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Abstract Bronchiolitis is a significant factor contributing to bronchial asthma in infants and young children. After treatment, recurrent wheezing symptoms often occur, especially in children with atopic constitution, who tend to have more severe conditions and poorer prognosis. Therefore, exploring the prognostic value of total serum immunoglobulin E (tIgE) and fractional exhaled nitric oxide (FeNO) levels in children with atopic constitution who suffer from bronchiolitis is of great significance. A total of 260 children with bronchiolitis admitted to our hospital from October 2020 to June 2022 were regarded as the research subjects with prospective study, according to whether the children had atopic constitution, they were grouped into non atopic constitution group (n = 156) and atopic constitution group (n = 104); after 6 months of treatment, children with atopic constitution were grouped into a good prognosis group (n = 58) and a poor prognosis group (n = 46) based on their prognosis; in addition, 260 healthy children who underwent physical examination and had clinical data consistent with those of children with bronchiolitis were regarded as the reference group. The serum tIgE and FeNO levels of each group were compared; multivariate Logistic regression was applied to analyze the prognostic factors of children with atopic constitution bronchiolitis; ROC curve was applied to analyze the predictive value of tIgE and FeNO levels after treatment for the prognosis of children with atopic constitution bronchiolitis. The tIgE levels in the control group, non-atopic group, and atopic group [(123.54 ± 29.62) IU/mL, (245.71 ± 30.59) IU/mL, (316.46 ± 31.78) IU/mL, respectively] increased sequentially, with statistically significant differences (F = 1766.954, P = 0.000). The FeNO levels in the control group, non-atopic group, and atopic group [(8.36 ± 3.57) ppb, (15.28 ± 3.69) ppb, (19.84 ± 3.58) ppb, respectively] also increased sequentially, with statistically significant differences (F = 765.622, P = 0.000). The tIgE, FeNO, proportion of patients with asthma family history, and proportion of patients with allergic family history in the poor prognosis group were obviously higher than those in the good prognosis group (P

Abstract Background Glucocorticoids are widely used in inhalation aerosol therapy for wheezing diseases. This study aims to explore guardians’ knowledge and attitude towards inhaled corticosteroids (ICS) aerosol therapy and the medication compliance of children with wheezing diseases in China. Methods This cross-sectional study enrolled guardians of children with wheezing diseases at the First Hospital Affiliated to Shaoyang College between October 2022 and February 2023. A self-administered questionnaire was developed to collect demographic information of the participants and evaluate their knowledge and attitude towards ICS aerosol therapy. The 8-item Morisky Medication Adherence Scale was used to assess the medication compliance of children. Results A total of 506 valid questionnaires were collected. 260 (51.38%) participants were guardians of a ≤ 3-year-old child and 327 (64.62%) were children’s mothers. The knowledge, attitude, and medication compliance scores of all participants were 12.61 ± 5.78, 20.95 ± 2.37, and 4.69 ± 2.18, respectively. Multivariate logistic regression showed that knowledge scores [OR = 1.053, 95% CI (confidence interval): 1.017–1.090, P = 0.003], attitude scores (OR = 1.121, 95% CI: 1.030–1.219, P = 0.008), guardians of children aged 4–6 years (OR = 0.385, 95% CI: 0.242–0.612, P

Objective Microtransplantation (MST) has been found to enhance clinical outcomes in elderly patients with newly diagnosed acute myeloid leukemia (AML) compared with chemotherapy alone. It is important to investigate clinical effectiveness and mechanisms.Methods From January 2012 to December 2022, a total of 40 patients over 60 years with newly diagnosed low – and medium-risk AML were analyzed retrospectively, which was divided into two groups: MST group (chemotherapy combined with donor peripheral blood stem cell [PBSC] injection, n = 20) and control group (chemotherapy alone, n = 20). Flow cytometry and commercial enzyme-linked immunosorbent assay (ELISA) kits were used to measure changes in the percentage of natural killer (NK) cells and the quantity of interferon IFN-γ. The complete remission (CR), 2-year overall survival (OS) and disease-free survival (DFS) were also calculated following therapy.Results After induction chemotherapy, the 20 MST patients had a CR rate of 60%, a 2-year OS of 61.8%, and a 2-year DFS of 51.6%.Conclusion MST has a faster hematological recovery and a greater CR, both of which can enhance OS and DFS in elderly AML patients. After MST, there is a significant correlation between the percentage of NK cells and the quantity of IFN-γ. This suggests that NK cells and IFN-γ are putative immunologic mechanisms of MST action.

ABSTRACT Human activity and climate change are widely considered to be primarily responsible for the extinction of Galliformes birds. Due to a decline in population, the Reeves's pheasant (Syrmaticus reevesii), a member of the Galliformes family, was recently elevated to first‐class national protected status in China. However, determining the causal factors of their extinction and carrying out protection measures appear to be challenging owing to a lack of long‐term data with high spatial and temporal resolutions. Here, based on a national field survey, we used habitat suitability models and integrated data on geographical environment, road development, land use, and climate change to predict the potential changes in the distribution and connectivity of the habitat of Reeves's pheasant from 1995 to 2050. Furthermore, ecological corridors were identified using the minimum cumulative resistance (MCR) model. The prioritized areas for habitat restoration were determined by integrating the importance indices of ecological sources and corridors. Our results indicated that both land use and climate change were linked to the increased habitat loss for the Reeves's pheasant. In more recent decades, road construction and land use changes have been linked to a rise in habitat loss, and future climate change has been predicted to cause the habitat to become even more fragmented and lose 89.58% of its total area. The ecological corridor for Reeves's pheasant will continue to decline by 88.55%. To counteract the negative effects of human activity and climate change on the survivorship of Reeves's pheasant, we recommend taking immediate actions, including bolstering cooperation among provincial governments, restoring habitats, and creating ecological corridors among important habitats.

Rechargeable Mg-ion batteries (MIBs) have attracted much more attentions by virtue of the high capacity from the two electrons chemistry. However, the reversible Mg2+ diffusion in cathode materials is restricted by the strong interactions between the high-polarized bivalent Mg2+ ions and anionic lattice. Herein, we design and propose a hetero-structural VO2(R)-VS4 cathode, in which the re-delocalized d-electrons can effectively shield the polarity of Mg2+ ions. Theoretically, the electrons should spontaneously transfer from VS4 to VO2(R) through the interfaces of hetero-structure due to the lower work function value of VS4. Furthermore, the internal electrons transfer lead to the electronic injection into VO2(R) from VS4 and the partially broken V-V dimers, indicating the presence of lone pair electrons and charge re-delocalization. Benefiting from the shield effect of re-delocalized electrons, and the weakened attraction between cations and O/S anions enables more S2−-S22− redox groups to participate the electrochemical reactions and compensate the double charge of Mg2+ ions. Accordingly, VO2(R)-VS4 hetero-structure exhibits a high specific capacity of 554 mA h g−1 at 50 mA g−1. It is believed that the charge re-delocalization of cathode extremely boost the Mg2+ ions migration for the high-capacity of MIBs.

Abstract Background Postoperative delirium (POD) represents a prevalent and noteworthy complication in the context of pediatric surgical interventions. In recent times, a hypothesis has emerged positing that cerebral ischemia and regional cerebral oxygen desaturation might serve as potential catalysts in the pathogenesis of POD. The primary aim of this study was to methodically examine the potential relationship between POD and regional cerebral oxygen saturation (rSO2) and to assess the predictive and evaluative utility of rSO2 in the context of POD. Methods This prospective observational study was conducted at the Children’s Hospital, Zhejiang University School of Medicine, Zhejiang, China, spanning the period from November 2020 to March 2021. The research cohort comprised children undergoing surgical procedures within this clinical setting. To measure rSO2 dynamics, cerebral near-infrared spectroscopy (NIRS) was used to monitor rSO2 levels both before and after surgery. In addition, POD was assessed in the paediatric patients according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria. The analysis of the association between the rSO2 index and the incidence of POD was carried out through the application of either the independent samples t-test or the nonparametric rank-sum test. To ascertain the threshold value of the adjusted rSO2 index for predictive and evaluative purposes regarding POD in the pediatric population, the Receiver Operating Characteristics (ROC) curve was employed. Results A total of 211 cases were included in this study, of which 61 (28.9%) developed POD. Participants suffering delirium had lower preoperative rSO2mean, lower preoperative rSO2min, and lower postoperative rSO2min, higher ∆rSO2mean, higher amount of ∆rSO2mean, lower ∆rSO2min (P

Based on the continuous development of new media and mobile communication technologies, social media has significantly influenced people’s daily thoughts and behaviors. For young people, social media is a platform for social interaction, and studies have found that social media helps Chinese graduates find employment. This study examined how social media use and its related factors affect employment anxiety. The data was collected from 1,204 Chinese youth through an online survey. The results showed that: (1) the intensity of social media use had a positive predictive effect on employment anxiety; (2) upward social comparison and online social support individually separately mediate the positive relationship between the intensity of social media use and employment anxiety; and (3) self-esteem negatively moderates the effect of upward social comparison and effect of online social support on employment anxiety. The study underscores the importance of reasonable social media usage strategies, positive social perception, and healthy self-perception for fostering a positive employment mindset among youth.

Bladder cancer is one of the leading causes of mortality globally. The development of bladder cancer is closely associated with alternative splicing, which regulates human gene expression and enhances the diversity of functional proteins. Alternative splicing is a distinctive feature of bladder cancer, and as such, it may hold promise as a therapeutic target. This review aims to comprehensively discuss the current knowledge of alternative splicing in the context of bladder cancer. We review the process of alternative splicing and its regulation in bladder cancer. Moreover, we emphasize the significance of abnormal alternative splicing and splicing factor irregularities during bladder cancer progression. Finally, we explore the impact of alternative splicing on bladder cancer drug resistance and the potential of alternative splicing as a therapeutic target.

Abstract The Forensic-Based Investigation (FBI) algorithm is a novel metaheuristic algorithm. Many researches have shown that FBI is a promising algorithm due to two specific population types. However, there is no sufficient information exchange between these two population types in the original FBI algorithm. Therefore, FBI suffers from many problems. This paper incorporates a novel self-adaptive population control strategy into FBI algorithm to adjust parameters based on the fitness transformation from the previous iteration, named SaFBI. In addition to the self-adaptive mechanism, our proposed SaFBI refers to a novel updating operator to further improve the robustness and effectiveness of the algorithm. To prove the availability of the proposed algorithm, we select 51 CEC benchmark functions and two well-known engineering problems to verify the performance of SaFBI. Experimental and statistical results manifest that the proposed SaFBI algorithm performs superiorly compared to some state-of-the-art algorithms.

Abstract Regulating nuclear export precisely is essential for maintaining mRNA homeostasis and impacts tumor progression. However, the mechanisms governing nuclear mRNA export remain poorly elucidated. Herein, it is revealed that the enhanced hypoxic long no‐ncoding RNA (lncRNA prostate cancer associated transcript 6 (PCAT6) in breast cancer (BC) promotes the nuclear export of m6A‐modified mRNAs, bolstering breast cancer stem cells (BCSCs) stemness and doxorubicin resistance. Clinically, hypoxic PCAT6 correlates with malignant BC features and poor prognosis. Mechanically, PCAT6 functions as a scaffold between interferon‐stimulated gene 15 (ISG15) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), leading to ISGylation of hnRNPA2B1, thus protecting hnRNPA2B1 from ubiquitination‐mediated proteasomal degradation. Interestingly, as an m6A reader, hnRNPA2B1 selectively mediates m6A‐tagged mRNAs nuclear export via the Aly/REF export factor (ALYREF)/ nuclear RNA export factor 1 (NXF1) complex, which promotes stemness‐related genes expression. HnRNPA2B1 knockdown or mRNA export inhibition can result in the retention of nuclear m6A‐tagged mRNA associated with stemness maintenance, which suppresses BCSCs self‐renewal and effectively improves the efficacy of doxorubicin therapy. These findings demonstrate the pivotal role of m6A‐modified mRNA nuclear export in BC progression, highlighting that the inhibition of m6A‐tagged mRNA and its nuclear export is a potential therapeutic strategy for the amelioration of cancer chemotherapy.

Abstract The treatment of diabetic periodontitis poses a significant challenge due to the presence of local inflammation characterized by excessive glucose concentration, bacterial infection, and high oxidative stress. Herein, mesoporous silica nanoparticles (MSN) are embellished with gold nanoparticles (Au NPs) and loaded with manganese carbonyl to prepare a carbon monoxide (CO) enhanced multienzyme cooperative hybrid nanoplatform (MSN‐Au@CO). The Glucose‐like oxidase activity of Au NPs catalyzes the oxidation of glucose to hydrogen peroxide (H2O2) and gluconic acid，and then converts H2O2 to hydroxyl radicals (•OH) by peroxidase‐like activity to destroy bacteria. Moreover, CO production in response to H2O2, together with Au NPs exhibited a synergistic anti‐inflammatory effect in macrophages challenged by lipopolysaccharides. The underlying mechanism can be the induction of nuclear factor erythroid 2‐related factor 2 to reduce reactive oxygen species, and inhibition of nuclear factor kappa‐B signaling to diminish inflammatory response. Importantly, the antibacterial and anti‐inflammation effects of MSN‐Au@CO are validated in diabetic rats with ligature‐induced periodontitis by showing decreased periodontal bone loss with good biocompatibility. To summarize, MSN‐Au@CO is fabricate to utilize glucose‐activated cascade reaction to eliminate bacteria, and synergize with gas therapy to regulate the immune microenvironment, offering a potential direction for the treatment of diabetic periodontitis.

Abstract Abnormal activation of the intestinal mucosal immune system, resulting from damage to the intestinal mucosal barrier and extensive invasion by pathogens, contributes to the pathogenesis of inflammatory bowel disease (IBD). Current first‐line treatments for IBD have limited efficacy and significant side effects. An innovative H2S‐releasing montmorillonite nanoformulation (DPs@MMT) capable of remodeling intestinal mucosal immune homeostasis, repairing the mucosal barrier, and modulating gut microbiota is developed by electrostatically adsorbing diallyl trisulfide‐loaded peptide dendrimer nanogels (DATS@PDNs, abbreviated as DPs) onto the montmorillonite (MMT) surface. Upon rectal administration, DPs@MMT specifically binds to and covers the damaged mucosa, promoting the accumulation and subsequent internalization of DPs by activated immune cells in the IBD site. DPs release H2S intracellularly in response to glutathione, initiating multiple therapeutic effects. In vitro and in vivo studies have shown that DPs@MMT effectively alleviates colitis by eliminating reactive oxygen species (ROS), inhibiting inflammation, repairing the mucosal barrier, and eradicating pathogens. RNA sequencing revealed that DPs@MMT exerts significant immunoregulatory and mucosal barrier repair effects, by activating pathways such as Nrf2/HO‐1, PI3K‐AKT, and RAS/MAPK/AP‐1, and inhibiting the p38/ERK MAPK, p65 NF‐κB, and JAK‐STAT3 pathways, as well as glycolysis. 16S rRNA sequencing demonstrated that DPs@MMT remodels the gut microbiota by eliminating pathogens and increasing probiotics. This study develops a promising nanoformulation for IBD management.

Abstract Bacterial infection in skin and soft tissue has emerged as a critical concern. Overreliance on antibiotic therapy has led to numerous challenges, including the emergence of multidrug-resistant bacteria and adverse drug reactions. It is imperative to develop non-antibiotic treatment strategies that not only exhibit potent antibacterial properties but also promote rapid wound healing and demonstrate biocompatibility. Herein, a novel multimodal synergistic antibacterial system (SNO-CS@MoS2) was developed. This system employs easily surface-modified thin-layer MoS2 as photothermal agents and loaded with S-nitrosothiol-modified chitosan (SNO-CS) via electrostatic interactions, thus realizing the combination of NO gas therapy and photothermal therapy (PTT). Furthermore, this surface modification renders SNO-CS@MoS2 highly stable and capable of binding with bacteria. Through PTT’s thermal energy, SNO-CS@MoS2 rapidly generates massive NO, collaborating with PTT to achieve antibacterial effects. This synergistic therapy can swiftly disrupt the bacterial membrane, causing protein leakage and ATP synthesis function damage, ultimately eliminating bacteria. Notably, after effectively eliminating all bacteria, the residual SNO-CS@MoS2 can create trace NO to promote fibroblast migration, proliferation, and vascular regeneration, thereby accelerating wound healing. This study concluded that SNO-CS@MoS2, a novel multifunctional nanomaterial with outstanding antibacterial characteristics and potential to promote wound healing, has promising applications in infected soft tissue wound treatment.

The efficient wind power forecasting is of great significance for the safety and stability of power grid. Analysis on the high order moment of wind power time series play an important role in improving the forecasting accuracy of wind power. With the rolling subsample generalized auto-regressive conditional heteroskedasticity with skewness and kurtosis (GARCHSK) model sequence, the analysis method for conditional skewness and conditional kurtosis of wind power time series is proposed. The dynamic curves of parameter are presented by estimating the characteristic parameters in the subsample models. Moreover, the time-varying structure of high order moment of the wind power time series is analyzed. A Generalized News Impact Curve (GNIC) is proposed, and the impact of news on the conditional skewness and conditional kurtosis are measured and evaluated by the third order GNIC and the fourth order GNIC. The result of case based on the wind power data of Jiangsu power grid demonstrates that the time-varying structure of high-order moments of wind power time series is steady relatively, and the time-varying characteristics of high-order moments are further verified by GNIC.

Abstract Background Genotypes are strongly associated with disease phenotypes, particularly in brain disorders. However, the molecular and cellular mechanisms behind this association remain elusive. With emerging multimodal data for these mechanisms, machine learning methods can be applied for phenotype prediction at different scales, but due to the black-box nature of machine learning, integrating these modalities and interpreting biological mechanisms can be challenging. Additionally, the partial availability of these multimodal data presents a challenge in developing these predictive models. Method To address these challenges, we developed DeepGAMI, an interpretable neural network model to improve genotype–phenotype prediction from multimodal data. DeepGAMI leverages functional genomic information, such as eQTLs and gene regulation, to guide neural network connections. Additionally, it includes an auxiliary learning layer for cross-modal imputation allowing the imputation of latent features of missing modalities and thus predicting phenotypes from a single modality. Finally, DeepGAMI uses integrated gradient to prioritize multimodal features for various phenotypes. Results We applied DeepGAMI to several multimodal datasets including genotype and bulk and cell-type gene expression data in brain diseases, and gene expression and electrophysiology data of mouse neuronal cells. Using cross-validation and independent validation, DeepGAMI outperformed existing methods for classifying disease types, and cellular and clinical phenotypes, even using single modalities (e.g., AUC score of 0.79 for Schizophrenia and 0.73 for cognitive impairment in Alzheimer’s disease). Conclusion We demonstrated that DeepGAMI improves phenotype prediction and prioritizes phenotypic features and networks in multiple multimodal datasets in complex brains and brain diseases. Also, it prioritized disease-associated variants, genes, and regulatory networks linked to different phenotypes, providing novel insights into the interpretation of gene regulatory mechanisms. DeepGAMI is open-source and available for general use.

Abstract Slime mold algorithm (SMA) is a nature-inspired algorithm that simulates the biological optimization mechanisms and has achieved great results in various complex stochastic optimization problems. Owing to the simulated biological search principle of slime mold, SMA has a unique advantage in global optimization problem. However, it still suffers from issues of missing the optimal solution or collapsing to local optimum when facing complicated problems. To conquer these drawbacks, we consider adding a novel multi-chaotic local operator to the bio-shock feedback mechanism of SMA to compensate for the lack of exploration of the local solution space with the help of the perturbation nature of the chaotic operator. Based on this, we propose an improved algorithm, namely MCSMA, by investigating how to improve the probabilistic selection of chaotic operators based on the maximum Lyapunov exponent (MLE), an inherent property of chaotic maps. We implement the comparison between MCSMA with other state-of-the-art methods on IEEE Congress on Evolution Computation (CEC) i.e., CEC2017 benchmark test suits and CEC2011 practical problems to demonstrate its potency and perform dendritic neuron model training to test the robustness of MCSMA on classification problems. Finally, the parameters’ sensitivities of MCSMA, the utilization of the solution space, and the effectiveness of the MLE are adequately discussed.

Weather conditions play a pivotal role in embryo development and parental incubation costs, potentially impacting the clutch size and incubation behavior of birds. Understanding these effects is crucial for bird conservation. Reeves's Pheasant (Syrmaticus reevesii) is a threatened species endemic to China, which is characterized by female-only incubation. However, there is a lack of information regarding the impact of weather conditions on clutch size and incubation behavior in this species. Using satellite tracking, we tracked 27 wild female Reeves's Pheasants from 2020 to 2023 in Hubei Province, China. We explored their clutch size and incubation behavior, as well as their responses to ambient temperature and precipitation. Clutch size averaged 7.75 ± 1.36, had an association with average ambient temperature and average daily precipitation during the egg-laying period, and was potentially linked to female breeding attempts. Throughout the incubation period, females took an average of 0.73 ± 0.46 recesses every 24 h, with an average recess duration of 100.80 ± 73.37 min and an average nest attendance of 92.98 ± 5.27%. They showed a unimodal recess pattern in which nest departures peaked primarily between 13:00 and 16:00. Furthermore, females rarely left nests when daily precipitation was high. Recess duration and nest attendance were influenced by the interaction between daily mean ambient temperature and daily precipitation, as well as day of incubation. Additionally, there was a positive correlation between clutch size and recess duration. These results contribute valuable insights into the life-history features of this endangered species.

Thermal performance of densely populated underground buildings is normally influenced by various factors, including the surrounding rock (SR), ventilation, and indoor heat sources. It is recognized that little experimental studies on thermal control for the above building was reported. In this article, a full-size 50-person mine refuge chamber (MRC) was newly constructed to test the thermal performance under natural convection and ventilation. The heat ducts were used to simulate the heat released from human body. Experimental results indicated that: (1) the intensity of the heat transfer between rock and air increases with the rise in heat source rate and ventilation temperature (VT), while it decreases as the initial surrounding rock temperature (ISRT) increases; (2) when considering the joint temperature control of pre-cooled SR, it is recommended to reduce the VT linearly during the evacuation period in order to ensure the thermal safety of personnel. During the non-refuge period, the cold amount should be stored as far as possible into the shallow SR body to make full use of it; (3) to ensure the thermal safety of an MRC with a capacity of 30 people for 96 h, cooling measures are required when the ISRT exceeds 21.3 °C. In addition, when the ISRT reaches 27.6 °C, the per capita ventilation is 0.19 m3/min, and the temperature is 26 °C, which can also meet the requirements. This study provides experimental verification as a basis for future research on underground space temperature control considering the influence of SR.

As one of continuous concern all over the world, the problem of water quality may cause diseases and poisoning and even endanger people's lives. Therefore, the prediction of water quality is of great significance to the efficient management of water resources. However, existing prediction algorithms not only require more operation time but also have low accuracy. In recent years, neural networks are widely used to predict water quality, and the computational power of individual neurons has attracted more and more attention. The main content of this research is to use a novel dendritic neuron model (DNM) to predict water quality. In DNM, dendrites combine synapses of different states instead of simple linear weighting, which has a better fitting ability compared with traditional neural networks. In addition, a recent optimization algorithm called AMSGrad (Adaptive Gradient Method) has been introduced to improve the performance of the Adam dendritic neuron model (ADNM). The performance of ADNM is compared with that of traditional neural networks, and the simulation results show that ADNM is better than traditional neural networks in mean square error, root mean square error and other indicators. Furthermore, the stability and accuracy of ADNM are better than those of other conventional models. Based on trained neural networks, policymakers and managers can use the model to predict the water quality. Real-time water quality level at the monitoring site can be presented so that measures can be taken to avoid diseases caused by water quality problems.

Chance theory is a mathematical methodology for modelling complex systems including both uncertainty and randomness. Based on chance theory, this paper introduces the optimal control model for a multistage uncertain random system. For solving such a model, recurrence equations are presented via Bellman’s principle. With the aid of recurrence equations, the bang-bang problem of optimal control model and indefinite linear quadratic (LQ) problem of optimal control model are studied. Meanwhile, the exact solutions of such problems are presented. Furthermore, numerical examples are provided on the proposed theorems to show the effectiveness of our results.

Abstract Background To assess the effectiveness and toxicity of radiation dose escalation for locally advanced nasopharyngeal carcinoma (LA-NPC) in patients with local and/or regional residual lesion(s) after standard treatment. Methods From November 2011 to November 2020, 259 LA-NPC patients who had local and/or regional residual lesion(s) after induction chemotherapy followed by concurrent chemoradiotherapy (IC + CCRT) from our hospital were included. The total dose of primary radiotherapy (RT) was 68.1–74.25 Gy (median, 70.4 Gy). The boost doses were 4.0–18.0 Gy (median, 9 Gy), 1.8–2.0 Gy/fraction. Results For all patients, the 5-year local relapse-free survival was 90.2%, regional relapse-free survival was 89.1%, locoregional relapse-free survival (LRRFS) was 79.5%, distant metastasis-free survival (DMFS) was 87.9%, failure-free survival (FFS) was 69.0%, and overall survival (OS) was 86.3%. LRRFS, DMFS, FFS, and OS in patients with age ≤ 65 versus > 65, plasma Epstein-Barr virus-deoxyribonucleic acid ≤ 500 versus > 500, T1–2 versus T3–4, N0–1 versus N2–3, and stage III versus stage IV showed no statistically significant differences. The interval between primary RT and boost was not a prognostic factor for LRRFS, DMFS, FFS, and OS. Males had a lower 3-year FFS rate than females (72.9% vs. 83.7%, P = 0.024). LA-NPCs with locally and regionally residual lesion(s) had the worst 3-year DMFS and OS rates compared with locally or regionally residual lesion(s) (77.7% vs. 98.8% vs. 87.4%, P = 0.014; 75.9% vs. 94.5% vs. 82.4%, P = 0.002). Conclusion Boost radiation was an option for LA-NPCs with locally and/or regionally residual lesions after receiving IC + CCRT. It warrants further prospective study. Trial registration: Retrospectively registered.

ABSTRACT: Pork price fluctuations are closely related to the national economy and people’s livelihoods in China. Based on the monthly pork price fluctuations in China from January 2011 to August 2022, this study uses ARCH family models to assess the characteristics and laws of these fluctuations in China. The pork price fluctuations show obvious clustering, with external shock information from the previous month affecting the pork price in the following period; the pork market price is characterized by risk compensation, with the high risk of pork supply driving the pork price up. In addition, the pork price fluctuations are characterized by asymmetry, with a greater impact of good than of bad news on the pork price. Due to the pork industry’ low entry threshold and the existence of sunk costs, positive information on the pork market has a stronger impact on price fluctuations than negative information. To guide pork supply, we recommend improving monitoring and early-warning mechanisms in the pork market to identify the pork price volatility threshold and measure the price volatility. In addition, price index insurance products should be constantly strengthened, with different types of insurance products being offered to meeting the insurance demand of various sectors in the pig meat supply chain.

The radiation tolerance of energy storage batteries is a crucial index for universe exploration or nuclear rescue work, but there is no thorough investigation of Li metal batteries. Here, we systematically explore the energy storage behavior of Li metal batteries under gamma rays. Degradation of the performance of Li metal batteries under gamma radiation is linked to the active materials of the cathode, electrolyte, binder, and electrode interface. Specifically, gamma radiation triggers cation mixing in the cathode active material, which results in poor polarization and capacity. Ionization of solvent molecules in the electrolyte promotes decomposition of LiPF6 along with its decomposition, and molecule chain breaking and cross-linking weaken the bonding ability of the binder, causing electrode cracking and reduced active material utilization. Additionally, deterioration of the electrode interface accelerates degradation of the Li metal anode and increases cell polarization, hastening the demise of Li metal batteries even more. This work provides significant theoretical and technical evidence for development of Li batteries in radiation environments.

Abstract Background Drug-induced hypersensitivity syndrome (DIHS) is a rare, potentially life-threatening systemic drug reaction. Antithyroid drugs (ATDs) causing DIHS have seldom been reported before. Case presentation We present a case of propylthiouracil (PTU)-induced DIHS, which included fever, skin rash, lymphadenopathy, hepatosplenomegaly, serious liver and kidney dysfunction, peripheral blood eosinophilia, and atypical lymphocytosis. Following supportive therapy, intravenous immunoglobulin (IVIG), and systemic corticosteroid, the patient experienced a resolution of fever and rash combined with progressive normalization of hematological index and organ function. These clinical features, and the skin lesion biopsy confirmed DIHS diagnosis. Conclusions To our knowledge, this is the second reported case of PTU-induced DIHS worldwide and the first human leukocyte antigen (HLA) typing of PTU-induced DIHS. Clinicians should cautiously distinguish hyperthyroidism etiology and identify the indication of ATDs. Timely recognition and formal DIHS treatment are required in patients with ATDs.

Abstract Evaluation of tool wear is vital in manufacturing system, since early detections on worn-out condition can ensure workpiece quality, improve machining efficiency. With the development of intelligent manufacturing, tool wear prediction technology plays an increasingly important role. However, traditional tool wear prediction methods rely on experience and knowledge of experts and are labor-extensive. Deep learning provides an effective way to extract features of raw data and establish the mapping relationship between features and targets automatically. In this paper, a new local-feature and global-dependency based tool wear prediction method is proposed. It is a hybrid approach combining manual features with automatic features. Firstly, an enhanced CNN network is designed and applied on the transformed wavelet scalogram to learn the local single-scale specific features and multi-scale correlation features automatically. Secondly, sequence of local feature vectors combining manual features with automatic features are fed into multi-layer LSTM step by step for the global dependency. A fully connected layer is then trained to predict tool wear. Finally, two statistics are proposed to illustrate the overall prediction performance and generalization ability of the model. An experiment illustrates the effectiveness of our proposed method under multiple working conditions.

ObjectiveTo examine the causal associations of diet-derived circulating antioxidants with knee osteoarthritis (OA), hip OA, and rheumatoid arthritis (RA) within the two-sample Mendelian randomization (MR) framework.MethodIndependent single-nucleotide polymorphisms (SNPs) significantly associated with circulating levels of diet-derived antioxidants (retinol, β-carotene, lycopene, vitamin C and vitamin E) were extracted as genetic instruments. Summary statistics of genetic instruments associated with knee OA, hip OA, and RA were obtained from corresponding genome-wide association studies (GWASs). The inverse-variance weighted (IVW) was applied as the primary analysis method, with four sensitivity analysis approaches employed to evaluate the robustness of the primary results.ResultsGenetically determined per unit increment of absolute circulating levels of retinol was significantly associated with a reduced risk of hip OA [odds ratio (OR) = 0.45, 95% confidence interval (CI) 0.26–0.78, p = 4.43 × 10−3], while genetically determined per unit increase in absolute circulating levels of β-carotene was suggestively associated with increased risk of RA (OR = 1.32, 95% CI 1.07–1.62, p = 9.10 × 10−3). No other causal association was found. Significant evidence for heterogeneity and pleiotropic outlier was only identified when absolute circulating vitamin C was evaluated as the exposure, whereas all sensitive analysis provided consistently non-significant results.ConclusionOur results demonstrated that genetically determined lifelong higher exposure to absolute circulating levels of retinol is associated with a decreased risk of hip OA. Further MR study with more genetic instruments for absolute circulating levels of antioxidants are needed to confirm our results.

Abstract Promoting industry applications of high‐energy Li metal batteries (LMBs) is of vital importance for accelerating the electrification and decarbonization of our society. Unfortunately, the time‐dependent storage aging of Ah‐level Li metal pouch cells, a ubiquitous but crucial practical indicator, has not yet been revealed. Herein, we first report the storage behaviors and multilateral synergistic aging mechanism of Ah‐level NCM811||Li pouch cells during the 120‐day long‐term storage under various conditions. Contrary to the conventional belief of Li‐ion batteries with graphite intercalation anodes, the significant available capacity loss of 32.8% on average originates from the major electrolyte‐sensitive anode corrosion and partial superimposed cathode degradation, and the irreversible capacity loss of 13.3% is essentially attributed to the unrecoverable interface/structure deterioration of NCM with further hindrance of the aged Li. Moreover, principles of alleviating aging have been proposed. This work bridges academia and industry and enriches the fundamental epistemology of storage aging of LMBs, shedding light on realistic applications of high‐energy batteries.

The development of functional wound dressings capable of both rapid hemostasis and high-efficiency antimicrobial is essential for the management of severe bleeding wounds. Cotton dressings are widely used in clinical practice; however, few dressings can simultaneously achieve rapid hemostasis and high-efficacy antimicrobial. Herein, a versatile cotton dressing (GCQCNF-5) was masterly developed by sequentially deposition catechol modified quaternary chitosan (CQCS) and gelatin onto a cotton nonwoven fabric (NF) surface. Because of the presence of a gelatin sponge layer with suitable thickness and porosity on its surface, GCQCNF-5 exhibits a notably enhanced hemostatic effect compared to NF both in vitro and in vivo, which is even slightly superior to that of MHS (a commercial gelatin hemostatic sponge). Moreover, after exerting a rapid hemostasis effect, GCQCNF-5 can further exploit CQCS to exert excellent immediate antimicrobial and long-lasting bacteriostatic effects. In vivo wound healing experiments further indicated that GCQCNF-5 could significantly promote rapid healing of infected wounds by effectively sterilizing, absorbing exudates, and providing moist healing environments. This study clearly demonstrated that GCQCNF-5 is a versatile wound dressing that can achieve simultaneously rapid hemostasis, high-efficiency antimicrobial, and promote rapid healing of infected wounds, with great application potential for the treatment of severe bleeding wounds.

Abstract Intellectual and Developmental Disabilities (IDDs), such as Down syndrome, Fragile X syndrome, Rett syndrome, and autism spectrum disorder, usually manifest at birth or early childhood. IDDs are characterized by significant impairment in intellectual and adaptive functioning, and both genetic and environmental factors underpin IDD biology. Molecular and genetic stratification of IDDs remain challenging mainly due to overlapping factors and comorbidity. Advances in high throughput sequencing, imaging, and tools to record behavioral data at scale have greatly enhanced our understanding of the molecular, cellular, structural, and environmental basis of some IDDs. Fueled by the “big data” revolution, artificial intelligence (AI) and machine learning (ML) technologies have brought a whole new paradigm shift in computational biology. Evidently, the ML-driven approach to clinical diagnoses has the potential to augment classical methods that use symptoms and external observations, hoping to push the personalized treatment plan forward. Therefore, integrative analyses and applications of ML technology have a direct bearing on discoveries in IDDs. The application of ML to IDDs can potentially improve screening and early diagnosis, advance our understanding of the complexity of comorbidity, and accelerate the identification of biomarkers for clinical research and drug development. For more than five decades, the IDDRC network has supported a nexus of investigators at centers across the USA, all striving to understand the interplay between various factors underlying IDDs. In this review, we introduced fast-increasing multi-modal data types, highlighted example studies that employed ML technologies to illuminate factors and biological mechanisms underlying IDDs, as well as recent advances in ML technologies and their applications to IDDs and other neurological diseases. We discussed various molecular, clinical, and environmental data collection modes, including genetic, imaging, phenotypical, and behavioral data types, along with multiple repositories that store and share such data. Furthermore, we outlined some fundamental concepts of machine learning algorithms and presented our opinion on specific gaps that will need to be filled to accomplish, for example, reliable implementation of ML-based diagnosis technology in IDD clinics. We anticipate that this review will guide researchers to formulate AI and ML-based approaches to investigate IDDs and related conditions.

Background Developmental hypothyroidism impairs learning and memory in offspring, which depend on extensive neuronal circuits in the entorhinal cortex, together with the hippocampus and neocortex. The entorhinal-dentate gyrus pathway is the main entrance of memory circuits. We investigated whether developmental hypothyroidism impaired the morphological development of the entorhinal-dentate gyrus pathway. Methods We examined the structure and function of the entorhinal-dentate gyrus pathway in response to developmental hypothyroidism induced using 2-mercapto-1-methylimidazole. Results 1,1´-Dioctadecyl-3,3,3´,3´-tetramethylindocarbocyanine perchlorate tract tracing indicated that entorhinal axons showed delayed growth in reaching the outer molecular layer of the dentate gyrus at postnatal days 2 and 4 in hypothyroid conditions. The proportion of fibers in the outer molecular layer was significantly smaller in the hypothyroid group than in the euthyroid group at postnatal day 4. At postnatal day 10, the pathway showed a layer-specific distribution in the outer molecular layer, similar to the euthyroid group. However, the projected area of entorhinal axons was smaller in the hypothyroid group than in the euthyroid group. An electrophysiological examination showed that hypothyroidism impaired the long-term potentiation of the perforant and the cornu ammonis 3–cornu ammonis 1 pathways. Many repulsive axon guidance molecules were involved in the formation of the entorhinaldentate gyrus pathway. The hypothyroid group had higher levels of erythropoietin-producing hepatocyte ligand A3 and semaphorin 3A than the euthyroid group. Conclusion We demonstrated that developmental hypothyroidism might influence the development of the entorhinal-dentate gyrus pathway, contributing to impaired long-term potentiation. These findings improve our understanding of neural mechanisms for memory function.

The behavior of lithium metal batteries at various gravity levels is not yet clearly understood. Here, the authors demonstrate the beneficial effect of supergravity in terms of battery performance improvement and favorable solid electrolyte interphase formation.

Identifying key factors affecting the resilience of a prefabricated building supply chain and exploring the effect mechanism of these factors can help to improve the resilience of the prefabricated building supply chain. The main factors affecting the resilience of the prefabricated building supply chain are sorted out first on the basis of Hall’s 3D theory and related research results. Then, the relationships between these factors and the dynamic change of influence of these factors on the resilience of the supply chain are studied through simulation by combining the fuzzy set theory, decision-making experimental analysis, and the system dynamics method. The results show that 10 s-level factors, such as disruption risk prediction and supply chain information sharing level, are active causal factors, while 9 s-level factors, such as disruption response time and disruption contingency plan, are passive result factors. Among the second-level factors, the disruption response time has the highest influence on the resilience of the prefabricated building supply chain, and component design versatility has the lowest influence on the resilience of the prefabricated building supply chain. The influence of the first-level factors, i.e., evolutionary ability, efficiency, and adaptability, descends in sequence. At last, specific suggestions for improving the resilience of the prefabricated building supply chain are put forward.

Objective. Acute myeloid leukemia (AML) is a heterogeneous malignancy with a low long-term survival rate. The aim of this study was to investigate the effects of decitabine (DAC) treatment cell proliferation and apoptosis in AML and role of the expression of LINC00599 and, consequently, miR-135a-5p. Materials and Methods. Human promyelocytic leukemia cells (HL-60) and human acute lymphatic leukemia (CCRF-CEM) cells were treated with various concentrations of DAC. Cell proliferation in each group was detected using the cell counting kit 8. For each group, apoptosis and reactive oxygen species (ROS) levels were detected using flow cytometry. Reverse transcription polymerase chain reaction (RT-PCR) was performed to examine the expression of lncRNA LINC00599. The expression of apoptosis-related proteins was analyzed using western blotting. The regulatory relationship between miR-135a-5p and LINC00599 was verified by constructing miR-135a-5p mimics, miR-135a-5p inhibit, wild type LINC00599 3′-untranslated region (UTR), and mutant LINC00599 3′-UTR. Ki-67 expression in the tumor tissues of nude mice was detected using immunofluorescent assays. Results. Both DAC and LINC00599 Inhibit groups were able to significantly reduce the proliferation of HL60 and CCRF-CEM cells, increase apoptosis, upregulate the expression of Bad, cleaved caspase-3, and miR-135a-5p, downregulate the expression of Bcl-2, and elevate ROS levels in cells, with these effects being more pronounced after combined treatment with DAC and LINC00599 Inhibit. In comparison to mimic NC, the miR-135a-5p mimic group significantly decreased the relative fluorescence activity ratio of LINC00599 3′-UTR wild-type CCRF-CEM cells. The LINC00599 Inhibit and miR-135a-5p mimic groups exhibited substantially reduced proliferation of HL60 and CCRF-CEM cells, increased apoptosis, upregulated Bad, cleaved caspase-3, and miR-135a-5p expression, along with downregulated Bcl-2 and LINC00599 expression and increased ROS levels in cells; these effects were more pronounced after LINC00599 Inhibit was combined with miR-135a-5p mimics. In vivo experiments revealed that both DAC and LINC00599 Inhibit were able to considerably reduce the long diameter, short meridian, volume, and mass of tumors, increase miR-135a-5p expression, and decrease LINC00599 and ki-67 expression in tumor tissues of nude mice. This effect was more pronounced when the DAC and LINC00599 Inhibit were used in combination. Conclusion. DAC regulates the expression of miR-135a-5p by regulating the expression of LINC00599, which in turn affects cell proliferation, apoptosis, and tumor proliferation. Our findings provide a theoretical basis for improving the clinical outcome of AML.

Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation. Currently, the therapeutic role of ferroptosis on cancer is gaining increasing interest. Baicalin an active component in Scutellaria baicalensis Georgi with anticancer potential various cancer types; however, the effects of baicalein on bladder cancer and the underlying molecular mechanisms remain largely unknown. In the study, we investigated the effect of baicalin on bladder cancer cells 5637 and KU-19-19. As a result, we show baicalin exerted its anticancer activity by inducing apoptosis and cell death in bladder cancer cells. Subsequently, we for the first time demonstrate baicalin-induced ferroptotic cell death in vitro and in vivo, accompanied by reactive oxygen species (ROS) accumulation and intracellular chelate iron enrichment. The ferroptosis inhibitor deferoxamine but not necrostatin-1, chloroquine (CQ), N-acetyl-l-cysteine, l-glutathione reduced, or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK) rescued baicalin-induced cell death, indicating ferroptosis contributed to baicalin-induced cell death. Mechanistically, we show that ferritin heavy chain 1 (FTH1) was a key determinant for baicalin-induced ferroptosis. Overexpression of FTH1 abrogated the anticancer effects of baicalin in both 5637 and KU19-19 cells. Taken together, our data for the first time suggest that the natural product baicalin exerts its anticancer activity by inducing FTH1-dependent ferroptosis, which will hopefully provide a prospective compound for bladder cancer treatment.

Accumulating evidence suggests that chronic inflammation may play a critical role in various malignancies, including bladder cancer. This hypothesis stems in part from inflammatory cells observed in the urethral microenvironment. Chronic inflammation may drive neoplastic transformation and the progression of bladder cancer by activating a series of inflammatory molecules and signals. Recently, it has been shown that the microbiome also plays an important role in the development and progression of bladder cancer, which can be mediated through the stimulation of chronic inflammation. In effect, the urinary microbiome can play a role in establishing the inflammatory urethral microenvironment that may facilitate the development and progression of bladder cancer. In other words, chronic inflammation caused by the urinary microbiome may promote the initiation and progression of bladder cancer. Here, we provide a detailed and comprehensive account of the link between chronic inflammation, the microbiome and bladder cancer. Finally, we highlight that targeting the urinary microbiome might enable the development of strategies for bladder cancer prevention and personalized treatment.

BackgroundRecent studies indicate that cell mechanics are associated with malignancy through its impact on cell migration and adhesion. Gliomas are the most common primary malignant brain tumors. Low-grade gliomas (LGGs) include diffuse LGGs (WHO grade II) and intermediate-grade gliomas (WHO grade III). Few studies have focused on membrane tension in LGGs. Herein, we assessed the prognostic value of plasma membrane tension-related genes (MTRGs) in LGGs.MethodsWe selected plasma MTRGs identified in previous studies for analysis. Based on LGG RNA sequencing (RNA-seq) data in The Cancer Genome Atlas, a prognostic signature containing four genes was constructed via log-rank testing, LASSO regression and stepwise multivariate Cox regression and was validated with other datasets. Additionally, functional annotation, pathway enrichment and immune and molecular characteristics of the prognostic model defined subgroups were analyzed. Thereafter, a predictive nomogram that integrated baseline characteristics was constructed to determine the 3, 5, and 10-year overall survival (OS) of patients with LGG. Differentially expressed genes were confirmed via quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC).ResultsOur MTRG prognostic signature was based on ARFIP2, PICK1, SH3GL2, and SRGAP3 expression levels. The high-risk group was more positively associated with apoptosis and cell adhesion pathways and exhibited a low IDH1 mutation rate, high TP53 mutation rate and a low 1p19q co-deletion rate. The high-risk group also exhibited incremental infiltration of immune cells, more forceful immune activities and high expression of immune checkpoints as well as benefited less from immune therapy compared with the low-risk group. Our prognostic model had better forecasting ability than other scoring systems. We found that the nomogram was a better tool for predicting outcomes for patients with LGG. Finally, qRT-PCR confirmed that SH3GL2 and SRGAP3 expression levels in glioma tissues were significantly lower than those in normal brain tissues. The results of IHC analysis confirmed that SH3GL2 protein expression was higher in patients with longer survival.ConclusionOur plasma membrane tension-related gene prognostic signature is a prospective tool that can differentiate between prognosis, gene mutation landscape, immune microenvironment, immune infiltration and immunotherapeutic efficacy in LGG.

Introduction: According to the competing failure theorem, the fractional-order Resistor Capacitance (RC) circuit system suffers not only from internal degradation but also from external shocks. However, due to the general differences of each failure type in the data availability and cognitive uncertainty, a better model is needed to describe the degradation process within the system. Also, a new reliability analysis method is needed for the circuit system under internal degradation and external shocks. Objectives: To demonstrate this problem, this paper proposes a novel class of Caputo-type uncertain random fractional-order model that focuses on the reliability analysis of a fractional-order RC circuit system. Methods: First, an uncertain Liu process is used to describe the internal degradation of soft faults and a stochastic process is used to describe the external random shocks of hard faults. Secondly, taking into account the correlation and competition among the fault types, an extreme shock model and a cumulative shock model are constructed, and chance theory is introduced to further explore the fault mechanisms, from which the corresponding reliability indices are derived. Finally, the predictor–corrector method is applied and numerical examples are given. Results: This paper presents a reliability analysis of a fractional-order RC circuit system with internal failure obeying an uncertain process and external failure obeying a stochastic process, and gives the calculation of the reliability indexes for different cases and the corresponding numerical simulations. Conclusion: A new competing failure model for a fractional-order RC circuit system is presented and analyzed for reliability, which is proved to be of practical importance by numerical simulations.

Alkaline soil has a high pH due to carbonate salts and usually causes more detrimental effects on crop growth than saline soil. Sodium hydrogen exchangers (NHXs) are pivotal regulators of cellular Na+/K+ and pH homeostasis, which is essential for salt tolerance; however, their role in alkaline salt tolerance is largely unknown. Therefore, in this study, we investigated the function of a soybean NHX gene, GmNHX6, in plant response to alkaline salt stress. GmNHX6 encodes a Golgi-localized sodium/hydrogen exchanger, and its transcript abundance is more upregulated in alkaline salt tolerant soybean variety in response to NaHCO3 stress. Ectopic expression of GmNHX6 in Arabidopsis enhanced alkaline salt tolerance by maintaining high K+ content and low Na+/K+ ratio. Overexpression of GmNHX6 also improved soybean tolerance to alkaline salt stress. A single nucleotide polymorphism in the promoter region of NHX6 is associated with the alkaline salt tolerance in soybean germplasm. A superior promoter of GmNHX6 was isolated from an alkaline salt tolerant soybean variety, which showed stronger activity than the promoter from an alkaline salt sensitive soybean variety in response to alkali stress, by luciferase transient expression assays. Our results suggested soybean NHX6 gene plays an important role in plant tolerance to alkaline salt stress.

Dysregulation of gene expression in Alzheimer's disease (AD) remains elusive, especially at the cell type level. Gene regulatory network, a key molecular mechanism linking transcription factors (TFs) and regulatory elements to govern gene expression, can change across cell types in the human brain and thus serve as a model for studying gene dysregulation in AD. However, AD-induced regulatory changes across brain cell types remains uncharted. To address this, we integrated single-cell multi-omics datasets to predict the gene regulatory networks of four major cell types, excitatory and inhibitory neurons, microglia and oligodendrocytes, in control and AD brains. Importantly, we analyzed and compared the structural and topological features of networks across cell types and examined changes in AD. Our analysis shows that hub TFs are largely common across cell types and AD-related changes are relatively more prominent in some cell types (e.g., microglia). The regulatory logics of enriched network motifs (e.g., feed-forward loops) further uncover cell type-specific TF-TF cooperativities in gene regulation. The cell type networks are also highly modular and several network modules with cell-type-specific expression changes in AD pathology are enriched with AD-risk genes. The further disease-module-drug association analysis suggests cell-type candidate drugs and their potential target genes. Finally, our network-based machine learning analysis systematically prioritized cell type risk genes likely involved in AD. Our strategy is validated using an independent dataset which showed that top ranked genes can predict clinical phenotypes (e.g., cognitive impairment) of AD with reasonable accuracy. Overall, this single-cell network biology analysis provides a comprehensive map linking genes, regulatory networks, cell types and drug targets and reveals cell-type gene dysregulation in AD.

Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with poor prognosis and limited treatment options. Hypoxia is a key hallmark of TNBC. Metabolic adaptation promotes progression of TNBC cells that are located within the hypoxic tumor regions. However, it is not well understood regarding the precise molecular mechanisms underlying the regulation of metabolic adaptions by hypoxia. Methods RNA sequencing was performed to analyze the gene expression profiles in MDA-MB-231 cell line (20% O2 and 1% O2). Expressions of Slc6a8, which encodes the creatine transporter protein, were detected in breast cancer cells and tissues by quantitative real-time PCR. Immunohistochemistry was performed to detect SLC6A8 protein abundances in tumor tissues. Clinicopathologic correlation and overall survival were evaluated by chi-square test and Kaplan-Meier analysis, respectively. Cell viability assay and flow cytometry analysis with Annexin V/PI double staining were performed to investigate the impact of SLC6A8-mediated uptake of creatine on viability of hypoxic TNBC cells. TNBC orthotopic mouse model was used to evaluate the effects of creatine in vivo. Results SLC6A8 was aberrantly upregulated in TNBC cells in hypoxia. SLC6A8 was drastically overexpressed in TNBC tissues and its level was tightly associated with advanced TNM stage, higher histological grade and worse overall survival of TNBC patients. We found that SLC6A8 was transcriptionally upregulated by p65/NF-κB and mediated accumulation of intracellular creatine in hypoxia. SLC6A8-mediated accumulation of creatine promoted survival and suppressed apoptosis via maintaining redox homeostasis in hypoxic TNBC cells. Furthermore, creatine was required to facilitate tumor growth in xenograft mouse models. Mechanistically, intracellular creatine bolstered cell antioxidant defense by reducing mitochondrial activity and oxygen consumption rates to reduce accumulation of intracellular reactive oxygen species, ultimately activating AKT-ERK signaling, the activation of which protected the viability of hypoxic TNBC cells via mediating the upregulation of Ki-67 and Bcl-2, and the downregulation of Bax and cleaved Caspase-3. Conclusions Our study indicates that SLC6A8-mediated creatine accumulation plays an important role in promoting TNBC progression, and may provide a potential therapeutic strategy option for treatment of SLC6A8 high expressed TNBC.

Abstract Understanding cell-type-specific gene regulatory mechanisms from genetic variants to diseases remains challenging. To address this, we developed a computational pipeline, scGRNom (single-cell Gene Regulatory Network prediction from multi-omics), to predict cell-type disease genes and regulatory networks including transcription factors and regulatory elements. With applications to schizophrenia and Alzheimer’s disease, we predicted disease genes and regulatory networks for excitatory and inhibitory neurons, microglia, and oligodendrocytes. Further enrichment analyses revealed cross-disease and disease-specific functions and pathways at the cell-type level. Our machine learning analysis also found that cell-type disease genes improved clinical phenotype predictions. scGRNom is a general-purpose tool available at https://github.com/daifengwanglab/scGRNom .

The low-frequency disturbances transmitted by flexible cables are difficult to be attenuated for a novel disturbance-free payload spacecraft, which decreases the payload’s pointing accuracy and stability. In this research, a new spacecraft configuration with a high-precision inertial reference unit composed of capacitive sensors and a spherical test mass is proposed. The disturbance attenuation and pointing control system is subdivided into four interconnected control loops. The payload can be isolated from disturbances in the all-frequency band by the active vibration isolation control loop and the drag-free control loops, and its high-precision pointing requirement can be satisfied with the attitude pointing control loop and the attitude tracking control loop. An integrated control strategy is proposed, and the control system is decoupled into 12 single-input single-output control loops by pre-compensating, which lays the foundation for feedback design. Through the amplitude-frequency response analysis, the control bandwidth is designed according to the Proportional-Integral-Differentive control algorithm. The numerical simulations show that the disturbance attenuation performance is better than −20 dB in the all-frequency band, and the pointing accuracy and the pointing stability are better than 10−6 deg and 10−7 deg/s, respectively. The new spacecraft configuration and the disturbance attenuation and pointing control system provide a general technical solution for payloads with high-precision and high-stability requirements.

Acute myeloid leukemia (AML) is usually associated with poor prognosis and low complete remission (CR) rate due to individual biological heterogeneity. Pyroptosis is a special form of inflammatory programmed cell death related to the progression, treatment response, and prognosis of multiple tumors. However, the potential connection of pyroptosis-related genes (PRGs) and AML still remains unclear. We described the genetic and transcriptional alterations of PRGs in 151 AML samples and presented a consensus clustering of these patients into two subtypes with distinct immunological and prognostic characteristics. Cluster A, associated with better prognosis, was characterized by relatively lower PRG expression, activated immune cells, higher immune scores in the tumor microenvironment (TME), and downregulation of immunotherapy checkpoints. Subsequently, a PRG score was constructed to predict overall survival (OS) of AML patients by using univariate and multivariate Cox regression analysis, and its immunological characteristics and predictive capability were further validated by 1,054 AML samples in external datasets. Besides an immune-activated status, low-PRG score cohorts exhibited higher chemotherapeutic drug sensitivity and significant positive correlation with the cancer stem cell (CSC) index. Combined with age, clinical French-American-British (FAB) subtypes, and PRG score, we successfully constructed a nomogram to effectively predict the 1-/3-/5-year survival rate of AML patients, and the predictive capability was further validated in multiple external datasets with a high area under the curve (AUC) value. The various transcriptomic analysis helps us screen significant pyroptosis-related signatures of AML and provide a new clinical application of PRG scores in predicting the prognosis and benefits of treatment for AML patients.

Objective: To investigate the characteristics and predictive roles of lymphocyte subsets in COVID-19 patients. Method: We evaluated lymphocyte subsets and other clinical features of COVID-19 patients, and analyzed their potential impacts on COVID-19 outcomes. Results: 1. Lymphocyte subset counts in the peripheral blood of patients with COVID-19 were significantly reduced, especially in patients with severe disease. 2. In patients with non-severe disease, the time from symptom onset to hospital admission was positively correlated with total T cell counts. 3. Among COVID-19 patients who did not reach the composite endpoint, lymphocyte subset counts were higher than in patients who had reached the composite endpoint. 4. The Kaplan-Meier survival curves showed significant differences in COVID-19 patients, classified by the levels of total, CD8+, and CD4+ T cells at admission. Conclusion: Our study showed that total, CD8+, and CD4+ T cell counts in patients with COVID-19 were significantly reduced, especially in patients with severe disease. Lower T lymphocyte subsets were significantly associated with a higher occurrence of composite endpoint events. These subsets may help identify patients with a high risk of composite endpoint events.

Objective: In this study, we aimed to develop an amino-terminal fragment (ATF) peptide-targeted liposome carrying β-elemene (ATF24-PEG-Lipo-β-E) for targeted delivery into urokinase plasminogen activator receptor-overexpressing bladder cancer cells combined with cisplatin (DDP) for bladder cancer treatment. Methods: The liposomes were prepared by ethanol injection and high-pressure microjet homogenization. The liposomes were characterized, and the drug content, entrapment efficiency, and in vitro release were studied. The targeting efficiency was investigated using confocal microscopy, ultra-fast liquid chromatography, and an orthotopic bladder cancer model. The effects of ATF24-PEG-Lipo-β-E combined with DDP on cell viability and proliferation were evaluated by a Cell Counting Kit-8 (CCK-8) assay, a colony formation assay, and cell apoptosis and cell cycle analyses. The anticancer effects were evaluated in a KU-19-19 bladder cancer xenograft model. Results: ATF24-PEG-Lipo-β-E had small and uniform sizes (˜79 nm), high drug loading capacity (˜5.24 mg/mL), high entrapment efficiency (98.37 ± 0.95%), and exhibited sustained drug release behavior. ATF24-PEG-Lipo-β-E had better targeting efficiency and higher cytotoxicity than polyethylene glycol (PEG)ylated β-elemene liposomes (PEG-Lipo-β-E). DDP, combined with ATF24-PEG-Lipo-β-E, exerted a synergistic effect on cellular apoptosis and cell arrest at the G2/M phase, and these effects were dependent on the caspase-dependent pathway and Cdc25C/Cdc2/cyclin B1 pathways. Furthermore, the in vivo antitumor activity showed that the targeted liposomes effectively inhibited the growth of tumors, using the combined strategy. Conclusions: The present study provided an effective strategy for the targeted delivery of β-elemene (β-E) to bladder cancer, and a combined strategy for bladder cancer treatment.

PURPOSE: In contrast to other studies, our previous study showed that adding induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) significantly worsened the prognosis of patients with stage II nasopharyngeal carcinoma (NPC). However, the population used was small; therefore, there is an urgent need to confirm the result in a larger population because IC is still widely used in certain sections of china for stage II NPC. METHODS AND MATERIALS: We retrospectively analyzed an additional 272 patients. Therefore, in total, we report the results for 445 patients with stage II NPC treated with IC + CCRT or CCRT between June 2003 to June 2016 at the Zhejiang Cancer Hospital and Sun Yat-Sen University Cancer Center. RESULTS: This study included 445 patients treated with IC + CCRT (n = 195) or CCRT (n = 250). By last analysis, 22 (11.3%) patients in the IC + CCRT group developed local-regional recurrence and 23 (11.8%) patients developed distant metastases. Twenty-four (9.6%) patients in the CCRT group developed local-regional recurrence and 12 (4.8%) patients developed distant metastases. Univariate analyses showed that adding IC to CCRT significantly decreased the 5-year disease-free survival (DFS) (80.6% vs. 88.5%, P = .043); however, there was no statistically significant difference in 5-year overall survival (OS) (90.5% vs. 95.0%, P = .375). CONCLUSION: Using a larger population, the present study showed that adding IC to CCRT had a negative effect on patients with stage II NPC, which warrants further investigation.

BackgroundNumerous preclinical studies have revealed the complex regulatory mechanisms between anti-angiogenesis and immune inhibition in the tumor immune microenvironment and have proposed the efficacy of combined immunotherapy and anti-angiogenic treatment. Moreover, the combination strategy had been confirmed in a number of clinical trials. In this study, we aimed to evaluate the safety and efficacy of this combination strategy in recurrent/metastatic head and neck squamous cell carcinoma.MethodsIn this real-world study, 43 patients who received the combination of programmed cell death protein 1 (PD-1) inhibitors and anti-vascular endothelial growth factor (VEGF) agents in Zhejiang cancer hospitals between March 2019 and December 2020 were reviewed. Clinical characteristics and follow-up data were collected, and the preliminary efficacy and safety of the combination therapy were assessed.ResultsThe median follow-up time was 12.4 months (range, 3.7-25.3 months), and the follow-up rate was 100%. The median duration of exposure was 9.5 months. Thirty-seven patients (86.0%) reported treatment-related adverse events (TRAEs) of any grade. The most frequently reported events were fatigue, decreased appetite, and hypertension. Grade 3 TRAEs occurred in 8 patients (18.6%), and no grade 4 or 5 TRAEs occurred. Twenty-four patients (55.9%) had an overall response to treatment: 6 (14.0%) had a complete response and 18 (41.9%) had a partial response. In addition, 5 (11.6%) patients had stable disease, and the disease control rate 12 was 67.4%. The median time to response was 1.6 months (range, 1.1-2.8 months). The median progression-free survival (PFS) was not reached, and the 1-year PFS rate was 69.1%. The 1-year overall survival (OS) rate was 87.7%. Patients with primary tumors located in the nasopharynx had better OS than those with tumors outside the nasopharynx. ECOG PS were related to PFS; patients with an ECOG PS of 0 had a slight survival advantage.ConclusionThe combination strategy of anti–PD-1 monoclonal antibodies and anti-VEGF agents was tolerable in patients with recurrent/metastatic head and neck cancer. This treatment exhibited antitumor potential despite the heavily pretreated population.