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Abstract Background and Aims Data on the safety and effectiveness of tenofovir alafenamide (TAF) plus peginterferon-alpha (Peg-IFN-α) in children with chronic hepatitis B (CHB) are lacking. The current study aimed to present the characteristics of four pediatric CHB patients who obtained a functional cure by using TAF and Peg-IFN-α. Methods In this case series study initiated in May 2019, ten children who had no clinical symptoms or signs received response-guided (HBV DNA undetectable, hepatitis B e antigen [HBeAg] loss or seroconversion, and hepatitis B surface antigen [HBsAg] loss or seroconversion) and functional cure-targeted (HBsAg loss or seroconversion) TAF (25 mg/d, orally) plus Peg-IFN-α-2b (180 µg/1.73m2, subcutaneously, once weekly) in combination (9/10) or sequential (1/10) therapy. The safety and effectiveness of these treatments were monitored. Results As of April 2024, four out of ten children obtained a functional cure after a mean of 31.5 months of treatment, and the other six children are still undergoing treatment. These four cured children, aged 2, 4, 8, and 6 years, were all HBeAg-positive and had alanine aminotransferase levels of 80, 47, 114, and 40 U/L; HBV DNA levels of 71200000, 93000000, 8220, and 96700000 IU/mL; and HBsAg levels of 39442.8, 15431.2, 22, and 33013.1 IU/mL, respectively. During treatment, all the children (10/10) experienced mild or moderate adverse events, including flu-like symptoms, anorexia, fatigue, and cytopenia. Notably, growth retardation (8/10) was the most significant adverse event; and it occurred in three cured children (3/4) treated with combination therapy and was present to a low degree in the other cured child (1/4) treated with sequential therapy. Fortunately, all three cured children recovered to or exceeded the normal growth levels at 9 months posttreatment. Conclusions TAF plus Peg-IFN-α-2b therapy is potentially safe and effective for pediatric CHB patients, which may provide important insights for future clinical practice and study designs targeting functional cures for children with CHB.

Aero engine design necessitates crucial components, such as turbine discs, to be highly stable in high-temperature environments. Therefore, the accurately determining of the mechanical properties and microstructure evolution of these components under long-term high-temperature exposure is ofs significant engineering and scientific value. Herein, we systematically analyzed the microstructure and performance evolution of a Ni-based superalloy during long-term high-temperature exposure, explored the relationship between service conditions and yield strength, and introduced novel strength decay factors, namely temperature (|α|) and time (|β|) decay factors. |α| was strongly positively correlated with the exposure temperature, whereas |β| exhibited a more complex behavior and was more affected by the microstructure before thermal exposure, especially at low temperatures (650–700 °C). Microstructural analysis revealed minimal changes in average grain size and Σ3 twin boundaries following long-term thermal exposure. However, γ′ particles coarsened after thermal exposure, particularly at higher temperatures and longer exposure times. The coarsening process under different conditions was examined using Lifshitz–Slyozov–Wagner and trans-interface diffusion-controlled models. The coarsening of γ′ particles led to mechanical degradation, as the critical failure stress decreased with increasing γ′-particle size.

Abstract Introduction Observational studies and clinical trials have supported the association between gut microbiota and psoriatic arthritis. However, the causal link between gut microbiota and psoriatic arthritis is still unclear. Methods A two-sample bi-directional Mendelian randomization analysis was performed using the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis (n = 13,266) conducted by the MiBioGen consortium. The summary statistics of psoriatic arthritis were extracted directly from the FinnGen consortium, which consists of 3186 psoriatic arthritis patients and 24,086 controls. Sensitivity analyses were conducted to assess the validity of our findings. Enrichment analyses were used to investigate the biofunction and pathways. Results Inverse variance weighted (IVW) estimates suggested that family Rikenellaceae (P = 0.032) and genus Ruminococcaceae UCG011 (P = 0.014) had a detrimental effect on psoriatic arthritis. We also noticed the negative association between the class Methanobacteria (P = 0.032), order Methanobacteriales (P = 0.032), family Methanobacteriaceae (P = 0.032), genus Eubacterium fissicatena group (P = 0.010), genus Methanobrevibacter (P = 0.031), and genus Butyricicoccus (P = 0.041) with psoriatic arthritis. Sensitivity analyses showed that genus Butyricicoccus had pleiotropy and heterogeneity. According to the results of reverse MR analysis, the causal effect of psoriatic arthritis was found on six taxa, respectivelyc family Clostridiaceae1, family Defluviitaleaceae, genus Butyrivibrio, genus Defluviitaleaceae UCG011, genus Clostridium sensu stricto1, and genus Ruminococcaceae UCG011. Conclusion This two-sample bidirectional Mendelian randomization analysis suggested that the gut microbiota had a causal effect on psoriatic arthritis and implied the potential role of probiotics in the management and prevention of psoriatic arthritis.

Abstract Aims The current management of patients with atrial fibrillation (AF) and concomitant heart failure (HF) remains a significant challenge. Catheter ablation (CA) has been shown to improve left ventricular ejection fraction (LVEF) in these patients, but which patients can benefit from CA is still poorly understood. The aim of our study was to determine the predictors of improved ejection fraction in patients with persistent atrial fibrillation (PeAF) complicated with HF undergoing CA. Methods and results A total of 435 patients with persistent AF underwent an initial CA between January 2019 and March 2023 in our hospital. We investigated consecutive patients with left ventricular systolic dysfunction (LVEF

Abstract Natural herbs, which contain pharmacologically active compounds, have been used historically as medicines. Conventionally, the analysis of chemical components in herbal medicines requires time-consuming sample separation and state-of-the-art analytical instruments. Nanopore, a versatile single molecule sensor, might be suitable to identify bioactive compounds in natural herbs. Here, a phenylboronic acid appended Mycobacterium smegmatis porin A (MspA) nanopore is used as a sensor for herbal medicines. A variety of bioactive compounds based on salvianolic acids, including caffeic acid, protocatechuic acid, protocatechualdehyde, salvianic acid A, rosmarinic acid, lithospermic acid, salvianolic acid A and salvianolic acid B are identified. Using a custom machine learning algorithm, analyte identification is performed with an accuracy of 99.0%. This sensing principle is further used with natural herbs such as Salvia miltiorrhiza, Rosemary and Prunella vulgaris. No complex sample separation or purification is required and the sensing device is highly portable.

Abstract Natural fruits contain a large variety of cis-diols. However, due to the lack of a high-resolution sensor that can simultaneously identify all cis-diols without a need of complex sample pretreatment, direct and rapid analysis of fruits in a hand-held device has never been previously reported. Nanopore, a versatile single molecule sensor, can be specially engineered to perform this task. A hetero-octameric Mycobacterium smegmatis porin A (MspA) nanopore modified with a sole phenylboronic acid (PBA) adapter is prepared. This engineered MspA accurately recognizes 1,2-diphenols, alditols, α-hydroxy acids and saccharides in prune, grape, lemon, different varieties of kiwifruits and commercial juice products. Assisted with a custom machine learning program, an accuracy of 99.3% is reported and the sample pretreatment is significantly simplified. Enantiomers such as DL-malic acids can also be directly identified, enabling sensing of synthetic food additives. Though demonstrated with fruits, these results suggest wide applications of nanopore in food and drug administration uses.

Abstract Background In the present study, we aimed to investigate the role of baseline (B), interim (I) and end-of-treatment (Eot) 18F-FDG PET/CT in assessing the prognosis of diffuse large B cell lymphoma (DLBCL), so as to identify patients who need intensive treatment at an early stage. Methods A total of 127 DLBCL patients (62 men; 65 women; median age 62 years) were retrospectively analyzed in this study. Baseline (n = 127), interim (n = 127, after 3–4 cycles) and end-of-treatment (n = 53, after 6–8 cycles) PET/CT images were re-evaluated; semi-quantitative parameters such as maximum standardized uptake value of lesion-to-liver ratio (SUVmax(LLR)) and lesion-to-mediastinum ratio (SUVmax(LMR)), total metabolic tumor volume (TMTV) and total metabolic tumor volume (TLG) were recorded. ΔTLG1 was the change of interim relative to baseline TLG (I to B), ΔTLG2 (Eot to B). ΔSUVmax and ΔTMTV were the same algorithm. The visual Deauville 5-point scale (D-5PS) has been adopted as the major criterion for PET evaluation. Visual analysis (VA) and semi-quantitative parameters were assessed for the ability to predict progression-free survival (PFS) and overall survival (OS) by using Kaplan–Meier method, cox regression and logistic regression analysis. When visual and semi-quantitative analysis are combined, the result is only positive if both are positive. Results At a median follow-up of 34 months, the median PFS and OS were 20 and 32 months. The survival curve analysis showed that advanced stage and IPI score with poor prognosis, ΔSUVmax(LLR) 1

Deep learning has attracted wide attention recently because of its excellent feature representation ability and end-to-end automatic learning method. Especially in clinical medical imaging diagnosis, the semi-supervised deep learning model is favored and widely used because it can make maximum use of a limited number of labeled data and combine it with a large number of unlabeled data to extract more information and knowledge from it. However, the scarcity of medical image data, the vast image size, and the instability of image quality directly affect the model’s robustness, generalization, and image classification performance. Therefore, this paper proposes a new semi-supervised learning model, which uses quadratic neurons instead of traditional neurons, aiming to use quadratic convolution instead of the conventional convolution layer to improve the feature extraction ability of the model. In addition, we introduce two Dropout layers and two fully connected layers at the end of the model to enhance the nonlinear fitting ability of the network. Experiments on two large medical public data sets - ISIC 2019 and Retinopathy OCT - show that our method can improve the model’s generalization performance and image classification accuracy.

Abstract Ferroptosis is an iron-dependent cell death mechanism involving the accumulation of lipid peroxides. As a critical regulator, glutathione peroxidase 4 (GPX4) has been demonstrated to be downregulated in epilepsy. However, the mechanism of ferroptosis in epilepsy remains unclear. In this study, bioinformatics analysis, analysis of epilepsy patient blood samples and cell and mouse experiments revealed strong associations among epilepsy, ferroptosis, microRNA-211-5p and purinergic receptor P2X 7 (P2RX7). P2RX7 is a nonselective ligand-gated homotrimeric cation channel, and its activation mainly increases neuronal activity during epileptic seizures. In our study, the upregulation of P2RX7 in epilepsy was attributed to the downregulation of microRNA (miR)-211-5p. Furthermore, P2RX7 has been found to regulate GPX4/HO-1 by alleviating lipid peroxidation induced by suppression of the MAPK/ERK signaling pathway in murine models. The dynamic decrease in miR-211-5p expression induces hypersynchronization and both nonconvulsive and convulsive seizures, and forebrain miR-211-5p suppression exacerbates long-lasting pentylenetetrazole-induced seizures. Additionally, in this study, induction of miR-211-5p expression or genetic-silencing of P2RX7 significantly reduced the seizure score and duration in murine models through the abovementioned pathways. These results suggest that the miR-211-5p/P2RX7 axis is a novel target for suppressing both ferroptosis and epilepsy.

To explore how chemical, physical and biological process impact the adsorption capacity of biochar for cations and anions, five kinds of spent mushroom substrate biochars including PB (carbonized Auricularia auricula substrate at 600 °C for 6 h), NB (Aged PB at 25 °C and 40 % moisture for 12 mon), AB (PB treated with 20 % mixed acid solution at 70 °C for 6 h), FB (PB subjected to 16 freeze–thaw cycles between − 20 °C and 25 °C) and MB (PB incubated with microbes from contaminated soil for 15 cycles) were prepared under simulated conditions, the internal mechanisms were revealed. Results showed that all aging processes caused a variation in crystal quantity and structure on different biochar. AB, NB and MB had higher hydrophilicity and polarity, and more positive charges than PB. Moreover, AB and MB had a higher cation exchange capacity (CEC) (70.7 and 75.3 cmol/kg) and more oxygen-containing functional groups than PB. MB has the maximum adsorption capacity for Cd(II) (24.2 mg/g), followed by PB (23.5 mg/g), FB (22.7 mg/g), NB (22.2 mg/g), and AB (22.0 mg/g). Langmuir model better described the Cd(II) adsorption onto NB, FB, and PB, while Freundlich better described AB and MB. As for Cr(VI), the maximum adsorption capacity followed the order: MB (24.1 mg/g) > AB (23.7 mg/g) > FB (23.5 mg/g) > PB (23.0 mg/g) > NB (22.7 mg/g). Langmuir model was better for Cr(VI) adsorption onto FB and PB, while Freundlich was better for AB, NB and MB. The pseudo-first-order kinetic model fits for Cd adsorption by FB，while the pseudo-second-order kinetic model fit for the adsorption of Cd and Cr by other biochars. The adsorption of Cr by all biochars was significantly related to the content of lactone group. Acidification and organic acids from microorganisms increased the pHPZC values of AB and MB, which was not conducive to the adsorption of Cd. The surface fragmentation of FB caused by the freezing and thawing process promoted its adsorption of Cd.

IntroductionCD8+T cell tolerance plays an important role in tumor escape. Recent studies have shown that CD45+ erythroid progenitor cells (CD45+EPCs) generated through splenic extramedullary erythropoiesis suppress tumor immunity. However, the mechanism underlying how CD45+EPCs mediate CD8+T cell tolerance remains incompletely understood and requires further research.MethodsIn this study, the antigen-processing abilities of CD45+EPCs was verified through both in vitro and in vivo experiments. We have used the method of co-culture in vitro and adoptive transfer experiments in vivo to explore the effects of CD45+EPCs on CD8+T cell tolerance. RNA-sequencing analysis and blocking experiments were used to evaluate the role of ROS in the CD45+EPC mediated tolerance of CD8+T cells. Finally, we incorporated uric acid into the adoptive transfer experiments to rescue the CD45+EPC mediated tumor-promoting effect.Results and discussionWe found that CD45+EPCs take up soluble proteins, present antigenic epitopes on their surface, and induce antigen-specific CD8+T cell anergy. In addition, we found that CD45+EPC directly nitrates tyrosine within the TCR/CD8 complex via the production of reactive oxygen species and peroxynitrite, preventing CD8+ T cells from responding to their specific peptide antigens. Furthermore, uric acid treatment effectively abolished the immunosuppressive effects of CD45+EPCs during CD8+T cell adoptive transfer, thereby enhancing the anti-tumor efficacy. These results demonstrated that CD8+T cell tolerance in tumor-bearing mice is induced by CD45+EPCs. The results of this study have direct implications for tumor immunotherapy.

Investigating the role of surface-modified 3D printed titanium implants in modulating oral soft tissue closure and antimicrobial properties. Eighteen 6-month-old healthy adult New Zealand White rabbits were selected as experimental animals, the left and right mandibular teeth of each experimental animal were randomly divided into two groups, and the bilateral first premolar teeth were extracted after general anesthesia, and one implant was implanted into each of the magnesium/zinc ionized surface-treated group (experimental group) and the surface-untreated group (control group), with a total of 36 implants, i.e., 18 implants for the experimental group and 18 implants for the control group. Bilateral mandibular samples from both groups were removed after 2 and 4 weeks of implantation to investigate the attachment and spreading of human gingival fibroblasts (HGFs) on the surface of the samples, their proliferative and migratory behaviors as well as the expression levels of related gene proteins (CoL-1 and TGF-β), and HE staining of the soft tissues of the samples and inflammatory cell counts. After 2 and 4 weeks of implantation, the experimental group’s HGFs adhesion and spreading were significantly better than that of the control group, the migration and proliferation of HGFs were significantly greater than that of the control group ( p < .05), and the expression of CoL-1 and TGF-β genes was significantly higher than that of the control group ( p < .05), and the inflammatory cell count was significantly smaller than that of the control group ( p < .05). Surface modification by magnesium and zinc ions enhances the sealing performance and antimicrobial performance of 3D printed titanium implants in oral soft tissues, with significant effects.

Ultrasound-stimulated contrast agents have gained significant attention in the field of tumor treatment as drug delivery systems. However, their limited drug-loading efficiency and the issue of bulky, imprecise release have resulted in inadequate drug concentrations at targeted tissues. Herein, we developed a highly efficient approach for doxorubicin (DOX) precise release at tumor site and real-time feedback via an integrated strategy of “programmable ultrasonic imaging guided accurate nanodroplet destruction for drug release” (PND). We synthesized DOX-loaded nanodroplets (DOX-NDs) with improved loading efficiency (15 %) and smaller size (mean particle size: 358 nm). These DOX-NDs exhibited lower ultrasound activation thresholds (2.46 MPa). By utilizing a single diagnostic transducer for both ultrasound stimulation and imaging guidance, we successfully vaporized the DOX-NDs and released the drug at the tumor site in 4 T1 tumor-bearing mice. Remarkably, the PND group achieved similar tumor remission effects with less than half the dose of DOX required in conventional treatment. Furthermore, the ultrasound-mediated vaporization of DOX-NDs induced tumor cell apoptosis with minimal damage to surrounding normal tissues. In summary, our PND strategy offers a precise and programmable approach for drug delivery and therapy, combining ultrasound imaging guidance. This approach shows great potential in enhancing tumor treatment efficacy while minimizing harm to healthy tissues.

Abstract Background Maintaining the repair phenotype of denervated Schwann cells in the injured distal nerve is crucial for promoting peripheral nerve regeneration. However, when chronically denervated, the capacity of Schwann cells to support repair and regeneration deteriorates, leading to peripheral nerve regeneration and poor functional recovery. Herein, we investigated whether neurotrophin-3 (NT-3) could sustain the reparative phenotype of Schwann cells and promote peripheral nerve regeneration after chronic denervation and aimed to uncover its potential molecular mechanisms. Methods Western blot was employed to investigate the relationship between the expression of c-Jun and the reparative phenotype of Schwann cells. The inducible expression of c-Jun by NT-3 was examined both in vitro and in vivo with western blot and immunofluorescence staining. A chronic denervation model was established to study the role of NT-3 in peripheral nerve regeneration. The number of regenerated distal axons, myelination of regenerated axons, reinnervation of neuromuscular junctions, and muscle fiber diameters of target muscles were used to evaluate peripheral nerve regeneration by immunofluorescence staining, transmission electron microscopy (TEM), and hematoxylin and eosin (H&E) staining. Adeno-associated virus (AAV) 2/9 carrying shRNA, small molecule inhibitors, and siRNA were employed to investigate whether NT-3 could signal through the TrkC/ERK pathway to maintain c-Jun expression and promote peripheral nerve regeneration after chronic denervation. Results After peripheral nerve injury, c-Jun expression progressively increased until week 5 and then began to decrease in the distal nerve following denervation. NT-3 upregulated the expression of c-Jun in denervated Schwann cells, both in vitro and in vivo. NT-3 promoted peripheral nerve regeneration after chronic denervation, mainly by upregulating or maintaining a high level of c-Jun rather than NT-3 itself. The TrkC receptor was consistently presented on denervated Schwann cells and served as NT-3 receptors following chronic denervation. NT-3 mainly upregulated c-Jun through the TrkC/ERK pathway. Conclusion NT-3 promotes peripheral nerve regeneration by maintaining the repair phenotype of Schwann cells after chronic denervation via the TrkC/ERK/c-Jun pathway. It provides a potential target for the clinical treatment of peripheral nerve injury after chronic denervation.

Fusarium head blight (FHB) is a major threat to global wheat production. Recent reviews of wheat FHB focused on pathology or comprehensive prevention and lacked a summary of advanced detection techniques. Unlike traditional detection and management methods, wheat FHB detection based on various imaging technologies has the obvious advantages of a high degree of automation and efficiency. With the rapid development of computer vision and deep learning technology, the number of related research has grown explosively in recent years. This review begins with an overview of wheat FHB epidemic mechanisms and changes in the characteristics of infected wheat. On this basis, the imaging scales are divided into microscopic, medium, submacroscopic, and macroscopic scales. Then, we outline the recent relevant articles, algorithms, and methodologies about wheat FHB from disease detection to qualitative analysis and summarize the potential difficulties in the practicalization of the corresponding technology. This paper could provide researchers with more targeted technical support and breakthrough directions. Additionally, this paper provides an overview of the ideal application mode of the FHB detection technologies based on multi-scale imaging and then examines the development trend of the all-scale detection system, which paved the way for the fusion of non-destructive detection technologies of wheat FHB based on multi-scale imaging.

Esketamine is a widely used intravenous general anesthetic. However, its safety, particularly its effects on the heart, is not fully understood. In this study, we investigated the effects of esketamine exposure on zebrafish embryonic heart development. Zebrafish embryos were exposed to esketamine at concentrations of 1, 10, and 100 mg/L from 48 h post-fertilization (hpf) to 72 hpf. We found that after exposure, zebrafish embryos had an increased hatching rate, decreased heart rate, stroke volume, and cardiac output. When we exposed transgenic zebrafish of the Tg(cmlc2:EGFP) strain to esketamine, we observed ventricular dilation and thickening of atrial walls in developing embryos. Additionally, we further discovered the abnormal expression of genes associated with cardiac development, including nkx2.5, gata4, tbx5, and myh6, calcium signaling pathways, namely ryr2a, ryr2b, atp2a2a, atp2a2b, slc8a3, slc8a4a, and cacna1aa, as well as an increase in acetylcholine concentration. In conclusion, our findings suggest that esketamine may impair zebrafish larvae’s cardiac development and function by affecting acetylcholine concentration, resulting in weakened cardiac neural regulation and subsequent effects on cardiac function. The insights garnered from this research advocate for a comprehensive safety assessment of esketamine in clinical applications.

Abstract Macrophages are heterogenic phagocytic cells that play distinct roles in physiological and pathological processes. Targeting different types of macrophages has shown potent therapeutic effects in many diseases. Although many approaches are developed to target anti‐inflammatory macrophages, there are few researches on targeting pro‐inflammatory macrophages, which is partially attributed to their non‐s pecificity phagocytosis of extracellular substances. In this study, a novel recombinant protein is constructed that can be anchored on an exosome membrane with the purpose of targeting pro‐inflammatory macrophages via antigen recognition, which is named AnCar‐ExoLaIMTS. The data indicate that the phagocytosis efficiencies of pro‐inflammatory macrophages for different AnCar‐ExoLaIMTS show obvious differences. The AnCar‐ExoLaIMTS3 has the best targeting ability for pro‐inflammatory macrophages in vitro and in vivo. Mechanically, AnCar‐ExoLaIMTS3 can specifically recognize the leucine‐rich repeat domain of the TLR4 receptor, and then enter into pro‐inflammatory macrophages via the TLR4‐mediated receptor endocytosis pathway. Moreover, AnCar‐ExoLaIMTS3 can efficiently deliver therapeutic cargo to pro‐inflammatory macrophages and inhibit the synovial inflammatory response via downregulation of HIF‐1α level, thus ameliorating the severity of arthritis in vivo. Collectively, the work established a novel gene/drug delivery system that can specifically target pro‐inflammatory macrophages, which may be beneficial for the treatments of arthritis and other inflammatory diseases.

Shen Qi Wan (SQW) has been proven to exert anti-inflammatory effects in the kidneys of CKD models accompanied by unclear therapeutic mechanisms. This study aims to evaluate the kidney-protective and anti-inflammatory effects of SQW and to elucidate its fundamental mechanisms for CKD treatment. Firstly, the main active components of SQW were identified by UPLC-Q-TOF/MS technique. Subsequently, we evaluated inflammatory factors, renal function and renal pathology changes following SQW treatment utilizing adenine-induced CKD mice and aquaporin 1 knockout (AQP1-/-) mice. Additionally, we conducted RNA-seq analysis and bioinformatics analysis to predict the SQW potential therapeutic targets and anti-nephritis pathways. Simultaneously, WGCNA analysis method and machine learning algorithms were used to perform a clinical prognostic analysis of potential biomarkers in CKD patients from the GEO database and validated through clinical samples. Lipopolysaccharide-induced HK-2 cells were further used to explore the mechanism. We found that renal collagen deposition was reduced, serum inflammatory cytokine levels decreased, and renal function was improved after SQW intervention. It can be inferred that β-defensin 1 (DEFB1) may be a pivotal target, as confirmed by serum and renal tissue samples from CKD patients. Furthermore, SQW assuages inflammatory responses by fostering AQP1-mediated DEFB1 expression was confirmed in in vitro and in vivo studies. Significantly, the renal-protective effect of SQW is to some extent attenuated after AQP1 gene knockout. SQW could reduce inflammatory responses by modulating AQP1 and DEFB1. These findings underscore the potential of SQW as a promising contender for novel prevention and treatment strategies within the ambit of CKD management.

Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a recently discovered autoimmune inflammatory disease of the central nervous system. It presents with a variety of clinical symptoms, including fever, seizures, psychiatric symptoms, limber weakness, and sensory symptoms. However, the symptoms of sleep disorders have not been sufficiently addressed. Here, we report a case of GFAP-A in which the patient complained of excessive daytime sleepiness and an excessive need for sleep. Our patient was a 58-year-old male who experienced excessive daytime sleepiness for 50 days following SARS-CoV-2 infection. He was diagnosed with coronavirus disease 2019 on June 1st. On the 7th of June, he experienced excessive daytime sleepiness, nausea, reduced food intake, lower limb weakness, and dysuria. Subsequently, his sleepiness significantly deteriorated on July 21st. Five months prior, the patient underwent laparoscopic partial right nephrectomy for clear-cell renal cell carcinoma. Brain MRI revealed abnormal hyperintense lesions in the pontine brain and around the mesencephalic aqueduct on T2 and T2-fluid attenuated inversion recovery (T2-FLAIR) sequences However, these lesions did not exhibit any pathological enhancement. Spinal cord MRI revealed lesions in the C6–C7 and T2–T3 segments on the T2 sequence. His Epworth Sleepiness Scale (ESS) score was 16 (reference range,

The water permeability of conditioned soils is one of the most essential properties for Earth Pressure Balance (EPB) tunnelling in coarse-grained soils. Permeability tests are conducted to study the influence of water heads on the permeability of foam-conditioned sands. The initial permeability coefficient of foam-conditioned sands increases with the water head, while the stable permeability coefficient and the initial stable period duration decrease. Meanwhile, a novel analytical model is proposed to estimate the initial permeability coefficient. In this model, the effect of the water head on the initial permeability coefficient is incorporated by calculating void ratios of the foam and effective diameters of foam bubbles under different water pressures. Experimental results are in close agreement with analytical solutions, indicating the excellent performance of the proposed calculation method. In addition, the physical mechanisms of how the water head affects the permeability of foam-conditioned sands are discussed from the contraction and evolution of foam bubbles.

Abstract Background PARP inhibitor (PARPi), as a kind of DNA damage repair inhibitor, has been shown to be effective in various solid tumors and hematologic malignancies. Natural killer/T cell lymphoma (NKTCL) is a highly aggressive malignancy, the treatment of which has long been a major challenge in the clinic. Here, we investigated the efficacy and mechanism of PARPi, and the therapeutic value of PARPi combined with cisplatin in NKTCL. Methods The cell proliferation, cell apoptosis, and cell cycle of NKTCL cells were detected respectively by CCK-8 and flow cytometry. The changes of mRNA expression and protein level were measured respectively by mRNA-sequencing, quantitative real-time PCR, western blotting, and immunofluorescence. LMO2 expression was detected by immunohistochemistry and western blotting. Targeted knockdown of LMO2 was conducted by short hairpin RNA. The tumor xenograft models were established to evaluate the efficacy of drugs in vivo. Results PARPi inhibited cell proliferation, promoted cell apoptosis, and induced S-phase cell cycle arrest in NKTCL cells. PARPi led to the accumulation of DNA damage by blocking DNA repair and DNA replication. Additionally, LMO2 deficiency reduced the sensitivity of NKTCL cells to PARPi. Finally, the combination of PARPi and cisplatin exhibited significant synergistic effects both in vitro and in vivo. Conclusions In summary, we found that PARPi exerted an anti-tumor effect via LMO2 and synergized with cisplatin in NKTCL, which provides the theoretical basis for the clinical application of PARPi.

Hypopharyngeal squamous cell carcinoma (HSCC) is a kind of malignant tumor with a poor prognosis and low quality of life in the otolaryngology department. It has been found that microRNA (miRNA) plays an important role in the occurrence and development of various tumors. This study found that the expression level of miRNA-107 (miR-107) in HSCC was significantly reduced. Subsequently, we screened out the downstream direct target gene Neuronal Vesicle Trafficking Associated 1 (NSG1) related to miR-107 through bioinformatics analysis and found that the expression of NSG1 was increased in HSCC tissues. Following the overexpression of miR-107 in HSCC cells, it was observed that miR-107 directly suppressed NSG1 expression, leading to increased apoptosis, decreased proliferation, and reduced invasion capabilities of HSCC cells. Subsequent experiments involving the overexpression and knockdown of NSG1 in HSCC cells demonstrated that elevated NSG1 levels enhanced cell proliferation, migration, and invasion, while the opposite effect was observed upon NSG1 knockdown. Further investigations revealed that changes in NSG1 levels in the HSCC cells were accompanied by alterations in ERK signaling pathway proteins, suggesting a potential regulatory role of NSG1 in HSCC cell proliferation, migration, and invasion through the ERK pathway. These findings highlight the significance of miR-107 and NSG1 in hypopharyngeal cancer metastasis, offering promising targets for therapeutic interventions and prognostic evaluations for HSCC.

The synergistic effects of boron (B) and rare earth (RE) elements on the microstructure and stress rupture properties were investigated in a Ni-based superalloy. The stress rupture lifetime at 650 °C/873 MPa significantly increased with the addition of B as a single element. Furthermore, the stress rupture lifetime reached its peak (303 h), with a certain amount of B and RE added together in test alloys. Although the grain size and morphology of the γ′ phase varied a little with the change in B and RE addition, they were not considered to be the main reasons for stress rupture performance. The enhancement in stress rupture lifetime was mostly attributed to the segregation of the B and RE elements, which increased the binding force of the grain boundary and improved its strength and plasticity. In addition, the enrichment of B and RE inhabited the precipitation of carbides along grain boundaries. Furthermore, nano-scale RE precipitates containing sulfur (S) and phosphorus (P) were observed to be distributed along the grain boundaries. The purification of grain boundaries by B and RE elements was favorable to further improve the stress rupture properties.

A recovery system for an automatic spraying robot to conduct the spraying operation outdoors for ships is designed in this paper, which addresses the pollution problem of volatile organic compounds (VOCs) by employing the vacuum recovery method. The recovery system consists of the recovery hood, nozzle, and vacuum tubes. The recovery hood is the critical part of the recovery system and is designed with internal and external cavities, as well as four vacuum tubes for recycling VOCs. Based on the computational fluid dynamics (CFD) method, simulation in the time domain of the gas–liquid interaction, droplet evaporation, and wall impingement is conducted. To identify the better recovery performance, three vacuum recovery-hood schemes are designed, and their performance is compared. The numerical results show that the distance between the vacuum tubes and the intake gap has a significant impact on the VOCs’ recovery effect. One of the main reasons for the escape of VOCs is that the swirling airflows in the baffle plane act as vortices which may capture VOCs, causing the accumulation of VOCs beyond the capacity of the external cavity. Dividing the external cavity into four chambers with deflectors (with each chamber equipped with one vacuum tube only) can significantly reduce the leakage rate of the recovery system. The recovery system provides a theoretical solution for implementing the prevention and control of VOCs in shipyards as soon as possible.

Background and Aims: Overweight/obese women with polycystic ovary syndrome (PCOS) have poorer pregnancy outcomes, compared to normal-weight women. Body mass index (BMI) is a risk factor of in vitro fertilization-embryo transfer (IVF-ET). This study is to compare the outcomes of IVF-ET between the overweight/obese and normal-weight women with PCOS. Method: We performed a retrospective cohort study in a large reproductive center of a university hospital. The participants were the women with PCOS who underwent IVF-ET. We compared live birth, miscarriage and other clinical outcomes between the women with BMI ≥25 (overweight/obese group) and 18≤BMI

Abstract Lupus nephritis (LN) is a type of immune-complex nephritis caused by systemic lupus erythematosus and is a major contributor to mortality and morbidity. Honokiol (HNK) has been found to have a therapeutic effect on LN, but its action mechanism remains unclear. In this study, we first demonstrated that HNK attenuates kidney injury in MRL/lpr mice. Results from RNA sequencing combined with ingenuity pathway analysis suggested that HNK plays an anti-LN role through inhibition of the NLRP3 inflammasome and IL33. GEO chip data, single-cell data, and clinical samples from LN patients demonstrated that the pyroptosis and IL-33/ST2 pathways are abnormally activated during the stage of LN. In vivo, similar to the results of the AAV-mediated NLRP3 shRNA MRL/lpr model, HNK downregulated serum and renal IL-33 levels, and suppressed NLRP3 inflammasome and the IL-33/ST2 axis in the kidney. In vitro, co-culturing NLRP3-overexpressing or IL-33 knocked-down rat renal macrophages with NRK-52E cells confirmed that NLRP3 activation in resident macrophages directly upregulates IL-33, which in turn mediates the IL-33/ST2/NF-κB pathway to promote the inflammatory response of renal tubular epithelial cells. Furthermore, a molecular docking model and surface plasmon resonance analysis were utilized to demonstrate a direct interaction between HNK and NLRP3. In conclusion, this study provides a novel anti-LN treatment strategy in which HNK plays a preventive and therapeutic role against LN by suppressing the abnormal crosstalk between renal resident macrophages and renal tubular epithelial cells by inhibiting the activation of the NLRP3/IL-33/ST2 axis.

IntroductionAlternative meats have the potential to shape a sustainable food system. This study examined young consumers’ perceptions of and preferences for plant-based and cultured meats. Since comparative studies on consumer preferences for alternative meats in different key Asian markets remain insufficient, this study was conducted in Japan and China, both of whom have promising alternative meat markets in Asia.MethodsWe conducted a discrete choice experiment and co-occurrence networks among 2006 (n = 887 in Japan and n = 1,119 in China) young consumers. This study adopted a treatment-control design where respondents in the treatment groups received health information on the use of antibiotics in meat production.ResultsRespondents in both countries perceived meat alternatives to be substitutes to conventional meat and associated them with plant-based proteins, processed products, and health benefits. In general, Japanese and Chinese respondents differed in their preferences for burger patties but had similar preferences for other attributes. Respondents in both countries were willing to pay a premium for “antibiotic-free,” “traceable,” and low carbon footprint labeling. This study reveals the heterogeneity of consumer preferences and the complexity of the impact of information interventions on consumer preferences.DiscussionPlant-based meat is already available on the market in both countries, whereas cultured meat is still in the research and development stage. Hence, young consumers were more familiar with plant-based meat than cultured meat. It is worth noting that young Japanese consumers preferred cultured meat to conventional meat. This is attributed to the concerns about food security and food animal welfare. Furthermore, this study found that information intervention can induce and direct respondents’ attention to an aspect of alternative meats that is negatively perceived. Based on the findings, this study has three implications for promoting alternative meat products: marketing messaging, food labeling, and product development.

Background We aim to investigate the potential value of cuproptosis-related lncRNA signaling in predicting clinical prognosis and immunotherapy and its relationship with drug sensitivity in head and neck squamous cell carcinoma (HNSCC). Methods We first identified the lncRNAs associated with cuproptosis genes in HNSCC and then conducted a series of analytical studies to investigate the expression and prognostic significance of these lncRNAs. Finally, we used RT-qPCR to validate our findings in a laryngeal squamous cell carcinoma cell line and 12 pairs of laryngeal squamous cell carcinoma and adjacent normal tissues. Results We identified 11 differentially expressed lncRNAs that were associated with cuproptosis genes in HNSCC and also served as prognostic markers for this cancer. Enrichment analysis revealed that these lncRNAs were related to immune-related functions that were suppressed in patients with oncogene mutations in the high-risk group. The patients with a high tumor mutation burden exhibited poor overall survival (OS). We used the tumor immune dysfunction and exclusion model to show that the patients in the high-risk group had great potential for immune evasion and less effective immunotherapy. We also identified several drugs that could be effective in treating HNSCC. Experimental validation showed that AC090587.1 and AC012184.3 exhibited differential expression between the TU686 and HBE cell lines, and SNHG16 showed differential expression among the TU686, TU212, and control HBE cells. Among the 12 pairs of cancer and adjacent tissues collected in the clinic, only SNHG16 showed differential expression. Targeted therapy against SNHG16 holds promise as a prospective novel strategy for the clinical management of HNSCC.

Functional Magnetic Resonance Imaging (fMRI) provides more precise spatial and temporal information to reconstruct stimulus images than other technologies that can be used to measure the human brain’s neural responses. The fMRI scans, however, generally show heterogeneity among different subjects. The majority of the existing methods aim primarily at mining correlations between stimuli and evoked brain activity, disregarding the heterogeneity among subjects. Therefore, this heterogeneity will impair the reliability and applicability of multi-subject decoding results, leading to sub-optimal results. The present paper proposes the functional alignment-auxiliary generative adversarial network (FAA-GAN) as a novel multi-subject approach for visual image reconstruction that employs functional alignment to alleviate the heterogeneity between subjects. Our proposed FAA-GAN includes three key components: 1) a generative adversarial network (GAN) module for reconstructing visual stimuli, which consists of a visual image encoder as the generator that uses a nonlinear network to convert stimuli images into an implicit representation and a discriminator that generates the images comparable to the original images in detail; 2) a multi-subject functional alignment module, which is used to precisely align the individual fMRI response space of each subject in a common space to reduce the heterogeneity among different subjects; and 3) a cross-modal hashing retrieval module used for similarity retrieval of two modalities of data, i.e., the visual images and the evoked brain responses. Experiments on real-world datasets show that our FAA-GAN method does better than other state-of-the-art deep learning-based reconstruction methods with fMRI.

Abstract Background Spatial chromatin structure is intricately linked with somatic aberrations, and somatic mutations of various cancer-related genes, termed co-mutations (CoMuts), occur in certain patterns during cancer initiation and progression. The functional mechanisms underlying these genetic events remain largely unclear in thyroid cancer (TC). With discrepant differentiation, papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) differ greatly in characteristics and prognosis. We aimed to reveal the spatial gene alterations and regulations between the two TC subtypes. Methods We systematically investigated and compared the spatial co-mutations between ATC (8305C), PTC (BCPAP and TPC-1), and normal thyroid cells (Nthy-ori-3–1). We constructed a framework integrating whole-genome sequencing (WGS), high-throughput chromosome conformation capture (Hi-C), and transcriptome sequencing, to systematically detect the associations between the somatic co-mutations of cancer-related genes, structural variations (SVs), copy number variations (CNVs), and high-order chromatin conformation. Results Spatial co-mutation hotspots were enriched around topologically associating domains (TADs) in TC. A common set of 227 boundaries were identified in both ATC and PTC, with significant overlaps between them. The spatial proximities of the co-mutated gene pairs in the two TC types were significantly greater than in the gene-level and overall backgrounds, and ATC cells had higher TAD contact frequency with CoMuts > 10 compared with PTC cells. Compared with normal thyroid cells, in ATC the number of the created novel three-dimensional chromatin structural domains increased by 10%, and the number of shifted TADs decreased by 7%. We found five TAD blocks with CoMut genes/events specific to ATC with certain mutations in genes including MAST-NSUN4, AM129B/TRUB2, COL5A1/PPP1R26, PPP1R26/GPSM1/CCDC183, and PRAC2/DLX4. For the majority of ATC and PTC cells, the HOXA10 and HIF2α signals close to the transcription start sites of CoMut genes within TADs were significantly stronger than those at the background. CNV breakpoints significantly overlapped with TAD boundaries in both TC subtypes. ATCs had more CNV losses overlapping with TAD boundaries, and noncoding SVs involved in intrachromosomal SVs, amplified inversions, and tandem duplication differed between ATC and PTC. TADs with short range were more abundant in ATC than PTC. More switches of A/B compartment types existed in ATC cells compared with PTC. Gene expression was significantly synchronized, and orchestrated by complex epigenetics and regulatory elements. Conclusion Chromatin interactions and gene alterations and regulations are largely heterogeneous in TC. CNVs and complex SVs may function in the TC genome by interplaying with TADs, and are largely different between ATC and PTC. Complexity of TC genomes, which are highly organized by 3D genome-wide interactions mediating mutational and structural variations and gene activation, may have been largely underappreciated. Our comprehensive analysis may provide key evidence and targets for more customized diagnosis and treatment of TC.

Abstract Background Icariin (ICA), a main active ingredient of Herba Epimedium, could promote bone formation, inhibit bone resorption and alleviate inflammatory responses. The aim of this study was to investigate the effect of ICA on the inhibition of bacteria associated with peri-implantitis, and fabricate a calcium phosphate cement (CPC) with ICA-loaded gelatin microspheres (GMs) as a local drug delivery system efficiently promoting bone formation and alleviating inflammation. Results In this study, ICA exhibited antibacterial activity against P. gingivalis with a MIC value of 1 × 10–4 mol/L. When the concentration of ICA was 0.5 mM, the encapsulation efficiency of GMs reached the maximum value of 76.26 ± 3.97%. GMs with ICA revealed a controlled release profile, 0.5 mM ICA exhibited a higher ICA release profile than the other groups during a 21 d monitoring span. The results of SEM and XRD demonstrated successful fabrication of a calcium phosphate cement with ICA-loaded GMs. ICA released from CPC/GMs (ICA) was slower than ICA released from GMs within 10 days. CPC/GMs (ICA) exhibited antibacterial activity against P. gingivalis, but the antibacterial rate of CPC/GMs (ICA) was only 17.15 ± 6.06%. In addition, CPC/GMs (ICA) promoted the proliferation of BMSCs and significantly stimulated the differentiation and maturation of BMSCs. In vivo, H&E and Masson staining experiments demonstrated that CPC/GMs (ICA) exhibited better capacity for bone regeneration than CPC/GMs and CPC, and the expression of TNF-α and IL-1β in the tissue around CPC/GMs (ICA) was significantly lower than CPC/GMs and CPC in IHC staining (P

Laser-based additive manufacturing has garnered significant attention in recent years as a promising 3D-printing method for fabricating metallic components. However, the surface roughness of additive manufactured components has been considered a challenge to achieving high performance. At present, the average surface roughness (Sa) of AM parts can reach high levels, greater than 50 μm, and a maximum distance between the high peaks and the low valleys of more than 300 μm, which requires post machining. Therefore, laser polishing is increasingly being utilized as a method of surface treatment for metal alloys, wherein the rapid remelting and resolidification during the process significantly alter both the surface quality and subsurface material properties. In this paper, the surface roughness, microstructures, microhardness, and wear resistance of the as-received, continuous wave laser polishing (CWLP), and pulsed laser polishing (PLP) processed samples were investigated systematically. The results revealed that the surface roughness (Sa) of the as-received sample was 6.29 μm, which was reduced to 0.94 μm and 0.84 μm by CWLP and PLP processing, respectively. It was also found that a hardened layer, about 200 μm, was produced on the Ti6Al4V alloy surface after laser polishing, which can improve the mechanical properties of the component. The microhardness of the laser-polished samples was increased to about 482 HV with an improvement of about 25.2% compared with the as-received Ti6Al4V alloy. Moreover, the coefficient of friction (COF) was slightly reduced by both CWLP and LPL processing, and the wear rate of the surface layer was improved to 0.790 mm3/(N∙m) and 0.714 mm3/(N∙m), respectively, under dry fraction conditions.

Crop lodging is an important cause of direct economic losses and secondary disease transmission in agricultural production. Most existing methods for segmenting wheat lodging areas use a large-volume network, which poses great difficulties for annotation and crop monitoring in real time. Therefore, an ultra-lightweight model, Lodging-U2NetP (L-U2NetP), based on a novel annotation strategy which crops the images before annotating them (Crop-annotation), was proposed and applied to RGB images of wheat captured with an unmanned aerial vehicle (UAV) at a height of 30 m during the maturity stage. In the L-U2NetP, the Dual Cross-Attention (DCA) module was firstly introduced into each small U-structure effectively to address semantic gaps. Then, Crisscross Attention (CCA) was used to replace several bulky modules for a stronger feature extraction ability. Finally, the model was compared with several classic networks. The results showed that the L-U2NetP yielded an accuracy, F1 score, and IoU (Intersection over Union) for segmenting of 95.45%, 93.11%, 89.15% and 89.72%, 79.95%, 70.24% on the simple and difficult sub-sets of the dataset (CA set) obtained using the Crop-annotation strategy, respectively. Additionally, the L-U2NetP also demonstrated strong robustness in the real-time detection simulations and the dataset (AC set) obtained using the mainstream annotation strategy, which annotates images before cropping (Annotation-crop). The results indicated that L-U2NetP could effectively extract wheat lodging and the Crop-annotation strategy provided a reliable performance which is comparable with that of the mainstream one.

Nitrogen (N) is one of the limiting nutrients for plant growth and metabolism in terrestrial ecosystems. Numerous studies have explored the effects of N addition on the eco-physiological traits and biomass production of plants, but the underlying mechanism of how N deposition influences biomass allocation patterns remains controversial, especially for urban greening trees. A greenhouse experiment was conducted for 7 months, using two dominant tree species of urban streets in North China, including the coniferous tree species Pinus tabuliformis and the broadleaved tree Fraxinus chinensis, under three levels of N addition: ambient, low N addition, and high N addition (0, 3.5, and 10.5 gN m−2 year−1). The plant growth, biomass distribution, functional traits, and soil nutrient properties of the two trees were determined. Overall, N addition had positive effects on the aboveground and belowground biomass of P. tabuliformis, which also shifted its functional traits to an acquisitive strategy, while F. chinensis only increased root biomass distribution and fast traits as N increased. Furthermore, N supply increased the soil N and phosphorus availability of both trees and improved their root nutrient uptake capacity, resulting in an increase in their root–shoot ratio. Optimal partitioning theory could better explain why trees would invest more resources in roots, changing root structure and nutrient uptake, thus increasing root biomass allocation to adapt to a resource-poor environment. These findings highlight the importance of plant functional traits in driving the responses of biomass allocation to environmental changes for urban greening dominant tree species and could help to come up with new tree growth strategies in silvicultural practice for urban green space.

PurposeTo conduct a systematic review and meta-analysis of observational studies of brain MRI, this paper assesses the effects of long-term exposure to high-altitude on brain structures in healthy people.MethodsObservational studies related to high-altitude, brain and MRI were systematically searched based on data retrieved from PubMed, Embase and Cochrane Library. The timescale for collecting literature was from the establishment of the databases to 2023. NoteExpress 3.2 was used to manage the literature. Two investigators performed literature screening and data extraction based on inclusion criteria, exclusion criteria, and literature quality. The quality of the literature was assessed using the NOS Scale. Finally, meta-analysis of included studies was performed using Reviewer Manager 5.3.ResultsInitially, 3,626 articles were retrieved. After screening, 16 articles (n = 756 participants) were included in the systematic review, and meta-analysis was performed on 6 articles (n = 350 participants). The overall quality of the included articles was at medium level, with a mean NOS score of 5.62. The results of meta-analysis showed that the differences between the HA group and LA group were not statistically significant, in total GM volume (MD: −0.60, 95% CI: −16.78 to 15.58, P = 0.94), WM volume (MD: 3.05, 95% CI: −15.72 to 21.81, P = 0.75) and CSF volume (MD: 5.00, 95% CI: −11.10 to 21.09, P = 0.54).The differences between HA and LA in FA values of frontotemporal lobes were not statistically significant: right frontal lobe (MD: −0.02, 95% CI: −0.07 to 0.03, P = 0.38), left frontal lobe (MD: 0.01, 95% CI: −0.02 to 0.04, P = 0.65), right temporal lobe (MD: −0.00, 95% CI: −0.03 to 0.02, P = 0.78) and left temporal lobe (MD: −0.01, 95% CI: −0.04 to 0.02, P = 0.62). However, there were significant differences in GM volume, GM density and FA values in local brain regions between HA group and LA group.ConclusionCompared with LA area, there were no significant differences in total GM, WM and CSF volumes in healthy people living at high-altitude area for long-term, while there were significant differences in GM volume and FA values in local brain regions. Long-term exposure to high-altitude area caused the adaptive structural changes in local brain regions. Since heterogeneity existed between the studies, further studies are needed to uncover the effects of high-altitude on brain of healthy people.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42023403491.

Background: Colorectal cancer (CRC) ranks the second malignancy with high incidence and mortality worldwide. Cancer stem cells (CSCs) function critically in cancer progression and metastasis via the interplay with immune cells in tumor microenvironment. This study aimed to identify important CSC marker genes and parsed the role of these marker genes in CRC.Materials and methods: CRC samples’ single-cell RNA sequencing data and bulk transcriptome data were utilized. Seurat R package annotated CSCs and identified CSC marker genes. Consensus clustering subtyped CRC samples based on CSC marker genes. Immune microenvironment, pathway and oxidative stress analysis was performed using ESTIMATE, MCP-counter analysis and ssGSEA analysis. A prognostic model was established by Lasso and stepAIC. Sensitivity to chemotherapeutic drugs was determined by the biochemical half maximal inhibitory concentration with pRRophetic R package.Results: We identified a total of 29 CSC marker genes related to disease-specific survival (DSS). Two clusters (CSC1 and CSC2) were determined, and CSC2 showed shorter DSS, a larger proportion of late-stage samples, and higher oxidative stress response. Two clusters exhibited differential activation of biological pathways associated with immune response and oncogenic signaling. Drug sensitivity analysis showed that 44 chemotherapy drugs were more sensitive to CSC2 that those in CSC1. We constructed a seven-gene prognostic model (DRD4, DPP7, UCN, INHBA, SFTA2, SYNPO2, and NXPH4) that was effectively to distinguish high-risk and low-risk patients. 14 chemotherapy drugs were more sensitive to high-risk group and 13 chemotherapy drugs were more sensitive to low-risk group. Combination of higher oxidative stress and risk score indicated dismal prognosis.Conclusion: The CSC marker genes we identified may help to further decipher the role of CSCs in CRC development and progression. The seven-gene prognostic model could serve as an indicator for predicting the response to immunotherapy and chemotherapy as well as prognosis of CRC patients.

This article provides a comprehensive review of the progress in the treatment and care of sensorineural hearing loss (SNHL), which is a common disease in the field of otolaryngology. In recent years, the incidence of SNHL has been on the rise due to factors such as fast-paced lifestyles, work pressure, and environmental noise pollution, which have a significant impact on the quality of life of patients. Therefore, the study of the treatment and care of SNHL remains a hot topic in the medical community. Despite significant advances in this field, there are still some challenges and limitations. For example, there is currently no single method that can completely cure SNHL, and the effectiveness of treatment may vary significantly among individuals. In addition, due to the complex etiology of SNHL, the prognosis of patients may vary greatly, requiring the development of personalized treatment plans and care strategies. To address these challenges, continuous research is needed to explore new treatment methods and care models to improve the quality of life of patients. In addition, there is a need for health education programs for the general public to raise awareness of SNHL and promote preventive measures to reduce its incidence. The ultimate goal is to ensure the sustainable development of the field of SNHL treatment and care, thus ensuring the health and well-being of affected individuals.

Background: Incretin impairment, characterized by insufficient secretion of L-cell-derived glucagon-like peptide-1 (GLP-1), is a defining step of type 2 diabetes mellitus (T2DM). Ginsenoside compound K (CK) can stimulate GLP-1 secretion; however, the potential mechanism underlying this effect has not been established. Methods: CK (40 mg/kg) was administered orally to male db/db mice for 4 weeks. The body weight, oral glucose tolerance, GLP-1 secretion, gut microbiota sequencing, bile acid (BA) profiles, and BA synthesis markers of each subject were then analyzed. Moreover, TGR5 expression was evaluated by immunoblotting and immunofluorescence, and L-cell lineage markers involved in L-cell abundance were analyzed. Results: CK ameliorated obesity and impaired glucose tolerance in db/db mice by altering the gut microbiota, especially Ruminococcaceae family, and this changed microbe was positively correlated with secondary BA synthesis. Additionally, CK treatment resulted in the up-regulation of CYP7B1 and CYP27A1 and the down-regulation of CYP8B1, thereby shifting BA biosynthesis from the classical pathway to the alternative pathway. CK altered the BA pool by mainly increasing LCA and DCA. Furthermore, CK induced L-cell number expansion leading to enhanced GLP-1 release through TGR5 activation. These increases were supported by the upregulation of genes governing GLP-1 secretion and L-cell differentiation. Conclusions: The results indicate that CK improves glucose homeostasis by increasing L-cell numbers, which enhances GLP-1 release through a mechanism partially mediated by the gut microbiota-BA-TGR5 pathway. Therefore, that therapeutic attempts with CK might be useful for patients with T2DM.

Abstract Background During the tumourigenesis and development of colorectal cancer (CRC), the inactivation of tumour suppressor genes is closely involved, although detailed molecular mechanisms remain elusive. Accumulating studies, including ours, have demonstrated that basic leucine zipper transcription factor ATF (activating transcription factor)‐like 2 (BATF2) is a capable tumour suppressor that localises in the nucleus. However, its different subcellular localisation, potential functions and underlying mechanisms are unclear. Methods The translocation of BATF2 and its clinical relevance were detected using CRC samples, cell lines and xenograft nude mice. Candidate BATF2‐binding proteins were screened using co‐immunoprecipitation, quantitative label‐free liquid chromatography–tandem mass spectrometry proteomic analysis, Western blotting and immunofluorescence. Recombinant plasmids, point mutations and siRNAs were applied to clarify the binding sites between BATF2 and chromosome region maintenance 1 (CRM1). Results The present study found that BATF2 was mainly localised in the cytoplasm, rather than nucleus, of CRC cells in vitro and in vivo, while cytoplasmic BATF2 expression was inversely correlated with the prognosis of CRC patients. Furthermore, we identified the nuclear export and subsequent ubiquitin‐mediated degradation of BATF2 in CRC cells. Mechanistically, a functional nuclear export sequence (any amino acid) was characterised in BATF2 protein, through which BATF2 bound to CRM1 and translocated out of nucleus, ultimately enhancing CRC growth via inducing activator protein 1 (AP‐1)/cyclin D1/phosphorylated retinoblastoma protein (pRb) signalling pathway. Additionally, nuclear export of BATF2 can be retarded by the mutation of NES in BATF2 or the knockdown of CRM1, whereas CRM1 expression was negatively associated with nuclear BATF2 expression and the prognosis of CRC patients. Conclusion These findings revealed the biological effects and underlying mechanisms of cytoplasmic localisation of BATF2. Furthermore, suppressing nuclear export of BATF2 via mutating its NES region or inhibiting CRM1 expression may serve as a promising therapeutic strategy against CRC.

While endocrine therapy is considered as an effective way to treat breast cancer, it still faces many challenges, such as drug resistance and individual discrepancy. Therefore, novel preventive and therapeutic modalities are still in great demand to decrease the incidence and mortality rate of breast cancer. Numerous studies suggested that G protein-coupled estrogen receptor (GPER), a membrane estrogen receptor, is a potential target for breast cancer prevention and treatment. It was also shown that not only endogenous estrogens can activate GPERs, but many phytoestrogens can also function as selective estrogen receptor modulators (SERMs) to interact GPERs. In this review, we discussed the possible mechanisms of GPERs pathways and shed a light of developing novel phytoestrogens based dietary supplements against breast cancers.

This paper proposes a Field Programmable Gate Array (FPGA)-based control system to implement micro-light-emitting diode (micro-LED) real-time display. The control system includes the interface control, video processing, memory management, image data transmission, control signal generation and correction. Then, we implement the micro-LED real-time display via memory management. We propose the brightness correction to achieve high grey-scale and high uniformity display. The LEDs are mounted on the glass substrate prepared using low-temperature polysilicon (LTPS) technology, and then we find the 24 × 46 pixels micro-LED panel. And the control system has been successfully applied to the panel of glass-based micro-LED displays. A new grey control method is proposed in this work, which can effectively improve the refresh rate of the micro-LED displays. The high grey-scale refresh rate is 2100 Hz, and the low grey-scale refresh rate is 300 Hz. The uniformity of the panel is increased to 85% after brightness correction.

Wireless sensors networks (WSNs) play an important role in life. With the development of 5G, its security issues have also raised concerns. Therefore, it is an important topic to study the offense and defense confrontation in WSNs. A complete information static game model is established to analyze the offense and defense confrontation problem of WSNs in 5G. An adaptive equilibrium optimizer algorithm (AEO) based on parameter adaptive strategy is proposed, which can jump out of the local optimal solution better. Experiments show that the optimization ability of AEO outperforms other algorithms on at least 80% of the 23 classical test functions of CEC. The convergence speed of AEO is better in the early stage of population iteration. The optimal offensive and defensive strategy under different offense and defense resources through simulation experiments is analyzed. The conclusion shows that when the offensive resources are large, the offender takes an indiscriminate attack. When the defense resources are small, the defender should defend the most important elements, and when the defense resources are large, the defender should allocate the same resources to defend each element to obtain the maximum benefit. This paper provides new solution ideas for the security problems under the offense and defense game in WSNs.

China has a vast scale of hydropower, and the small hydropower stations account for a large proportion. In flood season, the excessive inflow keeps these stations at a high reservoir level, leading to a worse condition of hindered power output and a great error in the calculation of power generation. Therefore, this paper proposes a mid-term optimal scheduling model for low-head cascaded hydropower stations considering inflow unevenness, in which the power output is controlled by the expected power output curve and daily inflow–maximum power output curve. A case study of nine hydropower stations on the Guangxi power grid shows that, regardless of considering the fitted curve or not, there are different degrees of error between the planned and actual situations. However, the error and power generation are decreased when considering the fitted curve, which reflects the impact of hindered power output. Meanwhile, according to the comparison, the weekly plan is more in line with the real condition when using this model to solve the problem. The results indicate that this model improves the accuracy of power output calculation for low-head hydropower stations with uneven inflow, playing a key role in the process of scheduling.

Abstract Background The main objective of this study was to investigate the risk factors for recollapse of new vertebral compression fractures (NVCFs) after percutaneous kyphoplasty (PKP) treatment for osteoporotic vertebral compression fracture (OVCF) and to construct a new nomogram model. Methods We retrospectively analysed single-level OVCFs from January 2017 to June 2020, randomizing patients to a training set and a testing set. In the training set, independent risk factors for NVCFs in OVCF patients treated with PKP were obtained by univariate and multivariate regression analyses. These risk factors were then used as the basis for constructing a nomogram model. Finally, internal validation of the built model was performed in the testing set using the consistency index (C-index), receiver operating characteristic (ROC) curves, calibration curves and decision curve analysis (DCA). Results In total, 371 patients were included in this study. NVCFs occurred in 21.7% of the training set patients, and multivariate regression analysis showed that a low Hounsfield unit (HU) value, cement leakage, and thoracolumbar (TL) junction fracture were independent risk factors for NVCF after PKP. The C-index was 0.81 (95% CI: 0.74–0.81), and the validation showed that the predicted values of the established model were in good agreement with the actual values. Conclusions In this study, three independent risk factors were obtained by regression analysis. A nomogram model was constructed to guide clinical work and to make clinical decisions relatively accurately to prevent the occurrence of vertebral recollapse fractures.

ABSTRACT A variety of electron transfer mechanisms link bacterial cytosolic electron pools with functionally diverse redox activities in the cell envelope and extracellular space. In Listeria monocytogenes, the ApbE-like enzyme FmnB catalyzes extracytosolic protein flavinylation, covalently linking a flavin cofactor to proteins that transfer electrons to extracellular acceptors. L. monocytogenes uses an energy-coupling factor (ECF) transporter complex that contains distinct substrate-binding, transmembrane, ATPase A, and ATPase A′ subunits (RibU, EcfT, EcfA, and EcfA′) to import environmental flavins, but the basis of extracytosolic flavin trafficking for FmnB flavinylation remains poorly defined. In this study, we show that the EetB and FmnA proteins are related to ECF transporter substrate-binding and transmembrane subunits, respectively, and are essential for exporting flavins from the cytosol for flavinylation. Comparisons of the flavin import versus export capabilities of L. monocytogenes strains lacking different ECF transporter subunits demonstrate a strict directionality of substrate-binding subunit transport but partial functional redundancy of transmembrane and ATPase subunits. Based on these results, we propose that ECF transporter complexes with different subunit compositions execute directional flavin import/export through a broadly conserved mechanism. Finally, we present genomic context analyses that show that related ECF exporter genes are distributed across members of the phylum Firmicutes and frequently colocalize with genes encoding flavinylated extracytosolic proteins. These findings clarify the basis of ECF transporter export and extracytosolic flavin cofactor trafficking in Firmicutes. IMPORTANCE Bacteria import vitamins and other essential compounds from their surroundings but also traffic related compounds from the cytosol to the cell envelope where they serve various functions. Studying the foodborne pathogen Listeria monocytogenes, we find that the modular use of subunits from a prominent class of bacterial transporters enables the import of environmental vitamin B2 cofactors and the extracytosolic trafficking of a vitamin B2-derived cofactor that facilitates redox reactions in the cell envelope. These studies clarify the basis of bidirectional small-molecule transport across the cytoplasmic membrane and the assembly of redox-active proteins within the cell envelope and extracellular space.

Dusty star-forming galaxies (DSFGs) are among the most massive and active star-forming galaxies during the cosmic noon. Theoretical studies have proposed various formation mechanisms of DSFGs, including major merger-driven starbursts and secular star-forming disks. Here, we report J0107a, a bright (∼8 mJy at observed-frame 888 μ m) DSFG at z = 2.467 that appears to be a gas-rich massive disk and might be an extreme case of the secular disk scenario. J0107a has a stellar mass M _⋆ ∼ 5 × 10 ^11 M _⊙ , molecular gas mass M _mol ≳ 10 ^11 M _⊙ , and a star formation rate of ∼500 M _⊙ yr ^−1 . J0107a does not have a gas-rich companion. The rest-frame 1.28 μ m JWST NIRCam image of J0107a shows a grand-design spiral with a prominent stellar bar extending ∼15 kpc. The Atacama Large Millimeter/submillimeter Array Band 7 continuum map reveals that the dust emission originates from both the central starburst and the stellar bar. 3D disk modeling of the CO(4–3) emission line indicates a dynamically cold disk with rotation-to-dispersion ratio ${V}_{\max }/\sigma \sim 8$ . The results suggest a bright DSFG may have a nonmerger origin, and its vigorous star formation may be triggered by the bar and/or rapid gas inflow.

Amino acid (AA) metabolism in vascular endothelium is important for sprouting angiogenesis. SLC38A5 (solute carrier family 38 member 5), an AA transporter, shuttles neutral AAs across cell membrane, including glutamine, which may serve as metabolic fuel for proliferating endothelial cells (ECs) to promote angiogenesis. Here, we found that Slc38a5 is highly enriched in normal retinal vascular endothelium, and more specifically, in pathological sprouting neovessels. Slc38a5 is suppressed in retinal blood vessels from Lrp5−/− and Ndpy/− mice, both genetic models of defective retinal vascular development with Wnt signaling mutations. Additionally, Slc38a5 transcription is regulated by Wnt/β-catenin signaling. Genetic deficiency of Slc38a5 in mice substantially delays retinal vascular development and suppresses pathological neovascularization in oxygen-induced retinopathy modeling ischemic proliferative retinopathies. Inhibition of SLC38A5 in human retinal vascular ECs impairs EC proliferation and angiogenic function, suppresses glutamine uptake, and dampens vascular endothelial growth factor receptor 2. Together these findings suggest that SLC38A5 is a new metabolic regulator of retinal angiogenesis by controlling AA nutrient uptake and homeostasis in ECs.

Mild cognitive impairment (MCI) belongs to the prodromal stage of Alzheimer’s disease (AD). Accurate diagnosis of MCI is very important for possibly deferring AD progression. Graph kernels, which measure the similarity between paired brain connectivity networks, have been widely used to diagnose brain diseases (e.g., MCI) and yielded promising classification performance. However, most of the existing graph kernels are based on unweighted graphs, and neglect the valuable weighted information of the edges in brain connectivity networks where edge weights convey the strengths of fiber connection or temporal correlation between paired brain regions. Accordingly, in this paper, we propose a new graph kernel called ordinal pattern kernel for measuring brain connectivity network similarity and apply it to brain disease classification tasks. Different from the existing graph kernels which measure the topological similarity of the unweighted graphs, our proposed ordinal pattern kernel can not only calculate the similarity of paired brain connectivity networks, but also capture the ordinal pattern relationship of edge weights in brain connectivity networks. To appraise the effectiveness of our proposed method, we perform extensive experiments in functional magnetic resonance imaging data of brain disease from Alzheimer’s Disease Neuroimaging Initiative database. The experimental results show that our proposed ordinal pattern kernel outperforms the state-of-the-art graph kernels in the classification tasks of MCI.

CRISPR/Cas systems have found widespread applications in gene editing due to their high accuracy, high programmability, ease of use, and affordability. Benefiting from the cleavage properties (trans- or cis-) of Cas enzymes, the scope of CRISPR/Cas systems has expanded beyond gene editing and they have been utilized in various fields, particularly in live-cell imaging and bioanalysis. In this review, we summarize some fundamental working mechanisms and concepts of the CRISPR/Cas systems, describe the recent advances and design principles of CRISPR/Cas mediated techniques employed in live-cell imaging and bioanalysis, highlight the main applications in the imaging and biosensing of a wide range of molecular targets, and discuss the challenges and prospects of CRISPR/Cas systems in live-cell imaging and biosensing. By illustrating the imaging and bio-sensing processes, we hope this review will guide the best use of the CRISPR/Cas in imaging and quantifying biological and clinical elements and inspire new ideas for better tool design in live-cell imaging and bioanalysis.