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Chinese tongue sole (Cynoglossus semilaevis) is a traditional, nutrient rich and economically valuable fish that is important for mariculture in China. It has small visceral masses, few spines, with tender and tasty flesh. Studies on the sexing mechanism of fish were carried out since the revelation of sexual reversal and hermaphroditism in the eel. Sex is the most common biological phenomenon and there are significant differences in morphology, reproductive strategies, and behavior between females and males of many organisms. Sole is a typical representative of the heterogeneous growth of males and females: adult females are approximately 2–4 times larger than males. This has constrained the sustainable development of the sole culture industry. Why do females grow faster than males? Do sex differentiation-related genes play a role in sex determination and size heteromorphism in sole? Answering these questions has important implications and applications in the genetic improvement and development of sole farming.Rimoc1 encodes a protein in the inner mitochondrial membrane that is involved in regulating the activity of complex Ⅰ of the mitochondrial respiratory chain that affects mitochondrial respiratory function. Rimoc1 interacts with the NDUFAF1 subunit of complex Ⅰ in the inner mitochondrial membrane and enhances its affinity for NADH. This increases the catalytic activity of complex Ⅰ and increases the rate of electron transfer in the mitochondrial respiratory chain. In addition, RIMOC1 interacts with proteins in other mitochondrial respiratory chain complexes (such as complex Ⅲ and complex Ⅳ) and may play a role in regulating the overall stability and function of the mitochondrial respiratory chain.This study aimed to investigate the expression differences of the rimoc1 gene in male and female Chinese tongue sole and determine its potential relationship with sex and growth. Rimoc1 expression was highest in the ovaries and muscles of females; it was not expressed in male tissues. Interestingly, its expression was relatively stable in the ovaries, but increased at 1.5- and 3-years post-hatching. Knocking out rimoc1 through siRNA interference in cell lines significantly reduced the expression levels of growth-related gene igf1, and sex differentiation-related genes sox9b and foxl2, while sox9a expression increased. Promoter activity analysis further demonstrated that the rimoc1 promoter strongly responded to transcription factors C/EBPdelta, Sox2, and c-Jun. This suggested their potential role in regulating rimoc1. Sex determination in semislipped sole occurs at approximately 50 days, while gonadal differentiation begins at 60 days. However, differentiation at the cellular level is relatively delayed, with ovarian cell differentiation usually occurring at 90–120 days with the emergence of an ovarian cavity followed by continued oocyte differentiation and sexual maturity at approximately 2 years of age. Thus, high rimoc1 expression at 90 days is consistent with the differentiation of naturally growing ovarian cells in semi-smooth tongue sole.Analysis of promoter activity showed that rimoc1 was transcriptionally active at 981 bp upstream and had strong initiation activity. The activity was enhanced following cotransfection with three transcription factors (C/EBPalpha, Sox2, and C-Jun), although only the C/EBPalpha group was significantly different. This suggested that these three transcription factors exert an enhancing effect on rimoc1 transcription. It is known that C/EBPalpha plays a major role in keratinocyte and adipocyte differentiation. However, its regulation of rimoc1 in hemipterous sole requires further investigation.There are few reports on the function of rimoc1 in sexual differentiation. Therefore, we performed the first functional investigation of rimoc1 by siRNA-mediated RNA interference in an ovarian cell line. Quantitative polymerase chain reaction showed that the expression levels of igf1, sox9a, sox9b, and foxl2 changed at different degrees after rimoc1 gene interference compared to the control group; sox9a expression was up-regulated, while the expression of igf1, sox9b, and foxl2 was down-regulated. Fish igf1 is closely related to reproductive function and gonadal development. Tilapia igf1 expression was detected from the early stages of oogenesis till oocyte maturation. At the same time, Igf1 is involved in regulating growth hormones and growth. Sexual growth dimorphism begins to appear in one-year old half-sauropod sole. The quantification of different developmental stages shows that rimoc1 expression starts to increase at 180 days until its peak expression at 1.5 years of age. It is worthwhile investigating whether rimoc1 has a potential regulatory function in growth.Sox9 is a key transcription factor that plays an important role in regulating the proliferation and differentiation of various cell types. It has a critical role in embryonic development, with expression occurring throughout this period. Its level is maintained in adult tissues and plays an important role in the repair of postnatal damage in endodermal and ectodermal organs. It has a role in sex differentiation, with sox9a and cyp19a together forming a regulatory pathway for sexual differentiation. We hypothesize that rimoc1 is involved in ovarian development and oogenesis by regulating the steroid hormone pathway. Sox9b is highly expressed in the gonads of early semi-smooth sole, and rimoc1 knockdown results in its reduced expression. This suggests that Rimoc1 and Sox9b act together to regulate Foxl2 and play a role in sex determination and differentiation, ovarian development and maintenance, embryonic development, and immune regulation in the animal. The foxl2 gene positively regulates ovarian differentiation in mice, and its sustained expression inhibits abnormal differentiation of ovarian cells to testicular cells during growth and development, thereby maintaining the female sex. Meanwhile foxl2 deletion can lead to poor ovarian development, and even female sterility. Rimoc1 knockdown results in its reduced expression, suggesting that rimoc1 may be closely associated with ovarian development in hemipelagic sole. Therefore, a deeper understanding of the function and regulatory mechanisms of rimoc1 may be the key to resolving sexual growth dimorphism.Our results suggest that rimoc1 plays a crucial role in sex differentiation and growth of Chinese tongue sole. These findings provide a foundation for further investigations into the sexual growth dimorphism of this species.

Background: Following recent research advancements, an increasing level of evidence had been published to indicate that celastrol exerted a therapeutic effect on a range of nervous system diseases. This study therefore aimed to investigate the potential involvement of celastrol on ferroptosis and the blood-brain barrier disruption in intracerebral haemorrhage. Methods: We established a rat intracerebral haemorrhage and adrenal pheochromocytoma cell (PC12) OxyHb models using an ACSL4 overexpression vector. Ferroptosis-related indices were assessed using corresponding assay kits, and immunofluorescence and flow cytometry were used to measure reactive oxygen species (ROS) levels. Additionally, quantitative PCR (qPCR) and western blot analyses were conducted to evaluate the expression of key proteins and elucidate the role of celastrol in intracerebral haemorrhage (ICH). Results: Celastrol significantly improved neurological function scores, blood-brain barrier integrity, and brain water content in rats with ICH. Moreover, subsequent analysis of ferroptosis-related markers, such as Fe2+, ROS, MDA, and SOD, suggested that celastrol exerted a protective effect against the oxidative damage induced by ferroptosis in ICH rats and cells. Furthermore, Western blotting indicated that celastrol attenuated ferroptosis by modulating the expression levels of key proteins, including acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and anti-transferrin receptor 1 (TFR1) both in vitro and in vivo. ACSL4 overexpression attenuated the neuroprotective effects of celastrol on ICH in vitro. Molecular docking analysis revealed that celastrol interacted with ACSL4 via the GLU107, GLN109, ASN111, and LYS357 binding sites. Conclusions: Celastrol exerted antioxidant properties and aids in neurological recovery after stroke by suppressing ACSL4 expression during ferroptosis. As such, this drug represented a promising pharmaceutical candidate for the treatment of ICH.

Abstract One of the focal points in the field of intelligent transportation is the intelligent control of traffic signals (TS), aimed at enhancing the efficiency of urban road networks through specific algorithms. Deep Reinforcement Learning (DRL) algorithms have become mainstream, yet they suffer from inefficient training sample selection, leading to slow convergence. Additionally, enhancing model robustness is crucial for adapting to diverse traffic conditions. Hence, this paper proposes an enhanced method for traffic signal control (TSC) based on DRL. This approach utilizes dueling network and double q-learning to alleviate the overestimation issue of DRL. Additionally, it introduces a priority sampling mechanism to enhance the utilization efficiency of samples in memory. Moreover, noise parameters are integrated into the neural network model during training to bolster its robustness. By representing high-dimensional real-time traffic information as matrices, and employing a phase-cycled action space to guide the decision-making of intelligent agents. Additionally, utilizing a reward function that closely mirrors real-world scenarios to guide model training. Experimental results demonstrate faster convergence and optimal performance in metrics such as queue length and waiting time. Testing experiments further validate the method's robustness across different traffic flow scenarios.

Abstract The dry reforming of methane provides an attractive route to convert greenhouse gases (CH4 and CO2) into valuable syngas, so as to resolve the carbon cycle and environmental issues. However, the development of high-performance catalysts remains a huge challenge. Herein, we report a 0.6% Ir/CeO2−x catalyst with a metal-support interface structure which exhibits high CH4 (~72%) and CO2 (~82%) conversion and a CH4 reaction rate of ~973 μmolCH4 gcat −1 s−1 which is stable over 100 h at 700 °C. The performance of the catalyst is close to the state-of-the-art in this area of research. A combination of in situ spectroscopic characterization and theoretical calculations highlight the importance of the interfacial structure as an intrinsic active center to facilitate the CH4 dissociation (the rate-determining step) and the CH2* oxidation to CH2O* without coke formation, which accounts for the long-term stability. The catalyst in this work has a potential application prospect in the field of high-value utilization of carbon resources.

ObjectiveTo evaluate the antitumor effects of diisopropylamine dichloroacetate (DADA) alone or in combination with chemotherapy/radiotherapy/immunotherapy in NSCLC and explore the underlying mechanisms involved.MethodsMTT, UV spectrophotometry, flow cytometry, fluorescence microscopy, and clonogenic survival assays were used. In LLC mouse models, the antitumor effects of radiotherapy, DADA, and the anti-PD-1 antibody alone or in combination were evaluated, and the T cell numbers were evaluated in different groups.ResultsDADA significantly inhibited lactate production and promoted apoptosis in NSCLC in vitro. Compared with pemetrexed or DADA alone, the combination of DADA with pemetrexed significantly inhibited proliferation and promoted apoptosis (p

Background: Intracranial metastasis of gastrointestinal stromal tumors (GISTs) is uncommon and the optimal management for these patients remains undefined. The introduction of selective tyrosine kinase inhibitors (TKI) has drastically improved survival in patients with GISTs. However, its efficacy in patients with intracranial metastasis of GISTs is uncertain due to poor penetration of the blood brain barrier. The role of surgery and radiotherapy in these patients has also not been established. No large-scale studies exist, and the literature is limited to case reports. We report a case treated at our institution, conducted a literature review of existing case reports, and discussed the optimal management of patients with intracranial metastasis of GISTs. Methods: A literature review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All studies with intracranial metastasis of GISTs were included, with data extracted and analyzed in totality. Results: 26 cases were included in the review. The median time to diagnosis of intracranial metastasis in patients with previously known GISTs was 66 months. Solitary metastasis was seen in 16 cases (59.3 %). 18 patients (69.72 %) underwent surgical resection; 14 had additive therapy with 9 receiving TKI. The mean duration of follow up was 11 months. Clinical response was seen in 3 patients in the non-surgical group, all 3 were treated with TKI alone. Conclusion: The effectiveness of TKI in intracranial GISTs metastasis is seen both as first-line therapy for asymptomatic lesions and as an additive treatment post-surgery. Surgery retains a key role in establishing histological and molecular diagnosis and for symptomatic relief of mass effect.

Summary: Background: MIL62, a novel glycoengineered type Ⅱ anti-CD20 monoclonal antibody, with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab in vitro and in vivo, respectively. Methods: This multicentre, single-arm, phase 1b/2 trial aimed to explore the efficacy, pharmacokinetics, and safety of MIL62 combined with lenalidomide in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL). Eligible patients included those who had histopathologically confirmed CD20 positive FL (grade 1–3a) or MZL and failed to be treated with rituximab. Patients received intravenously infused MIL62 1000 mg (cycle 1: day 1, 15; cycles 2–8: day 1, cycles 10 and 12: day 1) combined with oral lenalidomide (once a day, days 2–22, the initial dose was 10 mg, and the maximum dose was 20 mg) for 12 cycles, 28 days as a cycle. The primary endpoint was objective response rate (ORR) assessed by investigator per Lugano 2014 criteria every 3 cycles. This study was registered in ClinicalTrials.gov (NCT04110301). Findings: Between November 22, 2019 and December 22, 2020, 54 patients were enrolled from 11 hospitals in China and received study treatment. Fifty patients were included in the efficacy analysis set, and 43 patients (86%, 95% CI: 73, 94) achieved objective response, meeting the pre-specified primary endpoint. Disease control rate was 96% (48/50, 95% CI: 86, 100), proportion of patients with duration of response (DoR) > 6 months was 77% (33/43). The median follow-up for survival was 12.3 months (IQR 12.0–12.6). The 1-year progression-free survival rate was 72% (95% CI: 57, 83), 9-month DoR rate was 74% (95% CI: 58, 85), and 1-year overall survival rate was 98% (95% CI: 85, 100). Most common TRAEs were neutropenia (93%, 50/54), leukopenia (85% 46/54), thrombocytopenia (61% 33/54), lymphopenia (32% 17/54), and alanine aminotransferase increased (20% 11/54). Interpretation: MIL62 combined with lenalidomide showed promising efficacy in patients with R/R FL and MZL. A multicentre, randomized, open-label, phase Ⅲ trial of MIL62 combined with lenalidomide versus lenalidomide in anti-CD20 monoclonal antibody refractory FL patients is ongoing (NCT04834024). Funding: Beijing Mabworks Biotech Co. Ltd, Beijing China and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

Abstract Purpose This study evaluates biochar from crop residues as a solution to soil degradation in continuous monoculture within greenhouse agriculture, focusing on its impact on soil microbial communities and cucumber plant growth. Methods We analyzed biochar derived from tomato straw (TSB), sweet pepper straw (SPSB), and eggplant straw (ESB), assessing their nutrient content, cation exchange capacity, and adsorption rates. This study examined the effects of three concentrations (2.5%, 5%, and 7.5% w/w) of the more promising SPSB on soil properties and cucumber growth. Results SPSB showed significantly higher levels of nitrogen, phosphorus, and potassium, along with superior adsorption capacity compared to TSB and ESB. The 5% w/w SPSB concentration notably improved cucumber growth, increasing plant height by 13.01%, stem thickness by 20.79%, leaf area by 50.26%, and dry weight by 58.56% relative to the control. High-throughput sequencing revealed this concentration significantly altered soil microbial community structure, enhancing bacterial and fungal diversity. It increased beneficial bacterial groups (Firmicutes, Actinobacteria, Bacillus) and modified fungal communities, with a decrease in Ascomycota and Aspergillus and shifts in Penicillium abundance. Functional genomic analysis indicated enrichment in bacterial metabolic pathways and fungal replication and expression genes. Conclusion SPSB, especially at a 5% w/w concentration, emerges as an effective soil amendment in greenhouses affected by continuous monoculture. This approach represents a sustainable method to enhance soil health and crop productivity.

Abstract Background Functional role of filum terminale (FT) was not well studied though it contains structure basis for nerve impulse conduction. We aimed to explore the possible functions of the FT from the perspective of triggered electromyography (EMG) during surgery. Methods We retrospectively reviewed intraoperative neurophysiological monitoring data from pediatric patients who underwent intradural surgeries at the lumbar level in Shanghai Children’s. Hospital from January 2018 to March 2023. Altogether 168 cases with complete intraoperative neurophysiological recordings of the FT were selected for further analysis. Triggered EMG recordings of the filum originated from two main types of surgeries: selective dorsal rhizotomy (SDR) and fatty filum transection. Results 96 cases underwent SDR and 72 cases underwent fatty filum transection. Electrical stimulation of the FT with fatty infiltration did not elicit electromyographic activity in the monitored muscles with the maximum stimulus intensity of 4.0 mA, while the average threshold for FT with normal appearance was 0.68 mA, and 89 out of 91 FT could elicit electromyographic responses in monitored channels. The threshold ratio of filum to motor nerve roots at the same surgical segment was significantly higher in patients with fatty filum, and a cut-off point of 21.03 yielded an area under curve of 0.943, with 100% sensitivity and 85.71% specificity. Conclusion Filum with normal appearance can elicit electromyographic activity in the lower limbs/anal sphincter similar to the performance of the cauda equina nerve roots. The threshold of fatty filum is different from that of normal appearing FT. Triggered EMG plays an important role in untethering surgeries.

Abstract Objective To explore the clinical features, diagnosis, treatment and prognosis of Langerhans cell histiocytosis (LCH) of the skull in children. Methods This study retrospectively summarized the clinical manifestations, treatment methods and follow-up status of children with skull LCH who were admitted to the Department of Neurosurgery of Shanghai Children’s Hospital from January 2014 to June 2021. Results A total of 23 patients confirmed by histology as LCH received hospitalization treatment, including 14 males and 9 females, aged (5.76 ± 3.86) years old. The clinical manifestations were mostly incidentally discovered head masses that gradually enlarged (19 cases, 82.61%). Only 2 cases are affected by multiple systems, while the rest are affected by single systems. 9 patients were involved in multiple skull lesions, and 14 patients had local skull lesions. All patients underwent surgical intervention, with 17 patients undergoing total resection and 6 patients undergoing biopsy. 21 patients received chemotherapy after surgery. The median follow-up was 2.46 years (range 0.33–6.83 years). 21 patients had their symptoms and signs under control or even resolved, and 2 patients experienced recurrence during follow-up. The overall control rate reached 91.30%. Conclusion Personalized treatment plans according to different clinical types. Regular outpatient follow-up is crucial to monitor disease recurrence and late effects.

Abstract In mice, periodic cycles of a fasting mimicking diet (FMD) protect normal cells while killing damaged cells including cancer and autoimmune cells, reduce inflammation, promote multi-system regeneration, and extend longevity. Here, we performed secondary and exploratory analysis of blood samples from a randomized clinical trial (NCT02158897) and show that 3 FMD cycles in adult study participants are associated with reduced insulin resistance and other pre-diabetes markers, lower hepatic fat (as determined by magnetic resonance imaging) and increased lymphoid to myeloid ratio: an indicator of immune system age. Based on a validated measure of biological age predictive of morbidity and mortality, 3 FMD cycles were associated with a decrease of 2.5 years in median biological age, independent of weight loss. Nearly identical findings resulted from a second clinical study (NCT04150159). Together these results provide initial support for beneficial effects of the FMD on multiple cardiometabolic risk factors and biomarkers of biological age.

The combination of mobile edge computing (MEC) and radio frequency-based wireless power transfer (WPT) presents a promising technique for providing sustainable energy supply and computing services at the network edge. This study considers a wireless-powered mobile edge computing system that includes a hybrid access point (HAP) equipped with a computing unit and multiple Internet of Things (IoT) devices. In particular, we propose a novel multi-user cooperation scheme to improve computation performance, where collaborative clusters are dynamically formed. Each collaborative cluster comprises a source device (SD) and an auxiliary device (AD), where the SD can partition the computation task into various segments for local processing, offloading to the HAP, and remote execution by the AD with the assistance of the HAP. Specifically, we aims to maximize the weighted sum computation rate (WSCR) of all the IoT devices in the network. This involves jointly optimizing collaboration, time and data allocation among multiple IoT devices and the HAP, while considering the energy causality property and the minimum data processing requirement of each device. Initially, an optimization algorithm based on the interior-point method is designed for time and data allocation. Subsequently, a priority-based iterative algorithm is developed to search for a near-optimal solution to the multi-user collaboration scheme. Finally, a deep learning-based approach is devised to further accelerate the algorithm’s operation, building upon the initial two algorithms. Simulation results show that the performance of the proposed algorithms is comparable to that of the exhaustive search method, and the deep learning-based algorithm significantly reduces the execution time of the algorithm.

Abstract Background Non-invasive diagnosis of distal tibiofibular syndesmosis instability (DTSI) was a great challenge to clinicians. We designed a new method, the Standing on single foot-Binding test, and investigated the accuracy of the test in the diagnosis of distal tibiofibular syndesmosis instability in adults with a history of ankle injury. Methods 85 participants with ankle injury were subjected to the Standing on single foot-Binding test, MRI and palpation to detect the distal tibiofibular syndesmosis instability (DTSI) and the findings were compared with ankle arthroscopic results. Both participants and arthroscopist were blind to the predicted results of the clinical tests. Sensitivity, specificity, PPV, NPV, LR+, LR − and their 95% CIs were calculated for each of the clinical tests as well as for the positive clinical diagnosis. Results The Standing on single foot-Binding test (SOSF-B test) outperformed MRI and palpation, in terms of sensitivity (87.5%/84.38%), specificity (86.79%/86.79%), PPV (80%/79.41%), NPV (92%/91.2%), LR+ (6.625/6.39), LR- (0.14/0.18) and diagnostic accuracy (87.06/85.88), among others, in the diagnosis of distal tibiofibular syndesmosis instability (DTSI). The diagnostic performance of 20° SOSF-B test was virtually identical to that of 0° SOSF-B test. According to the prevalence (28.7%) of DTSI and LR of four tests, the post-test probability could be used in clinical practice for the prediction of DTSI. Conclusion This prospective and double-blind diagnostic test showed that the SOSF-B test is clinically feasible for the diagnosis of distal tibiofibular syndesmosis instability (DTSI), and new diagnostic tools for rapid screening of distal tibiofibular syndesmosis instability (DTSI). Level of evidence II.

Abstract Reactive oxygen species (ROS), such as superoxides (O2 •−) and hydroxyl groups (OH·), are short-lived molecules containing unpaired electrons. Intracellular ROS are believed to be mainly produced by the mitochondria and NADPH oxidase (NOX) and can be associated with various physiological processes, such as proliferation, cell signaling, and oxygen homeostasis. In recent years, many studies have indicated that ROS play crucial roles in regulating ultraviolet (UV)-induced photodamage of the skin, including exogenous aging, which accounts for 80% of aging. However, to the best of our knowledge, the detailed signaling pathways, especially those related to the mechanisms underlying apoptosis in which ROS are involved have not been reviewed previously. In this review, we elaborate on the biological characteristics of ROS and its role in regulating UV-induced photodamage of the skin.

Summary: Apolipoprotein E (apoE) plays a crucial role in the pathogenesis of Alzheimer’s disease (AD). Microglia exhibit a substantial upregulation of apoE in AD-associated circumstances, despite astrocytes being the primary source of apoE expression and secretion in the brain. Although the role of astrocytic apoE in the brain has been extensively investigated, it remains unclear that whether and how apoE particles generated from astrocytes and microglia differ in biological characteristic and function. Here, we demonstrate the differences in size between apoE particles generated from microglia and astrocytes. Microglial apoE particles impair neurite growth and synapses, and promote neuronal senescence, whereas depletion of GPNMB (glycoprotein non-metastatic melanoma protein B) in microglial apoE particles mitigated these deleterious effects. In addition, human APOE4-expressing microglia are more neurotoxic than APOE3-bearing microglia. For the first time, these results offer concrete evidence that apoE particles produced by microglia are involved in neuronal senescence and toxicity.

Abstract Single‐atom alloys (SAAs) have gained increasing prominence in the field of selective hydrogenation reactions due to their uniform distribution of active sites and the unique host‐guest metal interactions. Herein, 15 SAAs are constructed to comprehensively elucidate the relationship between host‐guest metal interaction and catalytic performance in the selective hydrogenation of 4‐nitrostyrene (4‐NS) by density functional theory (DFT) calculations. The results demonstrate that the SAAs with strong host‐guest metal interactions exhibit a preference for N─O bond cleavage, and the reaction energy barrier of the hydrogenation process is primarily influenced by the host metal. Among them, Ir1Ni SAA stands out as the prime catalyst candidate, showcasing exceptional activity and selectivity. Furthermore, the Ir1Ni SAA is subsequently prepared through precise synthesis techniques and evaluated in the selective hydrogenation of 4‐NS to 4‐aminostyrene (4‐AS). As anticipated, the Ir1Ni SAA demonstrates extraordinary catalytic performance (yield > 96%). In situ FT‐IR experiments and DFT calculations further confirmed that the unique host‐guest metal interaction at the Ir‐Ni interface site of Ir1Ni SAA endows it with excellent 4‐NS selective hydrogenation ability. This work provides valuable insights into enhancing the performance of SAAs catalysts in selective hydrogenation reactions by modulating the host‐guest metal interactions.

Comparative nutritional analysis of Porphyra yezoensis strains “Jianghai No. 1” and “Sutong No.1” revealed significant differences in crude protein, crude fat, crude fiber, crude ash, and total sugar. Both strains contained 16 amino acids, with alanine as the highest and histidine the lowest content. Methionine was determined to be the first limiting amino acid for both strains in both amino acid score and chemical score assessment. They also featured 24 fatty acids, differing notably in four saturated fatty acids and five unsaturated fatty acids. All 12 mineral elements were present, notably differing in sodium, magnesium, potassium, calcium, iron, and zinc. The “Jianghai No. 1” strain stands out with its nutrient-rich profile, featuring high protein content, low fat, and abundant minerals, which could potentially command higher market prices and generate greater economic benefits due to its superior nutritional, and set a strong foundation for its future large-scale promotion and cultivation.

The Internet of Things (IoT) provides a major contribution to the innovation of smart manufacturing and industrial automation. Due to IoT, network devices and intelligent machines exchange information through different types of Internet connection and processes are predominantly automated. This reduces significantly the need for more human intervention and supports high performance. Nevertheless, the utilization of IoT in industrial automation called Industrial IoT (IIoT) has several issues, including the management of applications and IIoT devices. Moreover, heterogeneous networks and tremendous devices deployed in the IIoT environment require flexible configuration and reconfiguration according to the change for ensuring dynamic performance. We argue that Software-Defined Networking (SDN) is one of the technologies that can be used to solve some of the previously mentioned issues. In this paper, we propose a survey for the implementation of SDN solutions in IIoT and discuss the pros and cons brought about by this synergy named “SDN-IIoT”. We explore the current articles on SDN-IIoT by considering different crucial domains such as flow installation techniques, fault tolerance, traffic routing optimization, resource management, energy efficiency, real-time, and network security. Furthermore, we analyze Artificial Intelligence (AI)/Machine Learning (ML) tasks to improve the performance of SDN-IIoT and the deployment of different technologies like Network Function Virtualization (NFV) and Time-Sensitive Networking (TSN) in SDN-IIoT. After observing the limitations of existing SDN-IIoT architectures, we propose an improved candidate architecture for SDN-IIoT based on a hierarchical distributed control plane. The new SDN-IIoT architecture contains AI, Industrial Backhaul Network (IBN), Dynamic Hash Table (DHT), AdaptFlow protocol, and edge/cloud storages. This paper selects the five most used SDN controllers by the literature review and identifies the features of each SDN controller. In the end, we provide open challenges and future research orientations in SDN-IIoT. We hope that this paper will be helpful for engineers, organizations, and researchers on the innovation of IIoT and SDN technologies.

Background: Few studies have studied the efficacy of using immersive virtual reality (iVR) to teach surgical skills, especially by using real-world iVR recordings rather than simulations. This study aimed to investigate whether viewing 360° iVR instructional recordings produces greater improvements in basic suturing skills of students without prior medical training, beyond traditional methods like reading written manuals or watching 2D instructional videos. Materials and methods: This was a partially blinded randomized cohort study. 44 pre-university students (aged 17) were randomized equally to either the written instruction manual, 2D instructional video, or iVR recordings. All students first watched a silent 2D demonstration video of the suturing task, before attempting to place three simple interrupted sutures on a piece of meat as a baseline. The time taken for the first attempt was recorded. Students were then given an hour to train using their allocated modality. They attempted the suturing task again, and timings were re-recorded. Four blinded surgically-trained judges independently assessed the quality of the stitches placed both pre and post-intervention. One-way analysis of variance tests (ANOVAs) and independent two-sample t-tests were used to determine the effect of training modality on improvements in suturing scores and time taken to complete suturing from pre to post-training. Results: For suturing scores, the iVR group showed significantly larger score improvements than the Written Manual group (p = 0.031, Cohen's D = 0.92), while this iVR advantage was less pronounced when compared with the 2D Video group (p = 0.16, Cohen's D = 0.65). Similarly for time taken to complete suturing, the iVR group had significantly larger time improvements than the Written Manual group (p = 0.045), although this difference was less robust compared to the 2D Instructional Video group (p = 0.34). Conclusion: This study demonstrates that iVR training using real-world 360° instructional recordings produced significantly greater training gains in suturing scores and efficiency compared to reading written text. iVR training also led to larger training gains in both outcome measures than viewing 2D instructional videos, although the differences between them did not reach statistical significance.

Purpose: TNF family members (TFMs) play a crucial role in different types of cancers, with TNF Receptor Superfamily Member 19 (TNFRSF19) standing out as a particularly important member in this category. Further research is necessary to investigate the potential impact of TFMs on prognosis prediction and to elucidate the function and potential therapeutic targets linked to TNFRSF19 expression in gliomas. Methods: Three databases provided the data on gene expression and clinical information. Fourteen prognostic members were found through univariate Cox analysis and subsequently utilized to construct TFMs-based model in LASSO and multivariate Cox analyses. TFMs-based subtypes based on the expression profile were identified using an unsupervised clustering method. Machine learning algorithm identified key genes linked to prognostic model and subtype. A sequence of immune infiltrations was evaluated using the ssGSEA and ESTIMATE algorithms. Immunohistochemistry was used to examine the patterns of expression and the clinical significance of TNFRSF19. Results: Our development of a prognostic model and subtypes based on the TNF family was successful, resulting in accurate predictions of prognosis. The findings indicate that TNFRSF19 exhibited strong performance. Upregulation of TNFRSF19 was correlated with malignant phenotypes and poor prognosis, which was confirmed through immunohistochemistry. TNFRSF19 played a role in reshaping the immunosuppressive microenvironment in gliomas, and multiple drug-targeted TNFRSF19 molecules were identified. Conclusions: The TMF-based prognostic model and subtype can facilitate treatment decisions for glioma. TNFRSF19 is an outstanding representative of a predictor of prognosis and immunotherapy effect in gliomas.

Abstract Copper-based catalysts serve as the predominant methanol steam reforming material although several fundamental issues remain ambiguous such as the identity of active center and the aspects of reaction mechanism. Herein, we prepare Cu/Cu(Al)O x catalysts with amorphous alumina-stabilized Cu2O adjoining Cu nanoparticle to provide Cu0−Cu+ sites. The optimized catalyst exhibits 99.5% CH3OH conversion with a corresponding H2 production rate of 110.8 μmol s−1 gcat −1 with stability over 300 h at 240 °C. A binary function correlation between the CH3OH reaction rate and surface concentrations of Cu0 and Cu+ is established based on kinetic studies. Intrinsic active sites in the catalyst are investigated with in situ spectroscopy characterization and theoretical calculations. Namely, we find that important oxygen-containing intermediates (CH3O* and HCOO*) adsorb at Cu0−Cu+ sites with a moderate adsorption strength, which promotes electron transfer from the catalyst to surface species and significantly reduces the reaction barrier of the C−H bond cleavage in CH3O* and HCOO* intermediates.

Background and objective The application of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibodies has greatly improved the clinical outcomes of lung cancer patients. Here, we retrospectively analyzed the efficacy of PD-1 antibody therapy in locally advanced non-surgical or metastatic lung cancer patients, and preliminarily explored the correlation between peripheral blood biomarkers and clinical responses. Methods We conducted a single center study that included 61 IIIA-IV lung cancer patients who received PD-1 antibody treatment from March 2020 to December 2021, and collected the medical record data on PD-1 antibody first-line or second-line treatment. The levels of multiple Th1 and Th2 cytokines in the patient's peripheral blood serum, as well as the phenotype of peripheral blood T cells, were detected and analyzed. Results All the patients completed at least 2 cycles of PD-1 monoclonal antibody treatment. Among them, 42 patients (68.9%) achieved partial response (PR); 7 patients (11.5%) had stable disease (SD); and 12 patients (19.7%) had progressive disease (PD). The levels of peripheral blood interferon gamma (IFN-γ) (P=0.023), tumor necrosis factor α (TNF-α) (P=0.007) and interleukin 5 (IL-5) (P=0.002) before treatment were higher in patients of the disease control rate (DCR) (PR+SD) group than in the PD group. In addition, the decrease in absolute peripheral blood lymphocyte count after PD-1 antibody treatment was associated with disease progression (P=0.023). Moreover, the levels of IL-5 (P=0.0027) and IL-10 (P=0.0208) in the blood serum after immunotherapy were significantly increased compared to baseline. Conclusion Peripheral blood serum IFN-γ, TNF-α and IL-5 in lung cancer patients have certain roles in predicting the clinical efficacy of anti-PD-1 therapy. The decrease in absolute peripheral blood lymphocyte count in lung cancer patients is related to disease progression, but large-scale prospective studies are needed to further elucidate the value of these biomarkers.

CuCrZr alloy has excellent conductivity, thermal conductivity, friction reduction and abrasion resistance, which can satisfy in different fields. Copper alloy porous structure is a new multifunctional structure with both structural and functional properties. Selective laser melting (SLM) technology has certain advantages for the preparation of periodic porous structures with triply periodic minimal surfaces (TPMS). Under the background of SLM technique, the quasi-static compression properties of Diamond and Gyroid porous structures were studied. The whole deformation of structures was captured by digital camera, and the failure mechanism was analyzed by finite element software. The effects of different heat treatments on the microstructure and mechanical properties of the CuCrZr were studied by scanning electron microscopy and compression tests. The microstructure morphologies show that the number of curved grains decreases and the grains become more regular after heat treatment. Heat treatment can optimize the mechanical properties and energy absorption capacity of the material, which is most obvious at 500 °C. These results indicate that specific heat treatment can improve the stability and predictability of the CuCrZr porous structure.

Abstract Nuclear receptor related-1 (Nurr1), a ligand-activated transcription factor, is considered a potential susceptibility gene for Parkinson’s disease (PD), and has been demonstrated to possess protective effects against inflammation-induced neuronal damage. Despite the evidence showing decreased NURR1 level and increased pro-inflammatory cytokines in cell and animal models as well as in PD patients’ peripheral blood mononuclear cells (PBMCs), the underlying mechanism remains elusive. In this study, we investigated the molecular mechanism of Nurr1 in PD-related inflammation. Through the miRNA-sequencing and verification in PBMCs from a cohort of 450 individuals, we identified a significant change of a Nurr1-dependent miRNA miR-30e-5p in PD patients compared to healthy controls (HC). Additionally, PD patients exhibited an elevated plasma interleukin-1β (IL-1β) level and increased nucleotide-binding domain-like receptor protein 3 (NLRP3) expression in PBMCs compared to HC. Statistical analyses revealed significant correlations among NURR1, miR-30e-5p, and NLRP3 levels in the PBMCs of PD patients. To further explore the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated PD pathology, we developed a mouse model (Nurr1flox+/Cd11b−cre+, Nurr1cKO) conditionally knocking out Nurr1 in Cd11b-expressing cells. Our investigations in Nurr1cKO mice unveiled significant dopaminergic neurodegeneration following lipopolysaccharide-induced inflammation. Remarkably, Nurr1 deficiency triggered microglial activation and activated NLRP3 inflammasome, resulting in increased IL-1β secretion. Coincidently, we found that miR-30e-5p level was significantly decreased in the PBMCs and primary microglia of Nurr1cKO mice compared to the controls. Furthermore, our in vitro experiments demonstrated that miR-30e-5p specifically targeted NLRP3. In Nurr1-knockdown microglia, NLRP3 expression was upregulated via miR-30e-5p. In summary, our findings highlight the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated neurodegeneration in PD, the results of which may offer promising prospects for developing PD biomarkers and targeted therapeutic interventions.

Abstract Background The glymphatic system actively exchanges cerebrospinal fluid (CSF) and interstitial fluid (ISF) to eliminate toxic interstitial waste solutes from the brain parenchyma. Impairment of the glymphatic system has been linked to several neurological conditions. Glioblastoma, also known as Glioblastoma multiforme (GBM) is a highly aggressive form of malignant brain cancer within the glioma category. However, the impact of GBM on the functioning of the glymphatic system has not been investigated. Using dynamic contrast-enhanced magnetic resonance imaging (CE-MRI) and advanced kinetic modeling, we examined the changes in the glymphatic system in rats with GBM. Methods Dynamic 3D contrast-enhanced T1-weighted imaging (T1WI) with intra-cisterna magna (ICM) infusion of paramagnetic Gd-DTPA contrast agent was used for MRI glymphatic measurements in both GBM-induced and control rats. Glymphatic flow in the whole brain and the olfactory bulb was analyzed using model-derived parameters of arrival time, infusion rate, clearance rate, and residual that describe the dynamics of CSF tracer over time. Results 3D dynamic T1WI data identified reduced glymphatic influx and clearance, indicating an impaired glymphatic system due to GBM. Kinetic modeling and quantitative analyses consistently indicated significantly reduced infusion rate, clearance rate, and increased residual of CSF tracer in GBM rats compared to control rats, suggesting restricted glymphatic flow in the brain with GBM. In addition, our results identified compromised perineural pathway along the optic nerves in GBM rats. Conclusions Our study demonstrates the presence of GBM-impaired glymphatic response in the rat brain and impaired perineural pathway along the optic nerves. Reduced glymphatic waste clearance may lead to the accumulation of toxic waste solutes and pro-inflammatory signaling molecules which may affect the progression of the GBM.

In view of the problem that the flow of intelligent substation traffic scheduling increases, resulting in the transmission delay also increases, this paper proposed a joint optimization method of Time Sensitive Network (TSN) path selection and scheduling, which combines the resource sensing K-Shortest Path Algorithm (KPA) path selection algorithm and the constraint based gating method. This method can select an optimal transmission path for TT flows and plan the transmission path for non TT flows. Based on the scheduling mechanism of TSN, constraints and optimization objective functions are established, and a gating scheduling method based on constraints is proposed. Finally, the test and verification platform of the scheme is designed and built. Through the test and verification platform, the data stream transmission delay and delay jitter of the scheme are analyzed, and the algorithms are compared and analyzed from the aspects of running time and schedulability. With the continuous evolution of the follow-up TSN technology and the in-depth promotion of the power industry, more and more TSN key technologies will be applied to the smart grid.

Ultra-high molecular weight polyethylene (UHMWPE) is esteemed for its superior wear resistance, making it a preferred material in various applications, including artificial joints, dental materials, and mechanical components. This study elucidates the effects of thermo-oxidative aging on the dry tribological performance and wear mechanisms of UHMWPE and zirconia (ZrO2) friction pairs using dynamic friction wear tests, scanning electron microscopy, and energy-dispersive x-ray spectroscopy. Results reveal that thermo-oxidative aging significantly compromises wear resistance and alters the degradation mechanisms of UHMWPE. The unaged UHMWPE exhibits exceptional wear resistance, indicated by minimal wear and pronounced polishing effects. Post-aging at 40 °C leads to the formation of fine scratches and rougher wear marks on UHMWPE surfaces, with the predominant wear mechanism transitioning from abrasive wear to fatigue wear as the number of cycles increases. Upon aging at 70 °C, more extensive spalling and pitting damages occur on UHMWPE, indicating more severe thermo-oxidative and wear damages that primarily exhibit fatigue wear and oxidative wear patterns. Notably, aging at 40 °C results in a friction coefficient increase to ∼0.165, whereas aging at 70 °C decreases the friction coefficient to around 0.118, indicating a complex relationship between aging temperature and tribological behavior. This research provides valuable insights into predicting and improving the durability of UHMWPE components used in orthopedic applications, thereby contributing to optimizing orthopedic implant materials for enhanced patient outcomes.

IntroductionGoatpox, a severe infectious disease caused by goatpox virus (GTPV), leads to enormous economic losses in the livestock industry. Traditional live attenuated vaccines cause serious side effects and exist a risk of dispersal. Therefore, it is urgent to develop efficient and safer vaccines to prevent and control of GTPV.MethodsIn the present study, we are aimed to design a multi-epitope subunit vaccine against GTPV using an immunoinformatics approach. Various immunodominant cytotoxic T lymphocytes (CTL) epitopes, helper T lymphocytes (HTL) epitopes, and B-cell epitopes from P32, L1R, and 095 proteins of GTPV were screened and liked by the AAY, GPGPG, and KK connectors, respectively. Furthermore, an adjuvant β-defensin was attached to the vaccine’s N-terminal using the EAAAK linker to enhance immunogenicity.ResultsThe constructed vaccine was soluble, non-allergenic and non-toxic and exhibited high levels of antigenicity and immunogenicity. The vaccine’s 3D structure was subsequently predicted, refined and validated, resulting in an optimized model with a Z-value of -3.4. Molecular docking results demonstrated that the vaccine had strong binding affinity with TLR2(-27.25 kcal/mol), TLR3(-39.84 kcal/mol), and TLR4(-59.42 kcal/mol). Molecular dynamics simulation results indicated that docked vaccine-TLR complexes were stable. Immune simulation analysis suggested that the vaccine can induce remarkable increase in antibody titers of IgG and IgM, higher levels of IFN-γ and IL-2.ConclusionThe designed GTPV multi-epitope vaccine is structurally stable and can induce robust humoral and cellular immune responses, which may be a promising vaccine candidate against GTPV.

To explore the complementary relationship between magnetic resonance imaging (MRI) radiomic and plasma biomarkers in the early diagnosis and conversion prediction of Alzheimer’s disease (AD), our study aims to develop an innovative multivariable prediction model that integrates those two for predicting conversion results in AD. This longitudinal multicentric cohort study included 2 independent cohorts: the Sino Longitudinal Study on Cognitive Decline (SILCODE) project and the Alzheimer Disease Neuroimaging Initiative (ADNI). We collected comprehensive assessments, MRI, plasma samples, and amyloid positron emission tomography data. A multivariable logistic regression analysis was applied to combine plasma and MRI radiomics biomarkers and generate a new composite indicator. The optimal model’s performance and generalizability were assessed across populations in 2 cross-racial cohorts. A total of 897 subjects were included, including 635 from the SILCODE cohort (mean [SD] age, 64.93 [6.78] years; 343 [63%] female) and 262 from the ADNI cohort (mean [SD] age, 73.96 [7.06] years; 140 [53%] female). The area under the receiver operating characteristic curve of the optimal model was 0.9414 and 0.8979 in the training and validation dataset, respectively. A calibration analysis displayed excellent consistency between the prognosis and actual observation. The findings of the present study provide a valuable diagnostic tool for identifying at-risk individuals for AD and highlight the pivotal role of the radiomic biomarker. Importantly, built upon data-driven analyses commonly seen in previous radiomics studies, our research delves into AD pathology to further elucidate the underlying reasons behind the robust predictive performance of the MRI radiomic predictor.

ABSTRACT GH72 family of β-(1,3)-glucanosyltransferases is required for cell wall biogenesis, morphogenesis, and virulence of fungi. Candida albicans PHR2 is an acidic pH-induced gene that encodes a GH72 enzyme involved in cross-linking of β−1,3- and β−1,6-glucans in the cell wall. In response to environmental pH changes, the expression of PHR2 is negatively regulated by the transcription factor CaRim101 through the pH-responsive Rim101 pathway. In this study, we have generated the inactivation mutant for PHR2 through the CRISPR/Cas9 approach. The PHR2 mutant is sensitive to both membrane- and cell wall-disturbing agents, SDS, Calcofluor white and casponfungi, but resistant to two azole antifungals, ketoconazole and fluconazole. Although the PHR2 mutant is not sensitive to calcium stress, it becomes sensitive to high levels of calcium stress in the presence of cyclosporin A, the specific inhibitor of calcineurin. In addition, we have demonstrated that the expression of PHR2, the downstream target of CaRim101, is positively controlled by the transcription factor CaCrz1 through its binding motif (5′ A-315TAGGCACAG 3′) in the PHR2 promoter. Furthermore, the deletion of PHR2 increases the cell precipitation rate in cell culture under acidic conditions. IMPORTANCE The fungal cell wall consists of glucans, mannoproteins, and chitin and is essential for cell viability, morphogenesis, and pathogenesis. The enzymes of the GH72 family are responsible for ß-(1,3)-glucan elongation and branching, which is crucial for the formation of the glucan-chitin polymer at the bud neck of yeast cells. In the human fungal pathogen Candida albicans, there are five GH72 enzyme-encoding genes: PHR1, PHR2, PHR3, PGA4, and PGA5. It is known that expression of PHR1 and PHR2 is controlled by the pH-responsive Rim101 pathway through the transcription factor Rim101. In this study, we have demonstrated that the transcription expression of PHR2 is also controlled by the transcription factor Crz1 through its binding motif in the promoter. Therefore, we have uncovered a dual-control mechanism by which PHR2 expression is negatively regulated via CaRim101 through the pH-responsive pathway and positively modulated by CaCrz1 through the calcium/calcineurin signaling pathway.

Abstract Calorie restriction (CR) or a fasting regimen is considered one of the most potent non-pharmacological interventions to prevent chronic metabolic disorders, ameliorate autoimmune diseases, and attenuate aging. Despite efforts, the mechanisms by which CR improves health, particularly brain health, are still not fully understood. Metabolic homeostasis is vital for brain function, and a detailed metabolome atlas of the brain is essential for understanding the networks connecting different brain regions. Herein, we applied gas chromatography-mass spectrometry-based metabolomics and lipidomics, covering 797 structurally annotated metabolites, to investigate the metabolome of seven brain regions in fasted (3, 6, 12, and 24 h) and ad libitum fed mice. Using multivariate and univariate statistical techniques, we generated a metabolome atlas of mouse brain on the global metabolic signature dynamics across multiple brain regions following short-term fasting (STF). Significant metabolic differences across brain regions along with STF-triggered region-dependent metabolic remodeling were identified. We found that STF elicited triacylglycerol degradation and lipolysis to compensate for energy demand under fasting conditions. Besides, changes in amino acid profiles were observed, which may play crucial roles in the regulation of energy metabolism, neurotransmitter signaling, and anti-inflammatory and antioxidant in response to STF. Additionally, this study reported, for the first time, that STF triggers a significant elevation of N-acylethanolamines, a class of neuroprotective lipids, in the brain and liver. These findings provide novel insights into the molecular basis and mechanisms of CR and offer a comprehensive resource for further investigation.

Abstract Salidroside is a natural product of phenols, which has a wide scape of pharmacological effects, but its pharmacological effects and molecular mechanism on endometrial cancer are not clear. To systematically explore the pharmacological effects and molecular mechanisms of salidroside on endometrial cancer through the method of network pharmacology. The possible target genes of salidroside were obtained through different pharmacological databases and analysis platforms, and then the relevant target genes of endometrial cancer were obtained through the GeneCards website, and the target genes were uniformly converted into standardized gene names with Uniprot. The collected data were then processed to obtain common target genes and further analyzed through the String website to construct a protein–protein interaction (PPI) network, followed by gene ontology (GO) functional annotation and Kyoto Gene and Genome Encyclopedia (KEGG) pathway analysis. We further interpreted the molecular mechanism of salidroside for the treatment of endometrial cancer by constructing a “drug component–target gene–disease” network. Finally, we performed molecular docking to validate the binding conformation between salidroside and the candidate target genes. There were 175 target genes of salidroside after normalization, among which 113 target genes interacted with endometrial cancer. GO analysis indicated that the anti-endometrial cancer effect of salidroside may be strongly related to biological processes such as apoptosis and response to drug. KEGG analysis indicated that its mechanism may be related to pathway in cancer and PI3K-AKT signaling pathway. Molecular docking showed that salidroside had high affinity with five key genes. Based on the novel network pharmacology and molecular docking validation research methods, we have revealed for the first time the potential mechanism of salidroside in the therapy of endometrial cancer.

Abstract Background Isatis tinctoria Linnaeus and Isatis indigotica Fortune are very inconsistent in their morphological characteristics, but the Flora of China treats them as the same species. In this work, a new technology that differs from conventional barcodes is developed to prove that they are different species and to clarify their classification. Results and methods I. indigotica was indistinguishable from I. tinctoria when using ITS2. CPGAVAS2 was used to construct the chloroplast genomes. MAFFT and DnaSP were used to calculate nucleotide polymorphism, the chloroplast genomes of the two have high diversity in the rpl32 ~ trnL-UAG short region. When using this region as a mini barcode, it was found that there are obvious differences in the base numbers of I. tinctoria and different ploidy I. indigotica were found, but diploid and tetraploid I. indigotica had the same number of bases. Moreover, the reconstruction of the maximum likelihood (ML) tree, utilizing the mini-barcode, demonstrated that I. tinctoria and both diploid and tetraploid I. indigotica are located on distinct branches. The genome size of tetraploid I. indigotica was approximately 643.773 MB, the heterozygosity rate was approximately 0.98%, and the repeat sequence content was approximately 90.43%. This species has a highly heterozygous, extremely repetitive genome. Conclusion A new method was established to differentiate between I. indigotica and I. tinctoria. Furthermore, this approach provides a reference and basis for the directional breeding of Isatis.

Steel/copper bimetallic structural materials combine the good strength and corrosion resistance of steel with the high thermal and wear resistance of copper and have been widely used in fusion reactors, conformal cooling channels, and heat transfer devices. Due to the large difference in thermal and physical properties of steel and copper, and the immiscibility of steel and copper, the bonding interface usually produces a large residual stress during the forming process, which leads to the formation of interface cracks. In order to combine CuCrZr with 316L stainless steel by using selective laser melting technology, IN718 was deposited on 316L stainless steel as a transition layer. The effects of the IN718 alloy transition layer on the microstructure, phase composition, and mechanical properties of the interface of 316L–CuCrZr were studied. IN718–316L had no defects such as pores and cracks at the interface and achieved good metallurgical bonding. The IN718–CuCrZr interface area and copper side had round key holes and relatively small pores. In the solidification process, IN718 preferentially solidified in the shape of fine particles, providing a nucleation point for the copper grain, thus forming equiaxed grains because of the high cooling rate of the interface. No macroscopic defects were observed at the bonding position of the 316L–IN718–CuCrZr samples, and the elements at the interface were fully diffused by each other. The tensile strength of the 316L–IN718–CuCrZr samples reached 403 MPa, and the interface strength was significantly improved upon the addition of the transition layer.

Clinical cognitive advancement within the Alzheimer’s disease (AD) continuum is intimately connected with sustained accumulation of tau protein pathology. The biological brain age and its gap show great potential for pathological risk and disease severity. In the present study, we applied multivariable linear support vector regression to train a normative brain age prediction model using tau brain images. We further assessed the predicted biological brain age and its gap for patients within the AD continuum. In the AD continuum, evaluated pathologic tau binding was found in the inferior temporal, parietal-temporal junction, precuneus/posterior cingulate, dorsal frontal, occipital, and inferior-medial temporal cortices. The biological brain age gaps of patients within the AD continuum were notably higher than those of the normal controls (p < 0.0001). Significant positive correlations were observed between the brain age gap and global tau protein accumulation levels for mild cognitive impairment (r = 0.726, p < 0.001), AD (r = 0.845, p < 0.001), and AD continuum (r = 0.797, p < 0.001). The pathologic tau-based age gap was significantly linked to neuropsychological scores. The proposed pathologic tau-based biological brain age model could track the tau protein accumulation trajectory of cognitive impairment and further provide a comprehensive quantification index for the tau accumulation risk.

The human immunodeficiency virus type-1 epidemic in Pakistan has significantly increased over the last two decades. In Karachi, Pakistan, there is a lack of updated information on the complexity of HIV-1 genetic diversity and the burden of drug resistance mutations (DRMs) that can contribute to ART failure and poor treatment outcomes. This study aimed to determine HIV-1 genetic diversity and identify drug-resistance mutations among people living with HIV in Karachi. A total of 364 HIV-positive individuals, with a median age of 36 years, were enrolled in the study. The HIV-1 partial pol gene was successfully sequenced from 268 individuals. The sequences were used to generate phylogenetic trees to determine clade diversity and also to assess the burden of DRMs. Based on the partial pol sequences, 13 distinct HIV-1 subtypes and recombinant forms were identified. Subtype A1 was the most common clade (40%), followed by CRF02_AG (33.2%). Acquired DRMs were found in 30.6% of the ART-experienced patients, of whom 70.7%, 20.7%, and 8.5% were associated with resistance to NNRTIs, NRTIs, and PIs, respectively. Transmitted DRMs were found in 5.6% of the ART-naïve patients, of whom 93% were associated with resistance against NNRTIs and 7% to PIs. The high prevalence of DRMs in ART-experienced patients poses significant challenges to the long-term benefits and sustainability of the ART program. This study emphasizes the importance of continuous HIV molecular epidemiology and drug resistance surveillance to support evidence-based HIV prevention, precise ART, and targeted AIDS care.

Moonlighting enzymes are multifunctional proteins that perform multiple functions beyond their primary role as catalytic enzymes. Extensive research and clinical practice have demonstrated their pivotal roles in the development and progression of cancer, making them promising targets for drug development. This article delves into multiple notable moonlighting enzymes, including GSK-3, GAPDH, and ENO1, and with a particular emphasis on an enigmatic phosphatase, PTP4A3. We scrutinize their distinct roles in cancer and the mechanisms that dictate their ability to switch roles. Lastly, we discuss the potential of an innovative approach to develop drugs targeting these moonlighting enzymes: target protein degradation. This strategy holds promise for effectively tackling moonlighting enzymes in the context of cancer therapy.

Abstract Portal hypertension (PH) refers to a collection of syndromes characterized by an increase in pressure within the portal venous system and/or elevated portal venous blood flow, most commonly caused by cirrhosis. This condition is frequently associated with viral hepatitis and chronic alcohol abuse, and its complications, such as ascites, hepatic encephalopathy, and esophageal varices, have a considerable impact on mortality. Dyskeratosis congenita (DC) is a rare genetic disorder that affects multiple systems, most notably manifesting as dystrophy of the fingernails and toenails, skin pigmentation, and mucosal leukoplakia. While cirrhotic PH is an uncommon complication of DC, we present a case of a young patient who presented with PH and had no history of hepatitis or heavy alcohol use. The patient underwent splenectomy and devascularization to treat hypersplenism and esophagogastric varices caused by PH but developed portal vein thrombosis following the surgery. Given the patient's cutaneous manifestations and cirrhosis that could not be attributed to common causes, we continued to search for the underlying cause of PH until the diagnosis of DC was finally made. The patient was subsequently treated with carvedilol to prevent variceal rebleeding and showed no significant complications or bleeding during follow‐up.

Abstract The metal-support interaction (MSI) in heterogeneous catalysts plays a crucial role in reforming reaction to produce renewable hydrogen, but conventional objects are limited to single metal and support. Herein, we report a type of RhNi/TiO2 catalysts with tunable RhNi-TiO2 strong bimetal-support interaction (SBMSI) derived from structure topological transformation of RhNiTi-layered double hydroxides (RhNiTi-LDHs) precursors. The resulting 0.5RhNi/TiO2 catalyst (with 0.5 wt.% Rh) exhibits extraordinary catalytic performance toward ethanol steam reforming (ESR) reaction with a H2 yield of 61.7%, a H2 production rate of 12.2 L h−1 gcat −1 and a high operational stability (300 h), which is preponderant to the state-of-the-art catalysts. By virtue of synergistic catalysis of multifunctional interface structure (Rh-Ni δ−-O v -Ti3+; O v denotes oxygen vacancy), the generation of formate intermediate (the rate-determining step in ESR reaction) from steam reforming of CO and CH x is significantly promoted on 0.5RhNi/TiO2 catalyst, accounting for its ultra-high H2 production.

Abstract Background Rootstocks can improve the chilling tolerance of grafted cucumbers, but their effectiveness varies. Rootstocks with strong de-blooming capacity may result in lower chilling tolerance of grafted cucumbers compared to those with weak de-blooming capacity, while also reducing the silicon absorption. However, it remains unclear whether this reduction in chilling tolerance is due to differences in rootstock genotypes or the reduction in silicon absorption. Results The chilling tolerance of cucumber seedlings was improved by using rootstocks and silicon nutrition. Rootstocks had a more significant effect than silicon nutrition, and the weak de-blooming rootstock ‘Yunnan figleaf gourd’ was superior to the strong de-blooming rootstock ‘Huangchenggen No. 2’. Compared to self-rooted cucumber, twelve miRNAs were regulated by two rootstocks, including seven identical miRNAs (novel-mir23, novel-mir26, novel-mir30, novel-mir37, novel-mir46, miR395a and miR398a-3p) and five different miRNAs (novel-mir32, novel-mir38, novel-mir65, novel-mir78 and miR397a). Notably, four of these miRNAs (novel-mir38, novel-mir65, novel-mir78 and miR397a) were only identified in ‘Yunnan figleaf gourd’-grafted cucumbers. Furthermore, six miRNAs (miR168a-5p, miR390a-5p, novel-mir26, novel-mir55, novel-mir67 and novel-mir70) were found to be responsive to exogenous silicon. Target gene prediction for 20 miRNAs resulted in 520 genes. Functional analysis of these target genes showed that ‘Yunnan figleaf gourd’ improves the chilling tolerance of cucumber by regulating laccase synthesis and sulfate metabolism, while ‘Huangchenggen No. 2’ and exogenous silicon reduced chilling stress damage to cucumber by regulating ROS scavenging and protein protection, respectively. Conclusion Among the identified miRNAs, novel-mir46 and miR398a-3p were found in cucumbers in response to chilling stress and two types of rootstocks. However, no identical miRNAs were identified in response to chilling stress and silicon. In addition, the differential expression of novel-mir38, novel-mir65, novel-mir78 and miR397a may be one of the important reasons for the differences in chilling tolerance of grafted cucumbers caused by two types of rootstocks.

Hyperuricemia is a metabolic disease caused by disturbances in purine metabolism and imbalances in the formation and excretion of uric acid. It is closely related to the gut microbiota, which is considered a therapeutic target. Some lactic acid bacteria with a uric acid lowering effect have the potential to ameliorate hyperuricemia in the host. However, the mechanism of action remains unclear. Here, we screened a strain of Lactobacillus acidophilus F02 that efficiently degrades uric acid precursors (inosine and guanosine) and further investigated its underlying mechanism on the alleviation of hyperuricemia in high fructose-adenine induced mice. Results showed that L. acidophilus F02 administration reduced serum uric acid levels in hyperuricemia mice by inhibiting xanthine oxidase and adenosine deaminase activity, while protecting hepatorenal injury and systemic inflammation by regulating the relative expression of NLRP3 inflammasome. Most importantly, it restored gut microbial homeostasis and the abundance of bacterial taxa (i.e., a balance in the relative abundance of Firmicutes and Actinobacteria and an increase in the abundance of Bacteroides, Ruminococcus and Lactobacillus). Furthermore, the ability of L. acidophilus F02 to lower uric acid and suppress NLRP3 inflammasome expression was confirmed in the HK-2 cell model, as well as the multiple immunomodulatory effects on RAW264.7 cells. Taken together, we speculate that fructose-adenine induced hyperuricemia triggers hepatorenal injury and gut microbiota dysbiosis, which is ameliorated by L. acidophilus F02. Collectively, the results suggest that lowering uric acid synthesis, increasing uric acid excretion and reducing NLRP3-related IL-1β levels are effective strategies to ameliorate hyperuricemia. Such information could inform future studies on the ecology of L. acidophilus and guide the use of this species for dietary applications in the food industry.

ABSTRACTObjectives: High-risk multiple myeloma (HRMM) is associated with poor survival, despite many advances in antimyeloma strategies. Autologous followed by allogeneic stem cell transplantation (auto-allo-SCT) has yielded controversial results compared to tandem autologous stem cell transplantation (auto-SCT) in patients with HRMM. We conducted this meta-analysis to compare the efficacy and safety of auto-allo-SCT and tandem-auto-SCT in patients with HRMM.Methods: Embase, Cochrane Library, and PubMed databases were searched until March 2023. Prospective or retrospective studies comparing the effects of auto-allo-SCT and tandem-auto-SCT were included. Hazard ratios (HRs) and 95% confidence intervals (CIs) for time-to-event outcomes, and odds ratios (ORs) and 95%CIs for dichotomous outcomes were pooled using random-effects models.Results: Three studies involving 491 patients were included. Despite auto-allo-SCT seemed to be associated with improvements in progression-free survival (PFS) (HR [95%CI], 0.71 [0.51–1.00]) and complete response (CR) (OR [95%CI], 3.16 [1.67–5.99]), and reduced relapse/progression rates (47% vs. 55%) in comparison with tandem-auto-SCT, no marked improvement in overall survival (OS). In comparison to tandem-auto-SCT, patients assigned to auto-allo-SCT exhibited a higher risk of transplant-related mortality (TRM) (11.9% vs. 4.1%) and non-relapse mortality (NRM) (12.3% vs. 3.1%).Conclusion: Auto-allo-SCT seemed to be associated with improvements in PFS and CR when compared to tandem-auto-SCT in patients with HRMM, but it did not lead to a significant improvement in OS. Furthermore, patients in the auto-allo-SCT group were at a higher risk of developing TRM and NRM. Auto-allo-SCT transplantation should not be routinely incorporated into HRMM therapy but rather should be considered investigational.

CuCrZr alloy is promising in many industrial applications because of its extremely high thermal conductance and conductivity. In this paper, the effects of aging heat treatment temperature and time on microstructure and mechanical properties of CuCrZr alloy fabricated by selective laser melting were investigated. The mechanical properties of CuCrZr alloy after aging heat treatment were investigated by high temperature tensile experiments. The results showed that the aging treatment did not change the grain size and morphology of CuCrZr alloy. Scanning electron microscope (SEM) and transmission electron microscope (TEM) observation showed that Cr precipitated in the microstructure after aging treatment and caused precipitation strengthening, which is an important factor for the mechanical properties of CuCrZr alloy manufactured by SLM. After aging heat treatment, the hardness of CuCrZr alloy increases to 185.7 ± 1.82HV. Tensile test results show that aging heat treatment can greatly improve the tensile strength of CuCrZr fabricated by SLM, and the maximum value is 515.5 ± 12.8 MPa. At the same time, the tensile property of CuCrZr alloy decreases with the increase of temperature, but can still reach 319.34 ± 0.49 MPa at 250 ℃.

Anthocyanins are the main pigments that affect the color and quality of purple-fruited sweet pepper (Capsicum annuum). Our previous study indicated that blue light can induce anthocyanin accumulation in purple pepper. In view of its underlying mechanism that is unclear, here, anthocyanin content was determined, and transcriptome analysis was performed on pepper fruits harvested from different light treatments. As a result, among the identified anthocyanin metabolites, the levels of delphinidin (Dp) glycosides, including Dp-3-O-rhamnoside, Dp-3-O-rutinoside, and Dp-3-O-glucoside, were highly accumulated in blue-light–treated fruit, which are mainly responsible for the appearance color of purple pepper. Correlation between anthocyanin content and transcriptomic analysis indicated a total of 1,619 upregulated genes were found, of which six structural and 12 transcription factor (TF) genes were involved in the anthocyanin biosynthetic pathway. Structural gene, for instance, CaUFGT as well as TFs such as CaMYC2-like and CaERF113, which were highly expressed under blue light and presented similar expression patterns consistent with Dp glycoside accumulation, may be candidate genes for anthocyanin synthesis in response to blue-light signal.

Bovine viral diarrhea virus (BVDV) is a significant pathogen that causes great economic losses in the global livestock industry. During the long-term interactions between BVDV and its hosts, the virus has evolved multiple strategies to evade the host’s innate immunity and adaptive immunity, thereby promoting viral survival and replication. This review focuses on the most recent research on immune evasion strategies employed by BVDV, including evading type I IFN signaling pathway, evading host adaptive immunity, mediating NF-κB signaling pathway, mediating cell apoptosis and inducing autophagy. Unraveling BVDV’s immune evasion strategies will enhance our understanding of the pathogenesis of BVDV and contribute to the development of more effective therapies for the prevention, control and eradication of BVDV.

Objective: To investigate the therapeutic effects of static magnetic field (SMF) and its regulatory mechanism in the repair of osteoarthritic cartilage. Methods: Fourteen-week-old female C57BL/6 mice were randomly divided into the sham operation group and the osteoarthritis (OA) groups with and without SMF application. SMF was applied at 200 ​mT for two consecutive weeks. Changes in knee cartilage were examined by histomorphometry, and the chondrogenesis and migration of endogenous stem cells were assessed. The expression of SRY-related protein 9 (SOX9), Collagen type II (COL2), matrix metallopeptidase 13 (MMP13), stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4), Piezo1 and other genes was evaluated, and the mechanism of SMF's action was tested using the CXCR4 inhibitor, AMD3100, and Piezo1 siRNA. Results: SMF significantly decreased the OARSI scores after induction of OA. SMF was beneficial to chondrogenesis by elevating SOX9. In the OA mouse model, an increase in MMP13 with a decrease in COL2 led to the destruction of the cartilage extracellular matrix, which was suppressed by SMF. SMF promoted the migration of cartilage-derived stem/progenitor cells and bone marrow-derived mesenchymal stem cells (MSCs). It increased SDF-1 and CXCR4, while the CXCR4 inhibitor significantly suppressed the beneficial effects of SMF. The application of Piezo1 siRNA inhibited the SMF-induced increase of CXCR4. Conclusion: SMF enhanced chondrogenesis and improved cartilage extracellular matrices. It activated the Piezo1-mediated SDF-1/CXCR4 regulatory axis and promoted the migration of endogenous stem cells. Collectively, it attenuated the pathological progression of cartilage destruction in OA mice. The Translational potential of this article: The findings in this study provided convincing evidence that SMF could enhance cartilage repair and improve OA symptoms, suggesting that SMF could have clinical value in the treatment of OA.

Abstract Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain and the pathological accumulation of misfolded α-synuclein (α-syn) in the brain. A growing body of evidence suggests that the formation of misfolded α-syn and aggregation may begin in the peripheral nervous system, specifically the enteric nervous system, and then propagate to the central nervous system via the vagus nerve. However, the PD-like neuropathology induced by the intestine and vagus nerve extracts is rarely investigated. In this work, we injected lysates of the intestine and vagus obtained from a diagnosed PD patient, which contained abnormal α-syn aggregates, into the rat striatum unilaterally. Strikingly, such an injection induced dopaminergic neurodegeneration and α-syn depositions in the striatum, substantia nigra, and other brain regions, including the frontal cortex, somatosensory cortex, hypothalamus, brain stem, and cerebellum. Moreover, significant activation of microglia and the development of astrogliosis were observed in the substantia nigra pars compacta of the injected rats. These findings provide essential information for our understanding of PD pathogenesis, as we established for the first time that the α-syn aggregates in the intestine and vagus of a PD patient were sufficient to induce prion-like propagation of endogenous α-syn pathology in wild-type rats.

The glymphatic system suggests the convective bulk flow of cerebrospinal fluid (CSF) through perivascular spaces and the interstitial spaces of the brain parenchyma for the rapid removal of toxic waste solutes from the brain. However, the presence of convective bulk flow within the brain interstitial spaces is still under debate. We first addressed this argument to determine the involvement of the glymphatic system in brain waste clearance utilizing contrast-enhanced 3D T1-weighted imaging (T1WI), diffusion tensor imaging (DTI), and confocal microscopy imaging. Furthermore, perivascular macrophages (PVMs), which are immune cells located within perivascular spaces, have not been thoroughly explored for their association with the glymphatic system. Therefore, we investigated tracer uptake by PVMs in the perivascular spaces of both the arteries/arterioles and veins/venules and the potential association of PVMs in assisting the glymphatic system for interstitial waste clearance. Our findings demonstrated that both convective bulk flow and diffusion are responsible for the clearance of interstitial waste solutes from the brain parenchyma. Furthermore, our results suggested that PVMs may play an important function in glymphatic system-mediated interstitial waste clearance. The glymphatic system and PVMs could be targeted to enhance interstitial waste clearance in patients with waste-associated neurological conditions and aging.

Experimental studies were conducted on the cultivation of tomatoes (Solanum lycopersicum L.) at Shandong Agricultural University, China, from 2022 to 2023. Three cultivation patterns were designed as follows: a north–south orientation with a row spacing of 1.40 m (NS-1.4m), a north–south orientation with a row spacing of 1.80 m (NS-1.8m) and an east–west orientation with a row spacing of 1.80 m (EW-1.8m). A functional–structural plant model using the open source interactive modeling platform of GroIMP was constructed for the cultivation of tomatoes. The growth of plants as well as the light distribution and light interception capacity of the crop canopy were simulated and analyzed. The impacts of these cultivation patterns on the growth, photosynthetic characteristics, fruit ripening time, quality and yield of tomato plants were analyzed. The studies revealed that compared with the NS-1.4m treatment, the canopy light interception of tomato plants under the NS-1.8m and EW-1.8m treatments increased by 6.08% and 9.80% in a winter–spring crop and 6.80% and 19.76% in an autumn–winter crop, respectively. Their plant height, leaf area, aboveground dry matter accumulation, leaf net photosynthesis rate as well as the lycopene, vitamin C and sugar–acid ratio of the fruit all exhibited increasing trends, while fruit ripening was accelerated. The yield of the NS-1.8m and EW-1.8m treatments increased by 3.92% and 6.18% in a winter–spring crop and 4.17% and 9.78% in an autumn–winter crop, respectively. Structural equation modeling was used to further analyze the data, confirming that the cultivation of an east–west orientation with wide row spacing is beneficial for tomato cultivation in Chinese solar greenhouses. This cultivation pattern maximizes the canopy’s light interception, thus leading to improved fruit quality and yield. Overall, this study provides valuable insights for optimizing the cultivation pattern of solar greenhouse crops.