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Enterotoxigenic Escherichia coli (ETEC) are a major cause of diarrheal illness in humans and animals, induced by enterotoxins produced by these pathogens. Despite the crucial role of neutrophils in combatting bacterial infections, our understanding of how enterotoxins impact neutrophil function is limited. To address this knowledge gap, we used heat-labile enterotoxin (LT) and heat-stable enterotoxin a (STa) to investigate their impact on the effector functions of neutrophils. Our study reveals that pSTa does not exert any discernible effect on the function of neutrophils. In contrast, LT altered the migration and phagocytosis of neutrophils and induced the production of inflammatory factors via activation of cAMP/PKA and ERK1/2 signaling. LT also attenuated the release of neutrophil extracellular traps by neutrophils via the PKA signaling pathway. Our findings provide novel insights into the impact of LT on neutrophil function, shedding light on the underlying mechanisms that govern its immunoregulatory effects. This might help ETEC in subverting the immune system and establishing infection.

Abstract Background Breast cancer has emerged as the foremost cause of female mortality worldwide, with triple negative breast cancer accounting for approximately 10–15% of all breast cancer cases. The triple negative breast cancer family has obvious familial heritability, but no potential pathogenic variation was found in BRCA1/2. Case presentation The patient was a 56-year-old woman of Han ethnicity. The clinical characteristics of this patient with breast cancer were summarized, peripheral blood of one normal female and two patients with breast cancer in this family was collected, DNA was extracted, and the potential pathogenic variation was analyzed by whole exome sequencing. The normal female and two patients with breast cancer in this family shared a maternal grandmother. The proband’s right breast mass was punctured, and the biopsy showed invasive carcinoma of the right breast, grade II–III, with necrosis. No mutation was found in BRCA1/2 gene test; immunohistochemical of surgical specimens showed triple negative breast cancer. Three mutation types and 17 gene mutation sites were detected through bioinformatics prediction analysis on the basis of co-segregation of genotype and phenotype within the family and whole exome sequencing results. Combined with the Cancer Genome Atlas database comprehensive analysis, the MT1E c.G107A (p.C36Y) mutation may be a potential pathogenic site. Conclusions Through whole exome sequencing, we identified a total of 17 potential pathogenic mutation loci, none of which have been reported thus far. Therefore, our work expanded the gene mutation spectrum of familial hereditary triple negative breast cancer, which can provide more basis for family genetic counseling.

Background: Radiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC); however, almost 20% of patients experience treatment failure due to radioresistance. Therefore, understanding the mechanisms of radioresistance is imperative. HOTAIRM1 is deregulated in various human cancers, yet its role in NPC radioresistance are largely unclear. Methods: This study investigated the association between HOTAIRM1 and radioresistance using CCK8, flow cytometry, and comet assays. Additionally, xenograft mice and patient-derived xenografts (PDX) models were employed to elucidate the biological functions of HOTAIRM1, and transcriptomic RNA sequencing was utilized to identify its target genes. Results: Our study revealed an upregulation of HOTAIRM1 levels in radioresistant NPC cell lines and tissues. Furthermore, a positive correlation was noted between high HOTAIRM1 expression and increased NPC cell proliferation, reduced apoptosis, G2/M cell cycle arrest, and diminished cellular DNA damage following radiotherapy. HOTAIRM1 modulates the acetylation and stability of the FTO protein, and inhibiting FTO elevates the m6A methylation level of CD44 precursor transcripts in NPC cells. Additionally, silencing the m6A reading protein YTHDC1 was found to increase the expression of CD44V. HOTAIRM1 enhances NPC cell resistance to ferroptosis and irradiation through the HOTAIRM1-FTO-YTHDC1-CD44 axis. Mechanistically, HOTAIRM1 interacts with the FTO protein and induces m6A demethylation of the CD44 transcript. The absence of m6A modification in the CD44 transcript prevents its recognition by YTHDC1, resulting in the transition from CD44S to CD44V. An abundance of CD44V suppresses ferroptosis induced by irradiation and contributes to NPC radioresistance. Conclusions: In conclusion, the results in this study support the idea that HOTAIRM1 stimulates CD44 alternative splicing via FTO-mediated demethylation, thereby attenuating ferroptosis induced by irradiation and promoting NPC radioresistance.

ABSTRACT: This study was aimed to investigate the effects of yeast polysaccharides (YPS) on growth performance, intestinal health, and aflatoxin metabolism in livers of broilers fed diets naturally contaminated with mixed mycotoxins (MYCO). A total of 480 one-day-old Arbor Acre male broilers were randomly allocated into a 2 × 3 factorial arrangement of treatments (8 replicates with 10 birds per replicate) for 6 wk to assess the effects of 3 levels of YPS (0, 1, or 2 g/kg) on the broilers fed diets contaminated with or without MYCO (95 μg/kg aflatoxin B1, 1.5 mg/kg deoxynivalenol, and 490 μg/kg zearalenone). Results showed that mycotoxins contaminated diets led to significant increments in serum malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels, mRNA expressions of TLR4 and 4EBP1 associated with oxidative stress, mRNA expressions of CYP1A1, CYP1A2, CYP2A6, and CYP3A4 associated with hepatic phase Ⅰ metabolizing enzymes, mRNA expressions of p53 associated with hepatic mitochondrial apoptosis, and AFB1 residues in the liver (P < 0.05); meanwhile dietary MYCO decreased the jejunal villus height (VH), villus height/crypt depth (VH/CD), the activity of serum total antioxidant capacity (T-AOC), mRNA expressions of jejunal HIF-1α, HMOX, and XDH associated with oxidative stress, mRNA expressions of jejunal CLDN1, ZO1, and ZO2, and mRNA expression of GST associated with hepatic phase Ⅱ metabolizing enzymes of broilers (P < 0.05). Notably, the adverse effects induced by MYCO on broilers were mitigated by supplementation with YPS. Dietary YPS supplementation reduced the concentrations of serum MDA and 8-OHdG, jejunal CD, mRNA expression of jejunal TLR2, and 4EBP1, hepatic CYP1A2, and p53, and the AFB1 residues in the liver (P < 0.05), and elevated the serum T-AOC and SOD, jejunal VH, and VH/CD, and mRNA expression of jejunal XDH, hepatic GST of broilers (P < 0.05). There were significant interactions between MYCO and YPS levels on the growth performance (BW, ADFI, ADG, and F/G) at d 1 to 21, d 22 to 42, and d 1 to 42, serum GSH-Px activity, and mRNA expression of jejunal CLDN2 and hepatic ras of broilers (P < 0.05). In contrast with MYCO group, the addition of YPS increased BW, ADFI, and ADG, the serum GSH-Px activity (14.31%–46.92%), mRNA levels of jejunal CLDN2 (94.39%–103.02%), decreased F/G, and mRNA levels of hepatic ras (57.83%–63.62%) of broilers (P < 0.05). In conclusion, dietary supplements with YPS protected broilers from mixed mycotoxins toxicities meanwhile keeping normal performance of broilers, presumably via reducing intestinal oxidative stress, protecting intestinal structural integrity, and improving hepatic metabolic enzymes to minimize the AFB1 residue in the liver and enhance the performance of broilers.

Aberrant expression of members of the proteasome subunit beta (PSMB) family (including PSMB2, PSMB4, PSMB7 and PSMB8) has been reported in hepatocellular carcinoma (HCC). However the role of PSMB5 in HCC is unclear. To address this issue, we examined the expression of PSMB5 in HCC tissues using the The Cancer Genome Atlas, International Cancer Genome Consortium and Gene Expression Omnibus databases. A quantitative real‐time PCR and immunohistochemistry were performed to validate the expression of PSMB5 in HCC. The survival mutation status and immune cell infiltration of PSMB5 were also evaluated in HCC. We then examined the effect of knocking down PSMB5 expression through RNA interference in the HCC cell line Huh7. High expression of PSMB5 was observed in HCC tissues and was associated with poor prognosis. PSMB5 expression and clinical characteristics were then incorporated to build a prognostic nomogram. We observed that PSMB5 expression was closely related to the abundance of B cells, CD4+ T cells, CD8+ T cells, dendritic cell macrophages and neutrophils. Moreover silencing of PSMB5 in Huh7 significantly suppressed cell proliferation and migration at the same time as increasing apoptosis. Inhibition of the phosphatidylinositol‐3‐kinase/Akt/mechanistic target of rapamycin pathway was observed after PSMB5 downregulation in Huh7 cells. Our findings suggest that PSMB5 may promote the proliferation of HCC cells by inactivating the phosphatidylinositol‐3‐kinase/Akt/mechanistic target of rapamycin signaling pathway and thus PSMB5 may have potential as a biomarker for diagnosis and prognosis of HCC.

IntroductionThe soybean cyst nematode (SCN) is a major disease in soybean production thatseriously affects soybean yield. At present, there are no studies on weighted geneco-expression network analysis (WGCNA) related to SCN resistance.MethodsHere, transcriptome data from 36 soybean roots under SCN HG Type 0 (race 3) stresswere used in WGCNA to identify significant modules.Results and DiscussionA total of 10,000 differentially expressed genes and 21 modules were identified, of which the module most related to SCN was turquoise. In addition, the hub gene GmHg1 with high connectivity was selected, and its function was verified. GmHg1 encodes serine/threonine protein kinase (PK), and the expression of GmHg1 in SCN-resistant cultivars (‘Dongnong L-204’) and SCN-susceptible cultivars (‘Heinong 37’) increased significantly after HG Type 0 stress. Soybean plants transformed with GmHg1-OX had significantly increased SCN resistance. In contrast, the GmHg1-RNAi transgenic soybean plants significantly reduced SCN resistance. In transgenic materials, the expression patterns of 11 genes with the same expression trend as the GmHg1 gene in the ‘turquoise module’ were analyzed. Analysis showed that 11genes were co-expressed with GmHg1, which may be involved in the process of soybean resistance to SCN. Our work provides a new direction for studying the Molecular mechanism of soybean resistance to SCN.

Type I and III Interferons (IFNs) are the initial antiviral cytokines produced in response to virus infection. These IFNs in turn bind to their respective receptors, trigger JAK-STAT signaling and induce the expression of IFN-stimulated genes (ISGs) to engage antiviral functions. Unlike the receptor for type I IFNs, which is broadly expressed, the expression of the type III IFN receptor is mainly confined to epithelial cells that line mucosal surfaces. Accumulating evidence has shown that type III IFNs may play a unique role in protecting mucosal surfaces against viral challenges. The porcine alphaherpesvirus pseudorabies virus (PRV) causes huge economic losses to the pig industry worldwide. PRV first replicates in the respiratory tract, followed by spread via neurons and via lymph and blood vessels to the central nervous system and internal organs, e.g. the kidney, lungs and intestinal tract. In this study, we investigate whether PRV triggers the expression of type I and III IFNs and whether these IFNs exert antiviral activity against PRV in different porcine epithelial cells: porcine kidney epithelial cells (PK-15), primary respiratory epithelial cells (PoREC) and intestinal porcine epithelial cells (IPEC-J2). We show that PRV triggers a multiplicity of infection-dependent type I IFN response and a prominent III IFN response in PK-15 cells, a multiplicity of infection-dependent expression of both types of IFN in IPEC-J2 cells and virtually no expression of either IFN in PoREC. Pretreatment of the different cell types with equal amounts of porcine IFN-λ3 (type III IFN) or porcine IFN-α (type I IFN) showed that IFN-α, but not IFN-λ3, suppressed PRV replication and spread in PK-15 cells, whereas the opposite was observed in IPEC-J2 cells and both types of IFN showed anti-PRV activity in PoREC cells, although the antiviral activity of IFN-α was more potent than that of IFN-λ3 in the latter cell type. In conclusion, the current data show that PRV-induced type I and III IFN responses and their antiviral activity depend to a large extent on the epithelial cell type used, and for the first time show that type III IFN displays antiviral activity against PRV in epithelial cells from the respiratory and particularly the intestinal tract.

Objective Transfer RNA-derived small RNAs (tsRNAs) are a novel type of non-coding RNA with various regulatory functions. They are associated with oxidative stress in various diseases, but their potential functions in radiation-induced lung injury (RILI) remain uncertain. Methods To explore the role of tsRNAs in RILI, we used X-rays to irradiate human bronchial epithelial cells and examined the expression profile of altered tsRNAs by RNA sequencing and bioinformatics analysis. Sequencing results were verified by qRT-PCR. tsRNA functions were explored using several methods, including CCK-8, reactive oxygen species (ROS) assays, cell transfection, and western blotting. Results Eighty-six differentially expressed tRNA-derived fragments (tRFs) were identified: 64 were upregulated, and 22 were downregulated. Among them, the regulation of tRF-Gly-GCC, associated with oxidative stress, may be mediated by the inhibition of cell proliferation, promotion of ROS production, and apoptosis in the occurrence and development of RILI. A Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the underlying molecular mechanism may involve the PI3K/AKT and the FOXO1 signaling pathways. Conclusion Our findings provide new insights into the molecular mechanisms underpinning RILI, advancing the clinical prevention and treatment of this disease.

S100A6, also known as calcyclin, is a low-molecular-weight Ca2+-binding protein from the S100 family that contains two EF-hands. S100A6 is expressed in a variety of mammalian cells and tissues. It is also expressed in lung, colorectal, pancreatic, and liver cancers, as well as other cancers such as melanoma. S100A6 has many molecular functions related to cell proliferation, the cell cycle, cell differentiation, and the cytoskeleton. It is not only involved in tumor invasion, proliferation, and migration, but also the pathogenesis of other non-neoplastic diseases. In this review, we focus on the molecular mechanisms and potential therapeutic targets of S100A6 in tumors, nervous system diseases, leukemia, endometriosis, cardiovascular disease, osteoarthritis, and other related diseases.

BackgroundKIF15 plays a vital role in many biological processes and has been reported to influence the occurrence and development of certain human cancers. However, there are few systematic evaluations on the role of KIF15 in human cancers, and the role of KIF15 in the diagnosis and prognosis of nasopharyngeal carcinoma (NPC) also remains unexplored. Therefore, this study aimed to conduct a pan-cancer analysis of KIF15 and evaluate its diagnostic and prognostic potential in NPC.MethodsThe expression pattern, prognostic value, molecular function, tumor mutation burden, microsatellite instability, and immune cell infiltration of KIF15 were examined based on public databases. Next, the diagnostic value of KIF15 in NPC was analyzed using the Gene Expression Omnibus (GEO) database and immunohistochemistry (IHC). Kaplan–Meier curves, Cox regression analyses, and nomograms were used to evaluate the effects of KIF15 expression on NPC prognosis. Finally, the effect of KIF15 on NPC was explored by in vitro experiments.ResultsThe expression of KIF15 was significantly upregulated in 20 out of 33 cancer types compared to adjacent normal tissue. Kyoto Encyclopedia of Genes and Genomes enrichment (KEGG) analysis showed that KIF15 could participate in several cancer-related pathways. The increased expression level of KIF15 was correlated with worse clinical outcomes in many types of human cancers. Additionally, KIF15 expression was related to cancer infiltration of immune cells, tumor mutation burden, and microsatellite instability. In the analysis of NPC, KIF15 was significantly upregulated based on the GEO database and immunohistochemistry. A high expression of KIF15 was negatively associated with the prognosis of patients with NPC. A nomogram model integrating clinical characteristics and KIF15 expression was established, and it showed good predictive ability with an area under the curve value of 0.73. KIF15 knockdown significantly inhibited NPC cell proliferation and migration.ConclusionsOur findings revealed the important and functional role of KIF15 as an oncogene in pan-cancer. Moreover, high expression of KIF15 was found in NPC tissues, and was correlated with poor prognosis in NPC. KIF15 may serve as a potential therapeutic target in NPC treatment.

Head and neck cancer is the sixth most frequent cancer all over the world, with the majority of subtypes of head and neck squamous cell carcinoma (HNSCC). Cellular senescence-associated genes have been confirmed to play a critical role in cancer and have the potential to be prognostic biomarkers for cancer. Clinical information of HNSCC samples and expression data were acquired from public databases. Expression profiles of genes related to cellular senescence were used to identify molecular subtypes by consensus clustering. To screen differentially expressed genes (DEGs) between different subtypes, differential analysis was performed. We used the univariate Cox regression to identify prognostic DEGs and performed least absolute shrinkage and selection operator (LASSO) to optimize and construct a prognostic model. CIBERSORT, ESTIMATE, and TIDE tools were applied to estimate immune characteristics. Four molecular subtypes were established based on cellular senescence-associated genes. Differential prognosis was observed among different subtypes with C4 having the longest overall survival and C1 having the worst prognosis. C4 subtype also showed the highest immune infiltration. We screened a total of eight cellular senescence prognosis-related genes and established a cellular senescence-related signature score (CSRS.Score) that could stratify samples into high-CSRS.Score and low-CSRS.Score groups. The high-CSRS.Score group had worse prognosis, lower immune infiltration, and lower response to immunotherapy. We further improved the prognostic model and survival prediction by combining CSRS.Score with clinicopathological features using a decision tree model, which had high predictive accuracy and survival prediction. This study demonstrated an important role of cellular senescence in HNSCC. The identified eight cellular senescence-associated genes have the potential to provide ideas for adjuvant treatment and personalized treatment of HNSCC patients.

Lithium–sulfur batteries have attracted extensive attention owing to their environmental friendliness, abundant reserves, high specific discharge capacity, and energy density. The shuttling effect and sluggish redox reactions confine the practical application of Li–S batteries. Exploring the new catalyst activation principle plays a key role in restraining polysulfide shuttling and improving conversion kinetics. In this respect, vacancy defects have been demonstrated to enhance the polysulfide adsorption and catalytic ability. However, inducing active defects has been mostly created by anion vacancies. In this work, an advanced polysulfide immobilizer and catalytic accelerator is developed by proposing FeOOH nanosheets with rich Fe vacancies (FeVs). The work provides a new strategy for the rational design and facile fabrication of cation vacancies to improve the performance of Li–S batteries.

Organophosphorus compounds are the core structure of many active natural products. The synthesis of these compounds is generally achieved by metal catalysis requiring specifically functionalized substrates or harsh conditions. Herein, we disclose the phospha-Michael addition reaction of biphenyphosphine oxide with various substituted β-nitrostyrenes or benzylidene malononitriles. This biocatalytic strategy provides a direct route for the synthesis of C-P bonds with good functional group compatibility and simple and practical operation. Under the optimal conditions (styrene (0.5 mmol), biphenyphosphine oxide (0.5 mmol), Novozym 435 (300 U), and EtOH (1 mL)), lipase leads to the formation of organophosphorus compounds in yields up to 94% at room temperature. Furthermore, we confirm the role of the catalytic triad of lipase in this phospha-Michael addition reaction. This new biocatalytic system will have broad applications in organic synthesis.

ObjectiveWhether the original dosimetric constraints of neuro-optic structures (NOS) are appropriate for patients with nasopharyngeal carcinoma (NPC) undergoing intensity-modulated radiotherapy (IMRT) remains controversial. The present study compared the survival rates and radiation-induced optic neuropathy (RION) occurrence between T4 NPC patients whose NOS were irradiated with a near maximum dose received by 2% of the volume (D2%) >55 Gy and ≤55 Gy. Moreover, the NOS dosimetric parameters and their correlation with RION occurrence were also evaluated.MethodsIn this retrospective study, 256 T4 NPC patients treated with IMRT between May 2009 and December 2013 were included. Patient characteristics, survival rates, dosimetric parameters, and RION incidence were compared between the D2% ≤55 Gy and D2% >55 Gy groups.ResultsThe median follow-up durations were 87 and 83 months for patients in the D2% >55 Gy and D2% ≤55 Gy groups, respectively. The 5-year local recurrence-free survival rates were 92.0 and 84.0% in the D2% >55 Gy and D2% ≤55 Gy groups (P = 0.043), respectively. There was no significant difference in the 5-year overall survival (OS) between both groups (D2% >55 Gy, 81.6%; D2% ≤55 Gy, 79.4%; P = 0.586). No patients developed severe RION (Grades 3–5), and there was no significant difference (P = 0.958) in the incidence of RION between the two groups. The maximum dose of NOS significantly affected the RION incidence, with a cutoff point of 70.77 Gy.ConclusionAppropriately loosening NOS dosimetric constraints in order to ensure a more sufficient dose to the target volume can provide a better 5-year local recurrence-free survival and acceptable neuro-optic toxicity in T4 NPC patients undergoing IMRT.

Background: In the context of recently updated strategies of pressure management, there is a paucity of evidence on the effect of diastolic blood pressure (DBP) level on adverse events among stroke patients. This study aimed to examine the effect of low DBP (

Background: The mechanism of obesity paradox in stroke is not clear. This study aimed to investigate whether uric acid (UA) contributes to obesity-stroke outcome paradox.Material and Methods: The study cohort consisted of 1,984 IS patients recruited in the ACROSS-China study. Serum UA and BMI were measured at admission. Low and high BMI groups were defined by the threshold of 24, and low and high UA by the age- and sex-specific median. Poor outcomes were defined as modified Rankin scale score ≥3 in 1 year after onset.Results: UA was significantly and positively correlated with BMI. Lower levels of UA and BMI were significantly associated with higher risk of poor outcomes. Incidence of the poor outcome was 34.5, 29.4, 27.7, and 23.5% in the BMI/UA groups of low/low, high/low, low/high and high/high, respectively, with p = 0.001 for trend. The association between low UA and poor outcome was significant in lower BMI groups (odds ratio = 1.36, p = 0.006 in quartile 1 and 1.28, p = 0.021 in quartile 2), but the odds ratios were not significant in the BMI quartile 3 and 4 groups, with p = 0.038 for trend. The adverse effect of lower UA was significant in males, but not in females, with p = 0.006 for sex difference.Conclusions: These findings suggest that low UA and low BMI have a joint effect on poor outcomes in IS patients. Across BMI categories, uric acid is differentially associated with functional outcome after stroke. This effect of low UA in the low BMI groups may be one of the mechanisms underlying the obesity-stroke paradox of the outcome in IS patients.

Background: Small-artery occlusion (SAO) subtype accounts for a quarter of the cases of ischemic stroke and is mainly caused by pathological changes in cerebral small vessels, which also involve in deep intracerebral hemorrhage (dICH). However, the factors that drive some cases to SAO and others to dICH remained incompletely defined.Material and Methods: This study is a cross-sectional study from the China National Stroke Registry that included consecutive patients with ischemic stroke or intracerebral hemorrhage between August 2007 and September 2008. We compared the risk profile between the two subgroups using multivariable logistic regression.Results: A total of 1,135 patients with SAO stroke and 1,125 dICH patients were included for analyses. Generally, patients with SAO stroke were more likely to be male (odds ratio = 0.74, confidence interval = 0.58–0.94) and have diabetes (0.30, 0.22–0.40), higher atherogenic lipid profiles, higher body mass index (0.96, 0.94–0.99), higher waist/height ratio (0.12, 0.03–0.48), higher platelet count (0.84, 0.77–0.91), and higher proportion of abnormal estimated glomerular filtration rate (

Aflatoxin B1 (AFB1) is a highly toxic mycotoxin that causes severe suppression of the immune system of humans and animals, as well as enhances reactive oxygen species (ROS) formation, causing oxidative damage. However, the mechanisms underlying the ROS formation and immunotoxicity of AFB1 are poorly understood. This study used the mouse macrophage RAW264.7 cell line and whole-transcriptome sequencing (RNA-Seq) technology to address this knowledge-gap. The results show that AFB1 induced the decrease of cell viability in a dose- and time-dependent manner. AFB1 also significantly increased intracellular productions of ROS and malondialdehyde and decreased glutathione levels. These changes correlated with increased mRNA expression of NOS2, TNF-α and CXCL2 and decreased expression of CD86. In total, 783 differentially expressed genes (DEGs) were identified via RNA-Seq technology. KEGG analysis of the oxidative phosphorylation pathway revealed that mRNA levels of ND1, ND2, ND3, ND4, ND4L, ND5, ND6, Cyt b, COX2, ATPeF0A and ATPeF08 were higher in AFB1-treated cells than control cells, whereas 14 DEGs were downregulated in the AFB1 group. Furthermore, seven immune regulatory pathways mediated by oxidative stress were identified by KEGG analysis. Altogether, these data suggest that AFB1 induces oxidative stress in macrophages via affecting the respiratory chain, which leads to the activation of several signaling pathways related to the inflammatory response.

Plutonium mononitride is one of the main fuels for Generation IV reactors and can be prepared from nitrogenation of plutonium hydride. We investigated the adsorption and dissociation of nitrogen on PuH2 (111) surface to elaborate the initial stage of nitrogenation. The adsorption energies varied greatly with respect to the adsorption sites and orientations of the adsorbed molecule. The nitrogen exhibited preferential adsorption above the ccp site, where the molecular nitrogen was nearly parallel to the PuH2 surface and pointed to the nearest Pu atom. The orbital hybridization and the electrostatic attraction between the Pu and N weakened the N-N bond in the adsorbed molecule. The mechanism of the dissociation process was investigated within transition state theory, and the analysis of the activation barrier indicated that dissociation of nitrogen is not the rate-determining step of nitrogenation. These findings can contribute to a better understanding of the nuclear fuel cycle.

Objectives To establish a new ambulatory blood pressure (ABP) parameter (24-hour ABP profile) and evaluated its performance on stroke outcome in ischaemic stroke (IS) or transient ischaemic attack (TIA) patients.Methods The prospective cohort consisted of 1996 IS/TIA patients enrolled for ABP monitoring and a 3-month follow-up for stroke recurrence as outcome. Profile groups of systolic blood pressure (SBP) were identified via an advanced functional clustering method, and the associations of the profile groups and conventional ABP parameters with stroke recurrence were examined in a Cox proportional hazards model.Results Three discrete profile groups (n=604, 781 and 611 in profiles 1, 2 and 3, respectively) in 24-hour ambulatory SBP were identified. Profile 1 resembled most to the normal diurnal blood pressure pattern; profile 2 also dropped at night, but climbed earlier and with higher morning surge; while profile 3 had sustained higher nocturnal SBP without significant nocturnal SBP decline. The incidence of stroke recurrence was 2.9%, 3.9% and 5.5% in profiles 1, 2 and 3, respectively. After adjustment for covariates, profile 3 was significantly associated with higher risk of stroke recurrence with profile 1 as reference (HR 1.76, 95% CI: 1.00 to 3.09), while no significant difference was observed between profiles 2 and 1 (HR 1.22, 95% CI: 0.66 to 2.25). None of conventional ABP parameters showed significant associations with the outcome.Conclusions Ambulatory 24-hour SBP profile is associated with short-term stroke recurrence. Profiles of ABP may help improve identification of stroke recurrence by capturing the additive effects of individual ABP parameters.

Objectives Incident ischaemic stroke (IS) risk may increase not only with lipids concentration but also with longer duration of exposure. This study aimed to investigate the impact of cumulative burden of lipid profiles on risk of incident IS.Methods A total of 43 836 participants were enrolled who participated in four surveys during 2006–2013. Individual cumulative lipid burden was calculated as number of years (2006–2013) multiplied by the levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C and triglyceride (TG), respectively. The primary outcome was defined as the incident IS during 2012–2017.Results During 4.67 years (±0.70 years) follow-up on average, we identified 1023 (2.33%) incident IS. Compared with respective reference groups, the HRs (95% CIs) of the upper tertile in cumulative TG burden, cumulative LDL-C burden, cumulative TC burden and cumulative non-HDL-C burden were 1.26 mmol/L (1.02–1.55 mmol/L), 1.47 mmol/L (1.25–1.73 mmol/L), 1.33 mmol/L (1.12–1.57 mmol/L) and 1.51 mmol/L (1.28–1.80 mmol/L) for incidence of IS, respectively. However, this association was not significant in cumulative HDL-C burden and IS (HR: 1.09; 95% CI: 0.79 to 1.52), after adjustment for confounding variables. Among 16 600 participants with low cumulative LDL-C burden, HRs (95% CI) for TC, TG, non-HDL-C and HDL-C with IS were 1.63 mmol/L (1.03–2.57 mmol/L), 1.65 mmol/L (1.19–2.31 mmol/L), 1.57 mmol/L (1.06–2.32 mmol/L) and 0.98 mmol/L (0.56–1.72 mmol/L), respectively.Conclusions We observed the correlation between cumulative burden of lipid profiles, except for cumulative burden of HDL-C, with the risk of incident IS. Cumulative burden of TC, TG and non-HDL-C may still predict IS in patients with low cumulative LDL-C burden.Trial registration number ChiCTR-TNRC-11001489.

Background and purpose The Treat Stroke to Target trial has confirmed the benefit of targeting low-density lipoprotein cholesterol (LDL-C) of

Fluid shear stress (FSS) is a ubiquitous mechanical stimulus that potently promotes osteoblast proliferation. Previously, we reported that extracellular signal-regulated kinase 5 (ERK5) is essential for FSS-induced osteoblast proliferation. However, the precise mechanism by which FSS promotes osteoblast proliferation via ERK5 activation is poorly understood. The aim of this study was to determine the critical role of Gαq in FSS-induced ERK5 phosphorylation and osteoblast proliferation, as well as the downstream targets of the Gαq-ERK5 pathway. MC3T3-E1 cells were transfected with 50 nM Gαq siRNA, treated with 5 mM XMD8-92 (a highly selective inhibitor of ERK5 activity), and/or exposed to FSS (12 dyn/cm(2)). Cell proliferation was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The protein expression levels of Gαq, P-ERK5, ERK5, Cyclin B1, and CDK1 were analyzed by Western blot. Physiological FSS exposure for 60 min remarkably promoted MC3T3-E1 cell proliferation, however, this effect was suppressed by siRNA-mediated Gαq knockdown or inhibition of ERK5 activity by XMD8-92 treatment, suggesting that Gαq and ERK5 might modulate FSS-increased osteoblast proliferation. Furthermore, ERK5 phosphorylation was dramatically inhibited by Gαq siRNA. In addition, our study further revealed that FSS treatment of MC3T3-E1 cells for 60 min markedly upregulated the protein expression levels of Cyclin B1 and CDK1, and this increased expression was predominantly blocked by Gαq siRNA or XMD8-92 treatment. We propose that FSS acts on the Gαq-ERK5 signaling pathway to upregulate Cyclin B1 and CDK1 expression, thereby resulting in MC3T3-E1 cell proliferation. Thus, the Gαq-ERK5 signaling pathway may provide useful information regarding the treatment of bone metabolic disease.

TNF-α is known to induce osteoblasts apoptosis, whereas mechanical stimulation has been shown to enhance osteoblast survival. In the present study, we found that mechanical stimulation in the form of fluid shear stress (FSS) suppresses TNF-α induced apoptosis in MC3T3-E1 cells. Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family that has been implicated in cell survival. We also demonstrated that FSS imposed by flow chamber in vitro leads to a markedly activation of ERK5, which was shown to be protective against TNF-α-induced apoptosis, whereas the transfection of siRNA against ERK5 (ERK5-siRNA) reversed the FSS-medicated anti-apoptotic effects. An initial FSS-mediated activation of ERK5 that phosphorylates AKT to increase its activity, and a following forkhead box O 3a (FoxO3a) was phosphorylated by activated AKT. Phosphorylated FoxO3a is sequestered in the cytoplasm, and prevents it from translocating to nucleus where it can increase the expression of FasL and Bim. The inhibition of AKT-FoxO3a signalings by a PI3K (PI3-kinase)/AKT inhibitor (LY294002) or the transfection of ERK5-siRNA led to the nuclear translocation of non-phosphorylated FoxO3a, and increased the protein expression of FasL and Bim. In addition, the activation of caspase-3 by TNF-α was significantly inhibited by aforementioned FSS-medicated mechanisms. In brief, the activation of ERK5-AKT-FoxO3a signaling pathways by FSS resulted in a decreased expression of FasL and Bim and an inhibition of caspase-3 activation, which exerts a protective effect that prevents osteoblasts from apoptosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Fluid shear stress (FSS) is a potent mechanical stimulus and prevents cells from TNF-a-induced apoptosis. Recently, Extracellular-signal-regulated kinase 5 (ERK5) has been found to be involved in regulation of cell survival. However, little is known about the role of ERK5 signaling pathway in FSS-mediated anti-apoptotic effects in osteoblast. In this study, we show that FSS blocks TNF-a-induced apoptosis of MC3T3-E1 cells via ERK5 signaling pathway. We found that physiological FSS for 1 h significantly decreased TNF-α-induced MC3T3-E1 cells apoptosis. After inhibition of ERK5 activity by XMD8-92, a highly-selective inhibitor of ERK5 activity, the ability of FSS to inhibit TNF-α induced apoptosis was significantly decreased. Analysis of anti-apoptotic mechanisms indicated that exposure of MC3T3-E1 cells to FSS for 1 h increased phosphorylation of Bad and inhibited caspase-3 activity. After treatment with XMD8-92, phosphorylation of Bad by FSS was significantly blocked, but caspase-3 activity was increased. In summary, these findings indicated that FSS inhibits TNF-α-mediated signaling events in osteoblast by a mechanism dependent on activation of ERK5, and Bad is a crucial downstream target for ERK5. Those results implied that ERK5 signaling pathway play a crucial role in FSS-mediated anti-apoptotic effect in osteoblast. Thus, ERK5 signaling pathway may be a new drug treatment target of osteoporosis and related bone-wasting diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)