Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation.

N6-methyladenosine (m6A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m6A regulates mammalian brain development is unknown. Here, we show that m6A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m6A depletion by Mettl3 knockdown also leads to a prolonged cell cycle and maintenance of radial glia cells. m6A sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, the cell cycle, and neuronal differentiation, and m6A tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional prepatterning in cortical neural stem cells. m6A signaling also regulates human cortical neurogenesis in forebrain organoids. Comparison of m6A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m6A tagging of transcripts related to brain-disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.

DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity.

The immunoproteasome is a specialized type of proteasome involved in MHC class I antigen presentation, antiviral adaptive immunity, autoimmunity, and is also part of a broader response to stress. Whether the immunoproteasome is regulated by DNA stress, however, is not known. We here demonstrate that mitochondrial DNA stress upregulates the immunoproteasome and MHC class I antigen presentation pathway via cGAS/STING/type I interferon signaling resulting in cell autonomous activation of CD8+ T cells. The cGAS/STING-induced adaptive immune response is also observed in response to genomic DNA and is conserved in epithelial and mesenchymal cells of mice and men. In patients with idiopathic pulmonary fibrosis, chronic activation of the cGAS/STING-induced adaptive immune response in aberrant lung epithelial cells concurs with CD8+ T-cell activation in diseased lungs. Genetic depletion of the immunoproteasome and specific immunoproteasome inhibitors counteract DNA stress induced cytotoxic CD8+ T-cell activation. Our data thus unravel cytoplasmic DNA sensing via the cGAS/STING pathway as an activator of the immunoproteasome and CD8+ T cells. This represents a novel potential pathomechanism for pulmonary fibrosis that opens new therapeutic perspectives.

The MdMYB44-MdTPR1 repressive complex inhibits MdCCD4 and MdCYP97A3 expression through histone deacetylation to regulate carotenoid biosynthesis in apple.

Carotenoids are photosynthetic pigments and antioxidants that contribute to different plant colors. However, the involvement of TOPLESS (TPL/TPR)-mediated histone deacetylation in the modulation of carotenoid biosynthesis through ethylene-responsive element-binding factor-associated amphiphilic repression (EAR)-containing transcription factors (TFs) in apple (Malus domestica Borkh.) is poorly understood. MdMYB44 is a transcriptional repressor that contains an EAR repression motif. In the present study, we used functional analyses and molecular assays to elucidate the molecular mechanisms through which MdMYB44-MdTPR1-mediated histone deacetylation influences carotenoid biosynthesis in apples. We identified two carotenoid biosynthetic genes, MdCCD4 and MdCYP97A3, that were confirmed to be involved in MdMYB44-mediated carotenoid biosynthesis. MdMYB44 enhanced ß-branch carotenoid biosynthesis by repressing MdCCD4 expression, whereas MdMYB44 suppressed lutein level by repressing MdCYP97A3 expression. Moreover, MdMYB44 partially influences carotenoid biosynthesis by interacting with the co-repressor TPR1 through the EAR motif to inhibit MdCCD4 and MdCYP97A3 expression via histone deacetylation. Our findings indicate that the MdTPR1-MdMYB44 repressive cascade regulates carotenoid biosynthesis, providing profound insights into the molecular basis of histone deacetylation-mediated carotenoid biosynthesis in plants. These results also provide evidence that the EAR-harboring TF/TPL repressive complex plays a universal role in histone deacetylation-mediated inhibition of gene expression in various plants.

Abscisic acid activates transcription factor module MdABI5-MdMYBS1 during carotenoid-derived apple fruit coloration.

Carotenoids are major pigments contributing to fruit coloration. We previously reported that the apple (Malus domestica Borkh.) mutant fruits of "Beni Shogun" and "Yanfu 3" show a marked difference in fruit coloration. However, the regulatory mechanism underlying this phenomenon remains unclear. In this study, we determined that carotenoid is the main factor influencing fruit flesh color. We identified an R1-type MYB transcription factor (TF), MdMYBS1, which was found to be highly associated with carotenoids and abscisic acid (ABA) contents of apple fruits. Overexpression of MdMYBS1 promoted, and silencing of MdMYBS1 repressed, ß-branch carotenoids synthesis and ABA accumulation. MdMYBS1 regulates carotenoid biosynthesis by directly activating the major carotenoid biosynthetic genes encoding phytoene synthase (MdPSY2-1) and lycopene ß-cyclase (MdLCYb). 9-cis-epoxycarotenoid dioxygenase 1 (MdNCED1) contributes to ABA biosynthesis, and MdMYBS1 enhances endogenous ABA accumulation by activating the MdNCED1 promoter. In addition, the basic leucine zipper domain TF ABSCISIC ACID-INSENSITIVE5 (MdABI5) was identified as an upstream activator of MdMYBS1, which promotes carotenoid and ABA accumulation. Furthermore, ABA promotes carotenoid biosynthesis and enhances MdMYBS1 and MdABI5 promoter activities. Our findings demonstrate that the MdABI5-MdMYBS1 cascade activated by ABA regulates carotenoid-derived fruit coloration and ABA accumulation in apple, providing avenues in breeding and planting for improvement of fruit coloration and quality.

Differential effects of specific emotions on spatial decision-making: evidence from cross-frequency functionally independent brain networks.

Emotions significantly shape the way humans make decisions. However, the underlying neural mechanisms of this influence remain elusive. In this study, we designed an experiment to investigate how emotions (specifically happiness, fear, and sadness) impact spatial decision-making, utilizing EEG data. To address the inherent limitations of sensor-level investigations previously conducted, we employed standard low-resolution brain electromagnetic tomography and functional independent component analysis to analyze the EEG data at the cortical source level. Our findings showed that across various spectral-spatial networks, positive emotion activated the decision-making network in the left middle temporal gyrus and inferior temporal gyrus, in contrast to negative emotions. We also identified the common spectral-spatial networks and observed significant differences in network strength across emotions. These insights further revealed the important role of the gamma-band prefrontal network. Our research provides a basis for deciphering the roles of brain networks in the impact of emotions on decision-making.

Exploring the interplay between triple-negative breast cancer stem cells and tumor microenvironment for effective therapeutic strategies.

Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic malignancy with poor treatment outcomes. The interaction between the tumor microenvironment (TME) and breast cancer stem cells (BCSCs) plays an important role in the development of TNBC. Owing to their ability of self-renewal and multidirectional differentiation, BCSCs maintain tumor growth, drive metastatic colonization, and facilitate the development of drug resistance. TME is the main factor regulating the phenotype and metastasis of BCSCs. Immune cells, cancer-related fibroblasts (CAFs), cytokines, mesenchymal cells, endothelial cells, and extracellular matrix within the TME form a complex communication network, exert highly selective pressure on the tumor, and provide a conducive environment for the formation of BCSC niches. Tumor growth and metastasis can be controlled by targeting the TME to eliminate BCSC niches or targeting BCSCs to modify the TME. These approaches may improve the treatment outcomes and possess great application potential in clinical settings. In this review, we summarized the relationship between BCSCs and the progression and drug resistance of TNBC, especially focusing on the interaction between BCSCs and TME. In addition, we discussed therapeutic strategies that target the TME to inhibit or eliminate BCSCs, providing valuable insights into the clinical treatment of TNBC.

Integrating bulk and single-cell sequencing data to construct a Scissor+ dendritic cells prognostic model for predicting prognosis and immune responses in ESCC.

Esophageal squamous cell carcinoma (ESCC) is characterized by molecular heterogeneity with various immune cell infiltration patterns, which have been associated with therapeutic sensitivity and resistance. In particular, dendritic cells (DCs) are recently discovered to be associated with prognosis and survival in cancer. However, how DCs differ among ESCC patients has not been fully comprehended. Recently, the advance of single-cell RNA sequencing (scRNA-seq) enables us to profile the cell types, states, and lineages in the heterogeneous ESCC tissues. Here, we dissect the ESCC tumor microenvironment at high resolution by integrating 192,078 single cells from 60 patients, including 4379 DCs. We then used Scissor, a method that identifies cell subpopulations from single-cell data that are associated bulk samples with genomic and clinical information, to stratify DCs into Scissorhi and Scissorlow subtypes. We applied the Scissorhi gene signature to stratify ESCC scRNAseq patient, and we found that PD-L1, TIGIT, PVR and IL6 ligand-receptor-mediated cell interactions existed mainly in Scissorhi patients. Finally, based on the Scissor results, we successfully developed a validated prognostic risk model for ESCC and further validated the reliability of the risk prediction model by recruiting 40 ESCC clinical patients. This information highlights the importance of these genes in assessing patient prognosis and may help in the development of targeted or personalized therapies for ESCC.

Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.

Microglia shape AgRP neuron postnatal development via regulating perineuronal net plasticity.

The hypothalamus plays a crucial role in controlling metabolism and energy balance, with Agouti-related protein (AgRP) neurons and proopiomelanocortin (POMC) neurons being essential components of this process. The proper development of these neurons is important for metabolic regulation in later life. Microglia, the resident immune cells in the brain, have been shown to significantly influence neurodevelopment. However, their role in shaping the postnatal development of hypothalamic neural circuits remains underexplored. In this study, we investigated the dynamic changes of microglia in the hypothalamic arcuate nucleus (ARC) during lactation and their impact on the maturation of AgRP and POMC neurons. We demonstrated that microglial depletion during a critical period of ARC neuron maturation increases the number of AgRP neurons and fiber density, with less effect on POMC neurons. This depletion also resulted in increased neonatal feeding behavior. Mechanistically, microglia can engulf perineuronal net (PNN) components surrounding AgRP neurons both in vivo and ex vivo. The absence of microglia leads to increased PNN formation and enhanced leptin sensitivity in ARC. Our findings suggest that microglia participate in the postnatal development of AgRP neurons by regulating the plasticity of PNN formation. This study contributes to a better understanding of microglia's role in shaping hypothalamic neural circuits during postnatal development and their impact on metabolism regulation.

Clinical profile analysis and nomogram for predicting in-hospital mortality among elderly severe community-acquired pneumonia patients: a retrospective cohort study.

BACKGROUND: Severe community-acquired pneumonia is one of the most lethal forms of CAP with high mortality. For rapid and accurate decisions, we developed a mortality prediction model specifically tailored for elderly SCAP patients. METHODS: The retrospective study included 2365 elderly patients. To construct and validate the nomogram, we randomly divided the patients into training and testing cohorts in a 70% versus 30% ratio. The primary outcome was in-hospital mortality. Univariate and multivariate logistic regression analyses were used in the training cohort to identify independent risk factors. The robustness of this model was assessed using the C index, ROC and AUC. DCA was employed to evaluate the predictive accuracy of the model. RESULTS: Six factors were used as independent risk factors for in-hospital mortality to construct the prediction model, including age, the use of vasopressor, chronic renal disease, neutrophil, platelet, and BUN. The C index was 0.743 (95% CI 0.719-0.768) in the training cohort and 0.731 (95% CI 0.694-0.768) in the testing cohort. The ROC curves and AUC for the training cohort and testing cohort (AUC = 0.742 vs. 0.728) indicated a robust discrimination. And the calibration plots showed a consistency between the prediction model probabilities and observed probabilities. Then, the DCA demonstrated great clinical practicality. CONCLUSIONS: The nomogram incorporated six risk factors, including age, the use of vasopressor, chronic renal disease, neutrophil, platelet and BUN, which had great predictive accuracy and robustness, while also demonstrating clinical practicality at ICU admission.

Curcumol Attenuates Portal Hypertension and Collateral Shunting Via Inhibition of Extrahepatic Angiogenesis in Cirrhotic Rats.

Liver cirrhosis can cause disturbances in blood circulation in the liver, resulting in impaired portal blood flow and ultimately increasing portal venous pressure. Portal hypertension induces portal-systemic collateral formation and fatal complications. Extrahepatic angiogenesis plays a crucial role in the development of portal hypertension. Curcumol is a sesquiterpenoid derived from the rhizome of Curcumae Rhizoma and has been confirmed to alleviate liver fibrosis by inhibiting angiogenesis. Therefore, our study was designed to explore the effects of curcumol on extrahepatic angiogenesis and portal hypertension. To induce cirrhosis, Sprague Dawley rats underwent bile duct ligation (BDL) surgery. Rats received oral administration with curcumol (30 mg/kg/d) or vehicle (distilled water) starting on day 15 following surgery, when BDL-induced liver fibrosis had developed. The effect of curcumol was assessed on day 28, which is the typical time of BDL-induced cirrhosis. The results showed that curcumol markedly reduced portal pressure in cirrhotic rats. Curcumol inhibited abnormal splanchnic inflow, mitigated liver injury, improved liver fibrosis, and attenuated portal-systemic collateral shunting in cirrhotic rats. These protective effects were partially attributed to the inhibition on mesenteric angiogenesis by curcumol. Mechanically, curcumol partially reversed the BDL-induced activation of the JAK2/STAT3 signaling pathway in cirrhotic rats. Collectively, curcumol attenuates portal hypertension in liver cirrhosis by suppressing extrahepatic angiogenesis through inhibiting the JAK2/STAT3 signaling pathway.

Relationship between readiness for interprofessional learning and academic self-efficacy among nursing students: a cross-sectional study.

BACKGROUND: Modern medicine emphasizes that medical professionals engage in interprofessional collaboration to better meet the diverse needs of patients from physical, psychological, and social perspectives. As nursing students are the future reserve of the clinical nursing workforce, nursing educators worldwide should pay close attention to nursing students' interprofessional learning attitudes and take responsibility for training qualified interprofessional nursing personnel. However, little is known about the relationship between nursing students' readiness for interprofessional learning and academic self-efficacy. Thus, this study aims to investigate the level of readiness for interprofessional learning and academic self-efficacy among nursing students, and to explore the relationship between the two. METHODS: A cross-sectional survey was conducted with a sample of 741 undergraduate nursing students pursuing four-year degrees from a school in Jinan, Shandong Province, China from November to December 2021. The social-demographic questionnaire, Readiness for Interprofessional Learning Scale, and Academic Self-efficacy Scale were used for data collection. Descriptive statistics used to analyze the data included: Cronbach's alpha, t-test, one-way ANOVA, Pearson's correlation, and multiple linear regression analysis. RESULTS: Readiness for interprofessional learning mean score was (3.91 ± 0.44) and mean academic self-efficacy was (3.47 ± 0.42). Significant differences were found in the research variables according to participants' sex, grade, choice of nursing profession, and frequency of communication with health-related major students in studies (p < 0.05, p < 0.001). Pearson correlation analysis showed that academic self-efficacy was positively related to readiness for interprofessional learning (r = 0.316, p < 0.01). The hierarchical regression analysis showed that academic self-efficacy was positively related to readiness for interprofessional learning (ß = 0.307, p < 0.001), The model explained 15.6% of the variance in readiness for interprofessional learning (F = 18.038, p < 0.001). CONCLUSIONS: Readiness for interprofessional learning and academic self-efficacy were in the middle level among nursing students. Moreover, there was a significant positive correlation between the two. Therefore, it is very important for nursing educators to improve nursing students' academic self-efficacy before improving their readiness for interprofessional learning.

[Effects of tetramethylpyrazine on pharmacokinetics in plasma and brain dialysate and neuropathic pain in rat model of spared sciatic nerve injury].

This study aims to explore the effects of tetramethylpyrazine(TMP) on pharmacokinetics in plasma and brain dialysate and neuropathic pain in the rat model of partial sciatic nerve injury(SNI), and to investigate the correlation between the analgesic effect of TMP and its concentrations in the plasma and brain dialysate. Male SD rats were randomized into Sham, SNI, and SNI+TMP groups. Mechanical stimulation with von frey filaments and cold spray method were employed to evaluate the mechanical sensitivity and cold sensitivity of rats. Another two groups, Sham+TMP and SNI+TMP, were used to intubate the common jugular vein and implant microdialysis probes into the anterior cingulate gyrus(ACC), respectively.After intraperitoneal injection of TMP at a dose of 80 mg·kg~(-1), automatic blood collection and intracerebral microdialysis(perfusion rate of 1 µL·min~(-1)) systems were used to collect the blood and brain dialysate for 24 h. HSS T3 C_(18) reversed-phase chromatographic column(2.1 mm×50 mm, 2.5 µm) was used for liquid chromatographic separation. Gradient elution was carried out with the mobile phase of methanol-water(containing 0.005% formic acid) at a flow rate of 0.25 mL·min~(-1). Electrospray ion source was used for mass spectrometry, and the scanning mode was multi-reaction monitoring under the positive ion mode. The ion pairs for quantitative analysis were TMP m/z 137/122 and aspirin m/z 179/137, respectively. DAS 2.11 was used to calculate the pharmacokinetic parameters. The optimal time of TMP to exert the analgesia effect and inhibit cold pain sensitivity was 60 min after treatment. The TMP in the plasma and brain dialysate of SNI rats showed the T_(max) of 15 min and 30 min, the C_(max) of(2 866.43±135.39) and(1 462.14±197.38) µg·L~(-1), the AUC_(0-t) of(241 463.30±28 070.31) and(213 115.62±32 570.07) µg·min·L~(-1), the MRT_(0-t) of(353.13±47.73) and(172.16±12.72) min, and the CL_Z of 0.73 and 0.36 L·min·kg~(-1), respectively. The analgesic effect of TMP had a significant correlation with the blood drug concentration in the ACC, which indicated that this method was suitable for the detection of TMP in rat plasma and brain dialysate. The method is accurate, reliable, and sensitive and can realize the important value of the application of correlation analysis theory of "automatic blood collection-microdialysis/PK-PD" in the research on neuropathic pain.

Unlocking the NIR-II AIEgen for High Brightness through Intramolecular Electrostatic Locking.

Fluorescent imaging and biosensing in the near-infrared-II (NIR-II) window holds great promise for non-invasive, radiation-free, and rapid-response clinical diagnosis. However, it's still challenging to develop bright NIR-II fluorophores. In this study, we report a new strategy to enhance the brightness of NIR-II aggregation-induced emission (AIE) fluorophores through intramolecular electrostatic locking. By introducing sulfur atoms into the side chains of the thiophene bridge in TSEH molecule, the molecular motion of the conjugated backbone can be locked through intramolecular interactions between the sulfur and nitrogen atoms. This leads to enhanced NIR-II fluorescent emission of TSEH in both solution and aggregation states. Notably, the encapsulated nanoparticles (NPs) of TSEH show enhanced brightness, which is 2.6-fold higher than TEH NPs with alkyl side chains. The in vivo experiments reveal the feasibility of TSEH NPs in vascular and tumor imaging with a high signal-to-background ratio and precise resection for tiny tumors. In addition, polystyrene nanospheres encapsulated with TSEH are utilized for antigen detection in lateral flow assays, showing a signal-to-noise ratio 1.9-fold higher than the TEH counterpart in detecting low-concentration antigens. This work highlights the potential for developing bright NIR-II fluorophores through intramolecular electrostatic locking and their potential applications in clinical diagnosis and biomedical research.

Antiviral CD8+ T-cell immune responses are impaired by cigarette smoke and in COPD.

BACKGROUND: Virus infections drive COPD exacerbations and progression. Antiviral immunity centres on the activation of virus-specific CD8+ T-cells by viral epitopes presented on major histocompatibility complex (MHC) class I molecules of infected cells. These epitopes are generated by the immunoproteasome, a specialised intracellular protein degradation machine, which is induced by antiviral cytokines in infected cells. METHODS: We analysed the effects of cigarette smoke on cytokine- and virus-mediated induction of the immunoproteasome in vitro, ex vivo and in vivo using RNA and Western blot analyses. CD8+ T-cell activation was determined in co-culture assays with cigarette smoke-exposed influenza A virus (IAV)-infected cells. Mass-spectrometry-based analysis of MHC class I-bound peptides uncovered the effects of cigarette smoke on inflammatory antigen presentation in lung cells. IAV-specific CD8+ T-cell numbers were determined in patients' peripheral blood using tetramer technology. RESULTS: Cigarette smoke impaired the induction of the immunoproteasome by cytokine signalling and viral infection in lung cells in vitro, ex vivo and in vivo. In addition, cigarette smoke altered the peptide repertoire of antigens presented on MHC class I molecules under inflammatory conditions. Importantly, MHC class I-mediated activation of IAV-specific CD8+ T-cells was dampened by cigarette smoke. COPD patients exhibited reduced numbers of circulating IAV-specific CD8+ T-cells compared to healthy controls and asthmatics. CONCLUSION: Our data indicate that cigarette smoke interferes with MHC class I antigen generation and presentation and thereby contributes to impaired activation of CD8+ T-cells upon virus infection. This adds important mechanistic insight on how cigarette smoke mediates increased susceptibility of smokers and COPD patients to viral infections.

Clinical application of calcium silicate-based bioceramics in endodontics.

Pulp treatment is extremely common in endodontics, with the main purpose of eliminating clinical symptoms and preserving tooth physiological function. However, the effect of dental pulp treatment is closely related to the methods and materials used in the process of treatment. Plenty of studies about calcium silicate-based bioceramics which are widely applied in various endodontic operations have been reported because of their significant biocompatibility and bioactivity. Although most of these materials have superior physical and chemical properties, the differences between them can also have an impact on the success rate of different clinical practices. Therefore, this review is focused on the applications of several common calcium silicate-based bioceramics, including Mineral trioxide aggregate (MTA), Biodentine, Bioaggregate, iRoot BP Plus in usual endodontic treatment, such as dental pulp capping, root perforation repair, regenerative endodontic procedures (REPs), apexification, root-end filling and root canal treatment (RCT). Besides, the efficacy of these bioceramics mentioned above in human trials is also compared, which aims to provide clinical guidance for their clinical application in endodontics.

Personalized radiomics signature to screen for KIT-11 mutation genotypes among patients with gastrointestinal stromal tumors: a retrospective multicenter study.

OBJECTIVES: Gastrointestinal stromal tumors (GISTs) carrying different KIT exon 11 (KIT-11) mutations exhibit varying prognoses and responses to Imatinib. Herein, we aimed to determine whether computed tomography (CT) radiomics can accurately stratify KIT-11 mutation genotypes to benefit Imatinib therapy and GISTs monitoring. METHODS: Overall, 1143 GISTs from 3 independent centers were separated into a training cohort (TC) or validation cohort (VC). In addition, the KIT-11 mutation genotype was classified into 4 categories: no KIT-11 mutation (K11-NM), point mutations or duplications (K11-PM/D), KIT-11 557/558 deletions (K11-557/558D), and KIT-11 deletion without codons 557/558 involvement (K11-D). Subsequently, radiomic signatures (RS) were generated based on the arterial phase of contrast CT, which were then developed as KIT-11 mutation predictors using 1408 quantitative image features and LASSO regression analysis, with further evaluation of its predictive capability. RESULTS: The TC AUCs for K11-NM, K11-PM/D, K11-557/558D, and K11-D ranged from 0.848 (95% CI 0.812-0.884), 0.759 (95% CI 0.722-0.797), 0.956 (95% CI 0.938-0.974), and 0.876 (95% CI 0.844-0.908), whereas the VC AUCs ranged from 0.723 (95% CI 0.660-0.786), 0.688 (95% CI 0.643-0.732), 0.870 (95% CI 0.824-0.918), and 0.830 (95% CI 0.780-0.878). Macro-weighted AUCs for the KIT-11 mutant genotype ranged from 0.838 (95% CI 0.820-0.855) in the TC to 0.758 (95% CI 0.758-0.784) in VC. TC had an overall accuracy of 0.694 (95%CI 0.660-0.729) for RS-based predictions of the KIT-11 mutant genotype, whereas VC had an accuracy of 0.637 (95%CI 0.595-0.679). CONCLUSIONS: CT radiomics signature exhibited good predictive performance in estimating the KIT-11 mutation genotype, especially in prediction of K11-557/558D genotype. RS-based classification of K11-NM, K11-557/558D, and K11-D patients may be an indication for choice of Imatinib therapy.

Marine biomaterials in biomedical nano/micro-systems.

Marine resources in unique marine environments provide abundant, cost-effective natural biomaterials with distinct structures, compositions, and biological activities compared to terrestrial species. These marine-derived raw materials, including polysaccharides, natural protein components, fatty acids, and marine minerals, etc., have shown great potential in preparing, stabilizing, or modifying multifunctional nano-/micro-systems and are widely applied in drug delivery, theragnostic, tissue engineering, etc. This review provides a comprehensive summary of the most current marine biomaterial-based nano-/micro-systems developed over the past three years, primarily focusing on therapeutic delivery studies and highlighting their potential to cure a variety of diseases. Specifically, we first provided a detailed introduction to the physicochemical characteristics and biological activities of natural marine biocomponents in their raw state. Furthermore, the assembly processes, potential functionalities of each building block, and a thorough evaluation of the pharmacokinetics and pharmacodynamics of advanced marine biomaterial-based systems and their effects on molecular pathophysiological processes were fully elucidated. Finally, a list of unresolved issues and pivotal challenges of marine-derived biomaterials applications, such as standardized distinction of raw materials, long-term biosafety in vivo, the feasibility of scale-up, etc., was presented. This review is expected to serve as a roadmap for fundamental research and facilitate the rational design of marine biomaterials for diverse emerging applications.

Formation of vinylphenolic pyranoanthocyanins by selected indigenous yeasts displaying high hydroxycinnamate decarboxylase activity during mulberry wine fermentation and aging.

The color of mulberry wine is difficult to maintain since the main chromogenic substances, anthocyanins, are severely degraded during fermentation and aging. This study selected Saccharomyces cerevisiae I34 and Wickerhamomyces anomalus D6, both displaying high hydroxycinnamate decarboxylase (HCDC) activity (78.49% and 78.71%), to enhance the formation of stable vinylphenolic pyranoanthocyanins (VPAs) pigments during mulberry wine fermentation. The HCDC activity of 84 different strains from eight regions in China was primarily screened via the deep well plate micro fermentation method, after which the tolerance and brewing characteristics were evaluated via simulated mulberry juice. The two selected strains and a commercial Saccharomyces cerevisiae were then inoculated individually or sequentially into the fresh mulberry juice, while the anthocyanin precursors and VPAs were identified and quantified via UHPLC-ESI/MS. The results showed that the HCDC-active strains facilitated the synthesis of stable pigments, cyanidin-3-O-glucoside-4-vinylcatechol (VPC3G), and cyanidin-3-O-rutinoside-4-vinylcatechol (VPC3R), highlighting its potential for enhancing color stability.

Bmp4 in Zebrafish Enhances Antiviral Innate Immunity through p38 MAPK (Mitogen-Activated Protein Kinases) Pathway.

Bone morphogenetic proteins (BMPs) are a group of structurally and functionally related signaling molecules that comprise a subfamily, belonging to the TGF-ß superfamily. Most BMPs play roles in the regulation of embryonic development, stem cell differentiation, tumor growth and some cardiovascular and cerebrovascular diseases. Although evidence is emerging for the antiviral immunity of a few BMPs, more BMPs are needed to determine whether this function is universal. Here, we identified the zebrafish bmp4 ortholog, whose expression is up-regulated through challenge with grass carp reovirus (GCRV) or its mimic poly(I:C). The overexpression of bmp4 in epithelioma papulosum cyprini (EPC) cells significantly decreased the viral titer of GCRV-infected cells. Moreover, compared to wild-type zebrafish, viral load and mortality were significantly increased in both larvae and adults of bmp4-/- mutant zebrafish infected with GCRV virus. We further demonstrated that Bmp4 promotes the phosphorylation of Tbk1 and Irf3 through the p38 MAPK pathway, thereby inducing the production of type I IFNs in response to virus infection. These data suggest that Bmp4 plays an important role in the host defense against virus infection. Our study expands the understanding of BMP protein functions and opens up new targets for the control of viral infection.