coastal vegetation management in tropical and subtropical regions.

Abstract Objective Clinical studies have demonstrated the effectiveness of arthrocentesis in managing temporomandibular joint disorders (TMDs). However, there is a lack of consensus among these studies regarding the selection of injectables. Furthermore, an increasing number of drugs have been tested for TMDs in recent years, complicating the decision-making process for clinicians. This study conducted a network meta-analysis of randomized controlled trials (RCTs) to compare the clinical efficacy of different arthrocentesis treatment regimens. Methods We conducted a comprehensive search of Embase, PubMed, Cochrane Library, and Web of Science to gather articles on RCTs pertaining to the management of TMDs using arthrocentesis. This search spanned from inception of these databases up to July 29, 2024. We then performed a network meta-analysis using Stata 17.0 software. The outcome indicators used were VAS scores and changes in unassisted maximum opening. To determine the efficacy of each regimen, we employed surface-under the cumulative ranking curve (SUCRA) ranking. Result Forty RCTs were included, encompassing 1904 temporomandibular joints (TMJs) cases. Treatment options encompass platelet-rich plasma (PRP), hyaluronic acid (HA), corticosteroids (CS), bone marrow concentrate (BMAC), injectable platelet-rich fibrin (i-PRF), concentrated growth factor (CGF), Tenoxicam (TX), microfragmented adipose tissue (FAT), and their combination regimens. The SUCRA ranking revealed that the most effective treatment options at 1-, 3-, and 6-months post-arthrocentesis were HA + PRP, i-PRF, and BMAC, respectively. Conclusion HA + PRP, i-PRF and BMAC may represent the optimal arthrocentesis agents for the management of TMDs symptoms and restoration of TMJ function in the short, medium, and long term, respectively. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD42024563975.

[Introduction] Facing the advancement of the national "carbon peaking and carbon neutrality" strategy, energy in various regions of China will develop towards low-carbon utilization based on its unique resource endowment. In order to understand the development level of low-carbon energy, it is necessary to conduct evaluation research on low-carbon energy utilization. [Method] This paper first analyzed the evaluation objects of energy low-carbon utilization; then classified and organized the evaluation indicators of energy low-carbon utilization. This paper sorted out and introduced the characteristics of each evaluation method and model, and explained the role of energy low-carbon utilization evaluation research. [Result] The evaluation objects of energy low-carbon utilization can be divided into energy system evaluation and regional energy evaluation. The evaluation indicators are summarized from three aspects: energy low-carbon indicators, energy utilization indicators and energy security indicators, and the subjective and objective weighting evaluation methods are rationally used. It is possible to more comprehensively and accurately assess and understand the situation of low-carbon energy utilization. [Conclusion] The current energy low-carbon utilization evaluation is usually only reflected as a part of the evaluation index system. With the development of low-carbon energy and the increase in the proportion of clean energy, the evaluation of low-carbon energy utilization will become more and more important.

BackgroundTo investigate the prognostic factors for stage IIb and IIIa lung adenocarcinoma following radical surgery and to explore the molecular mechanisms underlying these prognostic markers, focusing on the role of PIK3C2G.MethodsA retrospective analysis of patients with stage IIb or IIIa lung adenocarcinoma who underwent radical surgery between January 2017 and June 2023 was conducted. Baseline clinical and pathological data, surgical methods, and postoperative treatments were analyzed to assess overall survival (OS). Univariate and multivariate Cox regression analyses were conducted to identify prognostic factors. Whole-exome sequencing (WES) was performed on a subset of the patients with preserved tumor tissues and no matched targeted therapies to identify high-frequency mutated genes. Functional experiments in A549 lung adenocarcinoma cells were performed to evaluate the role of the significant genes in tumor progression through cell proliferation, migration, invasion, apoptosis, and cell cycle assays.ResultsThe survival analysis of 877 stage IIb and IIIa lung adenocarcinoma cases revealed significant differences in clinical characteristics and outcomes. Stage IIb patients had a median OS of 58 months compared to 37 months for stage IIIa, with 5-year OS rates of 46.9% and 30.5%, respectively. Univariate and multivariate Cox regression identified pathological stage, number of positive lymph nodes, age, and targeted therapy as independent prognostic factors. WES of 184 patients with no matched targeted therapies revealed high-frequency mutations in genes such as TP53 and PIK3C2G, with the latter emerging as the most significant prognostic marker. Functional assays demonstrated that the knockdown of PIK3C2G in A549 cells significantly reduced proliferation, migration and invasion while promoting apoptosis and disrupting cell cycle progression.ConclusionPIK3C2G was identified as a significant prognostic marker in stage IIb and IIIa lung adenocarcinoma, with functional data supporting its therapeutic potential. Taken together, this study integrates clinical and molecular findings, which could be used as a reference to guide personalized treatment strategies.

Background & Aims: The immunological mechanisms underpinning the pathogenesis of alcoholic-associated liver disease (ALD) remain incompletely elucidated. This study aims to explore the transcriptomic profiles of hepatic immune cells in ALD compared with healthy individuals and those with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: We utilized single-cell RNA sequencing to analyze liver samples from healthy subjects and patients with MASLD and ALD, focusing on the immune cell landscapes within the liver. Key alterations in immune cell subsets were further validated using liver biopsy samples from additional patient cohorts. Results: We observed a significant accumulation of CD4+ T cells in livers of patients with ALD, surpassing the prevalence of CD8+ T cells, in contrast to patients with MASLD and healthy counterparts, whereas natural killer (NK) cells and γδT cells exhibited reduced intrahepatic infiltration. In-depth transcriptional and developmental trajectory analyses unveiled that a distinct CD4+ subset characterized by granzyme K (GZMK) expression, displaying a tissue-resident signature and terminal effector state, prominently enriched among CD4+ T cells infiltrating the livers of patients with ALD. Subsequent examination of an independent ALD patient cohort corroborated the substantial enrichment of GZMK+CD4+ T lymphocytes, primarily within liver fibrotic zones, suggesting their potential involvement in disease progression. Additionally, we noted shifts in myeloid populations, with expanded APOE+ macrophage and FCGR3B+ monocyte subsets in ALD samples relative to MASLD and healthy tissues. Conclusions: In summary, this study unravels the intricate cellular diversity within hepatic immune cell populations, highlighting the pivotal immune pathogenic role of the GZMK+CD4+ T lymphocyte subset in ALD pathogenesis.

ABSTRACT Trimethylamine (TMA), a simple trace biogenic amine resulting from the decomposition of proteins and other macromolecules, is ubiquitous in nature. It is found in the human gut as well as in various terrestrial and marine ecosystems. While the role of TMA in promoting cardiovascular diseases and depolarizing olfactory sensory neurons in humans has only recently been explored, many microbes are well known for their ability to utilize TMA as a carbon, nitrogen, and energy source. Here, we report the first structure of a TMA transporter, TmaT, originally identified from a marine bacterium. TmaT is a member of the betaine-choline-carnitine transporter family, and we show that TmaT is an Na+/TMA symporter, which possessed high specificity and binding affinity toward TMA. Furthermore, the structures of TmaT and two TmaT-TMA complexes were solved by cryo-EM. TmaT forms a homotrimer structure in solution. Each TmaT monomer has 12 transmembrane helices, and the TMA transport channel is formed by a four-helix bundle. TMA can move between different aromatic boxes, which provides the structural basis of TmaT importing TMA. When TMA is bound in location I, residues Trp146, Trp151, Tyr154, and Trp326 form an aromatic box to accommodate TMA. Moreover, Met105 also plays an important role in the binding of TMA. When TMA is transferred to location II, it is bound in the aromatic box formed by Trp325, Trp326, and Trp329. Based on our results, we proposed the TMA transport mechanism by TmaT. This study provides novel insights into TMA transport across biological membranes.IMPORTANCEThe volatile trimethylamine (TMA) plays an important role in promoting cardiovascular diseases and depolarizing olfactory sensory neurons in humans and serves as a key nutrient source for a variety of ubiquitous marine microbes. While the TMA transporter TmaT has been identified from a marine bacterium, the structure of TmaT and the molecular mechanism involved in TMA transport remain unclear. In this study, we elucidated the high-resolution cryo-EM structures of TmaT and TmaT-TMA complexes and revealed the TMA binding and transport mechanisms by structural and biochemical analyses. The results advance our understanding of the TMA transport processes across biological membranes.

Summary: Glioblastoma (GBM) is a highly lethal malignant brain tumor with poor survival rates, and chemoresistance poses a significant challenge to the treatment of patients with GBM. Here, we show that transketolase (TKT), a metabolic enzyme in the pentose phosphate pathway (PPP), attenuates the chemotherapy sensitivity of glioma cells in a manner independent of catalytic activity. Mechanistically, chemotherapeutic drugs can facilitate the translocation of TKT protein from the cytosol into the nucleus, where TKT physically interacts with XRN2 to regulate the resolution and removal of R-loops. Depletion of TKT leads to increased R-loop accumulation and genome instability, increasing the susceptibility of glioma cells to chemotherapy. In conclusion, our study reveals a non-metabolic function of TKT in regulating R-loop dynamics, genome instability, and chemotherapy sensitivity in gliomas.

Ovarian cancer (OC) is a form of gynecological malignancy that is associated with worse patient outcomes than any other cancer of the female reproductive tract. Topoisomerase II α (TOP2A) is commonly regarded as an oncogene that is associated with malignant disease progression in a variety of cancers, its mechanistic functions in OC have yet to be firmly established. We explored the role of TOP2A in OC through online databases, clinical samples, in vitro and in vivo experiments. And initial analyses of public databases revealed high OC-related TOP2A expression in patient samples that was related to poorer prognosis. This was confirmed by clinical samples in which TOP2A expression was elevated in OC relative to healthy tissue. Kaplan-Meier analyses further suggested that higher TOP2A expression levels were correlated with worse prognosis in OC patients. In vitro, TOP2A knockdown resulted in the inhibition of OC cell proliferation, with cells entering G1 phase arrest and undergoing consequent apoptotic death. In rescue assays, TOP2A was confirmed to regulate cell proliferation and cell cycle through AKT/mTOR pathway activity. Mouse model experiments further affirmed the key role that TOP2A plays as a driver of OC cell proliferation. These data provide strong evidence supporting TOP2A as an oncogenic mediator and prognostic biomarker related to OC progression and poor outcomes. At the mechanistic level, TOP2A can control tumor cell growth via AKT/mTOR pathway modulation. These preliminary results provide a foundation for future research seeking to explore the utility of TOP2A inhibitor-based combination treatment regimens in platinum-resistant recurrent OC patients.

Supramolecular hydrogels based on host–guest interactions constitute a class of intriguing soft matter and have attracted great attention due to their unique properties, etc. In this study, we successfully synthesized 4-methylene-7-diethylaminocoumarin methacrylate (DEACMMA) monomer and carried out reversible addition-fragmentation chain transfer (RAFT) polymerization using methylated β-cyclodextrin via a host-guest encapsulation mechanism. This process led to the formation of ternary copolymer hydrogel supramolecular photoresponsive hydrogels through polymerization induced supramolecular gelation (PISG). The encapsulation of coumarin monomers by methylated cyclodextrins was confirmed using 2D ROESY NMR and fluorescence spectroscopy. We have carefully analyzed the microstructure of these supramolecular hydrogels by rheological profiles and scanning electron microscopy (SEM). Stimulated by UV light, the copolymers transition from non-luminescence to a bright fluorescent blue color, which is reminiscent of the self-transforming colors observed in jellyfish. The development of photostimuli-responsive hydrogels based on methylated β-cyclodextrin-coated coumarin esters opens new avenues in the fields of smart materials and clinical medicine.

Acute myeloid leukemia (AML), which has distinct genetic abnormalities, has unique clinical and biological features. In this study, the incidence, clinical characteristics, induction treatment response, and outcomes of a large cohort of Chinese AML pediatric patients treated according to the BCH-AML 2005 protocol were analyzed. RUNX1-RUNX1T1 was the most common fusion transcript, followed by the CBFβ-MHY11 and KMT2A rearrangements. FLT3-ITD and KIT mutations are associated with unfavorable clinical features and induction responses, along with KMT2A rearrangements, DEK-NUP214, and CBF-AML. The 5-year event-free survival (EFS) and overall survival (OS) rates of our cohort were 53.9 ± 3.7% and 58.5 ± 3.6%, with the best survival found among patients with CBFβ-MYH11 and the worst survival among those with DEK-NUP214. In addition, we found that patients with FLT3-ITD mutation had adverse outcomes and that KIT mutation had a negative impact on OS in RUNX1-RUNX1T1+ patients. Furthermore, the risk classification and response to treatment after each induction block also influenced the prognosis, and HSCT after first remission could improve OS in high-risk patients. Not achieving complete remission after induction 2 was found to be an independent prognostic factor for OS and EFS. These findings indicate that genetic abnormalities could be considered stratification factors, predict patient outcomes, and imply the application of targeted therapy.

Study region: Taihu Basin, China Study focus: Floods threaten humans, the environment, economic activity, and infrastructure. In this study, a new trend test and flood-frequency methods were adopted to detect extreme floods and their distributions based on flood-event identification. To fully understand the phased process of the influence of human activities on extreme hydrological processes, 12 copula functions were employed creatively in combined static and dynamic time-varying correlation aspects between extreme precipitation and floods. New hydrological insights for the region: Although both significant and insignificant increasing trends of the annual maximum water level in all three hydrological districts were examined, the periodic oscillations of all the stations were similar. Thus, it was significant to fully detect the periodical variation of floods. Extreme floods occurred mainly in the 1990s, as measured by frequency estimates. Generally, the nonstationary response relationship between heavy rain and an extreme water level was gradually strengthened; that is, a certain magnitude precipitation seemed to induce a greater-intensity flood event as time passed. Through the identification of historical flood events and the analysis of the rise and fall processes of floods, we found that the main reason for variation in the response relationship was the increase in the water level before the rising stage, rather than the water level rising in the Taihu Basin. Our study findings further existing knowledge on the regional flood-control design standard and can ensure the coexistence of humans and water systems in the future.

The study focuses on lung adenocarcinoma (LUAD), a predominant type of lung cancer. Despite advancements in diagnostics and molecular therapies, treatment remains challenging due to its low five-year survival rate. This study aims to investigate the role of the transmembrane protein TMEM164 in ferroptosis and anti-tumor immunity in LUAD, and to evaluate its potential as a therapeutic target. Through cellular experiments (such as QPCR, WB, CCK-8, EdU, Transwell, flow cytometry, CO-IP) and animal model experiments (including HE staining and IHC analysis), the relationship between TMEM164 expression and LUAD progression was explored, with particular attention to its mechanisms in ferroptosis and autophagy. The results show that TMEM164 expression is downregulated in LUAD and is associated with poor prognosis. Increasing TMEM164 expression significantly inhibits cell proliferation, migration, and invasion, while promoting an autophagy process dependent on ATG5 for autophagosome formation, thus facilitating ferroptosis. In mouse models, high TMEM164 expression combined with anti-PD-1 antibodies demonstrated synergistic anti-tumor effects. These findings highlight the critical role of TMEM164 in LUAD, suggesting that modulating TMEM164 expression could open new avenues for LUAD treatment.

Abstract Background This study was designed to develop a combined radiomics nomogram to preoperatively predict the risk categorization of thymomas based on contrast-enhanced computed tomography (CE-CT) images. Materials The clinical and CT data of 178 patients with thymoma (100 patients with low-risk thymomas and 78 patients with high-risk thymomas) collected in our hospital from March 2018 to July 2023 were retrospectively analyzed. The patients were randomly divided into a training set (n = 125) and a validation set (n = 53) in a 7:3 ratio. Qualitative radiological features were recorded, including (a) tumor diameter, (b) location, (c) shape, (d) capsule integrity, (e) calcification, (f) necrosis, (g) fatty infiltration, (h) lymphadenopathy, and (i) enhanced CT value. Radiomics features were extracted from each CE-CT volume of interest (VOI), and the least absolute shrinkage and selection operator (LASSO) algorithm was performed to select the optimal discriminative ones. A combined radiomics nomogram was further established based on the clinical factors and radiomics scores. The differentiating efficacy was determined using receiver operating characteristic (ROC) analysis. Results Only one clinical factor (incomplete capsule) and seven radiomics features were found to be independent predictors and were used to establish the radiomics nomogram. In differentiating low-risk thymomas (types A, AB, and B1) from high-risk ones (types B2 and B3), the nomogram demonstrated better diagnostic efficacy than any single model, with the respective area under the curve (AUC), accuracy, sensitivity, and specificity of 0.974, 0.921, 0.962 and 0.900 in the training cohort, 0.960, 0.892, 0923 and 0.897 in the validation cohort, respectively. The calibration curve showed good agreement between the prediction probability and actual clinical findings. Conclusions The nomogram incorporating clinical factors and radiomics features provides additional value in differentiating the risk categorization of thymomas, which could potentially be useful in clinical practice for planning personalized treatment strategies.

Abstract Camellia oleifera, a significant woody edible oil species, was examined using 48 germplasm resources from high-altitude regions in East Guizhou Province, China, to analyze fruit quality. The analysis aimed to identify high-performance germplasm, providing theoretical and research foundations for selecting and cross-breeding superior C. oleifera varieties in these regions. Fifteen primary traits of mature fruits were measured and analyzed, including four phenotypic traits (single fruit weight, transverse diameter, longitudinal diameter, peel thickness) and eleven quality traits (fresh seed yield rate, dry seed yield rate, dry kernel yield rate, seed kernel oil content, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, α-linolenic acid, cis-11-eicosenoic acid). A comprehensive evaluation employing cluster and principal component analyses (PCA) was conducted. The cluster analysis categorized the germplasms into five groups at a squared Euclidean distance of 14, with the first category comprising 17 germplasms, the second 28, and the third, fourth, and fifth each containing one. PCA reduced the 15 traits to five principal components (PCs), with PC1 having the highest eigenvalue of 3.57 and a contribution rate of 23.8%, mainly representing phenotypic traits. PC2, contributing 20.44%, represented linoleic acid, while PC3, PC4, and PC5, with contribution rates of 12.99%, 9.13%, and 7.45% respectively, predominantly represented seed kernel oil content, fresh seed yield, and palmitoleic acid. Employing a weighted sum method, a comprehensive evaluation function was developed to calculate total scores for each superior individual, forming the basis for rankings and selections. Notable variability was detected in single fruit weight, peel thickness, and fresh and dry seed yields, while oleic acid exhibited the lowest coefficient of variation. Dry seed yield showed a robust positive correlation with seed kernel oil content and the concentrations of palmitic and linoleic acids, whereas seed kernel oil content was inversely correlated with cis-11-eicosenoic acid levels. Five PCs with eigenvalues > 1 were identified, highlighting the top ten superior individuals: QD (Qian Dong: the code of eastern Guizhou Province)-33 > QD-34 > QD-48 > QD-38 > QD-27 > QD-15 > QD-35 > QD-5 > QD-14 > QD-36. Thus, the 48 C. oleifera germplasms from East Guizhou’s high-altitude areas demonstrate significant potential for enhancing traits such as single fruit weight, peel thickness, and fresh and dry seed yields. Specifically, QD-33, QD-34, and QD-48 exhibited superior comprehensive performance, designating them as prime candidates for variety selection and breeding.

This paper aimed to investigate the correlation between carbon emissions, fuel consumption, and speed limit. A theoretical model was derived based on the energy conservation law, which expresses the relationship between vehicle's fuel consumption and speed. Subsequently, a total of 40 sets of fuel consumption data were collected through field tests to verify the accuracy of the theoretical model at different speeds and different road longitudinal slope combinations. The fuel consumption was then converted to carbon emissions according to the carbon emission factors specified by Intergovernmental Panel on Climate Change (IPCC). In the field experiment, two types of cars and trucks, which are most common on the expressways in China, were selected. Finally, the travel speed under different posted speed limits was obtained through the previously established model, and the carbon emission changes of different vehicle types at different limited speeds are calculated. The results show that the speed limit has a significant impact on fuel consumption and carbon emissions. When the speed limit increased from 80 to 120 km/h, average vehicle speeds increased about 21%–27%, and fuel consumption and carbon emissions increased from approximately 33%–38%. Another interesting result was that the vehicle's fuel consumption and carbon emissions are only affected by speed. The results of the study explore the effect of speed limits on carbon emissions and provide evidence for road managers to set reasonable speed limits.

Abstract The diagnosis of neurodegenerative diseases (NDDs) remains challenging, and existing therapeutic approaches demonstrate little efficacy. NDD drug delivery can be achieved through the utilization of nanostructures, hence enabling multimodal NDD theranostics. Nevertheless, both biomembrane and non-biomembrane nanostructures possess intrinsic shortcomings that must be addressed by hybridization to create novel nanostructures with versatile applications in NDD theranostics. Hybrid nanostructures display improved biocompatibility, inherent targeting capabilities, intelligent responsiveness, and controlled drug release. This paper provides a concise overview of the latest developments in hybrid nanostructures for NDD theranostics and emphasizes various engineering methodologies for the integration of diverse nanostructures, including liposomes, exosomes, cell membranes, and non-biomembrane nanostructures such as polymers, metals, and hydrogels. The use of a combination technique can significantly augment the precision, intelligence, and efficacy of hybrid nanostructures, therefore functioning as a more robust theranostic approach for NDDs. This paper also addresses the issues that arise in the therapeutic translation of hybrid nanostructures and explores potential future prospects in this field.

Abstract Background Extracellular matrix (ECM) remodeling in skeletal muscle is a significant factor in the development of sarcopenia. This study aims to evaluate changes in ECM remodeling in the lumbar paravertebral muscles of sarcopenic rats using diffusion-tensor magnetic resonance imaging (DT-MRI) and compare them with histology. Methods Twenty 6-month-old female Sprague Dawley rats were randomly divided into the dexamethasone (DEX) group and the control (CON) group. Both groups underwent 3.0T MRI scanning, including Mensa, T2WI, and DT-MRI sequences. The changes in muscle fibers and extracellular matrix (ECM) of the erector spinal muscle were observed using hematoxylineosin and sirius red staining. The expressions of collagen I, III, and fibronectin in the erector spinae were detected by western blot. Pearson correlation analysis was employed to assess the correlation between MRI quantitative parameters and corresponding histopathology markers. Results The cross-sectional area and fractional anisotropy values of the erector spinae in the DEX group rats were significantly lower than those in the CON group (p

Abstract Background Selenium nanoparticles (SeNPs) are increasingly gaining attention due to its characteristics of low toxicity, high activity, and stability. Additionally, Bacillus licheniformis, as a probiotic, has achieved remarkable research outcomes in diverse fields such as medicine, feed processing, and pesticides, attracting widespread attention. Consequently, evaluating the activity of probiotics and SeNPs is paramount. The utilization of probiotics to synthesize SeNPs, achieving large-scale industrialization, is a current hotspot in the field of SeNPs synthesis and is currently the most promising synthetic method. To minimize production costs and maximize yield of SeNPs, this study selected agricultural by-products that are nutrient-rich, cost-effective, and readily available as culture medium components. This approach not only fulfills industrial production requirements but also mitigates the impact on downstream processes. Results The experimental findings revealed that SeNPs synthesized by B. licheniformis F1 exhibited a spherical morphology with diameters ranging from 110 to 170 nm and demonstrating high stability. Both the secondary metabolites of B. licheniformis F1 and the synthesized SeNPs possessed significant free radical scavenging ability. To provide a more robust foundation for acquiring large quantities of SeNPs via fermentation with B. licheniformis F1, key factors were identified through single-factor experiments and response surface methodology (RSM) include a 2% seed liquid inoculum, a temperature of 37 ℃, and agitation at 180 rpm. Additionally, critical factors during the optimization process were corn powder (11.18 g/L), soybean meal (10.34 g/L), and NaCl (10.68 g/L). Upon validating the optimized conditions and culture medium, B. licheniformis F1 can synthesize nearly 100.00% SeNPs from 5 mmol/L sodium selenite. Subsequently, pilot-scale verification in a 5 L fermentor using the optimized medium resulted in a shortened fermentation time, significantly reducing production costs. Conclusion In this study, the efficient production of SeNPs by the probiotic B. licheniformis F1 was successfully achieved, leading to a significant reduction in fermentation costs. The exploration of the practical applications of this strain holds significant potential and provides valuable guidance for facilitating the industrial-scale implementation of microbial synthesis of SeNPs.

Suzhou City, located in the Yangtze River Delta in China, is prone to flooding due to a complex combination of natural factors, including its monsoon climate, low elevation, and tidally influenced position, as well as intensive human activities. The Large Encirclement Flood Control Project (LEFCP) was launched to cope with serious floods in the urban area. This project changed the spatiotemporal pattern of flood processes and caused spatial diversion of floods from the urban area to the outskirts of the city. Therefore, this study developed a distributed flood simulation model in order to understand this transition of flood processes. The results revealed that the LEFCP effectively protected the urban areas from floods, but the present scheduling schemes resulted in the spatial diversion of floods to the outskirts of the city. With rainstorm frequencies of 10.0% to 0.5%, the water level differences between two representative water level stations (Miduqiao (MDQ) and Fengqiao (FQ)) located inside and outside the LEFCP area, ranged from 0.75 m to 0.24 m and from 1.80 m to 1.58 m, respectively. In addition, the flood safety margin at MDQ and the duration with the water level exceeding the warning water level at FQ ranged from 0.95 m to 0.43 m and from 4 h to 22 h, respectively. Rational scheduling schemes for the hydraulic facilities of the LEFCP in extreme precipitation cases were developed according to flood simulations under seven scheduling scenarios. This helps to regulate the spatial flood diversion caused by the LEFCP during extreme precipitation.

Abstract Introduction Balloon flower root-derived exosome-like nanoparticles (BDEs) have recently been proposed as physiologically active molecules with no cytotoxicity. However, the therapeutic effects of drug-induced hepatotoxicity of BDEs have not been elucidated. BDEs contain a large amount of platycodin D, which is widely known to be effective in regulating inflammation and ameliorating systemic toxicity. Thus, the main therapeutic activity of BDEs is attributed to inhibiting the inflammatory response and alleviating toxicity. In this study, we fabricated the hybrid BDEs fused with liposomes containing silymarin (SM) to enhance the synergistic effect on inhibition of acetaminophen-induced hepatotoxicity (APAP). Objective Considering the potential therapeutic effects of BDEs, and the potential to achieve synergistic effects to improve therapeutic outcomes, we constructed hybrid BDEs with a soy lecithin-based liposome loaded with SM. Since liposomes can provide higher thermal stability and have greater structural integrity, these might be more resistant to clearance and enzymatic degradation of drug molecules. Methods Hybrid BDEs with liposome-loaded SM (BDEs@lipo-SM) were fabricated by thin-film hydration and extrusion. BDEs@lipo-SM were characterized using dynamic light scattering and high-performance liquid chromatography. After confirmation of the physical properties of BDEs@lipo-SM, various therapeutic properties were evaluated. Results BDEs@lipo-SM were internalized by hepatocytes and immune cells and significantly decreased mRNA expression of apoptosis and inflammation-relevant cytokines by inhibiting the hepatocyte MAPK pathway. BDEs@lipo-SM significantly induced an increase in glutathione levels and inhibited APAP-induced hepatotoxicity. Conclusion From this study, we know that BDEs are reliable and safe nanovesicles containing natural metabolites derived from balloon flower, and they can facilitate intercellular communication. BDEs are also easily modified to enhance drug loading capacity, targeting effects, and long-term accumulation in vivo. BDEs@lipo-SM have therapeutic benefits for acute liver injury and can alleviate cell death and toxicity. They can be efficiently delivered to the liver and effectively inhibit APAP-induced hepatotoxicity by inhibiting the MAPK signaling pathway and apoptosis, which accelerates liver recovery in the APAP-induced acute liver injury model. These findings highlight that BDEs represent an attractive delivery vehicle for drug delivery. Graphical abstract

Abstract Background Percutaneous coronary intervention (PCI) with primary stenting, which stands for stent implantation regardless of obtaining satisfactory results with balloon angioplasty, has superseded conventional plain old balloon angioplasty with provisional stenting. With drug-coated balloon (DCB), primary DCB angioplasty with provisional stenting has shown non-inferiority to primary stenting for de novo coronary small vessel disease. However, the long-term efficacy and safety of such a strategy to the primary stenting on clinical endpoints in de novo lesions without vessel diameter restrictions remain uncertain. Study design The REC-CAGEFREE I is an investigator-initiated, multicenter, randomized, open-label trial aimed to enroll 2270 patients with acute or chronic coronary syndrome from 43 interventional cardiology centers in China to evaluate the non-inferiority of primary paclitaxel-coated balloons angioplasty to primary stenting for the treatment of de novo, non-complex lesions without vessel diameter restrictions. Patients who fulfill all the inclusion and exclusion criteria and have achieved a successful lesion pre-dilatation will be randomly assigned to the two arms in a 1:1 ratio. Protocol-guided DCB angioplasty and bailout stenting after unsatisfactory angioplasty are mandatory in the primary DCB angioplasty group. The second-generation sirolimus-eluting stent will be used as a bailout stent in the primary DCB angioplasty group and the treatment device in the primary stenting group. The primary endpoint is the incidence of Device-oriented Composite Endpoint (DoCE) within 24 months after randomization, including cardiac death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularization. Discussion The ongoing REC-CAGEFREE I trial is the first randomized trial with a clinical endpoint to assess the efficacy and safety of primary DCB angioplasty for the treatment of de novo, non-complex lesions without vessel diameter restrictions. If non-inferiority is shown, PCI with primary DCB angioplasty could be an alternative treatment option to primary stenting. Trial registration Registered on clinicaltrial.gov (NCT04561739).

The relationship between total phosphorus (TP) and benthic chlorophyll-a (chl-a), a vital indicator of algal biomass in freshwater ecosystems, has been well-established since the 1960s. Different machine learning models have been used to predict the benthic chl-a from the TP and dissolved P (DP), however, to the best of our knowledge, colloidal and particulate P (CP and PP) have never been used in predictive models for benthic chl-a. To address this gap, we applied two machine learning algorithms—random forest (RF), and artificial neural networks (ANN) to predict benthic chl-a concentrations by incorporating these specific P fractions as separate variables. Additionally, support vector regression (SVR) was used to predict chl-a concentrations across upstream, midstream, and downstream sections. A total of 125 freshwater samples were collected from these sections of the Thousand Island Lake (TIL) watershed for analysis. The RF model (R2 = 0.88, RMSE = 2.20) outperformed the ANN (R2 = 0.37, RMSE = 4.78). The SHapley Additive exPlanations (SHAP) were used to interpret the RF model, revealing CP as the most influential predictor of benthic chl-a levels. Lower concentrations of PP and DP significantly contributed to benthic chl-a predictions, suggesting possibly rapid biogeochemical transformations among these P fractions. The SVR analysis demonstrated the dominance of DP and CP upstream and downstream, respectively, while PP was more influential in the middle stream areas. This study highlights the differential impacts of P fractions on benthic chl-a and offers new insights into aquatic health assessments in the TIL watershed.

PurposeThis study aims to optimize neoadjuvant radiotherapy target area for locally advanced rectal cancer (LARC) patients undergoing total neoadjuvant therapy (TNT) by examining local recurrence patterns.Methods and materialsWe retrospectively analyzed the clinical data of rectal cancer patients who undergone local recurrence after surgery. Recurrence sites were categorized and compared with initial diagnosis imaging, focusing on visible and suspicious lesions.ResultsOf the 126 patients who met our criteria, 186 lesions were analyzed. Within these, 75.40% of cases (95/126) and 83.33% of lesions (155/186) were located within the pelvic cavity. Conversely, 3.97% of cases (5/126) and 3.33% of lesions (6/186) occurred outside the pelvic cavity. Additionally, 20.63% of cases (26/126) and 13.44% of lesions (25/186) were found in both regions. Recurrences were predominantly observed in mesenteric regions (MR) (40.86%, 76/186) and presacral regions (PR) (32.26%, 60/186). In addition, 86.51% of patients (109/126) had recurrent lesions in HRA and the suspected lesions areas. Further analysis showed that initial CEA levels and adjuvant therapy types were identified as independent predictors for recurrence in MR/PR and initially suspected lesions. 86.51% of patients had recurrent lesions in HRA and the suspected lesions areasConclusionThe MR, PR, and areas of initial suspicious lesions are high-risk zones for post-surgical recurrence of LARC. Exploratory study of involved-field irradiation (IFI) can be carried out in the context of TNT in LARC.

Melon seeds have received considerable attention in recent years because of their high protein content, but they have not yet been fully used. The modification of melon seed protein (MSP) using ultrasound-assisted pH-shifting treatment was investigated in this study by analyzing structural characteristics and functional properties. The particle size, free sulfhydryl content, surface hydrophobicity, solubility, secondary structure, water-holding capacity, oil-holding capacity, emulsification activity index, and emulsification stability index of MSP were determined. MSP treated with ultrasound-assisted, pH-shifting had a smaller particle size, lower free sulfhydryl content, higher surface hydrophobicity, and solubility increased from 43.67 % to 89.12 %. The secondary structure of MSP was affected by ultrasonic treatment, manifesting as an α-helix increase and β-helix, β-turn, and random coil content decrease, which may be the reason why the protein structure became more compact after treatment. The water and oil holding capacities of MSP increased from 2.74 g/g and 3.14 g/g in untreated samples to 3.19 g/g and 3.97 g/g for ultrasound-treated samples, and further increased to 3.97 g/g and 5.02 g/g for ultrasound-assisted, pH-shifting treatment at pH 9.0, respectively. The emulsification activity index of MSP was 21.11 m2/g before treatment and reached a maximum of 32.34 m2/g after ultrasound-assisted, pH-shifting treatment at pH 9.0. The emulsification stability of MSP was maximized by ultrasonic treatment at pH 7.0. Ultrasound-assisted, pH-shifting treatment can effectively improve the functional properties of MSP by modifying the protein structure, which improves the potential application of melon seed protein in the food industry.

Increasing evidence indicates that 2-hydroxyglutarate (2HG) is an oncometabolite that drives tumour formation and progression. Due to mutations in isocitrate dehydrogenase (IDH) and the dysregulation of other enzymes, 2HG accumulates significantly in tumour cells. Due to its structural similarity to α-ketoglutarate (αKG), accumulated 2HG leads to the competitive inhibition of αKG-dependent dioxygenases (αKGDs), such as KDMs, TETs, and EGLNs. This inhibition results in epigenetic alterations in both tumour cells and the tumour microenvironment. This review comprehensively discusses the metabolic pathways of 2HG and the subsequent pathways influenced by elevated 2HG levels. We will delve into the molecular mechanisms by which 2HG exerts its oncogenic effects, particularly focusing on epigenetic modifications. This review will also explore the various methods available for the detection of 2HG, emphasising both current techniques and emerging technologies. Furthermore, 2HG shows promise as a biomarker for clinical diagnosis and treatment. By integrating these perspectives, this review aims to provide a comprehensive overview of the current understanding of 2HG in cancer biology, highlight the importance of ongoing research, and discuss future directions for translating these findings into clinical applications.

Abstract Diabetic nephropathy (DN) is a frequent and costly complication of diabetes with limited understandings of mechanisms and therapies. Emerging evidence points to the important roles of interleukin‐33 (IL‐33) in acute kidney injury, yet its contribution to DN is still unclear. We here found a ubiquitous increase of IL‐33 and its receptor (ST2) in murine models and patients with DN. Surprisingly, both IL‐33 and ST2 knockdown aggravated renal lesions in DN, while overexpression of IL‐33 also exacerbated the condition. Further population‐based analyses revealed a positive correlation of IL‐33 expression with renal dysfunction in DN patients. Individuals with high IL‐33 expression‐related polygenic risk score had a higher DN risk. These findings confirmed the harmful effects of IL‐33 on DN. Conversely, endogenous and exogenous partial reduction of IL‐33 signaling conferred renoprotective effects in vivo and in vitro. Mechanistically, IL‐33 induced senescence by regulating cell cycle factors in HK‐2 cells, and accordingly senescence led to renal cell damage through the secretion of senescence‐related secretory phenotype (SASP) including IL‐33 and prostaglandins. Together, elevated IL‐33 accelerates cellular senescence to drive DN possibly by SASP production, while a partial blockage improves renal injury and senescence. Our findings pinpoint a possible and new avenue for DN interventions.

The All-DC wind power generation system can effectively solve the harmonic resonance problem caused by large-scale wind power AC collection and transmission, gradually becoming a hot topic in future research. However, there are few studies on the relay protection of the All-DC wind power transmission systems. In the All-DC wind power systems, there are differences in topology, control strategies, fault characteristics, boundary characteristics, etc. At the same time, existing pilot protection has problems such as strict information synchronization requirements and selection of setting values through simulation. Therefore, the proposed pilot protection based on the similarity of the traveling wave between the quadratic fitting curve and the calculated curve for the All-DC wind power system transmission lines. Firstly, the difference of the 1-mode initial current waveform characteristics is analyzed in the time domain at both ends. Then, the least squares method is introduced to fit the differential curves of the current forward and backward traveling waves at two terminals. The differential characteristics of the differences between the fitted curve, the calculated curve, and the measured curve under the influence of internal and external errors are analyzed. Finally, the calculated value of traveling wave current during external metallicity fault is used as the standard. By comparing the fitting curve of current traveling waves and the difference in the calculation curve to distinguish internal faults from external faults. The simulation results show that the proposed protection principle can fault resistance of 2200 Ω and noise interference of 20 dB. In addition, the proposed method does not require strict data synchronization, higher sampling frequency, and setting value through simulation.

The entry of Cd into soil-rice systems is a growing concern as it can pose potential risks to public health. To derive regional soil Cd threshold, a total of 333 paired soil and rice samples was collected in Anhui Province, Eastern China. The results showed that the total soil Cd and soil Zn/Cd were the most significant variables contributing to Cd content in polished rice. The Chinese Soil Quality Standards might overestimate risk posed by Cd-contaminated soil for rice production in the mining area due to high Zn/Cd values of some mining-associated soils. Cd levels in polished rice can be predictable using stepwise multiple linear regression (MLR) model. However, the derived soil Cd threshold based on the MLR model would be unrealistically high. The classification and regression tree method (CART) performed well in simulating Cd levels in polished rice and can be used to derive soil Cd threshold instead of MLR to minimize the uncertainty.

The modular multilevel converters (MMC) based high-voltage direct-current (HVDC) grids have a fast rise rate and higher peak value of fault current. The active current limiting control (ACLC) of MMC can effectively reduce the breaking current of DC circuit breakers (DCCB) and reduce the requirement for rapid fault identification in the line protection. However, the current ACLC based on changing the MMC control strategy cannot meet the selectivity requirements. The lack of selectivity may lead to power transmission on non-faulty lines in a multi-terminal DC power grid, thus expanding the range of fault influence. Therefore, this paper proposed a selective and staged ACLC. Firstly, the starting range of ACLC is determined according to the selective requirement and purpose of ACLC in the flexible DC power grid. Secondly, a staged ACLC approach was proposed to balance the speed and selectivity of ACLC. In this approach, the single end and both terminals electrical quantities of the line are fully utilized as the starting criteria for staged ACLC, and corresponding ACLC principles are proposed. Finally, the AC side current and MMC bridge arm current under ACLC were analyzed, and an ACLC scheme was proposed in coordination with DC circuit breakers (DCCB) and fault identification. The simulation results show that the proposed ACLC guarantees the current limiting ability and the MMC does not block during the whole fault period, and has a certain adaptability to the fault type, fault resistance, and noise.

BackgroundInflammation is associated with the pathophysiology of schizophrenia. The blood markers for systemic inflammation include neutrophil-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), lymphocyte-monocyte ratio (LMR), system inflammation response index (SIRI), and platelet-lymphocyte ratio (PLR). However, these inflammation markers and their relationships with clinical phenotypes among Han Chinese patients with first-episode adolescent-onset schizophrenia (AOS) is unclear. This investigation aimed to elucidate the impact of inflammation on Han Chinese AOS patients as well as the association of blood-based inflammation markers with clinical symptoms.MethodsAltogether, 203 Han Chinese individuals participated in this study, 102 first-episode AOS patients and 101 healthy controls. The assessment of inflammatory indices was based on complete blood cell count. Furthermore, schizophrenia-related clinical symptoms were evaluated using the five-factor model of the Positive and Negative Syndrome Scale (PANSS).ResultsIn Han Chinese first-episode AOS patients, levels of SIRI, PLR, SII, and NLR were significantly increased (p < 0.001), while LMR decreased (p < 0.001) compared to healthy controls. Furthermore, multivariate logistic regression showed that LMR, NLR, SII, and SIRI (all p < 0.05) were independently associated with AOS. Moreover, Receiver operating characteristics assessment indicated that NLR, SIRI, LMR, and SII could effectively distinguish AOS patients from healthy controls. Their areas under the curves were 0.734, 0.701, 0.715, and 0.730 (all p < 0.001). In addition, Correlation analysis revealed that LMR was negatively correlated with the PANSS total, negative, and cognitive factor scores (all p < 0.05); NLR was positively correlated with the cognitive factor score (p < 0.01); SII was negatively correlated with the positive factor score and positively with the negative and cognitive factor scores (all p < 0.05); SIRI was positively correlated with the PANSS total and cognitive factor scores (all p < 0.01).ConclusionsThis research established the involvement of peripheral blood inflammatory markers (LMR, NLR, SII, and SIRI) with the clinical manifestations and pathophysiology of schizophrenia, and these can serve as screening tools or potential indices of the inflammatory state and AOS symptoms severity.

Abstract The demand for high‐performance X‐ray detectors leads to material innovation for efficient photoelectric conversion and carrier transfer. However, current X‐ray detectors are often susceptible to chemical and irradiation instability, complex fabrication processes, hazardous components, and difficult compatibility. Here, we investigate a two‐dimensional (2D) material with a relatively low atomic number, Ti3C2Tx MXenes, and single crystal silicon for X‐ray detection and single‐pixel imaging (SPI). We fabricate a Ti3C2Tx MXene/Si X‐ray detector demonstrating remarkable optoelectronic performance. This detector exhibits a sensitivity of 1.2 × 107 μC Gyair−1 cm−2, a fast response speed with a rise time of 31 μs, and an incredibly low detection limit of 2.85 nGyair s−1. These superior performances are attributed to the unique charge coupling behavior under X‐ray irradiation via intrinsic polaron formation. The device remains stable even after 50 continuous hours of high‐dose X‐ray irradiation. Our device fabrication process is compatible with silicon‐based semiconductor technology. Our work suggests new directions for eco‐friendly X‐ray detectors and low‐radiation imaging system.

Abstract l‐2‐Hydroxyglutarate (l‐2‐HG) is a functionally compartmentalized metabolite involved in various physiological processes. However, its subcellular distribution and mitochondrial transport remain unclear owing to technical limitations. In the present study, an ultrasensitive l‐2‐HG biosensor, sfLHGFRH, composed of circularly permuted yellow fluorescent protein and l‐2‐HG‐specific transcriptional regulator, is developed. The ability of sfLHGFRH to be used for analyzing l‐2‐HG metabolism is first determined in human embryonic kidney cells (HEK293FT) and macrophages. Then, the subcellular distribution of l‐2‐HG in HEK293FT cells and the lower abundance of mitochondrial l‐2‐HG are identified by the sfLHGFRH‐supported spatiotemporal l‐2‐HG monitoring. Finally, the role of the l‐glutamate transporter SLC1A1 in mitochondrial l‐2‐HG uptake is elucidated using sfLHGFRH. Based on the design of sfLHGFRH, another highly sensitive biosensor with a low limit of detection, sfLHGFRL, is developed for the point‐of‐care diagnosis of l‐2‐HG‐related diseases. The accumulation of l‐2‐HG in the urine of patients with kidney cancer is determined using the sfLHGFRL biosensor.

ObjectivesPrevious studies have reported that immunoinflammatory responses have associations with mastitis. Here, we aimed to further figure out whether circulating inflammatory cytokines and immune cells causally impact mastitis liability.MethodsThe two-sample Mendelian randomization made use of genetic variances of 91 inflammatory cytokines from a large publicly available genome-wide association study (GWAS) containing 14,824 participants, 731 immunophenotypes data from 3,757 individuals as exposures separately, and mastitis from a GWAS summary (1880 cases and 211699 controls of European ancestry) as outcome. The primary analysis applied the inverse-variance weighted (IVW) method to estimate causal influences, with MR-Egger, weighted median, weighted mode and simple mode as supplementary approaches. Heterogeneity and pleiotropy were evaluated by the Cochrane Q test, MR-Egger intercept test, and MR-PRESSO global test.ResultsThe results indicated that CX3CL1 may be suggestively relevant to the risk of mastitis (odds ratio, OR = 1.434, 95% CI = 1.142~1.800, p = 0.002). Moreover, three immunophenotypes were identified as having a potential causal link to mastitis (p < 0.05). Significantly, CD28- CD8dim %CD8dim (OR = 1.058, 95% CI = 1.024 ~ 1.093, p = 0.0006) and CD45 on CD33br HLA DR+ (OR = 1.097, 95% CI = 1.039 ~ 1.157, p = 0.0008) were found to induce mastitis possibly. Conversely, CD39+ secreting Treg AC (OR = 0.929, 95% CI = 0.884~ 0.978, p = 0.005) pertained to protective factors of mastitis. Cochran’s Q test and MR-Egger intercept test indicated no significant heterogeneity (p > 0.05) or pleiotropy (p > 0.05), supporting the robustness and reliability of our findings.ConclusionOur study adds to current knowledge on the causal roles of inflammatory cytokines and immune cells on mastitis by genetic means, thus guiding future clinical research.

Abstract Due to the lack of sufficient labeled data for the prostate and the extensive and complex semantic information in ultrasound images, accurately and quickly segmenting the prostate in transrectal ultrasound (TRUS) images remains a challenging task. In this context, this paper proposes a solution for TRUS image segmentation using an end-to-end bidirectional semantic constraint method, namely the BiSeC model. The experimental results show that compared with classic or popular deep learning methods, this method has better segmentation performance, with the Dice Similarity Coefficient (DSC) of 96.74% and the Intersection over Union (IoU) of 93.71%. Our model achieves a good balance between actual boundaries and noise areas, reducing costs while ensuring the accuracy and speed of segmentation.

Abstract Background Helicase for meiosis 1 (HFM1), a putative DNA helicase expressed in germ-line cells, has been reported to be closely associated with premature ovarian insufficiency (POI). However, the underlying molecular mechanism has not been clearly elucidated. The aim of this study was to investigate the function of HFM1 in the first meiotic prophase of mouse oocytes. Results The results suggested that the deficiency of HFM1 resulting in increased apoptosis and depletion of oocytes in mice, while the oocytes were arrested in the pachytene stage of the first meiotic prophase. In addition, impaired DNA double-strand break repair and disrupted synapsis were observed in the absence of HFM1. Further investigation revealed that knockout of HFM1 promoted ubiquitination and degradation of FUS protein mediated by FBXW11. Additionally, the depletion of HFM1 altered the intranuclear localization of FUS and regulated meiotic- and oocyte development-related genes in oocytes by modulating the expression of BRCA1. Conclusions These findings elaborated that the critical role of HFM1 in orchestrating the regulation of DNA double-strand break repair and synapsis to ensure meiosis procession and primordial follicle formation. This study provided insights into the pathogenesis of POI and highlighted the importance of HFM1 in maintaining proper meiotic function in mouse oocytes.

Abstract Using the blueberry cultivar "Powderblue" after pollination, fruits at different developmental stages were collected for study. The transverse and longitudinal diameters, individual fruit weight, and fruit water content were measured during their development. Employing tissue sectioning and microscopy techniques, we systematically studied the morphological features and anatomical structures of the fruits and seeds at various developmental stages, aiming to elucidate the cytological patterns during blueberry fruit development. The results of our study revealed that the "Powderblue" blueberry fruit growth and development followed a double "S" curve. Mature "Powderblue" blueberries were blue-black in color, elliptical in shape, with five locules, an inferior ovary, and an average fruit weight of 1.73 ± 0.17 g, and a moisture content of 78.865 ± 0.9%. Blueberry fruit flesh cells were densely arranged with no apparent intercellular spaces, and mesocarp cells accounted for 52.06 ± 7.4% of fruit cells. In the early fruit development stages, the fruit flesh cells were rapidly dividing, significantly increasing in number but without greatly affecting the fruit's morphological characteristics. During the later stages of fruit development, the expansion of the fruit flesh cells became prominent, resulting in a noticeable increase in the fruit's dimensions. Except for the epidermal cells, cells in all fruit tissues showed varying degrees of rupture as fruit development progressed, with the extent of cell rupture increasing, becoming increasingly apparent as the fruit gradually softened. Additionally, numerous brachysclereids (stone cells) appeared in the fruit flesh cells. Stone cells are mostly present individually in the fruit flesh tissue, while in the placental tissue, they often group together. The "Powderblue" blueberry seeds were light brown, 4.13 ± 0.42 mm long, 2.2 ± 0.14 mm wide, with each fruit containing 50–60 seeds. The "Powderblue" seeds mainly consisted of the seed coat, endosperm, and embryo. The embryo was located at the chalazal end in the center of the endosperm and was spatially separated. The endosperm, occupying the vast majority of the seed volume, comprised both the chalazal and outer endosperm, and the endosperm developed and matured before the embryo. As the seed developed, the seed coat was gradually lignified and consisted of palisade-like stone cells externally and epidermal layer cells internally.

Abstract Although Chaenomeles is widely used in horticulture, traditional Chinese medicine and landscape greening, insufficient research has hindered its breeding and seed selection. This study investigated the floral phenology, floral organ characteristics, palynology, and breeding systems of Chaenomeles speciosa (Sweet) Nakai. The floral characteristics of C. speciosa were observed both visually and stereoscopically. The microstructures of the flower organs were observed using scanning electron microscopy. Pollen stainability was determined using triphenyl tetrazolium chloride staining. Stigma receptivity was determined using the benzidine-H2O2 method and the post-artificial pollination pollen germination method. The breeding system was assessed based on the outcrossing index and pollen–ovule ratio. The flowers of C. speciosa were bisexual with a flowering period from March to April. The flowering periods of single flowers ranged from 8 to 19 d, and those of single plants lasted 18–20 d. The anthers were cylindrical, with the base attached to the filament, and were split longitudinally to release pollen. The flower had five styles, with a connate base. The ovaries had five carpels and five compartments. The inverted ovules were arranged in two rows on the placental axis. The stigma of C. speciosa was dry and had many papillary protrusions. In the early flowering stage (1–2 d of flowering), the pollen exhibited high stainability (up to 84.24%), but all stainability was lost at 7 d of flowering. Storage at – 20 °C effectively delayed pollen inactivation. The stigma receptivity of C. speciosa lasted for approximately 7 days, and the breeding system was classified as outcrossing with partial self-compatibility.

Abstract Conventional food production is restricted by energy conversion efficiency of natural photosynthesis and demand for natural resources. Solar-driven artificial food synthesis from CO2 provides an intriguing approach to overcome the limitations of natural photosynthesis while promoting carbon-neutral economy, however, it remains very challenging. Here, we report the design of a hybrid electrocatalytic−biocatalytic flow system, coupling photovoltaics-powered electrocatalysis (CO2 to formate) with five-enzyme cascade platform (formate to sugar) engineered via genetic mutation and bioinformatics, which achieves conversion of CO2 to C6 sugar (L-sorbose) with a solar-to-food energy conversion efficiency of 3.5%, outperforming natural photosynthesis by over three-fold. This flow system can in principle be programmed by coupling with diverse enzymes toward production of multifarious food from CO2. This work opens a promising avenue for artificial food synthesis from CO2 under confined environments.

Abstract Uterine corpus endometrial carcinoma (UCEC) is becoming a main malignant cancer that threaten to women's health. Thymidine kinase 1 (TK1) is considering to be associated with tumorigenesis and development. Nevertheless, the function of TK1 in UCEC is still unclear. Herein, we analyzed the TK1 expression level in pan-cancer and found that TK1 was upregulated in a variety of cancers including UCEC. Patients of UCEC with high expression of TK1 were related to poor outcome. TK1 was also related to clinical stage, histologic grade and lymph node metastasis. Abnormal expression of TK1 in UCEC was related to promoter methylation while gene mutation was not frequent. TK1 and its associated genes appeared to be prominent in cell cycle and DNA replication, according to GO and KEGG analysis. Analysis of immune infiltration revealed a negative correlation between TK1 and CD8 + T cells, macrophages, and dendritic cells. In vitro experiments, TK1 knockdown resulted in the inhibition of proliferation, migration, invasion and EMT in UCEC cell lines.

Developing lithium-ion batteries (LIBs) with higher energy densities has been necessary in recent years to satisfy the increasing requirements of the energy storage and conversion fields. The limited performance of LIBs stems from their low available capacities and cycling stability. As one of the most important components of LIBs, the cathode material plays an essential role in determining the energy density and cycling stability of LIBs. Among the cathode materials, lithium-rich manganese-based materials are considered to be promising cathode materials for the next generation. This is due to their high specific capacity (theoretical capacity > 250 mA·h·g−1 for 1 Li+ extraction and approximately 378 mA·h·g−1 for 1.2 Li+ extractions), high energy density (approximately 900 W·h·kg−1 vs Li metal), and low cost. Despite these advantages, one major weakness of xLi2MnO3·(1–x) LiMO2 is its intrinsically poor rate capability. This has been recently verified to be associated with the retardation of mass transport of the rearranged surface after activating Li2MnO3 at >4.5 V charge. This rearrangement causes a large capacity loss. In addition, these materials exhibit fragile surface properties at high potentials, erosion from the electrolytes, and dissolution of transition metal ions. In addition, the high working voltage not only ensures high energy density but also triggers a side reaction between the electrode material and the electrolyte. This leads to problems such as transition metal dissolution, surface cracks, and laminated structure collapse during the cycling process, limiting the material’s commercial application. Surface coating can effectively alleviate the side reactions between the electrode and electrolyte, suppress the dissolution of transition metals, and thus improve the material’s coulombic efficiency and cycling stability during cycling. Until now, there have been many reports on the surface coating modification of Li-rich manganese-based materials; however, there are few review reports in this field. This paper summarizes the structure and characteristics of Li-rich manganese-based materials and their problems during the cycle process. Furthermore, it introduces the latest progress in the coating modification of Li-rich manganese-based cathode materials and systematically describes the application of different coating materials, such as electrochemically active materials, non-electrochemically active materials, and conductive polymers. Moreover, this study addresses the coating methods of single-layer coating, double-layer composite coating, and in situ coating and further analyzes the failure and enhancement mechanisms of cycling stability of the modification methods and coatings. Finally, a future development direction for Li1.2Mn0.54Ni0.13Co0.13O2 (LMNC) materials and modification methods is envisioned. This result provides a reference for the practical application of Li-rich cathode materials.

An effective approach to deal with the structural failures of transmission towers in tornadic events is to develop good structural health monitoring (SHM) systems for them. However, the strategy for SHM of transmission towers against tornados should be different from the conventional atmospheric boundary layer (ABL) winds oriented ones, as the non-stationary nature of the tornados significantly differentiates them from the ABL winds. To satisfy the need of obtaining the highly time-varying whole-field stress on the structure in the course of the tornadic event for effective SHM, an innovative transient tornadic load distribution identification method is proposed for use, which is based on the field structural mode shape measurement and dynamic finite-element (FE) model updating. Via a numerical case study, it is noted that good effectiveness is achieved for the new load distribution identification method. Employing the Modal Assurance Criteria based FE model updating technique, the new method has the advantage of being easily embraced in practical SHM systems. It is found that when the transient tornadic velocity profile to be identified is noticeably different from the mode shape of the structure without undertaking external loads, the identified load pattern is very accurate for the new approach.

Abstract Halogenation of Y‐series small‐molecule acceptors (Y‐SMAs) is identified as an effective strategy to optimize photoelectric properties for achieving improved power‐conversion‐efficiencies (PCEs) in binary organic solar cells (OSCs). However, the effect of different halogenation in the 2D‐structured large π‐fused core of guest Y‐SMAs on ternary OSCs has not yet been systematically studied. Herein, four 2D‐conjugated Y‐SMAs (X‐QTP‐4F, including halogen‐free H‐QTP‐4F, chlorinated Cl‐QTP‐4F, brominated Br‐QTP‐4F, and iodinated I‐QTP‐4F) by attaching different halogens into 2D‐conjugation extended dibenzo[f,h]quinoxaline core are developed. Among these X‐QTP‐4F, Cl‐QTP‐4F has a higher absorption coefficient, optimized molecular crystallinity and packing, suitable cascade energy levels, and complementary absorption with PM6:L8‐BO host. Moreover, among ternary PM6:L8‐BO:X‐QTP‐4F blends, PM6:L8‐BO:Cl‐QTP‐4F obtains a more uniform and size‐suitable fibrillary network morphology, improved molecular crystallinity and packing, as well as optimized vertical phase distribution, thus boosting charge generation, transport, extraction, and suppressing energy loss of OSCs. Consequently, the PM6:L8‐BO:Cl‐QTP‐4F‐based OSCs achieve a 19.0% efficiency, which is among the state‐of‐the‐art OSCs based on 2D‐conjugated Y‐SMAs and superior to these devices based on PM6:L8‐BO host (17.70%) and with guests of H‐QTP‐4F (18.23%), Br‐QTP‐4F (18.39%), and I‐QTP‐4F (17.62%). The work indicates that halogenation in 2D‐structured dibenzo[f,h]quinoxaline core of Y‐SMAs guests is a promising strategy to gain efficient ternary OSCs.