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Abstract Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs), possess immunomodulatory properties and have shown promising outcomes when combined with anti-PD-1 antibodies. The OASIS phase II trial (NCT04503967) is designed to determine the clinical activity and safety of nivolumab (anti-PD-1) and anlotinib hydrochloride (a multi-targets TKI) as second-line or above therapy in patients with advanced gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC). From December 2020 to September 2022, 45 patients with GAC and 3 with ESCC were enrolled in this study. The pre-specified endpoints were reached, with the primary endpoint of overall response rate achieving 29.2%. For secondary objectives, disease control rate was 64.6%; median progression-free survival was 4.0 months; and median overall survival was 11.1 months with a manageable toxicity profile. The exploratory analyses unveiled that the balance of gut bacteria and the presence of a pre-existing immune signature characterized by a high percentage of CD68+PD-L1+ PD-1+ macrophages and low pretreatment variant allele frequencies (VAF), as well as low expression of certain cytokines were significantly associated with improved clinical outcomes in patients with GAC.

Abstract Although histological and molecular classifications have been extensively studied for gastric cancer (GC), targeted therapies for GC remain limited. CDH1 mutations (MT) are characteristic of genomically stable GC and are associated with poor prognosis, but lack effective or targeted therapies. Here, we showed the overall mutation frequency of CDH1 was 9.7% (155 of 1596). CDH1-MT GC showed significantly lower rates of PD-L1 positivity (CPS score ≥1) than CDH1-wildtype (WT) GC (56.7% vs. 73.3%, p

Abstract PD‐1/PD‐L1 inhibitors have emerged as standard treatments for advanced solid tumors; however, challenges such as a low overall response rate and systemic side effects impede their implementation. Hypoxia drives the remodeling of the tumor microenvironment, which is a leading reason for the failure of immunotherapies. Despite some reported strategies to alleviate hypoxia, their individual limitations constrain further improvements. Herein, a novel two‐pronged strategy is presented to efficiently address hypoxia by simultaneously adopting atovaquone (ATO, inhibiting oxygen consumption) and oxyhemoglobin (HbO2, directly supplementing oxygen) within a multifunctional aggregate termed NPs‐aPD‐1/HbO2/ATO. In addition to eliminating hypoxia with these two components, this smart aggregate also includes albumin and an ROS‐responsive cross‐linker as a controlled release scaffold, along with PD‐1 antibody (aPD‐1) for immunotherapy. Intriguingly, NPs‐aPD‐1/HbO2/ATO demonstrates exceptional tumor targeting in vivo, exhibiting ≈4.2 fold higher accumulation in tumors than in the liver. Consequently, this aggregate not only effectively mitigates hypoxia and significantly assists aPD‐1 immunotherapy but also simultaneously resolves the targeting and systemic toxicity issues associated with individual administration of each component. This study proposes substantial implications for drug‐targeted delivery, addressing tumor hypoxia and advancing immunotherapy, providing valuable insights for advancing cancer treatment strategies.

PI3Kδ is a key signal transduction molecule in normal and malignant B cells, as well as in T-regulatory cells, making it a promising target for treatment of hematologic malignancies through both direct killing and anti-tumor immunity regulation. BGB-10188 is a highly selective inhibitor of PI3Kδ, showing more than 3000 folds selectivity over other PI3K isoforms and no significant inhibition across tested kinases. BGB-10188 potently inhibited PI3Kδ with IC50s ranging from 1.7-16 nM through various in vitro assays and showed a long-lasting and strong target inhibition in mouse B cells in vivo. BGB-10188 showed significant antitumor effects in human B cell lymphoma xenograft models as single agent or in combination with the BTK inhibitor zanubrutinib. BGB-10188 showed significant Treg inhibition in blood but not in colon, along with less drug accumulation in colon compared with idelalisib, which is an approved PI3Kdelta inhibitor with high incidence of gastrointestinal side effects in clinic. In summary, BGB-10188 is a novel PI3Kδ inhibitor with high selectivity, potency and improved safety profile shown in preclinical studies, which is showing the potential as a best-in-class PI3Kδ inhibitor.

Stem cells have been documented as a new therapeutic method for ovarian injuries such as premature ovarian failure (POF). However, effects of exosomes (Exos) derived from human endometrial stem cells (EnSCs) on diminished ovarian failure remain to be carefully elucidated. Our study aims to investigate the mechanisms of EnSC-Exos in the recovery of the cisplatin-induced granulosa cell injury model in vitro or POF mouses model in vivo and whether the Hippo signaling pathway is involved in the regulation. In this study, we established successful construction of the cisplatin-induced granulosa cell injury model and evaluated Hippo signaling pathway activation in cisplatin-damaged granulosa cells (GCs). Furthermore, laser scanning confocal microscope and immunofluorescence demonstrated that EnSC-Exos can be transferred to cisplatin-damaged GCs to decrease apoptosis. In addition, the enhanced expression of YAP at the protein level as well as YAP/TEAD target genes, such as CTGF, ANKRD1, and the increase of YAP into the nucleus in immunofluorescence staining after the addition of EnSC-Exos to cisplatin-damaged GCs confirmed the suppression of Hippo signaling pathway. While in vivo, EnSC-Exos successfully remedied POF in a mouse model. Collectively, our findings suggest that chemotherapy-induced POF was associated with the activating of Hippo signaling pathway. Human EnSC-Exos significantly elevated the proliferation of ovarian GCs and the ovarian function by regulating Hippo signaling pathway. These findings provide new insights for further understanding of EnSC-Exos in the recovery of ovary function.

Ultraviolet (UV) networks, owing to their advantages of low eavesdropping rates, low background noise, strong anti-interference abilities, and non–line-of-sight (NLOS) communication, have high prospects for application in the complex electromagnetic environment. In this study, UV network coverage was systematically evaluated based on the NLOS channel. Combined with a designed node model and a specific communication mode, a two-dimensional network coverage model was established and expressions of network coverage area and connectivity were derived mathematically. Subsequently, the effects of the transceiver elevation combination, number of nodes, data rate, and transmission power on the network coverage performance were analyzed, and the communication parameters were optimized to match different network scenarios. The results show that the bigger the transceiver elevation combination, the more stringent the communication parameters required by the UV network coverage. Finally, a coverage evaluation experiment with four-node network was conducted. This study provides theoretical reference information for actual network deployment.

Direct detection of miRNA is currently limited by the complex amplification and reverse transcription processes of existing methods, leading to low sensitivity and high operational demands. Herein, we developed a CRISPR/Cas13a-mediated photoelectrochemical (PEC) biosensing platform for direct and sensitive detection of miRNA-21. The direct and specific recognition of target miRNA-21 by crRNA-21 eliminates the need for pre-amplification and reverse transcription of miRNA-21, thereby preventing signal distortion and enhancing the sensitivity and precision of target detection. When crRNA-21 binds to miRNA-21, it activates the trans-cleavage activity of CRISPR/Cas13a, leading to the non-specific cleavage of biotin-modified DNA with uracil bases (biotin-rU-DNA). This cleavage prevents the biotin-rU-DNA from being immobilized on the electrode surface. As a result, streptavidin cannot attach to the electrode via specific biotin binding, reducing spatial resistance and causing a positively correlated increase in the photocurrent response. This Cas-PEC biosensor has good analytical capabilities, linear responses between 10 fM and 10 nM, a minimum detection limit of 9 fM, and an excellent recovery rate in the analysis of real human serum samples. This work presented an innovative solution for detecting other biomarkers in bioanalysis and clinical diagnostics.

(1) Background: Mitochondrial genomes have been extensively employed as a crucial marker in numerous dipteran families for understanding phylogenetics and systematics relations, thereby playing a pivotal role in molecular biology studies. The phylogenetic relationship of the Harnischia generic complex remains contentious due to the paucity of taxonomic and molecular data. Specifically, the evolutionary relationships among Cryptochironomus, Demicryptochironomus, and Harnischia are still unclear. (2) Methods: In this study, Polypedilum and Endochironomus were used as outgroups to analyze phylogenetic relationships among Cryptochironomus, Demicryptochironomus, and Harnischia, mitogenomes of four Cryptochironomus, two Demicryptochironomus, two Harnischia, and two Cladopelma were newly sequenced. Subsequently, we conducted a thorough analysis of the nucleotide composition, sequence length, and evolutionary rate. (3) Results: All mitogenomes exhibited structural conservation, with all genes consistently arranged in the identical order as that of the ancestral mitogenome. Nucleotide composition varied significantly among different genes, and the control region displayed the highest A + T content. All protein-coding genes undergo rigorous purification selection, with the ATP8 gene exhibiting the most rapid evolutionary rate among them. Utilizing Bayesian Inference (BI) and Maximum Likelihood (ML) methods across various databases, we reconstructed the phylogenetic relationships among the genera within the Harnischia generic complex, drawing insights from an analysis of 14 mitochondrial genomes. (4) Conclusions: Our results showed that the monophyly of the genera Harnischia was well supported in all topologies; Cryptochironomus is sister to Demicryptochironomus.

This paper investigates the problem of coordinated resource allocation for multiple unmanned aerial vehicles (UAVs) to address the scarcity of communication resources in disaster-affected areas. UAVs carrying modules of free space optical (FSO) and radio frequency (RF) serve as relay nodes and edge offloading nodes, presenting an FSO/RF dual-hop framework. Considering the varying urgency levels of tasks, we assign task priorities and transform the proposed problem into distributed collaborative optimization problem. Based on the K-means algorithm and the multi-agent deep deterministic policy gradient (MADDPG) algorithm, we propose a UAV-coordinated K-means MADDPG (KMADDPG) to maximize the number of completed tasks while prioritizing high-priority tasks. Simulation results show that KMADDPG is 5% to 10% better than the benchmark DRL methods in convergence performance.

The combined application of chemical and organic fertilizers has been recognized to enhance soil fertility and foster the soil microbial ecosystem. However, the optimal ratio of chemical and organic fertilizers in oilseed rape cultivation is still uncertain, and the role of rhizosphere effect is still unclear. Thus, this study aimed to elucidate the impacts of varying ratios of chemical and organic fertilizers on the structure and potential functionalities of rhizosphere and non-rhizosphere soil microbial communities. The interplay of microbial communities with soil properties and oilseed rape root exudates was investigated in controlled pot cultivations receiving varying ratios of chemical and organic fertilizers. Results indicated clear segregation in the soil bacterial community, influenced by both fertilization treatments and rhizosphere effects. The bacterial community structure significantly correlated with nitrate nitrogen, organic acids, and dissolved organic carbon (DOC) content. Rhizosphere effects led to increased bacteria abundance, reduced diversity, and decreased network stability. Notably, F3 treatment receiving 25% chemical and 75% organic fertilizers showed a significantly higher abundance at 1.43 × 1011 copies g−1 dry soil, accompanied by increased species and genetic diversity, and ecological network complexity. This treatment also yielded the highest aboveground biomass of oilseed rape. However, the application of organic fertilizers also increased the risk of plant pathogenicity. This study reveals the impact of fertilizers and rhizosphere effects on soil microbial community structure and function, shedding light on the establishment of more effective fertilization schemes for oilseed rape agriculture.

Summary: Amino acid formula (AAF) is increasingly consumed in infants with cow’s milk protein allergy; however, the long-term influences on health are less described. In this study, we established a mouse model by subjecting neonatal mice to an amino acid diet (AAD) to mimic the feeding regimen of infants on AAF. Surprisingly, AAD-fed mice exhibited dysbiotic microbiota and increased neuronal activity in both the intestine and brain, as well as gastrointestinal peristalsis disorders and depressive-like behavior. Furthermore, fecal microbiota transplantation from AAD-fed mice or AAF-fed infants to recipient mice led to elevated neuronal activations and exacerbated depressive-like behaviors compared to that from normal chow-fed mice or cow’s-milk-formula-fed infants, respectively. Our findings highlight the necessity to avoid the excessive use of AAF, which may influence the neuronal development and mental health of children.

Abstract Kagome metals AV3Sb5 (A = K, Cs, Rb) provide a rich platform for intertwined orders, where evidence for time-reversal symmetry breaking, likely due to the long-sought loop currents, has emerged in STM and muon spin relaxation experiments. An isotropic component in the spontaneous optical rotation has also been reported and was interpreted as the magneto-optic Kerr effect. Intriguingly, the observed rotations differ by five orders of magnitude between different wavelengths and samples, suggesting more intricate physics. Here we report optical rotation and polar Kerr measurements in CsV3Sb5 crystals at the same wavelength. We observe large isotropic components of 1 milliradian in the optical rotation that do not respond to applied magnetic fields, while the spontaneous Kerr signal is less than 20 nanoradians. Our results prove unambiguously that the reported isotropic rotation is not from time-reversal symmetry breaking but represents the long-sought specular optical rotation and indicates a new intertwined order.

In target detection, tracking, and recognition tasks, high-quality images can achieve better results. However, in actual scenarios, the visual effects and data quality of images are greatly reduced due to the influence of environmental factors, which affect subsequent detection, recognition, and other tasks. Therefore, this paper proposes an image rain removal algorithm based on multi-scale features, which can effectively remove rain streaks. First of all, this paper proposes a deraining algorithm that combines spatial information to improve the network’s generalization ability on real images, aiming at the problem of synthetic datasets used by previous deraining algorithms. Then, by proposing a multi-scale rain removal algorithm, it improves the feature extraction capabilities of existing deraining algorithms. Before extracting deep rain features, a preliminary fusion of multi-scale shallow features can be performed, which can show better performance in images of different sizes. In addition, a spatial attention module and channel are introduced. The attention module increases the ability to extract rain information at each scale; the resulting multi-scale feature image rain removal algorithm is called MFD. Finally, the rain removal algorithm is validated on the rain removal dataset, and the proposed method can effectively remove rain patterns, provide strong performance improvement on several datasets in the image rain removal task, and provide high-quality images for subsequent detection and recognition tasks.

Conventional straight fin (SF) radiators have difficulties meeting the cooling requirements of high-power electronic components. Therefore, based on the structure and technology of the detachable fin radiator, this paper proposes a kind of radiator embedded in the heat pipe base and uses the roll-bond flat heat pipe (RBFHP) to replace the traditional fin. The radiator has the advantages of modularity, easy manufacturing, low cost and good heat balance. In this study, the heat pipes (HPs)-RBFHPs radiator was tested in natural convection and forced convection to mimic the actual application scenario and compared with the conventional aluminum radiator. Heating power, angle, wind speed and other aspects were studied. The results showed that the cooling performance of the HPs-RBFHPs radiator was improved by 10.7% to 55% compared with that of the SF radiator under different working conditions. The minimum total thermal resistance in the horizontal state was only 0.37 °C/W. The temperature equalization of the base played a dominant role in the performance of the radiator at a large angle, and the fin group could be ineffective when the angle was greater than 60°. Under the most economical conditions with an inclination of 0° and a wind speed of 2 m/s, the input power was 340 W, the heat source temperature of the HPs-RBFHPs was only 64.2 °C, and the heat dissipation performance was 55.4% higher than that of SFs.

A point cloud is a simple and concise 3D representation, but point cloud generation is a long-term challenging task in 3D vision. However, most existing methods only focus on their effectiveness of generation and auto-encoding separately. Furthermore, both generative adversarial networks (GANs) and auto-encoders (AEs) are the most popular generative models. But there is a lack of related research that investigates the implicit connections between them in the field of point cloud generation. Thus, we propose a new bidirectional network (BI-Net) trained with collaborative learning, introducing more priors through the alternate parameter optimizations of a GAN and AE combination, which is different from the way of combining them at the network structure and loss function level. Specifically, BI-Net acts as a GAN and AE in different data processing directions, where their network structures can be reused. If optimizing only the GAN without the AE, there is no direct constraint of ground truth on the generator’s parameter optimization. This unique approach enables better network optimization and leads to superior generation results. Moreover, we propose a nearest neighbor mutual exclusion (NNME) loss to further homogenize the spatial distribution of generated points during the reverse direction. Extensive experiments were conducted, and the results show that the BI-Net produces competitive and high-quality results on reasonable structure and uniform distributions compared to existing state-of-the-art methods. We believe that our network structure (BI-Net) with collaborative learning could provide a new promising method for future point cloud generation tasks.

After the outbreak of COVID-19, the interaction of infectious disease systems and social systems has challenged traditional infectious disease modeling methods. Starting from the research purpose and data, researchers improved the structure and data of the compartment model or used agents and artificial intelligence based models to solve epidemiological problems. In terms of modeling methods, the researchers use compartment subdivision, dynamic parameters, agent-based model methods, and artificial intelligence related methods. In terms of factors studied, the researchers studied 6 categories: human mobility, nonpharmaceutical interventions (NPIs), ages, medical resources, human response, and vaccine. The researchers completed the study of factors through modeling methods to quantitatively analyze the impact of social systems and put forward their suggestions for the future transmission status of infectious diseases and prevention and control strategies. This review started with a research structure of research purpose, factor, data, model, and conclusion. Focusing on the post-COVID-19 infectious disease prediction simulation research, this study summarized various improvement methods and analyzes matching improvements for various specific research purposes.

Background The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5/CCL5 expression in CRC and to determine whether CCR5/CCL5 levels could impact treatment outcomes.Methods 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial.Results CCR5/CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5/CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5/CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. Low CCR5/CCL5 expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone.Conclusions Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.

Abstract BackgroundIn the context of training specialist nurses and nursing education, a game-based mobile app was used as a simulation to teach intensive critical care specialist nurses the knowledge and skills of extracorporeal membrane oxygenation (ECMO) pipeline preflushing. ObjectiveThis study aimed to evaluate the impact of a game-based mobile app on improving ECMO pipeline preflushing skills in intensive critical care specialist nurses. MethodsA total of 86 intensive critical care specialist nurses who were learning ECMO for the first time were included in this study. The nurses were divided into 2 groups: a control group (n=43) and an experimental group (n=43). Participants in the experimental group used a game-based mobile app for simulation exercises; the control group received no additional intervention. All participants took a theoretical test and a skill operation test at the beginning of the study and 1 week later. The differences in scores between the 2 groups were compared, and the learning curve of the experimental group was observed. ResultsThe final theoretical test scores (88.44 and 85.02) and skill operation test scores (89.42 and 86.33) of the experimental group and control group, respectively, were significantly higher than those of the initial tests (theoretical test scores: 75.88 and 74.42; skill operation test scores: 75.44 and 75.93; all PPP ConclusionsThis study suggests that a game-based mobile app may be more effective for intensive critical care specialist nurses in ECMO pipeline preflushing education than traditional Chinese lecture-practice education.

Systemic lupus erythematosus (SLE) is a chronic recurrent autoimmune disease affecting almost all organs. This study was conducted to investigate cognitive impairment of SLE mice (MRL/lpr mice), and explore associated pathological mechanism. Behavior tests (open-field test, elevated plus-maze test, forced swimming test, sucrose preference test, and Morris water maze test) were conducted in MRL/MPJ and MRL/lpr mice. ELISA test was performed to determine levels of antibodies (anti-dsDNA, anti-RPA, anti-ACA, and anti-NR2a/b) and inflammatory factors [tumour necrosis factor a (TNF-a), interleukin (IL)-6, IL-8, and IL-10]. Micro-vascular endothelial cells (MVECs) were isolated, identified, and divided into MVECs (NC), anti-NR2a/2b, memantine, glycine, dexamethasone, and IL-1b groups. Cell proliferation was measured using cell counting kit-8 (CCK-8) assay, and Western blotting was applied to evaluate ELAM-1, VCAM-1, ICAM-1, IKBa, p-IKBa expression. MRL/lpr mice demonstrated lower locomotion/exploration ability, higher anxiety, obvious depression symptoms, lower learning/memory capability compared with MRL/MPJ mice. MRL/lpr mice demonstrated high levels of anti-NR2a/b antibody and auto-antibodies. NMDA receptor antagonist (memantine) significantly increased, and NMDA receptor agonist (glycine) significantly decreased MVECs proliferation compared with NC group ( p < 0.05). Memantine significantly reduced and glycine predominantly enhanced TNF-a, IL-6, IL-8, and IL-10 levels compared with NC group ( p < 0.05). NMDA receptor antagonist and agonist modulated adhesion molecules expression in MVECs. ELAM-1, VCAM-1, and ICAM-1 expressions were significantly down-modulated in memantine group, and remarkably up-modulated in glycine group compared with NC group ( p < 0.05). NMDA receptor antagonist and agonist regulated phosphorylation of p-IKBa. The above effects of memantine evenly equaled to dexamethasone, and glycine evenly equaled to IL-1b. In conclusion, cognitive impairment of MRL mice might be associated with NMDA receptor-mediated inflammatory response and production of adhesion molecules in MRL/lpr mice-derived MVECs.

Background: Patient-based real-time quality control (PBRTQC) can be a valuable tool in clinical laboratories due to its cost-effectiveness and constant monitoring. More focus is placed on discovering and improving algorithms that compliment conventional internal control techniques. The practical implementation of PBRTQC with a biochemical instrument comparison is lacking. We aim to evaluate PBRTQC’s efficacy and practicality by comparing low-density lipoprotein cholesterol (LDL-C) test results to ensure consistent real-time monitoring across biochemical instrumentations in clinical laboratories. Method: From 1 September 2021 to 30 August 2022, the First Affiliated Hospital of Xi’an Jiaotong University collected data from 158,259 both healthy and diseased patients, including 84,187 male and 74,072 female patients, and examined their LDL-C results. This dataset encompassed a group comprising 50,556 individuals undergoing health examinations, a group comprising 42,472 inpatients (IP), and a group comprising 75,490 outpatients (OP) for the PBRTQC intelligent monitoring platform to conduct daily tests, parameter configuration, program development, real-time execution, and performance validation of the patients’ data. Moreover 40 patients’ LDL-C levels were assessed using two biochemical analyzers, designated as the reference and comparator instruments. A total of 160 LDL-C results were obtained from 40 both healthy and diseased patients, including 14 OP, 16 IP, and 10 health examination attendees, who were selected to represent LDL-C levels broadly. Two biochemical instruments measured LDL-C measurements from the same individuals to investigate consistency and reproducibility across patient statuses and settings. We employed exponentially weighted moving average (EWMA) and moving median (MM) methods to calculate inter-instrument bias and ensure analytical accuracy. Inter-instrument bias for LDL-C measurements was determined by analyzing fresh serum samples, different concentrations of quality control (QC), and commercialized calibrators, employing both EWMA and MM within two assay systems. The assessment of inter-instrumental bias with five different methods adhered to the external quality assessment standards of the Clinical Laboratory Center of the Health Planning Commission, which mandates a bias within ±15.0%. Result: We calculated inter-instrument comparison bias with each of the five methods based on patient big data. The comparison of fresh serum samples, different concentrations of QC, commercialized calibrators, and EWMA were all in the permissive range, except for MM. MM showed that the bias between two biochemical instruments in the concentration ranges of 1.5 mmoL/L–6.2 mmoL/L exceeded the permissible range. This was mainly due to the small number of specimens, affected by variations among individual patients, leading to increased false alarms and reduced effectiveness in monitoring the consistency of the inter-instrumental results. Moreover, the inter-comparison bias derived from EWMA was less than 3.01%, meeting the 15% range assessment criteria. The bias result for MM was lower than 24.66%, which was much higher than EWMA. Thus, EWMA is better than MM for monitoring inter-instrument comparability. PBRTQC can complement the use of inter-comparison bias between biochemical analyzers. EWMA has comparable inter-instrument comparability monitoring efficacy. Conclusions: The utilization of AI-based PBRTQC enables the automated real-time comparison of test results across different biochemical instruments, leading to a reduction in laboratory operating costs, enhanced work efficiency, and improved QC. This advanced technology facilitates seamless data integration and analysis, ultimately contributing to a more streamlined and efficient laboratory workflow in the biomedical field.

Vitamin C (VC) can be used to increase disease resistance in practice in intensive aquaculture. But it is still unconfirmed whether VC could alleviate inflammation and what dosage is suitable. This study investigated the effects of dietary VC on the immunity and enteritis of juvenile blunt snout bream (Megalobrama amblycephala) challenged with Aeromonas hydrophila. The fish were fed with VC levels ranging from 25.35 to 2231.98 mg/kg for 60 days. After that, fish fed with 150.65 mg/kg, 573.79 mg/kg, and 2231.98 mg/kg VC were challenged with A. hydrophila orally to simulate enteritis. The results showed that 285.39 and 573.79 mg/kg dietary VC significant improved growth performance and feed utilization. Dietary VC (573.79 and 1133.79 mg/kg) significantly enhanced the serum immune parameters, antioxidant enzymes’ activities, and relative gene expressions of ikbα and cat in the liver in the 60-day feeding trail. The survival rate was significantly higher in 573.79 mg/kg dietary VC group than the other two treatments. Cytokines were activated after the bacteria challenge. Dietary 573.79 mg/kg VC caused significantly higher TNF-α level at 12 hpi and maintained a high level of IL-8 at 48 to 72 h compared to other treatments. In conclusion, more than 500 mg/kg VC was needed to maintain the health of blunt snout bream juveniles. Suitable VC would activate cytokines to increase disease resistance along with antioxidant enzymes.

Ultraviolet (UV) networks are widely applied in complex electromagnetic environments. Designing an efficient multi-node medium access control (MAC) protocol for these networks is important. In this study, we proposed an enhanced clustering time division multiple access (TDMA) MAC protocol based on clustering and learning automata (LA). Subsequently, the effects of the network topology, class of service, and number of cluster nodes on the network performance under the proposed protocol were analyzed. Then, the protocol was compared with the TDMA protocol and clustering system. Results revealed that it obtained a better network performance, proving its suitability for multi-node UV networking.

The generation of test vectors is a key technique that affects the efficiency and fault detection rate of the boundary scan test. Aiming at the local optimal solution problem of the current common test vectors generation algorithm, this paper proposes a test vectors generation algorithm based on improved GA-AO* model, through which the test vectors are generated by using the idea of heuristic search and backtracking correction. In order to speed up the heuristic search, this paper designed a heuristic function with both prior and posterior parameters to describe the influence of typical faults on the failure probability index of the test vectors. At the same time, this paper used a genetic algorithm (GA) to determine the specific values of the posterior parameters iteratively. Finally, through theoretical analysis and physical verification, compared with the test vector generated by the traditional method, the test vector generated by this method is optimized on the prior failure probability index and performs better in the physical experiment.

Water and fertilizer managements are the most common practices to maximize crop yields, and their long-term impact on soil microbial communities has been extensively studied. However, the initial response of microbes to fertilization and soil moisture changes remains unclear. In this study, the immediate effects of nitrogen (N)-fertilizer application and moisture levels on microbial community of paddy soils were investigated through controlled incubation experiments. Amplicon sequencing results revealed that moisture had a stronger influence on the abundance and community composition of total soil bacteria, as well as ammonia oxidizing-archaea (AOA) and -bacteria (AOB). Conversely, fertilizer application noticeably reduced the connectivity and complexity of the total bacteria network, and increasing moisture slightly exacerbated these effects. NH4+-N content emerged as a significant driving force for changes in the structure of the total bacteria and AOB communities, while NO3−-N content played more important role in driving shifts in AOA composition. These findings indicate that the initial responses of microbial communities, including abundance and composition, and network differ under water and fertilizer managements. By providing a snapshot of microbial community structure following short-term N-fertilizer and water treatments, this study contributes to a better understanding of how soil microbes respond to long-term agriculture managements.

(1) Background: The evidence indicates that comorbidities are associated with an increase in the risk of death from coronavirus disease 2019 (COVID-19). It is unclear whether such an association is different for various combinations of chronic disease comorbidities. (2) Methods: From 16 March 2020 to 30 November 2021, 104,753 patients with confirmed COVID-19 from Khyber Pakhtunkhwa Province, Pakistan, were studied to determine the association between comorbidities and the duration from symptom onset to death in patients with COVID-19 by stratifying their comorbidity status. (3) Results: The patients with comorbidities had an 84% (OR, 0.16; 95% CI, 0.14 to 0.17) decrease in the duration from symptom onset to death, as opposed to patients without a comorbidity. Among the patients with only one comorbidity, chronic lung disease (OR, 0.06; 95% CI, 0.03 to 0.09) had a greater impact on the duration from symptom onset to death than hypertension (OR, 0.15; 95% CI, 0.13 to 0.18) or diabetes (OR, 0.15; 95% CI, 0.12 to 0.18). The patients with both hypertension and diabetes had the shortest duration (OR, 0.17; 95% CI, 0.14 to 0.20) among the patients with two comorbidities. (4) Conclusions: Comorbidity yielded significant adverse impacts on the duration from symptom onset to death in COVID-19 patients in Pakistan. The impact varied with different combinations of chronic disease comorbidities in terms of the number and type of comorbidities.

Endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) is very safe and has a high diagnostic rate for upper gastrointestinal lesions, especially pancreatic lesions, but its application in the lower gastrointestinal tract has rarely been reported. Due to the tortuous course of the colorectum, with the sigmoid colon particularly prone to perforation, most endoscopists are reluctant to perform lateral-sector endoscopic ultrasound scanning without a water-bag protection for the puncture. The ultrasonic endoscopy and flexible puncture needle techniques recently introduced into clinical practice have made ultrasound-guided puncture safer and more convenient. In addition, endoscopists have carefully tested various protective measures to improve the safety of the lower gastrointestinal puncture, substantially increasing its clinical feasibility. In this article, we review the iterations of endoscopic ultrasound equipment introduced in recent years and the many ingenious ideas proposed by endoscopists regarding lower gastrointestinal puncture.

The oxysterol receptor liver X receptor (LXR) is a nuclear receptor best known for its function in the regulation of lipid and cholesterol metabolism. LXRs, both the α and β isoforms, have been suggested as potential therapeutic targets for several cancer types. However, there was a lack of report on whether and how LXRα plays a role in the development of hepatocellular carcinoma (HCC). In the current study, we found that systemic activation of LXRα in the VP‐LXRα knock‐in (LXRαKI) mice or hepatocyte‐specific activation of LXRα in the VP‐LXRα transgenic mice sensitized mice to liver tumorigenesis induced by the combined treatment of diethylnitrosamine (DEN) and 3,3',5,5'‐tetrachloro‐1,4‐bis (pyridyloxy) benzene (TCPOBOP). Mechanistically, the LXRα‐responsive up‐regulation of interleukin‐6 (IL‐6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and the complement system, and down‐regulation of bile acid metabolism, may have contributed to increased tumorigenesis. Accumulations of secondary bile acids and oxysterols were found in both the serum and liver tissue of LXRα activated mice. We also observed an induction of monocytic myeloid–derived suppressor cells accompanied by down‐regulation of dendritic cells and cytotoxic T cells in DEN/TCPOBOP‐induced liver tumors, indicating that chronic activation of LXRα may have led to the activation of innate immune suppression. The HCC sensitizing effect of LXRα activation was also observed in the c‐MYC driven HCC model. Conclusion: Our results indicated that chronic activation of LXRα promotes HCC, at least in part, by promoting innate immune suppressor as a result of accumulation of oxysterols, as well as up‐regulation of the IL‐6/Janus kinase/STAT3 signaling and complement pathways.

Summary: Background: Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches glucose-dependent to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer (CRC). Therefore, we hypothesised that genetic variants in the lipid metabolism pathway may predict clinical outcomes [overall response rate (ORR), overall survival (OS) and progression-free survival (PFS)] in metastatic CRC (mCRC) patients receiving bevacizumab-based first-line treatment. Methods: Genomic DNA from blood samples of patients enrolled in FIRE-3 (a global, randomised, open-label, phase 3 trial, between 2007-6-23 and 2012-9-19, discovery cohort: FOLFIRI/bevacizumab arm, n = 107; control cohort: FOLFIRI/cetuximab arm, n = 129) and MAVERICC (a global, randomised, open-label, phase II study, between 2011–8 and 2015–7, in United States, Canada, Estonia, Ireland, Switzerland, Norway, and Portugal. Validation cohort: FOLFIRI/bevacizumab arm, n = 163) trials, was genotyped using the OncoArray-500 K beadchip panel. The impact on OS and PFS of 17 selected SNPs in 7 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1/2, CPT1A, FASN, ACACA) was analysed using Kaplan–Meier curves, the log-rank test for univariate analyses and likelihood ratio tests of Cox proportional hazards regression parameters for multivariable analyses. ORR and SNP associations were evaluated using Chi-square or Fisher's exact tests. Findings: In the discovery cohort, patients with FASN rs4485435 any C allele (n = 21) showed significantly shorter PFS (median PFS: 8.69 vs 13.48 months) compared to carriers of G/G (n = 62) in multivariable (HR = 2.87; 95%CI 1.4–5.9; p = 0.00675) analysis. These data were confirmed in the validation cohort in multivariable analysis (HR = 2.07, 95%CI: 1.15–3.74; p = 0.02), but no association was observed in the cetuximab cohort of FIRE-3. In the comparison of bevacizumab vs cetuximab arm in FIRE-3, a significant interaction was shown with FASN rs4485435 (p = 0.017) on PFS. Interpretation: Our study demonstrates for the first time, to our knowledge, that FASN polymorphisms may predict outcome of bevacizumab-based treatment in patients with mCRC. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF treatment. Funding: This work was supported by the National Cancer Institute [P30CA 014089 to H.-J.L.], Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Victoria and Philip Wilson Research Fund, San Pedro Peninsula Cancer Guild, Ming Hsieh Research Fund, Eddie Mahoney Memorial Research Fund, Shanghai Sailing Program (22YF1407000), China National Postdoctoral Program for Innovative Talents (BX20220084), China Postdoctoral Science Foundation (2022M710768), National Natural Science Foundation of China (82202892).

Abstract Objective To investigate the current situation of work stress in nurses returning to work in Chinese tertiary A general hospitals after giving birth to their second child and to analyze influencing factors. Methods From January to April 2021, 448 nurses returning to work after the birth of their second child, working in 23 general hospitals in China, were investigated and completed the postpartum work stress scale and self-rating depression scale. Results The total work stress score of returning nurses after giving birth to their second child was 90.40 ± 18.29, and the dimension with the highest score was the role commitment of the mother. Multiple linear regression analysis showed that family monthly income, turnover intention, time since returning to work, age of the first child, and depressive symptoms were the influencing factors on work stress. Conclusion It is important to reduce the work stress of the nurses returning to work after the birth of their second child. Nursing managers should pay attention to this group of postpartum nurses and formulate targeted measures to alleviate their work stress.

In order to improve the heat dissipation capability of motor controller for new energy vehicles, the water cooled radiator with multiple channels is optimized in this paper. The heat conduction between the heat source IGBT and the radiator, the convective heat transfer between the radiator and the coolant, the mechanical strength and the manufacturing cost are comprehensively considered during the optimization process. The power loss and thermal resistance of the IGBT unit are calculated at first, and finite element model of the radiator is established. On this basis, multi-physics coupling analysis of the water cooled radiator is carried out. Secondly, the sensitivity analysis is applied to verify the influence of structural parameters on the heat dissipation performance of the radiator system. The influence of coolant inlet velocity v , number of cooling ribs n , height of radiator ribs H on the maximum temperature rise T , the temperature difference ΔT between phase U and W, and the coolant pressure loss ΔP are analyzed in depth, and the optimal range of the structural parameters for heat dissipation is obtained. Finally, an experimental platform was set up to verify the performance of the proposed structure of water cooled radiator for motor controller of new energy vehicle. The results show that the heat dissipation capability of the proposed radiator is improved compared with the initial design.

Abstract Aim To establish a model for predicting adverse outcomes in advanced-age pregnant women with preterm preeclampsia in China. Methods We retrospectively collected the medical records of 896 pregnant women with preterm preeclampsia who were older than 35 years and delivered at the Affiliated Hospital of Qingdao University from June 2018 to December 2020. The pregnant women were divided into an adverse outcome group and a non-adverse outcome group according to the occurrence of adverse outcomes. The data were divided into a training set and a verification set at a ratio of 8:2. A nomogram model was developed according to a binary logistic regression model created to predict the adverse outcomes in advanced-age pregnant women with preterm preeclampsia. ROC curves and their AUCs were used to evaluate the predictive ability of the model. The model was internally verified by using 1000 bootstrap samples, and a calibration diagram was drawn. Results Binary logistic regression analysis showed that platelet count (PLT), uric acid (UA), blood urea nitrogen (BUN), prothrombin time (PT), and lactate dehydrogenase (LDH) were the factors that independently influenced adverse outcomes (P

Snow cover on the Tibetan Plateau has a shallow depth, plaque distribution, and repeated ablation. The applicability of the snow parameterization scheme in the current land surface process model on the TP needs to be further tested using observational data. In this paper, using the land surface process model CLM4.5 and ten fresh snow density parameterization schemes characterized by temperature, wind speed, and relative humidity, three discontinuous snow processes in Maqu, Madoi, and Yakou and two continuous snow processes in Madoi and Yakou were simulated. By comparing the simulated snow depth with the observed, it was found that this model can clearly describe repeated snow accumulation and ablation processes for the discontinuous snow cover process. The KW scheme, compared with the original Anderson scheme, performed the best regarding snow depth simulation. However, all schemes overestimated the melting rate of snow, and were not able to simulate continuous snow accumulation. The simulation effect of the Schmucki scheme on radiation and energy flux under discontinuous snow cover was significantly improved compared with other scheme. None of schemes performed perfectly, so future studies that focus on the simulations of snow depth, radiation flux, and energy flux under continuous snow cover for accurate and wide applications are recommended.

Purpose: By incorporating the cost of multiple tumor-marker tests, this work aims to comprehensively evaluate the financial burden of patients and the accuracy of machine learning models in diagnosing malignant pleural effusion (MPE) using tumor-marker combinations. Methods: Carcinoembryonic antigen (CEA), carbohydrate antigen (CA)19-9, CA125, and CA15-3 were collected from pleural effusion (PE) and peripheral blood (PB) of 319 patients with pleural effusion. A stacked ensemble (stacking) model based on five machine learning models was utilized to evaluate the diagnostic accuracy of tumor markers. We evaluated the discriminatory accuracy of various tumor-marker combinations using the area under the curve (AUC), sensitivity, and specificity. To evaluate the cost-effectiveness of different tumor-marker combinations, a comprehensive score (C-score) with a tuning parameter w was proposed. Results: In most scenarios, the stacking model outperformed the five individual machine learning models in terms of AUC. Among the eight tumor markers, the CEA in PE (PE.CEA) showed the best AUC of 0.902. Among all tumor-marker combinations, the PE.CA19-9 + PE.CA15-3 + PE.CEA + PB.CEA combination (C9 combination) achieved the highest AUC of 0.946. When w puts more weight on the cost, the highest C-score was achieved with the single PE.CEA marker. As w puts over 0.8 weight on AUC, the C-score favored diagnostic models with more expensive tumor-marker combinations. Specifically, when w was set to 0.99, the C9 combination achieved the best C-score. Conclusion: The stacking diagnostic model using PE.CEA is a relatively accurate and affordable choice in diagnosing MPE for patients without medical insurance or in a low economic level. The stacking model using the combination PE.CA19-9 + PE.CA15-3 + PE.CEA + PB.CEA is the most accurate diagnostic model and the best choice for patients without an economic burden. From a cost-effectiveness perspective, the stacking diagnostic model with PE.CA19-9 + PE.CA15-3 + PE.CEA combination is particularly recommended, as it gains the best trade-off between the low cost and high effectiveness.

Soil and climatic conditions are known to have close associations with plant morphological and stoichiometric traits at a regional scale along latitudinal gradients; however, how latitude drives biotic and abiotic factors affecting plant nutrient acquisition to accommodate environmental nutrient deficiency remains unclear. We quantified soil, root, leaf, and leaf litter nitrogen (N) and phosphorus (P) concentrations to determine the potentially limiting nutrient and the simultaneous responses of root capture and leaf resorption to nutrient deficiency in seven Quercus acutissima forests across the North–South Transect of Eastern China. The results showed that the mean leaf and root N:P ratios in Q. acutissima were 21.58 and 20.23, respectively, which markedly exceeded the P limitation threshold of 16 for terrestrial plants. The mean leaf litter N and P were 10.63 mg/g and 0.51 mg/g, respectively, indicating that P resorption proficiency was relatively higher than N resorption proficiency. N displayed higher stoichiometric homeostasis than P in the leaf. The leaf and root N:P ratios showed a quadratic variation that first decreased and then increased as latitude increased, whereas the phosphorus resorption efficiency and root-soil accumulation factor of P displayed the opposite trend. Partial least square path modeling (PLS-PM) analysis demonstrated that root nutrient capture and leaf nutrient resorption were regulated by different influential factors. Overall, these findings provide new insights into plant strategies to adapt to environmental nutrient deficiency, as well as the scientific basis for predicting the spatial and temporal patterns of nutrient acquisition in the context of climate change.

Ultraviolet (UV) networks are important approaches to modern wireless communications owing to their unique characteristics, such as non-line-of-sight communication, strong anti-interference ability, and all-weather working mode. Given the lack of media access control (MAC) protocols suitable for UV networks at present, a novel UV lossless contention MAC (UVLLC-MAC) protocol is proposed herein based on UV physical properties. A fully connected finite-population multinode UV model is adopted, and its network performance is systematically derived and mathematically analyzed under the UVLLC-MAC protocol. Compared with the time-slot ALOHA protocol, the UVLLC-MAC protocol achieves 36.7% better throughputs, with 13.2% drop in packet loss rates, and the excellent performance of the protocol is obtained and fully verified. The UVLLC-MAC protocol can provide guidance for multinode and multiservice UV networking.

ObjectiveTo explore the ability of PAX1 methylation (PAX1m) to predict the pathological upgrade of cervical intraepithelial neoplasia (CIN) before cold knife conization (CKC).MethodsA total of 218 women that underwent colposcopy-directed biopsy (CDB) pathology for the confirmation of CIN2 and CIN3 between December 2020 to September 2021 were enrolled in this study. The methylation levels of PAX1 (ΔCpPAX1) were determined by quantitative methylation-specific polymerase chain reaction (qMSP). Receiver operating characteristic curve was used to identify the optimal cut-off value of ΔCpPAX1 for predicting the pathological upgrade of disease.ResultsIn the CDB-confirmed CIN2 group, 36% of CIN2 was found to have pathologically upgraded to CIN3 and 30% regressed to low-grade squamous intraepithelial lesion (LSIL) and below, and none of CIN2 upgraded to early-stage cervical cancer (ESCC) after CKC. In the CDB-confirmed CIN3 group, 19.5% (23/118) of CDB-confirmed CIN3 were pathologically upgraded to ESCC after CKC. Regardless of CIN2 or CIN3, the ΔCpPAX1 level of women with upgraded pathology after CKC was significantly lower than that of women with degraded pathology. The optimal △CpPAX1 cut-off value in predicting CIN3 to be upgraded to ESCC after CKC was 6.360 and the area under the curve (AUC) was 0.814, with similar sensitivity (78.3%) and higher specificity (84.2%) than cytology≥LSIL (Se:78.3%;Sp:58.9%) and HPV16/18 positive (Se:73.9%;Sp:46.3%) patients.ConclusionsPAX1m could be a promising auxiliary marker in predicting the pathological upgrade of CIN before CKC. We found that if the △Cp PAX1 cut-off value is lower than 6.360, it is highly suggestive of invasive cervical cancer.

BackgroundMotion sickness is characterized by nausea and vomiting among a constellation of symptoms. Symptom severity is dynamic and distressing. Most validated motion sickness scales are time-intensive and effortful, with alternative scales having uncertain performance or non-specific measures. A validated instrument allowing for facile, rapid assessment of core motion sickness symptom severity would therefore be valuable. We assessed the performance of the Motion Sickness Severity Scale (MSSS), a six-item questionnaire designed to measure real-time motion sickness symptoms.MethodsMSSS construct validity was assessed as a secondary analysis of data from 63 healthy participants without antiemetic treatment in a clinical trial (Unique Identifier = NCT03772340) conducted to evaluate the safety and efficacy of Tradipitant-a novel neurokinin-1 receptor antagonist-in the treatment of motion sickness. Clinical outcome assessments included the MSSS, the Patient Global Impression of Severity (PGI-S), and the Motion Sickness Assessment Questionnaire (MSAQ). The performance of the MSSS through Pearson correlation coefficients, within-group analysis of variance, empirical cumulative distribution functions, and Kolmogorov-Smirnov tests.ResultsThe MSSS correlated very highly with the PGI-S (r = 0.93, p-valueDiscussionThe MSSS is a valid instrument for the assessment of the core motion sickness symptoms and is reflective of global disease severity. Implementation of the MSSS and comparable simplified, short questionnaires in motion sickness research will provide rapid and accurate measures of disease severity. These measures will enable further elucidation of motion sickness as an illness and inform the development and evaluation of motion sickness therapies.

Abstract Background Gestational diabetes mellitus (GDM) is one of the critical causes of adverse perinatal outcomes. A reliable estimate of GDM in early pregnancy would facilitate intervention plans for maternal and infant health care to prevent the risk of adverse perinatal outcomes. This study aims to build an early model to predict GDM in the first trimester for the primary health care centre. Methods Characteristics of pregnant women in the first trimester were collected from eastern China from 2017 to 2019. The univariate analysis was performed using SPSS 23.0 statistical software. Characteristics comparison was applied with Mann-Whitney U test for continuous variables and chi-square test for categorical variables. All analyses were two-sided with p < 0.05 indicating statistical significance. The train_test_split function in Python was used to split the data set into 70% for training and 30% for test. The Random Forest model and Logistic Regression model in Python were applied to model the training data set. The 10-fold cross-validation was used to assess the model’s performance by the areas under the ROC Curve, diagnostic accuracy, sensitivity, and specificity. Results A total of 1,139 pregnant women (186 with GDM) were included in the final data analysis. Significant differences were observed in age (Z=−2.693, p=0.007), pre-pregnancy BMI (Z=−5.502, p

In this study, we developed a novel on-line solid phase extraction (SPE)-ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS)-based analytical method for simultaneously quantifying 12 illicit drugs and metabolites (methamphetamine, amphetamine, morphine, codeine, 6-monoacetylmorphine, benzoylecgonine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, cocaine, ketamine, norketamine, and methcathinone) and cotinine (COT) in wastewater samples. The analysis was performed by loading 2 mL of the sample onto an Oasis hydrophilic-lipophilic balance cartridge and using a cleanup step (5% methanol) to eliminate interference with a total run time of 13 min. The isotope-labeled internal standard method was used to quantify the target substances and correct for unavoidable losses and matrix effects during the on-line SPE process. Typical analytical characteristics used for method validation were sensitivity, linearity, precision, repeatability, recovery, and matrix effects. The limit of detection (LOD) and limit of quantification (LOQ) of each target were set at 0.20 ng/L and 0.50 ng/L, respectively. The linearity was between 0.5 ng/L and 250 ng/L, except for that of COT. The intra- and inter-day precisions were

Abstract We conducted an observational research study to collect information on sleep–wake patterns from participants with a confirmed status of the cryptochrome circadian clock 1 (CRY1) splicing variant, CRY1Δ11 c.1657 + 3A > C, and their controls, defined as wild-type (WT) family members. Altogether, 67 participants were enrolled and completed this study in Turkey, recruited from a list of families with at least one CRY1-confirmed member. We measured sleep–wake patterns and metabolic output, specifically time and frequency of bowel movements, for all participants by daily post-sleep diaries over 28 days. The sleep diary measured self-reported bed time, wake time, midpoint of sleep, and latency to persistent sleep (LPS), and accounted for naps and awakenings for religious purposes. Wake time and midpoint of sleep were significantly later in the CRY1Δ11 variant group versus WT, and LPS was significantly greater in participants in the CRY1Δ11 variant group. The mean bed time on all nights of sleep was later in participants with a CRY1Δ11 variant versus WT. Additionally, participants with a CRY1Δ11 variant had significantly affected metabolic outputs, measured by later bowel movements than WT participants. These results demonstrate that, on average, individuals with the studied splicing variant experience pronounced delays in sleep period and circadian-related metabolic processes.

Flower-like cobalt–molybdenum mixed-oxide microspheres (CoMo-FMs) with hierarchical architecture were successfully synthesized via a hydrothermal process and subsequent calcination step. The characterization results show that CoMo-FMs were assembled from ultrathin mesoporous nanosheets with thicknesses of around 4.0 nm, providing the composite with a large pore volume and a massive surface area. The synthesized CoMo-FMs were employed as catalysts for the aerobic oxidative desulfurization (AODS) of fuel, and the reaction results show that the optimal catalyst (CoMo-FM-2) demonstrated an outstanding catalytic performance. Over CoMo-FM-2, various thiophenic sulfides could be effective removed at 80–110 °C under an atmospheric pressure, and a complete conversion of sulfides could be achieved in at least six consecutive cycles without a detectable change in chemical compositions. Further, the catalytic mechanism was explored by conducting systemic radical trapping and transformation experiments, and the excellent catalytic performance for CoMo-FMs should be mainly due to the synergistic effect of Mo and Co elements.

Amoxicillin appears to be clinically drug-resistant due to the presence of β-lactamase in bacteria. Here, we designed and prepared a hollow Prussian Blue (HPB)-based therapeutic nanoplatform that was constructed by encapsulating amoxicillin into polyethyleneimine with β-lactamase inhibitor 4-carboxyphenylboronic acid (4-Cpba) decorated HPB nanoparticles (CPA NPs). The antibacterial effect of the CPA NPs on drug-resistant bacteria was observed by in vitro colony-forming unit, minimum inhibitory concentration, scanning electron microscopy, and fluorescence tests. The results show that amoxicillin effectively inhibited Escherichia coli and Staphylococcus aureus-resistant bacteria in the presence of 4-Cpba. The in vivo experimental results show that the CPA NPs exhibited a synergistic anti-infective effect in vivo, which inhibited the inflammatory response and apoptosis induced by the drug-resistant bacterial infection, and promoted wound healing in mice. The hematoxylin and eosin staining and blood biochemical experiments revealed that the acute toxicity of the material was negligible and it had good biocompatibility. Our results verify our design that CPA NPs can restore the antibacterial activity of amoxicillin.

Methyglyoxal (MGO), an essential endogenous dicarbonyl metabolite, can lead to multiple physiological problems including hyperglycemia, kidney diseases, malignant tumors, beyond its normal concentration range. The glyoxalase system, making MGO maintained at a low level, links glycation to carcinogenesis, growth, metastasis, and cancer chemotherapy. The glyoxalase system comprises glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2), which is often overexpressed in various tumor tissues. However, very little is known about the glyoxalase system in breast cancer and gynecological cancer. In this review, we introduce the role of the glyoxalase system in breast cancer, endometrial cancer, ovarian cancer and cervical cancer, and highlight the potential of the glyoxalase system to be both as a marker for diagnosis and a novel target for antitumor therapy. However, the intrinsic molecular biology and mechanisms of the glyoxalase system in breast cancer and gynecological cancer need further exploration.

Juglans mandshurica is a native tree species in Northeast China. Due to habitat destruction and human disturbance, its population size has sharply decreased. Currently, information on molecular markers of J. mandshurica is limited and cannot meet the needs of germplasm resource evaluation and molecular marker-assisted breeding of J. mandshurica. Based on transcriptomic data from three tissues (leaves, bark, and fruit pericarp), we developed expressed sequence tag-simple sequence repeats (EST-SSRs) for J. mandshurica, and 15 polymorphic EST-SSR primers were initially selected. The average number of alleles (Na), expected heterozygosity (He), and the polymorphic information content (PIC) at different loci were 18.27, 0.670, and 0.797, respectively. Population genetic diversity analysis revealed that the average Na, He, and Shannon information indices (I) for 15 J. mandshurica populations were 6.993, 0.670, and 1.455, respectively. Among them, population Hunchun exhibited the highest genetic diversity (Na = 7.933, He = 0.723, and I = 1.617), while population Heihe exhibited the lowest genetic diversity (Na = 4.200, He = 0.605, and I = 1.158). STRUCTURE analysis, neighbor-joining method cluster analysis, and principal coordinate analysis showed that the 343 individuals of J. mandshurica from 15 populations were clustered into three categories. Category 1 (green) had 147 individuals from eight populations in Qingyuan, Caohekou, Jian, Ningan, Yongji, Baishishan, Helong, and Maoershan; category 2 (blue) had 81 individuals from three populations in Hulin, Boli, and Sanchazi; and category 3 (red) had 115 individuals from four populations in Heihe, Hunchun, Fangzheng, and Liangshui. Analysis of molecular variance (AMOVA) showed that genetic variations among and within individuals accounted for 16.22% and 21.10% of the total genetic variation, respectively, indicating that genetic variations within populations were greater than genetic variations among populations. The average genetic differentiation coefficient (Fst) and gene flow (Nm) between different populations were 0.109 and 4.063, respectively, implying moderate levels of genetic differentiation and gene flow. Based on the genetic diversity characteristics of different populations, we proposed various genetic conservation strategies for J. mandshurica.

Abstract Background Nano-Fenton reactors as novel strategy to selectively convert hydrogen peroxide (H2O2) into active hydroxyl radicals in tumor microenvironment for cancer therapy had attracted much attention. However, side effects and low efficiency remain the main drawbacks for cancer precise therapy. Results Here, ruthenium-loaded palmitoyl ascorbate (PA)-modified mesoporous silica (Ru@SiO2-PA) was successfully fabricated and characterized. The results indicated that Ru@SiO2-PA under pH6.0 environment displayed enhanced growth inhibition against human cancer cells than that of pH7.4, which indicated the super selectivity between cancer cells and normal cells. Ru@SiO2-PA also induced enhanced cancer cells apoptosis, followed by caspase-3 activation and cytochrome-c release. Mechanism investigation revealed that Ru@SiO2-PA caused enhanced generation of superoxide anion, which subsequently triggered DNA damage and dysfunction of MAPKs and PI3K/AKT pathways. Moreover, Ru@SiO2-PA effectively inhibited tumor spheroids and tumor xenografts growth in vivo by induction of apoptosis. The real-time imaging by monitoring Ru fluorescence in vitro and in vivo revealed that Ru@SiO2-PA mainly accumulated in cell nucleus and tumor xenografts. Importantly, Ru@SiO2-PA showed no side effects in vivo, predicting the safety and potential application in clinic. Conclusions Our findings validated the rational design that Ru@SiO2-PA can act as novel tumor microenvironment-response nano-Fenton reactors for cancer precise therapy. Graphic Abstract

Background: BRCA1/2 mutations have been shown to be associated with the development of many solid tumors including endometrial cancer (EC). The objectives of this study are to analyze the association between BRCA1/2 mutational status and clinicopathological characteristics as well as outcomes in EC patients. Methods: 510 eligible EC patients from the Cancer Genome Atlas database were included in the study. The association between clinicopathological characteristics and different BRCA1/2 mutational status was compared and analyzed. Analyses of the impact of BRCA mutations on survival in EC patients was conducted using Kaplan-Meier survival analyses and Cox regressions. In order to control confounding bias between groups, propensity score matching method was used. Results: Among the eligible patients, 11 (2.2%) harbored BRCA1 mutation, 43 (8.4%) harbored BRCA2 mutation, and 36 (7.1%) harbored both. Body mass index, rates of hypertension history, proportion of non-endometrioid histology and rates of positive peritoneal cytology were lower in patients with BRCA1/2 mutations compared with the group of wild-type counterpart (p = 0.020, 0.048, 0.001 and 0.012, respectively). Patients with BRCA1/2 mutations showed longer overall (OS) and recurrence-free survival (RFS) (in Kaplan-Meier analyses, p

Abstract Semiconducting piezoelectric α-In2Se3 and 3R MoS2 have attracted tremendous attention due to their unique electronic properties. Artificial van der Waals (vdWs) heterostructures constructed with α-In2Se3 and 3R MoS2 flakes have shown promising applications in optoelectronics and photocatalysis. Here, we present the first flexible α-In2Se3/3R MoS2 vdWs p-n heterojunction devices for photodetection from the visible to near infrared region. These heterojunction devices exhibit an ultrahigh photoresponsivity of 2.9 × 103 A W−1 and a substantial specific detectivity of 6.2 × 1010 Jones under a compressive strain of − 0.26%. The photocurrent can be increased by 64% under a tensile strain of + 0.35%, due to the heterojunction energy band modulation by piezoelectric polarization charges at the heterojunction interface. This work demonstrates a feasible approach to enhancement of α-In2Se3/3R MoS2 photoelectric response through an appropriate mechanical stimulus.

Computational fluid dynamics- (CFD-) based component-level numerical simulation technology has been widely used in the design of aeroengines. However, due to the strong coupling effects between components, the numerical simulation of the whole engine considering the full three-dimensional flow and multi-component chemical reaction is still very difficult at present. Aimed at this problem, an efficient implicit solver, ‘sprayDyMFoam’ for an unstructured mesh, is developed in this paper based on the Sunway TaihuLight supercomputer. This sprayDyMFoam solver improves the PIMPLE algorithm in the solution of aerodynamic force and adjusts the existing droplet atomization model in the solution of the combustion process so as to meet the matching situation between components and the combustion chamber in the solution process. Meanwhile, the parallel communication mechanism of AMI boundary processing is optimized based on the hardware environment of the Sunway supercomputer. The sprayDyMFoam solver is used to simulate a typical double-rotor turbofan engine: the calculation capacity and efficiency meet the use requirements, and the obtained compressor performance can form a good match with the test. The research proposed in this paper has strong application value in high-confidence computing, complex phenomenon capturing, and time and cost reduction for aeroengine development.