Peering through the hedge: Multiple datasets yield insights into the phylogenetic relationships and incongruences in the tribe Lilieae (Liliaceae).

The increasing use of genome-scale data has significantly facilitated phylogenetic analyses, contributing to the dissection of the underlying evolutionary mechanisms that shape phylogenetic incongruences, such as incomplete lineage sorting (ILS) and hybridization. Lilieae, a prominent member of the Liliaceae family, comprises four genera and approximately 260 species, representing 43% of all species within Liliaceae. They possess high ornamental, medicinal and edible values. Yet, no study has explored the validity of various genome-scale data in phylogenetic analyses within this tribe, nor have potential evolutionary mechanisms underlying its phylogenetic incongruences been investigated. Here, transcriptome, Angiosperms353, plastid and mitochondrial data, were collected from 50 to 93 samples of Lilieae, covering all four recognized genera. Multiple datasets were created and used for phylogenetic analyses based on concatenated and coalescent-based methods. Evolutionary rates of different datasets were calculated, and divergence times were estimated. Various approaches, including coalescence simulation, Quartet Sampling (QS), calculation of concordance factors (gCF and sCF), as well as MSCquartets and reticulate network inference, were carried out to infer the phylogenetic discordances and analyze their underlying mechanisms using a reduced 33-taxon dataset. Despite extensive phylogenetic discordances among gene trees, robust phylogenies were inferred from nuclear and plastid data compared to mitochondrial data, with lower synonymous substitution detected in mitochondrial genes than in nuclear and plastid genes. Significant ILS was detected across the phylogeny of Lilieae, with clear evidence of reticulate evolution identified. Divergence time estimation indicated that most of lineages in Lilieae diverged during a narrow time frame (ranging from 5.0 Ma to 10.0 Ma), consistent with the notion of rapid radiation evolution. Our results suggest that integrating transcriptomic and plastid data can serve as cost-effective and efficient tools for phylogenetic inference and evolutionary analysis within Lilieae, and Angiosperms353 data is also a favorable choice. Mitochondrial data are more suitable for phylogenetic analyses at higher taxonomic levels due to their stronger conservation and lower synonymous substitution rates. Significant phylogenetic incongruences detected in Lilieae were caused by both incomplete lineage sorting (ILS) and reticulate evolution, with hybridization and "ghost introgression" likely prevalent in the evolution of Lilieae species. Our findings provide new insights into the phylogeny of Lilieae, enhancing our understanding of the evolution of species in this tribe.

[Risk factors for initial non-invasive ventilation failure in very low birth weight infants with gestational age <32 weeks: a multicenter retrospective study]. / 胎龄<32å‘¨æžä½Žå‡ºç”Ÿä½“é‡å„¿åˆå§‹æ— åˆ›é€šæ°”å¤±è´¥çš„å½±å“å› ç´ åˆ†æžï¼šä¸€é¡¹å¤šä¸­å¿ƒå›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To investigate the risk factors and adverse prognosis associated with initial non-invasive ventilation (NIV) failure in very low birth weight infants (VLBWI) with gestational age <32 weeks. METHODS: A retrospective collection of clinical data from preterm infants admitted to the neonatal intensive care unit (NICU) in 28 tertiary hospitals in Jiangsu Province from January 2019 to December 2021 was conducted. Based on the outcomes of initial NIV, the infants were divided into a successful group and a failure group to analyze the risk factors for NIV failure and adverse prognosis. RESULTS: A total of 817 infants were included, with 453 males (55.4%) and 139 failures (17.0%). The failure group had lower gestational age, birth weight, and 1-minute and 5-minute Apgar scores compared to the successful group (P<0.05). The failure group also had a higher proportion of respiratory distress syndrome (RDS) diagnosed upon NICU admission, higher maximum positive end-expiratory pressure during NIV, and higher percentages of reaching the required maximum fraction of inspired oxygen (FiO2) ≥30%, ≥35%, and ≥40% throughout the initial NIV process compared to the successful group (P<0.05). Gestational age (OR=0.671, 95%CI: 0.581-0.772), RDS (OR=1.955, 95%CI: 1.181-3.366), and FiO2 ≥30% (OR=2.053, 95%CI: 1.106-4.044) were identified as risk factors for initial NIV failure in these infants with gestational age <32 weeks (P<0.05). The failure group had higher incidences of complications such as pulmonary infections, pneumothorax, retinopathy of prematurity, moderate to severe bronchopulmonary dysplasia, and severe intraventricular hemorrhage during hospitalization, as well as longer hospital stays and higher total costs compared to the successful group (P<0.05). CONCLUSIONS: Smaller gestational age, a diagnosis of RDS in the NICU, and achieving a maximum FiO2 ≥30% during the initial NIV process are risk factors for initial NIV failure in infants with gestational age <32 weeks. Initial NIV failure significantly increases the risk of adverse outcomes in this population.

A nomogram to predict the risk of death during hospitalization in Chinese neonates with respiratory failure.

Background: Neonatal respiratory failure (NRF) is a critical condition with high morbidity and mortality rates. This study aimed to develop a nomogram prediction model to early predict the risk of death in Chinese neonates with NRF. Methods: A retrospective analysis was conducted on NRF neonates from 21 tertiary neonatal intensive care units (NICUs) across 13 prefecture-level cities in Jiangsu Province, China, from March 2019 to March 2022. NRF neonates from one random NICU were selected as the external validation set, while those from the remaining 20 NICUs were divided into the training set and the internal validation set at a 7:3 ratio. Death was the primary outcome. LASSO regression and multivariate logistic regression were used to identify the predictive factors from the training set and then the nomogram was constructed. Results: A total of 5387 neonates with NRF were included in the analysis. Among them, 3444 were in the training set, 1470 were in the internal validation set, and 473 were in the external validation set. The nomogram was constructed based on the eight predictors of the 1-min Apgar score, birth weight, gestational age, the relationship between birth weight and gestational age, mode of first respiratory support, inhaled nitric oxide, antenatal corticosteroids, and vasoactive drugs. The area under the curve of the nomogram in the training set, internal validation set, and external validation set was 0.763, 0.733, and 0.891, respectively. The P-values of the Hosmer-Lemeshow goodness of fit test were 0.638, 0.273, and 0.253, respectively. Brier scores were 0.066, 0.072, and 0.037, respectively. The decision curve analysis demonstrated a significant net benefit in all cases. These data indicate the good performance of the nomogram. Conclusions: This nomogram can serve as a reference for clinicians to identify high-risk neonates early and reduce the incidence of neonatal mortality.

One step toward precision dosing of caffeine in preterm infants: An external evaluation of published population pharmacokinetic models.

BACKGROUND: Several population pharmacokinetic (PopPK) models of caffeine in preterm infants have been published, but the extrapolation of these models to facilitate model-informed precision dosing (MIPD) in clinical practice is uncertain. This study aimed to comprehensively evaluate their predictive performance using an external, independent dataset. METHODS: Data used for external evaluation were based on an independent cohort of preterm infants. Currently available PopPK models for caffeine in preterm infants were identified and re-established. Prediction- and simulation-based diagnostics were used to assess model predictability. The influence of prior information was assessed using Bayesian forecasting. RESULTS: 120 plasma samples from 76 preterm infants were included in the evaluation dataset. Twelve PopPK models of caffeine in preterm infants were re-established based on our previously published study. Although two models showed superior predictive performance, none of the 12 PopPK models met all the clinical acceptance criteria of these external evaluation items. Besides, the external predictive performances of most models were unsatisfactory in prediction- and simulation-based diagnostics. Nevertheless, the application of Bayesian forecasting significantly improved the predictive performance, even with only one prior observation. CONCLUSIONS: Two models that included the most covariates had the best predictive performance across all external assessments. Inclusion of different covariates, heterogeneity of preterm infant characteristics, and different study designs influenced predictive performance. Thorough evaluation is needed before these PopPK models can be implemented in clinical practice. The implementation of MIPD for caffeine in preterm infants could benefit from the combination of PopPK models and Bayesian forecasting as a helpful tool.

HADH suppresses clear cell renal cell carcinoma progression through reduced NRF2-dependent glutathione synthesis.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a serious threat to human life. It is very important to clarify the pathogenesis of ccRCC. In this study we evaluated the clinical value of HADH and explored its role and mechanism in the malignant progression of ccRCC. METHODS: HADH expression and its relationship with prognosis were analyzed using bioinformatics database. RT-PCR, Western blot and immunohistochemistry were used to examine the expression of HADH in ccRCC tissues and tissue microarrays. To examine the cell proliferation, apoptosis, migration and invasion ability, ccRCC cells with HADH overexpressed were constructed. Xenograft experiments were performed to determine the role of HADH. Non-target metabolomics was applied to explore the potential metabolic pathway by which HADH inhibited ccRCC progression. Plasmid pcDNA3.1-NRF2 was used to confirm whether HADH inhibited the process of ccRCC cells through NRF2-related glutathione (GSH) synthesis. RESULTS: Bioinformatics database analysis showed that HADH expression was significantly decreased in ccRCC tissues, and its low expression predicted a poor prognosis. Both ccRCC tissues and tissue microarrays exhibited a significantly decreased HADH level compared with adjacent normal renal tissues. HADH overexpression inhibited the malignant behaviors of ccRCC cells. Furthermore, HADH overexpression attenuated GSH synthesis and induced oxidative stress damage. Exogenously increased NRF2 effectively attenuated the inhibitive effect of HADH overexpression on ccRCC cells. CONCLUSION: Our data revealed that HADH suppressed the malignant behaviors of ccRCC cells by attenuating GSH synthesis through inhibition of NRF2 nuclear translocation, and HADH might be a novel therapeutic target for ccRCC treatment.

Genome-wide survey of KT/HAK/KUP genes in the genus Citrullus and analysis of their involvement in K+-deficiency and drought stress responses in between C. lanatus and C. amarus.

BACKGROUND: The KT/HAK/KUP is the largest K+ transporter family in plants, playing crucial roles in K+ absorption, transport, and defense against environmental stress. Sweet watermelon is an economically significant horticultural crop belonging to the genus Citrullus, with a high demand for K+ during its growth process. However, a comprehensive analysis of the KT/HAK/KUP gene family in watermelon has not been reported. RESULTS: 14 KT/HAK/KUP genes were identified in the genomes of each of seven Citrullus species. These KT/HAK/KUPs in watermelon were unevenly distributed across seven chromosomes. Segmental duplication is the primary driving force behind the expansion of the KT/HAK/KUP family, subjected to purifying selection during domestication (Ka/Ks < 1), and all KT/HAK/KUPs exhibit conserved motifs and could be phylogenetically classified into four groups. The promoters of KT/HAK/KUPs contain numerous cis-regulatory elements related to plant growth and development, phytohormone response, and stress response. Under K+ deficiency, the growth of watermelon seedlings was significantly inhibited, with cultivated watermelon experiencing greater impacts (canopy width, redox enzyme activity) compared to the wild type. All KT/HAK/KUPs in C. lanatus and C. amarus exhibit specific expression responses to K+-deficiency and drought stress by qRT-PCR. Notably, ClG42_07g0120700/CaPI482276_07g014010 were predominantly expressed in roots and were further induced by K+-deficiency and drought stress. Additionally, the K+ transport capacity of ClG42_07g0120700 under low K+ stress was confirmed by yeast functional complementation assay. CONCLUSIONS: KT/HAK/KUP genes in watermelon were systematically identified and analyzed at the pangenome level and provide a foundation for understanding the classification and functions of the KT/HAK/KUPs in watermelon plants.

Genome-wide characterization of DELLA gene family in blueberry (Vaccinium darrowii) and their expression profiles in development and response to abiotic stress.

BACKGROUND: The DELLA proteins, a class of GA signaling repressors, belong to the GRAS family of plant-specific nuclear proteins. Members of DELLA gene family encode transcriptional regulators with diverse functions in plant development and abiotic stress responses. To date, DELLAs have been identified in various plant species, such as Arabidopsis thaliana, Malus domestica, Populus trichocarpa, and other land plants. Most information of DELLA family genes was obtained from A. thaliana, whereas little is known about the DELLA gene family in blueberry. RESULTS: In this study, we identified three DELLA genes in blueberry (Vaccinium darrowii, VdDELLA) and provided a complete overview of VdDELLA gene family, describing chromosome localization, protein properties, conserved domain, motif organization, and phylogenetic analysis. Three VdDELLA members, containing two highly conserved DELLA domain and GRAS domain, were distributed across three chromosomes. Additionally, cis-acting elements analysis indicated that VdDELLA genes might play a critical role in blueberry developmental processes, hormone, and stress responses. Expression analysis using quantitative real-time PCR (qRT-PCR) revealed that all of three VdDELLA genes were differentially expressed across various tissues. VdDELLA2 was the most highly expressed VdDELLA in all denoted tissues, with a highest expression in mature fruits. In addition, all of the three VdDELLA genes actively responded to diverse abiotic stresses. Based on qRT-PCR analysis, VdDELLA2 might act as a key regulator in V. darrowii in response to salt stress, whereas VdDELLA1 and VdDELLA2 might play an essential role in cold stress response. Under drought stress, all of three VdDELLA genes were involved in mediating drought response. Furthermore, their transiently co-localization with nuclear markers in A. thaliana protoplasts demonstrated their transcriptional regulator roles. CONCLUSIONS: In this study, three VdDELLA genes were identified in V. darrowii genome. Three VdDELLA genes were closely related to the C. moschata DELLA genes, S. lycopersicum DELLA genes, and M. domestica DELLA genes, respectively, indicating their similar biological functions. Expression analysis indicated that VdDELLA genes were highly efficient in blueberry fruit development. Expression patterns under different stress conditions revealed the differentially expressed VdDELLA genes responding to salt, drought, and cold stress. Overall, these results enrich our understanding of evolutionary relationship and potential functions of VdDELLA genes, which provide valuable information for further studies on genetic improvement of the plant yield and plant resistance.

OsSNDP4, a Sec14-nodulin Domain Protein, is Required for Pollen Development in Rice.

Pollen is encased in a robust wall that shields the male gametophyte from various stresses and aids in pollination. The pollen wall consists of gametophyte-derived intine and sporophyte-derived exine. The exine is mainly composed of sporopollenin, which is biopolymers of aliphatic lipids and phenolics. The process of exine formation has been the subject of extensive research, yet the underlying molecular mechanisms remain elusive. In this study, we identified a rice mutant of the OsSNDP4 gene that is impaired in pollen development. We demonstrated that OsSNDP4, a putative Sec14-nodulin domain protein, exhibits a preference for binding to phosphatidylinositol (3)-phosphate [PI(3)P], a lipid primarily found in endosomal and vacuolar membranes. The OsSNDP4 protein was detected in association with the endoplasmic reticulum (ER), vacuolar membranes, and the nucleus. OsSNDP4 expression was detected in all tested organs but was notably higher in anthers during exine development. Loss of OsSNDP4 function led to abnormal vacuole dynamics, inhibition in Ubisch body development, and premature degradation of cellular contents and organelles in the tapetal cells. Microspores from the ossndp4 mutant plant displayed abnormal exine formation, abnormal vacuole enlargement, and ultimately, pollen abortion. RNA-seq assay revealed that genes involved in the biosynthesis of fatty acid and secondary metabolites, the biosynthesis of lipid polymers, and exosome formation were enriched among the down-regulated genes in the mutant anthers, which correlated with the morphological defects observed in the mutant anthers. Base on these findings, we propose that OsSNDP4 regulates pollen development by binding to PI(3)P and influencing the dynamics of membrane systems. The involvement of membrane systems in the regulation of sporopollenin biosynthesis, Ubisch body formation, and exine formation provides a novel mechanism regulating pollen wall development.

Development and application of a population pharmacokinetic model repository for caffeine dose tailoring in preterm infants.

BACKGROUND: Considerable interindividual variability for the pharmacokinetics of caffeine in preterm infants has been demonstrated, emphasizing the importance of personalized dosing. This study aimed to develop and apply a repository of currently published population pharmacokinetic (PopPK) models of caffeine in preterm infants to facilitate model-informed precision dosing (MIPD). RESEARCH DESIGN AND METHODS: Literature search was conducted using PubMed, Embase, Scopus, and Web of Science databases. Relevant publications were screened, and their quality was assessed. PopPK models were reestablished to develop the model repository. Covariate effects were evaluated and the concentration-time profiles were simulated. An online simulation and calculation tool was developed as an instance. RESULTS: Twelve PopPK models were finally included in the repository. Preterm infants' age and body size, especially the postnatal age and current weight, were identified as the most clinically critical covariates. Simulated blood concentration-time profiles across these models were comparable. Caffeine citrate-dose regimen should be adjusted according to the age and body size of preterm infants. The developed online tool can be used to facilitate clinical decision-making. CONCLUSIONS: The first developed repository of PopPK models for caffeine in preterm infants has a wide range of potential applications in the MIPD of caffeine.

MicroRNA-128-3p Affects Neuronal Apoptosis and Neurobehavior in Cerebral Palsy Rats by Targeting E3 Ubiquitin-Linking Enzyme Smurf2 and Regulating YY1 Expression.

This study was dedicated to investigating the effects of microRNA-128-3p (miR-128-3p) on neuronal apoptosis and neurobehavior in cerebral palsy (CP) rats via the Smurf2/YY1 axis.In vivo modeling of hypoxic-ischemic (HI) CP was established in neonatal rats. Neurobehavioral tests (geotaxis reflex, cliff avoidance reaction, and grip test) were measured after HI induction. The HI-induced neurological injury was evaluated by HE staining, Nissl staining, TUNEL staining, immunohistochemical staining, and RT-qPCR. The expression of miR-128-3p, Smurf2, and YY1 was determined by RT-qPCR and western blot techniques. Moreover, primary cortical neurons were used to establish the oxygen and glucose deprivation (OGD) model in vitro, cell viability was detected by CCK-8 assay, neuronal apoptosis was assessed by flow cytometry and western blot, and the underlying mechanism between miR-128-3p, Smurf2 and YY1 was verified by bioinformatics analysis, dual luciferase reporter assay, RIP, Co-IP, ubiquitination assay, western blot, and RT-qPCR.In vivo, miR-128-3p and YY1 expression was elevated, and Smurf2 expression was decreased in brain tissues of hypoxic-ischemic CP rats. Downregulation of miR-128-3p or overexpression of Smurf2 improved neurobehavioral performance, reduced neuronal apoptosis, and elevated Nestin and NGF expression in hypoxic-ischemic CP rats, and downregulation of Smurf2 reversed the effects of downregulation of miR-128-3p on neurobehavioral performance, neuronal apoptosis, and Nestin and NGF expression in hypoxic-ischemic CP rats, while overexpression of YY1 reversed the effects of Smurf2 on neurobehavioral performance, neuronal apoptosis, and Nestin and NGF expression in hypoxic-ischemic CP rats. In vitro, downregulation of miR-128-3p effectively promoted the neuronal survival, reduced the apoptosis rate, and decreased caspase3 protein expression after OGD, and overexpression of YY1 reversed the ameliorative effect of downregulation of miR-128-3p on OGD-induced neuronal injury. miR-128-3p targeted to suppress Smurf2 to lower YY1 ubiquitination degradation and decrease its expression.Inhibition of miR-128-3p improves neuronal apoptosis and neurobehavioral changes in hypoxic-ischemic CP rats by promoting Smurf2 to promote YY1 ubiquitination degradation and reduce YY1 expression.

Establishment and Validation of a Risk Prediction Model for Non-Invasive Ventilation Failure After Birth in Premature Infants with Gestational Age < 32 Weeks.

OBJECTIVES: This study was performed to construct and validate a risk prediction model for non-invasive ventilation (NIV) failure after birth in premature infants with gestational age < 32 weeks. METHODS: The data were derived from the multicenter retrospective study program - Jiangsu Provincial Neonatal Respiratory Failure Collaboration Network from Jan 2019 to Dec 2021. The subjects finally included were preterm infants using NIV after birth with gestational age less than 32 weeks and admission age within 72 h. After screening by inclusion and exclusion criteria, 1436 babies were subsequently recruited in the study, including 1235 infants in the successful NIV group and 201 infants in the failed NIV group. RESULTS: (1) Gestational age, 5 min Apgar, Max FiO2 during NIV, and FiO2 fluctuation value during NIV were selected by univariate and multivariate analysis. (2) The area under the curve of the prediction model was 0.807 (95% CI: 0.767-0.847) in the training set and 0.825 (95% CI: 0.766-0.883) in the test set. The calibration curve showed good agreement between the predicted probability and the actual observed probability (Mean absolute error = 0.008 for the training set; Mean absolute error = 0.012 for the test set). Decision curve analysis showed good clinical validity of the risk model in the training and test cohorts. CONCLUSION: This model performed well on dimensions of discrimination, calibration, and clinical validity. This model can serve as a useful tool for neonatologists to predict whether premature infants will experience NIV failure after birth.

Safety assessment of sildenafil use in neonates: a real-world data analysis based on the FDA adverse event reporting system (FAERS).

BACKGROUND: The safety of neonatal sildenafil use remains uncertain. This study aimed to investigate adverse events (AEs) associated with sildenafil use in neonates. RESEARCH DESIGN AND METHODS: We collected data on AEs associated with sildenafil use in neonates from the US Food and Drug Administration Adverse Event Reporting System database, spanning from its inception of the database in 2004 to 2023. Disproportionality measures were employed to analyze the correlation between AEs and sildenafil. RESULTS: Sildenafil was identified as the primary suspect drug in 75 AE reports, involving 214 AEs. Three system organ classes, namely, eye disorders, hepatobiliary disorders, and vascular disorders were associated with sildenafil use. Six preferred terms, namely, flushing, retinopathy of prematurity, hyperbilirubinemia, pulmonary hemorrhage, hypotension, and diarrhea were associated with sildenafil use. Notably, hyperbilirubinemia and pulmonary hemorrhage were previously unreported AEs associated with sildenafil use. CONCLUSION: The results highlight the ongoing uncertainty surrounding the safety of neonatal sildenafil use and provide vital support for risk monitoring and identification in neonates receiving sildenafil. Additionally, the study underscores the need for continuous safety surveillance in neonates treated with sildenafil and suggests further exploration of the precise causal relationships between AEs and sildenafil.

An AIE-active tetra-aryl imidazole-derived chemodosimeter for turn-on recognition of hydrazine and its bioimaging in living cells.

A new chemodosimeter SWJT-31 with an aggregation-induced emission (AIE) effect was designed and constructed. Upon increasing the water fraction in the solution, it exhibited typical AIE, which showed bright red fluorescence at 610 nm. SWJT-31 could sensitively and specifically recognize hydrazine by the TICT effect with an LOD of 33.8 nM, which was much lower than the standard of the USEPA. A portable test strip prepared using SWJT-31 was also developed for the visual detection of hydrazine. Eventually, it was successfully used for the detection of hydrazine in water samples and HeLa cells.

Regulation of anthocyanin synthesis in red lettuce in plant factory conditions: A review.

Anthocyanins, natural pigments known for their vibrant hues and beneficial properties, undergo intricate genetic control. However, red vegetables grown in plant factories frequently exhibit reduced anthocyanin synthesis compared to those in open fields due to factors like inadequate light, temperature, humidity, and nutrient availability. Comprehending these factors is essential for optimizing plant factory environments to enhance anthocyanin synthesis. This review insights the impact of physiological and genetic factors on the production of anthocyanins in red lettuce grown under controlled conditions. Further, we aim to gain a better understanding of the mechanisms involved in both synthesis and degradation of anthocyanins. Moreover, this review summarizes the identified regulators of anthocyanin synthesis in lettuce, addressing the gap in knowledge on controlling anthocyanin production in plant factories, with potential implications for various crops beyond red lettuce.

Neoadjuvant immunochemotherapy improves clinical outcomes of patients with esophageal cancer by mediating anti-tumor immunity of CD8+ T (Tc1) and CD16+ NK cells.

Background: Esophageal cancer (ESCA) is one of the most common tumors in the world, and treatment using neoadjuvant therapy (NT) based on radiotherapy and/or chemotherapy has still unsatisfactory results. Neoadjuvant immunochemotherapy (NICT) has also become an effective treatment strategy nowadays. However, its impact on the tumor microenvironment (TME) and regulatory mechanisms on T cells and NK cells needs to be further elucidated. Methods: A total of 279 cases of ESCA who underwent surgery alone [non-neoadjuvant therapy (NONE)], neoadjuvant chemotherapy (NCT), and NICT were collected, and their therapeutic effect and survival period were compared. Further, RNA sequencing combined with biological information was used to analyze the expression of immune-related genes. Immunohistochemistry, immunofluorescence, and quantitative real-time PCR (qRT-PCR) were used to verify the activation and infiltration status of CD8+ T and CD16+ NK cells, as well as the function and regulatory pathway of killing tumor cells. Results: Patients with ESCA in the NICT group showed better clinical response, median survival, and 2-year survival rates (p < 0.05) compared with the NCT group. Our RNA sequencing data revealed that NICT could promote the expression of immune-related genes. The infiltration and activation of immune cells centered with CD8+ T cells were significantly enhanced. CD8+ T cells activated by PD-1 inhibitors secreted more IFN-γ and cytotoxic effector factor cells through the transcription factor of EOMES and TBX21. At the same time, activated CD8+ T cells mediated the CD16+ NK cell activation and secreted more IFN-γ to kill ESCA cells. In addition, the immunofluorescence co-staining results showed that more CD276+ tumor cells and CD16+ NK cells were existed in pre-NCT and pre-NICT group. However, CD276+ tumor cells were reduced significantly in the post-NICT group, while they still appeared in the post-NCT group, which means that CD16+ NK cells can recognize and kill CD276+ tumor cells after immune checkpoint blocker (ICB) treatment. Conclusion: NICT can improve the therapeutic effect and survival period of resectable ESCA patients. NICT could promote the expression of immune-related genes and activate CD8+ T and CD16+ NK cells to secrete more IFN-γ to kill ESCA cells. It provides a theoretical basis and clinical evidence for its potential as an NT strategy in ESCA.

Differentiation of glioma and solitary brain metastasis: a multi-parameter magnetic resonance imaging study using histogram analysis.

BACKGROUND: Differentiation of glioma and solitary brain metastasis (SBM), which requires biopsy or multi-disciplinary diagnosis, remains sophisticated clinically. Histogram analysis of MR diffusion or molecular imaging hasn't been fully investigated for the differentiation and may have the potential to improve it. METHODS: A total of 65 patients with newly diagnosed glioma or metastases were enrolled. All patients underwent DWI, IVIM, and APTW, as well as the T1W, T2W, T2FLAIR, and contrast-enhanced T1W imaging. The histogram features of apparent diffusion coefficient (ADC) from DWI, slow diffusion coefficient (Dslow), perfusion fraction (frac), fast diffusion coefficient (Dfast) from IVIM, and MTRasym@3.5ppm from APTWI were extracted from the tumor parenchyma and compared between glioma and SBM. Parameters with significant differences were analyzed with the logistics regression and receiver operator curves to explore the optimal model and compare the differentiation performance. RESULTS: Higher ADCkurtosis (P = 0.022), frackurtosis (P<0.001),and fracskewness (P<0.001) were found for glioma, while higher (MTRasym@3.5ppm)10 (P = 0.045), frac10 (P<0.001),frac90 (P = 0.001), fracmean (P<0.001), and fracentropy (P<0.001) were observed for SBM. frackurtosis (OR = 0.431, 95%CI 0.256-0.723, P = 0.002) was independent factor for SBM differentiation. The model combining (MTRasym@3.5ppm)10, frac10, and frackurtosis showed an AUC of 0.857 (sensitivity: 0.857, specificity: 0.750), while the model combined with frac10 and frackurtosis had an AUC of 0.824 (sensitivity: 0.952, specificity: 0.591). There was no statistically significant difference between AUCs from the two models. (Z = -1.14, P = 0.25). CONCLUSIONS: The frac10 and frackurtosis in enhanced tumor region could be used to differentiate glioma and SBM and (MTRasym@3.5ppm)10 helps improving the differentiation specificity.

Hyperactivation of mTOR/eIF4E Signaling Pathway Promotes the Production of Tryptophan-To-Phenylalanine Substitutants in EBV-Positive Gastric Cancer.

Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon-γ (IFN-γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine-2,3-dioxygenase (IDO)- kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan-to-phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV-positive GC continuously secreted IFN-γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV-positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV-positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti-tumor immunotherapy.

Trends in the antimicrobial susceptibility among Chinese neonates from 2012 to 2021: a multicenter study.

BACKGROUND: Antibiotic resistance is a serious global public health issue. However, there are few reports on trends in antimicrobial susceptibility in Chinese neonates, and most of the existing evidence has been derived from adult studies. We aimed to assess the trends in antimicrobial susceptibility of common pathogens in full-term neonates with invasive bacterial infections (IBIs) in China. METHODS: This cross-sectional survey study analyzed the antimicrobial susceptibility in Chinese neonates with IBIs from 17 hospitals, spanning from January 2012 to December 2021. Joinpoint regression model was applied to illustrate the trends and calculate the average annual percentage change (AAPC). Using Mantel-Haenszel linear-by-linear association chi-square test, we further compared the antibiotic minimum inhibitory concentrations (MICs) by pathogens between 2019 and 2021 to provide precise estimates of changes. RESULTS: The proportion of Escherichia coli with extended-spectrum-beta-lactamase-negative strains increased from 0.0 to 88.5% (AAPC = 62.4%, 95% confidence interval (CI): 44.3%, 82.9%), with two breakpoints in 2014 and 2018 (p-trend < 0.001). The susceptibility of group B Streptococcus (GBS) to erythromycin and clindamycin increased by 66.7% and 42.8%, respectively (AAPC = 55.2%, 95% CI: 23.2%, 95.5%, p-trend = 0.002; AAPC = 54.8%, 95% CI: 9.6%, 118.6%, p-trend < 0.001), as did Staphylococcus aureus to penicillin (AAPC = 56.2%; 95% CI: 34.8%, 81.0%, p-trend < 0.001). However, the susceptibility of Enterococcus spp. to ampicillin declined from 100.0 to 25.0% (AAPC = - 11.7%, 95% CI: - 15.2%, - 8.1%, p-trend < 0.001), and no significant improvement was observed in the antibiotic susceptibility of Escherichia coli to ampicillin, gentamicin, and cephalosporin. Additionally, the proportion of GBS/Staphylococcus aureus with relatively low MIC values for relevant antibiotics also increased in 2021 compared to 2019. CONCLUSIONS: Antimicrobial susceptibility of the most prevalent pathogens in full-term neonates seemed to have improved or remained stable over the last decade in China, implying the effectiveness of policies and practice of antibiotic stewardship had gradually emerged.

High-brightness betatron emission from the interaction of a sub picosecond laser pulse with pre-ionized low-density polymer foam for ICF research.

Direct laser acceleration (DLA) of electrons in plasmas of near-critical density (NCD) is a very advancing platform for high-energy PW-class lasers of moderate relativistic intensity supporting Inertial Confinement Fusion research. Experiments conducted at the PHELIX sub-PW Nd:glass laser demonstrated application-promising characteristics of DLA-based radiation and particle sources, such as ultra-high number, high directionality and high conversion efficiency. In this context, the bright synchrotron-like (betatron) radiation of DLA electrons, which arises from the interaction of a sub-ps PHELIX laser pulse with an intensity of 1019 W/cm2 with pre-ionized low-density polymer foam, was studied. The experimental results show that the betatron radiation produced by DLA electrons in NCD plasma is well directed with a half-angle of 100-200 mrad, yielding (3.4 ± 0.4)·1010 photons/keV/sr at 10 keV photon energy. The experimental photon fluence and the brilliance agree well with the particle-in-cell simulations. These results pave the way for innovative applications of the DLA regime using low-density pre-ionized foams in high energy density research.