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IntroductionCurrently, hyperuricemia has shown a surprisingly rising trend, which attracts widespread attention due to potentially major health risks. Considering the inevitable side effects of long-term medicine, probiotics are emerging as potential therapeutics due to their ability to improve uric acid metabolism and superior safety.MethodsIn our study, two strains of probiotics, Lactobacillus gasseri LG08 (LG08) and Leuconostoc mesenteroides LM58 (LM58) isolated from kimchi were evaluated for the prebiotic properties in vitro and uric-lowering effects in vivo. Here, hyperuricemia animal model and 16S rRNA gene amplicons analysis were further studied to investigate whether these probiotics exert different effects in prevention and treatment.ResultsIn vivo indicators and intestinal flora immunity revealed that both LG08 and LM58 significantly prevent the development and progression of hyperuricemia, repair the antioxidant system and maintain intestinal flora balance in healthy rats, especially LM58. After hyperuricemia was formed, although the effect of LG08 and LM58 could decrease the level of uric acid, the effect to reverse and repair antioxidant levels in the body was limited.DiscussionIn our study, these findings have important implications for hyperuricemia prevention and therapy, and provided more mechanistic insights into the effect of probiotics in hyperuricemia.

Acute ischemic stroke (AIS) is a serious and life-threatening disease worldwide. Despite thrombolysis or endovascular thrombectomy, a sizeable fraction of patients with AIS have adverse clinical outcomes. In addition, existing secondary prevention strategies with antiplatelet and anticoagulant drugs therapy are not able to adequately decrease the risk of ischemic stroke recurrence. Thus, exploring novel mechanisms for doing so represents an urgent need for the prevention and treatment of AIS. Recent studies have discovered that protein glycosylation plays a critical role in the occurrence and outcome of AIS. As a common co- and post-translational modification, protein glycosylation participates in a wide variety of physiological and pathological processes by regulating the activity and function of proteins or enzymes. Protein glycosylation is involved in two causes of cerebral emboli in ischemic stroke: atherosclerosis and atrial fibrillation. Following ischemic stroke, the level of brain protein glycosylation becomes dynamically regulated, which significantly affects stroke outcome through influencing inflammatory response, excitotoxicity, neuronal apoptosis, and blood-brain barrier disruption. Drugs targeting glycosylation in the occurrence and progression of stroke may represent a novel therapeutic idea. In this review, we focus on possible perspectives about how glycosylation affects the occurrence and outcome of AIS. We then propose the potential of glycosylation as a therapeutic drug target and prognostic marker for AIS patients in the future.

Long-term fertilization can result in the changes in carbon (C) cycle in the maize rhizosphere soil. However, there have been few reports on the impacts of microbial regulatory mechanisms on the C cycle in soil. In the study, we analyzed the response of functional genes that regulate the C fixation, decomposition and methane (CH4) metabolism in maize rhizosphere soil to different fertilization treatments using metagenomics analysis. As the dominant C fixation pathway in maize rhizosphere soil, the abundance of the functional genes regulating the reductive citrate cycle (rTCA cycle) including korA, korB, and IHD1 was higher under the chemical nitrogen (N) fertilizer treatments [nitrogen fertilizer (N), compound chemical fertilization (NPK), the combination of compound chemical fertilizer with maize straw (NPKS)] than maize straw return treatments [maize straw return (S), the combination of phosphorus and potassium fertilizer with maize straw (PKS)]. The NPK treatment decreased the abundance of functional genes involved in 3-hydroxypropionate bicycle (3-HP cycle; porA, porB, and porD), which was one of the major C fixation pathways in soil aside from dicarboxylate-hydroxybutyrate (DC/4-HB cycle) and Calvin cycle. The abundance of functional genes related to C degradation was higher in S, PKS and NPKS treatments than N and NPK treatments, and chemical N fertilizer application had a significant effect on C degradation. The dominant Methanaogenesis pathway in maize rhizosphere soil, used acetate as a substrate, and was significantly promoted under chemical N fertilizer application. The functional genes that were related to CH4 oxidation (i.e., pmoA and pmoB) were reduced under N and NPK treatments. Moreover, soil chemical properties had a significant impact on the functional genes related to C fixation and degradation, with SOC (r2 = 0.79) and NO3−-N (r2 = 0.63) being the main regulators. These results implied that N fertilization rather than maize straw return had a greater influence on the C cycle in maize rhizosphere soil.

ObjectiveHypertension is a public health challenge worldwide due to its high prevalence and multiple complications. Hypertension-induced damage to the hippocampus leads to behavioral changes and various brain diseases. Despite the multifaceted effects of hypertension on the hippocampus, the mechanisms underlying hippocampal lesions are still unclear.MethodsThe 32-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were selected as the study subjects. Behavioral experiments such as an open field test (OFT), an elevated plus maze (EPM) test, and the Morris water maze (MWM) test were performed to show the behavioral characteristics of the rats. A comprehensive transcriptomic and metabolomic analysis was performed to understand the changes in the hippocampus at the metabolic and genetic levels.ResultsBehavioral tests showed that, compared to WKY rats, SHR showed not only reduced memory capacity but more hyperactive and impulsive behavior. In addition, transcriptomic analysis screened for 103 differentially expressed genes. Metabolomic analysis screened 56 metabolites with significant differences, including various amino acids and their related metabolites.ConclusionComprehensive analysis showed that hypertension-induced hippocampal lesions are closely associated with differential metabolites and differential genes detected in this study. The results provide a basis for analyzing the mechanisms of hypertension-induced hippocampal damage.

Background Frailty and cognitive impairment are common in the elderly, with various shared risk factors like hypertension. Frailty is a marker for future cognitive function. Moreover, whether intensive blood pressure interacted with frailty and cognitive impairment is unknown. Methods and Results We performed a post hoc analysis of data from SPRINT (Systolic Blood Pressure Intervention Trial). The relationship between frailty and a composite of probable dementia (PD) and mild cognitive impairment (MCI) was analyzed. Also, we evaluated the interaction of intensive blood pressure lowering in the relationship between frailty and cognitive impairment. A total of 8537 patients were included in our study, and 35.1% were women. The mean age of these participants was 67.9±9.3 years. According to the baseline frailty index, 1670, 4637, and 2230 patients were in fit, less fit, and frail statuses, respectively. During a mean follow‐up of 4.61 years, 871 cases of PD or MCI occurred. Compared with those in fit status, those with less fit (hazard ratio [HR], 2.14 [95% CI, 1.65–2.77]) and frailty (HR, 4.28 [95% CI, 3.26–5.61]) status had a higher incidence of a composite of PD and MCI. Blood pressure control strategy interacted with the correlation between frailty and cognitive impairment. Intensive blood pressure control (HR, 2.4 [95% CI, 2.0–2.8]) accelerated the relationship between frailty and incidence of PD and MCI compared with the standard treatment group (HR, 1.8 [95% CI, 1.5–2.1]; P for interaction=0.009). Conclusions This study found that the baseline frailty status was a possible marker for the incidence of a composite of PD and MCI. Intensive blood pressure control may strengthen this correlation. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT01206062.

Returning crop straw to the soil is an effective measure to increase soil fertility and maintain crop yield in agroecosystems. In this study, we conducted a 34-year field experiment (1984–2017) to investigate the relationships among the impacts of straw return on soil nutrients, phosphorus (P) fractions, phosphorus transformation-related functional microbial communities, and key genes in black soil. The results of the soil chemical properties showed that straw return could slow the decline in soil pH and increase soil nutrients, i.e., soil organic carbon (SOC), available K (AK), and available P (AP) concentrations, with the straw addition (PKS) treatment resulting in the highest soil AP and AK contents. Compared with conventional fertilizer (NPK) and conventional fertilizer with straw (NPKS), straw return alone (S) significantly increased the soil AP and AK contents by 1.1–42.8 and 38.3–114.3 mg/kg (p < 0.05), respectively. The results of the phosphorus fraction experiment indicated that long-term straw return promoted labile and moderately stable phosphorus content by altering the composition and increasing the relative abundances of functional genes regulating soil P activation (ugpQ, ppk, phoD, and gcd). The compositional changes in the phosphorus-cycling-related functional genes of the soil were affected mostly by soil total P (TP), AK, and NO3−-N, whereas pH, SOC, and available N (AN) were the main environmental factors influencing the phosphorus-cycling-related microbial community composition. These direct measurements provide insight into the soil phosphorus fractions, phosphorus-cycling-related functional genes, and microbial communities associated with straw returning, which enhances our understanding of the chemical and biogeochemical behavior of soil phosphorus upon straw incorporation.

This paper describes the synthesis of NIPU by using cardanol as starting material. A cardanol formaldehyde oligomer was first prepared through the reaction of cardanol and formaldehyde, catalyzed by citric acid. The resulting oligomer was then subjected to epoxidation with m-chloroperbenzoic acid to obtain an epoxide compound, which was subsequently used to fix carbon dioxide (CO2) and form a cyclic carbonate. Using this cyclic carbonate, along with an amine, cardanol-based isocyanate polyurethane (NIPU) was prepared. Different characterization methods, such as Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (NMR), gel permeation chromatography (GPC), and thermogravimetric analysis (TGA), were used to confirm the synthesis of the four intermediate products and NIPU in the reaction process. This study highlights the promise of bio-based NIPU as a sustainable alternative in a number of applications while offering insightful information on the synthesis and characterization of the material.

With the objectives of achieving “peak carbon” and “carbon neutrality”, accurately quantifying the carbon emissions of road transportation becomes crucial. It is challenging to accurately describe the energy consumption of vehicles at both temporal and spatial scales from a macro perspective. Therefore, focusing on the quantitative model of vehicle micro energy consumption and road meso energy consumption, this paper reviewed and summarized the energy consumption model of road traffic in terms of data collection, quantification accuracy, and scope of application. Based on this analysis, this paper identifies the challenges of the current road traffic energy consumption model. Finally, we look forward to future research directions for studying quantitative models of energy consumption from road transportation.

In the aerospace sector, the development of lightweight aircraft heavily relies on the utilization of advanced aluminum–lithium alloys as primary structural materials. This study introduces an investigation aimed at optimizing the composition of an Al-2.32Li-1.44Cu-2.78Mg-0.3Ag-0.3Mn-0.1Zr alloy. The optimization process involves the selection of alloying elements through the application of machine learning techniques, with a focus on expected improvements in the specific modulus of these alloys. Expanding upon the optimization of the benchmark alloy’s components, a more generalized modulus prediction model for Al–Li alloys was formulated. This model was then employed to evaluate the anticipated specific modulus of alloys within a virtual search space, encompassing substitutional elements. The study proceeded to validate six Al–Li alloys with a notably high potential for achieving an improved specific modulus. The results revealed that an alloy incorporating 0.96 wt.% of Ga as a substitutional element exhibited the most favorable microstructure. This alloy demonstrated optimal tensile strength (523 MPa) and specific modulus (31.531 GPa/(g·cm−3)), closely resembling that of the benchmark alloy. This research offers valuable insights into the application of compositional optimization to enhance the mechanical properties of Al–Li alloys. It emphasizes the significance of selecting alloying elements based on considerations such as their solid solubility thresholds and the expected enhancement of the specific modulus in Al–Li alloys.

Coffee cherries contain a crucial flavor-precursor and chemical substances influencing roasted bean quality, yet limited knowledge exists on metabolite changes during cherry ripening. Our study identified 1078 metabolites, revealing 46 core differential metabolites using a KEGG pathway analysis. At the GF vs. ROF stage, amino acid synthesis dominated; ROF vs. BRF featured nucleotide catabolism; BRF vs. PRF exhibited glycoside and flavonoid synthesis; and PRF vs. PBF involved secondary metabolite synthesis and catabolism. The PRF stage emerged as the optimal cherry-harvesting period. A correlation analysis identified core differential metabolites strongly linked to taste indicators, suggesting their potential as taste markers. Notably, nucleotides and derivatives exhibited significant negative correlations with glycosides and flavonoids during ripening. This research systematically analyzed flavor and active substances in green coffee beans during cherry ripening, offering valuable insights into substance formation in Coffea arabica L.

With the development of continuous speech recognition technology, users have put forward higher requirements in terms of speech recognition accuracy. Low-resource speech recognition, as a typical speech recognition technology under restricted conditions, has become a research hotspot nowadays because of its low recognition rate and great application value. Under the premise of low-resource speech recognition technology, this paper reviews the research status of feature extraction and acoustic models, and conducts research on resource expansion. Especially in terms of the technical challenges faced by this technology, solutions are proposed, and future research directions are prospected.

In this study, the 1991 rock avalanche, in Touzhai, Zhaotong, Yunnan, China, was considered the study object. The investigation of the landslide accumulation body revealed that the Touzhai rock avalanche accumulation body has the characteristics of wide gradation and poor sorting. A combination of field investigations, indoor and outdoor experiments, and numerical simulations were used to invert the occurrence and spreading range of rock avalanche-debris flow hazards. To invert and analyze its dynamics and the crushing process, a three-dimensional discrete element modeling was performed on the real terrain data. Simulation results showed that the movement time of the numerically simulated Touzhai rock avalanche was approximately 200 s. After 50 s of movement, the peak velocity reached 32 m/s, and the velocity gradually decayed after the sliding mass rubbed violently against the valley floor and collided with the mountain. Due to the meandering nature of the gully, the sliding mass makes its way down the gully and constantly collides with the mountain, making particles appear to climb, with some particles being blocked by the valley. After 150 s of movement, the average velocity rate decreased substantially, and the landslide-avalanche debris reached the mouth of the trench. After 200 s of movement, the average sliding velocity tends to 0 m/s, where the avalanche debris tends to stop and accumulate. When the rock avalanche movement reaches the mouth of the gully, the avalanche debris spreads to the sides as it is no longer bounded by the hills on either side of the narrow gully, eventually forming a ‘trumpet-shaped’ accumulation, and the granular flow simulation matched the findings of the landslide site accumulation.

The active peptide (APE) of Eupolyphaga sinensis Walker, which is prepared by bioenzymatic digestion, has significant antihyperlipidemic effects in vivo, but its mechanism of action on hyperlipidemia is not clear. Recent studies on amino acid metabolism suggested a possible link between it and hyperlipidemia. In this study, we first characterized the composition of APE using various methods. Then, the therapeutic effects of APE on hyperlipidemic rats were evaluated, including lipid levels, the inflammatory response, and oxidative stress. Finally, the metabolism-regulating mechanisms of APE on hyperlipidemic rats were analyzed using untargeted and targeted metabolomic approaches. The results showed that APE significantly reduced the accumulation of fat, oxidative stress levels, and serum pro-inflammatory cytokine levels. Untargeted metabolomic analysis showed that the mechanism of the hypolipidemic effect of APE was mainly related to tryptophan metabolism, phenylalanine metabolism, arginine biosynthesis, and purine metabolism. Amino-acid-targeted metabolomic analysis showed that significant differences in the levels of eight amino acids occurred after APE treatment. Among them, the expression of tryptophan, alanine, glutamate, threonine, valine, and phenylalanine was upregulated, and that of arginine and proline was downregulated in APE-treated rats. In addition, APE significantly downregulated the mRNA expression of SREBP-1, SREBP-2, and HMGCR. Taking these points together, we hypothesize that APE ameliorates hyperlipidemia by modulating amino acid metabolism in the metabolome of the serum and feces, mediating the SREBP/HMGCR signaling pathway, and reducing oxidative stress and inflammation levels.

The phenomenon of ordered self-assembly on solid substrates is a topic of interest in both fundamental surface science research and its applications in nanotechnology. The regulation and control of two-dimensional (2D) self-assembled supra-molecular structures on surfaces have been realized through applying external stimuli. By utilizing scanning tunneling microscopy (STM), researchers can investigate the detailed phase transition process of self-assembled monolayers (SAMs), providing insight into the interplay between intermolecular weak interactions and substrate–molecule interactions, which govern the formation of molecular self-assembly. This review will discuss the structural transition of self-assembly probed by STM in response to external stimuli and provide state-of-the-art methods such as tip-induced confinement for the alignment of SAM domains and selective chirality. Finally, we discuss the challenges and opportunities in the field of self-assembly and STM.

Crocodilians, which are a kind of animal secondary adaptation to an aquatic environment, their hindlimb can provide the power needed to engage in various life activities, even in low-oxygen water environments. The development of limbs is an important aspect of animal growth and development, as it is closely linked to body movement, support, heat production, and other critical functions. For the Chinese alligator, the hindlimb is one of the main sources of power, and its development and differentiation will directly influence the survival ability in the wild. Furthermore, a better understanding of the hindlimb developmental process will provide data support for the comparative evolutionary and functional genomics of crocodilians. In this study, the expression levels of genes related to hindlimb development in the Chinese alligator embryos during fetal development (on days 29, 35, 41, and 46) were investigated through transcriptome analysis. A total of 1675 differentially expressed genes (DEGs) at different stages were identified by using limma software. These DEGs were then analyzed using weighted correlation network analysis (WGCNA), and 4 gene expression modules and 20 hub genes were identified that were associated with the development of hindlimbs in the Chinese alligator at different periods. The results of GO enrichment and hub gene expression showed that the hindlimb development of the Chinese alligator embryos involves the development of the embryonic structure, nervous system, and hindlimb muscle in the early stage (H29) and the development of metabolic capacity occurs in the later stage (H46). Additionally, the enrichment results showed that the AMPK signaling pathway, calcium signaling pathway, HIF-1 signaling pathway, and neuroactive ligand–receptor interaction are involved in the development of the hindlimb of the Chinese alligator. Among these, the HIF-1 signaling pathway and neuroactive ligand–receptor interaction may be related to the adaptation of Chinese alligators to low-oxygen environments. Additionally, five DEGs (CAV1, IRS2, LDHA, LDB3, and MYL3) were randomly selected for qRT-PCR to verify the transcriptome results. It is expected that further research on these genes will help us to better understand the process of embryonic hindlimb development in the Chinese alligator.

Abstract With the continuous growth of the population and the continuous reduction of cultivated land, China’s food security is greatly threatened. In addition, China’s coal mining has been mainly underground mining, causing land subsidence and damaging existing cultivated land. This effect intensifies the contradiction between the growth of the risk population and the reduction of cultivated land. The reclamation of mining subsidence land with Yellow River sediment is often used as an effective way to improve the recovery rate of cultivated land. Shortening the reclamation time and realizing continuous filling are significant issues. The work presented in this paper studied the sediment settlement rate and consolidation time by combining theory, field filling and reclamation tests and numerical simulations. A field filling test study was carried out in the lowlands of Jibeiwang Village, Qihe County, Shandong Province, China. By calculating the drainage consolidation time, the consolidation factor of 0.015656 m2/d, and the time factor for sediment consolidation of 0.575 were determined. The sediment consolidation time for this test was 9.18 days. The calculation of sediment deposition rate and consolidation time is of great practical significance to guide the Yellow River sediment filling, realize continuous filling, and save reclamation time and cost.

The processability and ultimate quality of coffee (Coffea arabica) are determined by the composition of the matured fruits. The basis of genetic variation in coffee fruit quality could be explained by studying color formation during fruit maturation. Transcriptome profiling was conducted on matured fruits of four C. arabica varieties (orange colored fruits (ORF); purple colored fruits (PF); red colored fruits (RF) and yellow colored fruits (YF)) to identify key color-regulating genes, biosynthesis pathways and transcription factors implicated in fruit color formation. A total of 39,938 genes were identified in the transcriptomes of the four C. arabica varieties. In all, 2745, 781 and 1224 differentially expressed genes (DEGs) were detected in YF_vs_PF, YF_vs_RF and YF_vs_ORF, respectively, with 1732 DEGs conserved among the three pairwise groups. Functional annotation of the DEGs led to the detection of 28 and 82 key genes involved in the biosynthesis of carotenoids and anthocyanins, respectively. Key transcription factors bHLH, MYB, NAC, MADS, and WRKY implicated in fruit color regulation were detected. The high expression levels of gene-LOC113688784 (PSY), gene-LOC113730013 (β-CHY), gene-LOC113728842 (CCD7), gene-LOC113689681 (NCED) and gene-LOC113729473 (ABA2) in YF may have accounted for the yellow coloration. The differential expression of several anthocyanin and carotenoid-specific genes in the fruits substantially account for the purple (PF), red (RF), and orange (ORF) colorations. This study provides important insights into fruit color formation and variations in C. arabica and will help to develop coffee varieties with specific color and quality traits.

Abstract Blood–brain barrier (BBB) dysfunction has been recognized as an early pathological feature and contributing factor in multiple sclerosis. Endothelial-to-mesenchymal transition is a process associated with endothelial dysfunction leading to the disruption of vessel stability and barrier function, yet its functional consequence in multiple sclerosis remains unclear. Here, we demonstrated that endothelial-to-mesenchymal transition accompanied the blood–brain barrier dysfunction in several neurological disorders, especially in multiple sclerosis. The activity of transcription factor ETS1, which is highly expressed in endothelial cells (ECs) and responded to an inflammatory condition, is suppressed in the central nervous system (CNS) ECs in MS and its animal model experimental autoimmune encephalomyelitis. We identify ETS1 as a central regulator of endothelial-to-mesenchymal transition (EndMT) associated with the compromise of barrier integrity. These phenotypical and functional alterations can further induce high permeability, immune infiltration, and organ fibrosis in multiple sclerosis, thus promoting disease progression. Together, these results demonstrate a functional role of EndMT in blood–brain barrier dysfunction and propose ETS1 as a potential transcriptional switch of EndMT to target the development of multiple sclerosis.

A quantitative relationship between microstructure and tensile properties of Al–Zn–Mg–Cu alloys with various alloying degrees was investigated in this study. Three kinds of high strength Al–Zn–Mg–Cu alloys with little strength difference were used for the microstructural characteristic and statistical analysis. A strength model with high accuracy was established through the systematical calculation of strengthening theories, which was validated by the microstructure and ultimate tensile strength of a testing sample. The model gives the precise ratio of the contribution of precipitation hardening and even the component achieved from the bypass mechanism. Moreover, guidance on the regulation of precipitation phases was proposed from the strength model. It can be disclosed that the alloys will show the best strength when the precipitates of 7xxx series Al alloy are distributed near the right of critical radius, which is identified as 2.5 nm in this model.

Abstract To evaluate whether admission systolic blood pressure (SBP) is associated with the choice of initial antiplatelet therapy for minor stroke. Eligible patients retrospectively gathered from 2010 to 2018. Finally, 1312 of 1494 patients were divided into three groups: aspirin monotherapy (AM, n = 538, 41.0%), dual antiplatelet therapy with aspirin and load‐clopidogrel (clopidogrel loading dose of 300 mg on the first day, DAPT‐ALC, n = 474, 35.6%), and dual antiplatelet therapy with aspirin and unload‐clopidogrel (clopidogrel 75 mg daily with no loading dose, DAPT‐AUC, n = 300, 22.9%). The mean ± SD age of final patients was 62.0 ± 12.7 years old; 903 (70.9%) participants were male. Patients in the DAPT‐ALC group were more likely to be younger, to arrive earlier, and to have a lower proportion of intracerebral hemorrhage than those in the AM group. DAPT‐AUC group patients were more like to have a history of acute myocardial infarction and less likely to have a history of ICH than the AM group (4.7% vs. 1.7% and .3% vs. 2.6%, p

Abstract The assessment of the spatiotemporal evolution of habitat quality caused by land use changes can provide a scientific basis for the ecological protection and green development of mining cities. Taking Yanshan County as an example of a typical mining city, this article discussed the spatial pattern and evolution characteristics of habitat quality in 2000 and 2018 based on the ArcGIS platform and the InVEST model. The conclusions are as below: from 2000 to 2018, the area of farmland and construction land changed the most in the study area. Among them, the area of farmland decreased by 3.48%, and the area of industrial and mining land and construction land increased by 53.25%. Areas of low, relatively low and high habitat quality expanded, and areas of medium and relatively high habitat quality shrank, which is closely related to the distribution of land use. The areas with high habitat degradation degrees appear around cities, mining areas and watersheds, while the areas with low habitat degradation degrees are mainly distributed in the southern woodland. The distribution of cold and hot spots in the habitat quality distribution of Yanshan County presents a pattern of “hot in the south and cold in the north”. The results are of great significance to the precise implementation of ecosystem management decisions in mining cities and the creation of a landscape pattern of “beautiful countrysides, green cities, and green mines”.

Abstract Although an increasing number of patients benefit from immunotherapy and targeted therapies, melanoma remains incurable with increasing incidence. Drug repositioning and repurposing is an alternative strategy to discover and develop novel anticancer drugs or combined therapeutic regimens. In this study, we demonstrated that albendazole (ABZ), an Food and Drug Administration (FDA)-approved broad-spectrum antiparasitic agent, significantly inhibits the proliferation of melanoma cells in vitro and in vivo. RNA sequencing and flow cytometry analysis revealed that ABZ arrests melanoma cells at the G2/M phase of the cell cycle and induces cell apoptosis. More importantly, the CDK4/6 inhibitor palbociclib, as a member of the first and only class of highly specific CDK inhibitors approved for cancer treatment to date, showed significant synergistic effects with ABZ treatment in melanoma cells and mouse models. Taken together, we revealed a previously unappreciated function of ABZ in antimelanoma proliferation by inducing cell cycle arrest and apoptosis and provided a novel combined therapeutic regimen of ABZ plus CDK4/6 inhibitor treatment in melanoma.

Abstract Objective Subsequent vascular events are common after acute ischemic stroke during hospitalization. This study aimed to analyze the effectiveness of combination therapy with clopidogrel and aspirin among mild‐to‐moderate ischemic stroke patients treated within 72 h on the basis of a high‐intensity dose of statins. Methods In a retrospective and multicenter cohort study, acute (within 72 h of onset) mild‐to‐moderate stroke patients were divided into aspirin and clopidogrel‐aspirin groups on the basis of a high‐intensity dose of statin therapy. The primary outcome was compound vascular events during hospitalization. Cox's proportional hazards model was used to assess differences, with the study center as a random effect. Results Among the 506 patients meeting the eligibility criteria, all subjects received a high‐intensity dose of statins, including 20 mg rosuvastatin or 40 mg atorvastatin while in the hospital. In an unadjusted analysis, compound vascular events occurred in 7.2% of patients in the clopidogrel‐aspirin group compared with 13.7% of those in the aspirin group (p = 0.022). In a Cox proportional hazards regression analysis, clopidogrel‐aspirin was associated with a lower risk of compound vascular events (hazard ratio [95% CI], 0.47 [0.25–0.87]; p = 0.017) and ischemic vascular events (p = 0.008). Moderate and severe hemorrhage occurred in four patients (1.07%) in the clopidogrel‐aspirin group and three patients (2.30%) in the aspirin group (p = 0.626). Interpretation In this study based on high‐intensity statin therapy, clopidogrel‐aspirin reduced the risk of compound vascular events and did not increase the risk of hemorrhage during patients' hospitalization after mild‐to‐moderate ischemic stroke within 72 h.

Introduction: Photodynamic therapy (PDT) and photothermal therapy (PTT) are widely used in the treatment of tumors. However, their application in the treatment of clinical tumors is limited by the complexity and irreversible hypoxia environment generated by tumor tissues. To overcome this limitation, a nanoparticle composed of indocyanine green (ICG) and Fe-MOF-5 was developed.Methods: We prepared F-I@FM5 and measured its morphology, particle size, and stability. Its enzyme like ability and optical effect was verified. Then we used MTT, staining and flow cytometry to evaluated the anti-tumor effect on EMT-6 cells in vitro. Finally, the anti-tumor effect in vivo has been studied on EMT-6 tumor bearing mice.Results: For the composite nanoparticle, we confirmed that Fe-MOF-5 has the best nanozyme activity. In addition, it has excellent photothermal conversion efficiency and generates reactive oxygen species (ROS) under near-infrared light irradiation (808 nm). The composite nanoparticle showed good tumor inhibition effect in vitro and in vivo, which was superior to the free ICG or Fe-MOF-5 alone. Besides, there was no obvious cytotoxicity in major organs within the effective therapeutic concentration.Discussion: Fe-MOF-5 has the function of simulating catalase, which can promote the decomposition of excessive H2O2 in the tumor microenvironment and produce oxygen to improve the hypoxic environment. The improvement of tumor hypoxia can enhance the efficacy of PDT and PTT. This research not only provides an efficient and stable anti-tumor nano platform, but also has broad application prospects in the field of tumor therapy, and provides a new idea for the application of MOF as an important carrier material in the field of photodynamic therapy.

Archaeal viruses are one of the most mysterious parts of the virosphere because of their diverse morphologies and unique genome contents. The crenarchaeal viruses are commonly found in high temperature and acidic hot springs, and the number of identified crenarchaeal viruses is being rapidly increased in recent two decades. Over fifty viruses infecting the members of the order Sulfolobales have been identified, most of which are from hot springs distributed in the United States, Russia, Iceland, Japan, and Italy. To further expand the reservoir of viruses infecting strains of Sulfolobaceae, we investigated virus diversity through cultivation-dependent approaches in hot springs in Tengchong, Yunnan, China. Eight different virus-like particles were detected in enrichment cultures, among which five new archaeal viruses were isolated and characterized. We showed that these viruses can infect acidophilic hyperthermophiles belonging to three different genera of the family Sulfolobaceae, namely, Saccharolobus, Sulfolobus, and Metallosphaera. We also compared the lipid compositions of the viral and cellular membranes and found that the lipid composition of some viral envelopes was very different from that of the host membrane. Collectively, our results showed that the Tengchong hot springs harbor highly diverse viruses, providing excellent models for archaeal virus-host studies.

ObjectivePrevious observational studies have suggested that antioxidant imbalance is correlated with neurodegenerative diseases, while its cause–effect remains unclear. Thus, the goal of the present study is to explore the causal relationship between 11 antioxidant biomarkers and 3 most common neurodegenerative diseases [Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s disease (PD)].MethodsA bidirectional Mendelian randomization (MR) study was performed to investigate the causal effects by using 3 main methods (Variance Weighted (IVW), Weighted Median (WM), and MR-Egger regression) in the European population. The data of 11 antioxidant biomarkers were obtained from the open database by the most up-to-date Genome-Wide Association Studies (GWAS), the summary statistics of PD and ALS were obtained from the International Parkinson’s Disease Genomics Consortium (IPDGC) (33,674 cases, and 449,056 controls), and the International Amyotrophic Lateral Sclerosis Genomics Consortium (IALSC) (20,806 cases and 59,804 controls), respectively. For AD, we specifically used two recently published GWAS data, one from the International Genomics of Alzheimer’s Project (IGAP) (21,982 cases and 41,944 controls), and the other from a large meta-analysis (71,880 cases and 383,378 controls) as validation data.ResultsBased on the Bonferroni correction p

A small subpopulation of Vibrio splendidus AJ01 that was exposed to tetracycline at 10 times the minimal inhibitory concentration (MIC) still survived, named tetracycline-induced persister cells in our previous work. However, the formation mechanisms of persister is largely unknown. Here, we investigated tetracycline-induced AJ01 persister cells by transcriptome analysis and found that the purine metabolism pathway was significantly downregulated, which was consistent with lower levels of ATP, purine, and purine derivatives in our metabolome analysis. Inhibition of the purine metabolism pathway by 6-mercaptopurine (6-MP, inhibits ATP production), increased persister cell formation and accompanied with the decreasing intracellular ATP levels and increasing cells with protein aggresome. On the other hand, the persister cells had reduced intracellular tetracycline concentrations and higher membrane potential after 6-MP treatment. Inhibition of the membrane potential by carbonyl cyanide m-chlorophenyl hydrazone reversed 6-MP-induced persistence and resulted in higher levels of intracellular tetracycline accumulation. Meanwhile, cells with 6-MP treatment increased the membrane potential by dissipating the transmembrane proton pH gradient, which activated efflux to decrease the intracellular tetracycline concentration. Together, our findings show that reduction of purine metabolism regulates AJ01 persistence and is associated with protein aggresome formation and intracellular tetracycline efflux.

Background: As the coronavirus disease 2019 (COVID-19) pandemic progressed, especially with the emergence of the Omicron variant, the proportion of infected children and adolescents increased significantly. Some treatment such as Chinese herbal medicine has been administered for COVID-19 as a therapeutic option. Jin-Zhen Oral Liquid is widely used for pediatric acute bronchitis, while the efficacy and safety in the treatment of pediatric COVID-19 are unclear.Methods: We conducted a randomized controlled, open-label, multicenter, non-inferiority clinical study involving hospitalized children with mild to moderate COVID-19. Children eligible for enrollment were randomly assigned in a 1:1 ratio to Jin-Zhen Oral Liquid (the treatment group) and Jinhua Qinggan Granules (the positive control group) and received the respective agent for 14 days, followed by a 14-day follow-up after discontinuation of the treatment. The primary efficacy endpoint was the time to first negative viral testing. The secondary endpoints were the time and rate of major symptoms disappearance, duration of hospitalization, and the proportion of symptoms changed from asymptomatic or mild to moderate or severe/critical illness. In addition, the safety end points of any adverse events were observed.Results: A total of 240 child patients were assigned randomly into the Jin-Zhen Oral Liquid (117 patients) and Jinhua Qinggan Granules (123 patients) groups. There was no significant difference of the baselines in terms of the clinical characteristics and initial symptoms between the two groups. After 14-day administration, the time to first negative viral testing in the Jin-Zhen group (median 6.0 days, 95% CI 5.0-6.0) was significantly shorter compared with the positive control Jinhua Qinggan Granules group (median 7.0 days, 95% CI 7.0-8.0). The time and rate of major clinical symptoms disappearance were comparable to the positive control. The symptom disappearance time of pharyngalgia and hospitalization duration were significantly shortened in the Jin-zhen Oral Liquid group. No participants in either group experienced post-treatment exacerbation to severe or critical illness. No adverse events were observed in the Jin-Zhen Oral Liquid treatment group (0.0%) while 1 patient with adverse events occurred in the positive control Jinhua Qinggan granules group (0.8%). No serious adverse events were observed during the study period in both groups.Conclusion: Jin-Zhen Oral Liquid is safe and effective in the treatment of mild to medium COVID-19 in children. It is non-inferior to Jinhua Qinggan granules in shortening the time to first negative viral testing, the time and rate of major clinical symptoms disappearance, and the hospitalization duration. The results suggest that Jin-Zhen Oral Liquid can be a recommended drug for treatment of pediatric COVID-19 patients.

Automated counting of grape berries has become one of the most important tasks in grape yield prediction. However, dense distribution of berries and the severe occlusion between berries bring great challenges to counting algorithm based on deep learning. The collection of data required for model training is also a tedious and expensive work. To address these issues and cost-effectively count grape berries, a semi-supervised counting of grape berries in the field based on density mutual exclusion (CDMENet) is proposed. The algorithm uses VGG16 as the backbone to extract image features. Auxiliary tasks based on density mutual exclusion are introduced. The tasks exploit the spatial distribution pattern of grape berries in density levels to make full use of unlabeled data. In addition, a density difference loss is designed. The feature representation is enhanced by amplifying the difference of features between different density levels. The experimental results on the field grape berry dataset show that CDMENet achieves less counting errors. Compared with the state of the arts, coefficient of determination (R2) is improved by 6.10%, and mean absolute error and root mean square error are reduced by 49.36% and 54.08%, respectively. The code is available at https://github.com/youth-tang/CDMENet-main.

ObjectiveTo evaluate the association between gestational weight gain (GWG) and adverse neonatal outcomes in women who conceived using assisted reproductive technology (ART).MethodsThe National Vital Statistics System (NVSS) 2019-2021 provided data for this retrospective cohort study. Adverse neonatal outcomes included premature birth, small for gestational age (SGA), large for gestational age (LGA), macrosomia, low birth weight (LBW), and other abnormal conditions. Any adverse outcome was defined as at least one of the above six outcomes. Multivariate logistic regression analysis was employed to evaluate the associations between GWG and different outcomes, after adjusting for confounding factors. These associations were further assessed in subgroups of maternal age at delivery, paternal age at delivery, preconception body mass index (BMI), gestational age, maternal race, parity, gestational diabetes, and gestational hypertension.ResultsTotally 108201 women were included, with 22282 in the insufficient GWG group, 38034 in the sufficient GWG group, and 47885 in the excessive GWG group. Women with insufficient GWG [odds ratios (OR) = 1.11, 95%CI: 1.07-1.16, PConclusionInsufficient GWG and excessive GWG were associated with increased risks of any adverse outcome than sufficient GWG in women who conceived with ART, indicating the applicability of recommended GWG by the Institute of Medicine (IOM) in this population.

Abstract Multipores engineering composed of micro/mesopores is an effective strategy to improve potassium storage performance via providing enormous adsorption sites and shortened ions diffusion distance. However, a detailed exploration of the role played by macropores in potassium storage is still lacking and has been barely reported until now. Herein, a superstructure carbon hexahedron (DGN‐900) is synthesized using poly tannic acid (PTA) as precursor. Due to the spatially confined two‐step local contraction of PTA along different directions and dimensions during pyrolysis, defective nanosheets with macropores are formed, while realizing a balance between defects content and graphitization degree by regulating temperature. The presence of macropores is conducive to accelerating electrolyte ions rapid infiltration within electrode, and its pore volume can accommodate electrode structure fluctuation upon cycling, while the most suitable ratio of defects to graphitic provides rich ions adsorption sites and sufficient electrons transfer channels, simultaneously. These advantages enable a prominent electrochemical performance in DGN‐900 electrode, including high rate (202.9 mAh g−1 at 2 A g−1) and long cycling stability over 2000 cycles. This unique fabrication strategy, that is, defects engineering coupled with macropores structure, makes fast and durable potassium storage possible.

Power load forecasting (PLF) has a positive impact on the stability of power systems and can reduce the cost of power generation enterprises. To improve the forecasting accuracy, more information besides load data is necessary. In recent years, a novel privacy-preserving paradigm vertical federated learning (FL) has been applied to PLF to improve forecasting accuracy while keeping different organizations’ data locally. However, two problems are still not well solved in vertical FL. The first problem is a lack of a full data-processing procedure, and the second is a lack of enhanced privacy protection for data processing. To address it, according to the procedure in a practical scenario, we propose a vertical FL XGBoost-based PLF, where multiparty secure computation is used to enhance the privacy protection of FL. Concretely, we design a full data-processing PLF, including data cleaning, private set intersection, feature selection, federated XGBoost training, and inference. Furthermore, we further use RSA encryption in the private set intersection and Paillier homomorphic encryption in the training and inference phases. To validate the proposed method, we conducted experiments to compare centralized learning and vertical FL on several real-world datasets. The proposed method can also be directly applied to other practical vertical FL tasks.

This study investigated glass ceramics produced using coal gasification slag (CGS) and petrochemical incineration fly ash (PIFA) to immobilize hazardous heavy metals such as Cr and As. However, the crystallization kinetics and stabilization behavior mechanism of different heavy metals in the petrochemical incineration fly ash-derived glass-ceramics remains unclear. And X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and inductively coupled plasma mass spectrometry were used to characterize glass and crystalline products. In this paper, we reported the crystallization kinetics and chemical leaching characteristics of the glass ceramic. A low crystallization activation energy of 121.49 kJ/mol was achieved from crystallization peak of several different heating rates around 850°C, implying that it is easier to produce the glass ceramics at that temperature. The Avrami parameter of the former crystallization was determined to be 1.23 ± .12, which indicated two-dimensional crystal growth with heterogeneous nucleation. The toxicity characteristic leaching procedure results indicated that the heavy metals were well solidified, and that the leaching concentration was significantly lower than the limit specified by governmental agencies. The potentially toxic element index of the parent glass and the two glass ceramics were 11.7, 5.8, and 3.6, respectively. Therefore, the conversion of hazardous petrochemical incineration fly ash and other solid waste into environmentally friendly glass ceramics shows considerable potential and reliability.

IntroductionOral microbial homeostasis is a key factor affecting oral health, and saliva plays a significant role in maintaining oral microbial homeostasis. The submandibular gland (SMG) and sublingual gland (SLG) together produce the most saliva at rest. Organic ingredients, including antimicrobial proteins, are rich and distinctive and depend on the type of acinar cells in the SMG and SLG. However, the functions of the SMG and SLG in maintaining oral microbial homeostasis have been difficult to identify and distinguish, given their unique anatomical structuresMethodsIn this study, we independently removed either the SMG or SLG from mouse models. SMGs were aseptically removed in three mice in the SMG-removal group, and SLGs were aseptically removed in three mice in the SLG-removal group. Three mice from the sham-operated group were only anesthetized and incised the skin. After one month, we analyzed their oral microbiome through 16S rRNA sequencing. And then, we analyzed each gland using proteomics and single-cell RNA sequencing.ResultsOur study revealed that the microbiome balance was significantly disturbed, with decreased bacterial richness, diversity, and uniformity in the groups with the SMG or SLG removed compared with the sham-operated group. We identified eight secreted proteins in the SMG and two in the SLG that could be involved in maintaining oral microbial homeostasis. Finally, we identified multiple types of cells in the SMG and SLG (including serous acinar, mucinous acinar, ductal epithelial, mesenchymal, and immune cells) that express potential microbiota homeostasis regulatory proteins. Our results suggest that both the SMG and SLG play crucial roles in maintaining oral microbial homeostasis via excretion. Furthermore, the contribution of the SMG in maintaining oral microbial homeostasis appears to be superior to that of the SLG. These findings also revealed the possible antimicrobial function of gland secreta.DiscussionOur results suggest that control of oral microbial dysbiosis is necessary when the secretory function of the SMG or SLG is impaired. Our study could be the basis for further research on the prevention of oral diseases caused by microbial dysbiosis.

BackgroundGlioma is one of the most typical tumors in the central nervous system with a poor prognosis, and the optimal management strategy remains controversial. Lactate in the tumor microenvironment is known to promote cancer progression, but its impact on clinical outcomes of glioma is largely unknown.MethodsGlioma RNA-seq data were obtained from TCGA and GCGA databases. Lactate metabolism genes (LMGs) were then evaluated to construct an LMG model in glioma using Cox and LASSO regression. Immune cell infiltration, immune checkpoint gene expression, enriched pathways, genetic alteration, and drug sensitivity were compared within the risk subgroups. Based on the risk score and clinicopathological features, a nomogram was developed to predict prognosis in patients with glioma.ResultsFive genes (LDHA, LDHB, MRS2, SL16A1, and SL25A12) showed a good prognostic value and were used to construct an LMG-based risk score. This risk score was shown as an independent prognostic factor with good predictive power in both training and validation cohorts (p < 0.001). The LMG signature was found to be correlated with the expression of immune checkpoint genes and immune infiltration and could shape the tumor microenvironment. Genetic alteration, dysregulated metabolism, and tumorigenesis pathways could be the underlying contributing factors that affect LMG risk stratification. The patients with glioma in the LMG high-risk group showed high sensitivity to EGFR inhibitors. In addition, our nomogram model could effectively predict overall survival with an area under the curve value of 0.894.ConclusionWe explored the characteristics of LMGs in glioma and proposed an LMG-based signature. This prognostic model could predict the survival of patients with glioma and help clinical oncologists plan more individualized and effective therapeutic regimens.

BackgroundStress hyperglycemia has served as a reliable biomarker to predict poor outcomes after ischemic stroke. However, recent studies have reported some contrary conclusions. Different stroke subtypes may respond inconsistently to stress hyperglycemia. The progression of intracranial atherosclerotic stenosis (ICAS) is tightly related to hyperglycemia. Thus, this study aims to determine the relationship between stress hyperglycemia and recurrent stroke in ischemic stroke patients with or without intracranial atherosclerotic stenosis.MethodsThis is a multicenter retrospective observational cohort study. Patients with acute minor ischemic stroke and eligible computed tomography and magnetic resonance imaging data were enrolled. The severity of stress hyperglycemia is measured by the stress hyperglycemia ratio (SHR). SHR was calculated based on fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels. The primary outcome was stroke recurrence during hospitalization. The interaction of SHR levels with the presence of ICAS on the primary outcome was investigated using univariable and multivariable Cox proportional hazards models. Restricted cubic splines were applied to determine the nonlinear relationship between SHR and primary outcome. A two-piecewise linear regression model was used to identify the threshold of SHR.ResultsA total of 610 participants were included in the study. The average age of the patients was 61.4 ± 12.9 years old, and approximately 70% of participants were males. A total of 189 (30.98%) patients had ICAS. The patients were categorized into 3 groups based on the tertiles of SHR. Compared with the group with a lower SHR, a higher SHR was significantly associated with the risk of stroke recurrence in the ICAS group (hazard ratio [HR], 8.52, 95% confidence interval [CI], 3.16-22.96, P

Advanced aluminum-lithium alloys are the key structural materials urgently needed for the development of light-weighted aircraft in the aerospace field. In this study, we employ a machine learning approach accompanied by domain knowledge to realize the accelerated design of aluminum-lithium alloy with high specific modulus and specific strength by identifying an optimal combination of key features through a three-step feature filtering of datasets containing 145 alloys. The maximum specific modulus in the experimental alloys that screened from the predicted results increases by 4 % compared with the maximum specific modulus in the comparative dataset. The specific modulus of the designed alloy with the best comprehensive performance increased by 12.6 % compared with the widely used 2195-T8 alloy while maintaining a similar specific strength. Machine learning shows appealing feasibility and reliability in the field of materials design.

Abstract Background Pantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis. PANK-associated neurodegeneration (PKAN), formerly known as Hallervorden–Spatz disease, is a rare, life-threatening neurologic disorder that affects the CNS and arises from mutations in the human PANK2 gene. Pantazines, a class of small molecules containing the pantazine moiety, yield promising therapeutic effects in an animal model of brain CoA deficiency. A reliable technique to identify the neurometabolic effects of PANK dysfunction and to monitor therapeutic responses is needed. Methods We applied 1H magnetic resonance spectroscopy as a noninvasive technique to evaluate the therapeutic effects of the newly developed Pantazine BBP-671. Results 1H MRS reliably quantified changes in cerebral metabolites, including glutamate/glutamine, lactate, and N-acetyl aspartate in a neuronal Pank1 and Pank2 double-knockout (SynCre + Pank1,2 dKO) mouse model of brain CoA deficiency. The neuronal SynCre + Pank1,2 dKO mice had distinct decreases in Glx/tCr, NAA/tCr, and lactate/tCr ratios compared to the wildtype matched control mice that increased in response to BBP-671 treatment. Conclusions BBP-671 treatment completely restored glutamate/glutamine levels in the brains of the mouse model, suggesting that these metabolites are promising clinically translatable biomarkers for future therapeutic trials.

The static headspace(HS) combined with gas chromatography-mass spectrometry(GC-MS) was used to analyze the volatile flavor compounds of Zanthoxylum bungeanum from 45 producing areas in Shanxi, Shandong, Sichuan and Gansu. Using automatic mass spectrometry deconvolution qualitative system(AMDIS) and Kováts Retention index(RI) analysis, a total of 99 volatile compounds were obtained. 79, 69, 68 and 63 volatile compounds were identified in Zanthoxylum bungeanum from Shanxi, Gansu, Shandong and Sichuan province. A variety of mathematical models were established to identify the origin. Among them, the Orthogonal partial least squares(OPLS-DA) model could accurately distinguish Zanthoxylum bungeanum samples from 4 provinces, the model fitting parameter Q2 was 0.84, and the 6 key difference substances(VIP>2) were piperonone, pinene, terpinene, 3-carene, ocirene and α-phellandrene. Further application of GC-MS full-spectrum data combined with Random Forest(RF) model for origin identification could successfully distinguish Zanthoxylum bungeanum from Shanxi, Gansu, Shandong and Sichuan provinces, with an accuracy rate of 100%.

In the current work, a fast θ scheme combined with the Legendre spectral method was developed for solving a fractional Klein–Gordon equation (FKGE). The numerical scheme was provided by the Legendre spectral method in the spatial direction, and for the temporal direction, a θ scheme of order O(τ2) with a fast algorithm was taken into account. The fast algorithm could decrease the computational cost from O(M2) to O(MlogM), where M denotes the number of time levels. In addition, correction terms could be employed to improve the convergence rate when the solutions have weak regularity. We proved theoretically that the scheme is unconditionally stable and obtained an error estimate. The numerical experiments demonstrated that our numerical scheme is accurate and efficient.

Long-term fertilization can result in changes in the nitrogen (N) cycle in maize rhizosphere soil. However, there have been few reports on the impacts of plant–soil–microbe regulatory mechanisms on the N cycle in soil. In this study, soil samples were collected from a long-term experimental site located at Jilin Agricultural University, Changchun City, Jilin Province, Northeast China. We then analyzed the changes in the functional genes related to the N cycle, soil enzyme activity, and maize root exudates under long-term fertilizer application using metagenomics and liquid chromatography analysis. We aimed to investigate the response of the N cycle to long-term fertilizers, the interaction among plant, soil, and microbes, and the effect of the plant–soil–microbe system on the N cycle. Long-term fertilization had a significant effect on soil N contents, N2O emissions, and enzyme activity related to the N cycle in maize rhizosphere soil. The functional genes of the N cycle were mainly enriched in the N degradation pathway in maize rhizosphere soil. N fertilizer application decreased the abundance of functional genes related to N fixation and degradation, denitrification, and assimilatory nitrate reduction (ANRA) and increased the abundance of functional genes participating in dissimilatory nitrate reduction (DNRA) and anaerobic ammonia oxidation/hydroxylamine oxidation. The soil environment was positively related to soil enzyme activity and negatively related to the microbial community composition and amino acids in root exudates. The contribution rate of microorganisms to the N cycle was the highest (r2 = 0.900), followed by amino acids (r2 = 0.836) and the soil environment (r2 = 0.832). Therefore, we concluded that N fertilizer is the main factor limiting the soil N cycle and that microorganisms are the main factor regulating the N cycle in the plant–soil–microorganism system.

Medical image segmentation can effectively identify lesions in medicine, but some small and rare lesions cannot be well identified. Existing studies do not take into account the uncertainty of the occurrence of diseased tissue, and the problem of long-tailed distribution of medical data. Meanwhile, the grayscale image obtained from Magnetic Resonance Imaging (MRI) detection has problems, such as the features being difficult to extract and invalid features being difficult to distinguish. In order to solve these problems, we propose a new weighted attention ResUNet (WA-ResUNet) and a class weight formula based on the number of images contained in the class, which improves the performance of the model in the low-frequency class and the overall effect of the model by improving the degree of attention paid to the valid features and invalid ones and rebalancing the learning efficiency among the classes. We evaluated our method on an uterine MRI dataset and compared it with the ResUNet. WA-ResUNet increased Intersection over Union (IoU) in the low-frequency class (Nabothian cysts) by 21.87%, and the overall mIoU increased by more than 6.5%.

The quality of oocytes determines the development potential of an embryo and is dependent on their timely fertilization after ovulation. Postovulatory oocyte aging is an inevitable factor during some assisted reproduction technology procedures, which results in poor fertilization rates and impairs embryo development. We found that fisetin, a bioactive flavonol contained in fruits and vegetables, delayed postovulatory oocyte aging in mice. Fisetin improved the development of aged oocytes after fertilization and inhibited the Sirt1 reduction in aged oocytes. Fisetin increased the GSH level and Sod2 transcription level to inhibit ROS accumulation in aged oocytes. Meanwhile, fisetin attenuated aging-induced spindle abnormalities, mitochondrial dysfunction, and apoptosis. At the molecular level, fisetin decreased aging-induced aberrant expression of H3K9me3. In addition, fisetin increased the expression levels of the mitochondrial transcription factor Tfam and the mitochondrial genes Co2 and Atp8 by upregulating Sirt1 in aged oocytes. Finally, inhibition of Sirt1 reversed the anti-aging effects of fisetin. Taken together, fisetin delayed postovulatory oocyte aging by upregulating Sirt1.

Abstract Disordered chromatin remodeling regulation has emerged as an essential driving factor for cancers. Imitation switch (ISWI) family are evolutionarily conserved ATP-dependent chromatin remodeling complexes, which are essential for cellular survival and function through multiple genetic and epigenetic mechanisms. Omics sequencing and a growing number of basic and clinical studies found that ISWI family members displayed widespread gene expression and genetic status abnormalities in human cancer. Their aberrant expression is closely linked to patient outcome and drug response. Functional or componential alteration in ISWI-containing complexes is critical for tumor initiation and development. Furthermore, ISWI-non-coding RNA regulatory networks and some non-coding RNAs derived from exons of ISWI member genes play important roles in tumor progression. Therefore, unveiling the transcriptional regulation mechanism underlying ISWI family sparked a booming interest in finding ISWI-based therapies in cancer. This review aims at describing the current state-of-the-art in the role of ISWI subunits and complexes in tumorigenesis, tumor progression, immunity and drug response, and presenting deep insight into the physiological and pathological implications of the ISWI transcription machinery in cancers.

Abstract Parkinson’s disease (PD) is a multi-system neurodegenerative disorder. Patients with PD often suffer chronic pain. In the present study, we investigated motor, sensory and emotional changes in three different PD mice models. We found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treatment caused significant changes in all measurements. Mechanical hypersensitivity of PD model induced by MPTP peaked at 3 days and persisted for at least 14 days. Using Fos transgenic mice, we found that neurons in the anterior cingulate cortex (ACC) were activated after MPTP treatment. Inhibiting ACC by bilateral microinjection of muscimol significantly reduced mechanical hypersensitivity and anxiety-like responses. By contrast, MPTP induced motor deficit was not affected, indicating ACC activity is mostly responsible for sensory and emotional changes. We also investigated excitatory synaptic transmission and plasticity using brain slices of MPTP treated animals. While L-LTP was blocked or significantly reduced. E-LTP was not significantly affected in slices of MPTP treated animals. LTD induced by repetitive stimulation was not affected. Furthermore, we found that paired-pulse facilitation and spontaneous release of glutamate were also altered in MPTP treated animals, suggesting presynaptic enhancement of excitatory transmission in PD. Our results suggest that ACC synaptic transmission is enhanced in the animal model of PD, and cortical excitation may play important roles in PD related pain and anxiety.

Abstract Human Dachshund homolog 1 (DACH1) is usually defined as a tumor suppressor, which plays an influential role in tumor growth and metastasis in a variety of cancer cells. However, the underlying mechanisms in these process are not yet fully clarified. In this study, DACH1 inhibited the invasion and metastasis of breast cancer cells by decreasing MMP9 expression. Mechanistically, DACH1 represses the transcriptional level of MMP9 by interacting with p65 and c-Jun at the NF-κB and AP-1 binding sites in MMP9 promoter respectively, and the association of DACH1 and p65 promote the recruitment of HDAC1 to the NF-κB binding site in MMP9 promoter, resulting in the reduction of the acetylation level and the transcriptional activity of p65. Accordingly, the level of MMP9 was decreased. In conclusion, we found a new mechanism that DACH1 could inhibit the metastasis of breast cancer cells by inhibiting the expression of MMP9.

Protein neddylation is catalyzed by a three-enzyme cascade, namely an E1 NEDD8-activating enzyme (NAE), one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases. The physiological substrates of neddylation are the family members of cullin, the scaffold component of cullin RING ligases (CRLs). Currently, a potent E1 inhibitor, MLN4924, also known as pevonedistat, is in several clinical trials for anti-cancer therapy. Here we report the discovery, through virtual screening and structural modifications, of a small molecule compound HA-1141 that directly binds to NAE in both in vitro and in vivo assays and effectively inhibits neddylation of cullins 1–5. Surprisingly, unlike MLN4924, HA-1141 also triggers non-canonical endoplasmic reticulum (ER) stress and PKR-mediated terminal integrated stress response (ISR) to activate ATF4 at an early stage, and to inhibit protein synthesis and mTORC1 activity at a later stage, eventually leading to autophagy induction. Biologically, HA-1141 suppresses growth and survival of cultured lung cancer cells and tumor growth in in vivo xenograft lung cancer models at a well-tolerated dose. Taken together, our study has identified a small molecule compound with the dual activities of blocking neddylation and triggering ER stress, leading to growth suppression of cancer cells.