Lactobacillus rhamnosus GG improves cognitive impairments in mice with sepsis.

Background: Survivors of sepsis may encounter cognitive impairment following their recovery from critical condition. At present, there is no standardized treatment for addressing sepsis-associated encephalopathy. Lactobacillus rhamnosus GG (LGG) is a prevalent bacterium found in the gut microbiota and is an active component of probiotic supplements. LGG has demonstrated to be associated with cognitive improvement. This study explored whether LGG administration prior to and following induced sepsis could ameliorate cognitive deficits, and explored potential mechanisms. Methods: Female C57BL/6 mice were randomly divided into three groups: sham surgery, cecal ligation and puncture (CLP), and CLP+LGG. Cognitive behavior was assessed longitudinally at 7-9d, 14-16d, and 21-23d after surgery using an open field test and novel object recognition test. The impact of LGG treatment on pathological changes, the expression level of brain-derived neurotrophic factor (BDNF), and the phosphorylation level of the TrkB receptor (p-TrkB) in the hippocampus of mice at two weeks post-CLP (16d) were evaluated using histological, immunofluorescence, immunohistochemistry, and western blot analyses. Results: The CLP surgery induced and sustained cognitive impairment in mice with sepsis for a minimum of three weeks following the surgery. Compared to mice subjected to CLP alone, the administration of LGG improved the survival of mice with sepsis and notably enhanced their cognitive functioning. Moreover, LGG supplementation significantly alleviated the decrease in hippocampal BDNF expression and p-TrkB phosphorylation levels caused by sepsis, preserving neuronal survival and mitigating the pathological changes within the hippocampus of mice with sepsis. LGG supplementation mitigates sepsis-related cognitive impairment in mice and preserves BDNF expression and p-TrkB levels in the hippocampus.

The 14-3-3 protein nt GF14e interacts with CIPK2 and increases low potassium stress in tobacco.

Potassium (K+) plays a role in enzyme activation, membrane transport, and osmotic regulation processes. An increase in potassium content can significantly improve the elasticity and combustibility of tobacco and reduce the content of harmful substances. Here, we report that the expression analysis of Nt GF14e, a 14-3-3 gene, increased markedly after low-potassium treatment (LK). Then, chlorophyll content, POD activity and potassium content, were significantly increased in overexpression of Nt GF14e transgenic tobacco lines compared with those in the wild type plants. The net K+ efflux rates were severely lower in the transgenic plants than in the wild type under LK stress. Furthermore, transcriptome analysis identified 5708 upregulated genes and 2787 downregulated genes between Nt GF14e overexpressing transgenic tobacco plants. The expression levels of some potassium-related genes were increased, such as CBL-interacting protein kinase 2 (CIPK2), Nt CIPK23, Nt CIPK25, H+-ATPase isoform 2 a (AHA2a), Nt AHA4a, Stelar K+ outward rectifier 1(SKOR1), and high affinity K+ transporter 5 (HAK5). The result of yeast two-hybrid and luciferase complementation imaging experiments suggested Nt GF14e could interact with CIPK2. Overall, these findings indicate that NtGF14e plays a vital roles in improving tobacco LK tolerance and enhancing potassium nutrition signaling pathways in tobacco plants.

Acquired Fanconi syndrome in mixed cryoglobulinemia patients: a single-center case series.

PURPOSE: Cryoglobulinemia is a pathological condition characterized by the presence of cryoglobulins in the blood, with cryoglobulinemic glomerulonephritis being the most frequent form of renal involvement. Fanconi syndrome presents as a generalized dysfunction of the proximal tubule, characterized by the presence of polyuria, phosphaturia, glycosuria, proteinuria, proximal renal tubular acidosis, and osteomalacia. We aimed to present five cases co-occurring with Fanconi syndrome and cryoglobulinemia. METHODS: We retrospectively summarized the cases of five patients with Fanconi syndrome and cryoglobulinemia at Peking Union Medical College Hospital from January 2012 to June 2022. The clinical features, diagnosis, treatment, and prognosis were systematically analyzed. RESULTS: All five patients exhibited typical features of Fanconi syndrome, and cryoglobulinemia was concurrently detected in all cases. These patients also exhibit positive anti-nuclear antibody spectrum and hyperglobulinemia, and IgM constitutes the predominant monoclonal component in cryoglobulins. In addition to supplemental treatment, timely immunosuppressive therapy may potentially benefit the long-term renal prognosis of patients with this condition. CONCLUSION: Our findings highlight the rare co-occurrence of Fanconi syndrome and cryoglobulinemia in clinical practice. Despite the lack of causal evidence, the coexistence of Fanconi syndrome and tubulointerstitial injury is also noteworthy in patients with cryoglobulinemia, underscoring the importance of thorough evaluation and tailored management in patients presenting with overlapping renal manifestations. Key Points • Patients with mixed cryoglobulinemia can clinically present with tubulointerstitial injury, specifically manifesting as Fanconi syndrome. • In addition to typical symptoms of Fanconi syndrome, these patients also exhibit positive anti-nuclear antibody spectrum and hyperglobulinemia, while IgM constitutes the monoclonal component in cryoglobulins. • Timely immunosuppressive therapy may improve long-term renal prognosis in these patients.

Effect of nutrition impact symptoms on oral nutritional supplements energy intake and use days in patients with head and neck cancer: A cross-sectional study.

BACKGROUND: This study aims to explore the effect of nutritional impact symptoms (NIS) on oral nutritional supplements (ONS) energy intake and use days among head and neck cancer (HNC) patients. METHODS: A cross-sectional study was conducted among HNC patients in a hospital in western China between January 2019 and June 2020. The NIS was from the Patient-Generated Subjective Global Assessment (PG-SGA) scale. Mann-Whitney test was used to examine the differences between different kinds of NIS and ONS use days. Binary logistic regression was used to determine the effect of NIS on ONS energy intake. RESULTS: The most prevalent four NIS were no appetite (35.3%), dysphagia (29.4%), vomiting (13.2%) and oral pain (12.5%), respectively. All patients in the study were malnutrition. Patients with xerostomia or oral pain had less ONS use days than those without these symptoms. Patients with vomiting (OR 0.09, 95% CI 0.02-0.50) or pain (OR 0.15, 95% CI 0.02-0.89) were less likely to have ONS energy intake ≥400 kcal/day than those without these symptoms after adjusting the confounding factors. In addition, one-point increase in total NIS score was associated with a lower proportion of ONS energy intake ≥400 kcal/day (OR 0.77, 95% CI 0.59-0.99). CONCLUSION: Xerostomia, oral pain, vomiting and pain should be strengthened and intervened to improve ONS use and nutritional status among HNC patients with malnutrition.

Inactivation of ERK1/2 in cancer-associated hepatic stellate cells suppresses cancer-stromal interaction by regulating extracellular matrix in fibrosis.

The ERK1/2 pathway is involved in epithelial-mesenchymal transformation and cell cycle of tumor cells in hepatocellular carcinoma (HCC). In the present study, we investigated the involvement of ERK1/2 activation on hepatic stellate cells (HSCs). We identified ERK1/2 phosphorylation in activated HSCs of HCC samples. We found that tumor cells promoted the migration and invasion capacity of HSCs by activating ERK1/2 phosphorylation. Using high throughput transcriptome sequencing analysis, we found that ERK1/2 inhibition altered genes significantly correlated to signaling pathways involved in extracellular matrix remodeling. We screened genes and demonstrated that the ERK1/2 inhibition-related gene set significantly correlated to cancer-associated fibroblast infiltration in TCGA HCC tumor samples. Moreover, inhibition of ERK1/2 suppressed tumor cell-induced enhancement of HSC migration and invasion by regulating expression of fibrosis markers FAP, FN1 and COL1A1. In a tumor cell and HSC splenic co-transplanted xenograft mouse model, inhibition of ERK1/2 suppressed liver tumor formation by downregulating fibrosis, indicating ERK1/2 inhibition suppresses tumor-stromal interactions in vivo. Taken together, our data indicate that inhibition of ERK1/2 in tumor-associated HSCs suppresses tumor-stromal interactions and progression. Furthermore, inhibition of ERK1/2 may be a potential target for HCC treatment.

Two Mixed-Ligand Co(II) Complexes as Luminescent Materials and Loaded with Temozolomide-gel Particles in Nursing Against Glioma.

By employing a mixed-ligand strategy, we synthesized two new coordination polymers (CPs) featuring Co(II): {Co(H2L)(bib)]·2H2O}n (1) and {Co(L)(bib)2]·2H2O}n (2), where H4L represents 5-(3,5-dicarboxybenzyloxy) isophthalic acid, and bib denotes 1,4-bis(1-imidazolyl)benzene. These CPs were obtained through the reaction of H4L, a flexible carboxylic acid ligand, with Co(NO3)2·6H2O in various solvent mixtures, along with the N-donor co-ligand bib. Complexes 1 and 2 are formed through distinct coordination modes, resulting in their distinct structural features and excellent fluorescent properties. Based on ligand-centered fluorescence emission and the blue shift (CP 1) along with red shift (CP 2) characteristics, both complexes show promise for applications in fields such as blue fluorescence sensing materials and luminescent materials. After successfully synthesizing two CPs, CP 1 was chosen as the carrier for loading temozolomide (TMZ). Subsequently, leveraging the unique advantages of hydrogels, we developed a novel metal gel formulation loaded with TMZ. The inhibitory effect of this formulation on the growth of glioblastoma was evaluated. Our results demonstrate a significant suppression of glioblastoma cell proliferation by this system, providing an effective avenue for glioblastoma treatment.

N-glycosylation of SCAP exacerbates hepatocellular inflammation and lipid accumulation via ACSS2-mediated histone H3K27 acetylation.

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a widely expressed membrane glycoprotein that acts as an important modulator of lipid metabolism and inflammatory stress. N-glycosylation of SCAP has been suggested to modulate cancer development, but its role in nonalcoholic steatohepatitis (NASH) is poorly understood. In this study, the N-glycosylation of SCAP was analyzed by using sequential trypsin proteolysis and glycosidase treatment. The liver cell lines expressing wild-type and N-glycosylation sites mutated SCAP were constructed to investigate the N-glycosylation role of SCAP in regulating inflammation and lipid accumulation as well as the underlying mechanisms. The hepatic SCAP protein levels were significantly increased in C57BL/6J mice fed with Western diet and sugar water (WD + SW) and diabetic db/db mice, which exhibited typical liver steatosis and inflammation accompanied with hyperglycemia. In vitro, the enhanced N-glycosylation by high glucose increased the protein stability of SCAP and hence increased its total protein levels, whereas the ablation of N-glycosylation significantly decreased SCAP protein stability and alleviated lipid accumulation and inflammation in hepatic cell lines. Mechanistically, SCAP N-glycosylation increased not only the SREBP-1-mediated acetyl-CoA synthetase 2 (ACSS2) transcription but also the AMPK-mediated S659 phosphorylation of ACCS2 protein, causing the enhanced ACSS2 levels in nucleus and hence increasing the histone H3K27 acetylation (H3K27ac), which is a key epigenetic modification associated with NASH. Modulating ACSS2 expression or its location in the nuclear abolished the effects of SCAP N-glycosylation on H3K27ac and lipid accumulation and inflammation. In conclusion, SCAP N-glycosylation aggravates inflammation and lipid accumulation through enhancing ACSS2-mediated H3K27ac in hepatocytes.NEW & NOTEWORTHY N-glycosylation of SCAP exacerbates inflammation and lipid accumulation in hepatocytes through ACSS2-mediated H3K27ac. Our data suggest that SCAP N-glycosylation plays a key role in regulating histone H3K27 acetylation and targeting SCAP N-glycosylation may be a new strategy for treating nonalcoholic steatohepatitis (NASH).

Association Between CYP24A1 Polymorphisms and Bladder Cancer Risk in the Chinese Han Population.

In this cohort of 217 bladder cancer patients and 484 healthy controls, we explored the association between CYP24A1 variants (rs2762934, rs1570669, rs6068816, rs2296241) and bladder cancer risk in the Chinese Han population. Utilizing the Agena MassARRAY system, we genotyped four selected CYP24A1 polymorphisms. Logistic regression revealed a significant association of rs2762934 and rs1570669 with elevated bladder cancer risk, while rs6068816 exhibited a protective effect. Bioinformatics analysis of CYP24A1 expression in normal and cancerous bladder tissues indicated higher expression in normal tissue. In conclusion, our findings highlight the potential role of CYP24A1 variants in bladder cancer susceptibility.

Network pharmacology prediction, molecular docking and in vitro experiment explored the potential mechanism of Gaoyuan'an capsule in improving hypoxia tolerance.

BACKGROUND: Tibetan medicine Gaoyuan'an capsule (GYAC) is widely used to prevent pulmonary edema at high altitude, but the specific mechanism has not been explored. In this study, we analyzed the mechanism of GYAC in hypoxia tolerance, and provided a new idea for the prevention and treatment of altitude disease. METHODS: The effective components and corresponding targets of GYAC were screened out by the Chinese herbal medicine network database, and the key targets of hypoxia tolerance were retrieved by Genecards, OMIM and PubMed database. Cytoscape 3.7.2 was used to construct GYAC ingredient-target-hypoxia tolerance-related target network. GO function annotation and KEGG enrichment analysis were performed to predict the pathways in which target genes may be involved, and molecular docking was used to verify the binding ability of the compound to target genes. In vitro, the above results were further verified by molecular experiment. RESULTS: We found that GYAC can improve hypoxia tolerance by regulating various target genes, including IL6, IFNG, etc. The main regulatory pathways were HIF-1 signaling pathway. Molecular docking showed that the affinity between luteolin and target genes (IL6, IFNG) were better. In vitro, we observed that hypoxia can inhibit cell viability and promote apoptosis of H9C2 cell. And hypoxia can promote the expression of LDH. After the addition of luteolin, the decrease of cell viability, the increase of cell apoptosis, LDH release and the decrease of mitochondrial membrane potential were inhibited. Besides, inflammatory related factors (IL-6, IL-10, IL-2, IFNG and VEGFA) expression were also inhibited hypoxic cell models. CONCLUSIONS: The results of network pharmacology and molecular docking showed that luteolin, a monomeric component of GYAC, played a role in hypoxia tolerance through a variety of target genes, such as IL6, IFNG. What's more, we have discovered that luteolin can reduce the inflammatory response in cardiac myocytes, thereby alleviating mitochondrial damage, and ultimately enhancing the hypoxia tolerance of H9C2 cardiomyocytes.

Negative prognostic impact of Co-mutations in TGFß and TP53 pathways in surgically resected rectal tumors following neoadjuvant chemoradiotherapy.

BACKGROUND: Preoperative neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) is a common approach for treating patients with locally advanced rectal cancer. Nevertheless, the mutational profile and its prognostic impact in surgically resected tumor specimens after nCRT remains to be clarified. METHODS: The comprehensive analysis of mutational landscape was retrospectively conducted by target regions sequencing approach that covered 150 tumor-related genes. Univariate and multivariate logistic regression and Cox regression was used to examine the association of mutation status in genes and pathways with pathological response and prognosis. Data from Memorial Sloan Kettering Cancer Center (MSK) cohort was used for comparison with our results. RESULTS: The top five commonly mutated genes in resected rectal tumor tissue samples following nCRT were TP53 (42%), APC (31%), KRAS (27%), PIK3CA (14%) and FBXW7 (11%). Mutations in the WNT pathway, which was mainly represented by APC mutation, were found to be significantly associated with tumor regression grade (TRG) 3. In our cohort, co-mutations in the receptor tyrosine kinase (RTK)/RAS and WNT pathways were found to be independently associated with reduced risk of recurrent and significantly associated with longer disease-free survival (DFS). In both our cohort and the MSK cohort, co-mutations in the TGF-ß and TP53 pathways were significantly associated with worse DFS. CONCLUSIONS: Resected rectal tumor samples from patients without complete pathological response can be appropriately used to detect mutations. Co-mutations in the TGF-ß and TP53 pathways may provide more prognostic information beyond commonly used clinical factors.

Identifying plasma metabolic characteristics of major depressive disorder, bipolar disorder, and schizophrenia in adolescents.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are classified as major mental disorders and together account for the second-highest global disease burden, and half of these patients experience symptom onset in adolescence. Several studies have reported both similar and unique features regarding the risk factors and clinical symptoms of these three disorders. However, it is still unclear whether these disorders have similar or unique metabolic characteristics in adolescents. We conducted a metabolomics analysis of plasma samples from adolescent healthy controls (HCs) and patients with MDD, BD, and SCZ. We identified differentially expressed metabolites between patients and HCs. Based on the differentially expressed metabolites, correlation analysis, metabolic pathway analysis, and potential diagnostic biomarker identification were conducted for disorders and HCs. Our results showed significant changes in plasma metabolism between patients with these mental disorders and HCs; the most distinct changes were observed in SCZ patients. Moreover, the metabolic differences in BD patients shared features with those in both MDD and SCZ, although the BD metabolic profile was closer to that of MDD than to SCZ. Additionally, we identified the metabolites responsible for the similar and unique metabolic characteristics in multiple metabolic pathways. The similar significant differences among the three disorders were found in fatty acid, steroid-hormone, purine, nicotinate, glutamate, tryptophan, arginine, and proline metabolism. Interestingly, we found unique characteristics of significantly altered glycolysis, glycerophospholipid, and sphingolipid metabolism in SCZ; lysine, cysteine, and methionine metabolism in MDD and BD; and phenylalanine, tyrosine, and aspartate metabolism in SCZ and BD. Finally, we identified five panels of potential diagnostic biomarkers for MDD-HC, BD-HC, SCZ-HC, MDD-SCZ, and BD-SCZ comparisons. Our findings suggest that metabolic characteristics in plasma vary across psychiatric disorders and that critical metabolites provide new clues regarding molecular mechanisms in these three psychiatric disorders.

Effect of Tungsten Inert Gas Remelting on Microstructure and Corrosion Resistance of Q450NQR1 High-Strength Weathering Steel-Welded Joints.

In this paper, the corrosion environment of a railway coal truck was simulated with 1.0%H2SO4 + 3%NaCl solution. The effect of weld toe Tungsten Inert Gas (TIG) remelting on the microstructure and corrosion resistance of welded joints of Q450NQR1 high-strength weathering steel was studied. The results show that the weld toe melts to form a remelting area after TIG remelting. After TIG remelting, the weld geometry was improved, and the stress concentration factor decreased from 1.17 to 1.06 at the weld toe, a decrease of 9.4%. TIG remelting refines the microstructure of the weld toe and improves the corrosion resistance of the welded joint. The surface of the TIG-remelted sample is uniformly corroded with no "deep and narrow" pits after the removal of corrosion products. The weight loss rate and corrosion rate of remelted welds are lower than those of unremelted welds. The structure of corrosion products is loose at the initial stage of corrosion, and the corrosion products are transformed into Fe3O4 and Fe2O3 protective rust layers with a dense structure after 480 h of corrosion. With the extension of corrosion time, the tensile strength and percentage elongation of the specimen decreased linearly. The decreasing rates of tensile strength of remelted and unremelted specimens were 0.09 and 0.11, respectively, and the decreasing rates of elongation after fracture were 0.0061 and 0.0076, respectively.

Human MARCH1, 2, and 8 block Ebola virus envelope glycoprotein cleavage via targeting furin P domain.

Membrane-associated RING-CH (MARCH) family proteins were recently reported to inhibit viral replication through multiple modes. Previous work showed that human MARCH8 blocked Ebola virus (EBOV) glycoprotein (GP) maturation. Our study here demonstrates that human MARCH1 and MARCH2 share a similar pattern to MARCH8 in restricting EBOV GP-pseudotyped viral infection. Human MARCH1 and MARCH2 retain EBOV GP at the trans-Golgi network, reduce its cell surface display, and impair EBOV GP-pseudotyped virions infectivity. Furthermore, we uncover that the host proprotein convertase furin could interact with human MARCH1/2 and EBOV GP intracellularly. Importantly, the furin P domain is verified to be recognized by MARCH1/2/8, which is critical for their blocking activities. Besides, bovine MARCH2 and murine MARCH1 also impair EBOV GP proteolytic processing. Altogether, our findings confirm that MARCH1/2 proteins of different mammalian origins showed a relatively conserved feature in blocking EBOV GP cleavage, which could provide clues for subsequent MARCHs antiviral studies and may facilitate the development of novel strategies to antagonize enveloped virus infection.

NtERF283 positively regulates water deficit tolerance in tobacco (Nicotianatabacum L.) by enhancing antioxidant capacity.

Ethylene responsive factor (ERF) is a plant-specific transcription factor that plays a pivotal regulatory role in various stress responses. Although the genome of tobacco harbors 375 ER F genes, the functional roles of the majority of these genes remain unknown. Expression pattern analysis revealed that NtERF283 was induced by water deficit and salt stresses and mainly expressed in the roots and leaves. Subcellular localization and transcriptional activity assays confirmed that NtERF283 was localized in the nucleus and exhibited transcriptional activity. In comparison to the wild-type (WT), the NtERF283-overexpressing transgenic plants (OE) exhibited enhanced water deficit tolerance, whereas the knockout mutant erf283 displayed contrasting phenotypes. Transcriptional analysis demonstrated that several oxidative stress response genes were significantly altered in OE plants under water deficit conditions. 3,3'-diaminobenzidine (DAB) and nitroblue tetrazolium (NBT) staining showed that erf283 accumulated a higher level of reactive oxygen species (ROS) compared to the WT under water deficit conditions. Conversely, OE plants displayed the least amount of ROS accumulation. Furthermore, the activities of POD and SOD were higher in OE plants and lower in erf283, suggesting that NtERF283 enhanced the capacity to effectively eliminate ROS, consequently enhancing water deficit tolerance in tobacco. These findings strongly indicate the significance of NtERF283 in promoting tobacco water deficit tolerance through the activation of the antioxidant system.

Identification of Six Pathogenic Genes for Tibetan Familial Ventricular Septal Defect by Whole Exome Sequencing.

INTRODUCTION: Ventricular septal defect (VSD) is the most common congenital heart malformation in children. This study aimed to investigate potential pathogenic genes associated with Tibetan familial VSD. METHODS: Whole genomic DNA was extracted from eight Tibetan children with VSD and their healthy parents (a total of 16 individuals). Whole-exome sequencing was performed using the Illumina HiSeq platform. After filtration, detection, and annotation, single nucleotide variations and insertion-deletion markers were examined. Comparative evaluations using the Sorting Intolerant from Tolerant, PolyPhen V2, Mutation Taster, and Combined Annotation Dependent Depletion databases were conducted to predict harmful mutant genes associated with the etiology of Tibetan familial VSD. RESULTS: A total of six missense mutations in genetic disease-causing genes associated with the development of Tibetan familial VSD were identified: activin A receptor type II-like 1 (c.652 C > T: p.R218 W), ATPase cation transporting 13A2 (c.1363 C > T: p.R455 W), endoplasmic reticulum aminopeptidase 1 (c.481 G > A: p.G161 R), MRI1 (c.629 G > A: p.R210Q), tumor necrosis factor receptor-associated protein 1 (c.224 G > A: p.R75H), and FBN2 (c.2260 G > A: p.G754S). The Human Gene Mutation Database confirmed activin A receptor type II-like 1, MRI1, and tumor necrosis factor receptor-associated protein 1 as pathogenic mutations, while FBN2 was classified as a probable pathogenic mutation. CONCLUSIONS: This novel study directly screens genetic variations associated with Tibetan familial VSD using whole-exome sequencing, providing new insights into the pathogenesis of VSD.

Roxadustat and Oral Iron Absorption in Chinese Patients with Anemia of Chronic Kidney Disease: A Randomized, Open-Label, Phase 4 Study (ALTAI).

INTRODUCTION: Anemia of chronic kidney disease (CKD) has a high incidence and is associated with many disease conditions. Iron dysmetabolism is an important contributor to anemia in CKD patients. METHODS: ALTAI, a randomized, active-controlled, phase 4 trial, investigated the efficacy of roxadustat versus recombinant human erythropoietin (rHuEPO) on gastrointestinal iron absorption in patients with anemia of CKD (stage 4/5). The primary endpoint was change from baseline to day 15 in gastrointestinal iron absorption (serum iron area under the concentration-time curve; AUC0-3h) following single-dose oral iron. RESULTS: Twenty-five patients with a mean age of 55.1 years were randomized 1:1 to roxadustat (n = 13) or rHuEPO (n = 12). Baseline iron profiles were similar between treatment groups. Change from baseline to day 15 in serum iron AUC0-3h was not statistically significantly different between the roxadustat and rHuEPO groups. Mean (SD) change from baseline in serum iron AUC0-3h was 11.3 (28.2) g × 3 h/dl in the roxadustat group and - 0.3 (9.7) g × 3 h/dl in the rHuEPO group. Roxadustat treatment was associated with decreased hepcidin and also increased transferrin, soluble transferrin receptor, and total iron-binding capacity (TIBC), with nominal significance. The proportion of patients experiencing one or more adverse events was 38.5% when treated with roxadustat and 16.7% with rHuEPO. CONCLUSIONS: The study showed no significant difference between roxadustat and rHuEPO in iron absorption but was underpowered because of recruitment challenges. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04655027.

NRAMP6c plays a key role in plant cadmium accumulation and resistance in tobacco (Nicotiana tabacum L.).

Tobacco plants (Nicotiana tabacum L.) exhibit considerable potential for phytoremediation of soil cadmium (Cd) pollutants, owing to their substantial biomass and efficient metal accumulation capabilities. The reduction of Cd accumulation in tobacco holds promise for minimizing Cd intake in individuals exposed to cigar smoking. NRAMP transporters are pivotal in the processes of Cd accumulation and resistance in plants; however, limited research has explored the functions of NRAMPs in tobacco plants. In this investigation, we focused on NtNRAMP6c, one of the three homologs of NRAMP6 in tobacco. We observed a robust induction of NtNRAMP6c expression in response to both Cd toxicity and iron (Fe) deficiency, with the highest expression levels detected in the roots. Subsequent subcellular localization and heterologous expression analyses disclosed that NtNRAMP6c functions as a plasma membrane-localized Cd transporter. Moreover, its overexpression significantly heightened the sensitivity of yeast cells to Cd toxicity. Through CRISPR-Cas9-mediated knockout of NtNRAMP6c, we achieved a reduction in Cd accumulation and an enhancement in Cd resistance in tobacco plants. Comparative transcriptomic analysis unveiled substantial alterations in the transcriptional profiles of genes associated with metal ion transport, photosynthesis, and macromolecule catabolism upon NtNRAMP6c knockout. Furthermore, our study employed plant metabolomics and rhizosphere metagenomics to demonstrate that NtNRAMP6c knockout led to changes in phytohormone homeostasis, as well as shifts in the composition and abundance of microbial communities. These findings bear significant biological implications for the utilization of tobacco in phytoremediation strategies targeting Cd pollutants in contaminated soils, and concurrently, in mitigating Cd accumulation in tobacco production destined for cigar consumption.

[Safety of modified T-piece resuscitator versus nasal cannula oxygen in electronic bronchoscopy for infants: a prospective randomized controlled study]. / 改良Tç»„åˆå¤è‹å™¨ä¸Žé¼»å¯¼ç®¡å¸æ°§ç”¨äºŽå©´å„¿ç”µå­æ”¯æ°”ç®¡é•œæ£€æŸ¥çš„å®‰å ¨æ€§æ¯”è¾ƒï¼šä¸€é¡¹å‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To optimize the oxygen therapy regimens for infants with pulmonary diseases during bronchoscopy. METHODS: A prospective randomized, controlled, and single-center clinical trial was conducted on 42 infants who underwent electronic bronchoscopy from July 2019 to July 2021. These infants were divided into a nasal cannula (NC) group and a modified T-piece resuscitator (TPR) group using a random number table. The lowest intraoperative blood oxygen saturation was recorded as the primary outcome, and intraoperative heart rate and respiratory results were recorded as the secondary outcomes. RESULTS: Compared with the NC group, the modified TPR group had a significantly higher level of minimum oxygen saturation during surgery and a significantly lower incidence rate of hypoxemia (P<0.05). In the modified TPR group, there were 6 infants with mild hypoxemia, 2 with moderate hypoxemia, and 1 with severe hypoxemia, while in the NC group, there were 3 infants with mild hypoxemia, 5 with moderate hypoxemia, and 9 with severe hypoxemia (P<0.05). The modified TPR group had a significantly lower incidence rate of intraoperative respiratory rhythm abnormalities than the NC group (P<0.05), but there was no significant difference in the incidence rate of arrhythmias between the two groups (P>0.05). CONCLUSIONS: Modified TPR can significantly reduce the risk of hypoxemia in infants with pulmonary diseases during electronic bronchoscopy, and TPR significantly decreases the severity of hypoxemia and the incidence of respiratory rhythm abnormalities compared with traditional NC.

Multivitamin consumption and childhood asthma: a cross-sectional study of the NHANES database.

BACKGROUND: Dietary intakes of vitamins are associated with asthma. However, previous studies mainly explored the association between a single vitamin intake and asthma, which did not take the multivitamins into consideration. Herein, this study aims to explore the overall effect of dietary multivitamins consumption on childhood asthma. METHODS: Data of children and adolescents (aged 2-17 years old) were extracted from the National Health and Nutrition Examination Survey (NHANES) database in 2015-2018 in this cross-sectional study. Weighted univariate logistic regression analysis was used to screen covariates. The association between multivitamins (including vitamin A, C, D, E, B1, B2, B6, B12, K, niacin, folic acid, and choline) and childhood asthma was explored using univariate and multivariate logistic regression analyses. The evaluation indexes were odds ratio (OR) and 95% confidence interval (CI). We further introduced the Bayesian kernel machine regression (BKMR) to assess the joint effect of the twelve vitamins on childhood asthma, the impact of an individual vitamin as part of a vitamin mixture, and the potential interactions among different vitamins. RESULTS: Among 4,715 eligible children and adolescents, 487 (10.3%) had asthma. After adjusting for covariates including race, family history of asthma, pregnant smoking, BMI Z-score, energy intake, breast feeding, and low birth weight, we found that for each 1-unit increase in vitamin K consumption, the odds of childhood asthma decreased 0.99 (P=0.028). The overall effect analysis reported a trend of negative relationship between the multivitamins and childhood asthma, especially at the 75th percentile and over. According to the BKMR models, when other vitamins are fixed at the median level, the odds of childhood asthma increased along with the elevated vitamin D (VD) and vitamin B2 (VB2), whereas along with the depressed vitamin C (VC). In addition, no potential interaction has been found between every two vitamins of multivitamins on childhood asthma. CONCLUSION: Among children and adolescents who have high-risk of asthma, it may be beneficial to increase dietary consumption of multivitamins. Our findings recommended that children and adolescents should increase the intake of VC-rich foods, whereas control the dietary consumption of VD and VB2 in daily life.

Ellagic acid inhibits tumor growth and potentiates the therapeutic efficacy of sorafenib in hepatocellular carcinoma.

Background: Sorafenib is a classic molecular targeted drug approved for hepatocellular carcinoma (HCC) therapy. However, a poor response rate and increasing resistance to sorafenib make its therapeutic efficacy suboptimal. Combination treatment with an agent capable of potentiating sorafenib sensitivity may be a promising solution. Aim: The aim of this study was to determine the synergistic effect of ellagic acid (EA), a natural polyphenol, and sorafenib on HCC. Methods: CCK-8, EdU incorporation and colony formation assays were used to study the effect of EA on HCC cell proliferation. Apoptosis was detected by flow cytometry in HCC cells and TUNEL assay in xenograft tumors. Transcriptome analysis was utilized to investigate alterations in signaling pathways with EA treatment. A xenograft mouse model was used to confirm the synergistic effect of sorafenib and EA on HCC tumors in vivo. Results: We found that EA inhibited growth and induced apoptosis in both HCC cells and xenograft tumors. Mechanistically, EA treatment reduced the activation of the MAPK and Akt/mTOR signaling pathways in HCC cells. Furthermore, combined EA and sorafenib treatment further inhibited the MAPK and Akt/mTOR signaling pathways compared to EA or sorafenib alone. EA synergistically potentiated the anticancer activity of sorafenib against HCC both in vitro and in vivo. Conclusion: EA inhibits HCC growth by inducing apoptosis through attenuation of the MAPK and Akt/mTOR signaling pathways. EA potentiates the response of HCC tumors to sorafenib both in vitro and in vivo, an effect that may be attributed to further inhibition of the MAPK and Akt/mTOR signaling pathways. These results suggest that EA is an effective adjuvant option for sorafenib therapy.